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Mesenchymal stem cells (MSCs) are a promising cell source for stem cell therapy of intractable diseases in veterinary medicine, but donor-dependent cellular heterogeneity is an issue that influences therapeutic efficacy. Thus, we previously established immortalized cells that maintain the fundamental properties of primary cells, but functional evaluation had not been performed. Therefore, we evaluated the immunomodulatory capacity of the immortalized canine adipose-derived MSCs (cADSCs) in vitro and in vivo to investigate whether they maintain primary cell functions. C57BL/6J mice were treated with dextran sulfate sodium (DSS) to induce colitis, injected intraperitoneally with immortalized or primary cADSCs on day 2 of DSS treatment, and observed for 10 days. Administration of immortalized cADSCs improved body weight loss and the disease activity index (DAI) in DSS-induced colitic mice by shifting peritoneal macrophage polarity from the M1 to M2 phenotype, suppressing T helper (Th) 1/Th17 cell responses and inducing regulatory T (Treg) cells. They also inhibited the proliferation of mouse and canine T cells in vitro. These immunomodulatory effects were comparable with primary cells. These results highlight the feasibility of our immortalized cADSCs as a cell source for stem cell therapy with stable therapeutic efficacy because they maintain the immunomodulatory capacity of primary cells. [ABSTRACT FROM AUTHOR]

We aimed to elucidate details of comorbid chronic rhinosinusitis (CRS) in chronic eosinophilic pneumonia (CEP) under the collaboration between otolaryngologists and pulmonologists in a prospective study. The CEP diagnosis was performed by pulmonologists based on clinical symptoms, laboratory findings, and/or eosinophilia detected in bronchoalveolar lavage. All patients were referred to otolaryngologists before undergoing oral corticosteroid treatment for CEP. Ten CEP cases visited to otolaryngologists. All cases showed bilateral sinonasal inflammation in computed tomography (CT), indicating comorbid CRS. Nasal polyps (NPs) were observed in 50% of patients on endoscopy. Eighty percent of patients were diagnosed with eosinophilic CRS. In blood eosinophil levels and the mucosal eosinophil count, there were no significant differences between CRS without and with NPs. In Lund–Mackay CT total scores, among‐individual variability was observed in CRS with NPs. The collaboration revealed blood/sinonasal eosinophilia and the variability in Lund–Mackay CT total scores as remarkable findings about the comorbid CRS. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) secondary to respiratory disease is caused by pulmonary vascular remodeling and hypoxia. Severe PH can induce various clinical signs, including syncope and right‐sided heart failure. Hypothesis/Objectives: To investigate the echocardiographic characteristics in dogs with PH secondary to respiratory diseases. Animals: Thirty‐one dogs with respiratory diseases with or without PH and 15 healthy dogs. Methods: Prospective cross‐sectional study. Dogs were classified according to respiratory disease (obstructive airway/lung disease [OALD] or restrictive lung disease [RLD]) and PH‐relevant signs. The association between echocardiographic variables and PH (classified by respiratory disease and PH‐relevant signs) was investigated. Results: Twenty‐one dogs were diagnosed with PH; of these, 11 showed PH‐related signs (OALD, n = 2; RLD, n = 9), 14 had right ventricular hypertrophy, and 19 had pulmonary arterial enlargement. Right ventricular dysfunction and dilatation were observed only in dogs with PH‐related signs (n = 10). Left and right ventricular stroke volumes were significantly lower in dogs with PH (median [interquartile range]: 17.2 [12.4‐20.8] and 16.8 [15.3‐29.5] mL/m2, respectively). Dogs with RLD had higher echocardiography‐estimated pulmonary vascular resistance than those with OALD (median [interquartile range]: 3.1 [1.9‐3.3] and 1.6 [1.3‐2.2], respectively). Conclusions and Clinical Importance: Pulmonary arterial enlargement was the most common echocardiographic finding in dogs with PH secondary to respiratory diseases. Right ventricular dysfunction, dilatation, and decreased left and right ventricular stroke volume were significantly associated with the PH‐related signs, indicating that comprehensive echocardiography is recommended in dogs with respiratory disease. Restricted lung disease might induce more severe PH than OALD. [ABSTRACT FROM AUTHOR]

Background: Progression to combined post‐ and pre‐capillary pulmonary hypertension (PH) provides prognostic information in human patients with post‐capillary PH. Pulmonary vascular resistance estimated by echocardiography (PVRecho) is useful for the stratification of dogs with myxomatous mitral valve disease (MMVD) and detectable tricuspid regurgitation. Objectives: To evaluate the prognostic value of PVRecho in dogs with MMVD. Animals: Fifty‐four dogs with MMVD and detectable tricuspid regurgitation. Methods: Prospective cohort study. All dogs underwent echocardiography. The PVRecho was calculated based on tricuspid regurgitation and the velocity‐time integral of the pulmonary artery flow. To evaluate the influence of echocardiographic variables on cardiac‐related deaths, Cox proportional hazard analysis was performed. Additionally, Kaplan‐Meier curves classified by PVRecho tertiles were made and compared using log‐rank tests to evaluate the influence of PVRecho on all‐cause mortality and cardiac‐related death. Results: The median follow‐up time was 579 days. Forty‐one dogs with MMVD (PH severity [number]: no or mild, 21/33; moderate, 11/11; severe, 9/10) died during the study. In the multivariable Cox proportional hazard analysis adjusted for age, sildenafil administration, and American College of Veterinary Internal Medicine stage of MMVD, left atrial to aortic diameter ratio and PVRecho remained significant (adjusted hazard ratio [95% confidence interval]: 1.2 [1.1‐1.3] and 2.1 [1.6‐3.0], respectively). Higher PVRecho showed a significant association with lower survival rates. Conclusions and Clinical Importance: Left atrial enlargement and high PVRecho were independent prognostic factors in dogs with MMVD and detectable tricuspid regurgitation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Current-controlled electrical stimulation system was established for bacteria. • PEDOT-coated electrode allowed minimally-invasive stimulation of bacteria. • The threshold charge density to excite B. subtilis was roughly 530.8 µC cm−2. This paper proposes a minimally invasive current-controlled electric stimulation system based on a poly(3,4-ethylenedioxythiophene) (PEDOT)-modified electrode to characterize the dynamics of the membrane potential in Bacillus subtilis. A highly capacitive PEDOT-modified electrode enabled the injection of a large ionic charge to the surface of the cells suppressing cytotoxic pH change in the vicinity of the electrode. The current pulse induced a hyperpolarization response in B. subtilis around the electrode. Using quantitative charge injection through current-controlled electrical stimulation, the threshold charge density to excite B. subtilis was roughly estimated to be 530.8 µC cm−2 (of electrode surface area) for the first time. Our results provide the minimum electrical stimulation conditions necessary to minimal invasively control the bacterial membrane potential. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells are expected to be a cell source for stem cell therapy of various diseases in veterinary medicine. However, donor-dependent cell heterogenicity has been a cause of inconsistent therapeutic efficiency. Therefore, we established immortalized cells from canine adipose tissue-derived mesenchymal stem cells (ADSCs) to minimize cellular heterogeneity by reducing the number of donors, evaluated their properties, and compared them to the primary cells with RNA-sequencing. Immortalized canine ADSCs were established by transduction with combinations of the R24C mutation of human cyclin-dependent kinase 4 (CDKR24C), canine cyclin D1, and canine TERT. The ADSCs transduced with CDK4R24C, cyclin D1, and TERT (ADSC-K4DT) or with CDK4R24C and cyclin D1 (ADSC-K4D) showed a dramatic increase in proliferation (population doubling level > 100) without cellular senescence compared to the primary ADSCs. The cell surface markers, except for CD90 of the ADSC-K4DT and ADSC-K4D cells, were similar to those of the primary ADSCs. The ADSC-K4DT and ADSC-K4D cells maintained their trilineage differentiation capacity and chromosome condition, and did not have a tumorigenic development. The ability to inhibit lymphocyte proliferation by the ADSC-K4D cells was enhanced compared with the primary ADSCs and ADSC-K4DT cells. The pathway analysis based on RNA-sequencing revealed changes in the pathways mainly related to the cell cycle and telomerase. The ADSC-K4DT and ADSC-K4D cells had decreased CD90 expression, but there were no obvious defects associated with the decreased CD90 expression in this study. Our results suggest that ADSC-K4DT and ADSC-K4D cells are a potential novel cell source for mesenchymal stem cell therapy. [ABSTRACT FROM AUTHOR]

Although osimertinib is a standard first-line treatment for patients with advanced-stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, the incidence rate of pneumonitis associated with osimertinib is high. However, there are few reports about the safety and efficacy of osimertinib rechallenge after the development of pneumonitis. We conducted a retrospective multicentre cohort study of consecutive patients who developed pneumonitis associated with osimertinib as a first-line and received osimertinib rechallenge. The primary outcome was the incidence rate of any grade pneumonitis after osimertinib rechallenge. The secondary outcome was treatment efficacy in patients after osimertinib rechallenge. In total, 33 patients who received osimertinib rechallenge were included. Of them, 26 patients had grade 1, 6 patients had grade 2, and 1 patient had grade 3 initial pneumonitis. The median follow-up period after the osimertinib rechallenge was 16.9 months (interquartile range, 11.1–21.3 months). After the start of osimertinib rechallenge, five patients (15%) experienced mild relapsed pneumonitis. Three of the five patients had similar imaging patterns for initial and relapsed pneumonitis. No significant differences in characteristics were observed between patients with and without relapsed pneumonitis. The median progression-free survival after osimertinib rechallenge was not achieved (95% confidence interval: 10.3 months – not reached). Osimertinib rechallenge was feasible and effective for patients who developed initial pneumonitis associated with first-line osimertinib therapy. Osimertinib might be considered a treatment option even after the development of mild initial pneumonitis. • Large study of 33 patients with osimertinib continuation or re-administration after pneumonitis. • The incidence rate of relapsed pneumonitis was 15%, and all were mild. • Osimertinib may be safely and effectively administered after control of initial pneumonitis. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSC) are currently being investigated for their therapeutic applications in a wide range of diseases. Although many studies examined peripheral venous administration of MSC, few have investigated the detailed intravenous administration procedures of MSC from their preparation until they enter the body. The current study therefore aimed to explore the most efficient infusion procedure for MSC delivery by preparing and infusing them under various conditions. Canine adipose-derived mesenchymal stem cells (cADSC) were infused using different infusion apparatuses, suspension solutions, allogenic serum supplementation, infusion time and rates, and cell densities, respectively. Live and dead cell counts were then assessed by manual measurements and flow cytometry. Efficiency of live- and dead-cell infusion and cell viability were calculated from the measured cell counts and compared under each condition. Efficiency of live-cell infusion differed significantly according to the infusion apparatus, infusion rate, and combination of cell density and serum supplementation. Cell viability after infusion differed significantly between the infusion apparatuses. The optimal infusion procedure resulting in the highest cell delivery and viability involved suspending cADSC in normal saline supplemented with 5% allogenic serum at a density of 5 × 105 cells/mL, and infusing them using an automatic infusion device for 15 min. This procedure is therefore recommended as the standard procedure for the intravenous administration of ADSC in terms of cell-delivery efficiency. [ABSTRACT FROM AUTHOR]

Background: Osimertinib has demonstrated impressive efficacy as a first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive (m+) lung cancer. Drug-related pneumonitis (DRP) is a potentially lethal complication of osimertinib treatment, but reliable real-world data currently are lacking.Research Question: What is the prevalence of osimertinib-induced DRP in first-line settings? What are the characteristics, clinical impact, and risk factors of osimertinib-induced DRP?Study Design and Methods: We conducted a retrospective multicenter cohort study of patients who received osimertinib as a first-line treatment for advanced EGFR m+ non-small cell lung cancer (NSCLC) between August 2018 and December 2019. All chest CT scans and clinical information during osimertinib exposure were collected until June 2020. The primary end point was DRP incidence identified through central review.Results: A total of 452 patients from 18 institutions were evaluated. Eighty patients (18%) had a diagnosis of DRP (all grades), and 21 patients (4.6%) had a diagnosis of grade 3 or more DRP. Among the patients with DRP, 46% were identified as having transient asymptomatic pulmonary opacity (TAPO). Regarding the CT scan patterns, organizing pneumonia, simple pulmonary eosinophilia, hypersensitivity pneumonia, diffuse alveolar damage, and nonspecific interstitial pneumonia were found in 30, 21, 18, 9, and two patients (38%, 26%, 23%, 11%, and 3%), respectively. In multivariate analysis, smoking history was identified as an independent risk factor for DRP (hazard ratio, 1.72; 95% CI, 1.01-2.89; P = .046). In the 3-month landmark analysis, DRP was associated with poor treatment efficacy; however, the presence of TAPO did not affect treatment efficacy negatively.Interpretation: For osimertinib treatment in first-line settings, the frequency of DRP was considerably elevated to 18 %, and half of these patients exhibited TAPO features. [ABSTRACT FROM AUTHOR]

• This prospective study evaluated durvalumab used in patients with grade 1 RP. • Of 170 stage III NSCLC patients who received CCRT, 35 with grade 1 RP participated. • The median PFS was 11.4 months, and 31 % of patients developed grade ≥2 pneumonitis. • Durvalumab might be feasible and effective for these patients. Durvalumab was safe and effective in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT) in a phase 3 trial (PACIFIC trial). Although a history of radiation pneumonitis (RP) has been reported to increase the risk of exacerbation of pneumonitis associated with programmed death-1 axis inhibitors, the detailed clinical results of durvalumab treatment in patients with baseline grade 1 RP were not reported in the PACIFIC trial. Therefore, we aimed to evaluate the safety and effectiveness of durvalumab therapy in these patients. This was a multicenter prospective cohort study involving 35 patients. Patients were eligible if they met the following criteria: inoperable stage III NSCLC, administration of durvalumab within 42 days after CCRT using platinum-based chemotherapy, no disease progression after CCRT, Eastern Cooperative Oncology Group performance status of 0–1, and presence of grade 1 RP at baseline. We assessed the effectiveness and safety of durvalumab with a minimum 1-year follow-up period for all patients. Thirty-five patients were enrolled in our study from February 2019 to December 2019. The median progression-free survival was 11.4 months (95 % confidence interval, 7.1 months–not reached), and the median overall survival was not reached. Eleven (31 %) patients had grade ≥2 pneumonitis/RP, 10 (28 %) developed grade 2 pneumonitis/RP, and 1 (3 %) developed grade 5 pneumonitis/RP. Five (14 %) patients experienced treatment-related grade ≥3 adverse events. Durvalumab might be safe and effective in patients with stage III NSCLC with baseline grade 1 RP following chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Pulmonary hypertension is a potentially life-threatening disease among dogs that is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance. In veterinary medicine, a phosphodiesterase-5 inhibitor such as sildenafil is the most common drug used to treat pulmonary hypertension. However, the availability of sildenafil is limited because of its high cost, difficulty in obtaining the drug in some areas, and potential inter-individual variability in the response to sildenafil therapy. Beraprost sodium is one of the most common drugs used to treat pulmonary hypertension in humans. However, little is known about its efficacy in dogs with pulmonary hypertension. In this study, beraprost sodium showed significant pulmonary and systemic vasodilation without any adverse effects in sixteen dogs with pulmonary hypertension. Additionally, echocardiographic improvements in cardiac function and pulmonary and systemic circulation were observed. These results emphasize the potential efficacy of beraprost sodium in treating canine pulmonary hypertension. Pulmonary hypertension (PH) is a fatal condition that affects many dogs. In humans, PH is often treated with beraprost sodium (BPS). However, the effectiveness of BPS for canine PH has not been established. This study aimed to evaluate the clinical and cardiovascular response of BPS in canine patients with PH of various causes. Sixteen dogs with PH (post-capillary PH, n = 8; pre-capillary PH, n = 8) were included. BPS was continuously administered twice daily at 15 µg/kg. All dogs underwent echocardiography, including speckle-tracking analysis and blood pressure measurement, before and after BPS administration. Continuous BPS administration (range: 13.2–22.0 µg/kg) significantly decreased the pulmonary and systemic vascular impedance and increased left and right ventricular myocardial strain. In dogs with post-capillary PH, BPS administration caused no significant worsening of the left atrial pressure indicators. No side effects of BPS were observed in any dog. BPS also improved cardiac function and pulmonary circulation through pulmonary vasodilation, suggesting that BPS may be an additional treatment option for canine PH of various causes. Particularly, BPS increased left ventricular function and systemic circulation without worsening the left heart loading condition in dogs with post-capillary PH. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have excellent anti-inflammatory and immunomodulatory capabilities and therapeutic effects in some viral diseases. The therapeutic impact of MSCs mainly relies on the paracrine effects of various secreted substances. Feline calicivirus (FCV) and feline herpesvirus type 1 (FHV1) are common and highly prevalent pathogens causing upper respiratory diseases, and FCV is associated with gingivostomatitis in cats. Recently, feline MSC treatment has been reported to improve the clinical symptoms of feline chronic gingivostomatitis, but the antiviral effects of feline MSCs on FCV and FHV1 are not known. In this study, we evaluated the antiviral efficacy of using feline MSC secretome as a conditioned medium on FCV and FHV1 viral replication in Crandell–Reese feline kidney (CRFK) cells, and RNA sequencing was used to analyze how the CRFK cells were altered by the MSC secretomes. The feline MSC secretome did not inhibit FCV or FHV1 viral entry into the CRFK cells but had antiviral effects on the replication of both FCV and FHV1 in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the impact of social isolation and loneliness on the overall survival and death at home in patients with lung cancer.Methods: This prospective cohort study was conducted in a Japanese tertiary hospital. The enrollment period was from April 2018 to March 2020. Patients with pathologically diagnosed advanced lung cancer were included in this study. The primary outcome was overall survival, whereas the secondary outcome was death at home. The exposures were social isolation and loneliness.Results: A total of 211 patients were enrolled and divided into two groups and further into quartiles according to their social isolation and loneliness level, respectively. The hazard ratios of social isolation were 1.65 (95% confidence interval; 1.12 to 2.44) and 1.87 (95% confidence interval; 1.15 to 3.03) in the univariate analysis, while 1.40 (95% confidence interval; 0.92 to 2.13) in the multivariate analysis with complete case and multiple imputation. The odds ratio of death at home with social isolation was 3.47 (95% confidence interval; 1.08 to 11.1) in the multivariate analysis with multiple imputation. Loneliness was not associated with overall survival or death at home.Conclusions: Our study suggests that social isolation may be related to overall survival and death at home among patients with advanced lung cancer. More attention should be given to such patients at the time of diagnosis. [ABSTRACT FROM AUTHOR]

Background: Right ventricular (RV) functional assessment has received considerable attention in veterinary medicine since various diseases, such as cardiovascular, respiratory, endocrine, and neoplastic disease, may affect RV function. Heart rate (HR) is an important factor that can influence RV function through changes in loading condition and contractility. However, no study has yet evaluated the association between HR and RV function in the same individuals. This study aimed to evaluate the influence of elevated HR on RV function using right heart catheterization and echocardiography, and investigate the association between right heart catheterization and echocardiographic indices. Results: Right atrial pacing was performed in eight dogs at 120, 140, 160, and 180 bpm. With an increase in HR, the RV systolic volume, RV diastolic volume, and stroke volume significantly decreased; however, the cardiac output, end-systolic elastance (Ees), and effective arterial elastance (Ea) significantly increased. Significant changes were not observed in RV pressure and Ees/Ea. The RV area normalized by body weight, RV fractional area change normalized by body weight (RV FACn), and tricuspid annular plane systolic excursion normalized by body weight (TAPSEn) significantly decreased with increased HR. Peak systolic myocardial velocity of the lateral tricuspid annulus (RV s'), RV strain, and RV strain rate of only the RV free wall analysis (RV-SrL3seg) showed no significant changes with the increase in HR; however, there was an increase in the RV strain rate of the RV global analysis (RV-SrL6seg). Multiple regression analysis revealed that HR, RV FACn, and RV- SrL6seg had significant associations with the Ees, and the TAPSEn and RV-SrL3seg with Ees/Ea. Conclusions: Decreased venous return and shortened relaxation time decreased the RV FAC, TAPSE, RV s', and RV strain, and might underestimate the RV function. Ees increased with the increase in HR, reflecting the myocardial force-frequency relation; as a result, RV-SrL6seg could be a useful tool for Ees estimation. Additionally, the RV-SrL3seg could detect RV performance, reflecting the balance between RV contractility and RV afterload. [ABSTRACT FROM AUTHOR]

Real-time three-dimensional echocardiography (RT3DE) enables a noninvasive assessment of right ventricular (RV) morphology. However, no study has evaluated the relationship between RV function obtained by RT3DE and RV pressure-volume loops. This hypothesis-driven, experimental study aimed to assess the utility of RT3DE in the evaluation of RV morphology and function. Ten anesthetized beagle dogs sequentially underwent dobutamine infusion, acute infusion of lactated Ringer's solution, and furosemide administration to alter RV contractility and loading conditions. RV pressure-volume loop-derived hemodynamic measurements and echocardiography, including two-dimensional speckle-tracking echocardiography and RT3DE, were performed in each study protocol. Bland–Altman analysis showed strong agreement in RV volume, ejection fraction, and stroke volume obtained by right heart catheterization and RT3DE. Multiple regression analyses revealed that the peak myocardial velocity of the lateral tricuspid annulus (RV s') and global RV longitudinal strain rate were significantly associated with end-systolic elastance (adjusted r2 = 0.66, p < 0.001). RV s', RV free wall longitudinal strain, and RT3DE-derived stroke volume/end-systolic RV volume ratio were associated with RV pressure-volume loops-derived end-systolic/arterial elastance ratio (adjusted r2 = 0.34, p < 0.001). RT3DE could detect the changes in catheterization-derived RV volume with a strong agreement and might be useful in estimating RV-pulmonary arterial coupling. [ABSTRACT FROM AUTHOR]

[Display omitted] • Electric wiring between bacteria and an electrode via redox polymer was fabricated. • Electric wiring was established even for non-electroactive bacteria. • Selective measurement of wired bacteria was achieved in a bacterial suspension. Non-electroactive bacteria (n-EAB), constituting the majority of known bacteria to date, have been underutilized in electrochemical conversion technologies due to their lack of direct electron transfer to electrodes. In this study, we established an electric wiring between n-EAB (gram-positive Bacillus subtilis and gram-negative Escherichia coli) and an extracellular electrode via a ferrocene-polyethyleneimine-based redox polymer (Fc-PEI). Chronoamperometry recordings indicated that Fc-PEI can transfer intracellular electrons to the extracellular electrode regardless of the molecular organization of PEI (linear or branched) and the membrane structure of bacteria (gram-positive or -negative). As fluorescence staining suggested, Fc-PEI improves the permeability of the bacterial cell membrane, enabling electron carriers in the cell to react with Fc. In addition, experiments with Fc-immobilized electrodes without PEI suggested the existence of an alternative electron transfer pathway from B. subtilis to the extracellular Fc adsorbed onto the cell membrane. Furthermore, we proposed for the first time that the bacteria/Fc-linear PEI modified structure enables selective measurement of immobilized bacterial activity by physically blocking contact between the electrode surface and planktonic cells co-existing in the surrounding media. Such electrodes can be a powerful analytical tool for elucidating the metabolic activities of specific bacteria wired to the electrode even within complex bacterial communities. [ABSTRACT FROM AUTHOR]

Osimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation–positive lung cancer. However, clinical data and reliable prognostic biomarkers are insufficient. We performed a retrospective multicentre cohort study for 538 EGFR mutation–positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS). The median observation period was 14.7 months (interquartile range 11.4–20.0). The median PFS was 20.5 months (95% confidence interval [CI] 18.6−not reached). Multivariate analysis showed that sex (male) (hazard ratio [HR] 1.99, 95% CI 1.35–2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11–2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03–2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04–2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01–2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70–5.83, P < 0.001) were associated with PFS. PD-L1 expression of 1–49% (HR 1.66, 95% CI 1.05–2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17–4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05–2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%). During initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation. • Osimertinib is standard treatment for advanced EGFR mutation-positive lung cancer. • Clinical data and reliable prognostic biomarkers remain insufficient. • Tumour PD-L1 expression level is associated with progression-free survival. • Adverse events are a common reason for treatment discontinuation. [ABSTRACT FROM AUTHOR]

• We retrospectively evaluated 302 patients with NSCLC who started CRT. • Any grade of, symptomatic, or fatal pneumonitis occurred in 83%, 34%, and 1%. • The predictive factors for symptomatic pneumonitis were V20 ≥ 25% and MLD ≥ 10 Gy. • 41% of patients with pneumonitis requiring corticosteroids rechallenged durvalumab. • PACIFIC rechallenge criteria were adhered to in 81%, and did not cause severe relapse. The incidence of real-world pneumonitis and durvalumab rechallenge during chemoradiotherapy and durvalumab consolidation for non-small cell lung cancer is unknown. We retrospectively evaluated the medical records of 302 consecutive patients diagnosed with non-small cell lung cancer who started chemoradiotherapy between May 2018 and May 2019. Median age was 70 (range: 40–87) years. Volume of lung parenchyma that received 20 Gy (V20) exceeded 35% in 2% and mean lung dose exceeded 20 Gy in 1% of patients. Durvalumab consolidation was delivered to 225 patients (75%). Overall, 83% (n = 251), 34% (n = 103), 7% (n = 21), and 1% (n = 4) of the patients developed any grade of pneumonitis, symptomatic pneumonitis, ≥grade 3 pneumonitis, and fatal (grade 5) pneumonitis, respectively. Corticosteroids were administered to 25% of the patients to treat pneumonitis. Multivariate analysis identified the predictive factors for the development of symptomatic pneumonitis: V20 Gy or more ≥ 25% (odds ratio [OR]: 2.37, P = 0.008) and mean lung dose (MLD) ≥ 10 Gy (OR: 1.93, P < 0.0047). Of the 52 patients who received corticosteroids for pneumonitis after durvalumab initiation, 21 were rechallenged with durvalumab. Overall, 81% of patients met the PACIFIC study's rechallenge criteria and did not experience a severe pneumonitis relapse. High V20 and MLD were independent risk factors of symptomatic pneumonitis. More than 80% of the patients who were rechallenged with durvalumab after pneumonitis met the PACIFIC study's rechallenge criteria. Consequently, severe relapse did not occur. Cooperation between radiation and medical oncologists is important for safe chemoradiotherapy and the safe completion of durvalumab consolidation therapy. [ABSTRACT FROM AUTHOR]

Background: Restrictive cardiomyopathy (RCM) is a common myocardial disease in cats, characterized by diastolic dysfunction and atrial enlargement without myocardial hypertrophy. Especially, endomyocardial form of RCM, one of the subtypes in RCM, is characterized by endocardial fibrosis, endocardial scar bridging the interventricular septum and left ventricular (LV) free wall, and deformation and distortion of the LV. However, it is unclear how the myocardial dysfunction and the endocardial scar contribute to the pathophysiology of RCM disease progression. Case presentation: A 3 years and 2 months old, intact male, Domestic shorthaired cat was presented for consultation of cardiac murmur. At the first visit (day 0), the notable abnormal finding was echocardiography-derived chordae tendineae-like structure bridging the interventricular septum and the LV free wall, resulting high-speed blood flow in the left ventricle. Electrocardiography, thoracic radiography and noninvasive blood pressure measurements were normal. No left atrial enlargement was observed, and LV inflow velocity showed an abnormal relaxation pattern. Although there was no abnormality in tissue Doppler imaging-derived myocardial velocity, two-dimensional speckle tracking echocardiography (2D-STE) revealed a decrease in the LV longitudinal strain and an increase in endocardial to epicardial ratio of the LV circumferential strain on day 0. On day 468, obvious left atrium enlargement and smoke like echo in the left atrium were observed. The LV inflow velocity was fused, and the tissue Doppler imaging-derived early-diastolic myocardial velocity of the septal mitral annulus decreased. Regarding 2D-STE, LV circumferential strain was further decreased, and right ventricular strain was additionally decreased. Although the general condition was good, we made a clinical diagnosis of endomyocardial RCM based on the above findings. On day 503, the cat showed the radiographic evidence of pulmonary edema and congestive heart failure signs. Conclusions: Cats with abnormal LV structure and associated myocardial dysfunction like this case needs careful observation. Additionally, 2D-STE indices may be useful for early detection of myocardial dysfunction in feline RCM. [ABSTRACT FROM AUTHOR]

Background: Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved.Methods: We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions.Results: Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR.Conclusions: Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients. [ABSTRACT FROM AUTHOR]

Background: Inconsistency of treatment response in cats with obstructive hypertrophic cardiomyopathy is well recognized. We hypothesized that the difference in response to beta-blockers may be caused by myocardial functional abnormalities. This study was designed to compare myocardial function in cats with obstructive hypertrophic cardiomyopathy with and without response to beta-blockers. Twenty-one, client-owned, hypertrophic cardiomyopathy cats treated with carvedilol were analyzed. After carvedilol treatment, cats with decreased left ventricular outflow tract velocity were categorized as responders (n = 10); those exhibiting no response (no decrease in the left ventricular outflow tract velocity) were categorized as non-responders (n = 11). The cats were examined using layer-specific assessment of the myocardial function (whole, endocardial, and epicardial layers) longitudinally and circumferentially by two-dimensional speckle-tracking echocardiography, before and after carvedilol treatment. Results: The non-responder cats had a significantly higher age, end-diastolic left ventricular posterior-wall thickness, peak velocity of left ventricular outflow tract, and dose of carvedilol than the responders (p = 0.04, p < 0.01, p < 0.01, and p < 0.01, respectively). The circumferential strain in the epicardial layer was lower and circumferential endocardial to epicardial strain ratio was higher in non-responders than responders (p < 0.001 and p = 0.006). According to the multivariate analysis, circumferential strain in the epicardial layer was the only independent correlate of treatment response with carvedilol. Conclusions: Myocardial function, assessed by two-dimensional speckle-tracking echocardiography, differed in cats with hypertrophic cardiomyopathy with and without response to beta-blockers. The determination of layer-specific myocardial function may facilitate detailed pathophysiologic assessment and treatment response in cats with hypertrophic cardiomyopathy. [ABSTRACT FROM AUTHOR]

• Osimertinib safety and efficacy in elderly patients with NSCLC was analyzed. • Elderly patients had higher rates of drug discontinuation due to adverse events. • Median progression-free survival was shorter in the elderly than in the non-elderly. • The elderly had lower rates of transition to second-line treatment. Osimertinib is the primary treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer. However, evidence of the outcomes of osimertinib treatment in patients over 75 years of age in the real-world setting is limited. This retrospective study analyzed the data of 538 patients (203 elderly and 335 non-elderly) with EGFR mutation-positive lung cancer in whom osimertinib was initiated as first-line treatment between August 2018 and December 2019. Patients over 75 years of age were classified as elderly. The data cut-off date was February 28, 2022. The progression-free survival (PFS) did not significantly differ between the elderly and non-elderly groups [elderly group: median PFS, 16.9 months (95 % confidence interval (CI), 14.3–20.2); non-elderly group: median PFS, 22.1 months (95 % CI: 19.5–26.3); hazard ratio (HR) for the elderly against the non-elderly: 1.21 (95 % CI: 0.98–1.50), p = 0.079]. However, the time to treatment failure (TTF) was significantly shorter in the elderly than in the non-elderly [elderly group: median TTF, 14.0 months (95 % CI: 0.98–1.50); non-elderly group: median TTF, 21.8 months (95 % CI: 18.2–24.6); HR for the elderly against the non-elderly: 1.46 (95 % CI: 1.20–1.77), p < 0.001]. Furthermore, the rate of treatment discontinuation because of adverse events was 28.6 % in the elderly and 14.9 % in the non-elderly (p < 0.001). Among patients who discontinued treatment, the conversion rate to second-line treatment was 39.6 % in the elderly and 72.8 % in the non-elderly. In addition, the median overall survival was 30 months (95 % CI: 25.8–37.7) in the elderly and not reached (NR) (95 % CI: NR–NR) in the non-elderly (p < 0.001). In a real-world clinical setting, elderly patients receiving osimertinib as first-line treatment should be aware of the frequent inability to transition to second-line treatment due to adverse events. [ABSTRACT FROM AUTHOR]

Abstract: A collaborative study was conducted to evaluate whether a liver micronucleus assay using four-week-old male F344 rats can be used to detect genotoxic rat hepatocarcinogens using double-dosing with a single-sampling 4 days after the second dose. The assay methods were thoroughly validated by the seven laboratories involved in the study. Seven chemicals, 2,4-diaminotoluene, diethyl nitrosamine, p-dimethylaminoazobenzene, 1,2-dimethylhydrazine dihydrochloride, 2,4-dinitrotolunene, 2,6-dinitrotoluene and mitomycin C, known to produce positive responses in the single-dosing/triple-sampling method were selected for use in the present study, and each chemical was examined in two laboratories with the exception of 2,4-dinitrotolunene. Although several of the compounds were examined at lower doses for reasons of toxicity than in the single-dosing/triple-sampling method, all chemicals tested in the present study induced micronuclei in liver cells indicating a positive result. These findings suggest that the liver micronucleus assay can be used in young rats to detect genotoxic rat hepatocarcinogens using a double-dosing/single-sampling procedure. Further, the number of animals used in the liver micronucleus assay can be reduced by one-third to a half by using the double-dosing/single-sampling method. This reduction in animal numbers also has significant savings in time and resource for liver perfusion and hepatocyte isolation. [Copyright &y& Elsevier]

Abstract: We have been investigating a liver micronucleus assay to detect genotoxic chemicals using young rats for several years, and had established its advantages with respect to using autonomous proliferation of young rat hepatocytes. Nine chemicals known to induce hepatotoxic effects such as necrosis (2,6-dinitrotolune, bromobenzene, isoniazid, phenacetin, allyl alcohol and thioacetamide), cholestasis (chlorpromazine hydrochloride and α-naphthyl isothiocyanate) and oxidative stress (clofibrate) were selected for this study. A liver micronucleus assay was conducted in 4-week-old male F344 rats using two or three dose levels of test chemicals given orally by gavage to evaluate the compound''s ability to induce micronucleated hepatocytes. Several of these test chemicals were additionally examined in a peripheral blood micronucleus assay conducted concurrently and in the same animals. The genotoxic rodent hepatocarcinogen, 2,6-dinitrotoluene showed a positive result in the liver micronucleus assay, but the nongenotoxic hepatocarcinogens, clofibrate and thioacetamide gave negative responses. Bromobenzene, known to produce DNA adducts but is noncarcinogenic in rodent liver, was judged equivocal in this assay. α-Naphthyl isothiocyanate is noncarcinogenic and showed negative response in the liver. The other four chemicals, known to be either noncarcinogenic or carcinogenic in other non-liver target organs, showed negative results in the liver micronucleus assay. Based on the results in the present study and previous report described above, it was concluded that this technique is able to effectively predict genotoxic rodent hepatocarcinogenicity, and does not give false positives due to hepatotoxicity. [Copyright &y& Elsevier]

Simple Summary: The endomyocardial form of restrictive cardiomyopathy, a primary disorder of the myocardium, is one of the diseases with poor prognosis in cats. While two-dimensional speckle-tracking echocardiography has been known to identify myocardial deformations, its function relative to cats with the endomyocardial form of restrictive cardiomyopathy has yet to be characterized. We hypothesized that both the left and right myocardial functional abnormalities may occur in cats with the endomyocardial form of restrictive cardiomyopathy, causing this disease pathophysiology and clinical status. In the current study, cats were assessed for layer-specific myocardial function (whole, endocardial, and epicardial) in the left ventricular longitudinal and circumferential directions, and right ventricular longitudinal direction, via two-dimensional speckle-tracking echocardiography. Our study indicated that cats with restrictive cardiomyopathy have reduced left ventricular myocardial function. Notably, left ventricular systolic circumferential endocardial strain and circumferential endocardial-to-epicardial strain ratio were lower in cats with restrictive cardiomyopathy. Furthermore, some right ventricular myocardial deformations were also differerent in cats with restrictive cardiomyopathy. Myocardial function assessed by two-dimensional speckle-tracking echocardiography could reveal left and right myocardial dysfunction. The endomyocardial form of restrictive cardiomyopathy (EMF-RCM), a primary disorder of the myocardium, is one of the diseases with poor prognosis in cats. We hypothesized that both the left and right myocardial functional abnormalities may occur in cats with EMF-RCM, causing this disease pathophysiology and clinical status. Out of the 25 animals included in this study, 10 were client-owned cats with EMF-RCM, and 15 were healthy cats. In this study, cats were assessed for layer-specific myocardial function (whole, endocardial, and epicardial) in the left ventricular longitudinal and circumferential directions, and right ventricular longitudinal direction, via two-dimensional speckle-tracking echocardiography (2D-STE). Cats with EMF-RCM had depressed left ventricular myocardial deformations both in systole (whole longitudinal strain, epicardial longitudinal strain, and endocardial circumferential strain) and diastole (early and late diastolic longitudinal strain rates, and late diastolic circumferential strain rate) compared to controls. Furthermore, some right ventricular myocardial deformations (systolic longitudinal strain in epicardial layers, and endocardial-to-epicardial strain ratio) were significantly differerent in cats with EMF-RCM. Myocardial function assessed by 2D-STE could reveal left and right myocardial dysfunction. [ABSTRACT FROM AUTHOR]

Background: Vitamin D-dependent rickets is rare in animals and humans. Several types of this condition are associated with genetic variants related to vitamin D metabolism. This is the first report of type 1B vitamin D-dependent rickets in a cat. Case presentation: Here, we describe the case of a 3-month-old female domestic short-haired cat previously fed on commercial kitten food that presented at our clinic with seizures, lethargy, and generalized pain. Serum and ionized calcium concentrations and 1,25-dihydroxycholecalciferol in this cat were low, and radiographs showed skeletal demineralization and abnormally wide growth plates on the long bones. Initially, simple vitamin D deficiency was suspected; however, the cat's profile, which included fed a well-balanced commercial diet, together with the findings of additional laboratory tests and the cat's unresponsiveness to various treatments, raised the suspicion of vitamin D-dependent rickets. Examination of the DNA sequences of CYP2R1 and CYP27B1 genes, which are genes linked with vitamin D metabolism, showed a CYP2R1 frameshift mutation in exon 5 (where T is deleted at position c.1386). This mutation alters the amino acid sequence from position 462, while the stop codon introduced at position 481 prematurely truncates the 501 amino acid full-length protein. With this knowledge, a new treatment regime based on a standard dose of calcitriol was started and this markedly improved the cat's condition. Conclusions: To the best of our knowledge, the present case is the first description of type 1B vitamin D-dependent rickets linked with a genetic variant of CYP2R1 in a cat. [ABSTRACT FROM AUTHOR]

Objectives: Certain guidelines recommend caution when administering immunotherapy in patients with pre-existing interstitial lung disease (ILD) owing to the high incidence of pneumonitis induced by anti-cancer therapy. A prospective clinical trial assessing the safety of chemoimmunotherapy in patients with small-cell lung cancer (SCLC) and pre-existing ILD is warranted. Therefore, this study evaluated the safety and efficacy of chemoimmunotherapy in patients with extensive-stage (ES)-SCLC and mild idiopathic interstitial pneumonia (IIP)., Methods: In this multicenter prospective trial, patients with ES-SCLC and pre-existing mild chronic fibrosing IIP were recruited. Mild IIP was defined as the exclusion of poor pulmonary function, a definite usual interstitial pneumonia (UIP) pattern, and positivity for autoantibodies in blood tests. The patients received durvalumab, etoposide, and carboplatin every three weeks (induction phase), followed by 1,500 mg durvalumab every four weeks (maintenance phase). The primary endpoint was severe pneumonitis-free rate., Results: Twenty-one patients were included in the analysis. Among them, 13 patients displayed a probable UIP pattern, whereas eight patients exhibited an indeterminate for UIP pattern. Two patients (9.5 %) had pneumonitis of any grade during the induction phase; one had Grade 1 and the other had Grade 5 pneumonitis. No other patient developed pneumonitis during the maintenance phase. The severe pneumonitis-free rate was 95.2 % (95 % confidence interval (CI): 77.3-99.2 %). The median progression-free survival was 5.5 months (95 % CI: 3.6-6.4 months). Median overall survival was 10.7 months (95 % CI: 6.0 months to not reached)., Conclusions: Chemoimmunotherapy is a feasible treatment approach for patients with ES-SCLC and mild IIP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Daichi Fujimoto reports financial support provided by AstraZeneca K.K. Ryota Shibaki received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and MSD KK outside the submitted work. Daichi Fujimoto received grants from AstraZeneca K.K. during the study and personal fees from AstraZeneca KK, Boehringer Ingelheim Japan Inc., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Janssen Pharmaceutical KK, Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Novartis Pharma KK outside of the submitted work. Eisaku Miyauchi received personal fees from AstraZeneca KK, Boehringer Ingelheim Japan Inc., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd., Pfizer Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Amgen Inc., Thermo Fisher Scientific KK, Nippon Kayaku Co. Ltd., Sysmex Co. Ltd., KYORIN Pharmaceutical Co. Ltd., and Novartis Pharma KK outside the submitted work. Yoko Tsukita received personal fees from AstraZeneca KK, Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., and Boehringer Ingelheim Japan Inc. outside the submitted work. Daisuke Arai has received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Merck, and Nippon Kayaku Co. outside the submitted work. Yoshihiko Sakata received personal fees from AstraZeneca KK, Amgen, Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Takeda Pharmaceutical Co., Ltd., and Novartis Pharma KK outside the submitted work. Naoki Shingu received personal fees from AstraZeneca KK, Chugai Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Takeda Pharmaceutical Co. Ltd., and MSD KK outside the submitted work. Takashi Kijima received personal fees from Chugai Pharmaceutical Co. Ltd. outside the submitted work. Go Saito received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Ono Pharmaceutical Co. Ltd., Pfizer, Daiichi Sankyo Company, and Novartis Pharma KK outside the submitted work. Yuki Sato received personal fees from AstraZeneca KK, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Daiichi Sankyo Co. Ltd., and Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Nippon Kayaku Co., Ltd., and Novartis Pharma KK outside the submitted work. Shinya Sakata received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd. outside the submitted work. Yoshihiko Taniguchi received personal fees from AstraZeneca KK, Bristol-Myers Squibb Co. Ltd., and Chugai Pharmaceutical Co. Ltd. outside the submitted work. Akito Hata has received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan KK, Pfizer Inc., and Boehringer Ingelheim outside the submitted work. Hirotaka Matsumoto received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Ono Pharmaceutical Co. Ltd., and Boehringer Ingelheim outside the submitted work. Nobuyuki Yamamoto has received personal fees from AstraZeneca KK, Chugai Pharmaceutical Co. Ltd., MSD KK, Ono Pharmaceutical Co. Ltd., Daiichi Sankyo, Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Boehringer Ingelheim Japan Inc., Pfizer Inc., Amgen Inc., Janssen Pharmaceutical KK, Terumo, Eli Lilly Japan KK, Novartis Pharma KK, Merck Biopharma, Guardant Health Japan, Accuray Inc., AbbVie, Kyorin Pharmaceutical Co. Ltd., Tsumura & Co., and Miyarisan Pharmaceutical outside the submitted work. Other authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this study.]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The therapeutic efficacy of mesenchymal stromal cells (MSCs) in inflammatory bowel disease is not completely known and is not consistent. Priming with inflammatory cytokines has been proposed to adapt MSCs to an inflammatory environment to have them ready to counteract it, but may have undesirable effects on MSCs, such as increased immunogenicity. In this study, we hypothesized that priming MSCs with inflamed intestinal tissue would more effectively enhance their therapeutic effect on intestinal inflammation., Methods: The capacity of canine adipose-derived MSCs (cADSCs) primed with colon tissue homogenates from mice with experimentally induced colitis or a combination of tumor necrosis factor-α and interferon-γ to inhibit T-cell proliferation was analyzed, along with their own apoptosis, proliferation, cell surface marker expression, and transcriptome. In addition, colitis mice were treated with the primed cADSCs to assess colitis severity and immune cell profile., Results: Priming with cytokines induced apoptosis, decreased cell proliferation, and major histocompatibility complex-II gene expression in cADSCs, but these adverse effects were mild or absent with colitis-tissue priming. cADSCs primed with colitis tissue reduced the severity of colitis via the induction of M2 macrophages and T-regulatory cells and suppression of T-helper (Th)1/Th17-cell responses, and their effects were comparable to those of cytokine-primed cells., Discussion: Our results emphasize the importance of the activation of MSCs by the appropriate microenvironment to maximize their therapeutic effect., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yasumura, Teshima, Nagashima, Michishita, Taira, Suzuki and Matsumoto.)

Background: The optimal subsequent treatment strategy for locally advanced non-small cell lung cancer (LA-NSCLC) after chemoradiotherapy (CRT) and consolidative durvalumab therapy remains unknown. We aimed to determine the optimal subsequent treatment strategy for this clinical population., Materials and Methods: We retrospectively enrolled 523 consecutive patients with LA-NSCLC treated with CRT and analyzed the treatment outcomes of subsequent therapy after progression following CRT and consolidative durvalumab therapy. Patients who received tyrosine kinase inhibitors as subsequent therapy were excluded., Results: Out of 122 patients who received subsequent chemotherapy, 55% underwent platinum-based, 25% non-platinum-based, and 20% immune checkpoint inhibitor (ICI)-containing therapies. In the platinum-based group, patients with a durvalumab-progression-free survival (Dur-PFS) ≥ 1 year had a significantly longer median subsequent therapy-PFS (SubTx-PFS) than those with Dur-PFS < 1 year (13.2 months vs. 4.7 months; hazard ratio, 0.45; 95% confidence interval, 0.21-0.97; P = .04). Furthermore, among patients receiving non-platinum-based chemotherapy, the median SubTx-PFS was longer in the combined with angiogenesis inhibitor group than in the without group, although the difference was not statistically significant. No significant difference of SubTx-PFS was observed between the reason for durvalumab discontinuation and the outcomes of ICI-containing therapy., Conclusion: In clinical practice, platinum-based chemotherapy rechallenge is frequently employed following progression subsequent to CRT and consolidative durvalumab therapy for LA-NSCLC. Optimal treatment strategies may consider Dur-PFS and angiogenesis inhibitor feasibility. Further research is warranted to identify clinical biomarkers that can help identify patients who would benefit from ICI rechallenge., Competing Interests: Disclosure Hayato Kawachi reported receiving personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Motohiro Tamiya reported receiving personal fees from Amgen, Asahi Kasei Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical outside the submitted work. Yuko Oya reported receiving personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis Pharma KK, Pfizer, Taiho Pharmaceutical, Daiichi Sankyo, and Takeda Pharmaceutical Company Limited outside the submitted work. Go Saito reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo Company, MSD, Novartis Pharma KK, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical outside the submitted work. Yoshihiko Taniguchi reports receiving personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, MSD, and Ono Pharmaceutical outside the submitted work. Hirotaka Matsumoto reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Kyowa Kirin, MSD, Nippon Kayaku Co. Ltd., Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical Company Limited outside the submitted work. Yuki Sato reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis Pharma KK, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, and Takeda Pharmaceutical Company Limited outside the submitted work. Taiichiro Otsuki reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai Co. Ltd., MSD, Nippon Kayaku Co. Ltd., Ono Pharmaceutical, Takeda Pharmaceutical Company Limited, and Tsumura & Co. outside the submitted work. Hidekazu Suzuki reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, and Takeda Pharmaceutical Company Limited outside the submitted work. Yasushi Fukuda reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, MSD, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Satoshi Tanaka declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Yoko Tsukita reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, MSD, and Taiho Pharmaceutical outside the submitted work. Junji Uchida declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Yoshihiko Sakata reported receiving personal fees from AstraZeneca, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical Co Ltd, Eli Lilly, Kyowa KIRIN, MSD, Novartis Pharma KK, Taiho Pharmaceutical, Takeda Pharmaceutical Company Limited outside the submitted work. Yuki Nakatani declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Ryota Shibaki reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, and Taiho Pharmaceutical outside of the submitted work. Daisuke Arai reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Merck Biopharma Co. Ltd., MSD, Nippon Kayaku Co. Ltd., Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical Company Limited outside the submitted work. Asuka Okada reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyowa KIRIN, MSD, and Nippon Kayaku Co. Ltd. outside the submitted work. Satoshi Hara declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Koichi Takayama reported receiving research grants from Chugai Pharmaceutical and Ono Pharmaceutical and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, MSD, and Merck outside the purview of the submitted work. Kazumi Nishino reported receiving grants from Ono, TAIHO, MSD, AbbVie, DAIICHI SANKYO, Amgen, Eisai, Sanofi, Janssen, Novartis, Pfizer, Eli Lilly, Merck, Takeda, Chugai, and Merus; and personal fees from AstraZeneca, Bristol Myers Squibb, Chugai, Eli Lilly, Janssen, Nippon Boehringer Ingerheim, Nippon Kayaku, Merck, Novartis, Pfizer, and Roche outside the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

An 8-year-old Leonberger receiving immunosuppressive treatment with clinical signs of acute dyspnea, cyanosis, and difficulty standing was referred to our institution (Day 1). Treatment including oxygen, clopidogrel, and low-molecular-weight heparin was initiated for suspected pulmonary thrombosis. However, exertional dyspnea persisted until Day 10, and increased tricuspid regurgitation velocity, pulmonary vascular resistance, and McConnell's signs also were observed. Thus, beraprost sodium was administered PO on Day 11 to treat suspected pulmonary hypertension. On Day 13, contrast-enhanced computed tomography identified extensive contrast defects in the pulmonary arteries, and IV monteplase was administered on Days 14 and 18, with marked improvement in respiratory status and exertional dyspnea on Day 20. Right ventricular function and McConnell signs also improved, and tricuspid regurgitation velocity and pulmonary vascular resistance decreased. On Day 250, echocardiography indicated further improvement in pulmonary hypertension pathophysiology. The patient was still progressing well with antithrombotic and pulmonary vasodilator treatment 400 days later., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Previous reports have shown that various oral pulmonary vasodilators are effective against canine pulmonary hypertension (PH). However, no studies have compared their hemodynamic effects. We aimed to compare the hemodynamic effects of 15 µg/kg beraprost sodium, 1.0 mg/kg sildenafil, and their combination, in dogs with experimentally induced mitral regurgitation. This experimental crossover study evaluated the hemodynamic and functional effects of oral pulmonary vasodilators by application of right-sided heart catheterization and echocardiography. Beraprost significantly decreased pulmonary and systemic vascular resistance. Additionally, beraprost increased right-ventricular stroke volume and left-ventricular cardiac output without worsening left-heart size and left-atrial pressure. The pulmonary vasodilatory effects of sildenafil were stronger, and its systemic vasodilatory effects were weaker than those of beraprost. However, sildenafil significantly increased the left-ventricular volume, left-atrial pressure indicator, and right-ventricular cardiac output. Combination therapy resulted in the strongest pulmonary and systemic vasodilating effects without worsening the left-heart size and left-atrial pressure indicators. Both beraprost and sildenafil were effective against canine PH; however, sildenafil was associated with the risk of worsening left-heart loading. Combination therapy with beraprost and sildenafil synergistically dilated pulmonary and systemic vessels, indicating a more potent treatment option for severe PH cases.

This study demonstrated for the first time that skin surface pH can be monitored in real-time, using a screen-printed wearable pH sensor, to evaluate the buffering capacity of the human skin. The screen-printed pH sensor was composed of a polyaniline-based pH-sensitive electrode and a nitrocellulose membrane-based liquid junction type of Ag/AgCl reference electrode. This sensor showed a reliable and reversible potentiometric response to pH with long-term potential stability. Intermittent monitoring of the buffering capacity of skin surface pH demonstrated the reliability of the proposed wearable pH sensor, which was comparable to that of a commercially available flat-tip pH sensor. We found that contact of the wearable pH sensor with the subject's skin via aqueous electrolyte solutions was necessary for the sensor to continuously monitor the skin surface pH while sustaining the natural buffer capacity of the human skin surface., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this., Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC., Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020., Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population., Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group., Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes., Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

Background: In small-cell lung cancer (SCLC), the tumor immune microenvironment (TIME) could be a promising biomarker for immunotherapy, but objectively evaluating TIME remains challenging. Hence, we aimed to develop a predictive biomarker of immunotherapy efficacy through a machine learning analysis of the TIME., Methods: We conducted a biomarker analysis in a prospective study of patients with extensive-stage SCLC who received chemoimmunotherapy as the first-line treatment. We trained a model to predict 1-year progression-free survival (PFS) using pathological images (H&E, programmed cell death-ligand 1 (PD-L1), and double immunohistochemical assay (cluster of differentiation 8 (CD8) and forkhead box P3 (FoxP3)) and patient information. The primary outcome was the mean area under the curve (AUC) of machine learning models in predicting the 1-year PFS., Results: We analyzed 100,544 patches of pathological images from 78 patients. The mean AUC values of patient information, pathological image, and combined models were 0.789 (range 0.571-0.982), 0.782 (range 0.750-0.911), and 0.868 (range 0.786-0.929), respectively. The PFS was longer in the high efficacy group than in the low efficacy group in all three models (patient information model, HR 0.468, 95% CI 0.287 to 0.762; pathological image model, HR 0.334, 95% CI 0.117 to 0.628; combined model, HR 0.353, 95% CI 0.195 to 0.637). The machine learning analysis of the TIME had better accuracy than the human count evaluations (AUC of human count, CD8-positive lymphocyte: 0.681, FoxP3-positive lymphocytes: 0.626, PD-L1 score: 0.567)., Conclusions: The spatial analysis of the TIME using machine learning predicted the immunotherapy efficacy in patients with SCLC, thus supporting its role as an immunotherapy biomarker., Competing Interests: Competing interests: The authors declare the following financial interests/personal relationships, which may be considered potential competing interests. DF has received personal fees from AstraZeneca KK, Boehringer Ingelheim Japan; Ono Pharmaceutical; Bristol-Myers Squibb; Taiho Pharmaceutical; Chugai Pharmaceutical; MSD KK; Eli Lilly Japan KK; Kyowa Kirin; and Novartis Pharma KK, outside of the submitted work. YKitamura is the chief executive officer of N Lab Co., Ltd and its stockholder. JF is an advisor of N Lab Co., Ltd. YS has received personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, Ono Pharmaceutical, Novartis, Pizer, Taiho Pharmaceutical, Nippon Kayaku, Bristol-Myers Squibb, Eli Lilly, Takeda, and Kyowa Kirin, outside of the submitted work. TK has received personal fees and scholarship donations from Chugai Pharmaceutical, outside of the submitted work. HM has received personal fees from Chugai Pharmaceutical, outside of the submitted work. TY has received personal fees from Chugai Pharmaceutical, outside of the submitted work. SM has received personal fees from Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Boehringer-Ingelheim Japan, and Takeda Pharmaceutical, outside of the submitted work. AH has received personal fees from Chugai outside of this study, outside of the submitted work. YT has received personal fees from Chugai outside of this study, outside of the submitted work. HT has received personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim Japan, and Pfizer Japan, outside of the submitted work. NY has received research funds from Chugai Pharmaceutical, outside of the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Malaria infection elicits both protective and pathogenic immune responses, and IL-27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4 + T cell responses that is targeted by IL-27. Neutralization of IL-27 during acute infection with Plasmodium chabaudi expanded specific CD4 + T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium-specific CD4 + T cells in IL-27-neutralized mice consisted mainly of CD127 + KLRG1 - and CD127 - KLRG1 + subpopulations that displayed distinct cytokine production, proliferative capacity, and are maintained in a manner independent of active infection. Single-cell RNA-seq analysis revealed that these CD4 + T cell subsets formed independent clusters that express unique Th1-type genes. These IL-27-neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL-27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4 + T cells, suggesting potential implications for the development of vaccines and other strategic interventions., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Introduction: Although pretreatment autoantibodies have been associated with immune-related adverse events (irAEs) and immune checkpoint inhibitor treatment efficacy in some types of cancer, their importance has not been evaluated in patients with SCLC., Methods: A multicenter prospective observational study was conducted on a total of 52 patients with extensive-disease SCLC who received immune checkpoint inhibitors in combination with chemotherapy as the first-line treatment at either of the six participating centers in Japan. Pretreatment serum samples were collected and analyzed for autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid). Moreover, 12 antineuronal antibodies (AMPH, CV2, PNMA2, Ri, Yo, Hu, Recoverin, SOX1, Titin, Zic4, GAD65, and Tr) were analyzed using immunoblot assays. The primary end point was the incidence of irAEs with or without autoantibodies. The secondary end points were progression-free survival (PFS) and overall survival (OS) on the basis of the presence or absence of autoantibodies., Results: PFS and OS were 4.4 and 25.3 months, respectively. Autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid antibodies) were detected in 29 patients (56%). In total, irAEs were observed in 18 patients (35%); irAE incidence was 48% in the autoantibody-positive group and 17% in the autoantibody-negative group ( p  = 0.039). There was no difference in PFS or OS between patients with and without autoantibodies (4.4 mo versus 4.6 mo, p  = 0.36; 15.3 mo versus 18.2 mo, p  = 0.36). Antineuronal antibodies were detected in 16 patients (31%). However, the development of neurologic irAEs was not observed in both groups., Conclusions: Vigilance is required against the development of irAEs in pretreatment antibody-positive patients., (© 2023 The Authors.)

Background: Transcription factors (TFs) exhibit heterogeneous DNA-binding specificities in individual cells and whole organisms under natural conditions, and de novo motif discovery usually provides multiple motifs, even from a single chromatin immunoprecipitation-sequencing (ChIP-seq) sample. Despite the accumulation of ChIP-seq data and ChIP-seq-derived motifs, the diversity of DNA-binding specificities across different TFs and cell types remains largely unexplored., Results: Here, we applied MOCCS2, our k-mer-based motif discovery method, to a collection of human TF ChIP-seq samples across diverse TFs and cell types, and systematically computed profiles of TF-binding specificity scores for all k-mers. After quality control, we compiled a set of TF-binding specificity score profiles for 2,976 high-quality ChIP-seq samples, comprising 473 TFs and 398 cell types. Using these high-quality samples, we confirmed that the k-mer-based TF-binding specificity profiles reflected TF- or TF-family dependent DNA-binding specificities. We then compared the binding specificity scores of ChIP-seq samples with the same TFs but with different cell type classes and found that half of the analyzed TFs exhibited differences in DNA-binding specificities across cell type classes. Additionally, we devised a method to detect differentially bound k-mers between two ChIP-seq samples and detected k-mers exhibiting statistically significant differences in binding specificity scores. Moreover, we demonstrated that differences in the binding specificity scores between k-mers on the reference and alternative alleles could be used to predict the effect of variants on TF binding, as validated by in vitro and in vivo assay datasets. Finally, we demonstrated that binding specificity score differences can be used to interpret disease-associated non-coding single-nucleotide polymorphisms (SNPs) as TF-affecting SNPs and provide candidates responsible for TFs and cell types., Conclusions: Our study provides a basis for investigating the regulation of gene expression in a TF-, TF family-, or cell-type-dependent manner. Furthermore, our differential analysis of binding-specificity scores highlights noncoding disease-associated variants in humans., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial., Methods: Treatment-naïve patients with stage IV NSCLC harboring an activating EGFR mutation were enrolled. Alternating cycles of osimertinib (80 mg/day) followed by afatinib (20 mg/day) were administered every 8 weeks. Genomic analysis was performed using circulating tumor DNA obtained before and after the treatment., Results: Among the 46 enrolled patients, the median progression-free survival was 20.2 months. The overall response rate was 69.6%. The median overall survival was not reached. Among the 26 plasma samples obtained after the acquisition of resistance, 3 showed an increased MET gene copy number, and 1 showed BRAF mutation. Meanwhile, no EGFR secondary mutation was detected., Conclusion: The efficacy of our treatment was not significantly different from osimertinib alone, as reported previously in untreated advanced NSCLC patients with EGFR mutations. Although the sample size was limited, this treatment may prevent the emergence of EGFR secondary mutations that trigger drug resistance. Further studies are warranted to establish the significance of this treatment., Clinical Trial Registration: jRCTs051180009., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Two-dimensional cell cultures have contributed substantially to lung cancer research, but 3D cultures are gaining attention as a new, more efficient, and effective research model. A model reproducing the 3D characteristics and tumor microenvironment of the lungs in vivo , including the co-existence of healthy alveolar cells with lung cancer cells, is ideal. Here, we describe the creation of a successful ex vivo lung cancer model based on bioengineered lungs formed by decellularization and recellularization. Methods: Human cancer cells were directly implanted into a bioengineered rat lung, which was created with a decellularized rat lung scaffold reseeded with epithelial cells, endothelial cells and adipose-derived stem cells. Four human lung cancer cell lines (A549, PC-9, H1299, and PC-6) were applied to demonstrate forming cancer nodules on recellularized lungs and histopathological assessment were made among these models. MUC-1 expression analysis, RNA-seq analysis and drug response test were performed to demonstrate the superiority of this cancer model. Results: The morphology and MUC-1 expression of the model were like those of lung cancer in vivo . RNA sequencing revealed an elevated expression of genes related to epithelial-mesenchymal transition, hypoxia, and TNF-α signaling via NF-κB; but suppression of cell cycle-related genes including E2F. Drug response assays showed that gefitinib suppressed PC-9 cell proliferation equally well in the 3D lung cancer model as in 2D culture dishes, albeit over a smaller volume of cells, suggesting that fluctuations in gefitinib resistance genes such as JUN may affect drug sensitivity. Conclusions: A novel ex vivo lung cancer model was closely reproduced the 3D structure and microenvironment of the actual lungs, highlighting its possible use as a platform for lung cancer research and pathophysiological studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mizoguchi, Tsuchiya, Doi, Obata, Iwatake, Hashimoto, Matsumoto, Yukawa, Hayashi, Li, Yamamoto, Matsumoto, Miyazaki, Tomoshige and Nagayasu.)

Activation of the cholinergic anti-inflammatory pathway (CAP) via vagus nerve stimulation has been shown to improve acute kidney injury in rodent models. While alpha 7 nicotinic acetylcholine receptor (α7nAChR) positive macrophages are thought to play a crucial role in this pathway, their in vivo significance has not been fully understood. In this study, we used macrophage-specific α7nAChR-deficient mice to confirm the direct activation of α7nAChRs in macrophages. Our findings indicate that the administration of GTS-21, an α7nAChR-specific agonist, protects injured kidneys in wild-type mice but not in macrophage-specific α7nAChR-deficient mice. To investigate the signal changes or cell reconstructions induced by α7nAChR activation in splenocytes, we conducted single-cell RNA-sequencing of the spleen. Ligand-receptor analysis revealed an increase in macrophage-macrophage interactions. Using macrophage-derived cell lines, we demonstrated that GTS-21 increases cell contact, and that the contact between macrophages receiving α7nAChR signals leads to a reduction in TNF-α. Our results suggest that α7nAChR signaling increases macrophage-macrophage interactions in the spleen and has a protective effect on the kidneys., (© 2023. The Author(s).)

In recent years, hypertrophic cardiomyopathy (HCM) in cats has become much more common in clinical practice due to improvements in diagnostic techniques and equipment performance. One phenotype is obstructive HCM with left ventricular (LV) outflow tract obstruction (DLVOTO). It has been reported that the presence or absence of DLVOTO does not affect long-term prognosis in cats with HCM. In this study, we evaluated and compared myocardial function in HCM-affected cats with and without DLVOTO using the two-dimensional speckle-tracking echocardiography. LV longitudinal strain of the endocardial, epicardial, and whole layer and LV circumferential strain of the epicardium were significantly decreased in all HCM-affected cats compared to healthy cats. However, these values were not significantly different between those with and without DLVOTO. In contrast, the endocardial and whole layers of LV circumferential strain were only significantly decreased in HCM-affected cats with DLVOTO compared to healthy cats. This could be attributed to the fact that the LV pressure load associated with DLVOTO affected the endocardial myocardium more in the LV endocardial layer, and that lower values of LV endocardial strain lowered the values of LV strain in the whole layer. In conclusion, our results suggest that LV myocardial function may have been more compromised in the HCM-affected cats with DLVOTO., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Saito, Suzuki, Yuchi, Fukuoka, Satomi, Teshima and Matsumoto.)

Pulmonary hypertension (PH) is a life-threatening complication in dogs with cardiopulmonary disease. Epoprostenol is an intravenous pulmonary vasodilator used to treat PH in humans; however, its efficacy in dogs remains unknown. We investigated the cardiovascular effects of epoprostenol and several cardiac agents for acute heart failure in canine models of chronic PH. Six dogs with chronic PH were anesthetized and underwent right heart catheterization and echocardiography before and after infusion of epoprostenol, dobutamine, dopamine and pimobendane. (The drug administration order was the same for all dogs). High-dose epoprostenol (15-20 ng/kg/min) tended to decrease pulmonary arterial pressure (PAP) while significantly decreasing pulmonary and systemic vascular resistance and increasing left and right ventricular (LV and RV, respectively) function. Pimobendan significantly increased LV and RV functions without increasing PAP. Conversely, dobutamine and dopamine significantly increased LV and RV function as well as PAP. This study revealed the efficacy of epoprostenol in treating canine PH through its pulmonary and systemic vasodilating effects. Although catecholamines improve LV and RV function, they might worsen PH pathophysiology, and careful monitoring may be necessary when using these drugs. Pimobendan improved LV and RV function without increasing PAP; however, a stronger vasodilating effect was observed with epoprostenol.

Importance: Chemoimmunotherapy is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). However, whether findings from pivotal trials can be extrapolated to the clinical practice setting remains unclear., Objective: To compare treatment outcome gaps following first-line chemoimmunotherapy for patients with ES-SCLC between those who met and did not meet the eligibility criteria used in previous clinical trials., Design, Setting, and Participants: A prospective cohort study was conducted from September 1, 2019, to September 30, 2020, at 32 hospitals in Japan, with at least 12 months of follow-up. Participants included consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as first-line therapy., Exposures: Patients who met eligibility criteria for pivotal phase 3 clinical trials were considered trial-eligible., Main Outcomes and Measures: The primary outcome was 6-month progression-free survival. The secondary outcomes were differences in progression-free survival, overall survival, and safety according to whether key clinical trial eligibility criteria were met., Results: A total of 207 patients were analyzed (median age, 72 years; range, 46-87 years; 170 [82%] were male). Sixty-four patients (31%) were older adults (age ≥75 years), and most (184 [89%]) had an Eastern Cooperative Oncology Group performance status of 0 or 1. There were 132 (64%) trial-eligible patients. The 6-month progression-free survival rate for all patients was 38.8% (95% CI, 32.4%-45.7%). The median progression-free survival was 5.1 months in trial-eligible patients and 4.7 months in trial-ineligible patients (hazard ratio, 0.72; 95% CI, 0.53-0.97; P = .03). The proportion of patients who achieved disease control was 93% (118 of 127) in trial-eligible patients and 77% (55 of 71) in trial-ineligible patients (P = .002). The median overall survival was 15.8 months in trial-eligible patients and 13.1 months in trial-ineligible patients (hazard ratio, 0.73; 95% CI, 0.51-1.07; P = .10). The rate of severe adverse events was numerically higher among trial-ineligible patients than among trial-eligible patients (39% vs 27%; P = .07)., Conclusions and Relevance: In this cohort study, the overall treatment outcome was comparable to that reported in pivotal clinical trials. However, treatment outcomes after chemoimmunotherapy might differ between trial-eligible and trial-ineligible patients. These findings suggest that trial-eligibility criteria may be useful in clinical practice, and further studies using data from clinical practice settings are required to inform regulatory approval and clinical decision-making.

Objective: Parkinson's disease (PD) is a common neurodegenerative disease characterized by initial involvement of the olfactory bulb/amygdala or autonomic nerves followed by nigral degeneration. Although autonomic innervation strictly regulates multiorgan systems, including endocrine functions, circulation, and digestion, how dysautonomia in PD affects systemic metabolism has not been identified. In this study, we tried to estimate the pathogenic linkage of PD by nuclear medicine techniques, trans-omic analysis of blood samples, and cultured cell experiments., Methods: Thyroid mediastinum ratio of 123 I-metaiodobenzylguanidine (MIBG) scintigraphy was measured in 1,158 patients with PD. Furthermore, serum exosome miRNA transcriptome analysis and plasma metabolome analysis followed by trans-omic analysis were performed in patients with de novo PD and age-matched healthy control persons. Additionally, thyroid hormone was administered to skeletal muscle and liver derived cells to evaluate the effect of hypothyroidism for these organs., Results: Sympathetic denervation of thyroid correlating with its cardiac denervation was confirmed in 1,158 patients with PD by MIBG scintigraphy. Among patients with drug-naïve PD, comprehensive metabolome analysis revealed decreased levels of thyroxine and insufficient fatty acid β-oxidation, which positively correlate with one another. Likewise, both plasma metabolome data and transcriptome data of circulating exosomal miRNAs, revealed specific enrichment of the peroxisome proliferator-activated receptor (PPARα) axis. Finally, association of thyroid hormone with PPARα-dependent β-oxidation regulation was confirmed by in vitro experiments., Interpretation: Our findings suggest that interorgan communications between the thyroid and liver are disorganized in the early stage of PD, which would be a sensitive diagnostic biomarker for PD. ANN NEUROL 2023;93:303-316., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)