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Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.

Fluorogenic probes for bioimaging have become essential tools for life science and medicine, and the key to their development is a precise understanding of the mechanisms available for fluorescence off/on control, such as photoinduced electron transfer (PeT) and Förster resonance energy transfer (FRET). Here we establish a new molecular design strategy to rationally develop activatable fluorescent probes, which exhibit a fluorescence off/on change in response to target biomolecules, by controlling the twisted intramolecular charge transfer (TICT) process. This approach was developed on the basis of a thorough investigation of the fluorescence quenching mechanism of

Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance.Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/mCIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake.ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.

Introduction: Karyopherin alpha 2 (KPNA2) and karyopherin beta 1 (KPNB1) constitute nuclear transport protein complexes involved in nuclear import and are significant in tumor progression. Although high KPNA2 expression was associated with poor prognosis in solid tumors, the relationship between KPNA2 and KPNB1 expression and their prognostic role in gastric cancer (GC) remains unclear. Methods: Immunohistochemistry was used to correlate the expression of KPNA2 and KPNB1 with various features, including clinicopathological characteristics in 130 patients with GC and survival in 94 patients with invasive lesions extending to the submucosa or deeper. Results: High expression of KPNA2 and KPNB1 was found in 25% and 36% of the patients, respectively. Both were significantly related to tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, and Ki-67 expression. KPNA2 expression was significantly related to that of KPNB1 (p < 0.001). Patients with high KPNB1 expression had poorer prognosis than those with low expression (p = 0.027), as was also observed in case of KPNA2 (p < 0.001). Patients with high expression of both KPNA2 and KPNB1 accounted for 18% and had a poorer prognosis than those with high expression of either and those with low expression of both (p = 0.001). Multivariate analysis revealed that high expression of both KPNA2 and KPNB1 was an independent prognostic factor in patients with GC (hazard ratio, 3.46; 95% confidence interval, 1.64–2.73, p = 0.001). Conclusion: KPNA2 expression was correlated with KPNB1 expression, and high co-expression of KPNA2 and KPNB1 may represent a strong prognostic biomarker in GC.

Background: In advanced or metastatic ovarian cancer patients, the therapeutic impact of molecular targeted agents and immunotherapy is limited, and current chemotherapeutic algorithm is still far from personalized medicine. We recently demonstrated that intraperitoneal carboplatin with dose-dense paclitaxel (ddTCip) therapy is a promising front-line chemotherapy even in the patients with residual peritoneal tumors, which led us to this theranostic study for biomarker discovery to realize the precision medicine (ID: UMIN000001713 on Feb 16 th , 2009). Methods: We first validated previously suggested markers (41 genes and 3 predictive models for the therapeutic efficacy and 31 polymorphisms for the toxicity), sought out more active effective biomarkers through genome-wide transcriptome and genotyping analyses, and then developed multiplex statistical prediction models for progression free-survival (PFS) and toxicity. Multiple regression analysis following forward stepwise method and Classification and Regression Trees (CART) algorithm were mainly employed to develop multiplex prediction models. Results: The association analyses with PFS in 76 patients followed by the validation study using data sets in 189 patients published in The Cancer Genome Atlas revealed that SPINK1 expression could be a possible predictive biomarker of ddTCip efficacy even when used alone, and multiple regression analyses provided a potent efficacy prediction model using expression data of 5 genes. SPINK1 appeared to be a critical resistant determinant of ddTCip therapy, which indicates the potential of SPINK1 also to be a novel therapeutic target. As for the toxicity prediction, ABCB1rs1045642 and ERCC1rs11615 polymorphisms appeared to closely associate with grade2-4 hematologic toxicity and peripheral neuropathy, respectively. We further successfully composed robust multiplex prediction models for the adverse events-CART models using a total of 4 genotype combinations and further powerful multiple regression models using 15 polymorphisms on 12 genes-. Conclusions: We newly proposed SPINK1 expression as a powerful predictive biomarker of the efficacy for ddTCip therapy and confirmed the predictive values of ABCB1 and/or ERCC1 polymorphisms for the toxicity. Multiplex prediction models composed herein were also found to work well for the prediction of therapeutic response. These may raise the potential to realize a precision medicine in the essential treatment for metastatic ovarian cancer patients.

Background: In advanced or metastatic ovarian cancer patients, the therapeutic impact of molecular targeted agents and immunotherapy is limited, and current chemotherapeutic algorithms are still far from personalized medicine. We recently demonstrated that intraperitoneal carboplatin with dose-dense paclitaxel (ddTCip) therapy is a promising front-line chemotherapy even in patients with residual peritoneal tumors, which led us to this theranostic study for biomarker discovery to realize precision medicine (ID: UMIN000001713 on Feb 16th, 2009). Methods: We first validated previously suggested markers (41 genes and 3 predictive models for therapeutic efficacy and 31 polymorphisms for toxicity), sought out more active effective biomarkers through genome-wide transcriptome and genotyping analyses, and then developed multiplex statistical prediction models for progression-free survival (PFS) and toxicity. Multiple regression analysis following the forward stepwise method and the classification and regression tree (CART) algorithm were mainly employed to develop multiplex prediction models. Results: The association analyses with PFS in 76 patients followed by the validation study using data sets in 189 patients published in The Cancer Genome Atlas revealed that SPINK1 expression could be a possible predictive biomarker of ddTCip efficacy even when used alone, and multiple regression analyses provided a potent efficacy prediction model using expression data of 5 genes. SPINK1 appeared to be a critical resistant determinant of ddTCip therapy, which indicates the potential of SPINK1 as a novel therapeutic target. For toxicity prediction, ABCB1 rs1045642 and ERCC1 rs11615 polymorphisms appeared to be closely associated with grade 2-4 hematologic toxicity and peripheral neuropathy, respectively. We further successfully composed robust multiplex prediction models for adverse events - CART models using a total of 4 genotype combinations and further powerful multiple regression models using 15 polymorphisms on 12 genes-. Conclusions: We newly proposed SPINK1 expression as a powerful predictive biomarker of the efficacy of ddTCip therapy and confirmed the predictive values of ABCB1 and/or ERCC1 polymorphisms for toxicity. The multiplex prediction models composed herein were also found to work well for the prediction of therapeutic response. These findings may raise the potential to realize precision medicine in the essential treatment for metastatic ovarian cancer patients.

PURPOSE This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

Background: An evaluation of quadriceps tendon (QT) morphology preoperatively is an important step when selecting an individually appropriate autograft for anterior cruciate ligament (ACL) reconstruction. However, to our knowledge, there are no studies that have assessed the morphology of the entire QT in an ACL-injured knee preoperatively using ultrasound. Purpose: We aimed to investigate the morphological characteristics of the QT using preoperative ultrasound in ACL-injured knees. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 33 patients (mean age, 26.0 ± 11.5 years) with a diagnosed ACL tear undergoing primary ACL reconstruction were prospectively included. Using ultrasound, short-axis images of the QT were acquired in 10-mm increments from 30 to 100 mm proximal to the superior pole of the patella. The length of the QT was determined by 2 contiguous images that did and did not contain the rectus femoris muscle belly. The width of the superficial and narrowest parts of the QT, the thickness of the central and thickest parts of the QT, and the cross-sectional area at the central 10 mm of the superficial QT width were measured at each assessment location. The estimated intraoperative diameter of the QT autograft was calculated using a formula provided in a previous study. Results: There were no significant relationships between QT morphology and any of the demographic data collected. The length of the QT was less than 70 mm in 45.5% of patients (15/33). The width, thickness, cross-sectional area, and estimated intraoperative diameter of the QT autograft were significantly greater at 30 mm than at 70 mm proximal to the superior pole of the patella. Conclusion: Preoperative ultrasound may identify a QT that is too small for an all–soft tissue autograft in ACL reconstruction. Furthermore, harvesting a QT with a fixed width may result in autografts that are smaller proximally than they are distally. Assessing the morphology of the QT preoperatively using ultrasound may help surgeons to adequately reconstruct the native length and diameter of the ACL with a QT autograft.

Femtosecond time-resolved absorption measurements were carried out for the dark and signaling states of a BLUF (Blue Light Using FAD) protein, PixD, from the cyanobacterium Synechocystis. When the dark state was excited, FAD semiquinone radical (FADH•) was produced from the S1 state, and FADH• led to the signaling state. On the other hand, photoexcitation of the signaling state generated FADH• and FAD anion radical (FAD•-), and they decayed back to the original signaling state. In both cases, FADH• was formed and decayed with a proton-coupled electron transfer (PCET) via the hydrogen-bond network that involves FAD, Gln50, and Tyr8, and hence the kinetics of FADH• directly reflects the hydrogen-bond structure in the FAD-binding sites. It was found that the formation rate of FADH• was significantly different between the dark and signaling states, whereas the decay rate was the same. This indicates that the hydrogen-bond network of FAD-Gln50-Tyr8 in the dark and signaling states is initially different but it becomes indistinguishable after FADH• is formed, implying that the FAD-Gln50-Tyr8 hydrogen-bond network is rearranged during the PCET to generate FADH•. The present results best agree with the model in which the Gln tautomerizes without rotation in the signaling-state formation.

We investigate excited-state dynamics of the [Au(CN)2−] oligomers following photo-initiated intermolecular Au–Au bond formation by carrying out femtosecond time-resolved absorption and emission measurements at various concentrations.

The outcomes of hepatectomy alone for liver metastasis derived from non-cutaneous melanoma are insufficient, and the outcomes of systemic therapy alone are also insufficient, even since the development of immune checkpoint inhibitors (ICIs). We report the cases of three patients, in whom liver metastasis derived from non-cutaneous melanoma was treated with hepatectomy combined with ICI therapy, which was administered in various settings. One patient received ICI treatment for recurrent melanoma and survived 107 months after the first hepatectomy, one patient received both preoperative and adjuvant ICI treatment and has been disease-free for 27 months, and another patient received postoperative ICI treatment after reduction hepatectomy and has been alive with disease for 47 months. Since long-term survival is possible, hepatectomy combined with ICI therapy should be considered for the treatment of liver metastasis derived from non-cutaneous melanoma.

Ultrasound with superb microvascular imaging (SMI) is a novel microvascular imaging technology which may be useful to assess the vascularity of the torn anterior cruciate ligament (ACL) as a potential measure of healing potential following surgery. This study aimed to quantify the vascularity of the torn and intact ACL using ultrasound with SMI. 23 patients (mean age ± standard deviation, 27.1 ± 12.8 years), who were diagnosed with an ACL tear with an intact contralateral ACL were enrolled (ACL injury group). Ten healthy volunteers (36.1 ± 4.9 years) who had intact ACLs in both knees were also recruited (ACL healthy controls). The vascularity of the ACL was assessed using SMI within 15 mm from the tibial insertion in both knees. The amount of the vascular signal was assessed using a semi-quantitative grading scale (vascularity grade: grade 0–3) and a quantified ratio of vascularized area with respect to total area of the region of interest (vascularity ratio). In the ACL injury group, a significantly higher vascularity grade and ratio were observed in the torn ACL (vascularity grade 0–3: 1, 8, 7, and 7 patients, respectively; vascularity ratio: 1.3 ± 1.4%) than the contralateral intact ACL (vascularity grade 0–3: 21, 1, 1, and 0 patients, respectively; vascularity ratio: 0.1 ± 0.5%) (P

We studied ultrafast structural dynamics of photoactive yellow protein (PYP) using ultraviolet femtosecond stimulated Raman spectroscopy. By employing the Raman pump and probe pulses in the ultraviolet region, resonantly enhanced, rich vibrational features of the excited-state chromophore were observed in the fingerprint region. In contrast to the marked spectral change reported for the excited-state chromophore in solution, in the protein, all of the observed Raman bands in the fingerprint region did not show any noticeable spectral shifts nor band shape changes during the excited-state lifetime of PYP. This indicates that the significant skeletal change does not occur on the chromophore in the excited state of PYP and that the trans conformation is retained in its lifetime. Based on the femtosecond Raman data of PYP obtained so far, we discuss a comprehensive picture of the excited-state structural dynamics of PYP.

Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment.Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated.SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia.Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.

Since poor repeatability of the load and shift test using a grading scale has been reported, an objective and quantitative method to assess anterior translation should be established to assess glenohumeral joint function. The purpose of this study was to assess the accuracy and repeatability of the ultrasonographic techniques to quantify anterior translation of the glenohumeral joint. Eight fresh-frozen cadaveric shoulders were used. For the standard technique, the ultrasound transducer was positioned on the anterolateral aspect of the shoulder viewing the coracoid process, glenoid, and humeral head. For the revised technique, the transducer was positioned on the anterior aspect of the shoulder, perpendicular to the scapular plane, viewing the conjoint tendon, glenoid, and humeral head. During the load and shift test, the distance between anterior edges of the glenoid and the humeral head was measured. The difference between distances before and after applying an anterior load was calculated as an anterior translation and compared with the anterior translation assessed using a motion tracking system. The repeatability and accuracy of both techniques were analyzed statistically. Intra- and inter-observer repeatability was good–excellent for both ultrasonographic techniques (ICC, 0.889–0.998). The revised technique achieved a stronger correlation to the anterior translations obtained using the motion tracking system (R = 0.810–0.913, p

Toll-like receptors (TLRs) sense microbial infection through recognition of pathogen-associated molecular patterns. For example, TLR4 responds to the lipopolysaccharide of gram-negative bacteria, whereas TLR2 recognizes a broad range of microbial ligands. Both receptors are, therefore, compelling targets for treating sepsis. Here, we developed a TLR2xTLR4 tetravalent bispecific antibody designated ICU-1, which inhibits both receptors. The inhibitory activity of ICU-1 was comparable to that of the parental antibodies in neutralization assays using a human monocyte cell line. Moreover, ICU-1 completely blocked stimulation of human peripheral blood mononuclear cells by clinically relevant bacterial species. These findings provide convincing evidence that ICU-1 offers a novel approach for treating bacterial sepsis.

本学には，教員研修の高度化，体系化，組織化の実現に一層寄与することを目的としてNITS 四国アライアンス鳴門教育大学センターが設置された。本稿は，そこでの県教育委員会と連携して実 施している管理職養成講座についてまとめたものである。, The NITS Shikoku Alliance Naruto University of Education Center was established at this university with the aim to further contribute to the sophistication, systematization, and organization of teacher training. This paper is a summary of the Manager Training Course conducted in collaboration with the Prefectural Board of Education.

The multi-ionization processes of Kr and Xe in the K-edge photon energy region were investigated using short-pulse x-rays and time-of-flight apparatus. The generation of Kr13+ ions in this photon energy region was observed for the first time. The distribution characteristics observed in the experiment, such as the production of Kr13+ ions, high production ratios of Kr4+, Kr5+, and Kr6+ ions, and the existence of a small peak for Kr8+, were quantitatively reproduced by the Monte Carlo simulation for the charge distribution of Kr ions following 1s of inner shell ionization. The highly charged ions were suppressed in the experiments compared with those in the simulation, probably owing to the inhibition of certain Coster-Kronig processes in the highly charged ions, which were not considered for analysis. The charge distribution of Xe ions following 1s of inner shell ionization was also investigated. A similar charge distribution was observed when the photon energy was located between the K and L edges. This is because the Xe 1s hole state mainly undergoes ultrafast relaxation to the 2p hole state owing to the strong dipole transition moment between the 1s and 2p states.

Toll-like receptor 4 (TLR4) plays a critical role in the innate immune system and is involved in the pathogenesis of multiple diseases. Here, we report the antagonistic and ratized antibody, 52-1H4 e2 (e2), which completely inhibited lipopolysaccharide-induced interleukin-6 secretion

Femtosecond time-resolved absorption and picosecond time-resolved emission measurements were carried out for highly concentrated aqueous solutions of K2 [Pt(CN)4 ] to investigate excited-state dynamics of the [Pt(CN)4 2- ] oligomers formed with metallophilic interactions. Time-resolved absorption spectra exhibit complicated dynamics that are represented with five time constants. Among them, the 90-ps and 400-ps dynamics were assigned to the S1 → T1 intersystem crossing of the trimer and tetramer coexisting in the solution by comparison with the fluorescence decays. Clear oscillations of transient absorption were observed in the first few picoseconds, and the frequency-detected-wavelength 2D analysis revealed that the 135-cm-1 and 65-cm-1 oscillations arise from the Pt-Pt stretch motions of the S1 trimer and S1 tetramer, respectively. The obtained time-resolved spectroscopic data provide a clear view of the excited-state dynamics of the [Pt(CN)4 2- ] oligomers in the femto-/picosecond time region.

Background: Thoracic outlet syndrome is more common in overhead athletes. The anterior and middle scalene muscles have been associated with thoracic outlet syndrome; however, the relationship between the elastic moduli of the scalene muscles and the overhead-throwing position has not been evaluated. Purpose: To investigate the elastic moduli of the anterior and middle scalene muscles in simulated throwing positions using shear wave elastography. Study Design: Descriptive laboratory study. Methods: We enrolled collegiate baseball players who underwent preseason medical checkups in January and February 2020. The anterior and middle scalene muscles were visualized in the short-axis view using ultrasound. In this view, the elastic moduli of the anterior and middle scalene muscles were measured using shear wave elastography in the following arm and neck positions: (1) adduction and neutral rotation of the shoulder (neutral), (2) 90° of abduction and external rotation of the shoulder (ABER), and (3) ABER with neck rotation toward the nonthrowing side (ABER+NR). Repeated-measures analysis of variance and a paired t test were used to compare the elastic modulus values among the 3 positions and between the 2 muscles, respectively. Results: Overall, 30 baseball players were included. In both scalene muscles, the elastic moduli were significantly greater in the ABER versus neutral position (anterior scalene: 14.4 ± 3.8 vs 9.4 ± 2.0 kPa, respectively [ P < .001]; middle scalene: 15.8 ± 5.0 vs 10.9 ± 3.4 kPa, respectively [ P < .001]). In the neutral position, the elastic modulus was significantly greater in the middle scalene than the anterior scalene (10.9 ± 3.4 vs 9.4 ± 2.0 kPa, respectively; P = .03). In the ABER+NR position, the elastic modulus was significantly greater in the anterior scalene than the middle scalene (18.1 ± 4.6 vs 15.8 ± 2.6 kPa, respectively; P = .03). Conclusion: Because the ABER position was a simulation of the throwing position, these results indicate that this position could be associated with high elastic moduli of the scalene muscles, and both the anterior and middle scalene muscles may be involved.

Background: Ultrasonography can be used to quantitatively assess anterior humeral head translation (AHHT) at different degrees of shoulder abduction. Risk factors for recurrent shoulder instability have been identified. Hypothesis: It was hypothesized that the number of dislocations or glenoid or humeral bone loss would be associated with more AHHT as measured using ultrasound. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 39 patients who underwent surgery for anterior shoulder instability were prospectively studied. Ultrasound assessment of AHHT was performed immediately after general anesthesia was induced. The upper arm was placed at 0°, 45°, and 90° of abduction, and a 40-N anterior force was applied to the proximal third of the arm. The distance from the posterior edge of the glenoid to that of the humeral head was measured at each abduction angle using ultrasound with and without a 40-N anterior force, and the AHHT was calculated. The differences in translation at each shoulder angle were compared. Additionally, the authors investigated the association between AHHT and demographic, radiographic, and clinical data. Results: Compared with the AHHT at 0° of abduction (5.29 mm), translation was significantly larger at 45° of abduction (8.90 mm; P < .01) and 90° of abduction (9.46 mm; P < .01). The mean translation was significantly larger in female patients than in male patients at all degrees of abduction ( P ≤ .036 for all). There was no correlation between AHHT at any abduction angle and number of dislocations, clinical data, or radiographic data (including bone loss). Conclusion: Ultrasound assessment of AHHT showed larger amounts of laxity at 45° and 90° than at 0° of abduction. Anterior glenohumeral laxity was greater in female than male patients. Glenoid or humeral bone loss did not correlate with AHHT, thereby clarifying that bone loss has no direct effect on measurements of capsular laxity in neutral rotation.

The functional role of the calcaneofibular ligament (CFL) is still controversial. We aimed to investigate the anatomical features of the CFL on sonography and the elastic modulus of the CFL in different ankle positions using ultrasound shear-wave elastography (SWE).In 14 cadaveric ankles, the angle of the CFL with respect to the long axis of the fibula was measured in the following ankle positions: neutral (N), 30° plantar flexion (PF), and 20° dorsiflexion (DF). In addition, in 24 ankles of healthy adult volunteers, the elastic modulus of the CFL was evaluated with ultrasound SWE in the following ankle positions: neutral (N), 30° plantar flexion with inversion (PI), 30° plantar flexion with eversion (PE), 20° dorsiflexion with inversion (DI), and 20° dorsiflexion with eversion (DE).The mean angle of the CFL in N, PF, and DF positions was 139.9° ± 12.7°, 121.3° ± 14.1°, and 158.6° ± 13.1°, respectively. The angle of the CFL in N was significantly greater than that in PF and smaller than that in DF (P 0.0001, both). The mean elastic modulus of the CFL in the N, PI, PE, DI, and DE positions was: 63.6 ± 50.8, 148.0 ± 39.4, 75.8 ± 40.6, 88.1 ± 31.6, and 61.7 ± 29.4 kPa, respectively. The elastic modulus in PI was significantly higher than in other positions, while the values obtained in DI and DE were also significantly different (P 0.001, both).The angle of the CFL increased with DF. Moreover, ultrasound SWE showed that the CFL was tensed and likely to be injured in the PI position.

The purpose of the current study was to measure extrusion of the intact lateral meniscus as a function of knee flexion angle and loading condition and to compare the changes in extrusion with a posterior root tear using a robotic testing system and ultrasound.Controlled laboratory study.Eight fresh-frozen cadaveric knees were subjected to external loading conditions (passive path position (no external load), 200 axial compression, 5-N-m internal tibial torque, 5-N-m valgus torque) at full extension, 30°, 60° and 90° of flexion using a robotic testing system. A linear array transducer was placed in the longitudinal orientation. Extrusion and kinematics data were recorded for two meniscus states: intact and posterior lateral root deficiency. Therefore, a complete radial root tear in the lateral meniscus at 10 mm from the tibial insertion was made in all 8 cadaveric knees using arthroscopy. The resultant forces in the lateral meniscus were also quantified by reproducing recorded paths after the removal of the lateral meniscus.A lateral meniscus root tear resulted in a statistically significant increase (up to 250%) of extrusion for the lateral meniscus (p 0.05) in comparison to the intact lateral meniscus for all externally applied loads. Without external load (passive path position), significant differences were also found between the intact and posterior lateral root deficient meniscus except at full extension (1.0 ± 0.7 mm vs. 1.9 ± 0.4 mm) and 30° of flexion (1.4 ± 0.5 mm vs. 1.8 ± 0.5 mm). Overall, with increasing flexion angle, lateral meniscus extrusion decreased for the intact as well as for the posterior lateral root deficient meniscus, with the lowest measurements in response to internal tibial torque at 90° of flexion (-3.3 ± 1.1 mm). Knee kinematics were similar whether intact or posterior lateral root tear (n.s.). Ultrasound measurement of lateral meniscus extrusion showed good inter-rater (0.65 [0.30-0.97]-0.71 [0.34-0.94]) and excellent intra-rater reliability (0.81 [0.43-0.99]).Dynamic Ultrasound is a reliable diagnostic modality to measure the lateral meniscus extrusion which can be helpful in the diagnosis and quantification of lateral meniscal root tears.III.

The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in patients who cannot tolerate platinum-based regimens has not been clarified. We aimed to develop a new treatment regimen for patients with R/M SCCHN who are ineligible for platinum-based therapy, by evaluating the effects and safety of tegafur/gimeracil/oteracil (S-1) and cetuximab. Platinum-ineligibility was defined as: elderly (aged ≥ 75 years), poor PS, comorbidity, platinum resistance and refusal to undergo platinum-based therapy. Patients received S-1 (80 mg/m2/day for 14 days followed by a seven-day break) and cetuximab (initial dose, 400 mg/m2, followed by 250 mg/m2 weekly) until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Between September 2014 and September 2018, we enrolled 23 patients. Among the 21 patients who were evaluable, 20 were male [median age, 69 years (range 49–82)]. The ORR was 9 (43%) of 21 patients [95% confidence interval (CI) 22–66]. One and eight patients achieved complete response (CR) and partial response (PR), respectively. The median overall survival (OS) was 13.7 months (95% CI 9.0–18.3) and progression-free survival (PFS) was 5.7 months (95% CI 3.1–8.2). Grade 3/4 adverse events included acneiform rash and skin reactions (33%), hypomagnesemia (19%), hand-foot syndrome (14%), fatigue (14%), mucositis (10%), and anorexia (10%). Combination treatment with S-1 and cetuximab was effective and tolerated well by patients with platinum-ineligible R/M SCCHN. Registered clinical trial number: UMIN000015123

Combining surface-enhanced Raman scattering (SERS) with the coherent nonlinear Raman technique is a promising route for achieving higher sensitivity and time-resolved SERS measurements, yet such attempts have just been started. Here, we report time-domain Raman measurements of trans-1,2-bis(4-pyridyl)ethylene (BPE) adsorbed on gold nanoparticle assemblies (GNAs), which were carried out with impulsive stimulated Raman spectroscopy using sub-8 fs pulses. We observe coherent nuclear wavepacket motion of BPE on GNAs with drastic enhancement through the surface plasmon resonance, which provides information on the Raman-active vibrations in the time domain. Through Fourier transform of the measured time-domain Raman data, we obtained SERS spectra of BPE on GNAs with enhancement factors as high as 105-106. The present study not only demonstrates applicability of time-domain nonlinear Raman techniques in SERS, i.e., surface-enhanced impulsive stimulated Raman spectroscopy (SE-ISRS), but also provides a technical basis for femtosecond time-resolved SE-ISRS experiments to track ultrafast dynamics of the adsorbates.

Capability to control macroscopic molecular properties with external stimuli offers the possibility to exploit molecules as switching devices of various types. However, application of such molecular-level switching has often been limited by its speed and thus efficiency. Herein, we demonstrate ultrafast, photoinduced polarization switching in the crystal of a [CrCo] dinuclear complex by ultrafast pump-probe spectroscopy in the visible and mid-infrared regions. The photoinduced polarization switching was found to have a time constant of 280 fs, which makes the [CrCo] complex crystal the fastest polarization-switching material realized using the metastable state. Moreover, the pump-probe data in the visible region reveal the pronounced appearance of coherent nuclear wavepacket motion with a frequency as low as 22 cm-1 , which we attribute to a lattice vibrational mode. The pronounced non-Condon effect for its resonance Raman enhancement implies that this mode couples the relevant electronic states, thereby facilitating the ultrafast polarization switching.

Preoperative assessment to determine the sizes of potential autografts is necessary for individualized anterior cruciate ligament reconstruction (ACLR). However, no study has investigated the prediction of the intraoperative diameter of the quadriceps tendon (QT) autograft based upon preoperative imaging. This study investigated the correlation between the intraoperative diameter of a QT autograft and in situ thickness or cross-sectional area (CSA) measured using preoperative MRI. Thirty-one knees of 31 patients (mean age 20.9 ± 5.0 years) who underwent individualized anatomic ACLR using all soft tissue QT autograft were included retrospectively. At 15 mm proximal to the superior pole of the patella, the maximum QT thickness was assessed in the sagittal plane and the CSA was assessed at the central 10 mm of the QT in the axial plane. The angle between the axial plane and a line perpendicular to the QT longitudinal axis was used to calculate an adjusted CSA using a cosine function. Intraoperatively, each QT autograft was harvested with 10 mm width and the diameter was measured using a graft sizing device. Intra- and inter-observer reliabilities of all measurements using preoperative MRI were excellent (intra-class correlation coefficient, 0.833–0.970). Significant correlations were observed between the thickness, CSA, or adjusted CSA, and the intraoperative diameter (R = 0.434, 0.607, and 0.540, respectively; P

Background and Aim Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. Methods In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade >= 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade >= 3 after ICI initiation. The clinical course of grade >= 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade >= 3 irAE hepatitis. Conclusions Grade >= 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade >= 3 irAE hepatitis.

The Optimized Energy Degrading Optics (OEDO) beamline was constructed at RIBF to produce slowed-down, well-focused radioactive-isotope beams at 10–50 MeV/u, and began operation in June 2017. We examined the performance of the OEDO system by decelerating high-energy medium-mass radioactive ions. The main components of the OEDO beamline are two superconducting quadrupole triplet magnets and one radio-frequency deflector. This paper introduces the unique design of the ion optics of the beamline and describes the achieved performance of the beamline in the commissioning and following physics experiments. We will discuss the properties of energy-degraded beams produced by the OEDO beamline by comparison of simulations and the achieved performance.