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Abstract Autophagy can be classified as degradative and secretory based on distinct functions. The small GTPase proteins Rab8a and Rab37 are responsible for secretory autophagy‐mediated exocytosis of IL‐1β, insulin, and TIMP1 (tissue inhibitor of 54 metalloproteinase 1). Other Rab family members participating in secretory autophagy are poorly understood. Herein, we identified 26 overlapped Rab proteins in purified autophagosomes of mouse pancreatic β‐cell “Min‐6” and human lung cancer cell “CL1‐5‐Q89L” with high secretory autophagy tendency by LC–MS/MS proteomics analysis. Six Rab proteins (Rab8a, Rab11b, Rab27a, Rab35, Rab37, and Rab7a) were detected in autophagosomes of four cell lines, associating them with autophagy‐related vesicle trafficking. We used CL1‐5‐Q89L cell line model to evaluate the levels of Rab proteins colocalization with autophagy LC3 proteins and presence in purified autophagosomes. We found five Rab proteins (Rab8a, Rab11b, Rab27a, Rab35, and Rab37) are highly expressed in the autophagosome compared to the normal control by immunoblotting under active secretion conditions. However, only Rab8a, Rab35, and Rab37 showing high colocalization with LC3 protein by cofocal microscopy. Despite the discrepancy between the image and immunoblotting analysis, our data sustains the speculation that Rab8a, Rab11b, Rab27a, Rab35, and Rab37 are possibly associated with the secretory autophagy machinery. In contrast, Rab7a shows low colocalization with LC3 puncta and low level in the autophagosome, suggesting it regulates different vesicle trafficking machineries. Our findings open a new direction toward exploring the role of Rab proteins in secretory autophagy‐related cargo exocytosis and identifying the cargoes and effectors regulated by specific Rab proteins.

Abstract Autophagy is a self‐recycling machinery to maintain cellular homeostasis by degrading harmful materials in the cell. Autophagy‐related gene 5 (Atg5) is required for autophagosome maturation. However, the role of Atg5 in tumorigenesis under autophagy deficient conditions remains unclear. This study focused on the autophagy‐independent role of Atg5 and the underlying mechanism in tumorigenesis. We demonstrated that knockout of autophagy‐related genes including Atg5, Atg7, Atg9, and p62 in mouse embryonic fibroblast (MEF) cells consistently decreased cell proliferation and motility, implying that autophagy is required to maintain diverse cellular functions. An Atg7 knockout MEF (Atg7−/− MEF) cell line representing deprivation of autophagy function was used to clarify the role of Atg5 transgene in tumorigenesis. We found that Atg5‐overexpressed Atg7−/‐MEF (clone A) showed increased cell proliferation, colony formation, and migration under autophagy deficient conditions. Accordingly, rescuing the autophagy deficiency of clone A by overexpression of Atg7 gene shifts the role of Atg5 from pro‐tumor to anti‐tumor status, indicating the dual role of Atg5 in tumorigenesis. Notably, the xenograft mouse model showed that clone A of Atg5‐overexpressed Atg7−/− MEF cells induced temporal tumor formation, but could not prolong further tumor growth. Finally, biomechanical analysis disclosed increased Wnt5a secretion and p‐JNK expression along with decreased β‐catenin expression. In summary, Atg5 functions as a tumor suppressor to protect the cell under normal conditions. In contrast, Atg5 shifts to a pro‐tumor status under autophagy deprivation conditions.

Abstract Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor‐specific CD8+ T cells and their recruitment to tumor microenvironment. However, cDC1s are often underrepresented in the microenvironment. Systemic administration of Fms‐like tyrosine kinase 3 ligand, a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to cDC1 expansion in the periphery and recruitment into the microenvironment. FLT3 pathway stimulation using GS‐3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T‐cell mediated antitumor activity. This was a first‐in‐human, placebo‐controlled study of GS‐3583 in healthy participants to evaluate the safety, pharmacokinetics (PK), and pharmacodynamic (PD) of escalating single doses (75–2000 μg) of GS‐3583. Each dose cohort enrolled 8–12 healthy participants who received GS‐3583 or placebo as single IV infusion at 3:1 ratio. As part of the PD evaluation, the changes in the number of cDC1 cells were investigated. GS‐3583 was well‐tolerated in healthy participants up to the highest evaluated dose (2000 μg). There have been no serious or grade III or higher adverse events. PK analysis suggested a dose‐dependent increase in GS‐3583 exposure with target‐mediated disposition characteristics at low doses. PD analysis shows that administration of GS‐3583 resulted in transient, dose‐dependent increases in cDC1 cells that returned to baseline within 3 weeks of drug administration. The pharmacokinetics and pharmacodynamics of GS‐3583 following single dosing were characterized in this study which enabled subsequent phase Ib assessments in patients with advanced solid tumors.

Abstract Background Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF who have a suboptimal response or intolerance to beta‐blockers. Degenerative mitral regurgitation (MR) is a valvular heart disease often associated with the development of HF and atrial fibrillation (AF). However, studies comparing the effects of ivabradine and beta‐blockers on MR are lacking. Therefore, this study aimed to explore the potential therapeutic effects of ivabradine and carvedilol on MR using a rat model. Methods and results Using a novel echo‐guided mini‐invasive surgery, MR was created in 12‐weeks‐old Sprague–Dawley rats. After 2 weeks, the rats were randomized to receive either ivabradine or carvedilol for 4 weeks. Echocardiography was performed at baseline and at two‐week intervals. Following haemodynamic studies, postmortem tissues were analysed. Notably, the MR‐induced myocardial dysfunction did not improve considerably after treatment with ivabradine or carvedilol. However, in haemodynamic studies, pharmacological therapies, particularly carvedilol, mitigated MR‐induced chamber dilatation (end‐systolic volume and end‐diastolic volume; MR vs. MR + Carvedilol; P

Abstract In existing remote sensing image retrieval (RSIR) datasets, the number of images among different classes varies dramatically, which leads to a severe class imbalance problem. Some studies propose to train the model with the ranking‐based metric (e.g., average precision [AP]), because AP is robust to class imbalance. However, current AP‐based methods overlook an important issue: only optimising samples ranking before each positive sample, which is limited by the definition of AP and is prone to local optimum. To achieve global optimisation of AP, a novel method, namely Optimising Samples after positive ones & AP loss (OSAP‐Loss) is proposed in this study. Specifically, a novel superior ranking function is designed to make the AP loss differentiable while providing a tighter upper bound. Then, a novel loss called Optimising Samples after Positive ones (OSP) loss is proposed to involve all positive and negative samples ranking after each positive one and to provide a more flexible optimisation strategy for each sample. Finally, a graphics processing unit memory‐free mechanism is developed to thoroughly address the non‐decomposability of AP optimisation. Extensive experimental results on RSIR as well as conventional image retrieval datasets show the superiority and competitive performance of OSAP‐Loss compared to the state‐of‐the‐art.

Background Pulmonary artery hypertension (PAH) is a fatal disease characterized by a complex pathogenesis. Exosomes containing microRNAs (miRs) have emerged as a novel biomarker. Transpulmonary exosomal miRs offer valuable insights into pulmonary circulation microenvironments. Hereby, we aimed to explore the potentials of transpulmonary exosomal miRs as differentiating factors between idiopathic PAH and congenital heart disease (CHD)–related PAH. Methods and Results During right heart catheterization, we collected exosomes at pulmonary arteries in 25 patients diagnosed with idiopathic PAH and 20 patients with CHD‐related PAH. Next‐generation sequencing identified several candidate exosomal miRs. Using quantitative polymerase chain reaction, we validated the expressions of these miRs and revealed significantly elevated expressions of miR‐21, miR‐139‐5p, miR‐155‐5p, let‐7f‐5p, miR‐328‐3p, miR‐330‐3p, and miR‐103a‐3p in patients with CHD‐related PAH, in contrast to patients with idiopathic PAH. Among these miRs, miR‐21 exhibited the highest expression in patients with CHD‐related PAH. These findings were further corroborated in an external cohort comprising 10 patients with idiopathic PAH and 8 patients with CHD‐related PAH. Using an in vitro flow model simulating the shear stress experienced by pulmonary endothelial cells, we observed a significant upregulation of miR‐21. Suppressing miR‐21 rescued the shear stress–induced downregulation of the RAS/phosphatidylinositol 3‐kinase/protein kinase B pathway, leading to a mitigation of apoptosis. Conclusions Our study identified a pronounced expression of transpulmonary exosomal miR‐21, particularly in patients with CHD‐related PAH, through next‐generation sequencing analysis. Further investigation is warranted to elucidate the regulatory mechanisms involving miR‐21 in the pathophysiology of PAH.

Abstract Formosanin C (FC) is a natural compound extracted from Paris formosana Hayata with anticancer activity. FC induces both autophagy and apoptosis in human lung cancer cells. FC‐induced depolarization of mitochondrial membrane potential (MMP) may trigger mitophagy. In this study, we clarified the effect of FC on autophagy, mitophagy, and the role of autophagy in FC‐related cell death and motility. We found FC caused the continuous increase of LC3 II (representing autophagosomes) from 24 to 72 h without degradation after treatment of lung and colon cancer cells, indicating that FC blocks autophagic progression. In addition, we confirmed that FC also induces early stage autophagic activity. Altogether, FC is not only an inducer but also a blocker of autophagy progression. Moreover, FC increased MMP accompanied by overexpression of COX IV (mitochondria marker) and phosphorylated Parkin (p‐Parkin, mitophagy marker) in lung cancer cells, but no colocalization of LC3 with COX IV or p‐Parkin was detected under confocal microscopy. Moreover, FC could not block CCCP (mitophagy inducer)‐induced mitophagy. These results imply that FC disrupts mitochondria dynamics in the treated cells, and the underlying mechanism deserves further exploration. Functional analysis reveals that FC suppresses cell proliferation and motility through apoptosis and EMT‐related pathway, respectively. In conclusion, FC acts as an inducer as well as a blocker of autophagy that results in cancer cell apoptosis and decreased motility. Our findings shed the light on the development of combined therapy with FC and clinical anticancer drugs for cancer treatment.

Abstract Favorable prognostic factors and therapeutic strategies are important for patients with single large hepatocellular carcinoma (HCC). This retrospective study aimed to investigate the prognostic factors in patients with single large (≥5 cm) HCC with Child‐Pugh (CP) class A patients and to recommend therapeutic strategies. Overall, 298 HCC patients with single and large (≥5 cm) tumors with CP class A, but without distant metastasis and macrovascular invasion were included, and their clinicopathological data, overall survival (OS), and progression‐free survival (PFS) were recorded. OS and PFS was analyzed by the Kaplan–Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. The 298 HCC patients were 79.2% male and median age of 64 years. For the initial treatment, surgical resection (SR) and transarterial chemoembolization (TACE) was 50.8% and 49.2%, respectively. The OS and PFS were significantly higher in patients receiving SR than those receiving TACE before and after PSM. Furthermore, in multivariate analysis, cirrhosis (Hazard ratio [HR]: 2.04; 95% confidence interval [CI]: 1.35–3.03, p

Abstract Background Increasing research efforts have focused on understanding why some individuals develop severe psychopathology after exposure to adverse childhood experiences (ACEs). Sleep disturbances (insomnia, nightmares, and sleep disorders) are prevalent sequelae of ACEs and associated with psychopathology; however, there is no meta‐analytic evidence on whether sleep disturbance functions as a transdiagnostic mediator in the relationship between ACEs and psychopathology (internalizing/externalizing disorders and psychosis) in children and adolescents. Methods Systematic searches in three databases (PubMed; PsycINFO; Web of Science) identified 98 articles (N = 402,718; age range 1–17 years) and the present study used a novel two‐stage meta‐analytic structural equation model to investigate whether ACEs predict psychopathology through sleep disturbance. Subgroup analyses determined potential biases due to study design (cross‐sectional vs. longitudinal) and geographical differences (Western vs. non‐Western countries). Sensitivity analyses evaluated the influence of early childhood (

Abstract Background Despite recent advances in understanding the pathophysiology of cancer cachexia, prevention/treatment of this debilitating disease remains an unmet medical need. Methods We developed an integrated, multi‐tiered strategy involving both in vitro and in vivo muscle atrophy platforms to identify traditional Chinese medicine (TCM)‐based anti‐cachectic agents. In the initial screening, we used inflammatory cytokine‐induced atrophy of C2C12 myotubes as a phenotypic screening platform to assess the protective effects of TCMs. The selected TCMs were then evaluated for their abilities to protect Caenorhabditis elegans from age‐related reduction of mobility and contractility, followed by the C‐26 colon adenocarcinoma mouse model of cachexia to confirm the anti‐muscle atrophy effects (body/skeletal muscle weights, fibre size distribution, grip strengths, and serum IL‐6). Transcriptome analysis, quantitative real‐time polymerase chain reaction, and immunoblotting were performed to gain understanding of the potential mechanism(s) by which effective TCM protected against C26 tumour‐induced muscle atrophy. Results Of 29 widely used TCMs, Dioscorea radix (DR) and Mu Dan Pi (MDP) showed a complete protection (all P values, 0.0002) vis‐à‐vis C26 conditioned medium control in the myotube atrophy platform. MDP exhibited a unique ability to ameliorate age‐associated decreases in worm mobility, accompanied by improved total body contractions, relative to control (P

Abstract Objectives We aimed at investigating whether serum exosomal miR‐16‐5p could be utilized as an immunotherapy biomarker in lung adenocarcinoma (LUAD) patients administered by programmed cell death ligand‐1 (PD‐L1) inhibitors, and to evaluate its functions in LUAD progression. Methods Sixty LUAD sufferers and 20 healthy controls (HCs) were covered in this work. We applied both IHC and WB to examine PD‐L1 level in clinical tissue samples and utilized WB to quantify PD‐L1 expression in LUAD cells and LUAD xenograft tissues, respectively. Transmission electron microscopy (TEM), WB, and nanoparticle tracking analysis (NTA) were executed to confirm the exosomes isolated from serum specimens and cell culture media. To quantify of exosomal miR‐16‐5p level from serum and culture medium of cultured cell, qRT‐PCR experiment was utilized. The connection between tissue PD‐L1 level and serum exosomal miR‐16‐5p expression in PD‐L1‐positive sufferers administered by PD‐L1 inhibitors was verified using Spearman correlation coefficient analysis. In addition, the overall survival (OS) and progression‐free survival (PFS) rates among PD‐L1 inhibitor managed sufferers were acquired through a follow‐up visit. Finally, we used a group of assays, including 5‐bromo‐2′‐dexoyuridine (BrdU) and colony formation test, wound healing experiment, flow cytometry, and nude mice xenograft experiment, to explore the functions of circulating exosomal miR‐16‐5p on LUAD cell proliferation, apoptosis, and migration, as well as tumor development, respectively. Results PD‐L1 expression was positively related to T stage (tumor size stage), and PD‐L1 inhibitor treatment reduced the PD‐L1 expression and mitigated T stage in PD‐L1‐positive LUAD sufferers. For PD‐L1‐positive LUAD sufferers, elevated PD‐L1 expression or reduced serum exosomal miR‐16‐5p level were linked to longer PFS and OS upon PD‐L1 inhibitor treatment. The number of exosomes in patient's serum was more than that in the serum of healthy individuals, and PD‐L1 inhibitor treatment decreased the number of serum‐derived exosomes in PD‐L1‐positive LUAD sufferers. Exosome‐derived miR‐16‐5p was downregulated in patient's serum and cell culture medium, and this was negatively linked to tumor stage and PD‐L1 expression. Meanwhile, PD‐L1 inhibitor treatment could increase the serum exosomal miR‐16‐5p expression, and the expression change of serum exosomal miR‐16‐5p was diametrically related to PD‐L1 after the treatment. Moreover, the overexpression of PD‐L1 accelerated tumor growth and decreased the exosomal miR‐16‐5p content in cell culture media, while exosomal miR‐16‐5p overexpression in cell culture media inhibited tumor development by decreasing the PD‐L1 expression. Exosomal miR‐16‐5p overexpression in cell culture media also depressed LUAD cell proliferation and migration, and stimulated cell apoptosis, especially in the cells which cultured in the mediums with PD‐L1 inhibitor in vitro. Conclusions Serum exosomal miR‐16‐5p may be a latent tumor inhibitor and a new biomarker for PD‐L1 inhibitor‐dependent immunotherapy in LUAD by regulating the PD‐L1 expression.

Abstract Glioblastoma (GBM) is the most aggressive type of cancer. Its current first‐line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which are DNA damage‐inducing therapies but show very limited efficacy and a high risk of resistance. There is an urgent need to develop novel agents to sensitize GBM to DNA‐damaging treatments. Here it is found that the triterpene compound stellettin B (STELB) greatly enhances the sensitivity of GBM to ionizing radiation and TMZ in vitro and in vivo. Mechanistically, STELB inhibits the expression of homologous recombination repair (HR) factors BRCA1/2 and RAD51 by promoting the degradation of PI3Kα through the ubiquitin‐proteasome pathway; and the induced HR deficiency then leads to augmented DNA damage and cell death. It is further demonstrated that STELB has the potential to rapidly penetrate the blood‐brain barrier to exert anti‐GBM effects in the brain, based on zebrafish and nude mouse orthotopic xenograft tumor models. The study provides strong evidence that STELB represents a promising drug candidate to improve GBM therapy in combination with DNA‐damaging treatments.

Abstract Aims In contrast to Western patients with breast cancer, Asian patients are relatively younger at diagnosis, and most are free from traditional cardiovascular risk factors. Despite trastuzumab‐related major adverse cardiac and cerebrovascular event (MACCE) being reported, its incidence and predictors remain unknown in Taiwan. Methods and results Through a three‐hospital retrospective cohort study, we analysed the incidence of MACCE in 386 breast cancer patients' exposure to trastuzumab from 2010 to 2018. To further reconfirm our findings, in a nationwide study using the Taiwanese National Health Insurance Research Database and National Cancer Registry, we identified 13 502 women diagnosed with breast cancer who received chemotherapy from 2010 to 2015 and found 6751 women who received initial treatment with trastuzumab. After 1:1 propensity score matching with trastuzumab non‐users, the incidence of MACCE was measured with a median follow‐up of 36 months. In the hospital‐based study, among 386 patients receiving trastuzumab, the 5‐year incidences of MACCE and heart failure (HF) were 5.4 and 2.8%, respectively. In the national cohort, the crude incidences of MACCEs and HF were 4.67 and 3.21%, respectively. After adjustment for age and comorbidities, the hazard ratio of MACCE was 1.485 (95% CI 1.246–1.769). Notably, among the endpoints, only the hazard ratio of HF was significantly higher in patients receiving trastuzumab than in nonusers. In the subgroup analysis, except for patients also using taxanes, those receiving trastuzumab had a higher risk of MACCE than non‐users. Conclusions From clinical observations in a nationwide cohort, we found an increased risk of MACCE, especially HF, in patients receiving trastuzumab. Given that its cardiotoxicity is independent of traditional cardiovascular risks, our findings highlight critical concerns regarding the cardiac safety of trastuzumab use.

Abstract Purpose Helicobacter pylori (H. pylori) is a major risk factor for gastric cancer and may affect androgen activity in men. The association between H. pylori and androgen deprivation therapy (ADT) in patients with prostate cancer (PCa) remains unclear. Methods This retrospective cohort study linked National Health Insurance (NHI) data to Taiwan Cancer Registry (TCR) and Taiwan Death Registry (TDR) between 1995 and 2016. PCa patients who received ADT were classified into H. pylori infection and non‐H. pylori infection groups. The outcomes were overall mortality, prostate cancer‐specific mortality, and castration‐resistant prostate cancer (CRPC). Propensity score matching was adopted for the primary analysis and inverse probability of treatment weighting (IPTW) was used for the sensitivity analysis. Results Of the 62,014 selected PCa patients, 23,701 received ADT, of whom 3516 had H. pylori infections and 20,185 did not. After matching, there were 3022 patients in the H. pylori infection group and 6044 patients in the non‐H. pylori infection group. The mean follow‐up period for the matched cohort was 4.8 years. Compared to the non‐H. pylori group, the H. pylori group was significantly associated with decreased risks of all‐cause mortality (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.84–0.96) and prostate cancer‐specific mortality (HR 0.88; 95% CI 0.81–0.95) in the matched analysis. Conclusions H. pylori infection was associated with a reduced risk of mortality in PCa patients receiving ADT.

Abstract Aims The Registry to Evaluate Early and Long‐Term PAH Disease Management (REVEAL) risk scores differentiate survivals in patients with pulmonary arterial hypertension (PAH). However, measurements of N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) in the peripheral blood may not adequately reflect early‐stage decompensated heart failure (HF). Given that right heart catheterization (RHC) can facilitate measurements of intracardiac NT‐proBNP, in this study our aim was to evaluate the predictive role of right ventricular (RV) NT‐proBNP measurements in patients with PAH. Methods and results We prospectively collected intracardiac blood samples for NT‐proBNP measurements from patients diagnosed with World Health Organization Group I PAH during RHC. Clinical information including the aetiology of PAH (idiopathic, connective tissue disease, or congenital heart disease) and REVEAL scores were recorded. The primary endpoint was hospitalization for decompensated HF; median duration of follow‐up was 28 months. Among the 62 patients evaluated, 12 reached the designated endpoint. REVEAL risk scores were higher among patients hospitalized for HF. We detected no significant differences in plasma NT‐proBNP levels in peripheral circulation, in the right atrium, or in pulmonary arterial blood; however, significantly higher levels of NT‐proBNP were detected in the RV in patients diagnosed with PAH. RV NT‐proBNP was a sensitive predictor (cut‐off value 1500 pg/mL) of subsequent hospitalization for HF. Our findings indicate that RV NT‐proBNP levels add predictive value to REVEAL scores with respect to future hospitalization due to HF. Conclusions Right ventricular NT‐proBNP levels combined with REVEAL 2.0 could predict the development of subsequent HF in patients with PAH and may be a potential biomarker.

Abstract Species with similar ecological characters often compete with each other; however, a species may also facilitate the survival or reproduction of another ecologically similar species, although such interaction is rarely documented in birds. Here, we reported a facilitative species interaction between Asian house martins (Delichon dasypus) and russet sparrows (Passer cinnamomeus), both passerines using closed nests, in a montane farming area of Taiwan. We found that Asian house martins constructed dome‐shaped nests in human houses that provided additional nest sites for russet sparrows, secondary cavity nesters with greatly declining populations in Taiwan. Russet sparrows that used house martin nests had reproductive success comparable to those that used artificial nest boxes. However, Asian house martins avoided reclaiming sparrow‐used nests, which reduced their available nest sites. Interestingly, our results imply that man‐made structures may be used as a conservation tool to improve the breeding of the endangered russet sparrows via this facilitative interaction.

Abstract Recently published studies had shown that there may be a potential link between the Single nucleotide polymorphism (SNP) of Toll‐like receptor‐4 (TLR4), and the risk of urinary tract infection (UTI); however, no consensus was reached. To further understand the relationship between TLR SNPs and urinary tract infections, we searched for related studies published in PubMed, EMBASE, and Web of Science before October 30, 2018, for further systematic review and meta‐analysis. Our study accrued 10 case‐control studies, which included 1476 urinary tract infection patients and 1449 healthy controls in TLR4(rs4986790, rs4986791). R3.4.2 and Stata 15.0 software were used for the analysis. In general, there was no statistically significant association between rs4986790 and urinary tract infection in the four genetic models. However, in the subgroup analysis, the Asian population showed significantly difference in the allelic model (G vs A: OR = 1.88 [95% CI:1.42‐2.49], P = .03). In addition, there were also significant differences in the dominant model (GG + AG vs AA OR = 1.97 [95% CI:1.46‐2.66], P = .01). Due to the small number of available literatures, no meaningful conclusion can be drawn regarding the relationship between TLR4 (rs4986791) and the risk of urinary tract infections in general. Nevertheless, our meta‐analysis shows that in Asian populations, TLR4 (rs4986790) may be associated with risk of urinary tract infection.

Abstract Background The role of Axl and LC3 as predictors of tumor recurrence and overall survival (OS) after hepatocellular carcinoma (HCC) resection remains unclear. Methods We retrospectively included 535 HCC patients who underwent hepatectomy from 2010 to 2014 in this study. Axl and the autophagy‐related marker LC3 were immunohistochemically assessed in tumors. Results Axl expression was significantly associated with advanced clinicopathological features, including cirrhosis, microvascular invasion, macrovascular invasion, tumor size, BCLC stage, recurrence, and mortality. HCC recurrence occurred in 245 patients, and 219 patients died. The 5‐year cumulative incidences of HCC recurrence and OS rate after HCC resection were 53.3% and 58.8%, respectively. In the Cox proportional analyses, high Axl expression and high LC3 expression were significantly associated with HCC recurrence (hazard ratio [HR]: 3.85, 95% confidence interval [CI]: 2.95‐5.02, P

Abstract Acute phase hyperglycemia and exaggerated glucose fluctuation may be associated with poor outcomes in diabetic patients after acute myocardial infarction (AMI). This study aimed to determine whether intervention by clinical pharmacists can mitigate blood glucose and glucose fluctuations in these fragile patients. This retrospective study enrolled patients with diabetes and AMI, from 1 January 2019 to 30 June 2020 in our institution. Blood glucose and glucose fluctuations were calculated before and after the pharmacist's intervention and between patients who underwent intervention and those who did not. Propensity score matching (PSM) was used to reduce the impact of patient characteristics on the results. A total of 170 patients were included in our primary analysis, including 29 patients who received the pharmacist intervention and 141 patients who did not. After the pharmacist's intervention, blood glucose (fasting blood glucose‐FBG, from 11.9 to 9.8; postprandial blood glucose‐PBG, from 15.3 to 13.2; mean blood glucose‐BG, 14.5 to 12.3 mmol/L; p

Background Mitral regurgitation (MR) is a major contributor for heart failure (HF) and atrial fibrillation. Despite the advancement of MR surgeries, an effective medical therapy to mitigate MR progression is lacking. Sodium glucose cotransporter 2 inhibitors, a new class of antidiabetic drugs, has shown measurable benefits in reduction of HF hospitalization and cardiovascular mortality but the mechanism is unclear. We hypothesized that dapagliflozin (DAPA), a sodium glucose cotransporter 2 inhibitor, can improve cardiac hemodynamics in MR‐induced HF. Methods and Results Using a novel, mini‐invasive technique, we established a MR model in rats, in which MR induced left heart dilatation and functional decline. Half of the rats were randomized to be administered with DAPA at 10 mg/kg per day for 6 weeks. After evaluation of electrocardiography and echocardiography, hemodynamic studies were performed, followed by postmortem tissue analyses. Results showed that DAPA partially rescued MR‐induced impairment including partial restoration of left ventricular ejection fraction and end‐systolic pressure volume relationship. Despite no significant changes in electrocardiography at rest, rats treated with DAPA exhibited lower inducibility and decreased duration of pacing‐induced atrial fibrillation. DAPA also significantly attenuated cardiac fibrosis, cardiac expression of apoptosis, and endoplasmic reticulum stress‐associated proteins. Conclusions DAPA was able to suppress cardiac fibrosis and endoplasmic reticulum stress and improve hemodynamics in an MR‐induced HF rat model. The demonstrated DAPA effect on the heart and its association with key molecular contributors in eliciting its cardio‐protective function, provides a plausible point of DAPA as a potential strategy for MR‐induced HF.

Despite no significant differences of growth differentiation factor-15 expressions in peripheral, right atrial, and right ventricular blood, in the pulmonary arterial blood, there was a significantly high level of growth differentiation factor-15 in Group I pulmonary arterial hypertension patients subsequently developing heart failure. During right heart catheterization, collecting pulmonary blood samples is suggested to measure growth differentiation factor-15.

Various surgical techniques for canalicular laceration reconstruction have been described in previous study. But there are still two difficult points which may take time in the operation even with the assistance of magnification. We present a simple and effective way to achieve the bicanalicular nasal intubation for the single canalicular laceration. From Jan 2005 to Dec 2015, 20 patients (21 eyes) with upper or lower canalicular laceration were treated with the Crawford lacrimal intubation set by this stitch guide method. We used the eye pigtail probe and the steel probe of the intubation set to dispose a 4-0 Nylon suture as a guide to pull down the silicone tube to the nostril. The functional and anatomic success rates in the 20 eyes are 90% (18/20) and 85% (17/20) respectively. The average time for bicanalicular nasal intubation by this method is 6.87 ± 1.83 min. The result of stitch guide technique to achieve bicanalicular nasal intubation in single canalicular laceration reconstruction is almost the same as the traditional method. Our anatomic and functional success rates are 85% and 90% respectively which are comparable to the previous studies. But this new method takes less time to complete the intubation with little variation. The magnification with microscopy could be omitted and no new instrument is needed. The stitch guide technique for bicanalicular nasal intubation with Crawford intubation system is a reliable and easy way to perform in single canalicular laceration reconstruction. Keywords: Stitch guide, Bicanalicular nasal intubation, Canalicular laceration, Crawford

Background Evidence suggests differences in clinical characteristics, causes, and prognoses between heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Most studies have failed to support the prognostic relevance of anxiety in HFrEF or unclassified HF with mean left ventricular ejection fraction