Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis: Insights from transgenic mouse models.

Mutations in various type II transmembrane serine protease (TMPRSS) family members are associated with non-syndromic hearing loss, with some mechanisms still unclear. For instance, the mechanism underlying profound hearing loss and tectorial membrane (TM) malformations in hepsin/TMPRSS1 knockout (KO) mice remains elusive. In this study, we confirmed significantly elevated hearing thresholds and abnormal TM morphology in hepsin KO mice, characterized by enlarged TM with gaps and detachment from the spiral limbus. Transgenic mouse lines were created to express either wild-type or a serine protease-dead mutant of human hepsin in the KO background. The Tg68;KO line, expressing moderate levels of wild-type human hepsin in the cochlea, showed partial restoration of hearing function. Conversely, the Tg5;KO or TgRS;KO lines, with undetectable hepsin or protease-dead hepsin, did not show such improvement. Histological analyses revealed that Tg68;KO mice, but not Tg5;KO or TgRS;KO mice, had a more compact TM structure, partially attached to the spiral limbus. These results indicate that hepsin expression levels correlate with improvements in hearing and TM morphology, and its protease activity is critical for these effects. Hepsin's role was further examined by studying its relationship with α-tectorin (TECTA) and ß-tectorin (TECTB), non-collagenous proteins crucial for TM formation. Hepsin was co-expressed with TECTA and TECTB in the developing cochlear epithelium. Immunostaining showed decreased levels of TECTA and TECTB in hepsin KO TM, partially restored in Tg68;KO mice. These findings suggest that hepsin is essential for proper TM morphogenesis and auditory function, potentially by proteolytic processing/maturation of TECTA and TECTB and their incorporation into the TM.

Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase-both of which are vital for maintaining cellular redox balance-combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury.

Optimizing aesthetic results in Asian women with giant phyllodes tumors over 10 cm: the periareolar mastopexy approach.

Giant phyllodes tumors, typically exceeding 10 cm in size, are neoplastic lesions with malignant potential. Surgical excision in small-breasted Asian women presents unique challenges where expected poor aesthetic outcomes may delay timely medical intervention. The periareolar mastopexy technique offers a comprehensive solution, enabling complete tumor removal alongside mastopexy to achieve optimal breast contouring. This approach consistently delivers favorable aesthetic outcomes, enhancing symmetry and contour. Additionally, the periareolar approach minimizes visible scarring, thereby enhancing patient satisfaction with the cosmetic outcome. Herein, we present a case report of Asian women with giant phyllodes tumors exceeding 10 cm, successfully managed using the periareolar mastopexy technique, emphasizing the importance of optimizing aesthetic outcomes in these challenging cases.

Assessing mortality risk in Type 2 Diabetes patients with prolonged ASCVD risk factors: the inclusive Poh-Ai predictive scoring system with CAC Score integration.

PURPOSE: To enhance the predictive risk model for all-cause mortality in individuals with Type 2 Diabetes (T2DM) and prolonged Atherosclerotic Cardiovascular Disease (ASCVD) risk factors. Despite the utility of the Coronary Artery Calcium (CAC) score in assessing cardiovascular risk, its capacity to predict all-cause mortality remains limited. METHODS: A retrospective cohort study included 1929 asymptomatic T2DM patients with ASCVD risk factors, aged 40-80. Variables encompassed demographic attributes, clinical parameters, CAC scores, comorbidities, and medication usage. Factors predicting all-cause mortality were selected to create a predictive scoring system. By using stepwise selection in a multivariate Cox proportional hazards model, we divided the patients into three risk groups. RESULTS: In our analysis of all-cause mortality in T2DM patients with extended ASCVD risk factors over 5 years, we identified significant risk factors, their adjusted hazard ratios (aHR), and scores: e.g., CAC score > 1000 (aHR: 1.57, score: 2), CAC score 401-1000 (aHR: 2.05, score: 2), and more. These factors strongly predict all-cause mortality, with varying risk groups (e.g., very low-risk: 2.0%, very high-risk: 24.0%). Significant differences in 5-year overall survival rates were observed among these groups (log-rank test < 0.001). CONCLUSION: The Poh-Ai Predictive Scoring System excels in forecasting mortality and cardiovascular events in individuals with Type 2 Diabetes Mellitus and extended ASCVD risk factors.

Modelling Selective CO2 Absorption and Validation via Photosynthetic Bacteria and Chemical Adsorbents for Methane Purification in Anaerobic Fermentation Bioreactors.

This study delves into advanced methane purification techniques within anaerobic fermentation bioreactors, focusing on selective CO2 absorption and comparing photosynthetic bacteria (PNSB) with chemical adsorbents. Our investigation demonstrates that MgO-Mg(OH)2 composites exhibit remarkable CO2 selectivity over CH4, substantiated through rigorous bulk and surface modelling analyses. To address the challenges posed by MgCO3 shell formation on MgO particles, hindering CO2 transport, we advocate for the utilisation of MgO-Mg(OH)2 composites. In on-site experiments, these composites, particularly saturated MgO-Mg(OH)2 solutions (S2), achieved an astonishing 100% CO2 removal rate within a single day while preserving CH4 content. In contrast, solid MgO powder (S3) retained a mere 5% of CH4 over a 10 h period. Although PNSB (S1) exhibited slower CO2 removal, it excelled in nutrient recovery from anaerobic effluent. We introduce a groundbreaking hybrid strategy that leverages S2's swift CO2 removal and S1 PNSB's nutrient recovery capabilities, potentially resulting in a drastic reduction in bioreactor processing time, from 10 days when employing S1 to just 1 day with the use of S2. This represents a remarkable efficiency improvement of 1000%. This pioneering strategy has the potential to revolutionise methane purification, enhancing both efficiency and sustainability. Importantly, it can be seamlessly integrated into existing bioreactors through an additional CO2 capture step, offering a promising solution for advancing biogas production and promoting sustainable waste treatment practices.

Porous hydroxyapatite carrier enables localized and sustained delivery of honokiol for glioma treatment.

The objective of this study is to develop hydroxyapatite (HAp) particles for targeted delivery of honokiol to tumor sites after glioma surgical management. Honokiol is released from the HAp-honokiol particles inside cancer cells through endocytosis and subsequent acid lysosomal dissolution. HAp is synthesized using a co-precipitation method, and egg white is added to create porous structures. The HAp is then surface-modified with stearic acid to enhance its hydrophobicity and loaded with honokiol to form HAp-honokiol particles. The synthesized particles are of appropriate size and characteristics for cancer cell uptake. Honokiol remains attached on to the HAp particles in neutral environments due to its hydrophobic nature, but undergoes rapid burst release in acidic environments such as lysosomes. The HAp-honokiol treatment shows a delayed effect on cell viability and cytotoxicity, indicating sustained drug release without compromising drug efficacy. Flow cytometry analysis demonstrates the apoptosis pathway induced by HAp-honokiol in ALTS1C1 glioma cells. In the in vivo study using a mouse glioma model, MRI results showed a 40% reduction in tumor size after HAp-honokiol treatment. These findings suggest that HAp-honokiol particles have potential as an effective drug delivery system for the treatment of glioma.

Elevated Urinary Hepcidin Level and Hypoferremia in Infants with Febrile Urinary Tract Infection: A Prospective Cohort Study.

To evaluate the kinetics of serum and urinary hepcidin levels along with anemia-related parameters during the infection course of infants with febrile urinary tract infection (UTI), we enrolled febrile infants aged one to four months in this prospective study. Febrile patients with UTI were allocated into Escherichia coli (E. coli) or non-E. coli groups according to urine culture results. Septic workup, blood hepcidin, iron profile, urinalysis, and urinary hepcidin-creatinine ratio were collected upon admission and 3 days after antibiotic treatment. In total, 118 infants were included. On admission, the febrile UTI group showed a significant reduction in serum iron level and a significant elevation of urinary hepcidin-creatinine ratio compared to the febrile control counterpart. Moreover, urinary hepcidin-creatinine ratio had the highest odds ratio, 2.01, in logistics regression analysis. After 3 days of antibiotic treatment, hemoglobin and the urinary hepcidin-creatinine ratio were significantly decreased. Patients with an E. coli UTI had a significantly decreased urinary hepcidin-creatinine ratio after 3 days of antibiotics treatment, whereas the non-E. coli group showed insignificant changes. Our study suggested that the urinary hepcidin-creatinine ratio elevated during acute febrile urinary tract infection and significantly decreased after 3 days of antibiotics treatment, especially in E. coli UTI.

Gene therapy for hemophilia, a clinical viewpoint.

Gene therapy for hemophilia has been investigated for decades but no breakthroughs were made until Nathwani et al. achieved a significant and sustainable factor IX increase in hemophilia B patients in 2011. About eleven years later, in August 2022, the first hemophilia A gene therapy product was approved by the European Commission and hemophilia treatment entered a new era. This review does not focus on the newest advances but rather the practical aspects of gene therapy aiming to provide an overview for physicians who treat hemophiliacs who did not participate in the clinical trials. The current status of gene therapy, focusing particularly on products likely to be clinically available soon, are reviewed and summarized. Currently, possible limitations of gene therapy are pre-existing neutralizing antibodies toward the vector, liver health, age, and inhibitor status. Possible safety concerns include infusion reactions, liver damage, and adverse effects from immune suppressants or steroids. In summary, generally speaking, gene therapy is effective, at least for several years, but the exact effect may be unpredictable and intensive monitoring for several months is needed. It can also be considered safe with careful practice on selected patients. In its current form, gene therapy will not replace all hemophilia treatments. Advances in non-factor therapy will also improve hemophilia care greatly in the future. We envisage that gene therapy may be included in multiple novel therapies for hemophilia and benefit some hemophilia patients while novel non-factor therapies may benefit others, together fulfilling the unmet needs of all hemophilia patients.

Neoantigen vaccination augments antitumor effects of anti-PD-1 on mouse hepatocellular carcinoma.

Immune checkpoint inhibitors are groundbreaking resources for cancer therapy. However, only a few patients with hepatocellular carcinoma (HCC) have shown positive responses to anti-PD-1 therapy. Neoantigens are sequence-altered proteins resulting from somatic mutations in cancer. This study identified the neoantigens of Hep-55.1C and Dt81 Hepa1-6 HCCs by comparing their whole exome sequences with those of a normal C57BL/6 mouse liver. Immunogenic long peptides were pooled as peptide vaccines. The vaccination elicited tumor-reactive immune responses in C57BL/6 mice, as demonstrated by IFN-γ ELISPOT and an in vitro killing assay of splenocytes. In the treatment of three mouse HCC models, combined neoantigen vaccination and anti-PD-1 resulted in more significant tumor regression than monotherapies. Flow cytometry of the tumor-infiltrating lymphocytes showed decreased Treg cells and monocytic myeloid-derived suppressor cells, increased CD8+ T cells, enhanced granzyme B expression, and reduced exhaustion-related markers PD-1 and Lag-3 on CD8+ T cells in the combination group. These findings provide a strong rationale for conducting clinical studies of using neoantigen vaccination in combination with anti-PD-1 to treat patients with HCC.

In situ vaccination followed by intramuscular poly-ICLC injections for the treatment of hepatocellular carcinoma in mouse models.

The efficacy of treatment for advanced hepatocellular carcinoma (HCC) has remained limited. Polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) is a synthetic double-stranded RNA that serves as a viral mimic and induces an immune response. Intratumoral (IT) poly-ICLC injections can induce an autovaccination effect and prime the immune system, whereas intramuscular (IM) injection of poly-ICLC can attract and maintain tumor-specific cytotoxic T lymphocytes in tumors. We found that IT injection of poly-ICLC upregulated the expression of CD83 and CD86 on conventional type 1 dendritic cells in tumors. Combination therapy with IT followed by IM injections of poly-ICLC significantly inhibited tumor growth and increased the tumor-infiltrating CD8+ T cells in two syngeneic mouse models of HCC. Depletion of CD8+ T cells attenuated the antitumor effect. An IFN-γ enzyme-linked immunospot of purified tumoral CD8+ T cells revealed a significant proportion of tumor-specific T cells. Finally, the sequential poly-ICLC therapy induced abscopal effects in two dual-tumor models. This study provides evidence that the sequential poly-ICLC therapy significantly increased infiltration of tumor-specific CD8+ T cells in the tumors and induced CD8+ T cell-dependent inhibition of tumor growth, as well as abscopal effects.

Therapeutic Effects of Anti-PD1 Immunotherapy on Hepatocellular Carcinoma Under Administration of Tacrolimus.

BACKGROUND: Liver transplantation (LT) is the treatment of choice for patients with hepatocellular carcinoma (HCC). Recurrence of HCC after LT occurs in 10% to 20% of cases. Preclinical studies to evaluate immune checkpoint inhibitors in conjunction with immunosuppressant treatment in transplant recipients have been lacking. Here, we evaluated the efficacy, safety, and mechanism of programmed cell death-1 (PD1) blockade under tacrolimus treatment in transplant recipients. METHODS: We used a murine allogeneic skin transplantation model and murine syngeneic subcutaneous and orthotopic HCC models and measured the tumor volume and the change in tumor-infiltrating lymphocytes under PD1 blockade and tacrolimus treatment. RESULTS: Tacrolimus treatment prolonged allograft survival in the allogeneic transplantation model and enhanced tumor growth in both subcutaneous and orthotopic HCC models. PD1 blockade suppressed tumor growth and lung metastasis in correlation with the number of infiltrating CD8 + T cells. Under tacrolimus treatment, PD1 blockade still resulted in an antitumor effect accompanied by a significant increase in tumor-infiltrating CD8 + T cells, natural killer cells, dendritic cells, and natural killer T cells. Tacrolimus treatment rescued the acceleration of transplant rejection induced by PD1 blockade in the allogeneic transplantation model. CONCLUSIONS: Our data suggest that treatment with high-dose tacrolimus in conjunction with PD1 blockade has an antitumor effect and reduces transplant rejection in mouse models of allograft skin transplantation and HCC. Thus, these results suggest that a clinical trial of PD1 inhibitors for HCC in LT merits consideration.

Comparing Genetic Risk and Clinical Risk Classification in Luminal-like Breast Cancer Patients Using a 23-Gene Classifier.

Background: A 23-gene classifier has been developed based on gene expression profiles of Taiwanese luminal-like breast cancer. We aim to stratify risk of relapse and identify patients who may benefit from adjuvant chemotherapy based on genetic model among distinct clinical risk groups. Methods: There were 248 luminal (hormone receptor-positive and human epidermal growth factor receptor II-negative) breast cancer patients with 23-gene classifier results. Using the modified Adjuvant! Online definition, clinical high/low-risk groups were tabulated with the genetic model. The primary endpoint was a recurrence-free interval (RFI) at 5 years. Results: There was a significant difference between the high/low-risk groups defined by the 23-gene classifier for the 5-year prognosis of recurrence (16 recurrences in high-risk and 3 recurrences in low-risk; log-rank test: p < 0.0001). Among the clinically high-risk group, the 5-year RFI of high risk defined by the 23-gene classifier was significantly higher than that of the low-risk group (15 recurrences in high-risk and 2 recurrences in low-risk; log-rank test: p < 0.0001). Conclusion: This study showed that 23-gene classifier can be used to stratify clinically high-risk patients into distinct survival patterns based on genomic risks and displays the potentiality to guide adjuvant chemotherapy. The 23-gene classifier can provide a better estimation of breast cancer prognosis which can help physicians make a better treatment decision.

Left adrenal aldosteronism coexisting with left paraaortic paraganglioma presenting as bilateral adrenal and left paraaortic tumors- comprehensive adrenal evaluation aiding perfect management: a case report.

BACKGROUND: Coexistence of a catecholamine-secreting tumor and an adrenal cortical tumor is quite rare which makes both diagnosis and management challenging. The purpose of this article is to describe the presence of this condition, share a stepwise approach for preoperative evaluation, and review the related literature. CASE PRESENTATION: A 44-year-old male patient had a history of hypertension and aggravating hypokalemia for years. Abdominal computed tomography incidentally found concomitant bilateral adrenal and left para-aortic tumors. Comprehensive adrenal hormone tests revealed a high aldosterone renin ratio and mildly elevated 24-h urine vanillylmandelic acid and norepinephrine levels. Subsequently, a metaiodobenzylguanidine scan showed uptake over the left para-aortic tumor, and NP-59 adrenal scintigraphy showed uptake over the left adrenal tumor. Further confirmatory tests, including captopril suppression, irbesartan suppression, and saline infusion, all confirmed the diagnosis of hyperaldosteronism. Adrenal venous sampling following 2 months of preparation with an alpha blocker demonstrated a left aldosterone-producing adrenal adenoma. Combining hormonal analysis, imaging studies, and adrenal venous sampling, the patient was diagnosed with left adrenal aldosteronoma, right adrenal nonfunctional tumor, and left para-aortic paraganglioma (PGL). Accordingly, laparoscopic left adrenalectomy and left PGL excision were performed smoothly under alpha blocker maintenance. The pathology report confirmed left adrenal cortical adenoma and left para-aortic PGL. Postoperatively, the blood pressure, biochemical tests, and adrenal hormone assays returned to normal, and related symptoms disappeared and were relatively stable during the follow-up period of two years. CONCLUSIONS: This is the first case of left para-aortic PGL coexisting with an ipsilateral aldosterone-producing adenoma presenting as a left para-aortic tumor associated with bilateral adrenal tumors. Awareness of the rarity of this coexistence can avoid unexpected disasters during the process of evaluation and management.

CLIN_SKAT: an R package to conduct association analysis using functionally relevant variants.

BACKGROUND: Availability of next generation sequencing data, allows low-frequency and rare variants to be studied through strategies other than the commonly used genome-wide association studies (GWAS). Rare variants are important keys towards explaining the heritability for complex diseases that remains to be explained by common variants due to their low effect sizes. However, analysis strategies struggle to keep up with the huge amount of data at disposal therefore creating a bottleneck. This study describes CLIN_SKAT, an R package, that provides users with an easily implemented analysis pipeline with the goal of (i) extracting clinically relevant variants (both rare and common), followed by (ii) gene-based association analysis by grouping the selected variants. RESULTS: CLIN_SKAT offers four simple functions that can be used to obtain clinically relevant variants, map them to genes or gene sets, calculate weights from global healthy populations and conduct weighted case-control analysis. CLIN_SKAT introduces improvements by adding certain pre-analysis steps and customizable features to make the SKAT results clinically more meaningful. Moreover, it offers several plot functions that can be availed towards obtaining visualizations for interpretation of the analyses results. CLIN_SKAT is available on Windows/Linux/MacOS and is operative for R version 4.0.4 or later. It can be freely downloaded from https://github.com/ShihChingYu/CLIN_SKAT , installed through devtools::install_github("ShihChingYu/CLIN_SKAT", force=T) and executed by loading the package into R using library(CLIN_SKAT). All outputs (tabular and graphical) can be downloaded in simple, publishable formats. CONCLUSIONS: Statistical association analysis is often underpowered due to low sample sizes and high numbers of variants to be tested, limiting detection of causal ones. Therefore, retaining a subset of variants that are biologically meaningful seems to be a more effective strategy for identifying explainable associations while reducing the degrees of freedom. CLIN_SKAT offers users a one-stop R package that identifies disease risk variants with improved power via a series of tailor-made procedures that allows dimension reduction, by retaining functionally relevant variants, and incorporating ethnicity based priors. Furthermore, it also eliminates the requirement for high computational resources and bioinformatics expertise.

A variant NS1 protein from H5N2 avian influenza virus suppresses PKR activation and promotes replication and virulence in mammals.

Highly pathogenic avian influenza viruses (HPAIVs) frequently receive global attention as threats to public health. The NS1 protein is a key virulence factor known to impair host antiviral responses. The study herein revealed HPAIV H5N2 NS gene encoded additional protein; a truncated NS1 variant, designated NS3, produced by alternative splicing of the NS transcript. To examine the function of NS3 during infection, we generated recombinant viruses expressing either full-length NS1 (RG-AIV-T375G) or NS3 (RG-AIV-NS3). Interestingly, RG-AIV-NS3 virus produced higher titres than RG-AIV-T375G in multiple mammalian cell lines. However, RG-AIV-T375G exhibited a replication advantage over RG-AIV-NS3 in chicken DF-1 cells, indicating that host cell identity dictates the effect of NS3 on viral replication. In mice and mammalian cells, RG-AIV-NS3 infection elicited higher level of cytokines, including IFN-ß, MX and TNF-α, potentially due to its higher replication activity. Based on mini-genome assay, NS3 had pronounced effects on viral replication machinery. Surprisingly, NS3 retained an interaction with PKR and suppressed PKR activation despite its lack of amino-acid residues 126-167. The poor replication ability of RG-AIV-T375G was partially restored in cells deficient in PKR suggesting that full-length NS1 may be insufficient to suppress PKR function. Notably, virulence of the full-length NS1-expressing RG-AIV-T375G virus was highly attenuated in mice when compared to RG-AIV-NS3. In summary, our study reveals the existence and function of a previously unidentified H5N2 viral protein, NS3. We found that NS3 is functionally distinct from NS1 protein, as it enhances viral replication and pathogenicity in mammalian systems, potentially via suppression of PKR activity.

PCDHB15 as a potential tumor suppressor and epigenetic biomarker for breast cancer.

Breast cancer is among the most frequently diagnosed cancer types and the leading cause of cancer-related death in women. The mortality rate of patients with breast cancer is currently increasing, perhaps due to a lack of early screening tools. In the present study, using The Cancer Genome Atlas (TCGA) breast cancer dataset (n=883), it was determined that methylation of the protocadherin ß15 (PCDHB15) promoter was higher in breast cancer samples than that in normal tissues. A negative association between promoter methylation and expression of PCDHB15 was observed in the TCGA dataset and breast cancer cell lines. In TCGA cohort, lower PCDHB15 expression was associated with shorter relapse-free survival times. Treatment with the DNA methyltransferase inhibitor restored PCDHB15 expression in a breast cancer cell line; however, overexpression of PCDHB15 was shown to suppress colony formation. PCDHB15 methylation detected in circulating cell-free DNA (cfDNA) isolated from serum samples was higher in patients with breast cancer (40.8%) compared with that in patients with benign tumors (22.4%). PCDHB15 methylation was not correlated with any clinical parameters. Taken together, PCDHB15 is a potential tumor suppressor in cases of breast cancer, which can be epigenetically silenced via promoter methylation. PCDHB15 methylation using cfDNA is a novel minimally invasive epigenetic biomarker for the diagnosis and prognosis of breast cancer.

Molecular Characterization and Pathogenicity of the Novel Recombinant Muscovy Duck Parvovirus Isolated from Geese.

Goose parvovirus (GPV) and Muscovy duck parvovirus (MDPV) are the main agents associated with waterfowl parvovirus infections that caused great economic losses in the waterfowl industry. In 2020, a recombinant waterfowl parvovirus, 20-0910G, was isolated in a goose flock in Taiwan that experienced high morbidity and mortality. The whole genome of 20-0910G was sequenced to investigate the genomic characteristics of this isolate. Recombination analysis revealed that, like Chinese rMDPVs, 20-0910G had a classical MDPV genomic backbone and underwent two recombination events with classical GPVs at the P9 promoter and partial VP3 gene regions. Phylogenetic analysis of the genomic sequence found that this goose-origin parvovirus was highly similar to the circulating recombinant MDPVs (rMDPVs) isolated from duck flocks in China. The results of experimental challenge tests showed that 20-0910G caused 100% mortality in goose embryos and in 1-day-old goslings by 11 and 12 days post-inoculation, respectively. Taken together, the results indicated that this goose-origin rMDPV was closely related to the duck-origin rMDPVs and was highly pathogenic to young geese.

The transmembrane serine protease hepsin suppresses type I interferon induction by cleaving STING.

Many viral proteases mediate the evasion of antiviral innate immunity by cleaving adapter proteins in the interferon (IFN) induction pathway. Host proteases are also involved in innate immunity and inflammation. Here, we report that the transmembrane protease hepsin (also known as TMPRSS1), which is predominantly present in hepatocytes, inhibited the induction of type I IFN during viral infections. Knocking out hepsin in mouse embryonic fibroblasts (MEFs) increased the viral infection-induced expression of Ifnb1, an Ifnb1 promoter reporter, and an IFN-sensitive response element promoter reporter. Ectopic expression of hepsin in cultured human hepatocytes and HEK293T cells suppressed the induction of IFNß during viral infections by reducing the abundance of STING. These effects depended on the protease activity of hepsin. We identified a putative hepsin target site in STING and showed that mutating this site protected STING from hepsin-mediated cleavage. In addition to hepatocytes, several hepsin-producing prostate cancer cell lines showed reduced STING-mediated type I IFN induction and responses. These results reveal a role for hepsin in suppressing STING-mediated type I IFN induction, which may contribute to the vulnerability of hepatocytes to chronic viral infections.

Effectiveness of palonosetron versus granisetron in preventing chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) commonly occurs after chemotherapy, adversely affecting patients' quality of life. Recently, studies have shown inconsistent antiemetic effects of two common 5-hydroxytryptamine 3 receptor antagonists, namely, palonosetron and granisetron. Therefore, we conducted a meta-analysis to evaluate the effectiveness of palonosetron versus granisetron in preventing CINV. METHODS: Relevant studies were obtained from PubMed, Embase, and Cochrane databases. The primary outcome was the complete response (CR) rate. Secondary outcomes were headache and constipation events. RESULTS: In total, 12 randomized controlled trials and five retrospective studies were reviewed. Palonosetron was consistently statistically superior to granisetron in all phases in terms of the CR rate (acute phases: odds ratio [OR] = 1.28, 95% confidence interval [CI] = 1.06-1.54; delayed phases: OR = 1.38, 95% CI = 1.13-1.69; and overall phases: OR = 1.37, 95% CI = 1.17-1.60). Moreover, a non-significant difference was found between the two groups in terms of the headache event, but the occurrence of the constipation event was lower in the granisetron group than in the palonosetron group. CONCLUSION: Palonosetron showed a higher protective efficacy in all phases of CINV prevention, especially in delayed phases, and no relatively severe adverse effects were observed.

Sole adjuvant intraoperative breast radiotherapy in Taiwan: a single-center experience.

INTRODUCTION: Intraoperative radiotherapy (IORT) is more convenient than standard whole breast external beam radiotherapy (EBRT) as a sole adjuvant radiotherapy for breast cancer. The impact of age on breast cancer course and treatment strategy is still under investigation, and the peak age for breast cancer in Taiwan is much younger than that in Western countries. We aimed to review the oncological outcomes of sole IORT compared with standard EBRT in a country with younger breast cancer patients. PATIENTS AND METHODS: We reviewed patients with invasive breast cancer who received breast-conserving surgery (BCS) from September 2014 to December 2016. The clinicopathologic characteristics and oncological outcomes of eligible patients who received EBRT or IORT as sole adjuvant radiotherapy after BCS were collected and reviewed. RESULTS: A total of 170 patients were enrolled with a mean follow-up time of 3.53 ± 0.82 years. The risk of locoregional recurrence was 2.44% for EBRT versus 10.64% for IORT (p = 0.024). IORT was a significant risk factor of locoregional recurrence (p = 0.005). The hazard ratios (HRs) for locoregional recurrence in the IORT group compared with the EBRT group were significantly higher in non-suitable risk group patients (HR = 7.02, p = 0.009) and in patients under 50 years old (HR = 10.42, p = 0.011). CONCLUSIONS: Locoregional recurrence was significantly higher in patients who received IORT than in those who underwent EBRT. IORT should not be used alone in patients under 50 years old who do not belong to a suitable group.