Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and Dissection Through Regulation of Protein S-Sulfhydration.

BACKGROUND: Aortic aneurysm and aortic dissection (AAD) are life-threatening vascular diseases, with endothelium being the primary target for AAD treatment. Protein S-sulfhydration is a newly discovered posttranslational modification whose role in AAD has not yet been defined. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates AAD and its underlying mechanism. METHODS: Protein S-sulfhydration in endothelial cells (ECs) during AAD was detected and hub genes regulating homeostasis of the endothelium were identified. Clinical data of patients with AAD and healthy controls were collected, and the level of the cystathionine γ lyase (CSE)/hydrogen sulfide (H2S) system in plasma and aortic tissue were determined. Mice with EC-specific CSE deletion or overexpression were generated, and the progression of AAD was determined. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to determine the upstream regulators of the CSE/H2S system and the findings were confirmed in transgenic mice. RESULTS: Higher plasma H2S levels were associated with a lower risk of AAD, after adjustment for common risk factors. CSE was reduced in the endothelium of AAD mouse and aorta of patients with AAD. Protein S-sulfhydration was reduced in the endothelium during AAD and protein disulfide isomerase (PDI) was the main target. S-sulfhydration of PDI at Cys343 and Cys400 enhanced PDI activity and mitigated endoplasmic reticulum stress. EC-specific CSE deletion was exacerbated, and EC-specific overexpression of CSE alleviated the progression of AAD through regulating the S-sulfhydration of PDI. ZEB2 (zinc finger E-box binding homeobox 2) recruited the HDAC1-NuRD complex (histone deacetylase 1-nucleosome remodeling and deacetylase) to repress the transcription of CTH, the gene encoding CSE, and inhibited PDI S-sulfhydration. EC-specific HDAC1 deletion increased PDI S-sulfhydration and alleviated AAD. Increasing PDI S-sulfhydration with the H2S donor GYY4137 or pharmacologically inhibiting HDAC1 activity with entinostat alleviated the progression of AAD. CONCLUSIONS: Decreased plasma H2S levels are associated with an increased risk of aortic dissection. The endothelial ZEB2-HDAC1-NuRD complex transcriptionally represses CTH, impairs PDI S-sulfhydration, and drives AAD. The regulation of this pathway effectively prevents AAD progression.

Trps1 predicts poor prognosis in advanced high grade serous ovarian carcinoma.

TRPS1 is aberrantly expressed in a variety of tumors, including breast, prostate, and gastric cancers, and is strongly associated with tumorigenesis or prognosis. However, the role of TRPS1 in high grade serous ovarian carcinoma (HGSC) is unknown. We investigated the relationship between TRPS1 expression and clinicopathology in HGSC patients. The tumor-related regulatory mechanisms of TRPS1 was explored through in vivo and vitro experiments. The results showed that TRPS1 was highly expressed in HGSC compared to normal tissues. It was also linked to the cell proliferation index Ki67 and poor prognosis. In vivo experiments showed that knockdown of TRPS1 could inhibit tumor growth. In vitro experiments, knockdown of TRPS1 inhibited the proliferation of ovarian cancer cells. TRPS1 exerted its regulatory role as a transcription factor, binding to the PSAT1 promoter and promoting the expression of PSAT1 gene. Meanwhile, PSAT1 was positively correlated with CCND1 expression. These results suggest that TRPS1 affects HGSC proliferation and cell cycle by regulating PSAT1 and thus CCND1 expression.

Effects of Cerebellar Repetitive Transcranial Magnetic Stimulation in the Treatment of Post-Stroke Dysphagia: A Meta-Analysis and Systematic Review of Randomized Controlled Trials.

INTRODUCTION: This study aimed to comprehensively evaluate the therapeutic efficacy of cerebellar repetitive transcranial magnetic stimulation (rTMS) in the rehabilitation of post-stroke dysphagia (PSD). METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched PubMed, Cochrane Library, Embase, and Web of Science to identify relevant randomized controlled trials (RCTs) investigating the application of cerebellar rTMS in the treatment of PSD. Inclusion and exclusion criteria were rigorously applied during the screening process, and pertinent characteristics of the included RCTs were meticulously extracted. The I2 statistic was employed to assess heterogeneity, and meta-analysis was conducted using Stata 17 software. The Cochrane Risk of Bias 2 tool and PEDro scale were utilized to evaluate bias risk and literature quality. RESULTS: Our analysis encompassed a total of 5 RCTs involving 673 patients with dysphagia who met the inclusion criteria. The findings indicated a significant positive impact of cerebellar rTMS when combined with traditional swallowing exercises on PSD, demonstrating superior efficacy compared to conventional swallowing exercises in isolation. Furthermore, the study revealed no statistically significant differences based on stimulation site (unilateral vs. bilateral cerebellum), stimulation mode (rTMS vs. intermittent theta-burst stimulation), and stimulation frequency (5 Hz vs. 10 Hz). CONCLUSION: The amalgamation of cerebellar rTMS with conventional swallowing exercises demonstrates notable efficacy, surpassing the outcomes achievable with traditional exercises alone. The sustained effectiveness observed underscores the potential of cerebellar rTMS as an innovative avenue in the field of neurorehabilitation for PSD. This study contributes valuable insights into the prospect of utilizing cerebellar rTMS as an adjunctive therapeutic strategy in the management of PSD, emphasizing its relevance for further exploration and clinical application.

ACSL4: a double-edged sword target in multiple myeloma, promotes cell proliferation and sensitizes cell to ferroptosis.

Overactive fatty acid metabolism is usually found in hematological malignancies including multiple myeloma (MM), but the underlying mechanisms remain unclear. Here, we reveal that acyl-CoA synthetase long-chain family member 4 (ACSL4) is abnormally overexpressed in MM cell lines and MM patients compared to healthy donors. Knockdown of ACSL4 inhibited MM cell proliferation and reduced fatty acid levels possibly by regulating lipid metabolism genes including c-Myc and sterol regulatory element binding proteins (SREBPs). As a propellent in ferroptosis, ACSL4 also determines the sensitivity of MM cells to ferroptosis inducer RSL3. Knockdown of ACSL4 rendered MM cells resistance to ferroptosis. Our findings suggest that ACSL4 is a double-edged sword target in MM. Based on the high expression of ACSL4, ferroptosis induction represents a promising therapeutic strategy for MM.

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODS: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).

Homologous recombination repair gene mutations in colorectal cancer favors treatment of immune checkpoint inhibitors.

Immune checkpoint inhibitor (ICI) therapy is insensitive for Colorectal cancer (CRC) patients with microsatellite stable (MSS). Genomic data of three CRC cohort, n = 35), and the Cancer Genome Atlas (TCGA CRC cohort, n = 377), were analyzed. A cohort treated with ICIs from Memorial Sloan Kettering Cancer Center (MSKCC CRC cohort, n = 110) and two cases from the local hospital were characterized the impact of the HRR mutation on prognosis of CRC. Homologous recombination repair (HRR) gene mutations were more common in CN and HL cohorts (27.85%; 48.57%) than in TCGA CRC cohort (15.92%), especially in the MSS populations, the frequencies of HRR mutation were higher in CN and HL cohort (27.45%, 51.72%) than in TCGA cohort (6.85%). HRR mutations were associated with high tumor mutational burden (TMB-H). Although HRR mutation uncorrelated with an improved overall survival in the MSKCC CRC cohort (p = 0.97), HRR mutated patients had a significantly improved OS compared to the HRR wildtype population particularly in MSS subgroups (p = 0.0407) under ICI treatment. It probably contributed by a higher neoantigen and increased CD4+ T cell infiltration which found in the TCGA MSS HRR mutated CRC cohort. The similar phenomenon on cases was observed that MSS metastatic CRC patient with HRR mutation seemed more sensitive to ICI after multi-line chemotherapy in clinical practice than HRR wildtype. This finding suggests the feasibility of HRR mutation as an immunotherapy response predictor in MSS CRC, which highlights a potential therapeutic approach for these patients.

Clinical value of circulating tumor cells and hematological parameters in 617 Chinese patients with colorectal cancer: retrospective analysis.

BACKGROUND: Circulating tumor cells (CTCs) have been a non-invasive technique which allows investigation of tumor characteristics. The purpose of this study was to investigate the relationship between circulating tumor cells and colorectal cancer. METHODS: The clinical data of 617 patients with colorectal cancer from October 2019 to March 2022 were retrospectively collected to analyze the correlation between CTCs and clinicopathologic characteristics. RESULTS: The CTCs value increased with the progression of Tumor(T) stage,Metastasis(M) stage and Tumor Node Metastasis(TNM) stage (P < 0.05), but not with Node (N) stage (P > 0.05). Binary logistic regression analysis showed that CTCs, CEA, CA125 and CA199 were independent risk factors for CRC metastasis. Compared with CTCs, CEA, CA125 and CA199, the Logistic model had the highest AUC (AUC = 0.778,95%CI: 0.732-0.824), and the specificity and sensitivity were 82.9% and 63.2%, respectively. After operation, chemo-radiotherapy and other treatment for CRC, CTCs and CEA were significantly decreased compared with before treatment (P < 0.05). In addition, Spearman Correlation showed significant correlation between CTCs and IgG (P = 0.000). CONCLUSION: CTCs, CEA, CA125 and CA199 were independent risk factors for CRC metastasis.CTCs can be used for the prediction of tumur metastasis, and the evaluation of therapeutic effect.

Investigating the prognostic and predictive value of the type II cystatin genes in gastric cancer.

BACKGROUND: Accumulating evidence indicates that type II cystatin (CST) genes play a pivotal role in several tumor pathological processes, thereby affecting all stages of tumorigenesis and tumor development. However, the prognostic and predictive value of type II CST genes in GC has not yet been investigated. METHODS: The present study evaluated the expression and prognostic value of type II CST genes in GC by using The Cancer Genome Atlas (TCGA) database and the Kaplan-Meier plotter (KM plotter) online database. The type II CST genes related to the prognosis of GC were then screened out. We then validated the expression and prognostic value of these genes by immunohistochemistry. We also used Database for Annotation, Visualization, and Integrated Discovery (DAVID), Gene Multiple Association Network Integration Algorithm (GeneMANIA), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), nomogram, genome-wide co-expression analysis, and other bioinformatics tools to analyze the value of type II CST genes in GC and the underlying mechanism. RESULTS: The data from the TCGA database and the KM plotter online database showed that high expression of CST2 and CST4 was associated with the overall survival (OS) of patients with GC. The immunohistochemical expression analysis showed that patients with high expression of CST4 in GC tissues have a shorter OS than those with low expression of CST4 (HR = 1.85,95%CI: 1.13-3.03, P = 0.015). Multivariate Cox regression analysis confirmed that the high expression level of CST4 was an independent prognostic risk factor for OS. CONCLUSIONS: Our findings suggest that CST4 could serve as a tumor marker that affects the prognosis of GC and could be considered as a potential therapeutic target for GC.

Weight Loss During Neoadjuvant Therapy Is Associated With Poor Response Among the Patients With Gastrointestinal Cancer: A Propensity Score Matching Analysis.

PURPOSE: The aim of the current study was to identify the relationship between body composition changes during neoadjuvant therapy (NAT) and the treatment efficiency of NAT in gastrointestinal cancer (GC) patients. METHODS: From January 2015 to July 2020, 277 GC patients treated with NAT had included for retrospective analysis. The body mass index (BMI) and computed tomography (CT) imaging before and after NAT were recorded. The BMI change optimal cut-off value were calculated by ROC curve. Balancing essential characteristic variables using propensity score matching (PSM) method. Exploring the association between BMI changes and tumor response to NAT using logistic regression analysis. The survival outcome of matched patients between different BMI change groups was compared. RESULTS: A cutoff point of BMI change >2% during NAT was defined as BMI loss. Among the 277 patients, 110 (39.7%) patients showed BMI change with a loss after NAT. In total, 71 pairs of patients were selected for further analysis. The median follow-up time was 22 months (range 3 to 63 months). Univariate and multivariate logistic regression analyses in matched cohort showed that BMI change was a prognostic factor for tumor response after NAT in GC patients (odds ratio (OR), .471; 95% confidence interval (CI), .233-.953; P = .036). In addition, patients who experienced BMI loss after NAT showed worse overall survival than those who had BMI gain or stable. CONCLUSION: BMI loss during NAT probably may has negative effects on NAT efficiency and survival for gastrointestinal cancer patients. It is necessary to monitor and maintain weight for patients during treatment.

Causal inference with outcomes truncated by death in multiarm studies.

It is challenging to evaluate causal effects when the outcomes of interest suffer from truncation-by-death in many clinical studies; that is, outcomes cannot be observed if patients die before the time of measurement. To address this problem, it is common to consider average treatment effects by principal stratification, for which, the identifiability results and estimation methods with a binary treatment have been established in previous literature. However, in multiarm studies with more than two treatment options, estimation of causal effects becomes more complicated and requires additional techniques. In this article, we consider identification, estimation, and bounds of causal effects with multivalued ordinal treatments and the outcomes subject to truncation-by-death. We define causal parameters of interest in this setting and show that they are identifiable either using some auxiliary variable or based on linear model assumption. We then propose a semiparametric method for estimating the causal parameters and derive their asymptotic results. When the identification conditions are invalid, we derive sharp bounds of the causal effects by use of covariates adjustment. Simulation studies show good performance of the proposed estimator. We use the estimator to analyze the effects of a four-level chronic toxin on fetal developmental outcomes such as birth weight in rats and mice, with data from a developmental toxicity trial conducted by the National Toxicology Program. Data analyses demonstrate that a high dose of the toxin significantly reduces the weights of pups.

Subgroup analysis using Bernoulli-gated hierarchical mixtures of experts models.

When it is suspected that the treatment effect may only be strong for certain subpopulations, identifying the baseline covariate profiles of subgroups who benefit from such a treatment is of key importance. In this paper, we propose an approach for subgroup analysis by firstly introducing Bernoulli-gated hierarchical mixtures of experts (BHME), a binary-tree structured model to explore heterogeneity of the underlying distribution. We show identifiability of the BHME model and develop an EM-based maximum likelihood method for optimization. The algorithm automatically determines a partition structure with optimal prediction but possibly suboptimal in identifying treatment effect heterogeneity. We then suggest a testing-based postscreening step to further capture effect heterogeneity. Simulation results show that our approach outperforms competing methods on discovery of differential treatment effects and other related metrics. We finally apply the proposed approach to a real dataset from the Tennessee's Student/Teacher Achievement Ratio project.

Trps1 acts as a regulator of Sf-1 transcription and testosterone synthesis in mouse Leydig cells.

Infertility has attracted global concern, and disruption of testosterone is a common cause of male infertility. Exploring the critical factors in testosterone biosynthesis may provide new insights for disease research and clinical therapy. Research on trichorhinophalangeal syndrome-1 (Trps1) gene has recently been focus on cancers; it is yet unknown whether Trps1 produces a marked effect in the male reproductive system. In the current study, single-cell RNA sequencing analysis of trichorhinophalangeal syndrome-1 gene (Trps1) expression in mouse testes and cleavage under targets and tagmentation and RNA sequencing were utilized to investigate the functionality of Trps1 in mouse Leydig cells. Knockdown of Trps1 increased testosterone synthesis in vitro and vivo using adeno-associated viral delivery and conditional knockout models. The results showed that Trps1 was abundantly expressed in Leydig cells. The expression levels of both steroidogenic factor-1 (Sf-1) and steroidogenic enzymes (Cyp11a1, Hsd3b, Cyp17a1, and Hsd17b3) as well as testosterone secretion were increased after Trps1 deficiency in vivo and vitro. Furthermore, disruption of Trps1 reduced histone deacetylase 1/2 activity and increased histone H3 acetylation in the Sf-1 promoter, thereby promoting testosterone secretion. Interestingly, Sf-1 also regulated the transcription of Trps1 through activating transcription factor 2. These results indicate that Trps1 targets Sf-1 to affect steroidogenesis through histone acetylation and shed light on the critical role of Trps1 functioning in the mouse Leydig cells.

In situ preparation of highly graphitized N-doped biochar geopolymer composites for efficient catalytic degradation of tetracycline in water by H2O2.

Advanced oxidation processes (AOPs) hold great prospects for the treatment of antibiotic wastewater. N-doped biochar (NB) has received increasing attention as a catalyst for AOPs because of its green nature, abundant biomass resources, and low cost. However, NB catalysts are complicated to prepare and difficult to recover, limiting their practical application. In this study, an N-doped biochar geopolymer composite (NBGC) was synthesized via in situ doping, simultaneous carbonization, and activation (ISCA) of lignin and urea in the porous geopolymer flake, without additional activators. The ISCA process used a low-cost geopolymer flake that not only served as a carrier to immobilize NB and facilitate the recovery, but also applied its inherent strong alkalinity to activate NB. The composite catalyst obtained at 600 °C (NBGC-600) exhibited excellent activity in activating H2O2 to degrade tetracycline (∼100%, 50 mg/L). The EPR results indicated that NBGC-600 had a strong ability to activate and decompose H2O2 to •OH, which could be attributed to its rich persistent radicals, graphitized N and CO groups, as well as the high degree of graphitization of biochar. The degradation pathway and intermediates of tetracycline in the NBGC-600-H2O2 system were also discussed according to the HPLC-MS results. Moreover, NBGC-600 had excellent reusability and showed great potential for continuous treatment of tetracycline in water. This work paves a new way for the synthesis of cost-effective N-doped biochar composite catalysts for AOPs.

Berberine plays a cardioprotective role by inhibiting macrophage Wnt5a/ß-catenin pathway in the myocardium of mice after myocardial infarction.

Myocardial infarction (MI) is one of the diseases with high fatality rate. Berberine (BBR) is a monomer compound with various biological functions. And some studies have confirmed that BBR plays an important role in alleviating cardiomyocyte injury after MI. However, the specific mechanism is unclear. In this study, we induced a model of MI by ligation of the left anterior descending coronary artery and we surprisingly found that BBR significantly improved ventricular remodeling, with a minor inflammatory and oxidative stress injury, and stronger angiogenesis. Moreover, BBR inhibited the secretion of Wnt5a/ß-catenin pathway in macrophages after MI, thus promoting the differentiation of macrophages into M2 type. In summary, BBR effectively improved cardiac function of mice after MI, and the potential protective mechanism was associated with the regulation of inflammatory responses and the inhibition of macrophage Wnt5a/ß-catenin pathway in the infarcted heart tissues. Importantly, these findings supported BBR as an effective cardioprotective drug after MI.

Early-life maternal deprivation in rats increases sensitivity to the subsequent stressors: a pilot study.

Early life experiences, particularly maternal deprivation (MD), have long-lasting implications on emotional and cognitive development. Using Wistar rats as a model, this study explores the impact of MD followed by predator stress exposure (PSS) to simulate aspects of post-traumatic stress disorder (PTSD). A cohort of 41 male rat pups underwent MD from postnatal days 2 to 14, followed by PSS at day 90. Female rat pups were not included in the experiment. Behavior was subsequently assessed using the Elevated Plus Maze test 14 days post-PSS. While MD led to subtle changes such as decreased activity and increased anxiety-like behavior, PSS induced pronounced anxiogenic effects. Notably, PSS after MD resulted in decreased basal corticosterone levels, mirroring conditions observed in PTSD. The findings suggest that although MD itself does not induce significant behavioral changes, it predisposes individuals to heightened sensitivity to subsequent stressors. This study underscores the utility of a two-stage PSS model for more accurately reflecting the complexities inherent in stress-related disorders, including PTSD.

[Advances in live-imaging aging reporter mice].

Aging is an independent risk factor for chronic diseases in the elderly, and understanding aging mechanisms is one of the keys to achieve early prevention and effective intervention for the diseases. Aging process is dynamic and systemic, making it difficult for mechanistic study. With recent advances in aging biomarkers and development of live-imaging technologies, more and more reporter mouse models have been generated, which can live monitor the aging process, and help investigate aging mechanisms at systemic level and develop intervention strategies. This review summarizes recent advances in live-imaging aging reporter mouse models based on widely used aging biomarkers (p16Ink4a, p21Waf1/Cip1, p53 and Glb1), and discusses their applications in aging research.

S-nitrosylation of c-Jun N-terminal kinase mediates pressure overload-induced cardiac dysfunction and fibrosis.

Cardiac fibrosis (CF) is an irreversible pathological process that occurs in almost all kinds of cardiovascular diseases. Phosphorylation-dependent activation of c-Jun N-terminal kinase (JNK) induces cardiac fibrosis. However, whether S-nitrosylation of JNK mediates cardiac fibrosis remains an open question. A biotin-switch assay confirmed that S-nitrosylation of JNK (SNO-JNK) increased significantly in the heart tissues of hypertrophic patients, transverse aortic constriction (TAC) mice, spontaneously hypertensive rats (SHRs), and neonatal rat cardiac fibroblasts (NRCFs) stimulated with angiotensin II (Ang II). Site to site substitution of alanine for cysteine in JNK was applied to determine the S-nitrosylated site. S-Nitrosylation occurred at both Cys116 and Cys163 and substitution of alanine for cysteine 116 and cysteine 163 (C116/163A) inhibited Ang II-induced myofibroblast transformation. We further confirmed that the source of S-nitrosylation was inducible nitric oxide synthase (iNOS). 1400 W, an inhibitor of iNOS, abrogated the profibrotic effects of Ang II in NRCFs. Mechanistically, SNO-JNK facilitated the nuclear translocation of JNK, increased the phosphorylation of c-Jun, and induced the transcriptional activity of AP-1 as determined by chromatin immunoprecipitation and EMSA. Finally, WT and iNOS-/- mice were subjected to TAC and iNOS knockout reduced SNO-JNK and alleviated cardiac fibrosis. Our findings demonstrate an alternative mechanism by which iNOS-induced SNO-JNK increases JNK pathway activity and accelerates cardiac fibrosis. Targeting SNO-JNK might be a novel therapeutic strategy against cardiac fibrosis.

Avatrombopag improves thrombocytopenia in MYH9-related disorder following eltrombopag treatment failure.

MYH9-related disorder (MYH9-RD) is autosomal dominant thrombocytopenia caused by mutations in the MYH9 gene, which codes for the non-muscle myosin-IIA heavy chain. We present a case of a 24-year-old Chinese man with MYH9-RD who was initially misdiagnosed with immune thrombocytopenia. Whole-exome sequencing and Sanger sequencing revealed a novel missense mutation in the MYH9 gene at the position of c.4550 G > T (p.G1517V) in exon 32. The same phenotype was observed in the proband, his mother, and his brother, in addition to macrothrombocytopenia and Dohle-like bodies in neutrophil granulocytes without non-hematologic manifestations. Following failed treatment with eltrombopag, avatrombopag, which was not mentioned before in the MYH9-RD treatment, was administered to the patient, and thrombocytopenia improved. In this case report, we present a novel pathogenic mutation and show the potential of avatrombopag for temporarily increasing the platelet count in patients with MYH9-RD.

T-cell engager antibodies enable T cells to control HBV infection and to target HBsAg-positive hepatoma in mice.

BACKGROUND & AIMS: Current antiviral therapies control but rarely eliminate HBV, leaving chronic HBV carriers at risk of developing hepatocellular carcinoma (HCC). Lacking or dysfunctional virus-specific adaptive immunity prevents control of HBV and allows the virus to persist. Restoring antiviral T-cell immunity could lead to HBV elimination and cure of chronically infected patients. METHODS: We constructed bispecific T-cell engager antibodies that are designed to induce antiviral immunity through simultaneous binding of HBV envelope proteins (HBVenv) on infected hepatocytes and CD3 or CD28 on T cells. T-cell engager antibodies were employed in co-cultures with healthy donor lymphocytes and HBV-infected target cells. Activation of the T-cell response was determined by detection of pro-inflammatory cytokines, effector function (by cytotoxicity) and antiviral effects. To study in vivo efficacy, immune-deficient mice were transplanted with HBVenv-positive and -negative hepatoma cells. RESULTS: The 2 T-cell engager antibodies synergistically activated T cells to become polyfunctional effectors that in turn elicited potent antiviral effects by killing infected cells and in addition controlled HBV via non-cytolytic, cytokine-mediated antiviral mechanisms. In vivo in mice, the antibodies attracted T cells specifically to the tumors expressing HBVenv resulting in T-cell activation, tumor infiltration and reduction of tumor burden. CONCLUSION: This study demonstrates that the administration of HBVenv-targeting T-cell engager antibodies facilitates a robust T-cell redirection towards HBV-positive target cells and provides a feasible and promising approach for the treatment of chronic viral hepatitis and HBV-associated HCC. LAY SUMMARY: T-cell engager antibodies are an interesting, novel therapeutic tool to restore immunity in patients with chronic hepatitis B. As bispecific antibodies, they bind envelope proteins on the surface of the hepatitis B virus (HBV) and CD3 or CD28 on T cells. This way, they induce a potent antiviral and cytotoxic T-cell response that leads to the elimination of HBV-positive cells. These bispecific T-cell engager antibodies are exciting therapeutic candidates for chronic hepatitis B and HBV-associated hepatocellular carcinoma.

Analysis of presacral tissue structure in LARS and the prevention of LARS by reconstruction of presacral mesorectum with pedicled greater omentum flap graft.

BACKGROUND: The greater omentum has played a unique biological role in regenerative surgery. The aim of our study was to alter the anterior sacral structure by filling the anterior sacral space with the greater omentum and evaluate its effect on the low anterior resection syndrome (LARS) after total mesorectal excision (TME) surgery for low rectal cancer. METHODS: We retrospectively collected clinical data of patients with primary low rectal cancer who underwent TME and ileostomy closure in our hospital from March 2018 to March 2020. Spearman correlation analysis was conducted to analyze the correlation between postoperative mesorectal fascia (MRF) thickness and LARS score. Subsequently, we prospectively used a tipped greater omental flap graft to reconstruct the anterior rectal sacral structures (MRF reconstruction) in 17 patients and compared LARS scores and rectal compliance (RC) at week 12 after closure of the ileostomy in both groups. RESULTS: There were 47 patients with No-MRF reconstruction (31 males, mean age 60.68 ± 9.21 years) and 17 with MRF reconstruction (10 males, mean age 49.82 ± 14.74 years). Correlation analysis indicated that MRF thickness and RC were negatively correlated with LARS severity (p < 0.05). The LARS score of patients with MRF reconstruction at 12 weeks was significantly better than that of those with No-MRF reconstruction (32.97 ± 2.65 vs. 26.94 ± 1.52, p = 0.001), and the RC of MRF reconstruction were lower (2.80 ± 0.55 vs. 3.67 ± 0.38, p = 0.001). In addition, MRF reconstruction and No-MRF reconstruction have the similar incidence of postoperative complications (p = 0.156). No hemorrhage or necrosis of the greater omentum flap was observed in any of the patients. CONCLUSIONS: Greater omentum flap transplantation can significantly improve the symptoms of LARS at 12 weeks after ileostomy closure and we expect it to become a new surgical procedure for the treatment of low rectal cancer.