Bismuth-Containing Quadruple Therapy for Helicobacter pylori Eradication: A Randomized Clinical Trial of 10 and 14 Days.

BACKGROUND: Bismuth-containing quadruple therapy is the first-line treatment for eradicating Helicobacter pylori (H. pylori). The optimal duration for H. pylori eradication using bismuth-containing quadruple therapy remains controversial. Therefore, we aimed to compare the clinical effects of the 10- and 14-day bismuth-containing quadruple treatment regimen to eradicate H. pylori. METHODS: Treatment-naïve patients with H. pylori infection (n = 1300) were enrolled in this multicenter randomized controlled study across five hospitals in China. They were randomized into 10- or 14-day treatment groups to receive bismuth-containing quadruple therapy as follows: vonoprazan 20 mg twice daily; bismuth 220 mg twice daily; amoxicillin 1000 mg twice daily; and either clarithromycin 500 mg twice daily or tetracycline 500 mg four times daily. At least 6 weeks after treatment, we performed a 13C-urea breath test to evaluate H. pylori eradication. RESULTS: The per-protocol eradication rates were 93.22% (564/605) and 93.74% (569/607) (p < 0.001) and the intention-to-treat eradication rates were 88.62% (576/650) and 89.38% (581/650) (p = 0.007) for the 10- and 14-day regimens, respectively. Incidence of adverse effects was lower in patients who received 10- vs. 14 days of treatment (22.59% vs. 28.50%, p = 0.016). We observed no significant differences in the compliance to treatment or the discontinuation of therapy because of severe adverse effects between the groups. CONCLUSION: Compared with the 14-day bismuth-containing quadruple regimens, the 10-day regimen demonstrated a non-inferior efficacy and lower incidence of adverse effects. Therefore, the 10-day regimen is safe and tolerated and could be recommended for H. pylori eradication (NCT05049902).

The confusing pelvic mass: A case of small intestine lesion diagnosed by endoscopic ultrasound-guided fine-needle biopsy through the sigmoid colon.

Here we report a successful case of a small bowel lesion obtained through EUS-FNB via the sigmoid colon after routine small bowel endoscopy failed due to bowel volvulus. This case highlights the feasibility of EUS-FNB in small intestine lesion acquisition through sigmoid colon.

Clinical efficacy observation of calcipotriol combined with AYJ sodium alginate repair dressing in the treatment of psoriasis vulgaris and its effect on patients' neurological function.

OBJECTIVE: To observe the clinical efficacy of calcipotriol combined with AYJ(An Yi Jia) sodium alginate repair dressing in the treatment of psoriasis vulgaris (PV) and its effect on patients' neurological function. METHODS: A retrospective analysis was conducted on the clinical data of 103 patients with PV admitted to our hospital from January 2022 to January 2024. All patients met the inclusion and exclusion criteria. According to the treatment interventions received by the patients, they were divided into control group (n = 51, receiving calcipotriol monotherapy) and observation group (n = 52, receiving calcipotriol combined with AYJ sodium alginate repair dressing). The clinical treatment effects, severity of the disease (PSSI score), levels of T lymphocyte subsets (CD4+, CD8+), serum nerve growth factor (NGF), inflammatory factors [interferon-gamma (IFN-γ), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α)], and adverse reactions were compared between the two groups. RESULTS: ① Clinical treatment effects: The total effective rate in the observation group was higher than that in the control group (p < 0.05). ② Severity of the disease: The PASI scores of both groups gradually decreased with prolonged treatment time, and the observation group showed a greater magnitude of change (p < 0.05). ③ T lymphocyte subset cells and serum nerve growth factor: The levels of CD4+ were increased after treatment in both groups, while CD8+ and NGF levels were decreased compared to before treatment, with a greater magnitude of change in the observation group (p < 0.05). ④ Inflammatory factors: The levels of IFN-γ, IL-8, and TNF-α were decreased after treatment in both groups, with a greater magnitude of change in the observation group (p < 0.05). ⑤ Adverse reactions: There was no significant difference in the incidence of adverse reactions between the two groups (p > 0.05). CONCLUSION: Calcipotriol combined with AYJ sodium alginate repair dressing has ideal therapeutic effects in the treatment of PV. Compared with calcipotriol alone, the combined application of AYJ sodium alginate repair dressing can further improve patient efficacy, improve immune and neurological function, alleviate patient inflammatory responses, and does not increase the risk of adverse reactions in patients.

Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma.

Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC50 = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential anticancer agent.

A novel prognostic signature based on cancer stemness and metabolism-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma.

BACKGROUND: CESC is the second most commonly diagnosed gynecological malignancy. Given the pivotal involvement of metabolism-related genes (MRGs) in the etiology of multiple tumors, our investigation aims to devise a prognostic risk signature rooted in cancer stemness and metabolism. METHODS: The stemness index based on mRNA expression (mRNAsi) of samples from the TCGA dataset was computed using the One-class logistic regression (OCLR) algorithm. Furthermore, potential metabolism-related genes related to mRNAsi were identified through weighted gene co-expression network analysis (WGCNA). We construct a stemness-related metabolic gene signature through shrinkage estimation and univariate analysis, thereby calculating the corresponding risk scores. Moreover, we selected corresponding DEGs between groups with high- and low-risk score and conducted routine bioinformatic analyses. Furthermore, we validated the expression of four hub genes at the protein level through immunohistochemistry (IHC) in samples obtained from our patient cohort. RESULTS: According to the findings, it was found that six genes-AKR1B10, GNA15, ALDH1B1, PLOD2, LPCAT1, and GPX8- were differentially expressed in both TCGA-CSEC and GEO datasets among 23 differentially expressed metabolism-related genes (DEMRGs). mRNAsi exhibited a notable association with the extent of key oncogene mutation. The results showed that the AUC values for forecasting survival at 1, 3, and 5 years are 0.715, 0.689, and 0.748, individually. We observed a notable association between the risk score and different immune cell populations, along with enrichment in crucial signaling pathways in CESC. Four genes differentially expressed between different risk score groups were validated by IHC to be highly expressed in the CESC samples at the protein level. CONCLUSION: The current investigation indicated that a 3-gene signature based on stemness-related metabolic and 4 hub genes with differential expression between high and low-risk score subgroups may serve as valuable prognostic markers and potential therapeutic targets in CESC.

Emerging Insights into Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Induced by Immune Checkpoint Inhibitor and Tumor-Targeted Therapy.

Objective: Anticancer drugs have revolutionized tumor therapy, with cutaneous toxicities such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) being common immune-related adverse events. The debate over the efficacy of systemic corticosteroids in treating these conditions persists, while tumor necrosis factor (TNF)-alpha inhibitors show promise. This study aims to evaluate the effectiveness and safety of combination therapy involving the TNF-α inhibitor adalimumab for SJS/TEN induced by anticancer drugs. Methods: A literature review of SJS/TEN cases induced by anticancer drugs from 1992 to 2023 was conducted, alongside an analysis of patients admitted to the First Affiliated Hospital of Fujian Medical University during the same period. Clinical characteristics, skin healing time, mortality, and adverse events were evaluated in two treatment groups: SJS/TEN patients treated with targeted anticancer therapies and immunotherapies. Results: Among the 27 patients studied (18 with SJS or SJS-TEN overlapping and 9 with TEN), combination therapy with adalimumab significantly reduced mucocutaneous reepithelization time and healing duration compared to corticosteroid monotherapy. Patients receiving adalimumab combined with corticosteroids had lower actual mortality rates than those on corticosteroid monotherapy. The combination therapy also showed a trend towards reducing standardized mortality rates based on the Score of Toxic Epidermal Necrolysis (SCORTEN). Conclusion: The findings suggest that adalimumab in combination with corticosteroids provides significant clinical benefits and is safer than corticosteroids alone for treating SJS/TEN induced by targeted anticancer therapies and immunotherapies. This study contributes valuable insights into potential treatment strategies for severe cutaneous adverse reactions to anticancer drugs, highlighting the importance of exploring alternative therapies such as TNF-α inhibitors in managing these conditions effectively.

The emergence of tumor-initiating cells in an advanced hypopharyngeal tumor model exhibits enhanced angiogenesis and nuclear factor erythroid 2-related factor 2 associated antioxidant effects.

Hypopharyngeal cancer (HPC) is associated with the worst prognosis of all head and neck cancers and is typically identified in an advanced stage at the time of diagnosis. While oxidative stress might contribute to the onset of HPC in patients using tobacco or alcohol, the extent of this influence and the characteristics of HPC cells in advanced stage remain to be investigated. In this study, we explored whether HPC cells survived from necrotic xenograft tumors at late stage would display increased tumor resistance along with altered tolerance to oxidative stress. The remnant living HPC cells isolated from a late-stage xenograft tumor, named FaDu Ex-vivo cells showed stronger chemo- and radio-resistance, tumorigenesis, and invasiveness compared to parental FaDu cells. FaDu Ex-vivo cells also displayed increased angiogenic ability after re-transplantation to mice visualized by in vivo near infrared-II (NIR-II) fluorescence imaging modality. Moreover, FaDu Ex-vivo cells exhibited significant tumor-initiating cells (TICs) related properties accompanied by a reduction of the level of reactive oxygen species (ROS), which was associated with up-regulation of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Interestingly, inhibition of Nrf2 by the RNA interference and the chemical inhibitor could reduce TICs related properties of FaDu Ex-vivo cells. Oxidative stress potentially initiates HPC, but elevation of Nrf2-associated antioxidant mechanisms would be essential to mitigate this effect for promoting and sustaining the stemness of HPC at the advanced stage. Current data suggest that the antioxidant potency of advanced HPC would be a therapeutic target for the design of adjuvant treatm.

Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.

Aurora kinase A inhibition plus Tumor Treating Fields suppress glioma cell proliferation in a cilium-independent manner.

Tumor Treating Fields (TTFields) extend the survival of glioblastoma (GBM) patients by interfering with a broad range of tumor cellular processes. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis further suppress GBM cell proliferation in vitro. Aurora kinase A (AURKA) promotes both cilia disassembly and GBM growth. Inhibitors of AURKA, such as Alisertib, inhibit cilia disassembly and increase ciliary frequency in various cell types. However, we found that Alisertib treatment significantly reduced GBM cilia frequency in gliomaspheres across multiple patient derived cell lines, and in patient biopsies treated ex vivo. This effect appeared glioma cell-specific as it did not reduce normal neuronal or glial cilia frequencies. Alisertib-mediated depletion of glioma cilia appears specific to AURKA and not AURKB inhibition, and attributable in part to autophagy pathway activation. Treatment of two different GBM patient-derived cell lines with TTFields and Alisertib resulted in a significant reduction in cell proliferation compared to either treatment alone. However, this effect was not cilia-dependent as the combined treatment reduced proliferation in cilia-depleted cell lines lacking, ARL13B, or U87MG cells which are naturally devoid of ARL13B+ cilia. Thus, Alisertib-mediated effects on glioma cilia may be a useful biomarker of drug efficacy within tumor tissue. Considering Alisertib can cross the blood brain barrier and inhibit intracranial growth, our data warrant future studies to explore whether concomitant Alisertib and TTFields exposure prolongs survival of brain tumor-bearing animals in vivo.

Structural insights into the functional mechanism of the ubiquitin ligase E6AP.

E6AP dysfunction is associated with Angelman syndrome and Autism spectrum disorder. Additionally, the host E6AP is hijacked by the high-risk HPV E6 to aberrantly ubiquitinate the tumor suppressor p53, which is linked with development of multiple types of cancer, including most cervical cancers. Here we show that E6AP and the E6AP/E6 complex exist, respectively, as a monomer and a dimer of the E6AP/E6 protomer. The short α1-helix of E6AP transforms into a longer helical structure when in complex with E6. The extended α1-helices of the dimer intersect symmetrically and contribute to the dimerization. The two protomers sway around the crossed region of the two α1-helices to promote the attachment and detachment of substrates to the catalytic C-lobe of E6AP, thus facilitating ubiquitin transfer. These findings, complemented by mutagenesis analysis, suggest that the α1-helix, through conformational transformations, controls the transition between the inactive monomer and the active dimer of E6AP.

[Integrin and N-cadherin Co-Regulate the Polarity of Mesenchymal Stem Cells via Mechanobiological Mechanisms]. / æ•´åˆç´ å’ŒN-é’™é»ç´ ååŒè°ƒæŽ§é—´å è´¨å¹²ç»†èƒžæžæ€§çš„åŠ›å­¦ç”Ÿç‰©å­¦æœºåˆ¶ç ”ç©¶.

Objective: To investigate the synergistic regulation of the polarization of mesenchymal stem cells by integrin and N-cadherin-mediated mechanical adhesion and the underlying mechanobiological mechanisms. Methods: Bilayer polyethylene glyeol (PEG) hydrogels were formulated and modified with RGD and HAVDI peptides, respectively, to achieve mechanical adhesion to integrin and N-cadherin and to replicate the integrin-mediated mechanical interaction between cells and the extracellular matrix and the N-cadherin-mediated cell-cell mechanical interaction. The polar proteins, phosphatidylinositol 3-kinase (PI3K) and phosphorylated myosin light chain (pMLC), were characterized through immunofluorescence staining in individual cells with or without contact with HAVDI peptides under integrin-mediated adhesion, N-cadherin-mediated adhesion, and different intracellular forces. Their expression levels and polar distribution were analyzed using Image J. Results: Integrin-mediated adhesion induced significantly higher polar strengths of PI3K and pMLC in the contact group than in those in the no contact group, resulting in the concentration of the polar angle of PI3K to ß-catenin in the range of 135° to 180° and the concentration of the polar angle of pMLC to ß-catenin in the range of 0° to 45° in the contact group. Inhibition of integrin function led to inhibition of the polarity distribution of PI3K in the contact group, but did not change the polarity distribution of pMLC protein. The effect of N-cadherin on the polarity distributions of PI3K and pMLC was similar to that of integrin. However, inhibition of the mechanical adhesion of N-cadherin led to inhibition of the polarity intensity and polarity angle distribution of PI3K and pMLC proteins in the contact group. Furthermore, inhibition of the mechanical adhesion of N-cadherin caused weakened polarity intensity of integrin ß1, reducing the proportion of cells with polarity angles between integrin ß1 and ß-catenin concentrating in the range of 135° to 180°. Additionally, intracellular forces influenced the polar distribution of PI3K and pMLC proteins. Reducing intracellular forces weakened the polarity intensity of PI3K and pMLC proteins and their polarity distribution, while increasing intracellular forces enhanced the polarity intensity of PI3K and pMLC proteins and their polarity distribution. Conclusion: Integrin and N-cadherin co-regulate the polarity distribution of cell proteins and N-cadherin can play an important role in the polarity regulation of stem cells through local inhibition of integrin.

A prospective randomized trial comparing the pocket-creation method and conventional method of endoscopic submucosal dissection in early gastric cancers and precancerous lesions.

BACKGROUND: Endoscopic submucosal dissection (ESD) is widely used as a standard treatment regimen for early gastric cancers (EGCs). However, such an approach is time-consuming and has a high risk of perforation and bleeding in some corner-site lesions because of the obscured view and difficulty in submucosal lifting. The newly developed pocket-creation method (PCM) provides a clearer view and better traction of the submucosal layer than conventional ESD (c-ESD). Nevertheless, no prospective randomized study has evaluated the efficacy of the PCM in EGCs and precancerous lesions. METHODS: This was a prospective randomized controlled trial. Patients with superficial gastric neoplastic lesions≥20mm were randomly assigned to the PCM-ESD group or c-ESD group. The primary outcome was dissection speed. RESULTS: There were 28 patients in the PCM-ESD group and 27 in the c-ESD group. The median dissection speed was significantly higher in the PCM-ESD group than in the c-ESD group (21.5 mm2/min vs. 14.3 mm2/min, P<0.001). Meanwhile, the operation time in the PCM-ESD group was significantly shorter than that in the c-ESD group (30min vs. 40min，P=0.047). In multiple linear regression analysis, the treatment method was independently associated with the resection speed of ESD. CONCLUSIONS: PCM-ESD was an effective and safe treatment for EGCs and precancerous lesions.

A comprehensive analysis of liver safety across zibotentan oncology trials: knowledge of the past offers new perspectives on the present.

BACKGROUND: Endothelin receptor antagonists (ERAs) are associated with liver injury. We used data from previous oncology clinical trials to determine the liver safety profile of zibotentan, which is currently in clinical development (in combination with dapagliflozin) for chronic kidney disease and cirrhosis. RESEARCH DESIGN AND METHODS: Six global, double-blinded, phase 2b and 3 clinical trials from the zibotentan oncology development program were pooled to analyze liver safety. Descriptive statistics, proportion of liver-related adverse events, liver biochemistry parameter elevation, and shifts from baseline were analyzed, with individual case assessment. RESULTS: A total of 1532 patients received zibotentan for 285 days (mean), and 1486 patients received placebo for 320 days (mean). The frequency of any hepatic disorder preferred term was similar across zibotentan monotherapy (22/947 patients, 2.3%) and placebo monotherapy arms (30/881 patients, 3.4%). A total of 4 (0.4%) patients receiving zibotentan monotherapy experienced ALT elevations >5× ULN versus 8 (0.9%) receiving placebo. Of the seven patients receiving zibotentan who met criteria for potential Hy's Law, there were no cases of drug-induced liver injury. CONCLUSIONS: We found no evidence of zibotentan-related liver biochemistry changes among cancer-treated patients, suggesting that hepatotoxicity of ERAs is molecule-dependent, and allowing exploration of zibotentan for new indications.

The impact of secondhand smoke on failure of Helicobacter pylori therapy is not inferior to that of smoking.

BACKGROUND: Previous studies have shown the associations between smoking and failure to eradicate Helicobacter pylori (H. pylori), but less is known about the impact of secondhand tobacco smoke (SHS) on H. pylori eradication. METHODS: Between July 2022 to July 2023, 646 patients who received proton pump inhibitor (PPIs) as first-line H. pylori eradication therapy were recruited for the study. Information was obtained via the hospital database and a telephone questionnaire. Univariate and multivariate regression analysis were used to examine risk factors of H. pylori eradication failure. RESULTS: This was a single-center retrospective study consisting of 646 patients who received PPIs as first-line H. pylori eradication therapy. This included 122 smokers, 165 never-smokers with SHS, and 359 never-smokers with no SHS exposure. Compared with subjects in the "eradication success" group, those in the "eradication failure" group tended to have higher prevalence of smoke consumption and have higher prevalence of SHS exposure. In binary logistic regression analysis, smoking (OR 3.409, 95 % CI: 1.782- 6.522, P < 0.001) and SHS (OR 3.188, 95 % CI: 1.726-5.886, P < 0.001) were independent predictors of eradication failure. In addition, never-smokers with SHS exposure and smoking had similar effects on H. pylori eradication (OR, 0.893; 95 % CI, 0.464 to 1.717, P value = 0.734). CONCLUSION: Both smoking and SHS are independent risk factors for H. pylori eradication failure. Furthermore, the impact of SHS is not inferior to smoking.

Structure-based discovery of potent CARM1 inhibitors for colorectal cancer therapy.

Coactivator-associated arginine methyltransferase 1 (CARM1) plays an important role in cell proliferation and gene expression, and is highly expressed in a variety of tumor tissues. Guided by our previous reported structure of DCPR049_12, we focused on designing and evaluating selective CARM1 inhibitors, resulting in the identification of compound 11f as a promising lead candidate. Compound 11f displayed potent inhibition of CARM1 (IC50 = 9 nM). Comprehensive evaluations, including in vitro metabolic stability assessments, molecular modelling, cellular studies, and in vivo anti-tumor studies, confirmed that it induced cancer cell apoptosis and specifically inhibited CARM1's methylation function. Notably, compound 11f displayed significant anti-proliferative effects on colorectal cancer cell lines, showcasing its potential for targeted therapies against CARM1-related diseases. This study provides valuable insights for the future development of specific and effective CARM1 inhibitors.

Early adenocarcinoma mixed with a neuroendocrine carcinoma component arising in the gastroesophageal junction: A case report.

BACKGROUND: Early adenocarcinoma mixed with a neuroendocrine carcinoma (NEC) component arising in the gastroesophageal junctional (GEJ) region is rare and even rarer in young patients. Here, we report such a case in a 29-year-old Chinese man. CASE SUMMARY: This patient presented to our hospital with a 3-mo history of dysphagia and regurgitation. Upper endoscopy revealed an elevated nodule in the distal esophagus 1.6 cm above the GEJ line, without Barrett's esophagus or involvement of the gastric cardia. The nodule was completely resected by endoscopic submucosal dissection (ESD). Pathological examination confirmed diagnosis of intramucosal adenocarcinoma mixed with an NEC component, measuring 1.5 cm. Immunohistochemically, both adenocarcinoma and NEC components were positive for P53 with a Ki67 index of 90%; NEC was positive for synaptophysin and chromogranin. Next-generation sequencing of 196 genes demonstrated a novel germline mutation of the ERCC3 gene in the DNA repair pathway and a germline mutation of the RNF43 gene, a common gastric cancer driver gene, in addition to pathogenic somatic mutations in P53 and CHEK2 genes. The patient was alive without evidence of the disease 36 mo after ESD. CONCLUSION: Early adenocarcinoma with an NEC component arising in the distal esophageal side of the GEJ region showed evidence of gastric origin.

Extracorporeal photopheresis as a promising strategy for the treatment of GvHD after CAR-T cell therapy.

Graft-versus-host disease (GvHD) occurs in about 10-33% of patients receiving "al-logeneic" or "autologous" CAR-T cells after preceding allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to the substantial presence of alloreactive T cells. Extracorporeal photopheresis (ECP) shows promising clinical outcomes in the treatment of GvHD after allo-HSCT without hampering anti-tumor and anti-viral effects. This raises an interesting question: whether ECP might constitute a new way to treat patients with GvHD after CAR-T cell therapy without compromising CAR-T cells significantly. Third-generation CD19-specific CAR-T cells were generated and an in vitro ECP protocol was established. The impact of ECP on CAR-T cells was comprehensively investigated in two models: the non-dilution model reflects days following CAR-T cell infusion and the dilution model weeks after infusion. The ther-apeutic effect of ECP on GvHD was examined in an in vitro mixed lymphocyte reac-tion (MLR) assay. We found out that ECP treated CAR-T cells demonstrated reduced potency in inducing alloreaction compared to the group without ECP treatment in MLR assay. ECP could selectively induce apoptosis, thereby enriching the naive and central memory CAR-T cells with a reduced alloreactivity. The cytokine milieu of CAR-T cells could be switched from immune stimulation to immune tolerance in both models. Moreover, ECP could modulate the proliferative capacity of CAR-T cells without hampering their long-term functionality in the dilution model. In con-clusion, ECP constitutes a promising treatment strategy for GvHD after allo-HSCT and CAR-T cell transfusion, as ECP reduces the alloreactivity without hampering CAR-T cell functionality.

Emerging role of SENP1 in tumorigenesis and cancer therapy.

Acting as a cysteine protease, small ubiquitin-like modifier (SUMO)/sentrin-specific protease1 (SENP1) involved in multiple physiological and pathological processes through processing the precursor SUMO protein into mature form and deSUMOylating target protein. It has been reported that SENP1 is highly expressed and plays a carcinogenic role in various cancers. In this paper, we mainly explore the function and mechanism of SENP1 in tumor cell proliferation, apoptosis, invasion, metastasis, stemness, angiogenesis, metabolism and drug resistance. Furthermore, the research progress of SENP1 inhibitors for cancer treatment is introduced. This study aims to provide theoretical references for cancer therapy by targeting SENP1.

[Construction of prediction model of severe acute pancreatitis based on serum soluble T cell immunogloblulin and mucin domain-containing protein 3].

OBJECTIVE: To investigate the predictive value of the model based on soluble T cell immunogloblulin and mucin domain-containing protein 3 (sTIM3) for the progression of severe acute pancreatitis (SAP) in patients with acute pancreatitis (AP). METHODS: A retrospective cohort study was conducted. The AP patients admitted to Changzhou First People's Hospital and Changzhou Second People's Hospital from June 1, 2020 to June 30, 2022 were enrolled. Mild AP (MAP) and moderately severe AP (MSAP) patients were classified as non-SAP group, and SAP patients were classified as SAP group according to the progression of AP patients during hospitalization. The basic data, blood biological indicators, serum sTIM3 level, bedside index for severity in acute pancreatitis (BISAP), acute physiology and chronic health evaluation II (APACHE II) score, modified computed tomography severity index (MCTSI) score within 48 hours of admission, and prognosis indicators were collected. Multivariate Logistic regression analysis was conducted to analyze the risk factors of the progression of SAP in patients with AP during hospitalization. Based on the results of multivariate analysis and the best parameters selected based on the minimal Akaike information criterion (AIC), the SAP prediction model based on sTIM3 was constructed. The receive operator characteristic curve (ROC curve) was plotted to analyze the predictive efficacy of the model. RESULTS: A total of 99 AP patients were enrolled, 80 patients in the non-SAP group and 19 patients in the SAP group. Compared with the non-SAP group, body mass index (BMI), drinking history ratio, heart rate (HR), respiration rate (RR), white blood cell count (WBC), red blood cell count (RBC), C-reactive protein (CRP), alanine aminotransferase (ALT), serum creatinine (SCr), procalcitonin (PCT), interleukin-6 (IL-6), sTIM3, BISAP score, APACHE II score and MCTSI score were significantly increased, and pulse oxygen saturation (SpO2), direct bilirubin (DBil) and IL-10 were significantly decreased. The length of intensive care unit (ICU) stay and total length of hospital stay of patients in the SAP group were significantly longer than those in the non-SAP group [length of ICU stay (days): 1.0 (0, 1.5) vs. 0 (0, 0), total length of hospital stay (days): 17.11±9.39 vs. 8.40±3.08, both P < 0.01]. Multivariate Logistic regression analysis showed that HR [odds ratio (OR) = 1.059, 95% confidence interval (95%CI) was 1.010-1.110, P = 0.017], DBil (OR = 0.981, 95%CI was 0.950-0.997, P = 0.043), and sTIM3 (OR = 1.002, 95%CI was 1.001-1.003, P = 0.027) were independent risk factors for predicting the progression of SAP in patients with AP, and the SAP prediction model based on sTIM3 was constructed: Logit(P) = -14.602+0.187×BMI+0.057×HR+0.006×CRP-0.020×DBil+0.002×sTIM3. ROC curve analysis showed that among the aforementioned single factor quantitative indicators, IL-6 was the most effective in predicting the progression of AP patients to SAP during hospitalization, but the predictive performance of prediction model based on the sTIM3 was significantly better than IL-6 [area under the ROC curve (AUC) and 95%CI: 0.957 (0.913-1.000) vs. 0.902 (0.845-0.958), P < 0.05]. CONCLUSIONS: The model based on serum sTIM3 demonstrated good predictive value for the progression of SAP in patients with AP.