Link between mutations in ACVRL1 and PLA2G4A genes and chronic intestinal ulcers: A case report and review of literature.

BACKGROUND: Genetic factors of chronic intestinal ulcers are increasingly garnering attention. We present a case of chronic intestinal ulcers and bleeding associated with mutations of the activin A receptor type II-like 1 (ACVRL1) and phospholipase A2 group IVA (PLA2G4A) genes and review the available relevant literature. CASE SUMMARY: A 20-year-old man was admitted to our center with a 6-year history of recurrent abdominal pain, diarrhea, and dark stools. At the onset 6 years ago, the patient had received treatment at a local hospital for abdominal pain persisting for 7 d, under the diagnosis of diffuse peritonitis, acute gangrenous appendicitis with perforation, adhesive intestinal obstruction, and pelvic abscess. The surgical treatment included exploratory laparotomy, appendectomy, intestinal adhesiolysis, and pelvic abscess removal. The patient's condition improved and he was discharged. However, the recurrent episodes of abdominal pain and passage of black stools started again one year after discharge. On the basis of these features and results of subsequent colonoscopy, the clinical diagnosis was established as inflammatory bowel disease (IBD). Accordingly, aminosalicylic acid, immunotherapy, and related symptomatic treatment were administered, but the symptoms of the patient did not improve significantly. Further investigations revealed mutations in the ACVRL1 and PLA2G4A genes. ACVRL1 and PLA2G4A are involved in angiogenesis and coagulation, respectively. This suggests that the chronic intestinal ulcers and bleeding in this case may be linked to mutations in the ACVRL1 and PLA2G4A genes. Oral Kangfuxin liquid was administered to promote healing of the intestinal mucosa and effectively manage clinical symptoms. CONCLUSION: Mutations in the ACVRL1 and PLA2G4A genes may be one of the causes of chronic intestinal ulcers and bleeding in IBD. Orally administered Kangfuxin liquid may have therapeutic potential.

Camrelizumab plus gemcitabine and oxaliplatin for relapsed or refractory classical Hodgkin lymphoma: a phase II trial.

BACKGROUND: Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients. METHODS: Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m2 IV, and oxaliplatin 100 mg/m2 IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT. RESULTS: Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity. CONCLUSIONS: Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission. TRIAL REGISTRATION: ClinicalTrials.gov NCT04239170. Registered on January 1, 2020.

Management and clinical outcomes of follicular lymphoma across continuous lines of treatments: a retrospective analysis in China.

Background: Follicular lymphoma (FL) is characterized by an incurable course that frequently necessitates multiple lines of treatment. While a range of new approaches have broadened therapeutic options for patients in later lines, data regarding treatment patterns and outcomes of Chinese patients with relapsed/refractory(R/R) FL was scarcely reported. Methods: This retrospective single-center study included patients diagnosed with FL grades 1-3a at our institution between January 2002 and December 2019. Endpoints of interest were analyzed according to lines and types of interventions. The endpoints mainly included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: The study enrolled 566 biopsy-proven patients. Among them, 544 patients initiated the first line of treatment, followed by 240 initiating the second line, 146 initiating the third line, 88 initiating the fourth line, 47 initiating the fifth line, and 28 initiating the sixth line. In terms of treatment patterns, anti-CD20 chemotherapy was a major modality in the first and second lines. However, for patients in the third line and subsequent lines, treatment approaches were diverse, and participation in clinical trials for new medications was common, which correlated with a survival benefit. The study also revealed that clinical indicators (such as ORR, PFS, and OS) gradually decreased with each subsequent line of treatment. The ORR at the first line was 86.6%, but decreased to 48.6% at the third line and 40.4% at the sixth line, respectively. Similarly, median OS and PFS decreased to 88.8 and 7.1 months at the third line and further reduced to 21.7 and 2.8 months at the sixth line, respectively. A total of 133 patients developed progression within 24 months from the initiation of first line anti-CD20 chemotherapy (POD24), and these patients exhibited poorer response rates and outcomes in subsequent lines of therapycompared to the non-POD24 group. Conclusion: This study revealed the clinical routine practices and prognosis of R/R FL patients within the Chinese population. It underscored the unmet need for optimal strategies to improve survival and also served as a benchmark for future trials.

Comparison of Fecal Antimicrobial Resistance Genes in Captive and Wild Asian Elephants.

The Asian elephant (Elephas maximus) is a flagship species of tropical rainforests, and it has generated much concern. In this case, the gut bacterial communities of captive and wild Asian elephants are particularly noteworthy. We aim to compare the differences in bacterial diversity and antibiotic resistance gene (ARG) subtypes in fecal samples of Asian elephants from different habitats, which may affect host health. Analyses reveal that differences in the dominant species of gut bacteria between captive and wild Asian elephants may result in significant differences in ARGs. Network analysis of bacterial communities in captive Asian elephants has identified potentially pathogenic species. Many negative correlations in network analysis suggest that different food sources may lead to differences in bacterial communities and ARGs. Results also indicate that the ARG levels in local captive breeding of Asian elephants are close to those of the wild type. However, we found that local captive elephants carry fewer ARG types than their wild counterparts. This study reveals the profile and relationship between bacterial communities and ARGs in different sources of Asian elephant feces, providing primary data for captive breeding and rescuing wild Asian elephants.

Antitumor activity and safety of camrelizumab combined with apatinib in patients with relapsed or refractory peripheral T-cell lymphoma: An open-label, multicenter, phase II study.

Introduction: The treatment for relapsed/refractory peripheral T-cell lymphoma (r/r PTCL) is suboptimal. This open-label, multicenter, single-arm study aimed to investigate the antitumor activity and safety of camrelizumab (a PD-1 blockade) plus apatinib (an antiangiogenic agent) for patients with r/r PTCL. Methods: Eligible patients with r/r PTCL were enrolled and received camrelizumab 200 mg intravenously every 2 weeks and apatinib 500 or 250 mg orally once daily, 4 weeks as a cycle. The primary endpoint was overall response rate (ORR). Results: A total of 20 patients were enrolled and received study medications in the study, with a median number of prior treatment line of 3 (range 1-6). At the cutoff date of March 4, 2022, the median follow-up was 27.2 months (range: 0.5-39.9), and three patients remained on treatment. Six patients had early discontinuation without tumor response evaluation. For all patients, the ORR was 30% (6/20) (95% confidence interval [CI], 11.9% to 54.3%), with two patients (10%) achieving complete response. The median progression-free survival (PFS) and median overall survival for all patients were 5.6 months (95% CI, 1.8 to not reached) and 16.7 months (95% CI, 2.8 to not reached), respectively. Patients with PD-L1 expression ≥50% (3 patients) had a numerically higher ORR and longer median PFS than those with PD-L1 expression < 50% (5 patients). The most commonly reported grade 3 or higher adverse events were hyperlipidemia (15%), hypokalemia (15%) and anemia (15%). No treatment-related deaths occurred. Discussion: In this study, PD-1 inhibitors plus low-dose antiangiogenic drugs presented preliminary antitumor activity and manageable toxicity in patients with r/r PTCL.

Efficacy and safety of relmacabtagene autoleucel, an anti-CD19 chimeric antigen receptor T cell, in relapsed/refractory B-cell non-Hodgkin's lymphoma: 2-year results of a phase 1 trial.

This study reported 2-year efficacy and safety of relma-cel in Chinese patients with relapsed/refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL). In this phase 1 dose-escalating trial, patients received lymphodepleting chemotherapy for 3 days, followed by relma-cel as a single infusion in escalating dose levels (25 × 106, 50 × 106, 100 × 106, and 150 × 106 CAR-T cells). The endpoints included best objective response rate (ORR), best complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. A total of 23 patients were enrolled, including 60.9% with diffuse large B-cell lymphoma and 26.1% with follicular lymphoma. Twenty patients were evaluable for efficacy, and the best ORR was 85.0% and the best CRR was 75.0%. With a median follow-up of 24.2 months, 6 patients died and 2 had progressive disease, the median DOR, PFS, and OS were all not reached. The 2-year PFS and OS rates were 60.0% and 70.0%, respectively. Any grade and grade ≥ 2 cytokine release syndrome occurred in 18.2% and 13.6% of patients, respectively. Only 1(4.5%) patient had grade 3 CRS lasting 13 days, which was resolved by tocilizumab. No grade ≥ 2 neurotoxicity events or treatment-related deaths occurred. Patients with R/R B-NHL treated with relma-cel achieved durable response with favorable safety profile.

miR-29b-3p suppresses the malignant biological behaviors of AML cells via inhibiting NF-κB and JAK/STAT signaling pathways by targeting HuR.

BACKGROUND: HuR/ELAVL1 (embryonic lethal abnormal vision 1) was a downstream target of miR-29b in some cancer cells. HuR protein exerts important prognostic effects of involving in the pathogenesis and development of acute myeloid leukemia (AML). This study aims to investigate the role of miR-29b-3p in biological behaviors of AML cells by targeting HuR and the involvement of the NF-κB and JAK/STAT signaling pathways. METHODS: The expressions of HuR and miR-29b-3p in AML cells were determined using RT-qPCR and Western blot, and the association between them was analyzed using the Spearman method. Next, the target relationship between HuR and miR-29b-3p was predicted by biological information databases and verified by the dual-luciferase reporter gene assay. MTS, methyl cellulose, flow cytometry and transwell assay were employed to detect the cell proliferation, clone formation, cell cycle and apoptosis, invasion and migration respectively, the effect of miR-29b-3p targeted HuR on the biological behaviors of AML cells was explored after over- /down-expression of miR-29b-3p and rescue experiment. Then, immunofluorescence assay and western blot were employed to detect location expression and phosphorylation levels of NF-κB and JAK/STAT signaling pathways related molecules respectively. RESULTS: HuR was negatively correlated with miR-29b-3p, and was the downstream target of miR-29b-3p in AML cells. When miR-29b-3p was overexpressed in AML cells, HuR was down-regulated, accompanied by cell viability decreased, cell cycle arrest, apoptosis increased, invasion and migration weakened. Moreover, the opposite result appeared after miR-29b-3p was down-regulated. The rescue experiment showed that miR-29b-3p inhibitor could reverse the biological effect of HuR down-regulation in AML cells. Molecular pathway results showed that miR-29b-3p could inhibit p65 expression in nucleus and phosphorylation levels of p65, IκBα, STAT1, STAT3 and STAT5. CONCLUSION: miR-29b-3p can inhibit malignant biological behaviors of AML cells via the inactivation of the NF-κB and JAK/STAT signaling pathways by targeting HuR. miR-29b-3p and its target HuR can be used as a new potential molecular for AML treatment.

Effects of Naltrexone on Expression of Lipid Metabolism-Related Proteins in Liver Steatosis Induced by Endoplasmic Reticulum Stress in Mice.

This study aimed to explore the effect of naltrexone on the expression of lipid metabolism-related proteins in liver steatosis induced by endoplasmic reticulum stress in mice. Thirty inbred mice (C57BL/6J) were divided into three groups: group A (normal control group), group B (model control), and group C (naltrexone group). The male mice in group A were fed a regular diet, and the mice in groups B and C were fed a high-fat diet. Liver steatosis was observed by histopathological sections. Mouse liver (alanine aminotransferase (ALT) and triglyceride (TC)) content (glucose regulatory protein (GRP78), endoplasmic reticulum transmembrane protein kinase-1α (IRE-1α), C/EBP source protein (CHOP), cysteine-containing aspartate proteolytic enzyme 12 (caspase-12), B lymphoma-2 (Bcl-2), and cell death mediator (Bim)) was detected. Compared with group A, bodyweight, fat weight, ALT, TG, and hepatic steatosis were significantly increased in B and C groups (P < 0.05); compared with group B, group C showed a significant decrease in bodyweight, fat weight, ALT, TG, and hepatic steatosis (P < 0.05). Compared with group A, the expression levels of GRP78, IRE-1α, CHOP, caspase-12, and Bim in liver tissue of groups B and C mice were increased. Bcl-2 decreased (P < 0.05). Compared with group B and group C after naltrexone intervention, the expression levels of GRP78, IRE-1α, CHOP, caspase-12, and Bim decreased significantly, and Bcl-2 increased significantly (P < 0.05). Naltrexone can effectively reduce bodyweight and adipose tissue accumulation, reduce liver fat lesions, improve the expression of lipid metabolism-related proteins and endoplasmic reticulum stress, reduce liver lipid synthesis, and protect liver cells.

Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury.

OBJECTIVES: Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. METHODS: eIF2α phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells. RESULTS: Carbon tetrachloride (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. CONCLUSIONS: eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.

Phosphorylation of eIF2α mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury.

INTRODUCTION AND OBJECTIVES: Necroptosis and endoplasmic reticulum (ER) stress has been implicated in acute and chronic liver injury. Activated eukaryotic initiation factor 2 alpha (eIF2α) attenuates protein synthesis and relieves the load of protein folding in the ER. In this study, we aimed to analyze the impact of eIF2α phosphorylation on hepatocyte necroptosis in acute liver injury. MATERIALS AND METHODS: Male BALB/c mice were injected with tunicamycin or d-galactosamine, and LO2 cells were incubated with tunicamycin to induce acute liver injury. 4-Phenylbutyric acid (PBA) and salubrinal were used to inhibit ER stress and eIF2α dephosphorylation, respectively. We analyzed the eIF2α phosphorylation, ER stress, and hepatocyte necroptosis in mice and cells model. RESULTS: Tunicamycin or d-galactosamine significantly induced ER stress and necroptosis, as well as eIF2α phosphorylation, in mice and LO2 cells (p<0.05). ER stress aggravated tunicamycin-induced hepatocyte necroptosis in mice and LO2 cells (p<0.05). Elevated eIF2α phosphorylation significantly mitigated hepatocyte ER stress (p<0.05) and hepatocyte necroptosis in mice (34.37±3.39% vs 22.53±2.18%; p<0.05) and LO2 cells (1±0.11 vs 0.33±0.05; p<0.05). Interestingly, tumor necrosis factor receptor (TNFR) 1 protein levels were not completely synchronized with necroptosis. TNFR1 expression was reduced in d-galactosamine-treated mice (p<0.05) and cells incubated with tunicamycin for 12 and 24h (p<0.05). ER stress partially restored TNFR1 expression and increased necroptosis in tunicamycin-incubated cells (p<0.05). CONCLUSIONS: These results imply that ER stress can mediate hepatocyte necroptosis independent of TNFR1 signaling and elevated eIF2α phosphorylation can mitigate ER stress during acute liver injury.

Inhibiting alpha subunit of eukaryotic initiation factor 2 dephosphorylation protects injured hepatocytes and reduces hepatocyte proliferation in acute liver injury.

AIM: To investigate the impact of alpha subunit of eukaryotic initiation factor 2 (eIF2α) phosphorylation on liver regeneration. METHODS: Male BALB/c mice were intraperitoneally injected with carbon tetrachloride (CCl4) to induce liver injury. Human hepatocyte LO2 cells were incubated with thapsigargin to induce endoplasmic reticulum (ER) stress. Salubrinal, integrated stress response inhibitor (ISRIB), and DnaJC3 overexpression were used to alter eIF2α phosphorylation levels. RESULTS: CCl4 administration induced significant ER stress and eIF2α phosphorylation, and increased hepatocyte proliferation proportionally to the extent of injury. Inhibiting eIF2α dephosphorylation with salubrinal pretreatment significantly mitigated liver injury and hepatocyte proliferation. In LO2 cells, thapsigargin induced significant eIF2α phosphorylation and inhibited proliferation. Inhibiting eIF2α dephosphorylation partly restored cell proliferation during ER stress. CONCLUSIONS: In acute liver injury, inhibiting eIF2α dephosphorylation protects injured hepatocytes and reduces hepatocyte proliferation.