Inhibition of PCSK9 enhances the anti-hepatocellular carcinoma effects of TCR-T cells and anti-PD-1 immunotherapy.

T cells play important roles in antitumor immunity. However, given that the hepatocellular carcinoma (HCC) tumor microenvironment confers resistance to T cell-based immunotherapies, novel strategies to boost T cell-mediated antitumor efficacy are urgently needed for the treatment of HCC. Here, we show that high proprotein convertase subtilisin/kexin type9 (PCSK9) expression was negatively associated with HCC patient's overall survival and markers of CD8+ T cells. Pharmacological inhibition of PCSK9 enhanced tumor-specific killing and downregulated PD-1 expression of AFP-specific TCR-T. Inhibition of PCSK9 significantly enhances the anti-HCC efficacy of TCR-T cells and anti-PD-1 immunotherapy in vivo. Moreover, PCSK9 inhibitor suppressed HCC growth dependent on CD8+ T cells. Mechanically, pharmacological inhibition of PCSK9 promoted low-density lipoprotein receptor (LDLR)-mediated activation of mTORC1 signaling in CD8+ T cells. LDLR deficiency was shown to impair cellular mTORC1 signaling and the anti-HCC function of CD8 T cells. On the basis of our findings in this study, we propose a potential metabolic intervention strategy that could be used to enhance the antitumor effects of immunotherapy for HCC.

The nonlinear relationship between triglyceride glucose-waist circumference and stroke risk in middle-aged and elderly people: a nationwide prospective cohort study of the CHARLS.

BACKGROUND AND AIMS: Numerous research have focused on the relationship of metabolic markers and stroke risk, yet limited research has focused on the triglyceride glucose-waist circumference (TyG-WC) index. This study explored the possible association of TyG-WC and stroke among moderately aged and old Chinese adults over 45 years of age. METHODS: This observational cohort analysis involved 9054 participants from the Chinese Longitudinal Study of Health and Retirement and employed a standardized questionnaire administered via in-person interviews. Cox proportional hazard model, smoothed curve fitting, and threshold effect analysis were conducted for examining the potential nonlinear relationships among TyG-WC and stroke risk. RESULTS: Within an average follow-up period of six years, 463 new strokes occurred, representing 5.11% of the total number of patients. After adjusting for possible confounding factors, a nonlinear association between TyG-WC and stroke risk was identified, with a significant dose-response relationship (P = 0.023 for the log-likelihood ratio test). A turning point was identified at the TyG-WC level of 554.48, beyond that the likelihood of stroke increased markedly (HR = 1.323, 95% CI = 1.098-1.594, P = 0.003). CONCLUSION: This study revealed a specific curvilinear association with the TyG-WC score and stroke risk, identifying a key threshold value. This study focused on Chinese middle-aged and senior adults over the age of 45, emphasizing that increased stroke risk is linked to higher TyG-WC levels.

Inflammation unleashed: The role of pyroptosis in chronic liver diseases.

Pyroptosis, a newly identified form of programmed cell death intertwined with inflammatory responses, is facilitated by the Gasdermin family's pore-forming activity, leading to cell lysis and the release of pro-inflammatory cytokines. This process is a double-edged sword in innate immunity, offering protection against pathogens while risking excessive inflammation and tissue damage when dysregulated. Specifically, pyroptosis operates through two distinct signaling pathways, namely the Caspase-1 pathway and the Caspase-4/5/11 pathway. In the context of chronic liver diseases like fibrosis and cirrhosis, inflammation emerges as a central contributing factor to their pathogenesis. The identification of inflammation is characterized by the activation of innate immune cells and the secretion of pro-inflammatory cytokines such as IL-1α, IL-1ß, and TNF-α. This review explores the interrelationship between pyroptosis and the inflammasome, a protein complex located in liver cells that recognizes danger signals and initiates Caspase-1 activation, resulting in the secretion of IL-1ß and IL-18. The article delves into the influence of the inflammasome and pyroptosis on various liver disorders, with a specific focus on their molecular and pathophysiological mechanisms. Additionally, the potential therapeutic implications of targeting pyroptosis for liver diseases are highlighted for future consideration.

An Unusual Cause of Intestinal Ulcers Masquerading as Inflammatory Bowel Disease: A Case Report of Allied Disorders of Hirschsprung's Disease.

Background: Allied disorders of Hirschsprung's disease (ADHD) exhibit symptoms akin to those of Hirschsprung's disease, primarily characterized by intestinal obstruction, bowel dilatation, and chronic constipation. The occurrence of amyloid complications in patients with ADHD is infrequent. In this report, we present a case of ADHD with intestinal ulcers as the initial gastrointestinal manifestation, and subsequent pathological examination revealed the presence of amyloid deposits in the colonic mucosa. Case Report: A male patient, aged 20, exhibited recurring abdominal distension and intestinal obstruction for a duration of three years. Multiple colonoscopies revealed the presence of recurrent colonic ulcers, with pathological examination indicating the existence of amyloid deposits within the mucosal layer of the colon. Abdominal CT scans suggested colonic dilatation. Following a multidisciplinary consultation, a subtotal resection of the colon was performed, and subsequent postoperative pathology confirmed a decrease and absence of myenteric plexus ganglion cells. Considering the patient's symptoms and the findings from the postoperative pathology, a diagnosis of ADHD was made. The patient's symptoms resolved postoperatively and he was discharged from the hospital and followed up for 1 year in stable condition. Conclusion: Our study highlights the potential association between ADHD and the initial presentation of recurrent colonic ulcers, accompanied by amyloid deposition in the intestinal mucosa. This finding suggests a possible pathogenic mechanism for ADHD and offers a novel perspective on its diagnosis.

Unraveling the Molecular Regulation of Ferroptosis in Respiratory Diseases.

Ferroptosis, a type of programmed cell death that relies on iron, is distinct in terms of its morphological, biochemical and genetic features. Unlike other forms of cell death, such as autophagy, apoptosis, necrosis, and pyroptosis, ferroptosis is primarily caused by lipid peroxidation. Cells that die due to iron can potentially trigger an immune response which intensifies inflammation and causes severe inflammatory reactions that eventually lead to multiple organ failure. In recent years, ferroptosis has been identified in an increasing number of medical fields, including neurological pathologies, chronic liver diseases and sepsis. Ferroptosis has the potential to cause an inflammatory tempest, with many of the catalysts and pathological indications of respiratory ailments being linked to inflammatory reactions. The growing investigation into ferroptosis in respiratory disorders has also garnered significant interest to better understand the mechanism of ferroptosis in these diseases. In this review, the recent progress in understanding the molecular control of ferroptosis and its mechanism in different respiratory disorders is examined. In addition, this review discusses current challenges and prospects for understanding the link between respiratory diseases and ferroptosis.

Mesenchymal Stem Cell-Derived Exosomes in Various Chronic Liver Diseases: Hype or Hope?

Chronic liver conditions are associated with high mortality rates and have a large adverse effect on human well-being as well as a significant financial burden. Currently, the only effective treatment available for the effects of liver failure and cirrhosis resulting from the progression of several chronic liver diseases is liver transplantation carried out at the original location. This implies that developing novel and effective treatments is imperative. Regenerative medicine has long been associated with stem cell therapy. Mesenchymal stem cells (MSCs), a type of cell with great differentiation potential, have become the preferred source for stem cell therapy. According to recent studies, MSCs' paracrine products-rather than their capacity for differentiation-play a significant therapeutic effect. MSC exosomes, a type of extracellular vesicle (MSC-EV), came into view as the paracrine substances of MSCs. According to research, MSC exosomes can maintain tissue homeostasis, which is necessary for healthy tissue function. All tissues contain them, and they take part in a variety of biological activities that support cellular activity and tissue regeneration in order to preserve tissue homeostasis. The outcomes support the use of MSCs and the exosomes they produce as a therapeutic option for a range of diseases. This review provides a brief overview of the source of MSC-EVs and outlines their physiological roles and biochemical capabilities. The elucidation of the role of MSC-EVs in the recovery and repair of hepatic tissues, as well as their contribution to maintaining tissue homeostasis, is discussed in relation to different chronic liver diseases. This review aims to provide new insights into the unique roles that MSC-EVs play in the treatment of chronic liver diseases.

The Clinical Characteristics and Prognosis of Chinese Patients with Light-Chain Amyloidosis: A Retrospective Multicenter Analysis.

To retrospectively identify the critical characteristics and prognostic factors of light-chain amyloidosis. PATIENTS AND METHODS: Data were collected and compared from 91 patients who were diagnosed with light-chain amyloidosis at four hospitals between January 2010 and November 2018. We analyzed the clinical characteristics and performed an overall survival (OS) analysis. RESULTS: Patients (median age, 60 years) were diagnosed with organ involvement of the kidney (91.2%), heart (56%), liver (14.3%), soft tissue (18.7%), or gastrointestinal tract (15.4%), and 68.1% of patients had more than two organs involved. Patients were most treated with bortezomib-based regimens (56%), and only one patient had autologous stem cell transplantation (auto-ASCT). The median OS was 36.33 months and was influenced by the ECOG score, renal involvement, cardiac involvement, hepatic involvement, and persistence of positive immunofixation. Patients who received bortezomib-based treatment had a trend of favorable OS compared to those who received non-bortezomib-based treatments, but the difference was not statistically significant. Although the overall number of organs involved was not related to OS, the number of organs involved in the heart, liver and kidney was related. Multivariate analysis indicated that cardiac involvement and negative hematologic response with persistence of positive immunofixation were independent prognostic factors for OS. CONCLUSION: Cardiac involvement and the hematologic response to treatment were independent prognostic factors for OS in light-chain amyloidosis patients.

Mesenteric phlebosclerosis with amyloidosis in association with the long-term use of medicinal liquor: A case report.

BACKGROUND: Mesenteric phlebosclerosis (MP) is a rare disease of the colon. The clinical manifestations of this disease are nonspecific and it may easily be misdiagnosed. We report a case of MP with amyloidosis in the colonic vessel walls in a patient with hypertension who had been consuming Chinese medicinal liquor for 10 years. We also review the relevant literature and summarize the characteristics of MP in patients in mainland China. CASE SUMMARY: A 64-year-old man was referred to our department from his primary hospital because of abdominal pain, diarrhea, and fever for almost 10 d. Computed tomography showed colon wall thickening, with threadlike calcifications in the mesenteric vein in the transverse colon. Colonoscopy revealed purple-blue mucosa with multiple ulcers in the ascending and transverse colon. Biopsy showed thickening and calcification of the vein walls, perivascular and mucosal collagen degeneration, and amyloidosis. The patient had been consuming Chinese medicinal liquor, mainly that made from gardenia fruit, for 10 years. Based on these results, a diagnosis of MP with amyloidosis was made. After conservative treatment, the patient's discomfort subsided and he was followed closely. The use of Chinese herbal medicine was suspected to play a role in the pathogenesis of MP. CONCLUSION: The clinical manifestations of MP are nonspecific. Recognition of its typical imaging findings, including multiple calcifications on computed tomography and purple-blue mucosal discoloration on colonoscopy, is vital.