Book学术

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally with high mortality rates, highlighting the urgent need for novel therapeutic strategies. We investigated the efficacy of combining phosphoinositide 3-kinase gamma (PI3Kγ) inhibition with programmed death-ligand 1 (PD-L1) blockade in a poorly immunogenic HNSCC model.

Materials and methods: Mouse bone marrow-derived macrophages (BMDMs) were differentiated and polarized in the presence or absence of the PI3Kγ inhibitor IPI-549 or culture supernatants from MOC2 cells treated with or without IPI-549. MOC2 cells were orthotopically injected into C57BL/6 mice, and treated with anti-PD-L1, IPI-549, combined anti-PD-L1 and IPI-549 or vehicle control. Tumor burden, survival, and immunological responses were evaluated.

Results and conclusion: Dual inhibition of PI3Kγ (using IPI-549) and PD-L1 demonstrated nearly significant reduction in primary tumor burden and significantly increased survival compared to single or control treatments. PI3Kγ inhibition promoted macrophage differentiation toward an antitumoral M1 phenotype. In the bone marrow, dual therapy significantly increased MHC-II expression across various myeloid cell subsets and effectively normalized myelopoiesis. Notably, combination therapy increased CD8+ T-cell infiltration into tumors while decreasing T-cell exhaustion marker (LAG-3, CTLA-4, and TIM-3) and protumoral cytokine (IL-4). Combined PI3Kγ and PD-L1 inhibition offers a promising strategy for treating poorly immunogenic HNSCC by simultaneously targeting multiple immunosuppressive mechanisms. These findings provide a strong rationale for combining PI3Kγ and PD-L1 inhibitors as a therapeutic strategy for poorly immunogenic HNSCC, potentially improving clinical outcomes for patients.

Global populations are rapidly aging, posing significant challenges. Yet, ageism among clinicians and medical students persists, undermining empathy and care quality. Traditional short-term educational efforts have limited effect; sustained, relationship-based programs hold promise but remain understudied. To address this, we implemented a year-long service-learning project, where first-year medical students visit elderly individuals at their homes to engage in light physical activities and discuss life challenges. This qualitative study examines the project's impact on first, second, and third-year medical students.From August to October 2020, we recruited, via convenience sampling, first-year medical students of three consecutive cohorts (n = 313) that completed ten home visits with older adults; of these sixty (19%) students participated in focus groups/interviews and 128 (41%) submitted reflective assignments. Data was manually analyzed using Braun and Clarke's six-phase reflexive thematic approach until saturation. We adhered to the COREQ (Consolidated Criteria for Reporting Qualitative Research) checklist.Three major themes and seven sub-themes emerged. First, building trusting patient-physician relationships, characterized by empathy, trust, and effective communication, alongside a balance between physician responsibility and patient autonomy. Second, embracing uncertainty and holistic care, which involved navigating medical ambiguity and integrating psychosocial dimensions into clinical reasoning. Third, reflecting on vulnerability, aging, and mortality, encompassing the emotional impact of disability and decline; reframing aging positively; and processing experiences of death and loss. Participants described profound shifts in their perspectives on aging, care relationships, and their professional identities; changes that persisted throughout their pre-clinical training. To conclude, early and sustained engagement with older adults in their home environment through a structured service-learning project enhanced medical students' professional development, empathy, and attitudes toward aging. Incorporating similar programs into medical education curricula may provide substantial pedagogical benefits. Future research should assess long-term impacts on career choices and care quality.

Endogenous or adoptively transferred tumor-infiltrating lymphocytes (TILs) often lose their functional capacity due to the activation of intrinsic inhibitory pathways, which then limits their ability to control tumor growth. In this study, we examined the effects of blocking a key intracellular inhibitory enzyme, diacylglycerol kinase (DGK) in human T cells, using a novel inhibitor (DGKi) called INCB165451 that blocks both DGKα and DGKζ, the two primary DGK isoenzymes that negatively regulate T cells through the diacylglycerol (DAG) signaling pathway. We first evaluated the effects of the DGKi in enhancing the efficacy of adoptive human T cell transfer in a non-small cell lung cancer (NSCLC) mouse model and found that the DGKi significantly potentiated anti-tumor efficacy through multiple mechanisms, including increased intratumoral T cell infiltration, upregulation of genes associated with inflammatory responses, and reduction of TIL hypofunction, as evidenced by enhanced cytokine production following ex vivo anti-CD3 antibody stimulation. We next studied the effects of the DGKi on human TILs derived from tumor digests or studied in situ in precision-cut tumor slices of both head and neck cancer and NSCLC patient samples. After stimulation of the TILs with anti-CD3 antibodies, we found that the DGKi enhanced gene and protein expression of proinflammatory cytokines and chemokines. Finally, we demonstrated that the DGKi could augment T cell activation in human tumor slices that were stimulated by an anti-EGFR/anti-CD3 bispecific T cell engager (BiTE). These data demonstrate strong activity of the DGKi in human TILs and highlight promising potential avenues for clinical translation.

Regular exercise training can significantly improve the gut environment and influence the metabolic activity of the gut microbiota. These changes promote the production of beneficial metabolites, which may modulate blood pressure regulation through multiple mechanisms. The beneficial microbial species including Faecalibacterium prausnitzii, Bifidobacterium spp., Lactobacillus spp., Roseburia spp.,and Bacteroides spp. These beneficial microbes produce various metabolites during metabolism, including short-chain fatty acids, vitamins, lactic acid, bileacids, and gamma-aminobutyric acid. These metabolites are not only essential for maintaining gut health but also positively influence hypertension by modulating the nervous system, immune system, and improving metabolic function. This review aims to elucidate the complex interactions among exercise training, gut microbiota, and hypertension.

Objective: To introduce bilateral hypertensive retinopathy (HR) (grade 4) complicated with macular edema (ME) patients with binocular intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) treatment.

Methods: Three cases of hypertensive retinopathy were observed. The fundus examination was consistent with HR (grade 4). The patients received anti-VEGF intraocular injection.

Results: The patient's ME and optic nerve edema were significantly reduced, visual acuity was significantly improved, and a case of secondary choroidal neovascularization (CNV) in the fundus of HR (grade 4) was also noted.

Conclusions: The use of intravitreal anti-VEGF agents in stage IV hypertensive retinopathy appears satisfactory but not perfect. In severe cases with vitreous hemorrhage, early injection avoids vitrectomy.

Objective: Mitochondria are central to energy production and cellular homeostasis. Beyond importing diverse RNAs, they also encode hundreds of their own non-coding RNAs, contributing to a complex and dynamic RNA landscape. Early-life nutritional insults, such as fetal and postnatal protein deficiency, can impair mitochondrial function and increase the long-term diabetes risk. However, the mitochondrial non-coding transcriptome of pancreatic islets, particularly its responsiveness to nutritional cues, remains largely unexplored.

Methods: We performed RNA sequencing to profile small non-coding RNAs in mitochondrial fractions of islet cells from offspring of rats exposed to low-protein (LP) or control diets during gestation and lactation and employed mRNA-miRNA network analysis to explore the potential regulatory roles of differentially expressed mitomiRs in LP-exposed pups.

Results: Protein deficiency during gestation and lactation led to a profound remodeling of the small non-coding RNA landscape in whole islets, with microRNAs and piRNAs showing the most pronounced changes. In mitochondrial fractions, LP exposure resulted in a striking shift in microRNA composition, with 33 mitomiRs detected in control islets versus 23 in LP-exposed rats, and only 5 shared between groups. Notably, ten mitomiRs were selectively depleted from the cytosol and enriched in mitochondria of LP-exposed islets. Amongst these, miR-10a-5p and miR-126a-5p, are predicted to target genes involved in mitochondrial metabolism and structural organization.

Conclusion: Early-life protein restriction triggers a highly selective reorganization of the mitomiR landscape in pancreatic islets. The identified mitomiRs may serve as regulators of mitochondrial function and intracellular signaling, potentially influencing β-cell metabolic coupling and contributing to diabetes susceptibility.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease in the United States, yet therapeutic options remain limited. Emerging evidence implicates the gut‒liver axis and intestinal permeability in disease pathogenesis. Previous studies in animal models and human cell culture indicated that bile salt hydrolases (BSHs), which are gut bacterial enzymes that deconjugate host-derived bile acids, damage intestinal barrier integrity and cause liver damage through the generation of unconjugated bile acids (UBAs). However, the relevance of these findings to MASLD patients is unknown. Here, we demonstrate that BSH activity is elevated in fecal samples from MASLD patients with advanced liver fibrosis and correlates with reduced fecal bile acid levels, which is consistent with a proposed model of increased intestinal permeability during MASLD progression. Through anaerobic culturing and activity-guided screening, we identify diverse BSH-active bacteria from patient fecal samples, suggesting broad microbial contributions to bile acid deconjugation in MASLD patients. Importantly, small-molecule BSH inhibitors suppressed BSH activity in both fecal communities and monocultures from MASLD patients without affecting bacterial viability. These findings indicate that BSH activity is a microbial function associated with MASLD progression and suggest that BSH inhibitors could be developed as a microbiome-targeted strategy for MASLD treatment.

The recurrence following the discontinuation of medication is a formidable challenge in managing psoriasis. Changes in the microbiome accompany the onset of psoriasis relapse, highlighting a potential therapeutic modality. To evaluate the superiority of the topical administration of aptamer-functionalized curcumin mesoporous silica (Apt-GA+Cur@μmS) plus blue light (BL) in restoring dysbiosis and intervening in recurrence in a murine model, a psoriasis relapse murine model with double imiquimod induction was established. With a BL-responsive shell, Apt-GA+Cur@μmS released curcumin (Cur) to assist BL to improve the preventative and therapeutic effects in the psoriasis relapse murine model, as evidenced by the psoriasis area and severity index, histology, splenic index, and dorsal IL-17A level. We also observed a negative correlation between splenic nitric oxide (NO) levels and the splenic index, indicating a possible mechanism by which Apt-GA+Cur@μmS&BL may function in the treatment of splenomegaly. Treatment with Apt-GA+Cur@μmS&BL exhibited a higher alpha diversity than the model group, with levels similar to those of healthy mice, indicating that this combination could adjust the composition of the dorsal microbiome to a healthier state. A reduction in the combined relative abundance of Staphylococcus, Streptococcus, and Corynebacterium as well as restoration of dysbiosis was also verified through 16S rDNA gene sequencing in vivo. Collectively, BL and Apt-GA+Cur@μmS cotherapy alleviates psoriasiform lesions in a double imiquimod-induced murine model by inhibiting IL-17A and increasing splenic NO. Additionally, this cotherapy restores the eubiosis of the dorsal lesions. Thus, it is a promising and innovative therapeutic modality for psoriasis inflammation alleviation and recurrence intervention.

The pathogenesis of autoimmune thyroiditis (AIT) is intricately linked to immune dysregulation, endocrine imbalance, and gut microbiota dysbiosis. The immune system drives autoimmune attacks against thyroid tissue through Th1/Th2 cell imbalance, Treg dysfunction, and excessive release of proinflammatory cytokines. Thyroid hormone regulation primarily occurs via the hypothalamic-pituitary-thyroid (HPT) axis. Elevated levels of TPOAb and TgAb in AIT patients can lead to hypothyroidism by affecting the HPT feedback loop. Thyroid hormone regulation of immune cell metabolism and differentiation, in turn, affects immune homeostasis, forming a bidirectional regulatory network. Recent studies further reveal that the gut microbiota influences systemic immune tolerance by regulating intestinal barrier integrity and metabolites (e.g. short-chain fatty acids and secondary bile acids). Abnormal abundance of specific genera (e.g. Bacteroides and Prevotella) can promote the production of thyroid autoantibodies (TPOAb/TgAb), and increased intestinal permeability caused by microbiota dysbiosis may facilitate cross-reactivity between microbial antigens and thyroid antigens. Furthermore, the gut microbiota indirectly regulates thyroid function through the HPT axis. This review aims to summarize the current knowledge regarding the specific molecular mechanisms of gut microbiota-immune-endocrine interactions in AIT, offer important references for researching the treatment directions of AIT.