A common feature of severe COVID-19 and two common metabolic comorbidities, type 2 diabetes mellitus (T2DM) and obesity, is a persistent inflammatory response. Heat shock proteins (HSPs) are key regulators of cell proteostasis under stressful conditions, including inflammation, oxidative stress, hyperglycemia, and hyperlipidemia. The aim of the present study was to investigate associations between polymorphic variants in genes encoding HSPs and T2DM or obesity among patients with severe or critical COVID-19.

A total of 195 patients with severe or critical COVID-19 were included, of whom 39 had T2DM and 101 had obesity. T2DM and obesity were analyzed as separate, non-mutually-exclusive outcomes. Genotyping was performed using a TaqMan probe-based real-time polymerase chain reaction assay to detect single nucleotide polymorphisms (SNPs). Bioinformatics resources, including GTExPortal, eQTLGen, atSNP, and Gene Ontology, were used for functional annotation. Associations between HSP genetic variants and T2DM or obesity were analyzed. This study was conducted as a case-control analysis within a severe COVID-19 cohort and is reported in accordance with the STROBE guidelines.

Among patients with severe or critical COVID-19, SNP rs1043618 HSPA1A (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.01–3.27, Pperm = 0.04), rs910652 HSPA12B (OR = 2.23, 95% CI = 1.18–4.21, Pperm = 0.01), and rs4926222 DNAJB1 (OR = 2.15, 95% CI = 1.08–4.27, Pperm = 0.03) were associated with higher odds of T2DM, whereas rs13161158 HSPA4 (OR = 0.11, 95% CI = 0.01–0.91, Pperm = 0.0075) and rs7189628 DNAJA2 (OR = 0.08, 95% CI = 0.01–0.65, Pperm = 0.001) were associated with lower odds of T2DM. In addition, SNP rs753856 HSPA6 (effect allele G) was associated with higher odds of obesity (OR = 2.11, 95% CI = 1.07–4.19, Pperm = 0.03).

Selected HSP SNPs are associated with T2DM or obesity among patients with severe or critical COVID-19. Functional annotation suggests plausible biological mechanisms, including cell proteostasis, inflammatory pathways, glucose metabolism, and adipogenic differentiation; however, independent and functional validation is required.

Epithelial-myoepithelial neoplasms of the breast are biphasic tumors composed of both epithelial and myoepithelial cell populations. Their rarity, broad morphologic spectrum, and evolving molecular characterization pose substantial diagnostic challenges, underscoring the need for an integrated review of their diagnostic and molecular features. This review aims to provide a comprehensive overview of epithelial-myoepithelial neoplasms of the breast, emphasizing their morphologic spectrum, diagnostic challenges, and emerging molecular features.

This narrative review is based on a review of the pertinent English-language literature and the author’s firsthand experience as a practicing breast pathologist.

Benign epithelial-myoepithelial tumors include pleomorphic adenoma and classic adenomyoepithelioma. Pleomorphic adenoma of the breast closely resembles its salivary gland counterpart as well as the benign mixed tumor of the skin. In contrast, adenomyoepithelioma is unique to the breast and exhibits a broad spectrum of histomorphologic patterns. Most adenomyoepitheliomas follow a benign clinical course; however, atypical adenomyoepitheliomas may demonstrate more aggressive behavior, including local recurrence, malignant transformation, and, rarely, metastasis. Molecular studies have identified PLAG1/HMGA2 rearrangements in a subset of pleomorphic adenomas and recurrent HRAS Q61 and PI3K-AKT pathway alterations in adenomyoepitheliomas. In malignant adenomyoepithelioma, the malignant component may arise from the ductal epithelial cells, the myoepithelial cells, or both.

The rarity of epithelial-myoepithelial tumors, together with their marked histologic heterogeneity, makes them diagnostically challenging and underscores the potential for diagnostic pitfalls.

Neurodevelopmental, psychiatric, and neurodegenerative disorders are traditionally studied as distinct disease categories, yet they show overlapping disturbances in systems that regulate neural function and resilience. This article proposes maladaptive brain-state locking (MBSL) as a lifespan framework for examining whether otherwise distinct disorders may converge, in some contexts, on impaired biological-state reversibility. MBSL is defined as a failure of adaptive state-transition or recovery dynamics in which a maladaptive state becomes insufficiently reversible and the nervous system loses its normal capacity to terminate, recalibrate, or transition away from that state. Locking is therefore distinguished from persistence alone: an abnormal state maintained solely by a continuing pathological driver does not, by itself, constitute MBSL. Candidate operational features include abnormal persistence, impaired transition toward an adaptive state, delayed or incomplete recovery after perturbation reduction or removal, and history-dependent loss of flexibility. Lifespan timing, regional context, disease stage, severity, duration, and resilience are proposed to modify phenotypic consequences rather than assign disorder classes exclusively to specific age periods. Existing evidence is compatible with components of the hypothesis, but direct demonstration of MBSL will require longitudinal or perturbational evidence of impaired recovery or state-transition dynamics. Major limitations include etiological and pathological heterogeneity, nonspecific biomarkers, unresolved causality, and challenges in operationalizing multiscale state dynamics. If validated, the framework could support research focused on measurable reversibility, longitudinal monitoring, and interventions designed to restore adaptive state regulation rather than symptom improvement alone.

The huge burden of type 1 diabetes mellitus (T1DM) has been a source of concern globally since the Industrial Revolution in the 18th–19th centuries. To this end, studies have shown that certain environmental changes that accompanied the Revolution may have increased the risk and burden of the disease in genetically predisposed individuals. However, documented studies that synthesize these environmental triggers are scarce. As a result, the current study was conceived to synthesize the environmental triggers of T1DM to boost public awareness. Relevant information was retrieved from reputable academic databases; namely, Scopus, PubMed, SpringerLink, and Embase. The results showed that chemical exposure, viral infection, gut microbiome disruption, vitamin and mineral deficiencies, inadequate or exclusive breastfeeding, as well as early exposure to infant feeding formulas could increase the risk and burden of T1DM in genetically predisposed individuals. As a consequence, these triggers could compromise the expression of certain genes involved in insulin synthesis and immune function, such as the human leukocyte antigen (HLA), insulin (INS), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes. This would result in a dysfunctional immune system in which immune cells, such as T-cells and B-cells and molecules, such as cytokines would attack self-tissues, thus causing autoimmunity of the pancreatic beta cells. Environmental triggers could also induce the T1DM pathophysiology by modifying the epigenome of the mentioned genes. Furthermore, some epigenetic changes could be reversed, which would infer that treatment procedures that would include the pathophysiology of the environmental triggers could be more effective.

Emerging evidence suggests that RNA-binding motif (RBM) proteins are involved in hepatocarcinogenesis and act either as oncogenes or tumor suppressors. The objective of this study was to investigate the role of RBM34, an RBM protein, in hepatocellular carcinoma (HCC).

We first examined the expression of RBM34 across cancers. The correlation of RBM34 with clinicopathological features and the prognostic value of RBM34 for HCC was then investigated. Functional enrichment analysis of RBM34-related differentially expressed genes (DEGs) was performed to explore its biological function. RNA sequencing (RNA-seq) was applied to identify downstream genes and pathways affected upon RBM34 knockout. The correlation of RBM34 with immune characteristics was also analyzed. The oncogenic function of RBM34 was examined in in vitro and in vivo experiments.

RBM34 was highly expressed in hepatocellular carcinoma and correlated with poor clinicopathological features and prognosis. RBM34 was positively associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. A positive correlation was also observed between RBM34, T cell exhaustion, and regulatory T cell marker genes. Knockout of RBM34 significantly inhibited cell proliferation, migration, and xenograft tumor growth, and sensitized HCC cells to sorafenib treatment. RBM34 inhibition reduced FGFR2 expression and affected PI3K-AKT pathway activation in HCC cells.

Our study suggests that RBM34 may serve as a new prognostic marker and therapeutic target of HCC.

Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.

The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.

Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl4)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the in vivo results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.

Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.