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 prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) continues to increase worldwide, partly because of rising rates of obesity and metabolic syndrome. However, a substantial proportion of patients with MAFLD are neither overweight nor obese and are classified as having lean MAFLD. The increasingly recognized phenotype of lean MAFLD challenges the traditional paradigm linking obesity to metabolic risk. Despite a normal body mass index (BMI), lean MAFLD is associated with substantial metabolic dysfunction and a range of extrahepatic manifestations. Evidence from systematic reviews and meta-analyses including more than 10 million individuals indicates that patients with lean MAFLD have metabolic profiles comparable to those of overweight or obese patients with MAFLD, including insulin resistance, dyslipidemia, and hypertension. Importantly, although cardiovascular and cancer-related mortality appear broadly similar across BMI categories, liver-related mortality is consistently higher in lean individuals, suggesting distinct hepatocentric vulnerability. Variation in all-cause mortality estimates is influenced by disease severity, study design, and ethnicity. Important mechanistic factors include genetic susceptibility, sarcopenia, and visceral adiposity. These findings support comprehensive metabolic and hepatic assessment in lean MAFLD beyond BMI-based risk classification. This review examines lean MAFLD as a hepatocentric phenotype with systemic effects beyond BMI.

Hepatocellular carcinoma (HCC) exhibits profound metabolic reprogramming, with enhanced aerobic glycolysis and excess lactate production as defining features. Lactate, once regarded simply as a metabolic byproduct, is now recognized as a powerful epigenetic driver through lysine lactylation, while tumor cells co-opt autophagy to endure metabolic stress. Although traditionally investigated as separate hallmarks of cancer, growing evidence points to their functional intersection. Here, we propose the concept of a coordinated “lactylation-autophagy axis” and clarify its role in remodeling the tumor immune microenvironment. Within this integrated metabolic-epigenetic-proteostatic network, lactate-induced histone lactylation, such as H3K18la, exerts transcriptional control over tumor-associated macrophages, shifting them toward an immunosuppressive M2-like state. Excess extracellular lactate and robust autophagic adaptation cooperate to impair the effector functions of CD8+ T cells and natural killer cells, while providing regulatory T cells with metabolic advantages. We further explore the bidirectional crosstalk within this axis: lactate modulates autophagic flux, potentially through mTOR signaling and non-histone lactylation of autophagy-related proteins (e.g., VPS34, TFEB), whereas autophagy in turn regulates intracellular metabolite pools and lactylation substrates. Notably, several nodes, particularly non-histone lactylation of VPS34, TFEB, and mTOR (K921), have been demonstrated mainly in non-HCC systems; we therefore grade each mechanism as confirmed in HCC, extrapolated from other systems, or hypothetical. This proposed self-reinforcing axis may sustain tumor plasticity, contribute to immune evasion and immunotherapy resistance, and we discuss rational combinatorial strategies—combined targeting of lactate metabolism, lactylation machinery, and autophagic pathways—to sensitize advanced HCC to immune checkpoint blockade.

Metabolic dysfunction–associated steatotic liver disease (MASLD) and alcohol–associated liver disease (ALD) are leading causes of chronic liver injury with overlapping clinical and histological presentations. This study evaluated a composite histologic pattern, termed the Alcohol Liver Pathology Signature (ALPS), for potential use in the differential diagnosis of ALD and MASLD and to explore potential clinical and demographic correlates.

In this retrospective diagnostic-accuracy study, we reviewed 292 liver biopsies performed between 2021 and 2023. ALPS comprised five histologic features: ductular reaction, bile stasis, neutrophilic satellitosis, portal inflammation, and advanced fibrosis (stage 3–4). Cases were categorized as absent (0–1 features), partial (2–3 features), or full (4–5 features). ALPS performance was then further evaluated in an independent temporal validation cohort of de-identified, mixed, and blindly reviewed liver biopsies collected between 2024 and 2025.

MASLD was the most common diagnosis (25.3%), whereas ALD accounted for 4.8%. Full ALPS was present in 92.8% of clinically diagnosed ALD cases. In MASLD, individual ALPS features were common, but only 20.3% showed full ALPS, corresponding to 79.7% specificity for distinguishing clinically diagnosed ALD from MASLD. The independent temporal validation cohort showed findings consistent with those of the original cohort. Finally, within MASLD, full ALPS was more frequent in African American than non-African American patients (29.2% vs. 3.8%).

ALPS may serve as a histologic prompt for further assessment of potential alcohol exposure but should not be considered etiologically specific. Prospective validation incorporating objective measures of alcohol exposure is warranted.

Hepatic stellate cell (HSC) activation has traditionally been described as a binary transition from vitamin A-rich quiescent cells to alpha-smooth muscle actin-positive, collagen-producing myofibroblast-like cells. Advances in single-cell RNA sequencing, single-nucleus RNA sequencing, spatial transcriptomics, and chromatin-accessibility profiling now reveal a more complex and dynamic landscape. During chronic liver injury, HSCs can adopt five overlapping activation-associated states characterized by injury sensing, inflammatory signaling, proliferation, extracellular matrix production and contractility, together with a senescent state that represents a possible fate of activated HSCs. These states differ in their molecular markers, spatial distribution, regulatory pathways, and interactions with hepatocytes, liver sinusoidal endothelial cells, macrophages, natural killer cells, and cholangiocytes. Importantly, they are not fixed lineages and may coexist or interconvert during fibrosis progression and regression. This review revisits the classical quiescent-activated framework and proposes a state-based approach for interpreting HSC heterogeneity. We summarize the defining features and translational relevance of six major HSC functional states, discuss their multicellular niches, and highlight the opportunities and limitations of function-selective therapeutic targeting. A reproducible classification that integrates molecular identity, spatial context, and causal function may help refine antifibrotic treatment strategies.

Rising resistance in Helicobacter pylori to metronidazole, clarithromycin, and fluoroquinolones has significantly reduced eradication efficacy. This narrative review explores evidence-based strategies that minimize the impact of antibiotic resistance. Current practical approaches include empirical therapy (EMT), in which regimens are selected without individual susceptibility testing based on local or regional resistance patterns, previous antibiotic exposure, guideline recommendations, and expected effectiveness, and susceptibility-guided therapy (SGT), which avoids antibiotics to which the infecting strain is resistant. EMT does not simply exclude every antibiotic with a high resistance prevalence because regimen-level efficacy may remain high despite resistance to one component. When susceptibility testing is unavailable, optimized 14-day bismuth quadruple therapy is a guideline-preferred empirical regimen and can remain effective despite metronidazole resistance with adequate dosing and treatment duration. Rifabutin-based triple therapy provides an additional empirical or rescue option for selected patients without penicillin allergy. SGT is not universally superior to well-selected EMT, but may improve eradication rates in selected populations, particularly in settings with high clarithromycin resistance or where rapid molecular testing is available. However, susceptibility testing may be time-consuming, costly, and limited to only a few antibiotics. Emerging approaches include potassium-competitive acid blockers (PCABs), antimicrobial stewardship, probiotics, N-acetylcysteine, nanomaterial-based drug delivery, and vaccination. Among these, vonoprazan-based regimens are the most clinically mature. Vonoprazan-amoxicillin dual therapy can reduce exposure to resistance-prone antibiotics, although its use should reflect regional effectiveness, availability, and cost. Other non-antibiotic approaches remain investigational. In conclusion, management should move from undifferentiated empirical regimen selection toward risk-stratified precision treatment. Locally validated EMT remains appropriate when susceptibility testing is unavailable, whereas SGT should be prioritized after treatment failure or in patients at high risk of resistance. Rifabutin-based and vonoprazan-amoxicillin therapies provide additional options according to treatment history, penicillin allergy, regional evidence, and accessibility.