The aberrant activation of the mTOR pathway and its crosstalk with other signaling cascades represent key drivers of hepatocellular carcinoma (HCC) progression. mTOR-mediated ferroptosis suppression has been implicated in HCC resistance to chemotherapy. This study aimed to elucidate the mechanisms underlying mTOR inhibitor resistance and to evaluate the therapeutic potential of multidrug combinations in β-catenin-mutant HCC.

MHCC97H and SNU449 cells were transfected with 4EBP1WT, 4EBP1A4, or HSP90β expression plasmids and then treated with rapamycin to assess their effects on ferroptosis and rapamycin sensitivity. The role of 4EBP1 in regulating ferroptosis was further explored by Western blotting, co-immunoprecipitation, and immunofluorescence. The inhibitory effects of mTOR inhibitors (rapamycin, MLN0128), ERK inhibitors (PD901), and their combination (MLN0128 + PD901) on tumor cells were evaluated. HCC mouse models were generated via hydrodynamic tail vein injection of c-Met/β-cateninΔN90 or c-Met/β-cateninΔN90/4EBP1A4 plasmids to evaluate the therapeutic effects of the four treatment regimens.

Rapamycin more potently inhibited mTOR/RPS6 than mTOR/4EBP1 and concurrently induced ferroptosis. 4EBP1A4 promoted ferroptosis and potentiated rapamycin efficacy. Mechanistically, 4EBP1A4 competitively bound HSP90β, displacing Keap1, thereby increasing Keap1–Nrf2 complex formation and promoting Nrf2 degradation. Furthermore, rapamycin, MLN0128, PD901, and their combination reduced p-4EBP1 levels, induced ferroptosis, and inhibited HCC cell proliferation, thereby suppressing tumor growth, with the combination exhibiting the strongest effect.

4EBP1A4 enhances Nrf2 ubiquitination and degradation via the HSP90β/Keap1 axis, relieving mTOR-mediated ferroptosis suppression and synergistically improving rapamycin efficacy. Additionally, rapamycin, MLN0128, and PD901 suppress HCC progression by inducing ferroptosis, with their combination showing superior potency.

Chronic pelvic pain remains a significant clinical challenge, often refractory to conservative and interventional treatments. Superior hypogastric plexus block is an established technique; however, conventional anterior and posterior approaches may be limited by anatomical variability and potential risks to adjacent structures. Based on these anatomical findings, we propose that a posterior transosseous S1 pedicular approach represents a novel and anatomically robust corridor for accessing the superior hypogastric plexus. We hypothesize that the highly reproducible osseous anatomy of the S1 pedicle, combined with its consistent spatial relationship to the anterior sacral cortex and retroperitoneal compartment, may enable precise and fluoroscopically reproducible instrument guidance toward the plexus. Furthermore, this trajectory may mitigate the anatomical variability and procedural limitations associated with conventional anterior or paravertebral techniques while potentially reducing the risk of inadvertent injury to adjacent visceral, vascular, and neural structures. This concept is based on anatomical reasoning and fluoroscopic observations obtained during cadaveric anatomical orientation, suggesting that a transosseous trajectory through the S1 pedicle toward the anterior sacral cortex may offer improved spatial control and reproducibility compared with soft-tissue-based approaches. The proposed pathway remains conceptual and is not intended for clinical application at this stage. Further cadaveric, imaging-based, and clinical studies are required to evaluate its anatomical validity, safety, and potential clinical relevance.

Due to the lack of specific Western medicine therapies for post-coronavirus disease 2019 (COVID-19) syndrome in clinical practice, this study aimed to investigate the efficacy of traditional Chinese medicine (TCM) for post-COVID-19 syndrome using a cohort study design and to explore its clinical value in alleviating patients’ symptoms and improving clinical outcomes.

In this cohort study, patients were divided into two groups according to clinical treatment. The control group received conventional Western medicine, and the treatment group received additional TCM syndrome differentiation–based treatment. Propensity score matching methods were used to reduce selection bias by equating groups based on observed covariates. Clinical data, including TCM symptom scores, the Short Form 36 Health Survey, clinical efficacy, and adverse events at Day 7, were collected. The primary outcome was the efficacy rate, defined by improvement at Day 7 compared with the Day 0 score. Data were processed and analyzed using SPSS 23.0 and R 4.5.0 software.

A total of 434 patients were enrolled in the cohort, including 306 patients in the control group and 128 in the treatment group. After 1:1 matching, 94 matched pairs were analyzed. For the primary outcome, the effective rate in the treatment group was higher than that in the control group (30.8% vs. 17.2%; odds ratio (OR) = 2.17, 95% confidence interval (CI): 1.09–4.35, P = 0.003). After seven days of treatment, the TCM syndrome score improved more in the treatment group than in the control group (median difference (MD) = 2.00, 95% CI: 0.50–3.50, P = 0.009). Subgroup analyses showed generally favorable efficacy in the treatment group across subgroups, though not all reached statistical significance.

TCM syndrome differentiation–based therapy effectively relieves clinical symptoms in patients with post-COVID-19 syndrome.

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy arising from parafollicular C-cells with known variations in cytomorphologic and immunophenotypic features. New neuroendocrine markers pituitary homeobox 2 (PITX2), paired-like homeobox 2B (PHOX2B), and heart and neural crest derivatives expressed 2 (HAND2) have recently been introduced, but studies using these markers in MTC are limited. The aim of this study was to evaluate the expression and potential diagnostic utility of PITX2, PHOX2B, and HAND2 in primary and secondary MTCs and to compare their expression with chromogranin A, synaptophysin, insulinoma-associated protein 1 (INSM1), and calcitonin.

A total of 34 histologically confirmed cases of MTC with available cell blocks were included. Sixteen MTC samples were fine-needle aspirates from primary thyroid lesions, and eighteen were from secondary metastatic lesions. Twelve samples from thyroid carcinomas of follicular origin were included as controls.

PITX2 positivity was observed in 17 (50.0%) MTC samples and in 4 (33.3%) control samples (P = 0.502). PITX2 positivity was found in 43.8% of primary thyroid MTC lesions and in 55.6% of secondary MTC lesions (P = 0.366). Co-expression of PITX2 with chromogranin A, synaptophysin, INSM1, and calcitonin was observed. PHOX2B and HAND2 were negative in all MTC and control samples.

There were no significant differences in PITX2 expression between primary and secondary MTC samples. PITX2 did not show reliable utility in distinguishing MTC from thyroid carcinomas of follicular origin. PHOX2B and HAND2 were negative in all samples. These results suggest that these new markers do not offer diagnostic value for MTC as stand-alone markers or as additions to the diagnostic workup panel.

Myelodysplastic syndromes (MDS) are a group of hematopoietic disorders characterized by ineffective hematopoiesis, with manifestations of cytopenias in one, two, or three lineages. CD34+ micromegakaryocytes and giant platelets are very rarely seen in MDS patients but may lead to unnecessary treatments. Therefore, we report and follow up on an MDS case with such an unusual finding.

A 57-year-old male veteran with a history of MDS, alcoholic cirrhosis, and portal hypertension presented to the Emergency Department in 2020 for evaluation after a blackout, at which time peripheral blood samples and bone marrow biopsies were obtained. Flow cytometry analysis of his peripheral blood detected 8% CD34+ cells. This finding raised the possibility of acute leukemic transformation from MDS. Further studies revealed that these CD34+ cells represented dysplastic micromegakaryocytes and giant platelets rather than blasts. During his 4-year follow-up, the patient was alive and complained only of easy fatigability, lasting several weeks. His laboratory results showed pancytopenia and persistent iron-deficiency anemia.

The distinction between micromegakaryocytes and giant platelets versus megakaryoblasts is extremely important in patients with MDS. This distinction may prevent misdiagnosis of acute leukemia and unnecessary treatments such as chemotherapy.

Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease with an increasing global burden. Although hemolytic disorders are established causes of PAH, their contribution to the global PAH burden remains unclear. This study aimed to evaluate the association between hemolysis-associated disorders and PAH incidence and to identify the relative contribution of hemolytic disorder subtypes compared with socio-demographic factors.

Using Global Burden of Disease 2021 data, temporal trends in the age-standardized incidence rate (ASIR) of PAH were analyzed using Joinpoint regression. Pearson correlation analysis assessed associations between PAH ASIR and the age-standardized prevalence rates of hemolytic disorder subtypes, hemolysis-related infections, malnutrition, and the Socio-demographic Index (SDI). Random forest regression was used to quantify the contributions of hemolytic disorders to PAH ASIR. Geographic distributions of PAH incidence and hemolytic disorder prevalence were compared, and Bayesian age-period-cohort modeling was used to project their burdens through 2050.

Global PAH ASIR increased from 0.50 to 0.52 per 100,000 from 1990 to 2021. The prevalence of hemoglobinopathies and hemolytic anemias correlated positively with PAH ASIR (R = 0.61, P = 7.70 × 10⁻²²). The random forest model explained 73% of the variance in PAH ASIR (R² = 0.73, P = 0.01), with G6PD trait (percentage increase in mean squared error [%IncMSE]: 18.43), other hemoglobinopathies/hemolytic anemias of unknown etiology (%IncMSE: 18.38), and vitamin A deficiency (%IncMSE: 17.27) identified as the top predictors, surpassing SDI (%IncMSE: 13.25) and sex (%IncMSE: 1.25). Temporal changes in hemolytic disorder prevalence strongly mirrored changes in PAH incidence (R = 0.76, P = 6.34 × 10⁻³⁹). Exploratory analyses suggested that natural product exposures may contribute to the unexplained hemolytic burden that drives PAH. Projections indicated a continued rise through 2050 in both PAH burden (ASIR increasing from 0.52 in 2022 to 0.57 per 100,000) and hemolytic disease burden (prevalence rising from 27,760.54 to 31,863.72 per 100,000).

Hemolysis-associated disorders, particularly G6PD trait, other hemoglobinopathies/hemolytic anemias, and vitamin A deficiency, are the predominant contributors to the global PAH burden. The projected continued rise in hemolytic disorder prevalence through 2050 signals a persistent exacerbation of the global PAH burden, underscoring the urgent need for targeted prevention strategies.

Ulinastatin, a broad-spectrum serine protease inhibitor widely used in Asia, has attracted increasing interest for its potential role in critical care. This review summarizes current evidence on its efficacy and safety in acute pancreatitis, severe acute pancreatitis, sepsis, acute respiratory distress syndrome, and perioperative management in cardiac surgery with cardiopulmonary bypass. Meta-analyses suggest that ulinastatin may improve outcomes by reducing mortality, shortening intensive care unit and hospital stays, and attenuating inflammatory responses. In severe acute pancreatitis, its use has been associated with reduced mortality and shorter hospitalization. In sepsis and septic shock, ulinastatin appears to lower all-cause mortality, decrease organ dysfunction scores, and reduce inflammatory markers. Evidence in acute respiratory distress syndrome indicates improvements in the oxygenation index and possible mortality reduction. Perioperative administration during cardiac surgery may mitigate postoperative inflammation and shorten the duration of mechanical ventilation. Despite these encouraging findings, most available studies originate from Asia and are limited by small sample sizes, heterogeneous designs, and inconsistent dosing regimens, which restrict generalizability and prevent standardized recommendations. Additionally, although ulinastatin demonstrates a favorable safety profile with a low incidence of adverse drug reactions, long-term and multinational pharmacovigilance data remain limited. Well-designed international, multicenter randomized controlled trials are required to clarify optimal dosing strategies, confirm clinical efficacy across diverse populations, and determine its independent effects compared with combination therapies. Overall, ulinastatin shows promise as a potential adjunctive therapy in critical care through modulation of inflammation and organ protection, but broader global adoption will depend on higher-quality evidence addressing current methodological gaps.