Basidiobolomycosis is a fungal infection exhibiting a wide spectrum of clinical manifestations that frequently resemble abdominal malignancies or inflammatory conditions. This study elucidates the characteristic imaging features that can help make an accurate diagnosis.

We examined pretreatment imaging studies (CT, MRI, ultrasound) of 32 histopathologically proven cases of basidiobolomycosis at a tertiary referral center between 2015 and 2021. Two radiologists, blind to the pathology results, scrutinized the lesions for localization, morphology, enhancement pattern, and ancillary findings.

The cohort (mean age 9.8 ± 13.8 years and 53% male) demonstrated three basic imaging patterns: (1) hepatic lesions (21.9%) appearing as heterogeneously enhancing masses with necrotic cores; (2) gastrointestinal involvement (18.8%) showing circumferential wall thickening chiefly affecting the ileocecal region; and (3) mesenteric masses (15.6%) with peripheral enhancement and central necrosis. Other findings included regional lymphadenopathy (31.3%) and obstructive uropathy. At first, the misdiagnosis rate was 78%, most frequently as malignancy (37.5%) or appendicitis (31.2%). The follow-up indicated that 90.6% were responsive to treatment.

Basidiobolomycosis shows distinct imaging characteristics, especially necrotic hepatic masses, and segmental bowel wall thickening, which could help differentiate the condition from neoplasms or inflammatory diseases. These findings act as a compelling argument to always include fungal etiologies within the differential diagnosis in patients with pertinent imaging findings in endemic regions.

While pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis, a small fraction of patients show high microsatellite instability (MSI-H) and may respond to immune checkpoint inhibition. An MSI-H genotype is usually associated with deficiencies in the DNA mismatch-repair mechanism (MMRd). However, discordances between the mismatch-repair status by immunohistochemistry and the microsatellite status by molecular analyses have been noted. To date it is not clear whether PDAC patients with mutations in mismatch repair genes, which result in loss of protein expression (MMRd), who nonetheless retain microsatellite stability (MSS), can profit from checkpoint inhibitor therapy. Here, we present the case of a PDAC patient, diagnosed as MMRd/MSS, who responded to checkpoint inhibitor therapy after failing two lines of chemotherapy. Our data suggest that both MMR and microsatellite status should be determined in PDAC patients and that MMRd status alone, even in an MSS phenotype, can constitute an indication for checkpoint inhibitor therapy.

Chimeric antigen receptor (CAR)-T cells are effective in treating blood cancers but not solid cancers and can cause severe side effects, including cytokine release syndrome (CRS). One strategy to enhance the efficacy of CAR-T cells while avoiding CRS in cancer treatment is to deliver a single tumoricidal factor. TNFα is well known for triggering apoptosis signaling; however, it alone is not effective in treating cancers because it significantly increases the levels of inhibitor of apoptosis proteins (IAPs), a family of E3 ubiquitin ligases that block caspase-induced apoptosis. Thus, localized delivery of TNFα by targeting the tumors using the adoptive cells combined with an IAP antagonist, which degrades IAP proteins, could lead to improved outcomes in cancer treatment. This article reviews TNFα-induced apoptosis signaling pathway, outlines the principles for designing CAR-T cells, CAR-macrophages and CAR-dendritic cells expressing TNFα, used alone or in combination with IAP antagonists, and discusses the potential contraindications of IAP antagonists with several clinical used drugs for cancer treatment.

Immune checkpoint inhibition (ICI) has become a first-line treatment strategy for advanced hepatocellular carcinoma (HCC). However, treatment efficacy remains varied, and there are no reliable biomarkers of response. We used phage immunoprecipitation sequencing technology to measure circulating viral and bacterial antibodies as a biomarker of ICI response. The XGBoost Cox-proportional hazard model identified 23 viral and bacterial strains associated with survival. An antigen score developed from the 23 reactive microbial peptides significantly predicted overall survival (HR: 81.7, [95% CI]: 9.88 to 10,690.96, p<0.0001) and a high antigen score was predictive of progressive disease (HR: 4.03, [95% CI]: 0.78 to 20.87, p=0.09). The time-dependent area under the curve was 0.8 at 1 year. Findings were validated in an independent cohort and confirmed the antigen score association with survival (HR: 2.38, [95% CI 0.98 to 5.76, p=0.055). Our results suggest a unique microbial reactivity profile may serve as a potential biomarker of ICI response in patients with HCC.

Malignant perivascular epithelioid cell tumors (PEComas) are ultra-rare, aggressive mesenchymal neoplasms associated with poor outcomes. Standard-of-care systemic therapy includes mammalian target of rapamycin (mTOR) inhibition and chemotherapy. Immune checkpoint inhibition has not been previously studied in patients with advanced PEComas in a prospective clinical trial.

This is an open-label phase 2 trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) in rare tumors; here we report the cohort of patients with advanced malignant PEComa recruited from >1,000 sites across the USA. Primary end point was objective response rate, with progression-free survival, overall survival, and toxicity as secondary end points.

17 patients were enrolled (N=16 evaluable). Median age was 59.5 years (range, 22-77 years) and the majority were female (81%). Best responses included partial response (18.8%), stable disease for <6 months (25.0%), and progressive disease (56.3%). Median OS was 7.5 months (95% CI 3.4 to 34.6) and median PFS was 1.9 months (95% CI 1.8 to 11.8). PFS in responding patients was 11.8, 18.9, and 34.6 months. Available genomic sequencing showed TSC, ATRX, and TP53 mutations; no TFE3 fusions were identified (N=7). Nearly all patients experienced a treatment-related adverse event (AE) of any grade, while 37.5% experienced a grade 3-4 AE. Most common AEs were fatigue (43.8%), pruritus (37.5%), rash (25.0%), and aspartate aminotransferase increase (25.0%). There were no grade 5 AEs.

The combination of ipilimumab and nivolumab demonstrated responses in 18.8% of patients with advanced malignant PEComas. Dual immunotherapy may be an alternative treatment option for certain patients, including those who are unable to tolerate or do not desire prolonged treatment with chemotherapy or mTOR inhibition or have failed to respond to other therapies. Ipilimumab and nivolumab warrants further investigation in this and other rare soft tissue sarcomas.

Liver cancer, with hepatocellular carcinoma (HCC) as its predominant form, remains among the deadliest malignancies worldwide. Despite the expanding array of treatment options, current therapies benefit only a limited subset of patients. Metabolic reprogramming is a hallmark of cancer, with lipid metabolism playing a pivotal role in tumor progression, metastasis, and therapy resistance. HCC is profoundly influenced by alterations in lipid metabolic pathways, notably those involved in steatotic liver disease, a major risk factor. Key aspects such as de novo lipogenesis, lipid uptake, fatty acid oxidation, lipid peroxidation, biosynthesis of bioactive lipids, and cholesterol biosynthesis are all reprogrammed in liver cancer cells. These metabolic shifts modify the cancer cell lipidome-altering fatty acid unsaturation levels and other lipid profiles-to promote survival and resistance during therapy. Recent technological advances have deepened our understanding of dysregulated lipid metabolism in HCC. In this review, we examine how various facets of lipid metabolism contribute to HCC disease progression and resistance to standard treatments, including tyrosine kinase inhibitors, immune checkpoint inhibitors, and radiotherapy. We also explore the potential of targeting lipid metabolic pathways to enhance therapeutic efficacy and overcome resistance, highlighting dietary interventions as a promising, low-cost, low-side-effect strategy to resensitize resistant HCC cells.

Endometrial cancer (EC) represents the most prevalent gynecologic malignancy. We probed the mechanism of long noncoding RNA activated by DNA damage (lncRNA NORAD) regulating ferroptosis in EC cells (ECCs) by modifying glutathione peroxidase 4 (GPX4) through N6 methyladenosine (m6A) methylation.

The relationship between NORAD and EC clinically, and correlations of NORAD with GPX4 and fat mass and obesity-associated protein (FTO) levels were analyzed by Starbase database, Kaplan-Meier curve, and Pearson. Total m6A modification of EC tissues was detected by Dot blotting. Effects of regulating NORAD, GPX4, FTO and YTHDF2 on m6A modification and ferroptosis in EC were explored in ECCs and nude mouse xenograft tumor models. Mechanistically, NORAD-FTO, FTO-YTHDF2 and YTHDF2-GPX4 interactions were detected by RNA pull down, Co-IP and RIP assays. GPX4 mRNA stability was determined by Actinomycin D test.

NORAD was down-regulated in EC tissues and cells. Lowly-expressed NORAD in EC tissues predicted EC patients' poor prognoses, and negatively correlated with GPX4. NORAD overexpression promoted GPX4-mediated ferroptosis. NORAD promoted ECC ferroptosis by down-regulating GPX4. NORAD promoted YTHDF2-mediated m6A modification to reduce GPX4 mRNA stability by interacting with FTO. YTHDF2 silencing or FTO overexpression partially averted NORAD-promoted ECC ferroptosis by modulating GPX4. NORAD promoted m6A modification to down-regulate GPX4 by interacting with FTO, and promoted ferroptosis to inhibit tumor growth in vivo.

NORAD was down-regulated in EC and affected the EC prognosis. NORAD overexpression facilitated YTHDF2-mediated m6A modification by interacting with FTO to elevate GPX4 degradation, thereby stimulating ECC ferroptosis and hindering EC progression.

Polycystic ovary syndrome (PCOS) stands as a multifaceted endocrine disorder with implications beyond reproductive health, encompassing metabolic and immunological dimensions. This study delves into the immunological alterations within T cells in a murine PCOS model, unraveling novel insights into the molecular mechanisms contributing to T cell dysfunction.

A PCOS model was established in mice, followed by isolating T cells. Isolated T cells were activated by anti-CD3 and anti-CD28 antibodies. Cytokine levels were determined by enzyme-linked immunosorbent assay (ELISA) assay, and carboxyfluorescein succinimidyl ester (CFSE) dye was utilized for proliferation detection. Flow cytometry was utilized for analyzing exhaustion markers. RNA methylation analysis was determined by methylated RNA immunoprecipitation (Me-RIP) assay.

In the PCOS mouse model, T cells exhibited a state of exhaustion, including impaired activation, reduced cytokine secretion, and decreased proliferative capacity. Particularly, the expression of T cell immunoreceptor with Ig and ITIM domain (TIGIT) molecules on the surface of T cells was significantly increased, which was associated with T cell exhaustion. The stability of TIGIT mRNA was enhanced due to the increased level of N6 RNA methylation, in which the methyltransferase-like 3 (METTL3) methyltransferase played a key role. Experiments showed that by inhibiting N6-methyladenosine (M6A) methylation or knocking out METTL3, the activation phenotype of PCOS T cells could be reversed, and cytokine secretion and proliferative capacity could be restored.

Although acknowledging study limitations, such as the murine model's partial recapitulation of human PCOS complexity, this research provides a foundation for future investigations into the specific molecular mechanisms governing T cell function and potential therapeutic targets within the N6 RNA methylation pathway.

Oncogenic changes in the non-canonical ERK-RSK-EphA2 axis drive migratory behavior in non-small cell lung cancer cells. However, the role of SHP2, a tyrosine phosphatase that regulates the RAS-ERK pathway, in the activation of EphA2 remains unknown. We herein demonstrated that the allosteric SHP2 inhibitors, SHP099 and TNO155, suppressed both the TNF-α- and growth factor-induced non-canonical phosphorylation of EphA2 at Ser-897 via the ERK-RSK pathway. The significant impact of SHP2 inhibitors on non-canonical EphA2 activation in lung adenocarcinoma (LUAD) cells harboring the EGFR exon 19 deletion (PC-9, HCC827), EML4-ALK rearrangement (A925L), and KRAS mutation (A549) was also examined, and the results obtained showed a reduction in cell migration in vitro and early metastatic processes in vivo. In contrast, these inhibitors did not affect the signaling pathways leading to EphA2 induced by TPA in HeLa cells or by TNF-α in A549 cells, indicating the involvement of a complex signaling network in these processes. Collectively, the present results highlight the potential of allosteric SHP2 inhibitors as agents targeting the non-canonical activation of EphA2 in LUAD cells.

Chronic lymphocytic leukemia (CLL) is divided into unmutated (UM-CLL) and mutated (M-CLL) subtypes depending on somatic hypermutation (SHM) frequency in their immunoglobulin heavy chain V (IGHV) region. We previously demonstrated that CD27bright memory B cells (MBCs) are germinal center (GC)-dependent with higher mutation rate, whereas CD27dull MBCs accumulate fewer mutations and originate independently from the GC. We conducted a meta-transcriptomic analysis on bulk RNA data from 116 individuals combining four CLL cohorts and healthy B cell subsets (naïve, CD27dull and CD27bright MBCs) to decipher the transcriptional and mechanistic functions of CLL subtypes. CD27bright MBCs showed more transcriptional similarity to M-CLL rather than UM-CLL. Functional enrichment analysis revealed that LPL, ZNF667 and ZNF667-AS1 are potential informative biomarkers for stratification of CLL subtypes. They are part of the mechanistic regulatory pathways of CLL pathology through cholesterol and Epithelial Mesenchymal Transition (EMT) regulation. We applied markers for the GC B-cell substages to map in silico the CLL cohorts to their potential GC B cell counterpart. UM-CLL represented transcriptional mimicry to an early intermediary GC substage whereas M-CLL mimicked later substages in the GC. This could potentially explain the IGHV mutational status of M-CLL as well as hypothesize that CLL subtypes could derive from a GC-dependent pathway.