Gastric cancer (GC) remains a significant global health challenge due to its high mortality and frequent resistance to chemotherapy drugs like cisplatin (DDP). Carnosic acid (CA), a phenolic diterpene, exhibits potential anti-cancer properties. This study aimed to investigate the role of CA in regulating GC development and DDP sensitivity.

The half-maximal inhibitory concentration (IC₅₀) of DDP and cell viability were determined using a cell counting kit-8 assay. Cell proliferation was evaluated by a 5-Ethynyl-2'-deoxyuridine assay, while cell migration was assessed by a transwell assay. Cell death was analyzed through flow cytometry, fluorometric assay, and colorimetric assays. The targets of CA were identified using network pharmacology. Western blotting was employed to detect the protein expression of tumor protein p53 (TP53), solute carrier family 7 member 11 (SLC7A11), and arachidonate 12-lipoxygenase, 12 S type (ALOX12).

CA treatment significantly inhibited GC cell proliferation and migration and enhanced cell death. The treatment also elevated reactive oxygen species (ROS) and Fe²⁺ levels, while reducing glutathione (GSH) levels and the IC₅₀ value for DDP in GC cells. In addition, TP53 was identified as a target of CA, and its protein expression was upregulated by CA treatment in GC cells. Silencing TP53 attenuated the effects of CA on cell proliferation, migration, death, and the sensitivity of tumor cells to DDP. Further, CA regulated the TP53-mediated SLC7A11/ALOX12 pathway.

CA improved the sensitivity of GC cells to DDP and inhibited their malignant progression by regulating the TP53-mediated SLC7A11/ALOX12 axis, highlighting its potential clinical significance for GC treatment.

Myomatous erythrocytosis syndrome is an uncommon paraneoplastic syndrome of erythrocytosis associated with benign uterine leiomyomas. Fewer than 70 cases have been reported globally, and clinical awareness remains limited.

We report the case of a 45-year-old Middle Eastern premenopausal woman who presented with a several-month history of abdominal distension and a hemoglobin level of 22.5 g/dL. Imaging revealed a massive subserosal uterine leiomyoma (190 × 181 × 115 mm). Following total abdominal hysterectomy with left salpingo-oophorectomy, her hemoglobin level normalized to 15 g/dL within days. Histopathological analysis revealed no evidence of malignancy, consistent with a diagnosis of myomatous erythrocytosis syndrome.

Myomatous erythrocytosis syndrome should be considered in women presenting with unexplained erythrocytosis and large uterine leiomyomas. Timely diagnosis and surgical intervention can result in hematologic normalization and help prevent life-threatening thromboembolic complications.

Weight loss is a firmly established negative survival factor for individuals with cancer, yet effective biomarkers and targeted therapies remain elusive. In this study, we collected skeletal muscle, noncancerous, and cancerous tissues using the Illumina EPIC array to identify conserved DNA methylation probes associated with weight loss following bariatric surgery. Next, the consistency of the probes is evaluated and then the probes are integrated into a generalizable pathway enrichment score. Our results emphasize the gene-centered design, identifying KCNB1, PEAK1, SCG5, and TNIK as key targets of DNA methylation, as confirmed by mouse phenotype data and druggability resources. Moreover, an illustrative test of protein abundance in cell lines is conducted. Utilizing the Clinical Proteomic Tumor Analysis Consortium data, a positive correlation is established between the chromosomal instability scores and our generated score in tumor tissues. In addition, considering these correlation findings, the presence of identifiable methylation blocks in the co-occurring gain samples. Our findings also suggest that upstream molecular drivers may influence this pathway enrichment score, potentially leading to dysregulated methylation associated with weight loss. In summary, DNA methylation analysis not only identifies functional targets but also uncovers new gene-disease connections.

The prognostic assessment of metastatic spinal disease is predominantly tumour, rather than patient based. In 2021, Baumber et al. published a prognostic scoring system based on the patient as a whole rather than the tumour within the patient for metastatic disease of the appendicular skeleton. This paper assesses that prediction formula in those with metastatic disease of the spine.

Survival was recorded for 65 individuals who underwent surgery for spinal metastatic disease. Using the same parameters and hazard ratio as Baumber, the projected survival was longer than actually occurred (over-prediction of 39% at 6 months and 54% at 12 months). The relative contributions of the individual parameters as part of the overall survival was different between the groups with a greater contribution seen if the individual had hyponatraemia, hypoalbuminaemia and low levels of creatinine. The reasons for the differences seen between the spinal and appendicular groups with regards to these parameters are not clear but may represent a poorer level of general health or the behaviour of different types and subtypes of malignancy. Further work is required to develop a specific tool for the calculation of prognosis in a metastatic spinal cohort using a general health perspective.

Ovarian cancer (OC) is a highly malignant gynecological tumor with poor current treatment effects. Telomerase reverse transcriptase (TERT) is an important component of telomerase and plays an important role in the progression of ovarian cancer. Quercetin(QR) has been shown to inhibit the cell cycle and induce the apoptosis in various types of tumors. However, the mechanism of quercetin in ovarian cancer and whether it can be applied in the treatment of ovarian cancer has not been fully understood.

OC cells were intervened with QR in vitro and it was found that QR only inhibited the cell cycle but not induced cell apoptosis. By conducting network pharmacology, proteomics and TCGA-OV database analysis, we found that QR inhibited the cell cycle by binding to P53 and P21. However, in this study, overexpressed TERT in OC could bind to P53 and inhibit the binding of QR to P53, failing to induce tumor cell apoptosis. After TERT was knocked down, QR significantly suppressed the cell cycle of OC cells and induced apoptosis.To realize high drug delivery efficiency and drug targeting to improve the effect of inhibiting OC, we designed and prepared RGD-MSN/QR/shTERT nanoparticles for the combined administration of QR and shTERT. As confirmed by the in vivo experiments, RGD-MSN/QR/shTERT possessed good targeting ability and significant OC inhibiting effect, with no adverse reactions, and improved the survival benefits.

This study demonstrated the mechanistic and therapeutic advantages of combining QR with shTERT in the treatment of OC. Based on this mechanism, we synthesized the novel nanoparticles (RGD-MSN/QR/shTERT) and verified the favorable OC inhibiting effect in vivo, providing a novel strategy for the treatment of OC.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by mutations in the MEN1 gene located on the long arm of chromosome 11.

A 32-year-old male was admitted to the Division of Endocrinology with a three-year history of recurrent episodes of altered consciousness and abnormal mental behavior. Laboratory tests and imaging studies revealed primary hyperparathyroidism (PHPT), multiple pancreatic adenomas, and a pituitary adenoma. Genetic analysis identified a heterozygous germline mutation in exon 2 of the MEN1 gene (NM_130799; c.416A > T, p.(His139Leu)), confirming a diagnosis of Multiple Endocrine Neoplasia Type 1 (MEN1).

MEN1 patients should be evaluated for clinical manifestations of neuroglycopenia caused by pancreatic neuroendocrine tumors (pNETs). These neuroglycopenic symptoms (altered consciousness and abnormal mental behavior) should be distinguished from the neuropsychiatric and cognitive symptoms associated with PHPT. Furthermore, our report describes the identification of the first mutation associated with MEN1 as NM_130799.2: c.416A > T, p.(His139Leu). It provides valuable insight into the clinical presentation of multiple endocrine neoplasia type 1.

Atypical teratoid rhabdoid tumors (ATRTs) are aggressive central nervous system tumors mainly affecting young children. Extensive molecular characterization based on gene expression and DNA methylation patterns has solidly established three major ATRT subtypes (MYC, SHH and TYR), which show distinct clinical features, setting the basis for more effective, targeted treatment regimens. Transcriptional activity of transposable elements (TEs), like LINE1s and LTRs, is tightly linked with human cancers as a direct consequence of lifting epigenetic repression over TEs. The sole recurrent biallelic loss-of-function mutation in SMARCB1 in ATRTs, a core component of the SWI/SNF chromatin remodeling complex, raises the question of how TE transcription contributes to ATRT development. Here, we comprehensively investigate the transcriptional profiles of 1.9M LINE1 and LTR elements across ATRT subtypes in primary human samples. We find TE transcription profiles allow sample stratification into ATRT subtypes. The TE activity signature in the ATRT-MYC subtype is unique, setting these tumors apart from SHH and TYR ATRTs. More specifically, ATRT-MYC show broadly reduced transcript levels of LINE1 and ERVL-MaLR subfamilies. ATRT-MYC also displayed significantly less LTR and LINE1 loci with bidirectional promoter activity. Furthermore, we identify 849 differentially transcribed TEs in primary samples, which are predictive towards established ATRT-SHH and -MYC cell line models. In summary, including TE transcription profiles into the molecular characterization of ATRTs might reveal new tumor vulnerabilities leading to novel therapeutic interventions, such as immunotherapy.

Chloride intracellular channels (CLICs) are a family of six evolutionarily conserved proteins with diverse functions. Previously, we identified CLIC2, as the fifth-ranked master regulator associated with diffuse-type gastric cancer (dGC) showing increased expression in tumors. Here we used bulk, as well as single cell sequencing datasets of dGC, to demonstrate for the first time a direct association of CLIC2 with the microsatellite stable GC and, furthermore, the expression of CLIC2 in macrophages (MCs), and endothelial cells (ECs) populating gastric tissue. We generated CLIC2 knock-out THP-1 monocytic cells (THP-1CLIC2_KO) determining that while CLIC2 deletion had no observable effect on monocytes, THP-1CLIC2_KO macrophages exhibited significant morphological changes, including increased membrane protrusions, and upregulated expression of CD11b, CD11c, CD80, and CD86 markers. Furthermore, cytokine secretion profiling of THP-1CLIC2_KO differentiated cells revealed elevated secretion of CCL8, alongside reduced secretion of IL-1β, IL-6, and osteoprotegerin (OPG). Additionally, we observed increased phosphorylation of Shp1 phosphatase with the concomitant absence of Stat3 phosphorylation, which impaired downstream signaling, in line with the evidence that Clic2 interacts with both Shp1 and Stat3. Based on these findings, we suggest that CLIC2 plays a pivotal role in regulating monocyte-to-macrophage differentiation by modulating the Stat3 signaling pathway, thus enhancing gastric cancer progression by establishing a tumor-permissive microenvironment.

Resistance to chemotherapy remains a major clinical challenge in triple-negative breast cancer (TNBC), an intrinsic subtype with limited available therapeutic options. The expression of moesin (MSN) is upregulated in TNBC patients, but little is known about the role of MSN in breast carcinogenesis.

We investigated the MSN-dependent autocrine loop between extracellular interleukin 6 (IL-6) and NF-κB, along with a signaling cascade involving GTPase-mediated STAT3 phosphorylation. Various in vitro and in vivo assays were used to evaluate tumor initiation, growth, and stemness properties in TNBC models.

High MSN expression was correlated with shorter overall and disease-free survival in TNBC patients. In vivo, MSN promotes tumor initiation and growth. Mechanistically, MSN-mediated IL-6/NF-κB autoregulatory feedback enhances IL-6 transcription. IL-6 binding to LPAR1 activated MSN phosphorylation, which then sequentially phosphorylated the CDC42-PAK4 complex, triggering nuclear translocation of the pSTAT3-MSN complex. This led to pSTAT3-mediated activation of cancer stemness genes (IGFN1, EML1, and SRGN), contributing to Adriamycin resistance. Notably, combination treatment with the FDA-approved STAT3 inhibitor Atovaquone and Adriamycin restored drug sensitivity.

Our findings uncover the critical role of MSN in regulating STAT3-mediated cancer stemness via the IL-6/NF-κB signaling axis. These results provide a strong rationale for repositioning STAT3 inhibitors such as Atovaquone as a therapeutic strategy in Adriamycin-resistant TNBC patients exhibiting pSTAT3-MSN complex upregulation.

Genome instability is a fundamental feature and hallmark of cancer, associated with aggressiveness, drug resistance and poor prognosis. RAI2 was initially identified as a novel metastasis suppressor protein specifically associated with the presence of disseminated tumour cells in the bone marrow of breast cancer patients, but its molecular function is largely unknown.

We analysed the consequences of RAI2 depletion on gene expression and genomic stability in luminal breast cancer cell lines, performed cytotoxicity profiling using a library of pharmacologically active compounds, and characterized a potential function of the RAI2 protein in the DNA damage response. We performed in silico validation in different breast cancer datasets.

Analysis of clinical samples revealed that in primary breast tumours, low RAI2 gene expression is significantly associated with genomically unstable tumours and poor prognosis. RAI2 depletion in breast cancer cell lines resulted in loss of mitotic fidelity characterized by prolonged mitosis with increased chromosome segregation errors and micronuclei formation. Drug screening revealed increased sensitivity of RAI2-depleted breast cancer cells to topoisomerase I and Aurora A inhibitors. We also found that genotoxic stress induces the RAI2 protein, which has an affinity for and colocalises with poly-(ADP-ribose). We validated the association of RAI2 gene expression with DNA repair capacity in clinical samples.

Our findings support, for the first time, a functional role of RAI2 in the maintenance of genomic stability. Understanding the underlying the molecular mechanism could help to improve patient diagnosis and treatment.