Dysregulation of mitochondrial dynamics modulates malignant cell fate; however, the substantial heterogeneity in mitochondrial dynamics among tumor cells within individual tumor nodules and the resultant functional consequences remain inadequately characterized. In this study, we induced mosaic impairment of mitochondrial fusion in mouse liver under tumorigenic conditions and unexpectedly identified the formation of combined hepatocellular-cholangiocarcinoma (cHC), a monoclonal tumor displaying features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Restoration of the mitochondrial fusion protein MFN1 effectively suppressed cHC development. Analysis of human cHC samples revealed that ICC-like cells exhibit more pronounced mitochondrial fusion impairment compared to HCC-like cells. Mechanistically, increasing impairment of mitochondrial fusion resulted in a dose-dependent elevation of reactive oxygen species (ROS). Low levels of ROS upregulated HNF4α, promoting HCC-like differentiation, whereas high ROS levels activated HES1, facilitating ICC-like differentiation. Collectively, these results demonstrate that heterogeneity in mitochondrial dynamics is a critical determinant of cHC path-ogenesis.

Human papillomavirus (HPV) vaccination has emerged as the most effective method for preventing cervical cancer. Despite this, Ethiopia's HPV vaccine non-uptake rate remains high, with significant geographic variation, and there is limited evidence on the geospatial determinants of these inequities. This study aimed to map the geographic inequities in HPV vaccine non-uptake and identify its determinants among adolescent girls in Ethiopia.

We conducted a secondary data analysis using the Ethiopian National Immunization Survey dataset. A stratified two-stage cluster sampling technique was used to select 467 enumeration areas (EAs) and a weighted sample of 5,341 adolescent girls. The geographic inequity of HPV vaccine non-uptake was analyzed using Moran's I, Getis-Ord Gi statistics, and Kriging interpolation in ArcGIS 10.8. We employed geographically weighted regression analysis to identify geographic factors associated with inequity in HPV vaccine non-uptake.

Forty-six percent (46%, 95% CI: 44.7-47.8) of adolescent girls did not receive the HPV vaccine, and there were geographical variations in vaccine coverage. Higher proportions of HPV vaccine non-uptake were identified in eastern Amhara, eastern Oromia, central and northern Somali, central Afar, and the urban administrative units of Dire Dawa and Harari. Poor attitude and poor knowledge towards the HPV vaccine, not living with parents, and urban residence were predictors of geographic inequities in HPV vaccine non-uptake.

The proportion of HPV vaccine non-uptake varied across Ethiopia, with geographic inequities identified in the eastern and northeastern parts of Ethiopia. Poor attitudes and knowledge about the vaccine, not living with parents, and urban residence contributed to these inequities. These findings highlight the need for targeted educational campaigns in areas with high non-uptake to improve knowledge and attitudes, alongside tailored strategies for regions where urban residence and not living with parents influence uptake.

Non-operative management (NOM) of complicated appendicitis is increasingly accepted, but the role of interval appendicectomy (IA) remains contentious. Contemporary evidence has shifted decision-making from recurrence risk alone toward age-linked neoplasm risk and radiological features.

To synthesise contemporary randomised trials, prospective cohorts, and meta-analyses on recurrence after NOM of periappendiceal abscess, appendiceal tumour prevalence, and the diagnostic performance and harms of surveillance strategies (cross-sectional imaging and colonoscopy), to inform a pragmatic risk-stratified framework.

Recurrence after successful NOM is commonly reported at 12-24% and is concentrated within the first six months. In adults presenting with periappendiceal abscess, appendiceal tumour prevalence rises with age, reaching approximately 5-10% in patients aged 35-39 and 14-20% in cohorts of patients aged ≥40 years. Interval CT/MRI findings identify higher-risk patients in whom IA should be prioritised. Colonoscopy is best used selectively, particularly when caecal pathology is suspected, imaging is equivocal, or IA is not planned in older patients.

Interval appendicectomy should generally be considered for patients aged ≥40 years and for any patient with persistent symptoms or concerning radiological findings, while recognising that decisions must be individualised with shared decision making. Younger patients with complete radiological resolution and no red-flag features can usually be observed with structured imaging follow-up. A risk-stratified clinical algorithm is proposed to guide post-NOM management.

Cervical cancer (CC) remains a significant global health concern, characterized by high incidence rates. Concurrently, the obesity epidemic continues to expand, affecting millions worldwide. Dysregulation of pro- and anti-inflammatory cytokines can promote chronic inflammation, which contributes to the pathogenesis of various diseases, including cancer. This study aimed to evaluate the gene expression levels of TNF-α, IL-6, IL-8, IL-10, and VEGF during CC progression in patients across different weight categories: normal weight, overweight, and obese.

Cervical samples were classified according to cervical diagnosis and body mass index (BMI). Gene expression levels of TNF-α, IL-6, IL-8, IL-10, and VEGF were assessed through PCR, and the Relative Expression Index was calculated using the 18S gene as a housekeeping reference.

Eighty-one women from the Colposcopy Clinic of Health Jurisdiction II in Ciudad Juarez were evaluated and classified into four groups: no intraepithelial lesion (NIL) (n=18), low-grade squamous intraepithelial lesion (LSIL) (n=22), high-grade squamous intraepithelial lesion (HSIL) (n=24), and CC (n=17). These groups were also classified based on BMI. The overexpression of TNF-α (p=0.036), IL-6, and IL-10 increased with the severity of cervical lesions, whereas IL-8 expression was suppressed (p=0.53) as cervical pathology progressed. According to BMI, a trend toward overexpression of IL-6, IL-10, and TNF-α was observed with increasing adipose tissue in HSIL and CC. On the other hand, IL-8 and VEGF expression appeared to be repressed regardless of intraepithelial lesion grade or obesity status.

Obesity is a risk factor for the development of CC by promoting a proinflammatory environment combined with a VPH infection.

Immunosuppressive and nutritional treatments have improved the prognosis of Cronkhite-Canada syndrome (CCS). CCS-associated polyps are benign and categorized into hamartomatous, inflammatory, hyperplastic, and adenomatous polyps; however, the development of gastrointestinal cancer is considered the most significant prognostic factor for CCS. Although the adenoma-carcinoma sequence and inflammation-associated carcinogenesis are two major pathways for the development of colorectal cancers (CRCs), it remains largely unknown which pathway plays critical roles in the development of CRCs in CCS. Inflammation-associated carcinogenesis might be involved in the development of CRCs associated with CCS because CCS-associated polyps are characterized by submucosal infiltration of immune cells. Given the fact that proinflammatory cytokines including interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α underlie the pathogenesis of inflammation-associated carcinogenesis, we examined the involvement of proinflammatory cytokines in the transformation of CCS-associated polyps into CRCs.

Three cases of CCS were enrolled: two cases with concurrent CRCs and a single case without CRC. mRNA was isolated from non-cancerous CCS-associated polyps and subjected to reverse transcription quantitative polymerase chain reaction to determine expression of proinflammatory cytokines. Colonic biopsy samples were isolated from non-tumor portions of patients with colonic adenoma to determine mRNA expression of proinflammatory cytokines in healthy colonic mucosa.

Higher mRNA expression of IL-6, but not IL-1β or TNF-α, in non-cancerous CCS-associated polyps was observed in two patients with CCS and concurrent CRCs as compared with four healthy colonic mucosal samples and a patient with CCS without CRC.

IL-6-mediated inflammation-associated carcinogenesis might be involved in the transformation of CCS-associated polyps into CRC.

Breast cancer remains one of the leading causes of cancer-related mortality among women. The molecular heterogeneity of breast cancer, reflected in its numerous subtypes with variable responses to conventional and targeted therapies, necessitates the development of novel therapeutic strategies. Speckle-type POZ protein (SPOP), a substrate adaptor for Cul3-dependent ubiquitin ligase complexes, is frequently downregulated in breast cancer, yet the mechanisms linking SPOP loss to breast oncogenesis are poorly understood. This study aimed to elucidate the role of SPOP deficiency in breast cancer progression and identify potential therapeutic vulnerabilities associated with this molecular context.

MCF-7 breast cancer cells were subjected to SPOP knockdown to assess effects on cell proliferation and Sonic Hedgehog (SHH) signaling activity. A natural compound library was screened to identify agents selectively targeting SPOP-deficient cells. Candidate compounds were evaluated for effects on cell viability, GLI3 target gene expression, and clonogenic growth.

SPOP knockdown in MCF-7 cells increased proliferation and led to hyperactivation of GLI3-dependent SHH signaling. Screening of the natural compound library identified gossypol as a selective inhibitor of SPOP-deficient cells. Gossypol treatment significantly reduced cell viability, suppressed GLI3 target gene expression and impaired clonogenic growth in SPOP-deficient cells, while exerting minimal effects on control cells.

These findings identify a novel oncogenic role for SPOP loss in promoting breast cancer progression via GLI3-dependent SHH signaling. Furthermore, gossypol is highlighted as a potential targeted therapeutic agent for breast cancers characterized by SPOP deficiency.

CD46 is a membrane cofactor protein (MCP) essential for several physiological and pathological processes, including tumorigenesis and metastasis. In our previous studies, CD46 increased the production of matrix metalloproteinase 9 (MMP9) in bladder cancer cells by activating the p38 MAPK and PI3K/AKT signaling pathways. CD46 ultimately activated the phosphorylation of the AP-1 complex to stimulate the expression of MMP9. In this study, we assessed whether the inhibition of AP-1 suppresses cancer cell migration and invasion via the inactivation of MMP9.

Both bladder and colon cancer cells were used for western blot analysis and reporter transcription assays. AP-1 inhibitors used are AP-1 decoy oligonucleotide (AP1-ODN) and AP-1 specific inhibitor (SR11302). To test AP-1-mediated inhibition of cell migration and invasion, both wound healing scratch assay and transwell chamber assays with or without gelatin coating were utilized.

Both inhibitors significantly reduced the expression levels of MMP9, especially in CD46-overexpressing UM-UC-3 and 5637 bladder cancer cells. A reporter transcription assay also revealed the suppression of MMP9 promoter activity by AP-1 inhibitors. As expected, AP-1 inhibitors significantly reduced the migration and invasion of bladder cancer cells. CD46 overexpression also promoted the expression of MMP9 through regulation of p38 and AKT in some colon cancer cells (CRCs), including HCT116, CT26, MC38, and DLD-1. Moreover, SR11302 reduced the metastatic potential of colon cancer in vitro and in vivo.

Targeting AP-1 can effectively suppress CD46-mediated invasion and metastasis in bladder and colon cancers, in which CD46 is generally overexpressed.

Mitochondria activate inflammation and innate immunity to protect against infections, but the role in cancer is unknown. Here, we report that patients with pancreatic ductal adenocarcinoma (PDAC) with reduced levels of the mitochondrial scaffold, Mic60, or inner mitochondrial membrane protein, exhibit increased inflammation, high NFκB activity and production of TNFα. This is mediated by double-stranded RNA (dsRNA) released from structurally defective, Mic60-low mitochondria, which engages TLR3/RIG-I sensing, activates NFκB gene expression and reprograms transcriptional and signaling networks to promote PDAC proliferation. Preclinical targeting of mitochondrial dsRNA signaling triggers rapid cell death and inhibition of tumor growth, selectively in Mic60-knockdown PDAC, without overt toxicity, in vivo. Therefore, dsRNA released from defective mitochondria generates protumorigenic inflammation and provides an actionable therapeutic target in selected PDAC patients.

The host metabolic state can potentially affect the growth trajectories of tumors growing at local sites, which are highly variable and unpredictable among populations. The molecular links between systemic metabolism and tumor growth outcomes remain largely unclear. Here, we harnessed the genetic power of the Drosophila model to perform genetic screens and identified molecular players in the adipose tissue that can change the growth trajectory of remotely growing tumors. We found that variation of triacylglycerol (TAG) metabolism state in adipocytes, which is downstream of insulin signaling regulation, can strongly change the growth trajectory of distant tumors. Mechanistically, we identified that Wnt5, which is secreted from adipocytes and transported in circulation through a population of Nplp2-lipoprotein particles, is required for distant tumor growth. Perturbation of TAG metabolism or depletion of Nplp2-lipoprotein particle formation in adipocytes reduces Wnt5 in circulation and therefore restricts distant tumor growth.

The Sarco-Detect study aim was to test the suitability of bioimpedance analysis (BIA) as a cost-efficient and practical alternative to computed tomography (CT) for diagnosing sarcopenia and to assess the agreement between CT and BIA.

In this study, the skeletal muscle cross-sectional area (SMA) was measured at the third lumbar vertebra (L3) on CT images, and the skeletal muscle index (SMI) was calculated. BIA skeletal muscle mass (SMM) and appendicular SMM (ASMM) were determined using the manufacturer's software (SMM-Seca, ASMM-Seca) and using the Sergi and Kyle equations. All calculated masses were converted to height-normalized index values and compared with the European Working Group on Sarcopenia in Older People cut-offs.

A total of 70 patients were included, with mean (± standard deviation) age of 66±11 years, body mass index of 25±5 kg/m², CT-SMA of 135.55±32.01 cm², and CT-SMI of 44.28±8.14 cm². BIA results were 13.85±3.85 kg according to ASMM-Seca, 23.45±5.64 kg using ASMM-Sergi, and 21.86±5.74 kg using ASMM-Kyle. The highest Pearson correlation was determined between SMI-Seca and CT-SMI (r=0.839, p<0.01), followed by ASMI-Sergi (r=0.831, p<0.01). Comparing absolute SMM values, SMM-Seca showed the highest correlation with CT-SMA (r=0.917, p<0.01) followed by ASMM-Kyle and ASMM-Sergi (r=0.905 and r=0.904, respectively; p<0.01). When diagnosing sarcopenia, SMI-Seca showed the highest sensitivity of 50% (specificity 73%) followed by ASMI-Kyle at 38% (specificity 81%) and ASMI-Sergi at 13% (specificity 91%). Compared to the reference method (CT-SMI), 17 patients were falsely identified as having sarcopenia via the calculation of SMI-Seca and four patients with sarcopenia were not detected.

The results indicate limited congruence of BIA and CT in the diagnosis of sarcopenia.