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Mesenchymal stem/stromal cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) play a crucial role in human development and cancer biology. While they are known to facilitate tumorigenesis, these stem cell types also hold promise as therapeutic tools in cancer treatment. They can serve as delivery systems for targeted therapies, with potential applications in regenerative medicine and cancer stem cell-targeted therapies. Through mutations, epigenetic modifications, and influences from the tumor microenvironment, somatic or normal stem cells, as well as progenitor or differentiated cells, can evolve into cancer stem cells (CSCs). CSCs represent a small but critical subset of tumor cells involved in tumor formation, metastasis, and treatment resistance. This review examines the dual role of MSCs, NSCs, and iPSCs in cancer by exploring their contribution to tumor initiation and their potential as therapeutic targets. To provide a focused narrative synthesis, we reviewed peer-reviewed studies addressing MSCs, NSCs, iPSCs, CSC formation, and stem cell-based therapeutic strategies in oncology. Additionally, we explore the mechanisms by which somatic or normal stem cells transition into CSCs and the factors contributing to this transformation, along with emerging CSC-targeting therapies. Finally, the role of stem cells and their exosomes as carriers in cancer therapies is examined, alongside their applications in immunotherapy and regenerative medicine, and the challenges associated with their clinical use in cancer treatment.
Liposuction is a standard treatment for advanced-stage lipedema, often involving large volumes of tumescent fluid infiltration and aspiration. These shifts raise concerns about postoperative electrolyte imbalances, though systematic data are limited. This retrospective single-center study analyzed 116 women with stage 2 or 3 lipedema who underwent liposuction between 2019 and 2023. Pre- and postoperative (within 24 hours) laboratory values including hemoglobin, hematocrit, leukocytes, and electrolytes were compared using paired t-tests, and correlations with clinical variables were assessed. Postoperatively, lower hemoglobin (13.6 ± 0.9 to 11.8 ± 1.2 g/dL, p < .0001) and hematocrit (40.9 ± 2.5 to 35.1 ± 3.5%, p < .0001) levels were observed, alongside higher leukocyte counts (7.6 ± 3.1 to 13.1 ± 5.9 × 109/L, p < .0001). Electrolyte shifts included higher chloride (104.7 ± 2.2 to 106.0 ± 1.9 mmol/L, p < .0001) and slightly lower calcium (2.3 ± 0.1 to 2.2 ± 0.1 mmol/L, p < .0001), sodium (140.8 ± 2.1 to 140.2 ± 2.1 mmol/L, p = .01), and potassium (4.1 ± 0.35 to 4.0 ± 0.4 mmol/L, p = .02). All parameters remained within physiological ranges and were not associated with adverse outcomes. Calcium correlated with hemoglobin (r = 0.49) and hematocrit (r = 0.51) and inversely with aspirate volume (r = -0.41, p = 0.001). Post-liposuction electrolyte and hematologic changes are mild and clinically insignificant, reflecting predictable hemodilution rather than metabolic disturbance. Routine postoperative testing appears unnecessary for most patients, supporting selective monitoring in those with abnormal baseline values, high aspirate volumes, or relevant comorbidities. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Nigeria's 2025 PEPFAR funding suspension served as an unplanned natural experiment, uniquely demonstrating that behavioral instability among patients and providers precedes, and is in many respects more disruptive than, actual commodity shortages. This distinction, rarely documented in prior literature, has direct implications for how HIV program resilience should be designed and measured. We conducted in-depth key informant interviews with 15 healthcare providers at a major antiretroviral therapy (ART) facility in northern Nigeria, analyzed using Braun and Clarke's reflexive thematic analysis framework. Despite stable antiretroviral drug stocks, acute uncertainty triggered panic-driven patient visits, rumor-driven information gaps, and precautionary dispensing restrictions. Laboratory services deteriorated rapidly, and implementing partner staff worked without pay for up to two months, temporarily masking systemic fragility. Persistent structural barriers, transport costs, stigma, and treatment fatigue impeded adherence, independent of funding status. Providers distinguished technical capacity, which they judged sufficient, from political will, which they found lacking; transition structures existed but remained unimplemented. Sustaining ART delivery requires proactive crisis communication, protected multi-month dispensing, resilient laboratory financing, and governance reforms to reduce donor dependence. Political commitment is the central determinant of sustainable domestic HIV program ownership in Nigeria.
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory condition. While few diagnostic scores are established, none exist to predict both clinical course and time-point specific outcome of sHLH patients so far. We present a machine learning (ML)-based tool to predict Initial Disease Severity (IDS; defined as admission to intensive care units (ICU) OR death < 90 days without ICU admission) and mortality across different time points in sHLH patients. 167 adult sHLH patients from six study centers across three European countries were included retrospectively. Clinical and demographic features, course, survival, and laboratory data were assessed. Random forest models were trained with two sets of eight clinical and laboratory features: one to predict IDS, and five to predict mortality at distinct time points (30, 60, 90, 180 or 365 days). After calibration, the models were tested against hold-out test sets containing n = 32 (IDS) or n = 43 (mortality) sHLH patients. Overall, the models demonstrated strong discriminatory ability, overall performance, and accurate prediction of risk. Serum levels of the soluble interleukin-2 receptor (sIL-2R) and albumin (for IDS) or sIL-2R and platelet counts (for mortality prediction) showed the strongest contributions to the models' predictions. The HLH-Risk-Calculator is an exploratory tool predicting the clinical course of sHLH. External validation is critical to assess its validity, applicability, and robustness for real-world use. To this end, the calculator is available at www.hlh-risk-calculator.com for research use only, and is currently not intended for clinical decision-making.
Ginkgo biloba extract (EGb), a complementary and alternative medicinal option, has gained extensive application in addressing conditions like cerebrovascular and peripheral vascular disorders. We aim to assess the neuroprotective efficacy of EGb for retinal disorders and to clarify its potential mechanisms of action through a systematic review. We searched original literature about laboratory experiments from four databases which were released until April 2024. The methodological quality of included in vivo studies was assessed using the SYRCLE risk of bias tool. The results showed that out of the 398 studies initially collected, 26 articles met the requirements for full-text review. 20 of them presented in vivo data, 2 detailed both in vitro and in vivo evidence, and 4 were in vitro experiments. Results demonstrated the protective effects of EGb against several retinal disorders, including retinal ganglion cell injury, retinal degeneration, ischemia, vitreo- or pre-retinal proliferative disorder, uveitis, and diabetic retinopathy. Based on SYRCLE's evaluation of bias risk, the in vivo studies' quality scores varied from 4 to 7 points. The data indicated that EGb preserved visual function by maintaining retinal morphology and structure in preclinical models. Its action mechanism may be associated with suppressing apoptosis, attenuating oxidative stress, reducing inflammation, inhibiting angiogenesis, and suppressing proteolysis. These preclinical findings suggest that EGb may be a promising neuroprotective agent for retinal disorders. However, the methodological limitations of the included studies necessitate cautious interpretation; to demonstrate the effectiveness and safety of EGb, more extensive clinical randomized controlled trials are required.
Patients with esophageal cancer primarily face nutritional challenges due to swallowing difficulties and gastrointestinal side effects from treatment. This study aimed to evaluate whether, on the basis of sequential chemoradiotherapy combined with immunotherapy (sandwich regimen), proactive continuous nutrition management can improve patients' nutritional status, help maintain host immune homeostasis, reduce treatment-related severe toxicities, and enhance patients' treatment tolerance. We performed a single-center retrospective study including 60 esophageal cancer patients treated with sandwich regimen at The Third Affiliated Hospital of Nanjing Medical University from June 2021 to May 2023. Patients were divided into the proactive continuous nutritional management (PCNM) group and the reactive nutritional intervention (RNI) group by different nutritional support strategies during sandwich regimen, and compared pre-post nutritional intervention BMI changes, nutritional risk improvement, immune function, and physical performance status indicators, as well as evaluated the clinical efficacy and safety of the treatment. After intervention, the PCNM group showed significant improvements in BMI and nutritional risk status compared with the RNI group. Meanwhile, the PCNM group exhibited higher CD4+/CD8+ ratio, serum IgG and IgA levels, as well as a lower incidence of malnutrition and radiation esophagitis. Multivariate logistic and linear regression analyses further confirmed that PCNM was an independent protective factor for ameliorating nutritional risk and elevating ΔBMI. No significant intergroup difference was observed in objective tumor treatment efficacy. Proactive continuous nutritional management improves patients' nutritional status and immune-related laboratory parameters during sequential sandwich therapy.
Assessing disease activity in psoriatic arthritis (PsA) remains challenging, and additional biomarkers that can complement conventional inflammatory markers are still needed. The CRP-albumin-lymphocyte (CALLY) index integrates inflammatory, immune, and nutritional components into a single measure. This study examined the relationship between the CALLY index and disease activity in patients with PsA. This retrospective longitudinal cohort study included 150 patients with PsA and 50 age- and sex-matched healthy controls. Blood-derived inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), pan-immune inflammation value (PIV), and the CALLY index, were calculated using routine laboratory data. Disease activity was evaluated with the clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA). Correlation analyses, receiver operating characteristic (ROC) analyses, subgroup analyses, and multivariable logistic regression models were performed. Patients with moderate-to-high disease activity had markedly lower CALLY index values than those with remission or low disease activity. The CALLY index showed a moderate inverse correlation with cDAPSA scores (r = - 0.529, p < 0.001). During follow-up, CALLY values increased significantly in both csDMARD-treated and biologic-treated patients (both p < 0.001), whereas no significant differences were observed between treatment groups. In multivariable analysis, lower log-transformed CALLY index values remained independently associated with moderate-to-high disease activity (OR 0.39, 95% CI 0.23-0.66). The discriminative performance of the CALLY index was similar to that of CRP (AUC 0.724 vs. 0.738; p = 0.42). Lower CALLY index values were linked to greater disease activity in PsA and improved alongside reductions in inflammatory burden during follow-up. Although its performance was comparable to CRP rather than superior, the CALLY index may represent a useful complementary biomarker for disease activity assessment in PsA. Prospective studies are needed to further clarify its clinical utility.
Gasdermin E (GSDME), a pivotal executor of pyroptosis, has emerged as a central regulator of immune responses across a spectrum of diseases. Initially identified as a tumor suppressor and a deafness-associated gene (DFNA5), GSDME is now recognized for its complex, context-dependent roles in health and pathology. Its activation, primarily via caspase-3 cleavage, converts apoptotic signals into a lytic, pro-inflammatory form of cell death, releasing damage-associated molecular patterns and cytokines that profoundly shape the immune microenvironment. This review synthesizes the current research landscape of GSDME, detailing its structural characteristics and canonical activation mechanisms, alongside recent discoveries of non-canonical, cleavage-independent pathways. We systematically dissect its dualistic functions in major disease categories-cancer, inflammatory/autoimmune disorders, neurodegenerative conditions, and organ injuries-highlighting the key cell-type-specific signaling pathways and their resultant immunomodulatory outcomes. Furthermore, we evaluate the burgeoning clinical potential of GSDME as a diagnostic/prognostic biomarker and a therapeutic target. We critically analyze the functional characteristics of emerging pharmacological strategies designed to either activate or inhibit the GSDME pathway, including small molecules, epigenetic modulators, and advanced nanoplatforms. Finally, we outline future research directions and propose a framework for the clinical translation of GSDME-targeted therapies, emphasizing the need for precision medicine approaches to harness its immunostimulatory potential in oncology while restraining its pathological role in inflammatory diseases.
Referral delays and errors in inflammatory rheumatic diseases (IRDs) are common. RhePort is a German online self-referral tool that estimates IRD probability based on a structured questionnaire and expert-derived algorithm. This study evaluated whether machine learning could improve IRD discrimination of RhePort. In this retrospective internal validation study, 1,333 unique RhePort questionnaires linked to rheumatologist-confirmed diagnoses were analyzed. A shared stratified five-fold cross-validation design was used for Logistic Regression, Neural Network, XGBoost, and LightGBM models. For each algorithm, feature selection and Bayesian hyperparameter optimization were performed, followed by evaluation of ensemble strategies. Discrimination, calibration, clinically relevant operating points, and SHAP-based interpretability were assessed against the original RhePort score. IRD prevalence was 35.6% (475/1,333). LightGBM achieved the strongest individual performance, with an area under the receiver operating characteristic curve of 0.791 using 30 features. A weighted ensemble of LightGBM and Logistic Regression further improved performance to 0.815 and achieved the lowest Brier score (0.166). At 95% sensitivity, specificity increased from 9% for RhePort to 32%; at 90% sensitivity, specificity increased from 15% to 48%. The most influential predictors included C-reactive protein, painful small joints, dactylitis pattern, sex, and erythrocyte sedimentation rate. Ensemble AUC-ROC was 0.828 among 746 patients with CRP and/or ESR information and 0.786 among 587 patients without these laboratory data. Machine learning improved IRD classification over the current expert-derived RhePort score and identified questionnaire items that may be omitted without loss of performance, demonstrating the potential of machine learning to enhance rheumatology referral.
Performing germline genetic testing of family members following the identification of an individual with a pathogenic variant in a cancer predisposition gene, a process known as cascade testing, is a critical step in maximizing the preventive benefit of genetic testing for hereditary cancer. To determine how often family members undergo cascade testing and to evaluate demographic, socioeconomic, and clinical factors associated with this process. This retrospective cross-sectional study analyzed demographics, cancer history, genetic test results, and cascade testing data from probands who underwent multigene panel testing between December 2016 and August 2020 at a single diagnostic laboratory. The study cohort included probands found to have a pathogenic or likely pathogenic variant (P/LPV) in Lynch syndrome (MLH1, MSH2, MSH6, PMS2, or EPCAM) or hereditary breast and ovarian cancer (ATM, BRCA1, BRCA2, CHEK2, or PALB2) genes. Statistical analyses were conducted between June 2023 and March 2025. Identification of a P/LPV in a cancer predisposition gene. Variables assessed included proband age, sex, race and ethnicity, socioeconomic status (SES), availability of free testing for family members, cancer history, type of test ordered, and clinician credentials. Differences in cascade testing rates were calculated via 2-sided χ2 test. Of 22 932 probands (18 949 [81.38%] female; mean [SD] age at testing. 51.6 [14.5] years), 5559 (24.24%) had at least 1 family member who underwent cascade testing. Higher rates of cascade testing were seen in individuals aged 40 to 79 years compared with those aged 20 to 39 years (age 40-59 years: 2587 of 10 420 probands [24.83%]; P < .001; age 60-79 years: 1960 of 6869 probands [28.53%]; P < .001; age ≥80 years: 129 of 462 probands [27.92%]; P < .001), women (4740 of 18 948 female probands [25.02%] vs 817 of 3963 male probands [20.62%]; P < .001), non-Hispanic White individuals (3762 of 13 834 probands [27.19%]), those with a personal cancer history vs those without (4712 of 16 674 probands [39.43%] vs 847 of 6261 probands [15.64%]; P < .001), and those whose care involved genetic counselors vs those whose did not (3614 of 13 847 probands [26.10%] vs 1948 of 9088 probands [21.43%]; P < .001). People with BRCA1 or BRCA2 variants had higher cascade testing rates compared with those with ATM, CHEK2, or PALB2 variants (2614 of 9699 probands [26.95%] vs 2015 of 8973 probands [22.46%]; P < .001). Several disparities were identified, including lower rates of cascade testing among male probands and probands from racial or ethnic minority groups compared with non-Hispanic White probands (227 of 1406 African American or Black probands [16.15%]; P < .001; 175 of 875 Asian probands [20.00%]; P < .001; 319 of 1616 Hispanic probands [19.74%]; P < .001; 17 of 146 Middle Eastern probands [11.64%]; P < .001). SES had minimal associations with testing rates, and free family testing was not associated with boosting participation. In this retrospective cross-sectional study, cascade testing was underused, especially among specific demographic groups, with clinical and cultural factors appearing to play a larger role than financial barriers. These findings may guide efforts to address barriers preventing wider uptake of cascade testing and improve cancer prevention efforts, particularly among racial and ethnic minority groups.
Few studies have directly compared outcomes according to blood pressure (BP) levels across different age groups in hemodialysis (HD) patients. This study aimed to identify the optimal pre-dialysis BP range associated with key clinical outcomes across different age groups in a large cohort of patients undergoing HD. We analyzed 42,258 maintenance HD patients, retrospectively linked to claims and mortality data. Pre-dialysis BP was categorized into six systolic and six diastolic ranges. Baseline demographics, comorbidities, laboratory markers, and medication use were extracted. Patients were followed until June 2024 for all-cause mortality, cardiovascular events, dementia, and fractures. Outcomes were assessed with Kaplan-Meier curves and Cox proportional hazards models, adjusting for demographic, clinical, and treatment variables. Baseline characteristics differed significantly across age groups (< 65, 65-74, ≥ 75 years). Higher systolic and diastolic BP values were associated with increased risks of all-cause mortality and cardiovascular events in most groups. Mildly reduced BP levels were often protective, particularly against CVEs. In younger patients, elevated BP was linked to higher risks of dementia and fractures, while in older groups, associations were weaker or reversed. Overall, elevated BP conferred excess risk, whereas modestly lower BP tended to reduce adverse outcomes, highlighting age-specific variations in prognostic impact. Our results suggest that intensive BP control is necessary for favorable outcomes regardless of age, except in cases of severe hypotension in younger patients.
To apply group-based trajectory modeling (GBTM) to longitudinal real world data from patients with systemic lupus erythematosus (SLE) to identify distinct disease activity trajectories and factors associated with 6 month clinical status. A total of 91 patients with SLE treated between 2017 and 2024 were included. SLE Disease Activity Index 2000 (SLEDAI-2K) scores were assessed at baseline, 3 months, and 6 months. GBTM was used to characterize longitudinal disease activity patterns. Heatmap clustering analysis was performed to compare clinical laboratory variables and SLEDAI-2K scores across trajectory groups and to further explore their association with 6 month clinical status. Two distinct disease activity trajectories were identified. Class 1, comprising patients with higher initial SLEDAI-2K scores, was predominantly composed of nonremission cases (90.91%). Class 2, characterized by lower initial SLEDAI-2K scores, showed a more balanced distribution of nonremission (46.81%) and remission (53.19%) patients. At 6 months, the remission subgroup had significantly lower SLEDAI-2K scores and lower urinary biomarker levels, including 24 h urinary microalbumin (24 h-UMA), 24 h urinary micrototal protein (24 h-UMTP), UMA, and UMTP, than the nonremission subgroup. Longitudinal monitoring of SLEDAI-2K trajectories may help identify patients at risk for persistent high disease activity or nonremission at 6 months and those who may benefit from closer monitoring and treatment adjustment. These findings support a stratified management approach in SLE based on trajectory profiles.
Pediatric fever of unknown origin (FUO) remains a major diagnostic challenge encompassing infectious, autoimmune and autoinflammatory as well as malignant diseases. Despite improved diagnostical procedures, no underlying disease can be identified in approximately one third of patients. Current guidelines recommend stepwise diagnostical approaches based on potential diagnostic clues (PDC+). This prospective nation-wide surveillance study aims to evaluate basic and advanced diagnostic procedures in the diagnostic of FUO. Via the German Pediatric Surveillance Unit, children were pseudonymized enrolled based on the following inclusion criteria: fever ≥ 38.5 °C for at least five out of ten consecutive days and no identifiable cause after standard diagnostic workup. The questionnaire collected patient data, symptoms, performed diagnostic workup, and the final diagnosis, if applicable. Among 113 included children, an underlying disease was identified in 72 cases (63.7%). 26 patients (23.1%) had infections, 31 children (27.4%) had systemic onset juvenile idiopathic arthritis/Still's disease (sJIA/SD), and 15 children (13.3%) were classified as "other diagnoses" including autoinflammatory diseases, vasculitides, and malignancies. Children with sJIA/SD presented with more clinical symptoms (mean = 4.6, SD = 2.17) compared to those with infections (mean = 2.7, SD = 1.40, p=.002). Basic diagnostic workup revealed at least one PDC + in every case (mean = 6.6). Most PDC+ (mean = 3.1, SD = 1.82) were identified by history taking and physical examination as well as by laboratory testing and blood count (mean = 2.5 PDC+, SD = 1.32). A total of 370 basic imaging investigations, e.g. abdominal ultrasound and echocardiography, provided in total 50 PDCs+ demonstrating their high diagnostical yield. Primarily in children with unclear clinical presentation advanced imaging revealed PDC+. Overall, the number of misleading PDCs (PDC-) was low (mean = 1.0, SD = 1.14) with autoantibody testing being the basic diagnostic procedure accounting for the majority of PDC-. The results of this nation-wide surveillance study highlight the value of basic and advanced diagnostical approaches in the management of pediatric FUO. Careful history taking, physical examination, and targeted basic diagnostic testing can identify multiple PDC+ with only few misleading PDC-, which may contribute to diagnostic accuracy and avoid unnecessary testing. The findings can be introduced into guidelines in order to standardize and improve the diagnostic approaches in children with FUO.
Protein-DNA binding-site prediction is essential for understanding gene regulation and protein function, but remains difficult because DNA recognition depends on both sequence context and three-dimensional structure. We developed RGTBind, a graph transformer that combines multi-scale radial basis function distance encoding with a learnable threshold-gating mechanism to model spatially informative residue interactions. On the independent Test_129 and Test_181 benchmarks, RGTBind achieved the best F1, AUC, and MCC among the compared methods, supporting the value of distance-aware attention with structure-guided neighbor selection for residue-level protein-DNA binding-site prediction. Each protein was represented as a residue-level graph derived from AlphaFold2-predicted structures. Residue features included AlphaFold2 single representations, DSSP-derived structural descriptors, PSI-BLAST position-specific scoring matrices (PSSM), and HHblits hidden Markov model (HMM) profiles. Pairwise C α -C α distances were encoded using a multi-scale radial basis function scheme and incorporated into a graph transformer through spatially biased multi-head self-attention and a learnable threshold gate. Sequence redundancy was reduced with CD-HIT. The model was trained with AdamW using five-fold cross-validation on Train_573 and evaluated on the Test_129 and Test_181 benchmark datasets.
Ulcerative colitis treatment is hindered by side effects, relapse, individual variability, and poor intestinal barrier repair. Milk‑derived exosomes (exo) are safe; carry anti‑inflammatory miRNAs/proteins; and regulate immunity, epithelial repair, and gut microbiota. Here, we isolated donkey milk exo and characterized them. Exo showed typical features (TSG101, CD63, CD9) and contained 1212 miRNAs, with eca‑let‑7 g and eca‑miR‑148a being most abundant. Oral exo administration in DSS‑induced colitis mice significantly reduced body weight loss, colon shortening, and disease activity index. Exo enhanced intestinal barrier by upregulating Occludin, Claudin‑1, and ZO‑1; lowered pro‑inflammatory cytokines (IL‑1β, IL‑6, TNF‑α); increased anti‑inflammatory IL‑10; and attenuated oxidative stress and neutrophil infiltration. Mechanistically, eca‑let‑7 g directly targeted TLR4 3'UTR to inhibit NF‑κB, while eca‑miR‑148a targeted NLRP3 3'UTR to suppress the NLRP3‑Caspase‑1‑IL‑18 axis. Moreover, exo reshaped gut microbiota by reducing pathogenic Bacteroides and Desulfovibrio and enriching beneficial Akkermansia muciniphila and Turicibacter. Collectively, donkey milk exo alleviate DSS‑evoked colitis through two distinct mechanisms: miRNA‑mediated suppression of inflammatory pathways and gut microbiota modulation. These findings support donkey milk exo as a natural, orally deliverable therapeutic option for inflammatory bowel disease.
Keratinocytes, the dominant cell type in the melanoma microenvironment during tumor initiation, exhibit diverse effects on melanoma progression. Using a zebrafish model of melanoma and human cell co-cultures, we observed that keratinocytes undergo an epithelial-mesenchymal transition (EMT)-like transformation in the presence of melanoma, reminiscent of their behavior during wound healing. Surprisingly, overexpression of the EMT-transcription factor Twist in keratinocytes led to improved overall survival in zebrafish melanoma models, despite no change in tumor initiation rates. This survival benefit was attributed to reduced melanoma invasion, as confirmed by human cell co-culture assays. Single-cell RNA-sequencing revealed a unique melanoma cell cluster in the Twist-overexpressing condition, exhibiting a more differentiated, less invasive phenotype. Further analysis nominated homotypic jam3b-jam3b and pgrn-sort1a interactions between Twist-overexpressing keratinocytes and melanoma cells as potential mediators of the invasive restraint. Our findings suggest that EMT in the tumor microenvironment may paradoxically limit melanoma invasion through altered cell-cell interactions.
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RAD51 plays an essential role in maintaining genomic stability via homologous recombination (HR). Aberrant RAD51 expression compromises genomic integrity and influences cellular responses to DNA-damaging agents. RAD51 expression is tightly regulated in normal cells, and its increased expression is associated with therapeutic resistance and poor prognosis in various cancers. BRCA2, a tumor suppressor gene product, promotes HR by directly interacting with RAD51 via eight evolutionarily conserved BRC repeats (BRC1-8). Individual BRC repeats share relatively low sequence similarity and possess distinct biochemical properties. We previously reported that the expression of certain BRC repeat peptides alters RAD51 protein levels, suggesting that individual BRC repeats distinctly affect RAD51 expression. We aimed to identify the specific BRC repeat regions affecting RAD51 protein levels. Notably, BRC8 expression significantly elevated RAD51 protein levels and foci formation, possibly by inhibiting its ubiquitin-mediated degradation. Paradoxically, despite increased RAD51 foci formation, BRC8 expression significantly reduced HR repair efficiency and increased sensitivity to DNA-damaging agents. Our findings suggest that BRC8 overexpression stabilizes RAD51 by inhibiting ubiquitin-dependent degradation of RAD51, leading to increased persistence of RAD51 foci, indicating impaired timely removal of RAD51 from DNA damage sites and reduced HR efficiency. Moreover, altered cell cycle distribution may contribute to reduced non-homologous end-joining efficiency, further enhancing cellular sensitivity to DNA-damaging agents. Collectively, these findings provide a basis to further explore the potential of BRC8-based peptides as tools for modulating RAD51 stability and sensitizing cells to DNA damage.
The thalamus is a critical subcortical hub that relays sensorimotor information and regulates higher-order cognitive processes. Accurate delineation of thalamic nuclei is essential for elucidating disease mechanisms and tracking clinical progression. In this study, we compared two segmentation approaches implemented in FreeSurfer: the conventional structural method and a joint framework that integrates diffusion tensor imaging. Magnetic resonance imaging (MRI) data from 24 healthy controls (HC), 27 patients with cognitively normal Parkinson's disease (PD-CN), and 33 Parkinson's disease patients with mild cognitive impairment (PD-MCI) were analyzed. Segmentation methods were compared in HC to assess their effect on volume estimates. Group comparisons were then conducted separately for each method to evaluate sensitivity in detecting disease-related volumetric differences. Finally, nuclei with significant group effects in joint segmentation were tested for associations with Addenbrooke's Cognitive Examination-Revised (ACE-R) scores. Joint segmentation yielded systematically lower thalamic volume estimates than the structural method, with significant differences across hemispheres and nuclei in HC. Group-wise analyses revealed that joint segmentation, but not structural segmentation, detected significant atrophy in the right thalamus of PD-MCI patients. At the nuclei group level, joint segmentation showed greater sensitivity, identifying bilateral anterolateral and posterior nuclei as significantly reduced in PD-MCI relative to HC. Moreover, volumes of these nuclei correlated positively with ACE-R scores. These results highlight that methodological choices critically shape the detection of thalamic pathology in PD, suggesting that incorporating diffusion MRI into segmentation may improve sensitivity to cognitively relevant subnuclear changes and support early diagnosis and disease monitoring.
Non-O1/Non-O139 Vibrio cholerae isolates were recovered from three water samples from Lake Wonderwood near Seminole Beach, Florida. Two draft genomes assembled into five contigs (~4.1 Mb; GC 47.6%) and shared the same MLST type, whereas the third assembled into three contigs (~4.0 Mb; GC 47.4%) with a distinct MLST type.