SPIN1 facilitates chemoresistance and HR repair by promoting Tip60 binding to H3K9me3.

The tandem Tudor-like domain-containing protein Spindlin1 (SPIN1) is a transcriptional coactivator with critical functions in embryonic development and emerging roles in cancer. However, the involvement of SPIN1 in DNA damage repair has remained unclear. Our study shows that SPIN1 is recruited to DNA lesions through its N-terminal disordered region that binds to Poly-ADP-ribose (PAR), and facilitates homologous recombination (HR)-mediated DNA damage repair. SPIN1 promotes H3K9me3 accumulation at DNA damage sites and enhances the interaction between H3K9me3 and Tip60, thereby promoting the activation of ATM and HR repair. We also show that SPIN1 increases chemoresistance. These findings reveal a novel role for SPIN1 in the activation of H3K9me3-dependent DNA repair pathways, and suggest that SPIN1 may contribute to cancer chemoresistance by modulating the efficiency of double-strand break (DSB) repair.

A comparative analysis of MMR immunohistochemistry panels: Evaluating the utility of four-protein versus two-protein panels in endometrial cancer patients.

AIMS: This study aimed to assess the accuracy of a two-protein panel for mismatch repair (MMR) immunohistochemistry (IHC) compared to a four-protein panel in a cohort of endometrial cancer patients. METHODS: The study included patients diagnosed with endometrial cancer between January 2018 and December 2023 with patients underwent MMR IHC staining for the four-protein panel (MSH2, MSH6, MLH1, and PMS2) serving as the reference standard. Various combinations of two proteins were examined and evaluated for their accuracy against the four-protein panel. Sensitivity, negative predictive value (NPV), and negative likelihood ratio were calculated for each combination. McNemar's test was performed to assess discordance, and receiver operating characteristic (ROC) curves were generated to evaluate diagnostic accuracy. RESULTS: Of 593 patients, MMR deficiency defined as at least one protein loss was observed in 146 patients (24.62%). When compared with four-protein panel, the highest sensitivity was observed with the MSH6/PMS2 combination (99.32%), followed sequentially by MSH6/MLH1 (97.26%), MSH2/PMS2 (93.15%), MSH2/MLH1 (91.10%), MLH1/PMS2 (79.45%), and MSH2/MSH6 (21.92%). The MSH6/PMS2 combination also demonstrated the best NPV of 99.78% and negative likelihood ratio of 0.01, while MSH6/MLH1 showed satisfactory NPV of 99.11% and negative likelihood ratio of 0.03. McNemar's test revealed no statistical difference between the four-protein panel and the MSH6/PMS2 panel (p = 1.000), and the MSH6/MLH1 panel (p = 0.125). CONCLUSIONS: The two-protein panel, particularly MSH6/PMS2, offers high sensitivity and negative predictive value, suggesting its potential as a cost-effective alternative to the four-protein panel in MMR testing for endometrial cancer patients.

Perspectives from cystinosis: access to healthcare may be a confounding factor for variant classification.

Genetic variability persists across diverse populations, and it may impact the characterization of heritable diseases in different ancestral groups. Cystinosis is a metabolic disease caused by pathogenic variants in the CTNS gene causing the cellular accumulation of cystine. We attempted to assess the currently poorly characterized prevalence of cystinosis by employing a population genetics methodology. However, we encountered a significant challenge due to genetic variations across different populations, and the consideration of potential disparities in access to healthcare made our results inconclusive. Pathogenic CTNS variants were identified in a representative global population cohort using The Human Gene Mutation Database (HGMD) and the 1000 Genomes (1 KG) database. The c.124G>A (p.Val42Ile) variant was reported to be pathogenic based on an observation in the white population presenting with atypical phenotypes, but it would be reclassified as benign in the African ancestral group if applying the ACMG allele frequency guideline due to its high allele frequency specifically in this population. Inclusion or exclusion of this c.124G>A (p.Val42Ile) variant results in a significant change in estimated disease prevalence, which can impact the diagnosis and treatment of affected patients with a broad range of phenotypic presentations. This observation led us to postulate that pathogenic manifestations of the disease may be underdiagnosed due to variable expressivity and systemic inequities in access to care, specifically in the African subpopulation. We call for a more cautious and inclusive approach to achieve more equitable care across diverse populations.

Predictive value of the early postoperative hemoglobin-to-red blood cell distribution width ratio for acute kidney injury in elderly intertrochanteric fracture patients.

BACKGROUND: Hemoglobin-to-red blood cell distribution width ratio (HRR) had great predictive value for the prognosis of malignant tumors and cardiovascular disease. However, its predictive value for the occurrence of acute kidney injury (AKI) in elderly intertrochanteric fracture patients remains unclear. This study aims to analyze the correlation between the early postoperative HRR and the risk of postoperative AKI in elderly intertrochanteric fracture patients. METHODS: We reviewed the medical records of 307 elderly intertrochanteric fracture patients in this single-center retrospective cohort study. We performed univariate analysis on the relevant parameters, and parameters with significant differences were included in the following logistic regression model for multivariate analysis. Then, we used a receiver operating characteristic (ROC) curve to evaluate the predictive value of the early postoperative HRR level for AKI in elderly intertrochanteric fracture patients. Patients were divided into a high HRR group and a low HRR group according to the cutoff point determined by ROC curve analysis. Subsequently, the relevance between postoperative HRR and AKI was further determined using propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). RESULTS: The area under the curve of the early postoperative HRR for predicting postoperative AKI was 0.714 (95% CI: 0.618-0.809). The cutoff value was 5.44. The sensitivity was 72.7%, and the specificity was 70.8%. Patients were divided into low HRR (⩽ 5.44) and high HRR (> 5.44) groups according to the cutoff value. PSM and IPTW analysis indicated that the risk of AKI in the low HRR group was significantly higher than that in the high HRR group in both the matched cohort (OR = 6.914, 95% CI: 1.714-46.603, p = 0.016) and the weighted group (OR = 2.784, 95% CI: 1.415-5.811, p = 0.040). CONCLUSIONS: Early postoperative HRR is an accurate, accessible, and economical blood test parameter that can predict the risk of postoperative AKI in elderly patients with femoral intertrochanteric fracture.

Utilizing Plasma-Based Next-Generation Sequencing to Expedite the Diagnostic Process in Suspected Lung Cancer: A Case Report.

Lung cancer is the leading cause of cancer mortality worldwide. Fortunately, the advent of precision medicine, which includes targeted therapy and immunotherapy, offers hope. However, identifying specific mutations is imperative before initiating precise medications. Traditional methods, such as real-time PCR examination of individual mutations, are time-consuming. Contemporary techniques, such as tissue- and plasma-based next-generation sequencing (NGS), allow comprehensive genome analysis concurrently. Notably, plasma-based NGS has a shorter turnaround time (TAT) and thus a shorter time-to-treatment (TTT). In this case report, we demonstrate the benefits of plasma-based NGS before pathological diagnosis in a patient with image-suspected non-small cell lung cancer (NSCLC). An 82-year-old Taiwanese woman presented with lower back pain persisting for one month and left-sided weakness for two weeks. Whole-body computed tomography (CT) revealed lesions suspicious for brain and bone metastases, along with a mass consistent with a primary tumor in the left upper lobe, indicative of advanced NSCLC with T4N3M1c staging. The patient underwent a bronchoscopic biopsy on Day 0, and the preliminary report that came out on Day 1 was suggestive of metastatic NSCLC. Blood was also collected for plasma-based NGS on Day 0. The patient was Coronavirus disease 2019-positive and was treated with molnupiravir on Day 6. On Day 7, pathology confirmed pulmonary adenocarcinoma, and the results of plasma-based NGS included EGFR L858R mutation. The patient was started on targeted therapy (afatinib) on Day 9. Unfortunately, the patient died of hypoxic respiratory failure on Day 26, a complication of underlying viral infection. Plasma-based NGS offers a rapid and efficient means of mutation detection in NSCLC, streamlining treatment initiation and potentially improving the negative emotions of patients. Its utility, particularly in regions with a high prevalence of specific mutations, such as EGFR alterations in East Asian populations, highlights its relevance in guiding personalized therapy decisions.

Uptake of Typical Hydrophobic Organic Contaminants in Vegetables: Evidence From Passive Samplers.

Quantifying the root uptake of hydrophobic organic contaminants (HOCs) by plants remains challenging due to the lack of data on the freely available fractions of HOCs in soil porewater. We therefore hypothesized that a passive sampler could act as a useful tool to evaluate the root uptake potential and pathways of HOCs by plants in soil. We tested this hypothesis by exploring the uptake of polybrominated diphenyl ethers (PBDEs) and organophosphate esters (OPEs) by carrot and lettuce with the codeployment of passive samplers in a contaminated soil system. The results showed that the amounts of PBDEs enriched in carrot and lettuce were positively correlated with those in a passive sampler (r2 = 0.46-0.88). No concentration correlation was observed for OPEs between lettuce and passive samplers, due to possible degradation of OPEs in lettuce. The root-to-porewater ratios of PBDEs and OPEs, respectively, were 6.2 to 11 and 0.05 to 0.88 L g-1 for carrot, and 8.8 to 130 and less than reporting limits to 1.2 L g-1 for lettuce. The ratios were negatively correlated with log KOW values for carrot, but increased with increasing log KOW values over a range of 1.97 to 6.80, and then decreased with log KOW values greater than 6.80 for lettuce. This finding indicated that passive transport and partition were the accumulation pathways of PBDEs and OPEs in carrot and lettuce, respectively. Overall, passive samplers performed adequately in assessing the available fractions of persistent HOCs in plants, and can serve as a viable tool for exploring the pathways for plant root uptake of HOCs. Environ Toxicol Chem 2024;00:1-12. © 2024 SETAC.

Evolving treatment paradigms for platinum-resistant ovarian cancer: An update narrative review.

Platinum-resistant ovarian cancer (PROC) refers to disease progression within 6 months after the completion of platinum-based chemotherapy. Historically, treatment options for PROC were limited with a poor prognosis and non-platinum single agent plus bevacizumab has been the mainstay of treatment. Fortunately, there have been notable advancements in recent years, leading to an advance in treatment paradigms for this challenging disease. Various combinations of chemotherapy, targeted agents such as poly (ADP-ribose) polymerase (PARP) inhibitors, and immunotherapy are being explored for an improved treatment outcome. Antibody-drug conjugates targeting folate receptor alpha, which deliver a cytotoxic payload directly to cancer cells, have emerged as a promising therapeutic approach for PROC. WEE1 inhibitors, such as adavosertib, function by inhibiting the WEE1 kinase activity, leading to premature entry of a cell into mitosis phase and thus increased DNA damage. It has been observed that cancer cells with TP53 mutations may be more sensitive to WEE1 inhibitors. Biomarker testing such as analysis of the expression level of folate receptor alpha or mutation in TP53 may be applicable for identifying patients who are more likely to respond to the specific therapy, enabling a more personalized treatment approach. This overview summarizes key clinical findings on the efficacy and safety of theses novel biomarker-driven therapeutic approaches.

Chemoselectivity Switch between Enantioselective [2,3]-Wittig Rearrangement and Conia-Ene-Type Reactions of Propargyloxyoxindoles.

Despite the existence of three competing reactions for propargyloxyoxindoles, we report a chemoselectivity switch between enantioselective propargyl [2,3]-Wittig rearrangement and Conia-ene-type reactions, with suppression of the [1,2]-Wittig-type rearrangement. Using C1-symmetric imidazolidine-pyrroloimidazolone pyridine as the ligand and Ni(acac)2 as the Lewis acid, diverse 3-hydroxy 3-substituted oxindoles containing allenyl groups were obtained in up to 98% yield and 99% ee via asymmetric propargyl [2,3]-Wittig rearrangement. In the presence of AgOTf-Duanphos, chiral spiro dihydrofuran oxindoles were given in up to 98% yield and 91% ee through a Conia-ene-type reaction.

Cost-Utility Analysis of Bilateral Cochlear Implants for Children With Severe-to-Profound Sensorineural Hearing Loss in Taiwan.

OBJECTIVES: Cochlear implants are an option for children with sensorineural hearing loss who do not benefit from hearing aids. Although bilateral cochlear implantation (CI) has been shown to enhance hearing performance and quality of life, its cost-effectiveness remains unclear. This study aimed to evaluate the cost-effectiveness of bilateral CI compared with bimodal hearing for children with sensorineural hearing loss in Taiwan from both the perspectives of patients and Taiwan's National Health Insurance Administration (TNHIA). DESIGN: A four-state Markov model was utilized in the study, including "use the first internal device," "use the second internal device," "use the third internal device," and "death." Health utility values were obtained from a local survey of health professionals and then adjusted by a scale to reflect both the negative impact of aging on hearing and the time needed to develop the full benefit of treatment in the earliest years of life. The cost data were derived from a caregiver survey, hospital databases, clinical experts, and the TNHIA. The incremental cost-effectiveness ratio (ICER) was calculated over the lifetime horizon and presented as cost per quality-adjusted life year (QALY) to evaluate the cost-effectiveness of simultaneous bilateral CI, sequential bilateral CI, and bimodal hearing. In addition, one-way sensitivity analyses and probabilistic sensitivity analyses were conducted to investigate the impact of uncertainty and the robustness of the model. RESULTS: The base-case analysis showed that children with bilateral CI gained more QALYs while incurring more costs when compared with those with bimodal hearing. From the TNHIA perspective, compared with bimodal hearing, the ICER of simultaneous bilateral CI was New Taiwan Dollars 232,662 per QALY whereas from the patient perspective, the ICER was New Taiwan Dollars 1,006,965 per QALY. Moreover, simultaneous bilateral CI dominated sequential bilateral CI from both perspectives. Compared with bimodal hearing, the ICER of sequential bilateral CI did not exceed twice the gross domestic product per capita in Taiwan from either perspective. One-way sensitivity analysis demonstrated that the utility gain of bilateral CI compared with bimodal hearing was the most impactful parameter from both perspectives. Probabilistic sensitivity analysis confirmed the robustness of the base-case analysis results. CONCLUSIONS: Our findings reveal that bilateral CI was cost-effective when using the threshold of one to three times the 2022 gross domestic product per capita in Taiwan from both the TNHIA and patient perspectives. Future research incorporating cost and effectiveness data from other dimensions is needed to help decision-makers assess the cost-effectiveness of bilateral CI more comprehensively.

Enhanced native chemical ligation by peptide conjugation in trifluoroacetic acid.

Chemical ligation of peptides is increasingly used to generate proteins not readily accessible by recombinant approaches. However, a robust method to ligate "difficult" peptides remains to be developed. Here, we report an enhanced native chemical ligation strategy mediated by peptide conjugation in trifluoroacetic acid (TFA). The conjugation between a carboxyl-terminal peptide thiosalicylaldehyde thioester and a 1,3-dithiol-containing peptide in TFA proceeds rapidly to form a thioacetal-linked intermediate, which is readily converted into the desired native amide bond product through simple postligation treatment. The effectiveness and practicality of the method was demonstrated by the successful synthesis of several challenging proteins, including the SARS-CoV-2 transmembrane Envelope (E) protein and nanobodies. Because of the ability of TFA to dissolve virtually all peptides and prevent the formation of unreactive peptide structures, the method is expected to open new opportunities for synthesizing all families of proteins, particularly those with aggregable or colloidal peptide segments.

Association between Air Quality Index and the risk of rosacea: A Nationwide population-based Cohort Study.

BACKGROUND: Air pollution is associated with several inflammatory skin disorders. However, the association between air quality and rosacea remains unclear. OBJECTIVE: To investigate the association between air quality index and incidence of rosacea. METHODS: Overall, 21,709,479 participants without rosacea before 2008 were recruited from the Taiwan National Health Insurance Research Database. The long-term average air quality index (AQI) value for each participant was acquired from the Taiwan Air Quality Monitoring System Network and calculated from 2008/1/1 until the diagnosis of rosacea, withdrawal from the National Health Insurance, or December 31, 2018. RESULTS: We observed a significant association between AQI and the incidence of rosacea, with each unit elevation in AQI increasing the risk of rosacea by 5 %. Compared with the Q1 group, the Q2, Q3, and Q4 cohorts exhibited 1.82-fold, 4.48-fold and 7.22-fold increased risk of rosacea, respectively. Additionally, exposure to PM2.5, SO2 and CO increased the risk of rosacea, whereas exposure to PM10 was associated with a lower risk. CONCLUSION: This study supported a significant dose-response relationship between AQI and the incidence of rosacea.

Incidental Findings in Lung Cancer Screening.

While low-dose computed tomography (LDCT) for lung cancer screening (LCS) has been recognized for its effectiveness in reducing lung cancer mortality, it often simultaneously leads to the detection of incidental findings (IFs) unrelated to the primary screening indication. These IFs present diagnostic and management challenges, potentially causing unnecessary anxiety and further invasive diagnostic procedures for patients. This review article provides an overview of IFs encountered in LDCT, emphasizing their clinical significance and recommended management strategies. We categorize IFs based on their anatomical locations (intrathoracic-intrapulmonary, intrathoracic-extrapulmonary, and extrathoracic) and discuss the most common findings. We highlight the importance of utilizing guidelines and standardized reporting systems by the American College of Radiology (ACR) to guide appropriate follow-ups. For each category, we present specific IF examples, their radiologic features, and the suggested management approach. This review aims to provide radiologists and clinicians with a comprehensive understanding of IFs in LCS for accurate assessment and management, ultimately enhancing patient care. Finally, we outline a few key aspects for future research and development in managing IFs.

The correlation between the MYBL2/CDCA8 signaling pathway of malignant melanoma.

Objective: Investigating the effects of MYB proto-oncogene like 2 (MYBL2)-mediated regulation of Cell division cycle associated 8 (CDCA8) expression on the biological activity of cutaneous malignant melanoma cells. Methods: A375 cells with MYBL2 and CDCA8 overexpression and knockdown were evaluated using migration, invasion, and proliferation assays. Besides, cell apoptosis was quantified by flow cytometry. To investigate the tumorigenic effects of MYBL2 knockdown in vivo, A375 cells with MYBL2 knockdown were injected in BALB/C nude mice. Results: The levels of MYBL2 and CDCA8 gene expression were notably elevated in A375 cells in comparison to HaCat cells (P < 0.05). Downregulation of MYBL2 led to a notable reduction in the migratory and invasive capability of A375 cells in vitro (P < 0.001). On the contrary, overexpression of MYBL2 enhanced migration and invasion ability (P < 0.001). There existed a positive correlation between CDCA8 and MYBL2 gene and protein expression levels after overexpression or knockdown of MYBL2 (P < 0.001). In the in vivo tumorigenic study, the MYBL2 knockdown group displayed a substantial decrease in tumor volume (P < 0.01) and exhibited decreased CDCA8 expression in tumors in comparison to the control group. Conclusion: We arrived at such a conclusion that MYBL2 promoted the migration, invasion and proliferation ability of cutaneous malignant melanoma cells by targeted regulation of CDCA8 expression in this study.

Metabolic Engineering of Corynebacterium glutamicum for the High-Level Production of l-Valine under Aerobic Conditions.

l-Valine, an essential amino acid, serves as a valuable compound in various industries. However, engineering strains with both high yield and purity are yet to be delivered for microbial l-valine production. We engineered a Corynebacterium glutamicum strain capable of highly efficient production of l-valine. We initially introduced an acetohydroxy acid synthase mutant from an industrial l-valine producer and optimized a cofactor-balanced pathway, followed by the activation of the nonphosphoenolpyruvate-dependent carbohydrate phosphotransferase system and the introduction of an exogenous Entner-Doudoroff pathway. Subsequently, we weakened anaplerotic pathways, and attenuated the tricarboxylic acid cycle via start codon substitution in icd, encoding isocitrate dehydrogenase. Finally, to balance bacterial growth and l-valine production, an l-valine biosensor-dependent genetic circuit was established to dynamically repress citrate synthase expression. The engineered strain Val19 produced 103 g/L of l-valine with a high yield of 0.35 g/g glucose and a productivity of 2.67 g/L/h. This represents the highest reported l-valine production in C. glutamicum via direct fermentation and exhibits potential for its industrial-scale production, leveraging the advantages of C. glutamicum over other microbes.

A multi-orientation system for characterizing microstructure changes and mechanical responses of fine-grained gassy sediments associated with gas hydrates.

Fine-grained marine sediments containing veiny and nodular gas hydrates will evolve into fine-grained gassy sediments after hydrate dissociation due to climate-driven ocean warming. The mechanical properties of the fine-grained gassy sediments are basically acquired by ocean engineering design. However, they have not been fully understood, largely due to the lack of microstructure visualization. In this paper, a new system is developed to jointly conduct x-ray computed tomography scans, oedometer tests, and seismic wave testing on a single specimen with temperature being well controlled, allowing varieties of experimental data to be acquired effectively and automatically. The results show that stress history can hardly affect the undrained stiffness of fine-grained gassy sediments, while the drained stiffness of fine-grained sediments without gas bubbles is stress history dependent. After being unloaded, many microstructure changes remain, and examples include the free gas distribution being more concentrated and the connectivity among gas bubbles becoming much better. The multi-orientation system lays the foundation for further studies on the microstructure changes and mechanical responses of fine-grained gassy sediments associated with gas hydrates.

AssemblyQC: a Nextflow pipeline for reproducible reporting of assembly quality.

SUMMARY: Genome assembly projects have grown exponentially due to breakthroughs in sequencing technologies and assembly algorithms. Evaluating the quality of genome assemblies is critical to ensure the reliability of downstream analysis and interpretation. To fulfil this task, we have developed the AssemblyQC pipeline that performs file-format validation, contaminant checking, contiguity measurement, gene- and repeat-space completeness quantification, telomere inspection, taxonomic assignment, synteny alignment, scaffold examination through Hi-C contact-map visualization, and assessments of completeness, consensus quality and phasing through k-mer analysis. It produces a comprehensive HTML report with method descriptions, tables, and visualizations. AVAILABILITY AND IMPLEMENTATION: The pipeline uses Nextflow for workflow orchestration and adheres to the best-practice established by the nf-core community. This pipeline offers a reproducible, scalable, and portable method to assess the quality of genome assemblies-the code is available online at GitHub: https://github.com/Plant-Food-Research-Open/assemblyqc.

Amplifying hepatic L-aspartate levels suppresses CCl4-induced liver fibrosis by reversing glucocorticoid receptor ß-mediated mitochondrial malfunction.

Liver fibrosis is a determinant-stage process of many chronic liver diseases and affected over 7.9 billion populations worldwide with increasing demands of ideal therapeutic agents. Discovery of active molecules with anti-hepatic fibrosis efficacies presents the most attacking filed. Here, we revealed that hepatic L-aspartate levels were decreased in CCl4-induced fibrotic mice. Instead, supplementation of L-aspartate orally alleviated typical manifestations of liver injury and fibrosis. These therapeutic efficacies were alongside improvements of mitochondrial adaptive oxidation. Notably, treatment with L-aspartate rebalanced hepatic cholesterol-steroid metabolism and reduced the levels of liver-impairing metabolites, including corticosterone (CORT). Mechanistically, L-aspartate treatment efficiently reversed CORT-mediated glucocorticoid receptor ß (GRß) signaling activation and subsequent transcriptional suppression of the mitochondrial genome by directly binding to the mitochondrial genome. Knockout of GRß ameliorated corticosterone-mediated mitochondrial dysfunction and hepatocyte damage which also weakened the improvements of L-aspartate in suppressing GRß signaling. These data suggest that L-aspartate ameliorates hepatic fibrosis by suppressing GRß signaling via rebalancing cholesterol-steroid metabolism, would be an ideal candidate for clinical liver fibrosis treatment.

Longitudinal on-treatment circulating tumor DNA as a biomarker for real-time dynamic risk monitoring in cancer patients: The EP-SEASON study.

Recurrence risks of cancer patient can change during treatment as a result of treatment-related tumor evolution. However, biomarkers that can monitor these changes are lacking. Here, we investigated whether tracking circulating tumor DNA (ctDNA) dynamics through liquid biopsy can inform real-time recurrence risk. Nasopharyngeal carcinoma (NPC) provides an ideal model where cell-free Epstein-Barr virus (EBV) DNA (cfEBV DNA), a ctDNA, can be sensitively detected. We conducted the EP-SEASON study (NCT03855020) and prospectively recruited 1,000 NPC patients undergoing per-protocol cfEBV DNA assessments at 11 time points and receiving sequential chemo-radiotherapy. Longitudinal cfEBV DNA displayed distinct patterns during neoadjuvant chemotherapy and radiotherapy. Despite the prognostic significance of cfEBV DNA at each time point, real-time recurrence risks changed in sync with cfEBV DNA dynamics. Furthermore, we identified phenotypes of whole-course ctDNA changing dynamics associated with different survival outcomes. In conclusion, tracking longitudinal on-treatment ctDNA can forecast real-time recurrence risk, facilitating risk-adapted, individualized patient management.

How Progesterone Receptor Expression Impacts Platinum Sensitivity in Ovarian Clear Cell Carcinoma: Insights from Clinical and Experimental Perspectives.

Ovarian clear cell carcinoma (OCCC) is often considered a relatively platinum-resistant malignancy. The aim of this study was to explore the influence of progesterone receptor (PR) expression levels on platinum sensitivity and survival outcomes in people with OCCC. A retrospective analysis was conducted with 80 people with OCCC who underwent surgery followed by adjuvant chemotherapy. PR expression was assessed via immunohistochemical (IHC) staining and quantified using the H score. The platinum sensitivity and survival outcomes of patients with weak and strong PR expression were compared. Additionally, cisplatin viability and migration experiments were conducted with OCCC cell lines (ES-2 and TOV-21G) with varying PR isoform expressions. Among the 80 patients, 62 were classified as having platinum-sensitive disease, while 18 had platinum-resistant disease. The mean total PR H- score of platinum-sensitive tumors was significantly higher than that of platinum-resistant tumors (p = 0.002). Although no significant differences in progression-free and overall survival were observed between patients with high and low PR expression, those with high PR expression tended to have longer survival. While PR protein was only weakly detectable in ES-2 and TOV-21G cells, a transfection of the PR-A or PR-B gene resulted in a strong expression of PR-A or PR-B, which led to significantly reduced proliferation and migration in ES-2 and TOV-21G cells. Furthermore, overexpression of PR-A or PR-B enhanced cisplatin cytotoxicity in these cell lines. In conclusion, strong PR expression was associated with improved platinum sensitivity and survival outcomes, consistent with our experimental findings. The potential of PR as a tumor sensitizer to cisplatin in OCCC warrants further investigation.

Nomogram based on immune-inflammatory indicators and age-adjusted charlson comorbidity index score to predict prognosis of postoperative parotid gland carcinoma patients.

BACKGROUND: Parotid gland carcinoma (PGC) is a rare malignant tumor. The purpose of this study was to investigate the role of immune-inflammatory-nutrition indicators and age-adjusted Charlson comorbidity index score (ACCI) of PGC and develop the nomogram model for predicting prognosis. METHOD: All patients diagnosed with PGC in two tertiary hospitals, treated with surgical resection, from March 2012 to June 2018 were obtained. Potential prognostic factors were identified by univariate and multivariate Cox regression analyses. The nomogram models were established based on these identified independent prognostic factors. The performance of the developed prognostic model was estimated by related indexes and plots. RESULT: The study population consisted of 344 patients with PGC who underwent surgical resection, 285 patients without smoking (82.8%), and 225 patients (65.4%) with mucoepidermoid carcinoma, with a median age of 50.0 years. American Joint Committee on Cancer (AJCC) stage (p < 0.001), pathology (p = 0.019), tumor location (p < 0.001), extranodal extension (ENE) (p < 0.001), systemic immune-inflammation index (SII) (p = 0.004), prognostic nutrition index (PNI) (p = 0.003), ACCI (p < 0.001), and Glasgow prognostic Score (GPS) (p = 0.001) were independent indicators for disease free survival (DFS). Additionally, the independent prognostic factors for overall survival (OS) including AJCC stage (p = 0.015), pathology (p = 0.004), tumor location (p < 0.001), perineural invasion (p = 0.009), ENE (p < 0.001), systemic immune-inflammation index (SII) (p = 0.001), PNI (p = 0.001), ACCI (p = 0.003), and GPS (p = 0.033). The nomogram models for predicting DFS and OS in PGC patients were generated based on these independent risk factors. All nomogram models show good discriminative capability with area under curves (AUCs) over 0.8 (DFS 0.802, and OS 0.825, respectively). Decision curve analysis (DCA), integrated discrimination improvement (IDI), and net reclassification index (NRI) show good clinical net benefit of the two nomograms in both training and validation cohorts. Kaplan-Meier survival analyses showed superior discrimination of DFS and OS in the new risk stratification system compared with the AJCC stage system. Finally, postoperative patients with PGC who underwent adjuvant radiotherapy had a better prognosis in the high-, and medium-risk subgroups (p < 0.05), but not for the low-risk subgroup. CONCLUSION: The immune-inflammatory-nutrition indicators and ACCI played an important role in both DFS and OS of PGC patients. Adjuvant radiotherapy had no benefit in the low-risk subgroup for PGC patients who underwent surgical resection. The newly established nomogram models perform well and can provide an individualized prognostic reference, which may be helpful for patients and surgeons in proper follow-up strategies.