Genetics of Female Pelvic Organ Prolapse: Up to Date.

Pelvic organ prolapse (POP) is a benign disease characterized by the descent of pelvic organs due to weakened pelvic floor muscles and fascial tissues. Primarily affecting elderly women, POP can lead to various urinary and gastrointestinal tract symptoms, significantly impacting their quality of life. The pathogenesis of POP predominantly involves nerve-muscle damage and disorders in the extracellular matrix metabolism within the pelvic floor. Recent studies have indicated that genetic factors may play a crucial role in this condition. Focusing on linkage analyses, single-nucleotide polymorphisms, genome-wide association studies, and whole exome sequencing studies, this review consolidates current research on the genetic predisposition to POP. Advances in epigenetics are also summarized and highlighted, aiming to provide theoretical recommendations for risk assessments, diagnoses, and the personalized treatment for patients with POP.

Lipid metabolism reprogramming in endometrial cancer: biological functions and therapeutic implications.

BACKGROUND: Endometrial cancer is one of the major gynecological cancers, with increasing incidence and mortality in the past decades. Emerging preclinical and clinical data have indicated its close association with obesity and dyslipidemia. Metabolism reprogramming has been considered as the hallmark of cancer, to satisfy the extensive need of nutrients and energy for survival and growth. Particularly, lipid metabolism reprogramming has aroused the researchers' interest in the field of cancer, including tumorigenesis, invasiveness, metastasis, therapeutic resistance and immunity modulation, etc. But the roles of lipid metabolism reprogramming in endometrial cancer have not been fully understood. This review has summarized how lipid metabolism reprogramming induces oncogenesis and progression of endometrial cancer, including the biological functions of aberrant lipid metabolism pathway and altered transcription regulation of lipid metabolism pathway. Besides, we proposed novel therapeutic strategies of targeting lipid metabolism pathway and concentrated on its potential of sensitizing immunotherapy and hormonal therapy, to further optimize the existing treatment modalities of patients with advanced/metastatic endometrial cancer. Moreover, we expect that targeting lipid metabolism plus hormone therapy may block the endometrial malignant transformation and enrich the preventative approaches of endometrial cancer. CONCLUSION: Lipid metabolism reprogramming plays an important role in tumor initiation and cancer progression of endometrial cancer. Targeting the core enzymes and transcriptional factors of lipid metabolism pathway alone or in combination with immunotherapy/hormone treatment is expected to decrease the tumor burden and provide promising treatment opportunity for patients with advanced/metastatic endometrial cancer.

Somatic MED12 Mutations in Myometrial Cells.

Over 70% of leiomyoma (LM) harbor MED12 mutations, primarily in exon 2 at c.130-131 (GG). Myometrial cells are the cell origin of leiomyoma, but the MED12 mutation status in non-neoplastic myometrial cells is unknown. In this study, we investigated the mutation burden of MED12 in myometrium. As traditional Sanger or even NGS sequencing may not be able to detect MED12 mutations that are lower than 0.1% in the testing sample, we used duplex deep sequencing analysis (DDS) to overcome this limitation. Tumor-free myometria (confirmed by pathology evaluation) were dissected, and genomic DNA from MED12 exon 2 (test) and TP53 exon 5 (control) were captured by customer-designed probe sets, followed by DDS. Notably, DDS demonstrated that myometrial cells harbored a high frequency of mutations in MED12 exon 2 and predominantly in code c.130-131. In contrast, the baseline mutations in other coding sequences of MED12 exon 2 as well as in the TP53 mutation hotspot, c.477-488 were comparably low in myometrial cells. This is the first report demonstrating a non-random accumulation of MED12 mutations at c.130-131 sites in non-neoplastic myometrial cells which provide molecular evidence of early somatic mutation events in myometrial cells. This early mutation may contribute to the cell origin for uterine LM development in women of reproductive age.

Cadherin-18 loss in prospermatogonia and spermatogonial stem cells enhances cell adhesion through a compensatory mechanism.

Extracellular membrane proteins are crucial for mediating cell attachment, recognition, and signal transduction in the testicular microenvironment, particularly germline stem cells. Cadherin 18 (CDH18), a type II classical cadherin, is primarily expressed in the nervous and reproductive systems. Here, we investigated the expression of CDH18 in neonatal porcine prospermatogonia (ProSGs) and murine spermatogonial stem cells (SSCs). Disruption of CDH18 expression did not adversely affect cell morphology, proliferation, self-renewal, or differentiation in cultured porcine ProSGs, but enhanced cell adhesion and prolonged cell maintenance. Transcriptomic analysis indicated that the down-regulation of CDH18 in ProSGs significantly up-regulated genes and signaling pathways associated with cell adhesion. To further elucidate the function of CDH18 in germ cells, Cdh18 knockout mice were generated, which exhibited normal testicular morphology, histology, and spermatogenesis. Transcriptomic analysis showed increased expression of genes associated with adhesion, consistent with the observations in porcine ProSGs. The interaction of CDH18 with ß-catenin and JAK2 in both porcine ProSGs and murine SSCs suggested an inhibitory effect on the canonical Wnt and JAK-STAT signaling pathways during CDH18 deficiency. Collectively, these findings highlight the crucial role of CDH18 in regulating cell adhesion in porcine ProSGs and mouse SSCs. Understanding this regulatory mechanism provides significant insights into the testicular niche.

Platelet indices and the risk of pulmonary arterial hypertension: a two-sample and multivariable Mendelian randomization study.

Background: Recent epidemiological studies have indicated a correlation between platelet indices and pulmonary arterial hypertension (PAH), yet the causality between them remains unclear. To explore the causal relationship between four platelet indices and PAH, with the aim of providing a theoretical basis for clinical prevention and treatment. Methods: Single-nucleotide polymorphisms (SNPs) associated with platelet-related traits were selected as exposure factors from published genome-wide association studies (GWAS), including: platelet count (PLT), plateletcrit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW). Summary-level data for PAH were obtained from the FinnGen study (248 cases and 289,117 controls). Two-sample and multivariable Mendelian randomization (MR) analyses were conducted to assess the causal relationship between exposure factors and the risk of outcomes. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach, supplemented by weighted median, mode-based estimation, MR-Egger regression, and the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) test to detect and adjust for pleiotropy, ensuring the reliability of the results through sensitivity analysis. Results: (1) The IVW results from the two-sample MR analysis showed a positive causal association between PLT and the risk of developing PAH [(OR = 1.649, 95%CI: 1.206-2.256, P = 0.0017)], with the sensitivity analysis confirming the robustness of the causal relationship. The MR-Egger intercept analysis did not detect potential pleiotropy (P = 0.879). (2) The MVMR results showed no statistically significant causal relationship between these four markers and the risk of developing PAH. After adjusting for collinearity, a direct positive causal association was observed between PLT and the risk of developing PAH (OR = 1.525, 95%CI: 1.063-2.189, P = 0.022). Conclusion: The positive correlation between PLT and the risk of PAH suggests that correcting elevated platelet levels may reduce the risk of developing PAH.

Systematic Review and Meta-Analysis of Particle Beam Therapy versus Photon Radiotherapy for Skull Base Chordoma: TRP-Chordoma 2024.

[Objective] The aim of this study was to compare the efficacy of particle beam therapy (PT) with photon radiotherapy (RT) for treatment of skull base chordoma. [Methods] A systematic review was conducted for skull base chordoma treated with PT or photon RT reported from 1990 to 2022. Data were extracted for overall survival (OS) and progression-free survival (PFS), late adverse events, age, gender, gross total resection (GTR) rates, tumor volume, total irradiation dose, and treatment modality. Random-effects meta-regression analysis with the treatment modality as an explanatory variable was performed for each outcome to compare the modalities. [Results] A meta-analysis of 30 selected articles found 3- and 5-year OS rates for PT vs. photon RT or combined photon RT/proton beam therapy (PBT) of 90.8% (95% CI: 87.4-93.3%) vs. 89.5% (95% CI: 83.0-93.6%), p = 0.6543; 80.0% (95% CI: 75.7-83.6%) vs. 89.5% (95% CI: 83.0-93.6%), p = 0.6787. The 5-year PFS rates for PT vs. photon RT or photon RT/PBT were 67.8% (95% CI: 56.5-76.7%) vs. 40.2% (95% CI: 31.6-48.7%), p = 0.0004. A random-effects model revealed that the treatment modality (PT vs. photon RT or photon RT/PBT) was not a significant factor for 3-year OS (p = 0.42) and 5-year OS (p = 0.11), but was a significant factor for 5-year PFS (p < 0.0001). The rates of brain necrosis were 8-50% after PT and 0-4% after photon RT or photon RT/PBT. [Conclusion] This study shows that PT results in higher PFS compared to photon RT for skull base chordoma, but that there is a tendency for a higher incidence of brain necrosis with PT. Publication and analysis of further studies is needed to validate these findings.

Pan-cancer analysis of the disulfidptosis-related gene RPN1 and its potential biological function and prognostic significance in gliomas.

Background: Numerous studies have shown a strong correlation between disulfidptosis and various cancers. However, the expression and function of RPN1, a crucial gene in disulfidptosis, remain unclear in the context of cancer. Methods: Gene expression and clinical information on lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. RPN1 expression was analyzed using the Timer2.0 and the Human Protein Atlas (HPA) databases. Prognostic significance was assessed using Cox regression analysis and Kaplan-Meier curves. Genetic mutations and methylation levels were examined using the cBioPortal and UALCAN platforms, respectively. The relationship between RPN1 and tumor mutation burden (TMB) and microsatellite instability (MSI) across different cancer types was analyzed using the Spearman correlation coefficient. The relationship between RPN1 and immune cell infiltration was analyzed using the Timer2.0 database, whereas variations in drug sensitivity were explored using the CellMiner database. Receiver operating characteristic curves validated RPN1's diagnostic potential in glioma, and its correlation with immune checkpoint inhibitors (ICIs) was assessed using Spearman's correlation coefficient. Single-sample gene set enrichment analysis elucidated a link between RPN1 and immune cells and pathways. In addition, a nomogram based on RPN1 was developed to predict patient prognosis. The functional impact of RPN1 on glioma cells was confirmed using scratch and Transwell assays. Result: RPN1 was aberrantly expressed in various cancers and affected patient prognosis. The main mutation type of RPN1 in the cancer was amplified. RPN1 exhibited a positive correlation with myeloid-derived suppressor cells, neutrophils, and macrophages, and a negative correlation with CD8+ T cells and hematopoietic stem cells. RPN1 expression was associated with TMB and MSI in various cancers. The expression of RPN1 affected drug sensitivity in cancer cells. RPN1 was positively correlated with multiple ICIs in gliomas. RPN1 also affected immune cell infiltration into the tumor microenvironment. RPN1 was an independent prognostic factor for gliomas, and the nomogram demonstrated excellent predictive performance. Interference with RPN1 expression reduces the migratory and invasive ability of glioma cells. Conclusion: RPN1 exerts multifaceted effects on different stages of cancer, including immune infiltration, prognosis, and treatment outcomes. RPN1 expression affects the prognosis and immune microenvironment infiltration in patients with glioma, making RPN1 a potential target for the treatment of glioma.

Toll-Like Receptors Mediate Opposing Dendritic Cell Effects on Treg/Th17 Balance in Mice With Intracerebral Hemorrhage.

BACKGROUND: Dendritic cells (DCs) regulate the immune response associated with T lymphocytes, but their role in stroke remains unclear. In this study, we investigated the causal relationship between DCs and T-cell response in intracerebral hemorrhage (ICH) by focusing on TLRs (toll-like receptors) that may modulate the function of DCs. METHODS: We studied the effects of TLR4, TLR2, and TLR9 on DC-mediated T-cell response and the outcomes of ICH using male C57BL/6 and CD11c-DTx (diphtheria toxin) receptor mice. We administered specific agents intraperitoneally or orally and evaluated the results using flow cytometry, real-time polymerase chain reaction, Western blotting, immunofluorescence staining, histopathology, and behavioral tests. RESULTS: TLR4 and TLR2 activation induces DC maturation and reduces the ratio of regulatory T to T-helper 17 cells in the brain and periphery after ICH. When either of these receptors is activated, it can worsen neuroinflammation and exacerbate ICH outcomes. TLR9 also promotes DC maturation, stabilizing the number of DCs, particularly conventional DCs. TLR9 has the opposite effects on regulatory T/T-helper 17 balance, neuroinflammation, and ICH outcomes compared with TLR4 and TLR2. Upon stimulation, TLR4 and TLR9 may achieve these effects through the p38-MAPK (p38-mitogen-activated protein kinase)/MyD88 (myeloid differentiation primary response gene 88) and indoleamine 2,3-dioxygenase 1 (IDO1)/GCN2 (general control nonderepressible 2) signaling pathways, respectively. DCs act as intermediaries for TLR-mediated T-cell response. CONCLUSIONS: TLR-mediated opposing effects of DCs on T-cell response may provide novel strategies to treat ICH.

Clinical characteristics and treatment outcomes of patients with a septate uterus complicated by endometriosis.

OBJECTIVES: Patients with a septate uterus often have endometriosis, which can exacerbate their adverse pregnancy outcomes. We aimed to describe the clinical characteristics and treatment outcomes of patients with a septate uterus complicated by endometriosis. STUDY DESIGN: This retrospective study included patients who had a septate uterus complicated by endometriosis and were treated in Wuhan Tongji Hospital in the past 10 years. The characteristics of patients with a septate uterus and endometriosis were collected and described in terms of their preoperative and postoperative pregnancy outcomes. RESULTS: There were 24 cases with a complete septate uterus and 49 cases with an incomplete septate uterus.Combinations of other malformations are more common in patients with complete septate uterus. In patients with a septate uterus, endometriosis often affected the ovaries, most commonly the left side (P < 0.001). Non-significant difference in the staging of endometriosis between complete and incomplete septate uterus (P= 0.812). Surgical treatment greatly improved the reproductive function and increased the live birth rate of patients with a septate uterus complicated by endometriosis (P < 0.001). CONCLUSIONS: Compared to a septate uterus uncomplicated endometriosis, a septate uterus complicated by endometriosis significantly affects reproductive function. Surgical treatment can significantly improve the pregnancy outcomes of patients with a septate uterus and endometriosis. Clinicians should pay attention to timely diagnosing and treating these patients.

Late Changes in Renal Volume and Function after Proton Beam Therapy in Pediatric and Adult Patients: Children Show Significant Renal Atrophy but Deterioration of Renal Function Is Minimal in the Long-Term in Both Groups.

To compare late renal effects in pediatric and adult patients with malignancies after PBT involving part of the kidney. A retrospective study was conducted to assess changes in renal volume and function in 24 patients, including 12 children (1-14 years old) and 12 adults (51-80 years old). Kidney volumes were measured from CT or MRI images during follow-up. Dose-volume histograms were calculated using a treatment planning system. In children, the median volume changes for the irradiated and control kidneys were -5.58 (-94.95 to +4.79) and +14.92 (-19.45 to +53.89) mL, respectively, with a relative volume change of -28.38 (-119.45 to -3.87) mL for the irradiated kidneys. For adults, these volume changes were -22.43 (-68.7 to -3.48) and -21.56 (-57.26 to -0.16) mL, respectively, with a relative volume change of -5.83 (-28.85 to +30.92) mL. Control kidneys in children exhibited a marked increase in size, while those in adults showed slight volumetric loss. The percentage of irradiated volume receiving 10 Gy (RBE) (V10) and 20 Gy (RBE) (V20) were significantly negatively associated with the relative volume change per year, especially in children. The CKD stage based on eGFR for all patients ranged from 1 to 3 and no cases with severe renal dysfunction were found before or after PBT. Late effects on the kidneys after PBT vary among age groups. Children are more susceptible than adults to significant renal atrophy after PBT. V10 and V20 might serve as predictors of the degree of renal atrophy after PBT, especially in children. PBT has a minimal impact on deterioration of renal function in both children and adults.

Therapeutic and fluorescence evaluation of 20% 5-aminolevulinic acid-mediated photodynamic therapy in actinic keratosis.

BACKGROUND: Actinic keratosis (AK) is a precancerous lesion that occurs in areas that are chronically exposed to sunlight and has the potential to develop into invasive cutaneous squamous cell carcinoma (cSCC). We investigated the efficacy of 20 % 5-aminolevulinic acid-photodynamic therapy (ALA-PDT) with LED red light for the treatment of AK in Chinese patients by examining changes in dermoscopic features, histopathology and fluorescence after treatment. METHODS: Twenty-eight patients with fourty-six AK lesions from March 2022 to September 2023 were treated with 20 % ALA, and 3 h later, they were irradiated with LED red light (80-100 mW/cm2) for 20 min. A session of 20 % ALA-PDT was performed once a week for three consecutive weeks, and the dermoscopic, histopathological, fluorescent and photoaging outcomes were measured one week after the treatment. RESULTS: One week after ALA-PDT, complete remission (CR) was reached in 53.6 % of patients. The CR of Grade I AK lesions was 100 %, that of Grade II lesions was 71.4 %, and that of Grade III lesions was 38.1 %. There was a significant improvement in the dermoscopic features, epidermal thickness and fluorescence of the AK lesions. The presence of red fluorescence decreased, and there was an association between CR and post-PDT fluorescence intensity. ALA-PDT also exhibited efficacy in treating photoaging, including fine lines, sallowness, mottled pigmentation, erythema, and telangiectasias, and improved the global score for photoaging. There were no serious adverse effects during or after ALA-PDT, and 82.1 % of the patients were satisfied with the treatment. CONCLUSION: AK lesions can be safely and effectively treated with 20 % ALA-PDT with LED red light, which also alleviates photoaging in Chinese patients, including those with multiple AKs. This study highlights the possibility that fluorescence could be used to diagnose AK with peripheral field cancerization and evaluate the efficacy of ALA-PDT.

A systematic review and meta-analysis of radiotherapy and particle beam therapy for skull base chondrosarcoma: TRP-chondrosarcoma 2024.

Introduction: Chondrosarcoma is a rare malignant bone tumor. Particle beam therapy (PT) can concentrate doses to targets while reducing adverse events. A meta-analysis based on a literature review was performed to examine the efficacy of PT and photon radiotherapy for skull base chondrosarcoma. Methods: The meta-analysis was conducted using 21 articles published from 1990 to 2022. Results: After PT, the 3- and 5-year overall survival (OS) rates were 94.1% (95% confidence interval [CI]: 91.0-96.2%) and 93.9% (95% CI: 90.6-96.1%), respectively, and the 3- and 5-year local control rates were 95.4% (95% CI: 92.0-97.4%) and 90.1% (95% CI: 76.8-96.0%), respectively. Meta-regression analysis revealed a significant association of PT with a superior 5-year OS rate compared to three-dimensional conformal radiotherapy (p < 0.001). In the studies used in the meta-analysis, the major adverse event of grade 2 or higher was temporal lobe necrosis (incidence 1-18%, median 7%). Conclusion: PT for skull base chondrosarcoma had a good outcome and may be a valuable option among radiotherapy modalities. However, high-dose postoperative irradiation of skull base chondrosarcoma can cause adverse events such as temporal lobe necrosis.

WEE1 Inhibitors Mediate Antitumor Effects on Endometrial Cancer through Activation of Innate Immune Responses.

Introduction: Recurrence signifies the primary mortality factor in patients suffering from endometrial cancer, with few efficacious treatments currently available for recurrent cases. This research investigates the anti-tumoral capacities of WEE1 inhibitors within the context of endometrial cancer, aiming to establish a novel therapeutic avenue for high recurrence-risk patients. Materials and methods: We evaluated WEE1 expression in endometrial cancer patients utilizing immunohistochemistry on paraffin-embedded tissue sections. The cytotoxic potential of WEE1 inhibitors on endometrial cancer cells was assessed by CCK8 assay. Assays to gauge the influence of WEE1 inhibitors on cell proliferation and migration included clonal proliferation, wound healing, and transwell assays. We determined the impacts on apoptosis and cell cycle stages by flow cytometry. Employing qRT-PCR and western blotting, we investigated the mechanistic pathways underlying the anti-tumoral activity of WEE1 inhibitors. In vivo evaluations were executed to ascertain the inhibitory effect of WEE1 inhibitors on tumor growth in mice. Results: WEE1 exhibited high-level expression in endometrial cancer tissues, particularly pronounced in recurrent compared with non-recurrent patients. WEE1 inhibitors effectively eliminated endometrial cancer cells while inhibiting their proliferation and migration. Flow cytometric analyses revealed a significant promotion of apoptosis and an increase in G2/M phase cell proportion upon WEE1 inhibitor treatment. qRT-PCR and western blotting elucidated that WEE1 inhibitors activated the innate immune signaling pathway in endometrial cancer cells. Furthermore, in vivo assessments demonstrated substantial tumor growth suppression due to WEE1 inhibitors. Conclusions: WEE1 inhibitors initiated an innate immune response in endometrial cancer, exhibiting considerable anti-tumoral effects, which was promising for postoperative treatment of endometrial cancer, especially recurrent endometrial cancer patients.

An analysis of muscle growth after proton beam therapy for pediatric cancer.

Retardation of growth and development is a well-known late effect after radiotherapy for pediatric patients. The goal of the study was to examine the effect of proton beam therapy (PBT) on the growth of muscles included in the irradiated area. The subjects were 17 pediatric patients (age ≤ 5 years) who received PBT with a treatment field including a muscle on only one side out of a pair of symmetrical bilateral muscles and had imaging evaluations for at least 1 year after PBT. The thicknesses of the irradiated and non-irradiated (contralateral) muscles were measured retrospectively on CT or MRI axial images collected before and after PBT. The change of thickness divided by the period (years) for each muscle was compared between the irradiated and contralateral sides. Correlations of muscle growth with irradiation dose and age at the start of treatment were also evaluated. The median observation period was 39.2 months. The measurement sites included the erector spinae (n = 9), gluteus maximus (n = 5) and rhomboids + trapezius (n = 3) muscles. The average changes in muscle thickness were 0.24 mm/year on the irradiated side and 1.19 mm/year on the contralateral side, showing significantly reduced growth on the irradiated side (P = 0.001). Younger patients had greater muscle growth. Irradiation dose was not significant, but muscle growth tended to decrease as the dose increased, and muscles irradiated at >50 Gy (RBE) showed little growth. These results show that muscle growth is affected by PBT and that long-term follow-up is needed to evaluate muscle growth retardation.

Tumor Response on Diagnostic Imaging after Proton Beam Therapy for Hepatocellular Carcinoma.

BACKGROUND: Follow-up after treatment for hepatocellular carcinoma (HCC) can be mostly performed using dynamic CT or MRI, but there is no common evaluation method after radiation therapy. The purpose of this study is to examine factors involved in tumor reduction and local recurrence in patients with HCC treated with proton beam therapy (PBT) and to evaluate HCC shrinkage after PBT. METHODS: Cases with only one irradiated lesion or those with two lesions irradiated simultaneously were included in this study. Pre- and post-treatment lesions were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) by measuring the largest diameter. RESULTS: The 6-, 12-, and 24-month CR + PR rates after PBT were 33.1%, 57.5%, and 76.9%, respectively, and the reduction rates were 25.1% in the first 6 months, 23.3% at 6-12 months, and 14.5% at 13-24 months. Cases that reached CR/PR at 6 and 12 months had improved OS compared to non-CR/non-PR cases. CONCLUSIONS: It is possible that a lesion that reached SD may subsequently transition to PR; it is reasonable to monitor progress with periodic imaging evaluations even after 1 year of treatment.

Design of a sulfur host with CuCo2O4 supported on carbon cloth for lithium sulfur batteries.

A high-efficiency sulfur host with bimetallic oxide CuCo2O4 cubes supported on carbon cloth has been designed and used in lithium sulfur batteries, which can suppress the "shuttle effect" and boost the redox reaction kinetics. The unique three-dimensional cube-based structure realized a high sulfur loading of 7.1 mg cm-2, and the corresponding assembled lithium sulfur battery delivered excellent cycling stability over 100 cycles at 0.1C.

Cisplatin-induced PANDAR-Chemo-EVs contribute to a more aggressive and chemoresistant ovarian cancer phenotype through the SRSF9-SIRT4/SIRT6 axis.

OBJECTIVE: We previously elucidated that long non-coding RNA Promoter of CDKN1A Antisense DNA damage Activated RNA (PANDAR) as a p53-dependent oncogene to promote cisplatin resistance in ovarian cancer (OC). Intriguingly, high level of p53-independent PANDAR was found in cisplatin-resistant patients with p53 mutation. Here, our study probed the new roles and the underlying mechanisms of PANDAR in p53-mutant OC cisplatin-resistance. METHODS: A2780 and A2780-DDP cells were served as OC cisplatin-sensitive and cisplatin-resistant cells. HO-8910PM cells were subjected to construct chemotherapy-induced extracellular vesicles (Chemo-EVs). Transmission electron microscopy (TEM) and nanoparticle tracking analysis were employed to evaluate Chemo-EVs. Cell viability was assessed using cell counting kit-8 and colony formation assays. Cell apoptosis was assessed using Annexin V and propidium iodide staining. The relationships between PANDAR, serine and arginine-rich pre-mRNA splicing factor 9 (SRSF9) were verified by RNA immunoprecipitation and fluorescence in situ hybridization. Tumor xenograft experiment was employed to evaluate the effects of PANDAR-Chemo-EVs on OC cisplatin-resistance in vivo. Immunofluorescent staining and immunohistochemistry were performed in tumor tissue. RESULTS: PANDAR level increased in OC patients with p53-mutation. PANDAR efflux enacted via exosomes under cisplatin conditions. Additionally, exosomes from OC cell lines carried PANDAR, which significantly increased cell survival and chemoresistance in vitro and tumor progression and metastasis in vivo. During cisplatin-induced stress, SRSF9 was recruited to nuclear bodies by increased PANDAR and muted apoptosis in response to cisplatin. Besides, SRSF9 significantly increased the ratio of SIRT4/SIRT6 mRNA in OC. CONCLUSION: Cisplatin-induced exosomes transfer PANDAR and lead to a rapid adaptation of OC cell survival through accumulating SRSF9 following cisplatin stress exposure.

Proton therapy (PT) combined with concurrent chemotherapy for locally advanced non-small cell lung cancer with negative driver genes.

PURPOSE: To discuss the optimal treatment modality for inoperable locally advanced Non-Small Cell Lung Cancer patients with poor physical status, impaired cardio-pulmonary function, and negative driver genes, and provide clinical evidence. MATERIALS AND METHODS: Retrospective analysis of 62 cases of locally advanced non-small cell lung cancer patients with negative driver genes treated at Tsukuba University Hospital(Japan) and Qingdao University Affiliated Hospital(China).The former received proton therapy with concurrent chemotherapy, referred to as the proton group, with 25 cases included; while the latter underwent X-ray therapy with concurrent chemoradiotherapy followed by 1 year of sequential immunomodulatory maintenance therapy, referred to as the X-ray group, with 37 cases included.The treatment response and adverse reactions were assessed using RECIST v1.1 criteria and CTCAE v3.0, and radiotherapy planning and evaluation of organs at risk were performed using the CB-CHOP method.All data were subjected to statistical analysis using GraphPad Prism v9.0, with a T-test using P < 0.05 considered statistically significant. RESULTS: (1)Target dose distribution: compared to the X-ray group, the proton group exhibited smaller CTV and field sizes, with a more pronounced bragg peak.(2)Organs at risk dose: When comparing the proton group to the X-ray group, lung doses (V5, V20, MLD) and heart doses (V40, Dmax) were lower, with statistical significance (P < 0.05), while spinal cord and esophagus doses showed no significant differences between the two groups (P > 0.05).(3)Treatment-related toxicities: The incidence of grade 3 or higher adverse events in the proton group and X-ray group was 28.6% and 4.2%, respectively, with a statistically significant difference (P < 0.05). In terms of the types of adverse events, the proton group primarily experienced esophagitis and pneumonia, while the X-ray group primarily experienced pneumonia, esophagitis, and myocarditis. Both groups did not experience radiation myelitis or esophagotracheal fistula.(4)Efficacy evaluation: The RR in the proton group and X-ray group was 68.1% and 70.2%, respectively (P > 0.05), and the DCR was 92.2% and 86.4%, respectively (P > 0.05), indicating no significant difference in short-term efficacy between the two treatment modalities.(5)Survival status: The PFS in the proton group and X-ray group was 31.6 ± 3.5 months (95% CI: 24.7 ~ 38.5) and 24.9 ± 1.55 months (95% CI: 21.9 ~ 27.9), respectively (P > 0.05), while the OS was 51.6 ± 4.62 months (95% CI: 42.5 ~ 60.7) and 33.1 ± 1.99 months (95% CI: 29.2 ~ 37.1), respectively (P < 0.05).According to the annual-specific analysis, the PFS rates for the first to third years in both groups were as follows: 100%, 56.1% and 32.5% for the proton group vs. 100%, 54.3% and 26.3% for the X-ray group. No statistical differences were observed at each time point (P > 0.05).The OS rates for the first to third years in both groups were as follows: 100%, 88.2%, 76.4% for the proton group vs. 100%, 91.4%, 46.3% for the X-ray group. There was no significant difference in the first to second years (P > 0.05), but the third year showed a significant difference (P < 0.05). Survival curve graphs also depicted a similar trend. CONCLUSION: There were no significant statistical differences observed between the two groups in terms of PFS and OS within the first two years. However, the proton group demonstrated a clear advantage over the X-ray group in terms of adverse reactions and OS in the third year. This suggests a more suitable treatment modality and clinical evidence for populations with frail health, compromised cardio-pulmonary function, post-COVID-19 sequelae, and underlying comorbidities.

Development and validation of a nomogram for predicting recurrence-free survival in endometrial cancer: a multicenter study.

Recurrence is the main cause of death in patients with endometrial cancer (EC). This study aimed to construct and validate a nomogram to predict the recurrence-free survival of patients with EC. This was a multicenter retrospective study. A total of 812 patients from Wuhan Tongji Hospital were divided into training and validation cohorts, and 347 and 580 patients from People's Hospital of Peking University and Qilu Hospital of Shandong, respectively, were used for validation. Univariate and multivariate Cox regression analyses were used to construct a nomogram for predicting recurrence-free survival of EC. Calibration curves, receiver operating characteristic (ROC) curves, and consistency indexes (C-indexes) were used to estimate the performance of the model. Decision curve analysis (DCA) curves were used to assess the clinical utility of the model. Age (P = 0.013), cancer antigen 125 level (P = 0.014), lymphovascular space invasion (P = 0.004), International Federation of Gynecology and Obstetrics stage (P = 0.034), and P53 (P < 0.001) were independently associated with recurrence, and we constructed a nomogram based on these variables. The C-indexes of the validation cohorts were 0.880, 0.835, and 0.875, respectively. The calibration, ROC, and DCA curves revealed that this model had excellent performance and clinical utility. Combining clinical data, clinicopathological factors, serological indicators, and immunohistochemical marks, a multicenter externally verified nomogram with robust performance was constructed to predict the recurrence of patients with EC.

Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance.

Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments. Bidirectional interactions between epithelial-cytokeratin malignant cells and immunosuppressive cancer-associated fibroblasts form an immune exclusionary microenvironment through transforming growth factor ß pathway signaling mediated by FABP5. In Epi-Imm tumors, malignant cells interact with natural killer and T cells through interferon signaling. Preliminary analysis of samples from a cervical cancer clinical trial ( NCT04516616 ) demonstrated neoadjuvant chemotherapy induces a state transition to Epi-Imm, which correlates with pathological complete remission following treatment with immune-checkpoint blockade. These findings deepen the understanding of cellular state diversity in CSCC.