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Abstract Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder and metabolic abnormality disease that mainly affects women of reproductive age. LINC00173, a novel long noncoding RNA (lncRNA), has emerged as an important factor in the development of PCOS. However, the role of LINC00173 in PCOS development and its specific upstream and downstream mechanisms remain to be further clarified. Here, we found that LINC00173 was significantly upregulated in granulosa cells (GCs) of PCOS patients, and played a crucial role in promoting apoptosis of GCs. Mechanistically, we observed the activation of endoplasmic reticulum (ER) stress in the GCs of PCOS patients, and the ER stress sensor ATF4 could directly induce LINC00173 expression by binding to its promoter. LINC00173 further upregulated the expression of Harakiri (HRK) and subsequently inhibited downstream PI3K/AKT pathway. In conclusions, our study uncovered that ER stress-induced upregulation of LINC00173 leads to increased HRK expression and inhibition of the PI3K/AKT pathway, thereby promoting the progression of PCOS. These findings provide a new therapeutic strategy for the treatment of PCOS.

Abstract Break-induced replication (BIR) is mutagenic, and thus its use requires tight regulation, yet the underlying mechanisms remain elusive. Here we uncover an important role of 53BP1 in suppressing BIR after end resection at double strand breaks (DSBs), distinct from its end protection activity, providing insight into the mechanisms governing BIR regulation and DSB repair pathway selection. We demonstrate that loss of 53BP1 induces BIR-like hyperrecombination, in a manner dependent on Polα-primase-mediated end fill-in DNA synthesis on single-stranded DNA (ssDNA) overhangs at DSBs, leading to PCNA ubiquitination and PIF1 recruitment to activate BIR. On broken replication forks, where BIR is required for repairing single-ended DSBs (seDSBs), SMARCAD1 displaces 53BP1 to facilitate the localization of ubiquitinated PCNA and PIF1 to DSBs for BIR activation. Hyper BIR associated with 53BP1 deficiency manifests template switching and large deletions, underscoring another aspect of 53BP1 in suppressing genome instability. The synthetic lethal interaction between the 53BP1 and BIR pathways provides opportunities for targeted cancer treatment.

Abstract This paper presents a non‐isolated DC‐DC converter designed to validate ultra‐high voltage gain using a modified double boost mode. The objective is to achieve exceptionally high voltage gain by integrating a modified triple boost technique (MTBT), interleaved with second main and auxiliary third MOSFETs, and a modified switched inductor‐capacitor (MSLC), effectively doubling the voltage transfer gain. Furthermore, MSLC is combined with the auxiliary third and double main MOSFET to double the voltage gain while concurrently mitigating voltage stress on the auxiliary MOSFET and diodes in the proposed converter (the PC). Additionally, all diodes in the MTBT operate under zero current switching (ZCS) and the double main and auxiliary third MOSFET face very low current stress at ultra‐high voltage gain. The input current of the PC remains steady without pulsating at a low duty ratio, making the PC more suitable for renewable energy systems. The PC offers numerous advantages, exhibiting high efficiency and ensuring minimal voltage stress on power devices with low current stress on the power switches. Notably, PC aims to elevate input voltages from 30 V to a variable output range of 335 to 600 V, delivering 440 watts at 96.1% efficiency.

Objective In order to accomplish the objective of sustainable development and utilization of geothermal energy, it is imperative to elucidate the optimal production-reinjection well spacing considering varying quantities and temperatures of reinjection. Methods The thermal reservoir of the Guantao Formation in northern Shandong Province is selected as the research subject, and a conceptual model and mathematical model for layered thermal reservoir development are established. COMSOL Multiphysics multifield coupling simulation software is employed to develop a geothermal production-reinjection well spacing calculator. The accuracy of the model is validated through parameter fitting and simulation results. Results Based on the software APP development function, which is guided by the input of ordinary users, the relevant parameter input was simplified for ease of use, leading to the establishment of an application for calculating geothermal production-reinjection well spacing. In contrast to previous studies that solely focused on production-reinjection well spacing, this study calculates optimal spacings under various conditions to meet real-world operational needs. The results indicate that the optimal production-reinjection well spacings, without experiencing thermal breakthrough are 290, 330, 360 m and 390 m at flow rates of 40, 60, 80 and 100 m3/h respectively. Conclusion In the layered conductive sandstone thermal reservoir area of northern Shandong, a reliable geothermal production-reinjection well-spacing calculator was developed through simplification of the conceptual model and credible numerical simulation results. Hydrothermal numerical simulation serves as a robust approach to determine rational production-reinjection well spacings, which are crucial parameters for geothermal development and utilization projects including exploitation quantity, recharge quantity, injection temperature, and production-reinjection well spacing. These determinations contribute to the sustainable development and utilization of geothermal resources.

Abstract Objective To retrospectively explore the clinical significance of radiotherapy to the distant metastatic lymph nodes (cervical/ clavicular/ mediastinal et al.) in metastatic cervical cancer. Hereinto, these cervicothoracic lymph nodes were metastasized from IB1-IVA (initial stage at first treatment), and IVB initially had metastatic disease in these areas at diagnosis. Methods Metastatic cervical cancer only with the distant cervicothoracic metastatic lymph nodes (cervical/ clavicular/ mediastinal et al.), without distant parenchymal organs metastasis such as lung, liver, bone, and peritoneum, were enrolled in the analysis. These patients were classified into IB1-IVA and IVB based on their initial stage of first treatment. All patients received IMRT for the distant metastatic lymph nodes. The progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan–Meier method. Results Overall, the median PFS was 9 months, and the median OS was 27 months. The subgroup analysis showed that for IB1-IVA, the median PFS was 11 months, and the median OS was 30.5 months. For IVB, the median PFS was 8 months, and the median OS was 16 months. Conclusion Radiotherapy is beneficial to the distant metastatic lymph nodes (cervical/ clavicular/ mediastinal et al.), and could effectively bring the longer PFS and OS for metastatic cervical cancer.

Abstract Objective Endometrial cancer is stepping into the era of precision therapy. Genomic test is recommended for newly diagnostic patients. However, outpatients displayed more complex characteristics. Here, we elucidated the clinical characteristics and genomic profiling of outpatients with endometrial cancer at our institution. Methods Between 2018 and 2023, 68 endometrial cancer received genomic tests at outpatient department of Fudan University Shanghai Cancer Center. Data, including age, pathological histology, FIGO stage and treatment strategy were collected. Germline mutations, molecular subtypes and other somatic mutations were also summarized. Results Overall, 72.1% (49/68) of patients receive genomic tests at primary diagnosis, while 27.9% (19/68) of patients received tests at recurrence. Nine patients had deleterious germline mutations, including BRCA1(2), MLH1(1), MSH2(2, including one with co-mutation of RAD50), MSH6(2), FANCA(1), MUTYH(1). Molecular subtypes were recognized among 62 patients, as POLE super-mutation(4, 6.5%), MSI-H(7, 11.3%), CN-Low(36, 58.1%) and CN-High(15, 24.2%). Ten patients received anti-PD1 monotherapy or in combination with chemotherapy or anti-angiogenic therapy, with the duration of disease control of 1 to 35 months. The ORR rate was 30%, and six patients had stable disease. The median (range) follow-up time was 18(2–160) months. 23(33.8%) relapses were recorded, and CN-High subtype displayed worst PFS compared with other subtypes (P

Abstract Background Platinum-resistant or refractory ovarian cancer is a highly lethal gynecologic disease with limited treatment options. Chiauranib is a novel small-molecule selective inhibitor, which could effectively target multiple pathways including Aurora B and CSF-1R to inhibit cell cycle process and improve anti-tumor immune function, as long as VEGF pathway for tumor extinction. Methods A phase II study was sequentially conducted after a phase Ib monotherapy study to evaluate the efficacy of chiauranib combined with chemotherapy. Chinese patients with recurrent ovarian cancer were enrolled. Eligible patients received chiauranib combined with a maximum of six cycles of chemotherapy: etoposide (CE group) or weekly-paclitaxel (CP group). Patients, who exhibited a complete or partial response, or stable disease following combo treatment, progressed to maintenance phase to receive chiauranib monotherapy. Primary endpoint was progression-free survival (PFS) according to RECIST v1.1. Results From November 2017 to March 2019, 25 patients were enrolled in a phase 1b study and a median PFS of 3.7 months (95% CI 1.8–NE) was achieved by chiauranib monotherapy. From July 2019 to December 2020, a total of 47 patients were enrolled in the phase II study. One CP patient did not receive the study drugs, and three patients withdrew before the first tumor assessment. Thus, 43 patients (CE group: 22 patients; CP group: 21 patients) were included in the evaluation. The median PFS was 5·4 months (95% CI 2·8–5·6) and 5·6 months (95% CI 3·4–7·0), respectively. Conclusions This was the first study to evaluate chiauranib, a novel multi-targeted kinase inhibitor in patients with ovarian cancer. The administration of chiauranib along with etoposide or weekly-paclitaxel significantly enhanced the efficacy with manageable adverse events. This warrants further clinical studies on this novel treatment. A phase III study is promising and ongoing. Trial registration ClinicaTrials.gov identifier: NCT03901118 (phase II) and NCT03166891 (phase Ib).

Abstract Background Radioresistance is the leading cause of death in advanced cervical cancer (CC). Dysregulation of RNA modification has recently emerged as a regulatory mechanism in radiation and drug resistance. We aimed to explore the biological function and clinical significance of 5-methylcytosine (m5C) in cervical cancer radiosensitivity. Methods The abundance of RNA modification in radiotherapy-resistant and sensitive CC specimens was quantified by liquid chromatography-tandem mass spectrometry. The essential RNA modification-related genes involved in CC radiosensitivity were screened via RNA sequencing. The effect of NSUN6 on radiosensitivity was verified in CC cell lines, cell-derived xenograft (CDX), and 3D bioprinted patient-derived organoid (PDO). The mechanisms of NSUN6 in regulating CC radiosensitivity were investigated by integrative m5C sequencing, mRNA sequencing, and RNA immunoprecipitation. Results We found a higher abundance of m5C modification in resistant CC samples, and NSUN6 was the essential m5C-regulating gene concerning radiosensitivity. NSUN6 overexpression was clinically correlated with radioresistance and poor prognosis in cervical cancer. Functionally, higher NSUN6 expression was associated with radioresistance in the 3D PDO model of cervical cancer. Moreover, silencing NSUN6 increased CC radiosensitivity in vivo and in vitro. Mechanistically, NDRG1 was one of the downstream target genes of NSUN6 identified by integrated m5C-seq, mRNA-seq, and functional validation. NSUN6 promoted the m5C modification of NDRG1 mRNA, and the m5C reader ALYREF bound explicitly to the m5C-labeled NDRG1 mRNA and enhanced NDRG1 mRNA stability. NDRG1 overexpression promoted homologous recombination-mediated DNA repair, which in turn led to radioresistance in cervical cancer. Conclusions Aberrant m5C hypermethylation and NSUN6 overexpression drive resistance to radiotherapy in cervical cancer. Elevated NSUN6 expression promotes radioresistance in cervical cancer by activating the NSUN6/ALYREF-m5C-NDRG1 pathway. The low expression of NSUN6 in cervical cancer indicates sensitivity to radiotherapy and a better prognosis.

Diabetic foot ulcers (DFUs) represent a serious complication of diabetes with high incidence, requiring intensive treatment, prolonged hospitalization, and high costs. It poses a severe threat to the patient's life, resulting in substantial burdens on patient and healthcare system. However, the therapy of DFUs remains challenging. Therefore, exploring cell-free therapies for DFUs is both critical and urgent. Exosomes, as crucial mediators of intercellular communication, have been demonstrated potentially effective in anti-inflammation, angiogenesis, cell proliferation and migration, and collagen deposition. These functions have been proven beneficial in all stages of diabetic wound healing. This review aims to summarize the role and mechanisms of exosomes from diverse cellular sources in diabetic wound healing research. In addition, we elaborate on the challenges for clinical application, discuss the advantages of membrane vesicles as exosome mimics in wound healing, and present the therapeutic potential of exosomes and their mimetic vesicles for future clinical applications.

Tunnel construction subject to surrounding rock squeezing deformation can induce support cracking, intrusion, and collapse. Herein, the existing Wushaoling tunnel of Lanzhou–Wuwei second line railway and the new Wushaoling tunnel of Lanzhou–Zhangye third and fourth line railways are compared to analyze and discuss the progress in deformation control techniques for railway tunnels surrounded by squeezing rock. Further, a technical system for large deformation control is preliminarily established. The maximum support deformation of the Wushaoling tunnel do not exceed the reserved deformation. The large deformation of tunnel surrounding rock is generally controlled to achieve better support effect. The main control measures are as follows. (1) The section design method based on the deformation classification is suitable for squeezing surrounding rock. (2) The support structure design involves anti-releasing and early controlled releasing, and measures such as increased support stiffness, increased reserved deformation, and multi-layer supports can be employed. (3) The micro-bench method reduces the closure time of the inverted arch to control deformation. (4) To realize quick excavation and support and reduce the disturbance to the surrounding rock, a cantilever excavating machine can be used for excavation and an intelligent arch trolley can be utilized to realize unmanned vertical arch drilling, anchoring, and grouting.

BackgroundInsulin resistance (IR) is linked to an increased risk of neurological impairment following a stroke and may contribute to poor neurological prognosis in affected patients. The metabolic score for the insulin resistance index, shortened as the METS-IR, generally serves as a surrogate index for IR. However, its association with the severity of neurological impairment in patients with severe cerebral infarction (CI) in neurological intensive care units (ICU) has not been fully established.MethodsPatients with a diagnosis of CI, admitted to the neurological ICUs of Yangzhou University’s Affiliated Hospital and Xuzhou Medical University’s Affiliated Hospital, were included in the study. A multivariate logistic regression model and restricted cubic splines (RCS) were employed to explore the relationship between the METS-IR index and the severity of neurological impairment in these patients. The predictive capabilities of the METS-IR index and the triglyceride-glucose (TyG) index for outcome measures were compared through the ROC curve. Furthermore, a decision curve analysis was executed, and the integrated discrimination improvement (IDI) index was computed to evaluate the enhancements in predictive performance and clinical utility of various scoring systems with the inclusion of the METS-IR index. Subgroup analysis was conducted regarding age, BMI, and smoking status.ResultsThe study ultimately included 504 participants. Adjusted logistic regression and RCS results showed that as the METS-IR index increases, the risk of neurological impairment in patients with severe CI consistently grows (P for overall = 0.0146, P-nonlinear: 0.0689). The METS-IR index’s predictive capability for neurological impairment (AUC = 0.669) was superior to that of the TyG index (AUC = 0.519).ConclusionFrom the study results, the METS-IR index can serve as an important predictor for neurological impairment in ICU patients with severe CI. It can aid in the identification and early intervention of neurological impairment in these patients.

Abstract Pyroptosis may play an important role in the resistance of ovarian cancer (OC) to chemotherapy. However, the mechanism by which pyroptosis modulation can attenuate chemotherapy resistance has not been comprehensively studied in OC. Here, we demonstrated that RAS‐associated C3 botulinum toxin substrate 1 (RAC1) is highly expressed in OC and is negatively correlated with patient outcomes. Through cell function tests and in vivo tumor formation tests, we found that RAC1 can promote tumor growth by mediating paclitaxel (PTX) resistance. RAC1 can mediate OC progression by inhibiting pyroptosis, as evidenced by high‐throughput automated confocal imaging, the release of lactate dehydrogenase (LDH), the expression of the inflammatory cytokines IL‐1β/IL‐18 and the nucleotide oligomerization domain‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome. Mechanically, RNA‐seq, gene set enrichment analysis (GSEA), coimmunoprecipitation (Co‐IP), mass spectrometry (MS), and ubiquitination tests further confirmed that RAC1 inhibits caspase‐1/gasdermin D (GSDMD)‐mediated canonical pyroptosis through the P21‐activated kinase 4 (PAK4)/mitogen‐activated protein kinase (MAPK) pathway, thereby promoting PTX resistance in OC cells. Finally, the whole molecular pathway was verified by the results of in vivo drug combination tests, clinical specimen detection and the prognosis. In summary, our results suggest that the combination of RAC1 inhibitors with PTX can reverse PTX resistance by inducing pyroptosis through the PAK4/MAPK pathway.

Abstract Background Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. Methods This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. Results Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1 directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). Conclusions Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.

Abstract Background Recent studies showed heterogeneity in stage IVB patients. However, few studies focused on the prognosis of supraclavicular metastatic ovarian cancer. This study aimed to explore the prognostic factors and the role of primary debulking in IVB ovarian cancer patients with supraclavicular lymph node metastasis. Methods We retrospectively analyzed patients newly diagnosed as primary epithelial ovarian cancer with supraclavicular lymph node metastasis from January 2015 to July 2020. Supraclavicular lymph node metastasis was defined as either the pathological diagnosis by supraclavicular lymph node biopsy, or the radiological diagnosis by positron emission tomography-computed tomography (PET-CT). Results In 51 patients, 37 was diagnosed with metastatic supraclavicular lymph nodes by histology, 46 by PET-CT, and 32 by both methods. Forty-four (86.3%) with simultaneous metastatic paraaortic lymph nodes (PALNs) by imaging before surgery or neoadjuvant chemotherapy were defined as “continuous-metastasis type”, while the other 7 (13.7%) defined as “skip-metastasis type”. Nineteen patients were confirmed with metastatic PALNs by histology. Thirty-four patients were investigated for BRCA mutation, 17 had germline or somatic BRCA1/2 mutations (g/sBRCAm). With a median follow-up of 30.0 months (6.3–63.4 m), 16 patients (31.4%) died. The median PFS and OS of the cohort were 17.3 and 48.9 months. Survival analysis showed that “continuous-metastasis type” had longer OS and PFS than “skip-metastasis type” (OS: 50.0/26.6 months, PFS: 18.5/7.2months, p=0.005/0.002). BRCA mutation carriers also had longer OS and PFS than noncarriers (OS: 57.4 /38.5 m, p=0.031; PFS: 23.6/15.2m, p=0.005). Multivariate analysis revealed only metastatic PALNs was independent prognostic factor for OS (p=0.040). Among “continuous-metastasis type” patients, 22 (50.0%) achieved R0 abdominopelvic debulking, who had significantly longer OS (55.3/42.3 months, p =0.034) than those with residual abdominopelvic tumors. Conclusions In stage IVB ovarian cancer patients with supraclavicular lymph nodes metastasis, those defined as “continuous-metastasis type” with positive PALNs had better prognosis. For them, optimal abdominopelvic debulking had prognostic benefit, although metastatic supraclavicular lymph nodes were not resected. Higher BRCA mutation rate than the general population of ovarian cancer patients was observed in patients with IVB supraclavicular lymph node metastasis, leading to better survival as expected.

PURPOSEGenetic variants of ovarian cancer (OV) show ethnic differences, but data from the Chinese population are still insufficient. Here, we elucidate the inheritance landscape in Chinese patients with OV and examine the functional implications of a Chinese-enriched RAD51D variant.METHODSBetween 2015 and 2018, 373 consecutive patients with OV were prospectively enrolled. Variants of BRCA1/2, other homologous recombination repair (HRR) genes, and DNA mismatch repair (MMR) genes were analyzed using next-generation sequencing. An enriched RAD51D variant was identified, and its functional effects were examined using Cell Counting Kit-8, colony formation, transwell migration, and drug sensitivity assays.RESULTSOverall, 31.1% (116/373) of patients had at least one pathogenic or likely pathogenic germline variant. BRCA1 and BRCA2 accounted for 16.09% and 5.36%, respectively, with one patient having both variants. In addition, 32 (8.58%) patients carried other HRR gene variants, whereas three (0.8%) patients had MMR gene variants. The RAD51D variant ranked third (8/373, 2.1%), and its rate was much higher than that in other populations. Remarkably, all eight patients harbored the RAD51D K91fs variant (c.270_271dup, p.Lys91Ilefs*13) and demonstrated satisfactory platinum response and favorable prognosis. This variant confers enhanced sensitivity to poly (ADP-ribose) polymerase inhibitors in OV cells. However, the effects on platinum sensitivity were inconsistent across different cell lines. Against the background of the TP53 variant, RAD51D K91fs variant showed increased sensitivity to cisplatin.CONCLUSIONOur study revealed the inheritance landscape of OV and identified an enriched RAD51D variant in Chinese patients with OV. This can serve as an important reference for OV management and a potential therapeutic target.

With the advancements of IoT and blockchain, a novel era has emerged in the domain of smart building systems. At the same time, it also brings some problems and challenges. Most traditional solutions typically utilize the fully-replicated storage strategy that results in high storage costs, while recent solutions like coded blockchain may compromise query efficiency. Moreover, traditional reputation-based consensus schemes do not consider dynamic situations, limiting scalability. To handle these problems, we propose a novel hierarchical message aggregation scheme and a classified storage method under Reed–Solomon (RS) coding to minimize storage overhead while ensuring data recoverability and query performance. Additionally, we introduce a dynamic incentive reputation consensus mechanism to tackle scalability challenges such as preventing node monopolies, promoting new node integration, and enhancing fault tolerance. Through theoretical analysis and experimental simulation, the proposed scheme demonstrates a high degree of decentralization and scalability. Our scheme achieves a 20% reduction in the Gini coefficient compared to other approaches. Furthermore, our scheme can save 19 of storage overhead compared to traditional solutions while maintaining high query performance.

Summary: Patients with triple-negative breast cancer (TNBC) frequently experience resistance to chemotherapy, leading to recurrence. The approach of optimizing anti-tumoral immunological effect is promising in overcoming such resistance, given the heterogeneity and lack of biomarkers in TNBC. In this study, we focused on YTHDF2, an N6-methyladenosine (m6A) RNA-reader protein, in macrophages, one of the most abundant intra-tumoral immune cells. Using single-cell sequencing and ex vivo experiments, we discovered that YTHDF2 significantly promotes pro-tumoral phenotype polarization of macrophages and is closely associated with down-regulated antigen-presentation signaling to other immune cells in TNBC. The in vitro deprivation of YTHDF2 favors anti-tumoral effect. Expressions of multiple transcription factors, especially SPI1, were consistently observed in YTHDF2-high macrophages, providing potential therapeutic targets for new strategies. In conclusion, YTHDF2 in macrophages appears to promote pro-tumoral effects while suppressing immune activity, indicating the treatment targeting YTHDF2 or its transcription factors could be a promising strategy for chemoresistant TNBC.

Abstract Background The liver ranks as the sixth most prevalent site of primary cancer in humans, and it frequently experiences metastases from cancers originating in other organs. To facilitate the development of effective treatments and improve survival rates, it is crucial to comprehend the intricate and diverse transcriptome landscape of primary and metastatic liver cancers. Methods We conducted long-read isoform sequencing and short-read RNA sequencing using a cohort of 95 patients with primary and secondary liver cancer who underwent hepatic resection. We compared the transcriptome landscapes of primary and metastatic liver cancers and systematically investigated hepatocellular carcinoma (HCC), paired primary tumours and liver metastases, and matched nontumour liver tissues. Results We elucidated the full-length isoform-level transcriptome of primary and metastatic liver cancers in humans. Our analysis revealed isoform-level diversity in HCC and identified transcriptome variations associated with liver metastatis. Specific RNA transcripts and isoform switching events with clinical implications were profound in liver cancer. Moreover, we defined metastasis-specific transcripts that may serve as predictors of risk of metastasis. Additionally, we observed abnormalities in adjacent paracancerous liver tissues and characterized the immunological and metabolic alterations occurring in the liver. Conclusions Our findings underscore the power of full-length transcriptome profiling in providing novel biological insights into the molecular mechanisms underlying tumourigenesis. These insights will further contribute to improving treatment strategies for primary and metastatic liver cancers.

In response to the incidence of cervical intraepithelial neoplasia and cervical cancer in China and global screening strategies, a collaborative effort was undertaken by seven Chinese medical associations to develop this guideline for cervical cancer screening. The guideline recommends high-risk human papillomavirus (hr-HPV) testing as the preferred method for primary screening, which should have been approved by authoritative institutions and clinically validated for primary screening. In areas without access to HPV testing, cytology can be used as an alternative. However, it is recommended to replace cytology with HPV-based screening as conditions permit. Cotesting (HPV testing in combination with cytology) is recommended for areas with sufficient medical resources, opportunistic screening populations, and partial special populations. The guideline recommends that individuals with a cervix initiate cervical cancer screening at the age 25 years and undergo HPV testing alone or cotesting every five years, or cytology alone every three years. Women over the age of 65 who have had documented adequate negative prior screening in the past may terminate screening. Corresponding screening programs are proposed for different special populations. The development of these guidelines is an important step in the effort to eliminate cervical cancer in China.

BackgroundCervical cancer (CC) poses a global health challenge, with a particularly poor prognosis in cases of recurrence, metastasis, or advanced stages. A single biomarker is inadequate to predict CC prognosis or identify CC patients likely to benefit from immunotherapy, presumably owing to tumor complexity and heterogeneity.MethodsUsing advanced Olink proteomics, we analyzed 92 oncology-related proteins in plasma from CC patients receiving immunotherapy, based upon the comparison of protein expression levels of pre-therapy with those of therapy-Cycle 6 in the partial response (PR) group and progressive disease (PD) group, respectively.Results55 proteins were identified to exhibit differential expression trends across pre-therapy and post-therapy in both PR and PD groups. Enriched GO terms and KEGG pathways were associated with vital oncological and immunological processes. A logistic regression model, using 5 proteins (ITGB5, TGF-α, TLR3, WIF-1, and ERBB3) with highest AUC values, demonstrated good predictive performance for prognosis of CC patients undergoing immunotherapy and showed potential across different cancer types. The effectiveness of these proteins in prognosis prediction was further validated using TCGA-CESC datasets. A negative correlation and previously unidentified roles of WIF-1 in CC immunotherapy was also first determined.ConclusionOur findings reveal multi-biomarker profiles effectively predicting CC prognosis and identifying patients benefitting most from immunotherapy, especially for those with limited treatment options and traditionally poor prognosis, paving the way for personalized immunotherapeutic treatments and improved clinical strategies.

Purpose: To explore global/regional myocardial deformation across various layers, vascular distributions, specific levels and distinct walls in healthy individuals using cardiovascular magnetic resonance feature tracking (CMR-FT). Methods: We selected a cohort of 55 healthy participants and CMR cine images were used to obtain the left ventricular (LV) peak longitudinal, circumferential, radial strains (LS, CS, RS). The characteristics of normal LV strain in various layers (endocardium, myocardium, epicardium), territories [left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA)], levels (basal, middle, apical) and walls (anterior, septum, inferior, lateral) were compared. Results: The absolute values of the LV global LS and CS gradually decreased from endocardium to epicardium. The absolute LV global RS (65.7 ± 47.7%) was maximum relative to LS (−22.0 ± 10.8%) and CS (−22.8 ± 7.7%). The absolute values of the LCX territorial strain were the largest compared with the LAD and RCA territorial strains. Regional RS, endo-CS and endo-LS gradually increased from the basal to the apical level. The LV lateral walls had the highest strain values (CS, LS, and RS). Conclusions: Variations in normal LV strain values across various layers, territories, levels, and walls were observed, suggesting the necessity for careful clinical interpretation of these strain values. These findings also partially revealed the complexity of normal cardiac mechanics.

Fetal growth restriction (FGR) is one of the most common pregnancy complications culminating in adverse fetal outcome, including preterm birth, neonatal mortality and stillbirth. Compromised placental development and function, especially disruption in angiogenesis and inadequate nutrient supply are contributing factors. Fetal sex also influences placental function. Knowledge of gene expression changes and epigenetic factors contributing to placental dysfunction in FGR pregnancies will help identify biomarkers and help target interventions. This study tested the hypothesis that FGR pregnancies are associated with disruptions in miRNA - an epigenetic factor and mRNAs involving key mediators of angiogenesis and microvessel development. Changes in expression of key genes/proteins involved in placental dysfunction by RT-PCR and immunohistochemistry and miRNA changes by RNA sequencing were undertaken with term placenta from 12 control and 20 FGR pregnancies. Findings showed changes in expression of genes involved in steroidogenesis, steroid action, IGF family members, inflammatory cytokines and angiogenic factors in FGR pregnancies. In addition, upregulation of MIR451A and downregulation of MIR543 in placentas from FGR group with female newborns and upregulation of MIR520G in placentas from FGR group with male newborns were also noted. MIR451A and MIR543 have been implicated in angiogenesis. Consistent with gene changes, CD34, the microvessel angiogenesis marker, also showed reduced staining only in female FGR group. These findings provide evidence that epigentically regulated gene expression changes in angiogenesis and capillary development influence placental impairment in FGR pregnancies. Our preliminary observations also support for these changes to be driven in a sex-specific manner.

Abstract Vaccination is a fundamental tool in preventing infectious diseases. However, due to the wide array of vaccines available, comprehending the entire vaccine landscape can be a daunting task. To tackle this complexity, this study employs advanced network analysis methods capable of capturing the intricate relationships within multivariate datasets. The objective is to investigate how the vaccination landscape has evolved both before and after the COVID-19 pandemic. This study examined vaccination data in the Nanan District of Chongqing, China, spanning from 2016 to 2022. Additionally, the network topological characteristics were computed and scrutinized across 2326 sliding windows. The investigation focused on assessing alterations in the topological structure of the vaccination network before and after the COVID-19 pandemic, encompassing analyses at both macro and mesoscale levels. Furthermore, at the micro level, this study delved into the correlation degrees of selected vaccine nodes within the vaccination network. The analysis unveiled that the correlation and activity within the vaccination network showed a noticeable enhancement in strength in the wake of the COVID-19 pandemic, especially during the spring and winter months. However, the community structure and the average interactions between vaccines displayed a diminishing trend post-pandemic. Among the analyzed vaccines, the HepA vaccine emerged as the one with the highest average node-degree centrality rank. A closer examination of the node-degree centrality ranking chart within the vaccination network disclosed fluctuations in the rankings of various vaccine types across different time periods and seasons. In contrast, vaccines incorporated into NIP exhibited a remarkable degree of consistency, which is attributed to children adhering to a fixed vaccination schedule, rendering NIP vaccines less susceptible to disruptions and enhancing their stability within the vaccination network. This study offers valuable insights into the dynamics of the vaccination network, shedding light on the impact of the COVID-19 pandemic, seasonal variations, and the ever-shifting correlation patterns among different vaccine types. These discoveries enrich our comprehension of vaccination trends and have the potential to guide forthcoming endeavors aimed at refining vaccination strategies and enhancing public health outcomes, not only in the Nanan District but also in analogous settings.

Abstract Background According to the World Health Organization, foodborne disease is a significant public health issue. We will choose the best model to predict foodborne disease by comparison, to provide evidence for government policies to prevent foodborne illness. Methods The foodborne disease monthly incidence data from June 2017 to April 2022 were obtained from the Chongqing Nan’an District Center for Disease Prevention and Control. Data from June 2017 to June 2021 were used to train the model, and the last 10 months of incidence were used for prediction and validation The incidence was fitted using the seasonal autoregressive integrated moving average (SARIMA) model, Holt-Winters model and Exponential Smoothing (ETS) model. Besides, we used MSE, MAE, RMSE to determine which model fits better. Results During June 2017 to April 2022, the incidence of foodborne disease showed seasonal changes, the months with the highest incidence are June to November. The optimal model of SARIMA is SARIMA (1,0,0) (1,1,0)12. The MSE, MAE, RMSE of the Holt-Winters model are 8.78, 2.33 and 2.96 respectively, which less than those of the SARIMA and ETS model, and its prediction curve is closer to the true value. The optimal model has good predictive performance. Conclusion Based on the results, Holt-Winters model produces better prediction accuracy of the model.

Abstract This paper introduces an optimized DC–DC converter that employs a modified switched inductor-capacitor technique to achieve ultra-high voltage gain for renewable energy systems. The development is based on adding one cell of modified switched inductor (MSL1) with series diodes interleaved with the main switch in the proposed DC–DC converter. The (MSL1) with capacitor operates in resonant mode to reduce current stress across the main switch when the charge in capacitor becomes zero. This approach also reduces voltage stress across the main switch, all inductors, and diodes. Furthermore, modified switched inductors (MSL2) with an auxiliary switch and a coupled capacitor are incorporated to provide double boosting voltage and to achieve high voltage gain. Additionally, a main and auxiliary switch are integrated with modified switched capacitors (MSC) to provide ultra-high voltage gain and to reduce voltage stress across auxiliary switch. Moreover, the proposed converter exhibits a continuous input current with zero pulsating, even at very low duty cycles. The advantages of the proposed converter are high efficiency, low voltage stress, and low values of inductors and capacitors when utilizing a high switching frequency. A mathematical model for the proposed converter is developed for both continuous conduction mode and discontinuous conduction mode. In addition, the PCB design for the proposed converter is presented, and experimental tests are conducted to verify the simulation and laboratory results. The proposed converter aims to boost the voltage from 20 to 40 V to a variable output voltage between 200 and 400 V, delivering 400 watts of power with an efficiency of 96.2%.

Abstract Backgrounds Endometrial carcinoma (EC) is one of the most commonly diagnosed gynecologic malignancy in China. However, the genetic profile of Chinese EC patients has not been well established yet. Methods In current study, 158 Chinese EC patients were subjected to next-generation sequencing assay (74 took testing of EC-related 20-genes panel, and 84 took the expanded panel). Of the 158 patients, 91 patients were performed germline mutation testing using the expanded panel. Moreover, the public datasets from TCGA and MSKCC were utilized to compare the genomic differences between Chinese and Western EC patients. The proteomic and transcriptomic from CPTAC and TCGA were derived and performed unsupervised clustering to identify molecular subtypes. Results Among the 158 patients analyzed, a significant majority (85.4%) exihibited at least one somatic alteration, with the most prevalent alterations occurring in PTEN, PIK3CA, TP53, and ARID1A. These genomic alterations were mainly enriched in the PI3K, cell cycle, RAS/RAF/MAPK, Epigenetic modifiers/Chromatin remodelers, and DNA damage repair (DDR) signaling pathways. Additionally, we identified ten individuals (11.0%) with pathogenic or likely pathogenic germline alterations in seven genes, with the DDR pathway being predominantly involved. Compared to Western EC patients, Chinese EC patients displayed different prevalence in AKT1, MET, PMS2, PIK3R1, and CTCF. Notably, 69.6% of Chinese EC patients were identified with actionable alterations. In addition, we discovered novel molecular subtypes in ARID1A wild-type patients, characterized by an inferior prognosis, higher TP53 but fewer PTEN and PIK3CA alterations. Additionally, this subtype exhibited a significantly higher abundance of macrophages and activated dendritic cells. Conclusion Our study has contributed valuable insights into the unique germline and somatic genomic profiles of Chinese EC patients, enhancing our understanding of their biological characteristics and potential therapeutic avenues. Furthermore, we have highlighted the presence of molecular heterogeneity in ARID1A-wild type EC patients, shedding light on the complexity of this subgroup.

Abstract Background Cervical cancer is one of the most common gynecological cancers threatening women’s health worldwide. Double-stranded RNA-binding proteins (dsRBPs) regulate innate immunity and are therefore believed to be involved in virus-related malignancies, however, their role in cervical cancer is not well known. Methods We performed RNA-seq of tumor samples from cervical cancer patients in local cohort and also assessed the RNA-seq and clinical data derived from public datasets. By using single sample Gene Set Enrichment Analysis (ssGSEA) and univariate Cox analysis, patients were stratified into distinct dsRBP clusters. Stepwise Cox and CoxBoost were performed to construct a risk model based on optimal dsRBPs clusters-related differentially expressed genes (DEGs), and GSE44001 and CGCI-HTMCP-CC were employed as two external validation cohorts. Single cell RNA sequencing data from GSE168652 and Scissor algorithm were applied to evaluated the signature-related cell population. Results The expression of dsRBP features was found to be associated with HPV infection and carcinogenesis in CESC. However, only Adenosine deaminases acting on RNA (ADAR) and Dicer, Drosha, and Argonautes (DDR) exhibited significant correlations with the overall survival (OS) of CESC patients. Based on these findings, CESC patients were divided into three dsRBP clusters. Cluster 3 showed superior OS but lower levels of ADAR and DDR. Additionally, Cluster 3 demonstrated enhanced innate immunity, with significantly higher activity in cancer immunity cycles, immune scores, and levels of tumor-infiltrating immune cells, particularly CD8+ T cells. Furthermore, a risk model based on nine dsRBP cluster-related DEGs was established. The accuracy of survival prediction for 1 to 5 years was consistently above 0.78, and this model’s robust predictive capacity was confirmed by two external validation sets. The low-risk group exhibited significantly higher levels of immune checkpoints, such as PDCD1 and CTLA4, as well as a higher abundance of CD8+ T cells. Analysis of single-cell sequencing data revealed a significant association between the dsRBP signature and glycolysis. Importantly, low-risk patients showed improved OS and a higher response rate to immunotherapy, along with enduring clinical benefits from concurrent chemoradiotherapy. Conclusions dsRBP played a crucial role in the regulation of prognosis and tumor immunology in cervical cancer, and its prognostic signature provides a strategy for risk stratification and immunotherapy evaluation.

Objective(s): Hyperandrogenism is a key pathological characteristic of polycystic ovary syndrome (PCOS). Tumor necrosis factor α (TNF-α) is both an adipokine and a chronic inflammatory factor, which has been proven to be involved in the pathologic process of PCOS. This study aimed to determine how TNF-α affects glucose uptake in human granulosa cells in the presence of high testosterone concentration. Materials and Methods: KGN cell line was treated with testosterone and TNF-α alone or co-culture combination for 24 hr, or starved for 24 hr. Quantitative real-time polymerase chain reaction (qPCR) and western blot were performed to measure glucose transporter type 4 (GLUT4) message RNA (mRNA) and protein expression in treated KGN cells. Glucose uptake and GLUT4 expression were detected by immunofluorescence (IF). Furthermore, western blot was performed to measure the contents in the nuclear factor kappa-B (NF-κB) pathway. Meantime, upon addition of TNF-α receptor II (TNFRII) inhibitor or Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) antagonist to block the TNFRII-IKKβ-NF-κB signaling pathway, the glucose uptake in KGN cells and GLUT4 translocation to cytomembrane were detected by IF, and related proteins in TNFRII-IKKβ-NF-κB were detected by western blot.Results: The glucose uptake in Testosterone + TNF-α group was lowered significantly, and Total GLUT4 mRNA and proteins were reduced significantly. GLUT4 translocation to cytomembrane was tarnished visibly; concurrently, the phosphorylated proteins in the TNFRII-IKKβ-NF-κB signaling pathway were enhanced significantly. Furthermore, upon addition of TNFRII inhibitor or IKKβ inhibitor to block the TNFRII-IKKβ-NF-κB signaling pathway, the glucose uptake of treated granulosa cells was improved. Conclusion: TNFRII and IKKβ antagonists may improve glucose uptake in granulosa cells induced by TNF-α by blocking the TNFRII-IKKβ-NF-κB signaling pathway under high androgen conditions.

Objective: To use three different 3D CNN algorithms and five different computed tomography (CT) window settings to study the effect on the results of artificial intelligence classification of lung lesions in different CT window techniques. Method: A total of 172 cases of peripheral lung cancer and 185 of focal pneumonia who underwent chest CT were analyzed. Three different 3D CNN algorithms were selected (ResNet, ResNext, and DenseNet) to divide the lesions into two groups. Five different CT window settings, including lung window (1500, 600), mediastinal window (350, 40), custom window 1 (SW1) (1000, 40), and custom window 2 (SW2) (1000, 100), were used retrospectively. We calculated classification accuracy, receiver operating characteristic (ROC) curve, and area under the curve (AUC). The ROC curve was compared in pairs. Results: The average classification accuracy of ResNet was the lowest in the mediastinal window (85.732%; AUC value: 0.871) and the highest in the full window (91.596%; AUC value: 0.946). The average classification accuracy of ResNext was the lowest in the mediastinal window (81.528%; AUC value: 0.814) and the highest in the full window (86.568%; AUC value: 0.882). The average classification accuracy of DenseNet was the lowest in the mediastinal window (87.954%; AUC value: 0.906) and the highest in the SW2 window (93.274%; AUC value: 0.951). Medcalc was used to compare ROC curves under five windows of three 3D CNN. The AUC values between mediastinal window and lung window, mediastinal window and SW1, and mediastinal window and SW2 were statistically significant. Conclusion: There is little difference in the diagnostic efficacy of the three 3D CNN. Different CT window settings have an influence on the results of CNN classification of the lung lesions, and the diagnostic efficiency of the three 3D CNN is the worst under the mediastinal window.

Abstract Background Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women at increased risk of breast and ovarian cancer. We launched a prospective study of women receiving RRSO, including those with mutations in genes beyond BRCA1/2. Patients and methods 80 women were enrolled for RRSO with sectioning and extensively examining the fimbriae (SEE-FIM) protocol between October 2016 and June 2022. The majority of participants had inherited susceptibility gene mutations or a family history suggesting ovarian cancer risk, while patients with isolated metastatic high-grade serous cancer of unknown origin were also included. Results Overall, two patients had isolated metastatic high-grade serous cancer with unknown origin, and four patients had family histories but refused to take genetic tests. The rest 74 patients harbored deleterious susceptible gene, including 43 (58.1%) with BRCA1 mutation, and 26 (35.1%) with BRCA2 mutation, respectively. Other mutated genes included ATM (1), BRIP1(1), PALB2(1), MLH1(1) and TP53 (1) in each patient. Among the 74 mutation carriers, three (4.1%) cancers were recognized, one (1.4%) was found to have serous tubal intraepithelial carcinoma (STIC), and five patients (6.8%) was diagnosed with serous tubal intraepithelial lesions (STILs). P53 signature was recognized in 24 patients (32.4%). For other genes, MLH1 mutation carrier had endometrial atypical hyperplasia and p53 signature in fallopian tubes. The germline TP53 mutation carrier had STIC in the surgical specimens. Evidence for precursor escape was also recognized in our cohort. Conclusion Our study demonstrated clinic-pathological findings of patients at increased risk of breast and ovarian cancer, and expand the clinical application of SEE-FIM protocol.

Blockchain technology has attracted significant attention since its publication. However, most existing blockchain platforms are isolated systems, which makes it difficult to exchange data among different blockchains. The industry has proposed the notary schemes to enhance blockchain interoperability, which can exchange messages among different blockchains through a notary. However, conventional notary schemes are centralized, which suffers from single point of failures. To address these issues, this paper proposes a distributed cross-chain notary model with regulatory mechanisms, based on improved threshold group signatures. We improve the group signature scheme by setting up a group of tracing authorities to achieve distributed tracing. Furthermore, we incorporate this signature scheme into our notary scheme, where a group of notaries signs cross-chain transactions using group signatures. We also introduce a group of regulators to reveal the true identities of malicious notaries when disputes occur. Finally, we prove the security of our signature scheme based on the Random Oracle Model. In our experiments, when the number of notaries is 102 and the threshold is 2/3 of that, it takes 166 ms to set up and generate signature. Also, it takes 161 ms for regulators to reveal the true identities of malicious notaries.

In this study, we assessed the effects of MFG-E8 on the biological characteristics of ovarian cancer cells and explored the underlying mechanisms. Human ovarian cancer SKOV3 cells were transfected with MFG-E8 siRNA or NC siRNA. CCK-8, cell adhesion, scratch-wound, and Transwell assays were used to detect changes in cell metastatic processes. Effects of MFG-E8 silencing on the proteins involved in AKT/mTOR/S6K signalling pathway were assessed using qRT-PCR and Western blotting. Transient silencing of MFG-E8 in SKOV3 cells decreased cell proliferation and downregulated the expression of CDK4, cyclin D1, and caspase-3 proteins. Cell adhesion, migration, and invasion were also suppressed. p-AKT, p-mTORC1, and p-p70S6K levels decreased following MFG-E8 knockdown. Hence, MFG-E8 enhances carcinogenesis and affects the AKT/mTOR/S6K signalling pathway in ovarian cancer cells. In conclusion, our results suggested that MFG-E8 could promote ovarian cancer via AKT/mTOR/S6K signalling pathway which improved our understanding of the molecular mechanisms involved in ovarian cancer.IMPACT STATEMENT What is already known on this subject? Milk fat globule-epidermal growth factor 8 (MFG-E8) is expressed in several types of cancers such as oesophageal, breast, and liver. However, the mechanism of MFG-E8 involving in EOC remains unknown. We previously found that MFG-E8 expression was related to pathological staging, tissue differentiation, platinum sensitivity, ascites state, and other clinicopathological characteristics. What the results of this study add? Due to a series of in vitro studies, we confirmed that MFG-E8 is involved in the process of proliferation, invasion and metastasis. Our results show that silencing MFG-E8 can significantly inhibit the expression of cyclin D1 and CDK4 in EOC SKOV3 cells. MFG-E8 enhances carcinogenesis and affects the AKT/mTOR/S6K signaling pathway in ovarian cancer. What the implications are of these findings for clinical practice and/or further research? Taken together, our findings suggest that MFG-E8 may be an oncogene in EOC and provide new insights into the mechanism of MFG-E8 in the progression of EOC.

Objective: To study enzymatic properties of intracellular maltogenic amylase (BMAL) in Bacillus sp. B110, purification, gene cloning, heterologous expression and purification were performed. It laid a foundation for later research on the development of new starch processing enzymes. Method: The full-length of BMAL gene was amplified by PCR and over-expressed and heterologous expressed in Escherichia coli. The recombinant enzyme was purified with nickel affinity chromatography (Ni2+-NTA), and its enzymatic characteristic were determined. The amino acid sequence of BMAL was analyzed by sequence analysis tools BioEdit and MEGA tools, and the three-dimensional model was predicted by alpha fold2. Results: The nucleotide sequence analysis revealed an open reading frame (ORF) of 1770 bp encoded a putative protein of 589 aa residues. The recombinant enzyme was purified with nickel affinity chromatography (Ni2+-NTA). SDS-PAGE analysis of the purified enzyme revealed that the molecular mass of BMAL was 63 kDa. The primary structure of BMAL was similar to those of MAases from B. subtilis 168 and B. subtilis SUH4-2, such as possession of an extra domain at its N-terminal and had a catalytic triad Asp328-Glu357-Asp424. The purified recombinant enzyme rBMAL had an optimum temperature of 45 ℃ and an optimum pH around 6.0. The rBMAL retained about 60% activity after 7 h of incubation at below 30 ℃, but it lost 98% of the original activity after 2 h of incubation at 60 ℃. These results revealed that the rBMAL was inthermostability. The activity of rBMAL was stable in pH7.0~9.5 at 4 ℃ for 12 h. In the presence of 1 mmol/L metal ion Mg2+, the activity of rBMAL increased by 36%, while 1 mmol/L Ni2+, Fe3+, Co2+, Cu2+, Zn2+, Al3+, Ca2+ inhibited the activity of rBMAL, which decreased by 85%~48%. The recombinant enzyme activity was inhibited by methanol, acetone, ethanol, acetonitrile, EDTA and SDS, and the enzyme activity was decreased to 32.3%~64.8%. Conclusion: The intracellular maltose amylase BMAL from Bacillus sp. B110 had high catalytic capacity and pH stability, which had potential application in bread baking industry.

Abstract Background Most traditional procedures can destroy tissue natural structure, and the information on spatial distribution and temporal distribution of immune milieu in situ would be lost. We aimed to explore the potential mechanism of pelvic lymph node (pLN) metastasis of cervical cancer (CC) by multiplex immunofluorescence (mIF) and construct a nomogram for preoperative prediction of pLN metastasis in patients with CC. Methods Patients (180 IB1-IIA2 CC patients of 2009 FIGO (International Federation of Gynecology and Obstetrics)) were divided into two groups based on pLN status. Tissue microarray (TMA) was prepared and tumor-infiltrating immune markers were assessed by mIF. Multivariable logistic regression analysis and nomogram were used to develop the predicting model. Results Multivariable logistic regression analysis constructs a predictive model and the area under the curve (AUC) can reach 0.843. By internal validation with the remaining 40% of cases, a new ROC curve has emerged and the AUC reached 0.888. Conclusions This study presents an immune nomogram, which can be conveniently used to facilitate the preoperative individualized prediction of LN metastasis in patients with CC.

Abstract Background Homologous Recombination Deficiency (HRD) is a predictive biomarker for ovarian cancer treated with PARP inhibitors or for breast cancer treated with first-line platinum-based chemotherapy. However, limited research is documented on platinum-based treatment prediction with HRD as a biomarker in ovarian cancer patients, especially in the Chinese population. Methods We investigated the association between HRD status and the response of platinum-based chemotherapy in 240 Chinese HGSOC patients. Results The Pt-sensitive patients showed higher HRD scores than Pt-resistant ones, but this was not significant(median: 42.6 vs. 31.6, p = 0.086). (Pt)-sensitive rate was higher in HRD + BRCAm tumors and in HRD + BRCAwt tumors (HRD + BRCAm: 97%, p = 0.004 and HRD + BRCAwt: 90%, p = 0.04) compared with 74% in the HRD-BRCAwt tumors. We also found Pt-sensitive patients tend to be enriched in patients with BRCA mutations or non-BRCA HRR pathway gene mutations (BRCA: 93.6% vs 75.4%, p

In the study of the deep learning classification of medical images, deep learning models are applied to analyze images, aiming to achieve the goals of assisting diagnosis and preoperative assessment. Currently, most research classifies and predicts normal and cancer cells by inputting single-parameter images into trained models. However, for ovarian cancer (OC), identifying its different subtypes is crucial for predicting disease prognosis. In particular, the need to distinguish high-grade serous carcinoma from clear cell carcinoma preoperatively through non-invasive means has not been fully addressed. This study proposes a deep learning (DL) method based on the fusion of multi-parametric magnetic resonance imaging (mpMRI) data, aimed at improving the accuracy of preoperative ovarian cancer subtype classification. By constructing a new deep learning network architecture that integrates various sequence features, this architecture achieves the high-precision prediction of the typing of high-grade serous carcinoma and clear cell carcinoma, achieving an AUC of 91.62% and an AP of 95.13% in the classification of ovarian cancer subtypes.

Abstract One major characteristic of tumor cells is the aberrant activation of epigenetic regulatory elements, which remodel the tumor transcriptome and ultimately promote cancer progression and drug resistance. However, the oncogenic functions and mechanisms of ovarian cancer (OC) remain elusive. Here, super‐enhancer (SE) regulatory elements that are aberrantly activated in OC are identified and it is found that SEs drive the relative specific expression of the transcription factor KLF5 in OC patients and poly(ADP‐ribose) polymerase inhibitor (PARPi)‐resistant patients. KLF5 expression is associated with poor outcomes in OC patients and can drive tumor progression in vitro and in vivo. Mechanistically, KLF5 forms a transcriptional complex with EHF and ELF3 and binds to the promoter region of RAD51 to enhance its transcription, strengthening the homologous recombination repair (HRR) pathway. Notably, the combination of suberoylanilide hydroxamic acid (SAHA) and olaparib significantly inhibits tumor growth and metastasis of PARPi‐resistant OC cells with high KLF5. In conclusion, it is discovered that SEs‐driven KLF5 is a key regulatory factor in OC progression and PARPi resistance; and potential therapeutic strategies for OC patients with PARPi resistance and high KLF5 are identified.

Summary: Aerobic glycolysis is critical for cancer progression and can be exploited in cancer therapy. Here, we report that the human carboxymethylenebutenolidase homolog (carboxymethylenebutenolidase-like [CMBL]) acts as a tumor suppressor by reprogramming glycolysis in colorectal cancer (CRC). The anti-cancer action of CMBL is mediated through its interactions with the E3 ubiquitin ligase TRIM25 and the glycolytic enzyme phosphofructokinase-1 platelet type (PFKP). Ectopic CMBL enhances TRIM25 binding to PFKP, leading to the ubiquitination and proteasomal degradation of PFKP. Interestingly, CMBL is transcriptionally activated by p53 in response to genotoxic stress, and p53 activation represses glycolysis by promoting PFKP degradation. Remarkably, CMBL deficiency, which impairs p53’s ability to inhibit glycolysis, makes tumors more sensitive to a combination therapy involving the glycolysis inhibitor 2-deoxyglucose. Taken together, our study demonstrates that CMBL suppresses CRC growth by inhibiting glycolysis and suggests a potential combination strategy for the treatment of CMBL-deficient CRC.

As a result of significant advancements in living conditions, individuals have redirected their attention towards physical exercise. Skiing, as a widely popular sport, necessitates the real-time maintenance of correct posture during movement. Therefore, we present a dynamic skiing motion capture and human posture detection model that leverages wireless device tracking. Primarily, personnel tracking is enabled through the construction of service base stations and the utilization of wireless device tracking technology. Subsequently, a human posture detection model is formulated in the form of human posture key points, employing the image information of each frame obtained via wireless devices. Finally, we introduce a spatio-temporal Transformer structure that facilitates the detection and recognition of human posture in consecutive frames. Our results demonstrate that our approach can precisely locate and track the position of skiing personnel. Compared to the latest Blip and Conformer methods, our technique yields F values that surpass them by 1.20% and 4.51%, respectively. Moreover, our model can achieve convergent model parameters and accomplish training objectives more efficiently, thus enabling posture detection and dynamic capture of skiing personnel via image and video information.

Background: The pathogenic genes of colorectal cancer (CRC) have not yet been fully elucidated, and there is currently a lack of effective therapeutic targets. This study used bioinformatics methods to explore and experimentally validate the most valuable biomarkers for colorectal cancer and further investigate their potential as targets.Methods: We analyzed differentially expressed genes (DEGs) based on the Gene Expression Omnibus (GEO) dataset and screened out hub genes. ROC curve and univariate Cox analysis of The Cancer Genome Atlas (TCGA) dataset revealed the most diagnostically and prognostically valuable genes. Immunohistochemistry (IHC) experiments were then conducted to validate the expression level of these selected genes in colorectal cancer. Gene set enrichment analysis (GSEA) was performed to evaluate the enriched signaling pathways associated with the gene. Using the CIBERSORT algorithm in R software, we analyzed the immune infiltrating cell abundance in both high and low gene expression groups and examined the gene’s correlation with immune cells and immune checkpoints. Additionally, we performed drug sensitivity analysis utilizing the DepMap database, and explored the correlation between gene expression levels and ferroptosis based on the The Cancer Genome Atlas dataset.Results: The study identified a total of 159 DEGs, including 7 hub genes: SPP1, MMP1, CXCL8, CXCL1, TIMP1, MMP3, and CXCL10. Further analysis revealed TIMP1 as the most valuable diagnostic and prognostic biomarker for colorectal cancer, with IHC experiments verifying its high expression. Additionally, GSEA results showed that the high TIMP1 expression group was involved in many cancer signaling pathways. Analysis of the TCGA database revealed a positive correlation between TIMP1 expression and infiltration of macrophages (M0, M1, M2) and neutrophils, as well as the expression of immune checkpoint genes, including CTLA-4 and HAVCR2. Drug sensitivity analysis, conducted using the DepMap database, revealed that colorectal cancer cell lines exhibiting elevated levels of TIMP1 expression were more responsive to certain drugs, such as CC-90003, Pitavastatin, Atuveciclib, and CT7001, compared to those with low levels of TIMP1. Furthermore, TIMP1 expression was positively correlated with that of ferroptosis-related genes, such as GPX4 and HSPA5.Conclusion: TIMP1 can be used as a biomarker for colorectal cancer and is associated with the immunological microenvironment, drug sensitivity, and ferroptosis inhibition in this disease.

This paper introduces a DC-DC converter that employs a modified triple boosting architecture (MTB), interleaved with modified switched inductor capacitors (MSIC), to achieve ultra-high voltage gain in photovoltaic applications. The converter design also includes a modified switched inductor with a modified voltage multiplier mode (MVM), which interleaves with the main switch and effectively doubles the voltage transfer gain. Furthermore, a modified triple boosting mode technique, utilizing interleaved components and an auxiliary switch, is integrated into the converter design. The main switch and auxiliary switch, combined with modified voltage multiplyer, contribute to achieving high voltage gain. The proposed converter offers numerous advantages. It exhibits remarkable efficiency while ensuring low voltage stress across diodes and MOSFETs. Moreover, by utilizing low inductance and capacitance values at high switching frequencies, the converter’s overall performance is enhanced. To validate and substantiate the simulation and laboratory results, the converter has undergone PCB design and experimental testing. Specifically, this converter is designed to boost input voltage levels ranging from 30 V to 40 V to a variable output voltage between 200 V and 400 V, with a power output of 360 W and an efficiency rating of 96.5%.

The corrected special maps of components have revealed an outstanding role on valuating the off-design performance of micro gas turbine engines. The main purpose of this paper is to investigate the steady-state performance at design and off-design point of a micro turbojet engine capable of generating 400 N thrust. At present work, the experiments were conducted and the thrust and specific fuel consumption are 39.48 daN and 1.62kg/(daN h) at design point, respectively. Importantly, a present methodology, that is adjusting the values of Beta and N/sqrt(T) in specific map of the components when performing the off-design calculation of this engine, is proposed in this research, where results are compared with the data from experiment and other literature. Exemplarily, according to a comparison with the experimental results, there is less than 1% of the deviation in thrust at design point and 3% of the difference in the thrust at off-design point with the corrected specific map when performing the numerical simulation. This method enables evaluating the operating characteristics of both on design and off-design point, providing more accurate trend analysis of performance parameters in terms of engine compared to the researches which seldom used the scaling map.

Patients with recurrent or metastatic cervical cancer have limited therapeutic options. Here the authors report efficacy and safety of camrelizumab (anti-PD-1 antibody) in combination with famitinib (anti-angiogenic agent) in pre-treated recurrent or metastatic squamous cervical cancer.

Objective To evaluate the clinical efficacy and safety of low-intensity ultrasound (LIUS) in promoting uterine involution and relieving postpartum pain. Methods The randomized controlled clinical trial in this study was conducted at five centers in three regions across China from June 2014 to December 2014. A total of 498 subjects were randomly divided into two groups. The LIUS group received ultrasound treatment, and the control group received sham ultrasound treatment. The fundal height and visual analogue scale (VAS) scores of the subjects following cesarean section were recorded separately before and after five treatments. The incidence of adverse events was recorded, while the records on lochia duration were obtained by telephone follow-up. The Full Analysis Set (FAS) comprised all subjects randomized who received at least one treatment. The Per-Protocol Set (PPS) comprised all patients who did not seriously violate the study protocol and had good compliance with complete report forms. Efficacy analyses were performed based on the FAS and PPS. All safety analyses were performed based on the safety set (SS), which included all patients who received at least one treatment. Results In the analysis of PPS and FAS, the LIUS group performed better than the control group in reducing the fundal height, shortening the duration of lochia, and relieving postpartum pain, with a significant difference between the two groups (p

Modification of transcribed mRNAs enables regulation of transcription but its extent in cancer cells is incompletely understood. Here, the authors analyse transcript assembly in over 1000 cancer cell lines and find unannotated transcripts are common, and are associated with drug sensitivity.