Prognostic factors of 87 ovarian yolk sac tumor (OYST) patients and molecular characteristics of persistent and recurrent OYST.

OBJECTIVE: We aimed to explore the characteristics of OYST, particularly for persistent and recurrent OYST, in order to explore potential treatment options and thereby improve patient outcomes. METHODS: We retrospectively reviewed the clinical records of all patients with OYST at Fudan university Shanghai Cancer Center from December 3, 2005 to November 27, 2020. Furthermore, and performed whole-exome sequencing on 17 paired OYST (including 8 paired persistent and recurrent OYST) tumor and blood samples to elucidate the aberrant molecular features. RESULTS: Totally, 87 OYST patients were included between 2007/03/13 and 2020/11/17. With a median follow-up of 73 [3-189] months, 22 patients relapsed or disease persisted. Overall, 17 patients died with a median overall survival of 21 [3-54] months. Univariate and multivariate analysis revealed tumor histology and residual lesions were independently associated with event free survival and overall survival, cycles to AFP normalization were another independent risk factor for overall survival. For the 8 persistent and recurrent OYST: cancer driver genes including ANKRD36, ANKRD62, DNAH8, MUC5B, NUP205, RYR2, STARD9, MUC16, TTN, ARID1A and PIK3CA were frequently mutated; cell cycle, ABC transporters, HR, NHEJ and AMPK signal pathway demonstrated as the most significantly enriched pathways; TMB, DNA MMR gene mutation and MSI were significantly higher. Mutation signature 11, 19 and 30 were the dominant contributors in persistent and recurrent OYST mutation. CONCLUSION: Persistent and recurrent OYST associated with poor prognosis, and probably susceptible to immune checkpoint blockade therapy. Molecular characteristics contributed to predict the persistence and recurrence of OYST.

Prognostic factors and the role of primary debulking in operable stage IVB ovarian cancer with supraclavicular lymph node metastasis: a retrospective study in Chinese patients.

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.

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial.

Background: Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). Methods: This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/µL at baseline and 300 mg/day otherwise. OS was a secondary endpoint. Findings: Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Interpretation: Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Funding: Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

Myocardial deformation characteristics assessed by cardiovascular magnetic resonance feature tracking in a healthy Chinese population.

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.

Differential selection of yield and quality traits has shaped genomic signatures of cowpea domestication and improvement.

Cowpeas (tropical legumes) are important in ensuring food and nutritional security in developing countries, especially in sub-Saharan Africa. Herein, we report two high-quality genome assemblies of grain and vegetable cowpeas and we re-sequenced 344 accessions to characterize the genomic variations landscape. We identified 39 loci for ten important agronomic traits and more than 541 potential loci that underwent selection during cowpea domestication and improvement. In particular, the synchronous selections of the pod-shattering loci and their neighboring stress-relevant loci probably led to the enhancement of pod-shattering resistance and the compromise of stress resistance during the domestication from grain to vegetable cowpeas. Moreover, differential selections on multiple loci associated with pod length, grain number per pod, seed weight, pod and seed soluble sugars, and seed crude proteins shaped the yield and quality diversity in cowpeas. Our findings provide genomic insights into cowpea domestication and improvement footprints, enabling further genome-informed cultivar improvement of cowpeas.

Corrigendum: Integrated analysis of transcriptome and metabolome reveals the mechanism of chlorine dioxide repressed potato (Solanum tuberosum L.) tuber sprouting.

[This corrects the article DOI: 10.3389/fpls.2022.887179.].

FGR-associated placental insufficiency and capillary angiogenesis involves disruptions in human placental miRNAs and mRNAs.

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.

Pembrolizumab in patients from China with microsatellite instability-high/mismatch repair deficient tumors: KEYNOTE-158.

Aim: To evaluate pembrolizumab in patients of Chinese descent with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors enrolled in KEYNOTE-158 (Cohort L). Methods: Patients with MSI-H/dMMR advanced tumors received pembrolizumab 200 mg IV Q3W. Primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: 24 patients were enrolled (20 were evaluable for efficacy). With median follow-up of 12.4 months, the ORR was 70%. DOR, PFS and OS were all not reached. A total of 19 (79%) patients had a treatment-related adverse event (AE; grade ≥3 in 4 [17%]), and 8 (33%) had an immune-mediated AE (grade ≥3 in (4 [17%]). Conclusion: Pembrolizumab provided meaningful and durable responses with manageable safety. These results are consistent with those reported for the global trial.

Assessment of Non-Invasive Ventilation Combined with Naloxone for the Management of Acute Respiratory Failure in Patients with Chronic Obstructive Pulmonary Disease.

Background: Chronic obstructive pulmonary disease (COPD) poses a significant global health burden. Finding effective interventions for COPD is crucial to alleviating this health burden and enhancing patient outcomes and quality of life. Objective: This study aimed to evaluate the therapeutic efficacy of the combination of non-invasive ventilation and naloxone in the management of acute respiratory failure among patients with COPD. Methods: A retrospective analysis was conducted on the clinical data of 102 COPD patients experiencing acute respiratory failure who were treated at our hospital between October 2020 and October 2022. Patients were categorized into an observation group (receiving non-invasive ventilation combined with naloxone) and a control group (receiving non-invasive ventilation alone). Parameters such as lung function, blood gas levels, endocrine hormone concentrations, treatment efficacy, and patient prognosis were carefully recorded and compared. Results: The observation group demonstrated enhanced lung function, optimized endocrine hormone levels, and improved blood gas parameters compared to the control group. Following treatment, the observation group exhibited significant reductions in plasma renin activity (PRA), angiotensin II (AngII), aldosterone (ALD), and norepinephrine (NE) levels. The total effective rate was notably higher in the observation group. This group also presented higher scores for Acute Physiology and Chronic Health Evaluation II (APACHE II) and Chronic Obstructive Pulmonary Disease Assessment Test (CAT). Conclusions: The combination of non-invasive ventilation with naloxone emerged as a significantly effective strategy in managing acute respiratory failure in COPD patients. This approach led to improvements in lung function, endocrine hormone levels, and blood gas parameters and highlights its potential as an impactful treatment strategy for COPD patients experiencing acute respiratory failure.

A modified diffusion-weighted magnetic resonance imaging-based model from the radiologist's perspective: improved performance in determining the surgical resectability of advanced high-grade serous ovarian cancer.

BACKGROUND: Complete resection of all visible lesions during primary debulking surgery is associated with the most favorable prognosis in patients with advanced high-grade serous ovarian cancer. An accurate preoperative assessment of resectability is pivotal for tailored management. OBJECTIVE: This study aimed to assess the potential value of a modified model that integrates the original 8 radiologic criteria of the Memorial Sloan Kettering Cancer Center model with imaging features of the subcapsular or diaphragm and mesenteric lesions depicted on diffusion-weighted magnetic resonance imaging and growth patterns of all lesions for predicting the resectability of advanced high-grade serous ovarian cancer. STUDY DESIGN: This study included 184 patients with high-grade serous ovarian cancer who underwent preoperative diffusion-weighted magnetic resonance imaging between December 2018 and May 2023 at 2 medical centers. The patient cohort was divided into 3 subsets, namely a study cohort (n=100), an internal validation cohort (n=46), and an external validation cohort (n=38). Preoperative radiologic evaluations were independently conducted by 2 radiologists using both the Memorial Sloan Kettering Cancer Center model and the modified diffusion-weighted magnetic resonance imaging-based model. The morphologic characteristics of the ovarian tumors depicted on magnetic resonance imaging were assessed as either mass-like or infiltrative, and transcriptomic analysis of the primary tumor samples was performed. Univariate and multivariate statistical analyses were performed. RESULTS: In the study cohort, both the scores derived using the Memorial Sloan Kettering Cancer Center (intraclass correlation coefficients of 0.980 and 0.959, respectively; both P<.001) and modified diffusion-weighted magnetic resonance imaging-based models (intraclass correlation coefficients of 0.962 and 0.940, respectively; both P<.001) demonstrated excellent intra- and interobserver agreement. The Memorial Sloan Kettering Cancer Center model (odds ratio, 1.825; 95% confidence interval, 1.390-2.395; P<.001) and the modified diffusion-weighted magnetic resonance imaging-based model (odds ratio, 1.776; 95% confidence interval, 1.410-2.238; P<.001) independently predicted surgical resectability. The modified diffusion-weighted magnetic resonance imaging-based model demonstrated improved predictive performance with an area under the curve of 0.867 in the study cohort and 0.806 and 0.913 in the internal and external validation cohorts, respectively. Using the modified diffusion-weighted magnetic resonance imaging-based model, patients with scores of 0 to 2, 3 to 4, 5 to 6, 7 to 10, and ≥11 achieved complete tumor debulking rates of 90.3%, 66.7%, 53.3%, 11.8%, and 0%, respectively. Most patients with incomplete tumor debulking had infiltrative tumors, and both the Memorial Sloan Kettering Cancer Center and the modified diffusion-weighted magnetic resonance imaging-based models yielded higher scores. The molecular differences between the 2 morphologic subtypes were identified. CONCLUSION: When compared with the Memorial Sloan Kettering Cancer Center model, the modified diffusion-weighted magnetic resonance imaging-based model demonstrated enhanced accuracy in the preoperative prediction of resectability for advanced high-grade serous ovarian cancer. Patients with scores of 0 to 6 were eligible for primary debulking surgery.

MUC1 promotes RIF by regulating macrophage ROS-SHP2 signaling pathway to up-regulate inflammatory response and inhibit angiogenesis.

OBJECTIVE: To explore the effect of MUC1 on recurrent implantation failure (RIF) and its molecular mechanism. METHODS: Bioinformation analysis was used to find possible molecular mechanisms of specific genes in the pathogenesis of RIF. The number of M1 and M2 macrophages was measured by flow cytometry. Immunohistochemical staining and western blotting were used to detect the expression of related proteins. Angiogenesis capacity was measured by cell tube-formation assay. RESULTS: Bioinformatics analysis results suggest that MUC1 may play an important role in RIF. The results of flow cytometry showed that compared with NC group, M1 macrophages increased significantly and M2 macrophages decreased significantly in MUC1 OE group. The results of immunohistochemical staining showed that MUC1 could inhibit the expression of VEGF. Western blotting results showed that MUC1 could significantly increase the expression of P22, P47, gp91, p-TBK1, IFNγ and IL-1ß, and decrease the expression of p-SHP2, p-PI3K, p-mTOR, HIF1α and VEGF. After the addition of ROS inhibitor and PI3K inhibitor, the effect of MUC1 on the above proteins was eliminated. The results of tube formation experiments showed that MUC1 could inhibit vascular formation. CONCLUSION: As a promising biomarker for the diagnosis of RIF, MUC1 can promote RIF by regulating macrophage ROS-SHP2 signaling pathway to up-regulate inflammatory response and inhibit angiogenesis.

Using the sulfide-oxidizing bacterium Geobacillus thermodenitrificans to restrict H2S release during chicken manure composting.

Hydrogen sulfide (H2S) is a toxic gas massively released during chicken manure composting. Diminishing its release requires efficient and low cost methods. In recent years, heterotrophic bacteria capable of rapid H2S oxidation have been discovered but their applications in environmental improvement are rarely reported. Herein, we investigated H2S oxidation activity of a heterotrophic thermophilic bacterium Geobacillus thermodenitrificans DSM465, which contains a H2S oxidation pathway composed by sulfide:quinone oxidoreductase (SQR) and persulfide dioxygenase (PDO). This strain rapidly oxidized H2S to sulfane sulfur and thiosulfate. The oxidation rate reached 5.73 µmol min-1·g-1 of cell dry weight. We used G. thermodenitrificans DSM465 to restrict H2S release during chicken manure composting. The H2S emission during composting process reduced by 27.5% and sulfate content in the final compost increased by 34.4%. In addition, this strain prolonged the high temperature phase by 7 days. Thus, using G. thermodenitrificans DSM465 to control H2S release was an efficient and economic method. This study provided a new strategy for making waste composting environmental friendly and shed light on perspective applications of heterotrophic H2S oxidation bacteria in environmental improvements.

Prognostic model of ER-positive, HER2-negative breast cancer predicted by clinically relevant indicators

Purpose To study the clinicopathological variables connected with disease-free survival (DFS) as well as overall survival (OS) in patients who are ER-positive or HER2-negative and to propose nomograms for predicting individual risk. Methods In this investigation, we examined 585 (development cohort) and 291 (external validation) ER-positive, HER2-negative breast cancer patients from January 2010 to January 2014. From January 2010 to December 2014, we retrospectively reviewed and analyzed 291 (external validation) and 585 (development cohort) HER2-negative, ER-positive breast cancer patients. Cox regression analysis, both multivariate and univariate, confirmed the independence indicators for OS and DFS. Results Using cox regression analysis, both multivariate and univariate, the following variables were combined to predict the DFS of development cohort: pathological stage (HR = 1.391; 95% CI = 1.043–1.855; P value = 0.025), luminal parting (HR = 1.836; 95% CI = 1.142–2.952; P value = .012), and clinical stage (HR = 1.879; 95% CI = 1.102–3.203; P value = 0.021). Endocrine therapy (HR = 3.655; 95% CI = 1.084–12.324; P value = 0.037) and clinical stage (HR = 6.792; 95% CI = 1.672–28.345; P value = 0.009) were chosen as predictors of OS. Furthermore, we generated RS-OS and RS-DFS. According to the findings of Kaplan–Meier curves, patients who are classified as having a low risk have considerably longer DFS and OS durations than patients who are classified as having a high risk. Conclusion To generate nomograms that predicted DFS and OS, independent predictors of DFS in ER-positive/HER2-negative breast cancer patients were chosen. The nomograms successfully stratified patients into prognostic categories and worked well in both internal validation and external validation (AU)

PARP1-stabilised FOXQ1 promotes ovarian cancer progression by activating the LAMB3/WNT/ß-catenin signalling pathway.

Metastasis is an important factor that causes ovarian cancer (OC) to become the most lethal malignancy of the female reproductive system, but its molecular mechanism is not fully understood. In this study, through bioinformatics analysis, as well as analysis of tissue samples and clinicopathological characteristics and prognosis of patients in our centre, it was found that Forkhead box Q1 (FOXQ1) was correlated with metastasis and prognosis of OC. Through cell function experiments and animal experiments, the results show that FOXQ1 can promote the progression of ovarian cancer in vivo and in vitro. Through RNA-seq, chromatin immunoprecipitation sequencing (ChIP-seq), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), Western blotting (WB), quantitative real-time polymerase chain reaction (qRT‒PCR), immunohistochemistry (IHC), luciferase assay, and ChIP-PCR, it was demonstrated that FOXQ1 can mediate the WNT/ß-catenin pathway by targeting the LAMB promoter region. Through coimmunoprecipitation (Co-IP), mass spectrometry (MS), ubiquitination experiments, and immunofluorescence (IF), the results showed that PARP1 could stabilise FOXQ1 expression via the E3 ubiquitin ligase Hsc70-interacting protein (CHIP). Finally, the whole mechanism pathway was verified by animal drug combination experiments and clinical specimen prognosis analysis. In summary, our results suggest that PARP1 can promote ovarian cancer progression through the LAMB3/WNT/ß-catenin pathway by stabilising FOXQ1 expression.

Long-read transcriptome landscapes of primary and metastatic liver cancers at transcript resolution.

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.

Prognostic model of ER-positive, HER2-negative breast cancer predicted by clinically relevant indicators.

PURPOSE: To study the clinicopathological variables connected with disease-free survival (DFS) as well as overall survival (OS) in patients who are ER-positive or HER2-negative and to propose nomograms for predicting individual risk. METHODS: In this investigation, we examined 585 (development cohort) and 291 (external validation) ER-positive, HER2-negative breast cancer patients from January 2010 to January 2014. From January 2010 to December 2014, we retrospectively reviewed and analyzed 291 (external validation) and 585 (development cohort) HER2-negative, ER-positive breast cancer patients. Cox regression analysis, both multivariate and univariate, confirmed the independence indicators for OS and DFS. RESULTS: Using cox regression analysis, both multivariate and univariate, the following variables were combined to predict the DFS of development cohort: pathological stage (HR = 1.391; 95% CI = 1.043-1.855; P value = 0.025), luminal parting (HR = 1.836; 95% CI = 1.142-2.952; P value = .012), and clinical stage (HR = 1.879; 95% CI = 1.102-3.203; P value = 0.021). Endocrine therapy (HR = 3.655; 95% CI = 1.084-12.324; P value = 0.037) and clinical stage (HR = 6.792; 95% CI = 1.672-28.345; P value = 0.009) were chosen as predictors of OS. Furthermore, we generated RS-OS and RS-DFS. According to the findings of Kaplan-Meier curves, patients who are classified as having a low risk have considerably longer DFS and OS durations than patients who are classified as having a high risk. CONCLUSION: To generate nomograms that predicted DFS and OS, independent predictors of DFS in ER-positive/HER2-negative breast cancer patients were chosen. The nomograms successfully stratified patients into prognostic categories and worked well in both internal validation and external validation.

MutSß protects common fragile sites by facilitating homology-directed repair at DNA double-strand breaks with secondary structures.

Common fragile sites (CFSs) are regions prone to chromosomal rearrangements, thereby contributing to tumorigenesis. Under replication stress (RS), CFSs often harbor under-replicated DNA regions at the onset of mitosis, triggering homology-directed repair known as mitotic DNA synthesis (MiDAS) to complete DNA replication. In this study, we identified an important role of DNA mismatch repair protein MutSß (MSH2/MSH3) in facilitating MiDAS and maintaining CFS stability. Specifically, we demonstrated that MutSß is required for the increased mitotic recombination induced by RS or FANCM loss at CFS-derived AT-rich and structure-prone sequences (CFS-ATs). We also found that MSH3 exhibits synthetic lethality with FANCM. Mechanistically, MutSß is required for homologous recombination (HR) especially when DNA double-strand break (DSB) ends contain secondary structures. We also showed that upon RS, MutSß is recruited to Flex1, a specific CFS-AT, in a PCNA-dependent but MUS81-independent manner. Furthermore, MutSß interacts with RAD52 and promotes RAD52 recruitment to Flex1 following MUS81-dependent fork cleavage. RAD52, in turn, recruits XPF/ERCC1 to remove DNA secondary structures at DSB ends, enabling HR/break-induced replication (BIR) at CFS-ATs. We propose that the specific requirement of MutSß in processing DNA secondary structures at CFS-ATs underlies its crucial role in promoting MiDAS and maintaining CFS integrity.

Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial.

BACKGROUND: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer. METHODS: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866. FINDINGS: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy). INTERPRETATION: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care. FUNDING: AstraZeneca.

The Therapeutic Monoclonal Antibody Bamlanivimab Does Not Enhance SARS-CoV-2 Infection by FcR-Mediated Mechanisms.

As part of the non-clinical safety package characterizing bamlanivimab (SARS-CoV-2 neutralizing monoclonal antibody), the risk profile for antibody-dependent enhancement of infection (ADE) was evaluated in vitro and in an African green monkey (AGM) model of COVID-19. In vitro ADE assays in primary human macrophage, Raji, or THP-1 cells were used to evaluate enhancement of viral infection. Bamlanivimab binding to C1q, FcR, and cell-based effector activity was also assessed. In AGMs, the impact of bamlanivimab pretreatment on viral loads and clinical and histological pathology was assessed to evaluate enhanced SARS-CoV-2 replication or pathology. Bamlanivimab did not increase viral replication in vitro, despite a demonstrated effector function. In vivo, no significant differences were found among the AGM groups for weight, temperature, or food intake. Treatment with bamlanivimab reduced viral loads in nasal and oral swabs and BAL fluid relative to control groups. Viral antigen was not detected in lung tissue from animals treated with the highest dose of bamlanivimab. Bamlanivimab did not induce ADE of SARS-CoV-2 infection in vitro or in an AGM model of infection at any dose evaluated. The findings suggest that high-affinity monoclonal antibodies pose a low risk of mediating ADE in patients and support their safety profile as a treatment of COVID-19 disease.