Genomic profiling of a multi-lineage and multi-passage patient-derived xenograft biobank reflects heterogeneity of ovarian cancer.

Ovarian cancer (OC) manifests as a complex disease characterized by inter- and intra-patient heterogeneity. Despite enhanced biological and genetic insights, OC remains a recalcitrant malignancy with minimal survival improvement. Based on multi-site sampling and a multi-lineage patient-derived xenograft (PDX) establishment strategy, we present herein the establishment of a comprehensive PDX biobank from histologically and molecularly heterogeneous OC patients.

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

Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments.

BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors.

Background: Mismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect.

Multi-omics characterization of silent and productive HPV integration in cervical cancer.

Cervical cancer (CC) that is caused by high-risk human papillomavirus (HPV) remains a significant public health problem worldwide. HPV integration sites can be silent or actively transcribed, leading to the production of viral-host fusion transcripts. Herein, we demonstrate that only productive HPV integration sites were nonrandomly distributed across both viral and host genomes, suggesting that productive integration sites are under selection and likely to contribute to CC pathophysiology.

Akkermansia supplementation reverses the tumor-promoting effect of the fecal microbiota transplantation in ovarian cancer.

Ovarian cancer (OC) remains a clinical challenge for its difficulty in early diagnosis and insensitivity to treatments. Gut microbiota modulate multiple carcinoma progression through immunoregulation. The relationship between OC and gut microbiota has not been fully characterized.

Codelivery of adavosertib and olaparib by tumor-targeting nanoparticles for augmented efficacy and reduced toxicity.

Ovarian cancer (OC) ranks first among gynecologic malignancies in terms of mortality. The benefits of poly (ADP-ribose) polymerase (PARP) inhibitors appear to be limited to OC with BRCA mutations. Concurrent administration of WEE1 inhibitors (eg, adavosertib (Ada)) and PARP inhibitors (eg, olaparib (Ola)) effectively suppress ovarian tumor growth regardless of BRCA mutation status, but is poorly tolerated.

Spatial heterogeneity of infiltrating T cells in high-grade serous ovarian cancer revealed by multi-omics analysis.

Tumor-infiltrating lymphocytes (TILs), especially CD8 TILs, represent a favorable prognostic factor in high-grade serous ovarian cancer (HGSOC) and other tumor lineages. Here, we analyze the spatial heterogeneity of different TIL subtypes in HGSOC. We integrated RNA sequencing, whole-genome sequencing, bulk T cell receptor (TCR) sequencing, as well as single-cell RNA/TCR sequencing to investigate the characteristics and differential composition of TILs across different HGSOC sites.

Mutation profiles in circulating cell-free DNA predict acquired resistance to olaparib in high-grade serous ovarian carcinoma.

Although resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) has gradually become a major challenge in the maintenance therapy for high-grade serous ovarian carcinoma (HGSOC), there are no universal indicators for resistance monitoring in patients. A key resistance mechanism to PARPi is the restoration of homologous recombination repair (HRR), including BRCA reversion mutations and changes in DNA damage repair proteins. To explore mutation profiles associated with PARPi resistance, we undertook targeted 42-gene deep sequencing of circulating cell-free DNA (cfDNA) extracted from HGSOC patients pre- and post-treatment with olaparib maintenance therapy.

Inhibiting the IRE1α Axis of the Unfolded Protein Response Enhances the Antitumor Effect of AZD1775 in TP53 Mutant Ovarian Cancer.

Targeting the G2/M checkpoint mediator WEE1 has been explored as a novel treatment strategy in ovarian cancer, but mechanisms underlying its efficacy and resistance remains to be understood. Here, it is demonstrated that the WEE1 inhibitor AZD1775 induces endoplasmic reticulum stress and activates the protein kinase RNA-like ER kinase (PERK) and inositol-required enzyme 1α (IRE1α) branches of the unfolded protein response (UPR) in TP53 mutant (mtTP53) ovarian cancer models. This is facilitated through NF-κB mediated senescence-associated secretory phenotype.

The Immunological Role of CDK4/6 and Potential Mechanism Exploration in Ovarian Cancer.

Background: Ovarian cancer (OC) is one of the most lethal gynecologic cancers. Growing evidence has proven that CDK4/6 plays a key role in tumor immunity and the prognosis of many cancers. However, the expression and function of CDK4/6 in OC remain unclear.

AZD5153 reverses palbociclib resistance in ovarian cancer by inhibiting cell cycle-related proteins and the MAPK/PI3K-AKT pathway.

The CDK4/6 inhibitor, palbociclib has recently entered clinic-trial stage for breast cancer treatment. However, translating its efficacy to other solid tumors has been challenging, especially for aggressive solid tumors. We found that the effect of palbociclib as a single agent was limited due to primary and acquired resistance in multiple ovarian cancer (OC) models.

Impact of chemotherapy and immunotherapy on the composition and function of immune cells in COVID-19 convalescent with gynecological tumors.

Ongoing pandemic and potential resurgence of Coronavirus disease 2019 (COVID-19) has prompted urgent efforts to investigate the immunological memory of convalescent patients, especially in patients with active cancers. Here we performed single-cell RNA sequencing in peripheral blood samples of 3 healthy donors (HDs), 4 COVID-19 patients (Covs) and 4 COVID-19 patients with active gynecological tumor (TCs) pre- and post- anti-tumor treatment. All Covs patients had recovered from their acute infection.

WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway.

Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1.

Serum semaphorin 4C as a diagnostic biomarker in breast cancer: A multicenter retrospective study.

Background: To date, there is no approved blood-based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker.

Methods: We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital.

Trends and age-period-cohort effects on mortality of the three major gynecologic cancers in China from 1990 to 2019: Cervical, ovarian and uterine cancer.

Background: Gynecologic cancers seriously threaten women's life and health. This study aims to assess the long-term trends of mortality from the three major gynecologic cancers in China and to examine the age-, period-, and cohort-specific effects behind them during the period 1990 to 2019.

Methods: The mortality data of cervical, ovarian, and uterine cancer in China were obtained from the Global Burden of Disease Study 2019 and were analyzed with the age-period-cohort framework.

The Diversity of Vaginal Microbiota Predicts Neoadjuvant Chemotherapy Responsiveness in Locally Advanced Cervical Cancer.

The vaginal microbiota is closely related to HPV infection and cervical cancer (CC), but its relationship with platinum-based chemotherapy responsiveness is unknown. The study aimed to investigate the vaginal microbiota diversity of women with locally advanced cervical cancer (LACC) and compare the differences between responders and nonresponders. We characterized the 16S rRNA gene sequencing of vaginal microbiome of 66 vaginal samples, including 26 LACC patients before neoadjuvant chemotherapy and 40 healthy controls.

WEE1 inhibitor and ataxia telangiectasia and RAD3-related inhibitor trigger stimulator of interferon gene-dependent immune response and enhance tumor treatment efficacy through programmed death-ligand 1 blockade.

WEE1 plays an important role in the regulation of cell cycle G2/M checkpoints and DNA damage response (DDR). Inhibition of WEE1 can increase the instability of the genome and have anti-tumor effects in some solid tumors. However, it has certain limitations for multiple cancer cells from different lineages.

The trans-omics landscape of COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19) is a global health emergency. Various omics results have been reported for COVID-19, but the molecular hallmarks of COVID-19, especially in those patients without comorbidities, have not been fully investigated. Here we collect blood samples from 231 COVID-19 patients, prefiltered to exclude those with selected comorbidities, yet with symptoms ranging from asymptomatic to critically ill.

Clinical and molecular characteristics of COVID-19 patients with persistent SARS-CoV-2 infection.

The characteristics of COVID-19 patients with persistent SARS-CoV-2 infection are not yet well described. Here, we compare the clinical and molecular features of patients with long duration of viral shedding (LDs) with those from patients with short duration patients (SDs), and healthy donors (HDs). We find that several cytokines and chemokines, such as interleukin (IL)-2, tumor necrosis factor (TNF) and lymphotoxin α (LT-α) are present at lower levels in LDs than SDs.

Fecal microbiota transplantation mitigates vaginal atrophy in ovariectomized mice.

Vulvovaginal atrophy (VVA) is a common menopause-related symptom affecting more than 50% of midlife and older women and cancer patients whose ovarian function are lost or damaged. Regardless of estrogen deficiency, whether other factors such as the gut microbiota play role in VVA have not been thoroughly investigated. To this end, we performed ovariectomy on 12-weeks' old mice and follow-up at 4 weeks after ovariectomy, and observed atrophied vagina and an altered gut microbiota in ovariectomized mice.

MEK Inhibition Remodels the Immune Landscape of Mutant Tumors to Overcome Resistance to PARP and Immune Checkpoint Inhibitors.

Mutant tumors are associated with poor outcomes, at least in part, due to decreased therapeutic sensitivity. Here, we show that mutations are associated with resistance to monotherapy and combination therapy with PARP inhibitors (PARPi) and immune checkpoint blockade with anti-PD-L1 antibodies. In mutant tumors, inhibition of KRAS signaling with MEK inhibitors (MEKi) triggered and amplified PARPi-induced DNA damage, cytosolic double-stranded DNA accumulation, STING pathway activation, and CD8 T-cell recruitment.

Melatonin provides protection against cisplatin-induced ovarian damage and loss of fertility in mice.

Research Question: Can melatonin provide non-invasive ovarian protection against damage caused by cis-diamminedichloroplatinum (cisplatin) and preserve fertility in female cancer patients? And if so, what is the possible mechanism?

Design: Athymic BALB/c nude tumour-bearing female mice were used to demonstrate whether melatonin affects the antineoplastic effect when co-administrated with cisplatin. Sexually mature and newborn C57BL/6 female mice were used to evaluate the potential effects of melatonin on the ovarian follicle pool, pregnancy rate and litter number in cisplatin-treated mice. The ovaries underwent immunohistochemical, TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick-end labelling (TUNEL) and gene array analysis to explore the underlying mechanism.

Dynamics and Correlation Among Viral Positivity, Seroconversion, and Disease Severity in COVID-19 : A Retrospective Study.

Background: The understanding of viral positivity and seroconversion during the course of coronavirus disease 2019 (COVID-19) is limited.

Objective: To describe patterns of viral polymerase chain reaction (PCR) positivity and evaluate their correlations with seroconversion and disease severity.

Design: Retrospective cohort study.

Integrating pathology, chromosomal instability and mutations for risk stratification in early-stage endometrioid endometrial carcinoma.

Background: Risk stratifications for endometrial carcinoma (EC) depend on histopathology and molecular pathology. Histopathological risk stratification lacks reproducibility, neglects heterogeneity and contributes little to surgical procedures. Existing molecular stratification is useless in patients with specific pathological or molecular characteristics and cannot guide postoperative adjuvant radiotherapies.

Six Gynecological Cancer Patients Infected With SARS-CoV-2 After Surgery or Radio-/Chemo-Therapy Treatment: Case Series.

Objective: Recently, the number of gynecological cancer patients infected with SARS-CoV-2 has been increasing. This article was committed to studying the influence of gynecological tumor treatment history compared to the Coronavirus Disease 2019 (COVID-19), which was of great significance for the treatment of gynecological cancer patients during the outbreak of COVID-19.

Methods: We retrospectively analyzed the diagnosis and treatment of six gynecological cancer patients infected with SARS-CoV-2 in Tongji Hospital in Wuhan from January 30 to March 25, 2020.