Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors.

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.

Colonic epithelial cell-specific TFEB activation: a key mechanism promoting anti-bacterial defense in response to Salmonella infection.

Colitis caused by infections, especially Salmonella, has long been a common disease, underscoring the urgency to understand its intricate pathogenicity in colonic tissues for the development of effective anti-bacterial approaches. Of note, colonic epithelial cells, which form the first line of defense against bacteria, have received less attention, and the cross-talk between epithelial cells and bacteria requires further exploration. In this study, we revealed that the critical anti-bacterial effector, TFEB, was primarily located in colonic epithelial cells rather than macrophages. Salmonella-derived LPS significantly promoted the expression and nuclear translocation of TFEB in colonic epithelial cells by inactivating the mTOR signaling pathway in vitro, and this enhanced nuclear translocation of TFEB was also confirmed in a Salmonella-infected mouse model. Further investigation uncovered that the infection-activated TFEB contributed to the augmentation of anti-bacterial peptide expression without affecting the intact structure of the colonic epithelium or inflammatory cytokine expression. Our findings identify the preferential distribution of TFEB in colonic epithelial cells, where TFEB can be activated by infection to enhance anti-bacterial peptide expression, holding promising implications for the advancement of anti-bacterial therapeutics.

Integrated analysis identifies RAC3 as an immune-related prognostic biomarker associated with chemotherapy sensitivity in endometrial cancer.

Endometrial cancer (EC) is one of the most common gynaecological malignant tumours with a high incidence, leading to urgent demands for exploring novel carcinogenic mechanisms and developing rational therapeutic strategies. The rac family of small GTPase 3 (RAC3) functions as an oncogene in various human malignant tumours and plays an important role in tumour development. However, the critical roles of RAC3 in the progression of EC need further investigation. Based on TCGA, single-cell RNA-Seq, CCLE and clinical specimens, we revealed that the RAC3 was specifically distributed in EC tumour cells compared to normal tissues and functioned as an independent diagnostic marker with a high area under curve (AUC) score. Meanwhile, the RAC3 expression in EC tissues was also correlated with a poor prognosis. In detail, the high levels of RAC3 in EC tissues were reversely associated with CD8+ T cell infiltration and orchestrated an immunosuppressive microenvironment. Furthermore, RAC3 accelerated tumour cell proliferation and inhibited its apoptosis, without impacting cell cycle stages. Importantly, silencing RAC3 improved the sensitivity of EC cells to chemotherapeutic drugs. In this paper, we revealed that RAC3 was predominantly expressed in EC and significantly correlated with the progression of EC via inducing immunosuppression and regulating tumour cell viability, providing a novel diagnostic biomarker and a promising strategy for sensitizing chemotherapy to EC.

Suppression of GCH1 Sensitizes Ovarian Cancer and Breast Cancer to PARP Inhibitor.

Background: Breast and ovarian cancers are common malignancies among women, contributing to a significant disease burden, and are characterized by a high level of genomic instability, owing to the failure of homologous recombination repair (HRR). Pharmacological inhibition of poly(ADP-ribose) polymerase (PARP) could elicit the synthetic lethal effect of tumor cells in patients with homologous recombination deficiency, ultimately achieving a favorable clinical benefit. However, primary and acquired resistance remain the greatest hurdle, limiting the efficacy of PARP inhibitors; thus, strategies conferring or augmenting tumor cell sensitivity to PARP inhibitors are urgently required. Methods: Our RNA-seq data of niraparib-treated and -untreated tumor cells were analyzed by R language. Gene Set Enrichment Analysis (GSEA) was applied to assess the biological functions of GTP cyclohydrolase 1 (GCH1). Quantitative real-time PCR, Western blotting, and immunofluorescence were applied to confirm the upregulation of GCH1 upon niraparib treatment at transcriptional and translational levels. Immunohistochemistry of patient-derived xenograft (PDX)-derived tissue sections further validated that niraparib increased GCH1 expression. Tumor cell apoptosis was detected by flow cytometry, while the superiority of the combination strategy was confirmed in the PDX model. Results: The expression of GCH1 was aberrantly enriched in breast and ovarian cancers and increased after niraparib treatment via JAK-STAT signaling. GCH1 was also demonstrated to be associated with the HRR pathway. Subsequently, the enhancement of the tumor-killing effect of PARP inhibitors induced by GCH1 suppression using siRNA and GCH1 inhibitor was validated by flow cytometry in vitro. Finally, using the PDX model, we further demonstrated that GCH1 inhibitors markedly potentiated PARP inhibitors' antitumor efficacy in vivo. Conclusion: Our results illustrated that PARP inhibitors promote GCH1 expression via the JAK-STAT pathway. We also elucidated the potential relationship between GCH1 and the homologous recombination repair pathway and proposed a combination regimen of GCH1 suppression with PARP inhibitors in breast and ovarian cancers.

Effect of later cord clamping on umbilical cord blood gas in term neonates of diabetic mothers: a randomized clinical trial.

OBJECTIVE: To evaluate the effect of later cord clamping (LCC) on umbilical arterial blood gas in neonates of diabetic mothers. METHODS: This prospective study included a group of 160 diabetic mothers (DM) whose neonates were randomized to immediate cord clamping (ICC) (≤ 15 s after birth) or LCC (≥ 30 s after birth), and a group of 208 non-diabetic mothers (NDM) whose neonates were randomized to ICC or LCC as a reference. Cord arterial pH, base excess (BE), bicarbonate (HCO3-), partial pressure of carbon dioxide (pCO2), partial pressure of oxygen (pO2), lactate, hemoglobin, hematocrit and glucose were compared among groups. RESULTS: In neonates of DM, there was no significant difference in cord arterial pH between the ICC and LCC group. LCC of ≥ 30 s decreased umbilical arterial HCO3- and BE and increased lactate (ICC versus LCC, HCO3-: 24.3 (22.7, 25.8) versus 23.7 (22.3, 24.7) mmol/L, P = 0.01; BE: -2.70 (-4.80, -1.50) versus - 3.72 (-5.66, -2.36) mmol/L, P = 0.006; lactate: 2.1 (1.6, 3.7) versus 2.7 (2.1, 4.3) mmol/L, P = 0.005), without the alterations of pCO2, pO2, hemoglobin, hematocrit and glucose. Similar results were found in neonates of NDM (ICC versus LCC, HCO3-: 24.3 (23.1, 25.7) versus 23.5 (22.3, 24.8) mmol/L, P = 0.01; BE: -2.39 (-3.73, -1.51) versus - 3.40 (-4.73, -1.91) mmol/L, P = 0.001; lactate: 2.2 (1.9, 3.3) versus 2.5 (2.0, 4.3) mmol/L, P = 0.01), except for the higher level of hemoglobin in the LCC group. The majority of diabetic mothers (ICC: 92.0%; LCC: 91.8%) had good blood glucose control. No differences were observed in acid-base status and glucose between neonates of DM and neonates of NDM in both ICC and LCC, but hemoglobin and hematocrit were elevated after ICC in neonates of DM compared to neonates of NDM. CONCLUSIONS: Later cord clamping of ≥ 30 s resulted in a tendency towards metabolic acidosis of umbilical arterial blood in neonates of DM and NDM. Umbilical arterial blood gas parameters at birth were similar in neonates of DM and NDM. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04369313 ; date of registration: 30/04/2020 (retrospectively registered).

Effect of delayed cord clamping on jaundice and hypoglycemia in the neonates of mothers with gestational diabetes mellitus.

OBJECTIVE: To study the effect of delayed cord clamping (DCC) on the bilirubin levels and hypoglycemia in neonates with diabetic mothers (NDMs). METHODS: This is a comparison between a prospective cohort and a historical control cohort. Women with gestational diabetes mellitus who performed DCC were enrolled into the prospective cohort (n = 156), and those who performed early cord clamping (ECC) were enrolled into the historical control cohort (n = 161). RESULTS: NDMs who received DCC had higher transcutaneous bilirubin than those in the ECC group whether maternal glycemic control was good or poor. DCC increased the rate of neonatal hyperbilirubinemia and phototherapy when maternal blood glucose was well controlled but not when it was poorly controlled. No differences were found in initial blood glucose levels on days 1 to 3 of life between the two groups. CONCLUSION: Delayed cord clamping increased bilirubin levels, the risk of neonatal hyperbilirubinemia, and phototherapy in IDMs without improved initial blood glucose levels. Therefore, DCC was not recommended in NDMs.

The Endocrine Disruption of Prenatal Phthalate Exposure in Mother and Offspring.

Phthalates are a group of ubiquitous synthetic endocrine-disrupting chemicals. Fetal and neonatal periods are particularly susceptible to endocrine disorders, which prenatal exposure to phthalates causes. There is increasing evidence concerning the potential endocrine disrupting for phthalate exposure during pregnancy. This article aims to review the endocrine impairment and potential outcomes of prenatal phthalate exposure. Prenatal exposure phthalates would disrupt the levels of thyroid, sex hormone, and 25-hydroxyvitamin D in pregnant women or offspring, which results in preterm birth, preeclampsia, maternal glucose disorders, infant cryptorchidism, infant hypospadias, and shorter anogenital distance in newborns, as well as growth restriction not only in infants but also in early adolescence and childhood. The relationship of prenatal phthalate exposure with maternal and neonatal outcomes in human beings was often sex-specific associations. Because of the potentially harmful influence of prenatal phthalate exposure, steps should be taken to prevent or reduce phthalate exposure during pregnancy.

Timing of umbilical cord clamping and neonatal jaundice in singleton term pregnancy.

BACKGROUND: Delayed cord clamping was not adopted widely in China because of the potential effect of neonatal hyperbilirubinemia, jaundice and polycythemia, and the optimal cord clamping time remained controversial. AIM: To assess the effect of delayed cord clamping versus early cord clamping on neonatal jaundice for term infants. STUDY DESIGN: This retrospective study included 1981 mother-infant pairs, who were assigned to early cord clamping groups (n = 1005) and delayed cord clamping group (n = 949). The delayed cord clamping included three subgroups (30-60 s, 61-90 s, 91-120 s). The main outcomes were transcutaneous bilirubin levels at 0 to 4 days of age, the rate of jaundice requiring phototherapy, the neonatal hematological status at 1 to 3 days after birth. RESULTS: Compared with the early cord clamping group, the neonatal transcutaneous bilirubin level did not differ and the neonatal hematological status (hemoglobin and hematocrit levels) were improved in combined and three subgroups of delayed cord clamping group. Increasing the duration of cord clamping from 90 s to 120 s did not result in further increases in hemoglobin and hematocrit levels but led to a trend towards a higher risk of neonatal jaundice requiring phototherapy and neonatal polycythemia. CONCLUSIONS: Delayed cord clamping for <90 s in healthy term infants may not only improve the early hematological status of newborns but also avoid excessive neonatal jaundice requiring phototherapy.

Early versus delayed umbilical cord clamping on maternal and neonatal outcomes.

PURPOSE: Policies for timing of cord clamping varied from early cord clamping (ECC) in the first 30 s after birth, to delayed cord clamping (DCC) in more than 30 s after birth or when cord pulsation has ceased. DCC, an inexpensive method allowed physiological placental transfusion. The aim of this article is to review the benefits and the potential harms of early versus delayed cord clamping. METHODS: Narrative overview, synthesizing the findings of the literature retrieved from searches of computerized databases. RESULTS: Delayed cord clamping in term and preterm infants had shown higher hemoglobin levels and iron storage, the improved infants' and children's neurodevelopment, the lesser anemia, the higher blood pressure and the fewer transfusions, as well as the lower rates of intraventricular hemorrhage (IVH), chronic lung disease, necrotizing enterocolitis, and late-onset sepsis. DCC was seldom associated with lower Apgar scores, neonatal hypothermia of admission, respiratory distress, and severe jaundice. In addition, DCC was not associated with increased risk of postpartum hemorrhage and maternal blood transfusion whether in cesarean section or vaginal delivery. DCC appeared to have no effect on cord blood gas analysis. However, DCC for more than 60 s reduced drastically the chances of obtaining clinically useful cord blood units (CBUs). CONCLUSION: Delayed cord clamping in term and preterm infants was a simple, safe, and effective delivery procedure, which should be recommended, but the optimal cord clamping time remained controversial.

Physiological and pathological impact of AQP1 knockout in mice.

Aquaporin 1 (AQP1) is a glycoprotein responsible for water passive transport quickly across biological membrane. Here, we reviewed the structural and functional impacts of AQP1 knockout (AQP1-KO) in animal or cell culture models. AQP1 gene deletion can cause a large number of abnormalities including the disturbance in epithelial fluid secretion, polyhydramnios, deficiency of urinary concentrating function, and impairment of pain perception. AQP1-KO mice also displayed aberrations of cardiovascular, gastrointestinal and hepatobiliary, and kidney functions as well as placenta and embryo development. Moreover, AQP1-KO perturbed tumor angiogenesis and led to reduced brain injury upon trauma. On the cellular level, AQP1-KO caused neuroinflammation, aberrant cell proliferation and migration, and macrophages infiltration. Mechanistic studies confirmed that AQP1 gene products regulate the secretory function and participated in balancing the osmotic water flux across the peritoneal membrane. The available data indicated that AQP1 might serve as a potential target for developing novel therapeutic approaches against diverse human diseases.