Targeting the dendritic cell-secreted immunoregulatory cytokine CCL22 alleviates radioresistance.

PURPOSE: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that dendritic cells (cDC) maintain Treg we sought to identify and target cDC signaling to block Treg infiltration after radiation. EXPERIMENTAL DESIGN: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT, but associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT. RESULTS: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration. CONCLUSIONS: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration, and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy.

MUC16 can Predict the Pregnancy Outcomes in Human and Intraperitoneal Administration of MUC16 can Rescue Pregnancy Losses in Mouse Models.

Mucin 16 (MUC16) participates in the process of embryo implantation, but few studies have examined the association between MUC16 and pregnancy loss. To investigate this association, the expression of MUC16 in serum and decidua was compared between women with pregnancy loss and ongoing pregnancies. In vitro experiments and animal models were used to explore the role and underlying mechanisms of MUC16 in pregnancy loss. In human study, the expression of MUC16 in serum and decidua was both consistently lower in the women with pregnancy loss compared with those in women with ongoing pregnancies. In vitro experiments revealed the interaction of MUC16 with peripheral blood natural killer (pNK) cells. MUC16 changed the phenotype and reduced the pro-inflammation ability of pNK cells. MUC16 also inhibited the cytotoxicity of pNK cells through the Src homology region 2 domain-containing phosphatase-1/extracellular signal-regulated kinase (SHP-ERK) pathway. Furthermore, MUC16 promoted the migration, invasion and tube formation of trophoblast cells by co-culturing together with pNK cells. In vivo experiments, the mouse model of abortion was used to further confirm that intraperitoneal administration of MUC16 could rescue the pregnancy loss. This study reveals the still-unknown connection between MUC16 and pNK cells and indicates that MUC16 provides a novel method for future prediction and treatment of unfavorable pregnancy outcomes.

Maternal anaemia prevention and control in China: A policy review.

Maternal anaemia is a major public health problem. Developing maternal anaemia prevention and control policies is an important prerequisite for carrying out evidence-based interventions. This article reviews maternal anaemia prevention and control policies in China, identifies gaps, and provides references for other countries. We examined policies concerning maternal nutrition and other related literature in China, identified through key databases and government websites, and conducted a narrative review of the relevant documentations guided by the Smith Policy-Implementing-Process framework. A total of 65 articles and documents were identified for analysis. We found that Chinese government has committed to reducing maternal anaemia at the policy level, with established objectives and a clear time frame. However, most of policies were not accompanied by operational guidelines, standardized interventions, and vigorous monitoring and evaluation mechanisms, and 85% of the policies don't have quantifiable objectives on anaemia. Maternal anaemia prevention and control services offered in clinical settings were primarily nutrition education and anaemia screening. Population-based interventions such as iron fortification have yet to be scaled up. Furthermore, medical insurance schemes in some regions do not cover anaemia prevention and treatment, and in other regions that offer coverage, the reimbursement rate is low. The number and capacity of health professionals is also limited. Policy changes should focus on the integration of evidence-based interventions into routine antenatal care services and public health service packages, standardization of dosages and provision of iron supplementation, streamline of reimbursement for outpatient expenses, and capacity building of health professionals.

New Approach for Preparation of Porous Polymers with Reversible Pore Structures for a Highly Safe Smart Supercapacitor.

Porous polymers have many industrial applications, but their pore structures (open or closed) are usually fixed during polymerization. In this study, polymers with reversible and controllable pore structures, namely, thermosensitive porous hydrogels with regulated volume phase transition temperature, were prepared using a Pickering high-internal-phase emulsion as the template. Upon heating, the hydrogels transformed not only in their wettability (between hydrophilicity and hydrophobicity with water contact angles of 21.8 and 100.9°) but also their pore structure (between open through-holes and closed holes with pore throat sizes of 15.58 and 0 µm, respectively) in a short time (<10 s). When the hydrogel was used as a separator in smart supercapacitors (SCs), this behavior effectively limited the path of electrolyte migration, reducing the chance of conflagration accidents. Moreover, by utilizing the highly reversible pore structures and wettability of the porous hydrogel, reversible charging and discharging were restored after the system cooled down. This work not only provides great guidance for preparing porous polymers with reversible pore structures but also paves the way for designing smart SCs with enhanced safety.

Matching actions to needs: shifting policy responses to the changing health needs of Chinese children and adolescents.

China is home to the second largest population of children and adolescents in the world. Yet demographic shifts mean that the government must manage the challenge of fewer children with the needs of an ageing population, while considering the delicate tension between economic growth and environmental sustainability. We mapped the health problems and risks of contemporary school-aged children and adolescents in China against current national health policies. We involved multidisciplinary experts, including young people, with the aim of identifying actionable strategies and specific recommendations to promote child and adolescent health and wellbeing. Notwithstanding major improvements in their health over the past few decades, contemporary Chinese children and adolescents face distinct social challenges, including high academic pressures and youth unemployment, and new health concerns including obesity, mental health issues, and sexually transmitted infections. Inequality by gender, geography, and ethnicity remains a feature of health risks and outcomes. We identified a mismatch between current health determinants, risks and outcomes, and government policies. To promote the health of children and adolescents in China, we recommend a set of strategies that target government-led initiatives across the health, education, and community sectors, which aim to build supportive and responsive families, safe communities, and engaging and respectful learning environments. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Radiotherapy Enhances Metastasis Through Immune Suppression by Inducing PD-L1 and MDSC in Distal Sites.

PURPOSE: Radiotherapy (RT) is a widely employed anticancer treatment. Emerging evidence suggests that RT can elicit both tumor-inhibiting and tumor-promoting immune effects. The purpose of this study is to investigate immune suppressive factors of radiotherapy. EXPERIMENTAL DESIGN: We used a heterologous two-tumor model in which adaptive concomitant immunity was eliminated. RESULTS: Through analysis of PD-L1 expression and myeloid-derived suppressor cells (MDSC) frequencies using patient peripheral blood mononuclear cells and murine two-tumor and metastasis models, we report that local irradiation can induce a systemic increase in MDSC, as well as PD-L1 expression on dendritic cells and myeloid cells, and thereby increase the potential for metastatic dissemination in distal, nonirradiated tissue. In a mouse model using two distinct tumors, we found that PD-L1 induction by ionizing radiation was dependent on elevated chemokine CXCL10 signaling. Inhibiting PD-L1 or MDSC can potentially abrogate RT-induced metastasis and improve clinical outcomes for patients receiving RT. CONCLUSIONS: Blockade of PD-L1/CXCL10 axis or MDSC infiltration during irradiation can enhance abscopal tumor control and reduce metastasis.

Inhibitory Activity Against Rhizoctonia Solani and Chemical Composition of Extract from Moutan Cortex.

Rice sheath blight (RSB), caused by Rhizoctonia solani, is a significant disease of rice. The negative effects of chemical fungicides have created an urgent need for low-toxicity botanical fungicides. Our previous research revealed that the ethanol crude extract of Moutan Cortex (MC) exhibited superior antifungal activity against R. solani at 1000 µg/mL, resulting in a 100 % inhibition rate. The antifungal properties were mainly found in the petroleum ether extract. However, the active ingredients of the extract are still unclear. In this study, gas chromatography-mass spectrometry (GC-MS) was utilised for the analysis of its chemical components. The mycelium growth rate method was utilized to detect the antifungal activity. The findings indicated that paeonol constituted the primary active component, with a content of more than 96 %. Meanwhile, paeonol was the most significant antifungal active ingredient, the antifungal activity of paeonol (EC50=44.83 µg/mL) was much higher than that of ß-sitosterol and ethyl propionate against R. solani. Observation under an optical microscope revealed that paeonol resulted in abnormal mycelial morphology. This study provided theoretical support for identifying monomer antifungal compounds and developing biological fungicides for R. solani.

Identifying Hmga2 preserving visual function by promoting a shift of Müller glia cell fate in mice with acute retinal injury.

BACKGROUND: Unlike in lower vertebrates, Müller glia (MG) in adult mammalian retinas lack the ability to reprogram into neurons after retinal injury or degeneration and exhibit reactive gliosis instead. Whether a transition in MG cell fate from gliosis to reprogramming would help preserve photoreceptors is still under exploration. METHODS: A mouse model of retinitis pigmentosa (RP) was established using MG cell lineage tracing mice by intraperitoneal injection of sodium iodate (SI). The critical time point for the fate determination of MG gliosis was determined through immunohistochemical staining methods. Then, bulk-RNA and single-cell RNA seq techniques were used to elucidate the changes in RNA transcription of the retina and MG at that time point, and new genes that may determine the fate transition of MG were screened. Finally, the selected gene was specifically overexpressed in MG cells through adeno-associated viruses (AAV) in the mouse RP model. Bulk-RNA seq technique, immunohistochemical staining methods, and visual function testing were used to elucidate and validate the mechanism of new genes function on MG cell fate transition and retinal function. RESULTS: Here, we found the critical time point for MG gliosis fate determination was 3 days post SI injection. Hmga2 was screened out as a candidate regulator for the cell fate transition of MG. After retinal injury caused by SI, the Hmga2 protein is temporarily and lowly expressed in MG cells. Overexpression of Hmga2 in MG down-regulated glial cell related genes and up-regulated photoreceptor related genes. Besides, overexpressing Hmga2 exclusively to MG reduced MG gliosis, made MG obtain cone's marker, and retained visual function in mice with acute retinal injury. CONCLUSION: Our results suggested the unique reprogramming properties of Hmga2 in regulating the fate transition of MG and neuroprotective effects on the retina with acute injury. This work uncovers the reprogramming ability of epigenetic factors in MG.

Quality of childcare and delayed child development in left-behind children in China.

BACKGROUND: Inequalities in job opportunities and income prompts many Chinese parents to leave rural regions to work in urban regions. Their children are left behind in rural regions, subjected to worse quality of childcare that jeopardizes their development. This study aimed to examine the association between quality of childcare and delayed child development in under-three years children left behind in China. METHODS: Cross-sectional national survey was conducted in children left behind in rural China in 2017. Exploratory and confirmatory factor analysis was used to develop a quality of childcare index. Mutlilevel analyses determined factors associated with quality of childcare and child development on a province and individual level. RESULT: The largest population of at-risk children left behind were found in higher-GDP provinces. Children left behind had the lowest mean quality of childcare score. Multilevel analysis found that province level accounted for a great proportion of variance observed. CONCLUSIONS: While migration to urban regions for work may improve household income, a trade-off in worse quality of childcare and developmental delays exists. With improving household income often being the greatest contributing factor for parental migration, policies to reduce inequalities in job opportunities and wealth between rural and urban regions are required. IMPACT: Previous studies identified higher prevalence of developmental delays in children left behind in China. However, quality of childcare has not been examined. Based on WHO's Nurturing Care Framework, we developed a quality of childcare index to assess its association with child development in children left behind. Greatest proportion of children left behind at-risk of developmental delays resided in higher-GDP states, indicating a trade-off in worse quality of childcare and developmental delays. Since improving household income is the main factor for parental migration, policies to close inequalities in job opportunities and wealth between rural and urban regions are required.

Extracellular vesicles from organoid-derived human retinal progenitor cells prevent lipid overload-induced retinal pigment epithelium injury by regulating fatty acid metabolism.

Retinal degeneration (RD), a group of diseases leading to irreversible vision loss, is characterised by retinal pigment epithelium (RPE) or retinal neuron damage and loss. With fewer risks of immune rejection and tumorigenesis, stem cell-secreted extracellular vesicles (EVs) offer a new cell-free therapeutic paradigm for RD, which remains to be investigated. Human retinal organoid-derived retinal progenitor cells (hERO-RPCs) are an easily accessible and advanced cell source for RD treatment. However, hERO-RPCs-derived EVs require further characterisation. Here, we compared the characteristics of EVs from hERO-RPCs (hRPC-EVs) with those of human embryonic stem cell (hESC)-derived EVs (hESC-EVs) as controls. Based on in-depth proteomic analysis, we revealed remarkable differences between hRPC-EVs and hESC-EVs. A comparison between EVs and their respective cells of origin demonstrated that the protein loading of hRPC-EVs was more selective than that of hESC-EVs. In particular, hESC-EVs were enriched with proteins related to angiogenesis and cell cycle, whereas hRPC-EVs were enriched with proteins associated with immune modulation and retinal development. More importantly, compared with that of hESC-EVs, hRPC-EVs exhibited a lower correlation with cell proliferation and a unique capacity to regulate lipid metabolism. It was further confirmed that hRPC-EVs potentially eliminated lipid deposits, inhibited lipotoxicity and oxidative stress, and enhanced phagocytosis and survival of oleic acid-treated ARPE-19 cells. Mechanistically, hRPC-EVs are integrated into the mitochondrial network of oleic acid-treated ARPE-19 cells, and increased the level of mitochondrial fatty acid ß-oxidation-related proteins. Thus, organoid-derived hRPC-EVs represent a promising source of cell-free therapy for RD, especially for blinding diseases related to abnormal lipid metabolism in RPE cells.

Epitranscriptional regulation of TGF-ß pseudoreceptor BAMBI by m6A/YTHDF2 drives extrinsic radioresistance.

Activation of TGF-ß signaling serves as an extrinsic resistance mechanism that limits the potential for radiotherapy. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) antagonizes TGF-ß signaling and is implicated in cancer progression. However, the molecular mechanisms of BAMBI regulation in immune cells and its impact on antitumor immunity after radiation have not been established. Here, we show that ionizing radiation (IR) specifically reduces BAMBI expression in immunosuppressive myeloid-derived suppressor cells (MDSCs) in both murine models and humans. Mechanistically, YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) directly binds and degrades Bambi transcripts in an N6-methyladenosine-dependent (m6A-dependent) manner, and this relies on NF-κB signaling. BAMBI suppresses the tumor-infiltrating capacity and suppression function of MDSCs via inhibiting TGF-ß signaling. Adeno-associated viral delivery of Bambi (AAV-Bambi) to the tumor microenvironment boosts the antitumor effects of radiotherapy and radioimmunotherapy combinations. Intriguingly, combination of AAV-Bambi and IR not only improves local tumor control, but also suppresses distant metastasis, further supporting its clinical translation potential. Our findings uncover a surprising role of BAMBI in myeloid cells, unveiling a potential therapeutic strategy for overcoming extrinsic radioresistance.

Fullerol rescues the light-induced retinal damage by modulating Müller glia cell fate.

Excessive light exposure can damage photoreceptors and lead to blindness. Oxidative stress serves a key role in photo-induced retinal damage. Free radical scavengers have been proven to protect against photo-damaged retinal degeneration. Fullerol, a potent antioxidant, has the potential to protect against ultraviolet-B (UVB)-induced cornea injury by activating the endogenous stem cells. However, its effects on cell fate determination of Müller glia (MG) between gliosis and de-differentiation remain unclear. Therefore, we established a MG lineage-tracing mouse model of light-induced retinal damage to examine the therapeutic effects of fullerol. Fullerol exhibited superior protection against light-induced retinal injury compared to glutathione (GSH) and reduced oxidative stress levels, inhibited gliosis by suppressing the TGF-ß pathway, and enhanced the de-differentiation of MG cells. RNA sequencing revealed that transcription candidate pathways, including Nrf2 and Wnt10a pathways, were involved in fullerol-induced neuroprotection. Fullerol-mediated transcriptional changes were validated by qPCR, Western blotting, and immunostaining using mouse retinas and human-derived Müller cell lines MIO-M1 cells, confirming that fullerol possibly modulated the Nrf2, Wnt10a, and TGF-ß pathways in MG, which suppressed gliosis and promoted the de-differentiation of MG in light-induced retinal degeneration, indicating its potential in treating retinal diseases.

[Weidiao-3 Mixture Improves the Clinical Efficacy of Immunotherapy for Advanced Gastric Cancer by Regulating Intestinal Flora].

Objective To investigate the effects of Weidiao-3(WD-3)Mixture on the clinical efficacy of immunotherapy for advanced gastric cancer and the intestinal flora.Methods Fifty-one patients with advanced gastric cancer treated in Wuxi Traditional Chinese Medicine Hospital from January 2020 to December 2021 were randomized into a WD-3 group(immunotherapy + WD-3 Mixture,one dose per day)(n=25)and a gastric cancer(GC) group(only immunotherapy)(n=26)according to the admission time.Ten healthy volunteers were included as the healthy control group.The Karnofsky score and the Quality of Life Questionnare-Core score were evaluated before and after treatment,and the clinical efficacy was compared after treatment.After treatment,the stool samples were collected for 16SrRNA gene high-throughput sequencing and targeted metabolomics.The α and ß diversity and structure of the intestinal flora and the content of short-chain fatty acids were compared between groups.Results The quality of life in both groups improved after treatment and was better in the WD-3 group than in the GC group(P=0.035).The dry mouth(P=0.038)and altered taste(P=0.008)were mitigated in the WD-3 group after treatment,and the reflux(P=0.001)and dry mouth(P=0.022)were mitigated in the GC group after treatment.After treatment,the WD-3 group outperformed the GC group in terms of dysphagia(P=0.047)and dry mouth(P=0.045).The WD-3 group was superior to the GC group in terms of objective remission rate and disease control rate,with prolonged median progression-free survival and median overall survival(P=0.039,P=0.043).The α and ß diversity indexes of the intestinal flora showed no significant differences between WD-3 and GC groups(all P>0.05).At the phylum level,WD-3 and GC groups had lower relative abundance of Firmicutes(P=0.038,P=0.042)and higher relative abundance of Proteobacteria(P=0.016,P=0.015)than the healthy control group.The relative abundance of Actinomycetes in the GC group was lower than that in the healthy control group(P=0.035)and the WD-3 group(P=0.046).At the genus level,the GC group had lower relative abundance of Bifidobacteria and Coprococcus than the healthy control group and the WD-3 group(all P<0.001).LEfSe revealed the differences in the relative abundance of 6 intestinal bacterial taxa between the WD-3 group and the GC group.At the genus level,Saccharopolyspora had higher relative abundance in the WD-3 group than in the healthy control group and only existed in the WD-3 group.The content of isobutyric acid and isovaleric acid in the WD-3 group was higher than that in the healthy control group(P=0.037,P=0.004).Conclusion WD-3 Mixture may increase the relative abundance of Bifidobacteria and Coprococcus and the content of isobutyric acid and isovaleric acid to alter the intestinal microecology,thereby improving the efficacy of immunotherapy for gastric cancer.

Dysregulation of Histone Deacetylases Inhibits Trophoblast Growth during Early Placental Development Partially through TFEB-Dependent Autophagy-Lysosomal Pathway.

Dysregulated biological behaviors of trophoblast cells can result in recurrent spontaneous abortion (RSA)-whose underlying etiology still remains insufficient. Autophagy, a conserved intracellular physiological process, is precisely monitored throughout whole pregnancy. Although the exact mechanism or role remains elusive, epigenetic modification has emerged as an important process. Herein, we found that a proportion of RSA patients exhibited higher levels of autophagy in villus tissues compared to controls, accompanied with impaired histone deacetylase (HDAC) expression. The purpose of this study is to explore the connection between HDACs and autophagy in the pathological course of RSA. Mechanistically, using human trophoblast cell models, treatment with HDAC inhibitor (HDACI)-trichostatin A (TSA) can induce autophagy by promoting nuclear translocation and transcriptional activity of the central autophagic regulator transcription factor EB (TFEB). Specifically, overactivated autophagy is involved in the TSA-driven growth inhibition of trophoblast, which can be partially reversed by the autophagy inhibitor chloroquine (CQ) or RNA interference of TFEB. In summary, our results reveal that abnormal acetylation and autophagy levels during early gestation may be associated with RSA and suggest the potential novel molecular target TFEB for RSA treatment.

A pilot study of Kangaroo mother care in early essential newborn care in resource-limited areas of China: the facilitators and barriers to implementation.

BACKGROUND: Implementation of Kangaroo Mother Care (KMC) in resource-limited areas of China may face unique barriers, such as a lack of resources, geographic location and more traditional culture among others. This qualitative study analyses the facilitators and barriers to implementing KMC in county-level health facilities in resource-limited areas of China for the promotion of KMC on a larger scale. METHODS: Participants from 4 of the 18 pilot counties where early essential newborn care was implemented through the Safe Neonatal Project and 4 control counties not enrolled in Safe Neonatal Project were selected using purposive sampling. A total of 155 participants were interviewed, including stakeholders of the Safe Neonatal Project such as national maternal health experts, relevant government officials and medical staff. Thematic analysis was used to process and analyse the interview content in order to summarise the facilitators and barriers to implementing KMC. RESULTS: KMC was accepted in the pilot areas but still faced certain challenges due to institutional regulation, resource provision and the perceptions of health staff, postpartum mothers and their families as well as COVID-19 prevention and control regulations. The facilitators identified were government officials and medical staff acceptance and the incorporation of KMC into routine clinical care. The barriers identified were a lack of dedicated funding and other resources, the present scope of health insurance and KMC cost-sharing mechanism, providers' knowledge and practical abilities, parental awareness, postpartum discomfort, fathers' inadequate involvement, and the impact from COVID-19. CONCLUSION: The Safe Neonatal Project pilot experience indicated the feasibility of implementing KMC in more areas of China. Optimising institutional regulations, providing necessary supporting resources and enhancing education and training may help to refine the implementation and scale-up of KMC practice in China.

Design of Intelligent Protective Composite Material with Stress Rate Sensitivity, Strong Interface Adhesion, and Recyclability.

Poly(dimethyl siloxane) (PDMS) elastomers play a significant role in smart materials, actuators, and flexible electronics. However, current PDMS lacks adhesion abilities and intelligent responsive properties, which limit its further application. In this study, the polydimethylsiloxane-ureidopyrimidinone impact hardening polymer (PDMS-UI) composites are manufactured by a dual cross-linking compositing tactic. PDMS, a chemically stable cross-linked network, acts as a framework owing to its excellent mechanical strength, whereas UI, a reversible dynamic physically cross-linked network with quadruple hydrogen bonding, endows the PDMS-UI with excellent self-healing ability (efficiency > 90%) and energy absorption (75.23%). Impressively, owing to multivalent hydrogen bonds, the PDMS-UI exhibits superior adhesion performance: the adhesion strength on various substrates exceed 150 kPa and that on the Ferrum substrate reaches 570 kPa. These outstanding properties make the PDMS-UI a potential candidate for application in both well-developed fields, such as, wearable protective materials, artificial skin and soft robotics.

YTHDF2 inhibition potentiates radiotherapy antitumor efficacy.

RNA N6-methyladenosine (m6A) modification is implicated in cancer progression. However, the impact of m6A on the antitumor effects of radiotherapy and the related mechanisms are unknown. Here we show that ionizing radiation (IR) induces immunosuppressive myeloid-derived suppressor cell (MDSC) expansion and YTHDF2 expression in both murine models and humans. Following IR, loss of Ythdf2 in myeloid cells augments antitumor immunity and overcomes tumor radioresistance by altering MDSC differentiation and inhibiting MDSC infiltration and suppressive function. The remodeling of the landscape of MDSC populations by local IR is reversed by Ythdf2 deficiency. IR-induced YTHDF2 expression relies on NF-κB signaling; YTHDF2 in turn leads to NF-κB activation by directly binding and degrading transcripts encoding negative regulators of NF-κB signaling, resulting in an IR-YTHDF2-NF-κB circuit. Pharmacological inhibition of YTHDF2 overcomes MDSC-induced immunosuppression and improves combined IR and/or anti-PD-L1 treatment. Thus, YTHDF2 is a promising target to improve radiotherapy (RT) and RT/immunotherapy combinations.

Association of duration of skin-to-skin contact after cesarean delivery in China: a superiority, multicentric randomized controlled trial.

BACKGROUND: In China, the rates of early initiation and exclusive breastfeeding are low. The high cesarean delivery rates further contribute to low breastfeeding outcomes. Skin-to-skin contact, a key component of early essential newborn care, is known to be associated with improved breastfeeding initiation and exclusivity; however, the necessary duration has not been subjected to a randomized control trial. OBJECTIVE: This study aimed to determine the association of the duration of skin-to-skin contact after cesarean delivery with breastfeeding outcomes and maternal and neonatal health outcomes in China. STUDY DESIGN: This was a multicentric randomized controlled trial that was conducted at 4 hospitals in China. A total of 720 participants at ≥37 gestational weeks with a singleton pregnancy and who received an elective cesarean delivery with epidural anesthesia or spinal anesthesia or combined spinal-epidural anesthesia were randomly divided into 4 groups at a ratio of 1:1:1:1. The control group received routine care. Intervention group 1 (G1), 2 (G2), and 3 (G3) received 30, 60, and 90 minutes of skin-to-skin contact immediately after the cesarean delivery, respectively. RESULTS: Between January 3 and October 14, 2021, 659 participants were recruited, including 173 in the control group, 176 in G1, 146 in G2, and 164 in G3. Among G1, G2, and G3, the rate of early initiation of breastfeeding within 60 minutes of birth was 56%, 71%, and 72%, respectively, compared with 22% in the control group (P<.001). The exclusive breastfeeding rate at discharge was 69%, 62%, and 71%, respectively, compared with 57% in the control group (P=.003). Early essential newborn care practices were associated with a reduction in postpartum blood loss and neonatal intensive care unit or neonatal ward admission (P<.001; P=.022) . CONCLUSION: Our findings highlight that prolonged skin-to-skin contact after a cesarean delivery was associated with higher initiation and exclusive breastfeeding at discharge rates. It also found associations with reduced postpartum blood loss and neonatal intensive care unit or neonatal ward admission.

The association between parental risks and childhood development: findings from a community-based survey in East China.

BACKGROUND: Nurturing care is necessary for optimal early childhood development. This study aimed to investigate the prevalence of parental risks in rural East China and assess their impacts on early development in children younger than three years old. METHODS: This community-based cross-sectional survey was conducted among 3852 caregiver-child pairs in Zhejiang Province from December 2019 to January 2020. Children aged 0 to 3 years were recruited from China's Early Childhood Development Program (ECD). Local child health care providers conducted face-to-face interviews with the primary caregivers. Demographic information of the participants was collected by questionnaire. Each child was screened for parental risk through the Parental Risk Checklist designed by the ECD program. The Ages and Stages Questionnaire (ASQ) was used to identify children with potential developmental delays. Multinomial logistic regression model and linear trend test were applied to assess the association between parental risks and suspected developmental delays. RESULTS: Among the 3852 children included in the analyses, 46.70% had at least one parental risk and 9.01% presented suspected developmental delays in any domain of ASQ. Parental risk was statistically associated with the overall suspected developmental delay in young children (Relative Risk Ratio (RRR): 1.36; 95% confidence interval (CI): 1.08, 1.72; P = 0.010) after adjusting potential confounders. Compared with children with no parental risk, children exposed to 3 or more parental risks had 2.59, 5.76, 3.95, and 2.84 times higher risk of the suspected developmental delay in overall ASQ, communication, problem-solving, and personal-social domain, respectively (P values < 0.05). The linear trend tests found that the more parental risks, the higher possibility of developmental delay (P values < 0.05). CONCLUSIONS: Parental risks are prevalent among children under three years in rural East China, which may increase the risk of developmental delays in children. Meanwhile, parental risk screening can be used to recognize poor nurturing care in primary health care settings. Targeted interventions are warranted to improve nurturing care for optimal early childhood development.

OncoVee™-MiniPDX-guided anticancer treatment for HER2-negative intermediate-advanced gastric cancer patients: a single-arm, open-label phase I clinical study.

BACKGROUND: Chemotherapy is the main treatment strategy for patients with advanced HER2-negative gastric cancer (GC); yet, many patients do not respond well to treatment. This study evaluated the sensitivity of a mini patient-derived xenograft (MiniPDX) animal model in patients with HER2-negative intermediate-advanced GC. METHODS: In this single-arm, open-label clinical study, we consecutively recruited patients with HER2-negative advanced or recurrent GC from September 2018 to July 2021. Tumor tissues were subjected to MiniPDX drug sensitivity tests for screening individualized anti-tumor drugs; appropriate drug types or combinations were selected based on drug screening results. The primary endpoints were progression-free survival (PFS) and safety, and the secondary endpoints were overall survival (OS) and objective response rate (ORR). RESULTS: A total of 17 patients were screened, and 14 eligible patients were included.The median follow-up time was 9 (2-34) months. The median PFS time was 14.1 (2-34) months, the median OS time was 16.9 (2-34) months, ORR was 42.9% (6/14), and DCR was 92.9% (13/14). The most common treatment-related adverse events (TRAE) were fatigue (14 (100%)), anorexia (13 (93%)) and insomnia (12 (86%)), and the most common grade 3 or worse TRAE was fatigue (6 (43%)), and anorexia (6 (43%)). The occurrence rate of myelosuppression, nausea and vomiting, abnormal liver enzymes, and other grade 3-4 chemotherapy adverse reactions were relatively low, and no grade 5 treatment-related adverse events occurred. CONCLUSION: Screening HER2-negative medium-advanced GC/GJC chemotherapy regimens and targeted drugs based on MiniPDX animal models showed good tumor activity and safety.