Universal STING mimic boosts antitumour immunity via preferential activation of tumour control signalling pathways.

The efficacy of STING (stimulator of interferon genes) agonists is due to various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours, and a complex balance between tumour control and progression. Here we report a universal STING mimic (uniSTING) based on a polymeric architecture. UniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNPs) results in potent antitumour efficacy across established and advanced metastatic tumour models, including triple-negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2'3'-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the proinflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen-specific CD8+ T-cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitize dendritic cells via exosome-containing miRNAs that reduced the immunosuppressive Wnt2b, and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibits tumour growth and prolongs animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.

The Vi Capsular Polysaccharide of Salmonella Typhi Promotes Macrophage Phagocytosis by Binding the Human C-Type Lectin DC-SIGN.

Capsular polysaccharides are common virulence factors of extracellular, but not intracellular bacterial pathogens, due to the antiphagocytic properties of these surface structures. It is therefore paradoxical that Salmonella enterica subspecies enterica serovar Typhi, an intracellular pathogen, synthesizes a virulence-associated (Vi) capsule, which exhibits antiphagocytic properties. Here, we show that the Vi capsular polysaccharide has different functions when S. Typhi interacts with distinct subsets of host phagocytes. The Vi capsular polysaccharide allowed S. Typhi to selectively evade phagocytosis by human neutrophils while promoting human macrophage phagocytosis. A screen of C-type lectin receptors identified human DC-SIGN as the receptor involved in macrophage binding and phagocytosis of capsulated S. Typhi. Consistent with the anti-inflammatory activity of DC-SIGN, purified Vi capsular polysaccharide reduced inflammatory responses in macrophages. These data suggest that binding of the human C-type lectin receptor DC-SIGN by the Vi capsular polysaccharide contributes to the pathogenesis of typhoid fever. IMPORTANCE Salmonella enterica subspecies enterica serovar Typhi is the causative agent of typhoid fever. The recent emergence of S. Typhi strains which are resistant to antibiotic therapy highlights the importance of vaccination in managing typhoid fever. The virulence-associated (Vi) capsular polysaccharide is an effective vaccine against typhoid fever, but the role the capsule plays during pathogenesis remains incompletely understood. Here, we identify the human C-type lectin receptor DC-SIGN as the receptor for the Vi capsular polysaccharide. Binding of capsulated S. Typhi to DC-SIGN resulted in phagocytosis of the pathogen by macrophages and induction of an anti-inflammatory cytokine response. Thus, the interaction of the Vi capsular polysaccharide with human DC-SIGN contributes to the pathogenesis of typhoid fever and should be further investigated in the context of vaccine development.

University Staff's Perceptions of Community College Transfer Students' Transition Experiences Within a "2+2" Pathway in an Asian Educational Context.

Various countries have alternative pathway policies for 2-year community college graduates to articulate to 2-year university study, forming a "2+2" pathway. However, few studies have explored university staff members' perceptions of this "2+2" transfer pathway and their understanding of transfer students' (TSs) transition experiences. This descriptive qualitative study addressed this research gap. Forty-two academic and supporting staff participated in the focus group interviews. Specifically, the study explored the assets and challenges of the "2+2" pathway from the university staff perspective in Hong Kong. The articulation pathway and TSs are highly recognized for their prior learning, academic performances, and the value of the second chance. However, while the university staff were sympathetic to the challenges filling these transfer pathways, their offering of help was limited by government funding and policies restrictions. It is recommended that policies should be established at government and university levels to recognize and tackle TSs' unique needs to alleviate their heavy workloads through better articulation between community college and university studies. Improving articulation will allow TSs time for social involvement in university life and thus enhance their mental well-being.

Virulence factors perforate the pathogen-containing vacuole to signal efferocytosis.

Intracellular pathogens commonly reside within macrophages to find shelter from humoral defenses, but host cell death can expose them to the extracellular milieu. We find intracellular pathogens solve this dilemma by using virulence factors to generate a complement-dependent find-me signal that initiates uptake by a new phagocyte through efferocytosis. During macrophage death, Salmonella uses a type III secretion system to perforate the membrane of the pathogen-containing vacuole (PCV), thereby triggering complement deposition on bacteria entrapped in pore-induced intracellular traps (PITs). In turn, complement activation signals neutrophil efferocytosis, a process that shelters intracellular bacteria from the respiratory burst. Similarly, Brucella employs its type IV secretion system to perforate the PCV membrane, which induces complement deposition on bacteria entrapped in PITs. Collectively, this work identifies virulence factor-induced perforation of the PCV as a strategy of intracellular pathogens to generate a find-me signal for efferocytosis.

mRNA Delivery of a Bispecific Single-Domain Antibody to Polarize Tumor-Associated Macrophages and Synergize Immunotherapy against Liver Malignancies.

Liver malignancies are among the tumor types that are resistant to immune checkpoint inhibition therapy. Tumor-associated macrophages (TAMs) are highly enriched and play a major role in inducing immunosuppression in liver malignancies. Herein, CCL2 and CCL5 are screened as two major chemokines responsible for attracting TAM infiltration and inducing their polarization toward cancer-promoting M2-phenotype. To reverse this immunosuppressive process, an innovative single-domain antibody that bispecifically binds and neutralizes CCL2 and CCL5 (BisCCL2/5i) with high potency and specificity is directly evolved. mRNA encoding BisCCL2/5i is encapsulated in a clinically approved lipid nanoparticle platform, resulting in a liver-homing biomaterial that allows transient yet efficient expression of BisCCL2/5i in the diseased organ in a multiple dosage manner. This BisCCL2/5i mRNA nanoplatform significantly induces the polarization of TAMs toward the antitumoral M1 phenotype and reduces immunosuppression in the tumor microenvironment. The combination of BisCCL2/5i with PD-1 ligand inhibitor (PD-Li) achieves long-term survival in mouse models of primary liver cancer and liver metastasis of colorectal and pancreatic cancers. The work provides an effective bispecific targeting strategy that could broaden the PD-Li therapy to multiple types of malignancies in the human liver.

A Qualitative Exploration on the Challenges of Transfer Students in an Asian Educational Context.

Limited research has been conducted on community college (CC) transfer students' (TS) experiences in four-year universities, particularly in Asian contexts. To fill this research gap, in this qualitative study, 124 TS from various disciplines in a Hong Kong university participated in 39 focus groups and seven individual interviews. Unlike their Western counterparts, our TS were relatively better prepared and more academically adaptive. Nevertheless, their social integration was restricted by a lack of time for extra-curricular activities, a sense of inferiority and incompetence, and restricted social circles that did not enable interaction with non-TS. These challenges and their implications are discussed. In particular, this study has highlighted differences between the special education systems for CC transfer in Hong Kong and those in Western CC models. The study has also highlighted the study-induced stress, and poor self-perceptions that TS experience, despite their academic abilities.

A Nurse-Led Education Program for Pneumoconiosis Caregivers at the Community Level.

Pneumoconiosis is an irreversible chronic disease. With functional limitations and an inability to work, pneumoconiosis patients require support from family caregivers. However, the needs of pneumoconiosis caregivers have been neglected. This study aimed to evaluate the effectiveness of a nurse-led education program, which involved four weekly 90-min workshops led by an experienced nurse and guided by Orem's self-care deficit theory. A single-group, repeated-measure study design was adopted. Caregivers' mental health (Hospital Anxiety and Depression Scale, HADS, four single items for stress, worriedness, tiredness, and insufficient support), caregiving burdens (caregiving burden scale, CBS), and unmet direct support and enabling needs (Carer Support Needs Assessment Tool, CSNAT) were measured at the baseline (T0), immediately after (T1), and one month after intervention (T2); 49, 41, and 28 female participants completed the T0, T1, and T2 measurements. Mean age was 65.9 years old (SD 10.08) with a range between 37 and 85 years old. The program improved the caregivers' mental wellbeing, and reduced their caregiving burdens and their unmet support and enabling needs, both immediately (T1) and one-month after the intervention (T2). In particular, the intervention improved the caregivers' mental wellbeing significantly, specifically depression symptoms, stress, and tiredness immediately after the intervention; and reduced most of their unmet support needs and unmet enabling needs one-month after the intervention. This was the first nurse-led program for pneumoconiosis caregivers and should serve as a foundation for further studies to test the program with robust designs.

Anaerobic Respiration of NOX1-Derived Hydrogen Peroxide Licenses Bacterial Growth at the Colonic Surface.

The colonic microbiota exhibits cross-sectional heterogeneity, but the mechanisms that govern its spatial organization remain incompletely understood. Here we used Citrobacter rodentium, a pathogen that colonizes the colonic surface, to identify microbial traits that license growth and survival in this spatial niche. Previous work showed that during colonic crypt hyperplasia, type III secretion system (T3SS)-mediated intimate epithelial attachment provides C. rodentium with oxygen for aerobic respiration. However, we find that prior to the development of colonic crypt hyperplasia, T3SS-mediated intimate attachment is not required for aerobic respiration but for hydrogen peroxide (H2O2) respiration using cytochrome c peroxidase (Ccp). The epithelial NADPH oxidase NOX1 is the primary source of luminal H2O2 early after C. rodentium infection and is required for Ccp-dependent growth. Our results suggest that NOX1-derived H2O2 is a resource that governs bacterial growth and survival in close proximity to the mucosal surface during gut homeostasis.

Improved haplotype inference by exploiting long-range linking and allelic imbalance in RNA-seq datasets.

Haplotype reconstruction of distant genetic variants remains an unsolved problem due to the short-read length of common sequencing data. Here, we introduce HapTree-X, a probabilistic framework that utilizes latent long-range information to reconstruct unspecified haplotypes in diploid and polyploid organisms. It introduces the observation that differential allele-specific expression can link genetic variants from the same physical chromosome, thus even enabling using reads that cover only individual variants. We demonstrate HapTree-X's feasibility on in-house sequenced Genome in a Bottle RNA-seq and various whole exome, genome, and 10X Genomics datasets. HapTree-X produces more complete phases (up to 25%), even in clinically important genes, and phases more variants than other methods while maintaining similar or higher accuracy and being up to 10×  faster than other tools. The advantage of HapTree-X's ability to use multiple lines of evidence, as well as to phase polyploid genomes in a single integrative framework, substantially grows as the amount of diverse data increases.

Application of Physiologically-Based Pharmacokinetic Modeling to Predict Gastric pH-Dependent Drug-Drug Interactions for Weak Base Drugs.

Weak-base drugs are susceptible to drug-drug interactions (DDIs) when coadministered with gastric acid-reducing agents (ARAs). We developed PBPK models to evaluate the potential of such pH-dependent DDIs for four weak-base drugs, i.e., tapentadol, darunavir, erlotinib, and saxagliptin. The physiologically-based pharmacokinetic (PBPK) models of these drugs were first optimized using pharmacokinetic (PK) data following oral administration without ARAs, which were then verified with data from additional PK studies in the presence and absence of food. The models were subsequently used to predict the extent of DDIs with ARA coadministration. Sensitivity analysis was conducted to explore the impact of gastric pH on quantitative prediction of drug exposure in the presence of ARA. The results suggested that the PBPK models developed could adequately describe the lack of the effect of ARA on the PK of tapentadol, darunavir, and saxagliptin and could qualitatively predict the effect of ARA in reducing the absorption of erlotinib. Further studies involving more drugs with positive pH-dependent DDIs are needed to confirm the findings and broaden our knowledge base to further improve the utilization of PBPK modeling to evaluate pH-dependent DDI potential.

Challenges of university nursing transfer students in an Asian context: a qualitative study.

OBJECTIVES: To explore the social and academic experiences of nursing transfer students' (NTSs) in an Asian context. DESIGN: A descriptive qualitative study design using focus groups and individual interviews with Chinese NTSs. The data were transcribed verbatim and analysed by using qualitative content analysis. SETTING: A university offering preregistration nursing programmes in Hong Kong. PARTICIPANTS: Chinese NTSs studying in a 3-year special pattern within a 5-year Bachelor of Nursing programme in a university in Hong Kong. RESULTS: Four main categories were identified: 'expectations about study at the beginning of the programme', 'challenges during transition', 'coping by prioritising' and 'our world is small'. The NTSs had clear goals for becoming professional nurses and consequently aimed at higher academic achievements throughout the study. They anticipated enjoying university life at the beginning of their study; however, the challenges caused by heavy study workloads and transition from passive to independent learning approaches, compounded by the limited time of 3-year study, forced them to develop coping strategies to reconcile and prioritise their preconceived notions, academic pursuits, social engagements and personal well-being. Their high prioritisation of good academic performance confined their university lives to the small world of the academic arena. CONCLUSIONS: The study identified challenges faced by NTSs in adjusting to university study. Suggestions are offered to different stakeholders to address the issues at individual, institutional and government levels so as to enhance NTSs' learning experiences at university.

Differences in study workload stress and its associated factors between transfer students and freshmen entrants in an Asian higher education context.

Unlike the studies of freshmen entrants, the learning experiences of community college transfer (CCT) students in the receiving university is a topic that has only started to gain attention in recent decades. Little is known about the differences between CCT and freshmen entrants with regard to their study workload stress and its relationship with their perceptions of the teaching and learning environment, approaches to learning, self-efficacy and generic skills. The purpose of our study was to address this gap. This was a cross-sectional survey study conducted from April 2018 to November 2018 in a university in Hong Kong. The HowULearn questionnaire was adapted to local usage and validated for data collection. In total, 841 CCT students and 978 freshmen entrants completed the survey. The respondents were aged between 19 and 52 years (mean = 21.6, SD = 1.92), and 66.0% were women. The HowULearn questionnaire was determined by factor analyses to have eight factors. The reliabilities of the eight factors were found to be acceptable (Cronbach alphas = 0.709-0.918). The CCT students scored significantly higher than the freshmen entrants for perceived study workload stress and surface approaches to learning, but lower on teaching for understanding & encouraging learning, peer support, and self-efficacy beliefs. The surface approach to learning, deep & organized studying, alignment & constructive feedback, and generic skills were found to be predictors of study workload stress in both groups of students, and in the overall student data. This study has shown that CCT students and freshmen entrants differed with regard to their study workload stress and learning experiences. Our findings provide a message, both for educators in higher education and policy makers in the government-there is not a one-size-fits-all approach to different student populations when it comes to enhancing their learning experiences.

Perceptions of the English Use of College Transfer Nursing Students in a Non-English Speaking City: A Qualitative Study.

There has been limited research on nursing students' (NSs) language problems conducted in non-English speaking countries, especially research focusing on college transfer students. The purpose of this study was to explore the perceived needs and challenges of English use by college transfer NSs in a non-English speaking environment. A descriptive study design was adopted. Forty-five college transfer NSs from a university in Hong Kong participated in the study. Sixteen interviews were conducted. A qualitative content analysis was performed. Two main categories were identified: (a) Perceptions about English use (three sub-categories: (i) significance of having a good command of English; (ii) challenges in use of English; and (iii) low motivation and need to learn English), and (b) using English in nursing contexts (two sub-categories: (i) challenges in the use of English in nursing and (ii) improving English proficiency as a second priority in nursing students). In conclusion, college transfer NSs face challenges in general and discipline-specific English use, but their motivation to improve their English proficiency was not strong. Language centers should re-design the language courses to meet NSs' communication needs, while nursing educators should provide opportunities for students to strengthen their English use in research and clinical situations.

Fast characterization of segmental duplications in genome assemblies.

Motivation: Segmental duplications (SDs) or low-copy repeats, are segments of DNA > 1 Kbp with high sequence identity that are copied to other regions of the genome. SDs are among the most important sources of evolution, a common cause of genomic structural variation and several are associated with diseases of genomic origin including schizophrenia and autism. Despite their functional importance, SDs present one of the major hurdles for de novo genome assembly due to the ambiguity they cause in building and traversing both state-of-the-art overlap-layout-consensus and de Bruijn graphs. This causes SD regions to be misassembled, collapsed into a unique representation, or completely missing from assembled reference genomes for various organisms. In turn, this missing or incorrect information limits our ability to fully understand the evolution and the architecture of the genomes. Despite the essential need to accurately characterize SDs in assemblies, there has been only one tool that was developed for this purpose, called Whole-Genome Assembly Comparison (WGAC); its primary goal is SD detection. WGAC is comprised of several steps that employ different tools and custom scripts, which makes this strategy difficult and time consuming to use. Thus there is still a need for algorithms to characterize within-assembly SDs quickly, accurately, and in a user friendly manner. Results: Here we introduce SEgmental Duplication Evaluation Framework (SEDEF) to rapidly detect SDs through sophisticated filtering strategies based on Jaccard similarity and local chaining. We show that SEDEF accurately detects SDs while maintaining substantial speed up over WGAC that translates into practical run times of minutes instead of weeks. Notably, our algorithm captures up to 25% 'pairwise error' between segments, whereas previous studies focused on only 10%, allowing us to more deeply track the evolutionary history of the genome. Availability and implementation: SEDEF is available at https://github.com/vpc-ccg/sedef.

Women's views about the timing of birth.

BACKGROUND: Estimated date of birth (EDB) is used to guide the care provided to women during pregnancy and birth, although its imprecision is recognised. Alternatives to the EDB have been suggested for use with women however their attitudes to timing of birth information have not been examined. AIMS: To explore women's expectations of giving birth on or near their EDB, and their attitudes to alternative estimates for timing of birth. METHODS: A survey of pregnant women attending four public hospitals in Sydney, Australia, between July and December 2012. RESULTS: Among 769 surveyed women, 42% expected to birth before their due date, 16% after the due date, 15% within a day or so of the due date, and 27% had no expectations. Nulliparous women were more likely to expect to give birth before their due date. Women in the earlier stages of pregnancy were more likely to have no expectations or to expect to birth before the EDB while women in later pregnancy were more likely to expect birth after their due date. For timing of birth information, only 30% of women preferred an EDB; the remainder favoured other options. CONCLUSIONS: Most women understood the EDB is imprecise. The majority of women expressed a preference for timing of birth information in a format other than an EDB. In support of woman-centred care, clinicians should consider discussing other options for estimated timing of birth information with the women in their care.

Energy Taxis toward Host-Derived Nitrate Supports a Salmonella Pathogenicity Island 1-Independent Mechanism of Invasion.

UNLABELLED: Salmonella enterica serovar Typhimurium can cross the epithelial barrier using either the invasion-associated type III secretion system (T3SS-1) or a T3SS-1-independent mechanism that remains poorly characterized. Here we show that flagellum-mediated motility supported a T3SS-1-independent pathway for entering ileal Peyer's patches in the mouse model. Flagellum-dependent invasion of Peyer's patches required energy taxis toward nitrate, which was mediated by the methyl-accepting chemotaxis protein (MCP) Tsr. Generation of nitrate in the intestinal lumen required inducible nitric oxide synthase (iNOS), which was synthesized constitutively in the mucosa of the terminal ileum but not in the jejunum, duodenum, or cecum. Tsr-mediated invasion of ileal Peyer's patches was abrogated in mice deficient for Nos2, the gene encoding iNOS. We conclude that Tsr-mediated energy taxis enables S Typhimurium to migrate toward the intestinal epithelium by sensing host-derived nitrate, thereby contributing to invasion of Peyer's patches. IMPORTANCE: Nontyphoidal Salmonella serovars, such as S. enterica serovar Typhimurium, are a common cause of gastroenteritis in immunocompetent individuals but can also cause bacteremia in immunocompromised individuals. While the invasion-associated type III secretion system (T3SS-1) is important for entry, S Typhimurium strains lacking a functional T3SS-1 can still cross the intestinal epithelium and cause a disseminated lethal infection in mice. Here we observed that flagellum-mediated motility and chemotaxis contributed to a T3SS-1-independent pathway for invasion and systemic dissemination to the spleen. This pathway required the methyl-accepting chemotaxis protein (MCP) Tsr and energy taxis toward host-derived nitrate, which we found to be generated by inducible nitric oxide synthase (iNOS) in the ileal mucosa prior to infection. Collectively, our data suggest that S Typhimurium enhances invasion by actively migrating toward the intestinal epithelium along a gradient of host-derived nitrate emanating from the mucosal surface of the ileum.

Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of Salmonella.

The mammalian intestine is host to a microbial community that prevents pathogen expansion through unknown mechanisms, while antibiotic treatment can increase susceptibility to enteric pathogens. Here we show that streptomycin treatment depleted commensal, butyrate-producing Clostridia from the mouse intestinal lumen, leading to decreased butyrate levels, increased epithelial oxygenation, and aerobic expansion of Salmonella enterica serovar Typhimurium. Epithelial hypoxia and Salmonella restriction could be restored by tributyrin treatment. Clostridia depletion and aerobic Salmonella expansion were also observed in the absence of streptomycin treatment in genetically resistant mice but proceeded with slower kinetics and required the presence of functional Salmonella type III secretion systems. The Salmonella cytochrome bd-II oxidase synergized with nitrate reductases to drive luminal expansion, and both were required for fecal-oral transmission. We conclude that Salmonella virulence factors and antibiotic treatment promote pathogen expansion through the same mechanism: depletion of butyrate-producing Clostridia to elevate epithelial oxygenation, allowing aerobic Salmonella growth.

FDA Approval Summary: Ramucirumab for Gastric Cancer.

The FDA approved ramucirumab (CYRAMZA; Eli Lilly and Company) for previously treated patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma initially as monotherapy (April 21, 2014) and subsequently as combination therapy with paclitaxel (November 5, 2014). In the monotherapy trial, 355 patients in the indicated population were randomly allocated (2:1) to receive ramucirumab or placebo, 8 mg/kg intravenously every 2 weeks. In the combination trial, 665 patients were randomly allocated (1:1) to receive ramucirumab or placebo, 8 mg/kg intravenously every 2 weeks, in combination with paclitaxel, 80 mg/m(2) on days 1, 8, and 15 of 28-day cycles. Overall survival (OS) was increased in patients who received ramucirumab in both the monotherapy [HR, 0.78; 95% confidence interval (CI), 0.60-0.998; log rank P = 0.047] and combination trials (HR, 0.81; 95% CI, 0.68-0.96; P = 0.017). The most common adverse reactions were hypertension and diarrhea in the monotherapy trial and fatigue, neutropenia, diarrhea, and epistaxis in the combination trial. Because of concerns about the robustness of the monotherapy trial results, FDA approved the original application after receiving the results of the combination trial confirming the OS effect. Based on exploratory exposure-response analyses, there is residual uncertainty regarding the optimal dose of ramucirumab.

Women's beliefs about the duration of pregnancy and the earliest gestational age to safely give birth.

BACKGROUND: American evidence suggests women are not well informed about the optimal duration of pregnancy or the earliest time for safe birth. Similar evidence does not exist in Australia. AIMS: To explore pregnant women's beliefs about the duration of pregnancy and the earliest time for safe birth, and to compare the results with US data. METHODS: A cross-sectional survey of pregnant women attending antenatal clinics at four public hospitals in Sydney, Australia, included information on maternal and pregnancy characteristics, and two questions exploring women's beliefs about the duration of pregnancy, and the earliest time for safe birth. Responses were grouped as: late preterm (34-36 weeks), early term (37-38 weeks) and full term (39-40 weeks). RESULTS: Of the 784 surveyed women, 52% chose 39-40 weeks as the duration of a full-term pregnancy, while for the earliest time for safe birth, 10% chose 39-40 weeks and 57% chose 37-38 weeks. Some maternal characteristics were associated with women's beliefs, including having a medical and/or pregnancy complication, country of birth, level of education, employment status and attending a tertiary hospital. The associations were different for each question. In comparison with US studies, Australian women were more likely to choose later gestations for both the duration of pregnancy and the earliest time for safe birth. CONCLUSIONS: A significant proportion of women believe that full-term pregnancy and earliest time for safe birth occur before 39 weeks, suggesting opportunities for better communication about the benefits and risks of birthing at different gestations.

Topical hypochlorite ameliorates NF-κB-mediated skin diseases in mice.

Nuclear factor-κB (NF-κB) regulates cellular responses to inflammation and aging, and alterations in NF-κB signaling underlie the pathogenesis of multiple human diseases. Effective clinical therapeutics targeting this pathway remain unavailable. In primary human keratinocytes, we found that hypochlorite (HOCl) reversibly inhibited the expression of CCL2 and SOD2, two NF-κB-dependent genes. In cultured cells, HOCl inhibited the activity of inhibitor of NF-κB kinase (IKK), a key regulator of NF-κB activation, by oxidizing cysteine residues Cys114 and Cys115. In NF-κB reporter mice, topical HOCl reduced LPS-induced NF-κB signaling in skin. We further evaluated topical HOCl use in two mouse models of NF-κB-driven epidermal disease. For mice with acute radiation dermatitis, topical HOCl inhibited the expression of NF-κB-dependent genes, decreased disease severity, and prevented skin ulceration. In aged mice, topical HOCl attenuated age-dependent production of p16INK4a and expression of the DNA repair gene Rad50. Additionally, skin of aged HOCl-treated mice acquired enhanced epidermal thickness and proliferation, comparable to skin in juvenile animals. These data suggest that topical HOCl reduces NF-κB-mediated epidermal pathology in radiation dermatitis and skin aging through IKK modulation and motivate the exploration of HOCl use for clinical aims.