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Background Sepsis causes death and morbidity in young infants. Globally, an estimated 1.3 – 3.9 million young infants experience sepsis and 400,000 – 700,000 die from sepsis-related conditions annually. Even though there have been significant progress over the past twenty years in reducing young infant mortality, sepsis currently accounts for up to 15% of all young infant deaths. A thorough understanding of young infant sepsis can inform strategies that span prevention, diagnosis and intervention for young infant sepsis. Objectives We aimed to perform a systematic review and meta-analysis to investigate the case fatality rates (CFRs) among young infants less than 90 days with sepsis globally. Methods We used the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2009 guidelines. We searched PubMed, Cochrane Central, Embase and Web of Science for randomized clinical trials and observational studies in English language, published between 2010 to 2019. Studies involving young infants less than 90 days old with sepsis and reported CFRs were included. We obtained pooled CFRs estimates using the random effects model. Additional stratifications by gestation, birth weight, onset of sepsis (early onset was defined as Results Among 6314 articles screened, 240 studies with a total of 437,796 patients met the inclusion criteria and were included in our analysis. 99 came from high income countries, 44 from upper middle income countries, 82 from lower middle income countries, 6 from low income countries and 9 were conducted in multiple countries. Overall, the pooled CFR was 0.18 (95% CI, 0.17–0.19). The CFR was the highest in low income countries (0.25 [95% CI, 0.07–0.43]), followed by lower middle (0.24 [95% CI, 0.21–0.26]), upper middle (0.21 [95% CI, 0.18–0.24]) and lastly high income countries (0.12 [95% CI, 0.11–0.13]). Other factors associated with higher CFRs included prematurity (0.23 [95% CI, 0.19–0.26] vs term CFR 0.10 [95% CI, 0.08–0.13]), low birth weight (0.21 [95% CI, 0.19–0.24] vs normal birth weight 0.19 [95% CI, 0.18–0.20]), early onset sepsis (0.20 [95% CI, 0.17–0.24] vs combined (0.16 [95% CI, 0.14–0.18]) and hospital acquired infection (0.23 [95% CI, 0.17–0.30] vs community acquired infections 0.21 [95% CI, 0.10–0.33]). Time trend analysis showed higher CFRs in the low income countries than the middle and high income countries. A decreasing trend in CFRs over time was observed in high and upper middle income countries, as compared to an increasing trend in lower middle and low income countries. Conclusions While we saw a declining trend of young infant sepsis CFRs among high and upper middle income countries across the years, the increasing trend amongst lower middle and low income countries highlights a disparity in infant sepsis outcomes based on resource availability. We highlight specific vulnerable patient populations that should be further studied in order to reduce the global burden of young infant sepsis.

IntroductionThe effect of neonatal sepsis on the developing brain is not well documented. We aim to perform evidence synthesis to determine the outcome of neurodevelopmental impairment and intellectual disability among survivors of neonatal sepsis. The data gathered will inform on the long-term neurocognitive outcomes of neonates with sepsis and the measures used to document their developmental disability.Methods and analysisWe will perform a search based on the following parameters: neonates and infants less than 90 days old diagnosed with sepsis who had neurocognitive outcomes or measures of developmental disability reported. We will search PubMed, Cochrane Central, Embase and Web of Science for articles in English language published between January 2010 and December 2019. Clinical trials and observational studies will be included. Two independent reviewers will screen studies for eligibility. Data extraction will then be performed using a standardised form. The quality of evidence and risk of bias will be assessed using Cochrane Collaboration’s tool and Risk of Bias in Non-randomised Studies of Intervention (ROBINS-I). The results will be synthesised qualitatively and pooled for meta-analysis.Ethics and disseminationNo formal ethical approval is required as there is no collection of primary data. This systematic review and meta-analysis will be disseminated through conference meetings and peer-reviewed publications.PROSPERO registration numberRegistration submitted CRD42020164334

Elevated iron deposition has been reported in Parkinson's disease (PD). However, the route of iron uptake leading to high deposition in the substantia nigra is unresolved. Here, we show a mechanism in enhanced Fe2+uptake via S-nitrosylation of divalent metal transporter 1 (DMT1). While DMT1 could be S-nitrosylated by exogenous nitric oxide donors, in human PD brains, endogenously S-nitrosylated DMT1 was detected in postmortem substantia nigra. Patch-clamp electrophysiological recordings and iron uptake assays confirmed increased Mn2+or Fe2+uptake through S-nitrosylated DMT1. We identified two major S-nitrosylation sites, C23 and C540, by mass spectrometry, and DMT1 C23A or C540A substitutions abolished nitric oxide (NO)-mediated DMT1 current increase. To evaluatein vivosignificance, lipopolysaccharide (LPS) was stereotaxically injected into the substantia nigra of female and male mice to induce inflammation and production of NO. The intranigral LPS injection resulted in corresponding increase in Fe2+deposition, JNK activation, dopaminergic neuronal loss and deficit in motoric activity, and these were rescued by the NO synthase inhibitorl-NAME or by the DMT1-selective blocker ebselen. Lentiviral knockdown of DMT1 abolished LPS-induced dopaminergic neuron loss.SIGNIFICANCE STATEMENTNeuroinflammation and high cytoplasmic Fe2+levels have been implicated in the initiation and progression of neurodegenerative diseases. Here, we report the unexpected enhancement of the functional activity of transmembrane divalent metal transporter 1 (DMT1) by S-nitrosylation. We demonstrated that S-nitrosylation increased DMT1-mediated Fe2+uptake, and two cysteines were identified by mass spectrometry to be the sites for S-nitrosylation and for enhanced iron uptake. One conceptual advance is that while DMT1 activity could be increased by external acidification because the gating of the DMT1 transporter is proton motive, we discovered that DMT1 activity could also be enhanced by S-nitrosylation. Significantly, lipopolysaccharide-induced nitric oxide (NO)-mediated neuronal death in the substantia nigra could be ameliorated by usingl-NAME, a NO synthase inhibitor, or by ebselen, a DMT1-selective blocker.

IMPORTANCE: The global patterns and distribution of case-fatality rates (CFRs) in pediatric severe sepsis and septic shock remain poorly described. OBJECTIVE: We performed a systematic review and meta-analysis of studies of children with severe sepsis and septic shock to elucidate the patterns of CFRs in developing and developed countries over time. We also described factors associated with CFRs. DATA SOURCES: We searched PubMed, Web of Science, Excerpta Medica database, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Central systematically for randomized clinical trials and prospective observational studies from earliest publication until January 2017, using the keywords “pediatric,” “sepsis,” “septic shock,” and “mortality.” STUDY SELECTION: Studies involving children with severe sepsis and septic shock that reported CFRs were included. Retrospective studies and studies including only neonates were excluded. DATA EXTRACTION AND SYNTHESIS: We conducted our systematic review and meta-analysis in close accordance to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled case-fatality estimates were obtained using random-effects meta-analysis. The associations of study period, study design, sepsis severity, age, and continents in which studies occurred were assessed with meta-regression. MAIN OUTCOMES AND MEASURES: Meta-analyses to provide pooled estimates of CFR of pediatric severe sepsis and septic shock over time. RESULTS: Ninety-four studies that included 7561 patients were included. Pooled CFRs were higher in developing countries (31.7% [95% CI, 27.3%-36.4%]) than in developed countries (19.3% [95% CI, 16.4%-22.7%]; P

IntroductionNeonatal sepsis has a high mortality rate that varies across different populations. We aim to perform a contemporary global evidence synthesis to determine the case fatality rates of neonatal sepsis, in order to better delineate this public health urgency and inform strategies to reduce fatality in this high-risk population.Methods and analysisWe will search PubMed, Cochrane Central, Embase and Web of Science for articles in English language published between January 2010 and December 2019. All clinical trials and observational studies involving infants less than 90 days old with a clinical diagnosis of sepsis and reported case fatality rate will be included. Two independent reviewers will screen the studies and extract data on study variables chosen a priori. Quality of evidence and risk of bias will be assessed using Cochrane Collaboration’s tool and ROBINS-I. Results will be synthesised qualitatively and pooled for meta-analysis.Ethics and disseminationNo formal ethical approval is required as there is no collection of primary data. This systematic review and meta-analysis will be disseminated through conference meetings and peer-reviewed publications.PROSPERO registration numberCRD42020164321.

Ke Guo 1,2 , Jing Ping Tang 1,2 , Li Jie 1,2 , Abdul Qader O. Al-Aidaroos 2 , Cheng William Hong 3 , Cheng Peow Bobby Tan 2 , Jung Eun Park 2 , Leyon Varghese 2 , Zhiwei Feng 4 , Jianbiao Zhou 5 , Wee Joo Chng 6 and Qi Zeng 2,7 1 Denotes equal contribution 2 Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos, Singapore 138648, Republic of Singapore 3 Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue, Cleveland, OH 44195, USA 4 Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore 637551 5 Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456 6 Department of Haematology-Oncology, National University Cancer Institute, Singapore National University Health System, 5 Lower Kent Ridge Road, S119074 7 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Republic of Singapore Received: February 2, 2012; Accepted: February 21, 2012; Published: February 27, 2012; Keywords: PRL-3 monoclonal antibody, PRL-3 mouse/human chimeric antibody, antibody therapy, intracellular oncoprotein Correspondence: Qi Zeng, // // Abstract Antibodies are considered as ‘magic bullets’ because of their high specificity. It is believed that antibodies are too large to routinely enter the cytosol, thus antibody therapeutic approach has been limited to extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are localized within the cell. To explore the possibility of antibody therapies against intracellular targets, we generated a chimeric antibody targeting the intracellular PRL-3 oncoprotein to assess its antitumor activities in mice. Remarkably, we observed that the PRL-3 chimeric antibody could efficiently and specifically reduce the formation of PRL-3 expressing metastatic tumors. We further found that natural killer (NK) cells were important in mediating the therapeutic effect, which was only observed in a nude mouse model (T-cell deficient), but not in a Severe Combined Immunodeficiency’ ( scid ) mouse model (B- and T-cell deficient), indicating the anticancer effect also depends on host B-cell activity. Our study involving 377 nude and scid mice suggest that antibodies targeting intracellular proteins can be developed to treat cancer.

The review aims to elucidate the potential of microglia as a therapeutic target in alleviating Alzheimer's Disease (AD). Microglia are the resident immune cells in the brain which respond to the presence of the hallmarks of AD, amyloid-beta (A beta) plaques and neurofibrillary tangles (NFT). Activated microglia are able to phagocytose and secrete pro-inflammatory and anti-inflammatory cytokines. However, the eventual accumulation of excess A beta peptides and NFT in AD means that microglial clearance of pathogens has been impaired. Pro-inflammatory cytokines may also contribute to the neurodegeneration. Based on the amyloid cascade hypothesis, A beta-activated microglia can produce pro-inflammatory cytokines which may exacerbate the hyperphosporylation of tau proteins that forms NFT in AD pathology. Microglial activation can thus be manipulated to prevent neurodegeneration and promote neuroprotection through several therapeutic agents and methods. Further studies regarding comprehensive microglial response towards A beta and NFT are required to develop an effective treatment of AD involving microglia.

Antibody-based therapies have better specificity and thus improved efficacy over standard chemotherapy regimens, which result in extended survival and improved quality of life for cancer patients. Because antibodies are viewed as too large to access intracellular locations, antibody therapy has traditionally targeted extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are found within the cell (such as intracellular phosphatases/kinases and transcription factors) and have therefore not been pursued for antibody therapies. Here, we explored the possibility of antibody therapy or vaccination against intracellular proteins. As proofs of concept, we selected three representative intracellular proteins as immunogens for tumor vaccine studies: PRL-3 (phosphatase of regenerating liver 3), a cancer-associated phosphatase; EGFP (enhanced green fluorescent protein), a general reporter; and mT (polyomavirus middle T), the polyomavirus middle T oncoprotein. A variety of tumors that expressed these intracellular proteins were clearly inhibited by their respective exogenous antibodies or by antigen-induced host antibodies (vaccination). These anticancer activities were reproducibly observed in hundreds of C57BL/6 tumor-bearing mice and MMTV-PymT transgenic breast tumor mice. Our in vivo data suggest that immunotherapies can target not only extracellular but also intracellular oncoproteins.

Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. We demonstrated that combining ABT-869, a FLT3 inhibitor, with SAHA, a HDAC inhibitor, led to synergistic killing of the AML cells with FLT3 mutations and suppression of colony formation. We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines. Among these, we showed that downregulation of PTP4A3 (PRL-3) played a role in this synergism. PRL-3 is downstream of FLT3 signaling and ectopic expression of PRL-3 conferred therapeutic resistance through upregulation of STAT (signal transducers and activators of transcription) pathway activity and anti-apoptotic Mcl-1 protein. PRL-3 interacts with HDAC4 and SAHA downregulates PRL-3 via a proteasome dependent pathway. In addition, PRL-3 protein was identified in 47% of AML cases, but was absent in myeloid cells in normal bone marrows. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors. PRL-3 plays a potential pathological role in AML and it might be a useful therapeutic target in AML, and warrant clinical investigation.