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Teachers’ positive relationships with families contribute to the social, emotional, and intellectual development of children in early childhood education programs. Effectively involving, communicat...

Cancer can evade destruction by the immune system if aided by immunosuppressive regulatory T cells. These cells depend on a lipid-production pathway in the tumour environment, a vulnerability that might be used to target them. Lipid factory marks regulatory T cells found in tumours.

BackgroundRecent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood.MethodsWe used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC.ResultsWe propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients.ConclusionWe identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.

Liver regeneration is critical to survival after traumatic injuries, exposure to hepatotoxins, or surgical interventions, yet the underlying signaling and metabolic pathways remain unclear. In this study, we show that hepatocyte-specific loss of the mitochondrial deacetylase SIRT3 drastically impairs regeneration and worsens mitochondrial function after partial hepatectomy. Sirtuins, including SIRT3, require NAD as a cosubstrate. We previously showed that the NAD precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for NR to enhance liver regeneration. NR improves mitochondrial respiration in regenerating WT or mutant livers and rapidly increases oxygen consumption and glucose output in cultured hepatocytes. Our data support a direct enhancement of mitochondrial redox metabolism as the mechanism mediating improved liver regeneration after NAD supplementation and exclude signaling via SIRT1 and SIRT3. Therefore, we provide the first evidence to our knowledge for an essential role for a mitochondrial sirtuin during liver regeneration and insight into the beneficial effects of NR.

Acetyl-CoA is a vitally important and versatile metabolite used for many cellular processes including fatty acid synthesis, ATP production, and protein acetylation. Recent studies have shown that cancer cells upregulate acetyl-CoA synthetase 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in response to stresses such as low nutrient availability and hypoxia. Stressed cancer cells use ACSS2 as a means to exploit acetate as an alternative nutrient source. Genetic depletion of ACSS2 in tumors inhibits the growth of a wide variety of cancers. However, there are no studies on the use of an ACSS2 inhibitor to block tumor growth. In this study, we synthesized a small-molecule inhibitor that acts as a transition-state mimetic to block ACSS2 activity in vitro and in vivo. Pharmacologic inhibition of ACSS2 as a single agent impaired breast tumor growth. Collectively, our findings suggest that targeting ACSS2 may be an effective therapeutic approach for the treatment of patients with breast cancer. Significance: These findings suggest that targeting acetate metabolism through ACSS2 inhibitors has the potential to safely and effectively treat a wide range of patients with cancer.

To examine metabolic differences between renal allograft acute cellular rejection (ACR) and ischemic-reperfusion injury (IRI), we transplanted MHC-mismatched kidneys and induced 28 minutes warm-IRI, and collected the ACR and IRI kidneys as well as their respective native and collateral control kidneys. We extracted metabolites from the kidney tissues and found the lysine catabolite saccharopine 12.5-fold enriched in IRI kidneys, as well as the immunometabolites itaconate and kynurenine in ACR kidneys. Saccharopine accumulation is known to be toxic to mitochondria and may contribute to IRI pathophysiology, while itaconate and kynurenine may be reflective of counterregulatory responses to immune activation in ACR.

Background Intestinal Ultrasound (IUS) has been gaining momentum in the management of patients with inflammatory bowel disease (IBD). Underutilized in the United States(U.S.), we present the impact of IUS in management decisions in a cohort of IBD patients seen at a tertiary center. Methods This retrospective study analyzed all IBD patients seen at our institution undergoing IUS as part of routine clinical evaluation. Patient demographics, disease type, clinical activity, laboratory markers, and therapy was obtained. Patients with evidence of inflammation based on IUS characteristics of bowel wall thickening, with additional parameters of mural stratification, mesenteric fat, doppler flow, lymph nodes, dilated bowel, free fluid used as adjunct measures were compared to those without IUS features of activity. Subsequent management plan based on findings were evaluated. Results Of 148 patients seen for IUS (median age 41 (range 18–81), 67% female), 108(73%) had Crohn’s disease (CD), 39(26.4%) had ulcerative colitis (UC), 1(0.7%) had IBD-undetermined (IBD-U) with 111(75%) Caucasians, 9.5% Blacks, 8.8% Asians, and 6.8% Hispanics. Median disease duration was 8 years, range (0–43) with 113(94.1%) on biologic/small molecule therapy and 7(5.8%) on mesalamines. No differences in BMI were noted in those with active disease vs. those in remission. However, we noted 29(19.3%) had fatty liver on ultrasound, which correlated highly with high BMI (31 vs. 24) in those with normal liver (p On IUS, 110(66%) of our patients had evidence of disease activity and 56(34%) were in remission. Inflammatory markers ESR and CRP did not correlate to IUS activity. In our UC patients Mayo score correlated to IUS findings but not Harvey Bradshaw Index (HBI) for CD. For those with positive findings on IUS, 29.5% escalated therapy for their IBD, and 13.3% required change in drug mechanism. For those in remission, the majority of patients 43(84.3%) continued their therapy while 3(5.9%) successfully de-escalated therapy. Conclusion In our study, IUS was useful in providing management decisions in those with active disease especially as there was a lack of correlation to inflammatory markers and HBI scores.

Objective There are limited data on using more than one biologic or small molecule drug combined to treat patients with inflammatory bowel disease. The aim of our study was to determine the effectiveness and safety of combination biologic use in inflammatory bowel disease. Methods We identified patients with Crohn's disease or ulcerative colitis who received treatment with a combination of two biologics or a biologic and a small molecule drug from 2015 to 2019 for persistent disease activity or concomitant rheumatological or dermatological disease. The primary end-point was effectiveness, based on improvements in inflammatory markers, clinical, and endoscopic remission. The secondary end-point was safety. Results Of the 50 patients treated with combination therapy there were significantly more patients in clinical and endoscopic remission at follow-up compared to baseline (50% vs 14%, P = 0.0018, delta 36%, 95% confidence interval [CI] 0.13-0.53; and 34% vs 6%, P = 0.0039, delta 28%, 95% CI 0.09-0.47), respectively. Median erythrocyte sedimentation rate (17 mm/h vs 13 mm/h, P = 0.002) and C-reactive protein (5.00 mg/dL vs 2.35 mg/dL, P = 0.002) also decreased posttreatment. There were eight serious adverse events and no deaths CONCLUSIONS: Combination biologic therapy appears to be an effective option for patients with refractory inflammatory bowel disease or concomitant autoimmune disease that is inadequately controlled by biologic monotherapy. There was an increased risk of serious infection compared with biologic monotherapy; however, this risk might be minimized by discontinuing immunomodulators prior to initiating combination therapy. Large prospective studies are needed to confirm these findings.

Mitochondria require nicotinamide adenine dinucleotide (NAD+) to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD+ transporters have been identified in yeast and plants1,2, but their existence in mammals remains controversial3–5. Here we demonstrate that mammalian mitochondria can take up intact NAD+, and identify SLC25A51 (also known as MCART1)—an essential6,7 mitochondrial protein of previously unknown function—as a mammalian mitochondrial NAD+ transporter. Loss of SLC25A51 decreases mitochondrial—but not whole-cell—NAD+ content, impairs mitochondrial respiration, and blocks the uptake of NAD+ into isolated mitochondria. Conversely, overexpression of SLC25A51 or SLC25A52 (a nearly identical paralogue of SLC25A51) increases mitochondrial NAD+ levels and restores NAD+ uptake into yeast mitochondria lacking endogenous NAD+ transporters. Together, these findings identify SLC25A51 as a mammalian transporter capable of importing NAD+ into mitochondria. SLC25A51 is identified as a transporter of intact NAD+ into mammalian mitochondria and is required to maintain the mitochondrial NAD+ pool and respiratory function.

Significance Mitochondrial DNA (mtDNA) mutations have been associated with common metabolic and degenerative disease phenotypes, implying a bioenergetic etiology for these diseases. For example, the mtDNA tRNALeu(UUR) m.3243A > G mutation manifests as diabetes, neurodegenerative disease, or lethal pediatric disease, depending on the percentage of mutant mtDNAs within the cell (heteroplasmy). Cultured cybrid cell lines harboring 3243G heteroplasmy levels corresponding to the different clinical phenotypes have distinct transcriptional profiles. Exhaustive metabolomic and histone posttranscriptional modification analysis of these 3243G cybrids revealed that changes in mtDNA heteroplasmy cause changes in mitochondrial intermediates and redox state, which result in distinctive histone modification changes. Thus, changes in the mitochondrial genotype change mitochondrial metabolism, which change the epigenome and transcriptome, which induce distinct clinical phenotypes., Diseases associated with mitochondrial DNA (mtDNA) mutations are highly variable in phenotype, in large part because of differences in the percentage of normal and mutant mtDNAs (heteroplasmy) present within the cell. For example, increasing heteroplasmy levels of the mtDNA tRNALeu(UUR) nucleotide (nt) 3243A > G mutation result successively in diabetes, neuromuscular degenerative disease, and perinatal lethality. These phenotypes are associated with differences in mitochondrial function and nuclear DNA (nDNA) gene expression, which are recapitulated in cybrid cell lines with different percentages of m.3243G mutant mtDNAs. Using metabolic tracing, histone mass spectrometry, and NADH fluorescence lifetime imaging microscopy in these cells, we now show that increasing levels of this single mtDNA mutation cause profound changes in the nuclear epigenome. At high heteroplasmy, mitochondrially derived acetyl-CoA levels decrease causing decreased histone H4 acetylation, with glutamine-derived acetyl-CoA compensating when glucose-derived acetyl-CoA is limiting. In contrast, α-ketoglutarate levels increase at midlevel heteroplasmy and are inversely correlated with histone H3 methylation. Inhibition of mitochondrial protein synthesis induces acetylation and methylation changes, and restoration of mitochondrial function reverses these effects. mtDNA heteroplasmy also affects mitochondrial NAD+/NADH ratio, which correlates with nuclear histone acetylation, whereas nuclear NAD+/NADH ratio correlates with changes in nDNA and mtDNA transcription. Thus, mutations in the mtDNA cause distinct metabolic and epigenomic changes at different heteroplasmy levels, potentially explaining transcriptional and phenotypic variability of mitochondrial disease.

Nicotinamide adenine dinucleotide (NAD) levels fall with age or disease, and rise with exercise or caloric restriction. Moreover, the demonstration that supplemental NAD precursors drive beneficial effects in rodent models has driven a resurgence in interest in the basic biology of this molecule. Although NAD is present in the mitochondrial matrix and critical to the function of the organelle, the source of mitochondrial NAD has been debated. We recently used isotopic labeling to demonstrate that direct uptake of intact NAD is one mechanism by which mitochondria are able to obtain this nucleotide. Here, we show that this activity is sufficient to restore respiratory capacity in NAD-deficient isolated mitochondria, and identify SLC25A51 as a carrier that can mediate the transport of NAD across mitochondrial membranes. Understanding the compartment-specific regulation of NAD will be crucial to understanding how cells and tissues adapt their metabolism to changes in NAD availability. Funding: DK098656 to J.A.B., GM126897 to L.A.C.

Introduction Gonorrhoea is currently the second most common bacterial sexually transmitted infection and represents a serious public health threat. The increasing antimicrobial resistance in Neisseria gonorrhoeae (GC) to currently available therapies is driving an urgent need for new novel agents. Gepotidacin (GEP) is a novel, first in class triazaacenaphthylene antibacterial which inhibits bacterial DNA replication. This multicenter (11 US and 1 UK) trial evaluated GEP as a single oral dose in men and women. Methods Patients with signs and symptoms of urogenital gonorrhoea, a prior culture or nucleic acid amplification test (NAAT) positive for GC, a urethral Gram stain with intracellular diplococci, or who had sexual contact with an individual diagnosed with gonorrhoea in the past 14 days were eligible for enrollment. Participants were randomised 1:1 to receive either 1.5g or 3g GEP orally. The primary efficacy endpoint was culture confirmed microbiological eradication at test-of-cure (TOC) visit 3–7 days post dose. Results 106 patients (101 men and 5 women) were randomised and 105 received treatment. Baseline GC isolates were identified in 69 (65%) urogenital, 3 (3%) pharyngeal, and 4 (4%) rectal specimens. Microbiological success was achieved by 97% and 95% of subjects with urogenital GC in the 1.5g and 3g treatment groups, respectively. Isolates from 2 subjects developed resistance to GEP between baseline and TOC. The most common GEP-related AEs were gastrointestinal (diarrhoea, flatulence, abdominal pain and nausea) with the majority being mild or moderate in intensity. Treatment-related AEs of moderate intensity occurred with a higher incidence in the 3g treatment group than the 1.5g treatment group (15% and 10%, respectively). There were no AEs that led to study withdrawal and no SAEs were reported. Conclusions Both the GEP 1.5g and 3g single doses eradicated urogenital GC with microbiological success rates of 29/30 (97%) and 37/39 (95%), respectively. The data support further development of GEP in this indication. Support: This study was supported by GSK (BTZ116576; NCT02294682). This project was funded in whole or in part with Federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced. Research and Development Authority (BARDA), under agreement # HHSO100201300011C

SUMMARY Immune cell function is influenced by metabolic conditions. Low-glucose, high-lactate environments, such as the placenta, gastrointestinal tract, and the tumor microenvironment, are immunosuppressive, especially for glycolysis-dependent effector T cells. We report that nicotinamide adenine dinucleotide (NAD+), which is reduced to NADH by lactate dehydrogenase in lactate-rich conditions, is a key point of metabolic control in T cells. Reduced NADH is not available for NAD+-dependent enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate dehydrogenase (PGDH). We show that increased lactate leads to a block at GAPDH and PGDH, leading to the depletion of post-GAPDH glycolytic intermediates, as well as the 3-phosphoglycerate derivative serine that is known to be important for T cell proliferation. Supplementing serine rescues the ability of T cells to proliferate in the presence of lactate-induced reductive stress. Directly targeting the redox state may be a useful approach for developing novel immunotherapies in cancer and therapeutic immunosuppression., Graphical Abstract, In Brief Quinn et al. report that lactate has an acidity-independent suppressive effect on effector T cell proliferation mediated through a shift from NAD+ to NADH (lactate-induced reductive stress). This impairs glycolysis and glucose-derived serine production, which is required for effector T cell proliferation.

Ertapenem, a carbapenem antibacterial, has in vitro activity against many Gram- negative (including Enterobacteriaceae) and Gram-positive aerobic and anaerobic bacteria that are commonly associated with various infections.Once-daily parenteral (intravenous or intramuscular) ertapenem 1g was as effective as comparator antimicrobial agents (piperacillin/tazobactam or ceftriaxone +/- metronidazole) in patients with bacterial infections in randomised, double-blind, multicentre clinical trials. Response rates with ertapenem were 84% and 87% (combined microbiological and clinical) in patients with complicated intra-abdominal infections (CIAI), 82% (clinical) in patients with complicated skin and skin structure infections (CSSSI), 86% and 92% (microbiological) in patients with complicated urinary tract infections (CUTI), 92% (clinical) in patients with community-acquired pneumonia (CAP) associated with typical pathogens and 94% (clinical) in patients with acute pelvic infection. Respective response rates were statistically equivalent to those with comparators (81-94%). The efficacy of ertapenem was equivalent to that of piperacillin/tazobactam in patients infected with Enterobacteriaceae or anaerobes and to ceftriaxone in patients infected with Enterobacteriaceae. Ertapenem was generally well tolerated by patients with bacterial infections, with most adverse events being mild to moderate in severity. The most common ertapenem-associated adverse events were diarrhoea, infused vein complication, nausea, headache, vaginitis in females, phlebitis and/or thrombophlebitis and vomiting.Ertapenem is a broad-spectrum parenteral antibiotic with activity against many Gram-negative (including Enterobacteriaceae) and Gram-positive aerobic and anaerobic bacteria and is suitable for once-daily administration. Ertapenem has a role in the treatment of CAP associated with typical respiratory pathogens and is of particular value in the treatment of polymicrobial infections (such as CIAI, CSSSI, CUTI and acute pelvic infections), especially where Enterobacteriaceae and anaerobic bacteria are involved.

This year's Road Safety Week runs from 22-28 November and organisers, road safety charity Brake, are urging practitioners to educate our young children and to help prevent further tragic loss of life.

Four factors in Sparks's model of victim proneness were tested among 31 persons with mental retardation who were victims of a personal offense and 32 nonvictims with mental retardation. Factors were operationalized in terms of measures of anger, antisocial tendencies, eccentricities and odd mannerisms, interpersonal competence, recreational outings, and communication skills. Forty participants also responded to hypothetical scenarios depicting everyday situations commonly encountered. Results showed that victims were significantly more likely than nonvictims to report a hostile outlook and that they would display overt anger and aggression in a wide range of situations. Victims' responses to hypothetical scenarios were more likely to be confrontative or abusive to an initial approach by the perpetrator, whereas nonvictims were more likely to withdraw quietly. These indices of poorer interpersonal competence were independent from IQ and adaptive behavior.

Glatiramer acetate (Copaxone) is a synthetic copolymer composed of a random mixture of four amino acids that modifies the immune response that results in the CNS inflammation, demyelination and axonal loss characteristic of relapsing-remitting multiple sclerosis (RRMS). In three randomised, double-blind trials in patients with RRMS, subcutaneous glatiramer acetate 20 mg/day was significantly more effective than placebo for the primary outcome measure of each trial (mean relapse rate, proportion of relapse-free patients and number of gadolinium-enhancing lesions on magnetic resonance imaging [MRI] scans). The mean relapse rate was significantly reduced at endpoint (approximately one-third less) in the two larger trials (the US pivotal trial [primary endpoint] and the European/Canadian study [tertiary endpoint]) in patients receiving glatiramer acetate compared with those receiving placebo. The rate was 78% less for glatiramer acetate than placebo patients in the pilot trial that investigated a slightly different patient population. Glatiramer acetate significantly decreased disease activity and burden of disease, as assessed in the European/Canadian study using a range of MRI measures. Patients with RRMS treated with glatiramer acetate in the US trial were significantly more likely to experience improved disability (whereas placebo recipients were more likely to experience worsening disability) and their overall disability status was significantly improved compared with placebo recipients. Data from the active-treatment extension of the US trial suggest that glatiramer acetate has sustained clinical benefits up to 8 years. Glatiramer acetate was generally well tolerated; the most commonly reported treatment-related adverse events were localised injection-site reactions and transient post-injection systemic reactions. Both reactions were generally mild and self limiting but were responsible for the majority of withdrawals from treatment (up to 6.5% and 3.5%, respectively). Glatiramer acetate is not associated with the influenza-like syndrome or neutralising antibodies that are reported in patients treated with interferon-beta for RRMS. The cost effectiveness of glatiramer acetate has yet to be definitively determined as assessment of available data is confounded by very different models, data sources and assumptions. In conclusion, glatiramer acetate has shown efficacy in well controlled clinical trials in patients with RRMS; it reduces relapse rate and decreases MRI-assessed disease activity and burden. It is generally well tolerated and is not associated with the influenza-like symptoms and formation of neutralising antibodies seen with the interferons-beta. Based on available data and current management guidelines, glatiramer acetate is a valuable first-line treatment option for patients with RRMS.

It is a sad fact that in the UK today there will be at least six deaths and 70 serious injuries on our roads involving motorised vehicles. Many of these will be children. There is much we can do to prevent this.

Combination therapy regimens appear to be one of the next logical strategies for treating individuals with HIV infection. At the 10th International Conference on AIDS [Yokohama, Japan; August 1994] promising findings from several combination therapy studies were reported. In the words of leading AIDS researcher Professor Neil Graham from Johns Hopkins University, Baltimore, Maryland, US, ‘the era of monotherapy[for HIV disease]is rapidly drawing to a close; the way forward is with combination therapy’.

The eagerly-awaited results of the Concorde trial were revealed last week in theLancet [9 April].1Preliminary findings that were published just over a year ago in a letter to theLancet [April 3, 1993]* caused considerable controversy at the time. However, the original conclusions from the Concorde study remain unchanged, despite any minor differences in figures that may have emerged. According to the investigators, the results of the Concorde trial are sufficient to discourage the early use of zidovudine in symptom-free HIV-infected adults. Furthermore, in their view, doubt has now been cast on the‘uncritical use of CD4 counts as “surrogate endpoints” in trials’.Inevitably, controversy will continue to reign, especially in view of a number of criticisms that have been levelled at the study.

US researchers are moving closer towards using gene therapy to treat patients with HIV infection. At the 10th International Conference on AIDS [Yokohama, Japan; August 1994] Dr Flossie Wong-Staal discussed her group’s work on gene therapy. A particular focus was research into the use of a hairpin ribozyme gene.

A dextrin-fermenting strain of brewer's yeast was obtained by transformation with a recombinant plasmid (pLHCD6) containing a DEX gene. The transformant produced five-fold more extracellular amyloglucosidase (AMG) than the strain of Saccharomyces diastaticus from which DEX was cloned. The growth rate, however, was adversely affected and, consequently, the transformant fermented wort more slowly than the parental (untransformed) strain. A mixed culture was therefore used at pilot-scale, to maintain a rate of fermentation similar to that of the parental strain. The transformant by itself was capable of superattenuating wort (original gravity 1.040) to a specific gravity of 1.0023 (compared with 1.0046 for the parental strain). This represents the expected degree of dextrin breakdown by an AMG with no “debranching” activity which can only hydrolyse alpha-1,4 linkages. A high copy number for the plasmid pLHCD6 was maintained throughout fermentation. The beers produced using the Dex+ transformants were judged to be of sound quality.