An epitope-based approach of HLA-matched platelets for transfusion: a noninferiority crossover randomized trial.

Platelet transfusion refractoriness results in adverse outcomes and increased health care costs. Managing refractoriness resulting from HLA alloimmunization necessitates the use of HLA antigen-matched platelets but requires a large platelet donor pool and does not guarantee full matching. We report the first randomized, double-blind, noninferiority, crossover trial comparing HLA epitope-matched (HEM) platelets with HLA standard antigen-matched (HSM) platelet transfusions. Alloimmunized, platelet-refractory, thrombocytopenic patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia were eligible. HEM platelets were selected using HLAMatchMaker epitope (specifically eplet) matching. Patients received up to 8 prophylactic HEM and HSM transfusions provided in random order. The primary outcome was 1-hour posttransfusion platelet count increment (PCI). Forty-nine patients were randomized at 14 UK hospitals. For intention to treat, numbers of evaluable transfusions were 107 and 112 for HEM and HSM methods, respectively. Unadjusted mean PCIs for HEM and HSM methods were 23.9 (standard deviation [SD], 15) and 23.5 (SD, 14.1), respectively (adjusted mean difference, -0.1; 95% confidence interval [CI], -2.9 to 2.8). Because the lower limit of the 95% CI was not greater than the predefined noninferiority limit, the HEM approach was declared noninferior to the HSM approach. There were no differences in secondary outcomes of platelet counts, transfusion requirements, and bleeding events. Adequate 1-hour PCI was more frequently observed, with a mean number of 3.2 epitope mismatches, compared with 5.5 epitope mismatches for inadequate 1-hour increments. For every additional epitope mismatch, the likelihood of an adequate PCI decreased by 15%. Epitope-matched platelets should be considered to support HLA alloimmunized patients. This trial was registered at www.isrctn.com as #ISRCTN23996532.

Safety assessments undertaken using the BIOMASS methodology: lessons learnt and methodological enhancements.

The International Atomic Energy Agency has coordinated an international project addressing enhancements of methods for modelling in post-closure safety assessments of solid radioactive waste disposal. The project used earlier published work from the IAEA biosphere modelling and assessment (BIOMASS) project to further develop methods and techniques. The task was supported by a parallel on-going project within the BIOPROTA forum. The output from the project is described in detail in a forthcoming IAEA report. Here an overview of the work is given to provide researchers in the broader fields of radioecology and radioactive waste disposal with a summarised review of the enhanced BIOMASS methodology and the work that has been undertaken during the project. It is hoped that such dissemination will support and promote integrated understanding and coherent treatment of the biosphere component within the overall assessment process. The key activities undertaken in the project were: review and identification of those parts of the original BIOMASS methodology that needed enhancement, discussions on lessons learned from applying the BIOMASS method, using real examples to assess the methodology and its usefulness, and writing of those parts of the methodology that were considered could benefit from refinement or for which new guidance was required to take account of scientific developments. The work has shown that the overall approach in the original BIOMASS methodology has proven sound. However, the enhanced version clarifies the need for an iterative and holistic approach with system understanding central to the approach. Specifically, experience, especially in site-specific contexts, has emphasised that adequate system understanding is essential in underpinning safety assessments for radioactive waste disposal. The integral role of the biosphere within safety assessment is also emphasised in the enhanced methodology.

Approaches to the definition of potentially exposed groups and potentially exposed populations of biota in the context of solid radioactive waste.

A methodology for addressing the biosphere in safety assessments for solid radioactive waste disposal was developed through theme 1 of the IAEA coordinated research project on BIOsphere Modelling and ASSessment (BIOMASS) that ran from 1996 to 2001. This methodology provided guidance on how the biosphere can be addressed in safety assessments for disposal of solid radioactive waste. Since the methodology was developed, it has proven useful and has been widely referenced in assessments in a diversity of contexts encompassing both near-surface and deep geological disposal of solid radioactive waste. The principles that could be adopted for defining potentially exposed groups (PEGs) were an important aspect in the original BIOMASS methodology as the endpoint of an assessment usually includes the evaluation of individual dose or risk to human health. Identification of PEGs and definition of their characteristics are usually made to be consistent with the biosphere system description being developed, acknowledging that due to inherent uncertainties in projecting future human behaviour, the biosphere models adopted for assessing safety of a disposal system can only be illustrative. Since the publication of the original BIOMASS methodology, consideration has been extended to include potentially exposed populations of biota (PEPs), in the context of dose assessment and protection of the environment. Considering the need for the development of transfer pathways from a source term to an end point (for either PEGs or PEPs), the exposure modes that may occur and those to be assessed quantitatively should be identified. Within an expert working group (WG6) of the second phase of the IAEA coordinated project Modelling and Data for Radiological Impact Assessments (MODARIA II), the experience of participating organisations has been collected on topics associated with the definition of PEGs and PEPs using a questionnaire. The objective of the questionnaire was to review the current status and on-going discussions on the handling of issues related to definitions of PEGs and PEPs as an input to the development of biosphere models for assessing radiological impacts on human health and the environment. The answers received to the questionnaire provided a clear overview of the progress that has been made since the original BIOMASS methodology was published, together with the lessons learned from the application of that methodology in the development of safety cases. This paper summarises the questionnaire responses in five subject areas: (1) environment of the PEGs and its evolution; (2) linking the choice of PEGs to these environments; (3) food habits and consumption rates; (4) populations of non-human biota (PEPs) and (5) national and international regulations and guidance. We illustrate how the results of the questionnaire have been used to enhance the original BIOMASS methodology (IAEA Enhanced BIOMASS Methodology Report in press).

Parenteral lipid emulsions induce unique ileal fatty acid and metabolomic profiles but do not increase the risk of necrotizing enterocolitis in preterm pigs.

Necrotizing enterocolitis (NEC) is a manifestation of maladaptive intestinal responses in preterm infants centrally medicated by unattenuated inflammation. Early in the postnatal period, preterm infants develop a deficit in arachidonic and docosahexaenoic acid, both potent regulators of inflammation. We hypothesized that the fatty acid composition of parenteral lipid emulsions uniquely induces blood and intestinal fatty acid profiles which, in turn, modifies the risk of NEC development. Forty-two preterm pigs were randomized to receive one of three lipid emulsions containing 100% soybean oil (SO), 15% fish oil (MO15), or 100% fish oil (FO100) with enteral feedings over an 8-day protocol. Blood and distal ileum tissue were collected for fatty acid analysis. The distal ileum underwent histologic, proteomic, and metabolomic analyses. Eight pigs [3/14 SO (21%), 3/14 MO15 (21%), and 2/14 FO100 (14%)] developed NEC. No differences in NEC risk were evident between groups despite differences in induced fatty acid profiles in blood and ileal tissue. Metabolomic analysis of NEC versus no NEC tissue revealed differences in tryptophan metabolism and arachidonic acid-containing glycerophospholipids. Proteomic analysis demonstrated no differences by lipid group; however, 15 proteins differentiated NEC versus no NEC in the domains of tissue injury, glucose uptake, and chemokine signaling. Exposure to parenteral lipid emulsions induces unique intestinal fatty acid and metabolomic profiles; however, these profiles are not linked to a difference in NEC development. Metabolomic and proteomic analyses of NEC versus no NEC intestinal tissue provide mechanistic insights into the pathogenesis of NEC in preterm infants.NEW & NOTEWORTHY Exposure to parenteral lipid emulsions induces unique intestinal fatty acid and metabolomic profiles; however, these profiles are not linked to a difference in NEC risk in preterm pigs. Metabolomic and proteomic analyses provide mechanistic insights into NEC pathogenesis. Compared with healthy ileal tissue, metabolites in tryptophan metabolism and arachidonic acid-containing glycerophospholipids are increased in NEC tissue. Proteomic analysis differentiates NEC versus no NEC in the domains of tissue injury, glucose uptake, and chemokine signaling.

Dysregulation at multiple points of the kynurenine pathway is a ubiquitous feature of renal cancer: implications for tumour immune evasion.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO), the first step in the kynurenine pathway (KP), is upregulated in some cancers and represents an attractive therapeutic target given its role in tumour immune evasion. However, the recent failure of an IDO inhibitor in a late phase trial raises questions about this strategy. METHODS: Matched renal cell carcinoma (RCC) and normal kidney tissues were subject to proteomic profiling. Tissue immunohistochemistry and gene expression data were used to validate findings. Phenotypic effects of loss/gain of expression were examined in vitro. RESULTS: Quinolate phosphoribosyltransferase (QPRT), the final and rate-limiting enzyme in the KP, was identified as being downregulated in RCC. Loss of QPRT expression led to increased potential for anchorage-independent growth. Gene expression, mass spectrometry (clear cell and chromophobe RCC) and tissue immunohistochemistry (clear cell, papillary and chromophobe), confirmed loss or decreased expression of QPRT and showed downregulation of other KP enzymes, including kynurenine 3-monoxygenase (KMO) and 3-hydroxyanthranilate-3,4-dioxygenase (HAAO), with a concomitant maintenance or upregulation of nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme in the NAD+ salvage pathway. CONCLUSIONS: Widespread dysregulation of the KP is common in RCC and is likely to contribute to tumour immune evasion, carrying implications for effective therapeutic targeting of this critical pathway.

An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma.

LESSONS LEARNED: TKM-080301 showed a favorable toxicity profile at the studied dose.TKM-080301 targeting PLK1 through small interfering RNA mechanism did not demonstrate improved overall survival in patients with advanced hepatocellular carcinoma compared with historical control. Preliminary antitumor activity as shown in this early-phase study does not support further evaluation as a single agent. BACKGROUND: Polo-like kinase 1 (PLK1) is overexpressed in hepatocellular carcinoma (HCC). Knockdown of PLK1 expression by PLK1 small interfering RNA (siRNA) in an HCC cell line showed reduced expression in RNA-induced silencing complex and a reduction in cell proliferation. METHODS: A 3 + 3 dose escalation plus expansion cohort at the maximum tolerated dose (MTD) was implemented. Patients with HCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and Child-Pugh score A received TKM-080301 as an intravenous infusion once every week for 3 consecutive weeks, repeated every 28 days. RESULTS: The study enrolled 43 patients. The starting dose of TKM-080301 was 0.3 mg/kg, and MTD was declared at 0.75 mg/kg. Following the development of grade 4 thrombocytopenia in two subjects on the expansion cohort, the MTD was redefined at 0.6 mg/kg. Four patients did not have any evaluable postbaseline scan. Of the other 39 subjects who had received at least 0.3 mg/kg, 18 subjects (46.2%) had stable disease (SD) by independent RECIST 1.1 criteria. By Choi criteria, eight subjects (23.1%) had a partial response (PR). For 37 assessable subjects, with 2 subjects censored, median progression-free survival (PFS) was 2.04 months. Median survival for the whole study population was 7.5 months. CONCLUSION: TKM-080301 was generally well tolerated. In this early-phase study, antitumor effect for TKM 080301 was limited. Further evaluation as a single agent in large randomized trials is not warranted.

Developmental Accretion of Docosahexaenoic Acid Is Independent of Fatty Acid Transporter Expression in Brain and Lung Tissues of C57BL/6 and Fat1 Mice.

BACKGROUND: Developmental expression of fatty acid transporters and their role in polyunsaturated fatty acid concentrations in the postnatal period have not been evaluated. OBJECTIVE: We hypothesized that transporter expression is developmentally regulated, tissue-specific, and that expression can modulate fatty acid accretion independently of diet. METHODS: Brain and lung transporter expression were quantified in C57BL/6 wild-type (WT) and Fat1 mice. Pups were dam-fed until day 21. Dams were fed AIN-76A 10% corn oil to represent a typical North American/European diet. After weaning, mice were fed the same diet as dams. Gene expression of Fatp1, Fatp4, Fabp5, and Fat/cd36 was quantified by quantitative reverse transcriptase-polymerase chain reaction. Fatty acid concentrations were measured by GC-MS. RESULTS: Brain docosahexaenoic acid (DHA) concentrations increased from day 3 to day 28 in both genotypes, with higher concentrations at days 3 and 14 in Fat1 than in WT mice [median (IQR)]: 10.7 (10.6-11.2) mol% compared with 6.6 (6.4-7.2) mol% and 12.5 (12.4-12.9) mol% compared with 8.9 (8.7-9.1) mol%, respectively; P < 0.05). During DHA accrual, transporter expression decreased. Fold changes in brain Fatp4, Fabp5, and Fat/cd36 were inversely correlated with fold changes in brain DHA concentrations in Fat1 relative to WT mice (ρ = -0.85, -0.75, and -0.78, respectively; P ≤ 0.001). Lung DHA concentrations were unchanged across the 3 time points for both genotypes. Despite unchanging DHA concentrations, there was increased expression of Fatp1 at days 14 and 28 (5-fold), Fatp4 at day 14 (2.3-fold), and Fabp5 at day 14 (3.8-fold) relative to day 3 in Fat1 mice. In WT mice, Fatp1 increased almost 5-fold at day 28 relative to day 3. There was no correlation between lung transporters and DHA concentrations in Fat1 relative to WT mice. CONCLUSIONS: Development of fatty acid transporter expression in C57BL/6 WT and Fat1 mice is genotype and tissue specific. Further, postnatal accretion of brain DHA appears independent of transporter status, with tissue concentrations representing dietary contributions.

PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma.

BACKGROUND: The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. METHODS: The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. DISCUSSION: The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established. TRIAL REGISTRATION: PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017). TRIAL STATUS: At the time of submission, PRISM is open to recruitment and data collection is ongoing.

Effect of polyunsaturated fatty acids on postnatal ileum development using the fat-1 transgenic mouse model.

BACKGROUND: Long-chain polyunsaturated fatty acids (LCPUFAs) play a critical role in neonatal health. We hypothesized that LCPUFAs play an essential role in priming postnatal gut development. We studied the effect of LCPUFAs on postnatal gut development using fat-1 transgenic mice, which are capable of converting n-6 to n-3 LCPUFAs, and wild-type (WT) C57BL/6 mice. METHODS: Distal ileum sections were collected from fat-1 and WT mice on days 3, 14, and 28. Fatty acid analyses, histology, RT-qPCR and intestinal permeability were performed. RESULTS: Fat-1 mice, relative to WT mice, showed increased n-3 LCPUFAs levels (α-linolenic acid, docosahexaenoic acid, and eicosapentaenoic acid, p < 0.05) and decreased arachidonic acid levels (p < 0.05) in the ileum. Preweaning fat-1 mice, compared to WT, showed >50% reduced muc2, Tff3, TLR9, and Camp expression (p < 0.05), markers of the innate immune response. There was a >two-fold increased expression of Fzd5 and EphB2, markers of cell differentiation (p < 0.05), and Fabp2 and 6, regulators of fatty acid transport and metabolism (p < 0.05). Despite reduced expression of tight junction genes, intestinal permeability in fat-1 was comparable to WT mice. CONCLUSIONS: Our data support the hypothesis that fatty acid profiles early in development modulate intestinal gene expression in formative domains, such as cell differentiation, tight junctions, other innate host defenses, and lipid metabolism.

Factors Determining Optimal Fatty Acid Absorption in Preterm Infants.

OBJECTIVES: The aim of the present study was to quantify absorption coefficients of specific fatty acids in preterm infants as a function of diet, formula or breast milk (BM), and postnatal age; to identify the fatty acid structural characteristics that determine optimal fatty acid absorption. METHODS: Fatty acids from dietary and fecal samples were extracted and quantified by gas chromatography-mass spectroscopy. Fatty acid absorption coefficients (FA-CFAs) were calculated by comparing the total amount of fatty acids supplied by the diet to the amount quantified in the total fecal output during a 3-day period. RESULTS: A total of 18 infants (BM 8, formula 10) were studied at 2 weeks of age, and 20 infants (BM 10, formula 10) were studied at 6 weeks of age. FA-CFAs decreased with increasing carbon length in formula-fed infants at 2 and 6 weeks. Results were similar but less in magnitude in BM-fed infants at 2 weeks with no difference at 6 weeks. CONCLUSIONS: Preterm infants fed formula demonstrated lower FA-CFAs as a function of increasing carbon length. This is consistent with limited pancreatic lipase production and with lipase being present in BM but not in formula. The fact that this pattern was seen in BM-fed infants at 2 weeks but not 6 weeks of age suggests that intestinal immaturity may also play a role in impaired fatty acid absorption. These data highlight principles that need to be considered to optimize delivery and absorption of dietary long-chain polyunsaturated fatty acids in preterm infants.

Standard Versus Modified Ipilimumab, in Combination With Nivolumab, in Advanced Renal Cell Carcinoma: A Randomized Phase II Trial (PRISM).

PURPOSE: Ipilimumab (IPI), in combination with nivolumab (NIVO), is an approved frontline treatment option for patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC). We conducted a randomized phase II trial to evaluate whether administering IPI once every 12 weeks (modified), instead of once every 3 weeks (standard), in combination with NIVO, is associated with a favorable toxicity profile. METHODS: Treatment-naïve patients with clear-cell aRCC were randomly assigned 2:1 to receive four doses of modified or standard IPI, 1 mg/kg, in combination with NIVO (3 mg/kg). The primary end point was the proportion of patients with a grade 3-5 treatment-related adverse event (trAE) among those who received at least one dose of therapy. The key secondary end point was 12-month progression-free survival (PFS) in the modified arm compared with historical sunitinib control. The study was not designed to formally compare arms for efficacy. RESULTS: Between March 2018 and January 2020, 192 patients (69.8% intermediate/poor-risk) were randomly assigned and received at least one dose of study drug. The incidence of grade 3-5 trAEs was significantly lower among participants receiving modified versus standard IPI (32.8% v 53.1%; odds ratio, 0.43 [90% CI, 0.25 to 0.72]; P = .0075). The 12-month PFS (90% CI) using modified IPI was 46.1% (38.6 to 53.2). At a median follow-up of 21 months, the overall response rate was 45.3% versus 35.9% and the median PFS was 10.8 months versus 9.8 months in the modified and standard IPI groups, respectively. CONCLUSION: Rates of grade 3-5 trAEs were significantly lower in patients receiving modified versus standard IPI. Although 12-month PFS did not meet the prespecified efficacy threshold compared with historical control, informal comparison of treatment groups did not suggest any reduction in efficacy with the modified schedule.

A review of the evidence on technology-based interventions for the treatment of tobacco dependence in college health.

BACKGROUND: The college years are a critical time in the development of smoking behavior and tobacco use. Smoking is linked to 30% of cancer deaths, 80% of deaths from chronic obstructive pulmonary disease, and early cardiovascular disease and death. Effective cessation interventions at this time provide an opportunity to drastically reduce premature morbidity and mortality. AIMS: To review available evidence on Internet interventions with young adults, including methodology, theoretical frameworks and outcome measures for tobacco treatment to guide the development of a program in college health. METHODS: A comprehensive literature search for studies published from January 1999 to February 2011, in multiple databases was conducted, along with hand-searching of reference lists. Inclusion criteria were: participants aged 18-30 years, intervention involved the Internet through either Web sites or e-mail or texting, and outcome measurement of tobacco cessation/abstinence. Studies were evaluated utilizing a tool synthesized from guidelines presented by the Cochrane Collaboration. FINDINGS: Eight studies met the inclusion criteria (four randomized controlled trials, four cohort studies). Theoretical frameworks utilized were the Transtheoretical Model of Change, Health Belief Model, Theory of Social Support, and social cognitive theory. Interventions varied and included computer-generated advice letters, Web-based cessation guides, computer-generated text messages, and peer e-mail support. With smoking abstinence as the primary outcome measure, there was a statistically significant improvement in quit rates. Because of the use of multiple components, differences in interventions and the number of contacts, it is not clear what types of computer-based applications are most effective. Small sample sizes, lack of control groups, and inconsistency in outcome measures limit the ability to provide conclusive evidence to support these interventions-but support the feasibility to use in the design of future programs. CONCLUSIONS: Use of technology-based interventions, such as the Internet, may be an effective tool for tobacco treatment interventions, especially with college students. There is great potential to reach large numbers of students, many who may not identify themselves as smokers or seek traditional methods for treatment. Additional research is needed to determine which technology-based interventions are most effective and to provide more conclusive evidence.

Attitudes toward health care needs and utilization of a university health center among LGBT and non-LGBT college students.

Objective: First, to examine general health care attitudes and health care utilization of a University Health Service (UHS) at a large university. Second, to identify differences between LGBT and non-LBGT students. Participants: 2,943 university students were surveyed in Spring 2013; 7.8% LGBT, 67% undergraduate and 65% female. Methods: A cross-sectional mixed-methods online survey to assess health care utilization and attitudes. Results: A majority had utilized UHS and held positive attitudes in general. LGBT students were more likely to: use UHS for ongoing care, mental health, and preventive care; report concerns about utilization (e.g. confidentiality, sensitivity, and discrimination issues); report provider discomfort discussing sexuality; and hold positive attitudes toward the health care needs of LGBT students. Conclusions: University health centers have an important role in student health. Barriers to care should be removed, including perceived discrimination. Student health center staff should be trained on LGBT health issues.

Feasibility and acceptability of continuous glucose monitoring in pregnancy for the diagnosis of gestational diabetes: A single-centre prospective mixed methods study.

BACKGROUND: Undiagnosed diabetes in pregnancy is associated with stillbirth and perinatal complications, but standard testing for gestational diabetes using the oral glucose tolerance test (OGTT) is impractical and exacerbates healthcare inequalities. There is an urgent need to improve the accuracy, acceptability and accessibility of glucose testing in pregnancy. We qualitatively assessed the feasibility and acceptability of two alternative home-based methods of glucose testing in pregnant women, using continuous glucose monitoring (CGM), with or without a home-based OGTT. METHODS: We recruited women with a singleton pregnancy at 28 weeks' gestation with ≥1 risk factor for gestational diabetes attending antenatal glucose testing. A Dexcom G6 CGM device was sited and women were asked to take a 75g OGTT solution (Rapilose) on day 4 after an overnight fast. Qualitative interviews were performed with 20 participants using video conferencing according to a semi-structured interview schedule and thematically analysed using NVIVO software. RESULTS: 92 women were recruited; 73 also underwent a home OGTT. Women had an average of 6.9 days of glucose monitoring and found the CGM painless, easy to use with few or no adverse events. During the qualitative study, the main themes identified were reassurance and convenience. All women interviewed would recommend CGM and a home OGTT for diagnosis of gestational diabetes. CONCLUSIONS: CGM with or without a home OGTT is feasible and acceptable to pregnant women for diagnosis of gestational diabetes and offered advantages of convenience and reassurance. Further work is needed to clarify diagnostic thresholds for gestational diabetes using CGM metrics.

Fatty acid concentrations in preterm infants fed the exclusive human milk diet: a prospective cohort study.

OBJECTIVE: Quantify blood fatty acids and growth outcomes in preterm infants fed the exclusive human milk diet. METHODS: A prospective cohort study of 30 infants 24-34 weeks gestation and ≤1250 g fed the exclusive human milk diet. Blood fatty acids were quantified at two time points. Comparisons were made using two-sample t-tests and Wilcoxon rank sum. RESULTS: Donor human milk-fed (n = 12) compared to mother's own milk-fed infants (n = 18) from birth to after 28 days of life, had an increased interval change of linoleic to docosahexaenoic acid ratio (5.5 vs. -1.1 mole percent ratio, p = 0.034). Docosahexaenoic and eicosapentaenoic acid interval changes were similar between groups. The arachidonic acid change was similar between groups (-2.3 vs. -0.9 mole percent, p = 0.37), however, both experienced a negative change across time. At 36 weeks postmenstrual age, growth velocities were similar for groups. CONCLUSION: An exclusive human milk diet maintains birth docosahexaenoic and eicosapentaenoic acid concentrations. However, the postnatal deficit in arachidonic acid was not prevented.

CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer.

Chronic inflammation is a well-known risk factor for cancer. Proinflammatory mediators such as prostaglandin E2 (PGE2) promote colorectal tumor growth by stimulating angiogenesis, cell invasion, and cell growth, and inhibiting apoptosis. Molecules that regulate tumor-associated angiogenesis provide promising therapeutic targets for treatment of colorectal cancer (CRC) as indicated by the recent development of the novel anti-angiogenic agent bevacizumab (Avastin). However, use of this drug only prolongs survival by several months, highlighting the importance of finding more effective treatment regimens. We report here that PGE2 induces expression of CXCL1 (growth-regulated oncogene alpha), a pro-angiogenic chemokine, in human CRC cells. More importantly, CXCL1 released from carcinoma cells induces microvascular endothelial cell migration and tube formation in vitro. Furthermore, PGE2 promotes tumor growth in vivo by induction of CXCL1 expression, which results in increased tumor microvessel formation. These results have potential clinical significance because we found that CXCL1 expression correlates with PGE2 levels in human CRCs. Collectively, our findings show for the first time that CXCL1 is regulated by PGE2 and indicate that CXCL1 inhibitors should be evaluated further as potential anti-angiogenic agents for treatment of CRC.

Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling.

Pure squamous cell carcinoma (SCC) is the most common pure variant form of bladder cancer, found in 2-5% of cases. It often presents late and is unresponsive to cisplatin-based chemotherapy. The molecular features of these tumours have not been elucidated in detail. We carried out whole-exome sequencing (WES), copy number, and transcriptome analysis of bladder SCC. Muscle-invasive bladder cancer (MIBC) samples with no evidence of squamous differentiation (non-SD) were used for comparison. To assess commonality of features with urothelial carcinoma with SD, we examined data from SD samples in The Cancer Genome Atlas (TCGA) study of MIBC. TP53 was the most commonly mutated gene in SCC (64%) followed by FAT1 (45%). Copy number analysis revealed complex changes in SCC, many differing from those in samples with SD. Gain of 5p and 7p was the most common feature, and focal regions on 5p included OSMR and RICTOR. In addition to 9p deletions, we found some samples with focal gain of 9p24 containing CD274 (PD-L1). Loss of 4q35 containing FAT1 was found in many samples such that all but one sample analysed by WES had FAT1 mutation or deletion. Expression features included upregulation of oncostatin M receptor (OSMR), metalloproteinases, metallothioneins, keratinisation genes, extracellular matrix components, inflammatory response genes, stem cell markers, and immune response modulators. Exploration of differentially expressed transcription factors identified BNC1 and TFAP2A, a gene repressed by PPARG, as the most upregulated factors. Known urothelial differentiation factors were downregulated along with 72 Kruppel-associated (KRAB) domain-containing zinc finger family protein (KZFP) genes. Novel therapies are urgently needed for these tumours. In addition to upregulated expression of EGFR, which has been suggested as a therapeutic target in basal/squamous bladder cancer, we identified expression signatures that indicate upregulated OSMR and YAP/TAZ signalling. Preclinical evaluation of the effects of inhibition of these pathways alone or in combination is merited.

Safety, pharmacokinetics, and antiviral activity of the capsid inhibitor AB-506 from Phase 1 studies in healthy subjects and those with hepatitis B.

AB-506 is a potent, pan-genotypic small molecule capsid inhibitor that inhibits hepatitis B virus (HBV) pregenomic RNA encapsidation. We assessed the safety, pharmacokinetics, and antiviral activity of AB-506 in two randomized, double-blinded Phase 1 studies in healthy subjects (HS) and subjects with chronic HBV infection (CHB). Single ascending and multiple doses of AB-506 or placebo (30-1000 mg or 400 mg daily for 10 days) were assessed in HS. AB-506 or placebo was assessed at either 160 mg or 400 mg daily for 28 days in subjects with CHB. A second follow-up study examined AB-506 or placebo at 400 mg daily for 28 days in 14 Caucasian and 14 East-Asian HS. Twenty-eight days of AB-506 at 160 mg and 400 mg produced mean HBV-DNA declines from baseline of 2.1 log10 IU/ml and 2.8 log10 IU/ml, respectively. Four subjects with CHB (all Asian) had Grade 4 alanine aminotransferase (ALT) elevations (2 at each dose) as HBV DNA was declining; three events led to treatment discontinuation. In the second follow-up study, 2 Asian HS had serious transaminitis events leading to treatment and study termination. No subjects had bilirubin elevations or signs of hepatic decompensation. Conclusion: AB-506 demonstrated mean HBV-DNA declines of >2 log10 ; however, transient but severe ALT flares were observed in 4 Asian subjects with CHB. In the follow-up study in HS, 2 additional Asian HS had Grade 4 flares, suggesting that AB-506 hepatotoxicity contributed to the ALT elevations. The AB-506 development program was terminated because of these findings.

Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities.

OBJECTIVE: To measure the changes in whole blood fatty acid levels in premature infants and evaluate associations between these changes and neonatal morbidities. STUDY DESIGN: This was a retrospective cohort study of 88 infants born at <30 weeks' gestation. Serial fatty acid profiles during the first postnatal month and infant outcomes, including chronic lung disease (CLD), retinopathy of prematurity, and late-onset sepsis, were analyzed. Regression modeling was applied to determine the association between fatty acid levels and neonatal morbidities. RESULTS: Docosahexaenoic acid (DHA) and arachidonic acid levels declined rapidly in the first postnatal week, with a concomitant increase in linoleic acid levels. Decreased DHA level was associated with an increased risk of CLD (OR, 2.5; 95% CI, 1.3-5.0). Decreased arachidonic acid level was associated with an increased risk of late-onset sepsis (hazard ratio, 1.4; 95% CI, 1.1-1.7). The balance of fatty acids was also a predictor of CLD and late-onset sepsis. An increased linoleic acid:DHA ratio was associated with an increased risk of CLD (OR, 8.6; 95% CI, 1.4-53.1) and late-onset sepsis (hazard ratio, 4.6; 95% CI, 1.5-14.1). CONCLUSION: Altered postnatal fatty acid levels in premature infants are associated with an increased risk of CLD and late-onset sepsis.