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"Brenner, Kim"
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And then comes summer
From flip-flops and hide and seek to fireworks and ice-cream trucks, there is something for everyone in this bright and buoyant celebration of the summer season.
Book
Lactobacillus Acidophilus/Bifidobacterium Infantis Probiotics Are Beneficial to Extremely Low Gestational Age Infants Fed Human Milk
Objective: To evaluate the nutrition-related effects of prophylactic Lactobacillus acidophilus/Bifidobacterium infantis probiotics on the outcomes of preterm infants <29 weeks of gestation that receive human milk and/or formula nutrition. We hypothesize that human-milk-fed infants benefit from probiotics in terms of sepsis prevention and growth. Methods: We performed an observational study of the German Neonatal Network (GNN) over a period of six years, between 1 January, 2013 and 31 December, 2018. Prophylactic probiotic use of L. acidophilus/B. infantis was evaluated in preterm infants <29 weeks of gestation (n = 7516) in subgroups stratified to feeding type: (I) Exclusively human milk (HM) of own mother and/or donors (HM group, n = 1568), (II) HM of own mother and/or donor and formula (Mix group, n = 5221), and (III) exclusive exposure to formula (F group, n = 727). The effect of probiotics on general outcomes and growth was tested in univariate models and adjusted in linear/logistic regression models. Results: 5954 (76.5%) infants received L. acidophilus/B. infantis prophylactically for the prevention of necrotizing enterocolitis (NEC). Probiotic use was associated with improved growth measures in the HM group (e.g., weight gain velocity in g/day: effect size B = 0.224; 95% CI: 2.82–4.35; p < 0.001) but not in the F group (effect size B = −0.06; 95% CI: −3.05–0.28; p = 0.103). The HM group had the lowest incidence of clinical sepsis (34.0%) as compared to the Mix group (35.5%) and the F group (40.0%). Only in the Mix group, probiotic supplementation proved to be protective against clinical sepsis (OR 0.69; 95% CI: 0.59–0.79; p < 0.001). Conclusion: Our observational data indicate that the exposure to L. acidophilus/B. infantis probiotics may promote growth in exclusively HM-fed infants as compared to formula-fed infants. To exert a sepsis-preventive effect, probiotics seem to require human milk.
Journal Article
My son got help
I now volunteer with Parents for Children's Mental Health, as well as speak for Ad-Vox Wellington, a group that is Adding Voices together for children's mental health. Thank you for making people aware of this important issue.
Newspaper Article
Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
Background
In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours.
Methods
Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles.
Results
Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m
2
for hepatocellular carcinoma (HCC) and 93 mg/m
2
for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11–55).
Conclusion
MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy.
Clinical trial registration
NCT01829971.
Journal Article
Genomic Loss of microRNA-101 Leads to Overexpression of Histone Methyltransferase EZH2 in Cancer
Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and regulates the survival and metastasis of cancer cells. EZH2 is overexpressed in aggressive solid tumors by mechanisms that remain unclear. Here we show that the expression and function of EZH2 in cancer cell lines are inhibited by microRNA-101 (miR-101). Analysis of human prostate tumors revealed that miR-101 expression decreases during cancer progression, paralleling an increase in EZH2 expression. One or both of the two genomic loci encoding miR-101 were somatically lost in 37.5% of clinically localized prostate cancer cells (6 of 16) and 66.7% of metastatic disease cells (22 of 33). We propose that the genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.
Journal Article
Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors
Summary
Purpose
Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors.
Patients and Methods
Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles.
Results
Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC;
n
= 14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1–12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3%: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3%/G4%: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m
2
, with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m
2
. The half-life was >24 h, and C
max
and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles.
Conclusion
MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m
2
for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules of MRX34 have been explored to improve tolerability.
Journal Article
Lymphocyte innateness defined by transcriptional states reflects a balance between proliferation and effector functions
How innate T cells (ITC), including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells, maintain a poised effector state has been unclear. Here we address this question using low-input and single-cell RNA-seq of human lymphocyte populations. Unbiased transcriptomic analyses uncover a continuous ‘innateness gradient’, with adaptive T cells at one end, followed by MAIT, iNKT, γδ T and natural killer cells at the other end. Single-cell RNA-seq reveals four broad states of innateness, and heterogeneity within canonical innate and adaptive populations. Transcriptional and functional data show that innateness is characterized by pre-formed mRNA encoding effector functions, but impaired proliferation marked by decreased baseline expression of ribosomal genes. Together, our data shed new light on the poised state of ITC, in which innateness is defined by a transcriptionally-orchestrated trade-off between rapid cell growth and rapid effector function.
Innate T cells (ITC) contain many subsets and are poised to promptly respond to antigens and pathogens, but how this poised state is maintained is still unclear. Here the authors perform single-cell RNA-seq to align the various ITC subsets along an ‘innateness gradient’ that is associated with changes in proliferation and effector functions.
Journal Article
Dysglycemia and the airway microbiome in cystic fibrosis
Cystic fibrosis-related diabetes (CFRD) is one of the most common non-pulmonary complications in people living with cystic fibrosis (pwCF), seen in up to 50% of adults. Even when correcting for severity of CFTR mutations, those with CFRD have more pulmonary exacerbations, lower lung function, and increased mortality than those with normal glucose tolerance (NGT).
Expectorated sputum samples were collected from 63 pwCF during routine outpatient visits (29 with CFRD, 12 with IGT and 22 with NGT). Oral glucose tolerance test results, A1c levels, and pulmonary function tests closest to the time of sputum collection were obtained from the medical record. Samples underwent metagenomics sequencing and raw reads were processed through the bioBakery workflow for taxonomic profiling at the species level as well as predicted functional profiling and antibiotic resistance profiling. Viral profiling was performed with Marker-MAGu. Differences in alpha diversity, beta diversity, and differential abundance were assessed. Microbiome and phage signatures of CFRD were generated using sparse partial least squares models which were subsequently used as a primary predictor of lung function using multivariate linear regression.
In linear models, CFRD status compared to NGT was associated with a lower alpha diversity (reciprocal Simpson -1.98 [-3.80,-0.16], p = 0.033) and differences in microbial community composition (Bray Curtis dissimilarity PERMANOVA R2 0.17, p = 0.011). Pseudomonas aeruginosa and Streptococcus gordonii had higher relative abundance in CRFD vs NGT participants (2.43 [0.027, 4.82], unadjusted p = 0.056 and 1.11 [0.58, 1.64] unadjusted p= < .001 respectively). There were global differences between CFRD vs NGT in both functional pathways and antibiotic resistance genes. In multivariate models adjusting for age, sex, antibiotic use, and modulator therapies, virome but not microbiome signatures of CFRD were associated with lower FEV1 percent predicted (-6.4 [95% CI -10.2, -2.6]%, p = 0.001 for each 10% increase in virome score).
Differences in the airway microbiome in those with dysglycemia in CF are associated with poorer lung function.
Journal Article
Ultrafast orbital tomography of a pentacene film using time-resolved momentum microscopy at a FEL
Time-resolved momentum microscopy provides insight into the ultrafast interplay between structural and electronic dynamics. Here we extend orbital tomography into the time domain in combination with time-resolved momentum microscopy at a free-electron laser (FEL) to follow transient photoelectron momentum maps of excited states of a bilayer pentacene film on Ag(110). We use optical pump and FEL probe pulses by keeping FEL source conditions to minimize space charge effects and radiation damage. From the momentum microscopy signal, we obtain time-dependent momentum maps of the excited-state dynamics of both pentacene layers separately. In a combined experimental and theoretical study, we interpret the observed signal for the bottom layer as resulting from the charge redistribution between the molecule and the substrate induced by excitation. We identify that the dynamics of the top pentacene layer resembles excited-state molecular dynamics.
Ultrafast pulses are useful to investigate the electron dynamics in excited atoms, molecules and other complex systems. Here, the authors measure transient photoelectron momentum maps following the free-electron laser pulse-induced ionization of a bilayer pentacene thin film on Ag (110) by using time-resolved orbital tomography.
Journal Article
Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression
Overexpression of histone deacetylases (HDACs) in cancer commonly causes resistance to genotoxic-based therapies. Here, we report on the novel mechanism whereby overexpressed class I HDACs increase the resistance of glioblastoma cells to the S
N
1 methylating agent temozolomide (TMZ). The chemotherapeutic TMZ triggers the activation of the DNA damage response (DDR) in resistant glioma cells, leading to DNA lesion bypass and cellular survival. Mass spectrometry analysis revealed that the catalytic activity of class I HDACs stimulates the expression of the E3 ubiquitin ligase RAD18. Furthermore, the data showed that RAD18 is part of the
O
6
-methylguanine-induced DDR as TMZ induces the formation of RAD18 foci at sites of DNA damage. Downregulation of RAD18 by HDAC inhibition prevented glioma cells from activating the DDR upon TMZ exposure. Lastly, RAD18 or
O
6
-methylguanine-DNA methyltransferase (MGMT) overexpression abolished the sensitization effect of HDAC inhibition on TMZ-exposed glioma cells. Our study describes a mechanism whereby class I HDAC overexpression in glioma cells causes resistance to TMZ treatment. HDACs accomplish this by promoting the bypass of
O
6
-methylguanine DNA lesions via enhancing RAD18 expression. It also provides a treatment option with HDAC inhibition to undermine this mechanism.
Journal Article