Chemotherapy-induced weight gain in early-stage breast cancer: a prospective matched cohort study reveals associations with inflammation and gut dysbiosis.

Background: Early-stage breast cancer patients treated with chemotherapy risk the development of metabolic disease and weight gain, which can result in increased morbidity and reduced quality of life in survivorship. We aimed to analyze changes within the gastrointestinal microbiome of early-stage breast cancer patients treated with and without chemotherapy to investigate a potential relationship between dysbiosis, a systemic inflammatory response, and resultant anthropomorphic changes.

Methods: We undertook an a priori analysis of serially collected stool and plasma samples from 40 patients with early-stage breast cancer who underwent adjuvant endocrine therapy only, adjuvant chemotherapy only, or both.

Normoxic low-altitude simulation (at 714 mmHg) improves limb blood perfusion in mice with hindlimb ischemia.

Humans have fewer cardiovascular events and improved outcomes after cardiovascular events when living at low and moderate altitudes (<3000 m) above sea level. We have previously shown that low-altitude simulation using reductions in barometric pressure enhances vasodilation ex vivo in arterial segments and reduces systemic vascular resistance in vivo and can also improve left ventricular function after a myocardial infarction. We hypothesize that low-altitude simulation could also improve hindlimb ischemia, a model of peripheral artery disease in humans.

Low altitude simulation without hypoxia improves left ventricular function after myocardial infarction by reducing ventricular afterload.

Humans have a lower risk of death from myocardial infarction (MI) living at low elevations (<2500 m), which are not high enough to induce hypoxia. Both chronic hypoxia pre-MI, achieved by altitude simulation >5000 m, and intermittent hypobaric hypoxia post-MI can reduce MI size in rodents, and it is believed that hypoxia is the key stimulus. To explore mechanisms beyond hypoxia we studied whether altitude simulation <2500 m would also be associated with reduced infarct size.

A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation.

DNA transcription, replication, and repair are regulated by histone acetylation, a process that requires the generation of acetyl-coenzyme A (CoA). Here, we show that all the subunits of the mitochondrial pyruvate dehydrogenase complex (PDC) are also present and functional in the nucleus of mammalian cells. We found that knockdown of nuclear PDC in isolated functional nuclei decreased the de novo synthesis of acetyl-CoA and acetylation of core histones.

Attenuating endoplasmic reticulum stress as a novel therapeutic strategy in pulmonary hypertension.

Background: Evidence suggestive of endoplasmic reticulum (ER) stress in the pulmonary arteries of patients with pulmonary arterial hypertension has been described for decades but has never been therapeutically targeted. ER stress is a feature of many conditions associated with pulmonary arterial hypertension like hypoxia, inflammation, or loss-of-function mutations. ER stress signaling in the pulmonary circulation involves the activation of activating transcription factor 6, which, via induction of the reticulin protein Nogo, can lead to the disruption of the functional ER-mitochondria unit and the increasingly recognized cancer-like metabolic shift in pulmonary arterial hypertension that promotes proliferation and apoptosis resistance in the pulmonary artery wall.

Osmolarity affects Bvg-mediated virulence regulation by Bordetella pertussis.

Bordetella pertussis dramatically alters its phenotype by sensing its environment via the BvgAS regulatory system. Increased concentrations of specific chemicals are used in vitro to induce modulation of the bacterium from the Bvg(+) virulent phenotype to a fully Bvg(-) phenotype. Varied expression of sets of Bvg(-)regulated molecules depends on the modulating capacity of the environment.

Bordetella pertussis risA, but not risS, is required for maximal expression of Bvg-repressed genes.

Expression of virulence determinants by Bordetella pertussis, the primary etiological agent of whooping cough, is regulated by the BvgAS two-component regulatory system. The role of a second two-component regulatory system, encoded by risAS, in this process is not defined. Here, we show that mutation of B.

Reduced glutathione is required for pertussis toxin secretion by Bordetella pertussis.

The abilities of cysteine-containing compounds to support growth of Bordetella pertussis and influence pertussis toxin transcription, assembly, and secretion were examined. Cysteine is an essential amino acid for B. pertussis and must be present for protein synthesis and bacterial growth.

DsbA and DsbC are required for secretion of pertussis toxin by Bordetella pertussis.

The Dsb family of enzymes catalyzes disulfide bond formation in the gram-negative periplasm, which is required for folding and assembly of many secreted proteins. Pertussis toxin is arguably the most complex toxin known: it is assembled from six subunits encoded by five genes (for subunits S1 to S5), with 11 intramolecular disulfide bonds. To examine the role of the Dsb enzymes in assembly and secretion of pertussis toxin, we identified and mutated the Bordetella pertussis dsbA, dsbB, and dsbC homologues.