Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors—inexpensive drugs with decades of safe use—could be rapidly repurposed as cancer therapeutics.National Cancer Institute (U.S.) (Grant P01-CA080124)National Cancer Institute (U.S.) (Grant R01-CA126642)National Cancer Institute (U.S.) (Grant R01-CA085140)National Cancer Institute (U.S.) (Grant R01-CA115767)National Cancer Institute (U.S.) (Grant R01-CA098706)United States. Dept. of Defense. Breast Cancer Research Program (Innovator Award W81XWH-10-1-0016)Lustgarten Foundation (Dana-Farber Cancer Institute/David H. Koch Institute for Integrative Cancer Research at MIT Bridge Project Grant

Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients

Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning

Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics

Physiologic and environmental factors can modulate antibiotic activity and thus pose a significant challenge to antibiotic treatment. The quinolone class of antibiotics, which targets bacterial topoisomerases, fails to kill bacteria that have grown to high density; however, the mechanistic basis for this persistence is unclear. Here, we show that exhaustion of the metabolic inputs that couple carbon catabolism to oxidative phosphorylation is a primary cause of growth phase-dependent persistence to quinolone antibiotics. Supplementation of stationary-phase cultures with glucose and a suitable terminal electron acceptor to stimulate respiratory metabolism is sufficient to sensitize cells to quinolone killing. Using this approach, we successfully sensitize high-density populations of Escherichia coli, Staphylococcus aureus, and Mycobacterium smegmatis to quinolone antibiotics. Our findings link growth-dependent quinolone persistence to discrete impairments in respiratory metabolism and identify a strategy to kill non-dividing bacteria. Gutierrez et al. show that activation of cellular respiration is sufficient to sensitize antibiotic refractory bacteria at high densities to drugs targeting DNA topoisomerases. This suggests that the nutrient environment and metabolic state are key components of bacterial persistence phenotypes. Keywords: quinolones; drug persistence; antibiotic; oxidative phosphorylationDefense Threat Reduction Agency (DTRA) (Grant HDTRA1-15-1-0051

Combined Technologies for Microfabricating Elastomeric Cardiac Tissue Engineering Scaffolds

Polymer scaffolds that direct elongation and orientation of cultured cells can enable tissue engineered muscle to act as a mechanically functional unit. We combined micromolding and microablation technologies to create muscle tissue engineering scaffolds from the biodegradable elastomer poly(glycerol sebacate). These scaffolds exhibited well defined surface patterns and pores and robust elastomeric tensile mechanical properties. Cultured C2C12 muscle cells penetrated the pores to form spatially controlled engineered tissues. Scanning electron and confocal microscopy revealed muscle cell orientation in a preferential direction, parallel to micromolded gratings and long axes of microablated anisotropic pores, with significant individual and interactive effects of gratings and pore design.Micropatterning and microablation technologies were combined in the context of the biodegradable elastomer PGS to create a muscle tissue engineering scaffold. Scaffolds enabled cultured muscle cells to preferentially align in parallel to linear gratings and pore edges, with significant individual and interactive effects of surface topography and anisotropic pore design. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.American Recovery and Reinvestment Act - ARRA (1-R01-HL086521-01A2)NIH (DE013023)NSF (BES-0609182

Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors

The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.National Institutes of Health (U.S.) (Grant P01CA08012)National Institutes of Health (U.S.) (Grant R01CA126642

Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage

Understanding how antibiotics impact bacterial metabolism may provide insight into their mechanisms of action and could lead to enhanced therapeutic methodologies. Here, we profiled the metabolome of Escherichia coli after treatment with three different classes of bactericidal antibiotics (β-lactams, aminoglycosides, quinolones). These treatments induced a similar set of metabolic changes after 30 min that then diverged into more distinct profiles at later time points. The most striking changes corresponded to elevated concentrations of central carbon metabolites, active breakdown of the nucleotide pool, reduced lipid levels, and evidence of an elevated redox state. We examined potential end-target consequences of these metabolic perturbations and found that antibiotic-treated cells exhibited cytotoxic changes indicative of oxidative stress, including higher levels of protein carbonylation, malondialdehyde adducts, nucleotide oxidation, and double-strand DNA breaks. This work shows that bactericidal antibiotics induce a complex set of metabolic changes that are correlated with the buildup of toxic metabolic by-products

Depression in Childhood Asthma vs. Adult-Onset Asthma: A Cross-Sectional Study from the National Health and Nutrition Examination Survey (NHANES).

BACKGROUND: asthma, a chronic respiratory disease caused by inflammation and narrowing of the small airways in the lungs, is the most common chronic childhood disease. Prevalence of childhood asthma in the United States is 5.8%. In boys, prevalence is 5.7% and it is 6% in girls. Asthma is associated with other comorbidities such as major depressive disorder and anxiety disorder. This study explores the association between asthma and depression. METHODS: we conducted a retrospective cross-sectional study using NHANES data from 2013 to 2018. Asthma and childhood onset asthma were assessed using questionnaires MCQ010 and MCQ025, respectively. Sociodemographic variables were summarized, and univariate analysis was performed to determine the association between asthma and major depressive disorder and its individual symptoms. RESULTS: there were 402,167 participants from 2013-2018 in our study: no asthma in 84.70%; asthma in 15.30%. Childhood onset asthma (COA) included 10.51% and adult-onset asthma (AOA) included 4.79%. Median age of COA is 5 years and AOA is 41 years. Among the asthma groups, most AOA were females (67.77%, CONCLUSION: MDD and related symptoms were significantly higher and more severe in participants with asthma compared to no asthma. Between adult-onset asthma compared to childhood onset asthma, adult-onset asthma had slightly greater and more severe MDD and related symptoms compared to childhood onset asthma