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Paracrine effects of TLR4-polarised mesenchymal stromal cells are mediated by extracellular vesicles. - Journal of translational medicine
Mesenchymal stromal cells (MSCs) are adult stem cells able to give rise to bone, cartilage and fat cells. In addition, they possess immunomodulatory and immunosuppressive properties that are mainly mediated through secretion of extracellular vesicles (EVs). In a previous issue of Journal of Translational Medicine, Ti and colleagues demonstrated that preconditioning of MSCs with bacterial lipopolysaccharides results in secretion of EVs that can polarise macrophages towards anti-inflammatory M2 phenotype. Moreover, the authors suggest that EVs of â€‹lipopolysaccharide (LPS)-treated MSCs are superior to EVs of untreated MSCs concerning their ability to support wound healing. Our commentary critically discusses parallel efforts of other laboratories to generate conditioned media from stem cells for therapeutic applications, and highlights impact and significance of the study of Ti et al. Finally, we summarise its limitations and spotlight areas that need to be addressed to better define the underlying molecular mechanisms.
Evaluation of Skin Penetration of Diclofenac from a Novel Topical Non Aqueous Solution: A Comparative Bioavailability Study. - Journal of clinical and diagnostic research : JCDR
Different topical formulations of diclofenac have varying skin penetration profile. Recent advances in science and technology has led to the development of many new formulations of drugs for topical drug delivery. One such technological development has led to the innovation of Dynapar QPS, a novel, non-aqueous, quick penetrating solution (QPS) of diclofenac diethylamine.This study was aimed to measure the total exposure from the drug penetrating the skin in healthy human subjects and comparing the relative systemic bioavailability of Dynapar QPS(Â®) with diclofenac emulgel.A 200 mg of diclofenac from either Dynapar QPS(Â®) (5 ml) or emulgel (20 g) was applied on back of subject as per the randomisation schedule. Blood samples were collected up to 16 hours post drug application. Plasma concentration of diclofenac was measured by pre-validated HPLC method. Pharmacokinetic (PK) parameters like Cmax, Tmax, t1/2, AUC0-t, AUC0-âˆž, and Kel, of diclofenac were determined for both the formulations.Mean Cmax after administration of Dynapar QPS(Â®) and diclofenac emulgel were 175.93 and 40.04 ng/ml, respectively. Tmax of diclofenac was almost half with QPS compared to emulgel (5.24 hrs versus 9.53 hrs respectively). The mean AUC0-t and AUC0-âˆž after administration of Dynapar QPS(Â®) was higher as compared to diclofenac emulgel (AUC0-t: 1224.19 versus 289.78 ng.h/ml, respectively; AUC0-âˆž: 1718.21 versus 513.83 ng.h/ml, respectively). None of the subject experienced any adverse event during the study.The results indicate an enhanced penetration and subsequent absorption of diclofenac from Dynapar QPS(Â®) as compared to diclofenac emulgel. Higher penetration is likely to translate into better pain relief in patients.
Radiation and breast reconstruction: Algorithmic approach and evidence-based outcomes. - Journal of surgical oncology
Postmastectomy radiation (PMRT) in the setting of immediate breast reconstruction has been associated with increased complications and poorer aesthetic outcomes for both autologous and implant reconstructions. Many centers have attempted to mitigate the deleterious effects associated with radiation by implementing an algorithmic approach to breast reconstruction. Although the literature regarding the optimal timing of radiotherapy and breast reconstruction remains controversial, reported outcomes following various algorithms have been encouraging and warrant further consideration. J. Surg. Oncol. Â© 2016 Wiley Periodicals, Inc.Â© 2016 Wiley Periodicals, Inc.
Tumor neovasculature-targeted cationic PEGylated liposomes of gambogic acid for the treatment of triple-negative breast cancer. - Drug delivery
Gambogic acid (GA) is a naturally derived potent anticancer agent with extremely poor aqueous solubility. In the present study, positively charged PEGylated liposomal formulation of GA (GAL) was developed for parenteral delivery for the treatment of triple-negative breast cancer (TNBC). The GAL was formulated with a particle size of 107.3â€‰Â±â€‰10.6â€‰nm withâ€‰+32â€‰mV zeta potential. GAL showed very minimal release of GA over 24 h period confirming the non-leakiness and stability of liposomes. In vitro cytotoxicity assays showed similar cell killing with GA and GAL against MDA-MB-231 cells but significantly higher inhibition of HUVEC growth was observed with GAL. Furthermore, GAL significantly (pâ€‰<â€‰0.05) inhibited the MDA-MB-231 orthotopic xenograft tumor growth withâ€‰>50% reduction of tumor volume and reduction in tumor weight by 1.7-fold and 2.2-fold when compared to GA and controls, respectively. Results of western blot analysis indicated that GAL significantly suppressed the expression of apoptotic markers, bcl2, cyclinD1, survivin and microvessel density marker-CD31 and increased the expression of p53 and Bax compared to GA and control. Collectively, these data provide further support for the potential applications of cationic GAL in its intravenous delivery and its significant role in inhibiting angiogenesis against TNBC.
Investigating mechanisms underpinning the detrimental impact of a high-fat diet in the developing and adult hypermuscular myostatin null mouse. - Skeletal muscle
Obese adults are prone to develop metabolic and cardiovascular diseases. Furthermore, over-weight expectant mothers give birth to large babies who also have increased likelihood of developing metabolic and cardiovascular diseases. Fundamental advancements to better understand the pathophysiology of obesity are critical in the development of anti-obesity therapies not only for this but also future generations. Skeletal muscle plays a major role in fat metabolism and much work has focused in promoting this activity in order to control the development of obesity. Research has evaluated myostatin inhibition as a strategy to prevent the development of obesity and concluded in some cases that it offers a protective mechanism against a high-fat diet.Pregnant as well as virgin myostatin null mice and age matched wild type animals were raised on a high fat diet for up to 10 weeks. The effect of the diet was tested on skeletal muscle, liver and fat. Quantitate PCR, Western blotting, immunohistochemistry, in-vivo and ex-vivo muscle characterisation, metabonomic and lipidomic measurements were from the four major cohorts.We hypothesised that myostatin inhibition should protect not only the mother but also its developing foetus from the detrimental effects of a high-fat diet. Unexpectedly, we found muscle development was attenuated in the foetus of myostatin null mice raised on a high-fat diet. We therefore re-examined the effect of the high-fat diet on adults and found myostatin null mice were more susceptible to diet-induced obesity through a mechanism involving impairment of inter-organ fat utilization.Loss of myostatin alters fatty acid uptake and oxidation in skeletal muscle and liver. We show that abnormally high metabolic activity of fat in myostatin null mice is decreased by a high-fat diet resulting in excessive adipose deposition and lipotoxicity. Collectively, our genetic loss-of-function studies offer an explanation of the lean phenotype displayed by a host of animals lacking myostatin signalling.
Primary Gallbladder Lymphoma in a Male Patient with No Risk Factors Detected Incidentally by CT Colonography. - Case reports in surgery
Primary gallbladder lymphoma, although rare, usually presents in females with symptoms mimicking cholecystitis. We present a rare case of primary gallbladder in an 81-year-old male with no risk factors whose only symptom was weight loss. Routine blood tests including liver function tests were unremarkable. A CT colonography was carried out to exclude colonic malignancy. Unilateral gallbladder wall thickening and lymphadenopathy were incidentally detected and confirmed by ultrasound and a decision for the patient to undergo laparoscopic cholecystectomy and intraoperative cholangiogram was made. Histology confirmed extranodal marginal zone lymphoma with follow-up staging and biopsy of the bone marrow not demonstrating spread. Cholecystectomy was therefore deemed curative and no adjuvant therapy was necessary. Thickening of the gallbladder wall on any imaging with or without symptoms should not be ignored or assumed to be cholecystitis, even in males with no risk factors. In these patients urgent cholecystectomy with intraoperative cholangiogram is indicated with histology and haematology follow-up.
Prevalence and distribution of soil-borne zoonotic pathogens in Lahore district of Pakistan. - Frontiers in microbiology
A multidisciplinary, collaborative project was conducted to determine the prevalence and distribution of soil-borne zoonotic pathogens in Lahore district of Pakistan and ascertain its Public Health Significance. Using a grid-based sampling strategy, soil samples (n = 145) were collected from villages (n = 29, 5 samples/village) and examined for Bacillus anthracis, Burkholderia mallei/pseudomallei, Coxiella burnetii, Francisella tularensis, and Yersinia pestis using real time PCR assays. Chemical analysis of soil samples was also performed on these samples. The relationship between soil composition and absence or presence of the pathogen, and seven risk factors was evaluated. DNA of B. anthracis (CapB), B. mallei/pseudomallei (chromosomal gene), C. burnetii (IS1111, transposase gene), and F. tularensis (lipoprotein/outer membrane protein) was detected in 9.6, 1.4, 4.8, and 13.1% of soil samples, respectively. None of the samples were positive for protective antigen plasmid (PA) of B. anthracis and Y. pestis (plasminogen activating factor, pPla gene). The prevalence of B. anthracis (CapB) was found to be associated with organic matter, magnesium (Mg), copper (Cu), chromium (Cr), manganese (Mn), cobalt (Co), cadmium (Cd), sodium (Na), ferrous (Fe), calcium (Ca), and potassium (K). Phosphorous (P) was found to be associated with prevalence of F. tularensis while it were Mg, Co, Na, Fe, Ca, and K for C. burnetii. The odds of detecting DNA of F. tularensis were 2.7, 4.1, and 2.7 higher when soil sample sites were >1 km from animal markets, >500 m from vehicular traffic roads and animal density of < 1000 animals, respectively. While the odds of detecting DNA of C. burnetii was 32, 11.8, and 5.9 higher when soil sample sites were >500 m from vehicular traffic roads, presence of ground cover and animal density of < 1000 animals, respectively. In conclusion, the distribution pattern of the soil-borne pathogens in and around the areas of Lahore district puts both human and animal populations at a high risk of exposure. Further studies are needed to explore the genetic nature and molecular diversity of prevailing pathogens together with their seroconversion in animals and humans.
Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen. - Molecular cell
Endogenous formaldehyde is produced by numerous biochemical pathways fundamental to life, and it can crosslink both DNA and proteins. However, the consequences of its accumulation are unclear. Here we show that endogenous formaldehyde is removed by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), and Adh5(-/-) mice therefore accumulate formaldehyde adducts in DNA. The repair of this damage is mediated by FANCD2, a DNA crosslink repair protein. Adh5(-/-)Fancd2(-/-) mice reveal an essential requirement for these protection mechanisms in hematopoietic stem cells (HSCs), leading to their depletion and precipitating bone marrow failure. More widespread formaldehyde-induced DNA damage also causes karyomegaly and dysfunction of hepatocytes and nephrons. Bone marrow transplantation not only rescued hematopoiesis but, surprisingly, also preserved nephron function. Nevertheless, all of these animals eventually developed fatal malignancies. Formaldehyde is therefore an important source of endogenous DNA damage that is counteracted in mammals by a conserved protection mechanism.Copyright Â© 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Piperlongumine for Enhancing Oral Bioavailability and Cytotoxicity of Docetaxel in Triple-Negative Breast Cancer. - Journal of pharmaceutical sciences
Very low oral bioavailability due to extensive pre-systemic metabolism and P-gp efflux has constrained the oral metronomic chemotherapy of docetaxel (DTX). There is tremendous need of compounds facilitating oral delivery of DTX. The research was aimed to investigate the effect of piperlongumine (PPL) on human liver microsomal metabolism, Caco-2 permeability, and cytotoxicity of DTX in triple-negative breast cancer cell lines. Reduction in testosterone and DTX metabolism (twofold increase in half-life) by PPL was comparable to the standard CYP3A4 inhibitor, cyclosporine A. P-gp efflux ratio of DTX across caco-2 monolayer was reduced from 2.37 to 1.52 on co-incubation with PPL. The IC50 value of DTX was reduced three to five times and combination index values in all the cell lines were below 0.6. PPL at non-cytotoxic concentration showed significant enhancement of the antimigration effect of DTX. Expression of tumor markers such as survivin, bcl2, C-myc, and cyclin D1 were downregulated to a great extent with enhanced p53 expression when treated with combination instead of individual drug. Co-treatment with PPL led to 1.68-fold enhancement in DTX bioavailability in SD rats. PPL could be a potential candidate in overcoming the obstacles associated with oral DTX delivery with synergistic anticancer activity. Â© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:4417-4426, 2015.Â© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
Breast reconstruction and adjuvant therapy: A systematic review of surgical outcomes. - Journal of surgical oncology
The impact of adjuvant therapy on the surgical outcomes following breast reconstruction is poorly understood. The purpose of this systematic review was to evaluate surgical outcomes following autologous and prosthetic reconstruction in the setting of post-mastectomy radiation therapy (PMRT) and adjuvant chemotherapy.A systematic review of the English literature published from 2000 to 2015 in the Pubmed/MEDLINE database was performed to identify all manuscripts reporting outcome of breast reconstruction in patients receiving PMRT and/or adjuvant chemotherapy.Sixty-two manuscripts met the criteria for inclusion. This included 56 manuscripts (5437 patients) evaluating patients treated with PMRT and 11 manuscripts (820 patients) evaluating patients treated with chemotherapy. Pooled analysis of the PMRT cohort revealed significantly higher weighted incidences of re-operation (Pâ€‰<â€‰0.0001), total complications (Pâ€‰<â€‰0.0001), and reconstructive failure (Pâ€‰<â€‰0.0001) in prosthetic reconstruction compared to autologous. There was little evidence to suggest that postoperative chemotherapy is associated with poorer overall outcomes.PMRT was associated with an increased incidence of adverse events when compared to chemotherapy. There was little evidence to suggest that adverse events following breast reconstruction were related to adjuvant chemotherapy. Manipulating the method and timing of reconstruction may mitigate some of the undesirable outcomes associated with PMRT.Â© 2015 Wiley Periodicals, Inc.
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