Nonparetic Knee Extensor Strength Is the Determinant of Exercise Capacity of Community-Dwelling Stroke Survivors

Objective. To investigate the relationship among walking speed, exercise capacity, and leg strength in community dwelling stroke subjects and to evaluate which one was the leading determinant factor of them. Design. This is a descriptive, cross-sectional study. Thirty-five chronic stroke patients who were able to walk independently in their community were enrolled. Walking speed was evaluated by using the 12-meter walking test. A maximal exercise test was used to determine the stroke subjects’ exercise capacity. Knee extensor strength, measured as isokinetic torque, was assessed by isokinetic dynamometer. Results. The main walking speed of our subjects was 0.52 m/s. Peak oxygen uptake (VO2 peak) was 1.21±0.43 L/min. Knee extensor strength, no matter whether paretic or nonparetic side, was significantly correlated to 12-meter walking speed and exercise capacity. Linear regression also showed the strength of the affected knee extensor was the determinant of walking speed and that of the nonparetic knee extensor was the determinant of exercise capacity in community dwelling stroke subjects. Conclusions. Walking speed and peak oxygen uptake were markedly decreased after stroke. Knee extensor strength of nonparetic leg was the most important determinant of exercise capacity of the community-dwelling stroke subjects. Knee extensor strengthening should be emphasized to help stroke patient to achieve optimal community living

GPER-induced signaling is essential for the survival of breast cancer stem cells.

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER- /PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs

Superior Mesenteric Artery Syndrome: A Single-institution Experience

Background:Superior mesenteric artery syndrome (SMAS) is a rare disease in adult. SMAS is characterized by acute, or, more commonly, chronic nonspecific symptoms due to duodenal obstruction and severe malnutrition with reduced arterio-mesenteric angle and distance. Surgical treatment may be necessary in most cases with chronic symptoms or when conservative treatment fails in SMAS.Methods:A retrospective chart review was performed on patients who underwent operation for SMAS from January 2008 to August 2020 in Cardinal Tien Hospital. Patients’ clinical presentations, surgical intervention, and outcomes.Results:Data from a total of 14 patients diagnosed with SMAS were analyzed, of which seven were diagnosed with SMAS by abdominal computed tomography and upper gastrointestinal series with water-soluble barium contrast. Six of the confirmed cases underwent surgery, namely, gastric decompression using a nasogastric tube, andcorrection of electrolyte imbalance. The nasoduodenal tube was placed through the obstructed duodenum to provide a high-nutrient fluid supplement. After conservative treatment failure, the patients underwent surgery. Of the six patients, four underwent duodenojejunostomy, one underwent a mini-laparotomy duodenojejunostomy bypass, and the last one underwent Roux-en-Y duodenojejunal bypass with duodenal feeding tube insertion.Conclusion:Patients with SMAS should initially be treated conservative. Surgical intervention should be considered in patients in whom conservative treatments were not effective.Complete resolution of all symptoms may not always be guaranteed after surgical intervention. Laparoscopy is currently widely used. In well-selected patients, minimally invasive or mini-laparotomy duodenojejunostomy is a safe and effective treatment for SMAS. The main advantages of mini-laparotomy duodenojejunostomy over other surgical approaches include half-length surgical incision and a shorter operative time. Duodenojejunostomy is rapidly becoming the standard procedure of this condition, and it has excellent outcomes comparable with those of open surgery

Crystal structure of IcaR, a repressor of the TetR family implicated in biofilm formation in Staphylococcus epidermidis

Expression of the gene cluster icaADBC is necessary for biofilm production in Staphylococcus epidermidis. The ica operon is negatively controlled by the repressor IcaR. Here, the crystal structure of IcaR was determined and the refined structure revealed a homodimer comprising entirely α-helices, typical of the tetracycline repressor protein family for gene regulations. The N-terminal domain contains a conserved helix-turn-helix DNA-binding motif with some conformational variations, indicating flexibility in this region. The C-terminal domain shows a complementary surface charge distribution about the dyad axis, ideal for efficient and specific dimer formation. The results of the electrophoretic mobility shift assay and isothermal titration calorimetry suggested that a 28 bp core segment of the ica operator is implicated in the cooperative binding of two IcaR dimers on opposite sides of the duplex DNA. Computer modeling based on the known DNA-complex structure of QacR and site-specific mutagenesis experiments showed that direct protein–DNA interactions are mostly conserved, but with slight variations for recognizing the different sequences. By interfering with the binding of IcaR to DNA, aminoglycoside gentamicin and other antibiotics may activate the icaADBC genes and elicit biofilm production in S. epidermidis, and likely S. aureus, as a defense mechanism

Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways

Abstract\ud \ud Background\ud Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage.\ud \ud \ud Methods\ud Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects.\ud \ud \ud Results\ud The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%.\ud \ud \ud Conclusions\ud Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.FAPES

BPR1K653, a Novel Aurora Kinase Inhibitor, Exhibits Potent Anti-Proliferative Activity in MDR1 (P-gp170)-Mediated Multidrug-Resistant Cancer Cells

Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments