Complex roles of discoidin domain receptor tyrosine kinases in cancer

Discoidin domain receptors, DDR1 and DDR2 are members of the receptor tyrosine kinase (RTK) family that serves as a non-integrin collagen receptor and were initially identified as critical regulators of embryonic development and cellular homeostasis. In recent years, numerous studies have focused on the role of these receptors in disease development, in particular, cancer where they have been reported to augment ECM remodeling, invasion, drug resistance to facilitate tumor progression and metastasis. Interestingly, accumulating evidence also suggests that DDRs promote apoptosis and suppress tumor progression in various human cancers due to which their functions in cancer remain ill-defined and presents a case of an interesting therapeutic target. The present review has discussed the role of DDRs in tumorigenesis and the metastasis (AU)

In Silico Finite Element Analysis of the Foot Ankle Complex Biomechanics: A Literature Review.

Computational approaches, especially finite element analysis (FEA), have been rapidly growing in both academia and industry during the last few decades. FEA serves as a powerful and efficient approach for simulating real-life experiments, including industrial product development, machine design, and biomedical research, particularly in biomechanics and biomaterials. Accordingly, FEA has been a "go-to" high biofidelic software tool to simulate and quantify the biomechanics of the foot-ankle complex, as well as to predict the risk of foot and ankle injuries, which are one of the most common musculoskeletal injuries among physically active individuals. This paper provides a review of the in silico FEA of the foot-ankle complex. First, a brief history of computational modeling methods and finite element (FE) simulations for foot-ankle models is introduced. Second, a general approach to build an FE foot and ankle model is presented, including a detailed procedure to accurately construct, calibrate, verify, and validate an FE model in its appropriate simulation environment. Third, current applications, as well as future improvements of the foot and ankle FE models, especially in the biomedical field, are discussed. Finally, a conclusion is made on the efficiency and development of FEA as a computational approach in investigating the biomechanics of the foot-ankle complex. Overall, this review integrates insightful information for biomedical engineers, medical professionals, and researchers to conduct more accurate research on the foot-ankle FE models in the future.

Complex roles of discoidin domain receptor tyrosine kinases in cancer.

Discoidin domain receptors, DDR1 and DDR2 are members of the receptor tyrosine kinase (RTK) family that serves as a non-integrin collagen receptor and were initially identified as critical regulators of embryonic development and cellular homeostasis. In recent years, numerous studies have focused on the role of these receptors in disease development, in particular, cancer where they have been reported to augment ECM remodeling, invasion, drug resistance to facilitate tumor progression and metastasis. Interestingly, accumulating evidence also suggests that DDRs promote apoptosis and suppress tumor progression in various human cancers due to which their functions in cancer remain ill-defined and presents a case of an interesting therapeutic target. The present review has discussed the role of DDRs in tumorigenesis and the metastasis.

Minimalist style boot improves running but not walking economy in trained men.

This study examined movement economy under load with 1000 g minimalist (MIN) vs. 1600 g traditional (TRD) style boots. Fourteen trained, male participants completed a VO2peak test (46.6 ± 7.3 ml/kg/min) while wearing a 16 kg external load. Treadmill speeds for the running economy (RE) trials were determined by the slowest pace in which participants completed a full stage with a running gait pattern during the VO2peak test. Walking economy (WE) pace was 1.6 km/h slower than RE pace. During the second session, participants completed 5-min exercise bouts at WE and RE pace under load wearing MIN and TRD. There were no differences for any measured variables during WE trials. In contrast, RE (MIN = 2.95 ± 0.28 vs. TRD = 3.04 ± 0.30 L/min; p = .003: Cohen's d = 0.32), respiratory exchange ratio (p < .001), and perceptual measures (p < .05) were all improved while wearing MIN. Practitioner summary: In trained men, 1000 g/pair minimalist style boots (MIN) resulted in improvements of approximately 3% and 5% for running economy and respiratory exchange ratio versus 1600 g/pair traditional boots while wearing a 16 kg kit. Perceptual responses, including comfort, also favoured MIN. These effects were not found at walking pace. Abbreviations: MIN: minimalist style boots; TRD: traditional style boots; RE: running economy; WE: walking economy; ES: effect size; RER: respiratory exchange ratio; HR: heart rate.

CIP4 promotes lung adenocarcinoma metastasis and is associated with poor prognosis.

Aberrant epidermal growth factor receptor (EGFR) signaling in non-small cell lung cancer (NSCLC) is linked to tumor progression, metastasis and poor survival rates. Here we report the role of Cdc42-interacting protein 4 (CIP4) in the regulation of NSCLC cell invasiveness and tumor metastasis. CIP4 was highly expressed in a panel of NSCLC cell lines and normal lung epithelial cell lines. Stable knockdown (KD) of CIP4 in lung adenocarcinoma H1299 cells, expressing wild-type EGFR, led to increased EGFR levels on the cell surface and defects in sustained activation of Erk kinase in H1299 cells treated with EGF. CIP4 localized to leading edge projections in NSCLC cells, and CIP4 KD cells displayed defects in EGF-induced cell motility and invasion through extracellular matrix. This correlated with reduced expression and activity of matrix metalloproteinase-2 (MMP-2) in CIP4 KD cells compared with control. In xenograft assays, CIP4 silencing had no effect on tumor growth but resulted in significant defects in spontaneous metastases to the lungs from these subcutaneous tumors. This correlated with reduced expression of the Erk target gene Zeb1 and the Zeb1 target gene MMP-2 in CIP4 KD tumors compared with control. CIP4 also enhanced rates of metastasis to the liver and lungs in an intrasplenic experimental metastasis model. In human NSCLC tumor sections, CIP4 expression was elevated greater than or equal to twofold in 43% of adenocarcinomas and 32% of squamous carcinomas compared with adjacent normal lung tissues. Analysis of microarray data for NSCLC patients also revealed that high CIP4 transcript levels correlated with reduced overall survival. Together, these results identify CIP4 as a positive regulator of NSCLC metastasis and a potential poor prognostic biomarker in lung adenocarcinoma.

Transducer of Cdc42-dependent actin assembly promotes breast cancer invasion and metastasis.

Metastatic breast adenocarcinomas display activation signatures for signaling pathways that trigger cell motility and tissue invasion. Here, we report that the adaptor protein transducer of Cdc42-dependent actin assembly-1 (Toca-1) is expressed in highly invasive breast cancers and regulates their metastatic phenotypes. We show that Toca-1 localizes to the filamentous actin-rich core of invadopodial protrusions actively degrading the extracellular matrix (ECM). Toca-1 colocalizes with Cortactin, and we show that this interaction is mediated by the SH3 domain of Toca-1. Stable knockdown (KD) of Toca-1 expression in MDA-MB-231 cells led to a significant defect in epidermal growth factor (EGF)-induced cell migration and invasion. Toca-1 KD cells also showed significant defects in EGF- and Src-induced ECM digestion and formation of invadopodial membrane protrusions. To test the role of Toca-1 in metastasis, we achieved stable Toca-1 KD in both human and rat metastatic breast adenocarcinoma cell lines. Orthotopic tumor xenografting of control and Toca-1 KD cells in natural-killer /B-/T-cell-deficient mice revealed a significant defect in spontaneous lung metastases with Toca-1 silencing in vivo. In contrast, no defects in primary tumor growth or lung seeding following tail vein injection of Toca-1 KD cells was observed, suggesting that Toca-1 functions at an early step in the dissemination of metastatic breast tumor cells. Taken together, our results identify Toca-1 as a proinvasive protein in breast adenocarcinoma and a potential therapeutic target to limit tumor metastasis.

Self-catalytic synthesis, structure and properties of ultra-fine luminescent ZnO nanostructures for field emission applications.

A facile method to produce high-quality ZnO nanostructures; either tetrapod (TP), nanotetraneedle (NTN) or multipod (MP) with a high degree of homogeneity for advanced field emission (FE) applications is presented. Among these nanostructures, NTN has been successfully employed to demonstrate enhanced current densities (2.6 mA cm(-2)), turn-on field (1.5 V microm(-1)) and field-enhancement factors (6930) over conventional multiwalled carbon nanotubes (MWCNTs), TP, MP and ZnO-spheroids. A comparative study of FE from various ZnO nanostructures, morphologies and site densities has lead to the conclusion that diameter of the tip is one of the vital parameters in enhancing the overall FE properties.

Surgery for aortic valve endocarditis.

From March 1994 to March 1997, 36 patients with aortic valve endocarditis were managed surgically. Of these, 30 patients had native valve endocarditis and six had prosthetic valve endocarditis. In patients with native valve endocarditis, surgical procedures included aortic valve repair (n=6), homograft aortic valve replacement (n=9), Ross procedure (n=5) and prosthetic aortic valve replacement (n=10). There were three early and two late deaths in this group. In patients with prosthetic valve endocarditis, aortic valve replacement with a homograft was performed in all. Active infection and prosthetic valve endocarditis were the most important predictors of early mortality. The availability of a homograft valve provides an alternative to prosthetic valve replacement in patients with aortic valve endocarditis.

Experience with homograft mitral valve replacement.

BACKGROUND AND AIMS OF THE STUDY: Homograft mitral valve replacement may offer a superior alternative to replacement with a prosthetic valve. The authors' early experience with this technique is reported. METHODS: Between May 1994 and May 1995, 24 patients (19 males, five females; age range 17 to 49 years) underwent homograft mitral valve replacement (HMVR) at the authors' institution. The etiology was rheumatic in all patients; 22 had severe calcific mitral stenosis (MS) and two had combined MS and severe mitral regurgitation (MR). RESULTS: There were three early deaths (12%) and two late deaths (8%). In three patients the homograft had to be explanted due to severe MR at six weeks, 10 weeks and 12 months, respectively. Mean follow up was 18 months (range: 12 to 25 months). Postoperative echocardiography showed trivial or mild MR in 12 patients and moderate MR in four. Mitral stenosis was absent in all patients (mean mitral valve area 2.5 cm2). Sixteen patients showed satisfactory homograft valve function at follow up. The valve explanted after six weeks showed normal cusp architecture, endothelial growth and incorporation of the pericardial strip and complete healing of the papillary muscle junction. Magnetic resonance imaging in 12 patients showed normal appearance and function of the homografts. CONCLUSIONS: The authors' experience suggests that homograft mitral valve replacement can be performed with good early results.

Aortic valve replacement with biological substitute.

In the quest for an ideal aortic valve substitute, homografts and autografts are well-established options. We reviewed our results with homografts and autografts for aortic valve replacement during the last 5 years. From March 1992 through July 1997, 189 patients (138 male and 51 female), age 8 months to 68 years (mean 31.0+/-4.2 years), underwent aortic valve replacement with a human biological substitute. Of these, 93 patients received a cryopreserved or antibiotic-preserved aortic/pulmonary homograft, whereas 96 patients underwent a Ross procedure. Etiology was rheumatic in 143 (75.6%) patients, bicuspid aortic valve in 40 (21.2%), Marfan's disease in 5 (2.6%), and myxomatous aortitis in 1 (0.5%). Among the homograft group, a scalloped subcoronary implantation technique was used in 54 patients, whereas 32 patients underwent root replacement. Five patients required aortic root and ascending aortia replacement for annuloaortic ectasia. In all patients undergoing the Ross procedure, a root replacement technique was used. Operative mortality was 7.4% (14 patients). Late mortality was 5.3% (10 patients). Follow-up ranged from 1 to 46 months postoperatively. In patients with homograft aortic valve replacement, 76 patients (91.5%) had trivial to mild aortic regurgitation, while 7 patients (8.4%) had important aortic regurgitation. In patients with the Ross procedure, 78 patients (89.6%) had trivial to mild regurgitation. Moderate to severe aortic regurgitation was present in 9 patients (10.3%), all of whom had rheumatic heart disease and were young (< 30 years at surgery). We conclude that homografts and autografts provide an excellent substitute for the diseased aortic valve. Young age (< 30 years) with rheumatic etiology is a major risk factor for early progressive aortic regurgitation in patients undergoing the Ross procedure.

Interactions of liposomal amphotericin B with extracellular and intracellular Candida albicans.

The in-vitro activities of liposomal amphotericin B (AmBisome) and amphotericin B-desoxycholate (AmB-DOC) against extracellular Candida albicans during 6 h of incubation in the presence of human serum were determined. With AmB-DOC inhibition of germ tube formation and effective killing were observed at AmB-concentrations of 0.8 and 3.2 mg/L, respectively. With AmBisome for both parameters tested, 32-fold increased AmB concentrations were needed. Preincubation of AmBisome in human serum for 6 h did not influence the rate of killing of C. albicans. Antifungal activity against intracellular C. albicans was assessed at 4 h and 24 h after incubation of C. albicans-infected monolayers of mouse peritoneal macrophages with antifungal agent. In the absence of antifungal agent C. albicans grows intracellularly by formation of germ tubes, and within 24 h mycelium is formed. Antifungal activity was evaluated in terms of both stabilization of the state of infection, as well as eradication of C. albicans from infected macrophages. For AmBisome stabilization only was observed at a concentration of 102 mg/L after 24 h of incubation. For AmB-DOC stabilization and eradication were observed only after 24 h of incubation at 0.8 and 1.6 mg/L, respectively. After previous exposure of macrophages to AmBisome for 6 h before infection, increased antifungal activity of AmBisome was observed: stabilization was observed at 4 h of incubation at 102 mg/L; at 24 h of incubation stabilization and eradication were observed at 25.6 mg/L and 102 mg/L, respectively. Prolongation of the exposure time before C. albicans infection from 6 h up to 24 h resulted in a further increase in antifungal activity of AmBisome. Localization studies of AmBisome and C. albicans in macrophages were performed using fluorescent-labelled C. albicans and fluorescent-labelled AmBisome. The presence of AmBisome within a macrophage was found not to influence uptake of C. albicans by the same macrophage, or vice versa.

Pulmonary autograft aortic valve replacement. Early experience with the Ross procedure.

Aortic valve replacement with a pulmonary autograft was performed in 24 patients between October 1993 and October 1994, at the All India Institute of Medical Sciences, New Delhi. There were 20 (83.3%) males and 4 (16.7%) females. Their ages ranged from 10 to 56 years (mean, 21.46 +/- 11.45 years). Associated procedures included 10 mitral valve procedures (4 open commissurotomies, 5 mitral valve repairs, and 1 homograft mitral valve replacement) and 1 tricuspid valve repair. There were 4 (16.7%) early deaths, 3 of which were due to bleeding or its sequelae and 1 due to septicemia. There were no late deaths. Follow-up ranged from 1 to 13 months (mean, 198.3 +/- 111.1 days). Nineteen (95%) patients are in New York Heart Association functional class I, and 1 patient (5%) is in class II, due to poor left ventricular function. Only 1 patient showed grade 2/4 aortic regurgitation on follow-up examinations, and none has shown progression of aortic regurgitation. Our early results with the pulmonary autograft are encouraging; however, long-term evaluation is needed.

Surgical technique of multiple valve replacement with biological valves: a new option.

An eighteen-year-old male with rheumatic mitral and aortic regurgitation, and mixed tricuspid disease underwent surgery at our institution. Ross procedure, mitral homograft insertion and tricuspid valve repair was performed. We believe that this option is ideal for young patients with multivalvular disease.

Amine production by Streptococcus lactis under different growth conditions.

The highest amount of histamine, tyramine and tryptamine were produced by S. lactis at 30 degrees C in 24 h at pH = 5.0. Maximum amount of different amines was noted in a growth medium lacking NaCl. After addition of NaCl even at 0.5% concentration, slight inhibitory effect on the synthesis of these amines was obtained.

Changes in enterococcal population during storage of reconstituted infant food.

A six-fold increase in the enterococcal population was observed in reconstituted infant food samples after storage for 2 h at 37 degrees C. The increase in enterococcal counts at 40 degrees C and 45 degrees C was approximately five-fold during the same period. However, the corresponding total viable counts increased by twelve fold at these temperatures after 2 h. After 12 h, the enterococcal and total viable counts increased to 39 x 10(4) and 36 X 10(7) colony forming units per ml, at 37 degrees C respectively. A similar pattern in enterococcal and total bacterial count was observed at 40 degrees and 45 degrees C. TNase was detected in reconstituted infant food samples held at 37 degrees, 40 degrees and 45 degrees C, after 12 h, while pH values declined to 5.0, 5.1 and 5.2, respectively at the above temperatures. From TNase positive samples, an isolate S. faecium IF-100 capable to produce TNase was recovered. Storage of reconstituted infant food samples in the refrigerator (5 degrees C) resulted in a gradual increase in enterococcal population which reached 39 X 10(3) c.f.u. per ml after 12 days. However, TNase was not detected in any of these samples.

Enterocin typing of enterococci isolated from dried infant foods.

One hundred and fifty enterococcal isolates recovered from 16 market samples of infant foods and 35 from other sources were characterized and subjected to enterocin typing with 18 indicator strains. Among 150 enterococcal isolates, 114 (76%) were able to be typed by the indicator strains. Although 24 enterocin patterns were observed with these enterococci, the most prevalent types were X-9, 224, and 65-603. Occurrence of pattern X-9 either singly or in combination with many other types was most frequent. Many of the enterocin patterns in enterococcal isolates were recovered from samples of dairy water supply and hand washings of personnel working in a dairy plant that manufactured infant food; this suggests the possibility of these as sources of contamination. Enterocin typing of enterococci could prove useful in epidemiological studies.

Production of Lipase by Byssochlamys fulva.

Byssochlamys fulva exhibited maximum growth and lipase production at 30°C in 6 d at pH 7.0. Aeration enhanced lipase yield by 22%. Growth medium containing maltose showed maximum production of lipase followed by glucose, mannitol, fructose, xylose, sucrose and galactose in decreasing order. Among the nitrogen sources tested. lipase yield was maximum with 2% casamino acids. Tributyrin induced lipase synthesis, whereas other lipids inhibited lipase production.

Characterization of Deoxyribonuclease-Positive Enterococci Isolated from Milk and Milk Products.

Five hundred and ten isolates of enterococci recovered from milk and milk products were screened for deoxyribonuclease (DNase) production. Of the 166 (32.5%) DNase-positive cultures, 29 (5.7%) produced thermonuclease that resisted boiling for 15 min. Although the incidence of thermolabile DNase-positive enterococci was 50.5% in Cheddar cheese, the majority of thermonuclease-producing enterococci was recovered from dried milks and infant foods. On the basis of biochemical, physiological and serological tests, all DNase-producing enterococci were characterized as S. faecalis var. faecalis (21), S. faecalis var. zymogenes (9), S. faecalis var. liquefaciens (90), S. faecium (23) and S. durans (16). The predominant thermonuclease-positive type was S. faecalis var. faecalis followed by S. faecalis var. zymogenes . Six strains of enterococci were found to be toxigenic when tested in ligated rabbit ileal loops, infant mice and rabbit skin.