Epithelia can eliminate apoptotic cells by apical extrusion. This is a complex morphogenetic event where expulsion of the apoptotic cell is accompanied by rearrangement of its immediate neighbors to ...form a rosette. A key mechanism for extrusion is constriction of an actomyosin network that neighbor cells form at their interface with the apoptotic cell. Here we report a complementary process of cytoskeletal relaxation that occurs when cortical contractility is down-regulated at the junctions between those neighbor cells themselves. This reflects a mechanosensitive Src family kinase (SFK) signaling pathway that is activated in neighbor cells when the apoptotic cell relaxes shortly after injury. Inhibiting SFK signaling blocks both the expulsion of apoptotic cells and the rosette formation among their neighbor cells. This reveals the complex pattern of spatially distinct contraction and relaxation that must be established in the neighboring epithelium for apoptotic cells to be extruded.
The glutathione peroxidases, a family of selenocysteine-containing redox enzymes, play pivotal roles in balancing the signaling, immunomodulatory, and deleterious effects of reactive oxygen species ...(ROS). The glutathione peroxidase GPX3 is the only extracellular member of this family, suggesting it may defend cells against ROS in the extracellular environment. Notably, GPX3 hypermethylation and underexpression occur commonly in prostate, gastric, cervical, thyroid, and colon cancers. We took a reverse genetics approach to investigate whether GPX3 would augment inflammatory colonic tumorigenesis, a process characterized by oxidative stress and inflammation, comparing Gpx3(-/-) mice in an established two-stage model of inflammatory colon carcinogenesis. Gpx3-deficient mice exhibited an increased tumor number, though not size, along with a higher degree of dysplasia. In addition, they exhibited increased inflammation with redistribution toward protumorigenic M2 macrophage subsets, increased proliferation, hyperactive WNT signaling, and increased DNA damage. To determine the impact of acute gene loss in an established colon cancer line, we silenced GPX3 in human Caco2 cells, resulting in increased ROS production, DNA damage and apoptosis in response to oxidative stress, combined with decreased contact-independent growth. Taken together, our results suggested an immunomodulatory role for GPX3 that limits the development of colitis-associated carcinoma.
Contrast-enhanced MRI is routinely performed as part of preoperative work-up for patients with Colorectal Cancer Liver Metastases (CRLM). Radiomic biomarkers depicting the characteristics of CRLMs in ...MRI have been associated with overall survival (OS) of patients, but the reproducibility and clinical applicability of these biomarkers are limited due to the variations in MRI protocols between hospitals.
In this work, we propose a generalizable radiomic model for predicting OS of CRLM patients who received preoperative chemotherapy and delayed-phase contrast enhanced (DPCE) MRIs prior to hepatic resection. This retrospective two-center study included three DPCE MRI cohorts (n=221) collected between January 2006 and December 2012. A 10-minute delayed Gd-DO3A-butrol enhanced MRI discovery cohort was used to select features based on robustness across contrast agents, correlation with OS and pairwise Pearson correlation, and to train a logistic regression model that predicts 3-year OS.
The model was evaluated on a 10-minute delayed Gd-DO3A-butrol enhanced MRI validation cohort (n=121), a 20-minute delayed Gd-EOB-DTPA (n=72) cohort from the same institute, and a 5-minute delayed Gd-DTPA cohort (n=28) from an independent institute. Two features were selected: minor axis length and dependence variance. The radiomic signature model stratified high-risk and low-risk CRLM groups in the Gd-DO3Abutrol (HR = 6.29, p = .007), Gd-EOB-DTPA (HR = 3.54, p = .003) and Gd-DTPA (HR = 3.16, p = .04) validation cohorts.
While most existing MRI findings focus on a specific contrast agent, our study shows the potential of MRI features to be generalizable across main-stream contrast agents at delayed phase.
Thirteen introduced Astragalus and one Swainsona species were analyzed throughout the growing season for presence and concentration of toxic nitro compounds. Sicklepod milkvetch (A. falcatus) ...contained high levels of nitro compounds and acutely poisoned sheep, cattle, and 1-week-old chicks. A. siliquosus contained small amounts of nitro compounds that were slightly toxic to 1-week-old chicks. Other species tested contained little or no nitro compounds and were nontoxic to 1-week-old chicks.
An 8‐month‐old girl who seemed certain to die from the infantile form of hypophosphatasia, an inborn error of metabolism characterized by deficient activity of the tissue‐nonspecific isoenzyme of ...alkaline phosphatase (TNSALP), underwent the first trial of bone marrow cell transplantation for this heritable type of rickets. After cytoreduction, she was given T‐cell‐depleted, haplo‐identical marrow from her healthy sister. Chimerism in peripheral blood and bone marrow became 100% donor. Three months later, she was clinically improved, with considerable healing of rickets and generalized skeletal remineralization. However, 6 months post‐transplantation, worsening skeletal disease recurred, with partial return of host hematopoiesis. At the age of 21 months, without additional chemotherapy or immunosuppressive treatment, she received a boost of donor marrow cells expanded ex vivo to enrich for stromal cells. Significant, prolonged clinical and radiographic improvement followed soon after. Nevertheless, biochemical features of hypophosphatasia have remained unchanged to date. Skeletal biopsy specimens were not performed. Now, at 6 years of age, she is intelligent and ambulatory but remains small. Among several hypotheses for our patient's survival and progress, the most plausible seems to be the transient and long‐term engraftment of sufficient numbers of donor marrow mesenchymal cells, forming functional osteoblasts and perhaps chondrocytes, to ameliorate her skeletal disease.
IMPORTANCE In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. OBJECTIVE To evaluate the efficacy and tolerability ...of evolocumab when used in combination with a moderate- vs high-intensity statin. DESIGN, SETTING, AND PATIENTS Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries. INTERVENTIONS Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin 10 mg, simvastatin 40 mg, or rosuvastatin 5 mg) or high-intensity (atorvastatin 80 mg, rosuvastatin 40 mg) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies. MAIN OUTCOMES AND MEASURES Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12. RESULTS Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%). CONCLUSIONS AND RELEVANCE In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01763866
Watkins, CM, Barillas, SR, Wong, MA, Archer, DC, Dobbs, IJ, Lockie, RG, Coburn, JW, Tran, TT, and Brown, LE. Determination of vertical jump as a measure of neuromuscular readiness and fatigue. J ...Strength Cond Res 31(12): 3305-3310, 2017-Coaches closely monitor training loads and periodize sessions throughout the season to create optimal adaptations at the proper time. However, only monitoring training loads ignores the innate physiological stress each athlete feels individually. Vertical jump (VJ) is widely used as a measure of lower-body power, and has been used in postmatch studies to demonstrate fatigue levels. However, no pretraining monitoring by VJ performance has been previously studied. Therefore, the purpose of this study was to determine the sensitivity of VJ as a measure of readiness and fatigue on a daily sessional basis. Ten healthy resistance-trained males (mass = 91.60 ± 13.24 kg; height = 179.70 ± 9.23 cm; age = 25.40 ± 1.51 years) and 7 females (mass = 65.36 ± 12.29 kg; height = 162.36 ± 5.75 cm; age = 25.00 ± 2.71 years) volunteered to participate. Vertical jump and BRUNEL Mood Assessment (BAM) were measured 4 times: pre-workout 1, post-workout 1, pre-workout 2, and post-workout 2. Workout intensity was identical for both workouts, consisting of 4 sets of 5 repetitions for hang cleans, and 4 sets of 6 repetitions for push presses at 85% 1 repetition maximum (1RM), followed by 4 sets to failure of back squats (BSs), Romanian deadlift, and leg press at 80% 1RM. The major finding was that VJ height decrement (-8.05 ± 9.65 cm) at pre-workout 2 was correlated (r = 0.648) with BS volume decrement (-27.56 ± 24.56%) between workouts. This is important for coaches to proactively understand the current fatigue levels of their athletes and their readiness to resistance training.
Achieving NKF-K/DOQI™ bone metabolism and disease treatment goals with cinacalcet HCl.
The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI™) has established ...guidelines for treatment of secondary hyperparathyroidism (HPT). The ability of cinacalcet HCl (Sensipar™) treatment to improve achievement of target levels of parathyroid hormone (PTH), calcium, phosphorus, and calcium-phosphorus product (Ca × P) was investigated in subjects on dialysis with secondary HPT.
Data were combined from three placebo-controlled, double-blind, 26-week studies with similar design that randomized 1136 subjects on dialysis to receive traditional therapy plus cinacalcet or placebo. Oral cinacalcet was titrated from 30 to 180mg/day. Achievement of K/DOQI goals was determined for each treatment group overall and for subgroups defined by baseline intact PTH (iPTH) and Ca × P levels.
Cinacalcet-treated subjects were more likely to achieve a mean iPTH ≤300 pg/mL (31.8 pmol/L) than were control subjects on traditional therapy (56% vs. 10%, P < 0.001). Cinacalcet-treated subjects were more likely to achieve concentrations of serum calcium within 8.4 to 9.5mg/dL (2.10–2.37mmol/L) and serum phosphorus within 3.5 to 5.5mg/dL (1.13–1.78mmol/L) than were control subjects (49% vs. 24% and 46% vs. 33%, P < 0.001 for each). Cinacalcet also improved achievement of Ca × P < 55mg2/dL2 (4.44mmol2/L2) and concurrent achievement of Ca × P < 55mg2/dL2 (4.44mmol2/L2) and iPTH ≤300 pg/mL (31.8 pmol/L) (65% vs. 36% and 41% vs. 6%, P < 0.001 for each).
In subjects on dialysis with secondary HPT, cinacalcet facilitates achievement of the K/DOQI-recommended targets for PTH, calcium, phosphorus, and Ca × P.
Background. Fecal transplantation (FT) is a promising treatment for recurrent Clostridium difficile infection (CDI), but its true effectiveness remains unknown. We compared 14 days of oral vancomycin ...followed by a single FT by enema with oral vancomycin taper (standard of care) in adult patients experiencing acute recurrence of CDI. Methods. In a phase 2/3, single-center, open-label trial, participants from Ontario, Canada, experiencing recurrence of CDI were randomly assigned in a 1:1 ratio to 14 days of oral vancomycin treatment followed by a single 500-mL FT by enema, or a 6-week taper of oral vancomycin. Patients with significant immunocompromise, history of fulminant CDI, or irreversible bleeding disorders were excluded. The primary endpoint was CDI recurrence within 120 days. Microbiota analysis was performed on fecal filtrate from donors and stool samples from FT recipients, as available. Results. The study was terminated at the interim analysis after randomizing 30 patients. Nine of 16 (56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group experienced recurrence of CDI, corresponding with symptom resolution in 43.8% and 58.3%, respectively. Fecal microbiota analysis of 3 successful FT recipients demonstrated increased diversity. A futility analysis did not support continuing the study. Adverse events were similar in both groups and uncommon. Conclusions. In patients experiencing an acute episode of recurrent CDI, a single FT by enema was not significantly different from oral vancomycin taper in reducing recurrent CDI. Further research is needed to explore optimal donor selection, FT preparation, route, timing, and number of administrations. Clinical Trials Registration. NCT01226992.
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