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Mijailovich S.M.,Harvard University | Mijailovich S.M.,Steward St Elizabeth Medical Center | Li X.,Harvard University | Griffiths R.H.,University of Kent | Geeves M.A.,University of Kent
Journal of Molecular Biology | Year: 2012

The Hill two-state cooperativity model and the McKillop-Geeves (McK-G) three-state model predict very similar binding traces of myosin subfragment 1 (S1) binding to regulated actin filaments in the presence and absence of calcium, and both fit the experimental data reasonably well [Chen et al., Biophys. J., 80, 2338-2349]. Here, we compared the Hill model and the McK-G model for binding myosin S1 to regulated actin against three sets of experimental data: the titration of regulated actin with S1 and the kinetics of S1 binding of regulated actin with either excess S1 to actin or excess actin to S1. Each data set was collected for a wide range of specified calcium concentrations. Both models were able to generate reasonable fits to the time course data and to titration data. The McK-G model can fit all three data sets with the same calcium-concentration-sensitive parameters. Only K B and K T show significant calcium dependence, and the parameters have a classic pCa curve. A unique set of the Hill model parameters was extremely difficult to estimate from the best fits of multiple sets of data. In summary, the McK-G cooperativity model more uniquely resolves parameters estimated from kinetic and titration data than the Hill model, predicts a sigmoidal dependence of key parameters with calcium concentration, and is simpler and more suitable for practical use. © 2012 Elsevier Ltd. Source

Phillips E.A.,Boston Medical Center | Uberoi V.,Boston Medical Center | Tuerk I.A.,Steward St Elizabeth Medical Center
Journal of Endourology | Year: 2014

Background and Purpose: Radical cystectomy is the standard of care for muscle-invasive bladder cancer; however, few patients over age 75 undergo cystectomy. Morbidity and mortality rates in this age group approach 60% and 10%, respectively. We sought to determine if minimally invasive surgery, in the form of robot-assisted radical cystectomy (RARC), may reduce morbidity and mortality associated with this operation in elderly patients. Patients and Methods: After Institutional Review Board approval, all RARC performed between 2009 and 2012 from one institution were reviewed, and 23 cases in patients over the age of 80 were identified. Data analyzed included age, indication for cystectomy, American Society of Anesthesiologists score (ASA), Charlson Comorbidity Index, pathologic stage, estimated blood loss, transfusion rate, and 90-day morbidity and mortality rate. Results: Twenty-three patients over the age of 80 years underwent RARC by a single surgeon (IT) between April 2009 and October 2012. Average age was 83.7 years (range 80-88 years) with average Charlson Comorbidity Index score of 4.3 (age-weighted 8.3). Indication for cystectomy was oncologic in all cases (21 bladder malignancy, 2 hemorrhagic cystitis in the setting of prostate cancer). The average blood loss and operative times were 208 mL (range 50-650 mL) and 253 minutes (range 175-365 min). Seven (30.4%) patients needed blood transfusions. The average length of hospital stay was 8.2 days (range 6-24 days). The overall complication rate within 90 days was 34.8% (8 patients) with no mortality. Longest follow-up is 34 months. Conclusions: RARC should be strongly considered for patients over the age of 80 with clinical indications for cystectomy. The complication rate is acceptable even in complicated patients with multiple comorbidities and those with previous abdominal surgery or pelvic radiation. Hospital stay remains shorter than with open surgery, and complication rates appear to be lower than previously reported for this age group. © Copyright 2014, Mary Ann Liebert, Inc. 2014. Source

Sasi S.P.,GeneSys Research Institute | Bae S.,GeneSys Research Institute | Bae S.,Steward St Elizabeth Medical Center | Song J.,GeneSys Research Institute | And 12 more authors.
PLoS ONE | Year: 2014

Tumor necrosis factor-alpha (TNF) binds to two receptors: TNFR1/p55-cytotoxic and TNFR2/p75-pro-survival. We have shown that tumor growth in p75 knockout (KO) mice was decreased more than 2-fold in Lewis lung carcinoma (LLCs). We hypothesized that selective blocking of TNFR2/p75 LLCs may sensitize them to TNF-induced apoptosis and affect the tumor growth. We implanted intact and p75 knockdown (KD)-LLCs (>90%, using shRNA) into wild type (WT) mice flanks. On day 8 post-inoculation, recombinant murine (rm) TNF-α (12.5 ng/gr of body weight) or saline was injected twice daily for 6 days. Tumor volumes (tV) were measured daily and tumor weights (tW) on day 15, when study was terminated due to large tumors in LLC+TNF group. Tubular bones, spleens and peripheral blood (PB) were examined to determine possible TNF toxicity. There was no significant difference in tV or tW between LLC minus (-) TNF and p75KD/LLC-TNF tumors. Compared to 3 control groups, p75KD/LLC+TNF showed >2-5-fold decreases in tV (p<0.001) and tW (p<0.0001). There was no difference in tV or tW end of study vs. before injections in p75KD/LLC+TNF group. In 3 other groups tV and tW were increased 2.7-4.5-fold (p<0.01, p<0.0002 and p<0.0001). Pathological examination revealed that 1/3 of p75KD/LLC+rmTNF tumors were 100% necrotic, the remaining revealed 40-60% necrosis. No toxicity was detected in bone marrow, spleen and peripheral blood. We concluded that blocking TNFR2/p75 in LLCs combined with intra-tumoral rmTNF injections inhibit LLC tumor growth. This could represent a novel and effective therapy against lung neoplasms and a new paradigm in cancer therapeutics. © 2014 P Sasi et al. Source

Wamelink K.E.,Steward St Elizabeths Medical Center | Marcoux J.T.,Steward St Elizabeth Medical Center | Walrath S.M.,Resident
Journal of Foot and Ankle Surgery | Year: 2016

Before the report of English surgeon Robert Jones, who sustained a fracture to his fifth metatarsal while dancing around a tent pole, metatarsal fractures were thought to be the result of direct trauma to the foot. The mechanism of metatarsal fractures, in particular, those involving the fifth metatarsal, is now well understood. Patients with an adducted alignment of their forefoot can overload the fifth metatarsal base, putting them at an increased risk of fractures of this bone. Studies have reported that 2 distinct types of proximal diaphyseal or junctional fractures of the fifth metatarsal occur: the acute proximal diaphyseal or transverse proximal diaphyseal fracture and the proximal diaphyseal stress fracture. The radiographic characteristics associated with proximal diaphyseal stress fractures of the fifth metatarsal can vary by the chronicity; however, the findings typically entail a radiolucent fracture line with surrounding reactive sclerosis. In addition, a reduced medullary canal width can be appreciated. In the present retrospective analysis of patients with stress-related trauma to the fifth metatarsal base with an adducted forefoot, 2012 foot trauma cases were reviewed at 3 separate institutions. Of the 2012 cases, 22 (1.11%) met the outlined criteria of stress fractures of the fifth metatarsal base and underlying metatarsus adductus. © 2016 American College of Foot and Ankle Surgeons. Source

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