Citations

Bone metastases cause devastating clinical complications leading patients to have pain, poor quality of life, loss of mobility, and autonomy. Complications from osseous metastases cause a big economic burden reflected by repeated admissions for uncontrolled symptoms. Management of symptoms associated with bone metastasis includes systemic analgesics, glucocorticoids, radiation (external beam radiation and radiopharmaceuticals), ablative techniques (radiofrequency ablation and cryoablation), chemotherapeutic agents, hormonal therapies, interventional techniques (eg, kyphoplasty), and surgical approaches. Bisphosphonates have become a standard therapy for bony metastasis. They bind to bone eventually inhibiting osteoclast action. Bisphosphonates decrease fractures when given routinely. Adverse effects of bisphosphonates include osteonecrosis of the jaw and renal insufficiency. Late last year, the Food and Drug Administration approved denosumab to prevent skeletal-related events (SREs) associated with metastatic solid tumors. This drug is a monoclonal antibody that inhibits the receptor activator of nuclear factor κB (RANK)–RANK ligand interaction. Clinical trials have shown superiority over bisphosphonates for the prevention of SREs. This article reviews the mechanism of action, pharmacology, adverse effects, and clinical trial evidence for this new drug.

Abstract Mesenchymal stem cells (MSC) represent a new tool for delivery of therapeutic agents to cancer sites because of their strong tropism toward tumors. IL15 has demonstrated a potent antitumor activity in various animal models as well as clinical trials. However, because of its short half-life, effective therapeutic effects usually require a high dose, which often results in undesired side effects; thus, new strategies for overcoming this disadvantage are needed. In this study, human MSCs were isolated from umbilical cord blood as delivery vehicles and transduced with lentivirus vector expressing murine IL15 (MSC-IL15). In vitro assays of lymphocyte activation and proliferation demonstrated that IL15 produced by MSCs was biofunctional. In syngeneic mice bearing Pan02 pancreatic tumors, systemic administration of MSC-IL15 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice, which were associated with tumor cell apoptosis, and natural killer (NK)– and T-cell accumulation. Furthermore, we confirmed that MSC-IL15 could migrate toward tumor and secreted IL15 in tumor-specific sites. Depletion of NK and CD8+ T cells abolished the antitumor activity of MSC-IL15, suggesting that NK and CD8+ T cells play a key role for MSC-IL15–mediated effect. Interestingly, cured mice after MSC-IL15 treatment were resistant to Pan02 pancreatic tumor rechallenge, and adoptive transfer of lymphocytes from cured mice also could cause rejection of Pan02 tumor inoculation in naïve mice, indicating that MSC-IL15 induced tumor-specific T-cell immune memory response. Overall, these data support that MSCs producing IL15 might represent an innovative strategy for therapy of pancreatic tumor. Mol Cancer Ther; 13(8); 2127–37. ©2014 AACR.

Objectives Overweight and obesity are increasing in individuals over age 60 years. This systematic review quantifies the effect of exercise on body mass index (BMI), waist circumference (WC) and lipids in overweight and obese individuals over the age of 60 years. Settings Nine randomised controlled trials conducted in Brazil, Great Britain, Iceland, Japan and the USA compared aerobic and/or resistance exercise with a control group. Participants Final analysis reviewed 1166 participants over the age of 60 years for 3–9 months. Primary outcome measures This study reviewed the effects of exercise on BMI, WC and low-density lipoprotein (LDL). Results Exercise produced a significant reduction in BMI (−1.01 kg/m 2 , 95% CI −2.00 to −0.01) and WC (−3.09 cm, 95% CI −4.14 to −2.04) but not LDL cholesterol (−0.31 mg/dL, 95% CI −0.81 to 0.19). Analyses revealed substantial heterogeneity likely due to the type and intensity of exercise. Data on adverse effects were minimal. The overall level of evidence is moderate due to imprecision and heterogeneity. Conclusions Exercise in overweight and obese older individuals improves anthropometric measures such as BMI and WC. The effect of exercise on serum lipids is unclear.

ABSTRACTThe ionic liquid 1‐ethyl‐3‐methyl imidazolium chloride (EMIM Cl) and the amino acid l‐arginine hydrochloride (l‐ArgHCl) have been successfully used to improve the yield of oxidative refolding for various proteins. However, the molecular mechanisms behind the actions of such solvent additives—especially of ionic liquids—are still not well understood. To analyze these mechanisms, we have determined the transfer free energies from water into ionic liquid solutions of proteinogenic amino acids and of diketopiperazine as peptide bond analogue. For EMIM Cl and 1‐ethyl‐3‐methyl imidazolium diethyl phosphate, which had a suppressive effect on protein refolding, as well as for l‐ArgHCl favorable interactions with amino acid side chains, but no favorable interactions with the peptide backbone could be observed. A quantitative analysis of other ionic liquids together with their already published effects on protein refolding showed that only solvent additives within a certain range of hydrophobicity, chaotropicity and kosmotropicity were effective for the refolding of recombinant plasminogen activator. © 2014 Wiley Periodicals, Inc. Biopolymers 101: 1129–1140, 2014.

Object Traditionally, hemisacrectomy and internal hemipelvectomy procedures have required both an anterior and a posterior approach. A posterior-only approach has the potential to complete an en bloc tumor resection and spinopelvic reconstruction while reducing surgical morbidity. Methods The authors describe 3 cases in which en bloc resection of the hemisacrum and ilium and subsequent lumbopelvic and pelvic ring reconstruction were performed from a posterior-only approach. Two more traditional anterior and posterior staged procedures are also included for comparison. Results In all 3 cases, an oncologically appropriate surgery and spinopelvic reconstruction were performed through a posterior-only approach. Conclusions The advantage of a midline posterior approach is the ability to perform a lumbosacral reconstruction, necessary in cases in which the S-1 body is iatrogenically disrupted during tumor resection.

AbstractBackgroundSome cardiac transplant programs may upgrade listed patients to United Network for Organ Sharing (UNOS) 1A‐status during the holidays. Whether more transplants actually occur during holidays is unknown.MethodsWe assessed rates of single‐organ heart transplantation from 2001 to 2010 for recipients age ≥18 yr using the UNOS database. Patients were stratified by transplantation during holiday (±3 d, n = 2375) and non‐holiday periods (n = 16 112). Holidays included Easter/Spring break, Memorial Day, July 4th, Labor Day, Thanksgiving, and Christmas/New Years (winter holidays). Secondary analysis assessing transplant rates across seasons was also completed.ResultsDonor and recipient characteristics were similar between groups. Compared with non‐holidays, July 4th had higher transplant rates (5.69 vs. 5.09 transplants/d, p = 0.03) while the winter holiday had lower transplant rates (4.50 vs. 5.09 transplants/d, p < 0.01). There was a trend toward lower transplant rates for all holidays compared with non‐holidays (p = 0.06). Transplant rates were significantly different across seasons with greater rates in spring and summer (p < 0.01).ConclusionHeart transplant rates were higher during the July 4th and lower during the winter holidays. Although there was a higher likelihood of transplantation during the spring and summer seasons, upgrading patients to 1A status during most holidays may not improve their chances for transplantation.

Neurotensin (NT) is a neuropeptide that is closely associated with, and is thought to modulate, dopaminergic and other neurotransmitter systems involved in the pathophysiology of various mental disorders. This review outlines data implicating NT in the pathophysiology and management of major mental disorders such as schizophrenia, drug addiction, and autism. The data suggest that NT receptor analogs have the potential to be used as novel therapeutic agents acting through modulation of neurotransmitter systems dys-regulated in these disorders.