A Bitter Taste Receptor as a Novel Molecular Target on Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma.

Cancer-associated fibroblasts (CAFs) execute diverse and complex functions in cancer progression. While reprogramming the crosstalk between CAFs and cancer epithelial cells is a promising avenue to evade the adverse effects of stromal depletion, drugs are limited by their suboptimal pharmacokinetics and off-target effects. Thus, there is a need to elucidate CAF-selective cell surface markers that can improve drug delivery and efficacy. Here, functional proteomic pulldown with mass spectrometry was used to identify taste receptor type 2 member 9 (TAS2R9) as a CAF target. TAS2R9 target characterization included binding assays, immunofluorescence, flow cytometry, and database mining. Liposomes conjugated to a TAS2R9-specific peptide were generated, characterized, and compared to naked liposomes in a murine pancreatic xenograft model. Proof-of-concept drug delivery experiments demonstrate that TAS2R9-targeted liposomes bind with high specificity to TAS2R9 recombinant protein and exhibit stromal colocalization in a pancreatic cancer xenograft model. Furthermore, the delivery of a CXCR2 inhibitor by TAS2R9-targeted liposomes significantly reduced cancer cell proliferation and constrained tumor growth through the inhibition of the CXCL-CXCR2 axis. Taken together, TAS2R9 is a novel cell-surface CAF-selective target that can be leveraged to facilitate small-molecule drug delivery to CAFs, paving the way for new stromal therapies.

Unilateral vs bilateral total knee arthroplasty risk factors increasing morbidity.

Because surgeons are electing to perform simultaneous bilateral total knee arthroplasty (TKA), it is important to identify which patients are at increased risk. We performed a retrospective cohort analysis of 150 patients with unilateral TKA vs 150 patients with simultaneous bilateral TKA. The bilateral group demonstrated a 2.1 times greater mean overall complication rate as well as increased transfusion rates. Patients older than 70 years exhibited significantly higher complication rates. Having a preexisting pulmonary disorder in the bilateral cohort carried nearly a 3-fold risk of complications. Patients with body mass indices greater than 30 displayed a complication rate of 0.97 in the bilateral group as opposed to 0.44 in the control group. Our study demonstrated that age, body mass index, and a preexisting pulmonary disorder resulted in increased complications.

Primary care physical therapy practice models.

The purpose of this paper is to provide a brief background on the concept of primary care physical therapy, describe 3 existing models of primary care physical therapy, explore their similarities and differences, and discuss the potential implications and opportunities for the profession. The programs at US Army medical facilities, Kaiser Permanente Northern California, and the Department of Veterans Affairs Salt Lake City Health Care System are presented by the author affiliated with each respective program.

Glycophorin A somatic cell mutations in a population living in the proximity of the Semipalatinsk nuclear test site.

The glycophorin A (GPA) somatic mutation assay was performed to evaluate the magnitude of exposure to ionizing radiation among the human population living in the vicinity of the Semipalatinsk nuclear test site in Kazakhstan. All together, 113 blood samples were analyzed from three generations of people living in villages that were under the trail of the radioactive cloud from the first Soviet surface nuclear test performed in August 1949 and from later tests. The oldest generation (P0) lived in the area at the time of testing, whereas the younger generations (F1, F2) were exposed to smaller doses from the residual fallout and later tests. The GPA assay did not reveal significant differences in the variant cell frequencies for all subjects selected from the Semipalatinsk area compared with 74 matched controls living in a noncontaminated area. However, a significant increase (P < 0.05) in the mean allele-loss ON variant frequency was observed among the exposed P0 generation (12 x 10(-6)) in comparison to controls (7 x 10(-6)). Considering the sensitivity of the GPA assay, the results suggest that the mean dose to the P0 generation of the affected villages was relatively low, a finding which is in accordance to the conclusions obtained from other biological assays performed on the same population.

Case report: coronary steal secondary to a left main coronary artery-pulmonary artery fistula only manifest after coronary artery bypass surgery.

We report the case of a 64 year old man with two vessel coronary artery disease and a left main coronary artery to pulmonary artery fistula. He underwent coronary artery bypass grafting, but the coronary artery fistula was not closed. He developed recurrent angina due to coronary steal from the distal left anterior descending artery by the maturing coronary artery fistula. This was closed percutaneously by stenting the left main coronary artery with covered stents. The clinical implications and potential mechanisms of the coronary steal due to the coronary artery fistula are discussed.

Hypertension and myocardial ischemia.

Detailed studies over the past 30 years have built up an impressive evidence base for the presence of myocardial ischemia in patients who have hypertension. This relationship ranges from the obvious association with obstructive coronary artery disease to mechanisms related to hemodynamic, microcirculatory, and neuroendocrine abnormalities. All of these factors serve to destabilize the critical balance between myocardial oxygen supply and demand. We have at our disposal a range of sophisticated investigations that allow us to demonstrate the presence and extent of the ischemia and therefore to target specific therapies to reduce the risk to these patients. Achieving target BP and managing all reversible components of the patient's cardiovascular risk status reduce to a minimum the clinical sequelae of myocardial ischemia in this vulnerable population..

Addressing severe bone deficiency: what a cage will not do.

Managing severe acetabular bone loss in total hip arthroplasty revision can be a tremendous challenge. Osteolysis and migration of the acetabular component can lead to large uncontained defects. Traditionally, these deficiencies have been treated with allograft with or without the support of a cage. In severe cases, a majority of the cage support is via allograft instead of host bone. Sometimes, with remodeling and resorption of the allograft, the cage can lose structural support, leading to fatigue and failure. In these situations, trabecular metal has become a viable alternative. Deficiencies of acetabular bone can be independently addressed and reconstructed providing initial stability and, we believe, long-term biologic fixation to host bone.