The human heat-shock factor (HSF) regulates heat-shock genes in response to elevated temperature. When human cells are heated to 43 degrees C, HSF is modified post-translationally from a form that does not bind DNA to a form that binds to a specific sequence (the heat-shock element, HSE) found upstream of heat-shock genes. To investigate the transduction of the heat signal to HSF, and more generally, how mammalian cells respond at the molecular level to environmental stimuli, we have developed a cell-free system that exhibits heat-induced activation of human HSF in vitro. Comparison of HSF activation in vitro and in intact cells suggests that the response of human cells to heat shock involves at least two steps. First, an ATP-independent, heat-induced alteration of HSF allows it to bind the HSE; the temperature at which activation occurs in vitro implies that a human factor directly senses temperature. Second, HSF is phosphorylated. It is possible that similar multi-step activation mechanisms play a role in the response of eukaryotic cells to a variety of environmental stimuli, and that these mechanisms evolved to increase the range and flexibility of the response.

We present analyses of an extraordinary new dataset that reveals the path taken by individual shoppers in an actual grocery store, as provided by RFID (radio frequency identification) tags located on their shopping carts. The analysis is performed using a multivariate clustering algorithm not yet seen in the marketing literature that is able to handle data sets with unique (and numerous) spatial constraints. This allows us to take into account physical impediments (such as the location of aisles and other inaccessible areas of the store) to ensure that we only deal with feasible paths. We also recognize that time spent in the store plays an important role, leading to different cluster configurations for short, medium, and long trips. The resulting three sets of clusters identify a total of 14 "canonical path types" that are typical of grocery store travel, and we carefully describe (and cross-validate) each set of clusters These results dispel certain myths about shopper travel behavior that common intuition perpetuates, including behavior related to aisles, end-cap displays, and the "racetrack." We briefly relate these results to previous research (using much more limited datasets) covering travel behavior in retails stores and other related settings. AbstractWe present analyses of an extraordinary new dataset that reveals the path taken by individual shoppers in an actual grocery store, as provided by RFID (radio frequency identification) tags located on their shopping carts. The analysis is performed using a multivariate clustering algorithm not yet seen in the marketing literature that is able to handle data sets with unique (and numerous) spatial constraints. This allows us to take into account physical impediments (such as the location of aisles and other inaccessible areas of the store) to ensure that we only deal with feasible paths. We also recognize that time spent in the store plays an important role, leading to different cluster configurations for short, medium, and long trips. The resulting three sets of clusters identify a total of 14 "canonical path types" that are typical of grocery store travel, and we carefully describe (and cross-validate) each set of clusters. These results dispel certain myths about shopper travel behavior that common intuition perpetuates, including behavior related to aisles, end-cap displays, and the "racetrack." We briefly relate these results to previous research (using much more limited datasets) covering travel behavior in retail stores and other related settings.

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Single doses of TNX-355 reduced plasma HIV-1 RNA loads and increased CD4+ T cell counts in HIV-infected subjects. The further assessment of therapeutic potential awaits data from longer-duration trials.

Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log 10 ) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4 ؉ T-cell receptors was correlated with serum ibalizumab concentrations. There was no evidence of CD4 ؉ T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.

ObjectiveTo compare the perioperative outcomes of robotic partial nephrectomy (RPN) with laparoscopic PN (LPN) performed for small renal masses (SRMs), in a large multi-institutional series and to define a new composite outcome measure, termed 'optimal outcome' for the RPN group. Patients and MethodsRetrospective review of 2392 consecutive cases of RPN and LPN performed in five high-volume centres from 2004 to mid-2013. We limited our study to SRMs and cases performed by surgeons with significant expertise with the technique. The Trifecta was defined as negative surgical margin, zero perioperative complications and a warm ischaemia time of ≤25 min. The 'optimal outcome' was defined as achievement of Trifecta with addition of 90% estimated glomerular filtration rate preservation and no chronic kidney disease stage upgrading. Univariable and multivariable analysis were used to identify factors predicting Trifecta and 'optimal outcome' achievement. ResultsIn all, 1185 RPN and 646 LPN met our inclusion criteria. Patients in the RPN group were older and had a higher median Charlson comorbidity index and higher R.E.N.A.L. nephrometry score. The RPN group had lower warm ischaemia time (18 vs 26 min), overall complication rate (16.2% vs 25.9%), and positive surgical margin rate (3.2% vs. 9.7%). There was a significantly higher Trifecta rate for RPN (70% vs 33%) and the rate of achievement of 'optimal outcome' for the RPN group was 38.5%. ConclusionsIn this large multi-institutional series RPN was superior to LPN for perioperative surgical outcomes measured by Trifecta. Patients in the RPN group had better outcomes for all three components of Trifecta compared with their LPN counterparts. Our more strict definition for 'optimal outcome' might be a better tool for assessing perioperative and functional outcomes after minimally invasive PN. This tool needs to be externally validated.

Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) commonly affect older men. Age-related changes associated with metabolic disturbances, changes in hormone balance, and chronic inflammation may cause BPH development. The diagnosis of BPH hinges on a thorough medical history and focused physical examination, with attention to other conditions that may be causing LUTS. Digital rectal examination and urinalysis should be performed. Other testing may be considered depending on presentation of symptoms, including prostate-specific antigen, serum creatinine, urine cytology, imaging, cystourethroscopy, post-void residual, and pressure-flow studies. Many medical and surgical treatment options exist. Surgery should be reserved for patients who either have failed medical management or have complications from BPH, such as recurrent urinary tract infections, refractory urinary retention, bladder stones, or renal insufficiency as a result of obstructive uropathy.

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