Brain stimulation treatments in epilepsy: Basic mechanisms and clinical advances

Drug-resistant epilepsy, characterized by ongoing seizures despite appropriate trials of anti-seizure medications, affects approximately one-third of people with epilepsy. Brain stimulation has recently become available as an alternative treatment option to reduce symptomatic seizures in short and long-term follow-up studies. Several questions remain on how to optimally develop patient-specific treatments and manage therapy over the long term. This review aims to discuss the clinical use and mechanisms of action of Responsive Neural Stimulation and Deep Brain Stimulation in the treatment of epilepsy and highlight recent advances that may both improve outcomes and present new challenges. Finally, a rational approach to device selection is presented based on current mechanistic understanding, clinical evidence, and device features

Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity

The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 and subsequent decreased binding to the Hsp90 inhibitor ganetespib. Pharmacologic inhibition of histone deacetylases (HDACs) restores acetylation of Hsp90 and sensitizes Tsc1-mutant bladder cancer cells to ganetespib, resulting in apoptosis. Our findings suggest that TSC1 status may predict response to Hsp90 inhibitors in patients with bladder cancer, and co-targeting HDACs can sensitize tumors with Tsc1 mutations to Hsp90 inhibitors

Inference and Optimization of Real Edges on Sparse Graphs - A Statistical Physics Perspective

Inference and optimization of real-value edge variables in sparse graphs are studied using the Bethe approximation and replica method of statistical physics. Equilibrium states of general energy functions involving a large set of real edge-variables that interact at the network nodes are obtained in various cases. When applied to the representative problem of network resource allocation, efficient distributed algorithms are also devised. Scaling properties with respect to the network connectivity and the resource availability are found, and links to probabilistic Bayesian approximation methods are established. Different cost measures are considered and algorithmic solutions in the various cases are devised and examined numerically. Simulation results are in full agreement with the theory.Comment: 21 pages, 10 figures, major changes: Sections IV to VII updated, Figs. 1 to 3 replace

Microorganisms in the Stratosphere (MIST): In-flight Sterilization with UVC Leds

The stratosphere (10 km to 50 km above sea level) is a unique place on Earth for astrobiological studies of microbes in extreme environments due to the combination of harsh conditions (high ultraviolet radiation, low pressure, desiccation, and low temperatures). Microorganisms in the Stratosphere (MIST) will attempt to characterize the diversity of microbes at these altitudes using a balloon collection device on a meteorological weather balloon. A major challenge of such an aerobiology study is the potential for ground contamination that makes it difficult to distinguish between collected microbes and contaminants. One solution is to use germicidal ultraviolet light emitting diodes (UV LEDs) to sterilize the collection strip. To use this solution, an optimal spatial arrangement of the lights had to be determined to ensure the greatest chance of complete sterilization within the 30 to 60 minute time of balloon ascent. A novel, 3D-printed test stand was developed to experimentally determine viable Bacillus pumilus SAFR-032 spore reduction after exposure to ultraviolet radiation at various times, angles, and distances. Taken together, the experimental simulations suggested that the UV LEDs on the MIST flight hardware should be active for at least 15 minutes and mounted within 4 cm of the illuminated surface at any angle to achieve optimal sterilization. These findings will aid in the production of the balloon collection device to ensure pristine stratospheric microbial samples are collected. Flight hardware capable of in-flight self-sterilization will enable future life detection missions to minimize both forward contamination and false positives

Success rates of re-excision after positive margins for invasive lobular carcinoma of the breast.

Rates of positive margins after surgical resection of invasive lobular carcinoma (ILC) are high (ranging from 18 to 60%), yet the efficacy of re-excision lumpReceptor subtypeectomy for clearing positive margins is unknown. Concerns about the diffuse nature of ILC may drive increased rates of completion mastectomy to treat positive margins, thus lowering breast conservation rates. We therefore determined the success rate of re-excision lumpectomy in women with ILC and positive margins after surgical resection. We identified 314 cases of stage I-III ILC treated with breast conserving surgery (BCS) at the University of California, San Francisco. Surgical procedures, pathology reports, and outcomes were analyzed using univariate and multivariate statistics and Cox-proportional hazards models. We evaluated outcomes before and after the year 2014, when new margin management consensus guidelines were published. Positive initial margins occurred in 118 (37.6%) cases. Of these, 62 (52.5%) underwent re-excision lumpectomy, which cleared the margin in 74.2%. On multivariate analysis, node negativity was significantly associated with successful re-excision (odds ratio [OR] 3.99, 95% CI 1.15-13.81, p = 0.029). After 2014, we saw fewer initial positive margins (42.7% versus 25.5%, p = 0.009), second surgeries (54.6% versus 20.2%, p < 0.001), and completion mastectomies (27.7% versus 4.5%, p < 0.001). In this large cohort of women with ILC, re-excision lumpectomy was highly successful at clearing positive margins. Additionally, positive margins and completion mastectomy rates significantly decreased over time. These findings highlight improvements in management of ILC, and suggest that completion mastectomy may not be required for those with positive margins after initial BCS

Community-Based Health and Exposure Study around Urban Oil Developments in South Los Angeles.

Oilfield-adjacent communities often report symptoms such as headaches and/or asthma. Yet, little data exists on health experiences and exposures in urban environments with oil and gas development. In partnership with Promotoras de Salud (community health workers), we gathered household surveys nearby two oil production sites in Los Angeles. We tested the capacity of low-cost sensors for localized exposure estimates. Bilingual surveys of 205 randomly sampled residences were collected within two 1500 ft. buffer areas (West Adams and University Park) surrounding oil development sites. We used a one-sample proportion test, comparing overall rates from the California Health Interview Survey (CHIS) of Service Planning Area 6 (SPA6) and Los Angeles County for variables of interest such as asthma. Field calibrated low-cost sensors recorded methane emissions. Physician diagnosed asthma rates were reported to be higher within both buffers than in SPA6 or LA County. Asthma prevalence in West Adams but not University Park was significantly higher than in Los Angeles County. Respondents with diagnosed asthma reported rates of emergency room visits in the previous 12 months similar to SPA6. 45% of respondents were unaware of oil development; 63% of residents would not know how to contact local regulatory authorities. Residents often seek information about their health and site-related activities. Low-cost sensors may be useful in highlighting differences between sites or recording larger emission events and can provide localized data alongside resident-reported symptoms. Regulatory officials should help clarify information to the community on methods for reporting health symptoms. Our community-based participatory research (CBPR) partnership supports efforts to answer community questions as residents seek a safety buffer between sensitive land uses and active oil development