Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC

STANDARDIZATION IN VITRO ANTIOXIDANT ACTIVITY AND BRINE SHRIMP LETHALITY OF A POLYHERBAL FORMULATION

Shakti drops an Ayurvedic polyherbal formulation is an effective medicine for immuno modulatory activity. The formulation was prepared in the laboratory with authenticated organic plant drugs. The standardization procedure was conducted on the basis of physicochemical parameters and antimicrobial studies as directed by Ayurvedic formulary of India. Antioxidant activity is further performed based on its prescribed dose in three In-vitro antioxidant models. Physical characters remained unaltered throughout study, In antimicrobial activity total aerobic count was found to be 18×101 CFU/mL and total fungal count was found to be <10 CFU/mL. It is devoid of all tested microorganism i.e. Staphylococcus aureus, Salmonella typhi, Pseudomonas aeruginosa, Escherichia coli tested. In antioxidant activity the results of the study suggest that the Shiakti drops has potent antioxidant and free radical scavenging activity justifying its use in Rasayana

A New Method for Grain Texture Manipulation in Post-Deposition Niobium Films

Niobium films are frequently grown using forms of energetic condensation, with modest substrate temperatures to control grain structure. As an alternative, energetic deposition onto a cold substrate results in a dense amorphous film, with a much larger energy density than the re-crystallized state. Re-crystallization is then performed using a pulsed UV (HIPPO) laser, with minimal damage to the substrate. In addition, a graded interface between the substrate and Nb film is created during the early stages of energetic deposition. Experimental approach and apparatus are described

Guggulsterone Targets Smokeless Tobacco Induced PI3K/Akt Pathway in Head and Neck Cancer Cells

Epidemiological association of head and neck cancer with smokeless tobacco (ST) emphasizes the need to unravel the molecular mechanisms implicated in cancer development, and identify pharmacologically safe agents for early intervention and prevention of disease recurrence. Guggulsterone (GS), a biosafe nutraceutical, inhibits the PI3K/Akt pathway that plays a critical role in HNSCC development. However, the potential of GS to suppress ST and nicotine (major component of ST) induced HNSCC remains unexplored. We hypothesized GS can abrogate the effects of ST and nicotine on apoptosis in HNSCC cells, in part by activation of PI3K/Akt pathway and its downstream targets, Bax and Bad.Our results showed ST and nicotine treatment resulted in activation of PI3K, PDK1, Akt, and its downstream proteins--Raf, GSK3β and pS6 while GS induced a time dependent decrease in activation of PI3K/Akt pathway. ST and nicotine treatment also resulted in induction of Bad and Bax phosphorylation, increased the association of Bad with 14-3-3ζresulting in its sequestration in the cytoplasm of head and neck cancer cells, thus blocking its pro-apoptotic function. Notably, GS pre-treatment inhibited ST/nicotine induced activation of PI3K/Akt pathway, and inhibited the Akt mediated phosphorylation of Bax and Bad.In conclusion, GS treatment not only inhibited proliferation, but also induced apoptosis by abrogating the effects of ST/nicotine on PI3K/Akt pathway in head and neck cancer cells. These findings provide a rationale for designing future studies to evaluate the chemopreventive potential of GS in ST/nicotine associated head and neck cancer

Superconducting Prototype Cavities for the Spallation Neutron Source (SNS) Project

The Spallation Neutron Source project includes a superconducting linac section in the energy range from 186 MeV to 1000 MeV operating at a frequency of 805 MHz at 2.1 K. For this energy range two types of cavities are needed with geometrical Beta-values of Beta=0.61 and Beta=0.81. An aggressive cavity prototyping program is being pursued at JLab, which calls for fabricating and testing of four Beta=0.61 cavities and two Beta=0.81 cavities. Both types consist of six cells made from high purity niobium and feature one HOM coupler of the TESLA type on each beam pipe and a port for a high power coaxial input coupler. Three of the four Beta=0.61 cavities will be used for a cryomodule test in early 2002. At this time, four medium beta cavities and one high beta cavity have been completed and tested at JLab. In addition, the three medium beta cavities for the prototype cryomodule have been equipped with the integrated Ti-Helium vessel, successfully retested and will be assembled into a cavity string. Results from the cryo-module test should be available by the time of the conference. The tests on the Beta=0.61 cavity and the Beta=0.81 cavity exceeded the design values for gradient and Q - value: E{sub acc} =10.1 MV/m and Q = 5 x 10{sup 9} at 2.1K for Beta=0.61 and E{sub acc} = 12.3 MV/m and Q=5 x 10{sup 9} at 2.1K for Beta = 0.81. The medium beta cavities reached gradients between E{sub acc} = 15 MV/m and 21 MV/m. This paper will describe the test results obtained with the various cavities, some aspects of the HOM damping at cryogenic temperatures, results from microphonics and Lorentz force detuning tests and the cavity string assembly at the time of this workshop

Impact of measurement backaction on nuclear spin qubits in silicon

Phosphorus donor nuclear spins in silicon couple weakly to the environment making them promising candidates for high-fidelity qubits. The state of a donor nuclear spin qubit can be manipulated and read out using its hyperfine interaction with the electron confined by the donor potential. Here we use a master equation-based approach to investigate how the backaction from this electron-mediated measurement affects the lifetimes of single and multi-donor qubits. We analyze this process as a function of electric and magnetic fields, and hyperfine interaction strength. Apart from single nuclear spin flips, we identify an additional measurement-related mechanism, the nuclear spin flip-flop, which is specific to multi-donor qubits. Although this flip-flop mechanism reduces qubit lifetimes, we show that it can be effectively suppressed by the hyperfine Stark shift. We show that using atomic precision donor placement and engineered Stark shift, we can minimize the measurement backaction in multi-donor qubits, achieving larger nuclear spin lifetimes than single donor qubits

"My Children and I Will no Longer Suffer from Malaria": A Qualitative Study of the Acceptance and Rejection of Indoor Residual Spraying to Prevent Malaria in Tanzania.

The objective of this study was to identify attitudes and misconceptions related to acceptance or refusal of indoor residual spraying (IRS) in Tanzania for both the general population and among certain groups (e.g., farmers, fishermen, community leaders, and women). This study was a series of qualitative, semi-structured, in-depth interviews and focus group discussions conducted from October 2010 to March 2011 on Mainland Tanzania and Zanzibar. Three groups of participants were targeted: acceptors of IRS (those who have already had their homes sprayed), refusers (those whose communities have been sprayed, but refused to have their individual home sprayed), and those whose houses were about to be sprayed as part of IRS scale-up. Interviews were also conducted with farmers, fishermen, women, community leaders and members of non-government organizations responsible for community mobilization around IRS. Results showed refusers are a very small percentage of the population. They tend to be more knowledgeable people such as teachers, drivers, extension workers, and other civil servants who do not simply follow the orders of the local government or the sprayers, but are skeptical about the process until they see true results. Refusal took three forms: 1) refusing partially until thorough explanation is provided; 2) accepting spray to be done in a few rooms only; and 3) refusing outright. In most of the refusal interviews, refusers justified why their houses were not sprayed, often without admitting that they had refused. Reasons for refusal included initial ignorance about the reasons for IRS, uncertainty about its effectiveness, increased prevalence of other insects, potential physical side effects, odour, rumours about the chemical affecting fertility, embarrassment about moving poor quality possessions out of the house, and belief that the spray was politically motivated. To increase IRS acceptance, participants recommended more emphasis on providing thorough public education, ensuring the sprayers themselves are more knowledgeable about IRS, and asking that community leaders encourage participation by their constituents rather than threatening punishment for noncompliance. While there are several rumours and misconceptions concerning IRS in Tanzania, acceptance is very high and continues to increase as positive results become apparent

SuperTarget goes quantitative: update on drug–target interactions

There are at least two good reasons for the on-going interest in drug–target interactions: first, drug-effects can only be fully understood by considering a complex network of interactions to multiple targets (so-called off-target effects) including metabolic and signaling pathways; second, it is crucial to consider drug-target-pathway relations for the identification of novel targets for drug development. To address this on-going need, we have developed a web-based data warehouse named SuperTarget, which integrates drug-related information associated with medical indications, adverse drug effects, drug metabolism, pathways and Gene Ontology (GO) terms for target proteins. At present, the updated database contains >6000 target proteins, which are annotated with >330 000 relations to 196 000 compounds (including approved drugs); the vast majority of interactions include binding affinities and pointers to the respective literature sources. The user interface provides tools for drug screening and target similarity inclusion. A query interface enables the user to pose complex queries, for example, to find drugs that target a certain pathway, interacting drugs that are metabolized by the same cytochrome P450 or drugs that target proteins within a certain affinity range. SuperTarget is available at http://bioinformatics.charite.de/supertarget

The incidence of bilateral well-differentiated thyroid cancer found at completion thyroidectomy

The purpose of this study was to evaluate the surgical outcome of completion thyroidectomy in patients with presumed unilateral well-differentiated thyroid cancer (WDTC). The medical records of all patients having had unilateral thyroid lobectomy for WDTC, who subsequently underwent completion thyroidectomy, were reviewed. From 1980 to 1991, 60 patients with WDTC underwent completion thyroidectomy. Forty-seven patients had presumed unilateral WDTC, with no evidence of residual disease prior to their completion thyroidectomy. Twenty-five (53%) of these patients were found to have residual neoplastic disease in the neck. In 20 (43%) of 47 patients, a focus of cancer was found in the remaining thyroid lobe and in 5 additional patients no cancer was found in the contralateral lobe, however, unsuspected nodal disease was found. The remaining 13 of the 60 patients presented with either regional recurrence (n=12) or distant metastases (n=1) at the time of their completion thyroidectomy. All (92%) but 1 of these 13 patients had cancer in the remaining thyroid lobe. Multifocal disease in the primary lobe was associated with bilateral thyroid cancer ( p <0.01). Complications were infrequent; transient hypocalcemia occurred in 5 (8%) patients, permanent hypoparathyroidism occurred in 1 (1.7%) patient, and transient recurrent laryngeal nerve palsy occurred in 3 (5%) patients. Residual WDTC was found in 37 (62%) of 60 patients undergoing completion thyroidectomy. Multifocal disease in the primary resected lobe was associated with a high incidence of contralateral thyroid cancer. Completion thyroidectomy is a safe procedure and may prevent the development of regional recurrence by eliminating an unsuspected focus of cancer. Le but de cette étude était d'évaluer l'évolution chirurgicale après thyroïdectomie totale des patients ayant un cancer thyroïdien présumé bien différencié et unilatéral (CTBD). Les données médicales de tous les patients ayant eu une lobectomie unilatérale de la thyroïde pour CTBD et qui ont eu secondairement une totalisation de la thyroïdectomie ont été revues. Entre 1980 et 1991, 60 patients ayant un CTBD ont eu une totalisation de la thyroïdectomie, quarante sept avaient un CTBD présumé unilatéral, sans argument pour une pathologie résiduelle avant la totalisation de la thyroïdectomie (groupe 1). Vingt cinq d'entre eux (53%) se sont avérés avoir un reliquat néoplasique persistant au niveau de la région cervicale. Chez 20/47 (43%) patients, on a retrouvé un foyer de cancer dans le lobe restant de la thyroïde. Chez 5 patients supplémentaires il n'a pas été retrouvé de cancer dans le lobe controlatéral mais une dystrophie nodulaire non suspecte. Les 13/60 patients restants présentaient soit une récidive régionale (12) soit des métastases à distance (1) au moment de la totalisation de la thyroïdectomie (groupe 2). Tous les patients du groupe 2 sauf un (92%) avaient un cancer dans le lobe restant. Une atteinte plurifocale dans le premier lobe était associée avec l'existence d'un cancer bilatéral ( p <0.01). Les complications ont été rares: une hypocalcémie transitoire est survenue chez 5 (8%) patients, une hypoparathyroïdie définitive est apparue chez 1 (1.7%) patient. Une paralysie récurentielle transitoire a été retrouvée chez 3 (5%) patients. Conclusions: Un reliquat de TCBD a été retrouvé chez 37/60 (62%) patients opérés d'une totalisation de thyroïdectomie. L'atteinte multifocale dans le premier lobe réséqué était associée avec une incidence élevée de cancer thyroïdien controlatéral. La totalisation de la thyroïdectomie est une procédure sans risque qui peut prévenir le développement d'une récidive régionale en éliminant un foyer de cancer non suspecté. El propósito del presente estudio fue valorar el resultado quirúrgico de completar a una tiroidectomía total la resección tiroidea realizada en pacientes con cáncer presumiblemente unilateral y bien diferenciado de la glándula tiroides (CTBD). Se revisaron las historias clínicas de todos los pacientes sometidos a lobectomía tiroidea unilateral por CTBD, en quienes subsiguientemente se completó la tiroidectomía, procedimiento que fue realizado en 60 pacientes con CTBD en el período 1980–1991. Cuarenta y siete pacientes tenían CTBD presumiblemente unilateral, sin evidencia de enfermedad residual antes de completarse la tiroidectomía (grupo 1); en veinticinco (53%) de estos pacientes se halló neoplasia residual en el cuello. En 20/47 (43%) pacientes se encontró un foco de cáncer en el lóbulo tiroideo remanente y en 5 casos adicionales aunque no se encontró cáncer en el lóbulo contralateral, se halló extensión ganglionar no sospechada. Los 13/60 pacientes restantes presentaron recurrencia (12) o metástasis distantes (1) en el momento de completarse la tiroidectomía (grupo 2). Todos los pacientes del grupo 2, excepto 1 (92%), presentaban cáncer en el lóbulo remanente. La presencia de enfermedad multifocal en el lóbulo primario apareció asociada con cáncer tiroideo bilateral ( p <0.01). Las complicaciones fueron raras; se presentó hipocalcemia transitoria en 5 (8%) pacientes, hipotiroidismo permanente en 1 (1.7%) y parálisis parcial y transitoria del nervio laríngeo recurrente en 3 (5%). Conclusiones: Se encontró CTBD en 37/60 (62%) pacientes en quienes se completó la tiroidectomía. La presencia de enfermedad multifocal en el lóbulo primario resecado apareció asociada con una alta incidencia de cáncer contralateral. El procedimiento de completar la tiroidectomía aparece como una operación segura que puede prevenir el desarrollo recurrencia regional al eliminar focos insospechados de cáncer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41292/1/268_2005_Article_BF02067365.pd