Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts

The phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway is frequently deregulated in pancreatic cancers, and is believed to be an important determinant of their biological aggression and drug resistance. NVP-BEZ235 is a novel, dual class I PI3K/mammalian target of rapamycin (mTor) inhibitor undergoing phase I human clinical trials. To simulate clinical testing, the effects of NVP-BEZ235 were studied in five early passage primary pancreatic cancer xenografts, grown orthotopically. These tumours showed activated PKB/Akt, and increased levels of at least one of the receptor tyrosine kinases that are commonly activated in pancreatic cancers. Pharmacodynamic effects were measured following acute single doses, and anticancer effects were determined in separate groups following chronic drug exposure. Acute oral dosing with NVP-BEZ235 strongly suppressed the phosphorylation of PKB/Akt, followed by recovery over 24 h. There was also inhibition of Ser235/236 S6 ribosomal protein and Thr37/46 4E-BP1, consistent with the effects of NVP-BEZ235 as a dual PI3K/mTor inhibitor. Chronic dosing with 45 mg kg−1 of NVP-BEZ235 was well tolerated, and produced significant tumour growth inhibition in three models. These results predict that agents targeting the PI3K/Akt/mTor pathway might have anticancer activity in pancreatic cancer patients, and support the testing of combination studies involving chemotherapy or other molecular targeted agents

Lorentz violation, Gravity, Dissipation and Holography

We reconsider Lorentz Violation (LV) at the fundamental level. We show that Lorentz Violation is intimately connected with gravity and that LV couplings in QFT must always be fields in a gravitational sector. Diffeomorphism invariance must be intact and the LV couplings transform as tensors under coordinate/frame changes. Therefore searching for LV is one of the most sensitive ways of looking for new physics, either new interactions or modifications of known ones. Energy dissipation/Cerenkov radiation is shown to be a generic feature of LV in QFT. A general computation is done in strongly coupled theories with gravity duals. It is shown that in scale invariant regimes, the energy dissipation rate depends non-triviallly on two characteristic exponents, the Lifshitz exponent and the hyperscaling violation exponent.Comment: LateX, 51 pages, 9 figures. (v2) References and comments added. Misprints correcte

Source of Previous Treatment for Re-Treatment TB Cases Registered under the National TB Control Programme, India, 2010

BACKGROUND: In 2009, nearly half (289,756) of global re-treatment TB notifications are from India; no nationally-representative data on the source of previous treatment was available to inform strategies for improvement of initial TB treatment outcome. OBJECTIVES: To assess the source of previous treatment for re-treatment TB patients registered under India's Revised National TB control Programme (RNTCP). METHODOLOGY: A nationally-representative cross sectional study was conducted in a sample of 36 randomly-selected districts. All consecutively registered retreatment TB patients during a defined 15-day period in these 36 districts were contacted and the information on the source of previous treatment sought. RESULTS: Data was collected from all 1712 retreatment TB patients registered in the identified districts during the study period. The data includes information on 595 'relapse' cases, 105 'failure' cases, 437 'treatment after default (TAD)' cases and 575 're-treatment others' cases. The source of most recent previous anti-tuberculosis therapy for 754 [44% (95% CI, 38.2%-49.9%)] of the re-treatment TB patients was from providers outside the TB control programme. A higher proportion of patients registered as TAD (64%) and 'retreatment others' (59%) were likely to be treated outside the National Programme, when compared to the proportion among 'relapse' (22%) or 'failure' (6%). Extrapolated to national registration, of the 292,972 re-treatment registrations in 2010, 128,907 patients would have been most recently treated outside the national programme. CONCLUSIONS: Nearly half of the re-treatment cases registered with the national programme were most recently treated outside the programme setting. Enhanced efforts towards extending treatment support and supervision to patients treated by private sector treatment providers are urgently required to improve the quality of treatment and reduce the numbers of patients with recurrent disease. In addition, reasons for the large number of recurrent TB cases from those already treated by the national programme require urgent detailed investigation

Ambulatory Multi-Drug Resistant Tuberculosis Treatment Outcomes in a Cohort of HIV-Infected Patients in a Slum Setting in Mumbai, India

Background: India carries one quarter of the global burden of multi-drug resistant TB (MDR-TB) and has an estimated 2.5 million people living with HIV. Despite this reality, provision of treatment for MDR-TB is extremely limited, particularly for HIV-infected individuals. Médecins Sans Frontières (MSF) has been treating HIV-infected MDR-TB patients in Mumbai since May 2007. This is the first report of treatment outcomes among HIV-infected MDR-TB patients in India. Methods: HIV-infected patients with suspected MDR-TB were referred to the MSF-clinic by public Antiretroviral Therapy (ART) Centers or by a network of community non-governmental organizations. Patients were initiated on either empiric or individualized second-line TB-treatment as per WHO recommendations. MDR-TB treatment was given on an ambulatory basis and under directly observed therapy using a decentralized network of providers. Patients not already receiving ART were started on treatment within two months of initiating MDR-TB treatment. Results: Between May 2007 and May 2011, 71 HIV-infected patients were suspected to have MDR-TB, and 58 were initiated on treatment. MDR-TB was confirmed in 45 (78%), of which 18 (40%) were resistant to ofloxacin. Final treatment outcomes were available for 23 patients; 11 (48%) were successfully treated, 4 (17%) died, 6 (26%) defaulted, and 2 (9%) failed treatment. Overall, among 58 patients on treatment, 13 (22%) were successfully treated, 13 (22%) died, 7 (12%) defaulted, two (3%) failed treatment, and 23 (40%) were alive and still on treatment at the end of the observation period. Twenty-six patients (45%) experienced moderate to severe adverse events, requiring modification of the regimen in 12 (20%). Overall, 20 (28%) of the 71 patients with MDR-TB died, including 7 not initiated on treatment. Conclusions: Despite high fluoroquinolone resistance and extensive prior second-line treatment, encouraging results are being achieved in an ambulatory MDR-T- program in a slum setting in India. Rapid scale-up of both ART and second-line treatment for MDR-TB is needed to ensure survival of co-infected patients and mitigate this growing epidemic.</br

Surgical perspectives from a prospective, nonrandomized, multicenter study of breast conserving surgery and adjuvant electronic brachytherapy for the treatment of breast cancer

<p>Abstract</p> <p>Background</p> <p>Accelerated partial breast irradiation (APBI) may be used to deliver radiation to the tumor bed post-lumpectomy in eligible patients with breast cancer. Patient and tumor characteristics as well as the lumpectomy technique can influence patient eligibility for APBI. This report describes a lumpectomy procedure and examines patient, tumor, and surgical characteristics from a prospective, multicenter study of electronic brachytherapy.</p> <p>Methods</p> <p>The study enrolled 65 patients of age 45-84 years with ductal carcinoma or ductal carcinoma in situ, and 44 patients, who met the inclusion and exclusion criteria, were treated with APBI using the Axxent^®electronic brachytherapy system following lumpectomy. The prescription dose was 34 Gy in 10 fractions over 5 days.</p> <p>Results</p> <p>The lumpectomy technique as described herein varied by site and patient characteristics. The balloon applicator was implanted by the surgeon (91%) or a radiation oncologist (9%) during or up to 61 days post-lumpectomy (mean 22 days). A lateral approach was most commonly used (59%) for insertion of the applicator followed by an incision site approach in 27% of cases, a medial approach in 5%, and an inferior approach in 7%. A trocar was used during applicator insertion in 27% of cases. Local anesthetic, sedation, both or neither were administered in 45%, 2%, 41% and 11% of cases, respectively, during applicator placement. The prescription dose was delivered in 42 of 44 treated patients.</p> <p>Conclusions</p> <p>Early stage breast cancer can be treated with breast conserving surgery and APBI using electronic brachytherapy. Treatment was well tolerated, and these early outcomes were similar to the early outcomes with iridium-based balloon brachytherapy.</p

Transcultural Diabetes Nutrition Therapy Algorithm: The Asian Indian Application

India and other countries in Asia are experiencing rapidly escalating epidemics of type 2 diabetes (T2D) and cardiovascular disease. The dramatic rise in the prevalence of these illnesses has been attributed to rapid changes in demographic, socioeconomic, and nutritional factors. The rapid transition in dietary patterns in India—coupled with a sedentary lifestyle and specific socioeconomic pressures—has led to an increase in obesity and other diet-related noncommunicable diseases. Studies have shown that nutritional interventions significantly enhance metabolic control and weight loss. Current clinical practice guidelines (CPGs) are not portable to diverse cultures, constraining the applicability of this type of practical educational instrument. Therefore, a transcultural Diabetes Nutrition Algorithm (tDNA) was developed and then customized per regional variations in India. The resultant India-specific tDNA reflects differences in epidemiologic, physiologic, and nutritional aspects of disease, anthropometric cutoff points, and lifestyle interventions unique to this region of the world. Specific features of this transculturalization process for India include characteristics of a transitional economy with a persistently high poverty rate in a majority of people; higher percentage of body fat and lower muscle mass for a given body mass index; higher rate of sedentary lifestyle; elements of the thrifty phenotype; impact of festivals and holidays on adherence with clinic appointments; and the role of a systems or holistic approach to the problem that must involve politics, policy, and government. This Asian Indian tDNA promises to help guide physicians in the management of prediabetes and T2D in India in a more structured, systematic, and effective way compared with previous methods and currently available CPGs

Measuring Health Utilities in Children and Adolescents: A Systematic Review of the Literature.

BACKGROUND: The objective of this review was to evaluate the use of all direct and indirect methods used to estimate health utilities in both children and adolescents. Utilities measured pre- and post-intervention are combined with the time over which health states are experienced to calculate quality-adjusted life years (QALYs). Cost-utility analyses (CUAs) estimate the cost-effectiveness of health technologies based on their costs and benefits using QALYs as a measure of benefit. The accurate measurement of QALYs is dependent on using appropriate methods to elicit health utilities. OBJECTIVE: We sought studies that measured health utilities directly from patients or their proxies. We did not exclude those studies that also included adults in the analysis, but excluded those studies focused only on adults. METHODS AND FINDINGS: We evaluated 90 studies from a total of 1,780 selected from the databases. 47 (52%) studies were CUAs incorporated into randomised clinical trials; 23 (26%) were health-state utility assessments; 8 (9%) validated methods and 12 (13%) compared existing or new methods. 22 unique direct or indirect calculation methods were used a total of 137 times. Direct calculation through standard gamble, time trade-off and visual analogue scale was used 32 times. The EuroQol EQ-5D was the most frequently-used single method, selected for 41 studies. 15 of the methods used were generic methods and the remaining 7 were disease-specific. 48 of the 90 studies (53%) used some form of proxy, with 26 (29%) using proxies exclusively to estimate health utilities. CONCLUSIONS: Several child- and adolescent-specific methods are still being developed and validated, leaving many studies using methods that have not been designed or validated for use in children or adolescents. Several studies failed to justify using proxy respondents rather than administering the methods directly to the patients. Only two studies examined missing responses to the methods administered with respect to the patients' ages

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events