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Tremelimumab, an anti‐cytotoxic T‐lymphocyte antigen‐4 monoclonal antibody that enhances T‐cell activation, was evaluated in a randomized, double‐blind, placebo‐controlled, phase IIb study (NCT01843374) in patients with unresectable malignant mesothelioma. The study demonstrated no clinically meaningful differences in overall survival (OS). The objective of this analysis was to evaluate the relationship of exposure with OS. A population pharmacokinetic (PK) model adequately described the PK data. Three factors (sex, C‐reactive protein, and baseline tumor size) were identified as statistically significant PK predictors (P

Abstract Background TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists are attractive anti-tumor agents because of their capability to induce apoptosis in cancer cells by activating death receptors (DR) 4 and 5 with little toxicity against normal cells. Despite an attractive mechanism of action, previous clinical efforts to use TRAIL receptor agonists have been unsuccessful. In this study, we examined MEDI3039, a highly potent multivalent DR5 agonist, in breast cancer cell lines and in vivo models. Methods As in vitro model systems, we used 19 breast cancer cell lines that are categorized into four subtypes: ER+, HER2 amplified, basal A (triple-negative breast cancer) TNBC, and basal B TNBC. Cell viability was analyzed by MTS and RealTime live/dead assays. As in vivo model systems, MDA-MB231T orthotopic primary tumor growth in the mammary fat pad (MFP) and two experimental lung metastasis models were used. The effect of MEDI3039 on MFP tumors was assessed with immunohistochemical analysis. Lung metastases were analyzed with Bouin’s and H&E staining. Results MEDI3039 killed multiple breast cancer cell lines, but the sensitivity varied among different subtypes. Sensitivity was basal B TNBC >> basal A TNBC > HER2 amplified > ER+ (average IC50 = 1.4, 203, 314, 403 pM, respectively). While the pattern of relative sensitivity was similar to GST-TRAIL in most cell lines, MEDI3039 was at least two orders of magnitude more potent compared with GST-TRAIL. In the MFP model, weekly treatment with 0.1 or 0.3 mg/kg MEDI3039 for 5 weeks inhibited tumor growth by 99.05% or 100% (median), respectively, compared with the control group, and extended animal survival (p = 0.08 or p = 0.0032 at 0.1 or 0.3 mg/kg, respectively). MEDI3039-induced caspase activation was confirmed in tumors grown in MFP (p 4 mm], p

There are no approved drug therapies that can prevent or slow the progression of Parkinson's disease (PD). Accumulation and aggregation of α-synuclein protein is observed throughout the nervous system in PD. α-Synuclein is a core component of Lewy bodies and neurites that neuropathologically define PD, suggesting that α-synuclein may be a key causative agent in PD. Recent experimental data suggest that PD progression may arise due to spreading of pathological forms of extracellular α-synuclein throughout the brain via a cellular release, uptake and seeding mechanism. We have developed a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo. MEDI1341 binds both monomeric and aggregated forms of α-synuclein. In vitro, MEDI1341 blocks cell-to-cell transmission of pathologically relevant α-synuclein preformed fibrils (pffs). After intravenous injection into rats and cynomolgus monkeys, MEDI1341 rapidly enters the central nervous system and lowers free extracellular α-synuclein levels in the interstitial fluid (ISF) and cerebrospinal fluid (CSF) compartments. Using a novel lentiviral-based in vivo mouse model of α-synuclein spreading in the brain, we show that treatment with MEDI1341 significantly reduces α-synuclein accumulation and propagation along axons. In this same model, we demonstrate that an effector-null version of the antibody was equally as effective as one with effector function. MEDI1341 is now in Phase 1 human clinical trial testing as a novel treatment for α-synucleinopathies including PD with the aim to slow or halt disease progression.

Universal Health Coverage (UHC) is now the critical yardstick for countries to measure and track progress toward the “Sustainable Development Goals (SDGs).” Being a signatory, India has started taking measures to attain the targets laid out within the SDG framework and achieving the UHC. With India's National Health Policy (NHP) – 2017 in place, the policy environment for transforming country's health landscape coincides with that of the global approach toward strengthening of health systems and achieving UHC. It is imperative that for achieving the desired outcomes laid down in the SDGs and NHP-2017, coordinated actions are required including political action for making health an individual's right; effective stewardship from the National Ministry of Health and Family Welfare; reorganization of health-care service delivery implementing a “systems approach;” ensuring financial protection against health-care costs; and enhancing community participation and accountability. Undertaking these steps, imbibing the learning, and dwelling upon global experiences can help the country strongly move forward towards achieving global and national targets, thereby ensuring UHC for all its citizens.

The low response rate of immune checkpoint blockade in breast cancer has highlighted the need for predictive biomarkers to identify responders. While a number of clinical trials are ongoing, testing all possible combinations is not feasible. In this study, a quantitative systems pharmacology model is built to integrate immune–cancer cell interactions in patients with breast cancer, including central, peripheral, tumour-draining lymph node (TDLN) and tumour compartments. The model can describe the immune suppression and evasion in both TDLN and the tumour microenvironment due to checkpoint expression, and mimic the tumour response to checkpoint blockade therapy. We investigate the relationship between the tumour response to checkpoint blockade therapy and composite tumour burden, PD-L1 expression and antigen intensity, including their individual and combined effects on the immune system, using model-based simulations. The proposed model demonstrates the potential to make predictions of tumour response of individual patients given sufficient clinical measurements, and provides a platform that can be further adapted to other types of immunotherapy and their combination with molecular-targeted therapies. The patient predictions demonstrate how this systems pharmacology model can be used to individualize immunotherapy treatments. When appropriately validated, these approaches may contribute to optimization of breast cancer treatment.

Objectives: National Rural Health Mission (NRHM) – India was launched in 2005 to tackle urban-rural health inequalities, especially in maternal and child health. We examined national and state level trends in Infant Mortality Rates (IMR) from 2000 through 2009 to: 1) assess whether the NRHM had increased the average annual reduction rate (AARR) of IMR 2) evaluate state-wise progress towards Millennium Development Goals (MDG4) and estimate required AARRs for ‘off track’ states. Methods: Log-linear regression models were applied to national and state IMR data collated from the Sample Registration System (SRS)-India to estimate average annual reduction rates and compare AAARs before and after introduction of NRHM. The log-linear trend of infant mortality rates was also projected forward to 2015. Results: The infant mortality rate in rural India declined from 74 to 55/1000 live births between 2000 and 2009, with AARR of 3.0% (95% CI=2.6%-3.4%) and the urban-rural gap in infant mortality narrowed (p =0.036). However there was no evidence (p=0.49) that AARR in rural India increased post NRHM (3.4%, 95% CI 2.0-4.7%) compared to pre NRHM (2.8%, 95% CI 2.1%-3.5%). States varied widely in rates of infant mortality reduction. Projections of infant mortality rates suggested that only eight states might be on track to help India achieve MDG4 by 2015. Conclusions and Public Health Implications: Despite a narrowing urban-rural gap and high AARRs in some states, there was no evidence that the rate of reduction in infant mortality has increased in rural India post NRHM introduction. India appears unlikely to achieve child survival-related NRHM and millennium development goals. Government should revisit the child survival related NRHM strategies and ensure equitable access to health services. More robust monitoring and evaluation mechanisms must be inbuilt for following years.

Objectives: National Rural Health Mission (NRHM) – India was launched in 2005 to tackle urban-rural health inequalities, especially in maternal and child health. We examined national and state level trends in Infant Mortality Rates (IMR) from 2000 through 2009 to: 1) assess whether the NRHM had increased the average annual reduction rate (AARR) of IMR 2) evaluate state-wise progress towards Millennium Development Goals (MDG4) and estimate required AARRs for ‘off track’ states. Methods: Log-linear regression models were applied to national and state IMR data collated from the Sample Registration System (SRS)-India to estimate average annual reduction rates and compare AAARs before and after introduction of NRHM. The log-linear trend of infant mortality rates was also projected forward to 2015. Results: The infant mortality rate in rural India declined from 74 to 55/1000 live births between 2000 and 2009, with AARR of 3.0% (95% CI=2.6%-3.4%) and the urban-rural gap in infant mortality narrowed (p =0.036). However there was no evidence (p=0.49) that AARR in rural India increased post NRHM (3.4%, 95% CI 2.0-4.7%) compared to pre NRHM (2.8%, 95% CI 2.1%-3.5%). States varied widely in rates of infant mortality reduction. Projections of infant mortality rates suggested that only eight states might be on track to help India achieve MDG4 by 2015. Conclusions and Public Health Implications: Despite a narrowing urban-rural gap and high AARRs in some states, there was no evidence that the rate of reduction in infant mortality has increased in rural India post NRHM introduction. India appears unlikely to achieve child survival-related NRHM and millennium development goals. Government should revisit the child survival related NRHM strategies and ensure equitable access to health services. More robust monitoring and evaluation mechanisms must be inbuilt for following years. Key Words: India • National Rural Health Mission • Infant Mortality Rate • Millennium Development Goals • Health Systems Copyright © 2013 Narwal et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.