The landscape of advanced non-small lung cancer (NSCLC) therapies has rapidly been evolving beyond chemotherapy over the last few years. The discovery of oncogenic driver mutations has led to new ...ways in classifying NSCLC as well as offered novel therapeutic targets for anticancer therapy. Targets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with appropriate tyrosine kinase inhibitors (TKIs). Other driver mutations such as ROS, MET, RET, BRAF have also been investigated with targeted agents with some success in the early phase clinical setting. Novel strategies in the field of immune-oncology have also led to the development of inhibitors of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 receptor (PD-1), which are important pathways in allowing cancer cells to escape detection by the immune system. These inhibitors have been successfully tried in NSCLC and also now bring the exciting possibility of long term responses in advanced NSCLC. In this review recent data on novel targets and therapeutic strategies and their future prospects are discussed.
Developing an immunogen that elicits broadly neutralizing antibodies (bNAbs) is an elusive but important goal of HIV vaccine research, especially after the recent failure of the leading T cell based ...HIV vaccine in human efficacy trials. Even if such an immunogen can be developed, most animal model studies indicate that high serum neutralizing concentrations of bNAbs are required to provide significant benefit in typical protection experiments. One possible exception is provided by the anti-glycan bNAb 2G12, which has been reported to protect macaques against CXCR4-using SHIV challenge at relatively low serum neutralizing titers. Here, we investigated the ability of 2G12 administered intravenously (i.v.) to protect against vaginal challenge of rhesus macaques with the CCR5-using SHIV(SF162P3). The results show that, at 2G12 serum neutralizing titers of the order of 1:1 (IC(90)), 3/5 antibody-treated animals were protected with sterilizing immunity, i.e. no detectable virus replication following challenge; one animal showed a delayed and lowered primary viremia and the other animal showed a course of infection similar to 4 control animals. This result contrasts strongly with the typically high titers observed for protection by other neutralizing antibodies, including the bNAb b12. We compared b12 and 2G12 for characteristics that might explain the differences in protective ability relative to neutralizing activity. We found no evidence to suggest that 2G12 transudation to the vaginal surface was significantly superior to b12. We also observed that the ability of 2G12 to inhibit virus replication in target cells through antibody-mediated effector cell activity in vitro was equivalent or inferior to b12. The results raise the possibility that some epitopes on HIV may be better vaccine targets than others and support targeting the glycan shield of the envelope.
Rheumatic heart disease remains an important preventable cause of cardiovascular death and disability, particularly in low-income and middle-income countries. We estimated global, regional, and ...national trends in the prevalence of and mortality due to rheumatic heart disease as part of the 2015 Global Burden of Disease study.
We systematically reviewed data on fatal and nonfatal rheumatic heart disease for the period from 1990 through 2015. Two Global Burden of Disease analytic tools, the Cause of Death Ensemble model and DisMod-MR 2.1, were used to produce estimates of mortality and prevalence, including estimates of uncertainty.
We estimated that there were 319,400 (95% uncertainty interval, 297,300 to 337,300) deaths due to rheumatic heart disease in 2015. Global age-standardized mortality due to rheumatic heart disease decreased by 47.8% (95% uncertainty interval, 44.7 to 50.9) from 1990 to 2015, but large differences were observed across regions. In 2015, the highest age-standardized mortality due to and prevalence of rheumatic heart disease were observed in Oceania, South Asia, and central sub-Saharan Africa. We estimated that in 2015 there were 33.4 million (95% uncertainty interval, 29.7 million to 43.1 million) cases of rheumatic heart disease and 10.5 million (95% uncertainty interval, 9.6 million to 11.5 million) disability-adjusted life-years due to rheumatic heart disease globally.
We estimated the global disease prevalence of and mortality due to rheumatic heart disease over a 25-year period. The health-related burden of rheumatic heart disease has declined worldwide, but high rates of disease persist in some of the poorest regions in the world. (Funded by the Bill and Melinda Gates Foundation and the Medtronic Foundation.).
A comprehensive understanding of the development and evolution of human B cell responses induced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a ...high-throughput single B cell cloning technology to longitudinally track the human B cell response to the yellow fever virus 17D (YFV-17D) vaccine. The early memory B cell (MBC) response was mediated by both classical immunoglobulin M (IgM) (IgM⁺CD27⁺) and switched immunoglobulin (swIg⁺) MBC populations; however, classical IgM MBCs waned rapidly, whereas swIg⁺ and atypical IgM⁺ and IgD⁺ MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination.
Most animal studies using passive administration of HIV broadly neutralizing monoclonal antibodies (bnMAbs) have associated protection against high-dose mucosal viral challenge with relatively high ...serum concentrations of antibody. We recently identified several bnMAbs remarkable for their in vitro potency against HIV. Of these bnMAbs, PGT121 is one of the most broad and potent antibodies isolated to date and shows 10- to 100-fold higher neutralizing activity than previously characterized bnMAbs. To evaluate the protective potency of PGT121 in vivo, we performed a protection study in rhesus macaques. Animals were i.v. administered 5 mg/kg, 1 mg/kg, or 0.2 mg/kg PGT121 24 h before being vaginally challenged with a single high dose of chimeric simian-human immunodeficiency virus (SHIV) SF₁₆₂P₃. Sterilizing immunity was achieved in all animals administered 5 mg/kg and 1 mg/kg and three of five animals administered 0.2 mg/kg PGT121, with corresponding average antibody serum concentrations of 95 µg/mL, 15 µg/mL, and 1.8 µg/mL, respectively. The results suggest that a protective serum concentration for PGT121 is in the single-digit µg/mL for SHIV SF₁₆₂P₃, showing that PGT121 can mediate sterilizing immunity at serum concentrations that are significantly lower than those observed in previous studies and that may be achievable through vaccination with the development of a suitable immunogen.
The recent failure of the T-cell-based HIV vaccine trial led by Merck & Co., Inc. prompts the urgent need to refocus on the question of which T-cell responses are required to control HIV replication. ...The well-described association between the expression of particular MHC class I molecules and successful containment of HIV or, in the macaque model, SIV replication provide a valuable starting point from which to evaluate more precisely what might constitute effective CD8(+) T-cell responses. Here, we review recent studies of T-cell-mediated control of HIV and SIV infection, and offer insight for the design of a successful T-cell-based HIV vaccine in the future.
Most countries have made little progress in achieving the Sustainable Development Goal (SDG) target 3.4, which calls for a reduction in premature mortality from non-communicable diseases (NCDs) by a ...third from 2015 to 2030. In this Health Policy paper, we synthesise the evidence related to interventions that can reduce premature mortality from the major NCDs over the next decade and that are feasible to implement in countries at all levels of income. Our recommendations are intended as generic guidance to help 123 low-income and middle-income countries meet SDG target 3.4; country-level applications require additional analyses and consideration of the local implementation and utilisation context. Protecting current investments and scaling up these interventions is especially crucial in the context of COVID-19-related health system disruptions. We show how cost-effectiveness data and other information can be used to define locally tailored packages of interventions to accelerate rates of decline in NCD mortality. Under realistic implementation constraints, most countries could achieve (or almost achieve) the NCD target using a combination of these interventions; the greatest gains would be for cardiovascular disease mortality. Implementing the most efficient package of interventions in each world region would require, on average, an additional US$18 billion annually over 2023–30; this investment could avert 39 million deaths and generate an average net economic benefit of $2·7 trillion, or $390 per capita. Although specific clinical intervention pathways would vary across countries and regions, policies to reduce behavioural risks, such as tobacco smoking, harmful use of alcohol, and excess sodium intake, would be relevant in nearly every country, accounting for nearly two-thirds of the health gains of any locally tailored NCD package. By 2030, ministries of health would need to contribute about 20% of their budgets to high-priority NCD interventions. Our report concludes with a discussion of financing and health system implementation considerations and reflections on the NCD agenda beyond the SDG target 3.4 and beyond the SDG period.
Rheumatic heart disease (RHD) is a preventable heart condition that remains endemic among vulnerable groups in many countries. After a period of relative neglect, there has been a resurging interest ...in RHD worldwide over the past decade. In this Scientific Expert Panel, the authors summarize recent advances in the science of RHD and sketch out priorities for current action and future research. Key questions for laboratory research into disease pathogenesis and epidemiological research on the burden of disease are identified. The authors present a variety of pressing clinical research questions on optimal RHD prevention and advanced care. In addition, they propose a policy and implementation research agenda that can help translate current evidence into tangible action. The authors maintain that, despite knowledge gaps, there is sufficient evidence for national and global action on RHD, and they argue that RHD is a model for strengthening health systems to address other cardiovascular diseases in limited-resource countries.
Global vaccine production capacity in non-pandemic times is too small and too concentrated in a handful of pharmaceutical companies.2 The first pillar of our proposed compact would be for countries ...to adopt the idea of a fully immunised adult, and launch national adult vaccination programmes. Analogously, preliminary data in preprint suggest that annual influenza vaccination reduces the risk of innza pandemics and perhaps even COVID-19 infection.5 Should SARS-CoV-2 vaccination need to be seasonal, adult vaccination programmes establish a delivery platform. ...the world might well be entering the era where major zoonotic diseases are not events that happen once a century but once a decade. A third pillar requires rapidly expanding production capacity by private pharmaceutical companies without encouraging the rent-seeking behaviour enabled by patent law.2 In theory, the large pharmaceutical companies in the state of California, USA, could meet much of the world's COVID-19 vaccine needs if appropriately incentivised.
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