Immune checkpoint blockade (ICB) has emerged as a novel therapeutic tool for cancer therapy in the last decade. Unfortunately, a small number of patients benefit from approved immune checkpoint inhibitors (ICIs). Therefore, multiple studies are being conducted to find new ICIs and combination strategies to improve the current ICIs. In this review, we discuss some approved immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and also highlight newer emerging ICIs. For instance, HLA-E, overexpressed by tumor cells, represents an immune-suppressive feature by binding CD94/NKG2A, on NK and T cells. NKG2A blockade recruits CD8+ T cells and activates NK cells to decrease the tumor burden. NKG2D acts as an NK cell activating receptor that can also be a potential ICI. The adenosine A2A and A2B receptors, CD47-SIRPα, TIM-3, LAG-3, TIGIT, and VISTA are targets that also contribute to cancer immunoresistance and have been considered for clinical trials. Their antitumor immunosuppressive functions can be used to develop blocking antibodies. PARPs, mARTs, and B7-H3 are also other potential targets for immunosuppression. Additionally, miRNA, mRNA, and CRISPR-Cas9-mediated immunotherapeutic approaches are being investigated with great interest. Pre-clinical and clinical studies project these targets as potential immunotherapeutic candidates in different cancer types for their robust antitumor modulation.

Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, pro-inflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.

Alzheimer’s disease (AD), the major cause of dementia worldwide, is characterized by progressive loss of memory and cognition. The sporadic form of AD accounts for nearly 90% of the patients developing this disease. The last century has witnessed significant research to identify various mechanisms and risk factors contributing to the complex etiopathogenesis of AD by analyzing postmortem AD brains and experimenting with animal and cell culture based models. However, the treatment strategies, as of now, are only symptomatic. Accumulating evidences suggested a significant association between vitamin D deficiency, dementia, and AD. This review encompasses the beneficial role of vitamin D in neurocognition and optimal brain health along with epidemiological evidence of the high prevalence of hypovitaminosis D among aged and AD population. Moreover, disrupted signaling, altered utilization of vitamin D, and polymorphisms of several related genes including vitamin D receptor (VDR) also predispose to AD or AD-like neurodegeneration. This review explores the relationship between this gene-environmental influence and long term vitamin D deficiency as a risk factor for development of sporadic AD along with the role and rationale of therapeutic trials with vitamin D. It is, therefore, urgently warranted to further establish the role of this potentially neuroprotective vitamin in preventing and halting progressive neurodegeneration in AD patients.

The metabolic turnover of sphingolipids produces several signaling molecules that profoundly affect the proliferation, differentiation and death of cells. In particular, an enormous body of information is available that defines the varied role of ceramide and sphingosine-1-phosphate in cell death and survival. This review specifically examines the role of ceramide and sphingosine-1-phosphate in triggering neuronal death in Alzheimer's disease by analyzing the data from post-mortem studies and experimental research. There is compelling evidence that ceramide plays a key role in the neurodegeneration and amyloidogenesis occurring in the brain in Alzheimer's disease. Further, it appears that ceramide and amyloid beta protein orchestrate an attack on mitochondria to set in the pathways of cell death. However, the complexity of metabolic and signaling pathways of sphingolipid derivatives precludes an immediate identification of effective drug targets for the therapy of Alzheimer's disease.