Targeting PD-1/PD-L1 in cancer immunotherapy:An effective strategy for treatment of triple-negative breast cancer(TNBC)patients

Maintaining the balance between eliciting immune responses against foreign pro-teins and tolerating self-proteins is crucial for maintenance of homeostasis.The functions of programmed death protein 1(PD-1)and its ligand programmed death ligand 1(PD-L1)are to inhibit immune responses so that over-reacting immune cells does not cause any damage to its own body cells.However,cancer cells hijack this mechanism to attenuate immune cells functions and create an immunosuppressive environment that fuel their continuous growth and proliferation.Over the past few years’rapid development in cancer immunotherapy has opened a new avenue in cancer treatment.Blockade of PD-1 and PD-L1 has become a potential strategy that rescue the functions of immune cells to fight against cancer with high efficacy.Initially,immune checkpoint monotherapies were not very successful,making breast cancer less immunogenic.Although,recent reports support the presence of tumor infiltrating lympho-cytes(TILs)in breast cancer that make it favorable for PD-1/PD-L1 mediated immunotherapy,which is effective in PD-L1 positive patients.Recently,anti-PD-1(pembrolizumab)and anti-PD-L1(atezolizumab)gets FDA approval for breast cancer treatment and make PD-1/PD-L1 immunotherapy is meaningful for further research.Likewise,this article gathered understand-ing of PD-1 and PD-L1 in recent years,their signaling networks,interaction with other mole-cules,regulations of their expressions and functions in both normal and tumor tissue microenvironments are crucial to find and design therapeutic agents that block this pathway and improve the treatment efficacy.Additionally,authors collected and highlighted most of the important clinical trial reports on monotherapy and combination therapy.

DEAD-box RNA helicases with special reference to p68:Unwinding their biology,versatility,and therapeutic opportunity in cancer

In the era of advancement,the entire world continues to remain baffled by the increased rate of progression of cancer.There has been an unending search for novel thera-peutic targets and prognostic markers to curb the oncogenic scenario.The DEAD-box RNA he-licases are a large family of proteins characterized by their evolutionary conserved D-E-A-D(Asp-Glu-Ala-Asp)domain and merit consideration in the oncogenic platform.They perform multidimensional functions in RNA metabolism and also in the pathology of cancers.Their bio-logical role ranges from ribosome biogenesis,RNA unwinding,splicing,modification of second-ary and tertiary RNA structures to acting as transcriptional coactivators/repressors of various important oncogenic genes.They also play a crucial role in accelerating oncogenesis by pro-moting cell proliferation and metastasis.DDX5(p68)is one of the archetypal members of this family of proteins and has gained a lot of attention due to its oncogenic attribute.It is found to be overexpressed in major cancer types such as colon,brain,breast,and prostate cancer.It exhibits its multifaceted nature by not only coactivating genes implicated in cancers but also mediating crosstalk across major signaling pathways in cancer.Therefore,in this review,we aim to illustrate a comprehensive overview of DEAD-box RNA helicases especially p68 by focusing on their multifaceted roles in different cancers and the various signaling pathways affected by them.Further,we have also briefly discoursed the therapeutic interventional approaches with the DEAD-box RNA helicases as the pharmacological targets for designing in-hibitors to pave way for cancer therapy.

COVID-19 therapeutics:Clinical application of repurposed drugs and futuristic strategies for target-based drug discovery

Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)causes the compli-cated disease COVID-19.Clinicians are continuously facing huge problems in the treatment of patients,as COVID-19-specific drugs are not available,hence the principle of drug repurpos-ing serves as a one-and-only hope.Globally,the repurposing of many drugs is underway;few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials.Here in this review,our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs,the potential mechanism of actions,and the current clinical trial status of various drugs which are under repurposing since early 2020.At last,we briefly proposed the probable phar-macological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.

The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports

Glioma and cerebral ischemic stroke are two major events that lead to patient death worldwide.Although these conditions have different physiological incidences,~10%of ischemic stroke patients develop cerebral cancer,especially glioma,in the postischemic stages.Additionally,the high proliferation,venous thrombosis and hypercoagulability of the glioma mass increase the significant risk of thromboembolism,including ischemic stroke.Surprisingly,these events share several common pathways,viz.hypoxia,cerebral inflammation,angiogenesis,etc.,but the proper mechanism behind this co-occurrence has yet to be discovered.The hypercoagulability and presence of the D-dimer level in stroke are different in cancer patients than in the noncancerous population.Other factors such as atherosclerosis and coagulopathy involved in the pathogenesis of stroke are partially responsible for cancer,and the reverse is also partially true.Based on clinical and neurosurgical experience,the neuronal structures and functions in the brain and spine are observed to change after a progressive attack of ischemia that leads to hypoxia and atrophy.The major population of cancer cells cannot survive in an adverse ischemic environment that excludes cancer stem cells(CSCs).Cancer cells in stroke patients have already metastasized,but early-stage cancer patients also suffer stroke for multiple reasons.Therefore,stroke is an early manifestation of cancer.Stroke and cancer share many factors that result in an increased risk of stroke in cancer patients,and vice-versa.The intricate mechanisms for stroke with and without cancer are different.This review summarizes the current clinical reports,pathophysiology,probable causes of co-occurrence,prognoses,and treatment possibilities.

Chaperone-assisted E3 ligase CHIP:A double agent in cancer

The carboxy-terminus of Hsp70-interacting protein(CHIP)is a ubiquitin ligase and co-chaperone belonging to Ubox family that plays a crucial role in the maintenance of cellular homeostasis by switching the equilibrium of the folding-refolding mechanism towards the proteasomal or lysosomal degradation pathway.It links molecular chaperones viz.HSC70,HSP70 and HSP90 with ubiquitin proteasome system(UPS),acting as a quality control system.CHIP contains charged domain in between N-terminal tetratricopeptide repeat(TPR)and C-terminal Ubox domain.TPR domain interacts with the aberrant client proteins via chaperones while Ubox domain facilitates the ubiquitin transfer to the client proteins for ubiquitination.Thus,CHIP is a classic molecule that executes ubiquitination for degradation of client proteins.Further,CHIP has been found to be indulged in cellular differentiation,proliferation,metastasis and tumorigenesis.Additionally,CHIP can play its dual role as a tumor suppressor as well as an oncogene in numerous malignancies,thus acting as a double agent.Here,in this review,we have reported almost all substrates of CHIP established till date and classified them according to the hallmarks of cancer.In addition,we discussed about its architectural alignment,tissue specific expression,sub-cellular localization,folding-refolding mechanisms of client proteins,E4 ligase activity,normal physiological roles,as well as involvement in various diseases and tumor biology.Further,we aim to discuss its importance in HSP90 inhibitors mediated cancer therapy.Thus,this report concludes that CHIP may be a promising and worthy drug target towards pharmaceutical industry for drug development.