Immune checkpoint inhibitor-associated ophthalmic adverse events: current understanding of its mechanisms,diagnosis, and management

Immune checkpoint inhibitors(ICIs) targeting cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 receptor/ligand have revolutionized cancer treatment, achieving unprecedented efficacy in numerous malignancies. Despite the excellent therapeutic effects of ICIs, medications, such as pembrolizumab, ipilimumab, nivolumab, atezolizumab, avelumab, and durvalumab, typically cause a broad spectrum of toxicity events termed as immune-related adverse events(ir AEs). Out of all ir AEs, ophthalmic adverse events occur infrequently and are not comprehensively recognized. The current understanding of ophthalmic ir AEs is mainly derived from case reports and case series. In this review, based on relevant articles in the literature and current evidence, we summarize the incidences, manifestations, diagnoses, underlying mechanisms, treatments, and outcomes of ophthalmic ir AEs and discuss possible management strategies. A better understanding of these features is critical for managing patients with ICI-associated ophthalmic adverse events.

Targeted drug approvals in 2023:breakthroughs by the FDA and NMPA

According to the official website of China’s National Medicines and Pharmaceutical Administration(NMPA),a total of 87 novel drugs were approved in China in 2023,with targeted drugs accounting for 67.8%of the total,amounting to 59 drugs(Fig.1a;Table 1)[https://www.nmpa.gov.cn/yaopin/ypjgdt/index.html].Notably,domestic innovation is flourishing,with five first-in-class drugs,including Glumetinib,a c-Met inhibitor from Haihe Biopharma;Leritrelvir,a 3CL protease inhibitor from Raynovent;Anaprazole,a proton pump inhibitor from Xuanzhu Biopharm;Pegol-Sihematide,an EPO drug from Hansoh Pharma;and Zuberitamab from BioRay Biopharmaceutical Co.,Ltd.Additionally,the world’s first allosteric inhibitor targeting TYK2,Sotyktu(deucravacitinib),has been approved for the treatment of psoriasis and Selumetinib,a MEK inhibitor co-developed by AstraZeneca and Merck Sharp&Dohme(MSD),became the first approved drug in China for the treatment of neurofibromatosis type I(NF1).Beyond these drugs,the approval of novel drug types such as CAR-T cell products,siRNA,monoclonal antibodies,dual antibodies,and ADCs in China is a significant development in the country’s pharmaceutical industry(Fig.1a).

Small molecules targeting protein-protein interactions for cancer therapy

Protein-protein interactions(PPIs)are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases.Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases,especially tumours.Encouragingly,selective PPI-based therapeutic agents have been rapidly advancing over the past decade,providing promising perspectives for novel therapies for patients with cancer.In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects,focusing on PPIs in disease,drug design and discovery strategies,structure-activity relationships,inherent dilemmas,and future directions.

A promising small molecule binding pocket in class B GPCRs: expanding potential for drug development

Recently,Xu et al.1 have published in Nature,solved the high-resolution structure of a small molecule agonist PCO371 and Gs bound human parathyroid hormone receptor 1(PTH1R)by cryo-electron microscopy.This study reveals a novel conserved small molecule agonist binding pocket of class B G protein-coupled receptors(GPCRs)and provides new insights into drug develop-ment for various therapeutic indications.GPCRs are a family of receptors with a seven transmembrane(7TM)domains that mediate various downstream signals by activating G proteins or recruitingβ-arrestins.As the largest family of cell membrane receptors encoded by the human genome,GPCRs are widely involved in human physiological and patholo-gical processes and have become the most important therapeutic targets.

Recent advances of deep learning in psychiatric disorders

Deep learning(DL)is a recently proposed subset of machine learning methods that has gained extensive attention in the academic world,breaking benchmark records in areas such as visual recognition and natural language processing.Different fromconventional machine learning algorithm,DL is able to learn useful representations and features directly from raw data through hierarchical nonlinear transformations.Because of its ability to detect abstract and complex patterns,DL has been used in neuroimaging studies of psychiatric disorders,which are characterized by subtle and diffuse alterations.Here,we provide a brief review of recent advances and associated challenges in neuroimaging studies of DL applied to psychiatric disorders.The results of these studies indicate that DL could be a powerful tool in assisting the diagnosis of psychiatric diseases.We conclude our review by clarifying the main promises and challenges of DL application in psychiatric disorders,and possible directions for future research.

Ketogenic diet therapy for epilepsy:past 100 years of practice

Ketogenic diet(KD)is a classic therapy for epilepsy,in addition to the therapeutic medicines and surgeries.KD as the treatment for epilepsy entered the 100th year.The classic KD was proposed in the 1920s as a formula diet with a high proportion of fat(90%),a low proportion of carbohydrate,and appropriate proportions of protein and other nutrients,which does not affect normal growth and development,but is effective in treating some nervous system diseases,cancer and other diseases[1].

Current epidemiological and etiological characteristics and treatment of seizures or epilepsy in patients with HIV infection

Seizures or epilepsy is one of the common serious complications in patients with advanced human immunodeficiency virus(HIV)infection or diagnosed with immune deficiency syndrome,with higher incidence and prevalence than in the general population.Generalized seizures are the most common type in the patients.Opportunistic infections are a stereotypical predisposing factor for seizures in HIV patients,but a variety of pathogenic factors can also be found in these patients,such as metabolic perturbation and drug-drug interactions.The diagnostic criteria for seizures in these patients are the same as those in the general population.As HIV patients with seizures need to take both antivirals and antiepileptic drugs,the risk of drug-drug interactions is greatly increased,and the side effects of drugs may also become more prominent.At present,most experience in antiepileptic drug usage has come from the general population,and there is still a lack of guidance of antiepileptic drug use in special groups such as the HIV-infected people.Unlike the old-generation drugs that involve metabolisms through CYP450,the first-line antiepileptic drugs usually bypass CYP450,thus having less drug-drug interactions.In this review,we summarize the recent research progress on the above-mentioned widely discussed topics and make a prospect on future research direction.

Special issue on the battle against complex virus world in the human brain:seizure as a result of viral infection

Viruses are the smallest living things known to science,yet they hold the entire planet in their way.-from A Planet of Viruses,Carl Zimmer The corona virus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has become a big threat to human health.Studies have shown that SARS-CoV-2 can also invade the central nervous system(CNS)[1].Currently.

The role of picornavirus infection in epileptogenesis

Picornaviridae are a family of small positive-strand RNA viruses,and transmitted via the respiratory or fecal-oral route.The neurotropic picornaviruses can induce acute or late recurrent seizures following central nervous system infection,by infecting the peripheral nerve,crossing the blood-brain barrier and migrating in the Trojan-horse method.Theiler’s murine encephalomyelitis virus(TMEV),as a member of Picornaviridae family,can cause encephalitis,leading to chronic spontaneous seizures.TMEV-infected C57BL/6 mice have been used as an animal model for exploring the mechanism of epileptogenesis and assessing new antiepileptic drugs.Astrogliosis,neuronal death and microglial recruitment have been detected in the hippocampus following the picornaviruse-induced encephalitis.The macrophages,monocytes,neutrophils,as well as IL-6 and TNF-αreleased by them,play an important role in the epileptogenesis.In this review,we summarize the clinical characteristics of picornavirus infection,and the immunopathology involved in the TMEV-induced epilepsy.