Precise treatments for schizophrenia: where is the way forward?

Schizophrenia is a kind of chronic mental disorder that leads to disability,and it is characterized by the incoordination of perception, mind,emotion and behaviour, and the disconnection between mental activities and reality. It is recurrent and hard to cure. Schizophrenia has caused both agony to patients and their families, and heavy economic burden to their families and society.The appearance of chlorpromazine,the first antipsychotic drug in the1950s, brought about a revolutionary change in the treatment of schizophrenia. Even though the first-generation antipsychotic drug's effectiveness for schizophrenia (especially the positive symptoms) was absolutely positive, it did not

Research progress of individualized precision treatment for pancreatic cancer

Currently,there is the extremely poor prognosis for pancreatic cancer.Despite the continuous development of various technologies,the long-term survival rate is not improved well.With the rapid development of genomics and biotechnology,the concept of tumor precision treatment has attracted much attention.Gene sequencing technology and biomarker detection have been used to deeply explore the mechanism of the occurrence and development of pancreatic cancer and applied it to clinical diagnosis and treatment,making it possible for patients to carry out individualized precision treatment for pancreatic cancer.Multiple-factor analysis combined with meaningful biological indicators is more helpful to determine individualized diagnosis and treatment measures.This paper summarizes the research results in the above aspects.

Novel gene mutation in maturity-onset diabetes of the young:A case report

BACKGROUND Maturity-onset diabetes of the young(MODY)is the most common monogenic type of diabetes.Recently,14 gene mutations have been found to be associated with MODY.In addition,the KLF11 gene mutation is the pathogenic gene of MODY7.To date,the clinical and functional characteristics of the novel KLF11mutation c.G31A have not yet been reported.CASE SUMMARY We report of a 30-year-old male patient with a one-year history of nonketosisprone diabetes and a 3-generation family history of diabetes.The patient was found to carry a KLF11 gene mutation.Therefore,the clinical data of family members were collected and investigated.A total of four members of the family were found to have heterozygous mutations in the KLF11 gene c.G31A,which resulted in a change in the corresponding amino acid p.D11N.Three patients had diabetes mellitus,and one patient had impaired glucose tolerance.CONCLUSION The heterozygous mutation of the KLF11 gene c.G31A(p.D11N)is a new mutation site of MODY7.Subsequently,the main treatment included dietary interventions and oral drugs.

Identification of an immune classifier for predicting the prognosis and therapeutic response in triple-negative breast cancer

Triple-negative breast cancer(TNBC)poses a significant challenge due to the lack of reliable prognostic gene signatures and an understanding of its immune behavior.Methods:We analyzed clinical information and mRNA expression data from 162 TNBC patients in TCGA-BRCA and 320 patients in METABRIC-BRCA.Utilizing weighted gene coexpression network analysis,we pinpointed 34 TNBC immune genes linked to survival.The least absolute shrinkage and selection operator Cox regression method identified key TNBC immune candidates for prognosis prediction.We calculated chemotherapy sensitivity scores using the“pRRophetic”package in R software and assessed immunotherapy response using the Tumor Immune Dysfunction and Exclusion algorithm.Results:In this study,34 survival-related TNBC immune gene expression profiles were identified.A least absolute shrinkage and selection operator-Cox regression model was used and 15 candidates were prioritized,with a concomitant establishment of a robust risk immune classifier.The high-risk TNBC immune groups showed increased sensitivity to therapeutic agents like RO-3306,Tamoxifen,Sunitinib,JNK Inhibitor VIII,XMD11-85h,BX-912,and Tivozanib.An analysis of the Search Tool for Interaction of Chemicals database revealed the associations between the high-risk group and signaling pathways,such as those involving Rap1,Ras,and PI3K-Akt.The low-risk group showed a higher immunotherapy response rate,as observed through the tumor immune dysfunction and exclusion analysis in the TCGA-TNBC and METABRIC-TNBC cohorts.Conclusion:This study provides insights into the immune complexities of TNBC,paving the way for novel diagnostic approaches and precision treatment methods that exploit its immunological intricacies,thus offering hope for improved management and outcomes of this challenging disease.

Comprehensive proteomic signature and identification of CDKN2A as a promising prognostic biomarker and therapeutic target of colorectal cancer

BACKGROUND The carcinogenesis of colorectal cancer(CRC)involves many different molecules and multiple pathways,and the specific mechanism has not been elucidated until now.Existing studies on the proteomic signature profiles of CRC are relatively limited.Therefore,we herein aimed to provide a more comprehensive proteomic signature profile and discover new prognostic markers and therapeutic targets by performing proteomic analysis of CRC and paired normal tissues.AIM To investigate the proteomic signature and identify novel protein prognostic biomarkers of CRC.METHODS Cancer tissues and paired normal tissues were collected from 48 patients who underwent surgical removal at the China-Japan Friendship Hospital from January 2020 to June 2021.Data independent acquisition(DIA)quantitative proteomic analysis was performed using high-performance liquid chromatography–mass spectrometry/mass spectrometry(nano-UHPLC–MS/MS)to identify differen tially expressed proteins,among which those with a P adj value(t test,BH correction)<0.05 and an absolute fold change(|log2FC|)>2 were identified as potential markers.Differentially expressed proteins were selected by bioinformatics analysis and validated by immunohistochemical tissue microarrays,and their association with prognosis was further analyzed with the Gene Expression Profiling Interactive Analysis database to identify prognostic protein biomarkers of CRC.RESULTS Significantly differential protein expression was observed between cancer tissues and normal tissues.Compared with normal tissues,1115 proteins were upregulated and 705 proteins were downregulated in CRC based on P adj<0.05 and|log2FC|>2,and bioinformatics analysis revealed that the differentially expressed proteins were involved in multiple biological processes associated with tumorigenesis,including ribosome biogenesis in eukaryotes,focal adhesion,extracellular matrix-receptor interactions and other tumor metabolism processes.Moreover,cyclin-dependent kinase inhibitor 2A(CDKN2A)expression was markedly upregulated in CRC,as validated by immunohistochemistry(0.228 vs 0.364,P=0.0044),and was significantly enriched in tumor proliferation and signal transduction pathways such as the cell cycle and p53 signaling pathways.High CDKN2A expression was significantly correlated with poor prognosis(P=0.021).These results demonstrated that CDKN2A functions as a driver of CRC.CONCLUSION Our study provides a comprehensive proteomic signature of CRC and highlights CDKN2A as a potential powerful prognostic marker and precision therapeutic target.

Druggable monogenic immune defects hidden in diverse medical specialties:Focus on overlap syndromes

In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies:An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with infections.Some primary immune defects are due to hyperactive pathways that can be targeted by specific inhibitors,providing innovative precision treatments that can change the natural history of diseases.In this article we review some of these“druggable”inborn errors of immunity and describe how they can be suspected and diagnosed in diverse pediatric and adult medicine specialties.Since the availability of precision treatments can dramatically impact the course of these diseases,preventing the development of organ damage,it is crucial to widen the awareness of these conditions and to provide practical hints for a prompt detection and cure.

Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications

Cancer is the leading cause of death worldwide. Drugs play a pivotal role in cancer treatment, but the complex biological processes of cancer cells seriously limit the efficacy of various anticancer drugs. Autophagy, a self-degradative system that maintains cellular homeostasis, universally operates under normal and stress conditions in cancer cells. The roles of autophagy in cancer treatment are still controversial because both stimulation and inhibition of autophagy have been reported to enhance the effects of anticancer drugs. Thus, the important question arises as to whether we should try to strengthen or suppress autophagy during cancer therapy. Currently, autophagy can be divided into four main forms according to its different functions during cancer treatment: cytoprotective(cell survival), cytotoxic(cell death), cytostatic(growth arrest), and nonprotective(no contribution to cell death or survival). In addition, various cell death modes, such as apoptosis, necrosis, ferroptosis, senescence, and mitotic catastrophe, all contribute to the anticancer effects of drugs. The interaction between autophagy and these cell death modes is complex and can lead to anticancer drugs having different or even completely opposite effects on treatment. Therefore, it is important to understand the underlying contexts in which autophagy inhibition or activation will be beneficial or detrimental.That is, appropriate therapeutic strategies should be adopted in light of the different functions of autophagy. This review provides an overview of recent insights into the evolving relationship between autophagy and cancer treatment.

Mapping brain functional and structural abnormities in autism spectrum disorder:moving toward precision treatment

Autism spectrum disorder(ASD)is a formidable challenge for psychiatry and neuroscience because of its high prevalence,lifelong nature,complexity,and substantial heterogeneity.A major goal of neuroimaging studies of ASD is to understand the neurobiological underpinnings of this disorder from multi-dimensional and multi-level perspectives,by investigating how brain anatomy,function,and connectivity are altered in ASD,and how they vary across the population.However,ongoing debate exists within those studies,and neuroimaging findings in ASD are often contradictory.Over the past decade,we have dedicated to delineate a comprehensive and consistent mapping of the abnormal structure and function of the autistic brain,and this review synthesizes the findings across our studies reaching a consensus that the“social brain”are the most affected regions in the autistic brain at different levels and modalities.We suggest that the social brain network can serve as a plausible biomarker and potential target for effective intervention in individuals with ASD.

Inflammatory response-based subtyping and potential therapeutic strategies for triple-negative breast cancer

objective:Inflammatory response plays a crucial role in the development and treatment of cancer.However,the role of inflammatory response in triple-negative breast cancer(TNBC)remains unclear.Based on the heterogeneity of the inflammatory response,we classified TNBC,elucidated its subtype features,and revealed potential therapeutic strategies.Methods:We established inflammatory response subtyping based on the RNA sequencing data of TNBCs derived from a cohort at the Fudan University Shanghai Cancer Center(FUSCC).Next,we explored the features and potential therapeutic strategies for each subgroup by analyzing transcriptome data.Using a machine-learning method,we validated and generalized the TNBC inflammatory response subtypes in an external dataset.Results:A total of 360 TNBC samples and 88 normal tissues were collected from a cohort at FUSCC.Patients with TNBC were divided into four inflammatory response groups(IRGs)based on the expression of inflammatory response genes:high inflammatory response gene expression with pronounced pyroptosis phenotype and high immune cellinfiltration(IRG 1),low inflammatory response gene expression and low immune cell infiltration(IRG 2),ITGB8 specific inflammatory response with a predominant proliferation phenotype(IRG 3),and low M1/M2 ratio with a marked angiogenesis phenotype(IRG 4).Relapse-free survival(RFS)was better in iRG 1 and 2 and worse in IRG 3 and 4.Owing to their poor prognosis,we mainly focused on IRG 3 and IRG 4 to investigate potential treatment strategies.ITGB8 was highly expressed in IRG 3;thus,targeting ITGB8 may be a potential therapeutic strategy for patients in IRG 3.IRG 4 had a lower M1/M2 ratio and a marked angiogenesis phenotype;therefore,therapeutic strategies,such as anti-angiogenesis or M2 to M1 repolarization of macrophages,could be recommended for these patients.Additionally,we validated and generalized the TNBC inflammatory response subtyping in an external dataset using a machine-learning method.Conclusion:TNBC patients with different inflammatory response subtypes have different characteristics and may need subtype-specific treatment strategies.

Platinum-crosslinking polymeric nanoparticle for synergetic chemoradiotherapy of nasopharyngeal carcinoma

Despite extensive use of radiotherapy in nasopharyngeal carcinoma(NPC)treatment because of its high radiosensitivity,there have been huge challenges in further improving therapeutic effect,meanwhile obviously reducing radiation damage.To this end,synergistic chemoradiotherapy has emerged as a potential strategy for highly effective NPC therapy.Here,we developed RGD-targeted platinum-based nanoparticles(RGD-PtNPs,denoted as RPNs)to achieve targeted chemoradiotherapy for NPC.Such nanoparticles consist of an RGD-conjugated shell and a cis-platinum(CDDP)crosslinking core.Taking advantage of RGD,the RPNs may effectively accumulate in tumor,penetrate into tumor tissues and be taken by cancer cells,giving rise to a high delivery efficiency of CDDP.When they are fully enriched in tumor sites,the CDDP loaded RPNs can act as radiotherapy sensitizer and chemotherapy agents.By means of X-ray-promoted tumor cell uptake of nanoparticle and CDDP-induced cell cycle arrest in radiation-sensitive G2/M phases,RPNs may offer remarkable therapeutic outcome in the synergistic chemoradiotherapy for NPC.

The 150 most important questions in cancer research and clinical oncology series: questions 94-101

Since the beginning of 2017,Cancer Communications(former title:Chinese Journal of Cancer)has published a series of important questions regarding cancer research and clinical oncology,to provide an enhanced stimulus for can-cer research,and to accelerate collaborations between institutions and investigators.In this edition,the following 8 valuable questions are presented.Question 94.The origin of tumors:time for a new paradigm?Question 95.How can we accelerate the identification of biomarkers for the early detection of pancreatic ductal adenocarcinoma?Question 96.Can we improve the treatment outcomes of metastatic pancreatic ductal adenocarcinoma through precision medicine guided by a combination of the genetic and proteomic information of the tumor?Question 97.What are the parameters that determine a competent immune system that gives a complete response to cancers after immune induction?Question 98.Is high local concentration of metformin essential for its anti-cancer activity?Question 99.How can we monitor the emergence of cancer cells anywhere in the body through plasma testing?Question 100.Can phytochemicals be more specific and efficient at targeting P-glycoproteins to overcome multi-drug resistance in cancer cells?Question 101.Is cell migration a selectable trait in the natural evolution of carcinoma?

Precision medicine in inflammatory bowel disease

Inflammatory bowel disease(IBD)is an incurable disease characterized by remission-relapse cycles throughout its course.Both Crohn's disease(CD)and ulcerative colitis(UC),the two main forms of IBD,exhibit tendency to develop complications and substantial heterogeneity in terms of frequency and severity of relapse,thus posing great challenges to the clinical management for IBD.Current treatment strategies are effective in different ways in induction and maintenance therapies for IBD.Recent advances in studies of genetics,pharmacogenetics,proteomics and microbiome provide a strong driving force for identifying molecular markers of prognosis and treatment response,which should help clinicians manage IBD patients more effectively,and then,improve clinical outcomes and reduce treatment costs of patients.In this review,we summarize and discuss precision medicine in IBD,focusing on predictive markers of disease course and treatment response,and monitoring indices during therapeutic drug monitoring.