Potentials of ribosomopathy gene as pharmaceutical targets for cancer treatment

Ribosomopathies encompass a spectrum of disorders arising from impaired ribosome biogenesis and reduced functionality.Mutation or dysexpression of the genes that disturb any finely regulated steps of ribosome biogenesis can result in different types of ribosomopathies in clinic,collectively known as ribosomopathy genes.Emerging data suggest that ribosomopathy patients exhibit a significantly heightened susceptibility to cancer.Abnormal ribosome biogenesis and dysregulation of some ribosomopathy genes have also been found to be intimately associated with cancer development.The correlation between ribosome biogenesis or ribosomopathy and the development of malignancies has been well established.This work aims to review the recent advances in the research of ribosomopathy genes among human cancers and meanwhile,to excavate the potential role of these genes,which have not or rarely been reported in cancer,in the disease development across cancers.We plan to establish a theoretical framework between the ribosomopathy gene and cancer development,to further facilitate the potential of these genes as diagnostic biomarker as well as pharmaceutical targets for cancer treatment.

Screening of treatment targets for Alzheimer's disease from the molecular mechanisms of impairment by β-amyloid aggregation and tau hyperphosphorylation

β-Amyloid （Aβ） over-expression and tau hyperphosphorylation are considered to be the central events in the pathogenesis of Alzheimer＇s disease （AD）.Studies on them may help elucidate the precise molecular pathogenesis of AD.Until now,although tau protein and Aβ remain the foci of AD research,the etiopathogenesis of AD and effective drugs for AD treatment are still largely unsolved.The present review was mainly focused on the molecular mechanism of Aβ aggregation-related impairment and the pathways leading to tau hyperphosphorylation,based on which some promising therapeutic targets for AD were also proposed.

The seeming paradox of adenosine receptors as targets for the treatment of Alzheimer's disease: agonists or antagonists?

Alzheimer＇s disease （AD） is the most common neurodegenerative disorder, and its incidence is relatively high among elderly people, affecting about 1-2% of the population between 60-65 years old and rising dramatically （about 30%） in people aged 80 years or older （Selkoe, 2002）. Nowadays, considering the increasing mean lifespan of populations in developed countries, the disease is becoming more and more a health concern, and the search for an effective cure has turned into＂a real need＂.

Combined treatment promotes the long-range axon regeneration to right brain targets

Axons in the peripheral nervous system(PNS)can regenerate after injury.However,the adult mammalian central nervous system(CNS)loses the intrinsic regrowth ability.No robust axon regeneration occurs spontaneously after nerve injury,which was clearly observed by Ramon y Cajal in the early 20^(th) century(1,2).Due to lack

Treat to target in Crohn’s disease:A practical guide for clinicians

A treat-to-target(T2T)approach applies the principles of early intervention and tight disease control to optimise long-term outcomes in Crohn's disease.The Selecting Therapeutic Targets in Inflammatory Bowel Disease(STRIDE)-II guidelines specify short,intermediate,and long-term treatment goals,documenting specific treatment targets to be achieved at each of these timepoints.Scheduled appraisal of Crohn’s disease activity against pre-defined treatment targets at these timepoints remains central to determining whether current therapy should be continued or modified.Consensus treatment targets in Crohn’s disease comprise combination clinical and patient-reported outcome remission,in conjunction with biomarker normalisation and endoscopic healing.Although the STRIDE-II guidelines endorse the pursuit of endoscopic healing,clinicians must consider that this may not always be appropriate,acceptable,or achievable in all patients.This underscores the need to engage patients at the outset in an effort to personalise care and individualise treatment targets.The use of non-invasive biomarkers such as faecal calprotectin in conjunction with cross-sectional imaging techniques,particularly intestinal ultrasound,holds great promise;as do emerging treatment targets such as transmural healing.Two randomised clinical trials,namely,CALM and STARDUST,have evaluated the efficacy of a T2T approach in achieving endoscopic endpoints in patients with Crohn’s disease.Findings from these studies reflect that patient subgroups and Crohn’s disease characteristics likely to benefit most from a T2T approach,remain to be clarified.Moreover,outside of clinical trials,data pertaining to the real-world effectiveness of a T2T approach remains scare,highlighting the need for pragmatic real-world studies.Despite the obvious promise of a T2T approach,a lack of guidance to support its integration into real-world clinical practice has the potential to limit its uptake.This highlights the need to describe strategies,processes,and models of care capable of supporting the integration and execution of a T2T approach in real-world clinical practice.Hence,this review seeks to examine the current and emerging literature to provide clinicians with practical guidance on how to incorporate the principles of T2T into routine clinical practice for the management of Crohn’s disease.

Resistance to targeted therapy in metastatic colorectal cancer:Current status and new developments

Colorectal cancer(CRC)is one of the most lethal and common malignancies in the world.Chemotherapy has been the conventional treatment for metastatic CRC(mCRC)patients.However,the effects of chemotherapy have been unsatisfactory.With the advent of targeted therapy,the survival of patients with CRC have been prolonged.Over the past 20 years,targeted therapy for CRC has achieved substantial progress.However,targeted therapy has the same challenge of drug resistance as chemotherapy.Consequently,exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy,along with searching for novel effective regimens,is a constant challenge in the mCRC treatment,and it is also a hot research topic.In this review,we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.

Interleukin 17A deficiency alleviates neuroinflammation and cognitive impairment in an experimental model of diabetic encephalopathy

Interleukin 17A(IL-17A)was previously shown to be a key pro-inflammatory factor in diabetes mellitus and associated complications.However,the role of IL-17A in diabetic encephalopathy remains poorly understood.In this study,we established a mouse model of diabetic encephalopathy that was deficient in IL-17A by crossing Il17a-/-mice with spontaneously diabetic Ins2^(Akita)(Akita)mice.Blood glucose levels and body weights were monitored from 2-32 weeks of age.When mice were 32 weeks of age,behavioral tests were performed,including a novel object recognition test for assessing short-term memory and learning and a Morris water maze test for evaluating hippocampus-dependent spatial learning and memory.IL-17A levels in the serum,cerebrospinal fluid,and hippocampus were detected with enzyme-linked immunosorbent assays and real-time quantitative polymerase chain reaction.Moreover,proteins related to cognitive dysfunction(amyloid precursor protein,β-amyloid cleavage enzyme 1,p-tau,and tau),apoptosis(caspase-3 and-9),inflammation(inducible nitric oxide synthase and cyclooxygenase 2),and occludin were detected by western blot assays.Pro-inflammatory cytokines including tumor necrosis factor-α,interleukin-1β,and interferon-γin serum and hippocampal tissues were measured by enzyme-linked immunosorbent assays.Microglial activation and hippocampal neuronal apoptosis were detected by immunofluorescent staining.Compared with that in wild-type mice,mice with diabetic encephalopathy had higher IL-17A levels in the serum,cerebrospinal fluid,and hippocampus;downregulation of occludin expression;lower cognitive ability;greater loss of hippocampal neurons;increased microglial activation;and higher expression of inflammatory factors in the serum and hippocampus.IL-17A knockout attenuated the abovementioned changes in mice with diabetic encephalopathy.These findings suggest that IL-17A participates in the pathological process of diabetic encephalopathy.Furthermore,IL-17A deficiency reduces diabetic encephalopathy-mediated neuroinflammation and cognitive defects.These results highlight a role for IL-17A as a mediator of diabetic encephalopathy and potential target for the treatment of cognitive impairment induced by diabetic encephalopathy.

Targeted therapy in advanced metastatic colorectal cancer: Current concepts and perspectives

The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.

What ＂helps＂ tumors evade vascular targeting treatment？

Objective To throw a light on the possible factors which might induce resistance of vascular targeting treatment in tumors by reviewing the recent publications in the field of tumor angiogenesis and vascular targeting treatment. Data sources The data used in this review were mainly from Medline and PubMed for relevant English language articles published from 1971 to January 2008. The search terms were ＂angiogenesis＂, ＂ascular targeting treatment＂ and ＂endothelial progenitor cells＂. Study selection Articles involved in the possible influence factors during angiogenesis and vascular targeting treatment were selected, including angiogenic or anti-angiogenic mechanism, tumor vasculature, tumor cells, cancer stem cells and endothelial progenitor cells. Results As a promising strategy vascular targeting treatment still has experimental and clinical setbacks which may term tumor vasculature＇s resistance to anti-angiogenesis agents. There are several possible explanations for such a resistance that might account for clinical and preclinical failures of anti-angiogenic treatment against tumor. Proangiogenic effect of hypoxia, normal tumor vasculature, escape of tumor cells and tumor vasculogenesis are included. This review reveals some clues which might be helpful to direct future research in order to remove obstacles to vascular targeting treatment. Conclusions Generally and undoubtedly vascular targeting treatment remains a promising strategy. But we still have to realize the existence of a challenging future. Further research is required to enhance our knowledge of vascular targeting treatment strategy before it could make a more substantial success.

Targeted heat treatment of additively manufactured Ti-6Al-4V for controlled formation of Bi-lamellar microstructures

Laser powder bed fusion(L-PBF)was utilized to produce specimens in Ti-6Al-4V,which were subjected to a bi-lamellar heat treatment,which produces microstructures consisting of primary α-lamellae and a fine secondary α-phase inside the inter-lamellar β-regions.The bi-lamellar microstructure was obtained as(i)a direct bi-lamellar heat treatment from the asbuilt condition or(ii)a bi-lamellar heat treatment preceded by a β-homogenization.For the bi-lamellar treatment with β-homogenization,cooling rates in the range 1-500 K/min were applied after homogenization in β-region followed by inter-critical annealing in the α+β region at various temperatures in the range 850-950℃.The microstructures were characterized using various microscopical techniques.Mechanical testing with Vickers hardness indentation and tensile testing was performed.The bi-lamellar microstructure was harder when compared to a soft fully lamellar microstructure,because of the presence of fine α-platelets inside the β-lamellae.Final low temperature ageing provided an additional hardness increase by precipitation hardening of the primary α-regions.The age hardened bi-lamellar microstructure shows a similar hardness as the very fine,as-built martensitic microstructure.The bi-lamellar microstructure has more favorable mechanical properties than the as-built condition,which has high strength,but poor ductility.After the bi-lamellar heat treatment,the elongation was improved by more than 250%.Due to the very high strength of the as-built condition,loss of tensile strength is unavoidable,resulting in a reduction of tensile strength of~18%.

Deposition of Phase-pure Cr2AlC Coating by DC Magnetron Sputtering and Post Annealing Using Cr-Al-C Targets with Controlled Elemental Composition but Different Phase Compositions

Polycrystalline Cr2AlC coatings were prepared on M38G superalloy using a two-step method consisting of magnetron sputtering from Cr-Al-C composite targets at room temperature and subsequent annealing at 620 ℃. Particularly, various targets synthesized by hot pressing mixture of Cr, Al, and C powders at 650-1000 ℃ were used. It was found that regardless of the phase compositions and density of the com- posite targets, when the molar ratio of Cr：Al：C in the starting materials was 2：1：1, phase-pure crystalline Cr2AlC coatings were prepared by magnetron sputtering and post crystallization. The Cr2AIC coatings were dense and crack-free and had a duplex structure. The adhesion strength of the coating deposited on M38G superalloy from the 800 ℃ hot-pressed target and then annealed at 620 ℃ for 20 h in Ar exceeded 82 ± 6 MPa, while its hardness was 12 ± 3 GPa.

Management of bone metastases in renal cell carcinoma: bone-targeted treatments, systemic therapies, and radiotherapy

Metastatic renal cell carcinoma(mRCC)presents with bone metastases in around 20%-30%of patients enrolled in the most recent first-line clinical trials.Emergence of several new agents in first line,in both monotherapy and combination,has significantly improved patient outcomes.However,the activity of such agents on bone metastases is unclear and management of these patients is complex,due to potential complications that can significantly impair quality of life.This review addresses mRCC diagnosis and monitoring and summarizes the current evidence on systemic therapy,ablative therapies such as stereotactic ablative radiotherapy and surgery,and supportive therapy with bone-targeting agents for these patients,with the goal of improving their outcomes.

Functions and mechanisms of protein lysine butyrylation(Kbu):Therapeutic implications in human diseases

Post-translational modifications(PTM)are covalent modifications of proteins or peptides caused by proteolytic cleavage or the attachment of moieties to one or more amino acids.PTMs play essential roles in biological function and regulation and have been linked with several diseases.Modifications of protein acylation(Kac),a type of PTM,are known to induce epigenetic regulatory processes that promote various diseases.Thus,an increasing number of studies focusing on acylation modifications are being undertaken.Butyrylation(Kbu)is a new acylation process found in animals and plants.Kbu has been recently linked to the onset and progression of several diseases,such as cancer,cardiovascular diseases,diabetes,and vascular dementia.Moreover,the mode of action of certain drugs used in the treatment of lymphoma and colon cancer is based on the regulation of butyrylation levels,suggesting that butyrylation may play a therapeutic role in these diseases.In addition,butyrylation is also commonly involved in rice gene expression and thus plays an important role in the growth,development,and metabolism of rice.The tools and analytical methods that could be utilized for the prediction and detection of lysine butyrylation have also been investigated.This study reviews the potential role of histone Kbu,as well as the mechanisms underlying this process.It also summarizes various enzymes and analytical methods associated with Kbu,with the goal of providing new insights into the role of Kbu in gene regulation and diseases.

Roadmap toward subtype-specifc vulnerabilities in adult glioma

Gliomas are the most common primary malignancies in the adult central nervous system(CNS),and over the course of the last decades a wealth of data on their genomic characterization has been acquired.Nevertheless,attempts to stratify patients on the basis of this work has so far conspicuously failed to identify useful treatment targets,and no phase III clinical trials conducted to date have reached a favorable outcome.We suggest that these translational failures are due to inadequacies in classifcation schemes,which fail to capture the range of biologically distinct entities that give rise to gliomas.Treating gliomas of diferent subtypes together,rather than as a set of biologically distinct but related tumors,has resulted in a classifcation scheme rich in unexplained heterogeneities,and has restricted target identifcation eforts to cell cycle and cell growth regulators.We suggest that this failure of detailed genomic characterizations to identify useful treatment targets requires a re-assessment of our assumptions concerning glioma origins.We propose a re-interpretation of glioma subtypes in the light of knowledge of the developmental pathways of the various neural lineages that make up the adult CNS.Such a developmental subtype-specifc classifcation scheme based on dys-regulated cell fate decisions may not only improve classifcation and diagnosis but,more importantly,identify potentially druggable subtype-specifc developmental vulnerabilities.

Age-related macular degeneration: Epidemiology, genetics, pathophysiology, diagnosis, and targeted therapy

Age-related macular degeneration (AMD) is a complex eye disorder and is the leading cause of incurable blindness worldwide in the elderly. Clinically, AMD initially affects the central area of retina known as the macula and it is classified as early stage to late stage (advanced AMD). The advanced AMD is classified into the nonexudative or atrophic form (dry AMD) and the exudative or neovascular form (wet AMD). More severe vision loss is typically associated with the wet form. Multiple genetic factors, lipid metabolism, oxidative stress and aging, play a role in the etiology of AMD. Dysregulation in genetic to AMD is established to 46%–71% of disease contribution, with CFH and ARMS2/HTRA1 to be the two most notable risk loci among the 103 identified AMD associated loci so far. Chronic cigarette smoking is the most proven consistently risk living habits for AMD. Deep learning algorithm has been developed based on image recognition to distinguish wet AMD and normal macula with high accuracy. Currently, anti-vascular endothelial growth factor (VEGF) therapy is highly effective at treating wet AMD. Several new generation AMD drugs and iPSC-derived RPE cell therapy are in the clinical trial stage and are promising to improve AMD treatment in the near future.

Chinese registry of rheumatoid arthritis(CREDIT)V:sex impacts rheumatoid arthritis in Chinese patients

Background: The impact of sex on the clinical manifestations of rheumatoid arthritis (RA) were diversely reported in the literature. The Chinese Registry of rhEumatoiD arthrITis provides a platform for the investigation of this issue in Chinese patients.Methods: Demographic and clinical parameters were collected from all enrolled patients with RA and from patients with early RA (disease duration ≤6 months). The differences in data regarding disease activity, comorbidities, and medications for RA were compared between men and women. The proportions of patients who achieved remission and low disease activity were compared at enrollment and during 3-, 6-, and 12-month follow-up visits.Results: A total of 11,564 patients were enrolled, 83.6% of whom were female. In all the enrolled patients and patients with early RA, C-reactive protein (CRP, 12.0vs. 6.7 mg/L), pain visual analogue scale (4.8vs. 4.5), patient’s and physician’s global assessment (4.9vs. 4.5 and 4.9vs. 4.5), 28-joint disease activity score using DAS28-CRP (4.3vs. 4.0) simplified disease activity index (21.9vs. 19.9), and clinical disease activity index (19.3vs. 18.0) were significantly higher in men than in women. Additionally, the swollen joint count/tender joint count and DAS28 using erythrocyte sedimentation rate were higher in male patients than in female patients with early RA. More female patients with early RA reached the treatment target at baseline than male patients (23.4%vs. 18.2%, assessed by CDAI). At 3 months, 6 months, and 12 months, the proportion of remission and treatment target achievement was similar in both sexes. Coronary artery disease (CAD) and stroke were more frequent in men than in women.Conclusions: In Chinese patients with RA, men were found to have more active disease, as well as more cases of CAD and stroke. Therefore, sex should be carefully considered during the personalization of RA treatment.

Xenograft tumors derived from malignant pleural effusion of the patients with non-small-cell lung cancer as models to explore drug resistance

Background:Non-small cell lung cancer(NSCLC)patients with epidermal growth factor receptor(EGFR)mutations or anaplastic lymphoma kinase(ALK)fusions show dramatic responses to specific tyrosine kinase inhibitors(TKIs);however,after 10-12 months,secondary mutations arise that confer resistance.We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK-and EGFR-targeted TKIs crizotinib and osimertinib,respectively.Methods:Genotypes of patient biopsies and xenograft tumors were determined by whole exome sequencing(WES),and patients and xenograft-bearing mice received targeted treatment(crizotinib or osimertinib)accordingly.Xenograft mice were also treated for prolonged periods to identify whether the development of drug resistance and/or treatment responses were associated with tumor size.Finally,the pathology of patients biopsies and xenograft tumors were compared histologically.Results:The histological characteristics and chemotherapy responses of xenograft tumors were similar to the actual patients.WES showed that the genotypes of the xenograft and patient tumors were similar(an echinoderm microtu-bule-associated protein-like 4-ALK(EML4-ALK)gene fusion(patient/xenograft:CTC15035EML4-ALK)and EGFR L858R and T790M mutations(patient/xenograft:CTC15063EGFR L858R,T790M)).After continuous crizotinib or osimertinib treatment,WES data suggested that acquired ALK E1210K mutation conferred crizotinib resistance in the CTC15035EML4-ALK xenograft,while decreased frequencies of EGFR L858R and T790M mutations plus the appearance of v-RAF murine sarcoma viral oncogene homolog B(BRAF)G7V mutations and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha(PIK3C2A)A86fs frame shift mutations led to osimertinib resistance in the CTC15063EGFR L858R,T790M xenografts.Conclusions:We successfully developed a new method of generating drug resistance xenograft models from liquid biopsies using microfluidic technology,which might be a useful tool to investigate the mechanisms of drug resist-ance in NSCLC.