Anti-EGFR and anti-VEGF agents:Important targeted therapies of colorectal liver metastases

Colorectal liver metastasis (CLM) is common worldwide. Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials, and are now becoming standards for patients with CLM. The development and application of anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies represents significant advances in the treatment of this disease. However, new findings continue to emerge casting doubt on the efficacy of this approach. The Kirsten rat sarcoma viral oncogene (KRAS) has been proven to be a crucial predictor of the success of anti-EGFR treatment in CLM. Whereas a recent study summarized several randomized controlled trials, and showed that patients with the KRAS G13D mutation significantly benefited from the addition of cetuximab in terms of progress-free survival (PFS, 4.0 mo vs 1.9 mo, HR = 0.51, P = 0.004) and overall survival (OS, 7.6 mo vs 5.7 mo, HR = 0.50, P = 0.005). Some other studies also reported that the KRAS G13D mutation might not be absolutely predictive of non-responsiveness to anti-EGFR therapy. At the same time, “new” RAS mutations, including mutations in neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) and exons 3 and 4 of KRAS, have been suggested to be predictors of a poor treatment response. This finding was first reported by the update of the PRIME trial. The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations, panitumumab-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)4 treatment led to inferior PFS (HR = 1.28, 95%CI: 0.79-2.07) and OS (HR = 1.29, 95%CI: 0.79-2.10), which was consistent with the findings in patients with KRAS mutations in exon 2. Then, the update of the PEAK trial and the FIRE-III trial also supported this finding, which would reduce candidates for anti-EGFR therapy but enhance the efficacy. In first-line targeted combination therapy, the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-VII trial. Also, bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966 trial. By the update and further analysis of the COIN trial and the NORDIC-VII trial, cetuximab plus FOLFOX was reported to be reliable again. But bevacizumab plus oxaliplatin-based chemotherapy was still controversial. In addition, some trials have reported that bevacizumab is not suitable for conversion therapy. The results of the FIRE-III trial showed that cetuximab led to a significant advantage over bevacizumab in response rate (72% vs 63%, P = 0.017) for evaluable population. With the balanced allocation of second-line treatment, the FIRE-III trial was expected to provide evidence for selecting following regimens after first-line progression. There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM, although the combined regimen is often administered based on experience. Combination therapy with more than one targeted agent has been proven to provide no benefit, and even was reported to be harmful as first-line treatment by four large clinical trials. However, recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment. The mechanism of antagonism between different targeted agents deserves further study, and may also provide greater understanding of the development of resistance to targeted agents.

Current concepts in ameloblastoma-targeted therapies in B-raf proto-oncogene serine/threonine kinase V600E mutation: Systematic review

BACKGROUND Ameloblastomas are common benign epithelial odontogenic neoplasms that present an aggressive and unpredictable behavior that may modify treatment strategies.Different signaling pathways that participate in the progression of these tumors have been identified.B-raf proto-oncogene serine/threonine kinase(BRAF)is a protein involved in the behavior of ameloblastomas,and it is related to many cell mechanisms.BRAF gene mutations have been identified in ameloblastomas,of which the BRAF V600E(valine substituted by glutamic acid at amino acid 600)mutation has been the most common and can be present concomitantly with other mutations that may be involved in its behavior.Targeted therapies have been used as an alternative in the case of resistance or contraindications to conventional treatments.AIM To document the presence of BRAF V600E and additional mutations,their behavior,and targeted therapies in these tumors.METHODS An electronic literature search was conducted according to PRISMA guidelines in PubMed/MEDLINE,Cochrane,EMBASE,and SpringerLink using the terms“ameloblastomas”,“BRAF V600E”,“additional mutations”,and“targeted therapies”.Ameloblastomas were classified according to WHO guidelines.Inclusion criteria were articles in English,published not more than 10 years ago,and studies with laboratory works related to BRAF V600E.Articles were evaluated by two independent reviewers and retrieved for full-text evaluation.The EBLIP Critical Appraisal Checklist was used to evaluate the quality of the eligible studies.Descriptive statistical analysis was performed.RESULTS Two independent reviewers,with a substantial concordance indicated by a kappa coefficient of k=0.76,evaluated a total of 19 articles that were included in this study.The analysis registered 521 conventional ameloblastomas(AM),81 unicystic ameloblastomas(UA),13 ameloblastic carcinomas(AC),three metastatic ameloblastomas(MA),and six peripheral ameloblastomas(PA),of which the histopathological type,anatomic location,laboratory tests,expression of BRAF mutation,and additional mutations were registered.The BRAF V600E mutation was found in 297 AM(57%),63 UA(77.7%),3 AC(23%),1 MA(50%),and 5 PA(83.3%).Follicular type predominated with a total of 116 cases(40%),followed by plexiform type with 63 cases(22.1%).Furthermore,both types presented additional mutations,in which alterations in JAK3 P132T,SMARCB1,PIK3CA,CTNNB1,SMO,and BRAF G606E genes were found.Four case reports were found with targeted therapy to BRAF V600E.CONCLUSION The identification of BRAF V600E and additional mutations as an aid in targeted therapies has been a breakthrough in alternative treatments of ameloblastomas where surgical treatments are contraindicated.

Development of targeted therapies in treatment of glioblastoma

Glioblastoma （GBM） is a type of tumor that is highly lethal despite maximal therapy. Standard therapeutic approaches provide modest improvement in progression-free and overall survival, necessitating the investigation of novel therapies. Oncologic therapy has recently experienced a rapid evolution toward ＂targeted therapy＂, with drugs directed against specific targets which play essential roles in the proliferation, survival, and invasiveness of GBM cells, including numerous molecules involved in signal transduction pathways. Inhihitors of these molecules have already entered or are undergoing clinical trials. However, significant challenges in their development remain because several preclinical and clinical studies present conflicting results. In this article, we will provide an up-to-date review of the current targeted therapies in GBM.

Advances in radiotherapy and targeted therapies for rectal cancer

The last decade witnessed a significant progress in understanding the biology and immunology of colorectal cancer alongside with the technical innovations in radiotherapy.The stepwise implementation of intensitymodulated and image-guided radiation therapy by means of megavolt computed tomography and helical tomotherapy enabled us to anatomically sculpt dose delivery,reducing treatment related toxicity.In addition,the administration of a simultaneous integrated boost offers excellent local control rates.The novel challenge is the development of treatment strategies for medically inoperable patient and organ preserving approaches.However,distant control remains unsatisfactory and indicates an urgent need for biomarkers that predict the risk of tumor spread.The expected benefit of target?ed therapies that exploit the tumor genome alone is so far hindered by high cost techniques and pharmaceuticals,hence hardly justifying rather modest improvements in patient outcomes.On the other hand,the immune landscape of colorectal cancer is now better clarified with regard to the immunosuppressive network that promotes immune escape.Both N2 neutrophils and myeloid-derived suppressor cells(MDSC)emerge as useful clinical biomarkers of poor prognosis,while the growing list of anti-MDSC agents shows promising ability to boost antitumor T-cell immunity in preclinical settings.Therefore,integration of genetic and immune biomarkers is the next logical step towards effective targeted therapies in the context of personalized cancer treatment.

Combining chemotherapy and targeted therapies in metastatic colorectal cancer

Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.

Drug-and cell-based therapies for targeting neuroinflammation in traumatic brain injury

TBI pathology： Traumatic brain injury （TBI） is caused by an external force to the head, resulting in trauma to the brain. Approximately 1.7 million Americans suffer from TBI every year. Out of the 1.7 million suffering from TBI, an estimated 52,000 injuries result in death, leaving a mass amount of peo- ple with symptoms that could last a few days, a few years, or their entire life （Faul et al., 2010）. TBI can be classified as mild, moderate and severe. Depending on the classification and the extent of the injury, TBI can cause both physical symptoms and cognitive disorders （Lozano et al., 2015）.

Promising use of metformin in treating neurological disorders:biomarker-guided therapies

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas

Follicular lymphoma(FL)is the most common indolent B-cell lymphoma(BCL)globally.Recently,its incidence has increased in Europe,the United States,and Asia,with the number of gastrointestinal FL cases expected to increase.Genetic abnormalities related to t(14;18)translocation,BCL2 overexpression,NF-κB pathway-related factors,histone acetylases,and histone methyltransferases cause FL and enhance its proliferation.Meanwhile,microRNAs are commonly used in diagnosing FL and predicting patient prognosis.Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted,resulting in a marked improvement in therapeutic outcomes for FL.Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options,FL treatment has become more complex,requiring combinatorial therapeutic regimens.However,optimal treatment combinations have not yet been achieved,highlighting the importance of a complete understanding regarding the pathogenesis of gastrointestinal FL.Accordingly,this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations.Moreover,the results of clinical trials are summarized,with a particular focus on treating nodal and gastrointestinal FLs.

Advances in targeted therapies for gastric cancer:a mini-review

The incidence of gastric cancer ranks 4th in malignant tumors,and the mortality rate ranks 3rd in malignant tumors.Most patients with gastric cancer are already at the advanced stage when diagnosed.Although chemotherapy is the main treatment for patients with advanced gastric cancer,it can extend the overall survival.But adverse reactions are more prominent.With the rise of targeted therapy,the molecular mechanism of gastric cancer occurrence and development continues to develop,and molecular targeted therapy of gastric cancer has gradually emerged.The current targets for gastric cancer mainly include endothelial growth factor receptor,HER2,vascular endothelium growth factor,vascular endothelium growth factor receptor,mammalian rapamycin receptor,hepatocellular growth factor,et al.,but the clinical efficacy is still not satisfactory.At present,most of the studies on molecular targeted drugs for gastric cancer have ended in failure.The heterogeneity between patients and the prognosis of tumors in different parts may be different.It is suggested that screening targeted drugs according to the patient's pathological characteristics and molecular typing,and individualized treatment is the inevitable way of targeted treatment of gastric cancer.

Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma

BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.

Off-label use of targeted therapies in oncology

Off-label use is defined by the prescription of a marketed drug outside the conditions described in the summary of product characteristics.In oncology,off-label prescribing of targeted therapies may occur in patients with other tumor types expressing the same target.Agents associated to phenotypic approaches such as therapies against the tumoral vasculature(anti-angiogenic drugs) and new immunotherapies(checkpoint inhibitors) also carry the potential of alternative indications or combinations.Off-label use of targeted therapies is little documented and appears to be in the same range than that regarding older drugs with wide variations among agents.When compared with older agents,off-label use of targeted therapies is probably more rational through tumoral genotyping but is faced with a limited clinical support,reimbursement challenges related to the very high pricing and the cost of genotyping or molecular profiling,when applicable.

Glutamine transporters as effective targets in digestive system malignant tumor treatment

Glutamine is one of the most abundant non-essential amino acids in human plasma and plays a crucial role in many biological processes of the human body.Tumor cells take up a large amount of glutamine to meet their rapid proliferation requirements,which is supported by the upregulation of glutamine transporters.Targeted inhibition of glutamine transporters effectively inhibits cell growth and proliferation in tumors.Among all cancers,digestive system malignant tumors(DSMTs)have the highest incidence and mortality rates,and the current therapeutic strategies for DSMTs are mainly surgical resection and chemotherapy.Due to the relatively low survival rate and severe side effects associated with DSMTs treatment,new treatment strategies are urgently required.This article summarizes the glutamine transporters involved in DSMTs and describes their role in DSMTs.Additionally,glutamine transportertarget drugs are discussed,providing theoretical guidance for the further development of drugs DSMTs treatment.

Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments

BACKGROUND Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy.Glioma stem cells(GSCs),a subset within tumors,contribute to resistance,tumor heterogeneity,and plasticity.Recent studies reveal GSCs’role in therapeutic resistance,driven by DNA repair mechanisms and dynamic transitions between cellular states.Resistance mechanisms can involve different cellular pathways,most of which have been recently reported in the literature.Despite progress,targeted therapeutic approaches lack consensus due to GSCs’high plasticity.AIM To analyze targeted therapies against GSC-mediated resistance to radio-and chemotherapy in gliomas,focusing on underlying mechanisms.METHODS A systematic search was conducted across major medical databases(PubMed,Embase,and Cochrane Library)up to September 30,2023.The search strategy utilized relevant Medical Subject Heading terms and keywords related to including“glioma stem cells”,“radiotherapy”,“chemotherapy”,“resistance”,and“targeted therapies”.Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated re-sistance to radiotherapy resistance(RTR).RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI,452 papers were initially identified,with 203 chosen for full-text analysis.Among them,201 were deemed eligible after excluding 168 for various reasons.The temporal breakdown of studies illustrates this trend:2005-2010(33.3%),2011-2015(36.4%),and 2016-2022(30.3%).Key GSC models,particularly U87(33.3%),U251(15.2%),and T98G(15.2%),emerge as significant in research,reflecting their representativeness of glioma characteristics.Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(mTOR)(27.3%)and Notch(12.1%)pathways,suggesting their crucial roles in resistance development.Targeted molecules with mTOR(18.2%),CHK1/2(15.2%),and ATP binding cassette G2(12.1%)as frequent targets underscore their importance in overcoming GSC-mediated resistance.Various therapeutic agents,notably RNA inhibitor/short hairpin RNA(27.3%),inhibitors(e.g.,LY294002,NVP-BEZ235)(24.2%),and monoclonal antibodies(e.g.,cetuximab)(9.1%),demonstrate versatility in targeted therapies.among 20 studies(60.6%),the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance(51.5%),followed by reductions in carmustine resistance(9.1%)and doxorubicin resistance(3.0%),while resistance to RTR is reduced in 42.4%of studies.CONCLUSION GSCs play a complex role in mediating radioresistance and chemoresistance,emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.

Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Is 26S proteasome non-ATPase regulatory subunit 6 a potential molecular target for intrahepatic cholangiocarcinoma?

In this editorial we comment on the article by Tang et al published in the recent issue of World Journal of Hepatology.Drug therapy of intrahepatic cholangiocarcinoma(iCCA)poses an enormous challenge since only a small proportion of patients demonstrate beneficial responses to therapeutic agents.Thus,there has been a sustained search for novel molecular targets for iCCA.The study by Tang et al evaluated the role of 26S proteasome non-ATPase regulatory subunit 6(PSMD6),a 19S regulatory subunit of the proteasome,in human iCCA cells and specimens.The authors employed clustered regularly interspaced short palindromic repeat(CRISPR)knockout screening technology integrated with the computational CERES algorithm,and analyzed the human protein atlas(THPA)database and tissue microarrays.The results show that PSMD6 is a gene essential for the proliferation of 17 iCCA cell lines,and PSMD6 protein was overexpressed in iCCA tissues without a significant correlation with the clinicopathological parameters.The authors conclude that PSMD6 may play a promoting role in iCCA.The major limitations and defects of this study are the lack of detailed information of CRISPR knockout screening,in vivo experiments,and a discussion of plausible mechanistic cues,which,therefore,dampen the significance of the results.Further studies are required to verify PSMD6 as a molecular target for developing novel therapeutics for iCCA.In addition,the editorial article summarizes the latest advances in molecular targeted drugs and recently emerging immunotherapy in the clinical management of iCCA,development of proteasome inhibitors for cancer therapy,and advantages of CRISPR screening technology,computational methods,and THPA database as experimental tools for fighting cancer.We hope that these comments may provide some clues for those engaged in the field of basic and clinical research into iCCA.

Research Progress in Targeted Therapy for Esophageal Cancer

Esophageal cancer (EC) is a prevalent malignant tumor that affects the digestive system and is often linked to a poor prognosis. The absence of effective early screening methods results in the diagnosis of esophageal cancer (EC) patients at advanced or metastatic stages. While historically considered incurable, ongoing advancements in medical research have led to the integration of various treatment modalities as primary approaches for managing advanced endometrial cancer. These modalities include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Notably, the introduction of targeted therapy and immunotherapy has significantly enhanced the survival rates of individuals with EC. Immunotherapy has appeared as the predominant treatment for advanced esophageal cancer, while targeted therapy faces certain obstacles. Consequently, this review primarily focuses on the advancements in targeted therapy for esophageal cancer (EC), evaluating the effectiveness and safety of relevant medications, and aiming to provide guidance for the comprehensive management of EC based on current research findings.

Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

Survivin:Potential role in diagnosis,prognosis and targeted therapy of gastric cancer

Survivin is a protein that is highly expressed in a vast number of malignancies,but is minimally expressed in normal tissues. It plays a role as an inhibitor of cell death in cancer cells,thus facilitating the growth of these cells. In the case of gastric cancer,survivin is over-expressed in tumor cells and plays a role in the carcinogenesis process. Several studies on gastric cancer have indicated that there is a relationship between survivin expression and the ultimate behavior of the carcinoma. Since the expression pattern of survivin is selective to cancer cells,it has been described as an "ideal target" for cancer therapy. Currently,several pre-clinical and clinical trials are on-going to investigate the effects of interfering with survivin function in cancer cells as a biologic therapy. Survivin is a potentially significant protein in the diagnosis,prognosis and treatment of gastric tumors.