Molecular approaches for spinal cord injury treatment

Injuries to the spinal cord result in permanent disabilities that limit daily life activities.The main reasons for these poor outcomes are the limited regenerative capacity of central neurons and the inhibitory milieu that is established upon traumatic injuries.Despite decades of research,there is still no efficient treatment for spinal cord injury.Many strategies are tested in preclinical studies that focus on ameliorating the functional outcomes after spinal cord injury.Among these,molecular compounds are currently being used for neurological recovery,with promising results.These molecules target the axon collapsed growth cone,the inhibitory microenvironment,the survival of neurons and glial cells,and the re-establishment of lost connections.In this review we focused on molecules that are being used,either in preclinical or clinical studies,to treat spinal cord injuries,such as drugs,growth and neurotrophic factors,enzymes,and purines.The mechanisms of action of these molecules are discussed,considering traumatic spinal cord injury in rodents and humans.

Chemotherapy and molecular targeting therapy for recurrent cervical cancer

For patients with primary stage IVB, persistent, or recurrent cervical cancer, chemotherapy remains the standard treatment, although it is neither curative nor associated with long-term disease control. In this review, we summarized the history of treatment of recurrent cervical cancer, and the current recommendation for chemotherapy and molecular targeted therapy. Eligible articles were identified by a search of the MEDLINE bibliographical database for the period up to November 30, 2014. The search strategy included the following any or all of the keywords： ＂uterine cervical cancer＂, ＂chemotherapy＂, and ＂targeted therapies＂. Since cisplatin every 21 days was considered as the historical standard treatment for recurrent cervical cancer, subsequent trials have evaluated and demonstrated activity for other agents including paclitaxel, gemcitabine, topotecan and vinorelbine among others. Accordingly, promising agents were incorporated into phase III trials. To examine the best agent to combine with cisplatin, several landmark phase III clinical trials were conducted by Gynecologic Oncology Group （GOG） and Japan Clinical Oncology Group （JCOG）. Through, GOG204 and JCOG0505, paclitaxel/cisplatin （TP） and paclitaxel/carboplatin （TC） are now considered to be the recommended therapies for recurrent cervical cancer patients. However, the prognosis of patients who are already resistant to chemotherapy, are very poor. Therefore new therapeutic strategies are urgently required. Molecular targeted therapy will be the most hopeful candidate of these strategies. From the results of GOG240, bevacizumab combined with TP reached its primary endpoint of improving overall survival （OS）. Although, the prognosis for recurrent cervical cancer patients is still poor, the results of GOG240 shed light on the usefulness of molecular target agents to chemotherapy in cancer patients. Recurrent cervical cancer is generally considered incurable and current chemotherapy regiments offer only modest gains in OS, particularly for patients with multiple poor prognostic factors. Therefore, it is crucial to consider not only the survival benefit, but also the minimization of treatment toxicity, and maximization of quality of life （QOL）.

Molecular targeted therapy causes hepatic encephalopathy in patients after Transjugular intrahepatic portosystemic shunt(TIPS):A case report and literature review

We report two cases of hepatic encephalopathy caused by molecular targeted drugs after the Transjugular intrahepatic portosystemic shunt(TIPS)procedure in our center.The liver toxicities and anti-angiogenic effects induced by targeted drugs may generate an imbalance in ammonia metabolism,elevating blood ammonia levels.TIPS diverts partial blood supply from the liver,aggravates liver impairment,and shunts ammonia-rich blood from the intestine into the systemic circulation.These may be the mechanisms leading to hepatic encephalopathy caused by molecular targeted drugs following TIPS.When clinicians choose molecular targeted therapy as the second or third targeted therapy for patients who have undergone TIPS,the consequence of drug-induced hepatic encephalopathy should also be considered.

Chemotherapy for hepatocellular carcinoma:The present and the future

Hepatocellular carcinoma(HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it's still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatinand gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

Progression of targeted therapy in advanced cholangiocarcinoma

It is necessary to establish an effective therapy to improve the survival of patients with advanced eholangiocarcinoma （CCM. Recently, with the development of pathology research in CCA, a lot of special bio-markers such as EGFR, VEGF, HER2, and MEK et al. could be over expression or mutations in CCA patients. According to their changes, combinations of targeted therapy plus chemotherapy are now recognized as effective therapies for advanced CCA. The aim of this paper is to analyze recent promising studies about targeted therapy alone or combination with each other or with chemotherapies.

Novel molecular targets in hepatocellular carcinoma

Globally,hepatocellular carcinoma(HCC)is a leading cause of cancer and cancerrelated deaths.The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low,which results in a poor prognosis.The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease.However,the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group.Hence,in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC.Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways.Proteins involved in the Hedgehog and Notch signaling pathways,Polo-like kinase 1,arginine,histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC.Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance.Thus,emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.

Advances in understanding the molecular mechanism of pancreatic cancer metastasis

BACKGROUND： Pancreatic cancer（PC） is usually diagnosed at the late-stage and therefore, has widespread metastasis and a very high mortality rate. The mechanisms underlying PC metastasis are not well understood. Recent advances in genomic sequencing have identified groups of gene mutations that affect PC metastasis, but studies elucidating their roles are lacking. The present review was to investigate the molecular mechanisms of PC metastasis.DATA SOURCES： Relevant articles on PC metastasis were searched in MEDLINE via Pub Med prior to April 2015. The search was limited in English publications.RESULTS： PC metastatic cascades are multi-factorial events including both intrinsic and extrinsic elements. This review highlights the most important genetic alterations and other mechanisms that account for PC invasion and metastasis, with particular regard to epithelial-mesenchymal transition, inflammation, stress response, and circulating tumor cells.CONCLUSIONS： Analyses of relevant gene functions and signaling pathways are needed to establish the gene regulatory network and to define the pivotal modulators. Another promising area of study is the genotyping and phenotyping of circulating tumor cells, which could lead to a new era of personalized therapy by identifying specific markers and targets.

Immunotherapy for hepatocellular carcinoma:A promising therapeutic option for advanced disease

Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related deaths worldwide,and its incidence continues to increase.Despite improvements in both medical and surgical therapies,HCC remains associated with poor outcomes due to its high rates of recurrence and mortality.Approximately 50% of patients require systemic therapies that traditionally consist of tyrosine kinase inhibitors.Recently,however,immune checkpoint inhibitors have revolutionized HCC management,providing new therapeutic options.Despite these major advances,the different factors involved in poor clinical responses and molecular pathways leading to resistance following use of these therapies remain unclear.Alternative strategies,such as adoptive T cell transfer,vaccination,and virotherapy,are currently under evaluation.Combinations of immunotherapies with other systemic or local treatments are also being investigated and may be the most promising opportunities for HCC treatment.The aim of this review is to provide updated information on currently available immunotherapies for HCC as well as future perspectives.

Evaluation of Targeted Therapy for Locally Advanced or Metastatic Renal Cell Carcinoma in Tunisia

Introduction: Renal cell carcinoma (RCC) is known to be chemo resistant but with the introduction of targeted therapies;there has been a “revolution” in its treatment strategies. The only targeted therapy available in Tunisia for the treatment of metastatic and/or locally advanced RCC is sunitinib. Objective of the Study: To evaluate therapeutic results and tolerance of sunitinib in metastatic and/or locally advanced RCC. Subjects and Methods: This was a retrospective study covering a period of six years (from January 2008 to January 2014) conducted in 5 medical oncology departments in Tunisia. The population of the study consisted of 29 patients treated with sunitinib for metastatic and/or locally advanced RCC. Results: The mean age of patients was 51 years. Three patients had tumor recurrence and 26 patients had a metastatic RCC. The prognosis was good for 5 patients, intermediate for 19 patients and poor for 5 patients. The median duration of treatment was 5 months. Because of side effects, treatment was discontinued in 12.5% of cases and the dose was reduced in 10.3% of cases. Side effects consisted of asthenia (95.8%), stomatitis (70.8%), anemia (50%), hand-foot syndrome (55.8%) in addition to nausea and vomiting (54.2%). Objective response was observed in 37.5% of patients after 3 months of treatment and in 50% after 6 months. The median progression-free survival was 14 months (95% CI, 7.9 to 20.6). The median overall survival was 22 months (95% CI, 15.6 to 28.7). Conclusion: The prognosis of RCC in Tunisian patients has clearly improved with the introduction of sunitinib, but other therapies with a proven efficacy as a first and second line therapy should be considered.

Tra2βEnhances Cell Proliferation by Inducing the Expression of Transcription Factor SP1 in Cervical Cancer

Objective In this study,the role and potential mechanism of transformer 2β(Tra2β)in cervical cancer were explored.Methods The transcriptional data of Tra2βin patients with cervical cancer from Gene Expression Profiling Interactive Analysis(GEPIA)and cBioPortal databases were investigated.The functions of Tra2βwere evaluated by using Western blot,MTT,colony formation,Transwell assays,and nude mouse tumor formation experiments.Target genes regulated by Tra2βwere studied by RNA-seq.Subsequently,representative genes were selected for RT-qPCR,confocal immunofluorescence,Western blot,and rescue experiments to verify their regulatory relationship.Results The dysregulation of Tra2βin cervical cancer samples was observed.Tra2βoverexpression in Siha and Hela cells enhanced cell viability and proliferation,whereas Tra2βknockdown showed the opposite effect.Alteration of Tra2βexpression did not affect cell migration and invasion.Furthermore,tumor xenograft models verified that Tra2βpromoted cervical cancer growth.Mechanically,Tra2βpositively regulated the mRNA and protein level of SP1,which was critical for the proliferative capability of Tra2β.Conclusion This study demonstrated the important role of the Tra2β/SP1 axis in the progression of cervical cancer in vitro and in vivo,which provides a comprehensive understanding of the pathogenesis of cervical cancer.

Gastroenteropancreatic neuroendocrine neoplasms:A clinical snapshot

Our understanding about the epidemiological aspects,pathogenesis,molecular diagnosis,and targeted therapies of neuroendocrine neoplasms(NENs)have drastically advanced in the past decade.Gastroenteropancreatic(GEP)NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors.Most NENs are welldifferentiated,and slow growing.Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin,glucagon,vasoactive intestinal polypeptide,gastrin,somatostatin,adrenocorticotropin,growth hormone releasing hormone,parathyroid hormone-related peptide,serotonin,histamine,and 5-hydroxy indole acetic acid(5-HIAA).Biomarkers such as pancreatic polypeptide,human chorionic gonadotrophin subunits,neurotensin,ghrelin,and calcitonin are used in the diagnosis of non-functional NENs.5-HIAA levels correlate with tumour burden,prognosis and development of carcinoid heart disease and mesenteric fibrosis,however several diseases,medications and edible products can falsely elevate the 5-HIAA levels.Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs.Emerging novel biomarkers include circulating tumour cells,circulating tumour DNA,circulating micro-RNAs,and neuroendocrine neoplasms test(NETest)(simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood).NETest has high sensitivity(85%-98%)and specificity(93%-97%)for the detection of gastrointestinal NENs,and is useful for monitoring treatment response,recurrence,and prognosis.In terms of management,surgery,radiofrequency ablation,symptom control with medications,chemotherapy and molecular targeted therapies are all considered as options.Surgery is the mainstay of treatment,but depends on factors including age of the individual,location,stage,grade,functional status,and the heredity of the tumour(sporadic vs inherited).Medical management is helpful to alleviate the symptoms,manage inoperable lesions,suppress postoperative tumour growth,and manage recurrences.Several molecular-targeted therapies are considered second line to somatostatin analogues.This review is a clinical update on the pathophysiological aspects,diagnostic algorithm,and management of GEP NENs.

Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment

BACKGROUND： Hepatocellular carcinoma （HCC） is a com- plex and heterogeneous malignancy, frequently occurs in the setting of a chronically diseased organ, with multiple con- founding factors making its management challenging. HCC represents one of the leading causes of cancer-related mortal- ity globally with a rising trend of incidence in some of the de- veloped countries, which indicates the need for better surgical and nonsurgical management strategies.

Research on human glioma stem cells in China

Research on human glioma stem cells began early in the 21st century and since then has become a rapidly growing research field with the number of publications increasing year by year. The research conducted by our diverse group of investigators focused primarily on cell culture techniques, molecular regulation, signaling pathways, cancer treatment, the stem cell microenvironment and the cellular origin and function of glioma stem cells. In particular, we put forward our view that there are inverse or forward transformations among neural stem cells, glial cells and glioma stem cells in glioma tissues under certain conditions. Based on the background of the progress of international research on human glioma stem cells, we aim to share our progress and current findings of human glioma stem cell research in China with colleagues around the world.

Transarterial Chemoembolization Combined with Apatinib for Treatment of Advanced Hepatocellular Carcinoma:Analysis of Survival and Prognostic Factors

Objective Apatinib is a novel inhibitor of vascular endothelial growth factor receptor-2.The goal of this study was to evaluate overall survival(OS)after a combination of transarterial chemoembolization(TACE)and apatinib in patients with advanced hepatocellular carcinoma(HCC)and to identify the factors affecting patient survival.Methods Fifty-one patients with advanced HCC who received TACE in combination with apatinib in our hospital from June 2015 to May 2017 were enrolled.The OS and progression-free survival(PFS)were calculated using the Kaplan-Meier method.The log-rank test and Cox regression model were used to determine the factors affecting OS.Results The median OS and PFS of the patients were 15 months and 10 months,respectively.The 1-,2-,and 3-year survival rates were 64.7%,23.5%,and 1.8%,respectively.Univariate survival analysis showed that patients with Child-Pugh A(P=0.006),reduction rate of proper hepatic artery(P=0.016),hand-foot syndrome(P=0.005),secondary hypertension(P=0.050),and without ascites(P=0.010)had a better OS.Multivariate analysis showed that hand-foot syndrome(P=0.014),secondary hypertension(P=0.017),and reduction rate of proper hepatic artery(P=0.025)were independent predictors of better OS.Conclusion TACE combined with apatinib is a promising treatment for advanced HCC.Hand-foot syndrome,secondary hypertension,and the reduction rate of proper hepatic artery were associated with a better OS.

Successful hepatic resection for recurrent hepatocellular carcinoma after lenvatinib treatment:A case report

BACKGROUND Lenvatinib has been shown to be noninferior to sorafenib regarding prognosis and recurrence rate in patients with unresectable hepatocellular carcinoma(HCC)who have not received prior systemic chemotherapy.In patients treated with lenvatinib,40%of cases achieved sufficient tumor reduction to make potential surgery possible.However,the outcomes of such surgery are unknown.We report a successful case of hepatic resection for recurrent HCC after lenvatinib treatment.CASE SUMMARY A 69-year-old man underwent right anterior sectionectomy for HCC in segment 8 of the liver.Ten months later,he was found to have an intrahepatic HCC recurrence that grew rapidly to 10 cm in diameter with sternal bone metastases.After confirming partial response to lenvatinib administration for 2 mo,a second hepatectomy was performed.Pathological examination showed that 80%of the tumor was necrotic.The patient did not develop any adverse effects under lenvatinib treatment.He was discharged at 25 d after surgery.Radiation therapy for bone metastases continued to be given under lenvatinib,and the patient has remained alive for 1 year after the second hepatectomy.CONCLUSION The prognosis of patients with recurrent HCC may be improved by liver resection combined with prior lenvatinib therapy.

Realize molecular surgical knife in tumor therapy by nanotechnology

In cancer therapy,the main challenge is how to attack the tumor and avoid injuring any normal organs in the meantime.In the last decades,scientists have made great efforts to try targeting the tumors,but little progress is achieved because all of the known therapeutic techniques could not latch the tumor cells down and always bring

RON in hepatobiliary and pancreatic cancers:Pathogenesis and potential therapeutic targets

The receptor protein tyrosine kinase RON belongs to the c-MET proto-oncogene family.Research has shown that RON has a role in cancer pathogenesis,which places RON on the frontline of the development of novel cancer therapeutic strategies.Hepatobiliary and pancreatic(HBP)cancers have a poor prognosis,being reported as having higher rates of cancer-related death.Therefore,to combat these malignant diseases,the mechanism underlying the aberrant expression and signaling of RON in HBP cancer pathogenesis,and the development of RON as a drug target for therapeutic intervention should be investigated.Abnormal RON expression and signaling have been identified in HBP cancers,and also act as tumorigenic determinants for HBP cancer malignant behaviors.In addition,RON is emerging as an important mediator of the clinical prognosis of HBP cancers.Thus,not only is RON significant in HBP cancers,but also RON-targeted therapeutics could be developed to treat these cancers,for example,therapeutic monoclonal antibodies and small-molecule inhibitors.Among them,antibody-drug conjugates have become increasingly popular in current research and their potential as novel anti-cancer biotherapeutics will be determined in future clinical trials.

Anti-Cancer Effects of Novel Doxorubicin Prodrug PDOX in MCF-7 Breast Cancer Cells

Ac-Phe-Lys-PABC-DOX（PDOX） is a smart doxorubicin（DOX） prodrug designed to decrease toxicities while maintaining the potent anticancer effects of DOX. This study was aimed at elucidating the effectiveness and toxicities of DOX and PDOX in patient-derived MCF-7 breast cancer cells in vitro. The MCF-7 cells were exposed to both PDOX and DOX, and cytotoxicities, cell cycle and P53/P21 signaling alterations were studied. Abundant cathepsin B was found in the MCF-7 cells, and treatment with PDOX and DOX triggered dose- and time-dependent cytotoxicity and resulted in a significant reduction in cell viability. The IC50 of PDOX and DOX was 3.91 and 0.94 μmol/L, respectively. Both PDOX and DOX caused an up-regulation of the P53/P21-related signal pathway, and PDOX significantly increased expression of P53 and caspase 3, and arrested the cell cycle at the G1/G2 phase. As compared with DOX, PDOX reduced toxicities, and it may have different action mechanisms on breast cancer cells.

Difficulties in diagnosing anorectal melanoma: A case report and review of the literature

BACKGROUND Anorectal melanoma is a tumour that is difficult to identify due to its rarity and variability of presentation.Insufficient data published in the literature do not allow for diagnostic and treatment guidelines to be established.Anorectal melanoma has the worst prognosis among mucosal melanomas and is frequently misdiagnosed by standard identification methods.CASE SUMMARY A 66-year-old woman presented with intermittent anal bleeding,pain,and tenesmus in the past month,with no associated weight loss.Colonoscopy revealed a cauliflower-like tumour with a diameter of 1.5 cm,with exulcerated areas and an adherent clot but without obstruction.Biopsy results identified an inflammatory rectal polyp with nonspecific chronic rectitis.Tumour markers CA 19-9 and CEA were within the normal range.After 6 mo,due to the persistence of symptoms,a pelvic magnetic resonance imaging scan was performed.A lesion measuring 2.8 cm×2.7 cm×2.1 cm was identified at the anorectal junction,along with two adjacent lymphadenopathies.No distant metastases were detected.Immunohistochemistry was performed on the second set of biopsies,and a diagnosis of anorectal melanoma was established.Surgical treatment by abdominoperineal resection was performed.Evolution was marked by the appearance of lung metastases at 1 mo postoperatively,detected on a positron emission tomography-computer tomography scan,and perineal recurrence after 5 mo.After molecular testing,the patient was included in an immunotherapy trial.CONCLUSION This case highlights the difficulty of establishing a definitive early diagnosis of anorectal melanoma,the importance of performing histological analysis on a wellrepresented biopsy specimen,and the poor prognosis,even with radical surgery.

Improvement of lenvatinib-induced nephrotic syndrome after adaptation to sorafenib in thyroid cancer:A case report

BACKGROUND Target therapy is licensed by United States Food and Drug Administration on certain cancers.Both sorafenib and lenvatinib are tyrosine kinase inhibitor and indicated on radioactive iodine(RAI)-refractory differentiated thyroid cancer(DTC).Lenvatinib is more effective in cancers'control than sorafenib,but causes more nephrotoxicity than sorafenib does.This case is the second published case about the serial adaptions from lenvatinib to sorafenib for improving the proteinuria and,meanwhile,achieving the therapeutic goal.CASE SUMMARY A 56-year-old man suffered from bilateral edematous lower extremities after 1-mo prescription of lenvatinib of 20 mg/d for RAI-refractory DTC.Aside from this symptom,he also developed hypertension.His laboratory showed grade-3 proteinuria(estimated 24-h urine protein:9993 mg),hypoalbuminemia and hypercholesterolemia.Anti-vascular endothelial growth factor(VEGF)therapyinduced nephrotic syndrome was impressed.After reduced dosage of lenvatinib of 10 mg/d and related symptomatic drugs,limited improvement was observed in both adverse effects and caner control.Under this condition,we substituted sorafenib of 400 mg/d for lenvatinib of 10 mg/d.After a 5-mo prescription,not only hypertension and peripheral edema were greatly improved,but also proteinuria was improved from grade three to grade one(estimated 24-h urine protein:962 mg).At the same time the cancer control was achieved,judged from computed tomography and laboratory evidence[thyroglobulin(Tg)before prescription of sorafenib:354.7 ng/m L;Tg after prescription of sorafenib:108.9 ng/m L].CONCLUSION Adaption from lenvatinib to sorafenib is a feasible method to improve the antiVEGF therapy-induced nephrotic syndrome and achieve the therapeutic goal at the same time.