Background: Oral cancer is the 17th most common cancer worldwide, with a mortality rate of 1.8%. Their incidence varies considerably, with a clear prevalence in South Asian countries. In Africa, the mortality rate for cancers of the oral cavity is 1.3%. Senegal is a perfect illustration a perfect illustration of the seriousness and scale of this disease, with 177 new cases recorded in 2020, for a mortality rate of 1.4%. To add to the knowledge of the molecular mechanisms involved in the carcinogenesis of these pathologies in Senegal, mutations in the C-MYC proto-oncogene were examined in 22 patients with oral cavity cancers and compared with samples from 32 control individuals. Methods: Cancerous tissue (CT) and adjacent normal tissue (ANT) were sampled from diseased individuals, whereas whole blood was obtained from control individuals (C). A total of 67 samples were collected: 32 from controls, 22 from CTs, and 13 from ANTs of diseased individuals. Total DNA was extracted and polymerase chain reaction (PCR) amplification of exon 2 of the C-MYC gene was performed, followed by Sanger sequencing. Mutation analysis was performed using Mutation Surveyor Software v5.0.1. The effect of each non-synonymous mutation on the function of the encoded protein was determined using the POLYPHEN-2, PANTHER-PSEP, and PROVEAN algorithms. The probability of non-synonymous mutations causing diseases was predicted using Prediction of human Deleterious Single Nucleotide Polymorphism (PhD-SNP) and Predicting disease associated variations using GO terms (SNP&GO). The impact of non-synonymous variations on the stability of the encoded protein was determined using I-Mutant2 and In-silico analysis of Protein Stability (INPS). Results: Of the study participants, 63% were females. The mean age of patients was 46.43 ± 13 years, with extremes of 14 and 83 years and the age range of 40–70 years as the most representative age group. Only 5% of patients were alcohol drinkers and 15% were smokers. Most patients (80%) had stage III or IV tumors with lymph node invasion. A low polymorphism rate in exon 2 of the C-MYC proto-oncogene was identified, with one synonymous substitution (Q48Q) found in a diseased individual (CT and ANT). The non-synonymous substitutions (D31N, D31E, V33G, Y36N, and Y36D) found in the controls were predicted to be damaging and pathogenic, and might decrease the stability of the encoded protein. Conclusions: Our results indicate that the C-MYC protooncogene is not involved in the occurrence and progression of oral cavity cancers in Senegalese patients. However, the mutations found in controls could provide new markers for the early clinical diagnosis of oral cancer.
背景:口腔癌是全球第17大最常见的癌症，死亡率为1.8%。它们的发病率差别很大，在南亚国家明显流行。在非洲，口腔癌的死亡率为1.3%。塞内加尔是一个完美的例证，完美地说明了这种疾病的严重性和规模，2020年记录了177例新病例，死亡率为1.4%。为了进一步了解塞内加尔这些病理致癌性的分子机制，对22名口腔癌患者的C-MYC原癌基因突变进行了检查，并与32名对照个体的样本进行了比较。方法:取病变个体的癌组织(CT)和邻近正常组织(ANT)，取对照个体的全血(C)。共采集67份样本:对照组32份，CT 22份，病变个体蚂蚁13份。提取总DNA，对C-MYC基因外显子2进行聚合酶链反应(PCR)扩增，然后进行Sanger测序。使用Mutation Surveyor Software v5.0.1进行突变分析。每个非同义突变对编码蛋白功能的影响使用polyphen2, PANTHER-PSEP和PROVEAN算法确定。使用预测人类有害单核苷酸多态性(PhD-SNP)和使用GO术语预测疾病相关变异(SNP&GO)预测非同义突变导致疾病的概率。使用I-Mutant2和in - silicon analysis of protein stability (INPS)来确定非同义变异对编码蛋白稳定性的影响。结果:在研究参与者中，63%是女性。患者平均年龄46.43±13岁，极端年龄14岁、83岁，年龄40 ~ 70岁为最具代表性年龄组。只有5%的患者是饮酒者，15%是吸烟者。大多数患者(80%)为III期或IV期肿瘤伴淋巴结浸润。在C-MYC原癌基因的外显子2中发现了低多态性率，在患病个体中发现了一个同义替换(Q48Q) (CT和ANT)。在对照中发现的非同义取代(D31N、D31E、V33G、Y36N和Y36D)预计具有破坏性和致病性，并可能降低编码蛋白的稳定性。结论:我们的研究结果表明，C-MYC原癌基因与塞内加尔患者口腔癌的发生和进展无关。然而，在对照组中发现的突变可以为口腔癌的早期临床诊断提供新的标志物。
{"title":"Genetic Alterations of C-MYC Proto-Oncogene and Their Involvement in the Occurrence and Progression of Oral Cavity Cancers in Senegal","authors":"Diao Ba, Fatimata Mbaye, Henri Diatta, Mame Diarra Samb, Mouhamadou Makhtar Ndiaye, Silly Toure, Mbacke Sembene","doi":"10.31083/j.jmcm0601002","DOIUrl":"https://doi.org/10.31083/j.jmcm0601002","url":null,"abstract":"Background: Oral cancer is the 17th most common cancer worldwide, with a mortality rate of 1.8%. Their incidence varies considerably, with a clear prevalence in South Asian countries. In Africa, the mortality rate for cancers of the oral cavity is 1.3%. Senegal is a perfect illustration a perfect illustration of the seriousness and scale of this disease, with 177 new cases recorded in 2020, for a mortality rate of 1.4%. To add to the knowledge of the molecular mechanisms involved in the carcinogenesis of these pathologies in Senegal, mutations in the C-MYC proto-oncogene were examined in 22 patients with oral cavity cancers and compared with samples from 32 control individuals. Methods: Cancerous tissue (CT) and adjacent normal tissue (ANT) were sampled from diseased individuals, whereas whole blood was obtained from control individuals (C). A total of 67 samples were collected: 32 from controls, 22 from CTs, and 13 from ANTs of diseased individuals. Total DNA was extracted and polymerase chain reaction (PCR) amplification of exon 2 of the C-MYC gene was performed, followed by Sanger sequencing. Mutation analysis was performed using Mutation Surveyor Software v5.0.1. The effect of each non-synonymous mutation on the function of the encoded protein was determined using the POLYPHEN-2, PANTHER-PSEP, and PROVEAN algorithms. The probability of non-synonymous mutations causing diseases was predicted using Prediction of human Deleterious Single Nucleotide Polymorphism (PhD-SNP) and Predicting disease associated variations using GO terms (SNP&GO). The impact of non-synonymous variations on the stability of the encoded protein was determined using I-Mutant2 and In-silico analysis of Protein Stability (INPS). Results: Of the study participants, 63% were females. The mean age of patients was 46.43 ± 13 years, with extremes of 14 and 83 years and the age range of 40–70 years as the most representative age group. Only 5% of patients were alcohol drinkers and 15% were smokers. Most patients (80%) had stage III or IV tumors with lymph node invasion. A low polymorphism rate in exon 2 of the C-MYC proto-oncogene was identified, with one synonymous substitution (Q48Q) found in a diseased individual (CT and ANT). The non-synonymous substitutions (D31N, D31E, V33G, Y36N, and Y36D) found in the controls were predicted to be damaging and pathogenic, and might decrease the stability of the encoded protein. Conclusions: Our results indicate that the C-MYC protooncogene is not involved in the occurrence and progression of oral cavity cancers in Senegalese patients. However, the mutations found in controls could provide new markers for the early clinical diagnosis of oral cancer.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135167636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Functional neurological disorders may present with cognitive symptoms as functional cognitive disorders. This narrative review addresses the diagnosis and differential diagnosis of functional cognitive disorders encountered in the emergency department setting. Functional cognitive disorders, like other functional neurological disorders, can be clinically suspected and may be positively diagnosed in the emergency department setting following careful diagnostic evaluation, rather than being a diagnosis of exclusion. However, the differential diagnosis is broad, and the possibility of either stroke or seizure in particular needs to be considered. Functional cognitive disorders can be positively diagnosed in the emergency department setting, as for other forms of functional neurological disorder, and hence directed onward to appropriate services
{"title":"Functional Cognitive Disorders in the Emergency Department","authors":"Andrew J Larner","doi":"10.31083/j.jmcm0601001","DOIUrl":"https://doi.org/10.31083/j.jmcm0601001","url":null,"abstract":"Functional neurological disorders may present with cognitive symptoms as functional cognitive disorders. This narrative review addresses the diagnosis and differential diagnosis of functional cognitive disorders encountered in the emergency department setting. Functional cognitive disorders, like other functional neurological disorders, can be clinically suspected and may be positively diagnosed in the emergency department setting following careful diagnostic evaluation, rather than being a diagnosis of exclusion. However, the differential diagnosis is broad, and the possibility of either stroke or seizure in particular needs to be considered. Functional cognitive disorders can be positively diagnosed in the emergency department setting, as for other forms of functional neurological disorder, and hence directed onward to appropriate services","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135322802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Takashi Miyoshi, Fumihiko Kono, Yuta Shimazu, Keisuke Shindo, S. Imashuku
Background : The differential diagnosis of Burkitt lymphoma/leukemia (BL) and the double or triple hit lymphomas remains often problematic in terms of immunophenotyping in association with MYC gene analysis. In the past, BL-like B-cell malignancy with B-cell precursor phenotype (BCP-ALL) was described. Case Report : We report here an 84-year-old male with massive ascites without superficial lymphadenopathy. Abdominal paracentesis revealed chylous (non-bloody) ascites consisting of mostly abnormal BL-like blasts showing CD20-negative BCP phenotype. However, molecular study indicated no MYC/IGH , but probable involvements of MYC/IGL and BCL6/IGH translocations, which were confirmed by FISH studies. The patient was diagnosed as double hit lymphoma mimicking BCP-ALL.
{"title":"Double Hit Lymphoma Mimicking B Cell Precursor Phenotype Burkitt Lymphoma/Leukemia in an Elderly","authors":"Takashi Miyoshi, Fumihiko Kono, Yuta Shimazu, Keisuke Shindo, S. Imashuku","doi":"10.31083/j.jmcm0501002","DOIUrl":"https://doi.org/10.31083/j.jmcm0501002","url":null,"abstract":"Background : The differential diagnosis of Burkitt lymphoma/leukemia (BL) and the double or triple hit lymphomas remains often problematic in terms of immunophenotyping in association with MYC gene analysis. In the past, BL-like B-cell malignancy with B-cell precursor phenotype (BCP-ALL) was described. Case Report : We report here an 84-year-old male with massive ascites without superficial lymphadenopathy. Abdominal paracentesis revealed chylous (non-bloody) ascites consisting of mostly abnormal BL-like blasts showing CD20-negative BCP phenotype. However, molecular study indicated no MYC/IGH , but probable involvements of MYC/IGL and BCL6/IGH translocations, which were confirmed by FISH studies. The patient was diagnosed as double hit lymphoma mimicking BCP-ALL.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87769666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
For many decades, the folate antagonist methotrexate (MTX) has served as anchor drug in the treatment of selected cancer types, e.g., (pediatric) leukemia, and chronic inflammatory and joint destructive diseases like rheumatoid arthritis (RA). MTX treatment of leukemia commonly includes high dose MTX therapy (1–10 g/m) [1], whereas RA treatment is based on low-dose MTX therapy (7.5–30 mg/wk) [2]. In both treatment modalities, therapy-induced toxicities, e.g., mucositis with high dose MTX and liver toxicities with long-term low dose MTX, are antagonized by post-supplementation of folates; leucovorin (LV) after HD-MTX and folic acid with low-doseMTX. Despite longstanding experience with various MTX/folate supplementation schedules in clinical practice, it is still an unresolved issue what is the most optimal schedule of MTX and folate supplementation is in terms of dosing and timing of folate supplementation. Furthermore, given the large variation in folic acid supplementation dosages prescribed with MTX treatment of RA patients worldwide, awareness for folate over-supplementation and concomitant long term adverse effects is called for. This commentary will address this issue in light of recent insights from laboratory, nutritional and clinical studies.
{"title":"Folate supplementations for methotrexate therapies in cancer and arthritis: rationales revisited","authors":"G. Jansen","doi":"10.31083/j.jmcm0501001","DOIUrl":"https://doi.org/10.31083/j.jmcm0501001","url":null,"abstract":"For many decades, the folate antagonist methotrexate (MTX) has served as anchor drug in the treatment of selected cancer types, e.g., (pediatric) leukemia, and chronic inflammatory and joint destructive diseases like rheumatoid arthritis (RA). MTX treatment of leukemia commonly includes high dose MTX therapy (1–10 g/m) [1], whereas RA treatment is based on low-dose MTX therapy (7.5–30 mg/wk) [2]. In both treatment modalities, therapy-induced toxicities, e.g., mucositis with high dose MTX and liver toxicities with long-term low dose MTX, are antagonized by post-supplementation of folates; leucovorin (LV) after HD-MTX and folic acid with low-doseMTX. Despite longstanding experience with various MTX/folate supplementation schedules in clinical practice, it is still an unresolved issue what is the most optimal schedule of MTX and folate supplementation is in terms of dosing and timing of folate supplementation. Furthermore, given the large variation in folic acid supplementation dosages prescribed with MTX treatment of RA patients worldwide, awareness for folate over-supplementation and concomitant long term adverse effects is called for. This commentary will address this issue in light of recent insights from laboratory, nutritional and clinical studies.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85334075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Radiology Department, Unidade Local de Saúde da Guarda, 6300-035 Guarda, Portugal Radiology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisbon, Portugal Urology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisbon, Portugal Gynaecology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisbon, Portugal
{"title":"Value of magnetic resonance imaging in identifying mucosal urinary bladder metastasis from endometrial carcinomas: a case report","authors":"A. Pissarra, T. Cunha, R. Ramos, I. Santana","doi":"10.31083/j.jmcm0402006","DOIUrl":"https://doi.org/10.31083/j.jmcm0402006","url":null,"abstract":"Radiology Department, Unidade Local de Saúde da Guarda, 6300-035 Guarda, Portugal Radiology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisbon, Portugal Urology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisbon, Portugal Gynaecology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisbon, Portugal","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87548195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
There occurs a progressive weakness and wastage of skeletal muscle in different types of muscular dystrophy. The loss of muscle fibers in dystrophic muscle with impaired function is associated with leakage of intracellular enzymes, maldistribution of electrolyte content and metabolic defects in myocytes. Marked increases in the sarcolemma (SL) Na-K ATPase and Ca/Mg-ecto ATPase activities, as well as depressions in the sarcoplasmic reticulum (SR) Ca-uptake and Ca-pump ATPase activities were seen in dystrophic muscles of a hamster model of myopathy. In addition, impaired mitochondrial oxidative phosphorylation and decrease in the high energy stores as a consequence of mitochondrial Ca-overload were observed in these myopathic hamsters. In some forms of muscular dystrophy, it has been shown that deficiency of dystrophin produces marked alterations in the SL permeability and promotes the occurrence of intracellular Ca-overload for inducing metabolic defects, activation of proteases and contractile abnormalities in dystrophic muscle. Increases in SR Ca-release channels, SL Na-Ca exchanger and SL store-operated Ca-channels have been reported to induce Cahandling abnormalities in a mouse model of muscular dystrophy. Furthermore, alterations in lipid metabolism and development of oxidative stress have been suggested as mechanisms for subcellular remodeling and cellular damage in dystrophic muscle. Although, several therapeutic interventions including gene therapy are available, these treatments neither fully prevent the course of development of muscular disorder nor fully improve the function of dystrophic muscle. Thus, extensive reasearch work with some novel inhibitors of oxidative stress, SL Ca-entry systems such as store-operated Ca-channels, Na-Ca exchanger and Ca/Mg-ecto ATPase (Ca-gating mechanism), as well as SR Ca-release and Capump systems needs to be carried out in combination of gene therapy for improved beneficial effects in muscular dystrophy.
{"title":"Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles","authors":"S. Bhullar, M. Nusier, A. Shah, N. Dhalla","doi":"10.31083/j.jmcm0402005","DOIUrl":"https://doi.org/10.31083/j.jmcm0402005","url":null,"abstract":"There occurs a progressive weakness and wastage of skeletal muscle in different types of muscular dystrophy. The loss of muscle fibers in dystrophic muscle with impaired function is associated with leakage of intracellular enzymes, maldistribution of electrolyte content and metabolic defects in myocytes. Marked increases in the sarcolemma (SL) Na-K ATPase and Ca/Mg-ecto ATPase activities, as well as depressions in the sarcoplasmic reticulum (SR) Ca-uptake and Ca-pump ATPase activities were seen in dystrophic muscles of a hamster model of myopathy. In addition, impaired mitochondrial oxidative phosphorylation and decrease in the high energy stores as a consequence of mitochondrial Ca-overload were observed in these myopathic hamsters. In some forms of muscular dystrophy, it has been shown that deficiency of dystrophin produces marked alterations in the SL permeability and promotes the occurrence of intracellular Ca-overload for inducing metabolic defects, activation of proteases and contractile abnormalities in dystrophic muscle. Increases in SR Ca-release channels, SL Na-Ca exchanger and SL store-operated Ca-channels have been reported to induce Cahandling abnormalities in a mouse model of muscular dystrophy. Furthermore, alterations in lipid metabolism and development of oxidative stress have been suggested as mechanisms for subcellular remodeling and cellular damage in dystrophic muscle. Although, several therapeutic interventions including gene therapy are available, these treatments neither fully prevent the course of development of muscular disorder nor fully improve the function of dystrophic muscle. Thus, extensive reasearch work with some novel inhibitors of oxidative stress, SL Ca-entry systems such as store-operated Ca-channels, Na-Ca exchanger and Ca/Mg-ecto ATPase (Ca-gating mechanism), as well as SR Ca-release and Capump systems needs to be carried out in combination of gene therapy for improved beneficial effects in muscular dystrophy.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78528486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-12-20DOI: 10.31083/j.jmcm.2019.04.5061
Z. Vadas, J. Rubinstein, Z. Bahouth, S. Halachmi
therapy. Herein we review the current knowledge about Semaphorin-3A in UC.
治疗。在此，我们回顾了Semaphorin-3A在UC中的最新知识。
{"title":"Semaphorin-3A and urothelial carcinoma","authors":"Z. Vadas, J. Rubinstein, Z. Bahouth, S. Halachmi","doi":"10.31083/j.jmcm.2019.04.5061","DOIUrl":"https://doi.org/10.31083/j.jmcm.2019.04.5061","url":null,"abstract":"therapy. Herein we review the current knowledge about Semaphorin-3A in UC.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85492823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-12-20DOI: 10.31083/j.jmcm.2019.04.5121
M. Fernandes, J. Padrón
Pancreatic ductal adenocarcinoma (PDAC) is a relatively rare tumor, however it is the seventh cancer related leading cause of death worldwide. Mean survival time after PDAC diagnosis is less than 1 year and the median survival of PDAC patients has hardly changed in the past 40 years. Until now, cytotoxic and/or targeted therapy produced disappointing results in the treatment of PDAC. Currently, surgical resection offers the only hope for survival, but it is suited for only 15% of PDAC patients. To complicate matters, the vast majority of PDAC patients relapse after surgery. Thus, there is a burning need to develop better therapeutic strategies for PDAC treatment. PDAC cells have adapted to survive and proliferate in a tumor microenvironment that is constitutively under deprivation of nutrients and oxygen, via mechanisms triggered by oncogenic KRAS. In this review, we highlight the metabolic alterations observed in PDAC, with a particular emphasis on past and ongoing strategies to develop inhibitors of KRAS effector signaling. This review provides an up to date information reported in the literature on the most relevant inhibitors of metabolism targets in PDAC. The review specifically provides an overall picture of the current state of the art with the aim of being thought provoking for plausible novel chemotherapeutic strategies of intervention. We anticipate that with our increased collective understanding of PDAC metabolic behavior, PDAC patients could hopefully benefit from these novel therapies.
{"title":"Inhibition of glutamine metabolism as a therapeutic approach against pancreatic ductal adenocarcinoma","authors":"M. Fernandes, J. Padrón","doi":"10.31083/j.jmcm.2019.04.5121","DOIUrl":"https://doi.org/10.31083/j.jmcm.2019.04.5121","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a relatively rare tumor, however it is the seventh cancer related leading cause of death worldwide. Mean survival time after PDAC diagnosis is less than 1 year and the median survival of PDAC patients has hardly changed in the past 40 years. Until now, cytotoxic and/or targeted therapy produced disappointing results in the treatment of PDAC. Currently, surgical resection offers the only hope for survival, but it is suited for only 15% of PDAC patients. To complicate matters, the vast majority of PDAC patients relapse after surgery. Thus, there is a burning need to develop better therapeutic strategies for PDAC treatment. PDAC cells have adapted to survive and proliferate in a tumor microenvironment that is constitutively under deprivation of nutrients and oxygen, via mechanisms triggered by oncogenic KRAS. In this review, we highlight the metabolic alterations observed in PDAC, with a particular emphasis on past and ongoing strategies to develop inhibitors of KRAS effector signaling. This review provides an up to date information reported in the literature on the most relevant inhibitors of metabolism targets in PDAC. The review specifically provides an overall picture of the current state of the art with the aim of being thought provoking for plausible novel chemotherapeutic strategies of intervention. We anticipate that with our increased collective understanding of PDAC metabolic behavior, PDAC patients could hopefully benefit from these novel therapies.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78102519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-12-20DOI: 10.31083/j.jmcm.2019.04.4201
M. D. Bo, L. Baboçi, G. Toffoli
blood-brain-barrier (BBB), a semipermeable membrane of endothelial cells connected by tight junctions, capable of preventing the passage of the majority of the pharmaceutical compounds to the GBM tumor. The TME is characterized by an immunosuppressive state with few tumor-infiltrating lymphocytes (TILs) and other cells activating the immune system. The comprehensive characterization of the molecular landscape of somatic genomic alterations of GBM has lead to the identification of a plethora of mutated genes as well as of abnormal rearrangements of several receptors including the epidermal growth factor receptor and platelet derived growth factor receptor a . This has allowed the introduction of novel therapies, including the use of tyrosine kinase inhibitors (TKIs). More-over, the use of immune checkpoint inhibitors (ICIs) has been successfully introduced in numerous advanced cancers, as well as encouraging results have been obtained that endorse the use of these antibodies in untreated brain metastases from malignant melanoma and from non-small cell lung cancer. Programmed cell death protein (PD-1) receptor/programmed death ligand 1 (PD-L1) inhibitors has been also proposed for GBM treatment. TME, mutational landscape and clonal evolution of GBM tumors are key factors of paramount importance for the efficacy of TKIs and ICIs used in the treatment of GBM. The current review summarizes the principal molecular and TME features of GBM providing the rationale for the use of TKIs and ICI immunotherapy. The main targeted therapies with TKIs and approaches using ICIs, that have been recently proposed, are also discussed.
{"title":"Molecular and immunological rationale for the use of tyrosine kinase inhibitors and immune checkpoint inhibitors in glioblastomas","authors":"M. D. Bo, L. Baboçi, G. Toffoli","doi":"10.31083/j.jmcm.2019.04.4201","DOIUrl":"https://doi.org/10.31083/j.jmcm.2019.04.4201","url":null,"abstract":"blood-brain-barrier (BBB), a semipermeable membrane of endothelial cells connected by tight junctions, capable of preventing the passage of the majority of the pharmaceutical compounds to the GBM tumor. The TME is characterized by an immunosuppressive state with few tumor-infiltrating lymphocytes (TILs) and other cells activating the immune system. The comprehensive characterization of the molecular landscape of somatic genomic alterations of GBM has lead to the identification of a plethora of mutated genes as well as of abnormal rearrangements of several receptors including the epidermal growth factor receptor and platelet derived growth factor receptor a . This has allowed the introduction of novel therapies, including the use of tyrosine kinase inhibitors (TKIs). More-over, the use of immune checkpoint inhibitors (ICIs) has been successfully introduced in numerous advanced cancers, as well as encouraging results have been obtained that endorse the use of these antibodies in untreated brain metastases from malignant melanoma and from non-small cell lung cancer. Programmed cell death protein (PD-1) receptor/programmed death ligand 1 (PD-L1) inhibitors has been also proposed for GBM treatment. TME, mutational landscape and clonal evolution of GBM tumors are key factors of paramount importance for the efficacy of TKIs and ICIs used in the treatment of GBM. The current review summarizes the principal molecular and TME features of GBM providing the rationale for the use of TKIs and ICI immunotherapy. The main targeted therapies with TKIs and approaches using ICIs, that have been recently proposed, are also discussed.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76162658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-12-20DOI: 10.31083/j.jmcm.2019.04.3241
Tijana Stankovic, J. Stojšić, M. Dragoj, Z. Milovanović, Z. Milošević, Vedrana P. Milinković, V. Škodrić-Trifunović, Ljiljana Denić-Marković, M. Pešić, Sonja Stojković Burić, N. Tanić, Jasna Banković
resistance efflux transporters, P-glycoprotein (P-gp/ ABCB1 ), multidrug resistance associated protein (MRP1/ ABCC1) and breast cancer resistance protein (BCRP/ ABCG2 ) in non-small cell lung carcinoma (NSCLC) patients. Particularly, their role as molecular markers of chemosensitivity and prognosis of NSCLC patients receiving NACT was investigated. To that end, we specifically studied mRNA and protein expression of these three efflux transporters in two independent groups, each consisting of 35 NSCLC patients who did or did not receive platinum-based NACT. Alterations in the expression of MDR efflux transporters were statistically analyzed in relation to NACT status, and their associations were evaluated regarding patients' survival. The frequency of samples with positive MRP1 expression was significantly decreased in the NACT group, regardless of the applied platinum drugs which are known to induce MRP1 expression. On the other hand, the incidence of BCRP expressing tumor specimens, doubly positive BCRP and P-gp as well as triple positive samples increased in the NACT group. Impor-tantly, patients lacking P-gp expression had more favorable prognosis with NACT than without NACT, whereas the status of MRP1 and BCRP did not influence the patients' survival in both investigated groups. Collectively, we show that decreased MRP1 and increased BCRP expression after NACT could determine the chemosensitivity of NSCLC following adjuvant therapy, whereas P-gp expression status could be considered a prognostic marker for NSCLC patients who can benefit from NACT treatment.
{"title":"Chemosensitivity and survival of non-small cell lung carcinoma patients receiving neoadjuvant therapy depend on the expression of multidrug efflux transporters","authors":"Tijana Stankovic, J. Stojšić, M. Dragoj, Z. Milovanović, Z. Milošević, Vedrana P. Milinković, V. Škodrić-Trifunović, Ljiljana Denić-Marković, M. Pešić, Sonja Stojković Burić, N. Tanić, Jasna Banković","doi":"10.31083/j.jmcm.2019.04.3241","DOIUrl":"https://doi.org/10.31083/j.jmcm.2019.04.3241","url":null,"abstract":"resistance efflux transporters, P-glycoprotein (P-gp/ ABCB1 ), multidrug resistance associated protein (MRP1/ ABCC1) and breast cancer resistance protein (BCRP/ ABCG2 ) in non-small cell lung carcinoma (NSCLC) patients. Particularly, their role as molecular markers of chemosensitivity and prognosis of NSCLC patients receiving NACT was investigated. To that end, we specifically studied mRNA and protein expression of these three efflux transporters in two independent groups, each consisting of 35 NSCLC patients who did or did not receive platinum-based NACT. Alterations in the expression of MDR efflux transporters were statistically analyzed in relation to NACT status, and their associations were evaluated regarding patients' survival. The frequency of samples with positive MRP1 expression was significantly decreased in the NACT group, regardless of the applied platinum drugs which are known to induce MRP1 expression. On the other hand, the incidence of BCRP expressing tumor specimens, doubly positive BCRP and P-gp as well as triple positive samples increased in the NACT group. Impor-tantly, patients lacking P-gp expression had more favorable prognosis with NACT than without NACT, whereas the status of MRP1 and BCRP did not influence the patients' survival in both investigated groups. Collectively, we show that decreased MRP1 and increased BCRP expression after NACT could determine the chemosensitivity of NSCLC following adjuvant therapy, whereas P-gp expression status could be considered a prognostic marker for NSCLC patients who can benefit from NACT treatment.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75206166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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