Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: A review and report of personal experience

选择 cyclooxygenase (艇长)-2 禁止者(coxibs ) 作为反煽动性的药之一被开发避免 non-steroidal 的各种各样的副作用反煽动性的药(NSAID ) 。然而， coxibs 也有一个能力禁止各种各样的类型的肿瘤开发 NSAID 的一样的方法。用细胞线和动物模型的许多试验性的研究表明了一个能力阻止 COX-2 禁止者的肿瘤增长。在为息肉 chemoprevention 执行使随机化的研究以后，与家庭腺瘤息肉病( FAP )在病人学习，它证明有 celecoxib 的治疗， coxibs 之一，显著地减少了颜色的数字在 2000 的表面的息肉，美国食物药品管理局(食物及药品管理局)立即为 FAP 病人同意了临床的使用 celecoxib 。然而，某 coxibs 最近被报导包括心脏病和击增加严肃的心血管的事件的风险。在这篇文章，我们在胃肠道的致癌作用考察 COX-2 的一个角色，例如食管，胃和 colorectum，并且也为胃肠道肿瘤的 chemoprevention 分析 coxibs 的前景。

Is endoscopic ultrasound examination necessary in the management of esophageal cancer?

Despite substantial efforts at early diagnosis, accurate staging and advanced treatments, esophageal cancer(EC) continues to be an ominous disease worldwide. Risk factors for esophageal carcinomas include obesity, gastroesophageal reflux disease, hard-alcohol use and tobacco smoking. Five-year survival rates have improved from 5% to 20% since the 1970 s, the result of advances in diagnostic staging and treatment. As the most sensitive test for locoregional staging of EC, endoscopic ultrasound(EUS) influences the development of an optimal oncologic treatment plan for a significant minority of patients with early cancers, which appropriately balances the risks and benefits of surgery, chemotherapy and radiation. EUS is costly, and may not be available at all centers. Thus, the yield of EUS needs to be thoughtfully considered for each patient. Localized intramucosal cancers occasionally require endoscopic resection(ER) for histologic staging or treatment; EUS evaluation may detect suspicious lymph nodes prior to exposing the patient to the risks of ER. Although positron emission tomography(PET) has been increasingly utilized in staging EC, it may be unnecessary for clinical staging of early, localized EC and carries the risk of false-positive metastasis(over staging). In EC patients with evidence of advanced disease, EUS or PET may be used to define the radiotherapy field. Multimodality staging with EUS, crosssectional imaging and histopathologic analysis of ER, remains the standard-of-care in the evaluation of early esophageal cancers. Herein, published data regarding use of EUS for intramucosal, local, regional and metastatic esophageal cancers are reviewed. An algorithm to illustrate the current use of EUS at The University of Texas MD Anderson Cancer Center is presented.

Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype

AIM:To identify molecular biologic differences between two gastric adenocarcinoma subgroups presenting different prognoses through the analysis of microRNA and protein expression.METHODS:Array technologies were used to generate1146 microRNAs and 124 proteins expression profiles of samples from 60 patients with gastric cancer.For the integrative analysis,we used established mRNA expression data published in our previous study.Whole mRNA expression levels were acquired from microarray data for 60 identical gastric cancer patients.Two gastric adenocarcinoma subgroups with distinct mRNA expression profiles presented distinctly different prognoses.MicroRNA and protein expression patterns were compared between gastric cancer tissue and normal gastric tissue and between two different prognostic groups.Aberrantly expressed microRNA,associated mRNA,and protein in patients with poor-prognosis gastric cancer were validated by quantitative reverse transcription polymerase chain reaction and immunochemistry in independent patients.RESULTS:We obtained the expression data of 1146microRNAs and 124 cancer-related proteins.Four microRNAs were aberrantly expressed in the two prognostic groups and in cancer vs non-cancer tissues(P<0.05).In the poor-prognosis group,miR-196b,miR-135b,and miR-93 were up-regulated and miR-29c*was down-regulated.miR-196b expression positively correlated with Homeobox A10(HOXA10)expression(r=0.726,P<0.001),which was significantly increased in poor-prognosis patients(P<0.001).Comparing gastric cancer with non-cancer tissues,46/124 proteins showed differential expression(P<0.05);COX2(P<0.001)and cyclin B1(P=0.017)were clearly overexpressed in the poor-prognosis group.CONCLUSION:Co-activation of miR-196b and HOXA10characterized a poor-prognosis subgroup of patients with gastric cancer.Elucidation of the biologic function of miR-196b and HOXA10 is warranted.

Multi-institutional retrospective analysis of FOLFIRI in patients with advanced biliary tract cancers

BACKGROUND Gemcitabine plus platinum is the standard of care first-line treatment for advanced biliary tract cancers(BTC).There is no established second-line therapy,and retrospective reviews report median progression-free survival(PFS)less than 3 mo on second-line therapy.5-Fluorouracil plus irinotecan(FOLFIRI)is a commonly used regimen in patients with BTC who have progressed on gemcitabine plus platinum,though there is a paucity of data regarding its efficacy in this population.AIM To assess the efficacy of FOLFIRI in patients with biliary tract cancers.METHODS We retrospectively identified patients with advanced BTC who were treated with FOLFIRI at MD Anderson,University of Michigan and Mayo Clinic in Jacksonville.Data were collected on patient demographics,BTC subtype,response per RECIST v1.1,progression and survival.RESULTS Ninety-eight patients were included of which 74(75%)had metastatic and 24(25%)had locally advanced disease at the time of treatment with FOLFIRI.The median age was 60(range,22-86)years.The number of patients with extrahepatic cholangiocarcinoma,gall bladder cancer and intrahepatic cholangiocarcinoma were 10,17 and 71,respectively.FOLFIRI was used as 1st,2nd,3rd or 4th–Nth lines in 8,50,36 and 4 patients,respectively.Median duration on FOLFIRI in the entire cohort was 2.2(range,0.5-8.4)mo.The median PFS and overall survival were 2.4(95%confidence interval(CI):1.7-3.1)and 6.6(95%CI:4.7-8.4)mo,respectively.Median PFS for patients treated with FOLFIRI in 1st,2nd,3rd or 4th–Nth lines were 3.1,2.5,2.3 and 1.5 mo,respectively.Eighteen patients received concurrent bevacizumab(n=13)or EGFR-targeted therapy(n=5)with FOLFIRI,with a median PFS of 2.7 mo(95%CI:1.7-5.1).CONCLUSION In this largest multi-institution retrospective review of 98 patients with BTC treated with FOLFIRI,efficacy appears to be modest with outcomes similar to other cytotoxic chemotherapy regimens.

A pilot double-blind, randomized, placebo-controlled trial of curcumin/bioperine for lung cancer chemoprevention in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease is an inflammatory condition with increased risk of lung cancer. We hypothesized that curcumin/ bioperine (CB), which has anti-inflammatory effects, may reduce cytological abnormalities in the sputum of patients with COPD. We conducted a 3-month, three-to-one randomized, doubleblind, pilot trial of escalating doses of CB in patients with moderate or worse COPD who were capable of producing sputum. The primary efficacy endpoint was changed in sputum cytology. We also explored changes in fluorescence in situ hybridization (FISH). We obtained sputum samples for cytology and chromosome abnormalities at baseline and each monthly follow-up visit. We enrolled 57 participants, with 35 completing the study. The participants’ mean age (standard deviation [SD]) was 66.6 (8.2) years, and they were mainly male (91.2%), with an average of 63.8 pack-years of smoking history. Also, 42.1% of participants were active smokers and the mean (SD) FEV1 was 37% (13%). At baseline, 13 subjects had moderate or worse dysplasia (22.8%). Subjects with moderate to severe sputum dysplasia had more chromosome abnormalities in epithelial cells and neutrophils, as measured by deletion and aneuploidy in 10q22.3. The changes in sputum cytology and chromosome abnormalities did not differ between the active and placebo arms. CB was well tolerated at the bid doses of 1, 1.5, and 2 gm of curcumin and 5 mg of bioperine, with minor side effects related to the gastrointestinal tract. In this short pilot trial, CB compared to placebo did not alter cytological and chromosomal abnormalities seen in sputum of patients with COPD.

Methods for improving colorectal cancer annotation efficiency for artificial intelligence-observer training

BACKGROUND Missing occult cancer lesions accounts for the most diagnostic errors in retrospective radiology reviews as early cancer can be small or subtle,making the lesions difficult to detect.Secondobserver is the most effective technique for reducing these events and can be economically implemented with the advent of artificial intelligence(AI).AIM To achieve appropriate AI model training,a large annotated dataset is necessary to train the AI models.Our goal in this research is to compare two methods for decreasing the annotation time to establish ground truth:Skip-slice annotation and AI-initiated annotation.METHODS We developed a 2D U-Net as an AI second observer for detecting colorectal cancer(CRC)and an ensemble of 5 differently initiated 2D U-Net for ensemble technique.Each model was trained with 51 cases of annotated CRC computed tomography of the abdomen and pelvis,tested with 7 cases,and validated with 20 cases from The Cancer Imaging Archive cases.The sensitivity,false positives per case,and estimated Dice coefficient were obtained for each method of training.We compared the two methods of annotations and the time reduction associated with the technique.The time differences were tested using Friedman’s two-way analysis of variance.RESULTS Sparse annotation significantly reduces the time for annotation particularly skipping 2 slices at a time(P<0.001).Reduction of up to 2/3 of the annotation does not reduce AI model sensitivity or false positives per case.Although initializing human annotation with AI reduces the annotation time,the reduction is minimal,even when using an ensemble AI to decrease false positives.CONCLUSION Our data support the sparse annotation technique as an efficient technique for reducing the time needed to establish the ground truth.

T-cell/histiocyte-rich large B-cell lymphoma in a child:A case report and review of literature

T-cell/histiocyte-rich large B-cell lymphoma is uncommon in children population. There were few cases reported in the literature with wide range clinical presentations including advanced stage, and more involvement of liver, spleen and bone marrow. Head and neck lymphadenopathy tends to present in younger children. We report a case of 10-year-old boy who initially presented intermittent fever, headaches and neck lymphadenopathy. Subsequently, he developed diffuse lymphadenopathy and hepatosplenomegaly. T-cell/histiocyte-rich large B-cell lymphoma was diagnosed on a cervical lymph node biopsy. Cervical lymphadenopathy in this age group is most commonly reactive or nonmalignant processes. Lymphoma is much less frequent; mainly are non-Hodgkin lymphomas. However, a subset of large B-cell lymphoma called T-cell/histiocyte-rich B-cell lymphoma is rare in children.

Cytopathic effects and local immune responses in repeated neoadjuvant HSV-tk+ ganciclovir gene therapy for prostate cancer

Objective:Cytopathic effects and local immune response were analyzed histologically in prostatic cancer(PCa)with in situ herpes simplex virus-thymidine kinase(HSV-tk)/ganciclovir(GCV)gene therapy(GT).Methods:Four high-risk PCa patients who received HSV-tk/GCV GT were investigated.After two cycles of intraprostatic injection of HSV-tk and administration of GCV,radical prostatectomy was performed.Formalin-fixed,paraffin-embedded sections were evaluated using immunohistochemistry.PCa with hormone therapy(HT,n=3)or without neoadjuvant therapy(NT,n=4)that were equivalent in terms of risk were also examined as reference.Immunoreactively-positive cells were counted in at least three areas in cancer tissue.Labeling indices(LI)were calculated as percentage values.Results:ssDNA LI in GT increased,indicating apoptosis,as well as tumor-infiltrating lymphocytes and CD68-positive macrophages,compared with their biopsies.GT cases showed significantly higher numbers of single-stranded DNA(ssDNA)LI,CD4/CD8-positive T cells and CD68-positive macrophages including M1/M2 macrophages than HT or NT cases.However,there was no significant difference in CD20-positive B cells among the types of case.There were strong correlations between CD8+T cells and CD68+macrophages(ρ=0.656,p<0.0001)as well as CD4+T cells and CD20+B cells(ρ=0.644,p<0.0001)in PCa with GT.Conclusions:Enhanced cytopathic effect and local immune response might be indicated in PCa patients with HSV-tk/GCV gene therapy.

Testing Reliability and Validity of the Oulu Patient Classification Instrument—The First Step in Evaluating the RAFAELA System in Norway

Objective: To study reliability and validity of the Finnish Oulu Patient Classification instrument in Norway. Background: The Finnish patient classification system RAFAELA consists of three parts: 1) daily patient classification of nursing intensity using the Oulu Patient Classification instrument, 2) calculation of nursing resources providing bed side care per 24 hours, and 3) Professional Assessment of Optimal Nursing Care Intensity Level. The RAFAELA system has not been tested outside of Finland. Methods: A prospective, descriptive study was performed at 5 clinical units at Oslo University Hospital during 2011-2012. The interrater reliability of the Oulu Patient Classification instrument was tested by parallel classification including 100-167 patient classifications pr. unit, and analyzed by consensus in % and using Cohen’s Kappa. Convergent validity was tested by using the average Oulu Patient Classification instrument value to predict the average Professional Assessment of Optimal Nursing Care Intensity Level for the same calendar day by linear regression analysis. Results: The Oulu Patient Classification instrument consensus of parallel classifications varied between 70.1%-89%. Cohen’s Kappa within patient classes varied between 0.57 and 0.81, representing substantial interrater reliability. The Oulu Patient Classification instrument was valid as the instrument in average explained about 38% of the variation of the Professional Assessment of Optimal Nursing Care Intensity Level. Conclusions: Patient classification systems tested for psychometric properties are needed and this study provides evidence of satisfactory reliability and validity of the Oulu Patient Classification instrument as tested outside Finland, demonstrating that this instrument has international relevance within nursing.

A Qualitative Study of Manager Experiences Using the RAFAELA System

Objective: The objective was to explore manager experiences using the RAFAELA system. Background: The RAFAELA system was developed in Finland during the 1990s to create a work situation where patients’ care needs were balanced with personnel resources. The system is used in almost all hospitals in Finland and is implemented in several European countries. However, the system has never been evaluated outside Finland. This study, focusing on the managers’ perspective, represents the second report from a larger Norwegian evaluation project of the RAFAELA system. Methods: An explorative qualitative design was chosen. Data were collected by individual in-depth interviews at a university hospital in Norway during 2012-2013. A total of 10 informants in various management positions were interviewed. The tape-recorded interviews were transcribed verbatim, and the transcripts were analysed using Kvale’s method for content analysis. Results: Four main themes emerged from the qualitative data: making the invisible visible;a common language;a system for prospective planning;and a resource-demanding tool. Conclusions: The study indicated that the RAFAELA system provided useful information about the patients’ care needs and nursing activities. Also the system provided a common reference frame for discussing nursing, staffing and allocation. Although the managers considered the RAFAELA to be time consuming in the implementation phase, they considered the system to be an important tool.

华蟾素治疗肝癌、肺癌、胰腺癌的Ⅰ期临床研究:初步报道

背景与目的:华蟾素目前广泛应用于肿瘤的治疗中,由于在80年代上市,未进行临床Ⅰ期研究,无法确定其最大耐受剂量。因此本文旨在观察华蟾素治疗肝细胞癌、肺癌和胰腺癌的最大耐受剂量和不良反应,同时评价治疗疗效。方法:Ⅲ、Ⅳ期肝细胞癌、非小细胞肺癌和胰腺癌接受华蟾素治疗,采用静脉滴注,连续14 d,21 d为一疗程。如果没有出现剂量限制性毒性,治疗将持续2个疗程。剂量递增的方案为:10、20、40、60、90和120 m l/(m2.d)。结果:入组15例患者(每个剂量组为3例)中,11例为肝癌,2例胰腺癌和2例肺癌。第五剂量组结束时没有发现剂量限制性毒性(DLT)。其中14例患者可评价疗效,6例(42.9%)为SD,8例(57.1%)为PD。在第一剂量组中,1例肝癌患者肿瘤缩小20%并维持11个月。结论:本研究最高剂量达到常规剂量的8倍,尚未出现剂量限制性毒性。部分患者获得了肿瘤缩小或稳定的疗效。

与帮助 laparoscopy 的外科对待的 Stenotic ischemic 大肠炎

Ischemic colitis is the most common type of intestinal ischemia. The etiology of this condition is multifactorial, and the diagnosis is based on a combination of clinical symptoms, as well as endoscopic and histological findings. Although conservative therapy is effective in most cases, surgery still plays a key role in the treatment of ischemic colitis. Here, we describe a case of a 73-year-old man in whom laparoscopy-assisted left colectomy was performed 80 d after the onset of ischemic colitis. He recovered completely after surgery, and the pathological findings were consistent with ischemic colitis. To the best of our knowledge, there are no detailed reports of laparoscopic surgery for chronic segmental stenotic ischemic colitis. We discussed the usefulness of laparoscopic surgery, comparing it with endoscopic treatment, and we propose an optimatreatment strategy from a viewpoint of stenosis length and duration of disease.

Isolated intrapancreatic Ig G4-related sclerosing cholangitis

Immunoglobulin G4-related sclerosing cholangitis(Ig G4-SC) is frequently associated with type 1 autoimmune pancreatitis(AIP). Association with AIP can be utilized in the diagnosis of Ig G4-SC. However, some cases of Ig G4-SC are isolated from AIP, which complicates the diagnosis. Most of the reported cases of isolated Ig G4-SC displayed hilar biliary strictures, whereas isolated Ig G4-SC with intrapancreatic biliary stricture is very rare. Recently, we have encountered 5 isolated intrapancreatic Ig G4-SC cases that were not associated with AIP, three of which were pathologically investigated after surgical operation. They all were males with a mean age of 74.2 years. The pancreas was not enlarged in any of these cases. No irregular narrowing of the main pancreatic duct was found. Bile duct wall thickening in lesions without luminal stenosis was detected by abdominal computed tomography in all five cases, by endoscopic ultrasonography in two out of four cases and by intraductal ultrasonography in all three cases. In three cases, serum Ig G4 levels were within the normal limits. The mean serum Ig G4 level measured before surgery was 202.1 mg/d L(4 cases). Isolated intrapancreatic Ig G4-SC is difficult to diagnose, especially if the Ig G4 level remains normal. Thus, this type of Ig G4-SC should be suspected in addition to cholangiocarcinoma and pancreatic cancer if stenosis of intrapancreatic bile duct is present.

Repeat colonoscopy's value in gastrointestinal bleeding

AIM:To assess the diagnostic yield and clinical value of early repeat colonoscopies for indications other than colorectal cancer(CRC) screening/surveillance.METHODS:A retrospective review of patients who had more than one colonoscopy performed for the same indication within a three year time frame at our tertiary care referral hospital between January 1,2000 and January 1,2010 was conducted.Exclusion criteria included repeat colonoscopies performed for CRC screening/surveillance,poor bowel preparation,suspected complications from the index procedure,and incomplete initial procedure.Primary outcome was new endoscopic finding that led to an endoscopic therapeutic intervention or any change in clinical management.Clinical parameters including age,sex,race,interval between procedures,indication of the procedure,presenting symptoms,severity of symptoms,hemodynamic instability,duration between onset of symptoms and when the procedure was performed,change in endoscopist,withdrawal time,location of colonic lesions and improvement of quality of bowel preparation were analyzed using bivariate analysis and logistic regression analysis to examine correlation with this primary outcome.RESULTS:Among 19 772 colonoscopies performed during the above mentioned period,947 colonoscopies(4.79%) were repeat colonoscopies performed within 3 years from the index procedure.Out of these repeat colonoscopies,139 patient pairs met the inclusion criteria.The majority of repeat colonoscopies were for lower gastrointestinal bleeding(88.4%),change in bowel habits(6.4%) and abdominal pain(5%).Among 139 eligible patient pairs of colonoscopies,only repeat colonoscopies that were done for lower gastrointestinal bleeding and abdominal pain produced endoscopic findings that led to a change in management [25 out of 123(20.33%) and 2 out of 7(28.57%),respectively].When looking at only recurrent lower gastrointestinal bleeding cases,new endoscopic findings included 8 previously undetected hemorrhoid lesions(6.5%),7 actively bleeding lesions requiring endoscopic intervention,which included 3 bleeding arterio-venous malformations(2.43%),2 bleeding radiation colitis(1.6%),and 2 bleeding internal hemorrhoids(1.6%),5 previously undetected tubular adenomas [4 were smaller than 1 cm(4.9%) and 1 was larger than 1 cm(0.8%)],3 radiation colitis(2.43%),1 rectal ulcer(0.8%),and 1 previously undetected right sided colon cancer(0.8%).Of the 25 new endoscopic findings,18(72%) were found when repeat colonoscopy was done within the first year after the index procedure.These findings were 1 rectal ulcer,3 radiation colitis,4 new hemorrhoid lesions,3 previously undetected tubular adenomas,and 7 actively bleeding lesions requiring endoscopic intervention.Of all parameters analyzed,only the interval between procedures less than one year was associated with higher likelihood of finding a clinically significant change in repeat colonoscopy(odds ratios of interval between procedures of 1-2 year and 2-3 year compared to 0-1 year were 0.09;95%CI 0.01-0.74,P = 0.025 and 0.26;95%CI 0.09-0.72,P = 0.010 respectively).No complications were observed among all 139 colonoscopy pairs.CONCLUSION:There is clinical value of repeating a colonoscopy for recurrent lower gastrointestinal bleeding,especially within the first year after the index procedure.

HOXB13 and other high penetrant genes for prostate cancer

Cancer initiation and progression is the result of an accumulation of mutations inkey tumor suppressor genes, mismatch repair genes, or oncogenes, which impact cancer cell growth, death, and differentiation. Mutations occurring in cancer tissue are termed somatic; whereas, heritable mutatons that may be passed onto subsequent generations occur in germline DNA. It is these germline mutations that can lead to cancer family syndromeswhereby family members carrying a deleterious germline mutation have an increased susceptibility to certain cancer phenotypes. Common features of hereditary cancer syndromes include early age-of-onset, multiple affected generations, rare tumor types, and/or multiple primary malignancies.

重组nkx2.5腺病毒抑制过氧化氢诱导的H9c2细胞凋亡

为研究心脏发育关键基因nkx2.5的功能及应用价值,构建Ad-Nkx2.5重组腺病毒,并检测nkx2.5过表达拮抗氧化应激损伤的效应及机制。采用AdEasy腺病毒表达系统构建Ad-Nkx2.5重组腺病毒,建立H2O2诱导H9c2心肌细胞凋亡模型,分别用Ad-Nkx2.5重组病毒或对照病毒感染细胞,采用Hoechst33342染色观察细胞形态变化、MTT法检测细胞存活率,免疫印迹检测caspase-3活化、细胞色素C的胞浆含量。并通过Real-timePCR检测凋亡相关基因bcl-2和bax表达。结果发现,nkx2.5过表达促进H9c2细胞存活,抑制H2O2诱导的caspase-3活化及线粒体细胞色素C的释放。Nkx2.5过表达上调bcl-2表达,显著下调H2O2诱导的bax表达。并发现H2O2对Nkx2.5核定位无明显影响。结果显示重组腺病毒介导的Nkx2.5过表达可通过调控凋亡相关基因表达,抑制线粒体凋亡途径,保护心肌细胞抗氧化损伤。

套细胞淋巴瘤的免疫治疗

套细胞淋巴瘤(MCL)是一种恶性侵袭性非霍奇金淋巴瘤,以出现t(11;14)(q13;q32)以及细胞周期蛋白D1(Cyclin D1)过度表达为特征,预后很差.近年来,生物学、遗传学以及免疫学的发展推动了MCL的免疫治疗.单用利妥昔单抗的疗效有限,但将其与其他化疗方案如CHOP(环磷酰胺联合多柔比星、长春新碱、泼尼松)、hyperCVAD/MTX-Ara-C(高剂量环磷酰胺联合长春新碱、多柔比星、地塞米松与甲氨蝶呤或阿糖胞苷交替)、FCM(氟达拉滨联合环磷酰胺、米托蒽醌)等联合之后,无论作为MCL的一线治疗还是挽救治疗,疗效均有明显改善.利妥昔单抗用于维持治疗或与自体造血干细胞移植联合后可延长缓解持续时间.此外,替伊莫单抗以及妥司莫单抗、异基因造血干细胞移植、供者淋巴细胞输注、树突状细胞、独特型疫苗联合等,其他的免疫治疗如沙利度胺和雷利度胺联合利妥昔单抗在复发性或难治性MCL中也取得了一定进展.

Targeting the insulin-like growth factor-1 receptor in MTAP-deficient renal cell carcinoma

Renal cell carcinoma(RCC)has emerged as a metabolic disease characterized by dysregulated expression of metabolic enzymes.Patients with metastatic RCC have an unusually poor prognosis and near-universal resistance to all current therapies.To improve RCC treatment and the survival rate of patients with RCC,there is an urgent need to reveal the mechanisms by which metabolic reprogramming regulates aberrant signaling and oncogenic progression.Through an integrated analysis of RCC metabolic pathways,we showed that methylthioadenosine phosphorylase(MTAP)and its substrate methylthioadenosine(MTA)are dysregulated in aggressive RCC.A decrease in MTAP expression was observed in RCC tissues and correlated with higher tumor grade and shorter overall survival.Genetic manipulation of MTAP demonstrated that MTAP expression inhibits the epithelial-mesenchymal transition,invasion and migration of RCC cells.Interestingly,we found a decrease in the protein methylation level with a concomitant increase in tyrosine phosphorylation after MTAP knockout.A phospho-kinase array screen identified the type 1 insulin-like growth factor-1 receptor(IGF1R)as the candidate with the highest upregulation in tyrosine phosphorylation in response to MTAP loss.We further demonstrated that IGF1R phosphorylation acts upstream of Src and STAT3 signaling in MTAP-knockout RCC cells.IGF1R suppression by a selective inhibitor of IGF1R,linsitinib,impaired the cell migration and invasion capability of MTAP-deleted cells.Surprisingly,an increase in linsitinib-mediated cytotoxicity occurred in RCC cells with MTAP deficiency.Our data suggest that IGF1R signaling is a driver pathway that contributes to the aggressive nature of MTAP-deleted RCC.

Understanding sarcoma drug resistance one cell at a time

As true for any cancer,intrinsic and acquired drug resistance represent perhaps the single biggest obstacle limiting our ability to cure patients with metastatic disease.Yet,tackling this challenge has been particularly difficult for sarcoma.First and foremost,sarcomas are rare and diverse,which splits a class of tumors representing less than 1 percent of all malignancies into more than fifty smaller molecularly and histologically distinct entities,each having its own etiology,prognosis,and clinical presentation.Even the most“common”sarcoma subtypes(e.g.,liposarcoma,leiomyosarcoma,or gastrointestinal stromal tumors)have annual incidences in the thousands in the United States,whereas rarer subtypes like desmoplastic small round cell tumors number less than fifty per year.Due to their scarcity,it’s not uncommon for just a few cell lines,organoids,or patient-derived tumor explants to exist for each sarcoma subtype.This shortage limits their usefulness to model the wide variety of innate and adaptive mechanisms that exist in human tumors.Many times,no representative preclinical model exists.The scarcity of FDA-approved drugs aimed at sarcoma-specific targets,often fusion proteins and transcription factors,is also problematic.