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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

Signal Transduction and Targeted Therapy 2024年第8期9卷 3519-3532页

作者： Alvaro Quintanal-Villalonga Kenta Kawasaki Esther Redin Fathema Uddin Swanand Rakhade Vidushi Durani Amin Sabet Moniquetta Shafer Wouter R.Karthaus Samir Zaidi Yingqian A.Zhan Parvathy Manoj Harsha Sridhar Dennis Kinyua Hong Zhong Barbara P.Mello Metamia Ciampricotti Umesh K.Bhanot Irina Linkov Juan Qiu Radhika A.Patel Colm Morrsey Sanjoy Mehta Jesse Barnes Michael C.Haffner Nichlas D.Socci Richard P.Koche Elisa de Stanchina Sonia Molina-Pinelo Sohrab Salehi Helena A.Yu Joseph M.Chan Charles M.Rudin Department of Medicine Thoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Cancer Biology and Genetics Program Sloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Vagelos College of Physicians and Surgeons Columbia UniversityNew YorkNYUSA Weill Cornell Graduate School of Medical Sciences Weill Cornell MedicineNew YorkNYUA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Center for Epigenetics Research Memorial Sloan Kettering Cancer CenterNew YorkNYUSA pathology Core Facilty Department of Pathology and Laboratory MedicineMSKCCNew YorkNYUSA Antitumor Assessment Core Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Divisionsof Human Biology and clinical Research Fred Hutchinon Cancer CenterSeattleWAUSA Deparmentof Urology University of WashingtonSeattleWAUSA Gene Editing&Screening Core Facility Memorial Sloan Kettering Cancer Center New YorkNYUSA Department of Laboratory Medicine and pathology University of WashingtonSeattleWAUSA Bioinfomatics CoreFacility Memorial Soan Kettering Cancer CenterNew YorkNYUSA Institute of Biomedicine of Seille(Bis) HURCSCUniversidad de SevillaSevilleSpain Computational Oncology Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Well Cornell Medical College New York NYUSA Present address:Swiss Institute for Experimental Cancer Research(ISREC) School of Life SciencesEPFLLausanneSwitzerland

Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor *** to date,even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53(TP53)and Retinoblastoma Transcriptional Corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or delay histological *** of the cell cycle kinase Cell Division Cycle 7(CDC7)occurred in tumors during the initial steps of NE transformation,already after TP53/RB1 co-inactivation,leading to induced sensitivity to the CDC7 inhibitor ***7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen(MYC),implicated in stemness and histological *** overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy,even in the presence of ***7 inhibition also markedly extended response to standard cytotoxics(cisplatin,irinotecan)in lung and prostate small cell carcinoma *** results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors de novo or after *** simurosertib clinical efficacy trials are ongoing,this concept could be readily translated for patients at risk oftransformation.

关键词： tumors markedly transformation

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Profile of Radiological Examinations in the Radiology and Medical Imaging Department of the Medical clinic “KALALE” in Mali

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Open Journal of Medical Imaging 2024年第3期14卷 128-136页

作者： Traore Ousmane Diakite Siaka Sidibe Drissa Massan Diallo Ousmane Wélé Keita Modibo Diarra Ouncoumba Dembele Mamadou N’Diaye Mamadou Sangare Modibo Coulibaly Ibrahim Traore Chieck B Keita Adama Diaman Department of Radiology University Hospital Center of Point G Bamako Mali Faculty of Medicine and Odontostomatology University of Sciences Techniques and Technologies Bamako Mali Community Medicine service of the FMOS of Point G Bamako Mali Department of Radiology KALALE Medical Clinic Bamako Mali Department of Radiology Reference Health Center of Commune III Bamako Mali Laboratory of Analysis and Pathological Cytology University Hospital Center of Point G Bamako Mali

Introduction: Radiology and medical imaging examinations bring together the means of acquiring and restoring images of the human body from different physical phenomena such as the absorption of X-rays, nuclear magnetic resonance, reflection of ultrasound waves or radioactivity, with which we sometimes associate optical imaging techniques such as endoscopy. The objective of our study was to study the profile of radiological examinations in the radiology and medical imaging department of the “KALALE” medical clinic. Methodology: This was a descriptive, prospective study that took place over a period of six (6) months in the radiology and medical imaging department of the “KALALE” medical clinic and the centers of health of communes III and IV of Bamako in Mali. Data collection was carried out on a survey form. The parameters studied were sociodemographic data, clinical data, radiological data. Results: We recorded 6030 radiology examinations of which 19% of the examination frequency cases came from the “KALALE” medical clinic and 81% of the cases were referrals from the reference health centers of communes III and IV. There were 1500 X-rays or 24.9% of cases including 54% cases of bone X-rays;5% of cases of skull and face X-rays;5% of cases of Intravenous Urography (IVU);4% of cases of Hysterosalpingography (HSG);3% of cases of Retrograde Ureterocystography (UCR) and 1% of cases of X-ray of the Abdomen without preparation (ASP). We found 4530 ultrasounds or 75.1% of cases. Conclusion: Medical imaging has become essential in the study of the human body and now constitutes an essential tool for the detection and treatment of most pathologies, from simple fractures to the most serious tumors.

关键词： Profile Radiological Examinations KALALE clinic Mali

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Treatment of intermediate-risk prostate cancer with active surveillance in the routine care—Long-term outcomes of a prospective noninterventional study(HAROW)

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Current Urology 2024年第2期18卷 115-121页

作者： Lothar Weissbach Andreas Schwarte Edith A.Boedefeld Jan Herden Health Research for Men GmbH BerlinGermany Urological practice Borken BorkenGermany Department of Urology Uro-OncologyRobot-Assisted and Reconstructive UrologyFaculty of Medicine and University Hospital CologneUniversity of CologneCologneGermany PAN clinic Urological practiceCologneGermany

Background:We report here the long-term outcomes of patients with intermediate-risk prostate cancer(PCa)treated with active surveillance(AS)in a daily routine *** andmethods:HAROW(2008–2013)was a noninterventional,health service research study investigating themanagement of localized PCa in a community setting.A substantial proportion of the study centers were office-based urologists.A follow-up examination of all intermediate-risk patients with AS was ***,cancer-specific,metastasis-free,and treatment-free survival rates,as well as reasons for discontinuation,were determined and ***:Of the 2957 patients enrolled,52 with intermediate-risk PCa were managed with AS and were available for *** median follow-up was 6.8 years(interquartile range,3.4–8.6 years).Seven patients(13.5%)died of causes unrelated to PCa,of whom 4 were under AS or under watchful *** patients(3.8%)developed *** estimated 8-year overall,cancer-specific,metastasis-free,and treatment-free survival rates were 85%(95%confidence interval[CI],72%–96%),100%,93%(95%CI,82%–100%),and 31%(95%CI,17%–45%),*** analysis,prostate-specific antigen density of≥0.2 ng/mL2 was significantly predictive of receiving invasive treatment(hazard ratio,3.29;p=0.006).Reasons for discontinuation were more often due to patient's or physician's concerns(36%)than due to observed clinical ***:Although survival outcome data for intermediate-risk patients managed with AS in real-life health care conditions were promising,rates of discontinuation were high,and discontinuation was often a patient's decision,even when the signs of disease progression were *** might be an indication of higher levels of mental burden and anxiety in this specific subgroup of patients,which should be considered when making treatment *** a psychological perspective,not all intermediate-risk patients are optimal candidates for A

关键词： Active surveillance Intermediate-risk prostate cancer HAROW study Conservative management Outcomes research

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Mechanisms behind elevated serum levels of plasminogen activator inhibitor-1 in frontotemporal lobar degeneration

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Neural Regeneration Research 2025年第8期20卷 2317-2318页

作者： Francesco Angelucci Jakub Hort Memory clinic Department of NeurologySecond Faculty of MedicineCharles University and Motol University HospitalPragueCzech Republic International clinical Research Centre St.Anne’s University HospitalBrnoCzech Republic

Frontotemporal lobar degeneration(FTLD)is a form of progressive dementia characterized by degeneration of the frontal and temporal lobes of the *** pathology involves a series of cognitive,behavioral,and neurological ... 详细信息

关键词： degeneration elevated pathology

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Lymphocytic esophagitis: Still an enigma a decade later

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World Journal of Gastroenterology 2017年第6期23卷 949-956页

作者： Carol Rouphael Ilyssa O Gordon Prashanthi N Thota Department of General Internal Medicine Cleveland Clinic Foundation Department of pathology Cleveland Clinic Foundation Department of Gastroenterology and Hepatology Digestive Disease and Surgery InstituteCleveland Clinic Foundation

Lymphocytic esophagitis (LE) is a clinicopathologic entity first described by Rubio et al in 2006. It is defined as peripapillary intraepithelial lymphocytosis with spongiosis and few or no granulocytes on esophageal biopsy. This definition is not widely accepted and the number of lymphocytes needed to make the diagnosis varied in different studies. Multiple studies have described potential clinical associations and risk factors for LE, such as old age, female gender and smoking history. This entity was reported in inflammatory bowel disease in the pediatric population but not in adults. Other associations include gastroesophageal reflux disease and primary esophageal motility disorders. The most common symptom is dysphagia, with a normal appearing esophagus on endoscopy, though esophageal rings, webs, nodularities, furrows and strictures have been described. Multiple treatment modalities have been used such as proton pump inhibitors and topical steroids. Esophageal dilation seems to be therapeutic when dysphagia is present along with esophageal narrowing secondary to webs, rings or strictures. The natural history of the disease remains unclear and needs to be better delineated. Overall, lymphocytic esophagitis seems to have a chronic and benign course, except for two cases of esophageal perforation in the literature, thought to be secondary to this entity.

关键词： Lymphocytic esophagitis intraepithelial lymphocytes spongiosis gastroesophageal reflux disease CD4 T-cells dysphagia inflammatory bowel disease esophageal rings proton pump inhibitors esophageal dilation

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Assessment of the diagnostic performance and interobserver variability of endocytoscopy in Barrett's esophagus:A pilot ex-vivo study

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World Journal of Gastroenterology 2013年第46期19卷 8652-8658页

作者： Yutaka Tomizawa Prasad G Iyer Louis M Wongkeesong Navtej S Buttar Lori S Lutzke Tsung-Teh Wu Kenneth K Wang Barrett’s Esophagus Unit Division of Gastroenterology and Hepatology Mayo Clinic Rochester Department of Laboratory Medicine and pathology Mayo Clinic Rochester

AIM: To investigate a classification of endocytoscopy (ECS) images in Barrett’s esophagus (BE) and evaluate its diagnostic performance and interobserver variability.

关键词： Endocytoscopy, Barrett’ s esophagus, Dysplasia, Esophageal adenocarcinoma, Interobserver agreement

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Treatment of benign rectal stricture caused by repeated anal insertion by endoscopy and balloon dilation:A case report

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World Journal of Gastrointestinal Endoscopy 2024年第2期16卷 91-97页

作者： Shih-Hung Liu Jung-Cheng Kang Je-Ming Hu Chao-Yang Chen Kuan-Hsun Lin Ta-Wei Pu Department of Surgery Tri-Service General HospitalNational Defense Medical CenterTaipei 114Taiwan Division of Colon and Rectal Surgery Department of SurgeryTaiwan Adventist HospitalTaipei 105Taiwan Division of Colon and Rectal Surgery Department of SurgeryTri-Service General HospitalNational Defense Medical CenterTaipei 114Taiwan Division of Thoracic Surgery Department of SurgeryTri-Service General HospitalNational Defense Medical CenterTaipei 114Taiwan Division of Colon and Rectal Surgery Department of SurgerySongshan BranchTri-Service General HospitalNational Defense Medical CenterTaipei 105Taiwan

BACKGROUND Benign rectal strictures can be categorized as primary(disease-related)and secondary(surgical anastomosis-related).Secondary strictures arise from surgical complications,whereas primary strictures have diverse etiologies,including various inflammatory *** strictures are usually managed by surgery and *** present an unusual etiology of benign rectal stricture caused by the repeated insertion of foreign objects into the rectum for sexual purposes,resulting in rectal injury and subsequent chronic *** SUMMARY A 53-year-old man presented to the outpatient clinic of the Colorectal Surgery Department with symptoms of chronic constipation and bloody *** patient previously experienced rectal injury due to foreign object insertion for sexual *** revealed benign circumferential narrowing of the *** underwent treatment by endoscopic argon plasma coagulation and balloon dilation and follow-up as an outpatient for 4 months.A colonoscopy at the end of the follow-up period revealed no evidence of rectal stricture *** A history of rectal injury,followed by chronic inflammation,should be considered in patients with benign rectal *** with endoscopic argon plasma coagulation and balloon dilation can prevent the need for surgical resection of benign rectal strictures.

关键词： Chronic rectal inflammation Colonoscopy Benign rectal stricture Foreign body insertion Rectal injury Case report

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Magnetic resonance elastography is accurate in detecting advanced fibrosis in autoimmune hepatitis

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World Journal of Gastroenterology 2017年第5期23卷 859-868页

作者： Jin Wang Neera Malik Meng Yin Thomas C Smyrk Albert J Czaja Richard L Ehman Sudhakar K Venkatesh Department of Radiology Mayo Clinic College of MedicineMayo Clinic Department of Radiology the Third Affiliated HospitalSun Yat-Sen University Laboratory Medicine and pathology Mayo Clinic College of MedicineMayo Clinic Department of Gastroenterology and Hepatology Mayo Clinic College of MedicineMayo Clinic

AIM To assess the value of magnetic resonance elastography (MRE) in detecting advanced fibrosis/cirrhosis in autoimmune hepatitis (AIH). METHODS In this retrospective study, 36 patients (19 treated and 17 untreated) with histologically confirmed AIH and liver biopsy performed within 3 mo of MRE were identified at a tertiary care referral center. Liver stiffness (LS) with MRE was calculated by a radiologist, and inflammation grade and fibrosis stage in liver biopsy was assessed by a pathologist in a blinded fashion. Two radiologists evaluated morphological features of cirrhosis on conventional magnetic resonance imaging (MRI). Accuracy of MRE was compared to laboratory markers and MRI for detection of advanced fibrosis/cirrhosis. RESULTS Liver fibrosis stages of 0, 1, 2, 3 and 4 were present in 4, 6, 7, 6 and 13 patients respectively. There were no significant differences in distribution of fibrosis stage and inflammation grade between treated and untreated patient groups. LS with MRE demonstrated stronger correlation with liver fibrosis stage in comparison to laboratory markers for chronic liver disease (r = 0.88 vs -0.48-0.70). A trend of decreased mean LS in treated patients compared to untreated patients was observed (3.7 kPa vs 3.84 kPa) but was not statistically significant. MRE had an accuracy/sensitivity/specificity/positive predictive value/negative predictive value of 0.97/90%/100%/100%/90% and 0.98/92.3%/96%/92.3%/96% for detection of advanced fibrosis and cirrhosis, respectively. The performance of MRE was significantly better than laboratory tests for detection of advanced fibrosis (0.97 vs 0.53-0.80, p < 0.01), and cirrhosis (0.98 vs 0.58-0.80, p < 0.01) and better than conventional MRI for diagnosis of cirrhosis (0.98 vs 0.78, p = 0.002). CONCLUSION MRE is a promising modality for detection of advanced fibrosis and cirrhosis in patients with AIH with superior diagnostic accuracy compared to laboratory assessment and MRI.

关键词： autoimmune hepatitis advanced fibrosis magnetic resonance elastography liver stiffness cirrhosis

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Pathologic tumor response to neoadjuvant therapy in borderline resectable pancreatic cancer

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Hepatobiliary & Pancreatic Diseases International 2019年第4期18卷 373-378页

作者： June S Peng Jane Wey Sricharan Chalikonda Daniela S Allende R Matthew Walsh Gareth Morris-Stiff Department of General Surgery Digestive Disease and Surgery InstituteCleveland Clinic Foundation9500 Euclid AvenueClevelandOHUSA Department of pathology Pathology and Laboratory Medicine InstituteCleveland Clinic Foundation9500 Euclid AvenueClevelandOHUSA

Background:Previous studies have demonstrated the prognostic significance of pathologic tumor response in pancreatic adenocarcinoma following neoadjuvant therapy(NAT).The aim of this study was to determine the incidence of significant pathologic response to NAT in borderline resectable pancreatic cancer(BRPC),and association of NAT regimen and other clinico-pathologic characteristics with pathologic ***:Patients with BRPC who underwent NAT and pancreatic resection between January 2012 and June 2017 were *** response was assessed on a qualitative scale based on the College of American Pathologists grading *** and baseline characteristics,oncologic treatment,pathology,and survival outcomes were ***:Seventy-one patients were included for *** patients had complete pathologic responses(tumor regression score 0),12 patients had marked responses(score 1),42 had moderate responses(score 2),and 13 had minimal responses(score 3).Patients with complete or marked responses were more likely to have received neoadjuvant gemcitabine chemoradiation(62.5%,38.1%,and 23.1%of the complete/marked,moderate,and minimal response groups,respectively;P=0.04).Of the complete/marked,moderate,and minimal response groups,margins were negative in 75.0%,78.6%,and 46.2%(P=0.16);node negative disease was observed in 87.5%,54.8%,and 15.4%(P<0.01);and median overall survival was 50.0 months,31.7 months,and 23.2 months(P=0.563).Of the four patients with pathologic complete responses,three were disease-free at 66.1,41.7 and 31.4 months,and one was deceased with metastatic liver disease at 16.9 ***:A more pronounced pathologic tumor response to NAT in BRPC is correlated with node negative disease,but was not associated with a statistically significant survival benefit in this study.

关键词： Pancreatic cancer Borderline resectable Neoadjuvant therapy Pathologic response

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Low hypoxia inducible factor-1α(HIF-1α)expression in testicular germ cell tumors--a major reason for enhanced chemosensitivity?

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Chinese Journal of Cancer Research 2017年第4期29卷 374-378页

作者： niraj shenoy roxana dronca fernando quevedo stephen a boorjian john cheville brian costello manish kohli thomas witzig lance pagliaro division of oncology mayo clinicRochesterMN 55905usa department of urology mayo clinicRochesterMN 55905usa division of clinical pathology mayo clinicRochesterMN 55905usa

The molecular basis for enhanced chemosensitivity of testicular germ cell tumors （GCT） has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far, however, the increased sensitivity of C＆T has been variously attributed to multiple factors -- an inability to detoxify cisplatin, a lack of export pumps, an inability to repair the DNA damage, an intact apoptotic cascade and lack of p53 mutation; but a unifying underlying etiology leading to the aforementioned processes and having a translational implication has so far been elusive. Herein, we offer evidence to support a potential significant role for the previously demonstrated low hypoxia inducible factor-la （HIF-la） expression in mediating the general exquisite chemosensitivity of testicular GCT, through the aforementioned processes. This molecular mechanism based hypothesis could have a significant translational implication in platinum refractory GCT as well as other platinum resistant malignancies.

关键词： Hypoxia inducible factor-la (HIF-la) testicular germ cell tumor chemosensitivity

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