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Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics

Cancer Biology & Medicine 2019年第2期16卷 247-263页

作者： Jelena Grahovac Tatjana Srdic-Rajic Juan Francisco Santibanez Marijana Pavlovic Milena Cavic Sinisa Radulovic1 Laboratory for Experimental Pharmacology Institute for Oncology and Radiology of Serbia Belgrade 11000 Serbia Department of Molecular oncology Institute for Medical Research University of Belgrade Belgrade 11000 Serbia Integrative Center for Biology and Applied Chemistry (CIBQA) Bernardo O'Higgins University Santiago 8370854 Chile

Objective: Despite recent advancements in targeted therapy and immunotherapies, prognosis for metastatic melanoma patients remains extremely poor. Development of resistance to previously effective treatments presents a serious challenge and new approaches for melanoma treatment are urgently needed. The objective of this study was to examine the effects of telmisartan, an AGTR1 inhibitor and a partial agonist of PPARγ, on melanoma cells as a potential agent for repurposing in melanoma ***: Expression of AGTR1 and PPARγ m RNA in melanoma patient tumor samples was examined in publicly available datasets and confirmed in melanoma cell lines by qRT-PCR. A panel of melanoma cell lines was tested in viability, apoptosis and metabolic assays in presence of telmisartan by flow cytometry and immunocytochemistry. A cytotoxic effect of combinations of telmisartan and targeted therapy vemurafenib was examined using the Chou-Talalay combination index ***: Both AGTR1 and PPARγ mRNA were expressed in melanoma patient tumor samples and decreased compared to the expression in the healthy skin. In vitro, we found that telmisartan decreased melanoma cell viability by inducing cell *** glucose uptake, but not utilization, in the presence of telmisartan caused the fission of mitochondria and release of reactive oxygen species. Telmisartan altered the cell bioenergetics, thereby synergizing with vemurafenib in vitro, and even sensitized vemurafenib-resistant cells to the ***: Given that the effective doses of telmisartan examined in our study can be administered to patients and that telmisartan is a widely used and safe antihypertensive drug, our findings provide the scientific rationale for testing its efficacy in treatment of melanoma progression.

关键词： Melanoma telmisartan apoptosis mitochondria reactive oxygen species targeted therapy

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Adaptability of language-related brain network in a low-grade glioma patient

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Neural Regeneration Research 2011年第30期6卷 2372-2375页

作者： Olivera Sveljo Katarina Koprivsek Milos Lucic Diagnostic Imaging Centre Oncology Institute of VojvodinaSremska KamenicaSerbia

Because functional magnetic resonance imaging can be used for dynamic observation of functional cortical changes after brain injuries, we followed up functional magnetic resonance imaging manifestations of a language-related brain network in a low-grade glioma patient. Disease progression and therapy during a 3-year period were followed up at different time points： before and after reoperation, after radiation therapy, and 1 year after irradiation. During the whole 3-year follow-up period, the patient exhibited no neurological deficits while functional magnetic resonance imaging revealed different topologies of the language-related brain network. During disease progression and after irradiation, the language-related brain network was extended or completely transferred to the nondominant （right） hemisphere. In addition, after reoperation and 1 year after irradiation, language areas were primarily found in the language dominant （left） hemisphere. Our results suggest a high level of adaptability of the language-related cortical network of the bilateral hemispheres in this low-grade glioma patient.

关键词： functional magnetic resonance imaging low-grade glioma cortical changes language-related brain network

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Immunotherapy in the treatment of lymphoma

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World Journal of Stem Cells 2021年第6期13卷 503-520页

作者： Lazar S Popovic Gorana Matovina-Brko Maja Popovic Milica Popovic Ana Cvetanovic Ivan Nikolic Biljana Kukic Dragana Petrovic Department for Medical oncology Oncology Institute of VojvodinaUniversity of Novi SadNovi Sad 21000Serbia Department for Medical oncology Oncology Institute of VojvodinaNovi Sad 21000Serbia Department for Nephrology and Clinical Immunology Clinical Center of VojvodinaUniversity of Novi SadNovi Sad 21000Serbia Department for Medical oncology Clinical Center of NisUniversity of NisNis 18000Serbia

Relapsed or refractory non-Hodgkin’s lymphomas,especially diffuse large B-cell lymphoma as well as relapsed or refractory Hodgkin lymphomas are hard-to-treat *** who do not respond to initial therapy or experience relapse are treated with salvage regimens,and if eligible for aggressive therapy,treatment is continued with high-dose chemotherapy and autologous stem cell *** therapy options can cure substantial numbers of patients,however for some it is still an uncurable *** new drugs and cell therapies are being investigated for the treatment of relapsed or refractory *** types of immunotherapy options have shown promising results,and some have already become the standard of ***,we review immunotherapy options for the treatment of lymphoma and discuss the results,positions,practical aspects,and future directions of different drugs and cellular therapies for the treatment of this disease.

关键词： Immunotherapy Receptors Chimeric antigen Antibodies Monoclonal Immunoconjugates Hodgkin disease Lymphoma Large B-cell Diffuse

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Comethylation of p16 and MGMT genes in colorectal carcinoma:Correlation with clinicopathological features and prognostic value

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World Journal of Gastroenterology 2007年第8期13卷 1187-1194页

作者： Koviljka Krtolica Milena Krajnovic Slavica Usaj-Knezevic Dragan Babic Dusan Jovanovic Bogomir Dimitrijevic Laboratory for Radiobiology and Molecular Genetics Institute of Nuclear Sciences "Vinca" P. O. BOX 522 Belgrade Serbia institute of oncology Sremska KamenicaSerbia institute for Medical Statistics of Medical University BelgradeSerbia

AIM: To investigate the significance of p16 and O6- methylguanine-DNA methyltransferase (MGMT) genes promoter hypermethylation and K-ras mutations on colorectal tumorigenesis and progression. METHODS: p16 and MGMT methylation status was examined on 47 tumor samples, and K-ras mutational status was examined on 85 tumor samples. For methylation analysis, a methylation specific PCR (MS-PCR) method was used. RESULTS: p16 and MGMT promoter methylation was found in 51% (24/47) and 43% (20/47) of CRCs, respectively, and the K-ras mutation was found in 44% (37/85) of CRCs. Comethylation of p16 and MGMT genes was significantly associated with lower aggressiveness of the disease within a two-year period of observation. Only 27% of patients with simultaneous p 16 and MGMT methylation showed the detectible occurrence of metastasis and/or death, compared to 67% of patients without double methylation or with no methylation (3/11 vs 22/33, P < 0.05, χ2-test). In addition, p16 and MGMT comethylation showed a trend toward an association with longer survival in patients with CRCs (35.5 ± 6.0 mo vs 23.1 ± 3.2 mo, P = 0.072, Log-rank test). Progression of the disease within a two-year period was observed in 66% of patients carrying the K-ras mutation, compared to only 19% of patients with wild type K-ras (29/44 vs 7/37, P < 0.001, χ2-test). The presence of the K-ras mutation significantly correlated to shortened overall survival (20.0 ± 1.9 mo vs 37.0 ± 1.8 mo, P < 0.001, Log-rank test). The comethylation of p16 and MGMT genes was significantly associated with lower aggressiveness of the disease even when K-ras mutations were included in the analysis as an independent variable. CONCLUSION: Our data suggest that comethylation of promoters of p 16 and MGMT genes could have a prognostic value in patients with CRC. Specifically, concurrent methylation of both genes correlates with better prognosis.

关键词： Colorectal carcinoma DNA methylation p16 MGMT K-ras mutation

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Pharmacological methods for ovarian function and fertility preservation in women with cancer:A literature review

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oncology Research 2024年第8期32卷 1309-1322页

作者： ANA S.CVETANOVIC MATTEO LAMBERTINI KEVIN PUNIE GORANA G.MATOVINA BRKO NIKOLA D.ZIVKOVIC MAJA J.POPOVIC MARIJANA M.MILOVIC KOVACEVIC LAZAR S.POPOVIC Department for oncology Medical Faculty NisUniversity of NisNis18000Serbia Clinic of oncology University Clinical Centre NisNis18000Serbia Department of Internal Medicine and Medical Sciences(DiMI) School of MedicineUniversity of GenovaGenova16100Italy Department of Medical oncology U.O.C Clinica di Oncologia MedicaIRCCS Ospedale Policlinico San MartinoGenova16100Italy Department of General Medical oncology and Multidisciplinary Breast Centre Leuven Cancer InstituteUniversity Hospitals LeuvenLeuven3001Belgium Department of Medical oncology Oncology Institute of VojvodinaSremska Kamenica21208Serbia Department for Pathology Medical Faculty NisUniversity of NisNis18000Serbia Center for Pathology University Clinical Centre NisNis18000Serbia Faculty of Medicine University of Novi SadNovi Sad21000Serbia Department of Medical oncology Institute of Oncology and Radiology SerbiaBelgrade11000Serbia

Oncofertility is an extremely signiﬁcant topic that is increasingly being discussed owing to increased evidence indicating that fertility preservation does not affect the treatment outcomes of patients with cancer but signiﬁcantly contributes to preserving life *** effect of chemotherapy can range from minimal effects to complete ovarian *** data are available on the effects of monoclonal antibodies and targeted therapies on the ovaries and *** ovarian suppression by administering a gonadotropin-releasing hormone agonist(GnRHa)during chemotherapy decreases the gonadotoxic effect of chemotherapy,thereby diminishing the chance of developing premature ovarian insufﬁciency(POI).At present,the concomitant administration of GnRH analogs during chemotherapy is the only accepted pharmacological method for preserving ovarian ***,most randomized studies on the effectiveness of luteinizing hormone-releasing hormone agonists during chemotherapy in preventing POI have been conducted in women with breast cancer,with a considerably small number of studies on patients with hematological ***,most randomized controlled trials on breast cancer have revealed a decrease in treatment-induced POI risk,regardless of the hormone receptor *** addition,studies on hematological malignancies have yielded negative results;nevertheless,theﬁndings must be interpreted with caution owing to numerous *** guidelines from the American Society of Clinical oncology and ESMO Clinical Practice Guidelines recommend sperm,oocyte,and embryo cryopreservation as a standard practice and only offering GnRHa to patients when proven fertility preservation methods are not *** this manuscript,we present a comprehensive literature overview on the application of ovarian suppression with GnRHa during chemotherapy in patients with cancer by addressing preclinical and clinical data,as well as future perspectives in thisﬁeld

关键词： Gonadotropin-releasing hormone agonists(GnRHa) Fertility preservation Premature ovarian insufficiency(POI) Premenopausal patients

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Intraoperative endoscopy in obstructive hypopharyngeal carcinoma

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World Journal of Gastroenterology 2006年第28期12卷 4561-4564页

作者： Predrag Pesko Milos Bjelovic Predrag Sabljak Dejan Stojakov Ebrahimi Keramatollah Dejan Velickovic Bratislav Spica Branka Nenadic Aleksandra Djuric-Stefanovic Djordjije Saranovic Vera Todorovic Department of Esophagogastric Surgery First Surgical University HospitalClinical Center of SerbiaBelgradeSerbia and Montenegro institute of Anesthesiology First Surgical University HospitalClinical Center of SerbiaBelgradeSerbia and Montenegro Department of radiology First Surgical University HospitalClinical Center of SerbiaBelgradeSerbia and Montenegro institute of Medical Investigations BelgradeSerbia and Montenegro

AIM： To demonstrate the necessity of intraoperative endoscopy in the diagnosis of secondary primary tumors of the upper digestive tract in patients with obstructive hypopharyngeal carcinoma. METHODS： Thirty-one patients with hypopharyngeal squamous cell carcinoma had been operated, with radical intent, at our Institution in the period between 1978 and 2004. Due to obstructive tumor mass, in 7 （22.6%） patients, preoperative endoscopic evaluation of the esophagus and stomach could not be performed. In those patients, intraoperative endoscopy, made through an incision in the cervical esophagus, was standard diagnostic method for examination of the esophagus and stomach. RESULTS： We found synchronous foregut carcinomas in 3 patients （9.7%）. In two patients, synchronous carcinomas had been detected during preoperative endoscopic evaluation, and in one （with obstructive carcinoma） using intraoperative endoscopy. In this case, preoperative barium swallow and CT scan did not reveal the existence of second primary tumor within esophagus, despite the fact that small, but T2 carcinoma, was present. CONCLUSION： It is reasonable to use intraoperative endoscopy as a selective screening test in patients with obstructive hypopharyngeal carcinoma.

关键词： Hypopharynx Neoplasms Squamous cell Endoscopy Multiple primary Synchronous tumors

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Impact of Microstructural and Surface Modifications on the Ti-45Nb Alloy’s Response to Bio-Environment

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Acta Metallurgica Sinica(English Letters) 2024年第7期37卷 1215-1230页

作者： Ivana Cvijović-Alagić Slađana Laketić MilošMomčilović Jovan Ciganović Jelena Bajat Vesna Kojić Vinča institute of Nuclear Sciences-National institute of the Republic of serbia University of BelgradeMike Petrovića Alasa 12-1411000BelgradeSerbia Faculty of Technology and Metallurgy University of BelgradeKarnegijeva 411000BelgradeSerbia oncology institute of Vojvodina Faculty of MedicineUniversity of Novi SadPut Doktora Goldmana 4Sremska Kamenica21204Sremska KamenicaSerbia

The Ti-45Nb (mass%) alloy’s corrosive and biocompatible response in simulated physiological conditions was investigated before and after its additional high-pressure torsion (HPT) and laser irradiation processing. The grain size reduction from 2.76 µm to ~ 200 nm and the appearance of laser-induced morphologically altered and highly oxidized surface led to the significant improvement of alloy corrosion resistance and cell–implant interaction. Moreover, an additional increase of the laser pulse energy from 5 to 15 mJ during the alloy irradiation in the air led to an increase in the surface oxygen content from 13.64 to 23.89% accompanied by an increase of excellent cell viability from 127.18 to 134.42%. As a result of the controlled alloy microstructural and surface modifications, the formation of protective bi-modal mixed Ti- and Nb-oxide external scale was enabled. The presence of this surface oxide scale enhanced the alloy’s resistance to corrosion deterioration and simultaneously boosted cell viability and proliferation.

关键词： Ti-45Nb alloy High-pressure torsion Laser surface scanning Corrosion resistance Biocompatible properties

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Isolated splenic metastasis from colon cancer: Case report

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World Journal of Gastroenterology 2016年第18期22卷 4610-4614页

作者： Jiddou Abdou Youssef Omor Saber Boutayeb Basma Elkhannoussi Hassan Errihani Medical oncology Department National Institute of Oncology Sidi Mohamed Ben Abdallah radiology Department National Institute of Oncology Sidi Mohamed Ben Abdallah Pathology Department National Institute of Oncology Sidi Mohamed Ben Abdallah

Isolated splenic metastases from colorectal cancer are very rare clinical entities and when they are present, they usually manifest widely disseminated disease. In this paper we report a case of metachronous solitary isolated splenic metastasis from colon cancer in a 64-year-old woman who was successfully treated by laparoscopic splenectomy. We discuss the pathological and clinical aspects of this condition. We furthermore comment on the diagnostic and therapeutic options of this rare entity through our observation of the case and consideration of the 31 case reports published in the literature.

关键词： Isolated splenic metastases Colon cancer Splenectomy

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Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure

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World Journal of Gastrointestinal oncology 2021年第2期13卷 119-130页

作者： Mojca Tuta Nina Boc Erik Brecelj Monika Peternel Vaneja Velenik Division of radiology Institute of OncologyLjubljana 1000Slovenia Faculty of Medicine University of LjubljanaLjubljana 1000Slovenia Division of Surgery Institute of OncologyLjubljana 1000Slovenia Division of Radiotherapy Institute of OncologyLjubljana 1000Slovenia

BACKGROUND For locally advanced rectal cancer(LARC),standard therapy[consisting of neoadjuvant chemoradiotherapy(CRT),surgery,and adjuvant chemotherapy(ChT)]achieves excellent local ***,survival is still poor due to distant metastases,which remains the leading cause of death among these *** recent years,the concept of total neoadjuvant treatment(TNT)has been developed,whereby all systemic ChT-mainly affecting micrometastases-is applied prior to *** To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for *** In a retrospective study,we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with ***-risk for failure was defined according to the presence of at least one of the following factors:T4 stage;N2 stage;positive mesorectal fascia;extramural vascular invasion;positive lateral lymph *** consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid,fluorouracil and oxaliplatin,CRT with capecitabine,and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid,fluorouracil and oxaliplatin prior to *** primary endpoint was pathological complete response(pCR).In total,72 patients treated with standard therapy and 89 patients treated with TNT were included in the *** Compared to standard therapy,TNT showed a higher proportion of pCR(23%vs 7%;P=0.01),a lower neoadjuvant rectal score(median:8.43 vs 14.98;P<0.05),higher T-and N-downstaging(70%and 94%vs 51%and 86%),equivalent R0 resection(95%vs 93%),shorter time to stoma closure(mean:20 vs 33 wk;P<0.05),higher compliance during systemic ChT(completed all cycles 87%vs 76%;P<0.05),lower proportion of acute toxicity grade≥3 during ChT(3%vs 14%,P<0.05),and equivalent acute toxicity and compliance during CRT and in the postoperative *** pCR rate in patients treated with TNT was significantly higher in patients

关键词： Locally advanced rectal cancer Total neoadjuvant therapy Pathological complete response Neoadjuvant rectal cancer score

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circRNAs in drug resistance of breast cancer

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oncology Research 2022年第4期30卷 157-172页

作者： SEMA MISIR SERAP OZER YAMAN NINA PETROVIĆ CEREN SUMER CEYLAN HEPOKUR YUKSEL ALIYAZICIOGLU Department of Biochemistry Faculty of PharmacySivas Cumhuriyet UniversitySivas58010Turkey Department of Medical Biochemistry Karadeniz Technical University Faculty of MedicineTrabzon61000Turkey Laboratory for Radiobiology and Molecular genetics “VINČA”Institute of Nuclear Sciences-National Institute of the Republic of SerbiaUniversity of BelgradeBelgrade11000Serbia Department of Experimental oncology Institute for Oncology and Radiology of SerbiaBelgrade11000Serbia Comprehensive Cancer Center Faculty of Life Science&MedicineKing’s College LondonLondonSE11ULUnited Kingdom

Breast cancer(BC)is the most common heterogeneous disease in women and one of the leading causes of cancer-related ***,chemotherapy,radiotherapy,hormone,and targeted therapy are the gold standards for BC *** of the significant challenges during the treatment of BC represents resistance to chemotherapeutics,resistance that severely limits the use and effectiveness of the drugs used for BC ***,it is essential to develop new strategies to improve therapeutic *** RNAs(circRNAs)are a large group of non-coding RNAs that covalently form closed circular loops by joining their 5′,and 3′;*** evidence suggests that circRNAs have a vital role in cancer development,progression,and BC resistance to *** purpose of this review is to discuss the biological properties of circRNAs,and how circRNAs induce resistance to conventional therapeutic anti-cancer drugs used in BC treatment,by emphasizing and summarizing the potential roles of circRNAs in mechanisms of drug resistance,such as drug efflux,apoptosis dysfunction,autophagy,and DNA damage *** are associated with drug resistance via ATP-binding cassette(ABC)efflux transporters,while some others by inhibition of cell apoptosis,thus leading to resistance to tamoxifen in BC *** contrast,others are involved in the promotion of BC cells chemoresistance by doxorubicininduced *** may have clinical significance in regulating or overcoming BC drug resistance and may give directions towards a novel approach to personalized BC *** may significantly contribute to the identification of new therapeutic targets for the prevention of BC chemoresistance.

关键词： Breast cancer Chemotherapy circRNAs Drug resistance Non-coding RNA

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