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Dive into the research topics where Michal Kushnir is active.

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Featured researches published by Michal Kushnir.


PLOS ONE | 2008

Serum MicroRNAs Are Promising Novel Biomarkers

Shlomit Gilad; Eti Meiri; Yariv Yogev; Sima Benjamin; Danit Lebanony; Noga Yerushalmi; Hila Benjamin; Michal Kushnir; Hila Cholakh; Nir Melamed; Zvi Bentwich; Moshe Hod; Yaron Goren; Ayelet Chajut

Background Circulating nucleic acids (CNAs) offer unique opportunities for early diagnosis of clinical conditions. Here we show that microRNAs, a family of small non-coding regulatory RNAs involved in human development and pathology, are present in bodily fluids and represent new effective biomarkers. Methods and Results After developing protocols for extracting and quantifying microRNAs in serum and other body fluids, the serum microRNA profiles of several healthy individuals were determined and found to be similar, validating the robustness of our methods. To address the possibility that the abundance of specific microRNAs might change during physiological or pathological conditions, serum microRNA levels in pregnant and non pregnant women were compared. In sera from pregnant women, microRNAs associated with human placenta were significantly elevated and their levels correlated with pregnancy stage. Conclusions and Significance Considering the central role of microRNAs in development and disease, our results highlight the medically relevant potential of determining microRNA levels in serum and other body fluids. Thus, microRNAs are a new class of CNAs that promise to serve as useful clinical biomarkers.


European Journal of Heart Failure | 2012

Serum levels of microRNAs in patients with heart failure

Yaron Goren; Michal Kushnir; Barak Zafrir; Sarit Tabak; Basil S. Lewis; Offer Amir

Diagnosis and risk stratification of patients with heart failure remain a challenge. The small non‐coding RNAs known as microRNAs regulate gene expression and seem to play an important role in the pathogenesis of heart failure. In the current study, we aim to characterize the levels of microRNAs in the sera of chronic systolic heart failure patients vs. controls and assess the possible correlation between elevation in the levels of specific microRNAs and clinical prognostic parameters in heart failure patients.


Gynecologic Oncology | 2009

Tumor microRNA expression patterns associated with resistance to platinum based chemotherapy and survival in ovarian cancer patients

Ram Eitan; Michal Kushnir; Gila Lithwick-Yanai; Miriam Ben David; Moshe Hoshen; Marek Glezerman; Moshe Hod; Gad Sabah; Shai Rosenwald; Hanoch Levavi

BACKGROUND Ovarian cancer, the leading cause of gynecologic cancer deaths, is usually diagnosed in advanced stages. Prognosis relates to stage at diagnosis and sensitivity to platinum based chemotherapy. We aimed to assess the expression of microRNAs in ovarian tumors and identify microRNA expression patterns that are associated with outcome, response to chemotherapy and survival. METHODS Patients, who were surgically treated for ovarian cancer between January 2000 and December 2004 were identified. Patient charts were reviewed for clinicopathologic information, follow-up and survival. Total RNA was extracted from tumor samples and microRNA expression levels were measured by microarrays. Expression levels were compared between groups of samples and statistically analyzed. RESULTS Fifty-seven patients were identified to fit study criteria. Of them, 19 patients had stage I disease at diagnosis, and 38 patients, stage III. All patients received platinum based chemotherapy as first line treatment. 18 microRNAs were differentially expressed (p<0.05) between stage I and stage III disease. Seven microRNAs were found to be significantly differentially expressed in tumors from platinum-sensitive vs. platinum-resistant patients (p<0.05). Five microRNAs were associated with significant differences (p<0.05) in survival or recurrence-free survival. High expression of hsa-mir-27a identified a sub-group of patients with very poor prognosis. CONCLUSIONS We have found an array of tumor specific markers that are associated with response to platinum based first line chemotherapy. Expression of some of these miRNAs also correlated closely with prognosis. This approach can potentially be used to tailor chemotherapy and further management to specific patient needs.


World Journal of Gastroenterology | 2011

MicroRNAs as a potential prognostic factor in gastric cancer

Baruch Brenner; Moshe Hoshen; Ofer Purim; Miriam Ben David; Karin Ashkenazi; Gideon Marshak; Yulia Kundel; Ronen Brenner; Sara Morgenstern; Marisa Halpern; Nitzan Rosenfeld; Ayelet Chajut; Yaron Niv; Michal Kushnir

AIM To compare the microRNA (miR) profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer. METHODS The study group included 45 patients who underwent curative gastrectomies from 1995 to 2005 without adjuvant or neoadjuvant therapy and for whom adequate tumor content was available. Total RNA was extracted from formalin-fixed paraffin-embedded tumor samples, preserving the small RNA fraction. Initial profiling using miR microarrays was performed to identify potential biomarkers of recurrence after resection. The expression of the differential miRs was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 mo of surgery (bad-prognosis group, n = 14, 31%) and those who did not (good-prognosis group, n = 31, 69%). RESULTS Three miRs, miR-451, miR-199a-3p and miR-195 were found to be differentially expressed in tumors from patients with good prognosis vs patients with bad prognosis (P < 0.0002, 0.0027 and 0.0046 respectively). High expression of each miR was associated with poorer prognosis for both recurrence and survival. Using miR-451, the positive predictive value for non-recurrence was 100% (13/13). The expression of the differential miRs was verified by qRT-PCR, showing high correlation to the microarray data and similar separation into prognosis groups. CONCLUSION This study identified three miRs, miR-451, miR-199a-3p and miR-195 to be predictive of recurrence of gastric cancer. Of these, miR-451 had the strongest prognostic impact.


The Journal of Molecular Diagnostics | 2012

Classification of the four main types of lung cancer using a microRNA-based diagnostic assay.

Shlomit Gilad; Gila Lithwick-Yanai; Iris Barshack; Sima Benjamin; Irit Krivitsky; Tina Bocker Edmonston; Marluce Bibbo; Craig Thurm; Laurie Horowitz; Yajue Huang; Meora Feinmesser; J. Steve Hou; Brianna St. Cyr; Ilanit Burnstein; Hadas Gibori; Nir Dromi; Mats Sanden; Michal Kushnir; Ranit Aharonov

For patients with primary lung cancer, accurate determination of the tumor type significantly influences treatment decisions. However, techniques and methods for lung cancer typing lack standardization. In particular, owing to limited tumor sample amounts and the poor quality of some samples, the classification of primary lung cancers using small preoperative biopsy specimens presents a diagnostic challenge using current tools. We previously described a microRNA-based assay (miRview squamous; Rosetta Genomics Ltd., Rehovot, Israel) that accurately differentiates between squamous and nonsquamous non-small cell lung cancer. Herein, we describe the development and validation of an assay that differentiates between the four main types of lung cancer: squamous cell carcinoma, nonsquamous non-small cell lung cancer, carcinoid, and small cell carcinoma. The assay, miRview lung (Rosetta Genomics Ltd.), is based on the expression levels of eight microRNAs, measured using a sensitive quantitative RT-PCR platform. It was validated on an independent set of 451 samples, more than half of which were preoperative cytologic samples (fine-needle aspiration and bronchial brushing and washing). The assay returned a result for more than 90% of the samples with overall accuracy of 94% (95% CI, 91% to 96%), with similar performance observed in pathologic and cytologic samples. Thus, miRview lung is a simple and reliable diagnostic assay that offers an accurate and standardized classification tool for primary lung cancer using pathologic and cytologic samples.


International Journal of Oncology | 2012

Tumor microRNA-29a expression and the risk of recurrence in stage II colon cancer

Alina Weissmann-Brenner; Michal Kushnir; Gila Lithwick Yanai; Ranit Aharonov; Hadas Gibori; Ofer Purim; Yulia Kundel; Sara Morgenstern; Marissa Halperin; Yaron Niv; Baruch Brenner

There is emerging evidence for the prognostic role of various microRNA (miRNA) molecules in colon cancer. The aim of this study was therefore to compare the miRNA profiles in the primary tumor of patients with recurrent and non-recurrent colon cancer. The study population included 110 patients, 51 (46%) with stage I and 59 (54%) with stage II disease, who underwent curative colectomies between 1995 and 2005 without adjuvant therapy and for whom reliable miRNA expression data were available. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor samples. Initial profiling, using microarrays, was done in order to identify potential biomarkers of recurrence. The miRNA expression was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 months of surgery (bad prognosis group, n=23, 21%) and those who did not (good prognosis group, n=87, 79%) in the entire group and within each stage. The results showed that in stage I, none of the 903 miRNAs tested showed differential expression between patients with good prognosis compared with those with poor prognosis. In contrast, in stage II, one miRNA, miR-29a, showed a clear differential expression between the groups (p=0.028). High expression of miR-29a was associated with a longer disease-free survival (DFS), on both univariate and multivariate analyses. Using miR-29a, the positive predictive value for non-recurrence was 94% (2 recurrences among 31 patients). The differential expression of miR-29a was verified by qRT-PCR, showing a similar impact of this miR on DFS. In conclusion, this study demonstrated a significant impact of miR-29a on the risk of recurrence in patients with stage II but not in patients with stage I colon cancer. Based on these results, a validation study is planned.


PLOS ONE | 2010

Telomere Shortening Sensitizes Cancer Cells to Selected Cytotoxic Agents: In Vitro and In Vivo Studies and Putative Mechanisms

Orit Uziel; Einat Beery; Vladimir Dronichev; Katty Samocha; Sergei M. Gryaznov; Lola Weiss; Shimon Slavin; Michal Kushnir; Yardena Nordenberg; Claudette Rabinowitz; Baruch Rinkevich; Tania Zehavi; Meir Lahav

Background Telomere/telomerase system has been recently recognized as an attractive target for anticancer therapy. Telomerase inhibition results in tumor regression and increased sensitivity to various cytotoxic drugs. However, it has not been fully established yet whether the mediator of these effects is telomerase inhibition per se or telomere shortening resulting from inhibition of telomerase activity. In addition, the characteristics and mechanisms of sensitization to cytotoxic drugs caused by telomerase inhibition has not been elucidated in a systematic manner. Methodology/Principal Findings In this study we characterized the relative importance of telomerase inhibition versus telomere shortening in cancer cells. Sensitization of cancer cells to cytotoxic drugs was achieved by telomere shortening in a length dependent manner and not by telomerase inhibition per se. In our system this sensitization was related to the mechanism of action of the cytotoxic drug. In addition, telomere shortening affected also other cancer cell functions such as migration. Telomere shortening induced DNA damage whose repair was impaired after administration of cisplatinum while doxorubicin or vincristine did not affect the DNA repair. These findings were verified also in in vivo mouse model. The putative explanation underlying the phenotype induced by telomere shortening may be related to changes in expression of various microRNAs triggered by telomere shortening. Conclusions/Significance To our best knowledge this is the first study characterizing the relative impact of telomerase inhibition and telomere shortening on several aspects of cancer cell phenotype, especially related to sensitivity to cytotoxic drugs and its putative mechanisms. The microRNA changes in cancer cells upon telomere shortening are novel information. These findings may facilitate the development of telomere based approaches in treatment of cancer.


Journal of Clinical Pathology | 2017

Multicentre validation of a microRNA-based assay for diagnosing indeterminate thyroid nodules utilising fine needle aspirate smears

Gila Lithwick-Yanai; Nir Dromi; Alexander Shtabsky; Sara Morgenstern; Yulia Strenov; Meora Feinmesser; Vladimir Kravtsov; Marino E Leon; Marian Hajduch; Syed Z. Ali; Christopher J. VandenBussche; Xinmin Zhang; Leonor Leider-Trejo; Asia Zubkov; Sergey Vorobyov; Michal Kushnir; Yaron Goren; Sarit Tabak; Etti Kadosh; Hila Benjamin; Temima Schnitzer‐Perlman; Hagai Marmor; Maria Motin; Danit Lebanony; Sharon Kredo-Russo; Heather Mitchell; Melissa Noller; Alexis Smith; Olivia Dattner; Karin Ashkenazi

Aims The distinction between benign and malignant thyroid nodules has important therapeutic implications. Our objective was to develop an assay that could classify indeterminate thyroid nodules as benign or suspicious, using routinely prepared fine needle aspirate (FNA) cytology smears. Methods A training set of 375 FNA smears was used to develop the microRNA-based assay, which was validated using a blinded, multicentre, retrospective cohort of 201 smears. Final diagnosis of the validation samples was determined based on corresponding surgical specimens, reviewed by the contributing institute pathologist and two independent pathologists. Validation samples were from adult patients (≥18 years) with nodule size >0.5 cm, and a final diagnosis confirmed by at least one of the two blinded, independent pathologists. The developed assay, RosettaGX Reveal, differentiates benign from malignant thyroid nodules, using quantitative RT-PCR. Results Test performance on the 189 samples that passed quality control: negative predictive value: 91% (95% CI 84% to 96%); sensitivity: 85% (CI 74% to 93%); specificity: 72% (CI 63% to 79%). Performance for cases in which all three reviewing pathologists were in agreement regarding the final diagnosis (n=150): negative predictive value: 99% (CI 94% to 100%); sensitivity: 98% (CI 87% to 100%); specificity: 78% (CI 69% to 85%). Conclusions A novel assay utilising microRNA expression in cytology smears was developed. The assay distinguishes benign from malignant thyroid nodules using a single FNA stained smear, and does not require fresh tissue or special collection and shipment conditions. This assay offers a valuable tool for the preoperative classification of thyroid samples with indeterminate cytology.


Leukemia Research | 2015

MicroRNA signature is indicative of long term prognosis in diffuse large B-cell lymphoma

Daniel Shepshelovich; Ron Ram; Orit Uziel; Michal Kushnir; Gila Lithwick-Yanai; Moshe Hoshen; Meora Feinmesser; Osnat Bairey; Meir Lahav

PURPOSE To compare microRNA (miR) expression between patients with diffuse large B-cell lymphoma (DLBCL) who had a poor prognosis to those who had a favorable prognosis. METHODS The study group included 83 patients with diffuse large B-cell lymphoma (DLBCL) treated between the years 1995 and 2003 without rituximab in a single tertiary center for whom adequate tumor content was available. miR signature from tissue biopsies was compared between patients who relapsed within nine months from commencement of treatment (defined as poor prognosis, n=43) and those with disease-free survival of at least five years (defined as good prognosis, n=40). RNA was analyzed using custom microarrays. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for technical validation of microarray results. An independent set of 13 samples was used for further validation. RESULTS Eight miRs were found to be differently expressed between the two prognostic groups. The expression of the different miRs was verified by qRT-PCR, showing high correlation with the microarray data in both verification and independent set groups. No added value to the clinically based International Prognostic Index was found. CONCLUSION miR signature from DLBCL biopsies can discriminate between patients with favorable and poor prognoses.


Journal of Clinical Oncology | 2011

New microRNA-based diagnostic test for lung cancer classification.

Tina Bocker Edmonston; Hadas Gibori; Michal Kushnir; G. Lithwick Yanai; Hila Benjamin; Marluce Bibbo; Craig Thurm; Laurie Horowitz; Yajue Huang; Meora Feinmesser; Iris Barshack; S. j. Hou; Shlomit Gilad; S. Benjamin; K. Ashkenazi; Meital Ezagouri; Y. Goren; C. Hogan; Ayelet Chajut

10531 Background: Lung cancer is the leading cause of cancer deaths in the USA. Treatment options are determined by tumor subtyping, for which there is a lack of standardized techniques. Moreover, in about 20% of cases a subclassification is not possible on preoperative specimens. MicroRNA expression profiling is a promising new strategy for the accurate subclassification of lung cancers. Using microRNA microarray data generated from over a hundred formalin-fixed, paraffin-embedded (FFPE) primary lung cancer samples, we have identified microRNA expression profiles that differ significantly for the lung cancer subtypes. Based on these findings, we present here the development and clinical validation of a microRNA-based qRT-PCR assay that differentiates primary lung cancers into four types: squamous cell carcinoma, non-squamous non-small cell lung cancer (NSCLC), carcinoid and small cell carcinoma. This assay can be used on resection specimens, small biopsies and cell blocks from cytology. METHODS Over 550 FFPE and cell blocks from different histological subtypes of lung cancer, taken from primary lung cancer resection or pre-operative diagnostic procedures, were collected. High-quality RNA was extracted from the samples using proprietary protocols. Expression levels of potential microRNA biomarkers were profiled using a sensitive and specific qRT-PCR platform. Classifiers were developed to utilize the information in microRNA expression patterns for the subclassification of lung cancers. A validation set of more than 350 independent samples were analyzed blindly and classified using the developed assay. RESULTS Using expression levels of 8 microRNAs in qRT-PCR, accurate classification of the lung tumors into the four above-mentioned categories could be obtained. A diagnostic assay based on this technology was developed and validated using an independent, blinded sample set. CONCLUSIONS We identified microRNAs that represent excellent biomarkers for the classification of lung primary tumors into four categories that are relevant for patient management decisions. These findings are the basis for the development of a standardized diagnostic assay that can be used to subclassify resection specimens as well as cytology samples.

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