Publications by authors named "Alexey V Sorokin"

15 Publications

  • Page 1 of 1

Bordetella hinzii: An Unexpected Pathogen in Native Valve Endocarditis.

Can J Cardiol 2019 Nov 21;35(11):1604.e17-1604.e19. Epub 2019 Aug 21.

Broward Health Medical Center, Department of Cardiology, Fort Lauderdale, Florida, USA.

Bordetella hinzii's route of transmission to human hosts and its pathogenicity remain unclear. Only a few cases have established this species as an opportunistic zoonotic disease. We introduce the first reported case of native aortic valve endocarditis presenting with fulminant aortic valve insufficiency that responded to conventional medical and surgical treatment. The patient did not have predisposing factors to this unusual infection. This case may provide a better understanding of the disease process, transmission, and pathogenicity of Bordetella hinzii.
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http://dx.doi.org/10.1016/j.cjca.2019.08.016DOI Listing
November 2019

Platelet Metabolism and Other Targeted Drugs; Potential Impact on Immunotherapy.

Front Oncol 2018 20;8:107. Epub 2018 Apr 20.

Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

The role of platelets in cancer progression has been well recognized in the field of cancer biology. Emerging studies are elaborating further the additional roles and added extent that platelets play in promoting tumorigenesis. Platelets release factors that support tumor growth and also form heterotypic aggregates with tumor cells, which can provide an immune-evasive advantage. Their most critical role may be the inhibition of immune cell function that can negatively impact the body's ability in preventing tumor establishment and growth. This review summarizes the importance of platelets in tumor progression, therapeutic response, survival, and finally the notion of immunotherapy modulation being likely to benefit from the inclusion of platelet inhibitors.
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http://dx.doi.org/10.3389/fonc.2018.00107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919962PMC
April 2018

Modeling of Patient-Derived Xenografts in Colorectal Cancer.

Mol Cancer Ther 2017 07 3;16(7):1435-1442. Epub 2017 May 3.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient-derived xenografts (PDX) in colorectal cancer are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target, and drug discovery. Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 colorectal cancer patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2-82.6) vs. biopsy 35% (95% CI: 22.1%-50.6%)] to be the key determinant for successful PDX engraftment. These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modeling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of colorectal cancer patients. .
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562363PMC
July 2017

Transportin-1-dependent YB-1 nuclear import.

Biochem Biophys Res Commun 2016 Nov 26;480(4):629-634. Epub 2016 Oct 26.

Institute of Protein Research, Russian Academy of Sciences, 4 Institutskaya St., 142290, Pushchino, Moscow Region, Russia. Electronic address:

The DNA/RNA-binding protein YB-1 (Y-box binding protein 1) performs multiple functions both in the cytoplasm and the nucleus of the cell. Generally localized to the cytoplasm, under certain conditions YB-1 is translocated to the nucleus. Here we report for the first time a transport factor that mediates YB-1 nuclear import - transportin-1. The YB-1/transportin-1 complex can be isolated from HeLa cell extract. Nuclear import of YB-1 and its truncated form YB-1 (1-219) in in vitro transport assay was diminished in the presence of a competitor substrate and ceased in the presence of transportin-1 inhibitor M9M. Inhibitors of importin β1 had no effect on YB-1 transport. Furthermore, transport of YB-1 (P201A/Y202A) and YB-1 (1-219) (P201A/Y202A) bearing inactivating mutations in the transportin-1-dependent nuclear localization signal was practically abolished. Together, these results indicate that transportin-1 mediates YB-1 nuclear translocation.
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http://dx.doi.org/10.1016/j.bbrc.2016.10.107DOI Listing
November 2016

Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation.

Cancer Discov 2016 12 11;6(12):1352-1365. Epub 2016 Oct 11.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAF metastatic colorectal cancer, further augmented by irinotecan. The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAF-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAF circulating cell-free DNA (cfDNA) trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression.

Significance: Vemurafenib, in combination with irinotecan and cetuximab, was well tolerated in patients with refractory, BRAF-mutated metastatic colorectal cancer, and both survival outcomes and response rates exceeded prior reports for vemurafenib and for irinotecan plus cetuximab in BRAF metastatic colorectal cancer. In vivo models demonstrated regressions with the triplet, in contrast with vemurafenib and cetuximab alone. cfDNA predicted radiographic response and identified mutations reactivating the MAPK pathway upon progression. Cancer Discov; 6(12); 1352-65. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1293.
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http://dx.doi.org/10.1158/2159-8290.CD-16-0050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562357PMC
December 2016

Defining the Protein-Protein Interaction Network of the Human Protein Tyrosine Phosphatase Family.

Mol Cell Proteomics 2016 09 18;15(9):3030-44. Epub 2016 Jul 18.

§Department of Developmental and Cell Biology, University of California, Irvine, California 92697

Protein tyrosine phosphorylation, which plays a vital role in a variety of human cellular processes, is coordinated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Genomic studies provide compelling evidence that PTPs are frequently mutated in various human cancers, suggesting that they have important roles in tumor suppression. However, the cellular functions and regulatory machineries of most PTPs are still largely unknown. To gain a comprehensive understanding of the protein-protein interaction network of the human PTP family, we performed a global proteomic study. Using a Minkowski distance-based unified scoring environment (MUSE) for the data analysis, we identified 940 high confidence candidate-interacting proteins that comprise the interaction landscape of the human PTP family. Through a gene ontology analysis and functional validations, we connected the PTP family with several key signaling pathways or cellular functions whose associations were previously unclear, such as the RAS-RAF-MEK pathway, the Hippo-YAP pathway, and cytokinesis. Our study provides the first glimpse of a protein interaction network for the human PTP family, linking it to a number of crucial signaling events, and generating a useful resource for future studies of PTPs.
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http://dx.doi.org/10.1074/mcp.M116.060277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013315PMC
September 2016

Aberrant Expression of proPTPRN2 in Cancer Cells Confers Resistance to Apoptosis.

Cancer Res 2015 May 15;75(9):1846-58. Epub 2015 Apr 15.

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The protein tyrosine phosphatase receptor PTPRN2 is expressed predominantly in endocrine and neuronal cells, where it functions in exocytosis. We found that its immature isoform proPTPRN2 is overexpressed in various cancers, including breast cancer. High proPTPRN2 expression was associated strongly with lymph node-positive breast cancer and poor clinical outcome. Loss of proPTPRN2 in breast cancer cells promoted apoptosis and blocked tumor formation in mice, whereas enforced expression of proPTPRN2 in nontransformed human mammary epithelial cells exerted a converse effect. Mechanistic investigations suggested that ProPTPRN2 elicited these effects through direct interaction with TRAF2, a hub scaffold protein for multiple kinase cascades, including ones that activate NF-κB. Overall, our results suggest PTPRN2 as a novel candidate biomarker and therapeutic target in breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417433PMC
May 2015

The proteolytic YB-1 fragment interacts with DNA repair machinery and enhances survival during DNA damaging stress.

Cell Cycle 2013 Dec 7;12(24):3791-803. Epub 2013 Oct 7.

Institute of Protein Research; Russian Academy of Sciences; Pushchino, Moscow Region, Russian Federation.

The Y-box binding protein 1 (YB-1) is a DNA/RNA-binding nucleocytoplasmic shuttling protein whose regulatory effect on many DNA and RNA-dependent events is determined by its localization in the cell. We have shown previously that YB-1 is cleaved by 20S proteasome between E219 and G220, and the truncated N-terminal YB-1 fragment accumulates in the nuclei of cells treated with DNA damaging drugs. We proposed that appearance of truncated YB-1 in the nucleus may predict multiple drug resistance. Here, we compared functional activities of the full-length and truncated YB-1 proteins and showed that the truncated form was more efficient in protecting cells against doxorubicin treatment. Both forms of YB-1 induced changes in expression of various genes without affecting those responsible for drug resistance. Interestingly, although YB-1 cleavage did not significantly affect its DNA binding properties, truncated YB-1 was detected in complexes with Mre11 and Rad50 under genotoxic stress conditions. We conclude that both full-length and truncated YB-1 are capable of protecting cells against DNA damaging agents, and the truncated form may have an additional function in DNA repair.
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http://dx.doi.org/10.4161/cc.26670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905071PMC
December 2013

Novel findings on endoribonuclease activity of proteasomes.

Cell Cycle 2010 Mar 15;9(6):1028. Epub 2010 Mar 15.

Russian Academy of Sciences, Moscow, Russia.

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March 2010

The accuracy of aneroid sphygmomanometers in the ambulatory setting.

Prev Cardiol 2008 ;11(2):90-4

Division of Cardiology, Department of Medicine, Beth Israel Medical Center, New York, NY, USA.

The mercury sphygmomanometer is the undisputed gold standard for the indirect measurement of blood pressure. Some public health advocates have recently expressed concern about the use of mercury in medical practice.(2) This concern has prompted many medical facilities to replace mercury manometers with aneroid devices. The present report examined the performance of 282 aneroid sphygmomanometers in outpatient medical practices. Results were examined for predetermined end points within +/-3 mm Hg from the reference values and to indicate zero at no pressure. Ninety-three devices (33%) failed to perform at > or = 1 pressure levels. Most (76%) of the failures were due to low readings. Only 7 of the 93 failing units did not rest at zero, making this an unreliable indicator of accuracy. Inaccurate readings of aneroid sphygmomanometers may result in a failure to diagnose and treat hypertension, thereby placing hypertensive patients at risk for end-organ damage and cardiovascular events.
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http://dx.doi.org/10.1111/j.1751-7141.2008.06600.xDOI Listing
June 2008

Phytosterols and vascular disease.

Curr Opin Lipidol 2007 Feb;18(1):35-40

Section of Preventive Cardiology, Division of Cardiology, The Henry Low Heart Center, Hartford Hospital, Hartford, Connecticut 06102, USA.

Purpose Of Review: Phytosterols and stanols are plant derivatives that compete with cholesterol for intestinal absorption and thereby lower serum cholesterol concentrations. They have been developed as food additives to help lower serum cholesterol but there is concern that these additives could inadvertently increase cardiovascular risk. This concern arises from the observation that patients with the rare genetic condition phytosterolemia overabsorb phytosterols and develop premature atherosclerosis. This review evaluates the relationship between phytosterol and stanol supplementation and cardiovascular risk.

Recent Findings: Plant sterol supplementation produces minimal increases in blood phytosterol concentrations in humans. Recent animal studies suggest that phytosterols reduce atherosclerosis in the Apo-E deficient mouse model. The evidence from human studies is mixed and does not prove or disprove an increase in atherosclerotic risk from serum phytosterol levels. An increase in risk seems unlikely, but additional studies should address this possibility.

Summary: Phytosterols are effective in lowering low-density lipoprotein-cholesterol levels, and do not appear to increase atherosclerotic risk, but additional research on this topic is necessary.
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http://dx.doi.org/10.1097/MOL.0b013e328011e9e3DOI Listing
February 2007

Rhabdomyolysis associated with pomegranate juice consumption.

Am J Cardiol 2006 Sep 14;98(5):705-6. Epub 2006 Jul 14.

Section of Preventive Cardiology, Division of Cardiology, Henry Low Heart Center, Hartford Hospital, Hartford, Connecticut, USA.

This 48-year-old man with possible underlying myopathy was successfully treated with ezetimibe 10 mg/day and rosuvastatin 5 mg every other day for 17 months. Three weeks before presentation, he began drinking pomegranate juice (200 ml twice weekly). He presented urgently with thigh pain and an elevated serum creatine kinase level (138,030 U/L, normal < 200 U/L). In conclusion, because both grapefruit and pomegranate juice are known to inhibit intestinal cytochrome P450 3A4, this report suggests that pomegranate juice may increase the risk of rhabdomyolysis during rosuvastatin treatment, despite the fact that rosuvastatin is not known to be metabolized by hepatic P450 3A4.
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http://dx.doi.org/10.1016/j.amjcard.2006.03.057DOI Listing
September 2006

Akt-mediated YB-1 phosphorylation activates translation of silent mRNA species.

Mol Cell Biol 2006 Jan;26(1):277-92

Department of Pathology, British Columbia Research Institute for Children's and Women's Health, Vancouver, BC, Canada V5Z 163.

YB-1 is a broad-specificity RNA-binding protein that is involved in regulation of mRNA transcription, splicing, translation, and stability. In both germinal and somatic cells, YB-1 and related proteins are major components of translationally inactive messenger ribonucleoprotein particles (mRNPs) and are mainly responsible for storage of mRNAs in a silent state. However, mechanisms regulating the repressor activity of YB-1 are not well understood. Here we demonstrate that association of YB-1 with the capped 5' terminus of the mRNA is regulated via phosphorylation by the serine/threonine protein kinase Akt. In contrast to its nonphosphorylated form, phosphorylated YB-1 fails to inhibit cap-dependent but not internal ribosome entry site-dependent translation of a reporter mRNA in vitro. We also show that similar to YB-1, Akt is associated with inactive mRNPs and that activated Akt may relieve translational repression of the YB-1-bound mRNAs. Using Affymetrix microarrays, we found that many of the YB-1-associated messages encode stress- and growth-related proteins, raising the intriguing possibility that Akt-mediated YB-1 phosphorylation could, in part, increase production of proteins regulating cell proliferation, oncogenic transformation, and stress response.
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http://dx.doi.org/10.1128/MCB.26.1.277-292.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1317623PMC
January 2006

Proteasome-mediated cleavage of the Y-box-binding protein 1 is linked to DNA-damage stress response.

EMBO J 2005 Oct 29;24(20):3602-12. Epub 2005 Sep 29.

Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, Russian Federation.

YB-1 is a DNA/RNA-binding nucleocytoplasmic shuttling protein whose regulatory effect on many DNA- and RNA-dependent events is determined by its localization in the cell. Distribution of YB-1 between the nucleus and the cytoplasm is known to be dependent on nuclear targeting and cytoplasmic retention signals located within the C-terminal portion of YB-1. Here, we report that YB-1 undergoes a specific proteolytic cleavage by the 20S proteasome, which splits off the C-terminal 105-amino-acid-long YB-1 fragment containing a cytoplasmic retention signal. Cleavage of YB-1 by the 20S proteasome in vitro appears to be ubiquitin- and ATP-independent, and is abolished by the association of YB-1 with messenger RNA. We also found that genotoxic stress triggers a proteasome-mediated cleavage of YB-1 in vivo and leads to accumulation of the truncated protein in nuclei of stressed cells. Endoproteolytic activity of the proteasome may therefore play an important role in regulating YB-1 functioning, especially under certain stress conditions.
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http://dx.doi.org/10.1038/sj.emboj.7600830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1276713PMC
October 2005

Structural organization of mRNA complexes with major core mRNP protein YB-1.

Nucleic Acids Res 2004 19;32(18):5621-35. Epub 2004 Oct 19.

Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region 142290, Russia.

YB-1 is a universal major protein of cytoplasmic mRNPs, a member of the family of multifunctional cold shock domain proteins (CSD proteins). Depending on its amount on mRNA, YB-1 stimulates or inhibits mRNA translation. In this study, we have analyzed complexes formed in vitro at various YB-1 to mRNA ratios, including those typical for polysomal (translatable) and free (untranslatable) mRNPs. We have shown that at mRNA saturation with YB-1, this protein alone is sufficient to form mRNPs with the protein/RNA ratio and the sedimentation coefficient typical for natural mRNPs. These complexes are dynamic structures in which the protein can easily migrate from one mRNA molecule to another. Biochemical studies combined with atomic force microscopy and electron microscopy showed that mRNA-YB-1 complexes with a low YB-1/mRNA ratio typical for polysomal mRNPs are incompact; there, YB-1 binds to mRNA as a monomer with its both RNA-binding domains. At a high YB-1/mRNA ratio typical for untranslatable mRNPs, mRNA-bound YB-1 forms multimeric protein complexes where YB-1 binds to mRNA predominantly with its N-terminal part. A multimeric YB-1 comprises about twenty monomeric subunits; its molecular mass is about 700 kDa, and it packs a 600-700 nt mRNA segment on its surface.
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http://dx.doi.org/10.1093/nar/gkh889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC524299PMC
November 2004