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Jayaprakash Periasamy, Vadiraj Kurdekar, Subbarao Jasti, Mamatha B Nijaguna, Sanjana Boggaram, Manjunath A Hurakadli, Dhruv Raina, Lokavya Meenakshi Kurup, Chetan Chintha, Kavyashree Manjunath, Aneesh Goyal, Gayathri Sadasivam, Kavitha Bharatham, Muralidhara Padigaru, Vijay Potluri, Ashok R Venkitaraman
Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity...
March 9, 2018: Cell Chemical Biology
Xavier Carette, John Platig, David C Young, Michaela Helmel, Albert T Young, Zhe Wang, Lakshmi-Prasad Potluri, Cameron Stuver Moody, Jumei Zeng, Sladjana Prisic, Joseph N Paulson, Jan Muntel, Ashoka V R Madduri, Jorge Velarde, Jacob A Mayfield, Christopher Locher, Tiansheng Wang, John Quackenbush, Kyu Y Rhee, D Branch Moody, Hanno Steen, Robert N Husson
Tuberculosis is the leading killer among infectious diseases worldwide. Increasing multidrug resistance has prompted new approaches for tuberculosis drug development, including targeted inhibition of virulence determinants and of signaling cascades that control many downstream pathways. We used a multisystem approach to determine the effects of a potent small-molecule inhibitor of the essential Mycobacterium tuberculosis Ser/Thr protein kinases PknA and PknB. We observed differential levels of phosphorylation of many proteins and extensive changes in levels of gene expression, protein abundance, cell wall lipids, and intracellular metabolites...
March 6, 2018: MBio
Kristen M Tecson, David Brown, James W Choi, Georges Feghali, Gonzalo V Gonzalez-Stawinski, Baron L Hamman, Robert Hebeler, Stuart R Lander, Brian Lima, Srini Potluri, Jeffrey M Schussler, Robert C Stoler, Carlos Velasco, Peter A McCullough
BACKGROUND: Patients at high risk for developing post-procedural complications may receive iodixanol, an iso-osmolar contrast, during coronary angiography to minimize the risk of renal toxicity. For those who additionally require cardiac surgery, the wait-time between angiography and surgery may be a modifiable factor capable of mitigating poor surgical outcomes; however, there have been inconsistsent reports regarding the optimal wait-time. We sought to determine the effects of wait time between angiogram and cardiac surgery, as well as contrast induced acute injury (CI-AKI) on the development of major adverse renal and cardiac events (MARCE)...
February 2, 2018: Annals of Thoracic Surgery
Steven Coutre, Michael Choi, Richard R Furman, Herbert Eradat, Leonard Heffner, Jeffrey A Jones, Brenda Chyla, Lang Zhou, Suresh Agarwal, Tina Waskiewicz, Maria Verdugo, Rod A Humerickhouse, Jalaja Potluri, William G Wierda, Matthew S Davids
B-cell receptor pathway inhibitors (BCRi) have transformed treatment for chronic lymphocytic leukemia (CLL); however, efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRi is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi prior to enrollment...
January 5, 2018: Blood
Oliver J Ziff, Paul R Carter, John McGowan, Hardeep Uppal, Suresh Chandran, Stuart Russell, Kevin R Bainey, Rahul Potluri
BACKGROUND: There is concern that the development of heart failure and atrial fibrillation has a detrimental influence on clinical outcomes. The aim of this study was to assess all-cause mortality and length of hospital stay in patients with chronic and new-onset concomitant AF and HF. METHODS: Using the ACALM registry, we analysed adults hospitalised between 2000 and 2013 with AF and HF and assessed prevalence, mortality and length of hospital stay. Patients with HF and/or AF at baseline (study-entry) were compared with patients who developed new-onset disease during follow-up...
February 1, 2018: International Journal of Cardiology
Jeffrey A Jones, Anthony R Mato, William G Wierda, Matthew S Davids, Michael Choi, Bruce D Cheson, Richard R Furman, Nicole Lamanna, Paul M Barr, Lang Zhou, Brenda Chyla, Ahmed Hamed Salem, Maria Verdugo, Rod A Humerickhouse, Jalaja Potluri, Steven Coutre, Jennifer Woyach, John C Byrd
BACKGROUND: Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy...
January 2018: Lancet Oncology
A G Sanford, T T Schulze, L P Potluri, R M Hemsley, J J Larson, A K Judge, S J Zach, X Wang, S A Charman, J L Vennerstrom, P H Davis
We profiled three novel T. gondii inhibitors identified from an antimalarial phenotypic high throughput screen (HTS) campaign: styryl 4-oxo-1,3-benzoxazin-4-one KG3, tetrahydrobenzo[b]pyran KG7, and benzoquinone hydrazone KG8. These compounds inhibit T. gondii in vitro with IC50 values ranging from 0.3 to 2μM, comparable to that of 0.25 to 1.5μM for the control drug pyrimethamine. KG3 had no measurable cytotoxicity against five mammalian cell lines, whereas KG7 and KG8 inhibited the growth of 2 of 5 cell lines with KG8 being the least selective for T...
April 2018: Parasitology International
E C Schwalbe, D Hicks, G Rafiee, M Bashton, H Gohlke, A Enshaei, S Potluri, J Matthiesen, M Mather, P Taleongpong, R Chaston, A Silmon, A Curtis, J C Lindsey, S Crosier, A J Smith, T Goschzik, F Doz, S Rutkowski, B Lannering, T Pietsch, S Bailey, D Williamson, S C Clifford
Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis...
October 18, 2017: Scientific Reports
Phani R Potluri, Jean Chamoun, James A Cooke, Myriam Badr, Joanna A Guse, Roni Rayes, Nicole M Cordina, Dane McCamey, Piotr G Fajer, Louise J Brown
The absence of a crystal structure of the calcium free state of the cardiac isoform of the troponin complex has hindered our understanding of how the simple binding of Ca2+ triggers conformational changes in troponin which are then propagated to enable muscle contraction. Here we have used continuous wave (CW) and Double Electron-Electron Resonance (DEER) pulsed EPR spectroscopy to measure distances between TnI and TnC to track the movement of the functionally important regulatory 'switch' region of cardiac Tn...
December 2017: Journal of Structural Biology
Luisa Quinti, Sharadha Dayalan Naidu, Ulrike Träger, Xiqun Chen, Kimberly Kegel-Gleason, David Llères, Colúm Connolly, Vanita Chopra, Cho Low, Sébastien Moniot, Ellen Sapp, Adelaide R Tousley, Petr Vodicka, Michael J Van Kanegan, Linda S Kaltenbach, Lisa A Crawford, Matthew Fuszard, Maureen Higgins, James R C Miller, Ruth E Farmer, Vijay Potluri, Susanta Samajdar, Lisa Meisel, Ningzhe Zhang, Andrew Snyder, Ross Stein, Steven M Hersch, Lisa M Ellerby, Eranthie Weerapana, Michael A Schwarzschild, Clemens Steegborn, Blair R Leavitt, Alexei Degterev, Sarah J Tabrizi, Donald C Lo, Marian DiFiglia, Leslie M Thompson, Albena T Dinkova-Kostova, Aleksey G Kazantsev
The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2...
June 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
B L Loudon, N D Gollop, P R Carter, H Uppal, S Chandran, R Potluri
BACKGROUND: Traditional risk factors for cardiovascular disease (CVD) have been thoroughly investigated. We aimed to investigate the impact of comorbid cardiovascular risk factors and diseases on length of stay (LOS) and mortality in patients presenting with acute coronary syndromes (ACS). METHODS: We examined prevalence of CVD, LOS and mortality from 25,287 consecutive admissions for ACS from seven hospitals across North West England between 2000 and 2013 using the ACALM (Algorithm for Comorbidities, Associations, Length of stay and Mortality) protocol using ICD-10 and OPCS-4 coding systems...
October 1, 2016: International Journal of Cardiology
Richard J Vargo, Anitha Potluri, Richard E Bauer, Raja R Seethala, Elizabeth A Bilodeau
This report and review of the literature describes a case of benign intraoral lesions of perineurial origin in a patient with symptomatic hemimandibular hyperplasia causing partial denture soreness. Perineuriomas are a benign peripheral nerve sheath tumor composed of perineurial cells. Intraoral perineuriomas are an extremely rare entity. Two main types of perineuriomas have been described: intraneural and extraneural perineuriomas. A third, similar entity, called an intraneural pseudoperineuriomatous proliferation, has recently been proposed in the literature as a separate and distinctive diagnosis...
December 2016: Head and Neck Pathology
Rosie M Hayes, Paul R Carter, Nicholas D Gollop, Hardeep Uppal, Jaydeep Sarma, Suresh Chandran, Rahul Potluri
No abstract text is available yet for this article.
June 1, 2016: International Journal of Cardiology
Vishnu S Potluri, Chirag R Parikh, Isaac E Hall, Joseph Ficek, Mona D Doshi, Isabel Butrymowicz, Francis L Weng, Bernd Schröppel, Heather Thiessen-Philbrook, Peter P Reese
BACKGROUND AND OBJECTIVES: Data reported to the Organ Procurement and Transplantation Network (OPTN) are used in kidney transplant research, policy development, and assessment of center quality, but the accuracy of early post-transplant outcome measures is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Deceased Donor Study (DDS) is a prospective cohort study at five transplant centers. Research coordinators manually abstracted data from electronic records for 557 adults who underwent deceased donor kidney transplantation between April of 2010 and November of 2013...
February 5, 2016: Clinical Journal of the American Society of Nephrology: CJASN
R Potluri, S Ranjan, R Khurana, A M Lele, V Prabhakar, H Bhandari
No abstract text is available yet for this article.
November 2015: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
R Potluri, A M Farr, I Hirji, C Davis, H Bhandari, A Oukessou
No abstract text is available yet for this article.
November 2015: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
N Kubitz, R Potluri, M Mehra
No abstract text is available yet for this article.
November 2015: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
Subrahmanya D Vallabhapurapu, Sunil K Noothi, Derek A Pullum, Charles H Lawrie, Rachel Pallapati, Veena Potluri, Christian Kuntzen, Sohaib Khan, David R Plas, Robert Z Orlowski, Marta Chesi, W Michael Kuehl, P Leif Bergsagel, Michael Karin, Sivakumar Vallabhapurapu
Although transcriptional activation by NF-κB is well appreciated, physiological importance of transcriptional repression by NF-κB in cancer has remained elusive. Here we show that an HDAC4-RelB-p52 complex maintains repressive chromatin around proapoptotic genes Bim and BMF and regulates multiple myeloma (MM) survival and growth. Disruption of RelB-HDAC4 complex by a HDAC4-mimetic polypeptide blocks MM growth. RelB-p52 also represses BMF translation by regulating miR-221 expression. While the NIK-dependent activation of RelB-p52 in MM has been reported, we show that regardless of the activation status of NIK and the oncogenic events that cause plasma cell malignancy, several genetically diverse MM cells including Bortezomib-resistant MM cells are addicted to RelB-p52 for survival...
October 12, 2015: Nature Communications
Peter P Reese, Ofole Mgbako, Adam Mussell, Vishnu Potluri, Zahra Yekta, Simona Levsky, Scarlett Bellamy, Chirag R Parikh, Justine Shults, Karen Glanz, Harold I Feldman, Kevin Volpp
OBJECTIVE: Among chronic hemodialysis patients, hyperphosphatemia is common and associated with mortality. Behavioral economics and complementary behavior-change theories may offer valuable approaches to achieving phosphorus (PO4) control. The aim was to determine feasibility of implementing financial incentives and structured coaching to improve PO4 in the hemodialysis setting. DESIGN AND METHODS: This pilot randomized controlled trial was conducted in 3 urban dialysis units for 10 weeks among 36 adults with elevated serum PO4 (median >5...
November 2015: Journal of Renal Nutrition
Robert M Havey, Jeremy Goodsitt, Saeed Khayatzadeh, Muturi Muriuki, Tejaswy Potluri, Leonard I Voronov, Laurie M Lomasney, Avinash G Patwardhan
STUDY DESIGN: Cadaveric study to accurately measure lumbar neuroforaminal area and height throughout the flexion-extension range of motion (ROM). OBJECTIVE: Create a new computed tomography (CT)-based specimen-specific model technique to provide insight on the effects of kinematics on lumbar neuroforamen morphology during flexion-extension ROM. SUMMARY OF BACKGROUND DATA: Nerve root compression is a key factor in symptomatic progression of degenerative disc disease because these changes directly affect neuroforaminal area...
July 15, 2015: Spine
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