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Jiang X.,New York University | Burke V.,New York University | Totrov M.,Molsoft LLC | Williams C.,New York University | And 5 more authors.
Nature Structural and Molecular Biology | Year: 2010

Binding of the third variable region (V3) of the HIV-1 envelope glycoprotein gp120 to the cell-surface coreceptors CCR5 or CXCR4 during viral entry suggests that there are conserved structural elements in this sequence-variable region. These conserved elements could serve as epitopes to be targeted by a vaccine against HIV-1. Here we perform a systematic structural analysis of representative human anti-V3 monoclonal antibodies in complex with V3 peptides, revealing that the crown of V3 has four conserved structural elements: an arch, a band, a hydrophobic core and the peptide backbone. These are either unaffected by or are subject to minimal sequence variation. As these regions are targeted by cross-clade neutralizing human antibodies, they provide a blueprint for the design of vaccine immunogens that could elicit broadly cross-reactive protective antibodies. © 2010 Nature America, Inc. All rights reserved.


Carney K.,New York University | Aytaman A.,Divisions of Gastroenterology | Aytaman A.,Brooklyn College | Tenner C.T.,New York University | And 2 more authors.
Hepatology | Year: 2013

Although injection drug use (IDU) and blood transfusions prior to 1992 are well-accepted risk factors for hepatitis C virus (HCV) infection, many studies that evaluated tattooing as a risk factor for HCV infection did not control for a history of IDU or transfusion prior to 1992. In this large, multicenter, case-control study, we analyzed demographic and HCV risk factor exposure history data from 3,871 patients, including 1,930 with chronic HCV infection (HCV RNA-positive) and 1,941 HCV-negative (HCV antibody-negative) controls. Crude and fully adjusted odds ratios (ORs) of tattoo exposure by multivariate logistic regression in HCV-infected versus controls were determined. As expected, IDU (65.9% versus 17.8%; P < 0.001), blood transfusion prior to 1992 (22.3% versus 11.1%; P < 0.001), and history of having one or more tattoos (OR, 3.81; 95% CI, 3.23-4.49; P < 0.001) were more common in HCV-infected patients than in control subjects. After excluding all patients with a history of ever injecting drugs and those who had a blood transfusion prior to 1992, a total of 1,886 subjects remained for analysis (465 HCV-positive patients and 1,421 controls). Among these individuals without traditional risk factors, HCV-positive patients remained significantly more likely to have a history of one or more tattoos after adjustment for age, sex, and race/ethnicity (OR, 5.17; 95% CI, 3.75-7.11; P < 0.001). Conclusion: Tattooing is associated with HCV infection, even among those without traditional HCV risk factors such as IDU and blood transfusion prior to 1992. © 2013 American Association for the Study of Liver Diseases.


Prabhu V.,New York University | Taksler G.B.,New York University | Sivarajan G.,New York University | Laze J.,New York University | And 3 more authors.
Journal of Urology | Year: 2014

Purpose The prevalence of lower urinary tract symptoms increases with age and impairs quality of life. Radical prostatectomy has been shown to relieve lower urinary tract symptoms at short-term followup but the long-term effect of radical prostatectomy on lower urinary tract symptoms is unclear. Materials and Methods We performed a prospective cohort study of 1,788 men undergoing radical prostatectomy. The progression of scores from the self-administered AUASS (American Urological Association symptom score) preoperatively, and at 3, 6, 12, 24, 48, 60, 84, 96 and 120 months was analyzed using models controlling for preoperative AUASS, age, prostate specific antigen, pathological Gleason score and stage, nerve sparing, race and marital status. This model was also applied to patients stratified by baseline clinically significant (AUASS greater than 7) and insignificant (AUASS 7 or less) lower urinary tract symptoms. Results Men exhibited an immediate worsening of lower urinary tract symptoms that improved between 3 months and 2 years after radical prostatectomy. Overall the difference between mean AUASS at baseline and at 10 years was not statistically or clinically significant. Men with baseline clinically significant lower urinary tract symptoms experienced immediate improvements in lower urinary tract symptoms that lasted until 10 years after radical prostatectomy (13.5 vs 8.81, p <0.001). Men with baseline clinically insignificant lower urinary tract symptoms experienced a statistically significant but clinically insignificant increase in mean AUASS after 10 years (3.09 to 4.94, p <0.001). The percentage of men with clinically significant lower urinary tract symptoms decreased from baseline to 10 years after radical prostatectomy (p = 0.02). Conclusions Radical prostatectomy is the only treatment for prostate cancer shown to improve and prevent the development of lower urinary tract symptoms at long-term followup. This previously unrecognized long-term benefit argues in favor of the prostate as the primary contributor to male lower urinary tract symptoms.


Weiner D.E.,Tufts University | McClean M.D.,Boston University | Kaufman J.S.,Veterans Affairs New York Harbor Healthcare System | Brooks D.R.,Boston University
Clinical Journal of the American Society of Nephrology | Year: 2013

Recent reports have described an apparent epidemic of CKD along the Pacific coast of Central America, such that CKD is a leading cause of death among working-age men in lower-altitude agricultural communities in this region. Given the limited availability of kidney replacement therapies in this region, CKD often is a terminal diagnosis, lending greater urgency to the identification of a modifiable cause. This article discusses the epidemiology of CKD in this region, reviews the clinical features of this CKD outbreak, discusses potential causes and the evidence supporting these hypotheses, and highlights the wider implications of this epidemic of CKD. Copyright © 2013 by the American Society of Nephro.


Castillo A.B.,New York University | Castillo A.B.,Veterans Affairs New York Harbor Healthcare System | Leucht P.,New York University
Current Rheumatology Reports | Year: 2015

Mechanical loading is a potent anabolic regulator of bone mass, and the first line of defense for bone loss is weight-bearing exercise. Likewise, protected weight bearing is the first prescribed physical therapy following orthopedic reconstructive surgery. In both cases, enhancement of new bone formation is the goal. Our understanding of the physical cues, mechanisms of force sensation, and the subsequent cellular response will help identify novel physical and therapeutic treatments for age- and disuse-related bone loss, delayed- and nonunion fractures, and significant bony defects. This review highlights important new insights into the principles and mechanisms governing mechanical adaptation of the skeleton during homeostasis and repair and ends with a summary of clinical implications stemming from our current understanding of how bone adapts to biophysical force. © 2015, Springer Science+Business Media New York.


Wu X.-R.,New York University | Wu X.-R.,Veterans Affairs New York Harbor Healthcare System
Urolithiasis | Year: 2014

Genetically engineered mouse models (GEMMs) have been highly instrumental in elucidating gene functions and molecular pathogenesis of human diseases, although their use in studying kidney stone formation or nephrolithiasis remains relatively limited. This review intends to provide an overview of several knockout mouse models that develop interstitial calcinosis in the renal papillae. Included herein are mice deficient for Tamm-Horsfall protein (THP; also named uromodulin), osteopontin (OPN), both THP and OPN, Na+-phosphate cotransporter Type II (Npt2a) and Na+/H+ exchanger regulatory factor (NHERF-1). The baseline information of each protein is summarized, along with key morphological features of the interstitial calcium deposits in mice lacking these proteins. Attempts are made to correlate the papillary interstitial deposits found in GEMMs with Randall’s plaques, the latter considered precursors of idiopathic calcium stones in patients. The pathophysiology that underlies the renal calcinosis in the knockout mice is also discussed wherever information is available. Not all the knockout models are allocated equal space because some are more extensively characterized than others. Despite the inroads already made, the exact physiological underpinning, origin, evolution and fate of the papillary interstitial calcinosis in the GEMMs remain incompletely defined. Greater investigative efforts are warranted to pin down the precise role of the papillary interstitial calcinosis in nephrolithiasis using the existing models. Additionally, more sophisticated, second-generation GEMMs that allow gene inactivation in a time-controlled manner and “compound mice” that bear several genetic alterations are urgently needed, in light of mounting evidence that nephrolithiasis is a multifactorial, multi-stage and polygenic disease. © 2014, Springer-Verlag Berlin Heidelberg.


Mayr L.M.,New York University | Cohen S.,New York University | Spurrier B.,New York University | Kong X.-P.,New York University | And 2 more authors.
PLoS ONE | Year: 2013

In the case-control study of the RV144 vaccine trial, the levels of antibodies to the V1V2 region of the gp120 envelope glycoprotein were found to correlate inversely with risk of HIV infection. This recent demonstration of the potential role of V1V2 as a vaccine target has catapulted this region into the focus of HIV-1 research. We previously described seven human monoclonal antibodies (mAbs) derived from HIV-infected individuals that are directed against conformational epitopes in the V1V2 domain. In this study, using lysates of SF162 pseudoviruses carrying V1V2 mutations, we mapped the epitopes of these seven mAbs. All tested mAbs demonstrated a similar binding pattern in which three mutations (F176A, Y177T, and D180L) abrogated binding of at least six of the seven mAbs to ≤15% of SF162 wildtype binding. Binding of six or all of the mAbs was reduced to ≤50% of wildtype by single substitutions at seven positions (168, 180, 181, 183, 184, 191, and 193), while one change, V181I, increased the binding of all mAbs. When mapped onto a model of V2, our results suggest that the epitope of the conformational V2 mAbs is located mostly in the disordered region of the available crystal structure of V1V2, overlapping and surrounding the α4β7 binding site on V2. © 2013 Mayr et al.


He F.,New York University | He F.,Veterans Affairs New York Harbor Healthcare System | Melamed J.,New York University | Tang M.-S.,New York University | And 3 more authors.
Cancer Research | Year: 2015

Muscle-invasive urothelial carcinomas of the bladder (MIUCB) exhibit frequent receptor tyrosine kinase alterations, but the precise nature of their contributions to tumor pathophysiology is unclear. Using mutant HRAS (HRAS∗) as an oncogenic prototype, we obtained evidence in transgenic mice that RTK/RAS pathway activation in urothelial cells causes hyperplasia that neither progresses to frank carcinoma nor regresses to normal urothelium through a period of one year. This persistent hyperplastic state appeared to result from an equilibrium between promitogenic factors and compensatory tumor barriers in the p19-MDM2-p53-p21 axis and a prolonged G2 arrest. Conditional inactivation of p53 in urothelial cells of transgenic mice expressing HRAS∗ resulted in carcinoma in situ and basal-subtype MIUCB with focal squamous differentiation resembling the human counterpart. The transcriptome of microdissected MIUCB was enriched in genes that drive epithelial-to-mesenchymal transition, the upregulation of which is associated with urothelial cells expressing multiple progenitor/stem cell markers. Taken together, our results provide evidence for RTK/RAS pathway activation and p53 deficiency as a combinatorial theranostic biomarker that may inform the progression and treatment of urothelial carcinoma. © 2015 American Association for Cancer Research.


Pan R.,New York University | Gorny M.K.,New York University | Zolla-Pazner S.,New York University | Zolla-Pazner S.,Veterans Affairs New York Harbor Healthcare System | Kong X.-P.,New York University
Journal of Virology | Year: 2015

The region consisting of the first and second variable regions (V1V2) of gp120 plays vital roles in the functioning of the HIV-1 envelope (Env). V1V2, which harbors multiple glycans and is highly sequence diverse, is located at the Env apex and stabilizes the trimeric gp120 spike on the virion surface. It shields V3 and the coreceptor binding sites in the prefusion state and exposes them upon CD4 binding. Data from the RV144 human HIV-1 vaccine trial suggested that antibody responses targeting the V1V2 region inversely correlated with the risk of infection; thus, understanding the antigenic structure of V1V2 can contribute to vaccine design. We have determined a crystal structure of a V1V2 scaffold molecule (V1V2ZM109-1FD6) in complex with 830A, a human monoclonal antibody that recognizes a V1V2 epitope overlapping the integrin-binding motif in V2. The structure revealed that V1V2 assumes a five-stranded beta barrel structure with the region of the integrin-binding site (amino acids [aa] 179 to 181) included in a "kink" followed by an extra beta strand. The complete barrel structure naturally presents the glycans on its outer surface and packs into its core conserved hydrophobic residues, including the Ile at position 181 which was highly correlated with vaccine efficacy in RV144. The epitope of monoclonal antibody 830A is discontinuous and composed of three segments: (i) Thr175, Tyr177, Leu179, and Asp180 at the kink overlapping the integrin-binding site; (ii) Arg153 and Val154 in V1; and (iii) Ile194 at the C terminus of V2. This report thus provides the atomic details of the immunogenic "V2i epitope". © 2015, American Society for Microbiology.


News Article | October 28, 2016
Site: www.prweb.com

The American Kidney Fund (AKF), the nation’s largest nonprofit organization serving people with, and at risk for, kidney disease, will honor a local nephrologist and a biopharmaceutical company at its regional fundraising event, “A Pairing for Prevention,” to be held Nov. 1, 2016 at Terrace on the Park in Queens, New York. “The community that cares for people with kidney disease knows how devastating this condition can be physically, emotionally and financially,” said LaVarne A. Burton, president and chief executive officer of the American Kidney Fund. “The support of the New York region for our programs and services helps to ensure that we can fulfill our mission of helping people fight kidney disease and live healthier lives.” The corporate honoree, Retrophin, is dedicated to delivering life-changing therapies to people living with rare diseases who have few, if any, treatment options. The company’s work in kidney disease centers on cystinuria, a rare and chronic genetic disorder characterized by the formation of cystine kidney stones, and focal segmental glomerulosclerosis, a rare condition characterized by progressive scarring of the kidney that often leads to end-stage renal disease. “We are honored to be recognized by the American Kidney Fund, and stand alongside the organization in its efforts to serve the community of patients impacted by kidney disease,” said Stephen Aselage, CEO of Retrophin. “As a company that is dedicated to developing new treatments and broadening access to our approved medications, we share in AKF’s mission to ensure that kidney patients receive the care they need.” David S. Goldfarb, M.D. will also be honored at the event as the area’s “Nephrologist of the Year.” Dr. Goldfarb is chief of nephrology at the Department of Veterans Affairs New York Harbor Healthcare System, clinical chief of nephrology at NYU Langone Medical Center, and professor of medicine and physiology at NYU School of Medicine. In his efforts to care for others, Dr. Goldfarb complements his vast medical expertise by drawing upon his own experiences as a patient who has had kidney stones. All funds raised at “A Pairing for Prevention” will support the mission of AKF, ensuring that every kidney patient has access to health care, and that every person at risk for kidney disease is empowered to prevent it. Now celebrating its 45th anniversary, AKF has helped more than 1 million low-income dialysis patients access lifesaving medical care. To learn more, or to purchase tickets, please visit the event webpage or contact AKF’s Northeast Regional Office at (516) 513-5247. About the American Kidney Fund As the nation’s leading nonprofit working on behalf of the 31 million Americans with kidney disease, the American Kidney Fund is dedicated to ensuring that every kidney patient has access to health care, and that every person at risk for kidney disease is empowered to prevent it. AKF provides a complete spectrum of programs and services: prevention outreach, top-rated health educational resources, and direct financial assistance enabling 1 in 5 U.S. dialysis patients to access lifesaving medical care, including dialysis and transplantation. For more information, please visit KidneyFund.org, or connect with us on Facebook, Twitter and Instagram. About Retrophin Retrophin is a fully integrated biopharmaceutical company dedicated to delivering life-changing therapies to people living with rare diseases who have few, if any, treatment options. The Company's approach centers on its pipeline featuring clinical-stage assets targeting rare diseases with significant unmet medical needs, including sparsentan for focal segmental glomerulosclerosis (FSGS), a disorder characterized by progressive scarring of the kidney often leading to end-stage renal disease, and RE-024 for pantothenate kinase-associated neurodegeneration (PKAN), a life-threatening neurological disorder that typically begins in early childhood. Research exploring the potential of early-stage assets in several rare diseases is also underway. Retrophin's R&D efforts are supported by revenues from the Company's commercial products Thiola®, Cholbam® and Chenodal®. For more information, please visit Retrophin.com

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