Publications by authors named "Joseph Ippolito"

80 Publications

Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations.

ACS Cent Sci 2021 Mar 22;7(3):467-475. Epub 2021 Feb 22.

Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.

Starting from our previous finding of 14 known drugs as inhibitors of the main protease (M) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. 20 nM IC values in a kinetic assay. Free-energy perturbation (FEP) calculations for M-ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to M. Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acscentsci.1c00039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931627PMC
March 2021

Single-cell Spatial Proteomic Revelations on the Multiparametric MRI Heterogeneity of Clinically Significant Prostate Cancer.

Clin Cancer Res 2021 Mar 26. Epub 2021 Mar 26.

Molecular Oncology, Division of Oncology, Department of Medicine, Washington University, St Louis, Missouri.

Purpose: Multiparametric MRI (mpMRI) has become an indispensable radiographic tool in diagnosing prostate cancer. However, mpMRI fails to visualize approximately 15% of clinically significant prostate cancer (csPCa). The molecular, cellular, and spatial underpinnings of such radiographic heterogeneity in csPCa are unclear.

Experimental Design: We examined tumor tissues from clinically matched patients with mpMRI-invisible and mpMRI-visible csPCa who underwent radical prostatectomy. Multiplex immunofluorescence single-cell spatial imaging and gene expression profiling were performed. Artificial intelligence-based analytic algorithms were developed to examine the tumor ecosystem and integrate with corresponding transcriptomics.

Results: More complex and compact epithelial tumor architectures were found in mpMRI-visible than in mpMRI-invisible prostate cancer tumors. In contrast, similar stromal patterns were detected between mpMRI-invisible prostate cancer and normal prostate tissues. Furthermore, quantification of immune cell composition and tumor-immune interactions demonstrated a lack of immune cell infiltration in the malignant but not in the adjacent nonmalignant tissue compartments, irrespective of mpMRI visibility. No significant difference in immune profiles was detected between mpMRI-visible and mpMRI-invisible prostate cancer within our patient cohort, whereas expression profiling identified a 24-gene stromal signature enriched in mpMRI-invisible prostate cancer. Prostate cancer with strong stromal signature exhibited a favorable survival outcome within The Cancer Genome Atlas prostate cancer cohort. Notably, five recurrences in the 8 mpMRI-visible patients with csPCa and no recurrence in the 8 clinically matched patients with mpMRI-invisible csPCa occurred during the 5-year follow-up post-prostatectomy.

Conclusions: Our study identified distinct molecular, cellular, and structural characteristics associated with mpMRI-visible csPCa, whereas mpMRI-invisible tumors were similar to normal prostate tissue, likely contributing to mpMRI invisibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-4217DOI Listing
March 2021

The role of social media in clubfoot: information sharing and social support.

J Child Orthop 2021 Feb;15(1):81-88

Department of Orthopaedic Surgery, New Jersey Medical School, Newark, USA.

Purpose: Clubfoot is the most common congenital foot deformity in children. Caregivers often seek medical information on the internet. The aim of the study was to characterize how social media is used by caregivers to access medical information.

Methods: A search was performed on Facebook, Twitter and YouTube platforms. Information was quantitatively assessed. Comments were qualitatively assessed, and the Kruskal-Wallis test was used to study thematic comment distribution.

Results: In total, 58 Facebook groups and pages, 109 YouTube accounts and ten Twitter accounts related to clubfoot were discovered from 2007 to 2019. Facebook groups and pages had a collective 56 123 members and 80 544 total likes, respectively. YouTube had a collective 3 280 454 views, with 54 969 total comments throughout the accounts. Comment themes most commonly included sharing information and advice (38.7%), appreciation and success stories (12.8%), emotional support (12.7%) and social media as a second opinion (11.9%). Facebook groups contained a significantly higher number of comments related to 'social media as a second opinion' compared with Facebook pages (p = 0.001), Twitter (p = 0.016) and YouTube (p < 0.0001) while YouTube contained a significantly lower number of comments related to 'sharing information' compared with Facebook groups, pages and Twitter (p < 0.0001).

Conclusion: Social media continues to be a growing tool for information sharing and the findings of this study highlight the importance placed by caregivers on the advice of their peers. The online presence of caregivers may represent an opportunity for orthopaedic surgeons to communicate with patients and help them make informed decisions.

Level Of Evidence: IV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1302/1863-2548.15.200176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907770PMC
February 2021

Covalent Inhibition of Wild-Type HIV-1 Reverse Transcriptase Using a Fluorosulfate Warhead.

ACS Med Chem Lett 2021 Feb 6;12(2):249-255. Epub 2021 Jan 6.

Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.

Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) are reported. Three compounds derived from catechol diether non-nucleoside inhibitors (NNRTIs) with addition of a fluorosulfate warhead are demonstrated to covalently modify Tyr181 of HIV-RT. X-ray crystal structures for complexes of the CRTIs with the enzyme are provided, which fully demonstrate the covalent attachment, and confirmation is provided by appropriate mass shifts in ESI-TOF mass spectra. The three CRTIs and six noncovalent analogues are found to be potent inhibitors with both IC values for in vitro inhibition of WT RT and EC values for cytopathic protection of HIV-1-infected human T-cells in the 5-320 nM range.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.0c00612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883463PMC
February 2021

Management of Large Segmental Bone Defects at the Knee With Intramedullary Stabilized Antibiotic Spacers During Two-Stage Treatment of Endoprosthetic Joint Infection.

J Arthroplasty 2021 Jan 18. Epub 2021 Jan 18.

Department of Orthopaedics, Rutgers New Jersey Medical School, Newark, NJ.

Background: Following debridement of infected prostheses that require reconstruction with an endoprosthetic replacement (EPR), instability related to segmental residual bone defects present a challenge in management with 2-stage reimplantation.

Methods: We retrospectively reviewed all patients treated for revision total joint or endoprosthetic infection at the knee from 1998 to 2018. At our institution, patients with skeletal defects >6 cm following explant of prosthesis and debridement (stage 1) were managed with intramedullary nail-stabilized antibiotic spacers. Following stage 1, antimicrobial therapy included 6 weeks of intravenous antibiotics and a minimum of 6 weeks of oral antibiotics. Following resolution of inflammatory markers and negative tissue cultures, reimplantation (stage 2) of an EPR was performed.

Results: Twenty-one patients at a mean age of 54 ± 21 years were treated for prosthetic joint infection at the knee. Polymicrobial growth was detected in 38% of cases, followed by coagulase-negative staphylococci (24%) and Staphylococcus aureus (19%). Mean residual skeletal defect after stage 1 treatment was 20 cm. Prosthetic joint infection eradication was achieved in 18 (86%) patients, with a mean Musculoskeletal Tumor Society score of 77% and mean knee range of motion of 100°. Patients with polymicrobial infections had a greater number of surgeries prior to infection (P = .024), and were more likely to require additional debridement prior to EPR (odds ratio 12.0, P = .048).

Conclusion: Management of large segmental skeletal defects at the knee following explant using intramedullary stabilized antibiotic spacers maintain stability and result in high rates of limb salvage with conversion to an endoprosthesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.arth.2021.01.026DOI Listing
January 2021

NCCN Guidelines Insights: Prostate Cancer, Version 1.2021.

J Natl Compr Canc Netw 2021 02 2;19(2):134-143. Epub 2021 Feb 2.

Huntsman Cancer Institute at the University of Utah; and.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel's discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2021.0008DOI Listing
February 2021

Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2.

ACS Med Chem Lett 2020 Dec 25;11(12):2526-2533. Epub 2020 Oct 25.

Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.

A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (M) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses of the predicted structures of their complexes with M, 17 were chosen for evaluation in a kinetic assay for M inhibition. Remarkably 14 of the compounds at 100-μM concentration were found to reduce the enzymatic activity and 5 provided IC values below 40 μM: manidipine (4.8 μM), boceprevir (5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM), and efonidipine (38.5 μM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1', and P2 pockets of M. Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.0c00521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605328PMC
December 2020

Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway.

Nat Commun 2020 12 2;11(1):6164. Epub 2020 Dec 2.

Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump α2-Na/K ATPase cause familial hemiplegic migraine, but the mechanisms by which α2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we show that mice in which α2-Na/K ATPase is conditionally deleted in astrocytes display episodic paralysis. Functional neuroimaging reveals that conditional α2-Na/K ATPase knockout triggers spontaneous cortical spreading depression events that are associated with EEG low voltage activity events, which correlate with transient motor impairment in these mice. Transcriptomic and metabolomic analyses show that α2-Na/K ATPase loss alters metabolic gene expression with consequent serine and glycine elevation in the brain. A serine- and glycine-free diet rescues the transient motor impairment in conditional α2-Na/K ATPase knockout mice. Together, our findings define a metabolic mechanism regulated by astrocytic α2-Na/K ATPase that triggers episodic motor paralysis in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19915-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710756PMC
December 2020

Comparison of hyperpolarized C and non-hyperpolarized deuterium MRI approaches for imaging cerebral glucose metabolism at 4.7 T.

Magn Reson Med 2021 04 28;85(4):1795-1804. Epub 2020 Nov 28.

Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, USA.

Purpose: The purpose of this study was to directly compare two isotopic metabolic imaging approaches, hyperpolarized (HP) C MRI and deuterium metabolic imaging (DMI), for imaging specific closely related segments of cerebral glucose metabolism at 4.7 T.

Methods: Comparative HP- C and DMI neuroimaging experiments were conducted consecutively in normal rats during the same scanning session. Localized conversions of [1- C]pyruvate and [6,6- H ]glucose to their respective downstream metabolic products were measured by spectroscopic imaging, using an identical 2D-CSI sequence with parameters optimized for the respective experiments. To facilitate direct comparison, a pair of substantially equivalent 2.5-cm double-tuned X/ H RF surface coils was developed. For improved results, multidimensional low-rank reconstruction was applied to denoise the raw DMI data.

Results: Localized conversion of HP [1- C]pyruvate to [1- C]lactate, and [6,6- H ]glucose to [3,3- H ]lactate and Glx-d (glutamate and glutamine), was detected in rat brain by spectroscopic imaging at 4.7 T. The SNR and spatial resolution of HP- C MRI was superior to DMI but limited to a short time window, whereas the lengthy DMI acquisition yielded maps of not only lactate, but also Glx production, albeit with relatively poor spectral discrimination between metabolites at this field strength. Across the individual rats, there was an apparent inverse correlation between cerebral production of HP [1- C]lactate and Glx-d, along with a trend toward increased [3,3- H ]lactate.

Conclusion: The HP- C MRI and DMI methods are both feasible at 4.7 T and have significant potential for metabolic imaging of specific segments of glucose metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mrm.28612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018714PMC
April 2021

Evaluating the Readability of Online Patient Education Materials Related to Orthopedic Oncology.

Orthopedics 2021 Jan 3;44(1):38-42. Epub 2020 Nov 3.

The internet is increasingly used to access patient education materials. The average American reading level has been found to be that of a 7th- to 8th-grade student, prompting the National Institutes of Health (NIH) and the American Medical Association (AMA) to advise that patient education materials be written between the 4th- to 6th-grade reading level. The purpose of this study was to evaluate the reading level of current patient education materials for the most common musculoskeletal oncological tumors. A Google search was performed with all location filters off to account for geographic variability for patient education materials related to 28 orthopedic primary or secondary tumors. All patient education articles from the first 10 website hits for each tumor type were analyzed. Patient education materials from these websites were evaluated using 8 validated readability scales. Patient resources were found to be written at an average grade level nearly double the NIH and AMA recommendation. Patient education materials for soft tissue chondromas were written at the highest level (14.8±1.9), whereas education materials for chordomas (10.1±1.0) most closely approached national recommendations, despite still being written at a readability level nearly 4 grade levels higher than has been recommended. The Flesch Reading Ease assessment provided a mean score of 46.5±7.7, corresponding with a "difficult to read" result. Current patient education materials regarding oncological musculoskeletal-related patient education materials are written significantly above the recommended reading level. Further modification of these resources is warranted to ensure adequate comprehension and informed decision making in the clinical setting. [Orthopedics. 2021;44(1):38-42.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3928/01477447-20201012-04DOI Listing
January 2021

Sex differences in health and disease: A review of biological sex differences relevant to cancer with a spotlight on glioma.

Cancer Lett 2021 02 29;498:178-187. Epub 2020 Oct 29.

Mathematical NeuroOncology Laboratory, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA; Department of Neurological Surgery, Mayo Clinic, Phoenix, AZ, USA; School of Mathematical and Statistical Sciences, Arizona State University, Tempe, AZ, USA. Electronic address:

The influence of biological sex differences on human health and disease, while being increasingly recognized, has long been underappreciated and underexplored. While humans of all sexes are more alike than different, there is evidence for sex differences in the most basic aspects of human biology and these differences have consequences for the etiology and pathophysiology of many diseases. In a disease like cancer, these consequences manifest in the sex biases in incidence and outcome of many cancer types. The ability to deliver precise, targeted therapies to complex cancer cases is limited by our current understanding of the underlying sex differences. Gaining a better understanding of the implications and interplay of sex differences in diseases like cancer will thus be informative for clinical practice and biological research. Here we review the evidence for a broad array of biological sex differences in humans and discuss how these differences may relate to observed sex differences in various diseases, including many cancers and specifically glioblastoma. We focus on areas of human biology that play vital roles in healthy and disease states, including metabolism, development, hormones, and the immune system, and emphasize that the intersection of sex differences in these areas should not go overlooked. We further propose that mathematical approaches can be useful for exploring the extent to which sex differences affect disease outcomes and accounting for those in the development of therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2020.07.030DOI Listing
February 2021

Technical Note: Automatic segmentation of CT images for ventral body composition analysis.

Med Phys 2020 Nov 3;47(11):5723-5730. Epub 2020 Oct 3.

Washington University School of Medicine, 660 S Euclid Ave, Campus, Box 8131, St Louis, MO, 63110, USA.

Purpose: Body composition is known to be associated with many diseases including diabetes, cancers, and cardiovascular diseases. In this paper, we developed a fully automatic body tissue decomposition procedure to segment three major compartments that are related to body composition analysis - subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and muscle. Three additional compartments - the ventral cavity, lung, and bones - were also segmented during the segmentation process to assist segmentation of the major compartments.

Methods: A convolutional neural network (CNN) model with densely connected layers was developed to perform ventral cavity segmentation. An image processing workflow was developed to segment the ventral cavity in any patient's computed tomography (CT) using the CNN model, then further segment the body tissue into multiple compartments using hysteresis thresholding followed by morphological operations. It is important to segment ventral cavity firstly to allow accurate separation of compartments with similar Hounsfield unit (HU) inside and outside the ventral cavity.

Results: The ventral cavity segmentation CNN model was trained and tested with manually labeled ventral cavities in 60 CTs. Dice scores (mean ± standard deviation) for ventral cavity segmentation were 0.966 ± 0.012. Tested on CT datasets with intravenous (IV) and oral contrast, the Dice scores were 0.96 ± 0.02, 0.94 ± 0.06, 0.96 ± 0.04, 0.95 ± 0.04, and 0.99 ± 0.01 for bone, VAT, SAT, muscle, and lung, respectively. The respective Dice scores were 0.97 ± 0.02, 0.94 ± 0.07, 0.93 ± 0.06, 0.91 ± 0.04, and 0.99 ± 0.01 for non-contrast CT datasets.

Conclusion: A body tissue decomposition procedure was developed to automatically segment multiple compartments of the ventral body. The proposed method enables fully automated quantification of three-dimensional (3D) ventral body composition metrics from CT images.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mp.14465DOI Listing
November 2020

An Analysis of Trends in National Residency Matching Program Match Data for Orthopedic Surgery.

Orthopedics 2020 Nov 22;43(6):e616-e622. Epub 2020 Sep 22.

Due to electronic residency applications, US Medical Licensing Examination Step 1 scores are frequently used by orthopedic surgery program directors to screen applicants. Prospective applicants therefore often use Step 1 scores as a proxy for specialty competitiveness. The goal of this investigation was two-fold: (1) to determine whether trends in Step 1 scores are indicative of trends in competitiveness of orthopedic surgery and (2) to report the characteristics that optimize a US medical student's match success. A retrospective review of published National Resident Matching Program data from 2009 to 2018 was performed for orthopedic surgery residency applicants. Additional data from the Charting Outcomes reports were used for specific analyses of applicant characteristics. From 2009 to 2018, the number of orthopedic surgery residency positions grew at an annual rate of 1.51% (95% confidence interval [CI], 1.37% to 1.64%; P<.001), accommodating the 1.26% (95% CI, 0.63% to 1.90%; P=.006) annual increase in the number of applicants who ranked orthopedic surgery as their preferred specialty choice (only choice or first choice). There were no significant changes in the applicant-to-position ratio (95% CI, -0.85% to 0.37%; P=.483) or the match rate for US seniors who ranked orthopedic surgery as their preferred choice (95% CI, -0.23% to 0.87%; P=.313). Increases in mean Step 1 scores of matched orthopedic surgery applicants parallel national Step 1 growth trends (0.49% vs 0.44%, respectively). Although orthopedic surgery is currently a competitive specialty to match into, this has been the case since 2009. Increasing Step 1 scores of matched applicants is not unique to orthopedic surgery and should not be misinterpreted as a proxy for increasing competitiveness of the specialty. [Orthopedics. 2020;43(6):e616-e622.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3928/01477447-20200910-03DOI Listing
November 2020

Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2.

bioRxiv 2020 Aug 28. Epub 2020 Aug 28.

A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (M ) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses of the predicted structures of their complexes with M , 17 were chosen for evaluation in a kinetic assay for M inhibition. Remarkably 14 of the compounds at 100-μM concentration were found to reduce the enzymatic activity and 5 provided IC values below 40 μM: manidipine (4.8 μM), boceprevir (5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM), and efonidipine (38.5 μM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1', and P2 pockets of M . Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.08.28.271957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457600PMC
August 2020

A new role for orthopaedic surgeons: ongoing changes, lessons learned, and perspectives from a level I trauma center during the COVID-19 pandemic.

J Shoulder Elbow Surg 2020 Oct 30;29(10):1951-1956. Epub 2020 Jul 30.

Department of Orthopaedics, Rutgers New Jersey Medical School, Newark, NJ, USA.

The COVID-19 pandemic has redefined global health care. With almost 13 million confirmed cases worldwide, medical professionals have been forced to modify their practice to take care of an expanded, critically ill population. Institutions have been challenged to implement innovative ways to maximize the utility and the safety of residents and personnel. Guided by lessons learned from prior mass causalities, wars, and previous pandemics, adjustments have been made in order to provide optimal care for all patients while still protecting limited resources and the lives of health care workers. Specialists who are trained in the management of lethal aspects of this disease continue to have a high demand and obvious role. Orthopedic surgeons, with ill-defined roles, have been redeployed to manage complex medical problems. Still, the need to manage trauma, fractures, infections, tumors, and dislocations remains a necessity. Various innovative measures have been taken to maximize the utility and safety of residents in the inpatient and outpatient setting. Commonalities to most measures and distinct changes in practice philosophy can be identified and applied to both current and future pandemic responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jse.2020.07.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390768PMC
October 2020

Risk factors of venous thromboembolism in patients with benign and malignant musculoskeletal tumors: a dual database analysis.

Int Orthop 2020 10 11;44(10):2147-2153. Epub 2020 Jul 11.

Department of Orthopaedics, Rutgers New Jersey Medical School, 140 Bergen Street, ACC D1610, Newark, NJ, 07103, USA.

Purpose: Venous thromboembolism (VTE) is a potentially life-threatening condition associated with both orthopaedic surgery and tumour growth. In this study, we identify risk factors associated with VTE in patients with musculoskeletal tumours using two national datasets.

Methods: The ACS-NSQIP and NIS databases were queried for patients undergoing surgery with a diagnosis of benign or malignant musculoskeletal tumours. Chi-square and binary logistic regression analyses were used to determine risk factors for VTE.

Results: The incidence of VTE was 2% in both databases. Patients with malignant tumours, those with tumours of the pelvis, sacrum, or coccyx, obesity, arrhythmias, paralysis, metastatic disease, coagulopathy, and recent weight loss were at increased risk for VTE. In patients with benign tumours, those who were African American, those with tumours of the pelvis, sacrum, or coccyx, diabetes, anaemia, and coagulopathy were at increased risk of VTE.

Conclusions: Patients with malignant or benign lesion are at greater risk of VTE if they are age 30 and over, of the African American population, or with tumors of the pelvis/sacrum/coccyx, or any of the following comorbidities: pulmonary disease, paralysis, other neurological disorders, or coagulopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00264-020-04707-6DOI Listing
October 2020

Structural investigation of 2-naphthyl phenyl ether inhibitors bound to WT and Y181C reverse transcriptase highlights key features of the NNRTI binding site.

Protein Sci 2020 09 5;29(9):1902-1910. Epub 2020 Aug 5.

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.

Human immunodeficiency virus (HIV)-1 remains as a global health issue that is primarily treated with highly active antiretroviral therapy, a combination of drugs that target the viral life cycle. One class of these drugs are non-nucleoside reverse transcriptase inhibitors (NNRTIs) that target the viral reverse transcriptase (RT). First generation NNRTIs were troubled with poor pharmacological properties and drug resistance, incentivizing the development of improved compounds. One class of developed compounds are the 2-naphthyl phenyl ethers, showing promising efficacy against the Y181C RT mutation. Further biochemical and structural work demonstrated differences in potency against the Y181C mutation and binding mode of the compounds. This work aims to understand the relationship between the binding mode and ability to overcome drug resistance using macromolecular x-ray crystallography. Comparison of 2-naphthyl phenyl ethers bound to Y181C RT reveal that compounds that interact with the invariant W229 are more capable of retaining efficacy against the resistance mutation. Additional modifications to these compounds at the 4-position, computationally designed to compensate for the Y181C mutation, do not demonstrate improved potency. Ultimately, we highlight important considerations for the development of future HIV-1 drugs that are able to combat drug resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pro.3910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454559PMC
September 2020

Outcomes following periacetabular tumor resection: A 25-year institutional experience.

J Surg Oncol 2020 Oct 28;122(5):949-954. Epub 2020 Jun 28.

Department of Orthopaedics, Rutgers New Jersey Medical School, Newark, New Jersey.

Backgrounds And Objectives: Following tumor resection involving the acetabulum (periacetabular), various methods of reconstruction exist. The objective of this study was to analyze functional outcomes and complication rates by extent of periacetabular tumor resection, as well as by method of reconstruction.

Methods: Twenty-three patients underwent periacetabular resection for a primary pelvic bone tumor from 1993-2018 at a single institution. Complications were documented and functional outcomes were assessed using the Musculoskeletal Tumor Society (MSTS) scoring system.

Results: Mean age was 42.8 ± 22.6 years. Mean follow-up was 107 ± 75 months. MSTS scores were highest in patients with allograft reconstruction (80.2%) and lowest in saddle reconstruction (38.0%). MSTS scores were higher in patients with Type II periacetabular resection alone compared with Type II + additional resection (78.6% vs 60.3%; P = .019). Complications were lower in patients with Type II periacetabular resection alone (75% vs 28.6%; P = .036). Complications were highest following allograft reconstruction (78%) and lowest following hemipelvectomy without reconstruction (20%).

Conclusion: Patients who underwent allograft/APC or nonsaddle metallic reconstruction experienced the highest functional outcome scores, but also sustained a higher complication rate than patients with hemipelvectomy without reconstruction. Patients with resection of ilium and/or pubis in addition to the periacetabular region had lower functional outcome scores and higher risk for complication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.26088DOI Listing
October 2020

ACR Stakeholder Prostate Summit.

J Am Coll Radiol 2020 Aug 29;17(8):1068-1070. Epub 2020 Apr 29.

Section Chief, Body Imaging, Department of Radiology; Director, Health Policy; Director, Prostate Imaging NYU Langone, New York, New York.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacr.2020.03.031DOI Listing
August 2020

Identification of Risk Factors for Readmission in Patients Undergoing Anterior Cervical Discectomy Fusion: A Predictive Risk Scale.

Clin Spine Surg 2020 11;33(9):E426-E433

Department of Orthopaedics, Rutgers-New Jersey Medical School, Newark, NJ.

Study Design: This was a retrospective cohort study.

Objective: The objective of this study was to analyze readmission rates among patients undergoing anterior cervical discectomy and fusion (ACDF), determine which factors were associated with higher readmission rates, and develop a scale for utilization during surgical planning.

Summary Of Background Data: ACDF is the most common surgical treatment for many cervical disk pathologies. With the Centers for Medicare and Medicaid Services selecting readmissions as a measure of health care quality, there has been an increased focus on reducing readmissions.

Materials And Methods: There were 114,174 recorded ACDF surgeries in the derivation cohort, the State Inpatient Database (SID) of New York and California between 2006 and 2014. There were 115,829 ACDF surgeries recorded in the validation cohort, the SID from Florida and Washington over the same time period. After identification of risk factors using univariate and multivariate analysis of the derivation cohort, a predictive scale was generated and tested utilizing the validation cohort.

Results: Overall, readmission rates within 30 days of discharge were 5.87% and 5.52% in the derivation and validation cohorts, respectively. On multivariate analysis of the derivation cohort, age older than 80 years [odds ratio (OR), 1.67] male sex (OR, 1.16), Medicaid insurance (OR, 1.90), Medicare insurance (OR, 1.64), revision ACDF (OR, 1.43), anemia (OR, 1.45), chronic lung disease (OR, 1.23), coagulopathy (OR, 1.42), congestive heart failure (OR, 1.31), diabetes (OR, 1.23), fluid and electrolyte disorder (OR, 1.56), liver disease (OR, 1.37), renal failure (OR, 1.59), and myelopathy (OR, 1.19) were found to be statistically significant predictors for readmission. These factors were incorporated into a numeric scale that, that when tested on the validation cohort, could explain 97.1% of the variability in readmission rate.

Conclusions: Overall, 30-day readmission following ACDF surgery was 5%-6%. A novel risk scale based on factors associated with increased readmission rates may be helpful in identifying patients who require additional optimization to reduce perioperative morbidity.

Level Of Evidence: Level III-prognostic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BSD.0000000000000962DOI Listing
November 2020

Surgical Reconstruction of the Acetabulum and Pelvis in Metastatic Bone Disease.

Instr Course Lect 2019 ;68:593-606

Management of a painful metastatic acetabular lesion is complex and requires the assessment of tumor size and location, remaining integrity of the acetabulum, analgesic requirements, ability to use postoperative radiation, and projected patient survival. Patients presenting with suspected periacetabular metastasis frequently have groin pain aggravated by weight bearing. After a complete physical examination, advanced imaging and a complete laboratory workup should be performed to assess the extent of local and systemic disease. If a patient has a previously identified metastatic lesion, it is beneficial to communicate with the patient's medical oncologist to gather information on responses to chemotherapeutic agents, hormonal agents, and radiation therapy. Management may be nonsurgical, interventional, or surgical. Despite the limited life expectancy of patients with periacetabular metastasis, when performed in the appropriate setting, reconstruction by using anti-protrusio cages, screws, and cemented hip arthroplasty can improve quality of life by aiding independent ambulation and decreasing pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2020

Correction to: Inhibition of the key metabolic pathways, glycolysis and lipogenesis, of oral cancer by bitter melon extract.

Cell Commun Signal 2019 Nov 19;17(1):151. Epub 2019 Nov 19.

Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO, 63104, USA.

Following publication of the original article [1], it was reported that Fig. 1c was not entirely readable due to overlapping Fig. 1d. The publishers apologise for this error.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12964-019-0475-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864944PMC
November 2019

Physiologic widening of the medial clear space: What's normal?

J Clin Orthop Trauma 2019 Oct 23;10(Suppl 1):S62-S64. Epub 2019 Apr 23.

Department of Orthopaedics, Rutgers New Jersey Medical School, 140 Bergen Street, ACC Building, Suite D1610, Newark, NJ, USA.

Background: Literature has validated the use of stress radiographs for evaluation of ankle stability. However, to our knowledge no study has reported the amount of physiological widening that occurs with manual external rotation stress test in uninjured ankles. The purpose of this study was to assess the amount of medial clear space widening that occurs with a manual external rotation stress test in uninjured ankles.

Methods: A cohort of adult patients undergoing operative fixation of unstable ankle fractures were prospectively enrolled to have their contralateral ankle undergo manual external rotation stress examination. Fluoroscopic images of the unaffected ankle were performed in the OR. A non-stressed mortise view and manual external rotation stress view were obtained with a standardized marker to correct for magnification differences. The images were de-identified, presented in a randomized order and reviewers who were blinded. Each reviewer measured the medial clear space.

Results: Thirty fluoroscopic images on fifteen patients were obtained. The mean medial clear space on the non-stressed mortise view was 3.1 mm (SD-0.69; Range 1.9 to 4.2, 95% CI [2.75, 3.45]) versus a mean of 3.2 mm (SD-0.71; Range 2.0 to 4.7, 95% CI [2.94, 3.66]) in the stressed mortise view group. Inter-rater reliability was excellent between all observers for medial clear space (ICC-0.88; CI [0.78, 0.94]).

Conclusions: Our results support the previous literature and allow us to advocate for ankle fractures with >5 mm medial clear space after external rotational stress to be considered unstable. Additionally, ankles with a medial clear space between 4 and 5 mm, instability should be considered only if lateral shift is > 2 mm on stress examination. Our data shows that no physiologically healthy ankles widened beyond these established cut-offs before or after the manual external rotation stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcot.2019.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823741PMC
October 2019

Inhibition of the key metabolic pathways, glycolysis and lipogenesis, of oral cancer by bitter melon extract.

Cell Commun Signal 2019 10 21;17(1):131. Epub 2019 Oct 21.

Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO, 63104, USA.

Background: Metabolic reprogramming is one of the hallmarks of cancer which favours rapid energy production, biosynthetic capabilities and therapy resistance. In our previous study, we showed bitter melon extract (BME) prevents carcinogen induced mouse oral cancer. RNA sequence analysis from mouse tongue revealed a significant modulation in "Metabolic Process" by altering glycolysis and lipid metabolic pathways in BME fed group as compared to cancer group. In present study, we evaluated the effect of BME on glycolysis and lipid metabolism pathways in human oral cancer cells.

Methods: Cal27 and JHU022 cells were treated with BME. RNA and protein expression were analysed for modulation of glycolytic and lipogenesis genes by quantitative real-time PCR, western blot analyses and immunofluorescence. Lactate and pyruvate level was determined by GC/MS. Extracellular acidification and glycolytic rate were measured using the Seahorse XF analyser. Shotgun lipidomics in Cal27 and JHU022 cell lines following BME treatment was performed by ESI/ MS. ROS was measured by FACS.

Results: Treatment with BME on oral cancer cell lines significantly reduced mRNA and protein expression levels of key glycolytic genes SLC2A1 (GLUT-1), PFKP, LDHA, PKM and PDK3. Pyruvate and lactate levels and glycolysis rate were reduced in oral cancer cells following BME treatment. In lipogenesis pathway, we observed a significant reduction of genes involves in fatty acid biogenesis, ACLY, ACC1 and FASN, at the mRNA and protein levels following BME treatment. Further, BME treatment significantly reduced phosphatidylcholine, phosphatidylethanolamine, and plasmenylethanolamine, and reduced iPLA2 activity. Additionally, BME treatment inhibited lipid raft marker flotillin expression and altered its subcellular localization. ER-stress associated CHOP expression and generation of mitochondrial reactive oxygen species were induced by BME, which facilitated apoptosis.

Conclusion: Our study revealed that bitter melon extract inhibits glycolysis and lipid metabolism and induces ER and oxidative stress-mediated cell death in oral cancer. Thus, BME-mediated metabolic reprogramming of oral cancer cells will have important preventive and therapeutic implications along with conventional therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12964-019-0447-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802351PMC
October 2019

How else can we approach prostate cancer biomarker discovery?

Expert Rev Mol Diagn 2020 02 10;20(2):123-125. Epub 2019 Sep 10.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14737159.2019.1665507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035159PMC
February 2020

The Effect of Sex on Orthopaedic Surgeon Income.

J Bone Joint Surg Am 2019 Sep;101(17):e87

Department of Orthopaedics, Rutgers New Jersey Medical School, Newark, New Jersey.

Background: Several studies have identified discrepancies in salary between male and female surgeons. Our aim was to investigate the impact of sex on an orthopaedic surgeon's yearly earnings by evaluating stratified income and specialty data from a large sample survey of orthopaedic surgeons.

Methods: Self-reported data were obtained from the 2014 and 2008 American Academy of Orthopaedic Surgeons (AAOS) biennial censuses. Responses were received from 6,805 (24.26%) of those who were surveyed. The census form is a 19-question survey that includes information regarding work status (full time versus part time), sex, years in practice, practice type (private versus academic), specialty, hours worked, case volume, and income. The main outcome evaluated was self-reported income, and a multivariate regression model was used to control for confounding variables.

Results: Male surgeons reported higher incomes than female colleagues working equivalent hours ($802,474 versus $560,618; p = 0.016); however, male surgeons reported a greater case volume for the same number of hours. Among surgeons who performed ≥26 procedures per month, male and female surgeons reported comparable incomes ($949,508 versus $872,903; p = 0.649). Incomes of those in practice for >20 years also were comparable. Regression analysis controlling for subspecialty choice, hours worked, work status, case volume, years in practice, and practice setting revealed that income was $62,032.51 less for women than men (p < 0.001).

Conclusions: Income disparity between male and female orthopaedic surgeons remains significant, and the gap increased from 2008 to 2014. Although subspecialty choice, practice setting, years in practice, and amount and distribution of procedures performed can partially explain salary differences, our regression analysis suggests persistence of an income gap based on sex in orthopaedic surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2106/JBJS.18.01247DOI Listing
September 2019

Diagnostic Performance of Prostate Multiparametric Magnetic Resonance Imaging in African-American Men.

Urology 2019 Dec 13;134:181-185. Epub 2019 Aug 13.

Washington University School of Medicine, St. Louis, MO.

Objective: To compare test performance of multiparametric magnetic resonance imaging (mpMRI) for detection of prostate cancer (PCa) in African-American men (AAM) and white men (WM) using the Prostate Imaging Reporting and Data System in unmatched groups as well as a cohort matched for clinical factors.

Methods: We examined our database of men who underwent prostate mpMRI prior to biopsy between October 2014 and June 2017 (n = 601; 60 AAM, 541 WM). Test performance was defined using Prostate Imaging Reporting and Data System classification 4 or 5 considered test positive and Gleason grade group 2 or greater from any biopsy core considered outcome positive. A subset analysis was performed using a propensity score caliper matching algorithm to match AAM to WM in a 1:2 ratio using the variables age, PSA, and PSA density.

Results: No significant differences in test performance were found with similar sensitivity (86.7% vs 83.6, P = 1.00), specificity (45.9% vs 49.1%, P = .71), positive predictive value (50.0% vs 46.9%), and negative predictive value (85.0% vs 84.8%, P = 1.00) for AAM and WM. Similar results were noted in our matched comparison. The rate of upgrading between targeted and systematic biopsy cores did not statistically differ between AAM and WM in both unmatched (12.2% vs. 15.8%, P = .66) and matched (12.2% vs 12.8%, P = .92) comparisons.

Conclusion: Our findings provide supporting evidence that AAM have similar outcomes to WM in PCa detection using mpMRI. We suggest that mpMRI should not be withheld or offered preferentially on the basis of race when used for the detection of PCa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2019.08.007DOI Listing
December 2019

Current Status of MRI and PET in the NCCN Guidelines for Prostate Cancer.

J Natl Compr Canc Netw 2019 05;17(5):506-513

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.

Prostate cancer (PCa) represents a significant source of morbidity and mortality for men in the United States, with approximately 1 in 9 being diagnosed with PCa in their lifetime. The role of imaging in the evaluation of men with PCa has evolved and currently plays a central role in diagnosis, treatment planning, and evaluation of recurrence. Appropriate use of multiparametric MRI (mpMRI) and MRI-guided transrectal ultrasound (MR-TRUS) biopsy increases the detection of clinically significant PCa while decreasing the detection of clinically insignificant PCa. This process may help patients with clinically insignificant PCa avoid the adverse effects of unnecessary therapy. In the setting of a known PCa, patients with low-grade disease can be observed using active surveillance, which often includes a combination of prostate-specific antigen (PSA) testing, serial mpMRI, and, if indicated, follow-up systematic and targeted TRUS-guided tissue sampling. mpMRI can provide important information in the posttreatment setting, but PET/CT is creating a paradigm shift in imaging standards for patients with locally recurrent and metastatic PCa. This article examines the strengths and limitations of mpMRI for initial PCa diagnosis, active surveillance, recurrent disease evaluation, and image-guided biopsies, and the use of PET/CT imaging in men with recurrent PCa. The goal of this review is to provide a rational basis for current NCCN Clinical Practice Guidelines in Oncology for PCa as they pertain to the use of these advanced imaging modalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2019.7306DOI Listing
May 2019

Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2019 05;17(5):479-505

Stanford Cancer Institute.

The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2019.0023DOI Listing
May 2019

Reconstruction with Custom Unicondylar Hemiarthroplasty following Tumor Resection: A Case Series and Review of the Literature.

J Knee Surg 2020 Aug 8;33(8):818-824. Epub 2019 May 8.

Department of Orthopaedics, Rutgers New Jersey Medical School, Newark, New Jersey.

For patients with tumors of the distal femur, options for limb salvage include tumor resection followed by reconstruction. While reconstruction commonly involves a distal femoral replacement, careful selection of patients with tumor involvement limited to a single condyle may be candidates for reconstruction with distal femur hemiarthroplasty. In these procedures, resection spares considerably more native anatomy. Three consecutive patients who underwent resection and reconstruction at the distal femur with custom unicondylar hemiarthroplasty are presented in this case series at a mean follow-up of 45 months (range, 26-78). In two cases, prostheses were utilized as a secondary procedure after failure of initial reconstruction. In one case, the custom prosthesis was utilized as the primary method of reconstruction. Mean Musculoskeletal Tumor Society disease-specific scores were 26.7 (range, 25-28). All patients achieved a return to full weight bearing, activities of daily living, and functional range of motion. In appropriately selected patients with tumors of the distal femur, reconstruction with custom unicondylar hemiarthroplasty provides benefits including optimal function postoperatively via preservation of tumor-free bone and ligamentous structures. Additionally, maintenance of greater bone stock may confer benefits to patients with pathology at a high likelihood for recurrence and need for subsequent procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-1688556DOI Listing
August 2020