Digital Commons Network^™

From Stigma To Validation: A Qualitative Assessment Of A Novel National Program To Improve Retention Of Physician-Scientists With Caregiving Responsibilities, Rochelle D. Jones, Victoria J. Fraser, Et Al.

Open Access Publications

No abstract provided.

Roles Of The Vagina And The Vaginal Microbiota In Urinary Tract Infection: Evidence From Clinical Correlations And Experimental Models, Amanda L Lewis, Nicole M Gilbert

Open Access Publications

Mounting evidence indicates that the vagina can harbor uropathogenic bacteria. Here, we consider three roles played by the vagina and its bacterial inhabitants in urinary tract infection (UTI) and urinary health. First, the vagina can serve as a reservoir for

Nanoscale Integrin Cluster Dynamics Controls Cellular Mechanosensing Via Faky397 Phosphorylation, Bo Cheng, Wanting Wan, Guoyou Huang, Yuhui Li, Guy M Genin, Mohammad R K Mofrad, Tian Jian Lu, Feng Xu, Min Lin

Open Access Publications

Transduction of extracellular matrix mechanics affects cell migration, proliferation, and differentiation. While this mechanotransduction is known to depend on the regulation of focal adhesion kinase phosphorylation on Y397 (FAKpY397), the mechanism remains elusive. To address this, we developed a mathematical model to test the hypothesis that FAKpY397-based mechanosensing arises from the dynamics of nanoscale integrin clustering, stiffness-dependent disassembly of integrin clusters, and FAKY397 phosphorylation within integrin clusters. Modeling results predicted that integrin clustering dynamics governs how cells convert substrate stiffness to FAKpY397, and hence governs how different cell types transduce mechanical signals. Existing experiments on MDCK cells and HT1080 cells, …

Pancreatic Triglyceride Lipase Mediates Lipotoxic Systemic Inflammation, Cristiane De Oliveira, Mark E Lowe, Et Al

Open Access Publications

Visceral adipose tissue plays a critical role in numerous diseases. Although imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self-limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ failure. Acute pancreatitis-associated adipose tissue had ongoing lipolysis in the absence of adipocyte triglyceride lipase (ATGL). Pancreatic lipase injected into mouse visceral adipose tissue hydrolyzed adipose triglyceride and generated excess nonesterified fatty acids (NEFAs), which caused organ failure in the absence …

Multiple Network Disconnection In Anosognosia For Hemiplegia, Elena Monai, Francesca Bernocchi, Marta Bisio, Antonio Luigi Bisogno, Alessandro Salvalaggio, Maurizio Corbetta

Open Access Publications

Anosognosia for hemiplegia (AHP) is a complex syndrome whose neural correlates are still under investigation. One hypothesis, mainly based on lesion mapping studies, is that AHP reflects a breakdown of neural systems of the right hemisphere involved in motor function. However, more recent theories have suggested that AHP may represent a disorder of cognitive systems involved in belief updating, self-referential or body processing. Two recent studies, using a method to estimate the degree of white matter disconnection from lesions, have indeed shown that patients with AHP suffer from damage of several long-range white matter pathways in association cortex. Here, we …

Development Of Volumetric Independent Dose Calculation System For Verification Of The Treatment Plan In Image-Guided Adaptive Brachytherapy, Sang-Won Kang, Jin-Beom Chung, Kyeong-Hyeon Kim, Ji-Yeon Park, Hae-Jin Park, Woong Cho, Sven Olberg, Tae Suk Suh, Justin C Park

Open Access Publications

No abstract provided.

Sequencing-Based Measurable Residual Disease Testing In Acute Myeloid Leukemia, Jennifer M Yoest, Cara Lunn Shirai, Eric J Duncavage

Open Access Publications

Next generation sequencing (NGS) methods have allowed for unprecedented genomic characterization of acute myeloid leukemia (AML) over the last several years. Further advances in NGS-based methods including error correction using unique molecular identifiers (UMIs) have more recently enabled the use of NGS-based measurable residual disease (MRD) detection. This review focuses on the use of NGS-based MRD detection in AML, including basic methodologies and clinical applications.

Dopamine Buffering Capacity Imaging: A Pharmacodynamic Fmri Method For Staging Parkinson Disease, Kevin J Black, Haley K Acevedo, Jonathan M Koller

Open Access Publications

We propose a novel pharmacological fMRI (phMRI) method for objectively quantifying disease severity in Parkinson disease (PD). It is based on the clinical observation that the benefit from a dose of levodopa wears off more quickly as PD progresses. Biologically this has been thought to represent decreased buffering capacity for dopamine as nigrostriatal cells die. Buffering capacity has been modeled based on clinical effects, but clinical measurements are influenced by confounding factors. The new method proposes to measure the effect objectively based on the timing of the known response of several brain regions to exogenous levodopa. Such responses are robust …

Positive Allosteric Modulation Of Cd11b As A Novel Therapeutic Strategy Against Lung Cancer, Terese Geraghty, Anugraha Rajagopalan, Rabail Aslam, Alexander Pohlman, Ishwarya Venkatesh, Andrew Zloza, David Cimbaluk, David G Denardo, Vineet Gupta

Open Access Publications

Lung cancer is one of the leading causes of cancer-related deaths in the United States. A major hurdle for improved therapies is immune suppression mediated by the tumor and its microenvironment. The lung tumor microenvironment (TME) contains large numbers of tumor-associated macrophages (TAMs), which suppress the adaptive immune response, increase neo-vascularization of the tumor, and provide pro-tumor factors to promote tumor growth. CD11b is highly expressed on myeloid cells, including TAMs, where it forms a heterodimeric integrin receptor with CD18 (known as CD11b/CD18, Mac-1, CR3, and αMβ2), and plays an important role in recruitment and biological functions of these cells, …

The Role Of Ct-Quantified Body Composition On Longitudinal Health-Related Quality Of Life In Colorectal Cancer Patients: The Colocare Study, Biljana Gigic, Graham A Colditz, Adetunji T Toriola, Et Al

Open Access Publications

BACKGROUND: Obesity, defined by body mass index (BMI), measured at colorectal cancer (CRC) diagnosis has been associated with postoperative complications and survival outcomes. However, BMI does not allow for a differentiation between fat and muscle mass. Computed tomography (CT)-defined body composition more accurately reflects different types of tissue and their associations with health-related quality of life (HRQoL) during the first year of disease, but this has not been investigated yet. We studied the role of visceral and subcutaneous fat area (VFA and SFA) and skeletal muscle mass (SMM) on longitudinally assessed HRQoL in CRC patients.

METHODS: A total of 138 …

Matriptase Cleaves Epcam And Trop2 In Keratinocytes, Destabilizing Both Proteins And Associated Claudins, Chuan-Jin Wu, Michael Lu, Xu Feng, Gaku Nakato, Mark C Udey

Open Access Publications

The homologs EpCAM and TROP2, which both interact with claudin-1 and claudin-7, are frequently coexpressed in epithelia including skin. Intestine uniquely expresses high levels of EpCAM but not TROP2. We previously identified EpCAM as a substrate of the membrane-anchored protease matriptase and linked HAI-2, matriptase, EpCAM and claudin-7 in a pathway that is pivotal for intestinal epithelial cells (IEC) homeostasis. Herein, we reveal that TROP2 is also a matriptase substrate. Matriptase cleaved TROP2 when purified recombinant proteins were mixed in vitro. TROP2, like EpCAM, was also cleaved after co-transfection of matriptase in 293T cells. Neither EpCAM nor TROP2 cleavage was …

Development And Evaluation Of Machine Learning Models For Voxel Dose Predictions In Online Adaptive Magnetic Resonance Guided Radiation Therapy, M Allan Thomas, Yabo Fu, Deshan Yang

Open Access Publications

PURPOSE: Daily online adaptive plan quality in magnetic resonance imaging guided radiation therapy (MRgRT) is difficult to assess in relation to the fully optimized, high quality plans traditionally established offline. Machine learning prediction models developed in this work are capable of predicting 3D dose distributions, enabling the evaluation of online adaptive plan quality to better inform adaptive decision-making in MRgRT.

METHODS: Artificial neural networks predicted 3D dose distributions from input variables related to patient anatomy, geometry, and target/organ-at-risk relationships in over 300 treatment plans from 53 patients receiving adaptive, linac-based MRgRT for abdominal cancers. The models do not include any …

Structural Mechanism For Gating Of A Eukaryotic Mechanosensitive Channel Of Small Conductance, Zengqin Deng, Grigory Maksaev, Angela M. Schlegel, Jingying Zhang, Michael Rau, James A. J. Fitzpatrick, Elizabeth S. Haswell, Peng Yuan

Open Access Publications

No abstract provided.

Tumor Burden, Inflammation, And Product Attributes Determine Outcomes Of Axicabtagene Ciloleucel In Large B-Cell Lymphoma, Frederick L. Locke, Armin Ghobadi, Et Al.

Open Access Publications

No abstract provided.

Enhanced Recovery With Paravertebral And Transversus Abdominis Plane Blocks In Microvascular Breast Reconstruction, Ryan Guffey, Grace Keane, Austin Y. Ha, Rajiv Parikh, Elizabeth Odom, Li Zhang, Terence M. Myckatyn

Open Access Publications

No abstract provided.

Association Of Radial Longitudinal Deficiency And Thumb Hypoplasia: An Update Using The Could Registry, Malka Forman, Maria F Canizares, Deborah Bohn, Michelle A James, Julie Samora, Suzanne Steinman, Lindley B Wall, Andrea S Bauer, Could Study Group

Open Access Publications

BACKGROUND: Deficiency of the radial aspect of the forearm and hand is the most common congenital longitudinal deficiency of the upper limb. Radial longitudinal deficiency is associated with several named syndromes. The purpose of the present study was to explore patterns of radial longitudinal deficiency and thumb hypoplasia in syndromes and to examine the severity of these differences across various syndromes.

METHODS: Data were collected from the Congenital Upper Limb Differences (CoULD) registry. Congenital differences are classified in the registry with use of the Oberg-Manske-Tonkin (OMT) classification system. Diagnosis of a syndrome by a physician as noted in the CoULD …

Using Digital Technology To Reduce The Prevalence Of Mental Health Disorders In Populations: Time For A New Approach, C Barr Taylor, Josef I Ruzek, Ellen E Fitzsimmons-Craft, Shiri Sadeh-Sharvit, Naira Topooco, Ruth Striegel Weissman, Daniel Eisenberg, David Mohr, Andrea Graham, Corinna Jacobi, Brian Oldenburg

Open Access Publications

Digital technology, which includes the collection, analysis, and use of data from a variety of digital devices, has the potential to reduce the prevalence of disorders and improve mental health in populations. Among the many advantages of digital technology is that it allows preventive and clinical interventions, both of which are needed to reduce the prevalence of mental health disorders, to be feasibly integrated into health care and community delivery systems and delivered at scale. However, the use of digital technology also presents several challenges, including how systems can manage and implement interventions in a rapidly changing digital environment and …

Canonical Signaling By Tgf Family Members In Mesenchymal Stromal Cells Is Dispensable For Hematopoietic Niche Maintenance Under Basal And Stress Conditions, Joseph Ryan Krambs, Grazia Abou Ezzi, Juo-Chin Yao, Daniel C. Link

Open Access Publications

Mesenchymal stromal cells are an important component of the bone marrow hematopoietic niche. Prior studies showed that signaling from members of the transforming growth factor (TGF) superfamily in mesenchymal stromal cells is required for normal niche development. Here, we assessed the impact of TGF family signaling on niche maintenance and stress responses by deleting Smad4 in mesenchymal stromal cells at birth, thereby abrogating canonical TGF signaling. No alteration in the number or spatial organization of CXCL12-abundant reticular (CAR) cells, osteoblasts, or adipocytes was observed in Osx-Cre, Smad4fl/fl mice, and expression of key niche factors was normal. Basal hematopoiesis and stress …

Diet-Induced Metabolic Dysregulation In Female Mice Causes Osteopenia In Adult Offspring, Yu Shi, Jessica L. Saben, Guangxu He, Kelle H. Moley, Fanxin Long

Open Access Publications

Bone mass and quality in humans are controlled by numerous genetic and environmental factors that are not fully understood. Increasing evidence has indicated that maternal metabolic dysregulation impairs multiple physiological processes in the adult offspring, but a similar effect on bone health is yet to be established. Here, we have analyzed the bones of first-generation offspring from murine dams that present metabolic syndrome due to a high-fat and high-sugar (HF/HS) diet. Micro-CT analyses show that the long bones of HF/HS offspring possess lower cortical bone mass and weaker mechanical strength than normal, even though the trabecular bone is not affected. …

Rev-Erb Agonism Improves Liver Pathology In A Mouse Model Of Nash, Kristine Griffett, Gonzalo Bedia-Diaz, Bahaa Elgendy, Thomas P. Burris

Open Access Publications

Non-alcoholic fatty liver disease (NAFLD) affects a significant number of people worldwide and currently there are no pharmacological treatments. NAFLD often presents with obesity, insulin resistance, and in some cases cardiovascular diseases. There is a clear need for treatment options to alleviate this disease since it often progresses to much more the much more severe non-alcoholic steatohepatitis (NASH). The REV-ERB nuclear receptor is a transcriptional repressor that regulates physiological processes involved in the development of NAFLD including lipogenesis and inflammation. We hypothesized that pharmacologically activating REV-ERB would suppress the progression of fatty liver in a mouse model of NASH. Using …

Functional Profiling Of Fsh And Estradiol In Ovarian Granulosa Cell Tumors, Ulla-Maija Haltia, Marjut Pihlajoki, Noora Andersson, Lotta Mäkinen, Johanna Tapper, Alejandra Cervera, Hugo M. Horlings, Ursula Turpeinen, Mikko Anttonen, Ralf Bützow, Leila Unkila-Kallio, Olli Carpén, David B. Wilson, Markku Heikinheimo, Anniina Färkkilä

Open Access Publications

Adult-type granulosa cell tumors (AGCTs) are sex-cord derived neoplasms with a propensity for late relapse. Hormonal modulators have been used empirically in the treatment of recurrent AGCT, albeit with limited success. To provide a more rigorous foundation for hormonal therapy in AGCT, we used a multimodal approach to characterize the expressions of key hormone biomarkers in 175 tumor specimens and 51 serum samples using RNA sequencing, immunohistochemistry, RNA

Human Ipsc-Derived Neuronal Cells From Ctbp1-Mutated Patients Reveal Altered Expression Of Neurodevelopmental Gene Networks, S Vijayalingam, Eric Tycksen, Christina A Gurnett, Et Al

Open Access Publications

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Meningioma: A Review Of Clinicopathological And Molecular Aspects, Kristin Huntoon, Angus Martin Shaw Toland, Sonika Dahiya

Open Access Publications

Meningiomas are the most the common primary brain tumors in adults, representing approximately a third of all intracranial neoplasms. They classically are found to be more common in females, with the exception of higher grades that have a predilection for males, and patients of older age. Meningiomas can also be seen as a spectrum of inherited syndromes such as neurofibromatosis 2 as well as ionizing radiation. In general, the 5-year survival for a WHO grade I meningioma exceeds 80%; however, survival is greatly reduced in anaplastic meningiomas. The standard of care for meningiomas in a surgically-accessible location is gross total …

Genomic Profiling Of Circulating Tumor Dna From Cerebrospinal Fluid To Guide Clinical Decision Making For Patients With Primary And Metastatic Brain Tumors, Lori A Ramkissoon, Sonika Dahiya, Et Al.

Open Access Publications

Despite advances in systemic therapies for solid tumors, the development of brain metastases remains a significant contributor to overall cancer mortality and requires improved methods for diagnosing and treating these lesions. Similarly, the prognosis for malignant primary brain tumors remains poor with little improvement in overall survival over the last several decades. In both primary and metastatic central nervous system (CNS) tumors, the challenge from a clinical perspective centers on detecting CNS dissemination early and understanding how CNS lesions differ from the primary tumor, in order to determine potential treatment strategies. Acquiring tissue from CNS tumors has historically been accomplished …

Protocol For A Proof-Of-Concept Observational Study Evaluating The Potential Utility And Acceptability Of A Telemedicine Solution For The Post-Anesthesia Care Unit, Thaddeus P Budelier, Christopher Ryan King, Shreya Goswami, Anchal Bansal, Stephen H Gregory, Troy S Wildes, Joanna Abraham, Sherry L Mckinnon, Amy Cooper, Ivan Kangrga, Jackie L Martin Jr., Melissa Milbrandt, Alex S Evers, Michael S Avidan

Open Access Publications

No abstract provided.

Hitting The Target: Natural History Of The Hip Based On Achieving An Acetabular Safe Zone Following Periacetabular Osteotomy, Cody C Wyles, Juan S Vargas, Mark J Heidenreich, Kristin C Mara, Christopher L Peters, John C Clohisy, Robert T Trousdale, Rafael J Sierra

Open Access Publications

BACKGROUND: Periacetabular osteotomy (PAO) remains the gold-standard treatment for acetabular dysplasia in skeletally mature patients with preserved cartilage. The purpose of this multicenter cohort study was to delineate the long-term radiographic natural history of the dysplastic hip following PAO based on the final position of the acetabular fragment.

METHODS: We evaluated patients who underwent PAO performed by 4 hip preservation surgeons to treat acetabular dysplasia with or without concomitant retroversion from 1996 to 2012 at 3 academic institutions. There were 288 patients with a mean clinical and radiographic follow-up of 9 years (range, 5 to 21 years). Postoperative radiographs made …

Surgical Treatment Of Femoroacetabular Impingement: Hip Arthroscopy Versus Surgical Hip Dislocation: A Propensity-Matched Analysis, Jeffrey J Nepple, Ira Zaltz, Christopher M Larson, Paul E Beaulé, Young-Jo Kim, Michael B Millis, Rafael J Sierra, John C Clohisy, Anchor Group

Open Access Publications

BACKGROUND: Surgical treatment of femoroacetabular impingement (FAI) continues to evolve and is most commonly approached with either hip arthroscopy (HA) or surgical dislocation (SD) of the hip. The purpose of this study was to compare the outcomes of similar patients undergoing surgical treatment of FAI with either HA or SD.

METHODS: A prospective multicenter cohort study of patients undergoing primary surgical treatment of FAI was performed. Follow-up at a minimum of 1 year (mean, 4.3 years) was available for 621 hips (81.7%), including 399 procedures with HA and 222 procedures with SD. Propensity scores were calculated and reflect the likelihood …

Understanding Patient Transfers Across Multiple Clinics In Zambia Among Hiv Infected Adults, Kombatende Sikombe, Aaloke Mody, Jillian Kadota, Jesse Jake Pry, Sandra Simbeza, Ingrid Eshun-Wilson, Sitali Richard Situmbeko, Chama Bukankala, Laura Beres, Njekwa Mukamba, Mwanza Wa Mwanza, Carolyn Bolton-Moore, Charles B. Holmes, Elvin H. Geng, Izukanji Sikazwe

Open Access Publications

Many patients in HIV care in Africa considered lost to follow up (LTFU) at one facility are reportedly accessing care in another. The success of these unofficial transfers as measured by time to re-entry at the new-facility, prevalence of treatment interruptions, speed of ART-initiation, and overall continuity of care is not well characterized but may reveal opportunities for improvement. We traced a random sample of LTFU HIV-infected patients in Zambia. Among those found alive and reported in care at a new-facility, we reviewed records at the receiving facility to verify transfer; and when verified, documented the transfer experience. We used …

The Herbivore's Dilemma: Trends In And Factors Associated With Heterosexual Relationship Status And Interest In Romantic Relationships Among Young Adults In Japan-Analysis Of National Surveys, 1987-2015, Cyrus Ghaznavi, Haruka Sakamoto, Shuhei Nomura, Anna Kubota, Daisuke Yoneoka, Kenji Shibuya, Peter Ueda

Open Access Publications

BACKGROUND: It has been suggested that an increasing proportion of young adults in Japan have lost interest in romantic relationships, a phenomenon termed "herbivorization". We assessed trends in heterosexual relationship status and self-reported interest in heterosexual romantic relationships in nationally representative data.

METHODS: We used data from seven rounds of the National Fertility Survey (1987-2015) and included adults aged 18-39 years (18-34 years in the 1987 survey; sample size 11,683-17,675). Current heterosexual relationship status (married; unmarried but in a relationship; single) was estimated by sex, age group and survey year, with singles further categorized into those reporting interest vs. no …

A Feasibility Study To Evaluate Early Treatment Response Of Brain Metastases One Week After Stereotactic Radiosurgery Using Perfusion Weighted Imaging, Jiayi Huang, Mikhail Milchenko, Yuan J. Rao, Pamela Lamontagne, Christopher Abraham, Clifford G. Robinson, Yi Huang, Joshua S. Shimony, Keith M. Rich, Tammie Benzinger

Open Access Publications

BACKGROUND: To explore if early perfusion-weighted magnetic resonance imaging (PWI) may be a promising imaging biomarker to predict local recurrence (LR) of brain metastases after stereotactic radiosurgery (SRS).

METHODS: This is a prospective pilot study of adult brain metastasis patients who were treated with SRS and imaged with PWI before and 1 week later. Relative cerebral blood volume (rCBV) parameter maps were calculated by normalizing to the mean value of the contralateral white matter on PWI. Cox regression was conducted to explore factors associated with time to LR, with Bonferroni adjusted p<0.0006 for multiple testing correction. LR rates were estimated with the Kaplan-Meier method and compared using the log-rank test.

RESULTS: Twenty-three patients were enrolled from 2013 through …