tbuckley/cabot-search huggingface dataset:
Rate and Predictors of Finding Monoclonal Gammopathy of Renal Significance (MGRS) Lesions on Kidney Biopsy in Patients with Monoclonal Gammopathy
Authors: Nattawat Klomjit, Nelson Leung, Fernando Fervenza, Sanjeev Sethi, Ladan Zand
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement It is not known how frequently a kidney biopsy specimen reveals monoclonal gammopathy (MG) of renal significance (MGRS) in patients with MG or what factors predict this finding. In a review of medical records of 6300 patients with MG, the authors found that only 160 (2.5%) had a biopsy. Of those, 96 (60%) had lesions unrelated to MG, with arteriosclerosis and diabetic nephropathy accounting for most cases. Among 64 patients with MGRS, amyloid light chain amyloidosis and proliferative GN with monoclonal Ig deposition were the most common lesions. An elevated serum free light chain ratio, proteinuria ≥1.5 g/d, and hematuria were the strongest independent predictors of finding MGRS on biopsy specimens. These findings will assist nephrologists in determining which patients with MG and CKD would be at high risk of having MGRS. Background Little is known about the rate and predictors of finding lesions of monoclonal gammopathy (MG) of renal significance (MGRS) on kidney biopsy specimens among patients with MG. Methods We reviewed the medical records from 2013 to 2018 at the Mayo Clinic in Rochester, Minnesota, to identify patients with MG and whether they had undergone a kidney biopsy. In a more select group of patients with MG from 2017 to 2018, we conducted a review of records to determine how many had underlying CKD, which of those with CKD had undergone a kidney biopsy, and reasons for deferring a kidney biopsy. Results Between 2013 and 2018, we identified 6300 patients who had MG, 160 (2.5%) of whom had undergone a kidney biopsy. Of the 160 patients, 64 (40%) had an MGRS lesion; amyloid light chain amyloidosis, the most common finding, accounted for nearly half of these lesions. In the non-MGRS group comprising 96 patients, 23 had arteriosclerosis, the most common finding. In multivariate analysis, strong predictors of finding an MGRS lesion included the presence of an elevated free light chain ratio, proteinuria, and hematuria. Among 596 patients with CKD and MG from 2017 to 2018, 62 (10.4%) underwent a kidney biopsy. Kidney biopsy was deferred for 70 patients (20%); for 62 of the 70, the diagnosis was already known, and eight were not candidates for therapy. Younger age and higher proteinuria and serum creatinine levels increased the likelihood that the patient would undergo a kidney biopsy. Conclusions Proteinuria ≥1.5 g/d, hematuria, and an elevated free light chain ratio increase the likelihood of finding MGRS, and a kidney biopsy should be highly considered in such patients.
Abstract B19: Identification of physiologically relevant EWS-FLI1 target genes in Ewing’s sarcoma via CRISPRa screening
Authors: Vadim Saratov, Qui A. Ngo, Gloria Pedot, Felix K. Niggli, Beat W. Schaefer
Journal: Cancer Research (2020)

Abstract Ewing’s sarcoma is an aggressive pediatric bone and soft-tissue cancer with a pathognomonic chromosomal translocation t(11;22) resulting in expression of EWS-FLI1, an “undruggable” fusion protein acting as a transcriptional modulator. Identification and ranking of repressed EWS-FLI1 target genes essential for cancer cell survival will potentially provide much-needed insights to develop novel therapeutic strategies. We performed a CRISPR activation (CRISPRa) dropout screen in Ewing cells. We generated a clonal SKNMC cell line homogenously expressing the synergistic activation mediator (SAM) CRISPRa system to functionally interrogate repressed EWS-FLI1 target genes. The systems functionality was tested using CD44, a surface marker absent on the surface of Ewing cells. We found robust and stable expression of CD44 after introduction of promoter-targeting gRNAs. The library of repressed EWS-FLI1 target genes, named LIBerty, was constructed to target 872 genes bioinformatically selected from publicly available silenced EWS-FLI1 RNA-Seq datasets as well as genes identified as repressed signature genes in Ewing’s sarcoma via meta-analysis with 3,777 unique guideRNAs. LIBerty was lentivirally delivered into SAM SKNMC cells and data from four biologic replicates were gathered at three time points: three, ten, and 21 days after infection. Cells were harvested and samples were prepared for next-generation sequencing (NGS) via PCR. The NGS data were evaluated with the analysis tool PinAPL-Py. Preliminary analysis of the screen revealed efficient selection of the positive control genes BAD and BBC3. In addition, high-ranking hits included CDKN1A and CDKN1C, both cell cycle regulators and known tumor-suppressor genes. Furthermore, we identified PCDH7 and TGFBR2, two genes already known from the literature to play a role in Ewing’s sarcoma. The presence of validated genes amid highest-ranking candidates confirms robustness of the conducted CRISPRa screen. Further analysis and validation of previously unexplored targets and pathways is currently ongoing. Our CRISPRa screen revealed both known as well as previously unknown EWS-FLI1 repressed genes whose absence of function is essential for tumor cell survival. Citation Format: Vadim Saratov, Qui A. Ngo, Gloria Pedot, Felix K. Niggli, Beat W. Schaefer. Identification of physiologically relevant EWS-FLI1 target genes in Ewing’s sarcoma via CRISPRa screening [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B19.
Development of a rat model of simultaneous mammary and ovarian cancer: Expression of putative early markers of cancer risk and progression
Authors: Brian K. Petroff, Ossama Tawfik, Steve L. Gum, Anna Nynca, Kelli E. Valdez, Bruce F. Kimler, Carol J. Fabian
Journal: Cancer Research (2005)

6075  Although most women at increased risk for breast cancer are also at increased risk for ovarian cancer, preventive agents that decrease the risk for one disease may increase risk for the other (e.g. oral contraceptives). An animal model with simultaneous preneoplastic changes in both the mammary glands and ovaries to allow preclinical testing has yet to be developed. To address this need, we tested combinations of existing rat models of mammary and ovarian cancer. In the current study, Fisher 344 rats were hemiovariectomized and the remaining ovary was treated locally with vehicle or dimethylbenzanthacene (DMBA) to initiate ovarian neoplasia. Rats were then treated systemically with vehicle, DMBA (10 mg/kg p.o.), methynitrosourea (MNU, 50 mg/kg i.p.) or a sustained release implant containing estradiol-17β (E2, 3 mg) as mammary carcinogen resulting in four treatment combinations. These combinations were 1) vehicle (local ovarian)/vehicle (systemic), 2) DMBA/DMBA, 3) DMBA/MNU and 4) DMBA/E2, respectively. Rats from each group (n=6) were sacrificed at 3 and 6 months post-treatment and ovarian and mammary tissues examined (total = 48 animals). Ovarian DMBA and systemic E2 treatment was associated with aberrant ovarian follicular morphology by 3 months post-treatment and cystic or glandular epithelial changes in 40% of rats by 6 months. The DMBA/E2 group developed marked mammary hyperplasia by 3 months post-treatment. Additional pathologic changes varying from dysplastic foci, to ductal carcinoma in situ and invasive adenocarcinoma were noted in mammary tissue following treatment with DMBA/E2 for 6 months. Vehicle controls exhibited no preneoplastic changes in ovarian or mammary tissue. These preliminary data suggest that the combination of local ovarian DMBA and systemic estradiol supplementation provides simultaneous ovarian and mammary carcinogenesis with early changes mimicking human disease. This work was supported in part by the University of Alabama-Birmingham SPORE in Breast Cancer (5P50CA89019).
Landscape of G-quadruplex DNA structural regions in breast cancer
Authors: Robert Hänsel-Hertsch, Angela Simeone, Abigail Shea, Winnie W. I. Hui, Katherine G. Zyner, Giovanni Marsico, Oscar M. Rueda, Alejandra Bruna, Alistair Martin, Xiaoyun Zhang, Santosh Adhikari, David Tannahill, Carlos Caldas, Shankar Balasubramanian
Journal: Nature Genetics (2020)
Prevalence of Health Care Worker Burnout During the Coronavirus Disease 2019 (COVID-19) Pandemic in Japan
Authors: Takahiro Matsuo, Daiki Kobayashi, Fumika Taki, Fumie Sakamoto, Yuki Uehara, Nobuyoshi Mori, Tsuguya Fukui
Journal: JAMA Network Open (2020)

The coronavirus disease 2019 (COVID-19) pandemic has placed considerable psychological strain on frontline health care workers (HCWs).1 Although the problem of burnout, which overlaps with the symptoms of depression,2 remains urgent, few studies have addressed it comprehensively. The objective of this study was to evaluate the prevalence of burnout among frontline HCWs during the COVID-19 pandemic in Japan based on job categories and other factors.
Protein phosphatase 2A B55β limits CD8+ T cell lifespan following cytokine withdrawal
Authors: Noé Rodríguez-Rodríguez, Iris K. Madera-Salcedo, J. Alejandro Cisneros-Segura, H. Benjamín García-González, Sokratis A. Apostolidis, Abril Saint-Martin, Marcela Esquivel-Velázquez, Tran Nguyen, Dámaris P. Romero-Rodríguez, George C. Tsokos, Jorge Alcocer-Varela, Florencia Rosetti, José C. Crispín
Journal: Journal of Clinical Investigation (2020)

How T cells integrate environmental cues into signals that limit the magnitude and length of immune responses is poorly understood. Here, we provide data that demonstrate that B55β, a regulatory subunit of protein phosphatase 2A, represents a molecular link between cytokine concentration and apoptosis in activated CD8+ T cells. Through the modulation of AKT, B55β induced the expression of the proapoptotic molecule Hrk in response to cytokine withdrawal. Accordingly, B55β and Hrk were both required for in vivo and in vitro contraction of activated CD8+ lymphocytes. We show that this process plays a role during clonal contraction, establishment of immune memory, and preservation of peripheral tolerance. This regulatory pathway may represent an unexplored opportunity to end unwanted immune responses or to promote immune memory.
3D Bioprinting: 3D Bioprinting of Oxygenated Cell‐Laden Gelatin Methacryloyl Constructs (Adv. Healthcare Mater. 15/2020)
Authors: Ahmet Erdem, Mohammad Ali Darabi, Rohollah Nasiri, Sivakoti Sangabathuni, Yavuz Nuri Ertas, Halima Alem, Vahid Hosseini, Amir Shamloo, Ali S. Nasr, Samad Ahadian, Mehmet R. Dokmeci, Ali Khademhosseini, Nureddin Ashammakhi
Journal: Advanced Healthcare Materials (2020)
Reply to van den Berg and van der Hoeven: In Patients with ARDS, Optimal PEEP Should Not Be Determined Using the Intersection of Relative Collapse and Relative Overdistention
Authors: Philip van der Zee, Peter Somhorst, Henrik Endeman, Diederik Gommers
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

With great interest, we read the article by van der Zee and colleagues suggesting an individualized approach for setting the correct amount of positive end-expiratory pressure (PEEP) in ventilated patients with coronavirus disease (COVID-19) (1).In their cohort of 15 mechanically ventilated patients with COVID-19, they used electrical impedance tomography to study the relative overdistention and relative collapse curves.The authors state that optimal PEEP for these patients is at the intersection of these curves and close to the values suggested in the high PEEP/FI O 2 table.This intersection has indeed been used to set optimal PEEP but only for mechanical ventilation during surgery (2).Using the intersection of relative collapse and relative overdistention suggests that both phenomena are equally harmful for patients with acute respiratory distress syndrome.Unfortunately, there is no evidence in the literature that supports this assumption.In fact, several studies and reviews suggest the opposite: overdistention may be more harmful (3-5).We fully agree with the authors that an individualized approach for mechanical ventilation for patients with COVID-19 (or any form of acute respiratory distress syndrome for that matter) is very important.But instead of recruitment of the lung with high PEEP, prone positioning with lower PEEP levels could be considered to improve oxygenation and to recruit parts of the lung.In 14 patients admitted to our ICU, we have shown that using more PEEP often leads to reduction in lung compliance and increase in dead space ventilation, which suggests overdistention of alveoli (6).In conclusion, although atelectrauma decreases with higher levels of PEEP, hyperinflation increases, which is potentially even more harmful.Therefore, using the intersection of the relative overdistention and relative collapse with electrical impedance tomography in patients with COVID-19 is not the technique to determine optimal PEEP for the individual patient.What van der Zee and colleagues do very elegantly show us with their research, however, is that there is always a tradeoff with higher levels of PEEP.
Care Churn — Why Keeping Clinic Doors Open Isn’t Enough to Ensure Access to Abortion
Authors: Michelle L. McGowan, Alison H. Norris, Danielle Bessett
Journal: New England Journal of Medicine (2020)

Restrictions and nonregulatory factors may cause fluctuations in the availability of abortion services, even when clinics remain open continuously. Such shifts are highly disruptive for clinics, create barriers for patients seeking abortions, and can be disorienting.
Abstract B68: Spatial and temporal conditions for Smarcb1 deletion determines mouse AT/RT (atypical teratoid/rhabdoid tumor) subtype
Authors: Zhi-Yan Han, Mamy Andrianteranagna, Maria Jesus-Lobon-Iglesias, Arnault Tauziède-Espariat, Kevin Beccaria, Paul Fréneaux, Joshua J. Waterfall, Julien Masliah-Planchon, Christine Bourneix, Gaelle Pierron, Amaury Leruste, Céline Chauvin, Didier Surdez, Pascale Varlet, Christelle Dufour, Olivier Delattre, Volodia Dangouloff-Ros, Franck Bourdeaut
Journal: Cancer Research (2020)

Abstract The cell(s) of origin of AT/RTs remain(s) unknown. We previously developed a mouse model consisting of tamoxifen inducible system in a Smarcb1Flox/Flox;Rosa26-CreERT2 background. We obtained two molecular subgroups of intracranial tumors, one with neuronal and the other with non-neuronal features, consistent with the diversity observed in human AT/RTs. To investigate the potential cell(s) of origin of these various AT/RTs, we first explored whether different time points of Smarcb1 inactivation correlated with anatomic location and/or molecular subgroups. We observed that the neuronal group, primarily developing from the subventricular zone and the spinal cord, was almost exclusively obtained with the earliest inactivation time points (E6-E7). In contrast, the non-neuronal group emerged upon Smarcb1 inactivation at any time point (E6-E10) and showed intracranial but extra-parenchymal/meningeal origins. High-resolution analysis of anatomic distribution of 55 human AT/RT and molecular subgroups is in progress. In order to more specifically identify the cell(s) of origin for the neuronal group, we next generated developmental stage-specific conditional knockout mice carrying Smarcb1 inactivation by restricting Cre expression with promoters characteristic for various neural stem cells/progenitors. While Smarcb1Flox/Flox;Atoh1CreERT2 showed ataxia but failed to give rise to any tumor at any embryonal time point, Smarcb1Flox/Flox;Ascl1CreERT2 did not show any phenotype. Targeting Nestin-expressing cells led to tumors with morphologic rhabdoid features; these tumors again showed molecular diversity as observed in human AT/RTs. In conclusion, we show that deletion of Smarcb1 determines mouse AT/RT subtypes depending on spatial and temporal factors. Our new mouse models not only give insight into the cell(s) of origin, but also provide interesting preclinical models of AT/RTs. Citation Format: Zhi-Yan Han, Mamy Andrianteranagna, Maria Jesus-Lobon-Iglesias, Arnault Tauziède-Espariat, Kevin Beccaria, Paul Fréneaux, Joshua J. Waterfall, Julien Masliah-Planchon, Christine Bourneix, Gaelle Pierron, Amaury Leruste, Céline Chauvin, Didier Surdez, Pascale Varlet, Christelle Dufour, Olivier Delattre, Volodia Dangouloff-Ros, Franck Bourdeaut. Spatial and temporal conditions for Smarcb1 deletion determines mouse AT/RT (atypical teratoid/rhabdoid tumor) subtype [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B68.
Abstract B49: Modeling a pathogenic <i>SAMD9</i> mutation in human induced pluripotent stem cells
Authors: Jason R. Schwartz, Jon P. Connelly, Shondra M. Pruett-Miller, Jeffery M. Klco
Journal: Cancer Research (2020)

Abstract Germline mutations in SAMD9 are the molecular determinants of some pedigrees with familial monosomy 7 and myelodysplastic syndrome (MDS) (OMIM 252270), MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy), and other nonsyndromic pediatric MDS. Mutations identified thus far have been associated with decreased growth of hematopoietic stem and progenitor cells (HSPCs) and bone marrow hypocellularity. Previous studies suggest that the wild-type function of SAMD9 is growth restrictive; therefore, the mutations identified in pediatric MDS have been deemed gain-of-function (GoF), given the exaggerated antiproliferative phenotype demonstrated in overexpression systems within nonhematopoietic cell lines, most commonly HEK-293T. To date, no model systems are available to study the impact of these mutations in their endogenous locus, a locus known to be induced by inflammatory stimuli, namely interferon (IFN). Here we report our development, using CRISPR/Cas9 genomic engineering, of two separate isogenic human induced pluripotent stem cell (iPSC) lines, derived from a non-neoplastic iPSC line (BJFF.6), containing a known pathogenic SAMD9 mutation (c.3406G&amp;gt;C; p.E1136Q), which we previously identified in a family with monosomy 7 and MDS. From this mutated iPSC line we are able to successfully differentiate hematopoietic precursors and myeloid cells that contain a pathogenic SAMD9 mutation. Using our novel pediatric MDS model system, we demonstrate that in the presence of IFN, viability of HSPCs (CD34+) and differentiated myeloid cells (CD13+) is significantly decreased when the SAMD9 p.E1136Q mutation is present (CD34+; WT=16.7% vs Mut=11.5% (p=0.05), CD13+; WT=22.6% vs. Mut=3.5% (p&amp;lt;0.0001)). Furthermore, we show that the genomically engineered SAMD9 locus of our iPSC-derived CD34+ and CD13+ cells remains robustly responsive to IFN stimulation. The basal level of SAMD9 expression is higher in differentiated myeloid cells than in HSPCs, a finding consistent with expression levels within normal hematopoiesis. These data suggest that we have a SAMD9 mutant pediatric MDS model system that provides a plentiful source of cells in which the effect of specific mutations on hematopoietic differentiation, proliferation, and viability may be investigated. Citation Format: Jason R. Schwartz, Jon P. Connelly, Shondra M. Pruett-Miller, Jeffery M. Klco. Modeling a pathogenic SAMD9 mutation in human induced pluripotent stem cells [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B49.
The Utility of Perforated Appendix Rate as a Proxy for Timely Access to Care—Reply
Authors: Frederick Thurston Drake, Reece A. Golz, Sabrina E. Sanchez
Journal: JAMA Surgery (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Patient and Plan Spending after State Specialty-Drug Out-of-Pocket Spending Caps
Authors: Kai Yeung, Douglas Barthold, Stacie B. Dusetzina, Anirban Basu
Journal: New England Journal of Medicine (2020)

Specialty drugs are used to treat complex or life-threatening conditions, often at high financial costs to both patients and health plans. Three states - Delaware, Louisiana, and Maryland - passed legislation to cap out-of-pocket payments for specialty drugs at $150 per prescription. A concern is that these caps could shift costs to health plans, increasing insurance premiums. Estimates of the effect of the caps on patient and health-plan spending could inform future policies.We analyzed a sample that included 27,161 persons under 65 years of age who had rheumatoid arthritis, multiple sclerosis, hepatitis C, psoriasis, psoriatic arthritis, Crohn's disease, or ulcerative colitis and who were in commercial health plans from 2011 through 2016 that were administered by three large nationwide insurers. The primary outcome was the change in out-of-pocket spending among specialty-drug users who were in the 95th percentile for spending on specialty drugs. Other outcomes were changes in mean out-of-pocket and health-plan spending for specialty drugs, nonspecialty drugs, and nondrug health care and utilization of specialty drugs. We compared outcomes in the three states that enacted caps with neighboring control states that did not, 3 years before and up to 3 years after enactment of the spending cap.Caps were associated with an adjusted change in out-of-pocket costs of -$351 (95% confidence interval, -554 to -148) per specialty-drug user per month, representing a 32% reduction in spending, among users in the 95th percentile of spending on specialty drugs. This finding was supported by multiple sensitivity analyses. Caps were not associated with changes in other outcomes.Caps for spending on specialty drugs were associated with substantial reductions in spending on specialty drugs among patients with the highest out-of-pocket costs, without detectable increases in health-plan spending, a proxy for future insurance premiums. (Funded by the Robert Wood Johnson Foundation Health Data for Action Program.).