tbuckley/cabot-search huggingface dataset:
Marked efficacy of rituximab in two patients with Waldenstrom macroglobulinemia-like multiple myeloma.
Authors: Christoph J. Heuck, Saad Zafar Usmani, Erming Tian, Qing Zhang, Frits Van Rhee, Sarah Waheed, Bijay P. Nair, Nathan Petty, Xenofon Papanikolaou, John D. Shaughnessy, Bart Barlogie
Journal: Journal of Clinical Oncology (2012)

e18548 Background: Rituximab (R) has been deemed to be ineffective in multiple myeloma (MM), despite CD20 expression in 10-15% of MM. Here we report two cases, selected by a genomic approach, with an excellent response to single agent R. Methods: as below Results: Patient 1: A 49 yr old male with IgG lambda MM with 80% bone marrow (BM) plasma cells (PC) and IgG level of 23 g/L had been treated elsewhere with one cycle of CRD. Here, we noted CD-2 subclass by gene expression profilin (GEP), however without spiked expression of CCND1 and CCND3 genes as manifestation of a t[11:14] or a t[6:14]. GEP further revealed a del 6q and overexpression of EBI2, both commonly seen in Waldenstrom Macroglobulinemia (WM). All findings were confirmed by FISH. Unsupervised clustering in the context of MGUS, untreated MM and WM-PC, confirmed WM-like MM in this patient. Sole therapy with R (750 mg/m2/d x 5d, weekly x 4, bi-weekly x 4 and then monthly) resulted in a reduction of IgG from 1850 mg/dL to 950 mg/dl and BM PC from 60% to 10% at 9 months and a decrease in sLFLC from 68 mg/dL to 10 mg/dL at 12 months follow up. Patient 2: Based on the above observation, we identified a second patient. This 37-yr old male had been diagnosed with lambda light chain MM 42 months earlier with a BM PC of 15%, lambda light-chain proteinuria of 1.9 g/d and sLFLC in the 200mg/dL range. Because of absence of CRAB criteria, he was followed expectantly. Rising BM PC to 50% and concern for end-organ damage motivated a detailed examination of GEP data. GEP showed high expression of CD20 and EBI2 and absence of CCND1 and CCND3 spikes. This was confirmed by FISH, which also revealed a del 6q. As in the first case, this patient co-segregated with WM. R treatment on the same schedule resulted in a reduction of sLFLC levels from 249 mg/dL to 29.9 mg/dl and of Bence Jones proteinuria from 1766 mg/d to 242 mg/d. Conclusions: The presumed lack of activity of R in MM needs to be revisited in light of the marked response noted in these 2 patients. Studies are in progress (a) to extend R therapy to similar cases, and (b) to more fully characterize the prevalence of genetic/phenotypic characteristics, as seen in these 2 cases, among several thousand MM patients. This updated information will be presented at the meeting.
Fever, Diarrhea, and Weight Loss in a Man With Inflammatory Polyarthritis
Authors: Arjun R. Sondhi, Kevin D. Platt, Amit Gupta
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Active Surveillance for Black Men with Low-Risk Prostate Cancer in the United States
Authors: Bashir Al Hussein Al Awamlh, Xiaoyue Ma, Paul Christos, Jim C Hu, Jonathan E Shoag
Journal: New England Journal of Medicine (2019)

Surveillance for Black Men with Low-Risk Prostate Cancer in the United StatesTo the Editor: Active surveillance is considered to be appropriate treatment for men with lowrisk prostate cancer.An analysis of data from the Surveillance, Epidemiology, and End Results (SEER) program from 2015 showed that black men were less likely to undergo active surveillance than men of other races in the United States. 1 However, these data do not account for regional variation in care, despite evidence of substantial geographic variation in the management of localized prostate cancer. 2Therefore, we assessed whether racial disparities exist in the use of active surveillance for low-risk prostate cancer after adjustment for regional differences in care.We used the SEER Prostate with Watchful Waiting Database to characterize the use of competing treatments for localized low-risk prostate cancer (defined as a prostate-specific antigen [PSA] level of <10 ng per milliliter, a clinical stage of T1 to T2a, and a Gleason score of 6) among men according to race during the period from 2010 through 2015.Multivariable logistic-regression analyses were used to examine the independent effect of black race on the use of active surveillance, after adjustment for age, PSA level, number of positive biopsy cores, socioeconomic status, insurance type, and U.S. Census region.In an analysis that did not include socioeconomic status or insurance type, black men were less likely to undergo active surveillance (odds ratio, 0.94; 95% confidence interval [CI], 0.88 to 0.99).After adjustment for socioeconomic status and insurance type, the likelihood that black men would undergo active surveillance was similar to that of other races (odds ratio, 1.06; 95% CI, 1.00 to 1.12).When the U.S. Census
Perspectives From Patients and Gastroenterologists on De-escalating Therapy for Crohn’s Disease
Authors: Corey A. Siegel, Kimberly D. Thompson, Danielle Walls, Jan Gollins, Anne Buisson, Alain Olympie, Laurent Beaugerie, Jean-Frederic Colombel, Edouard Louis
Journal: Clinical Gastroenterology and Hepatology (2019)
Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors
Authors: Michael C Frühwald, Martin Hasselblatt, Karolina Nemes, Susanne Bens, Mona Steinbügl, Pascal D Johann, Kornelius Kerl, Peter Hauser, Eduardo Quiroga, Palma Solano-Paez, Veronica Biassoni, Maria Joao Gil-da-Costa, Martha Perek-Polnik, Marianne van de Wetering, David Sumerauer, Jane Pears, Niklas Stabell, Stefan Holm, Heinz Hengartner, Nicolas U Gerber, Michael Grotzer, Joachim Boos, Martin Ebinger, Stefan Tippelt, Werner Paulus, Rhoikos Furtwängler, Pablo Hernáiz-Driever, Harald Reinhard, Stefan Rutkowski, Paul-Gerhardt Schlegel, Irene Schmid, Rolf-Dieter Kortmann, Beate Timmermann, Monika Warmuth-Metz, Uwe Kordes, Joachim Gerss, Karsten Nysom, Reinhard Schneppenheim, Reiner Siebert, Marcel Kool, Norbert Graf
Journal: Neuro-Oncology (2019)

Abstract Background Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses. Methods Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009–2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors. Results Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ± 4.5% and 30.5 ± 4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age &amp;lt;1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P &amp;lt; 0.05). An adjusted multivariate model identified age &amp;lt;1 year and a non-TYR signature as independent negative predictors of OS: high risk (&amp;lt;1 y + non-TYR; 5-y OS = 0%), intermediate risk (&amp;lt;1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ± 8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ± 12.2%). Conclusions Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.
Гендерные особенности уровня маркеров воспаления кишечника у больных неспецифическим язвенным колитом
Authors: Yu.M. Stepanov, I.V. Psareva, A.M. Tatarchuk, M.V. Stoykevich, O.P. Petishko, E.V. Simonova
Journal: GASTROENTEROLOGY (2019)

Актуальность. Сегодня разработка и внедрение неинвазивных методов диагностики неспецифического язвенного колита являются актуальной задачей научного сообщества, решение которой позволит вовремя назначить адекватное лечение и улучшить качество жизни больных. Учитывая то, что различия между женщинами и мужчинами в параметрах, определяющих состояние здоровья, являются общепризнанными, целью работы стало определение гендерных особенностей уровня биологических маркеров воспаления кишечника у больных неспецифическим язвенным колитом. Материалы и методы. Обследованы 60 больных неспецифическим язвенным колитом, среди которых мужчин было 31 (51,7 %), женщин — 29 (48,3 %), средний возраст обследованных составил (40,28 ± 1,34) года. В группу сравнения вошли 20 пациентов с синдромом раздраженной кишки. Иммуноферментным методом с помощью анализатора StatFax 303 Plus (США) и тест-набора фирмы Immundiagnostik (Германия) определяли уровень фекальной миелопероксидазы и содержание α1-антитрипсина в сыворотке крови и кале, уровень фекального кальпротектина — тест-набором Bühlmann (Швейцария). Результаты. Фекальные миелопероксидаза и кальпротектин являются специфическими маркерами воспаления кишечника, что подтверждается установленными корреляционными связями между эндоскопической активностью воспаления кишечника и его содержимым: r = 0,632; р &lt; 0,05 и r = 0,532; р &lt; 0,05 соответственно. Концентрация α1-антитрипсина в кале мужчин в 3 раза превышает аналогичный показатель у женщин (р &lt; 0,05), а уровень α1-антитрипсина в крови, наоборот, выше у пациентов женского пола по сравнению с мужчинами (р &lt; 0,05). Обнаруженная корреляционная зависимость между содержанием α1-антитрипсина в кале и мужским полом (r = 0,528; р &lt; 0,05) свидетельствует о более высокой активности воспалительного процесса в толстой кишке у мужчин. Выводы. Гендерные различия уровня неинвазивных маркеров активности неспецифического язвенного колита следует учитывать при оценке клинической картины больных и для мониторинга эффективности их лечения.
Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function
Authors: Cameron S. Field, Francesc Baixauli, Ryan L. Kyle, Daniel J. Puleston, Alanna M. Cameron, David E. Sanin, Keli L. Hippen, Michael Loschi, Govindarajan Thangavelu, Mauro Corrado, Joy Edwards-Hicks, Katarzyna M. Grzes, Edward J. Pearce, Bruce R. Blazar, Erika L. Pearce
Journal: Cell Metabolism (2019)

Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate uptake and intracellular lipid trafficking. One family member, FABP5, is expressed in T cells, but its function remains unclear. We show that in Tregs, genetic or pharmacologic inhibition of FABP5 function causes mitochondrial changes underscored by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. FABP5 inhibition in Tregs triggers mtDNA release and consequent cGAS-STING-dependent type I IFN signaling, which induces heightened production of the regulatory cytokine IL-10 and promotes Treg suppressive activity. We find evidence of this pathway, along with correlative mitochondrial changes in tumor infiltrating Tregs, which may underlie enhanced immunosuppression in the tumor microenvironment. Together, our data reveal that FABP5 is a gatekeeper of mitochondrial integrity that modulates Treg function.
Genomic characterization and high-throughput therapeutic screening of malignant mesothelioma to reveal novel tumor dependencies.
Authors: Constantine Alifrangis, Josine Quispel Janssen, Hilda de Vries, Laurel Schunselaar, Graham Bignell, Mathew Garnett, Jacques Neefjes, Anton Berns, Paul Baas, Ultan McDermott
Journal: Journal of Clinical Oncology (2013)

7581 Background: Clinical trials of targeted therapeutics in mesothelioma have demonstrated limited efficacy. It has been suggested that combinations of targeted agents may be more effective in this disease, but given the unknown status of tractable oncogenic mutations it has been difficult to ascertain which key signalling nodes drive these tumours that may lend themselves to therapeutic intervention. We therefore aimed to characterise a representative panel of mesothelioma cell lines at the genomic level, and then determine critical “nodes” utilising a high throughput screen of targeted agents. Methods: 19 mesothelioma cell lines and 6 mesothelioma primary tumour early passage lines underwent Illumina whole exome sequencing and copy number analysis. In parallel a high throughput screen was performed utilising a panel of targeted therapeutics enabling each mesothelioma to be screened across 48 compounds. Efficacy was confirmed in 3D spheroid culture. Results: Exome sequencing of the mesothelioma panel revealed mutations in tumour suppressor genes previously described in mesothelioma including NF2, as well as previously unreported mutations in this disease affecting histone modifying genes MLL2 and SETD2. Notably an absence of mutated “driver” oncogenes was observed. High throughput screening demonstrated limited activity for most small molecule inhibitors as single agents. However, despite an absence of mutations in PIK3CAor related genes, PI3K/mTORC inhibition had the broadest single agent efficacy. Conclusions: We demonstrate that mutations in cell lines are similar to those found in patient-derived tumours implying fidelity at the genomic level. Mesotheliomas harbour multiple mutations in tumour suppressors, but lack commonly tractable oncogenic mutations which may explain poor efficacy seen in clinical trials to date. We further demonstrate that PI3K may represent a critical node therapeutically that may be useful in combinatorial approaches.
The impact of exposure to desert dust on infants’ symptoms and countermeasures to reduce the effects
Authors: Toshiko Itazawa, Kumiko T. Kanatani, Kei Hamazaki, Hidekuni Inadera, Akiko Tsuchida, Tomomi Tanaka, Takeo Nakayama, Tohshin Go, Kazunari Onishi, Yoichi Kurozawa, Yuichi Adachi
Journal: Allergy (2019)

The association between particulate matter (PM), including desert dust, and allergic symptoms has not been well studied. We examined whether PM exacerbated nose/eye/respiratory symptoms in infants, with a focus on the desert dust element, and assessed possible countermeasures.We conducted a panel study of 1492 infants from October 2014 to July 2016 in 3 regions in Japan as an adjunct study of the Japan Environment and Children's Study. Infants' daily symptom scores and behaviors were acquired by web-based questionnaires sent to mothers, who answered within a day using mobile phones. Odds ratios (OR) for symptom development per increased fine PM or desert dust exposure were estimated. Regular use of medications and behaviors on the day of exposure were investigated as possible effect modifiers.Infants developed nose/eye/respiratory symptoms significantly more often in accordance with fine particulate levels (adjusted OR per 10 µg/m3 increase: 1.04, 95% confidence interval [CI]: 1.01-1.07). A model including both fine particulates and desert dust showed reduced OR for fine particulates and robust OR for desert dust (adjusted OR per 0.1/km increase: 1.16, 95% CI: 1.09-1.23). An increased OR was observed both in infants who had previously wheezed and in those who had never wheezed. Receiving information on the particulate forecast, reducing time outdoors, closing windows, and regular use of leukotriene receptor antagonists were significant effect modifiers.Transborder desert dust arrival increased the risk of nose/eye/respiratory symptoms development in infants. Regular use of leukotriene receptor antagonists and other countermeasures reduced the risk.
57 Colonoscopy for weight loss – a waste of resources or an important indication?
Authors: D Storan, G Harkin, J Rasool, K Nawawi, M Altarrah, E Slattery
Journal: Gut (2017)

Background  Unintentional weight-loss is a common clinical encounter. Frequently, these patients are referred for colonoscopy to rule out lower gastrointestinal pathology.  Aim  Determine the diagnostic yield in colonoscopies performed for unintentional weight-loss (WL-O) versus weight-loss and associated GI symptoms (WL-GIs).  Method  Retrospective analysis of colonoscopies performed in our centre (May 2013-July 2016). Data was obtained from the Endoscopic Reporting System. Baseline characteristics were established. For sub-analysis, we stratified our cohort into four age groups ( 75 years).  Results  Of 5290 colonoscopies performed, 240 met our inclusion criteria (WL-O n=83, WL-GIs n=157). Baseline demographics were similar in both groups (WL-O Male 54%, mean age 56 years (SD ±16.6) compared with WL-GIs Male 52%, mean age 58 years (SD ±17.2)). Caecal intubation rates were similar in both groups (88% WL-O, 86% WL-GIs). Overall, colonoscopy was normal in 37.9% (64/169). Diverticulosis was detected in 24.9% (42/169), Colitis in 3% (5/169) and adenoma/polyp in 35.4% (85/240). For diagnostic yield between WL-O and WL-GIs, advanced adenoma detection rate was 7.2% (n=6) versus 8.3% (n=13) and CRC detection rate was 2.4% (n=2) versus 2.5% (n=4). CRC plus advanced adenomas was 9.6% (n=8) versus 10.8% (n=17)(p=0.774). Notably, in the WL-O group no high risk pathology was detected in colonoscopies in patients>75 years compared with n=3 in the WL-GIs group.  Conclusions  For both groups diagnostic yield was low, comparable to the asymptomatic generapopulation. Diagnostic yield is extremely low in colonoscopies for weight-loss only in patients>75 years. Weight-loss may not be a valid indication for colonoscopy, particularly in >75 years.
Wide Complex Tachycardia in a Woman in Her 30s With Electrolyte Derangements
Authors: Paul J. Marano, Adam Lee, Byron K. Lee
Journal: JAMA Cardiology (2019)

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 Cardiology 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 Cardiology journal
Mutational profile and benefit of gemtuzumab ozogamicin in acute myeloid leukemia
Authors: Elise Fournier, Nicolas Duployez, Benoît Ducourneau, Emmanuel Raffoux, Pascal Turlure, Denis Caillot, Xavier Thomas, Alice Marceau-Renaut, Sylvain Chantepie, Jean-Valère Malfuson, Emilie Lemasle, Meyling Cheok, Karine Celli-Lebras, Estelle Guerin, Christine Terré, Juliette Lambert, Cécile Pautas, Hervé Dombret, Sylvie Castaigne, Claude Preudhomme, Nicolas Boissel
Journal: Blood (2019)
Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy
Authors: Xu Chen, Yaqiao Li, Chao Wang, Yinyan Tang, Sue-Ann Mok, Richard M. Tsai, Julio C. Rojas, Anna Karydas, Bruce L. Miller, Adam L. Boxer, Jason E. Gestwicki, Michelle Arkin, Ana Maria Cuervo, Li Gan
Journal: Molecular Neurodegeneration (2020)

Abstract Background The trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown. Method We investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation. Results Increased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo. Conclusions We report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy.