tbuckley/cabot-search huggingface dataset:
Gastrointestinal Myeloid Sarcoma
Authors: Trisha S Pasricha, Diane Abraczinskas
Journal: New England Journal of Medicine (2020)

A 59-year-old man who had undergone hematopoietic stem-cell transplantation for acute myeloid leukemia presented with a 3-month history of abdominal pain after eating. Multiple polypoid masses in the stomach and duodenum were seen on esophagogastroduodenoscopy, and a diagnosis of myeloid sarcoma was made.
Dosing patterns in patients with renal cell carcinoma treated with sorafenib or sunitinib: A retrospective claims database analysis
Authors: S. Keefe, E. Moyneur, V. Barghout, K. T. Flaherty
Journal: Journal of Clinical Oncology (2009)

5097 Background: Tyrosine kinase inhibitors (TKIs; sorafenib [SR], sunitinib [SU]) are FDA approved for the treatment of advanced renal cell carcinoma (RCC). Dose reduction may be needed for management of treatment-related adverse events. We analyzed the dose reduction patterns in pts with RCC treated with SR, approved Dec 05, or SU, approved Jan 06. Methods: A retrospective analysis was conducted using data from a US claims-based database (MarketScan MedStat) covering ≥18 million lives for 2002–2008 in all US census regions. Inclusion criteria were ≥2 claims for RCC (ICD9 189.0 or 198.0), continuous healthcare coverage, &gt;180 days of coverage before RCC diagnosis, no claim for SR or SU prior to RCC diagnosis, initial standard daily RCC dose per package insert recommendation (800 mg for SR or 50 mg for SU), and ≥2 consecutive dispensings. Initial episode was defined as the time from the date of the first drug dispensing (index date) to the first switch to another TKI, end of healthcare coverage, end of treatment, or March 31, 2008. Pt and pt-time level analyses for dose reductions between treatments were conducted. Results: SR- (n = 189) and SU-treated (n = 304) pts met the inclusion criteria. No significant differences in baseline demographics existed between the groups except for a higher incidence of stroke (7.9% vs 3.6%, p = 0.037) and other cancer site (93.7% vs 87.8%, p = 0.036) in the SR group. Significantly more pts who received SU (23%) required dose reductions during the first 3 months of therapy and for all initial episodes than did pts who received (4.2%) SR (p &lt; 0.001 for both). For all episodes, the mean time to dose reduction was 104 days for SU versus 162 days with SR (p = 0.0028). The majority (65%) of dose reductions with SU occurred within the first 3 months, whereas dose reduction with SR was 25% during this time (p &lt; 0.001). After controlling for different lengths of exposure time, 2 to 6 times more dose reductions were observed in pts who received SU than with SR (p &lt; 0.001). Conclusions: This US retrospective claims analysis showed more dose reductions, including number of patients and total number of days, in pts who initially received sunitinib compared with those who received sorafenib. [Table: see text]
Cis and trans effects differentially contribute to the evolution of promoters and enhancers
Authors: Kaia Mattioli, Winona Oliveros, Chiara Gerhardinger, Daniel Andergassen, Philipp G. Maass, John L. Rinn, Marta Melé
Journal: Genome biology (2020)

Abstract Background Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects are caused by genetic variants located on the same DNA molecule as the target gene, trans effects are due to genetic variants that affect diffusible elements. Previous studies have mostly assessed the impact of cis and trans effects at the gene level. However, how cis and trans effects differentially impact regulatory elements such as enhancers and promoters remains poorly understood. Here, we use massively parallel reporter assays to directly measure the transcriptional outputs of thousands of individual regulatory elements in embryonic stem cells and measure cis and trans effects between human and mouse. Results Our approach reveals that cis effects are widespread across transcribed regulatory elements, and the strongest cis effects are associated with the disruption of motifs recognized by strong transcriptional activators. Conversely, we find that trans effects are rare but stronger in enhancers than promoters and are associated with a subset of transcription factors that are differentially expressed between human and mouse. While we find that cis - trans compensation is common within promoters, we do not see evidence of widespread cis - trans compensation at enhancers. Cis - trans compensation is inversely correlated with enhancer redundancy, suggesting that such compensation may often occur across multiple enhancers. Conclusions Our results highlight differences in the mode of evolution between promoters and enhancers in complex mammalian genomes and indicate that studying the evolution of individual regulatory elements is pivotal to understand the tempo and mode of gene expression evolution.
Re: Yunjin Bai, Yubo Yang, and Yin Tang's Letter to the Editor re: Andrea Necchi, Marco Bandini, Giuseppina Calareso, et al. Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study. Eur Urol 2020;77:636–43. Eur Urol 2020;77:e158
Authors: Helena Vila-Reyes, G. Joel DeCastro, James M. McKiernan
Journal: European Urology (2020)
Combination of needle-knife and hemostatic forceps in a novel hybrid knife (Blossom-knife) improves endoscopic submucosal dissection in porcine model
Authors: Xiao Hu, Sheng-xi Han, Wei-hui Liu
Journal: Endoscopy (2020)

As a widely used treatment of early gastrointestinal neoplasms, endoscopic submucosal dissection (ESD) requires specifically designed surgical instruments, primarily an endoknife for dissection and hemostatic forceps for hemostasis [1]. Because switchover of different instruments makes ESD challenging in terms of skills, as well as time-consuming [2] [3] [4], there is an urgent need to develop hybrid instruments that can be used to perform ESD more safely and easily [5]. Here we report on the use of our newly invented hybrid knife (Blossom-knife), which perfectly integrates a needle-knife and hemostatic forceps ([Fig. 1]), to achieve effective hemostasis and reliable dissection during ESD in a porcine model ([Video 1]).
PHorecasting Heritable Pulmonary Arterial Hypertension: Are We Nearly There Yet?
Authors: Micheala A. Aldred
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

in the projected financial and human toll of a global strategy versus the continuation of the status quo, Menzies and colleagues demonstrate the true costs to the United States of failing to invest in a global tuberculosis control strategy.This thoughtful and detailed analysis by Menzies and colleagues shows that investing in a comprehensive approach to tuberculosis control in high-burden settings-both directly and through global partners-makes sense for our nation.As the United States congress rethinks the nation's global strategy for combating tuberculosis (the End Tuberculosis Now Act), there is an opportunity to redefine our approach to global tuberculosis eradication.Menzies and colleagues have given us a strong push in the right direction.Their conclusions are difficult to refute and should be immediately adopted by advocates, policy makers, and funding agencies.
Risk factors for frontal fibrosing alopecia: A case-control study in a multiracial population
Authors: Paulo Müller Ramos, Alessandra Anzai, Bruna Duque-Estrada, Debora Cadore Farias, Daniel Fernandes Melo, Fabiane Mulinari-Brenner, Giselle Martins Pinto, Leonardo Spagnol Abraham, Leopoldo Duailibe Nogueira Santos, Rodrigo Pirmez, Hélio Amante Miot
Journal: Journal of the American Academy of Dermatology (2020)
A multicenter randomized phase II study of nonpegylated liposomal doxorubicin plus vinorelbine versus nonpegylated liposomal doxorubicin plus cyclophosphamide as first line in locally advanced breast cancer (LABC) or metastatic breast cancer (MBC): Safety results
Authors: V. Lorusso, S. Leo, M. Ciccarese, F. Giotta, R. Bordonaro, G. Filippelli, S. Del Prete, A. Piano, V. Gebbia, S. Pisconti, G. Colucci
Journal: Journal of Clinical Oncology (2009)

1116 Background: We conducted a multicenter randomized phase II trial to assess activity and tolerability of the combination of nonpegylated liposomal doxorubicin plus vinorelbine versus standard nonpegylated liposomal doxorubicin plus cyclophosphamide. Methods: This multicenter randomized phase II study was planned to enrol 140 patients (pts). Elegibile pts must have LABC or MBC, PS (ECOG) ≤ 2, and measurable disease. Adjuvant or neoadjuvant chemotherapy with anthracyclines was allowed as well as prior endocrine therapy. Pts assigned to arm A received nonpegylated liposomal doxorubicin 60 mg/m 2 plus cyclophosphamide 600 mg/m 2 on day 1 of a 21-day cycle. Pts assigned to arm B received nonpegylated liposomal doxorubicin 50 mg/m 2 plus vinorelbine 25 mg/m 2 iv on day 1, and 60 mg/m 2 on day 8 po, every 3 weeks. The primary outcome measure was response rate (RR), whereas safety was one of the secondary endpoints. Results: Between July 2006 and July 2008 110 women were treated; for 80 of these, safety results are available. Patient characteristics: Arm A pts (N=41): median age, 59 (range 37–69); ER status ±/unk, 26/15/0; Her-2 status ±/unk, 5/34/2; PS 0/1/2, 26/14/1; prior adjuvant treatment with anthracyclines 10 pts (24%); dominant site of disease visceral 31 pts (76%). Arm B pts (N=39): median age, 61 (range 25–70); Er status ±/unk, 29/10/0; Her-2 status ±/unk, 3/35/1; prior adjuvant treatment with anthracyclines 14 pts (36%); dominant site of disease visceral in 28 pts (72%). There was no study discontinuation due to AE either in arm A or in arm B, nor study-related deaths. Conclusions: The combination regimen of nonpegylated liposomal doxorubicin plus vinorelbine appears to be associated with a slight increase of hematological and nonhematological toxicity when compared with nonpegylated liposomal doxorubicin plus cyclophosphamide. No increase in cardiotoxicity was seen. The trial is ongoing and we plan to give preliminary efficacy results at the time of the Meeting. [Table: see text] No significant financial relationships to disclose.
First-line lapatinib combined with letrozole versus letrozole alone for hormone receptor positive (HR+) metastatic breast cancer (MBC): Subgroup analyses of borderline FISH+, IHC 2+, HER2 unknown (UNK), and treatment-naive (TN) populations from EGF30008
Authors: L. O'Rourke, M. Pegram, M. Press, J. Pippen, X. Pivot, H. Gomez, A. Florance, J. Maltzman, S. Johnston, S. Johnston
Journal: Journal of Clinical Oncology (2009)

1062 Background: This double-blind, placebo-controlled, phase III trial assessed the benefit of adding lapatinib, an oral EGFR/HER2 tyrosine-kinase inhibitor, to letrozole alone in patients (pts) with HR+ MBC. The previously reported primary endpoint, investigator (INV) assessed PFS in HER2+ tumors, showed a significant benefit from dual therapy. Median PFS in the HR+ HER2+ population increased from 3 months (mo) in the letrozole/placebo group to 8.2 mo in the letrozole/lapatinib group [Hazard Ratio (95% CI)=0.71 (0.53,0.96), stratified log rank p = 0.019]. The HER-2-ve population did not derive benefit from the combination. Benefit from combined treatment was evaluated in a number of pre-planned exploratory subsets, including a noted trend in the HER2-ve population who progressed within 6 mo of receiving prior tamoxifen. Methods: 1286 pts were randomized to letrozole/lapatinib or letrozole/placebo. HER2 positivity was defined by a positive FISH ratio or by immunohistochemistry (IHC) 3+ in a central laboratory. INV assessed PFS in the sub-populations were analyzed using Kaplan-Meier with stratified log rank to compare treatment arms. These included tumor samples that were FISH borderline1.8–2.2 (n = 52), IHC 2+ (n = 215), HER2 status UNK (n = 115), and neo/adjuvant TN (n = 656). Results: INV assessed PFS demonstrated no significant prolongation for dual therapy for any of the exploratory populations [Hazard Ratio: (95%CI), p-value]; FISH 1.8–2.2 [1.03 (0.55, 1.95), p = 0.918]; IHC 2+ [1.13 (0.82, 1.57), p = 0.441]; HER2 UNK [0.71 (0.45,1.11), p = 0.126]; TN [0.88 (0.73, 1.07), [p = 0.199]. Conclusions: The combination of letrozole and lapatinib did not significantly improve PFS in any of the pts with lower levels of HER2 expression (borderline FISH, IHC 2+, or HER2 UNK) or in TN pts. These data confirm the HER2-ve result previously reported and substantiate that only tumors with the target benefit from the addition of a targeted therapy. [Table: see text]
Acute myeloid leukemia: 2021 update on risk‐stratification and management
Authors: Elihu H. Estey
Journal: American Journal of Hematology (2020)

Management of AML involves choosing between purely palliative care, standard therapy and investigational therapy ("clinical trial"). Even most older patients likely benefit from treatment. Based on randomized trials CPX 351, midostaurin, gemtuzumab ozogamicin, and venetoclax, the latter three when combined with other drugs, should now be considered standard therapy. Knowledge of the likely results with these therapies is essential in deciding whether to recommend them or participate in a clinical trial, possibly including these drugs. Hence here, in the context of established prognostic algorithms, we review results with the recently- approved drugs compared with their predecessors and describe other potential options. We discuss benefit/risk ratios underlying the decision to offer allogeneic transplant and emphasize the importance of measurable residual disease. When first seeing a newly-diagnosed patient physicians must decide whether to offer conventional treatment or investigational therapy, the latter preferably in the context of a clinical trial. As noted below, such trials have led to changes in what today is considered "conventional" therapy compared to even 1-2 years ago. In older patients decision making has often included inquiring whether specific anti-AML therapy should be offered at all, rather than focusing on a purely palliative approach emphasizing transfusion and antibiotic support, with involvement of a palliative care specialist.
Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma
Authors: Jonathan D. Schoenfeld, Glenn J. Hanna, Vickie Y. Jo, Bhupendra Rawal, Yu-Hui Chen, Paul S. Catalano, Ana Lako, Zoe Ciantra, Jason L. Weirather, Shana Criscitiello, Adrienne Luoma, Nicole Chau, Jochen Lorch, Jason I. Kass, Donald Annino, Laura Goguen, Anupam Desai, Brendan Ross, Hina J. Shah, Heather A. Jacene, Danielle N. Margalit, Roy B. Tishler, Kai W. Wucherpfennig, Scott J. Rodig, Ravindra Uppaluri, Robert I. Haddad
Journal: JAMA Oncology (2020)

Novel approaches are needed to improve outcomes in patients with squamous cell carcinoma of the oral cavity. Neoadjuvant immunotherapy given prior to surgery and combining programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitors are 2 strategies to enhance antitumor immune responses that could be of benefit.
OP0126 Cd28 directly initiates il-4 gene transcription and induces tcr independent th2 cell differentiation in human memory cd4 t cells
Authors: A Skapenko, PE Lipsky, JR Kalden, H Schulze-Koops
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Evidence suggests that human autoimmune diseases might be driven by pro-inflammatory Th1 cells whereas immunomodulatory Th2 cells are rarely found. Th1 dominated immunity might result from disordered regulation of memory T cell differentiation with insufficient generation of Th2 cells to down-modulate inflammation. <h3>Objectives</h3> To gain insights into the mechanisms regulating human Th2 effector differentiation, we investigated Th2 differentiation in isolated human CD4<sup>pos</sup> naive and memory T cells <i>in vitro</i>. <h3>Methods</h3> A cell culture system was employed that permitted Th2 cell differentiation after short term priming. The phenotype of freshly isolated and primed T cells was determined by cytometric analysis of intracellular cytokines. Analysis of mRNA was performed using semiquantitative RT-PCR. <h3>Results</h3> Th2 cells could be generated from resting cord blood naive CD4<sup>pos</sup> T cells by priming with anti-CD3 and anti-CD28. Exogenous IL-4 was not required for Th2 cell differentiation from naive T cells and did only marginally increase Th2 priming efficiency. In striking contrast, co-stimulation of memory T cells through CD3 and CD28 increased Th2 cell frequencies only minimally if at all. When recombinant IL-4 was added during priming, an increase in Th2 effectors was noted. Of marked interest, however, significant Th2 cell differentiation was induced by priming of CD4<sup>pos</sup> memory T cells with anti-CD28 in the absence of TCR mediated signals. CD28 induced Th2 cell differentiation was dependent on IL-4 as neutralising of IL-4 inhibited the generation of Th2 effecors. As no exogenous IL-4 was required for CD28 mediated Th2 cell differentiation, the impact of CD28 ligation on IL-4 gene transcription in memory T cells was evaluated. IL-4 mRNA levels increased after CD28 engagement. To distinguish whether the increase in IL-4 mRNA levels after anti-CD28 stimulation resulted from initiation of transcription or from stabilisation of preformed mRNA, purified CD4<sup>pos</sup> memory T cells were stimulated with anti-CD28 in the presence or absence of actinomycin D. Actinomycin D completely inhibited the CD28 induced increase of IL-4 mRNA. Furthermore, when actinomycin was added when IL-4 mRNA levels were already increased, IL-4 mRNA levels declined markedly with a half-life of app. 60 min, indicating that the increase in IL-4 mRNA after CD28 engagement is caused to a significant extent by the induction of IL-4 gene transcription. <h3>Conclusion</h3> CD28 ligation directly initiated IL-4 gene transcription and induced Th2 differentiation in a TCR independent manner in memory but not in naive T cells. TCR independent generation of Th2 effectors might provide a way to control Th1 dominated cellular inflammation.
A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling
Authors: Carine Bonnard, Naveenan Navaratnam, Kakaly Ghosh, Puck Wee Chan, Thong Teck Tan, Oz Pomp, Alvin Yu Jin Ng, Sumanty Tohari, Rishita Changede, David Carling, Byrappa Venkatesh, Umut Altunoglu, Hülya Kayserili, Bruno Reversade
Journal: The Journal of Experimental Medicine (2020)

Failure of neural tube closure during embryonic development can result in anencephaly, one of the most common birth defects in humans. A family with recurrent anencephalic fetuses was investigated to understand its etiology and pathogenesis. Exome sequencing revealed a recessive germline 21-bp in-frame deletion in NUAK2 segregating with the disease. In vitro kinase assays demonstrated that the 7–amino acid truncation in NUAK2, a serine/threonine kinase, completely abrogated its catalytic activity. Patient-derived disease models including neural progenitor cells and cerebral organoids showed that loss of NUAK2 activity led to decreased Hippo signaling via cytoplasmic YAP retention. In neural tube–like structures, endogenous NUAK2 colocalized apically with the actomyosin network, which was disrupted in patient cells, causing impaired nucleokinesis and apical constriction. Our results establish NUAK2 as an indispensable kinase for brain development in humans and suggest that a NUAK2-Hippo signaling axis regulates cytoskeletal processes that govern cell shape during neural tube closure.
Atypical Hemolytic Uremic Syndrome-Clinical Presentation, Treatment, and Short Term Outcomes: The Mayo Clinic Experience
Authors: Meera Sridharan, Roshini Abraham, Hatem Amer, Fernando Fervenza, C. Christopher Hook, Nelson Leung, Ariela L. Marshall, David L. Murray, Rajiv K. Pruthi, Sanjeev Sethi, Maria Alice V. Willrich, Jeffrey L. Winters, Ronald S. Go
Journal: Blood (2017)
Hand–Schüller–Christian Disease
Authors: O. Güven, O. Güven
Journal: New England Journal of Medicine (1943)

Hand-Schuller-Christian disease is a chronic dissem inated form of Hystiocytosis-X in which there is mini mal or moderate visceral involvement in addition to bone lesions.The manifestations of the disease usually begin at two or three years of age.The com monest site of origin is the intraosseous reticulum and its derivatives.In this paper a case of Hand-Schuller-Christian disease and its clinical and radio logical findings have been presented.
Denosumab for prevention of fractures in men receiving androgen deprivation therapy (ADT) for prostate cancer (PC)
Authors: F. Saad, M. R. Smith, B. Egerdie, T. L. Tammela, R. A. Feldman, J. Heracek, M. Szwedowski, C. Ke, B. Leder, C. Goessl
Journal: Journal of Clinical Oncology (2009)

5056 Background: ADT increases bone resorption, reduces bone mineral density (BMD), and increases fracture risk. Previously, we reported that denosumab, a fully human monoclonal antibody against RANKL, increased BMD and reduced the incidence of vertebral fractures in men with PC on ADT. We now describe in further detail the effects of denosumab on fractures at other skeletal sites. Methods: Men receiving ADT for nonmetastatic PC were randomized to receive subcutaneous denosumab 60 mg every 6 months (n = 734) or placebo (n = 734), with daily calcium and vitamin D supplements for 3 years. Men &lt; 70 years old were required to have low BMD or a history of osteoporotic fracture. The primary endpoint was percentage change in lumbar spine BMD at 24 months. Key secondary endpoints were subject incidence of new vertebral fractures and fractures at any site (excluding fractures from severe trauma or pathologic fractures) over 3 years. Here, we evaluate the frequency of all fractures and fractures at key osteoporotic sites. The planned sample size (N = 1226) provided power to differentiate effects of denosumab from placebo for the primary and key secondary endpoints. Results: As previously reported, denosumab reduced the incidence of new vertebral fractures by 62% (p = 0.006), fractures at any site by 28% (p = 0.10), and multiple fractures at any site by 72% (p = 0.006) over 3 years. In a post-hoc analysis, we found a consistent trend showing a positive effect of denosumab on nonvertebral fractures. The occurrence of any fractures (counting all fractures within a subject) over 3 years was lower with denosumab than placebo (43 vs 77, p &lt; 0.01). The subject incidence of fractures at 6 high-risk sites (wrist, humerus, hip, pelvis, leg [excluding patella], and clavicle) was numerically lower with denosumab (15 vs 24 placebo; p = 0.12). Also, fewer subjects in the denosumab arm than in the placebo arm reported fractures at key osteoporotic sites (e.g., 2 for denosumab vs 10 for placebo at the radius). Overall rates of adverse events were balanced between treatment arms. Conclusions: Denosumab significantly reduced the incidence of new vertebral fractures and in a post-hoc analysis, showed a trend toward a positive effect on nonvertebral fractures in men receiving ADT for nonmetastatic PC. [Table: see text]
Could a Pragmatic Detection Strategy Be the Gateway for Effective Population Health for CKD?
Authors: Andrew S. Narva, Jenna M. Norton
Journal: Journal of the American Society of Nephrology (2020)

The ongoing coronavirus disease 2019 pandemic has strained our healthcare system to its breaking point and, along with the rising awareness of racial injustice in our country, has shaken many widely held assumptions about the equity of our health system. As we question our longstanding assumptions
Recurrent STAT3 Mutations in the Lymphocytes of Pure Red Cell Aplasia without T-Cell Large Granular Lymphocytic Leukemia
Authors: Toru Kawakami, Nodoka Sekiguchi, Toshiya Otsuka, Tatsuya Imi, Sayaka Nishina, Noriko Senoo, Yasushi Senoo, Hitoshi Sakai, Toshiro Ito, Tomonobu Koizumi, Shinji Nakao, Hideyuki Nakazawa, Fumihiro Ishida
Journal: Blood (2017)