tbuckley/cabot-search huggingface dataset:
Response and Survival Outcomes to Ibrutinib Monotherapy for Patients With Waldenström Macroglobulinemia on and off Clinical Trials
Authors: Jorge J. Castillo, Joshua N. Gustine, Kirsten Meid, Catherine A. Flynn, Maria G. Demos, Maria L. Guerrera, Cristina Jimenez, Amanda Kofides, Xia Liu, Manit Munshi, Nicholas Tsakmaklis, Christopher J. Patterson, Lian Xu, Guang Yang, Zachary R. Hunter, Steven P. Treon
Journal: HemaSphere (2020)

Abstract Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The approval was based on a single, multicenter, phase II trial in previously treated WM patients. We sought to evaluate whether there were differences in clinical characteristics, response, and survival outcomes to ibrutinib monotherapy between WM patients treated on and off clinical trials. Treatment naïve and previously treated patients who received ibrutinib monotherapy at our institution and participated in two prospective studies (ON trial; n = 72) or a prospective database (OFF trial; n = 157) were included. The median times from WM diagnosis to ibrutinib initiation were 3.1 and 3.5 years for ON and OFF trial patients, respectively (p = 0.38). Similar rates of categorical response at 6, 12, and 24 months and at best response were also observed between ON trial and OFF trial patients. The 4‐year PFS and OS rates for ON trial and OFF trial patients were 72% and 63%, respectively (log‐rank p = 0.14) and 83% and 81%, respectively (log‐rank p = 0.14). CXCR4 mutations impacted response and survival outcomes to ibrutinib monotherapy. The 4‐year rates of ibrutinib discontinuation in ON and OFF trial patients were 36% and 44%, respectively (p = 0.11). Ibrutinib is effective in the routine clinical care of both treatment‐naïve and previously treated WM patients. The findings of our study validate the efficacy of ibrutinib monotherapy reported in multiple phase II clinical trials.
Asterid Phylogenomics/Phylotranscriptomics Uncover Morphological Evolutionary Histories and Support Phylogenetic Placement for Numerous Whole-Genome Duplications
Authors: Caifei Zhang, Taikui Zhang, Federico Luebert, Yezi Xiang, Chien-Hsun Huang, Yi Hu, Mathew Rees, Michael W Frohlich, Ji Qi, Maximilian Weigend, Hong Ma
Journal: Molecular Biology and Evolution (2020)

Abstract Asterids are one of the most successful angiosperm lineages, exhibiting extensive morphological diversity and including a number of important crops. Despite their biological prominence and value to humans, the deep asterid phylogeny has not been fully resolved, and the evolutionary landscape underlying their radiation remains unknown. To resolve the asterid phylogeny, we sequenced 213 transcriptomes/genomes and combined them with other data sets, representing all accepted orders and nearly all families of asterids. We show fully supported monophyly of asterids, Berberidopsidales as sister to asterids, monophyly of all orders except Icacinales, Aquifoliales, and Bruniales, and monophyly of all families except Icacinaceae and Ehretiaceae. Novel taxon placements benefited from the expanded sampling with living collections from botanical gardens, resolving hitherto uncertain relationships. The remaining ambiguous placements here are likely due to limited sampling and could be addressed in the future with relevant additional taxa. Using our well-resolved phylogeny as reference, divergence time estimates support an Aptian (Early Cretaceous) origin of asterids and the origin of all orders before the Cretaceous–Paleogene boundary. Ancestral state reconstruction at the family level suggests that the asterid ancestor was a woody terrestrial plant with simple leaves, bisexual, and actinomorphic flowers with free petals and free anthers, a superior ovary with a style, and drupaceous fruits. Whole-genome duplication (WGD) analyses provide strong evidence for 33 WGDs in asterids and one in Berberidopsidales, including four suprafamilial and seven familial/subfamilial WGDs. Our results advance the understanding of asterid phylogeny and provide numerous novel evolutionary insights into their diversification and morphological evolution.
P-98 HGCSG1902: Multicenter, prospective, observational study for cases with dysgeusia caused by chemotherapy for gastrointestinal cancer
Authors: T. Ando, K. Ito, S. Yuki, R. Saito, S. Nakano, H. Nakatsumi, Y. Kawamoto, M. Dazai, K. Miyashita, K. Hatanaka, K. Harada, T. Miyagishima, H. Hisai, A. Ishiguro, A. Ueda, T. Kato, T. Sasaki, Y. Shindo, I. Yokota, R. Takagi, Y. Sakata, Y. Komatsu
Journal: Annals of Oncology (2020)
SO-24 AMG 510, a novel small molecule inhibitor of KRAS G12C, for patients with advanced gastrointestinal cancers: Results from the CodeBreak 100 phase 1 trial
Authors: J. Strickler, M. Fakih, T. Price, J. Desai, G. Durm, J. Krauss, Y. Kuboki, T. Kim, A. Sacher, H. Henary, J. Kim, D. Hong
Journal: Annals of Oncology (2020)
P-33 Regorafenib and trifluridine/tipiracil efficacy and safety in chemorefractory metastatic colorectal cancer patients: A single Bulgarian centre retrospective study
Authors: M. Penkova, D. Stoyanov, T. Panayotova, I. Donev, M. Petrova, N. Conev
Journal: Annals of Oncology (2020)
The Gut Microbiota in Prediabetes and Diabetes: A Population-Based Cross-Sectional Study
Authors: Hao Wu, Valentina Tremaroli, Caroline Schmidt, Annika Lundqvist, Lisa M. Olsson, Manuela Krämer, Anders Gummesson, Rosie Perkins, Göran Bergström, Fredrik Bäckhed
Journal: Cell Metabolism (2020)
PD-9 Universal screening for Lynch syndrome: Reflex testing to improve appropriateness of genetic counseling and diagnosis
Authors: A. Puccini, A. Damiani, L. Varesco, S. Zupo, L. Battistuzzi, G. Bregni, C. Bruzzone, M. Iaia, L. Mastracci, F. Grillo, S. Sciallero
Journal: Annals of Oncology (2020)
A three-dimensional biomimetic peripheral nerve model for drug testing and disease modelling
Authors: Afonso Malheiro, Francis Morgan, Matthew Baker, Lorenzo Moroni, Paul Wieringa
Journal: Biomaterials (2020)

In vitro peripheral nerve models provide valuable tools to study neurobiology questions and assess drug performance, in a regenerative or pathology context. To this end, we have developed a representative model of the peripheral nerve that displays three-dimensional (3D) neural anisotropy and myelination, which we showcase here as a simple and low-cost platform for drug screening. The model is composed of three main parts, including rat primary Schwann cells (SCs) seeded onto an electrospun scaffold to create bands of Büngner (BoB), primed PC12 cells as neuronal cell population, and a fibrin hydrogel to provide three-dimensionality. We also validated the use of primed PC12 as a neuron population by comparing it to rat dorsal root ganglions (DRGs) neurons. In both models we could obtain well aligned neurites and mature myelin segments. In short term cultures (7 days), we found that the addition of exogenous SCs enhanced neurite length and neurite growth area, compared to scaffolds with a laminin coating only. Addition of fibrin also lead to increased outgrowth of DRG and primed PC12 neurites, compared to 2D cultures. Moreover, neurite outgrowth in fibrin cultures was simultaneously multiplanar and anisotropic, suggesting that the SC-seeded scaffold can direct not only the growth of adjacent neurites, but also those growing above it. These results highlight the feasibility of the combination of a SC pre-seeded scaffold with a fibrin hydrogel, to direct and improve neurite growth in 3D. To demonstrate the model potential, we tested our platform at an immature (7 days in vitro) and mature state (28 days in vitro) of development. At the immature stage we could inhibit neurite growth through protein blocking (via antibody binding) and show suramin (200 μM) neurotoxicity on cells. At the mature stage, when myelin is compact, we exposed cells to hyperglycemic conditions (45 mM glucose) to mimic diabetic conditions and showed that myelin deforms consequently. Moreover, we demonstrated that by supplementing cultures with epalrestat (1 μM), myelin deformation can be partly prevented. In sum, we developed a biomimetic nerve platform using an affordable and accessible cell line as neuronal population, which displays similar results to primary neurons, but does not require recurrent animal sacrifice. This platform holds great promise as it can be used to conveniently and inexpensively perform drug screenings on peripheral nerve-like tissue, in a normal or pathological state.
The Association Between HbA1c and Time in Hypoglycemia During CGM and Self-Monitoring of Blood Glucose in People With Type 1 Diabetes and Multiple Daily Insulin Injections: A Randomized Clinical Trial (GOLD-4)
Authors: Shilan Seyed Ahmadi, Klara Westman, Aldina Pivodic, Arndís F. Ólafsdóttir, Sofia Dahlqvist, Irl B. Hirsch, Jarl Hellman, Magnus Ekelund, Tim Heise, William Polonsky, Magnus Wijkman, Erik Schwarcz, Marcus Lind
Journal: Diabetes Care (2020)

According to recent guidelines, individuals with type 1 diabetes should spend <4.0% of time per day with glucose levels <3.9 mmol/L (<70 mg/dL) and <1.0% per day with glucose levels <3.0 mmol/L (<54 mg/dL).In the GOLD randomized crossover trial, 161 individuals with type 1 diabetes treated with multiple daily insulin injections (MDI) were randomized to continuous glucose monitoring (CGM) or conventional therapy with self-monitoring of blood glucose (SMBG) and evaluated over 16 months. We estimated the association between time spent in hypoglycemia and various mean glucose and HbA1c levels.Time spent in hypoglycemia (<3.9 mmol/L and <3.0 mmol/L) increased significantly with lower mean HbA1c and mean glucose levels during both CGM and conventional therapy. During CGM, 24 (57.1%) individuals with HbA1c <7.5% (<58 mmol/mol) had <1.0% time spent in hypoglycemia <3.0 mmol/L and 23 (54.8%) had <4.0% time spent in hypoglycemia <3.9 mmol/L. During CGM, mean time spent in hypoglycemia for individuals with mean HbA1c 7.0% (52 mmol/mol) was estimated to be 5.4% for <3.9 mmol/L and 1.5% for <3.0 mmol/L. The corresponding values during SMBG were 9.2% and 3.5%, respectively. Individuals with mean glucose levels of 8 mmol/L spent 4.9% units more time with glucose levels <3.9 mmol/L and 2.8% units more time <3.0 mmol/L during SMBG compared with CGM.Reaching current targets for time in hypoglycemia while at the same time reaching HbA1c targets is challenging for patients with type 1 diabetes treated with MDI both with CGM and SMBG monitoring. However, CGM is associated with considerably less time in hypoglycemia than SMBG at a broad range of HbA1c levels and is crucial for patients with MDI treatment if they are to have a chance to approach hypoglycemia targets.
SAT0141 The effects of mirtazapine in the treatment of fibromyalgia syndrome
Authors: W Samborski, M Lezañska-Szpera, JK Rybakowski
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Some previous study has documented the efficacy of 5-HT3 receptors antagonists in the treatment of fibromyalgia. <h3>Objectives</h3> The mirtazapine (Remeron), a new generation antidepressive agent, characterised by blocking of 5-HT2 and 5-HT3 receptors and stimulation of 5HT-1 and noradrenergic receptors was used in the treatment of patients with Fibromyalgia syndrome (FS). <h3>Methods</h3> Twenty patients (18 female, 2 male), age range 20–64 years, mean 43,58, fulfilling the 1990 ACR criteria for fibromyalgia, entered 6 weeks open study and were given 30 mg mirtazapine per day. Before the administration of the first dose, during the study and at the final visite, the following parameters were measured using the visual analogue scale 0–10 (VAS): pain, morning stiffness (minutes) fatigue, sleep disturbances and other vegetative and functional symptoms. Severity of depression was also evaluated with Hamilton Depression Rating Scale, 17-item version (HDRS). <h3>Results</h3> 12 from 17 patients (70%) showed a clinical improvement at the end of the study as a consequence of the reduced intensity of pain (8,1 before, 4,6 after therapy, p &lt; 0,001), morning stiffness (57,6 min.vs 36,8 min., p &lt; 0,005), fatigue (8,3 vs 5,3, p &lt; 0,001), sleep disturbances (8,2 vs 2,5, p &lt; 0,0005), headache (7,1 vs 4,2, p &lt; 0,005), gastrointestinal symptoms (6,1 vs 2,4, p &lt; 0,005) or paresthesia (8,5 vs 4,8, p &lt; 0,005). The reduced severity of depressive symptoms was also observed (17,7 vs 6,8, p &lt; 0,001). Six patients complained of sleepiness and hypotension during the first days of therapy, in three cases dosis of mirtazapine was reduced to 15 mg and treatment continued, three patients (female) were excluded from the study. <h3>Conclusion</h3> Our data suggest that mirtazapine could be an effective and promissing method in the treatment of fibromyalgia patients. During the treatment of FS patients strict cooperation beetween rheumatologists and psychiatrist is needed.
Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits
Authors: Elyza Kelly, Fantao Meng, Hirofumi Fujita, Felipe Morgado, Yasaman Kazemi, Laura C. Rice, Chongyu Ren, Christine Ochoa Escamilla, Jennifer M. Gibson, Sanaz Sajadi, Robert J. Pendry, Tommy Tan, Jacob Ellegood, M. Albert Basson, Randy D. Blakely, Scott V. Dindot, Christelle Golzio, Maureen K. Hahn, Nicholas Katsanis, Diane M. Robins, Jill L. Silverman, Karun K. Singh, Rachel Wevrick, Margot J. Taylor, Christopher Hammill, Evdokia Anagnostou, Brad E. Pfeiffer, Catherine J. Stoodley, Jason P. Lerch, Sascha du Lac, Peter T. Tsai
Journal: Nature Neuroscience (2020)
Microtubule-drug interactions studied by Hydrogen-Deuterium exchange and mass spectrometry.
Authors: Hui Xiao, Pascal Verdier-Pinard, Narcis Fernandez-Fuentes, Andras Fiser, Ruth H. Angeletti, George A. Orr, Susan B. Horwitz
Journal: Cancer Research (2006)

5720  Microtubules are the target of antitumor drugs such as Taxol. GTP bound to the β subunit of the α/β tubulin heterodimer is hydrolyzed upon assembly of tubulin to microtubules. Taxol induces the assembly of stable microtubules. Although photoaffinity labeling and electron crystallography have localized the binding pocket for Taxol on β-tubulin, they do not provide insight into the mechanism by which Taxol stabilizes microtubules. Hydrogen/Deuterium exchange (HDX) in combination with Liquid Chromatograph-Electrospray ionization mass spectrometry (LC-ESI MS) permits studies of structure and dynamics of biomolecules in solution. A time course of deuterium incorporation was carried out with purified chicken erythrocyte tubulin heterodimers, or microtubules assembled in the presence of GTP or GTP plus Taxol. The global exchange kinetics of tubulin dimers and microtubules was monitored by LC-ESI MS and the deuterium incorporation into tubulin polypeptide chains was calculated by taking into account the deuterium loss during the HPLC step. After 100 minutes of exchange, 251 (430 total exchangeable amide protons) of the amide hydrogens in the tubulin α-chain were replaced by deuterium. The corresponding number for the β-chain was 263 (425 total exchangeable amide protons). After Taxol-induced polymerization, a marked reduction in deuterium incorporation is apparent with only 188 and 178 amide protons in the tubulin α-chain and β-chain, respectively, replaced by deuterium. This protection reflects decreased solvent accessibility or a more rigid conformation in both polypeptide chains. GTP-dependent polymerization reduced the flexibility of microtubules to a lesser extent. The reduced flexibility is preferentially on the β-chain, as suggested by the significantly reduced deuterium incorporation (243 amide protons) on the β-chain, while only slightly reduced deuterium level was observed on the α-chain (248 amide protons). Local HDX on microtubules was analyzed on peptic peptides by LC-MS. As expected, peptides from the Taxol binding pocket were protected against HDX. A comparison of the deuterium incorporation in the presence or absence of GTP- and Taxol allowed us to determine not only the regions involved in Taxol binding, but also the longitudinal and lateral dimer-dimer interactions. The data demonstrate that HDX coupled to mass spectrometry can be used to study microtubule-drug interactions.
A&amp;E doctor who had sexual relations with two patients he traced through hospital records is struck off
Authors: Clare Dyer
Journal: BMJ (2020)

An accident and emergency doctor who used hospital records to look up the phone numbers of two patients, and had sexual relations with both, has been struck off the UK medical register.

Christopher Uzodike, who worked at the Norfolk and Norwich University Hospital, contacted the two female patients after they visited the emergency department in 2016. After drinks, he had a one night stand with one of them, referred to as Patient B. He texted her soon after her hospital visit, telling her he could not let her “curves walk past.”

With the other woman, known as Patient A, the married doctor had an emotional and sexual relationship that lasted for nearly two years, ending in April 2018. He knew she had just come …
Genomic landscape of metastatic breast cancer identifies preferentially dysregulated pathways and targets
Authors: Matt R. Paul, Tien-chi Pan, Dhruv K. Pant, Natalie N.C. Shih, Yan Chen, Kyra L. Harvey, Aaron Solomon, David Lieberman, Jennifer J.D. Morrissette, Danielle Soucier-Ernst, Noah G. Goodman, S. William Stavropoulos, Kara N. Maxwell, Candace Clark, George K. Belka, Michael Feldman, Angela DeMichele, Lewis A. Chodosh
Journal: Journal of Clinical Investigation (2020)

Nearly all breast cancer deaths result from metastatic disease. Despite this, the genomic events that drive metastatic recurrence are poorly understood. We performed whole-exome and shallow whole-genome sequencing to identify genes and pathways preferentially mutated or copy-number altered in metastases compared with the paired primary tumors from which they arose. Seven genes were preferentially mutated in metastases - MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2, and ESR1 - 5 of which are not significantly mutated in any type of human primary cancer. Four regions were preferentially copy-number altered: loss of STK11 and CDKN2A/B, as well as gain of PTK6 and the membrane-bound progesterone receptor, PAQR8. PAQR8 gain was mutually exclusive with mutations in the nuclear estrogen and progesterone receptors, suggesting a role in treatment resistance. Several pathways were preferentially mutated or altered in metastases, including mTOR, CDK/RB, cAMP/PKA, WNT, HKMT, and focal adhesion. Immunohistochemical analyses revealed that metastases preferentially inactivate pRB, upregulate the mTORC1 and WNT signaling pathways, and exhibit nuclear localization of activated PKA. Our findings identify multiple therapeutic targets in metastatic recurrence that are not significantly mutated in primary cancers, implicate membrane progesterone signaling and nuclear PKA in metastatic recurrence, and provide genomic bases for the efficacy of mTORC1, CDK4/6, and PARP inhibitors in metastatic breast cancer.
Decreased Antihyperglycemic Drug Use Driven by High Out-of-Pocket Costs Despite Medicare Coverage Gap Closure
Authors: Mugdha Gokhale, Stacie B. Dusetzina, Virginia Pate, Danielle S. Chun, John B. Buse, Til Stürmer, Emily W. Gower
Journal: Diabetes Care (2020)

OBJECTIVE Using the 2016 Medicare Part D coverage gap as an example, we explored effects of increased out-of-pocket costs on adherence to branded dipeptidyl peptidase 4 inhibitors (DPP-4i) in patients without financial subsidies relative to subsidized patients who do not experience increased spending during the gap. We also explored seasonality of reinitiation, because discontinuers may be more likely to reinitiate in January when benefits reset. RESEARCH DESIGN AND METHODS We identified DPP-4i or sulfonylurea initiators, aged ≥66 years, from a 20% sample of 2015–2016 Medicare claims. Difference-in-differences Poisson regression was used to compare adherence before and after entering the coverage gap between nonsubsidized and subsidized patients. Among discontinuers, monthly hazard ratios (HRs) for reinitiation relative to January 2016 were derived with Cox models. As a second control, we repeated analyses using sulfonylureas, generic low-cost alternatives. RESULTS In 2016, 8,096 subsidized and 6,173 nonsubsidized DPP-4i initiators entered the coverage gap. For nonsubsidized patients, copayment in the coverage gap was 45% ($227 per DPP-4i prescription), and adherence decreased from 68.4% to 49.0% after gap entry. Accounting for adherence differences in subsidized patients, nonsubsidized patients demonstrated reduced adherence to DPP-4i (difference-in-difference: −16.9%; 95% CI −18.7%, −15.1%) but not sulfonylureas (−1.6%; 95% CI −3.4%, 0.2%). Reinitiation was lowest in the months before January (HR 0.4–0.5) among nonsubsidized DPP-4i patients, demonstrating a strong seasonal pattern. CONCLUSIONS Increased out-of-pocket costs negatively affect adherence and reinitiation of branded antihyperglycemic drugs among patients without financial subsidies. Despite closure of the coverage gap, affordability remains a concern given increasing list prices for many drugs on Medicare and the growing use of deductibles and coinsurance by commercial health plans.
O-11 Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma: A randomized, phase 2, multicenter, open-label study (DESTINY-Gastric01)
Authors: K. Yamaguchi, Y. Bang, S. Iwasa, N. Sugimoto, M. Ryu, D. Sakai, H. Chung, H. Kawakami, H. Yabusaki, J. Lee, K. Saito, Y. Kawaguchi, T. Kamio, A. Kojima, M. Sugihara, K. Shitara
Journal: Annals of Oncology (2020)
P-7 Induction chemotherapy in locally advanced rectal cancer: Retrospective report of efficacy and safety in an Argentinean university institution, a feasibility perspective
Authors: M. Diaz, S. Reyes, A. Adur, V. Cuartero, T. Leon, I. Raffa, P. Sanchez, M. Dioca
Journal: Annals of Oncology (2020)
Quality of Life and Patient Satisfaction After Antibiotic Therapy vs Appendectomy for Uncomplicated Appendicitis
Authors: Adel Elkbuli, Aaron Shepherd, Mark McKenney
Journal: JAMA Surgery (2020)

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