tbuckley/cabot-search huggingface dataset:
Abstract B052: Leveraging the metabolic stress of polyamine biosynthesis in prostate cancer towards a novel therapeutic approach
Authors: Hayley C. Affronti, Anthony J. Pellerite, Aryn Rowsam, Spencer R. Rosario, Robert A. Casero, Mikhail A. Nikiforov, James Phillips, Dominic J. Smiraglia
Journal: Cancer Research (2018)

Abstract Prostatic epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen. This distinctive characteristic places added strain on connected pathways, forcing increased metabolite production from both one-carbon metabolism and the methionine cycle to maintain nucleotide and S-adenosylmethionine (SAM) pools, respectively. More importantly, this stress is increased in prostate cancer (CaP) due to increased polyamine biosynthesis, DNA synthesis, and proliferation. The metabolic flux is driven by the activity of spermidine/spermine N1-acetyltransferase (SSAT), which acetylates the polyamines leading to their secretion into the lumen, which drives demand for biosynthesis of polyamines. To overcome this stress, the methionine salvage pathway (MSP) recycles the one-carbon unit lost to polyamine biosynthesis back to the methionine cycle, allowing for replenishment of SAM pools. The rate-limiting enzyme involved in this process is methylthioadenosine phosphorylase (MTAP). We have found that CaP relies on the MSP to relieve the strain caused by high polyamine biosynthesis and that both genetic and pharmacologic inhibition of MTAP blocks CaP xenograft growth. We hypothesized that this dependence can be enhanced by increasing the activity of SSAT. Recent results from our lab have shown that pharmacologic inhibition of MTAP alongside SSAT upregulation is synergistic in multiple androgen-sensitive and castration-recurrent CaP cell lines. We are currently exploring the effects of our combination treatment in castration-recurrent xenografts in vivo as well as in human CaP treatment-naïve tumors from radical prostatectomies grown as ex vivo explants. Preliminary results reveal that our treatments are effective at slowing growth in a subset of xenografts in vivo as well as impacting our target enzymes, polyamine levels, and increasing apoptosis in our ex vivo system. We expect that simultaneous targeting of multiple, converging pathways that are exceptionally important for prostate will lead to significant delay or prevention of disease recurrence. Citation Format: Hayley C. Affronti, Anthony J. Pellerite, Aryn Rowsam, Spencer R. Rosario, Robert A. Casero, Mikhail A. Nikiforov, James Phillips, Dominic J. Smiraglia. Leveraging the metabolic stress of polyamine biosynthesis in prostate cancer towards a novel therapeutic approach [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B052.
NOTCH1 Aberrant Activation Is a Common Nonmutational Early Event in Chronic Lymphocytic Leukemia Hematopoietic Stem-Cells
Authors: Mauro Di Ianni, Baldoni Stefano, Beatrice Del Papa, Erica Dorillo, Elisa Albi, Giancola Raffaella, Accorsi Patrizia, Screpanti Isabella, Emanuela Rosati, Paolo Di Bartolomeo, Franca Falzetti, Paolo Sportoletti
Journal: Blood (2017)
Gαs-coupled receptor signaling and sleep regulate integrin activation of human antigen-specific T cells
Authors: Stoyan Dimitrov, Tanja Lange, Cécile Gouttefangeas, Anja T.R. Jensen, Michael Szczepanski, Jannik Lehnnolz, Surjo Soekadar, Hans-Georg Rammensee, Jan Born, Luciana Besedovsky
Journal: The Journal of Experimental Medicine (2019)

Efficient T cell responses require the firm adhesion of T cells to their targets, e.g., virus-infected cells, which depends on T cell receptor (TCR)–mediated activation of β2-integrins. Gαs-coupled receptor agonists are known to have immunosuppressive effects, but their impact on TCR-mediated integrin activation is unknown. Using multimers of peptide major histocompatibility complex molecules (pMHC) and of ICAM-1—the ligand of β2-integrins—we show that the Gαs-coupled receptor agonists isoproterenol, epinephrine, norepinephrine, prostaglandin (PG) E2, PGD2, and adenosine strongly inhibit integrin activation on human CMV- and EBV-specific CD8+ T cells in a dose-dependent manner. In contrast, sleep, a natural condition of low levels of Gαs-coupled receptor agonists, up-regulates integrin activation compared with nocturnal wakefulness, a mechanism possibly underlying some of the immune-supportive effects of sleep. The findings are also relevant for several pathologies associated with increased levels of Gαs-coupled receptor agonists (e.g., tumor growth, malaria, hypoxia, stress, and sleep disturbances).
Comprehensive landscape of gene amplifications (amps) in tissue and circulating tumor DNA (ctDNA) in metastatic colorectal cancer (mCRC).
Authors: Kanwal Pratap Singh Raghav, Rona Yaeger, Jonathan M. Loree, Arvind Dasari, Van K. Morris, Bryan K. Kee, Victoria M. Raymond, Rebecca J Nagy, Richard B. Lanman, John H. Strickler, Ryan Bruce Corcoran, Michael J. Overman, Scott Kopetz
Journal: Journal of Clinical Oncology (2019)

604 Background: Amps, as oncogenic and resistance drivers, have therapeutic implications, but unlike mutations, have been sparsely described in mCRC. Functional account is piecemeal due to vague definitions, limited data on co-occurring alterations and use of primary tissue samples nonrepresentative of tumor heterogeneity. Our aim was to define the amp landscape in mCRC using tissue and ctDNA sequencing. Methods: We performed systematic analyses of copy-number variation in 2 cohorts of mCRC patients (pts) [tissue (TC) (N = 1,134) and ctDNA (BC) (N = 3,218)] who had high sensitivity targeted sequencing with MSK-IMPACT (341-468 genes) or Guardant Health (70-73 genes) panel, respectively. For BC, plasma copy number was adjusted (ApCN) to account for variable tumor DNA shedding using max allele frequency and high amp (HAmp) was defined as &gt; 4 copies (similar to predefined tissue cutoff). Results: 166 (15%) and 405 (13%) pts in TC and BC harbored amp in at least one of 18 genes assessed by both panels (Table). Amp prevalence for individual gene was similar in both cohorts ( r = 0.9; P &lt; .01) with RTK amps ( EGFR, ERBB2, MET, FGFR1/2, PDGFRA) seen in 8% pts. Key RTK amps were enriched in RAS/BRAF wild type (RB WT) compared to mutant (RB MUT) (OR 3.5; P &lt; .01) pts in both cohorts, in contrast to low prevalence RTK and non-RTK amps. Median ApCN was higher for RTKs in RB WT vs MUT cases ( ERBB2: 12 vs 5; P = .02). Using validated EGFRab exposure (EGFRi) ctDNA signature, we found that EGFRi pts had higher prevalence of EGFR, MET, BRAF, KRAS, PIK3CA and FGFR1 amps compared to EGFRab naïve pts. Conclusions: While individually uncommon, amps occur across key oncogenic pathways in mCRC and after adjusting for ctDNA shedding, are seen at similar prevalence in tissue and plasma. Amps in RTKs are seen in 10-12% of RB WT tumors, suggesting clinically relevant roles as oncogenic effectors and targets. After EGFRi, a number of amps emerge, including PIK3CA and FGFR1 amps, not previously implicated in acquired resistance. [Table: see text]
Checkmate-040: Nivolumab (NIVO) in patients (pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) status.
Authors: Masatoshi Kudo, Ana Matilla, Armando Santoro, Ignacio Melero, Antonio Cubillo Gracian, Mirelis Acosta-Rivera, Su Pin Choo, Anthony B. El-Khoueiry, Ryoko Kuromatsu, Bassel F. El-Rayes, Kazushi Numata, Yoshito Itoh, Francesco Di Costanzo, Oxana V. Crysler, Maria Reig, Yun Shen, Jaclyn Neely, Christine Marie Dela Cruz, Carlos Baccan, Bruno Sangro
Journal: Journal of Clinical Oncology (2019)

327 Background: Pts with aHCC and CPB liver status are often excluded from clinical trials of novel therapies due to their poor prognosis (Greten British J Cancer 2005). Historical overall survival (OS) for these pts when treated with sorafenib (SOR) has ranged ≈3–5 mo in retrospective or descriptive studies (Abou-Alfa Gastrointest Cancer Res 2011; Da Fonseca Mol Clin Oncol 2015; Pressiani Ann Oncol 2013; Chiu Cancer 2012); thus, novel treatment options are needed for these pts. The PD-1 inhibitor NIVO is approved in the US, Canada, and elsewhere, most recently Australia, for SOR-treated pts with aHCC based on results from CheckMate-040 (NCT01658878) (El-Khoueiry Lancet 2017). Here we report data from the CPB cohort of CheckMate-040, the first prospective study of immunotherapy in this pt group. Methods: Pts with CPB (B7–B8) aHCC who were SOR-naïve (n = 25) or -experienced (n = 24) received NIVO 240 mg IV for 30 min Q2W until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) (investigator assessed [INV], RECIST v1.1) and duration of response (DOR). Safety was assessed in all treated pts using NCI CTCAE v4.0. Results: Of 49 analyzed pts, 28 (57.1%) had vascular invasion or extrahepatic spread. During a follow-up range of 6–18 mo, INV ORR was 10.2% with 5 pts responding; disease control rate (DCR) was 55.1%. Median (m) time to response was 2.7 mo and mDOR was 9.9 mo; 2 pts had ongoing responses at data cutoff. The mOS was 7.6 mo (mOS follow-up was 7.4 mo); mOS in SOR-naïve and -treated pts was 9.8 and 7.3 mo, respectively. Treatment-related adverse events (TRAEs) were reported in 25 (51%) pts; 4 (8.2%) pts had select hepatic TRAEs. TRAEs led to discontinuation in 2 pts (4.1%). NIVO safety profile in these pts appeared comparable to cohorts of pts with CPA aHCC. Comparison data for pts with CPA aHCC and extended follow-up for pts with CPB aHCC will be presented. Conclusions: Encouraging DCR and durable responses were observed in pts with CPB aHCC treated with NIVO. AEs were manageable and did not lead to higher discontinuation compared with pts with CPA aHCC. NIVO showed promising efficacy and tolerability compared with historical data, supporting further investigation. Clinical trial information: NCT01658878.
A young woman with headache and vomiting
Authors: Gareth M Dobson, Craig H Robson, John Williams, Nitin Mukerji
Journal: BMJ (2019)

A 31 year old woman of Indian origin, now living in the UK, was admitted to the neurosurgical ward with a two month history of headache and nausea. Her symptoms had progressively worsened over two weeks and she now reported increasingly severe morning headaches, worse on lying down, and episodes of vomiting. On admission her Glasgow coma scale score was 15/15 and she had no ascertainable neurological deficit on either peripheral nerve assessment or cranial nerve assessment.

Her medical history included multidrug resistant pulmonary tuberculosis (TB) diagnosed around five years earlier. She underwent successful treatment for this in the form of a two year course of pyrazinamide, moxifloxacin, linezolid, and azithromycin. She had no history of immunocompromising medical conditions or medications. She also had hypothyroidism.

Blood tests on admission were suggestive of mild neutrophilia: haemoglobin was 111 g/L (reference range 115-160), white blood cell count was 11.3×109/l (4-11), neutrophil count 9.6×109/l (2-7.5) and C reactive protein was <5 mg/L.

Computed tomography showed a posterior fossa lesion with associated hydrocephalus. Magnetic resonance imaging showed a mixed signal mass within the middle of the cerebellar hemispheres (fig 1).



Fig 1 
Axial fat suppression T1W magnetic resonance imaging with contrast showing a multilobular, well defined ring enhancing lesion within the posterior fossa



1.  What is the most likely diagnosis?

2.  How is this diagnosis confirmed?

3.  How would you manage …
Next-Generation Sequencing (NGS) in Childhood Myeloproliferative Diseases (MPD)
Authors: Michelina Santopietro, Giovanna Palumbo, Maria Luisa Moleti, Anna Maria Testi, Luisa Cardarelli, Nicola Monaco, Francesco Malaspina, Camilla Presicce, Sonia Maria Orlando, Alessandro Pancrazzi, Annalisa Pacilli, Giada Rotunno, Alessandro M. Vannucchi, Robin Foà, Fiorina Giona
Journal: Blood (2018)
Editor Profiles: Guest Editors of Special Issue on Enhancement of Dissolution and Oral Bioavailability of Poorly Water-soluble Drugs
Authors: Wei Wu, Yi Lu, Jianping Qi
Journal: Acta Pharmaceutica Sinica B (2019)

His research interest is in the field of oral drug delivery systems and in vivo fate of drug nanocarriers.He and coworkers invented novel water-quenching ACQ fluorescent dyes to probe the in vivo fate of versatile nanoparticles administered via different routes.
(Not Giving Up) The Marathon Race of MET Targeting Therapy: Are We There Yet?
Authors: Patrick C. Ma
Journal: Clinical Cancer Research (2019)

Abstract Among the various MET aberrations, MET amplification and METex14 have emerged as valid predictive biomarkers for MET inhibition. Despite challenges that have limited the development of MET inhibitors, we can learn from the latest efforts in biomarker-based therapy to better identify the patients who will benefit from treatment with these agents. See related articles by Hong et al., p. 2403 and Van Cutsem et al., p. 2414
Characterization of the Long-Term Efficacy and Safety of Duvelisib Monotherapy in Patients with Relapsed/Refractory CLL/SLL on Treatment for &gt; 2 Years across 4 Clinical Studies
Authors: Ian W. Flinn, Marco Montillo, Zsolt Nagy, Zoltán Gasztonyi, Matthew S. Davids, Klaus Geissler, Jose J. Rifon Roca, Leanne Berkhan, Fritz Offner, NgocDiep Le, Stephanie Lustgarten, Julio Delgado
Journal: Blood (2018)
Diagnostic Accuracy of a Device for the Automated Detection of Diabetic Retinopathy in a Primary Care Setting
Authors: Frank D. Verbraak, Michael D. Abramoff, Gonny C.F. Bausch, Caroline Klaver, Giel Nijpels, Reinier O. Schlingemann, Amber A. van der Heijden
Journal: Diabetes Care (2019)

OBJECTIVE To determine the diagnostic accuracy in a real-world primary care setting of a deep learning–enhanced device for automated detection of diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS Retinal images of people with type 2 diabetes visiting a primary care screening program were graded by a hybrid deep learning–enhanced device (IDx-DR-EU-2.1; IDx, Amsterdam, the Netherlands), and its classification of retinopathy (vision-threatening [vt]DR, more than mild [mtm]DR, and mild or more [mom]DR) was compared with a reference standard. This reference standard consisted of grading according to the International Clinical Classification of DR by the Rotterdam Study reading center. We determined the diagnostic accuracy of the hybrid deep learning–enhanced device (IDx-DR-EU-2.1) against the reference standard. RESULTS A total of 1,616 people with type 2 diabetes were imaged. The hybrid deep learning–enhanced device’s sensitivity/specificity against the reference standard was, respectively, for vtDR 100% (95% CI 77.1–100)/97.8% (95% CI 96.8–98.5) and for mtmDR 79.4% (95% CI 66.5–87.9)/93.8% (95% CI 92.1–94.9). CONCLUSIONS The hybrid deep learning–enhanced device had high diagnostic accuracy for the detection of both vtDR (although the number of vtDR cases was low) and mtmDR in a primary care setting against an independent reading center. This allows its’ safe use in a primary care setting.
Women and Children First: Promoting Empowerment Through Resistance Education
Authors: Kimberly I. McClelland, Stephen M. Petrany, Todd H. Davies
Journal: JAMA Internal Medicine (2019)

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Implementing DPYD*2A genotyping in clinical practice, the Quebec experience.
Authors: Catherine Jolivet, Carl Amireault, Jean-Pierre M. Ayoub, Patrice Beauregard, Normand Blais, Christian Carrier, Alexis-Simon Cloutier, Alexandra Desnoyers, Jacques Jolivet, Anne-Sophie Lemay, Frederic Lemay, Francois Letendre, Rasmy Loungnarath, Denis Soulieres, Mustapha Tehfe, Daniel Viens, Xiaoduan Weng, Francine Aubin
Journal: Journal of Clinical Oncology (2019)

650 Background: Fluoropyrimidines (FU) are part of chemotherapy combinations for multiple gastrointestinal cancers. Deficient dihydropyrimidine deshydrogenase (DPD) activity can lead to severe life-threatening toxicities in 3-5% of populations tested. The DPYD*2A polymorphism leading to deficient DPD activity is one of the most studied variants. Methods: We retrospectively performed chart reviews of all patients that tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec (Canada). The study objective was to document the impact of implementing this test in routine clinical practice, including the effects on treatment types, delays and toxicities. Results: 2,617 patients were tested by PCR for the presence of DPYD*2A in a period of 17 months: 25 patients tested positive. All were Caucasian. 24 of the 25 patients were heterozygous (0.92%) and one was homozygous (0.038%). A chart review was available for 20 patients: 15 were tested upfront while five were performed following severe toxicities on the first cycle of FU-based chemotherapy. Of the five patients identified following toxicities, all had grade 4 cytopenias, 80% grade ≥ 3 mucositis, 20% grade 3 rash and 20% grade 3 diarrhea, with an average of 15 days of hospitalisations due to febrile neutropenia. Seven of the 13 patients identified upfront received FU-based chemotherapy at reduced initial doses ranging from 25 to 50%. The average dose during the course of chemotherapy was 50% and two patients reached 100% dosage. No grade ≥ 3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation according to 99% of queried physicians. Conclusions: Upfront genotyping before FU-based treatment is feasible in clinical practice. It may prevent severe toxicities and hospitalisations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A.
Efficacy and Safety of Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Extremes in Body Weight
Authors: Stefan H. Hohnloser, Marat Fudim, John H. Alexander, Daniel M. Wojdyla, Justin A. Ezekowitz, Michael Hanna, Dan Atar, Ziad Hijazi, M. Cecilia Bahit, Sana M. Al-Khatib, Jose Luis Lopez-Sendon, Lars Wallentin, Christopher B. Granger, Renato D. Lopes
Journal: Circulation (2019)

Background: Guidelines caution against the use of non–vitamin K antagonist oral anticoagulants in patients with extremely high (&gt;120 kg) or low (≤60 kg) body weight because of a lack of data in these populations. Methods: In a post hoc analysis of ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n=18 201), a randomized trial comparing apixaban with warfarin for the prevention of stroke in patients with atrial fibrillation, we estimated the randomized treatment effect (apixaban versus warfarin) stratified by body weight (≤60, &gt;60–120, &gt;120 kg) using a Cox regression model and tested the interaction between body weight and randomized treatment. The primary efficacy and safety outcomes were stroke or systemic embolism and major bleeding. Results: Of the 18 139 patients with available weight and outcomes data, 1985 (10.9%) were in the low-weight group (≤60 kg), 15 172 (83.6%) were in the midrange weight group (&gt;60–120 kg), and 982 (5.4%) were in the high-weight group (&gt;120 kg). The treatment effect of apixaban versus warfarin for the efficacy outcomes of stroke/systemic embolism, all-cause death, or myocardial infarction was consistent across the weight spectrum (interaction P value&gt;0.05). For major bleeding, apixaban had a better safety profile than warfarin in all weight categories and even showed a greater relative risk reduction in patients in the low (≤60 kg; HR, 0.55; 95% CI, 0.36–0.82) and midrange (&gt;60–120 kg) weight groups (HR, 0.71; 95% CI, 0.61–0.83; interaction P value=0.016). Conclusions: Our findings provide evidence that apixaban is efficacious and safe across the spectrum of weight, including in low- (≤60 kg) and high-weight patients (&gt;120 kg). The superiority on efficacy and safety outcomes of apixaban compared with warfarin persists across weight groups, with even greater reductions in major bleeding in patients with atrial fibrillation with low to normal weight as compared with high weight. The superiority of apixaban over warfarin in regard to efficacy and safety for stroke prevention seems to be similar in patients with atrial fibrillation across the spectrum of weight, including in low- and very high–weight patients. Thus, apixaban appears to be appropriate for patients with atrial fibrillation irrespective of body weight. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00412984.
Association of socioeconomic status with incidence and outcomes of gastric cancer in a Michigan cohort.
Authors: Lilit Karapetyan, Ling Wang, Joseph Gardiner, Heather Laird-Fick
Journal: Journal of Clinical Oncology (2019)

25 Background: The purpose of this study is to examine the association between socioeconomic factors and gastric cancer (GC) outcome in a cohort of patients in Michigan. Methods: We reviewed data for patients enrolled in the Michigan Cancer Surveillance Program, with diagnosis between 1990 and 2014 and follow up through 2016. Data extracted were age and stage at diagnosis, gender, race, zip code (as a proxy for family income), receipt of treatments, and survival status at last follow up. The poverty level (PL) was defined as average income by zip code &lt; $24,600. Statistical comparisons were assessed by chi-square tests in contingency tables, by the log-rank test for survival, and Poisson regression for incidence rate comparisons. Results: We identified 10,828 GC patients (22.39% below PL, 64.64% between PL and 200% PL, 12.98% above 200% PL) with complete data for analysis. By race/ethnicity, 68.12% non-Hispanic blacks, 21.05% American Indian/Alaska Natives, 8.59% Asian/Pacific Islanders, 23.83% Hispanics, and 12.63% non-Hispanic whites lived in areas with average income below PL. The socioeconomic status by race among GC patients was significantly different (p &lt; 0.0001). There was significant association of socioeconomic status and receipt of treatments. Patients living in areas below PL tended to have less information available about treatment received: unknown compared to no radiation (OR = 1.45, 95% CI 1.30-1.63), unknown compared to no chemotherapy (OR = 1.39, 95% CI 1.23-1.57), unknown compared to no surgery (OR = 1.49, 95% CI = 1.32-1.69). There was no significant relationship between stage at diagnosis and socioeconomic status (p = 0.153). The Poisson regression results showed that as average income increased in $10,000 increments in the area, incidence of gastric cancer is expected to decrease by 0.0642 (p &lt; 0.0001). As income in the area increases by $10,000, risk of death is expected to decrease (HR 0.977, p = 0.0025). Conclusions: In Michigan, socioeconomic factors are associated with race, incidence of GC, receipt of treatments, and survival, but not stage at diagnosis.