tbuckley/cabot-search huggingface dataset:
A phase I study of S-222611 an oral reversible dual inhibitor of EGFR and HER2, in patients with solid tumors.
Authors: Richard D Baird, Sophie Papa, Nicola Cresti, Helen Hatcher, Linda Hogarth, Mariam Jamal-Hanjani, Eugene P. Frenkel, Kirsteen Donaldson, John Posner, Izumi Kawabata, Duncan Ian Jodrell, Ruth Plummer, James F. Spicer
Journal: Journal of Clinical Oncology (2012)

3100 Background: S-222611 is a novel oral, potent, reversible tyrosine kinase inhibitor with antiproliferative activity in human tumor cell lines expressing EGFR and/or HER2 in vitro and in mouse xenograft models. We conducted the first study in patients (pts) with solid tumors expressing EGFR or HER2. Methods: Daily oral doses of S-222611 were escalated in successive cohorts from 100 mg to a maximum 1600 mg, using a 3 + 3 design. Full plasma pharmacokinetic (PK) profiles were obtained in all pts for 7 days after a single dose on Day 1 and for 24 h following 21 days of once daily dosing (Cycle 1). Trough PK samples were drawn weekly during the first 3 weeks of daily dosing. A CT scan was performed at baseline and every 8 weeks post-dose to assess response (RECIST). Results: Of 23 treated pts (16 male) aged 24-77y, 19 completed Cycle 1. One dose-limiting toxicity (DLT) has been seen to date, a rash at 1200 mg, which resolved on interruption and dose reduction. Other adverse events related to drug, diarrhea, rash, and nausea, were mild (grade 1 or 2) but more frequent at higher doses. Tumor responses have been seen over a wide range of doses. One complete clinical response was observed at 1200 mg in a pt with HER2 positive breast carcinoma previously treated with lapatinib and trastuzumab. Two pts showed confirmed partial responses (one with EGFR positive renal cell carcinoma at 200 mg daily and one with EGFR and HER2 positive esophageal carcinoma at 400 mg daily); 2 pts showed unconfirmed partial responses and 3 pts (with vaginal, gastric and pancreatic adenoCa) showed stable disease for &gt;6 months (mo); 2 pts have been treated for &gt;12 mo. Plasma C max , AUC and steady state concentrations increased with dose up to 1200 mg, exceeding those eliciting maximal responses in mice. The plasma t ½ is &gt;24 h. Conclusions: S-222611 was generally tolerated well in doses up to 1200 mg, with only one DLT; rash, diarrhea and nausea have been readily manageable. PK data support once daily dosing to achieve highly effective concentrations. A substantial proportion of patients with HER2 or EGFR expressing tumors have shown partial responses or stable disease (&gt;6 mo) and one patient has shown a complete clinical response.
The androgen receptor regulates a druggable translational regulon in advanced prostate cancer
Authors: Yuzhen Liu, Jessie L. Horn, Kalyan Banda, Asha Z. Goodman, Yiting Lim, Sujata Jana, Sonali Arora, Alexandre A. Germanos, Lexiaochuan Wen, William R. Hardin, Yu C. Yang, Ilsa M. Coleman, Robin G. Tharakan, Elise Y. Cai, Takuma Uo, Smitha P. S. Pillai, Eva Corey, Colm Morrissey, Yu Chen, Brett S. Carver, Stephen R. Plymate, Slobodan Beronja, Peter S. Nelson, Andrew C. Hsieh
Journal: Science Translational Medicine (2019)

The androgen receptor (AR) regulates mRNA-specific translation through 4EBP1, which is a druggable vulnerability in AR-deficient prostate cancer.
4 The hidden burden of Hepatitis C related advanced liver disease in the community
Authors: N Iqbal, C Murphy, T McHugh, A Singleton, S Keating, J Flanagan, G Hawthorne, D Crowley, H Gallagher, F Savage, J Maloney, JS Lambert, S Stewart
Journal: Gut (2017)

Background  In Ireland there are large numbers of HCV+ve patients receiving methadone in drug treatment centre (DTCs) who do not attend hepatology services. Most of these patients have never had their liver disease staged. Fibroscan (FS) is a non-invasive tool to assess liver stiffness which correlates closely with hepatic fibrosis. Clinically relevant cut-offs are 8.5 kPa (access to DAAs in Ireland), 25 kPa (significant portal hypertension) and 35 kPa (10%–20% risk of decompensation per year).  Aim  To use FS to risk stratify patients receiving methadone in Dublin DTCs.  To determine the impact of active alcohol consumption on FS score.  Method  We performed FS on sequential clients receiving methadone in the six larger Dublin DTCs regardless of their HCV status. Clients were also asked regarding alcohol intake and grouped as being –abstinent or not abstinent.  Results  A total of 618 consecutive patients (75% male, mean age 38±7.2) were assessed. HCV status was known in 91% (561) of patients with 70% (391) being HCV+ve. The mean FS score was higher in HCV+ve patients than HCV–ve (11.0 kPa ±12.4 vs 5.6 kPa ±4.0;p=0.001). In HCV+ve group, patients that drank alcohol (35%) had a higher score than those that were abstinent (13.2 kPa ±16.4 vs 9.7 kPa ±9.9;p=0.02). There were 128 (33% of total cohort) HCV+ve patients with FS ≥8.5 kPa, 34 (9%) with FS ≥25 kPa and 21 (5%) with FS ≥35 kPa.  Conclusions  This study has identified a large number of HCV+ve patients that do not attend hepatology services yet qualify for DAAs. Within this group there are significant numbers of patients at high risk of decompensation. On-going alcohol use is associated with a significantly higher FS score.
Sensitivity of refractory hairy cell leukemia to BRAF inhibition.
Authors: Sascha Dietrich, Nicola Lehners, Jennifer Huellein, Mindaugas Andrulis, Michael Hundemer, Alexander Jethwa, David Capper, Stefan Froehling, Christof V. Kalle, Anthony D. Ho, Hanno Glimm, Thorsten Zenz
Journal: Journal of Clinical Oncology (2012)

6519 Background: Thorough understanding of genetic lesions in cancer and targeted intervention against driver mutations are beginning to transform cancer treatment. An activating mutation of the BRAF serine/threonine protein kinase, BRAF V600E occurs in a proportion of malignant melanomas, and colorectal, thyroid, and other cancers. In hairy-cell leukemia (HCL), BRAF V600E is nearly always present, suggesting oncogene dependence. Methods: Here, we present a patient with HCL who was refractory to three lines of purine analogue-based treatment. The BRAF V600E mutation was demonstrated. After intensive counseling, the patient and his family provided written consent for vemurafenib (mutant BRAF-specific inhibitor) treatment. Results: Before vemurafenib treatment, the patient had subtotal bone marrow infiltration and massive splenomegaly (24.8 x 8.3 cm) leading to severe cytopenia (leukocytes 680/µl, hemoglobin 10.0 g/dl, platelets 36.000/µl). Treatment with vemurafenib was started with 240 mg twice daily and was slowly escalated to 1920 mg/d. Within two days of treatment, the spleen softened and decreased in size. Serum CD25 (sCD25) level fell rapidly from 24.800 U/ml to normal levels (&lt;900), and platelets, hemoglobin, and leukocyte counts rose. After 16 days of vemurafenib treatment, the spleen size had shrunk to 14 x 5 cm. By day 28 of treatment (on 720 mg/d), platelet counts and sCD25 levels had normalized. Bone marrow infiltration by HCL had decreased from 70% to 20% on day 16 and complete remission was achieved on day 35. We terminated treatment on day 57 when there was no evidence of any circulating hairy cells by immunophenotyping. Conclusions: The striking therapeutic activity of vemurafenib in our patient provides the first in vivo evidence to substantiate the BRAF V600E allele as a driver and validates mutant BRAF as a therapeutic target in HCL. Proof of principle for a molecularly targeted therapy of HCL adds to the recent success of targeting oncogenic kinases in oncogene addicted malignancies. Given the rarity of HCL, introducing new therapeutic modalities may be challenging. Future studies are needed that compare short-term inhibition of BRAF with low doses of vemurafenib (or alternative BRAF inhibitors) and standard therapy.
Severe falls among older adults with resected stage II/III colon cancer receiving chemotherapy.
Authors: Noelle K. LoConte, Glenn Allen, Ticiana A.B. Leal, Jennifer Weiss, Heather B. Neuman, David Y Greenblatt, Jessica Schmacher, Arlene Angela Gayle, Erin S O'Connor, Maureen Smith
Journal: Journal of Clinical Oncology (2013)

e14550 Background: Falls have significant implications for morbidity and mortality. The etiology of falls in elders includes cognitive change, polypharmacy, dizziness and anemia, all of which can be exacerbated by chemotherapy (chemo). We sought to determine the relation between chemotherapy receipt and falls resulting in injury and/or death among elders with colon cancer. Methods: Medicare beneficiaries &gt;64 years with resected stage II or III colon cancer diagnosed from 1992-2005 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Falls within one year of surgery that resulted in hospitalization or ER visit were defined by E-codes. χ 2 and 2-way ANOVA assessed differences in falls resulting or not resulting in death. Multivariable multinomial logistic regression models predicted a four-level falling/mortality variable (not falling (death), falling (death), not falling (no death), and falling (no death)) for patients receiving or not receiving chemo. Models controlled for patient demographics and tumor characteristics. We further controlled for use of mobility device, surgical complications, falls, hospitalizations and ER visits in the year before surgery, comorbidity risk score, frailty including dementia, and Medicaid status. Adjusted predicted probabilities and 95% CIs were calculated to assess the probability of each of the four outcome categories by receipt of chemotherapy. Results: Among 36,781 elders, falling was not increased among those who received adjuvant chemo. 14% of the total population fell during the year following surgery. The receipt of chemotherapy was not associated with increased rates of falls. Conclusions: Falling is not increased with the use of adjuvant chemo for stage II and III colon cancer among adults aged 65 years and above. The results suggest that oncologists may choose patients at least risk for functional decline when deciding upon chemo. [Table: see text]
ADF/Cofilin-Mediated Actin Turnover Promotes Axon Regeneration in the Adult CNS
Authors: Andrea Tedeschi, Sebastian Dupraz, Michele Curcio, Claudia J. Laskowski, Barbara Schaffran, Kevin C. Flynn, Telma E. Santos, Sina Stern, Brett J. Hilton, Molly J.E. Larson, Christine B. Gurniak, Walter Witke, Frank Bradke
Journal: Neuron (2019)
Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to conventional DMARDs: a randomised, double-blind, placebo-controlled phase III trial (RAJ3)
Authors: Yoshiya Tanaka, Tsutomu Takeuchi, Sakae Tanaka, Atsushi Kawakami, Manabu Iwasaki, Yeong Wook Song, Yi-Hsing Chen, James Cheng-Chung Wei, Sang-Heon Lee, Mitsuhiro Rokuda, Hiroyuki Izutsu, Satoshi Ushijima, Yuichiro Kaneko, Rio Akazawa, Teruaki Shiomi, Emi Yamada
Journal: Annals of the Rheumatic Diseases (2019)

To investigate the efficacy and safety of peficitinib, an oral Janus kinase inhibitor, in patients with rheumatoid arthritis (RA).In this double-blind phase III study, patients with RA and an inadequate response to prior disease-modifying anti-rheumatic drugs (DMARDs) were randomised to peficitinib 100 mg once daily, peficitinib 150 mg once daily, placebo or open-label etanercept for 52 weeks' treatment; placebo-treated patients were switched at week 12 to peficitinib 100 or 150 mg once daily. The primary endpoint was American College of Rheumatology (ACR)20 response at week 12/early termination (ET). Secondary endpoints (assessed throughout) included ACR20, ACR50 and ACR70 response, changes from baseline in disease activity scores (DAS)28 and ACR core parameters, adverse events (AEs) and changes in clinical or laboratory measurements.In total, 507 patients received treatment. ACR20 response rates at week 12/ET were significantly higher in the peficitinib 100 mg (57.7%) and 150 mg (74.5%) groups versus placebo (30.7%) (p<0.001). ACR50/70 response rates were also higher for both peficitinib doses versus placebo. Improvements in ACR response were maintained until week 52. Changes from baseline in DAS28-C-reactive protein/erythrocyte sedimentation rate and the ACR core set were significantly greater for both peficitinib doses versus placebo at week 12/ET (p<0.001). AE incidence was similar across treatment arms. Incidence of serious infection and herpes zoster-related disease was higher with peficitinib versus placebo, but with no clear dose-dependent increase.In patients with RA and inadequate response to DMARDs, peficitinib 100 mg once daily or 150 mg once daily was efficacious in reducing RA symptoms and was well tolerated compared with placebo.NCT02308163.
Extramedullary leukemia behaving as solid cancer: clinical, histologic, and genetic clues to chemoresistance in organ sites
Authors: Isabel Cunningham, Diane Hamele‐Bena, Yan Guo, Takayuki Shiomi, Audrey C. Papp, Bandana Chakravarti, Jianqi Yang, Yu Shyr, Rory A. Fisher
Journal: American Journal of Hematology (2019)

Recent studies of leukemic tumors in individual extramedullary sites showed they adopt the clinical and metastatic behavior of solid cancers originating in those sites. To elucidate features of leukemic tumors that render them resistant to agents effective against marrow leukemia, we analyzed a series of AML breast tumors by histology, immunohistochemistry, and RNA sequencing. Striking histologic similarities to solid cancers were found: a single-filing architectural pattern virtually identical to that of invasive lobular breast carcinoma and dense desmoplastic keloid-like fibrosis similar to colon, gallbladder, and pancreas carcinomas. Sequencing found 2157 genes significantly downregulated in AML breast tumors compared to normal breast. Comparison to triple-negative breast cancer found 859 genes similarly downregulated. At least 30 of these genes have been associated with poor prognosis in breast cancers. Five were reported in AML marrow studies to correlate with poor prognosis. The findings of this pilot study suggest the seed-and-soil interaction recognized in solid cancer growth may help explain how leukemic cells, in some patients, adopt solid tumor behavior in non-marrow sites. Transformed cells that metastasize from tumor to marrow can impart chemoresistance and be an unrecognized cause of treatment failure and death. Further studies comparing leukemic tumor to simultaneous marrow could potentially identify biomarkers that predict extramedullary resistance and lead to new therapeutic targets. Recognizing the potential for leukemia to adopt solid tumor phenotype, and implementation of body scanning and ablative tumor treatment, could decrease the persistently high rates of marrow resistance and treatment failure.
Pharmacological enhancement of <i>KCC2</i> gene expression exerts therapeutic effects on human Rett syndrome neurons and <i>Mecp2</i> mutant mice
Authors: Xin Tang, Jesse Drotar, Keji Li, Cullen D. Clairmont, Anna Sophie Brumm, Austin J. Sullins, Hao Wu, Xiaoxiao Shawn Liu, Jinhua Wang, Nathanael S. Gray, Mriganka Sur, Rudolf Jaenisch
Journal: Science Translational Medicine (2019)

KCC2 expression–enhancing small molecules rescue cellular and behavior deficits in human RTT neurons and Mecp2 mutant mice.
Abstract 16494: Rapamycin Enhances Protective Effect of Sildenafil against Doxorubicin Cardiotoxicity and Potentiates Cancer Cell Killing
Authors: David E Durrant, Anindita Das, Fadi N Salloum, Rakesh C Kukreja
Journal: Circulation (2012)

Background: Doxorubicin (DOX) is one of the most widely used chemotherapeutics for the treatment of various cancers. However, its use has been limited due to severe cardiotoxicity. Sildenafil (Sild...
When suspected ‘runner’s colitis’ in a marathon runner turns out to be cancer−and in the end leads to a new personal best marathon time
Authors: Peter Steiner
Journal: British Journal of Sports Medicine (2019)

In the autumn of 2016, I completed my second marathon. I was an ambitious 35-year-old athlete, participating year-round in activities that included running, road cycling, triathlon and alpine skiing. I was fit and well, and apart from pollen allergies I had not had any medical treatment. Approximately 3 hours after the marathon, I developed my first episode of bloody diarrhoea. As a doctor, I suspected this to be runner’s colitis but was not overly concerned. I knew that a proportion of marathon runners report gastrointestinal complaints.1 

In the following days, my diarrhoea disappeared, but the blood in my stool persisted.

Without any worrisome thoughts, I first underwent a proctoscopy which showed small haemorrhoids. These were treated, but because I still had blood in my stool I had a sigmoidoscopy a few weeks later. At this investigation, the gastroenterologist showed me the tumour in my rectum, and I knew what this meant. I had a biopsy, and the information from this (and the requisite additional imaging) meant that I was needed radiochemotherapy and surgery.

Before the operation, I searched for additional support from sport and exercise medicine specialists as I knew this would help me through my therapy. I was …
Nanoengineered Bioinks: Printing Therapeutic Proteins in 3D using Nanoengineered Bioink to Control and Direct Cell Migration (Adv. Healthcare Mater. 11/2019)
Authors: Charles W. Peak, Kanwar Abhay Singh, Mu'ath Adlouni, Jeffrey Chen, Akhilesh K. Gaharwar
Journal: Advanced Healthcare Materials (2019)

In article number 1801553 by Charles W. Peak, Akhilesh K. Gaharwar, and co-workers, a nanoengineered bioink loaded with therapeutic proteins is designed to direct cell function in a 3D printed construct. This approach to design biologically active inks to control and direct cell migration can be used to engineer 3D vascularized tissue structure for regenerative medicine.
Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study
Authors: Mette Deleuran, Diamant Thaçi, Lisa A. Beck, Marjolein de Bruin-Weller, Andrew Blauvelt, Seth Forman, Robert Bissonnette, Kristian Reich, Weily Soong, Iftikhar Hussain, Peter Foley, Michihiro Hide, Jean-David Bouaziz, Joel M. Gelfand, Lawrence Sher, Marie L.A. Schuttelaar, Chen Wang, Zhen Chen, Bolanle Akinlade, Abhijit Gadkari, Laurent Eckert, John D. Davis, Manoj Rajadhyaksha, Heribert Staudinger, Neil M.H. Graham, Gianluca Pirozzi, Marius Ardeleanu
Journal: Journal of the American Academy of Dermatology (2019)

Significant unmet need exists for long-term treatment of moderate to severe atopic dermatitis (AD).To assess the long-term safety and efficacy of dupilumab in patients with AD.This ongoing, multicenter, open-label extension study (NCT01949311) evaluated long-term dupilumab treatment in adults who had previously participated in phase 1 through 3 clinical trials of dupilumab for AD. This analysis examined patients given 300 mg dupilumab weekly for up to 76 weeks at data cutoff (April 2016). Safety was the primary outcome; efficacy was also evaluated.Of 1491 enrolled patients (1042.9 patient-years), 92.9% were receiving treatment at cutoff. The safety profile was consistent with previously reported trials (420.4 adverse events/100 patient-years and 8.5 serious adverse events/100 patient-years), with no new safety signals; common adverse events included nasopharyngitis, conjunctivitis, and injection-site reactions. Sustained improvement was seen up to 76 weeks in all efficacy outcomes, including measures of skin inflammation, pruritus, and quality of life.Lack of control arm, limited number of patients with 76 weeks or longer of treatment (median follow-up, 24 weeks), and patients not receiving the approved dose regimen of 300 mg every 2 weeks.The safety and efficacy profile from this study supports the role of dupilumab as continuous long-term treatment for patients with moderate to severe AD.
Screening for Pancreatic Cancer
Authors: Douglas K. Owens, Karina W. Davidson, Alex H. Krist, Michael J. Barry, Michael Cabana, Aaron B. Caughey, Susan J. Curry, Chyke A. Doubeni, John W. Epling, Martha Kubik, C. Seth Landefeld, Carol M. Mangione, Lori Pbert, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2019)

<h3>Importance</h3> Pancreatic cancer is an uncommon cancer with an age-adjusted annual incidence of 12.9 cases per 100 000 person-years. However, the death rate is 11.0 deaths per 100 000 person-years because the prognosis of pancreatic cancer is poor. Although its incidence is low, pancreatic cancer is the third most common cause of cancer death in the United States. Because of the increasing incidence of pancreatic cancer, along with improvements in early detection and treatment of other types of cancer, it is estimated that pancreatic cancer may soon become the second-leading cause of cancer death in the United States. <h3>Objective</h3> To update the 2004 US Preventive Services Task Force (USPSTF) recommendation on screening for pancreatic cancer. <h3>Evidence Review</h3> The USPSTF reviewed the evidence on the benefits and harms of screening for pancreatic cancer, the diagnostic accuracy of screening tests for pancreatic cancer, and the benefits and harms of treatment of screen-detected or asymptomatic pancreatic cancer. <h3>Findings</h3> The USPSTF found no evidence that screening for pancreatic cancer or treatment of screen-detected pancreatic cancer improves disease-specific morbidity or mortality, or all-cause mortality. The USPSTF found adequate evidence that the magnitude of the benefits of screening for pancreatic cancer in asymptomatic adults can be bounded as no greater than small. The USPSTF found adequate evidence that the magnitude of the harms of screening for pancreatic cancer and treatment of screen-detected pancreatic cancer can be bounded as at least moderate. The USPSTF reaffirms its previous conclusion that the potential benefits of screening for pancreatic cancer in asymptomatic adults do not outweigh the potential harms. <h3>Conclusions and Recommendation</h3> The USPSTF recommends against screening for pancreatic cancer in asymptomatic adults. (D recommendation)
Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer
Authors: Wenhan Zhu, Naoteru Miyata, Maria G. Winter, Alexandre Arenales, Elizabeth R. Hughes, Luisella Spiga, Jiwoong Kim, Luis Sifuentes-Dominguez, Petro Starokadomskyy, Purva Gopal, Mariana X. Byndloss, Renato L. Santos, Ezra Burstein, Sebastian E. Winter
Journal: The Journal of Experimental Medicine (2019)

Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing E. coli strains, are risk factors for the development of colorectal cancer. Here, we sought to determine whether precision editing of gut microbiota metabolism and composition could decrease the risk for tumor development in mouse models of colitis-associated colorectal cancer (CAC). Expansion of experimentally introduced E. coli strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways. Oral administration of sodium tungstate inhibited E. coli molybdoenzymes and selectively decreased gut colonization with genotoxin-producing E. coli and other Enterobacteriaceae. Restricting the bloom of Enterobacteriaceae decreased intestinal inflammation and reduced the incidence of colonic tumors in two models of CAC, the azoxymethane/dextran sulfate sodium colitis model and azoxymethane-treated, Il10-deficient mice. We conclude that metabolic targeting of protumoral Enterobacteriaceae during chronic inflammation is a suitable strategy to prevent the development of malignancies arising from gut microbiota dysbiosis.