tbuckley/cabot-search huggingface dataset:
Doctors urge US Congress to investigate spread of disease at child detention centres
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Doctors and public health experts have written to the US House of Representatives calling for a congressional investigation into the “poor conditions” and “increasing health risks” inside the detention centres holding children who have crossed the US southern border.

In a letter sent on 1 August and seen by The BMJ , the group from Harvard and Johns Hopkins universities warned representatives about the “threat of infectious diseases—particularly influenza” and pointed to the autopsy results of three children—aged …
The Clinician as Investigator
Authors: Ellis W. Lader, Christopher P. Cannon, E. Magnus Ohman, L. Kristin Newby, Daniel P. Sulmasy, Robyn J. Barst, Joan M. Fair, Marcus Flather, Jane E. Freedman, Robert L. Frye, Mary M. Hand, Robert L. Jesse, Frans Van de Werf, Fernando Costa
Journal: Circulation (2004)

The rapid development of new drugs, therapies, and devices has created a dramatic increase in the number of trials needed to properly evaluate them. The majority of patients treated today, many of whom could be eligible for participation in these studies, are seen in community hospitals and medical practices that are not affiliated with an academic medical center. Thus, there is a demonstrable need for physicians in private practice to enlist as investigators in these trials. This article is intended to encourage those physicians by describing the need and providing the rationale for their participation. It covers basic requirements for participating in clinical trials and outlines ethical, regulatory, financial, and other logistical issues of importance for the potential investigator and provides an algorithm for selecting a study for participation. Finally, the appendices review basic elements of study design and statistical principles, which may be of interest to a potential investigator.
<i>Iiteglin</i>α<i>4</i> (<i>ITG</i>α<i>4</i>) rs7562325 polymorphism was associated with better survivals in Austrian but not in Japanese patients with gastric cancer.
Authors: Syma Iqbal, Takeru Wakatsuki, Pierre Oliver Bohanes, Wu Zhang, Armin Gerger, Mizutomo Azuma, Michael Stotz, Dongyun Yang, Yan Ning, Nico Benjamin Volz, Sebastian Stintzing, Rita Elie El-Khoueiry, Melissa Janae Labonte, Joseph Ethan Li, Martin K. H. Maus, Wasaburo Koizumi, Masahiko Watanabe, Afsaneh Barzi, Heinz-Josef Lenz, Anthony B. El-Khoueiry
Journal: Journal of Clinical Oncology (2013)

e15009 Background: Integrins mediate cell-extracellular matrix and cell-cell interactions. It has been demonstrated that integrins may play a crucial role in carcinogenesis, progression, and metastasis.Recently, we demonstrated that ITGα4 rs7562325 C/T, ITGβ1 rs2298141, and ITGβ3 rs4642 were associated with outcomes in stage II and III adjuvant colorectal cancer in the US cohort. To apply these results in gastric cancer, we tested whether ITGpolymorphisms could predict outcome in two ethnically and epidemiologically different GC cohorts from Japan and Austria. Methods: Sixty-three (stage Ib-III) Austrian patients and one-hundred and sixty-nine Japanese (stage Ib-IV) with histopathologically-confirmed localized GC (AJCC-6 th ) were enrolled from 2001 to 2010. Both cohorts were treated with D2 lymphadenectomy based surgery. Results: The median DFS and OS in the Austrian cohort were 4.0 and 4.8 years, while median DFS and OS in the Japanese cohort were 4.8 and 5.8 years, respectively. Adjuvant chemotherapy was conducted 109 (64%) patients in the Japanese cohort, while 14 (22%) patients in the Austrian cohort. Only ITGα4rs7562325 C/T were associated with survivals in the Austrian cohort; patients homozygous T/T (n=10) showed a median DFS of 20.1+ years vs. 2.8 years in patients harboring at least one-C allele (n=53) (HR: 9.18 [95%CI: 1.25-67.5] p=0.029). Similar finding was also seen for OS; patients homozygous T/T showed a median OS of 20.1+ years vs. 4.3 years in patients harboring at least one-C allele (HR: 9.33 [95%CI: 1.27-68.6] p=0.028). In multivariate analysis stratified by stage and gender, this result was conserved in DFS (HR: 9.40 [95%CI: 1.26-69.9] p=0.029), but not in OS (HR: 1.77 [95%CI: 0.87-3.62] p=0.112). These results were consistent with previous our results of adjuvant CRC in the US cohort; however, we could not validate these findings in patients with GC in the Japanese cohort. Conclusions: ITGα4 rs7562325 polymorphism was associated with longer DFS in Austrian patients with GC, not in Japanese patients. Ethnic difference and different implementation rates of adjuvant chemotherapy between Austria and Japan may influence these results.
Preclinical modeling of the AKT inhibitor MK2206 and topotecan in small cell lung cancer (SCLC).
Authors: William S. Holland, Danielle C. Chinn, Primo Lara, David R. Gandara, Philip C Mack, Karen Kelly
Journal: Journal of Clinical Oncology (2012)

e17537 Background: Extensive-stage small cell lung cancer (SCLC) is an aggressive and lethal tumor. Despite its exquisite chemosensitivity, median survival is only 9-11 months. Topotecan is the only approved drug for relapsed SCLC and new treatments with demonstrated antitumor activity are urgently needed. Defects in PTEN and PI3KCA are common to SCLC (identified in 10-15% of tumor specimens), suggesting that inhibitors of the PI3K/AKT pathway should be evaluated. MK-2206 is a first- in-class oral allosteric AKT inhibitor that is both potent and highly selective against all AKT isoforms. Our aim is to determine if MK-2206 plus topotecan has superior anticancer activity compared to either agent alone in SCLC cell lines. Methods: Three SCLC cell lines (H526- PTEN/PI3K wild type; H69- PTEN wild type/PI3K mutated; H2196- PTEN mutated/PI3K wild type) were treated with MK2206, topotecan or the combination. Median Effect Analysis was conducted using proliferation assays to test the combination for synergy. Immunoblotting was performed to explore the targeted effect on the PI3K/AKT pathway while flow cytometry was used to determine cell cycle effects. Results: H526 cells were refractory to selective AKT inhibition, but sensitive to topotecan. In contrast, H69 cells were responsive to single-agent MK2206, but two orders of magnitude less sensitive to topotecan. The H2196 cell line was sensitive to both agents. All cell lines showed decreased phosphoAKT (S473) with MK2206. In the combination experiments, additive to moderately synergistic interactions were detected in all cell lines with the greatest synergism observed in the H69 cells. Increased PARP cleavage was observed in response to the combination treatment compared to single-agent topotecan suggesting that AKT inhibition improved the activity of topotecan. In H69, a prolonged G1/S-phase arrest was observed in the combination compared to single-agent treatment. Conclusions: MK2206 demonstrated antitumor activity in SCLC cell lines harboring PI3K or PTEN mutations and enhanced the activity of topotecan in wild type and mutant cell lines. Based on this data, a SWOG clinical trial of topotecan plus MK2206 versus topotecan in relapsed SCLC is in development.
MEK Inhibition Modulates Cytokine Response to Mediate Therapeutic Efficacy in Lung Cancer
Authors: Mengyu Xie, Hong Zheng, Ranjna Madan-Lala, Wenjie Dai, Nicholas T. Gimbrone, Zhihua Chen, Fumi Kinose, Sarah A. Blackstone, Keiran S.M. Smalley, W. Douglas Cress, Eric B. Haura, Uwe Rix, Amer A. Beg
Journal: Cancer Research (2019)

Activating mutations in BRAF, a key mediator of RAS signaling, are present in approximately 50% of melanoma patients. Pharmacologic inhibition of BRAF or the downstream MAP kinase MEK is highly effective in treating BRAF-mutant melanoma. In contrast, RAS pathway inhibitors have been less effective in treating epithelial malignancies, such as lung cancer. Here, we show that treatment of melanoma patients with BRAF and MEK inhibitors (MEKi) activated tumor NF-κB activity. MEKi potentiated the response to TNFα, a potent activator of NF-κB. In both melanoma and lung cancer cells, MEKi increased cell-surface expression of TNFα receptor 1 (TNFR1), which enhanced NF-κB activation and augmented expression of genes regulated by TNFα and IFNγ. Screening of 289 targeted agents for the ability to increase TNFα and IFNγ target gene expression demonstrated that this was a general activity of inhibitors of MEK and ERK kinases. Treatment with MEKi led to acquisition of a novel vulnerability to TNFα and IFNγ-induced apoptosis in lung cancer cells that were refractory to MEKi killing and augmented cell-cycle arrest. Abolishing the expression of TNFR1 on lung cancer cells impaired the antitumor efficacy of MEKi, whereas the administration of TNFα and IFNγ in MEKi-treated mice enhanced the antitumor response. Furthermore, immunotherapeutics known to induce expression of these cytokines synergized with MEKi in eradicating tumors. These findings define a novel cytokine response modulatory function of MEKi that can be therapeutically exploited. SIGNIFICANCE: Lung cancer cells are rendered sensitive to MEK inhibitors by TNFα and IFNγ, providing a strong mechanistic rationale for combining immunotherapeutics, such as checkpoint blockers, with MEK inhibitor therapy for lung cancer.See related commentary by Havel, p. 5699.
Case 24-2019: A 39-Year-Old Woman with Palpitations, Abdominal Pain, and Vomiting
Authors: Victor Chiappa, Mark A. Anderson, Conor D. Barrett, Nikolaos Stathatos, Melis N. Anahtar
Journal: New England Journal of Medicine (2019)

A 39-year-old woman with cyclic vomiting syndrome and polysubstance use disorder presented to the emergency department with abdominal pain, vomiting, and odd behavior. Supraventricular tachycardia developed and was treated with adenosine. A diagnostic test was performed.
Abstract 15451: Reduced Hippocampal Volume, Mood, and Memory Deficits in Adolescents With Single Ventricle Heart Disease
Authors: Nancy A Pike, Stefanie L Moye, Bhaswati Roy, Sadhana Singh, Nancy J Halnon, Alan B Lewis, Mary A Woo, Rajesh Kumar
Journal: Circulation (2017)

Introduction: Adolescents with single ventricle congenital heart disease (SVHD) show brain related functional deficits, particularly in mood and memory. Hippocampi are key brain structures of mood ...
Progress in the development of antiplatelet agents: Focus on the targeted molecular pathway from bench to clinic
Authors: Qian Xiang, Xiaocong Pang, Zhenming Liu, Guoping Yang, Weikang Tao, Qi Pei, Yimin Cui
Journal: Pharmacology & Therapeutics (2019)

Antiplatelet drugs serve as a first-line antithrombotic therapy for the management of acute ischemic events and the prevention of secondary complications in vascular diseases. Numerous antiplatelet therapies have been developed; however, currently available agents are still associated with inadequate efficacy, risk of bleeding, and variability in individual response. Understanding the mechanisms of platelet involvement in thrombosis and the clinical development process of antiplatelet agents is critical for the discovery of novel agents. The functions of platelets in thrombosis are regulated by two major mechanisms: the interaction between surface receptors and their ligands, and the downstream intracellular signaling pathways. Recently, most of the progress made in antiplatelet drug development has been achieved with P2Y receptor antagonists. Additionally, the usage of GP IIb/IIIa receptor antagonists has decreased, because it is associated with a higher risk of bleeding and thrombocytopenia. Agents targeting other platelet surface receptors such as PARs, TP receptor, EP3 receptor, GPIb-IX-V receptor, P-selectin, as well as intracellular signaling factors, such as PI3Kβ, have been evaluated in an attempt to develop the next generation of antiplatelet drugs, reduce or eliminate interpatient variability of drug efficacy and significantly lower the risk of drug-induced bleeding. The aim of this review is to describe the pathways of platelet activation in thrombosis, and summarize the development process of antiplatelet agents, as well as the preclinical and clinical evaluations performed on these agents.
Hepatitis C: voluntary drug licences improve treatment uptake in lower income countries
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Voluntary licences that allow low and middle income countries to manufacture patented hepatitis C medicines improve patient access and boost treatment uptake, a study has found.1

Researchers from Imperial College London compared 19 countries that had voluntary licences with 16 countries that did not, and the licences were associated with an increase in the yearly number of people accessing hepatitis C treatment of 53.6 per 1000 diagnoses.

Hepatitis C virus (HCV) infects the liver and leads to an estimated 700 000 deaths worldwide every year. Highly effective direct acting antivirals are available to treat the condition, but access …
Racial/ethnic differences in treatment delay in a multiethnic sample of women with breast cancer
Authors: M. Mujahid, S. Hawley, N. K. Janz, A. Hamilton, J. Graff, S. J. Katz
Journal: Journal of Clinical Oncology (2009)

6503 Background: Factors contributing to racial/ethnic variation in breast cancer treatment delay remain understudied, especially in multi-ethnic population-based samples. Methods: 3,252 women with non-metastatic breast cancer diagnosed between 6/05–2/07 and reported to the Los Angeles County and Detroit, Surveillance Epidemiologic and End Results (SEER) registries were surveyed after initial treatment (mean time from diagnosis = 8.9 months). Latina and African American (AA) women were over- sampled (n=2260, eligible response rate 72.1%). Treatment delay was defined as the patient's report of the duration between when breast cancer was first diagnosed and first surgical procedure (&lt; 1month, 1–3months, ≥4 months) . Multinomial logistic regression models were used to estimate the relative odds of treatment delay by race/ethnicity before and after adjustment for sociodemographics (age, education, income, marital status), clinical factors (number of co-morbidities, health status at diagnosis), and access barriers (difficulty: finding doctors to treat cancer, scheduling surgical procedure, getting to doctor's office). Results: Of the 2195 women who had a surgical procedure, 6.9 % experienced treatment delay of ≥4 months (10.4% Latina, 9.3% AA, 5.5% white women). Latina and AA women were more likely to experience longer treatment delay than white women [OR for ≥4 months/1–3 months vs. &lt; 1 month: 2.18/1.77 for Latinas; 1.78/1.50 for AA (p&lt;.001)] (Table). Racial/ethnic differences persisted after adjustment for sociodemographic, clinical factors, and access barriers [OR for ≥4 months/1–3 months vs. &lt; 1 month: 1.31/1.79 for Latinas; 1.64/1.55 for AA, (p&lt;.001)] (Table), although Latina vs. white differences were no longer statistically significant. Conclusions: Our results confirm that racial/ethnic minorities are vulnerable to delay in receipt of breast cancer treatment in a large population based sample of breast cancer patients. Further work is needed to evaluate the underlying causes of this delay. [Table: see text] No significant financial relationships to disclose.
Concurrent stereotactic robotic radiosurgery and hyperthermia for palliation of pain in recurrent advanced malignancies.
Authors: Sridhar Papaiah Susheela, Mallarajapatna Govindarajan, Sudhan Rajan, Ramesh s Bilimaga, Pichandi Anchineyan, Jerrin Amalraj, Monica Gupta, Madhusudan D, Mohan Pundalika, Basavalinga S. Ajaikumar
Journal: Journal of Clinical Oncology (2012)

e19619 Background: The management of advanced recurrent malignancy after definitive treatment is challenging. Palliation of pain in these cases by medication alone may not be sufficient. The role of Radiotherapy and hyperthermia were tried in the past with little benefit but side effects of radiation were considerably high due to large volume of disease. This study aims at Concurrent Robotic radiosurgery with hyperthermia for large volume disease for palliation of pain in recurrent advanced malignancy. Methods: Ten cases of recurrent advanced malignancy with Visual analog pain scale (VAS) score of &gt; 8 were treated by concurrent stereotactic robotic radiosurgery and hyperthermia between July 2010 to Jan 2012. All patients underwent PET CT based radiosurgery planning,Sterotactic Robotic Radiosurgery was delivered to Gross Tumor Volume (GTV) to dose of 30Gy in 3-5 fractions using fiducial tracking method.Hyperthermia was delivered using Celsius 42 locoregional hyperthermia device for an hour after stereotactic robotic radiosurgery on alternate day for 3-5 sessions. All patients received premedication and pain medications during treatment. All patients were analyzed for tolerance of treatment, acute toxicity and pain control. Pain control was assessed at the end of treatment and 6 weeks. Results: Among 10 patients 7 were female and 3 were male, age ranged from 40 to 72 years. 4 patients were carcinoma cervix, 2 were carcinoma rectum, 1 cholangiosarcoma, 1 carcinoma pancreas, 1 carcinoma esophagus with supraclavicular lymphnode, 1 mucoepidermoid ca of maxilla. All patients completed the planned treatment of concurrent Sterotactic Robotic Radiosurgery and Hyperthermia without any acute toxicity. At the end of treatment all patients had reduction in the pain. 7 patients had more than 60% reduction. At the end of 6 weeks 8 patients had &gt;80% reduction and off the analgesics. Conclusions: Concurrent Sterotactic Robotic Radiosurgery and hyperthermia is well tolerated and may gives good palliation of pain with improved quality of life in recurrent advanced malignancy. However randomized trial in this regard will be required.
The design of a thermoresponsive surface for the continuous culture of human pluripotent stem cells
Authors: Tzu-Cheng Sung, Jia-Sin Yang, Chih-Chen Yeh, Ya-Chu Liu, Yi-Peng Jiang, Ming-Wei Lu, Qing-Dong Ling, S. Suresh Kumar, Yung Chang, Akihiro Umezawa, Hao Chen, Akon Higuchi
Journal: Biomaterials (2019)
A Phase 2 Study of Cpi-0610, a Bromodomain and Extraterminal (BET) Inhibitor, in Patients with Myelofibrosis (MF)
Authors: Marina Kremyanskaya, Ronald Hoffman, John Mascarenhas, Srdan Verstovsek, Jennifer Mertz, Fiona Garner, Adrian Senderowicz
Journal: Blood (2018)
RETRACTED: miR-135b Delivered by Gastric Tumor Exosomes Inhibits FOXO1 Expression in Endothelial Cells and Promotes Angiogenesis
Authors: Ming Bai, Jialu Li, Haiou Yang, Haiyang Zhang, Zhengyang Zhou, Ting Deng, Kegan Zhu, Tao Ning, Qian Fan, Guoguang Ying, Yi Ba
Journal: Molecular Therapy (2019)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the editors. Molecular Therapy is retracting this article. After investigating concerns of image duplication raised by a reader, evidence for image duplication in identical or altered fashion in Figure 7B was identified. This reuse (and in part, misrepresentation) of data without appropriate attribution represents a severe abuse of the scientific publishing system. The authors do not agree to the retraction. Retraction Notice to: miR-135b Delivered by Gastric Tumor Exosomes Inhibits FOXO1 Expression in Endothelial Cells and Promotes AngiogenesisBai et al.Molecular TherapyMay 23, 2022In Brief(Molecular Therapy 27, 1772–1783, October 2019) Full-Text PDF
Phase I dose escalation study of oral lapatinib in combination with docetaxel in patients with HER2-positive locally advanced or metastatic breast cancer (LAMBC): Initial safety and tolerability results.
Authors: Pierre Fumoleau, Florence Dalenc, Audrey Mailliez, Corinne Veyret, Jacques Bonneterre, Cecile Guillemet, Sylvie Zanetta, Cristian Moldovan, Séverine Guiu, Jeremy Skrzypski, Mélanie Gauthier, Bruno P. Coudert, Nicolas Isambert
Journal: Journal of Clinical Oncology (2013)

e11529 Background: Previous studies evidenced that the combination docetaxel (D) (75 mg/m²) + lapatinib (L) (1,250 mg/d) is well tolerated in heavily pretreated HER2-positive metastatic breast cancer patients (pts) in association with systematic G-CSF. This phase I study was conducted to assess safety, optimal tolerated regimen (OTR) and clinical activity of D + L in naïve treatment pts with HER-2 positive LAMBC without primary use of growth factor. Methods: Women with HER2+ LAMBC, naïve of treatment for advanced or metastatic disease, ECOG PS 0-2, were eligible for this study. Pts received once daily oral dosing of L with intravenous D on day 1 of every 3 week cycle. Initial dose was D (75 mg/m²) + L (1,250 mg/d) escalating up to D 100 mg/m² and L 1,500 mg/d until the Maximal Tolerated Dose (MTD) was reached. An expansion cohort of 6 pts was treated at the OTR level. Primary use of G-CSF was not permitted. Results: From Aug 2008 to Nov 2011, 17 pts were enrolled: median age 54.4 years [34.6-77], 59% were PS 0. All patients have metastatic disease with lung (29,4%), bone (41,2%), liver (76.5%) and lymph nodes (35.3%) metastasis. 7 pts received previously chemotherapy in adjuvant setting, 5 pts hormonotherapy and 7 pts radiotherapy. All but two pts were evaluable for dose limiting toxicities (DLT). 1 DLT/6 pts (FN) was observed at dose level (DL) 1 (D 75 mg/m² + L 1,250 mg/d) and 2 DLT/3 pts (gr 3 diarrhoea; gr4 neutropenia &gt;7 d) at DL2 (D 75 mg/m² + L 1,500 mg/d). Only one DLT (FN) was observed in expansion cohort at OTR (D 75 mg/m² + L 1,250 mg/d; 6 pts). Over all C1, other significant toxicities (% pts) included gr4 neutropenia 53%, gr3 transaminase increase 6%, gr2 skin rash 36%, gr2 nausea/vomiting 18%, gr2 diarrhoea 12%, gr2 stomatitis 12%, gr2 hand-foot syndrome 6%; no decrease of cardiac function occurred. Conclusions: OTR for D and L was 75 mg/m² once every 3 weeks and 1,250 mg once daily respectively. This study demonstrates that this combination could be administered without systematic use of G-CSF in non pretreated pts with LAMBC. Additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation. Clinical trial information: NCT01044485.
Risk factors for sporadic pancreatic neuroendocrine tumors (PNETs): Updated results from a single-center case control study.
Authors: Thorvardur Ragnar Halfdanarson, William R Bamlet, Robert R. McWilliams, Timothy J. Hobday, Patrick A. Burch, Gloria M. Petersen
Journal: Journal of Clinical Oncology (2012)

e14594 Background: PNETs are uncommon malignancies and little is known about risk their factors and association with other cancers. Our aim was to evaluate smoking, alcohol use, personal history of diabetes and a family history of PNET and other cancers as potential risk factors. Methods: PNET cases seen at Mayo Clinic Rochester from 2000 to 2011 were evaluated. Insulinoma and high-grade PNETs were excluded. Primary care patients served as controls and were matched (2:1 ratio) to cases on age, sex and region of residence. Cases and controls completed questionnaires at the time of evaluation. Categorical variables were compared with the chi-square test; continuous variables were compared using a two-sample t test. Results: 355 cases were evaluated, mean age was 56.6 years, 52% were males and 96% were White. Personal smoking history was not associated with PNETs (cases 51%, controls 47%, p=0.24). Ever-alcohol use was less common among cases (54% vs. 67%, p=0.001). 19% of cases reported a history of diabetes compared with 11% of controls (p&lt;0.001). Cases were more likely than controls to report a family member with sarcoma (p=0.02), PNET (p=0.024), gall bladder cancer (p=0.024), ovarian cancer (p=0.04) and stomach cancer (p=0.01). Conclusions: Cases with PNETs were more likely than controls to report a history of diabetes and less likely to report alcohol use. There was no association with smoking. Several types of cancer were more commonly reported in family members of cases than controls.