tbuckley/cabot-search huggingface dataset:
Heart Failure, the Hidden Problem of Pain
Authors: Joy R Goebel, Lynn Doering, Lisa R Shugarman, Steven M Asch, Cathy D Sherbourne, Andy B Lanto, Lorraine S Evangelista, Adeline M Nyamathi, Sally L Maliski, Karl A Lorenz
Journal: Circulation (2008)

CLINICAL SCIENCE Abstract 4056: Heart Failure, the Hidden Problem of Pain Jfl!/ R Goebel, Lynn V Doering, Uea R Shugarman, Steven M Asch, Cathy D Sherbourne, Andy B Lanto, Lorraine S Evangellata, Adellne M Nyamathl, Sally L Mallskl and Karl A Lorenz Published: October 28, 2008 Artlcle Info & Metrics eletters .,,. Jumpto Abstract Background: Although dyspnea and fatigue are hallmark symptoms of chronic heart failure (HF), clinicians may under-recognize the burden of pain, despite the fact that it is debilitating to patients and poses unique therapeutic challenges. Guided by the conceptual model of 'total pain,' this study assessed pain in chronic HF and identified contributing factors. Methods and results: As part of a multicenter study to improve pain management in veterans (Help-Vets), 96 veterans with chronic HF (96% male, aged 67 ± 11 years) completed self-report measures of symptom frequency, pain severity and interference (Brief Pain Inventory [BPI]), functional status (Functional Morbidity Index [FMI]} and psychological state (Patient Health Questionnaire [PHQ]-2 for depression and Generalized Anxiety Disorders [GAD]-2 for anxiety). Single items from BPI interference and the Quality of Life End of Life (QOL-e) measured social and spiritual well-being. Demographic and clinical variables were obtained by chart audit. Correlation and linear regression models evaluated physical, emotional, social, and spiritual factors associated with pain. Fifty three (55.2%) HF patients reported having current pain with a majority of those (36 [67 .9%]) rating their pain as moderate to severe (pain >or 4/10). The presence of any pain was reported more frequently than dyspnea (67 [71.3%]) vs. 58 [61.7%]). In bivariate analyzes age (p 0.02), psychological (depression: p = 0.002; anxiety: p 0.001 ), social (p < 0.001 ), spiritual (p = 0.010) and physical (health status: p = 0.001; symptom frequency: p = 0.000; functional status: p= 0.002) well being were correlated with pain severity. In the resulting model, 38% of the variance in pain severity was explained (p < .001 ); only interference with social relations (p < 0.001) and the number of other symptoms present (p = 0.007) contributed significantly to pain severity. Conclusion: In this pilot study, a majority of patients reported pain, and most of those reported it as moderate to severe. The presence of pain was more common than dyspnea. The strong, independent association of overall pain with social factors underscores the potential role of multidisciplinary support to improve symptoms and well being in HF.
Secreted protein acidic and rich in cysteine (SPARC) activates focal adhesion kinase and integrin-linked kinase to induce AKT-dependent glioma survival and invasion
Authors: Qing Shi, Shideng Bao, Darell D. Bigner, Jeremy N. Rich
Journal: Cancer Research (2006)

1683  Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix glycoprotein overexpressed in malignant gliomas and other solid cancers. In a gene expression study, we recently demonstrated that increased SPARC expression is associated with poor prognosis in older glioblastoma patients. Forced expression of SPARC increases glioma invasion associated with increased matrix metalloproteinase expression. Also, SPARC activates the pro-survival AKT pathway to increase glioma tumor cell survival upon serum withdrawal. To determine potential SPARC signal transducers upstream of AKT, we examined the activation state of kinases that are activated in gliomas and mediate invasion. While several transmembrane growth factor receptor tyrosine kinases are not activated by SPARC, we now demonstrate that SPARC acutely activates both focal adhesion kinase (FAK) and integrin-linked kinase (ILK). SiRNA suppression of either FAK or ILK expression reduces SPARC activation of AKT with a near complete inhibition by combined targeting of FAK and ILK expression. SPARC-mediated activation of FAK and ILK contribute to the biological effects of SPARC as suppression of FAK or ILK expression attenuates the effects of SPARC on both glioma invasion and cellular survival. SPARC induces a novel interaction of ILK and FAK as both exogenous SPARC and genetic expression of SPARC induces a complex of ILK and FAK. SPARC has been linked to tumor progression in several advanced cancers. The identification of a signal transduction pathway mediating the effects of SPARC may provide a marker of tumor dependence on specific signal transduction elements.
Response to Letters Regarding Article, “Role of Microvolt T-Wave Alternans in Assessment of Arrhythmia Vulnerability Among Patients With Heart Failure and Systolic Dysfunction: Primary Results From the T-Wave Alternans Sudden Cardiac Death in Heart Failure Trial Substudy”
Authors: Michael R. Gold, John H. Ip, Otto Costantini, Jeanne E. Poole, Gust H. Bardy, Steve McNulty, Daniel B. Mark, Kerry L. Lee
Journal: Circulation (2009)
Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma
Authors: Ute I. Scholl, Laura Abriola, Chengbiao Zhang, Esther N. Reimer, Mark Plummer, Barbara I. Kazmierczak, Junhui Zhang, Denton Hoyer, Jane S. Merkel, Wenhui Wang, Richard P. Lifton
Journal: Journal of Clinical Investigation (2017)

Aldosterone-producing adenomas (APAs) are benign tumors of the adrenal gland that constitutively produce the salt-retaining steroid hormone aldosterone and cause millions of cases of severe hypertension worldwide. Either of 2 somatic mutations in the potassium channel KCNJ5 (G151R and L168R, hereafter referred to as KCNJ5MUT) in adrenocortical cells account for half of APAs worldwide. These mutations alter channel selectivity to allow abnormal Na+ conductance, resulting in membrane depolarization, calcium influx, aldosterone production, and cell proliferation. Because APA diagnosis requires a difficult invasive procedure, patients often remain undiagnosed and inadequately treated. Inhibitors of KCNJ5MUT could allow noninvasive diagnosis and therapy of APAs carrying KCNJ5 mutations. Here, we developed a high-throughput screen for rescue of KCNJ5MUT-induced lethality and identified a series of macrolide antibiotics, including roxithromycin, that potently inhibit KCNJ5MUT, but not KCNJ5WT. Electrophysiology demonstrated direct KCNJ5MUT inhibition. In human aldosterone-producing adrenocortical cancer cell lines, roxithromycin inhibited KCNJ5MUT-induced induction of CYP11B2 (encoding aldosterone synthase) expression and aldosterone production. Further exploration of macrolides showed that KCNJ5MUT was similarly selectively inhibited by idremcinal, a macrolide motilin receptor agonist, and by synthesized macrolide derivatives lacking antibiotic or motilide activity. Macrolide-derived selective KCNJ5MUT inhibitors thus have the potential to advance the diagnosis and treatment of APAs harboring KCNJ5MUT.
Use of tumor necrosis factor receptor 2 (TNFR2)/p75 and TNF-α as an antitumor strategy.
Authors: Sanggyu Bae, Sharath Sasi, Jin Song, Aleksandr Perepletchikov, Douglas Schneider, David Goukassian
Journal: Journal of Clinical Oncology (2013)

e22010 Background: TNF-α has two receptors, TNFR1/p55 and TNFR2/p75, with diverse signaling roles: p55 - predominantly cytotoxic and p75 - prosurvival and proangiogenic. Compared to WT and p55KO/p75KO, growth of tumors in p75 knockout (KO) mice was decreased &gt;50% in Lewis lung carcinoma (LLC) and B16 melanomas (Sasi et al., Oncogene, 2012). This was associated with increased apoptosis and decreased capillary density in tumos. We hypothesized that selective blocking of p75 receptor in tumors may sensitize them to TNF induced apoptosis. Methods: p75 receptor was knockdown (KD) in LLCs using shRNA. LLC and p75KD LLCs were implanted into WT mice flanks. On day 8 post-inoculation, mouse recombinant (mr) TNF (12.5 ng/g/injection) or saline was injected x2 daily for 6 days. Tumor volumes (tV) were measured daily and tumor weights (tW) on day 16. Tumors, tubular bones and spleens were examined by 2 pathologists blindfolded to treatments. Results: Mouse weights remianed stable throughout the study in all groups. There was no difference in tV or tW between LLC minus(-) TNF and p75KD LLC-TNF tumors on day 16 (2 d days after last injection). Compared to 3 control groups, p75KD LLC+TNF showed &gt;2-5-fold decreases in tV (p&lt;0.001, n=8) and tW (p&lt;0.0001, n=8). There was NO difference in tV or tW (p=ns) end of study vs before injections in p75KD LLC+TNF group whereas in 3 control groups tV and tW were increased 2.7-, 4.5- and 3.2-fold (p&lt;0.01, p&lt;0.0002 and p&lt;0.0001). Pathology revealed that 1/3 of tumors in p75KD LLC+TNF group were nearly 100% necrotic. Bone marrow and spleens did not show significant TNF-induced systemic toxic effect. There was an inflammatory response in the BM and spleens of mice with necrotic tumors in +TNF group, reflected by shift of myeloid/erythroid radio in the BM and moderate increases in lymphoid follicles in the spleen. Conclusions: Our results suggest that blocking p75 expression in tumor tissue combined with administration of small exogenous doses of TNF significantly inhibits aggressive LLC tumor growth and induces nearly 100% tumor necrosis in 1/3 of the experimental group in six days, with no detectible systemic toxicity. This may represent new and effective therapy against lung neoplasms and potentially solid tumors of other origin.
A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer.
Authors: Kevin Kalinsky, Prabhjot Singh Mundi, Codruta Chiuzan, Melissa Kate Accordino, Meghna S. Trivedi, Joseph A. Sparano, Sun Young Oh, Amy Tiersten, Ruth O'Regan, Francisco J. Esteva, Sarika Jain, Ingrid A. Mayer, Andres Forero, Lea N. Baer, Katherine D. Crew, Dawn L. Hershman, Christos Vaklavas
Journal: Journal of Clinical Oncology (2017)

TPS1112 Background: CDK4/6i, including palbociclib and ribociclib (R), have demonstrated remarkable benefit in progression free survival (PFS) in patients (pts) with HR+, HER2- MBC with anti-estrogen therapy. Switching between anti-estrogen therapies at disease progression is standard of care in the treatment of HR+ MBC. We evaluate the strategy of switching anti-estrogen therapy to fulvestrant (F) and maintaining CDK4/6 inhibition with R in pts with HR+, HER2- MBC who have progressed on an AI + CDK4/6i. Methods: Trial Design Phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate F +/- R in pts with HR+, HER2- MBC who have previously progressed on any AI + CDK4/6i: Screened at 2 different scenarios: Scenario 1: Before receiving any CDK4/6i Scenario 2: Time of progression of disease (POD) while being treated with an AI + CDK4/6i Intervention At randomization, pts assigned 1:1 to either a) F + R or b) F + placebo, with treatment given in 4-week cycles. Major Eligibility Criteria 1, Metastatic BC, 2. HR+ HER2-, 3. Measurable or unmeasurable disease Specific Aims Primary: PFS. Secondary: Objective response rate, clinical benefit rate, overall survival, and duration of response. Biomarker assessment: amplification of cyclin D1 and cyclin E, phosphoRb and TK1 expression, Rb1 and p16 loss, and ctDNA for ESR1 and PIK3CA mutations. Statistical Methods Assuming a median PFS of 3.8 months with F alone, we predict that F + R will lead to a median PFS of at least 6.5 months. A one-sided log-rank test with a sample size of N = 120 and alpha = 0.025, achieves 80% power to detect a difference in PFS of 2.7. With a 10% dropout, n = 132. Clinical trial registry number NCT02632045.
A highly adhesive and naturally derived sealant
Authors: Alexander Assmann, Andrea Vegh, Mohammad Ghasemi-Rad, Sara Bagherifard, George Cheng, Ehsan Shirzaei Sani, Guillermo U. Ruiz-Esparza, Iman Noshadi, Antonio D. Lassaletta, Sidhu Gangadharan, Ali Tamayol, Ali Khademhosseini, Nasim Annabi
Journal: Biomaterials (2017)
Irbestartan is projected to be cost and life saving in the USA for treatment of patients with type 2 diabetes, hypertension, and microalbuminuria
Authors: AJ Palmer, Lieven Annemans, S Roze, M Lamotte, P Lapuerta, S Gabriel, R Chen, P Carita, I Villadary, RA Rodby, D De Zeeuw, HH Parving
Journal: Journal of the American Society of Nephrology (2003)
Neoliberal policies threaten the FDA’s regulatory mission
Authors: Mark Wilson
Journal: BMJ (2017)

Doshi and Godlee identify a serious accountability gap in the integrity of information in medical journals.1 Can the Food and Drug Administration close it? 

In principle the FDA can ensure that the information published in medical journals is aligned with its reviews. But the agency is beset by problems rooted in neoliberal market policies that undermine effective …
Response to a wild poliovirus type 2 (WPV2)-shedding event following accidental exposure to WPV2, the Netherlands, April 2017
Authors: Erwin Duizer, Wilhelmina LM Ruijs, Charlie P van der Weijden, Aura Timen
Journal: Eurosurveillance (2017)

On 3 April 2017, a wild poliovirus type 2 (WPV2) spill occurred in a Dutch vaccine manufacturing plant. Two fully vaccinated operators with risk of exposure were advised on stringent personal hygiene and were monitored for virus shedding. Poliovirus (WPV2-MEF1) was detected in the stool of one, 4 days after exposure, later also in sewage samples. The operator was isolated at home and followed up until shedding stopped 29 days after exposure. No further transmission was detected.
Long-term risk of second malignancies in women with ductal carcinoma in situ or early-stage invasive breast cancer after breast conservation treatment.
Authors: Carolyn J. Kushner, Wei-Ting Hwang, Lawrence J. Solin, Neha Vapiwala
Journal: Journal of Clinical Oncology (2017)

e12103 Background: Women with ductal carcinoma in situ (DCIS) or early stage breast cancer have a good prognosis after breast conservation treatment (BCT), and are at risk for second malignant neoplasms (SMNs). The long-term risk of SMNs is not well established and carries important public health implications. Methods: A total of 755 women with DCIS or stage I-II invasive breast cancer underwent breast-conserving surgery followed by definitive breast irradiation between 1995 and 2001. Systemic therapy (chemotherapy and/or hormonal therapy) was given to 73% of the patients. We have previously described patient demographics and 15-year oncologic outcomes in detail (Vapiwala, Cancer, 2017). The patient records were reviewed for development of SMNs. SMNs of any anatomic site (other than contralateral breast cancer and basal/squamous cell carcinoma of the skin) were included for analysis. The Kaplan-Meier method was used to determine the rate of SMNs over time. Median follow-up was 13.8 years. Results: The 5-, 10-, and 15-year rates of developing any SMN were 3.6% (95% CI 2.4-5.3%), 7.8% (95% CI 6.0-10.2%), and 12.7% (95% CI 10.2-15.8%). The most common SMNs were uterine (n=12), leukemia/lymphoma (n=11), melanoma (n=10), ovarian (n=9), and lung (n=7). Conclusions: Development of SMNs is a substantial risk for a protracted period of time following BCT. Clinical patterns of specific SMN histologies, locations and time course of development suggest potential opportunities for screening and treatment to guide patient survivorship clinics and protocols.
Ultrasound-sensitive nanoparticle aggregates for targeted drug delivery
Authors: Anne-Laure Papa, Netanel Korin, Mathumai Kanapathipillai, Akiko Mammoto, Tadanori Mammoto, Amanda Jiang, Robert Mannix, Oktay Uzun, Christopher Johnson, Deen Bhatta, Garry Cuneo, Donald E. Ingber
Journal: Biomaterials (2017)
Evidence-Based Guidelines: Optimizing Imaging in Cancer Care
Authors: Pamela J. DiPiro
Journal: Journal of the National Comprehensive Cancer Network (2017)

The "Image Wisely" campaign was founded in 2010 by the Radiological Society of North America, the American College of Radiology (ACR), the American Association of Physicists in Medicine, and the American Society of Radiologic Technologists.The campaign's objective was to reduce medically necessary radiation to the lowest amount required for best image quality (stressing the principle of "ALARA"-As Low As Reasonably Achievable) and to eliminate unnecessary studies.The marked increase in imaging use and associated dramatic increase in costs have drawn the attention of policymakers; if oncologists are unable to self-regulate and reduce the use of unnecessary examinations, new policies may stifle potential future advances in imaging. 1 This topic is discussed in the study by Dull et al in this issue, "Overuse of Chest CT in Patients With Stage I and II Breast Cancer: An Opportunity to Increase Guidelines Compliance at an NCCN Member Institution" (page 783).I commend the authors of this study for addressing the overuse of chest CT in early-stage breast cancer at their own institution.
TLR9 agonist lefitolimod to improve antitumor effect of checkpoint inhibitors in vivo.
Authors: Manuel Schmidt, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig
Journal: Journal of Clinical Oncology (2017)

e14625 Background: TLR9 agonists are potent activators of the immune system via induction of cellular and humoral responses. Preclinical and ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. Lefitolimod/MGN1703 is a covalently-closed dumbbell-like immune surveillance reactivator (ISR) with a broad immunomodulatory potential. Due to promising data from a phase 2 trial (IMPACT) as maintenance therapy after first-line chemotherapy in mCRC patients lefitolimod is recently evaluated in a phase 3 trial in mCRC patients (IMPALA). Furthermore, lefitolimod is currently investigated in a phase 2 trial in SCLC patients (IMPULSE) and in a phase 1 / 2 trial in HIV patients (TEACH). Methods: It was shown that lefitolimod reduces tumor growth in several murine tumor models. Since the mode-of-action of lefitolimod starts upstream of the initiation points of checkpoint inhibitors like anti-CTLA-4 or anti-PD-1/anti-PD-L1 a combinatory approach may result in an enhanced anti-tumor effect. Therefore, two syngeneic murine models were used – a colon carcinoma CT26 and a lymphoma A20 model – for evaluation of the anti-tumor effect in vivo. Results: In the CT26 model treatment with anti-PD-L1 (i.p.) had no effect on the tumor growth, whereas addition of lefitolimod (s.c.) to anti-PD-L1 led to an anti-tumor effect (tumor growth inhibition, TGI 48%) which consequently resulted in prolonged survival of the mice. This combinatory effect was even more pronounced in the A20 model where treatment with anti-PD-1 (i.p.) alone had a moderate anti-tumor effect which was vastly increased by the combination (TGI – anti-PD-1: 46%, anti-PD-1/lefitolimod 99%). Conclusions: In conclusion, we showed that lefitolimod, a member of dSLIM ® family of TLR9 agonists and an ISR, can enhance the limited anti-tumor effects of checkpoint inhibitors in pilot studies in murine colon carcinoma and lymphoma tumor models in vivo. These data show the promising potential for the combination with checkpoint inhibitors. Notably, a clinical trial in cooperation with MD Anderson evaluating the benefit of lefitolimod in combination with ipilimumab is currently ongoing.
Demodex-Positive Acneiform Eruption Responsive to Ivermectin in a Patient Taking an Epidermal Growth Factor Inhibitor
Authors: Trevor B. Parker, Adam B. Blechman, Barbara B. Wilson
Journal: JAMA Dermatology (2017)

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Phase I study of alpelisib (BYL-719) and T-DM1 in HER2-positive metastatic breast cancer after trastuzumab and taxane therapy.
Authors: Sarika Jain, Cesar Augusto Santa-Maria, Alfred Rademaker, Francis J. Giles, Massimo Cristofanilli, William John Gradishar
Journal: Journal of Clinical Oncology (2017)

1026 Background: Constitutive activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a mechanism of trastuzumab resistance in HER2-positive metastatic breast cancer (MBC). Alpelisib (BYL-719) is the first oral PI3K inhibitor that selectively inhibits the PI3Kα isoform. We aimed to determine the maximum tolerated dose (MTD), safety, and activity of alpelisib with ado-trastuzumab emtansine (T-DM1) in HER2-positive MBC that failed standard therapy. Methods: In this phase I study, pts received alpelisib daily (cohort 1: 300 mg, (-1): 250 mg) and T-DM1 3.6 mg/m 2 on Day 1 every 21 days using a 3+3 design with dose expansion at MTD. Dose-limiting toxicity (DLT) was defined as CTCAE Grade 3/4 adverse events (AE) during cycle 1. Data cut-off is Jan. 1, 2017. Results: 17 pts were enrolled. Median age was 53 (40-66). Median prior lines of therapy in metastatic setting was 4.5 (0-13) including 9 pts who progressed on prior T-DM1 (after median 8 cycles). Median number of metastatic sites was 2 (1-5). Median number of cycles per pt who completed at least 1 cycle was 8 (1-19). Five pts were enrolled in cohort 1 with 2 DLTs (grade 3 rash), leading to cohort (-)1, in which there were no DLTs. The most common alpelisib-related AEs were hyperglycemia (n = 9, 53%), fatigue (n = 9, 53%), nausea (n = 7, 35%), and rash (n = 8, 47%). Grade 3 alpelisib-related AEs included rash (n = 7), hyperglycemia (n = 3), weight loss (n = 1), hypertension (n = 2), and pancreatitis (n = 1). Grade 3 rash occurred during cycle 1, which resolved with interruption and subsequent dose reduction of alpelisib and use of steroids. Grade 3 hyperglycemia was reversible with oral anti-diabetic treatment. One Grade 4 AE occurred (thrombocytopenia) likely due to T-DM1. MTD for alpelisib was established as 250 mg daily. Median follow-up was 11.6 months (0.3-19.5). Median PFS was 6 months (95% CI 2.9-10.6). In 11 pts without prior T-DM1 mPFS was 4.3 months (95% CI 2.0-8.8) and in 6 pts with prior T-DM1 it was 10.6 months (95% CI 1.6-12.6), p = 0.18. Conclusions: The combination of alpelisib 250 mg daily and T-DM1 appears to be safe in HER2-positive MBC pts with significant anti-tumor activity, even in pts previously treated with T-DM1. A phase II study is planned. Clinical trial information: NCT02038010.