tbuckley/cabot-search huggingface dataset:
Skin-Mountable Biosensors and Therapeutics: A Review
Authors: Eun Kwang Lee, Min Ku Kim, Chi Hwan Lee
Journal: Annual Review of Biomedical Engineering (2019)

Miniaturization of electronic components and advances in flexible and stretchable materials have stimulated the development of wearable health care systems that can reflect and monitor personal health status by health care professionals. New skin-mountable devices that offer seamless contact onto the human skin, even under large deformations by natural motions of the wearer, provide a route for both high-fidelity monitoring and patient-controlled therapy. This article provides an overview of several important aspects of skin-mountable devices and their applications in many medical settings and clinical practices. We comprehensively describe various transdermal sensors and therapeutic systems that are capable of detecting physical, electrophysiological, and electrochemical responses and/or providing electrical and thermal therapies and drug delivery services, and we discuss the current challenges, opportunities, and future perspectives in the field. Finally, we present ways to protect the embedded electronic components of skin-mountable devices from the environment by use of mechanically soft packaging materials.
The Tobacco Industry and the creation of an epidemic of smoking-related lung adenocarcinoma: Surveillance-Epidemiology And End Results (SEER) analysis, 1973-2011.
Authors: Gary M. Strauss, Alejandro Moreno-Koehler, Matthew Finkelman
Journal: Journal of Clinical Oncology (2015)

e12625 Background: When epidemiologic research first demonstrated an association between cigarette smoking and lung cancer in the early 1950s, adenocarcinoma comprised about 5% of lung cancers and appeared to be unrelated to smoking. In the 1960s and 1970s, adenocarcinoma increased sharply, and became strongly related to cigarette smoking. Methods: We analyzed time trends in lung histology with changes in cigarette design and Tobacco Industry actions over six decades. We utilized SEER data on 419,941 lung cancers diagnosed between 1973 and 2011 to analyze time trends of age-standardized incidence rates of five histologic subtypes: adenocarcinoma, squamous cell, small cell, large cell, and adenosquamous carcinoma. Results: Over time, the percentage of lung cancers that were adenocarcinomas increased from 29% (in 1973-1974) to 55% (in 2010-2011). During this 38-year period, the percentage of lung cancers that were squamous cell carcinomas decreased from 41% to 26%.Among all patients, adenocarcinoma incidence surpassed squamous carcinoma by 1985-1989 to become the most common histologic subtype. Adenocarcinoma surpassed squamous cell in 1990-1994 in men, while it was already most common in women by 1973-1974. Adenocarcinoma rose 77% in men from 1973-1974 to 1990-1994, while it rose 197% in women between 1973-1974 and 2005-2006. Among whites, adenocarcinoma surpassed squamous carcinoma by 1985-1989, while this occurred among blacks by 1990-1994. It was already most common among other race individuals in 1973-1974. Adenocarcinoma was already most common among patients < 50 yrs of age by 1973-1974, while adenocarcinoma rapidly increased and surpassed squamous carcinoma in all other age groups by 1990-1994. Conclusions: Lung adenocarcinoma currently comprises approximately 55% of US lung cancers. It is the most common histology in men and women, in whites, blacks, and other-races, and in all age groups. The role of Big Tobacco in helping to create this epidemic will be addressed in a companion abstract that has been submitted to ASCO-2015.
Phase I trial of the HSP-90 inhibitor PU-H71.
Authors: John F. Gerecitano, Shanu Modi, Raajit Rampal, Alexander E. Drilon, Matthew G. Fury, Mrinal M. Gounder, James J. Harding, David Michael Hyman, Anna M. Varghese, Martin Henner Voss, Fallon Olga France, Tony Taldone, Erica Gomes DaGama, Mohammad Uddin, Gabriela Chiosis, Jason Stuart Lewis, Serge K. Lyashchenko, Steven M. Larson, Christina Pressl, Mark Dunphy
Journal: Journal of Clinical Oncology (2015)

2537 Background: PU-H71 (PU) is an HSP-90 inhibitor that can be labeled with 124I without altering its biochemical properties. Intratumoral drug concentration can be calculated based on 124I-PU-H71 (*PU) PET imaging, leading to a surrogate marker of intratumoral pharmacokinetics. Methods: Patients (pts) with previously treated solid tumors, lymphoma and myeloproliferative neoplasms (MPN) on ruxolitinib were eligible. PU was given days 1, 4, 8, 11 each 21 days at escalating dose levels using a Continuous Reassessment Method (CRM). The primary objective was determination of the MTD. Secondary objectives included plasma and intratumoral PKs measured by pre- and on-treatment core needle biopsies (CNB) and by *PU PET imaging. Results: To date, 40 pts have received PU at doses from 10-400mg/m2. 37 are currently evaluable for DLT, and the last 3 pts needed (per CRM) are being enrolled. Five pts experienced DLTs: 1 (of 2) at 400 mg/m2 - grade 3 mucositis; 4 (of 7) at 350 mg/m2 – 1 pt grade 3 AST and ALT, 1 pt grade 3 nausea/vomiting + grade 2 intolerable myalgia, 1 pt grade 3 anemia, 1 pt grade 2 intolerable headache. Related grade 3 toxicities seen in more than one pt include: AST (n = 2), atrial fibrillation (n = 2), diarrhea (n = 2), hypertension (n = 2), hyponatremia (n = 3), lymphopenia (n = 6) and WBC decrease (n = 2). Grade 4 toxicities include lymphopenia (n = 2), amylase (n = 1), and urine output decrease (n = 1). Intratumoral concentrations of 0.5 – 8 µM (greater than the IC50 for most cancer cells) were consistently achieved 24h after first dose at doses of 50 - 300 mg/m2, suggesting that target saturation may be achieved below DLT-related doses. Tumor regressions included: 22.6% in a cervical SCC pt (140 mg/m2), 8.3% in a triple negative breast cancer pt (300 mg/m2), 25.6% in an ER positive breast cancer pt (400 mg/m2), 20.8% in a penile SCC (350 mg/m2) pt and 20.6% in a Marginal Zone Lymphoma pt (50 mg/m2). One MPN pt decreased WBC and increased hemoglobin > 1 unit. 23 pts had *PU PET imaging. 13 of these had CNBs. Intratumoral concentrations measured both ways were in close concordance. Conclusions: PU is a well tolerated HSP-90 inhibitor with signals of activity seen in several tumor types.*PU can be used to visualize PU uptake and *PU PET scans can be used to estimate intratumoral concentrations of PU. Clinical trial information: NCT01393509.
Phase 1 Study of Elotuzumab in Combination with Autologous Stem Cell Transplantation and Lenalidomide Maintenance for Multiple Myeloma
Authors: Keren Osman, Ajai Chari, Samir Parekh, Christine Pun, Gillian Morgan, Erika Florendo, Elaine Chan, Marisa Shields, Gina Strumolo, Lisa La, John Mandeli, James Geerlof, Sundar Jagannath, Hearn Jay Cho
Journal: Blood (2016)
Indeed, not really a brain disorder: Implications for reductionist accounts of addiction
Authors: Matt Field, Nick Heather, Reinout W. Wiers
Journal: Behavioral and Brain Sciences (2019)

Abstract Borsboom et al.’s formulation provides an opportunity for a fundamental rethink about the “brain disease model” of addiction that dominates research, treatment, policy, and lay understanding of addiction. We also demonstrate how the American opioid crisis provides a contemporary example of how “brain disease” is not moderated by the environmental context but is instead crucially dependent upon it.
Results from a phase I/Ib trial of enzalutamide and gemcitabine and cisplatin in metastatic bladder cancer (mBC).
Authors: Shilpa Gupta, Jasreman Dhillon, Anthony Martin Magliocco, John Puskas, Gisela Caceres, Fadzai Masawi, Yulia Doronin, Jingsong Zhang
Journal: Journal of Clinical Oncology (2019)

471 Background: Novel targeted therapies are an unmet need in mBC. Androgen receptor (AR) is a rational target in BC and we conducted a phase 1/1b trial assessing safety and tolerability of AR antonist, enzalutamide (ENZ) in combination with gemcitabine and cisplatin (GC) in mBC. Methods: The dose escalation phase allowed patients with mBC regardless of the AR status (assessed on routine IHC) and dose expansion cohort allowed only AR+ pts. The dose escalation phase had 2 cohorts testing ENZ at doses of 80 and 160 mg respectively with GC (G 1000 mg/m2 on days 1, 8 and C 70 mg/m2 on day 1 every 21 days). After 6 cycles of ENZ+GC, pts. continued maintenance ENZ until disease progression. Primary objective was safety and tolerability of ENZ and GC. Secondary objectives were PFS, OS and objective tumor response. Exploratory objectives included evaluation of AR expression in tumor tissues and correlation with outcomes and CTC evaluation at baseline and prior to cycle 3, including AR expression in CTCs and correlation with clinical outcomes. Key eligibility criteria included ECOG PS of 0-1, and no contraindications to ENZ and GC. Results: A total of 10 pts were enrolled between Nov. 2014 and Jan. 2017; 6 pts were enrolled on the dose escalation phase, there were no DLTs observed and ENZ dose of 160 mg was used for the dose expansion cohort, which enrolled 4 pts. The combination of ENZ and GC was well tolerated with expected toxicities, mainly from GC. Median age was 65.6 yrs, 9/10 pts were male; of the 8 evaluable pts, 1 had CR, 4 had PR, 2 had SD and 1 had PD; median OS was 10.59 mos and median PFS was 7.68 mos. CTCs were detectable in 9/10 pts and correlated with disease response. The pt with CR was a female pt with strongly AR + tumor (&gt;90%) and continues to remain in CR 24 months from starting treatment. Exploratory analysis from CTCs and is ongoing. Conclusions: This is the 1 st clinical trial to target AR signaling in mBC with ENZ and to evaluate safety of ENZ with GC. While there were limited number of pts enrolled, the results from this study provide early evidence that AR is a rational target in BC and anti-AR therapies can be safely combined with chemotherapy. Clinical trial information: NCT02300610.
Abstract 011: Comprehensive Cardiovascular Risk Reduction Trial in Persons With Serious Mental Illness (IDEAL Trial)
Authors: Gail L Daumit, Lawrence Appel, Nae-Yuh Wang
Journal: Circulation (2019)

Introduction: Persons with serious mental illness (SMI) are at high risk for cardiovascular disease (CVD), with CVD mortality with rates at least twice those of the overall US. Potentially modifiable CV risk behaviors (tobacco smoking, obesity, physical inactivity, unhealthy diet) and risk factors (hypertension, diabetes, dyslipidemia) are all markedly elevated in persons with SMI. This vulnerable population often has substantial challenges related to cognitive impairment and psychiatric symptoms in addition to high prevalence of substance use, low income and social isolation. Accomplishing meaningful reductions in CVD risk for persons with SMI will require special efforts to develop interventions to promote CV health in this high-risk group. Our objective was to determine the effectiveness of an 18-month comprehensive CVD risk reduction intervention in adults with SMI. Hypothesis: The active intervention is more effective than the control condition in reducing CVD risk as assessed by the global Framingham Risk Score (FRS). Methods: We conducted a NHLBI-sponsored RCT in 269 adults with SMI who had at least one of the following CV risk behaviors/ factors: BMI≥25 kg/m 2 , tobacco smoking, hypertension, diabetes, or dyslipidemia. Participants were recruited from four locations of an outpatient community mental health organization. Those in the active intervention received an 18-month individual-level intervention delivered by a health coach and a nurse providing 1) tailored CVD risk reduction counseling; 2) collaboration with physicians to implement appropriate management of CVD health risks; and 3) coordination with mental health staff and social supports to encourage and motivate attainment of individual CV health goals. We also provided training and resources to promote group physical activity classes, and a dietician to consult with kitchen staff to provide healthier meals (accessible to all mental health program attendees). Results: At baseline, mean(SD) age was 48.8(11.9) years, range 21-71. Of 269, 48% (N=128) were male, 46% (125) were African-American, 84%(226) received disability, 59%(159) had schizophrenia/schizoaffective disorder, 25%(67) had bipolar disorder, and 14%(38) had depression. BMI was 33.7(7.2) kg/m 2 ; 51% (138) smoked tobacco, 52% (141) had hypertension, 35% (93) had diabetes, 65%(175) had dyslipidemia. Mean(SD) baseline global FRS was 12.1(12.1)% overall, 16.9(14.6)% for men, 7.9(6.8)% for women. By October 15, 2018, 94%(253 of 269) participants completed the trial and had 18-month data collected. Eighteen-month data collection for the trial will conclude in November, 2018. Conclusion: Unless effective interventions that effect CV health outcomes are implemented, populations with SMI will continue to lag far behind the nation’s CVD goals. The IDEAL intervention is well positioned to address all CV risks in persons with SMI.
Acquired resistance to HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in adult and pediatric glioblastoma cell lines
Authors: nathalie gaspar, Swee Sharp, Simon Pacey, Chris Jones, Mike Walton, Gilles Vassal, Andrew Pearson, Paul Workman
Journal: Cancer Research (2008)

2461    Introduction.  The molecular chaperone heat shock protein 90 (HSP90) is an exciting anticancer drug target due to its role in maintaining the stability and function of oncogenic client proteins. The HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), in phase II clinical trials, binds to the N-terminal of HSP90 and inhibits its ATPase activity. 17-AAG inhibits the growth of glioblastoma (GB) cell lines. However, drug resistance account for poor GB prognosis.  Objective.  To explore acquired resistance to HSP90 inhibitors in GB cells.  Methods and results.  By continuous exposure to increasing 17-AAG concentrations, acquired resistance to 17-AAG was generated in both adult (SF268, U87MG) and pediatric (SF188, KNS42) GB cell lines. High levels of resistance with resistance indices (RI=IC50 of resistant line/IC50 of parental line; sulforhodamine B assay) of 20-137 were obtained rapidly (2-8 weeks). After cessation of 17-AAG, RI were decreased (6-25), except for the pediatric line KNS42. After 7-26 weeks, the RI remained stable in all cell lines. Cross-resistance was found with other 17-AAG related ansamycin benzoquinones (17-DMAG, 17-AG) but not with structurally unrelated HSP90 inhibitors, radicicol and our synthetic potent resorcinylic pyrazole/isoxazole amide compounds (VER-49009, VER-50589). An inverse correlation between NAD(P)H:quinone oxidoreductase 1 (NQO1) expression (western blot) / activity (enzymatic assay) and 17-AAG IC50 was observed with the resistant lines. The NQO1 inhibitor ES936 abrogated the differential effects on 17-AAG sensitivity between the parental and resistant lines. These results suggested that NQO1 plays a major role in 17-AAG resistance in GB cells. However, after 17-AAG cessation in the pediatric resistant line SF188-RA6, NQO1 protein/activity returned to parental level although 17-AAG resistance was retained, suggesting an additional mechanism of resistance, albeit restricted to ansamycin benzoquinones. NQO1 mRNA levels (quantatitive RT-PCR) inversely correlated with 17-AAG IC50 in the adult resistant lines, but levels remained stable in the pediatric resistant lines, suggesting different mechanisms of NQO1 down-regulation between adult and pediatric lines. NQO1 was also the mechanism of resistance in an acquired 17-AAG resistant melanoma cell line. Interestingly, we were unable to generate acquired resistant lines to the resorcinylic pyrazole/isoxazole amide agents.  Conclusion.  Low NQO1 activity is a likely mechanism of acquired resistance to 17-AAG in GB and in other cell types (e.g. melanoma), underlining the problematic metabolism of 17-AAG. New series of HSP90 inhibitors, such as the resorcinylic pyrazole/isoxazole amide analogues, are able to circumvent this mechanism of resistance, providing additional support for their clinical development.
Prognostic value of gain of chromosome 5q in localized renal cell carcinoma.
Authors: Cedric Michel Lebacle, Aydin Pooli, Nagesh Rao, Erika Louise Wood, Nils Kroeger, Sandy Liu, Izak Faiena, Karim Chamie, Arie S. Belldegrun, Brian Shuch, Alexandra Drakaki, Allan J. Pantuck
Journal: Journal of Clinical Oncology (2019)

623 Background: While gain of chromosome 5q is a frequently seen cytogenetic abnormality noted to occur in patients with renal cell carcinoma (RCC), little is known about its prognostic significance. We investigated the association of gain of 5q with disease-free survival (DFS) in patients with localized (non-metastatic T1-2) RCC. Methods: All patients from UCLA with primary tumor stage T1-2 RCC who had tumor cytogenetic analysis on tumor specimen were included. Alterations in chromosome 5q was specifically reviewed in this study. Logistic regression analyses were used to assess association of gain of 5q with final histopathology, ISUP grading, and T-stage. Cox proportional hazard modeling and Kaplan-Meier analyses were used to assess the impact of gain of 5q on DFS. Recurrence was defined as any local recurrence or development of new metastasis. Results: A total of 676 patients were included in this study. Gain of 5q occurred in 108 (16%) patients and was more commonly seen in clear cell versus non-clear cell tumors (19% vs. 9%, p = .002). Gain of 5q was associated with low grade ISUP (1 or 2) of clear-cell RCC (p = 0.011). On survival analysis, there was a 67% decreased risk of RCC recurrence for patients with gain of 5q (HR = 0.33, p = 0.018). The 5- and 10-year risk of recurrence was 2% vs. 16% and 14% vs. 28% for patients with and without gain of 5q, respectively (p = 0.013). In multivariable Cox analysis, the gain of 5q was an independent prognostic factor (p = .026 with ISUP grade and p = .025 with T-stage). These findings were confirmed among clear-cell RCC subgroup. Conclusions: Gain of chromosome 5q is an independent prognostic factor associated with decreased risk of recurrence in patients with localized T1-2 renal cell carcinoma. Identifying patients with a gain of 5q will improve the stratification of the risk of recurrence, could allow to adapt the follow-up protocols and avoid adjuvant treatment.
Meta-analysis of the relationship between EGFR mutation and the new lung adenocarcinoma classification.
Authors: Yao Yue, Li Liang
Journal: Journal of Clinical Oncology (2015)

e13555 Background: To investigate the relationship between EGFR mutation and The New Lung Adenocarcinoma Classification by evidence-based evaluation. Methods: A computer-based retrieval of Pumbed was performed for case-control studies investigating the EGFR and the new lung adenocaicinoma from the year of 2011 to the year of 2014, and supplemented by a manual search, and we get 26 papers. After evaluating methodological quality of studies, 8 papers met the inclusion criteria, we analyzed the data with meta analysis using RevMan 5.3 software. Results: For micropapillary predominant, involving 2238 case of adenocaicinoma, EGFR mutations and Non-mutations were 907(account for 40.5%) and 1331 case(account for 59.5%), while micropapillary predominant and non- micropapillary predominant were 156 and 2083 case, respectively. For lepidic predominant, involving 2128 case of adenocaicinoma, EGFR mutations and Non-mutations were 843(account for 39.6%) and 1285 case(account for 60.4%), while lepidic predominant and non-lepidic predominant were 245 and 1883 case, respectively. Meta analysis results showed that EGFR mutations in micropapillary predominant and lepidic predominant adenocaicinoma were significantly higher than in non-micropapillary predominant [odd ratio (OR) = 2.70, 95% confidence interval(CI)(1.90,3.86), P < 0.00001] and also in non-lepidic predominant adenocaicinoma[odd ratio (OR) = 2.31, 95% confidence interval(CI)(1.73,3.10), P < 0.00001]. Conclusions: The existing research results of Meta indicate that EGFR mutation has positive relationship with micropapillary predominant and lepidic predominant adenocaicinoma in the new lung adenocarcinoma classification..
A centrosome clustering protein, HSET, as a potential biomarker for ovarian adenocarcinomas.
Authors: Ritu Aneja, Karuna Mittal, Vaishali Pannu, Sergey Klimov, Guilherme Henrique Cantuaria, Ralph Sams, Padmashree C.G. Rida
Journal: Journal of Clinical Oncology (2015)

e16562 Background: Beyond their role as beacons of malignancy, supernumerary centrosomes drive aggressive disease course. Paradoxically, amplified centrosomes might compromise cell viability by consigning mitotic cells to a multipolar configuration resulting in high-grade death-inducing aneuploidy. Nonetheless, cancer cells employ clever tricks to suppress multipolarity by huddling their extra centrosomes by deploying clustering mechanisms to maintain pseudobipolarity associated with low-grade aneuploidy, an edge to their survival. HSET, a nonessential minus end-directed motor of the kinesin-14 family, is a centrosome clustering molecule essential for viability of extra centrosome-bearing cancer cells. Given that ovarian cancers robustly display amplified centrosomes in this study we examined the selective overexpression of HSET in human ovarian tumor. Methods: We interrogated single-channel microarray data from publically-available Gene Expression Omnibus (GEO) and Cancer Genome Atlas (TCGA) databases for HSET expression levels in serous ovarian adenocarcinoma (n = 1090) and normal ovarian (n = 38) tissue. To verify in silico results, we immunostained tissue microarrays with ovarian adenocarcinomas (n = 129) and normal ovarian (n = 13) samples, using an anti-HSET antibody. Results: Our in silico data indicated higher average (7.72 vs 5.86) HSET expression in serous ovarian carcinoma (n = 1090) compared to normal ovarian (n = 38) tissue (p < 0.05). Also, HSET expression increased with tumor grade (Grade 1-6.53, Grade 2-7.85, Grade 3-8.25) (p < 0.001). Immunohistochemical data corroborated with our in silico findings; ovarian adenocarcinomas exhibited (i) significantly higher (p < 0.005) nuclear HSET expression in comparison to the normal tissues, and (ii) a grade-wise increase in HSET expression (p = 0.0183). Conclusions: An increase in HSET levels was associated with increasing grade suggesting that an aggressive disease course in ovarian adenocarcinoma patients can be attributed to high levels of this centrosomal clustering molecule, thus, emphasizing the usefulness of HSET as a prognostic biomarker in ovarian cancers.