tbuckley/cabot-search huggingface dataset:
Efficacy of systemic treatment for metastatic renal cell carcinoma (mRCC) guided by comprehensive genomic profiling (CGP).
Authors: Paulo Gustavo Bergerot, Cristiane Decat Bergerot, Nazli Dizman, Nicholas Salgia, Joann Hsu, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2019)

63 Background: Comprehensive genomic profiling (CGP) has been used to guide treatment selection in metastatic renal cell carcinoma (mRCC). This study sought to determine if genomic alterations guided treatment and contributed to improved outcomes. Methods: From a single institution, patients (pts) diagnosed with mRCC who had CGP in the course of clinical care were identified. Pts were tested on a CLIAA-certified platform (FoundationOne; Cambridge, MA). Pts who died/initiated hospice within the 30 days after the test was performed or who were lost to follow-up were excluded. Duration of therapy (DOT) was measured as months between first and last day of therapy following CGP test. The Kaplan-Meier method was undertaken to estimate the association of CGP-directed therapy with overall survival (OS). Cox regression was also performed and adjusted for histologic subgroup. Results: A total of 64 patients underwent CGP between February 2014 and August 2018. From this group, 15 patients were excluded due to death/hospice within 30 d (n = 10) and lack of follow-up (n = 5). Median age at diagnosis was 60 years (range, 24-84), and 79% were male. Most patients (69%) were diagnosed with clear cell RCC. The median identified genomic alterations (GAs) was 3 (range, 0-7). The most common GAs were VHL (54%), PBRM1 (28%), TERT (21%), TP53 (15%), BAP1 (13%), and SETD2 (13%). Of the 49 patients included in this analysis, 47% had actionable mutations based on their CGP results. Of those, 13 patients received directed-therapy of whom 57% had stable disease, 28% had partial response, and 14% had progressive disease. The median time from CGP test to treatment was 1 month (range, 0-17). The median duration of directed-therapy was 12 months (range, 1-28) and of non-directed therapy was 4 months (range, 1-40) (P = 0.04). Directed-therapy was significantly associated with better OS (adjusted HR, 0.32 [95% CI, 0.13 to 0.82]; P = 0.018) compared to non-directed therapy. Conclusions: This study provides preliminary evidence to justify CGP-guided therapy in mRCC. Forthcoming studies should prospectively explore the use of CGP in treatment allocation for mRCC to validate these findings.
Reduction of Graft Rejection By Fludarabine Combined Busulfan, Cyclophosphamide and Antithymocyte Globulin Conditioning in Cord Blood Transplantation for Children with Wiskott-Aldrich Syndrome
Authors: Peifang Xiao, Jun Lu, Jie Li, Defei Zheng, Li Gao, Ailian Guo, Hu Liu, Suxiang Liu, Hailong He, Shaoyan Hu
Journal: Blood (2018)
Abstract 276: Maternal High Fat, High Sucrose Diet-induced Cardiac Mitochondrial Abnormalities in the Offspring are Transmitted via the Oocyte Nucleus
Authors: Jeremie L Ferey, Meghan Ruebel, Michaela Reid, Keith E Latham, Kelle H Moley, Abhinav Diwan
Journal: Circulation Research (2019)

Introduction: Maternal obesity correlates with higher cardiovascular disease risk in human offspring. We found high fat, high sucrose (HF/HS) diet results in accretion of abnormal mitochondria in mouse oocytes, and chow-fed offspring of HF/HS-fed dams exhibit transgenerational transmission of abnormal cardiac mitochondria through male and female germlines. Nuclear or mitochondrial inheritance can occur via the female germline, whereas male germline inheritance implicates nuclear epigenetic changes. However, recent reports indicate sperm mitochondria transmission is possible. Whether the mechanism is via effects on the nucleus or germ cell mitochondria is unknown. Hypothesis: Maternal HF/HS-feeding results in cardiac mitochondrial dysfunction in offspring due to effects on the oocyte nucleus. Methods: C57BL/6 female mice were chow- or HF/HS-fed, and mated to chow-fed C57BL/6 males. Female pronuclei were exchanged between embryos obtained from chow- and HF/HS-fed dams. Embryos without pronuclear transfer were additional controls. All embryos were transferred into chow-fed ICR dams. Cardiac mitochondrial structure (transmission electron microscopy) and function (high-resolution respirometry) were evaluated in 12-week-old offspring. Results: Adult offspring born of embryos having maternal pronuclei from chow-fed dams and ooplasm from chow- or HF/HS-fed dams had mitochondrial structure or oxygen consumption levels comparable to offspring born of control chow-fed dam embryos. In contrast, offspring born from embryos with maternal pronuclei from HF/HS-fed dams and ooplasm from chow-fed dams had abnormal cardiac mitochondrial structure (round shape, cristal rarefaction) and reduced oxygen consumption (~40%), comparable to embryo transfer offspring of HF/HS-fed dams. Conclusion: Shown for the first time, abnormal cardiac mitochondria in obese dam offspring result from HF/HS diet effects on the oocyte nucleus (likely epigenetic changes during oogenesis). Elucidating diet/obesity-induced oocyte epigenetic changes, and the mechanisms for induction and transgenerational transmission, could enable therapies to target inheritable heart disease risk in humans.
Multiple Myeloma Patients With Prior Knowledge Of MGUS Have a Better Survival Compared To Multiple Myeloma Patients Without Prior Knowledge Of MGUS
Authors: Elin Edda Sigurdardottir, Ingemar Turesson, Sigrun Helga Lund, Ebba K Lindqvist, Neha Korde, Sham Mailankody, Magnus Björkholm, Ola Landgren, Sigurdur Y Kristinsson
Journal: Blood (2013)
Patient navigation (PN) for colorectal cancer screening (CRC): Experience in program implementation for underserved neighborhoods of Cleveland, Ohio.
Authors: Katherine Glass, Aqeel Seals
Journal: Journal of Clinical Oncology (2019)

147 Background: Cleveland, Ohio has high rates of colorectal cancer (CRC). 50% of CRC in Cleveland is late stage, and rates of CRC screening in Cleveland are low. Colonoscopy is a screening method for CRC, but barriers exist for the underserved population of Cleveland. The Fecal Immunohistochemical Test (FIT) is a less-costly and non-invasive CRC screening method that has demonstrated increased uptake in CRC screening for underserved populations. Previous literature has demonstrated that Patient Navigation (PN) can increase screening rates in underserved populations through education and assistance to overcome barriers to care. Little, however, has been published about the impact of pairing PN with a program that encourages either colonoscopies or FIT utilization to complete screening. Methods: Community members were educated about both colonoscopies and FIT in a neutral manner. After education, interested participants provided preference for screening type. Participants received follow-up calls from patient navigators. Navigators provided encouragement to complete screening and collected information about barriers. Results: N = 612 patients received PN for CRC. 72% of the population (n = 442) were Black. 47% (n = 290) chose colonoscopy, and n = 322 chose FIT. 44% (n = 263) completed a screening. 19% (n = 55) of those choosing colonoscopy completed screening. 66% (n = 213) choosing FIT completed screening. Women who chose FIT were more likely than men who chose FIT to complete screening (86% vs. 45%, p &lt; 0.001). Barriers to screening included appointment coordination, transportation, and insurance. Conclusions: When offered PN and choice of CRC screening, community members in Cleveland equally chose colonoscopy vs. FIT. Those that chose FIT were more likely to complete screening (p &lt; 0.001). Barriers suggest access and use of healthcare remain challenging for underserved communities. The simplicity of FIT paired with PN may remove barriers for this population and increase screening uptake. More research needs to be done to understand the impact of PN on sustained rate of completion.
Abstract 920: Mutual Potentiation Between Myofibril Assembly and Serum Response Factor in Cardiomyocyte Maturation
Authors: Yuxuan Guo, Blake Jardin, Isha Sethi, Behzad Moghadaszadeh, Alan Beggs, William Pu
Journal: Circulation Research (2019)

Cardiomyocyte (CM) maturation is characterized by transcriptional, morphological and functional specializations that are essential for robust and sustained CM contractions throughout lifetime. The signal networks that govern CM maturation remain poorly defined, which obscures the role of CM maturation in inherited cardiomyopathies and myocardial regeneration and impairs efforts to engineer mature cardiac tissues in vitro . Our prior studies established the transcription factor serum response factor (SRF) as a key regulator of CM maturation: SRF regulates major CM maturation events including myofibril expansion, mitochondria biogenesis, transverse-tubule formation, and cellular hypertrophy. Myofibrillar genes were identified as direct SRF downstream targets that are required for other aspects of CM maturation. To further understand the role of myofibrils in CM maturation, here we report the generation and investigation of a floxed allele of Actn2 in mice, which encodes a central component of sarcomere Z-lines. We applied to these mice a low dose of adeno-associated virus that expressed Cre recombinase specifically in neonatal CMs to generate hearts with mosaic Actn2 mutation. This approach circumvented the confounding secondary effects of cardiac dysfunction in Actn2 mutants and revealed cell-autonomous gene functions. Strikingly, Actn2 ablation triggered dramatic transcriptional dysregulation in addition to the expected myofibrillar disassembly phenotypes in CMs, which strongly correlated with observations in SRF-depleted CMs. Actn2 mutation increased the amount of monomeric actin in CMs, which perturbed the nuclear localization of SRF cofactors MRTF-A/-B. Overexpression of a dominant-negative MRTF-A isoform was sufficient to recapitulate the transcriptional and morphological defects in Actn2 or Srf mutant CMs. Together, these data demonstrate mutual potentiation between myofibril assembly and MRTF-A/B-SRF signaling in CM maturation. This positive feedback loop underlies a novel mechanism by which mechanical forces regulate CM maturation, disruption of which likely contributes to cardiomyopathies caused by sarcomere gene mutations.
Follow-up Care for Breast Cancer Survivors
Authors: Kathryn J Ruddy, Jeph Herrin, Lindsey Sangaralingham, Rachel A Freedman, Ahmedin Jemal, Tufia C Haddad, Summer V Allen, Tina Hieken, Judy C Boughey, Patricia A Ganz, Rachel D Havyer, Nilay D Shah
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Breast cancer survivorship guidelines recommend at least annual follow-up visits, yet the degree to which this occurs in clinical practice is uncertain. Claims data from a US commercial insurance database (OptumLabs) were used to identify women treated with curative intent surgery for newly diagnosed breast cancer between 2006 and 2014. In 25 035 women, median follow-up was 3 years. In the second year after surgery, 9.6% of the patients did not visit a primary care provider, an oncologist, or a surgeon (guideline-nonadherent). The guideline-nonadherent proportion increased from 7.8% in women diagnosed in 2006 to 12.2% in those diagnosed in 2014 (two-sided Wald P &amp;lt; .001). During years 2–6, guideline-nonadherence was also associated with older age, nonwhite race, no radiation, no chemotherapy, no endocrine therapy, and increasing time after surgery. There is a substantial and increasing rate of inadequate follow-up among breast cancer survivors. This has the potential to impair outcomes.
Development of Systems of Care for ST-Elevation Myocardial Infarction Patients
Authors: David P. Faxon
Journal: Circulation (2007)

A dvances in the treatment of ST-elevation myocardial infarction (STEMI) over the past 20 years have resulted in dramatic reductions in death attributable to STEMI.In large part, this reduction has been due to early reperfusion and advances in medical therapy. 1 The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines and the European Society of Cardiology guidelines for STEMI are in agreement that early and complete reperfusion is optimal, with the goal of door-to-balloon times within 90 minutes and door-to-needle times within 30 minutes. 2,3Most disturbing is that as many as one third of patients do not receive any reperfusion therapy in the absence of contraindications to its use. 1,4In the group of patients who do not receive any reperfusion, both short-and long-term outcomes are significantly worse.Advances in medical therapy, including use of aspirin, heparin, ␤-blockers, and angiotensin-converting enzyme inhibitors, have also dramatically improved outcomes.][7] In addition, one of the major delays in patients receiving rapid reperfusion is the delay in the patient seeking care and arrival at the emergency department. 8The National Heart, Lung, and Blood Institute, the AHA, and others have initiated a number of programs to attempt to improve public awareness of this problem and to reduce the time between symptom onset and hospital arrival.Despite these programs, little progress has been made. 9The European Society of Cardiology has identified the need for the establishment of networks for reperfusion at regional and national levels with the ready availability of primary percutaneous coronary intervention (PCI) and adequate quality control. 10Although there are some differences in the delivery of STEMI care between the United States and Europe, both locations are characterized by wide variability in care that would be improved by a more effective and uniform system of care
Predictors Factors of Death during Induction Therapy of Acute Myeloblastic Leukemias (Western Algeria, multicenter experience)
Authors: Brahim Benzineb, Mesli Naima, Bendahmane Ahmed Fouad, Chekkaf Ismahane, Faiza Bensmail, Benkhira Nadjia, Amina Krim, Mohammed Amine Bekadja, Samira Zouani, Djamel Saidi, Hadj Touhami, Mohamed Aberkane, Aissa Bachiri, Asma Hadjeb, Zouaoui Zahia, Nemra Mehalhal, Othman Ibraheem
Journal: Blood (2018)
Enhancing effects of unique amino acids, taurine and theanine, on the antitumor activity of doxorubicin
Authors: Tomomi Sugiyama, Maki Kubodera, Chieko Inoue, Yasuyuki Sadzuka
Journal: Cancer Research (2004)

558  We previously confirmed that theanine, a specific amino acid in green tea, enhanced antitumor activity of doxorubicin (DOX) with decrease of DOX induced adverse reaction. This action of theanine was contributed to reduction of DOX efflux from tumor cells caused by suppression of glutamate transporter. This suppression by theanine decreased glutamate uptake, intracellular glutathione synthesis, and glutathione-DOX conjugate level, and subsequently reduced extracellular transport of DOX from tumor cell. Taurine (2-amino ethanesulfonic acid) is a major amino acid found in fish and also in all tissues in mammalian. In clinical therapy, taurine is applied for protection of liver and improvement of congestive cardiac failure. We have investigated a novel efficacy of taurine on the antitumor activity of DOX, as well as theanine. The effects of both amino acids on DOX influx or efflux were examined in M5076 ovarian sarcoma cells. Similar to theanine, taurine did not affect DOX influx, whereas taurine inhibited DOX efflux by 70 % at 120 min incubation, compared to control level. Namely, the DOX concentration in tumor cells increased. This suggested that taurine might change the therapeutic efficacy of DOX. In order to clarify the effect of taurine on antitumor activity of DOX in vivo, M5076 ovarian sarcoma cells were subcutaneously transplanted onto the backs of BDF1 mice. DOX ( 2.0 mg/kg/day x 4 days ) and taurine ( 10 mg/kg/day x 4 days ) were intraperitoneally injected in turn to M5076 ovarian sarcoma bearing mice from the 22nd day after transplantation. Although tumor weight in DOX alone group slightly reduced, compared to that in the non-treated group, the combination of taurine with DOX significantly decreased tumor weight to 70 % of the non-treated level. This effect was supported by an increase of DOX concentration in the tumor of taurine combined group. In addition, no increment of DOX concentrations in normal tissues was observed by taurine combination. Thus, we concluded that taurine enhanced DOX efficacy without increase of adverse toxicity. These results revealed the enhancing effects of these amino acids, taurine and theanine, on antitumor activity of DOX. There has been not a report that the intake of foods and their components improved cancer chemotherapy. According to these novel evidences, we hope that foods and/or their components lead to success of cancer chemotherapy.
Assessing time to treatment initiation and care delivery among patients with cancer and co-occurring Alzheimer's disease and related dementia using claims data.
Authors: Melody K Schiaffino
Journal: Journal of Clinical Oncology (2019)

161 Background: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in Americans. Prognosis for survival is better if cancer is detected at an early stage, the patient is from a majority racial/ethnic group, and not a member of an older age cohort ( &gt; 65). Risk is also exacerbated when a patient is dealing with concurring condition such as Alzheimer's Disease or dementia (ADRD)which affects approximately 10% of older adults. Methods: A SEER-Medicare cohort of patient with CRC from 2004-2013 was obtained from the NCI. After appropriate criteria were applied, only cases with all data for cancer and ADRD and first cancer-related treatment were included for an analysis sample of N = 54, 357. Results: The prevalence of concurrent ADRD and CRC in our sample was 3.1%. Mean time to treatment initiation (TTI) was 34.99 days for all patients, and 35.19 days for patients in the CRC-only group vs ~ 27 days in the CRC+ADRD group. Most patients in either group were Stage II though TTI decreased as patient stage at diagnosis increased. Conclusions: Using claims data to assess TTI in cancer patients suggests that TTI is shorter for patients with concurrent ADRD. While this may be attributable to ADRD patients existing interactions with the care delivery systems and the role of caregivers it is evident that additional contextual research is necessary to consider these systems and non-clinical factors.
hMLH1 Abnormality in 180 Sporadic Colorectal Carcinomas
Authors: Yu Na Kang, Sun Young Kwon, Hye Soon Kim, Hye Ra Jung, Mi Sun Choe, Sang Pyo Kim, Kun Young Kwon, Sang Sook Lee, Seong Il Suh
Journal: Cancer Research (2007)

1989  Pathogenesis of colorectal carcinomas has known to be involved with numerous chromosomes and genetic abnormalities. One of them is microsatellite instability (MSI) due to defective DNA mismatch repair (MMR) genes. The MMR gene abnormality is associated with promoter methylation as well as genetic mutation. Recently immunohistochemical detection of DNA MMR protein is able to suggest of the presence of MMR gene abnormality. The aim of this study was to evaluate the role of immunohistochemical stain of hMLH1 as a screening tool for carcinomas with defective DNA mismatch repair (MMR) genes. In this study, 180 colorectal carcinoma tissue were obtained in the fresh status for MSI phenotype, hMLH1 promoter methylation, hMLH1 mutation analysis. Of the 180 colorectal carcinomas, nine cases (5.0%) were MSI-H, nine cases (5.0%) had hMLH1 mutation on exon 1, 7, 12, and 16. Twenty one cases (11.7%) showed loss of hMLH1 protein expression on immunohistochemistry, and sixty one cases (33.9%) were methylated at the hMLH1 promoter. Status of MSI-H was correlated with younger age below 50 years old (p=0.004), tumor location of right colon (p
Abstract 796: Dysfunctional Immune Cell Clock Contributes to Heart Failure Progression
Authors: Samir Rana, Guihua Zhou, Tariq Hamid, Gregg Rokosh, M. Ameen Ismahil, Martin E. Young, Sumanth D. Prabhu
Journal: Circulation Research (2019)

Objective: Inappropriately sustained activation of monocytes/macrophages contributes to heart failure (HF) progression. Time-of-day greatly influences cardiovascular and immune systems, in part through cell autonomous circadian clocks. Here, we propose that disruption of monocyte/macrophage circadian clocks contributes to pathologic inflammation and HF progression following myocardial infarction (MI). Methods: MI-induced HF was achieved by permanent ligation of coronary artery in myeloid-specific Bmal1 knockout (MBK) mice and wild-type (WT) mice. Left ventricular (LV) function was assessed echocardiography. Flow cytometry was utilized for immune cell profiling. RNAseq and qRT-PCR was utilized for gene-expression studies. Tissue fibrosis was quantified using Masson-trichrome staining. Results: WT (C57Bl/6) HF mice exhibited altered Ly6C hi monocyte circadian clock gene expression as compared with sham-operated mice, with significantly reduced expression of the key clock effector Bmal1 . Genetic disruption of the monocyte clock in MBK mice had no effect on macrophage inflammatory markers during unstressed, baseline conditions. However, MBK-HF mice (4 w post-MI) exhibited increased infiltrating CCR2 + heart macrophages (2642±803 vs. 937±190 per heart, p&lt;0.05), augmented cardiac fibrosis (22±1 vs. 14±3 %, p&lt;0.05), greater LV dysfunction [ejection fraction 19.7±2 vs. 28.4±4 %, p&lt;0.05), increased LV end-diastolic and end-systolic volume (EDV 140.4±10 vs. 100±8 μl, p&lt;0.01; ESV 115±10 vs. 74±9 μl, p&lt;0.01) and cardiac hypertrophy (heart weight/tibia length 12.1±0.6 vs. 10.5±0.4 mg/mm, p&lt;0.05) as compared with WT HF littermate control mice. Moreover, circulating monocyte levels in MBK-HF mice were significantly increased at zeitgeber time 6 versus WT HF littermate controls (296±58 vs. 131±17 cells/μl, p&lt;0.05). Conclusion/Broader Impact: Monocyte/macrophage circadian gene dysregulation resulting from Bmal1 loss-of-function exacerbates pathological LV remodeling, systemic and cardiac inflammation, and tissue fibrosis in chronic ischemic HF. Restoration of circadian clock function in innate immune cells may represent a potential therapeutic approach to immunomodulation in chronic HF.