tbuckley/cabot-search huggingface dataset:
Blockade of ARV7:HIF1α heterodimers after topotecan reverses enzalutamide resistance in 22Rv1 cells.
Authors: John P. Fruehauf, Nathan Farrokhian, Sarmen Sarkissian, Jai-Hyun Kim
Journal: Journal of Clinical Oncology (2016)

e16594 Background: Although enzalutamide (ENZ) is effective for the treatment of castration-resistant prostate cancer (CRPC), development of ENZ resistance is inevitable. One well characterized mechanism for resistance is the emergence of an alternative splicing variant of androgen receptor (AR), ARV7, which lacks the androgen binding and hinge region domains. Nuclear translocation of full length AR utilizes the hinge region to couple to tubulin. ARV7 protein appears to gain nuclear entry independent of tubulin. Hypoxia inducible factor 1-α (HIF1α) has been reported to bind to full length AR. We hypothesized that HIF1α may also heterodimerize with ARV7, facilitating its nuclear localization and transcriptional activity. We determined if HIF1α was bound to ARV7 in resistant cells and if HIF1α knockdown by topotecan (TPT) would block ARV7 nuclear localization and re-sensitize ARV7 expressing cells to enzalutamide. Methods: The 22Rv1 prostate cancer cell line expresses full length AR and ARV7 and is resistant to ENZ. Cobalt chloride treated 22Rv1 cells were used to mimic hypoxia and to stabilize HIF1α. Cytoplasmic and nuclear extracts from 22Rv1 cells were used for co-immunoprecipitation (Co-IP). The effects of TPT on HIF1α expression and AR/ARV7 localization were determined by western blot. The effects of ENZ and TPT on 22Rv1 cells were evaluated in the Luminescent cell viability assay. Results: Immunoprecipitation of 22Rv1 whole cell lysates and nuclear extracts with HIF1α-specific antibodies yielded both full length AR and ARV7 protein bands on western blots. Compared with control cells, TPT treated 22Rv1 cells grown under hypoxic conditions showed HIF1α knockdown and decreased ARV7 nuclear localization. TPT demonstrated synergistic activity with ENZ. Conclusions: These data indicate that HIF1α forms heterodimers with both full length AR and ARV7. TPT-mediated HIF1α knockdown of hypoxic 22Rv1 cells leads to diminished nuclear localization of ARV7. Decreased nuclear ARV7 levels after TPT was associated with increased sensitivity to ENZ, supporting further exploration of TPT to modulate ENZ resistance in the clinic.
Immune-related adverse events (IRAE) of elderly patients (PTS) with advanced melanoma (AMEL) treated with checkpoint inhibitors (CI) in a community setting: The experience (EXP) at Kaiser Permanente (KP) California.
Authors: Thach-Giao Truong, Helen Moon, Timothy Chiu, Christopher Yamamoto, Michele M. Spence, Juraj Kavecansky, Fang Niu, Rita L. Hui
Journal: Journal of Clinical Oncology (2018)

e21583 Background: CI have transformed treatment (TX) and survival for PTS with (w) AMEL. Our knowledge of TX outcomes (OUTC) and IRAEs is still largely informed by clinical trials enrolling younger and fitter patients (PTS). Here, we report the EXP of our large community practice, where a diverse group of PTS received CI for AMEL Methods: We conducted a retrospective cohort (COH) study, including PTS who were ≥65 years old (yo) and received (rec) CI for AMEL between (btw) July 2014 to September 2016, w follow-up through December 2016, death or end of KP membership, whichever occurred first. Through data-mining of our electronic medical record and formal chart review, we evaluated the incidence of IRAE and TX OUTC, stratified by age, ethnicity, gender, and co-morbidity index (CCI) Results: Our analysis included 118 PTS. Of these, 70% were male and 10% were non-Caucasian. 79% of PTS were age 65-79 yo and 21% were ≥80 yo (range 80-94 yo). 22% of PTS had a CCI > 4. 21% had AMEL w BRAF mutation. 86% of PTS rec TX w single-agent anti-PD1 (SAPD) and 14% rec concurrent TX w ipilimumab and nivolumab (IPINIVO). 2 PTS rec SAPD for adjuvant TX. Only 1 PT ≥80 yo rec IPINIVO. G3/4 IRAE were noted in 29% of all PTS and 81% of those who rec IPINIVO. 30% of PTS experienced a G3/4 IRAE age 65-79 yo and 24% of PTS age ≥80 yo, p = 0.55 . 49% PTS rec steroids while on CI. ORR and clinical benefit (CB) rate were 39 and 58% in the 65-79 yo COH (20% CR, 19%PR, 19%SD) and 52 and72% in the ≥80yo COH (32%CR, 20%PR, 20%SD) respectively, p = 0. 48. ORR was 31 % w 50% CB for PTS who rec IPINIVO (19% CR, 13%PR, 19%SD). PTS age 65-79 yo rec SAPD for a median of 3.8 mos (IQR 1.0-7.0), compared to 5 mos (IQR 2-9) for PTS ≥80 yo; p = 0.37. Median overall survival was similar for PTS 65-79 yo (17.8 mos, IQR 3.5-22.9) and those ≥80 yo (19.6 mos, IQR 6.2-30.3), p = 0.23 Conclusions: This is the first report of TX OUTC w CI in elderly PTS w AMEL in a real-world setting. We found IRAE rates and TX OUTC to be similar for PTS age 65-79 yo and ≥ 80 yo. W rising cancer incidence among an aging population and expanding indications for CI, it is important to understand how this drug class affects older PT groups to improve their cancer OUTC
Components of tissue fibrinolytic system as markers for processes in tumors of female reproductive organs.
Authors: Marina I. Vereskunova, Elena Mikhaylovna Frantsiyants, Larisa Kozlova, Valeria Bandovkina, Natalia D. Cheryarina, Natalya Chugunova, Natalya S. Saforian, Oleg I. Kit, Maria Ezhova
Journal: Journal of Clinical Oncology (2017)

e17032 Background: Components of tissue fibrinolytic system are now considered as important agents providing progressive tumor growth. The purpose of the study was to analyze fibrinolytic system components in uterine and breast tumors. Methods: We studied tumor samples in breast cancer (BC, n=24), nodular type of fibrocystic breast disease (FBD, n-15) and uterine myoma (UM, n=14) and in synchronous BC and UM (n=12). Intact breast tissues (IBT, n=16) and intact myometrium (IM, n=14) were used as the control. Activity of plasmin (P), total content and activity of uPA-Ag and uPA-act, tPA-Ag and tPA-act were determined by ELISA; plasminogen (PG) concentration was measured by spectrophotometry (ACTICHROME PLG, USA). Results: uPA-Ag in solitary BC was 6.5 times higher and uPA-act – 4.5 times higher than in IBT. Concentration of tPA-Ag in 75% of BC patients exceeded the value in IBT by 2.1 times, and tPA-act in 87.5% – by 1.5 times. tPA-Ag and tPA-act in FBD tissues were similar to IBT values, while uPA-Ag and uPA-act were increased by 2.2 times each. uPA-Ag in BC in BC+UM exceeded the norm by 10.6 times, uPA-act – by 5.5 times; tPA-Ag in 75% of samples was 3.8 times higher than in IBT, and tPA-act – 2.7 times higher. uPA-Ag and uPA-act levels in UM in BC+UM were similar to IM values, while tPA-Ag and tPA-act exceeded the norm by 1.8 and 1.5 times, respectively. Both uPA and tPA levels and activity in solitary UM did not differ significantly from IM. Conclusions: The results show an active conversion of plasminogen into plasmin in both solitary and synchronous BC and in synchronous UM. Components of tissue fibrinolytic system can be considered as reliable markers for processes in solitary and synchronous tumors of female reproductive organs.
Breast-feeding among women exposed to polybrominated biphenyls in Michigan.
Authors: A R Thomas, M Marcus, R H Zhang, H M Blanck, P E Tolbert, V Hertzberg, A K Henderson, C Rubin
Journal: Environmental Health Perspectives (2001)

In the early 1970s, the largest industrial accident in the United States resulted in widespread contamination of the food supply in Michigan with polybrominated biphenyls (PBBs). The chemical similarity of PBBs to compounds implicated as endocrine disruptors has raised the question of whether PBBs could affect the reproductive system. In the present analysis we examine the relation between serum measurements of PBBs and the frequency and duration of lactation. Persons who lived on or received food from farms exposed to PBBs were enrolled in a registry by the Michigan Department of Public Health. Female members of the cohort were invited to participate in a telephone survey of reproductive outcomes. The three outcomes of interest in the present analysis were a) the decision to breast-feed (yes/no); b) the duration, in months, of breast-feeding as the main source of nutrition; and c) the total duration, in months, of breast-feeding. None of the three outcomes was significantly associated with serum PBB levels, even after controlling for maternal age, previous history of breast-feeding, body mass index, maternal education, household income, history of smoking in the year before pregnancy, consumption of alcohol during the first trimester of pregnancy, history of thyroid disorder, gestational age of the infant in weeks, time to pregnancy, and year of birth.
Optimized management of nivolumab (NIVO) and ipilimumab (IPI) in advanced renal cell carcinoma (OMNIVORE): A response-based phase II study.
Authors: Xiao X. Wei, Rana R. McKay, Kathryn P. Gray, Walter Michael Stadler, David F. McDermott, Bradley Alexander McGregor, Neeraj Agarwal, Christos Kyriakopoulos, Benedito A. Carneiro, Tracy Lynn Rose, Yousef Zakharia, David A. Braun, Kenneth J Livak, Catherine J. Wu, Eliezer Mendel Van Allen, Sabina Signoretti, Joshua Michael Lang, F. Stephen Hodi, Toni K. Choueiri, Lauren Christine Harshman
Journal: Journal of Clinical Oncology (2018)

TPS4600 Background: CheckMate 025 established NIVO as a standard of care (SOC) option for advanced clear cell RCC (ccRCC) after prior antiangiogenic therapy. The combination of IPI plus NIVO is anticipated to become a new SOC option for intermediate/poor risk patients (pts) with treatment-naïve advanced ccRCC based on CheckMate 214. Outstanding questions include optimal treatment duration in responders, ability of IPI to convert NIVO non-responders to responders, activity of these agents in non-clear cell RCC (nccRCC), and discovery of predictive biomarkers. Methods: This phase II, open-label, non-randomized trial enrolls treatment-naïve or previously treated pts with advanced ccRCC or nccRCC (NCT03203473). Pts previously treated with immune checkpoint inhibitor(s) are excluded. All pts start NIVO alone and subsequent management is based on RECIST response within the first 6 months of NIVO. Pts with confirmed partial response (PR) or complete response (CR) discontinue NIVO and are observed. At progression, NIVO is reinitiated, and if further progression, 2 doses of IPI are added to NIVO (Arm A). Pts with stable disease (SD) or progressive disease (PD) on initial NIVO will receive 2 doses of IPI with NIVO continuation until PD (Arm B). NIVO monotherapy dose is 240mg Q2W, and 3mg/kg Q3W when given with IPI. IPI dose is 1mg/kg Q3W. The co-primary endpoints are proportion of pts with durable CR/PR at 1-year (yr) after NIVO discontinuation (Arm A) and proportion of pts with SD or PD on NIVO alone who convert to PR/CR at 1-yr after adding IPI to NIVO (Arm B). Enrollment of 17 pts is planned for Arm A to achieve 90% power to assess a true 1-yr PR/CR rate of ≥35% vs a null PR/CR rate of 10%. Enrollment of 41 pts is planned for Arm B to achieve 90% power to assess a true 1-yr conversion rate of 20% vs a null conversion rate of 5%. Fresh tumor biopsy is required at baseline and optional at progression time points. Correlative studies are tightly integrated including circulating immune cells, cytokines/chemokines, circulating tumor cells, cfDNA, tumor immunohistochemistry, bulk genomic profiling, and bulk and single-cell transcriptomic analysis. As of February 2018, 18 of planned 58 patients have been accrued. Clinical trial information: NCT03203473.
SP0007 Dealing with psychological distress to optimise outcomes for arthritis pain
Authors: R.J. Smeets
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> As clinicians we are often confronted with patients who suffer from arthritis pain. As most of us working in the field of arthritis, we are specifically trained to assess and treat medical causes in order to relieve pain. However, in daily practice we experience that many patients will develop chronic pain with huge problems in staying active and experiencing moderate to high levels of disability and lower level of quality of life. In my opinion all clinicians should be able to identify psychosocial factors that contribute to the persistence of arthritis pain associated disability and loss of quality of life. Besides these patient relevant psychosocial factors, I will specifically focus on the important role clinician's beliefs/attitudes regarding pain in better treating and coaching patients with chronic arthritis pain. Participants will learn how to look for these potentially contributing factors, how to diagnose the level of functioning of these patients and how to inform patients about their pain and role of important contributing psychosocial factors. I will discuss the way how you might better prescribe pain medication and other pain relieving treatments and finally how you can help them to stay active despite being in pain, reduce the risk of iatrogenic damage, and what type of treatments exist to address contributing psychosocial factors. Finally, I will specifically elaborate on the Fear Avoidance Model as one of the currently most often used theoretical models to assess patients and on which basis a very successful treatment called graded exposure <i>in vivo</i> has been developed. <h3>Disclosure of Interest</h3> None declared
Comparison of mismatch repair status between primary and matched metastatic sites in patients with colorectal cancer.
Authors: Wen-Zhuo He, Wan-ming Hu, Chang Jiang, Xiao-jun Xia, Liang-ping Xia
Journal: Journal of Clinical Oncology (2018)

3563 Background: Mismatch repair (MMR) status is crucial in the management of patients with metastatic colorectal cancer (mCRC) to predict responses to anti-PD-1 therapy. This study compares the MMR status between primary and matched metastatic tumors in patients with mCRC. Methods: 331 patients were analyzed in this study. The expression of four most common MMR proteins, MLH1, MSH2, MSH6 and PMS2 were tested by immunohistochemistry. Polymerase chain reaction (PCR) analysis was performed to test microsatellite instability (MSI) when MMR status was inconsistent between primary and metastatic sites. Results: A total of 331 patients were included; 23 patients had dMMR primary tumors. Among these, 17 (73.9%) and 6 (26.1%) patients showed dMMR and pMMR metastatic tumors, respectively. The remaining 308 patients showed pMMR primary tumors:11 (3.6%) dMMR and 297 (96.4%) pMMR metastatic tumors were observed. For patients who had inconsistent MMR status between primary and metastatic sites, the detailed results were shown in the table, including PCR results. Conclusions: Our study suggests a notable discrepancy in mismatch repair status between primary and matched metastatic tumors in patients with mCRC. Case Age Sex Primary Metastatic Synchronous /metachronous Primary tumor Metastatic tumor MLH1 MSH2 MSH6 PMS Microsatellite MLH1 MSH2 MSH6 PMS Microsatellite 1 64 M Rectal Liver S + + - + MSI-L + + + + MSI-L 2 35 F Rectal Peritoneum S - + + + MSI-H + + + + MSI-H 3 44 F Descending colon Ovarian S - + + + MSI-H + + + + MSS 4 51 M Descending colon Distant lymph node S + + + - MSI-H + + + + MSI-H 5 35 M Rectal Peritoneum M + - - + MSI-L + + + + MSS 6 62 F Ascending colon Ovarian M - + + - MSI-H + + + + MSS 7 24 F Rectal Distant lymph node M + + + + MSI-L - + + - MSI-L 8 61 M Ascending colon Lung M + + + + MSI-L - + + + MSI-L 9 46 F Ascending colon Uterus S + + + + MSS + + + - MSS 10 63 F Sigmoid colon Peritoneum S + + + + MSI-H - + + + MSI-H 11 56 M Rectal Peritoneum S + + + + MSI-H - + - + MSI-H 12 28 F Sigmoid colon Liver S + + + + MSI-L - + + + MSI-H 13 43 M Rectal Distant lymph node M + + + + MSI-H + + + - MSI-H 14 75 F Ascending colon Peritoneum S + + + + MSS + + + - MSS 15 65 F Sigmoid colon Peritoneum S + + + + MSS + + - + MSI-H 16 60 F Sigmoid colon Uterus S + + + + MSS - + + + MSI-L 17 70 M Sigmoid colon Peritoneum S + + + + MSS - + + + MSS
Mifamutide treatment plus chemotherapy results in pediatric osteosarcoma patients in Ankara University Medical School Department of Pediatric Oncology: A single center experience.
Authors: Nurdan Tacyildiz, Emel Cabi Unal, Handan Dincaslan, Mine cakmak Tokuc, Gulsah Oktay Tanyildiz, Dilvin celik Ates, Sonay incesoy Ozdemir, Kenan Kose, Gulsan Yavuz
Journal: Journal of Clinical Oncology (2018)

e22500 Background: Osteosarcoma (OS) is the most common primary malignant bone tumor.Almost 90% of the patients have micrometastasis during diagnosis. Doxorubicin, cisplatin, high-dose methotrexate with leucovorin rescue, and ifosfamide are well known chemotherapy agents.The immunomodulator mifamurtide (liposomal muramyl tripeptide phosphatidyl ethanolamine [L-MTP-PE]; activates macrophages and monocytes, has been safely given together with standard adjuvant chemotherapy in high-grade OS patients. Our aim was to use mifamurtid to get better survival rate for children with OS beside to establish side effects and tolerability of it. Methods: : After 2012 to 2018 January 17 pts with OS have been received mifamutid ( 2mg/m2/twice weekly for 12 weeks, than weekly for 24 weeks, total 48 doses/each pts) plus their classical chemo. Side effects and tolerability has been recorded. Beside,19 pts who have not been received mifamurtid but only classical chemo has been compared for the risk of metastasis, life expectancy etc. Results: Age of the total 36 pts were 7,6 to 16,5 years (mean: 12,3).For mifamurtid group ( Most common side effects were chills and fever (16/17) followed by myalgia, arthralgia, headache and back pain. Mostly resolved after first cycles. One patient had tinnitus and mild hearing lost. Percentage of having lung metastasis during follow up ( 8 to 43 months follow up; median: 27 months) for mifamurtid group was 29,4% while it was 47,4 % for classic chemo group. Conclusions: Mifamurtide is generally well tolerated in pediatric OS patiens, with the majority of side effects reported as either mild or moderate, and it can be given in the out-patient setting. According to our preliminary results, mifamurtid has tendancy to reduce lung metastasis but data needs more follow up and more studies for confirmation.
Abstract 11958: Predicting Heart Failure With Preserved and Reduced Ejection Fraction: The International Collaboration on Heart Failure Subtypes
Authors: Jennifer E Ho, Frank P Brouwers, Danielle Enserro, Sanjiv J Shah, Bruce M Psaty, Traci M Bartz, Rajalakshmi Santhanakrishnan, Douglas S Lee, Kiang Liu, Michael J Blaha, Hans L Hillege, Pim van der Harst, Wiek H van Gilst, Willem J Kop, Ron T Gansevoort, Ramachandran S Vasan, Julius M Gardin, Jorge R Kizer, Daniel Levy, John S Gottdiener, Rudolf A de Boer, Martin G Larson
Journal: Circulation (2015)

Introduction: Heart failure (HF) is a major growing public health burden, and preventive strategies focused on at-risk individuals are needed. Recent initiatives have advocated for early prevention and aggressive treatment in ACC/AHA stage A/B HF, but prior HF risk prediction models remain poorly defined and validated. Moreover, risk factors for HF-specific subtypes have not yet been examined. Methods: We developed and validated separate HF risk prediction models for preserved and reduced ejection fraction (HFPEF, HFREF) in four community-based prospective cohorts (FHS, CHS, PREVEND, MESA). Fine-Gray proportional sub-distribution hazards models were used to account for competing risks (death, other HF subtype, and unclassified HF). FHS, CHS, and PREVEND samples were combined and a 2:1 random split was used for derivation and internal validation. MESA served for external validation. Results: There were 982 incident HFPEF and 909 HFREF events among 28,820 participants during follow-up (median 12 years). We created a HFPEF-specific model which included age, sex, systolic blood pressure, body mass index, hypertension treatment, and prior myocardial infarction; it had good discrimination in derivation (c-statistic 0.80, 95% CI 0.78-0.82) and validation samples (internal 0.79, 95% CI 0.77-0.82; external 0.76, 95% CI 0.71-0.80). The HFREF-specific model added smoking, left ventricular hypertrophy (LVH), left bundle branch block (LBBB), and diabetes; it had good discrimination in derivation (c-statistic 0.82, 95% CI 0.80-0.84) and validation samples (internal 0.80, 95% CI 0.78-0.83; external 0.76, 95% CI 0.71-0.80). Age had a greater effect on HFPEF risk, whereas male sex, LVH, LBBB, previous myocardial infarction, and smoking had greater effects on HFREF risk (P for comparison ≤ 0.02 for all). Conclusions: We describe and validate risk prediction models that are distinct for HF subtypes, and we demonstrate good discrimination in four community-based cohorts. Some risk factors differed in HFPEF vs HFREF, supporting distinct pathogenesis between HF subtypes. Studies are needed to examine the clinical utility of risk models, with the ultimate goal of targeted preventive strategies.
Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus–Host Protein Network
Authors: Manon Eckhardt, Wei Zhang, Andrew M. Gross, John Von Dollen, Jeffrey R. Johnson, Kathleen E. Franks-Skiba, Danielle L. Swaney, Tasha L. Johnson, Gwendolyn M. Jang, Priya S. Shah, Toni M. Brand, Jacques Archambault, Jason F. Kreisberg, Jennifer R. Grandis, Trey Ideker, Nevan J. Krogan
Journal: Cancer Discovery (2018)

Abstract We have mapped a global network of virus–host protein interactions by purification of the complete set of human papillomavirus (HPV) proteins in multiple cell lines followed by mass spectrometry analysis. Integration of this map with tumor genome atlases shows that the virus targets human proteins frequently mutated in HPV− but not HPV+ cancers, providing a unique opportunity to identify novel oncogenic events phenocopied by HPV infection. For example, we find that the NRF2 transcriptional pathway, which protects against oxidative stress, is activated by interaction of the NRF2 regulator KEAP1 with the viral protein E1. We also demonstrate that the L2 HPV protein physically interacts with the RNF20/40 histone ubiquitination complex and promotes tumor cell invasion in an RNF20/40-dependent manner. This combined proteomic and genetic approach provides a systematic means to study the cellular mechanisms hijacked by virally induced cancers. Significance: In this study, we created a protein–protein interaction network between HPV and human proteins. An integrative analysis of this network and 800 tumor mutation profiles identifies multiple oncogenesis pathways promoted by HPV interactions that phenocopy recurrent mutations in cancer, yielding an expanded definition of HPV oncogenic roles. Cancer Discov; 8(11); 1474–89. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333