tbuckley/cabot-search huggingface dataset:
Association of Filaggrin Loss-of-Function Variants With Race in Children With Atopic Dermatitis
Authors: David J. Margolis, Nandita Mitra, Bradley Wubbenhorst, Kurt D’Andrea, Adam A. Kraya, Ole Hoffstad, Saloni Shah, Katherine L. Nathanson
Journal: JAMA Dermatology (2019)

Atopic dermatitis (AD) is a common chronic illness that has been associated with variation in the filaggrin gene (FLG). Four variants are most often evaluated.To comprehensively describe and compare results from targeted sequencing of FLG loss-of-function (LoF) variants in children of African and European ancestry and the association of these variants with onset and persistence of AD.This prospective US cohort study assessed the genetic subcohort of the Pediatric Eczema Elective Registry (PEER). Children with mild to moderate AD were included in the analysis. Massively parallel sequencing (MPS) was used to focus on FLG LoF variation in white and African American children. Patients were enrolled from June 2005 through July 2017. Data were analyzed from January 25 through May 10, 2019.Associations of FLG LoF variation with white and African American ancestry and with the risk and persistence of AD.A total of 741 children were included in the analysis (394 [53.2%] female and 347 [46.8%] male; mean [SD] age at onset, 1.97 [2.72] years); of these, 394 (53.2%) were white, 326 (44.0%) were African American, and 21 (2.8%) were of other ancestries. Using MPS technology, 23 FLG LoF variants were found in children with AD. The prevalence of FLG LoF variants was 177 participants (23.9%) in the full cohort, 124 white participants (31.5%), and 50 African American participants (15.3%). The odds ratio for carrying any FLG LoF variant in a white child compared with an African American child with AD was 2.44 (95% CI, 1.76-3.39). Some FLG LoF variants are only found in children of a specific ancestry (eg, p.S3316* and p.R826* were not seen in white patients). Children with an FLG LoF were more likely to have persistent AD (odds ratio, 0.67; 95% CI, 0.56-0.80).The FLG LoF variants in a US cohort of children with mild to moderate AD differ significantly by race and their association with the persistence of AD. Conventional testing of the 4 frequently evaluated variants is inadequate. Any planned genetic diagnostic test for AD based on FLG LoF variants must be inclusive and not rely on the most frequently studied variants.
Treatment of diseased quality of life in specific dimensions: Effectiveness of quality-of-life diagnosis and treatment in a community-based RCT in women with breast cancer.
Authors: Monika Klinkhammer-Schalke, Michael Koller, Brunhilde Steinger, Patricia Lindberg, Ferdinand Hofstädter, Wilfried Lorenz
Journal: Journal of Clinical Oncology (2012)

e16520 Background: Many studies described deficits in quality of life (QoL) in cancer patients. We developed a new pathway with QoL diagnosis and treatment which was implemented as complex intervention with theory building, modeling, exploratory trial and RCT, integrated in a population based (2.1 mio) Tumorcenter. Methods: We conducted a two-armed, randomized clinical trial with 200 breast cancer patients.QoL was measured prospectively in 10 specific dimensions in first year after surgery. Along new QoL pathway patients in intervention group (IG) received QoL diagnosis and treatment consisting of 5 therapeutic options (eg physiotherapy, psychotherapy, social counseling). Members of control group (CG) received standard postoperative care. Primary endpoint was rate of patients with diseased QoL (&lt;50 points on at least one scale with 0=bad, 100=good QoL). χ2-tests were performed to compare rates of diseased QoL (Klinkhammer-Schalke et al, BrJCancer, 2012). Results: At begin of study there were no significant differences in both groups considering QoL. 6 months after surgery rate of patients with diseased QoL was significantly lower for emotion in IG (19.8%) vs CG (38.4%, p=.007), and for global QoL almost reached significance in IG (17.6%) vs CG (29.8%, p=.064). For other dimensions (except family life) there was a trend showing better QoL in IG, but results were not significant. Rates of patients with diseased QoL in 10 dimensions 6 months after surgery in intervention group [%] vs control [%]: Global QoL 17.6% vs 29.8%!, Physical functioning 4.7% vs 5.7%, Role functioning 26.4% vs 29.9%, Arm symptoms 13.8% vs 23.3%, Body image 13.8% vs 22.1%, Pain 19.5% vs 24.4%, Emotion 19.8 %vs 38.4%xx, Concentration, remembering 10.5% vs 17.4%, Fatigue 37.9 %vs 46.5%, Family life, social encounters 17.4% vs 16.3% (χ2-test: p&lt;.10!, p&lt;.01xx). Conclusions: Results confirm effectiveness of QoL pathway: 6 months after surgery IG showed better QoL in 2 important dimensions. Lower rates of diseased QoL in other dimensions support the result. Cancer patients will benefit from the QoL system implemented in clinical routine (long term implementation).
Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human AML.
Authors: Kapil N. Bhalla, Warren Fiskus, Karissa Peth
Journal: Journal of Clinical Oncology (2013)

11107 Background: The bromodomain-containing protein 4 (BRD4) is a member of the BET (bromodomain and extraterminal) protein family, which regulate the assembly of chromatin complexes and transcriptional regulators at the target gene promoters, e.g., of Myc and BCL2. JQ1 competitively binds and inhibits the bromodomains of the BET proteins, including BRD4. Treatment with JQ1 attenuates Myc and BCL2 levels and promotes growth arrest, differentiation and apoptosis of AML cells. Methods: Here, we determined the growth inhibitory, differentiation and apoptotic effects of JQ1 (100 to 500 nM) alone and in combination with low concentrations of the deacetylase inhibitor panobinostat (PS) (5 to 20 nM) (gift from Novartis) in cultured (OCI-AML3, MV4-11 and MOLM13) and primary AML blast progenitor cells. We also determined the in vivo anti-AML activity of JQ1 (50 mg/kg/day IP) and/or PS (5 mg/kg/MWF IP) for 3 weeks against the OCI-AML3 xenograft in the NOD/SCID mice. Results: Treatment with JQ1 decreased the binding of BRD4 at the chromatin associated with Myc and BCL2 promoters (by ChIP-qPCR) and attenuated the mRNA and protein levels of Myc, BCL2 and cyclin D1, while increasing the levels of p21, CEBPα, BIM and cleaved PARP in the cultured and primary AML blasts. This was associated with an increase in the % of G1 phase cells, attenuation of the colony growth, and induction of apoptosis of the cultured (OCI-AML3 &gt;MV4-11 &gt;MOLM13) and primary AML cells. JQ1 treatment also dose-dependently inhibited the viability of CD34+ primary AML progenitor cells (n=10). Gene expression microarray analysis revealed a JQ1 treatment-associated signature of the most up- and down-regulated mRNAs that correlated with its anti-AML effects. Co-treatment with JQ1 and PS synergistically induced apoptosis of AML cells (by isobologram analysis; CI &lt; 1.0). As compared to the mice treated with vehicle alone, or with each agent alone, co-treatment with JQ1 and PS, without inducing toxicity, significantly improved the survival of the OCI-AML3 engrafted NOD/SCID mice (p &lt; 0.01). Conclusions: These pre-clinical findings warrant further in vivo evaluation of the efficacy of the combination of a BRD4 antagonist and PS, and its predictive biomarkers, against human AML.
Melanoma Incidence Among Non-Hispanic Whites in All 50 US States From 2001 Through 2015
Authors: Aaron P Thrift, Franciska J Gudenkauf
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background The United States has large regional variation in primary prevention campaigns for skin cancer. We collected data from all 50 states to examine changes in melanoma incidence and performed age-period-cohort analyses to describe the simultaneous effects of age, period, and cohort on incidence rates. Methods Annual melanoma incidence rates for non-Hispanic whites from 2001 to 2015 were extracted from the US Cancer Statistics registry. Secular trends were examined overall and by sex and state. We used joinpoint regression to compute annual percent change and average annual percent change and corresponding 95% confidence intervals (CIs). We also analyzed incidence trends by 5-year age group and birth cohort using incidence rate ratios and age-period-cohort modeling. Results Melanoma incidence increased from 20.7 per 100 000 (95% CI = 20.5 to 20.9) in 2001 to 28.2 per 100 000 (95% CI = 28.0 to 28.5) in 2015, increasing by 3.90% (95% CI = 2.36% to 5.48%) annually between 2001 and 2005 and 1.68% (95% CI = 1.37% to 1.99%) annually from 2005 through 2015. The average annual percent change in melanoma incidence rates were similar for men (2.34%, 95% CI = 1.91 to 2.78) and women (2.25%, 95% CI = 1.60 to 2.91). Age-specific relative risk by birth cohort increased from circa 1921 to 1981 before decreasing. Compared with adults born circa 1956, those born circa 1991 had lower melanoma risk (incidence rate ratio = 0.85; 95% CI = 0.77 to 0.94). Geographic variation was observed; some states still have melanoma rates trending upwards in all birth cohorts. Conclusions The continued increase in melanoma incidence among non-Hispanic whites, particularly in states where rates continue to rise among recent and current birth cohorts, underscores the need for increased public health campaigns aimed at reducing sun exposure.
A phase I trial of S-1 plus vinorelbine in patients with unresectable advanced or metastatic non-small cell lung cancer
Authors: H. Suyama, Y. Shigeoka, T. Igishi, S. Matsumoto, M. Kodani, K. Takeda, T. Sumikawa, M. Morita, Y. Ueda, E. Shimizu
Journal: Journal of Clinical Oncology (2009)

e19098 Background: We reported the efficacy of the combination treatment of tegafur-uracil (UFT) and vinorelbine (VNR) for the elderly patients (pts) (&gt;70) with advanced non-small cell lung cancer (NSCLC) in ASCO 2007 (Abstract - No. 18075). Although the cisplatin-based doublets are still milestone for the pts with advanced NSCLC, non-platinum based doublet regimens remain as a matter of development judging from recent meta-analysis. Tegafur-5-chloro-2,4-dihydroxypyridine-potassium oxonate (S-1), a new oral fluoropyrimidine, has been studied extensively, and appears promising for various kinds of cancers including NSCLC. Thus, we conducted this phase I trial using VNR and new oral fluoropyrimidine, S-1. Methods: Pts with advanced NSCLC, who had received at least one prior platinum-containing regimen, were eligible. In this phase I study, VNR was infused on days 1 and 8, and S-1 was administered from day 2 to day 6 and from day 9 to day 13 of a 3-week cycle. The starting dose of S-1 was 80 mg/m 2 /day and, if necessary, the dose was decreased to 65 mg/m 2 /day; VNR was increased from 20 to 25 mg/m 2 in this trial. Results: From August 14, 2007 to April 1, 2008, 8 pts enrolled in this study. Median age was 61 (range 49–75). Dose limiting toxicity (DLT) was evaluated during the first 6 weeks of the treatment. No DLT was observed at dose level I (80 mg/m 2 /day S-1, 20 mg/m 2 VNR). At dose level II (80 mg/m 2 /day S-1, 25 mg/m 2 VNR), DLT in the form of neutropenia, hyperglycemia and hyponatremia was observed in 3 of 5 pts. The maximum tolerated dose (MTD) for the present treatment was 80 mg/m 2 /day S-1 and 25 mg/m 2 VNR; the recommended tolerable dose for future phase II trials is therefore 80 mg/m 2 /day S-1 and 20 mg/m 2 VNR. Conclusions: Three-week cycle of VNR (20 mg/m 2 ), infused on days 1 and 8; S-1 (80 mg/m 2 /day), administered from day 2 to day 6 and from day 9 to day 13, is being examined in our phase II trial for first-or second-line treatment of NSCLC. No significant financial relationships to disclose.
Blood Pressure Variability and Arterial Stiffness—Chicken or Egg?
Authors: Franz H. Messerli, Stefano F. Rimoldi, Sripal Bangalore
Journal: JAMA Cardiology (2019)

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Prospective multicenter trial of sentinel node mapping for gastric cancer
Authors: Y. Kitagawa, H. Takeuchi, Y. Takagi, S. Natsugoe, M. Terashima, N. Murakami, T. Fujimura, J. Sakamoto, T. Aikou, M. Kitajima
Journal: Journal of Clinical Oncology (2009)

4518 Background: The sentinel node (SN) concept has revolutionized the approach to the surgical staging of both melanoma and breast cancer, and these techniques can yield patient benefit by avoiding various complications due to unnecessary prophylactic regional lymph node dissection in cases with negative SN for cancer metastasis. Clinical application of SN mapping for early gastric cancer had been controversial for years. However, single institutional results of SN mapping for early gastric cancer are almost acceptable results in terms of detection rate and accuracy to determine lymph node status. We hypothesized that SN mapping plays a key role to obtain individual information and allows modification of the surgical procedure for early gastric cancer. Methods: The Japan Society of Sentinel Node Navigation Surgery (JSNNS) has conducted a prospective multicenter trial of SN mapping by a dual tracer method with radioactive colloid and blue dye. Between September 2004 and March 2008, 433 patients with early gastric cancer were accrued at 12 comprehensive hospitals. Patients were enrolled under JSNNS and each institutional review board-approved protocols. Eligibility criteria were that patients had clinically T1N0M0 or T2N0M0 single tumor with diameter of primary lesion less than 4cm without any previous treatments. Technetium-99m tin colloid and isosulfan blue were utilized as dual tracers for SN mapping. Results: SN mapping has been performed for 397 patients with early gastric cancer. Detection rate of hot and/or blue node using our procedure was 97.5% (387/397). The mean number of sentinel nodes per case was 5.6. Fifty-three of 57 cases with lymph node metastasis showed positive sentinel nodes. The sensitivity to detect metastasis based on SN status was therefore 93% in our experience. Accuracy of metastatic status based on SN was 99% (383/387). In two of the four SN false-negative cases, the tumor involved to pT2, and only one case showed the metastatic lymph node beyond the SN basin. Conclusions: Our results suggest that SN concept for clinically N0 early gastric cancer could be validated, and minimized gastrectomy with individualized selective and modified lymphadenectomy for early gastric cancer with negative SN should become feasible and clinically useful as less invasive surgical procedures. No significant financial relationships to disclose.
Neural correlates of individual differences in affective benefit of real-life urban green space exposure
Authors: Heike Tost, Markus Reichert, Urs Braun, Iris Reinhard, Robin Peters, Sven Lautenbach, Andreas Hoell, Emanuel Schwarz, Ulrich Ebner-Priemer, Alexander Zipf, Andreas Meyer-Lindenberg
Journal: Nature Neuroscience (2019)
Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response
Authors: Roy M Fleischmann, Mark C Genovese, Jeffrey V Enejosa, Eduardo Mysler, Louis Bessette, Charles Peterfy, Patrick Durez, Andrew Ostor, Yihan Li, In-Ho Song
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> In SELECT-COMPARE, a randomised double-blind study, upadacitinib 15 mg once daily was superior to placebo or adalimumab on background methotrexate (MTX) for treating rheumatoid arthritis signs and symptoms and inhibited radiographical progression versus placebo at 26 weeks. Here we report 48-week safety and efficacy in patients who continued their original medication or were rescued to the alternative medication for insufficient response. <h3>Methods</h3> Patients on MTX received upadacitinib 15 mg, placebo or adalimumab for 48 weeks. Rescue without washout, from placebo or adalimumab to upadacitinib or upadacitinib to adalimumab occurred if patients had &lt;20% improvement in tender joint count (TJC) or swollen joint count (SJC) (weeks 14/18/22) or Clinical Disease Activity Index (CDAI) &gt;10 (week 26); remaining placebo patients were switched to upadacitinib at week 26. Efficacy was analysed by randomised group (non-responder imputation), as well as separately for rescued patients (as observed). Treatment-emergent adverse events per 100 patient-years were summarised. <h3>Results</h3> Consistent with responses through week 26, from weeks 26 to 48, responses by randomised group including low disease activity, clinical remission and improvements in pain and function remained superior for upadacitinib versus adalimumab; radiographical progression remained lower for upadacitinib versus placebo (linear extrapolation). Although both switch groups responded, a higher proportion of patients rescued to upadacitinib from adalimumab achieved CDAI ≤10 at 6 months postswitch versus patients rescued from upadacitinib to adalimumab. Safety at week 48 was comparable to week 26. <h3>Conclusion</h3> Upadacitinib+MTX demonstrated superior clinical and functional responses versus adalimumab+MTX and maintained inhibition of structural damage versus placebo+MTX through week 48. Patients with an insufficient response to adalimumab or upadacitinib safely achieved clinically meaningful responses after switching to the alternative medication without washout.
A regression model for predicting conditional survival for head and neck cancer patients: A SEER analysis
Authors: S. J. Wang, C. D. Fuller, D. F. Sittig, J. M. Holland, C. R. Thomas
Journal: Journal of Clinical Oncology (2007)

6527 Background: Survival probability changes as patients survive longer periods of time after diagnosis, and estimates of prognosis at diagnosis are no longer valid. Conditional survival (CS) accounts for the changing hazard rate over time and is a more accurate estimate of survival probability for these cancer survivors. The specific aim of this project was to build a statistical model and web-based tool to predict conditional survival for an individual head &amp; neck cancer patient based on tumor and patient characteristics. Methods: Using 27,825 patients diagnosed with head &amp; neck cancer between 1988–97 from the Surveillance, Epidemiology, and End Results 17 (SEER) database, we built a multivariate Cox proportional hazards regression prediction model. Patient and tumor characteristics included as covariates were age, sex, race, tumor site, stage, and grade. The primary endpoint was conditional overall survival. The model was validated for discrimination using the concordance index and a calibration plot was constructed. Bootstrapping was used to correct for optimistic bias. We also built a web-browser software tool to allow a user to enter patient information into the model and calculate conditional survival probability. Results: The regression model showed very good calibration and discrimination with a bootstrap-corrected C-index of 0.71. For a 65-yr old white male with a moderately-differentiated tonsil cancer with regional lymph nodes, the model predicted that the 5-yr conditional overall survival would increase from 50% at the time of diagnosis to 63% at 3 years after diagnosis. For a 75-yr old black male with a well-differentiated localized lip cancer, 5-yr conditional survival would improve from 58% at diagnosis to 70% by 3 years from diagnosis. Conclusions: Our regression model can accurately predict conditional survival for head &amp; neck cancer patients based upon specific patient and tumor characteristics. This tool allows the calculation of more specific prognosis predictions for individual cancer patients who have already survived a period of time after diagnosis and treatment. No significant financial relationships to disclose.
Myeloproliferative Neoplasm (MPN) Blastic Transformation Occurs at the Level of Both Short and Long Term Hematopoietic Stem Cells
Authors: Xiaoli Wang, Cing Siang Hu, Raajit K. Rampal, Joseph Tripodi, Vesna Najfeld, Bruce Petersen, John Mascarenhas, Ronald Hoffman
Journal: Blood (2017)
Direct activation of Type I protein kinase a (PKA) by oxidants independently of cAMP is mediated by RI subunit interprotein disulphide bond formation
Authors: Jonathan P. Brennan, Sonya C. Bardswell, Joseph R. Burgoyne, William Fuller, Ewald Schroder, Robin Wait, Shajna Begum, Jonathan C. Kentish, Philip Eaton
Journal: Circulation (2006)
Specific and sensitive detection of BRAF and KRAS mutations in clinical samples.
Authors: Vanessa Kelchner, Sergey Chupreta, Anjali Mishra, Ron Beaubien, Laurie Kurihara, Julie Laliberte, Andrey Mikheykin, David G. Beer, Vladimir Makarov
Journal: Journal of Clinical Oncology (2012)

10587 Background: The development of highly sensitive and specific genotyping assays that are suitable for clinical research and molecular diagnostics opens new opportunities for the detection, assessment, and research of cancer. Swift Biosciences has developed myT Primer qPCR technology which has unique structural and thermodynamic properties that enables highly sensitive mismatch discrimination. The myT Primer reagents can detect 1% mutant BRAF or KRAS present in a background of 10 3 wild-type genomic DNA copies with no background signal from wild-type. A separate ultrasensitive BRAF format has been developed which enables the detection of a single mutant BRAF copy in &gt; 10 4 wild-type genomic DNA copies, representing 0.01% detection. Methods: To evaluate the performance on clinical samples, DNA was prepared from 26 melanoma, 40 colorectal, and 49 lung tumor fresh frozen and FFPE samples, and their corresponding normal adjacent samples. qPCR was performed using standard cycling conditions in single tube format with allele-specific myT primers to assess two BRAF alleles or seven KRAS alleles. Performance of the assay was evaluated on the ABI 7500, CFX96, and Roche LightCycler. A subset of samples were selected for validation by Sanger sequencing. Results: Mutations of BRAF in melanoma, colorectal, and lung tumors were observed to be 46%, 5%, and 2%, in concordance with published data for the frequency of BRAF mutations. Mutations of KRAS in colorectal cancer were observed to be in 17/40, or 42% of samples, consistent with published reports of KRAS in colorectal cancer. 34% of lung cancer samples had a KRAS mutation, also consistent with available statistics. Mutation status was confirmed with Sanger sequencing in the subset of selected samples. Conclusions: The extreme selectivity of the myT BRAF Primers makes them well suited for genotyping of conventional FFPE and frozen tissue samples, whereas the ultrasensitive format is ideal for use with difficult samples such as needle biopsies, CTCs, and serum. The extreme selectivity of these primers results in a definitive Yes/No answer and eliminates the need to use a delta Ct method.