tbuckley/cabot-search huggingface dataset:
Abstract 10978: In Vivo Evidence that Adenylyl Cyclase and Sarcoplasmic Reticulum Pumping Regulate the Intrinsic Rate of Heart’s Pacemaker
Authors: Ismayil Ahmet, Yael Yaniv, Syevda Sirenko, Edward G Lakatta
Journal: Circulation (2013)

Studies in isolated sinoatrial nodal (SAN) cells have led to a theory that a coupled-clock system drives normal automaticity: A Ca2+ clock in the sarcoplasmic reticulum (SR) generates rhythmic loca...
Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma
Authors: Yohann Loriot, Andrea Necchi, Se Hoon Park, Jesus Garcia-Donas, Robert Huddart, Earle Burgess, Mark Fleming, Arash Rezazadeh, Begoña Mellado, Sergey Varlamov, Monika Joshi, Ignacio Duran, Scott T. Tagawa, Yousef Zakharia, Bob Zhong, Kim Stuyckens, Ademi Santiago-Walker, Peter De Porre, Anne O’Hagan, Anjali Avadhani, Arlene O. Siefker-Radtke
Journal: New England Journal of Medicine (2019)

Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine kinase inhibitor of FGFR1–4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with FGFR alterations.
Retrospective analysis of the use of cetuximab (CTX) and paclitaxel (PTX) combination in recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).
Authors: Ainara Soria Rivas, Mercedes Rodriguez Garrote, Maria Eugenia Olmedo Garcia, Maria López, Pilar Garrido López, Alfredo Carrato
Journal: Journal of Clinical Oncology (2012)

e16029 Background: Combination of platinum/5-FU and cetuximab is a 1st line standard treatment approach for R/M SCCHN. Results of a phase II study (Ann Oncol Aug 23, 2011) have shown an encouraging activity and tolerability of the combination of CTX and weekly PTX in this setting suggesting an alternative for unfit patients (pts) or when platinum-based chemotherapy is contraindicated. Methods: A retrospective analysis of our database was performed to evaluate outcomes in pts with R/M SSCHN who were treated under compassionate use with weekly PTX (80 mg/m 2 IV) and CTX (initially 400 mg/m 2 followed by 250 mg/m 2 ) until progression or intolerance in a single institution in Madrid (Spain) between November, 2008 and July, 2011. Results: 16 pts were included (73% male) with a mean age of 58 years. Mainly squamous carcinomas: pharynx (7), larynx (2), tonsil (2), tongue (3), paranasal sinuses (1) and cavum lymphoepithelioma (1). Twenty percent of the pts received this treatment in 1st line; 67% in 2nd line treatment and only 2 pts received it as 3rd line treatment. Out of those who received PTX-CTX as 2nd or 3rd line treatment, 40% had received CTX as part of the 1st line treatment. Pts received a median of 13.87 cycles. All pts were evaluable for response and toxicity. Disease control rate was 47% (7% CR, 27% PR and 13% SD). With a median follow up of 10.3 months the median PFS was 4.7 months. PFS was 5.2 months for 1st line and 4 months for 2nd line after CTX. Acne-like rash appeared in 100% of the pts. It was G 1-2 in 87% of the pts and G 4 only in one patient, forcing to discontinue CTX. Main related toxicities (G 2-3) were diarrhea (13.34%) and hand-foot syndrome (13.33%). Hematological toxicity was mild, more remarkable in 3rd line treatment, and being managed with dose delays and, in two cases, with a 20% reduction of the PTX dose. Conclusions: The combination of cetuximab and weekly paclitaxel was active, well tolerated and manageable. It may be a first-line option for pts with poor performance status or non eligible for platinum as well as second line treatment for those who have failed first line platinum +/- cetuximab containing chemotherapy.
Confirmation of the distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene expression analysis
Authors: S. J. Van Laere, I. Van der Auwera, G. G. Van den Eynden, X. Trinh, P. Van Hummelen, P. van Dam, E. A. Van Marck, P. B. Vermeulen, L. Y. Dirix
Journal: Journal of Clinical Oncology (2007)

21055 Background: We have shown with cDNA microarrays that inflammatory breast cancer (IBC) and non-IBC are distinct biological entities. The purpose of this study was to confirm our previous results using Affymetrix chips. Methods: RNA was extracted from 19 IBC samples and 42 non-stage matched non-IBC samples. RNA was hybridized onto Affymetrix HG U133 Plus 2.0 chips. Gene expression data were normalized using GCRMA and genes with a gene expression of at least 250 in 50% of the cases were filtered in. Hierarchical clustering and principle component analysis was executed. Identification of the different cell-of-origin subtypes in our expression data set was done using the intrinsic gene list. A NFkB signature, a MAPK signature and our own IBC signature were tested by clustering analysis. Results: Clustering using 11341 genes resulted in the identification of two clusters: one containing 14/19 IBC samples and a second containing 32/42 non-IBC (Pearson χ 2 ; p&lt;0.0001). Principle component analysis separated IBC from non-IBC samples along the first principle component. Interestingly, IBC samples more closely resemble T1 - T2 tumours than T3 - T4 tumours. Application of the intrinsic gene set to our IBC/non-IBC data set resulted in the classification of 14/19 IBC samples as basal-like or ErbB2-overexpressing tumours compared to only 4/42 non-IBC tumours (Pearson χ 2 ; p&lt;0.0001). Our own IBC signature was confronted with the new data set and performed well in separating IBC specimens form non-IBC specimens. Clustering identified three clusters from which one cluster contained 18 samples, including 12 IBC specimens (p&lt;0.0001). Using the NFkB and MAPK signatures, similar results were obtained. Conclusions: These results confirm our findings that IBC is a distinct biologic phenotype, characterized by activation of NFkB, possibly through activation of MAPK's. IBC tumours more often demonstrate characteristics from basal-like and ErbB2-overexpressing breast tumours. The fact that IBC tumours are rapidly developing tumours instead of longstanding tumourigenic processes might explain the close resemblance of the IBC gene expression profile to the gene expression profile of T1 and T2 tumours. No significant financial relationships to disclose.
Combined versus single use 20 G fine-needle biopsy and 25 G fine-needle aspiration for endoscopic ultrasound-guided tissue sampling of solid gastrointestinal lesions
Authors: Priscilla A. van Riet, Paolo Giorgio Arcidiacono, Mariachiara Petrone, Nam Quoc Nguyen, Masayuki Kitano, Kenneth Chang, Alberto Larghi, Julio Iglesias-Garcia, Marc Giovannini, Schalk van der Merwe, Erwin Santo, Francisco Baldaque-Silva, Juan Carlos Bucobo, Marco J. Bruno, Harry R. Aslanian, Djuna L. Cahen, James Farrell
Journal: Endoscopy (2019)

Instead of choosing one endoscopic ultrasound (EUS) needle over the other, some advocate the use of fine-needle aspiration (FNA) and fine-needle biopsy (FNB) consecutively. We explored the yield of combined use of 20 G FNB and 25 G FNA needles in patients with a suspicious solid gastrointestinal lesion.Patients from the ASPRO study who were sampled with both needles during the same procedure were included. The incremental yield of dual sampling compared with the yield of single needle use on the diagnostic accuracy for malignancy was assessed for both dual sampling approaches - FNA followed by FNB, and vice versa.73 patients were included. There were 39 (53 %) pancreatic lesions, 18 (25 %) submucosal masses, and 16 (22 %) lymph nodes. FNA was used first in 24 patients (33 %) and FNB was used first in 49 (67 %). Generally, FNB was performed after FNA to collect tissue for ancillary testing (75 %), whereas FNA was used after FNB to allow for on-site pathological assessment (76 %). Diagnostic accuracy for malignancy of single needle use increased from 78 % to 92 % with dual sampling (P = 0.002). FNA followed by FNB improved the diagnostic accuracy for malignancy (P = 0.03), whereas FNB followed by FNA did not (P = 0.13).Dual sampling only improved diagnostic accuracy when 25 G FNA was followed by 20 G FNB and not vice versa. As the diagnostic benefit of the 20 G FNB over the 25 G FNA needle has recently been proven, sampling with the FNB needle seems a logical first choice.
David Oliver: NHS continuing care confusion
Authors: David Oliver
Journal: BMJ (2019)

Every year the NHS Ombudsman receives hundreds of complaints about assessment, funding, and provision of free NHS continuing healthcare (CHC) for people with complex health needs or near the end of life.1 The National Audit Office published a major report in 2017, partly in response to numerous complaints.2 In 2018 the Public Accounts Committee published another, also looking at future threats to funding from targeted savings drives by clinical commissioning groups (CCGs).3

In June this year the BBC reported on the personal impact felt by already distressed people struggling to access such complex care, particularly in getting CCGs to agree funding.4 This followed reports of thousands of people dying while funding decisions were delayed.5

It’s no coincidence that both the ombudsman’s office6 and NHS England7 have public information on processes, entitlements, …
Loss at long arm of chromosome 4 as a predictive factor for recurrence of human hepatocellular carcinoma after orthotopic living-donor liver transplantation.
Authors: Takafumi Nishimura, Yukiko Mori, Shinji Uemoto, Naoshi Nishida
Journal: Journal of Clinical Oncology (2013)

e15054 Background: Living-donor liver transplantation (LDLT) is one of the curative treatments of hepatocellular carcinoma (HCC) that confined to the liver. To extend the indication of LDLT where candidate donors are more likely to be found than in liver transplantation from brain death, the Kyoto criteria (maximum tumor diameter &lt; 5 cm, number of tumor &lt; 10 nodules, serum PIVKA-II &lt; 400 mAU/ml) has been proposed in addition to Millan criteria (&lt; 5 cm for solitary nodule, or &lt; 3 cm and &lt; 3 nodules). The aim of this study was to identify genetic or epigenetic changes that predict recurrence in this setting. Methods: With informed consent, tumor and non-tumor tissues were obtained from 51 patients with HCC at the time of LDLT surgery. DNA copy number alterations were determined by microsatellite analysis and single nucleotide polymorphism array analysis. Mutational analyses for TP53 and CTNNB1 were performed by direct sequencing. DNA methylation status of 18 tumors was further analyzed using BeadChip Human Methylation 450. Results: Identified factors that indicate high risk for recurrence were: exceeding the Millan criteria (p = 0.0245, Log-rank test), exceeding the Kyoto criteria (p = 0.0007), hepatitis B virus infection (p = 0.0057), poorly differentiated tumor (p = 0.0245), loss of 4q34.3 (p = 0.0003), 14q (p = 0.0003), 17p (p = 0.0103), and gain of 8q24 (p = 0.0101), and high fractional allelic loss index (p &lt; 0.0001). In patients who exceeded the Kyoto criteria for LDLT loss of 4q were associated with recurrences (5 recurrences for 6 cases with loss of 4q vs. no recurrence for 6 cases with retaining 4q). Conclusions: Genetic and epigenetic analysis combined with clinico-pathological features may help extending the indication for LDLT in patients with HCC.
Acute hepatitis B notification rates in Flanders, Belgium, 2009 to 2017
Authors: Özgür Koc, Pierre Van Damme, Dana Busschots, Rob Bielen, Anmarie Forier, Frederik Nevens, Geert Robaeys
Journal: Eurosurveillance (2019)

Background Belgium is a low-endemic country for hepatitis B. Universal hepatitis B vaccination in infants with catch-up in the age cohort of 10–13 year-olds began in 1999. Aims Our objective was to evaluate the effect of prevention and control strategies on acute hepatitis B notification rates in Flanders (Belgium) from 2009 to 2017. Methods This observational study collected demographic data and risk factors for acute hepatitis B from mandatory notifications to the Agency for Care and Health. Results In Flanders, acute hepatitis B notification rates per 100,000 population decreased from 1.6 in 2009 to 0.7 in 2017. These rates declined in all age groups: 0–4-year-olds: 0.6 to 0.0, 5–14-year-olds: 0.2 to 0.0, 15–24-year-olds: 0.8 to 0.7, 25–34-year-olds: 3.4 to 1.1 and ≥ 35-year-olds: 1.59 to 0.7. There was also a downward trend in acute hepatitis B notification rates in native Belgians and first-generation migrants. Among 15–24-year-olds and 25–34-year-olds, a possible reversal of the decreasing trend was observed in 2016 and 2015, respectively. Among 548 acute hepatitis B cases, the main route of transmission was sexual activity (30.7%), and the pattern of transmission routes over time showed an increasing proportion of sexual transmission in men who have sex with men (MSM) after 2014. During the period from 2009 to 2017, five mother-to-child transmissions were reported. Conclusions Prevention and control strategies were effective in reducing the acute hepatitis B notification rate. However, stronger prevention and control measures are needed in adult risk groups, particularly MSM.
Multicenter, open-end, randomized controlled study using P53 gene recombinant adenovirus injection (rAd-p53) combined with chemotherapy for orofacial carcinoma (OFC): Phase IV clinical trial—Progress report and conclusion.
Authors: Maolin Yang, Longjiang Li
Journal: Journal of Clinical Oncology (2013)

6080 Background: The gene therapy product (Gendicine, rAd-p53) had pre-market studies done around 1998 indicated its efficacy in the treatment of squamous cell nasopharyngeal carcinoma in multi-modality treatment regimen. Gendicine has been used successfully in treating over 40 cancer types since then. With the advancement in optimization of combined treatment methods over the years, there was a need for a medium term efficacy study. This report summarizes our phase IV study. Methods: Patient selection, intervention and allocation were done according to GCP and supported by statistical analysis. Orofacial cancer (OFC) patients of advanced stages (III/IV) from multiple hospitals (n=30) in China were recruited for this open-end, randomized, controlled study (2009.7--2012.06). The 2 groups were rAd-p53+chemotherapy (GT+CT) (n=743) and CT alone (n=232). Patient exclusion rate were 20.81% (n=128) and 13.9% (n=28) respectively. Virus particles were delivered intra-tumorally at a dose of 10 9 (tumor cell/cm 2 tumor area) x area x100 (virus multiplicity of infection, MOI), every 3d totally 10 times on d 1-28 inclusive. In synchrony with GT, 5-fluorouracil (5-FU, 250 mg/m 2 /d), on d 7-11 and d 25-29 along with carbocisplatin (KP, 400 mg/m 2 /d, i.v.), and with methotrexate (MTX, 50mg/m 2 /d) on d 7, 14, 25, 32 were administered. The control group received 5-FU, KP and MTX. Results: For advanced OFC treated with GT+CT, the efficacy and QoL were significantly (p&lt;=0.001) improved, the result was in accordance with our phase II/ III studies. Conclusions: This study proved rAd-p53 when used as an adjunct is safe and efficacious. The side-effect was mostly self-limiting low-grade to mild fever. The combined treatment modality had complete remission (CR) improved by 21.38%, relief ratio (RR) by 11.53% and clinical benefit ratio by 20.82% over GT-CT. Long-term follow-up will be continued.
12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat
Authors: Luiz Osório Leiria, Chih-Hao Wang, Matthew D. Lynes, Kunyan Yang, Farnaz Shamsi, Mari Sato, Satoru Sugimoto, Emily Y. Chen, Valerie Bussberg, Niven R. Narain, Brian E. Sansbury, Justin Darcy, Tian Lian Huang, Sean D. Kodani, Masaji Sakaguchi, Andréa L. Rocha, Tim J. Schulz, Alexander Bartelt, Gökhan S. Hotamisligil, Michael F. Hirshman, Klaus van Leyen, Laurie J. Goodyear, Matthias Blüher, Aaron M. Cypess, Michael A. Kiebish, Matthew Spite, Yu-Hua Tseng
Journal: Cell Metabolism (2019)
A call for revamping socio-emotional ability research in autism
Authors: Sally Olderbak, Mattis Geiger, Oliver Wilhelm
Journal: Behavioral and Brain Sciences (2019)

Abstract In light of Jaswal &amp; Akhtar's compelling argument, we argue there should instead be more focus on deficits in socio-emotional abilities. However, current research is limited by the psychometric problems with most measures. We discuss specific problems, outlining examples for theory of mind. We conclude with recommendations for new lines of research derived from findings in the individual differences literature.
Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis
Authors: Siyi Li, Chao Li, Yiting Zhang, Xiu He, Xi Chen, Xinning Zeng, Fangwei Liu, Ying Chen, Jie Chen
Journal: Theranostics (2019)

Silicosis is pneumoconiosis of the lung, usually resulting from prolonged exposure to crystalline silica (CS). The hallmark of silicosis is excessive extracellular matrix (ECM) deposition produced by activated fibroblasts. Recent work demonstrated that excessive ECM-forming mechanical cues play an essential role in promoting fibroblast activation and perpetuating fibrotic pathologies. However, the detailed molecular mechanism still needs to be uncovered. Methods: NIH-3T3 fibroblasts were cultured on either 1 kappa (soft) or 60 kappa (stiff) gel-coated coverslips. A series of knockdown and reverse experiments in vitro were performed to establish the signaling for mechanics-induced fibroblast activation. An experimental model of silicosis was established by one-time intratracheal instillation of CS suspension. The cluster of differentiation 44 (CD44) antibody (IM7), dihydrotanshinone I (DHI) and verteporfin (VP) were used to explore the effect of CD44-RhoA-YAP signaling blockade on mechanics-induced fibroblast activation and CS-induced pulmonary fibrosis. Results: Matrix stiffness could induce nuclear translocation of the Yes-associated protein (YAP) through CD44 in fibroblasts. This effect required RhoA activity and F-actin cytoskeleton polymerization but was independent of Hippo pathway kinases, Mst 1 and Lats 1, forming CD44-RhoA-YAP signaling pathway. Pharmacological upstream blocking by CD44 antibody or downstream blockade of YAP by DHI or VP could attenuate fibroblast migration, invasion, proliferation, and collagen deposition. Furthermore, CD44-RhoA-YAP signaling blockade could alleviate CS-induced fibrosis and improve pulmonary function in vivo. Conclusion: CD44-RhoA-YAP signaling mediates mechanics-induced fibroblast activation. Targeting this pathway could ameliorate crystalline silica-induced silicosis and provide a potential therapeutic strategy to mitigate fibrosis.
Prediction of Lymph Node Metastasis in Breast Cancer by Gene Expression and Clinicopathological Models: Development and Validation within a Population-Based Cohort
Authors: Looket Dihge, Johan Vallon-Christersson, Cecilia Hegardt, Lao H. Saal, Jari Häkkinen, Christer Larsson, Anna Ehinger, Niklas Loman, Martin Malmberg, Pär-Ola Bendahl, Åke Borg, Johan Staaf, Lisa Rydén
Journal: Clinical Cancer Research (2019)

More than 70% of patients with breast cancer present with node-negative disease, yet all undergo surgical axillary staging. We aimed to define predictors of nodal metastasis using clinicopathological characteristics (CLINICAL), gene expression data (GEX), and mixed features (MIXED) and to identify patients at low risk of metastasis who might be spared sentinel lymph node biopsy (SLNB).Experimental Design: Breast tumors (n = 3,023) from the population-based Sweden Cancerome Analysis Network-Breast initiative were profiled by RNA sequencing and linked to clinicopathologic characteristics. Seven machine-learning models present the discriminative ability of N0/N+ in development (n = 2,278) and independent validation cohorts (n = 745) stratified as ER+HER2-, HER2+, and TNBC. Possible SLNB reduction rates are proposed by applying CLINICAL and MIXED predictors.In the validation cohort, the MIXED predictor showed the highest area under ROC curves to assess nodal metastasis; AUC = 0.72. For the subgroups, the AUCs for MIXED, CLINICAL, and GEX predictors ranged from 0.66 to 0.72, 0.65 to 0.73, and 0.58 to 0.67, respectively. Enriched proliferation metagene and luminal B features were noticed in node-positive ER+HER2- and HER2+ tumors, while upregulated basal-like features were observed in node-negative TNBC tumors. The SLNB reduction rates in patients with ER+HER2- tumors were 6% to 7% higher for the MIXED predictor compared with the CLINICAL predictor accepting false negative rates of 5% to 10%.Although CLINICAL and MIXED predictors of nodal metastasis had comparable accuracy, the MIXED predictor identified more node-negative patients. This translational approach holds promise for development of classifiers to reduce the rates of SLNB for patients at low risk of nodal involvement.
A phase II trial of ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) for previously untreated stage I, II extranodal natural killer/T-cell lymphoma, nasal type (NTCL): A multicenter study of the Korean Cancer Study Group.
Authors: Tae Min Kim, Dong-Wan Kim, Yoon-Koo Kang, Goon Jae Cho, Hong-Suk Song, Hyo Jung Kim, Byung Soo Kim, Jong-Seok Lee, Hawk Kim, Sung Hyun Yang, Young Jin Yuh, Sung Hwa Bae, Kyung-Hee Lee, Yoon-Kyung Jeon, Chul Woo Kim, Dae Seog Heo
Journal: Journal of Clinical Oncology (2013)

8521 Background: Combination chemotherapy of IMEP was active as a first-line as well as a second-line treatment for NTCL in a retrospective analysis. Thus, we conducted a prospective, multicenter, phase II study of IMEP chemotherapy in previously, untreated stage I/II NTCL. Methods: Patients with chemo-naïve stage I/II NTCL were enrolled between December 2004 and February 2009 and they received 6 cycles of IMEP (ifosfamide 1.5 g/m 2 on days 1 to 3; methotrextate 30mg/m 2 on days 3 and 10; etoposide 100mg/m 2 on days 1 to 3; and prednisolone 60mg/m 2 /day on days 1 to 5) followed by involved field radiotherapy (IFRT). Response was evaluated every 2 cycles of chemotherapy and 4 to 8 weeks after completion of IFRT using modified Response Evaluation Criteria in Solid Tumors. Results: Overall, 44 patients including 29 males were analyzed by the intent-to-treat principle. Overall response rates were 73% (complete remission [CR], 11 [27%] of 41 evaluable patients) after IMEP chemotherapy and 78% (CR, 18 [67%] of 27) after IMEP followed by IFRT. Grade 3 to 4 neutropenia and thrombocytopenia were documented in 33 (75%) and 7 (16%) patients, respectively. Only 8 (18%) patients experienced grade 3 febrile neutropenia. 2-year progression-free survival (PFS) and overall survival (OS) were 56% and 66%, respectively. High Ki-67 (≥ 70%) and Ann Arbor stage II independently reduced PFS (hazard ration [HR]=5.6, 95% confidence interval [CI] 1.8-17.6; P=.004) and OS (HR=4.8, 95% CI 1.9-12.2; P=.001), respectively. Conclusions: IMEP followed by IFRT is active and safe against patients with previously untreated stage I/II NTCL.