tbuckley/cabot-search huggingface dataset:
DISRUPTION OF LAMIN A LEADS TO EARLY-ONSET CARDIAC CONDUCTION DYSFUNCTION IN ZEBRAFISH MODELS OF LAMINOPATHY
Authors: Ryota Teramoto, Kenshi Hayashi, Manu Beerens, Micah Burch, David Chiang, Aaron P. Kithcart, Yao Zu, Tuomas Kiviniemi, Eva Buys, Akihiro Nomura, Masayuki Takamura, Calum A. MacRae
Journal: Journal of the American College of Cardiology (2020)
BASELINE TRICUSPID REGURGITATION IS ASSOCIATED WITH WORSE OUTCOME IN PATIENTS UNDERGOING MITRACLIP THERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Jakrin Kewcharoen, Nishant Trivedi, Chol Techorueangwiwat, Chanavuth Kanitsoraphan, Narut Prasitlumkum, Pattara Rattanawong, Wasawat Vutthikraivit
Journal: Journal of the American College of Cardiology (2020)
Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis
Authors: Lúcia Moreira-Teixeira, Olivier Tabone, Christine M. Graham, Akul Singhania, Evangelos Stavropoulos, Paul S. Redford, Probir Chakravarty, Simon L. Priestnall, Alejandro Suarez-Bonnet, Eleanor Herbert, Katrin D. Mayer-Barber, Alan Sher, Kaori L. Fonseca, Jeremy Sousa, Baltazar Cá, Raman Verma, Pranabashis Haldar, Margarida Saraiva, Anne O’Garra
Journal: Nature Immunology (2020)
LEFT ATRIAL STRAIN AS A PREDICTOR OF ATRIAL FIBRILLATION IN PATIENTS WITH AN ACUTE CORONARY SYNDROME
Authors: Tomas Miranda-Aquino, Silvia Perez-Topete, Michel Machuca-Hernandez, Jorge Hernandez-del Rio, Carlos del Cid-Porras, Christian Gonzalez-Padilla, Oscar Lomeli-Sanchez, Williams Ortega-Pantoja, Luis Meneses, Carlos Gomez-Vazquez, Ramon Miguel Esturau Santalo
Journal: Journal of the American College of Cardiology (2020)
Use of the PRO Onc Assay (Prometheus) to measure HER2 overexpression/activation in circulating tumor cells (CTCs) in women with HER2-negative metastatic breast cancer (MBC): A Sarah Cannon Research Institute (SCRI) trial.
Authors: John D. Hainsworth, Howard A. Burris, Patrick Brian Murphy, Ruth E. Lamar, Mythili Shastry, Lindsey H. Finney, Denise Aysel Yardley
Journal: Journal of Clinical Oncology (2012)

618 Background: HER2- targeted therapy has markedly improved the treatment of women with HER2- positive breast cancer. FISH testing for HER2 overexpression is the most reliable assay method; treatment decisions are usually based on HER2 expression of the breast primary tumor. Accurate determination of HER2 status by testing CTCs may improve patient management by allowing ongoing assessment of HER2 status during treatment and/or identifying additional patients (pts) for HER2- targeted therapy. Methods: The PRO Onc assay uses a multiplexed immunoassay format to provide expression and activation profiling of HER2 and other signal transduction molecules. The assay can detect overexpression and activation (phosphorylation) of HER2, with sensitivity at a single CTC level. We obtained blood specimens from 57 women with metastatic HER2- negative breast cancer who were receiving standard chemotherapy. In these women, HER2 status had previously been determined by FISH (32) or 0 – 1+ IHC testing (25). All specimens were tested for the presence of CTCs; the PRO Onc assay was performed when CTCs were identified. The HER2 overexpression cutoff (&gt;3.0 CU) was based on the reference value (average + 4SD) determined by analyzing normal blood obtained from 42 healthy donors. Results: 31 of 57 pts (54%) had CTCs identified. 6 of 31 pts (19%) had HER2 overexpressed, and 4 pts (13%) had HER2 activation without overexpression. 7 of 10 pts with HER2 overexpression/activation by PRO Onc Assay were FISH- negative; 3 were IHC- negative. Since initial HER2 determination, these 10 pts had received a median of 3 chemotherapy regimens (range 1 - 5). Conclusions: When CTCs were present, the PRO Onc assay identified HER2 overexpression or activation in 31% of women with HER2- negative MBC. The therapeutic significance of this finding is unknown. Since the predetermined threshold of ≥10% HER2- positive assay results was exceeded, this trial will proceed to a planned second portion, in which women with HER2- negative MBC (by FISH testing) and HER2 overexpression or activation in CTCs will receive a trial of HER2- targeted therapy.
Barrett’s surveillance: take the full package or leave it altogether
Authors: Massimiliano di Pietro
Journal: Endoscopy (2019)

Barrett’s esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), the solid malignancy with the steepest increase in incidence rate over the past 4 – 5 decades and one of the most aggressive cancers, with an overall 5-year survival of only 15 % [1]. It is therefore intuitive that most gastroenterology guidelines recommend endoscopic surveillance of BE with the aim of detecting neoplasia at the pre-invasive (dysplasia) or early invasive (T1) stage [2 – 4]. This opens a window to offer patients timely treatment with minimally invasive modalities, such as endoscopic resection and/or ablation, which are highly effective for the eradication of BE and related neoplasia. Endoscopic treatment also offers the possibility of preserving the anatomy and avoiding the mortality and morbidity related to esophagectomy. It is not surprising that evidence indicates that endoscopic surveillance is associated with detection of cancer at earlier stage; however, studies looking at the impact of endoscopic monitoring on patient outcome are conflicting, with some studies suggesting that mortality from EAC detected within surveillance programs does not differ from that of patients diagnosed de novo with symptomatic cancer [5,6]. An interesting Dutch population study recently investigated the relationship between EAC mortality in patients who had a prior BE diagnosis and the adequacy of endoscopic surveillance, defined as adherence to recommended monitoring intervals [7]. Using patients with known BE who did not receive any surveillance as reference, it was found that only patients who received adequate surveillance had a significantly lower adjusted hazard ratio for EAC mortality (0.79, 95 % confidence intervals 0.64 – 0.92), whereas those who received inadequate monitoring did not benefit from it. These results help to explain why some studies have failed to find an association between improved cancer and endoscopic surveillance, if the latter is not performed adequately. However, surveillance interval is not the only key element of adequacy of clinical management, which also relies on strict adherence to biopsy and standardized endoscopic protocols.
Phase II study of letrozole in estrogen receptor (ER) positive relapsed epithelial ovarian cancer (EOC)
Authors: C. Gourley, J. F. Smyth, M. Mackean, A. Stevenson, A. Williams, T. Rye, N. Reed, P. Vasey, H. Gabra, S. Langdon
Journal: Journal of Clinical Oncology (2006)

5025 Background: Letrozole is a potent oral aromatase inhibitor which rapidly suppresses circulating estrogen levels by 99% in postmenopausal women. By comparison with cytotoxic agents it is very well tolerated. We previously demonstrated an ‘endocrine sensitive’ subgroup of ovarian cancer patients with ER histoscore cutoff of ≥150 (Bowman et al, Clin Can Res 2002). Methods: This was a phase II study with a planned sample size of 33 patients. Eligible patients had relapsed EOC or primary peritoneal cancer with an ER histoscore of ≥150 and a rising CA125 that had progressed according to Rustin’s criteria. Patients were treated with letrozole 2.5mg daily until clinical or marker evidence of disease progression. The primary endpoint was response according to CA125 and RECIST criteria. Biomarker analysis by tissue microarray is also being performed. Results: 46 patients were accrued, 45 of whom were eligible. The median age was 61 (range 39–81). 24, 10 and 10 patients had received 1,2 and &gt;2 previous lines of chemotherapy respectively. Of 43 patients evaluable for CA125 response, 7 (16%) had a response (decrease of &gt;50%) and 16 (37%) patients had not progressed (doubling of CA125) following 12 weeks on treatment. In the CA125 responders, the nadir CA125 ranged from 0.7–49% of baseline (actual % of baseline: 0.7, 2.6, 11.1, 17.6, 23.6, 42.6, 49). Of the 7 responding patients, 5 had received only one previous line of chemotherapy. The time taken to achieve the nadir CA125 value ranged from 10 to 36 weeks, with a median of 13 weeks. Of 33 patients evaluable for radiological response, 3 (9%) had a PR and 14 (42%) had stable disease at 12 weeks. Overall, 11 patients (26%) had a PFS of &gt;6 months and 2 patients (5%) had a PFS of ≥2 years. Conclusions: To our knowledge this is the first study of a hormonal agent in a selected ER +ve population of ovarian cancer patients. Promising efficacy of the agent is demonstrated in this population of pre-treated patients, many with a considerable bulk of disease. Given the median time of 13 weeks to response, we suggest that this strategy should be tested in ER+ve ovarian cancer patients in the adjuvant setting following first line chemotherapy No significant financial relationships to disclose.
Salivary Gland Mucosa‐Associated Lymphoid Tissue–Type Lymphoma From Sjögren’s Syndrome Patients in the Majority Express Rheumatoid Factors Affinity‐Selected for IgG
Authors: Richard J. Bende, Jerry Janssen, Anna Beentjes, Thera A. M. Wormhoudt, Koen Wagner, Erlin A. Haacke, Frans G. M. Kroese, Jeroen E. J. Guikema, Carel J. M. van Noesel
Journal: Arthritis & Rheumatology (2020)

Objective Patients with Sjӧgren's syndrome ( SS ) have an increased risk of developing malignant B cell lymphomas, particularly mucosa‐associated lymphoid tissue ( MALT )–type lymphomas. We have previously shown that a predominant proportion of patients with SS ‐associated salivary gland MALT lymphoma express somatically hypermutated IgM with strong amino acid sequence homology with stereotypic rheumatoid factors ( RF s). The present study was undertaken in a larger cohort of patients with SS ‐associated MALT lymphoma to more firmly assess the frequency of RF reactivity and the significance of somatic IGV ‐region mutations for RF reactivity. Methods B cell antigen receptors ( BCR s) of 16 patients with SS ‐associated salivary gland MALT lymphoma were analyzed. Soluble recombinant IgM was produced of 12 MALT lymphoma samples, including 1 MALT lymphoma sample that expressed an IgM antibody fitting in a novel IGHV 3‐30 –encoded stereotypic IGHV subset. For 4 of the 12 IgM antibodies from MALT lymphoma samples, the somatically mutated IGHV and IGKV gene sequences were reverted to germline configurations. Their RF activity and binding affinity were determined by enzyme‐linked immunosorbent assay and surface plasmon resonance, respectively. Results Nine (75%) of the 12 IgM antibodies identified in patients with SS ‐associated salivary gland MALT lymphoma displayed strong monoreactive RF activity. Reversion of the IGHV and IGKV mutations to germline configuration resulted in RF affinities for IgG that were significantly lower for 3 of the 4 somatically mutated IgM antibodies. In stereotypic IGHV 3‐7 / IGKV 3‐15 –encoded RF s, a recurrent replacement mutation in the IGKV 3‐15 –third complementarity‐determining region was found to play a pivotal role in the affinity for IgG‐Fc. Conclusion A majority of patients with SS‐associated salivary gland MALT lymphoma express somatically mutated BCRs that are selected for monoreactive, high‐affinity binding of IgG‐Fc. These data underscore the notion that soluble IgG, most likely in immune complexes in inflamed tissues, is the principal autoantigen in the pathogenesis of a variety of B cell lymphomas, particularly SS‐associated MALT lymphomas.
Correlation between VEGF and VEGF-R polymorphisms, toxicity, and clinical outcome in HCC patients receiving sorafenib.
Authors: Luca Faloppi, Mario Scartozzi, Maristella Bianconi, Cristian Loretelli, Gianluca Svegliati Baroni, Samuele De Minicis, Alessandra Mandolesi, Riccardo Giampieri, Alessandro Bittoni, Michela Del Prete, Elena Maccaroni, Luca Cecchini, Italo Bearzi, Antonio Benedetti, Stefano Cascinu
Journal: Journal of Clinical Oncology (2013)

4123 Background: The introduction of sorafenib for the treatment of advanced HCC radically changed patients’ clinical outcome. However response to treatment as well as toxicity are still largely unpredictable in the single patient. We previously reported that VEGF and VEGFR polymorphisms may have a predictive and prognostic role in this setting, but little is known about the possible correlation with toxicity. The aim of our study was to evaluate whether VEGF and VEGFR genotyping was able to correlate with toxicity in HCC patients receiving sorafenib. Methods: 73 histological samples of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients time to progression (TTP), overall survival (OS) and toxicities were analysed. Results: VEGF-A rs833061 T&gt;C, rs699947 C&gt;A and rs2010963 C&gt;G polymorphisms were statistically significant associated with any grade global (respectively: p=0.031; p=0.018; p=0.003) and cutaneous toxicities (respectively: p=0.043; p=0.019; p=0.025). Furthermore patients with any grade global and cutaneous toxicities showed a better progression free survival and overall survival (global toxicity PFS: 7.0 vs 5.0 months, p=0.016; OS: 26.8 vs 13.0 months, p=0.023) (cutaneous toxicity PFS: 7.6 vs 5.1 months, p=0.033; OS: 22.7 vs 13.3 months, p=0.014) Conclusions: In our analysis patients with polymorphism T at rs833061, C at rs699947 and C at rs2010963 showed a higher rate of toxicities and, accordingly to our previous report, this correlates with a better PFS and OS. Analysis of VEGF and its receptor genes polymorphisms represents a clinical tool to identify patients with favourable response to sorafenib presumably related to a more efficient control of tumour growth. The occurrence of toxicity could be an interesting clinical surrogate during sorafenib treatment and may help clinicians in a more cautious and aware management of HCC patients.
APPLICABILITY OF THE MADIT-CRT SCORE FOR PREDICTION OF THE LONG-TERM CLINICAL BENEFIT OF THE CARDIAC RESYNCHRONIZATION THERAPY BY QRS MORPHOLOGY
Authors: Arwa Younis, May Goldenberg, Valentina Kutyifa, Bronislava Polonsky, Scott McNitt, Wojciech Zareba, Gregory Golovchiner, Alon Barsheshet
Journal: Journal of the American College of Cardiology (2020)
TWO- AND THREE-YEAR OUTCOMES OF ENDOVASCULAR INTERVENTIONS FOR PERIPHERAL ARTERIAL DISEASE STRATIFIED BY RUTHERFORD CLASSIFICATION
Authors: Stefanos Giannopoulos, Jihad A. Mustapha, William A. Gray, Gary M. Ansel, George Adams, Eric Secemsky, Ehrin J. Armstrong
Journal: Journal of the American College of Cardiology (2020)
Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions
Authors: Seiji Kaji, Takakuni Maki, Tomoyuki Ishimoto, Hodaka Yamakado, Ryosuke Takahashi
Journal: Translational Neurodegeneration (2020)

Abstract Multiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease severity warrants urgent development of disease-modifying therapy, but the disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions (GCIs), which are insoluble α-synuclein accumulations within oligodendrocytes (OLGs). Thus, preventive strategies against GCI formation may suppress disease progression. However, although numerous studies have tried to elucidate the molecular pathogenesis of GCI formation, difficulty remains in understanding the pathological interaction between the two pivotal aspects of GCIs; α-synuclein and OLGs. The difficulty originates from several enigmas: 1) what triggers the initial generation and possible propagation of pathogenic α-synuclein species? 2) what contributes to OLG-specific accumulation of α-synuclein, which is abundantly expressed in neurons but not in OLGs? and 3) how are OLGs and other glial cells affected and contribute to neurodegeneration? The primary pathogenesis of GCIs may involve myelin dysfunction and dyshomeostasis of the oligodendroglial cellular environment such as autophagy and iron metabolism. We have previously reported that oligodendrocyte precursor cells are more prone to develop intracellular inclusions in the presence of extracellular fibrillary α-synuclein. This finding implies a possibility that the propagation of GCI pathology in MSA brains is mediated through the internalization of pathological α-synuclein into oligodendrocyte precursor cells. In this review, in order to discuss the pathogenesis of GCIs, we will focus on the composition of neuronal and oligodendroglial inclusions in synucleinopathies. Furthermore, we will introduce some hypotheses on how α-synuclein pathology spreads among OLGs in MSA brains, in the light of our data from the experiments with primary oligodendrocyte lineage cell culture. While various reports have focused on the mysterious source of α-synuclein in GCIs, insights into the mechanism which regulates the uptake of pathological α-synuclein into oligodendroglial cells may yield the development of the disease-modifying therapy for MSA. The interaction between glial cells and α-synuclein is also highlighted with previous studies of post-mortem human brains, cultured cells, and animal models, which provide comprehensive insight into GCIs and the MSA pathomechanisms.
Changes in circulating endothelial cells (CEL) in patients receiving trastuzumab for metastatic breast cancer predict response to treatment
Authors: P. Spadaro, M. Ingemi, G. Dottore, G. Toscano, R. Maisano
Journal: Journal of Clinical Oncology (2006)

579 Background: Amplification or overexpression of HER-2/neu has been identified in 10–20% of invasive breast cancers and is associated with shorter overall survival times; furthermore HER-2/neu is a predictive factor with regard to monoclonal antibody therapy with Trastuzumab. The observed association between the overexpression of HER-2/neu and higher VEGF expression indicates that HER-2/neu is involved, at least partly, in the regulation of angiogenesis in human breast cancer. Recently circulating endothelial cells (CECs) have been proposed as a marker of tumor progression and/or a response to antiangiogenic therapy; thus, we have performed a phase II study to explore the correlation between CECs and treatment with Trastuzumab in metastatic breast cancer Methods: 22 women aged ≥ 18 years with histologically proven Her-2-positive, ECOG performance status 0 to 2 who were not eligible for, or who wished to delay receiving chemotherapy received a standard loading dose of Trastuzumab 4 mg/Kg followed by 2 mg/Kg weekly. The weekly maintenance dose was continued until disease progression. A panel of monoclonal antibodies including anti CD45 to exclude hematopoietic cells, anti CD31, CD34, CD36, CD105, CD106, CD133, and KDR and appropriate analysis gates were used to enumerate resting and activated circulating endothelial cells Results: The overall response rate (RC + RP) to treatment was 25% (2 RC + 3RP). In healthy controls (N° 20) mean values of resting and activated CECs were 7.6/μL (4.6 - 11.2/μL) and 1.3/μL (0.1 - 2.4 /μL) respectively. Before treatment with Trastuzuamb the mean resting and activated CECs were 41.1/μL (16.4 - 60.5/μL) and 6.9/μL (5.1 - 8.7/μL). At a first assessment (6 wks) a significant decrease in CECs (p&lt;0.001)was found in patients responding to treatment but not in the patients who did not achieve a remission Conclusions: Our finding has shown that resting and activated CECs are increased in metastatic breast cancer patients and decline during treatment in responding patients, furthermore, these data underline the crucial role of angiogenesis in this setting and support the rationale for a combination of Bevacizumab with Trastuzumab. No significant financial relationships to disclose.
Management of octogenarians with female breast cancer in a rural oncology program.
Authors: Mir Asif Alikhan, Dianne L Limesand, Mark Schmelzel, Thomas McGlone, David Powers, Osmaan Khawaja, Russell F. Johnson, Frank Pikul
Journal: Journal of Clinical Oncology (2012)

e16513 Background: Despite the fact that chronological age alone does not determine tolerance to cancer treatment, there is a general perception that elderly cancer patients do not receive standard treatment. We sought to review breast cancer patients above 80 years in our practice. Methods: Retrospective analysis was performed ofall women with breast cancer over the age of 80 either at the time of diagnosis or at the time of relapse since July 2005 till July 2011. Results: There were total of 492 breast cancer patients seen during the study period, 207 below 65, 213 between 66-79 and 70 above 80. 59 women met the study criteria. The median age was 86 (81to 99 years). 47 had activities of independent living, 8 were in an assisted living facility and 4 in nursing homes. Median Charlson Co morbidity Index was 2 (0-5). Pathological types: DCIS 2, Invasive ductal carcinoma 50, invasive lobular carcinoma 6 and 1 had apocrine carcinoma. 50 had ER+, PR+ and Her-, 2 patients had triple negative disease and 4 Her+. 2 patients had stage 0, 22 stage I, 23 Stage II, 7 stage III and 5 stage IV. All patients stage 0-III had surgical management, 39 had breast conservative surgery with sentinel node biopsy and 15 had mastectomy. Out of 28 patients referred for adjuvant radiation therapy 17 received it. 49 patients received hormone treatment (39 aromatase inhibitors- AIs and 14 tamoxifen) Chemotherapy was offered but refused by two stage III patients. 2 Her + patients received and tolerated well trastuzumab based chemotherapy. After a median follow up of 48 months (8-120 months) there was 1 local recurrence, 1 distant relapse and 14 deaths ( 11 from other causes 3 from breast cancer). Conclusions: In ourpractice, a majority of octogenarians and nonagenarians live independently and have minimal co morbidities and tolerate standard surgical and hormonal treatment. Although radiation therapy would be considered optional in this group of women, it was offered based on predicted longevity. Mortality form other causes was higher than that from breast cancer ( 18% vs 5%).