tbuckley/cabot-search huggingface dataset:
Profitability of Large Pharmaceutical Companies Compared With Other Large Public Companies
Authors: Fred D. Ledley, Sarah Shonka McCoy, Gregory Vaughan, Ekaterina Galkina Cleary
Journal: JAMA (2020)

<h3>Importance</h3> Understanding the profitability of pharmaceutical companies is essential to formulating evidence-based policies to reduce drug costs while maintaining the industry's ability to innovate and provide essential medicines. <h3>Objective</h3> To compare the profitability of large pharmaceutical companies with other large companies. <h3>Design, Setting, and Participants</h3> This cross-sectional study compared the annual profits of 35 large pharmaceutical companies with 357 companies in the S&amp;P 500 Index from 2000 to 2018 using information from annual financial reports. A statistically significant differential profit margin favoring pharmaceutical companies was evidence of greater profitability. <h3>Exposures</h3> Large pharmaceutical vs nonpharmaceutical companies. <h3>Main Outcomes and Measures</h3> The main outcomes were revenue and 3 measures of annual profit: gross profit (revenue minus the cost of goods sold); earnings before interest, taxes, depreciation, and amortization (EBITDA; pretax profit from core business activities); and net income, also referred to as<i>earnings</i>(difference between all revenues and expenses). Profit measures are described as cumulative for all companies from 2000 to 2018 or annual profit as a fraction of revenue (margin). <h3>Results</h3> From 2000 to 2018, 35 large pharmaceutical companies reported cumulative revenue of $11.5 trillion, gross profit of $8.6 trillion, EBITDA of $3.7 trillion, and net income of $1.9 trillion, while 357 S&amp;P 500 companies reported cumulative revenue of $130.5 trillion, gross profit of $42.1 trillion, EBITDA of $22.8 trillion, and net income of $9.4 trillion. In bivariable regression models, the median annual profit margins of pharmaceutical companies were significantly greater than those of S&amp;P 500 companies (gross profit margin: 76.5% vs 37.4%; difference, 39.1% [95% CI, 32.5%-45.7%];<i>P</i> &lt; .001; EBITDA margin: 29.4% vs 19%; difference, 10.4% [95% CI, 7.1%-13.7%];<i>P</i> &lt; .001; net income margin: 13.8% vs 7.7%; difference, 6.1% [95% CI, 2.5%-9.7%];<i>P</i> &lt; .001). The differences were smaller in regression models controlling for company size and year and when considering only companies reporting research and development expense (gross profit margin: difference, 30.5% [95% CI, 20.9%-40.1%];<i>P</i> &lt; .001; EBITDA margin: difference, 9.2% [95% CI, 5.2%-13.2%];<i>P</i> &lt; .001; net income margin: difference, 3.6% [95% CI, 0.011%-7.2%];<i>P</i> = .05). <h3>Conclusions and Relevance</h3> From 2000 to 2018, the profitability of large pharmaceutical companies was significantly greater than other large, public companies, but the difference was less pronounced when considering company size, year, or research and development expense. Data on the profitability of large pharmaceutical companies may be relevant to formulating evidence-based policies to make medicines more affordable.
Evidence From Family Studies for Autoimmunity in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Alida L.P. Caforio, Federica Re, Andrea Avella, Renzo Marcolongo, Pasquale Baratta, Mara Seguso, Nicoletta Gallo, Mario Plebani, Alvaro Izquierdo-Bajo, Chun-Yan Cheng, Petros Syrris, Perry M. Elliott, Giulia d’Amati, Gaetano Thiene, Cristina Basso, Dario Gregori, Sabino Iliceto, Elisabetta Zachara
Journal: Circulation (2020)

Background: Serum anti-heart autoantibodies (AHAs) and anti-intercalated disk autoantibodies (AIDAs) are autoimmune markers in myocarditis. Myocarditis has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC). To provide evidence for autoimmunity, we searched for AHAs and AIDAs in ARVC. Methods: We studied: 42 ARVC probands, 23 male, aged 42, interquartile range 33–49, 20 from familial and 22 nonfamilial pedigrees; 37 clinically affected relatives (ARs), 24 male aged 35, interquartile range 18–46; and 96 healthy relatives, 49 male, aged 27, interquartile range 17–45. Serum AHAs and AIDAs were tested by indirect immunofluorescence on human myocardium and skeletal muscle in 171 of the 175 ARVC individuals and in controls with noninflammatory cardiac disease (n=160), ischemic heart failure (n=141), and healthy blood donors (n=270). Screening of 5 desmosomal genes was performed in probands; when a sequence variant was identified, cascade family screening followed, blind to immunologic results. Results: AHA frequency was higher (36.8%) in probands, ARs (37.8%), and healthy relatives (25%) than in noninflammatory cardiac disease (1%), ischemic heart failure (1%), or healthy blood donors (2.5%; P =0.0001). AIDA frequency was higher in probands (8%, P =0.006), in ARs (21.6%, P =0.00001), and in healthy relatives (14.6%, P =0.00001) than in noninflammatory cardiac disease (3.75%), ischemic heart failure (2%), or healthy blood donors (0.3%). AHA-positive status was associated with higher frequency of palpitation ( P =0.004), implantable cardioverter defibrillator implantation ( P =0.021), lower left ventricular ejection fraction ( P =0.004), AIDA-positive status with both lower right ventricular and left ventricular ejection fractions ( P =0.027 and P =0.027, respectively). AHA- and/or AIDA-positive status in the proband and at least one of the respective relatives was more common in familial (17/20, 85%) than in sporadic (10/22, 45%) pedigrees ( P =0.007). Conclusions: The presence of AHAs and AIDAs provides evidence of autoimmunity in the majority of familial and in almost half of sporadic ARVC. In probands and in ARs, these antibodies were associated with features of disease severity. Longitudinal studies are needed to clarify whether they may predict ARVC development in healthy relatives or if they be a result of manifest ARVC.
Assessment of functional impact of germline BRCA1/2 variants located in noncoding regions in families with breast-ovarian cancer predisposition.
Authors: Elizabeth Santana dos Santos, Mathilde Gendrot, Sandrine Caputo, Adrien Briaux, Magali Breault, Laurent Castera, Dominique Vaur, Sophie Krieger, Claude Houdayer, Ivan Bieche, Dominique Stoppa-Lyonnet, François Lallemand, Etienne Rouleau
Journal: Journal of Clinical Oncology (2015)

1542 Background: The molecular mechanism of cancer susceptibility remains unclear for the majority of breast and/or ovarian cancer patients. The screening of the key genes BRCA1 and BRCA2 identifies a causal mutation in less than 15% of the families tested. Even if some germline mutations in the regulatory non-coding regions of these genes have been described, their screening is still limited to the coding regions and intron-exon junctions. The aim of this study was to evaluate the potential contribution of non-coding variants on the BRCA1/2 promoter activity and then in breast-ovarian cancer predisposition. Methods: The variants tested were selected from the ENIGMA database (Evidence based Network for the Interpretation of Germline Mutant Alleles) and from the screening of 2 cohorts of patients with BRCA1/2 negative status and whose personal and/or family history were suggesting a breast-ovarian cancer predisposition. The latter was performed on 4 BRCA1/2 non-coding regions (promoter regions and intronic regions). The impact of the variants on the BRCA1/2 gene expression was tested in vitro, after transient transfection in MCF-7 and MDA-MB231 breast cancer cells, by Luciferase gene reporter assay. Results: A total of 12 BRCA1 and 8 BRCA2 variants were tested. We delimited a BRCA1 promoter region with 3 functionally active variants with a clear repressor impact on the promoter activity. This DNA sequence region corresponds to a putative DP1/E2F1 transcription factor binding site, which has never been described. One BRCA2 variant in the promoter also showed a significant reduction in the transcriptional level. Two BRCA1 in the promoter and in intron 2 and two BRCA2 variants in the promoter increased the promoter activity. All the others were shown to have no impact in our functional assay. Conclusions: Through Luciferase gene reporter assay, we identified 8 non-coding and rare variants with a significant impact on BRCA1/2 promoter activity, 3 of them showing a significant reduction in the transcriptional levels. As further investigation is needed, this approach has helped us to prioritize the studies on those variants.
Periostin and Epithelial–Mesenchymal Transition Score as Novel Prognostic Markers for Leiomyosarcoma, Myxofibrosarcoma, and Undifferentiated Pleomorphic Sarcoma
Authors: Maria Assunta Piano, Antonella Brunello, Rocco Cappellesso, Paola Del Bianco, Adriana Mattiolo, Chiara Fritegotto, Barbara Montini, Carolina Zamuner, Paolo Del Fiore, Marco Rastrelli, Antonio Sommariva, Gian Luca De Salvo, Maria Cristina Montesco, Carlo Riccardo Rossi, Vittorina Zagonel, Maria Luisa Calabrò
Journal: Clinical Cancer Research (2020)

Interpatient clinical variability in soft-tissue sarcomas (STS) highlights the need for novel prognostic markers supporting patient risk stratification. As sarcomas might exhibit a more mesenchymal or a more epithelial state, we focused on epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT/MET) for prognostic clues, and selected three histotypes with variable aggressiveness.The expression of EMT/MET-related factors was measured by qRT-PCR in 55 tumor samples from patients with leiomyosarcoma, myxofibrosarcoma, or undifferentiated pleomorphic sarcoma. The identified marker was further evaluated by IHC in 31 leiomyosarcomas and by measuring its circulating levels in 67 patients. The prognostic value of a sarcoma-tailored EMT score was analyzed. Epirubicin chemosensitivity and migration were studied in primary STS cultures. Associations with overall survival (OS) were assessed using Kaplan-Meier and Cox regression methods.High expression of periostin, a mesenchymal matricellular protein, in sarcoma tissues (P = 0.0024), its high stromal accumulation in leiomyosarcomas (P = 0.0075), and increased circulation (>20 ng/mL, P = 0.0008) were associated with reduced OS. High periostin expression [HR 2.9; 95% confidence interval (CI), 1.3-6.9; P = 0.0134] and circulation (HR 2.6; 95% CI, 1.3-5.1; P = 0.0086), and a mesenchymal EMT score (mesenchymal vs. transitioning; HR, 5.2; 95% CI, 2.1-13.0, P = 0.0005) were associated with increased risk in multivariable models. An intrinsic or induced mesenchymal state enhanced chemoresistance and migration in sarcoma cell lines.Although limited to a pilot study, these findings suggest that periostin might contribute prognostic information in the three studied STS histotypes. Moreover, a transitioning EMT score measured in the tumor might predict a less active and a more chemosensitive disease.
SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair
Authors: Manchao Zhang, Wuying Du, Scarlett Acklin, Shengkai Jin, Fen Xia
Journal: Journal of Clinical Investigation (2020)

Platinum-based chemotherapy–induced peripheral neuropathy is one of the most common causes of dose reduction and discontinuation of life-saving chemotherapy in cancer treatment; it often causes permanent impairment of quality of life in cancer patients. The mechanisms that underlie this neuropathy are not defined, and effective treatment and prevention measures are not available. Here, we demonstrate that SIRT2 protected mice against cisplatin-induced peripheral neuropathy (CIPN). SIRT2 accumulated in the nuclei of dorsal root ganglion sensory neurons and prevented neuronal cell death following cisplatin treatment. Mechanistically, SIRT2, an NAD+-dependent deacetylase, protected neurons from cisplatin cytotoxicity by promoting transcription-coupled nucleotide excision repair (TC-NER) of cisplatin-induced DNA cross-links. Consistent with this mechanism, pharmacological inhibition of NER using spironolactone abolished SIRT2-mediated TC-NER activity in differentiated neuronal cells and protection of neurons from cisplatin-induced cytotoxicity and CIPN in mice. Importantly, SIRT2’s protective effects were not evident in lung cancer cells in vitro or in tumors in vivo. Taken together, our results identified SIRT2’s function in the NER pathway as a key underlying mechanism of preventing CIPN, warranting future investigation of SIRT2 activation–mediated neuroprotection during platinum-based cancer treatment.
Coronary Plaque Instability is Linked with Inflammatory Activity of Multiple Organs Including Carotid Plaques and Visceral Adipose Tissue: A Pilot F-18 FDG PET/CT Study
Authors: Kisoo Pahk, Hyun Woo Kwon, Jae Seon Eo, Hong Seog Seo, Won-Ki Kim, Sungeun Kim
Journal: Metabolism (2020)
Oral vinorelbine in first line treatment of NSCLC in elderly: Updated results of a low dose schedule in a single institution experience
Authors: M. Tomirotti, B. Galassi
Journal: Journal of Clinical Oncology (2007)

18192 Background: Oral Vinorelbine has been reported as an effective treatment option for advanced NSCLC in patients not suitable for CDDP containing schedules. Methods: With the aim to improve the toxicity profile of oral Vinorelbine therapy in the elderly setting, from 01/2004 to 05/2006, 31 patients with stage IIIB-IV NSCLC were treated with single agent oral Vinorelbine at the dose of 60 mg/m 2 day 1,8,15 every 3 weeks. Median age of patients was 75 (range 65 to 82) and M/F ratio 1,6. All patients were untreated and received oral Vinorelbine as first line chemotherapy. 24/31 pts were first diagnosed and not suitable for surgery (14/24 locally advanced, 4/24 not operable for comorbidity, 6/24 stage IV at diagnosis), 7/31 recurring after surgery. Pathology reports 15/31 adenocarcinoma, 9/31 squamous, 7/31 non-small cells (citology). Sites of distant metastases were as follow: liver in 13%, bone in 16%, mediastinal lymph nodes in 71%. Median Karnofsky performance status was 80 (range 60–90). Results: Adverse event were experienced by 35% of patients, but were generally mild (grade 1–2). In particular fatigue was reported by 13%, parhestesias by 16%, gastrointestinal disconfort (mild nausea/diarrea) by 26%, costipation/abdominal pain by 10%, trombocytopenia by 6%; no patient experienced anorexia, emesis nor febrile neutropenia. Dose reduction was never required.Complete reversal of adverse effects was always documented. No patient experienced CR; 6/31 (19%) PR and 8/31 (26%) SD were reported with clinical benefit in 14/31 patients (45%). Median time to progression and overall survival were 4,2 and 9 months, not different from data reported in recent literature for higher intensity schedule (Gridelli C, et al.: Eur J Cancer 40:2424–43, 2004) Conclusions: Treatment with oral Vinorelbine at the 60 mg/m 2 day 1,8,15 every 3 weeks schedule has a low toxicity profile and seems to be better tolerated than the conventional dose of 80 mg/m 2 , representing a valide alternative for elderly patients with advanced NSCLC. No significant financial relationships to disclose.
Abstract P2-13-04: Risk of osteoporosis and osteoporotic fracture in breast cancer survivors: A nation-wide study
Authors: Il Yong Chung, Jihyoun Lee, Heba Alqudaihi, Jong Won Lee, Byung Ho Son, Sei Hyun Ahn, Ji Sung Lee
Journal: Cancer Research (2020)

Abstract Background: Referring to American Society of Clinical Oncology (ASCO) 2015 guidelines, they recommend bone screening every two years for premenopausal women receiving tamoxifen, considering it as a risk factor for developing osteoporosis. This nationwide study aimed to investigate the incidence of osteoporosis and osteoporotic fractures, and to assess whether the known factors increase the risk of osteoporosis and/or osteoporotic fractures among breast cancer survivors in South Korea. Methods: A nationwide retrospective study was conducted using the Health Insurance Review and Assessment Service (HIRA) data. The incidence rates of osteoporosis and osteoporotic fracture were calculated by dividing the number of incident cases by the total follow-up period (person-years). The risk factors for osteoporosis and osteoporotic fracture were investigated using Cox proportional hazard regression models. Results: From Jan 2009 to Dec 2014, a total of 47,649 breast cancer survivors were included in this analysis. During the study period, 5,955 osteoporosis events were observed from 252,396 person-year. The incidence rate of osteoporosis in breast cancer survivors was 23.59 per 1000 person-year (95% CI 23.00 - 24.20). Osteoporotic fracture incidence was assessed 2.40 per 1000 person-year (95% CI 2.23 - 2.60), with 647 events out of 269,075 person-years. In age&amp;lt;40 subgroup, use of ovarian function suppression (OFS) was significantly related to incidence of osteoporosis (Incidence rate 7.06 95% CI 5.47 - 9.11). However, the use of tamoxifen did not show an increased risk of osteoporosis (HR 1.24, 95% CI 0.85 - 1.82). Nine osteoporotic fracture was found in 7,121 patients in age under 40. In 40-49 age group, use of chemotherapy (HR 1.41, 95% CI 1.24-1.60, p&amp;lt;.0001), aromatase inhibitor (HR 2.45, 95% C.I. 2.05- 2.92, p&amp;lt;.0001), and OFS (HR 1.19, 95% CI 1.01-1.40, p =.0113) showed a significant increase of osteoporosis. Osteoporotic fracture were associated with use of AI and OFS in 40-49. Use of tamoxifen significantly decreased osteoporosis diagnosis in age 40-49, 50-59, and 60-69. Tamoxifen was also related to decreased incidence of osteoporotic fracture in age 40-49 (HR 0.49, 95% CI 0.31-0.76, p&amp;lt;.0001) and 50-59 (HR 0.37, 95% CI 0.23-0.60, p&amp;lt;.0001). Conclusions: Tamoxifen is not associated with the increased risk of osteoporosis and osteoporotic fracture in breast cancer survivors. Keywords: Breast Neoplasms, Survivorship, Osteoporosis, Bone Fractures, adverse effects Citation Format: Il Yong Chung, Jihyoun Lee, Heba Alqudaihi, Jong Won Lee, Byung Ho Son, Sei Hyun Ahn, Ji Sung Lee. Risk of osteoporosis and osteoporotic fracture in breast cancer survivors: A nation-wide study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-04.
Abstract P531: Immigrants Prioritize Language Over Geography When Accessing Health Care
Authors: Rienna Russo, Simona Kwon, Jennifer Tsui, Stella S Yi
Journal: Circulation (2020)

Introduction: Nationally, New York City (NYC) has one of the largest immigrant populations and highest gentrification rates. Satellite ethnic enclaves are increasingly prevalent as residents relocate to more affordable neighborhoods. Ethnic immigrant communities already face unique challenges to accessing health care, including linguistic and cultural discordance regarding health-related beliefs and norms. Residence outside of ethnic enclaves may further hinder health care utilization, as culturally appropriate services may become less accessible. Characterization of immigrants visiting doctors’ offices within and outside of ethnic enclaves may inform efforts to retain these populations in care. Hypothesis: We compared immigrants accessing health care within major ethnic enclaves to immigrants accessing care elsewhere to ascertain differences in 1) demographic characteristics; 2) reasons for choosing health care facilities; and 3) distances traveled for health care. Methods: Data were from the 2018 Examining Norms and Behaviors Linked to Eating (ENABLE) Pilot Study. Chinese American participants were recruited using venue-based and snowball sampling methods, with assistance from NYC community-based organizations. Surveys included detailed questions on demographics and health-related factors. Participants were included in the analysis if doctor’s office and home zip code data were available (n=143). Data were analyzed using RStudio v.1.2.5 and STATA v.15.0. Results: The majority of participants saw a Chinatown-based doctor (64%; 92 of 143); and were not Chinatown residents (81%; 116 of 143). A greater number of individuals who saw Chinatown-based doctor had less than a college education; were living with food insecurity; were on public insurance; and were less acculturated. Individuals accessing care in Chinatown prioritized doctor’s offices where doctors and medical staff spoke their language more so than individuals accessing care elsewhere. Overall, people who saw a Chinatown-based doctor traveled significantly further (β=1.51 miles [approximately 15 minutes via subway]; 95% CI 0.25, 2.77). Of people who saw a Chinatown-based doctor, 75% (69 of 92) were not Chinatown residents. On average, these individuals traveled 5.14 miles (SD=3.38) to the doctor. Conclusion: In conclusion, there is a need to expand in-language services for immigrant communities. Immigrants visiting doctors in ethnic enclaves are demographically different and travel further distances for health care. Accessing in language services is a priority for these individuals. Immigrants may prioritize language access over geographic access when choosing their health care providers. Strategies to strengthen community-clinical linkages, including connecting community members with bilingual community health workers, may increase healthcare access of under-served, ethnic populations.
Abstract #2751: Inhibition of fatty acid synthase suppresses c-met kinase overexpression in diffuse large B-cell lymphoma
Authors: Shahab Uddin, Azhar Hussain, Saeeda Ahmed, Maqbool Ahmed, Rong Bu, Fouad Al-Dayel, Prashant Bavi, Khawla Al-Kuraya
Journal: Cancer Research (2009)

Targeted approaches are expected to revolutionize cancer treatment in the near future. Fatty acid synthase (FASN), the enzyme responsible for the de novo synthesis of fatty acids, has emerged as a potential therapeutic target for several human cancers however its role in diffuse large B-cell lymphoma (DLBCL) has not been elucidated. In this study, we first analyzed the immunohistrochemical expression of FASN in a tissue micro array cohort of 301 DLBCL patients. Then we investigated the biological significance of inhibition of FASN in DLBCL using pharmacological FAS inhibitors and small interfering RNA (siRNA) on a panel of DLBCL cell lines. FASN was found to be expressed in 62.6% (162/259) DLBCL samples and was seen in highly proliferative tumors manifested by high Ki67 (p  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2751.