tbuckley/cabot-search huggingface dataset:
Schwann cells induce cancer cell dispersion and invasion
Authors: Sylvie Deborde, Tatiana Omelchenko, Anna Lyubchik, Yi Zhou, Shizhi He, William F. McNamara, Natalya Chernichenko, Sei-Young Lee, Fernando Barajas, Chun-Hao Chen, Richard L. Bakst, Efsevia Vakiani, Shuangba He, Alan Hall, Richard J. Wong
Journal: Journal of Clinical Investigation (2016)

Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression.
Philosophical foundations of French and U.S. nosology
Authors: J Kroll
Journal: American Journal of Psychiatry (1979)

The author examines the philosophical foundations of French and American nosology with a view toward understanding the relatively minor influence of French psychiatry in America. Despite the excellence of its descriptive psychiatry, much of French nosological writing is based on philosophical viewpoints that are antithetical to the empirical and pragmatic traditions of American psychiatry. French nosology, which is closely involved with the metaphysical issues of existentialism, phenomenalism, and structuralism, reveals these interests in language and concepts that do not easily permit its hypotheses to be scientifically tested, a prerequisite for any American classification.
Effects of Hormones and 7, 12-Dimethylbenz[<italic>a</italic>]anthracene on Rat Mammary Tissue Grown in Organ Culture<xref ref-type="fn" rid="FN2">2</xref>
Authors: Hiroki Koyama, Dilip Sinha, Thomas L. Dao
 3
Journal: JNCI Journal of the National Cancer Institute (1972)

Mammary glands from 50- to 60-day-old female Sprague-Dawley rats were cultivated for 6–12 days in a synthetic medium supplemented with insulin, estrogen, cortisol, progesterone, and prolactin, singly or in different combinations. Insulin was essential for maintenance of the glands in culture. Of all the other hormones studied, progesterone greatly stimulated mammary gland expiants. This stimulation, as measured by labeling index and mitotic index, reached a maximum level when insulin, estrogen, prolactin, and progesterone were combined. Progesterone combined with insulin alone or with other hormones induced lobuloalveolar development. The increased DNA synthesis resulting from the hormonal stimulation produced by hormone combination, however, did not alter the duration of DNA synthesis. The carcinogenic polycyclic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) added in excess of 1 μg/ml of medium was severely toxic to the mammary epithelial cells. However, 1 μg of DMBA/ml of medium, was suitable for our study. DMBA increased DNA synthesis in the mammary expiants during 6 days of culture in the presence of insulin. This increased DNA synthesis was more pronounced when DMBA was used with insulin, progesterone, and prolactin. Of 10 mammary gland expiants cultured in media containing DMBA and hormone combinations of insulin, progesterone, estrogen, and prolactin, 7 developed squamous metaplasia and 4 had anaplastic changes.
Neoantigen: A Long March toward Cancer Immunotherapy
Authors: Yang Liu
Journal: Clinical Cancer Research (2016)

Abstract Somatic mutations in cancer give rise to neoantigens. Technology revolutions in cancer genomics and immunology have made it possible to rapidly identify neoantigens for cancer vaccines. Leisegang and colleagues report that it is practical to rapidly identify neoantigens for adoptive T-cell therapy in a mouse tumor model. Clin Cancer Res; 22(11); 2602–4. ©2016 AACR. See related article by Leisegang et al., p. 2734
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)
Authors: A.G. Olsson, J McMurray, G Thorgeirsson, C Spaulding, J Slattery, K Pyorala, O Faergeman, RA Wright, K Berg, L Wilhelmsen, TR Pedersen, T. A. Miettinen, HD White, J Kjekshus, Michael Gnant
Journal: The Lancet (1994)
Phase I/II study of GC1008: A human anti-transforming growth factor-beta (TGFβ) monoclonal antibody (MAb) in patients with advanced malignant melanoma (MM) or renal cell carcinoma (RCC)
Authors: J. C. Morris, G. I. Shapiro, A. R. Tan, D. P. Lawrence, T. E. Olencki, B. J. Dezube, F. J. Hsu, M. Reiss, J. A. Berzofsky
Journal: Journal of Clinical Oncology (2008)

9028 Background: TGFβ is a pleiotropic cytokine that normally helps maintain tissue homeostasis. However, in advanced cancers, TGFβ is often overexpressed and associated with higher pathologic grade, increased frequency of metastases, and poorer survival. In such cancers, TGFβ signaling is often altered, and TGFβ becomes a tumor promoter by stimulating tumor cell proliferation/migration/invasion and angiogenesis, by activating stromal cells, and by suppressing anti-tumor immunity. GC1008 is a human IgG4 MAb capable of neutralizing TGFβ isoforms 1, 2, & 3. We report the results of an ongoing, first in cancer, multi-center trial examining the safety and effectiveness of GC1008. Methods: Cohorts of patients (Pts) with advanced MM or RCC who had failed ≥ 1 prior therapy (Tx) were treated with GC1008 at 1 of 6 dose levels (0.1, 0.3, 1, 3, 10 or 15mg/kg) in a 3+3 design. If no DLTs occurred within 28 days of the first dose, 3 additional doses were administered 2wks apart. Tumor response was determined by RECIST. Extended Tx (GC1008 q2wk x 4) was offered to Pts achieving SD, PR, or CR. Results: 22 Pts (21 MM, 1 RCC) were treated in Phase I, including 6 Pts at 15mg/kg. No DLTs were observed and the highest dose level of GC1008, 15mg/kg, was determined to be a safe dose. Adverse events reported as at least possibly related to GC1008 included skin rash (including 2 cases of eruptive keratoacanthomas), fatigue, headache, epistaxis, gingival bleeding, and GI symptoms; all were grade 1 or 2. 9/22 Pts reported SAEs, most of which were related to underlying disease. To date, the only SAE considered possibly related to GC1008 Tx is a well-differentiated squamous cell cancer of the skin in a Pt with a history of this cancer. So far, 5 Pts achieved SD or better and received extended Tx. Of these responders, 3/5 Pts had mixed responses with shrinkage of liver metastases and other sites; 1/5 Pts with skin disease achieved a PR with >75% reduction of target lesions. Conclusion: GC1008 is well tolerated and neutralization of TGFβ holds promise as a novel cancer Tx. A Phase II protocol expansion is planned for Pts with metastatic MM. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genzyme Genzyme Genzyme Genzyme Genzyme
Breast Cancer Risk Reduction and Counseling: Lifestyle, Chemoprevention, and Surgery
Authors: Martin C. Mahoney
Journal: Journal of the National Comprehensive Cancer Network (2007)

Qualitative and quantitative approaches to risk assessment are useful for identifying women at increased risk for developing breast cancer for whom genetics consultation, individualized surveillance recommendations, or chemoprevention may be appropriate. A comprehensive medical and family history review can be used to stratify women into categories of breast cancer risk. A quantitative estimate of the probability of developing breast cancer can be determined using risk assessment tools, such as the Gail and Claus models. Women at increased risk for breast cancer may benefit from individualized approaches to breast cancer risk reduction. Prevention strategies for reducing breast cancer risk include lifestyle modifications, chemoprevention, surgical approaches, and pharmacotherapy.
Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation
Authors: Shannon Elf, Nouran S. Abdelfattah, Edwin Chen, Javier Perales-Patón, Emily A. Rosen, Amy Ko, Fabian Peisker, Natalie Florescu, Silvia Giannini, Ofir Wolach, Elizabeth A. Morgan, Zuzana Tothova, Julie-Aurore Losman, Rebekka K. Schneider, Fatima Al-Shahrour, Ann Mullally
Journal: Cancer Discovery (2016)

Abstract Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN), but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of patients with CALR-mutant MPN. We further show that the thrombopoietin receptor MPL is required for mutant CALR-driven transformation through JAK–STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition. Finally, we demonstrate that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the C-terminus of the mutant protein, which is necessary for physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel paradigm of cancer pathogenesis and reveal how CALR mutations induce MPN. Significance: The mechanism by which CALR mutations induce MPN remains unknown. In this report, we show that the positive charge of the CALR mutant C-terminus is necessary to transform hematopoietic cells by enabling binding between mutant CALR and the thrombopoietin receptor MPL. Cancer Discov; 6(4); 368–81. ©2016 AACR. See related commentary by Stanley and Steidl, p. 344. This article is highlighted in the In This Issue feature, p. 331
EPA Awards Grants to Assist Small Public Water Systems
Authors: Julie A. Jacob
Journal: JAMA (2016)

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The Sonographic Findings and Differing Clinical Implications of Simple, Complicated, and Complex Breast Cysts
Authors: John G Huff
Journal: Journal of the National Comprehensive Cancer Network (2009)

Although palpable and mammographic breast masses are common and frequently reflect underlying fibrocystic change, they must be distinguished from breast malignancy. Clinical characterization of these masses is often unreliable, and mammographic appearances alone cannot distinguish between those that are solid and those that are cystic. Sonography is an important adjunct to characterize these abnormalities further. Management of solid masses is well established, but overlap in appearance of cystic lesions has led to variability in reporting and management. With current high-resolution ultrasound, specific observations can accurately characterize most cystic masses, thereby facilitating management decisions.
Economic Consequences of Diabetes Mellitus in the U.S. in 1997
Journal: Diabetes Care (1998)

Diabetes is a significant public health problem resulting in substantial morbidity and mortality. The objectives of this study were 1) to determine the direct medical and indirect costs attributable to diabetes and 2) to calculate total and per capita expenditures of people with and without diabetes.Direct medical and indirect expenditures attributable to diabetes in 1997 were estimated at $98 billion. Medical expenditures for the treatment of diabetes were estimated for all individuals in the U.S. in 1997 by age-group, sex, race, type of condition, and site of service. Productivity costs due to disability and premature mortality were also estimated for selected patient cohorts. Etiological fractions based on national health care survey data and published literature were used to estimate the proportion of health service utilization and mortality associated with diabetes-related chronic complications and general medical conditions.Direct medical expenditures attributable to diabetes in 1997 totaled $44.1 billion and comprised $7.7 billion for diabetes and acute glycemic care, $11.8 billion due to the excess prevalence of related chronic complications, and $24.6 billion due to the excess prevalence of general medical conditions. The majority of attributable expenditures were for inpatient care (62%), followed by outpatient services (25%) and nursing home care (13%). Two-thirds of all medical costs for diabetes were borne by elderly people. Attributable indirect costs totaled $54.1 billion and comprised $17.0 billion resulting from premature mortality and $37.1 billion from disability. Total medical expenditures incurred by people with diabetes totaled $77.7 billion or $10,071 per capita, compared with $2,669 for people without diabetes.The economic burden of diabetes mellitus in the U.S. is enormous. Medical innovations that can delay the onset and slow the progression of diabetes have tremendous potential to mitigate the associated clinical and cost repercussions.
Abstract 18148: CMR Mapping of Mechanical Activation Time in Patients with Heart Failure and Left Bundle Branch Block: Methods and Initial Results
Authors: Daniel A Auger, Sophia X Cui, Xiao Chen, Kenneth C Bilchick, Frederick H Epstein
Journal: Circulation (2014)

Introduction:  The nonresponse rate to cardiac resynchronization therapy (CRT) in patients with heart failure (HF) is 30-50% using current clinical indicators and implementation methods. A frequent cause of CRT nonresponse is suboptimal positioning of the left ventricular (LV) lead, which should be located in a late-activated region of the LV. In contrast to the the current trend to measure time to peak strain to identify late contraction, we aimed to develop and evaluate MRI strain imaging for mapping the onset of mechanical activation in the LV in CRT patients.   Methods:  Cine DENSE MRI was performed in 18 patients with HF and left bundle branch block (LBBB) and in 6 healthy subjects. Circumferential strain was computed using previously described semiautomatic methods. Circumferential strain as a function of time and LV segment was refined using singular value decomposition (SVD), and an active contour was used to find the time of the onset of contraction (Fig. 1A), which was defined as the mechanical activation time.   Results:  The mean time of latest mechanical activation was 56 ± 23 ms in HF-LBBB patients and 19 ± 9 ms in healthy subjects (p   Conclusions:  Assessment of regional strain onset in heart failure can be determined using SVD of cine DENSE circumferential strain. Mechanically late-activated regions were identified in all 18 patients with HF and LBBB, with significant variability in the site of latest LV free wall activation. This heterogeneity of late-activated segments in LBBB suggests that activation mapping holds potential for pre-procedure identification of optimal LV lead implantation sites for individual patients undergoing CRT.
Relationship of Aurora-A kinase and EGFR inhibition in non-small cell lung cancer (NSCLC) cell lines.
Authors: J. Zhang, X. Pan, I. A. Astsaturov, B. Egleston, H. Borghaei
Journal: Journal of Clinical Oncology (2011)

e13038 Background: NSCLC is the leading cause of cancer related death in the US. Inhibitors of the epidermal growth factor receptor (EGFR) are active in only a subset of patients. Capitalizing on our recent observation of synergistic activity of combined inhibition of EGFR and Aurora-A pathways, we investigated combined activity of Aurora-A and EGFR antagonists in several refractory lung cancer cell lines in culture and xenograft models. Methods: The Aurora-A gene copy number in five human lung cancer cell lines (A549, H322M, H358, H1299 and PC-9) with known EGFR and KRas status was determined by genomic qPCR. The cytotoxcity of erlotinib (E) and MLN8237 (MLN, Millennium) were determined for each cell line using Cell Titer Blue assay. We used the Chou-Talalay method to establish combined activity of MLN and E. Animal xenograft studies with A549 and H322M lung cancer cell lines were conducted by sub-Q inoculations of 4M cells and treatment given on daily (E) or BID (MLN) basis. Tumor sizes were monitored thrice weekly. Activity of Aurora A and EGFR effectors: AKT and RalA, was determined in tumor tissues. Results: The AURKA copy number was 4.37 in PC-9 cells, the other cell lines had normal or low (A549 1.8) copy numbers. PC-9 was most sensitive to both E and MLN with IC50 0.031 uM and 3.05 uM, respectively. In contrast, A549 was resistant to either of the drugs (IC50, E=24.4 uM and MLN= 30.5 uM). Combined treatment of A549 xenografts with erlotinib (10 mg/kg/day) or MLN8237 c(20mg/kg/bid) showed tumor regression while either agent alone were less effective. Similar tumor blocking effect was observed in H322M xenografts. Western blot analysis of the tumor lysates to investigate signaling inhibition in the combined treatment group is ongoing and data will be presented at the meeting. Conclusions: Combination therapy with erlotinib and MNL8237 has synergistic activity in lung cancer cell lines in vitro and in vivo. Western blot analysis to investigate signaling events is ongoing. A clinical trial in patients with advanced NSCLC testing this combination is now ongoing at our center.
Reactivation of latent viral hepatitis infection in patients of chronic myeloid leukemia treated with imatinib mesylate: Experience from a tertiary cancer center in India.
Authors: V. Ostwal, N. Ghadyalpatil, K. Prabhash, H. Menon, R. Nair, M. Sengar, V. Noronha, S. Biswas, B. Bhosale, S. Banavali
Journal: Journal of Clinical Oncology (2010)

6593 Background: Imatinib mesylate (IM) is considered standard first-line therapy for patients with chronic myeloid leukemia (CML). Reactivation of hepatitis B virus (HBV) and hepatitis C (HCV) virus infection is a well known complication for patients with latent infection who are being treated with cytotoxic or immunosuppressive therapy. However, it is still unclear whether IM induces the reactivation of HBV and HCV in patients with a latent infection. Methods: We analyzed 1,100 patients of CML treated with IM. All patients were screened at the start of therapy by Enzyme linked Immuno Sorbent Assay (ELISA) for hepatitis B and C virus. These patients were prospectively followed up for viral reactivation. Results: Twenty-five patients were found to be positive for latent HBV (16 patients: 13 males, 3 females) and HCV (9 patients: 6 males, 3 females) infection at baseline evaluation (prevalence of 2.54%). No patient confirmed past history of jaundice or blood transfusion. All patients had normal liver function tests (LFTs) at baseline. Median follow-up of these patients was 33 months (range 6-67 months). None of these patients developed altered LFTs on follow-up while IM was continued. Importantly, no viral reactivation was seen in any of these patients. However, 3 patients who were initially negative for viral hepatitis markers, had seroconversion for hepatitis B virus (mean time 10 months). Out of these, LFTs were deranged in two patients, of which 1 patient developed acute hepatitis B. (Patient was symptomatic with raised viral DNA copies by PCR and positive HBe antigen by ELISA).This patient was treated with lamivudine following which patient had complete recovery and LFTs gradually normalized. This patient did not have subsequent flare of viral hepatitis on IM. Conclusions: Though the prevalence of viral hepatitis in CML in this study is same as seen in general population in India, the reactivation of this infection is not a common phenomenon. Imatinib can be safely continued in these CML patients without concern of increased risk of viral reactivation or alteration of liver functions. No significant financial relationships to disclose.