tbuckley/cabot-search huggingface dataset:
Expression of the deleted in liver cancer-1 gene is regulated by DNA methylation and is a target for therapy in Waldenström’s Macroglobulinemia
Authors: L. Xu, E. Hatjiharissi, B. T. Ciccarelli, A. M. Roccaro, S. Adamia, A. Sacco, Z. R. Hunter, R. J. Manning, L. Ioakimidis, C. J. Patterson, S. P. Treon
Journal: Journal of Clinical Oncology (2008)

19505 Background: The deleted in liver cancer-1 (DLC-1) gene encodes a Rho GTPase activating protein (RhoGAP) with tumor-suppressor activity. Hypermethylation of the DLC-1 promoter leads to transcriptional silencing of DLC-1, and its re-expression blocks proliferation and/or induces apoptosis. We therefore sought to determine the methylation status of the DLC-1 promoter and its impact on DLC-1 transcription and tumor growth in Waldenström’s macroglobulinemia (WM). Materials and Methods: The methylation status of the DLC-1 promoter was analyzed in WM (BCWM.1 and WM-WSU), multiple myeloma (INA6, MM1S, MM1R, RPMI 8226 and U266), and bone marrow CD19+ cells from 19 WM patients and 4 healthy individuals using methylation-specific PCR. The methylation pattern was subsequently determined by cloning and bisulfite DNA sequencing. DLC-1 mRNA expression was measured by quantitative RT-PCR. Results: The DLC- 1 promoter was completely methylated in WM-WSU and partially methylated in BCWM.1 WM cells. In myeloma cells, complete methylation was observed in RPMI 8226 and U266 cells; partial methylation in INA6 cells; and was undetectable in MM.1S and MM.1R cells. In WM and myeloma cells with complete methylation, DLC-1 transcripts were not expressed, whereas transcript expression was decreased in WM and myeloma cells with partial DLC-1 methylation. Treatment with the DNA methyltransferase inhibitor decitabine resulted in up-regulation of DLC-1 in BCWM.1 (7.4 fold) and re-expression of DLC-1 in WM-WSU WM cells. Importantly, decitabine abrogated cell growth in BCWM.1 and WM-WSU cells, and induced apoptosis of WM-WSU WM cells. Of the 19 WM patients examined, 13 (68%) had methylation in the DLC-1 promoter region. No methylation was seen in healthy individuals, and DLC-1 transcript expression was significantly lower in WM patients relative to the normal controls (p = 0.014). Conclusions: Methylation of CpG islands in the DLC-1 promoter region is a frequent epigenetic modification and contributes to down-regulation of DLC-1 in WM. Treatment with decitabine leads to up-regulation of DLC-1 expression and inhibits growth and/or induces apoptosis in WM cells setting the framework for the study of demethylating agents in WM. No significant financial relationships to disclose.
A retrospective audit of lidocaine use at bronchoscopy in a UK district general hospital
Authors: Claire Lawless, Salim Meghjee
Journal: European Respiratory Journal (2011)

Introduction and aims:  Bronchoscopy is a commonly used investigation and Lidocaine is widely used as a local anaesthetic agent. Toxic side-effects of Lidocaine include cardiac collapse and seizures. The recommended dose in cardiac/hepatic insufficiency is 5mg/kg and 8.2mg/kg in all other patients. It is postulated that some patients may be given above the recommended dose.   Methods:  26 patients were identified retrospectively over a 39 month period. The patients were identified on the hospital bronchoscopy database. Case-notes were also analysed.   Results:  Patient Mean age was 62.25years (30-86). 12 males (46.15%). Patient weight 71.54kg (42.65-117). 5 patients had cardiovascular disease. 4 patients had hepatic disease. 7 (77%) of these 9 patients received a dose of Lidocaine over the maximum for their weight. None of the patients without cardiac/hepatic disease received over the maximum dose of Lidocaine. All patients who were given over their maximum calculated Lidocaine dose or who were given within 100mg of their maximum dose were reviewed with particular reference to their weight. The Mean weight in this subset was 60.6kg.   Discussion:  Patients in this group were frequently given more than their calculated maximum dose of Lidocaine at bronchoscopy. Those most at risk had cardiac or hepatic insufficiency. Patients who were given too much Lidocaine or who were within 100mg of being given too much had a lower Mean weight than that of the whole of the group by 10.94kg.   Conclusions:  Lidocaine use is necessary for patient comfort and success of bronchoscopy. However, it seems more commonplace than previously thought to give higher doses of Lidocaine than those recommended.
Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer
Authors: Nuray Gül, Marjolein van Egmond
Journal: Cancer Research (2015)

Abstract Nowadays, it is impossible to imagine modern cancer treatment without targeted therapies, such as mAbs, that bind to tumor-associated antigens. Subsequently, mAbs can use a wide range of effector functions that mostly engage the immune system. mAbs can bridge immune effector cells with tumor cells, which can result in antibody-dependent cytotoxicity. Increasing evidence, however, identified macrophages as prominent effector cells and induction of antibody-dependent cell phagocytosis as one of the primary mechanisms of action mediated by mAbs. Macrophages are extremely effective in eliminating tumor cells from the circulation. Several immunosuppressive mechanisms may, however, hamper their function, particularly in solid malignancies. In this review, we discuss the evolving insight of macrophages as effector cells in mAb therapy and address novel (co)therapeutic strategies that may be used to fully unleash their cytotoxic capacity for the treatment of cancer. Cancer Res; 75(23); 5008–13. ©2015 AACR.
The artificial kidney
Authors: W J Kolff, H T Berk, M ter Welle, A J van der LEY, E C van Dijk, J van Noordwijk
Journal: Journal of the American Society of Nephrology (1997)

Journal of the American Society of Nephrology : JASN 8(12):p 1959-1965, December 1997. | DOI: 10.1681/ASN.V8121959
Association between obstetric care and risk of suicide
Authors: D J Gunnell, A. Ness, E. Whitley, B. Jacobson, M. Bygdeman
Journal: BMJ (1999)

Editor—Jacobson and Bygdeman present intriguing data suggesting that the risk of suicide is influenced by birth trauma; they argue that this may explain recent increases in suicide among adolescents.1 However, deficiencies in the design and analysis of this case-control study should be addressed before the findings are accepted or possible mechanisms are considered.

The significant findings in Jacobson and Bygdeman’s paper are confined to a subgroup of men who committed suicide using violent methods, were born and died in the catchment area of Stockholm’s forensic medicine department, and had siblings whose birth records were available. The 175 males for whom the significant associations were found probably represent 25% of all suicides. The authors’ suggestion that the association is restricted to violent suicides might be tested by presenting separate risk estimates for violent and non-violent suicides. Furthermore, there is overlap in the cases included in this analysis and those included in a previous study which reported highly significant associations between the risk of suicide and perinatal factors.2 This overlap is likely to have influenced the current findings.

In case-control studies, controls should be selected from the population giving rise to the cases.3 In Jacobson and Bygdeman’s study, cases were restricted to the study catchment area but the same restriction was not applied to controls. Migration may be associated with socioeconomic and health related factors which in turn may confound the associations observed.4

Finally, confounding factors are those associated with both the disease and the exposure under investigation. The statistical significance (or non-significance) of a factor as a predictor of a disease does not justify its inclusion (or exclusion) in a multivariable model. The important issue is whether inclusion of the factor influences the strength of the observed association.3 Factors likely to be associated with the risk of suicide and obstetric practice, such as year of birth, were not included in the final model, and so risk estimates may be biased.

The epidemiology of suicide is complex, and it seems unlikely that the factors investigated in this study explain the high proportion of suicides. This view is supported by another investigation of this issue.5 Further analyses of these data are required to clarify the nature of the associations. These analyses should include both violent and non-violent suicides and make appropriate adjustment for confounding factors. The cases included in the earlier study should be excluded along with controls who no longer reside in the study area.
Characterization of a novel breast cancer xenograft and the corresponding cell line derived from a BRCA2 germ-line mutation carrier patient’s tumor.
Authors: Ludmilla DePlater, Nathalie Auger, Franck Assayag, Patricia DeCremoux, Laetitia Durand, Charlotte Guyader, Elisabetta Marangoni, Sophie Piperno-Neumann, Brigitte Sigal-Zafrani, Dominique Stoppa-Lyonnet, Olivier Delattre, Didier Decaudin, Marie-France Poupon
Journal: Cancer Research (2008)

5493  Inherited mutation in BRCA2 gene predisposes to breast cancer (BC) with an earlier appearance of the disease and a high risk of controlateral breast cancer and ovarian cancer. Only few in vivo models with BRCA2 gene mutation are nowadays available and new established xenografts and cell lines should be useful to study the biology of BRCA2-deficient breast cancers.  Here, we describe a human tumor xenograft (HBCx-17) established from a breast cancer of a 37-year old woman (HBC-17) with her consent. The patient with BRCA2 germ-line mutation (c.6033_6034delTT; p.Ser2012GlnfsX5) was treated by radical surgery, anthracyclin-based chemotherapy and radiotherapy for a first BC. Five years later, she presented a controlateral breast cancer which was treated by mastectomy, taxane-based chemotherapy and parietal radiotherapy. The patient developed lung and mediastinal metastases within one year, tumor control was achieved with cisplatinum-ifosfamide combination. The xenograft was obtained from the relapsed tumor and a cell-line (HBCc-17) was derived from the xenograft.  A characterization of both xenograft and cell line was performed and compared to that of patient’s tumor, including histological analysis, BRCA2 gene sequencing, p53 status determination, genetic analysis by comparative genomic hybridization, and spectral karyotyping.  Histological and receptor profiles identified HBC-17 as a triple negative breast cancer (ER-, PR-, ERBB2-) with a high EGFR expression. The xenograft presented the same features than the primary tumor. Gene expression was estimated by western blotting and quantitative reverse transcription-PCR. Genetic and cytogenetic analyses of xenograft and cell line showed a tetraploid profile with 86 to 110 chromosomes per metaphases. The karyotype was complex and array CGH analysis showed a very high number of alterations such as gene amplifications.  Therapeutic assessment of the xenograft showed sensitivity to anthracyclin-based chemotherapy and resistance to taxane. Moreover, HBCx-17 was highly sensitive to gimatecan, a new topoisomerase I inhibitor (Novartis). Sensitivity to radiotherapy and cisplatin-based treatments are still on-going.  In conclusion, this study describes a new human breast cancer xenograft model obtained from a BRCA2 gene mutated patient, a unique in vivo model of triple negative tumor and determined the in vivo response profile to different cytotoxic agents.
Inadequate Diagnosis and Treatment of Malaria Among Travelers Returning from Africa During the Ebola Epidemic — United States, 2014–2015
Authors: Kathrine R. Tan, Karen A. Cullen, Emilia H. Koumans, Paul M. Arguin
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Among 1,683 persons in the United States who developed malaria following international travel during 2012, more than half acquired disease in one of 16 countries in West Africa. Since March 2014, West Africa has experienced the world's largest epidemic of Ebola virus disease (Ebola), primarily affecting Guinea, Sierra Leone, and Liberia; in 2014, approximately 20,000 Ebola cases were reported. Both Ebola and malaria are often characterized by fever and malaise and can be clinically indistinguishable, especially early in the course of disease. Immediate laboratory testing is critical for diagnosis of both Ebola and malaria, so that appropriate lifesaving treatment can be initiated. CDC recommends prompt malaria testing of patients with fever and history of travel to an area that is endemic for malaria, using blood smear microscopy, with results available within a few hours. Empiric treatment of malaria is not recommended by CDC. Reverse transcription-polymerase chain reaction (RT-PCR) testing is recommended to diagnose Ebola. During the Ebola outbreak in West Africa, CDC received reports of delayed laboratory testing for malaria in travelers returning to the United States because of infection control concerns related to Ebola. CDC reviewed documented calls to its malaria consultation service and selected three patient cases to present as examples of deficiencies in the evaluation and treatment of malaria among travelers returning from Africa during the Ebola epidemic.
Doctors, patients, and the drug industry: Partners, friends, or foes?
Authors: Krumholz Harlan M, Ross Joseph S, 肖月, 张孔来
Journal: BMJ (2009)

药品企业、学者、医疗专家和患者之间的关系一直以来都不被人看好，这些群体都希望能改善彼此间的关系。皇家外科学院本周提出了42条建议，旨在促进各方和药品企业建立更有成效的关系。这里我们列出有关药品企业和医生与患者之间应该具有什么理想关系的5种观点以及需要采取的相应措施。
Metronomic chemotherapy for hormone refractory prostate cancer (HRPC)
Authors: S. Hoshi, K. Numahata, K. Hoshi, K. Suzuki, K. Ono, O. Sugano, S. Ihidoya, S. Saito, Y. Arai
Journal: Journal of Clinical Oncology (2007)

15649 Background: Low dose continuous chemotherapy (metronomic chemotherapy) is trying to many advanced cancers. Metronomic chemotherapy has important anti-angiogenic activity to tumor vessels. For patients who progressed after docetaxel, no standard options exist. We have experienced complete regression of bone metastases on super scan by low does cisplatin, UFT, diethylstilbestrol, and dexamethasone (CUDD) in a patient with HRPC (Int JCO, 8,118, 2003). Methods: CUDD consisting of weekly 5 mg/body of cisplatin plus 125 mg/body of diethylstilbestrol and daily 300–450 mg of UFT/day plus 0.5–1 mg of dexamethasone were given to 47 HRPC patients, (median and range of age: 66 and 52–72, respectively). The ECOG performance status was 0 to 1. Gleason score was 7 in 10 patients and 8 in 17 patients and 9 in 20 patients, respectively. Metastatic site was bone in 45 (EOD grade 1:10, 2:18, 3: 15, 4:2), lymph node in 8. Six cases became refractory to docetaxel were treated with CUDD plus CPM (50 mg/day). Results: Among the 45 patients assessable for bone metastasis, 12 (27 %) obtained marked improvement on bone scan. One was EOD grade 4 (super bone scan) and 9 were EOD grade 1–3. Eighteen (40 %) were stable and 15 (33%) progressed on bone scan. Among 8 patients of lymph node metastasis, 3 (38%) showed partial response, 2 (25%) no change and 3 (38%) progression. Twenty-five (53 %) out of 47 patients showed a PSA decline of 50% or greater. Among the 25 patients assessable for bone pain, 7 (28%) improved, 12 (48%) remained stable and 6 (24%) progressed. Their median response duration and median survival time were 8 months (range; 2 to 44 months) and 20 months (range, 4 to 48 months), respectively. Their median response duration was 3 months. Three of 6 refractory to docetaxel were responded to CUDD plus CPM. Their median response duration was 10 months. Conclusions: CUDD is effective in almost half of hormone refractory prostate cancer patients and has advantage of minimal side effect. Three of 6 docetaxel refractory cases also responded to CUDD plus CPM. No significant financial relationships to disclose.
Manifestations of malignancies during the course of sarcoidosis
Authors: Jelica Videnovic-Ivanov, Violeta Vucinic, Snezana Filipovic, Vladimir Zugic, Jelena Stojsic
Journal: European Respiratory Journal (2011)

Introduction:  Sarcoidosis is the granulomatous disorder with chronic course which can involve any organ in human body. Coexistance of two disorders is potential.   Method of the work:  Analysis were restrospective.All patients with histologically proved sarcoidosis were obtained. Patients were ambulatory or hospitaly treated in the Clinic for lung diseases and tuberculosis. Malignincies were also histologycally proved.   Results:  Among 1307 patients with sarcoidosis (ACCES group, ERS) only 15 patients with malignicies were obtained.Mean ages were 47.3 years, and 11 F/4 M ratio was find out.In 5 patients malignicies were the first obtained diagnosis in patients life as followed: carcinoma mammae (2 patients), carcinoma renis, fibrosarcoma and chronic laeucemia.The mean time in which sarcoidosis were manifested - 3,1 years. All patients were treated for carcinoma, till nowdays. In 11 patients, malignincies followed the sarcoidosis in mean time of 7.7 years: M. Hodgkin, adenocarcinoma ovarii, melanoma malignum, carcinoma cutis (3 female patients), adenocarcinoma intestine, carcinoma recti (2 patients), carcinoma mammae.Mean time of sarcoidosis duration were 8.3 years. All patients with sarcoidosis were mediacally treated even for relapses. In this group 3 lethal outcomes were obtained.   Conclusion:  Comorbidities exists even in sarcoidosis.The question is what is the cause for manifesting sarcoidosis and malignincies. Is immunodefitientia one of the potential factors in manifesting sarcoidosis and in manifesting malignincies. Another question is due to cytostatic drugs delivering during the treatment from malignincies. One of the known cytostatics which can cause granulomatous disorders is vinblastin.
Abstract IA22: Developing improved diffuse intrinsic pontine glioma mouse models
Authors: Oren Josh Becher
Journal: Cancer Research (2015)

Abstract Recent genomic studies have identified novel drivers in DIPG pathogenesis. These include gain of function histone mutations (K27M in H3.3 or H3.1) found in 80% of DIPGs as well as activating mutations in Activin A Receptor, Type I (ACVR1) found in 25% of DIPGs. These studies also provide support for the existence of subtypes of DIPG with H3.3K27M mutations co-occurring with PDGFRA amplifications with an older age at presentation and H3.1K27M mutations co-occurring with ACVR1 mutations with a younger age at presentation. My laboratory has been using the RCAS/tv-a system to develop genetic mouse models for these DIPG subtypes that recapitulate the genetic alterations of the human disease. Our results thus far suggest that H3.3K27M is not sufficient to drive brainstem gliomagenesis on its own or with p53 loss in the early postnatal period but cooperates with platelet-derived growth factor-B (PDGF-B) in brainstem gliomagenesis. Similarly, mutant ACVR1 (R206H or G328V) cooperates with H3.1K27M and p53 loss to induce glioma-like lesions in mice. By contrast to the PDGF-B; H3.3K27M lesions that express Olig2, the mutant ACVR1; H3.1K27M; p53 deficient lesions are Olig2 negative but express CD44 and nestin. To examine whether the cell-of-origin will influence DIPG tumor incidence or latency, we induced murine DIPGs with PDGF-B, H3.3K27M, and p53 loss in three cell populations that express the following markers in the postnatal mouse brainstem: nestin, pax3 and Olig2. We will highlight the differential expression of these markers in the postnatal brainstem and resulting differences in tumorigenesis between these murine DIPGs induced in these three putative cells-of-origin. Lastly we will demonstrate the use of these models as preclinical tools. Citation Format: Oren Josh Becher. Developing improved diffuse intrinsic pontine glioma mouse models. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA22.
Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis
Authors: Sarah E. Headland, Hefin R. Jones, Lucy V. Norling, Andrew Kim, Patricia R. Souza, Elisa Corsiero, Cristiane D. Gil, Alessandra Nerviani, Francesco Dell’Accio, Costantino Pitzalis, Sonia M. Oliani, Lily Y. Jan, Mauro Perretti
Journal: Science Translational Medicine (2015)

Neutrophils generate chrondroprotective AnxA1-containing microvesicles that enter immune cell–impenetrable cartilage.
Phase II randomized trial of docetaxel (D) monotherapy vs epirubicin plus docetaxel (ED) as neoadjuvant treatment of operable breast cancer (BC)
Authors: P. Bougnoux, M. Combe, M.-J. Goudier, T. Facchini, V. Lotz
Journal: Journal of Clinical Oncology (2004)

599 Background: The combination of E and D has demonstrated clinical objective response rates (ORR) of up to 81% as neoadjuvant therapy for operable BC (Luporsi, ASCO 2000). The RR for D monotherapy in this setting has been up to72% (Amat, ASCO 2000). This phase II trial evaluated the pCR of D vs ED in the neoadjuvant setting. Methods: Eligible patients (pts) with histologically proven unilateral BC, unilateral, T2-T3, M0, clinically and radiologically measurable lesions ≥3 cm, adequate heart and organ functions and conservative surgery rate were randomized to 3-weekly treatment with either D 100mg/m2 maximum 8 cycles or E 100 mg/m2+D 75mg/m2+G-CSF, maximum 6 cycles. The primary endpoint was the pCR rate; secondary endpoints were clinical and radiological RR, rate of breast conserving surgery, relapse free survival, and safety. Results: From February 2001 to June 2003, we treated 31 pts with D and 29 pts with ED, with a respective median age 48.6 (30.2–65.8) and 51.7 (29.8–63.6) years and median tumour diameter 6(3–11) and 5(3–10) cm. To date, 29 pts (D) vs 27 pts (ED) were evaluable for clinical response: ORR was respectively 82.8% (34.5%CR, 48.3%PR) vs 88.9% (29.6%CR, 59.3%PR). The radiological ORR was evaluated in 21 (D) vs 16 (ED) pts, with ORR 80.9% (23.8%CR, 57.1%PR) vs 68.8% (12.5%CR, 56.3%PR), respectively. pCR (Chevallier classification) was 18% with (D) among 22 evaluated pts vs 10% with (ED) among 20 evaluated pts. Using the Salatoff classification, pCR was 19% with (D) among 21 evaluated pts vs 16% with (ED) among 19 evaluated pts. Grade 3–4 toxicities (% pts) were (D, ED, respectively): febrile neutropenia (0, 3.7), neutropenia (93, 70), asthenia (16.7, 11) and nail disorders (13, 3.7). Conclusions: This preliminary analysis suggests that D monotherapy (100mg/m2) for 8 cycles is at least as good as ED combination therapy for 6 cycles when used as neoadjuvant treatment for operable BC. No significant financial relationships to disclose.
Effects of BM-573, a dual thromboxane A2 receptor antagonist and thromboxane synthase inhibitor, on osteogenic sarcoma cell-induced platelet aggregation
Authors: X. de Leval, Jean-Louis David, P. Neven, V. Benoit, Bernard Pirotte, Marie-Paule Merville, Vincent Bours, Jean-Michel Dogné
Journal: Blood (2001)