tbuckley/cabot-search huggingface dataset:
Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors
Authors: Tomomasa Yokomizo, Naoki Watanabe, Terumasa Umemoto, Junichi Matsuo, Ryota Harai, Yoshihiko Kihara, Eri Nakamura, Norihiro Tada, Tomohiko Sato, Tomoiku Takaku, Akihiko Shimono, Hitoshi Takizawa, Naomi Nakagata, Seiichi Mori, Mineo Kurokawa, Daniel G. Tenen, Motomi Osato, Toshio Suda, Norio Komatsu
Journal: The Journal of Experimental Medicine (2019)

Before the emergence of hematopoietic stem cells (HSCs), lineage-restricted progenitors, such as erythro-myeloid progenitors (EMPs), are detected in the embryo or in pluripotent stem cell cultures in vitro. Although both HSCs and EMPs are derived from hemogenic endothelium, it remains unclear how and when these two developmental programs are segregated during ontogeny. Here, we show that hepatic leukemia factor (Hlf) expression specifically marks a developmental continuum between HSC precursors and HSCs. Using the Hlf-tdTomato reporter mouse, we found that Hlf is expressed in intra-aortic hematopoietic clusters and fetal liver HSCs. In contrast, EMPs and yolk sac hematopoietic clusters before embryonic day 9.5 do not express Hlf. HSC specification, regulated by the Evi-1/Hlf axis, is activated only within Hlf+ nascent hematopoietic clusters. These results strongly suggest that HSCs and EMPs are generated from distinct cohorts of hemogenic endothelium. Selective induction of the Hlf+ lineage pathway may lead to the in vitro generation of HSCs from pluripotent stem cells.
Abstract P5-09-10: Uptake of genetic testing and prevalence of mutations among minority populations: A retrospective cohort study
Authors: P Nagireddy, P Ganschow
Journal: Cancer Research (2019)

Abstract Background: Hereditary cancer syndromes account for 5-10% of cancers. Limited data exists on the uptake of genetic testing and the prevalence of mutations in minority populations. Objective: To estimate genetic testing uptake and prevalence of mutations in a minority population seeking care in a safety net healthcare system. Methods: We conducted a retrospective cohort study of patients who were assessed at John H Stroger Jr., Hospital of Cook County cancer genetics risk clinic between October 2015 and March 2018 to determine the uptake of genetic testing and the prevalence of genetic mutations. Patients who met National Comprehensive Cancer Network (NCCN) guidelines for genetic testing for hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome and familial adenomatous polyposis were included. Data was abstracted through chart review to obtain age, socio-demographics, personal cancer history, primary language, personal and family history of cancer including type of cancer and age at diagnosis, insurance status, genetic testing status and test results. Uptake of testing was calculated as the percentage of patients who underwent testing among those patients who met NCCN criteria for testing. Prevalence of mutations among those patients who underwent testing was determined and compared between different ethnicities using Chi-square test. Results: Of 510 patients offered genetic counseling &amp; testing, 478 (94%) underwent genetic testing. Among those who tested, 34% (n=165) were African American and 45% (n=212) were of Hispanic origin. Prevalence of any mutation was 48%(n=232), Pathogenic mutations were identified in 11% (n=54) of testers and variants of uncertain significance (VUS) were identified in 37% (n=178). Deleterious mutations and VUS rates in patients affected with hereditary cancer syndromes were 13% (n=42) and 39 % (n=132) respectively. Deleterious mutations and VUS rates in women unaffected with cancer were 9% (n=12) and 33 % (n=46) respectively. Overall mutation prevalence did not differ between affected and unaffected patients (p=0.12) or between Black and Hispanic patients (p=0.96). Deleterious mutation rate in Hispanic patients was 15.6% (CI 20.5%-10.7%) and in Black patients was 3.6% (CI 3%-4%). There was a significant difference in the percentage of deleterious mutations between Hispanic and Black patients (p=0.0009) . Conclusion: Genetic testing uptake was high in minority populations. In the Population who were tested prevalence of pathogenic mutations was higher among Hispanics than African Americans. Citation Format: Nagireddy P, Ganschow P. Uptake of genetic testing and prevalence of mutations among minority populations: A retrospective cohort study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-10.
A new start
Authors: Katherine Bettany
Journal: BMJ (2013)

A rock star once asked to be woken up when September was over—and he didn’t have to contend with starting medical school for the first time. This month, thousands of freshers will descend on medical schools all over the world, beginning the process that in a few short years will transform them into junior doctors. Wouldn’t it be great if you could have received a letter of advice at the start of medical school from the version of yourself at the end? Well, we don’t have a time machine here at the Student BMJ , but we have asked six final year medical …
Inequalities in healthcare and medical education in Brazil
Authors: Ricardo Dahmer Tiecher
Journal: BMJ (2014)

Brazil is a continental country with its population concentrated in the coastal, urban areas. After two decades of rule by military government, a new constitution was ratified in 1988, and with it came a public health system that was free of charge to the Brazilian population. Although the public healthcare system has contributed to a steady and widespread improvement in health indices over the past three decades, large inequalities persist. For example, a Lancet article in 2011 reported that child mortality rate in Northeastern Brazil was 2.24 times higher than in Southern Brazil.1

Most medical education takes place in the public health system. Medical students like me are able to see at first …
Naming, blaming, shaming, and rating doctors online
Authors: Maryam Ahmad
Journal: BMJ (2010)

As doctors we have to accept that, despite trying our best, sometimes we are unable to save patients’ lives. In some instances the grieving family of the patient will channel their anger and blame towards us. Relatives might physically assault or verbally abuse a doctor, or they might vent their opinions on the internet, causing permanent damage to a doctor’s reputation. 

Before starting a placement in the United States, I “googled” the …
Abstract PD8-06: Fluorescence guided breast conserving surgery
Authors: CK Sharma, P Ranjan, D Qaiser, A Dhar, A Srivastava, K Kataria
Journal: Cancer Research (2019)

Abstract Background. Palpation guided breast conserving surgery for breast cancer is associated with tumor involved margins in up to 41% of cases. Ultrasound guided breast conserving surgery and frozen section biopsy result in a significant reduction in margin positivity. However, intra-operative USG and Frozen section biopsy are not widely available. We aimed to find a simple and effective technique for intra-operative margin assessment during breast conserving surgery. Hypothesis. Intravenously injected Fluorescein reaches tumor tissue in high concentration due to increased tumor blood flow and increased capillary permeability which can be detected by blue light (494 nm). Objective. To find diagnostic accuracy of fluorescence guided identification of tumor margins during breast conserving surgery. Methods. A total of 60 patients with T1–T2 invasive breast cancer who underwent breast conserving surgery at AIIMS, New Delhi between March, 2016 to Feb, 2018 were included. Each patient received 2 ml of intra-venous 20% Fluorescein sodium just before skin incision. Breast conserving surgery was performed under USG guidance. Specimen was bisected and examined under blue light. Fluorescent tumor margins were identified and six biopsies taken from non-fluorescent area 5mm outside from fluorescent tumor margins at 2,4,6,8,10 and 12 o'clock position. The involvement of USG guided margin was compared with Fluorescence guided margins on histopathology. Results. Mean age of the patient was 51.2 (SD=6.4) years. Fourteen patients (20.3 %) had T1 tumors while 46 patients(69.7%) had T2 tumors. Axillary nodes were involved in 19 patients (20.1%) and all underwent axillary node dissection. Eight patients (13.3%) received NACT. Fluorescent margins in two (3.3%) out of 60 patients were involved by tumor while USG guided margins in all the 60 patients were free. The specificity of fluorescence in identifying uninvolved tumor margins during breast conserving surgery is 96.7%. No patient developed adverse drug reactions. Conclusion. The fluorescence identifies tumor free margins with 96.7% accuracy. It is simple, effective and affordable method of identifying margin positivity in breast conservation surgery. Citation Format: Sharma CK, Ranjan P, Qaiser D, Dhar A, Srivastava A, Kataria K. Fluorescence guided breast conserving surgery [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD8-06.
Novel techniques for advancing our understanding of pulmonary arterial hypertension
Authors: Emily M. Beck, Nathan D. Hatton, John J. Ryan
Journal: European Respiratory Journal (2019)

Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary vasculature characterised by progressive remodelling and narrowing of the pulmonary arteries due to pathological abnormalities of fibroblasts, inflammatory cells, endothelial cells and smooth muscle cells [1]. Decades of clinical, translational and bench research have advanced our understanding of the underlying mechanisms contributing to the development of PAH. However, despite considerable heterogeneity of this disease, current diagnostic and treatment guidelines remain largely standardised. Aside from cohorts with long-term response to calcium channel blockers, individualised treatment options targeted at the various phenotypes of PAH have not been identified. New, sophisticated tools are being used to advance our knowledge of PAH and facilitate individualised treatment based on phenotypes <http://ow.ly/qP6h30ocllp>
Abstract P1-08-21: Association of depression and anxiety disorder with the risk of mortality in breast cancer: A national health insurance service study in South Korea
Authors: YS Kim, E-J Shim, JW Lee, J Cho, HK Jung, NH Kim, JE Lee, J Min, WC Noh, S-H Park
Journal: Cancer Research (2019)

Abstract PURPOSE: To examine whether depression, anxiety disorder and their co-occurrence would increase the risk of mortality in patients with breast cancer, and whether antidepressant treatment would reduce the same. PATIENTS AND METHODS: Data were retrieved from the database of the Korean National Health Insurance Service. Of 145,251 patients diagnosed with breast cancer between 2007 and 2014, 20,870 patients diagnosed with depression or anxiety disorder one year before breast cancer diagnosis were excluded. Thus, data of 124,381 patients were included in this study. RESULTS: Anxiety disorder was more prevalent than depression in patients with breast cancer, and similar factors were associated with both depression and anxiety disorder. Overall, female sex, older age, residence in metropolitan areas, lower income, higher comorbidity, carcinoma in situ, and the receipt of any type of cancer therapies were associated with an increased risk of depression or anxiety disorder. Depression and anxiety disorder were associated with an increased risk of mortality (Hazard Ratio (HR) = 1.26, 95% CI=1.18–1.36; HR=1.14, 95% CI=1.08–1.22, respectively) and their co-occurrence further increased the risk (HR=1.38, 95% CI=1.24–1.54). Antidepressant treatment was related to a reduced risk of mortality. Compared to patients with no depression, among those with depression, the risk of mortality was 2.18 times higher (95% CI=1.69–2.81) in patients who did not receive antidepressant treatment and 1.25 times higher (95% CI =1.17–1.32) in those who received antidepressant treatment. CONCLUSION: The current findings suggest that psychiatric comorbidities are markers of increased mortality risk in patients with breast cancer. This underscores the need for screening and treating depression and anxiety disorders to improve survival in breast cancer. Citation Format: Kim YS, Shim E-J, Lee JW, Cho J, Jung HK, Kim NH, Lee JE, Min J, Noh WC, Park S-H. Association of depression and anxiety disorder with the risk of mortality in breast cancer: A national health insurance service study in South Korea [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-21.
Abstract P1-15-02: Withdrawn
Authors: R Schwab, A Clark, C Yau, D Wolf, AJ Chien, M Majure, C Ewing, A Wallace, E Roesch, T Helsten, A Forero, E Stringer-Reasor, C Vaklavas, R Nanda, N Jaskowiak, J Boughey, T Haddad, H Han, C Lee, K Albain, C Isaacs, A Elias, E Ellis, P Shah, J Lang, J Lu, D Tripathy, K Kemmer, D Yee, B Haley, L Korde, K Edmiston, D Northfelt, R Viscusi, Q Khan, WF Symmans, J Perlmutter, N Hylton, H Rugo, M Melisko, A Wilson, R Singhrao, S Asare, L van't Veer, A DeMichele, D Berry, L Esserman
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Schwab R, Clark A, Yau C, Wolf D, Chien AJ, Majure M, Ewing C, Wallace A, Roesch E, Helsten T, Forero A, Stringer-Reasor E, Vaklavas C, Nanda R, Jaskowiak N, Boughey J, Haddad T, Han H, Lee C, Albain K, Isaacs C, Elias A, Ellis E, Shah P, Lang J, Lu J, Tripathy D, Kemmer K, Yee D, Haley B, Korde L, Edmiston K, Northfelt D, Viscusi R, Khan Q, I-SPY 2 Consortium, Symmans WF, Perlmutter J, Hylton N, Rugo H, Melisko M, Wilson A, Singhrao R, Asare S, van't Veer L, DeMichele A, Berry D, Esserman L. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-02.
Lentiviral Vector-Mediated Expression of Exoenzyme C3 Transferase Lowers Intraocular Pressure in Monkeys
Authors: Junkai Tan, Guo Liu, Xianjun Zhu, Zhijian Wu, Ningli Wang, Liang Zhou, Xiaoguang Zhang, Ning Fan, Xuyang Liu
Journal: Molecular Therapy (2019)

Primary open-angle glaucoma (POAG) is considered a lifelong disease characterized by optic nerve deterioration and visual field damage. Although the disease progression can usually be controlled by lowering the intraocular pressure (IOP), therapeutic effects of current approaches do not last long. Gene therapy could be a promising method for persistent treatment of the disease. Our previous study demonstrated that gene transfer of exoenzyme C3 transferase (C3) to the trabecular meshwork (TM) to inhibit Rho GTPase (Rho), the upstream signal molecule of Rho-associated kinase (ROCK), resulted in lowered IOP in normal rodent eyes. In the present study, we show that the lentiviral vector (LV)-mediated C3 expression inactivates RhoA in human TM cells by ADP ribosylation, resulting in disruption of the actin cytoskeleton and altered cell morphology. In addition, intracameral delivery of the C3 vector to monkey eyes leads to persistently lowered IOP without obvious signs of inflammation. This is the first report of using a vector to transduce the TM of an alive non-human primate with a gene that alters cellular machinery and physiology. Our results in non-human primates support that LV-mediated C3 expression in the TM may have therapeutic potential for glaucoma, the leading cause of irreversible blindness in humans. Primary open-angle glaucoma (POAG) is considered a lifelong disease characterized by optic nerve deterioration and visual field damage. Although the disease progression can usually be controlled by lowering the intraocular pressure (IOP), therapeutic effects of current approaches do not last long. Gene therapy could be a promising method for persistent treatment of the disease. Our previous study demonstrated that gene transfer of exoenzyme C3 transferase (C3) to the trabecular meshwork (TM) to inhibit Rho GTPase (Rho), the upstream signal molecule of Rho-associated kinase (ROCK), resulted in lowered IOP in normal rodent eyes. In the present study, we show that the lentiviral vector (LV)-mediated C3 expression inactivates RhoA in human TM cells by ADP ribosylation, resulting in disruption of the actin cytoskeleton and altered cell morphology. In addition, intracameral delivery of the C3 vector to monkey eyes leads to persistently lowered IOP without obvious signs of inflammation. This is the first report of using a vector to transduce the TM of an alive non-human primate with a gene that alters cellular machinery and physiology. Our results in non-human primates support that LV-mediated C3 expression in the TM may have therapeutic potential for glaucoma, the leading cause of irreversible blindness in humans.
Great contributions: medical students in research
Authors: Katherine Bettany
Journal: BMJ (2014)

The pressure to get involved in research at medical school can be huge, and some will wonder what skills they have to offer to a research team as a relatively inexperienced medical student. Yet some of the most prestigious scientific breakthroughs have been made by medical students. The identification of the islets of Langerhans, shown on our cover, was made by German medical student Paul Langerhans in 1869. Then, in 1922, Charles Best, a Canadian medical student, was part of a team that isolated insulin from the islets of Langerhans, and successfully used it to …
Instinct based medicine?
Authors: Yassar Abdullah S Alamri
Journal: BMJ (2011)

Evidence based medicine is a relatively new approach to medical practice. It uses the findings and recommendations of the best available scientific research. Decision analysis and evidence based medicine began to appear in the medical literature in the early 1980s and have gradually been encouraged and advocated.1 But what defines “evidence?”

During a neurology elective at one of Saudi Arabia’s biggest hospitals, I discussed the case of a patient with severe internal carotid artery stenosis with a consultant neurologist. Trying to …
Abstract 4917: The Fallopian tube epithelium as the field of origin for ovarian serous carcinoma
Authors: Keren Levanon, Vivian Ng, Paola D Vermeer, Ronny I Drapkin
Journal: Cancer Research (2008)

Abstract Ovarian cancer is the most lethal gynecological malignancy in Western countries. Serous carcinoma is the most aggressive sub-type, yet a clear understanding of its pathogenesis, including identification of precursor lesions, is lacking. Research on ovarian carcinogenesis has traditionally focused on the ovarian surface epithelium (OSE), or surface-derived intracortical Mullerian inclusions as the fields of origin. Our recent studies suggest that the Fallopian tube (FT) fimbria, rather than the OSE, may be the site of origin for over 50% of sporadic and hereditary serous carcinomas. The earliest precursor lesion identified, the ‘p53 signature’, is characterized by DNA damage, p53 gene mutations and p53 protein accumulation in normal-appearing secretory epithelial cells. Thus the FT secretory epithelial cell (FTSEC) emerges as a candidate cell-of-origin for most serous carcinomas. We hypothesize that the FTSEC is susceptible to DNA damaging effects associated with ovulation and that repeated and prolonged genotoxic stress leads to the development of precursor lesions, and, eventually, carcinoma. To address this possibility we have taken two approaches. First, using genome-scale approaches, we are defining the unique genetic ‘fingerprint’ of each morphologic step along the continuum from benign FT epithelium to p53 signatures, to intraepithelial carcinoma, and to invasive serous carcinoma. This investigation has identified key elements of signaling pathways that participate in the neoplastic process of serous cells. In addition, we have identified candidate biomarkers that may serve as sentinels of early stage disease. To experimentally address the biology and susceptibility of the serous cell to transformation, we have established an ex vivo co-culture system of FTSECs and ciliated cells that enables us to experimentally manipulate and characterize this epithelium. Specifically, we found that the serous cell has a unique DNA damage response compared to the neighboring ciliated cells. This altered response may contribute to its susceptibility to genotoxic stressors and neoplastic transformation. We have also identified markers that uniquely mark serous versus ciliated cells in this culture system. These markers enabled us to isolate pure FTSECs and immortalize them in culture. We are now able to study the effects of define genetic alterations (for instance, p53, BRCA mutations, c-myc, Akt activation) both in vitro and in vivo with the goal of understanding the underlying mechanism of transformation in this cell type. We hope that this novel approach will provide new insights into the nature of the ‘p53 signature’ and the molecular events that drive tumorigenesis. A firm understanding of these processes is essential for the development of new prevention strategies and therapeutic modalities.
Abstract P5-09-12: Germline mutation in <i>TP53</i> gene in a cohort of 2,561 Chinese high-risk breast cancer patients using multigene panel testing
Authors: A Kwong, V Shin, CH Au, C Ho, T Slavin, J Weitzel, TL Chan, E Ma
Journal: Cancer Research (2019)

Abstract Background: Li-Fraumeni syndrome (LFS) is a rare autosomal genetic disorder with germline TP53 mutations. Patients with TP53 mutations have a higher risk of developing breast cancer than those harboring BRCA mutations. Although limited studies have shown that TP53 mutation carriers are less responsive to low dose radiation and more susceptible to induce new malignancies from radiotherapy. Moreover screening strategies allows early detection of a spectrum of cancers related to TP53 mutations. From work of BRCA mutations where over 40% novel mutations were detected in Chinese cohort, it is important to evaluate the frequency of TP53 mutation in Chinese to better understand the spectrum to guide appropriate clinical management of these high risk individuals. Methods: TP53 gene mutation screening was performed on 2,561 high-risk breast cancer patients using multigene panel testing. The patients were accrued by Hong Kong Hereditary and High Risk Breast Cancer Program from March 2007 to May 2018. All detected pathogenic mutations were further validated by bi-directional DNA sequencing and analyzed by our in-house developed bioinformatics pipeline. Results: Sixteen distinct pathogenic or likely pathogenic variants were identified, and 3 of them were de novo TP53 mutations (18.75%). The mean age of patients who harbored TP53 mutation was 30.44 years (range 18-44), and 50% of the tumors were bilateral breast cancer. Of sixteen different pathogenic mutations, majority of them were missense mutation (87.5%), and 2 were nonsense mutation (12.5%). Four of the sixteen TP53 mutation carriers had family history of breast cancer, while others had a family history of lung cancer (43.75%). Conclusion: This study revealed that seven patients were found to habor TP53 mutation even when they did not meet the criteria of LFS of LFS-like phenotype, implicated the importance of using multigene panel test for probands and their relatives to offer a comprehensive surveillance programe for TP53 carriers. Citation Format: Kwong A, Shin V, Au CH, Ho C, Slavin T, Weitzel J, Chan TL, Ma E. Germline mutation in TP53 gene in a cohort of 2,561 Chinese high-risk breast cancer patients using multigene panel testing [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-12.