tbuckley/cabot-search huggingface dataset:
Gateway to deLiver: How malaria sporozoites cross the sinusoidal barrier
Authors: David Sacks
Journal: The Journal of Experimental Medicine (2015)

The Journal of Experimental MedicineAfter their inoculation by mosquitos and entry into the bloodstream, malaria sporozoites must cross the liver sinusoidal barrier to gain access to hepatocytes, where they can multiply as erythrocyte-infecting forms.In this issue, Cha et al. provide further evidence that Kupffer cells (KCs) offer a gateway for entry of sporozoites into the liver parenchyma and identify the receptor on the KCs that directs the passage of the parasite through this portal.A remarkably fruitful phage display strategy led to the identification of a peptide, P39, that bound to KCs.P39 strongly inhibited sporozoite entry into KCs in vitro and reduced liver infection in vivo.It was also shown to bind specifically to CD68, a heavily glycosylated transmembrane protein similar to LAMPs in its cellular distribution, sequence, and structure.Furthermore, the expression of CD68, at least in the liver, is confined to KCs.The function of CD68 as a receptor for sporozoite entry into KCs in vitro was supported by silencing, overexpression, and ectopic expression of the CD68 gene and by antibody inhibition.More critically, parasite liver burden in CD68 knockout mice was reduced by 71%, substantiating CD68 as a key receptor for sporozoite interaction with KCs in vivo, and KCs as the paramount gateway cells.Finally, CD68 knockout mice treated with clodronate to deplete KCs showed liver parasite burdens that were comparable to clodronate-treated, wild-type mice, which in turn had comparable infections to untreated wildtype mice.The authors conclude that CD68 serves as such an efficient gateway that sporozoite transit to the liver parenchyma proceeds as if the sinusoidal barrier did not exist.These findings still need to be reconciled with prior quantitative imaging studies that attribute a greater role for endothelial cells in sinusoid traversal and that reveal a negative impact of KCs on sporozoite survival.Beyond its function as a receptor for sporozoite entry, the nature and consequences of CD68 engagement need to be further explored.Does CD68-mediated sporozoite entry into KCs involve active penetration or phagocytosis?Is there damage to the host cell?Does CD68 engagement inhibit antigen presentation function and/or trigger release of antiinflammatory cytokines that contribute to the state of relative immune tolerance in the liver?And, crucially, what is the parasite ligand for CD68?Assuming its accessibility for antibody targeting in its native state, it would seem an ideal component of a pre-erythrocytic vaccine.
Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer
Authors: Akash Kumar, Ilsa Coleman, Colm Morrissey, Xiaotun Zhang, Lawrence D True, Roman Gulati, Ruth Etzioni, Hamid Bolouri, Bruce Montgomery, Thomas White, Jared M Lucas, Lisha G Brown, Ruth F Dumpit, Navonil DeSarkar, Celestia Higano, Evan Y Yu, Roger Coleman, Nikolaus Schultz, Min Fang, Paul H Lange, Jay Shendure, Robert L Vessella, Peter S Nelson
Journal: Nature Medicine (2016)
Neoadjuvant and adjuvant methotrexate, cisplatin, and fluorouracil in multimodal therapy of head and neck cancer.
Authors: E E Vokes, W J Moran, R Mick, R R Weichselbaum, W R Panje
Journal: Journal of Clinical Oncology (1989)

To increase the complete response (CR) rate of patients with locally advanced head and neck cancer after three cycles of neoadjuvant chemotherapy, we added sequential methotrexate to the combination of cisplatin and continuous infusion fluorouracil (5-FU). We also evaluated the feasibility of administering three additional cycles of the same regimen as adjuvant chemotherapy. Thirty-eight patients were treated; the median age was 53 years and 36 patients had stage IV disease. Chemotherapy consisted of methotrexate 120 mg/m2 followed 24 hours later by cisplatin 100 mg/m2 and a five-day continuous infusion of 5-FU at 1,000 mg/m2/d. Of 34 patients evaluable for response to neoadjuvant chemotherapy, nine had a CR, 21 a partial response (PR), two a minimal response (MR), and one patient each stable disease (SD) and no response (NR). Of 31 patients who received local therapy, 15 were treated with surgery and radiotherapy and 16 with radiotherapy alone. Of 25 patients eligible to receive adjuvant chemotherapy only ten received all three intended cycles, while 15 received less or no adjuvant chemotherapy because of patient refusal, cumulative toxicity, or early disease progression. With a median follow-up time of 39 months, the median survival is estimated to be 20 months. Of eight patients with nasopharyngeal or paranasal sinus cancer, none has had disease recurrence. Patients with good initial performance status and low N-stage also had a significant survival advantage. Chemotherapy-related toxicities consisted mainly of mucositis, requiring 5-FU dose reduction in the majority of patients; similar toxicities were exacerbated in the adjuvant setting. The addition of methotrexate did not increase the CR rate over what has been reported for the combination of cisplatin and 5-FU alone. Certain subsets of patients appear to have a good prognosis when treated in this fashion. The administration of adequate adjuvant chemotherapy in patients with head and neck cancer remains difficult due to toxicity and poor patient compliance.
Breaking down barriers for refugee doctors
Authors: R. Parker
Journal: BMJ (2000)

Editor—Adams and Borman were right to draw attention to the need for the medical profession to help refugee doctors.1 The United Examining Board does provide a method for these doctors to qualify in the United Kingdom and to be registered with the General Medical Council. It replaced three examinations—the conjoint examination run by the Royal Colleges of Physicians of London and Surgeons of England, the Scottish triple examinations run by the three Scottish royal colleges, and the licence of the Society of Apothecaries of London. Before candidates can sit these examinations they have to undergo a period of training and assessment in a British university.

Adams and Borman say that a mechanism needs to be established to identify refugee doctors with a good chance of re-establishing their medical careers. The United Examining Board provides this identification as it has established a preliminary examination that is used by the universities to decide who might most benefit by clinical attachment in a university hospital prior to taking the qualifying examination.

This is the only examining board route for refugee medical students who have yet to qualify as doctors. The United Examining Board has certain medical schools that organise the necessary clinical training—for example, St George's Hospital Medical School in London. For more information please contact the board's office at the Society of Apothecaries.
Atheroprotective properties of human Omentin-1 in experimental atherosclerosis
Authors: Saskia C.A. De Jager, Gerard Pasterkamp
Journal: Cardiovascular Research (2016)

This editorial refers to ‘Omentin attenuates atherosclerotic lesion formation in apolipoprotein E-deficient mice’, by M. Hiramatsu-Ito et al. , pp. 107–117. 

This editorial refers to ‘Counteractive effects of omentin-1 against atherogenesis’, by K. Watanabe et al. , pp. 118–128. 

It has been clearly established that adipocytes are not merely involved in energy storage, but function as an endocrine organ involved in different metabolic and inflammatory responses. For this reason, the role of adipose tissue in cardiovascular and metabolic diseases has gained increasing interest. In mammals, two types of adipose tissue can be distinguished, white and brown fat. Brown fat is more abundant in newborns and is relevant for the generation of heat. Two different types of white adipose tissue can be distinguished, subcutaneous and visceral fat, of which the latter is metabolically active. Under healthy conditions, visceral adipose tissue has balanced, non-metabolic, and non-inflammatory properties. In diseased state, as seen in obese or cardiovascular patients, the white adipose tissue reveals a shift towards a disbalanced metabolic and pro-inflammatory state.1 Diseased fat can exert systemic effects resulting in insulin resistance and metabolic syndrome, which both attribute to the onset of cardiovascular disease (CVD).2 In addition, epicardial and peri-adventitial adipose deposits can also focally influence atherosclerotic lesion …
Association of Financial Strain With Symptom Burden and Quality of Life for Patients With Lung or Colorectal Cancer
Authors: Christopher S. Lathan, Angel Cronin, Reginald Tucker-Seeley, S. Yousuf Zafar, John Z. Ayanian, Deborah Schrag
Journal: Journal of Clinical Oncology (2016)

Purpose To measure the association between patient financial strain and symptom burden and quality of life (QOL) for patients with new diagnoses of lung or colorectal cancer. Patients and Methods Patients participating in the Cancer Care Outcomes Research and Surveillance study were interviewed about their financial reserves, QOL, and symptom burden at 4 months of diagnosis and, for survivors, at 12 months of diagnosis. We assessed the association of patient-reported financial reserves with patient-reported outcomes including the Brief Pain Inventory, symptom burden on the basis of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, and QOL on the basis of the EuroQoL-5 Dimension scale. Multivariable linear regression models were fit for each outcome and cancer type, adjusting for age, race/ethnicity, sex, income, insurance, stage at diagnosis, and comorbidity. Results Among patients with lung and colorectal cancer, 40% and 33%, respectively, reported limited financial reserves (≤ 2 months). Relative to patients with more than 12 months of financial reserves, those with limited financial reserves reported significantly increased pain (adjusted mean difference, 5.03 [95% CI, 3.29 to 7.22] and 3.45 [95% CI, 1.25 to 5.66], respectively, for lung and colorectal), greater symptom burden (5.25 [95% CI, 3.29 to .22] and 5.31 [95% CI, 3.58 to 7.04]), and poorer QOL (4.70 [95% CI, 2.82 to 6.58] and 5.22 [95% CI, 3.61 to 6.82]). With decreasing financial reserves, a clear dose-response relationship was present across all measures of well-being. These associations were also manifest for survivors reporting outcomes again at 1 year and persisted after adjustment for stage, comorbidity, insurance, and other clinical attributes. Conclusion Patients with cancer and limited financial reserves are more likely to have higher symptom burden and decreased QOL. Assessment of financial reserves may help identify patients who need intensive support.
CBIO-33INVESTIGATING GLIOMA CELL PHENOTYPES WITH SMALL MOLECULES
Authors: Euan Polson, Verena Kuchler, Christopher Abbosh, Anjana Patel, Barbara Da Silva, Ryan Mathew, Jennifer Williams, Edith Ross, Florian Markowetz, Robin Bon, Simon Allison, Paul Chumas, Mihaela Lorger, Alan Melcher, Susan Short, Heiko Wurdak
Journal: Neuro-Oncology (2015)

High-grade brain tumours are characterized by inter- and intratumour heterogeneity and remain incurable despite current multi-modality treatment. The cellular aggressiveness within brain tumours includes tumour cell invasion of healthy brain tissue, resistance to conventional therapy, and greatly enhanced growth potential. This has been attributed to undifferentiated/stem cell-like features and clonal expansion under therapeutic pressure. The evolving notion of cancer cell plasticity implies that tumour cells may alter their phenotype both randomly and in response to external cues. In this context, we aim to elucidate the molecular mechanisms regulating glioma cell fate. We investigate selective small molecule-induced phenotypic changes such as ‘forced’ differentiation, surface-molecule expression, neurite outgrowth, autophagy, and apoptosis using patient-derived glioma models. Notably, these models display variability in cellular stemness/differentiation characteristics as well as glioma subtype-related classifiers. We therefore further analyse these small molecule-induced phenotypes at the single cell level using gene expression analysis. In addition to chemical/genetic-inspired approaches in vitro, we evaluate the tumour growth and invasion potential of glioma cell phenotypes in vivo. Together, these approaches have revealed molecular vulnerabilities (for example the TACC3-ARNT and HIF axis) that are required for aggressive glioma cell behaviour and may be pharmacologically exploitable for combination therapy.
Oncogenic <i>ALK</i> Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target
Authors: Evgeny Yakirevich, Murray B. Resnick, Shamlal Mangray, Michael Wheeler, Cynthia L. Jackson, Kara A. Lombardo, Jeeyun Lee, Kyoung-Mee Kim, Anthony J. Gill, Kai Wang, Kyle Gowen, James Sun, Vincent A. Miller, Philip J. Stephens, Siraj M. Ali, Jeffrey S. Ross, Howard Safran
Journal: Clinical Cancer Research (2016)

Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN-ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort. Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed. Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib. Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831-40. ©2016 AACR.
Identification of high-grade serous ovarian cancer miRNA species associated with survival and drug response in patients receiving neoadjuvant chemotherapy: a retrospective longitudinal analysis using matched tumor biopsies
Authors: M. Petrillo, G.F. Zannoni, L. Beltrame, E. Martinelli, A. DiFeo, L. Paracchini, I. Craparotta, L. Mannarino, G. Vizzielli, G. Scambia, M. D'Incalci, C. Romualdi, S. Marchini
Journal: Annals of Oncology (2016)
Effects of magnesium supplementation on the incidence of acute kidney injury in critically ill patients presenting with hypomagnesemia
Authors: Elisa Baldessar Barbosa, Cristiane Damiani Tomasi, Danusa de Castro Damasio, Marcelo Vinhas, Bruno Lichtenfels, Vanessa de Luca Francisco, Cassiana Mazon Fraga, Cristiane Ritter, Felipe Dal-Pizzol
Journal: Intensive Care Medicine (2016)
Some &lt;italic&gt;In Vitro&lt;/italic&gt; Requirements of Cells of C3H Mouse, Chinese Hamster, Green Monkey, and Human Origin
Authors: Floyd M. Price, Harold A. Kerr, William F. Andresen, Jay C. Bryant, Virginia J. Evans
Journal: JNCI Journal of the National Cancer Institute (1966)

Nutritional studies have been continued on 3 cell strains reported previously. Two of these, HeLa and Chinese hamster (Cricetulus griseus), required vitamin B12 and inositol, although 1 substrain of Chinese hamster cells grew in medium without inositol. Neither liver line NCTC 4067 nor liver line NCTC 4242 cells from the same clone needed vitamin B12 or inositol. Initial studies indicated that vitamin A, or perhaps the vehicle Tween 80, may be a nutritional requirement for liver line NCTC 4067 cells. Nutritional studies were extended to a fourth cell strain. The adaptation of the BS-C-1 green monkey kidney cells (Cercopithecus aethiops) to growth in chemically defined media NCTC 135, 117, and 126 is also reported; growth in medium 126 indicates that this cell strain required neither inositol nor vitamin B12.
A mild topical steroid leads to progressive anti-inflammatory effects in the skin of patients with moderate-to-severe atopic dermatitis
Authors: Patrick M. Brunner, Saakshi Khattri, Sandra Garcet, Robert Finney, Margeaux Oliva, Riana Dutt, Judilyn Fuentes-Duculan, Xiuzhong Zheng, Xuan Li, Kathleen M. Bonifacio, Norma Kunjravia, Israel Coats, Inna Cueto, Patricia Gilleaudeau, Mary Sullivan-Whalen, Mayte Suárez-Fariñas, James G. Krueger, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2016)
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations
Authors: Weiping Zou, Jedd D. Wolchok, Lieping Chen
Journal: Science Translational Medicine (2016)

PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota. We further clarify the mechanisms of action of these markers and their roles in shaping, being shaped, and/or predicting therapeutic responses. We also discuss a variety of combinations with PD pathway blockade and their scientific rationales for cancer treatment.
Baseline Characteristics and Symptom Burden in RESPONSE: A Randomized, Open-Label, Phase 3 Study of Ruxolitinib In Polycythemia Vera Patients Resistant to or Intolerant of Hydroxyurea
Authors: Alessandro M. Vannucchi, Jean-Jacques Kiladjian, Martin Griesshammer, Tamás Masszi, Simon Durrant, Pierre Zachee, Fabrizio Pane, Claire N Harrison, Shui He, Lance Leopold, Jingjin Li, Ulrich Pirron, Tomasz Lawniczek, Srdan Verstovsek
Journal: Blood (2013)
Mortality Among a Large Cohort of Chemical Manufacturing Employees
Authors: Gregory G. Bond, Rita J. Shellenberger, William A. Fishbeck, Janice B. Cartmill, Bernie J. Lasich, Karen T. Wymer, Ralph R. Cook
Journal: JNCI Journal of the National Cancer Institute (1985)

Cause-specific mortality was surveyed among 19,608 male employees with 1 or more years of service between 1940 and 1980 at the Texas Operations of Dow Chemical U.S.A. Vital status was ascertained through 1980 for 97.3% of the cohort members, and death certificates were obtained for 96.4% of the 3,444 decedents. Mortality risks were found to vary, depending upon which of 3 population groups (United States, Texas, and local counties) was used for comparison, although significantly fewer than expected deaths from all causes was a common finding due to significant deficits in diabetes, diseases of the circulatory system, and cirrhosis of the liver. Significantly more deaths were from ill-defined conditions and cancers of unspecified sites. Lung cancer was significantly elevated in comparisons with the incidences in the United States and Texas, but not in comparison with those in the local counties. The influence of age at hire, period of hire, duration of employment, interval since entry into cohort, employment status, and two measures of social class—educational level and job category—were explored with the use of the Mantel-Haenszel method as adapted for a cohort study. Findings from these analyses are discussed in relation to the observations of other investigators and in the context of the possible impact of these findings on future studies of this work force.
Phylogenetic relationships of neopterygian fishes, inferred from mitochondrial DNA sequences.
Authors: B B Normark, A R McCune, R G Harrison
Journal: Molecular Biology and Evolution (1991)

To investigate the relationships among the three main groups of extant neopterygian fishes--Amiidae, Lepisosteidae, and Teleostei--we sequenced fragments of three mitochondrial genes from 12 different actinopterygian fishes and translated the nucleotide sequences into amino acid sequences. When all three regions are considered together, Amiidae clusters with Lepisosteidae in the most parsimonious cladograms, but other clades, such as Neopterygii and Teleostei, that are well supported by morphological evidence fail to emerge as monophyletic. When the cytochrome b sequences are analyzed together with previously published sequences for other taxa, the majority-rule consensus tree is consistent with the monophyly of Teleostei and Neopterygii and marginally supports the Amiidae + Lepisosteidae clade. In either analysis, when Neopterygii and Teleostei are constrained to monophyly, all the most-parsimonious cladograms support the Amiidae + Lepisosteidae topology. Where molecules and morphology disagree, provisional morphology-based constraints on the analysis of molecular data offer a practical means of integrating the two types of data.
Updated results from a phase II study of sequential treatment epirubicin, cyclophosphamide (EC), surgery and docetaxel (DTX) in stage II and III breast cancer
Authors: D. Grecea, L. Neamtiu, R. Tanasescu, A. Rancea, L. Resiga, M. Galatar, D. Postescu, D. Daicoviciu, V. Popita, N. Ghilezan
Journal: Journal of Clinical Oncology (2007)

11096 Background: The study was designed to evaluate the efficacy and safety of sequential administration of epirubicin plus cyclophosphamide (EC) followed by surgery and docetaxel (DTX). Methods: All patients (74) with untreated breast cancer stage II and III received epirubicin (E) 100mg/m2 given in 30 min followed by cyclophosphamide (C) 600mg/m2(q3w).After four cycles of neoadjuvant chemotherapy, the pts were evaluated for response: 46 ( 62.1%) presented PR, 2 (2.7%) CR and 26 ( 35.2%) SD and then they underwent surgery: conservative (17.57%) or radical mastectomy (82.43%).After surgery, the patients received four cycles of docetaxel (DOC) 100mg/m2 (1 hour , q3w). The median age was 46 ( 24–66) years, with 51 ( 69%) premenopausal and 23 (31%) postmenopausal patients. Results: The pathological response was pT1 lower to 2 cm, 41 patients ( 55.41%), pT 2–5 cm, 33 pts ( 44. 59%); pN+ 1–3: 13 pts ( 17.56%); pN+ = 4 and more than four: 61 pts ( 82.44%). Overall survival at 60 months was 59. 57% and DFS was 41.25%. For patients with pN+1–3 , at 5 years DFS was 46.35% and for those with pN+ = 4 and more 4, DFS was 38.25% (p=0.045).Overall survival at 5 years follow-up was 65.74% for pts with pN+ 1–3 and 57.36% for those with pN+=4 and more than 4. Conclusions: Previous interim analysis results of sequential chemotherapy with DTX demonstrate the efficacy and safety of these treatment in breast cancer stage II and III. At 5 years follow-up, we conclude that the use of four cycles of EC followed by sugery and then four cycles of DTX is a reasonable treatment choice for at least some patients with breast cancer st II and III. No significant financial relationships to disclose.