tbuckley/cabot-search huggingface dataset:
Transplantation Studies on Polyoma Virus-Infected Cultures of Mouse Tooth Germs2
Authors: J. H. P. Main, R. J. McComb, D. Mock
Journal: JNCI Journal of the National Cancer Institute (1974)

Organ cultures of tooth germs infected with polyoma virus and grown in vitro for >30 days were transplanted to the subcutaneous tissue of the back of C3H/Bi/Mai or C3H/Bi/Lw mice <24 hours old. Mice were divided into 5 series: 1) Fourteen mice received unmodified infected cultures: 2) 47 received cultures treated briefly with a crude polyoma antiserum; 3) 115 received cultures rinsed 4 times in Hanks' solution; 4) 65 received cultures treated with polyoma-hyperimmune antiserum; and 5) 38 controls received transplants of noninfected tooth germs. With 4 exceptions, the host mice from series 1 died early due to the early effects of the virus. The survivors were killed when moribund at day 34. Host mice in series 2 and 5 were killed when 56 days old. Hosts in series 3 and 4 were allowed to live as long as possible. Transplants consisting of dysplastic,proliferating squamous epithelium were recovered from the 4 surviving mice in series 1 and from 32 mice in series 3, the latter having a mean age of 28 days. The transplants recovered from 9 recipients in series 2 consisted of degenerating squamous epithelium surrounded by lymphocytes. Four recipients from series 4, 200–320 days old, developed fibrosarcomas at the transplantation sites. Normally structured teeth developed from transplants in 16 controls of series 5.
Topoisomerase I in Human Disease Pathogenesis and Treatments
Authors: Min Li, Yilun Liu
Journal: Genomics Proteomics & Bioinformatics (2016)

Mammalian topoisomerase 1 (TOP1) is an essential enzyme for normal development. TOP1 relaxes supercoiled DNA to remove helical constraints that can otherwise hinder DNA replication and transcription and thus block cell growth. Unfortunately, this exact activity can covalently trap TOP1 on the DNA that could lead to cell death or mutagenesis, a precursor for tumorigenesis. It is therefore important for cells to find a proper balance between the utilization of the TOP1 catalytic activity to maintain DNA topology and the risk of accumulating the toxic DNA damages due to TOP1 trapping that prevents normal cell growth. In an apparent contradiction to the negative attribute of the TOP1 activity to genome stability, the detrimental effect of the TOP1-induced DNA lesions on cell survival has made this enzyme a prime target for cancer therapies to kill fast-growing cancer cells. In addition, cumulative evidence supports a direct role of TOP1 in promoting transcriptional progression independent of its topoisomerase activity. The involvement of TOP1 in transcriptional regulation has recently become a focus in developing potential new treatments for a subtype of autism spectrum disorders. Clearly, the impact of TOP1 on human health is multifold. In this review, we will summarize our current understandings on how TOP1 contributes to human diseases and how its activity is targeted for disease treatments.
Abstract 1999: Gestational Age Below 40 Weeks is Associated With Increased Death Rates in Infants With Congenital Heart Disease
Authors: James F Cnota, Resmi Gupta, Erik C Michelfelder, Richard F Ittenbach
Journal: Circulation (2009)

Background: Outcomes for infants with congenital heart disease (CHD) may be impacted by the national trend toward lower gestational age (GA) at delivery. Few population based data assess the signif...
Epidemiologic and Clinical Characteristics of Thalassemia (Thal) Intermedia (TI) in the United States
Authors: Elliott P. Vichinsky, Janet Kwiatkowski, Patricia J. Giardina, Carole Paley, Francis Vekeman, Wendy Y. Cheng, Joseph Damron, Nora McCormick, Medha Sasane, Ying Qiu, Mei Sheng Duh, Alexis A. Thompson
Journal: Blood (2015)
A phase II single arm feasibility trial of neoadjuvant chemotherapy (NAC) with oxaliplatin/fluorouracil (OxMdG) then short-course preoperative radiotherapy (SCPRT) then immediate surgery in operable rectal cancer (ORC): COPERNICUS (NCT01263171).
Authors: Simon Gollins, David Sebag-Montefiore, Richard Adams, Mark P. Saunders, Robert Grieve, Nigel Scott, Gina Brown, Philip Quirke, Laura Butlin, Ruby Ray, Gareth Griffiths, Chris Hurt
Journal: Journal of Clinical Oncology (2015)

3609 Background: Feasibility was assessed of giving NAC prior to SCPRT then immediate surgery in ORC at high risk of metastatic relapse. Methods: Patients (pts) had non-metastatic rectal adenocarcinoma. Pre-treatment pelvic MRI showed resection margin was not at risk (disease > 1mm from mesorectal fascia) but adverse risk factors were present (disease > T3b or node positive or extramural vascular invasion). Pts received 4x2-weekly cycles of oxaliplatin 85mg/m² + levofolinic acid 175 mg, fluorouracil (FU) 400 mg/m² (bolus), then FU 2400 mg/m² (continuous IV in 46 hr). Within 14 days pts had pelvic SCPRT to 25 Gy in 5 daily fractions. Definitive surgery then occurred within a week. Post surgery pts received 16 weeks of OxMdG or oxaliplatin/capecitabine. The primary endpoint was the proportion of pts completing protocol treatment including surgery. Results: 60 UK pts were recruited May 2012-June 2014. At baseline: male 44 (73%), median age 63 (IQR: 56.5-70), WHO PS 0/1 55/5. On pre-treatment MRI tumour was T2/3x/3a/3b/3c/3d/4 in 2/2/16/24/12/1/3 and N0/1/2 in 7/40/13 pts. All pts commenced OxMdG with 57(95%) receiving all 4 cycles. 20 pts (33%) needed a dose reduction and 22 (37%) a dose delay. 58 pts commenced SCPRT (all received full dose) and 57 underwent surgery: anterior resection in 43 (75%), abdominoperineal resection in 11 (19%), Hartmanns in 3 (5%). Three pts withdrew prior to surgery: one lost to follow up after SCPRT, one pt choice and one due to cardiospasm during NAC. Median gap between OxMdG and starting SCPRT was 10 days (IQR: 5-15) and between completing SCPRT and surgery 10 days (IQR: 5-13). Postoperative histology was T0/1/2/3a/3b/3c/4a in 7/3/19/8/9/10/1 pts, N0/1/2 in 39/13/5 pts and ypT0ypN0 in 7/57 pts (12%). All 57 resected pts had a clear (R0) resection margin with no 30 day postoperative mortality. Conclusions: This is the first trial to report on giving NAC prior to SCPRT then surgery within a short time interval in ORC, which proved feasible with good compliance and promising efficacy. The UK NCRI intend to include a similar regimen in a future phase III trial. Clinical trial information: NCT01263171.
Exploiting single-cell expression to characterize co-expression replicability
Authors: Megan Crow, Anirban Paul, Sara Ballouz, Z. Josh Huang, Jesse Gillis
Journal: Genome biology (2016)

Co-expression networks have been a useful tool for functional genomics, providing important clues about the cellular and biochemical mechanisms that are active in normal and disease processes. However, co-expression analysis is often treated as a black box with results being hard to trace to their basis in the data. Here, we use both published and novel single-cell RNA sequencing (RNA-seq) data to understand fundamental drivers of gene-gene connectivity and replicability in co-expression networks. We perform the first major analysis of single-cell co-expression, sampling from 31 individual studies. Using neighbor voting in cross-validation, we find that single-cell network connectivity is less likely to overlap with known functions than co-expression derived from bulk data, with functional variation within cell types strongly resembling that also occurring across cell types. To identify features and analysis practices that contribute to this connectivity, we perform our own single-cell RNA-seq experiment of 126 cortical interneurons in an experimental design targeted to co-expression. By assessing network replicability, semantic similarity and overall functional connectivity, we identify technical factors influencing co-expression and suggest how they can be controlled for. Many of the technical effects we identify are expression-level dependent, making expression level itself highly predictive of network topology. We show this occurs generally through re-analysis of the BrainSpan RNA-seq data. Technical properties of single-cell RNA-seq data create confounds in co-expression networks which can be identified and explicitly controlled for in any supervised analysis. This is useful both in improving co-expression performance and in characterizing single-cell data in generally applicable terms, permitting cross-laboratory comparison within a common framework.
Annual Report of the Editor, 1966
Authors: Joseph Garland
Journal: New England Journal of Medicine (1967)

As a means of recognizing Dr. Joseph Garland's editorship of the New England Journal of Medicine, the Committee on Publications of the Massachusetts Medical Society has requested publication of the Editor's Annual Report for 1966. This succinct record, the Committee believes, epitomizes far better than any other device the accomplishments of the past two decades.IN presenting my twentieth and final annual report, I shall deal at somewhat greater length than usual with the affairs of the Journal during the period since it became the property of the Massachusetts Medical Society. The Boston Medical and Surgical Journal, having . . .
Low birth weight is associated with increased deaths in infancy and adolescence, shows study
Authors: Susan Mayor
Journal: BMJ (2016)

Low birth weight is associated with increased death rates in infancy, later childhood, and adolescence, shows a study of live births in England and Wales that underlines the importance of women’s health before pregnancy in improving the health of their children.1

Researchers followed up all live births in England and Wales from 1 January 1993 to 31 December 2011. They categorised the 12 355 251 babies in the study by birth weight, defining very low birthweight babies as weighing 500-1499 g (n=139 608) and low birthweight babies as 1500-2499 g (n=759 283). Normal birthweight babies were categorised into two groups: …
Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) in newly diagnosed multiple myeloma (MM) patients: A phase III trial.
Authors: M. Boccadoro, F. Cavallo, A. Nagler, D. Ben Yehuda, P. Omedè, M. Cavalli, A. Levi, C. Crippa, A. Siniscalchi, P. Brasca, A. M. Carella, B. A. Zanetti, F. Patriarca, S. Pezzati, V. Montefusco, A. Stanevsky, B. Lupo, T. Caravita, F. Di Raimondo, A. P. Palumbo
Journal: Journal of Clinical Oncology (2011)

8020 Background: The introduction of novel agents questions the role of autologous stem-cell transplantation (ASCT). This is the first prospective randomized study comparing conventional chemotherapy plus novel agents (MPR) with tandem high-dose melphalan (MEL200) and ASCT in newly diagnosed MM patients (Pts). Methods: All pts (N=402) received four 28-day cycles of lenalidomide (25 mg, d1-21) and low-dose dexamethasone (40 mg, d1,8,15,22) (Rd) as induction. Pts (N=202) were then randomized to MPR [six 28-day cycles of melphalan (0.18 mg/kg d1-4), prednisone (2 mg/kg d1-4) and lenalidomide (10 mg d1-21); pts (N=200)] or MEL200 (tandem melphalan 200 mg/m2 with stem-cell support). Primary end point was PFS. Results: Response rates were similar in the two groups (MPR vs MEL200): ≥ VGPR (60% vs. 58%, p=0.24) and CR (20% vs. 25% p=0.49). After a median follow-up of 20 months, the 18-months PFS was 68% in MPR and 78% in MEL200 (HR=0.58, p=0.006). CR prolonged the 18-months PFS in the MPR (90% vs 66%) and in the MEL200 group (87% vs 76%). The 18-months OS was similar (91% vs 95%; p=0.073). In the MPR and MEL200 groups, G3-4 neutropenia was 55% vs 89% (p <.001); G3-4 infections were 0% vs 17% (p <.001); G3-4 gastrointestinal toxicity was 0% vs. 21% (p<.001); DVT was 2.44% vs 1.13% (p=0.43); second tumors were 0.005% in both arms. Conclusions: MEL200 was superior to MPR for PFS, although toxicities were significantly higher. This is the first report showing a PFS advantage for ASCT in comparison with combinations including novel agents. At present OS is not significantly different in the two groups.
A phase 1/2 study investigating the combination of RAD001 (R) (everolimus) and erlotinib (E) as 2nd and 3rd line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy (C): Phase 1 results
Authors: V. Papadimitrakopoulou, G. R. Blumenschein, N. B. Leighl, J. Bennouna, J. C. Soria, H. A. Burris, S. Dimitrijevic, T. Kunz, L. Di Scala, B. E. Johnson
Journal: Journal of Clinical Oncology (2008)

8051 Background: R is an oral inhibitor of the mammalian target of rapamycin (mTOR) in clinical development as an anticancer agent. Clinical benefit including objective tumor responses were observed in pts with NSCLC receiving R. E is an oral epidermal growth factor receptor inhibitor (EGFRI) approved for the treatment of NSCLC pts failing C. Preclinical evidence suggests that R may enhance EGFRI anti-tumor activity and reduce resistance to EGFRI. Methods: Patients with advanced NSCLC, failing ≤ 2 prior C regimens, ECOG PS ≤2, adequate bone marrow and liver function were eligible. Phase 1 part assessed the combination of R and E using a standard "6+6" dose-escalation design based on the rate of dose-limiting toxicity (DLT) and pharmacokinetic (PK) drug- drug interaction (DDI) during the first 28 days of combined treatment. A range of R doses administered in either a daily (qd) or a weekly (qw) schedule were evaluated in combination with different daily doses of E. Results: 61 pts treated in 7 cohorts: Male/Female 32/29, ever smoker/never smoker 49/12, prior therapies 1/2 31/30. Doses and schedules evaluated: R 2.5mg qd, 5mg qd, 30mg qw, 50mg qw in combination with qd doses of E 75mg, 100mg, and 150mg. R 2.5mg qd + E 150mg qd, R 5mg qd + E 75mg qd, and R 50mg qw + E 150 mg qd, were established as feasible dose regimens. DLTs observed were: mucositis (5), rash (4), diarrhea (4), vomiting (1) and neutropenia (1). Available duration of exposure of the combination was 0.2–25.8 months in daily cohorts and 0.1–2.9 months in weekly cohorts. Preliminary best overall response based on RECIST as per Investigator lesion assessment was: CR (1), PR (3), SD (17), PD (18). Conclusions: Phase 1 part of the study established feasible doses of R in combination with E with promising early indication of clinical efficacy. Phase 2 of the study will evaluate the efficacy of dose regimens established in the phase 1 part. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Genzyme Novartis Novartis
TCT-339 The Ratio of Contrast Medium Dose and Estimated Glomerular Filtration Predicts Contrast-induced Acute Kidney Injury among Patients for Elective Percutaneous Coronary Intervention
Authors: Arnel G. Gabriel, Dax Rinzi Sandoval, Vonn P. Velasco, Francisco P. Dalangin
Journal: Journal of the American College of Cardiology (2013)
A memorable patient: Happiness is...
Authors: Nick Jefferies
Journal: BMJ (2004)

It has been observed in these pages that having a parent's health problem referred to a geriatrician is nature's way of telling you to grow up. The call to the psychogeriatrician is often the signal that a cherished relationship has undergone an irrevocable change and that a new order has taken its place as the prelude to an unwelcome full independence.

And so one day the time came to admit that my father's forgetfulness, irrational behaviour, and wandering were no longer just subjects for resigned family humour but were becoming a hazard to him and a nuisance to the local community. Thus, he and I came to sit in the psychogeriatrician's office—all very friendly, with me probably more nervous than anybody. The initial orientation challenges established the severity of Dad's problems—a receptive and expressive dysphasia behind which it was difficult to imagine a functioning intellect. There was a pause (was there any point continuing?), and then a little “comprehension” exercise: “What is happiness?”

Was this fair on a man in such a condition? I sometimes wonder if it wasn't just a gambit in the hope of passing a few minutes that loomed empty, since it's a question that I suspect would have many of us scrabbling for a useful response.

And what have other, working minds contributed? My Concise Oxford Dictionary has “happiness” merely as the noun associated with the word “happy,” whose own entry seems to consist of synonyms: “lucky, fortunate, contented with one's lot.” Those who work with words have fitted the concept with diverse associations. Here are a few examples: something the pursuit of which is “an inalienable right of man” (Thomas Jefferson, American Declaration of Independence); that which when recalled leads to the greatest misery (Dante); the result of an annual income of twenty pounds with expenditure of nineteen pounds nineteen shillings and sixpence (Charles Dickens, Pickwick Papers); or simply the effect of “a good bank balance, a good cook, and a good appetite” (Thoreau).

Perhaps a waste of time, then, asking an old man who can't tell you what day of the week it is. But an answer came. “Happiness is a thing, like this,” a wave of the hands. “You lose some and then you get some back.” And that was that. The rest of the consultation was brief, and the offer of care at a day centre no surprise and, sadly, little help.

But my father's answer has stayed with me. Was it actually worth anything? Was it just random gibberish from an ischaemic temporoparietal zone? Or a final haiku from an old man withdrawing from the world, illustrated not with a calligrapher's flourish but with a hand jive? Whatever, he lived another nine months, and it stands as the last (possibly) sensible thing he said. I have always found it useful as a piece of philosophical advice, and I thought I'd share it with you.
Feast or famine
Authors: G. Dunea
Journal: BMJ (1997)

For more than a century various interested parties have been arguing over how many doctors we need, and whether we have too many or too few. Should there be a glut in desirable areas so there can be trickle down to less attractive ones? Should you regulate numbers or let market forces decide? Perceptions on these points have varied over the years, and so have official health policies, because in fact medical education in the United States is tightly regulated by professional licensing bodies and heavily subsidised by the government.

There seemed to be a shortage some 30 years ago. At the time even the rich often had to wait for weeks for a doctor's appointment. Whole counties …
Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack
Authors: S. Claiborne Johnston, Pierre Amarenco, Gregory W. Albers, Hans Denison, J. Donald Easton, Scott R. Evans, Peter Held, Jenny Jonasson, Kazuo Minematsu, Carlos A. Molina, Yongjun Wang, K.S. Lawrence Wong
Journal: New England Journal of Medicine (2016)

Ticagrelor may be a more effective antiplatelet therapy than aspirin for the prevention of recurrent stroke and cardiovascular events in patients with acute cerebral ischemia.We conducted an international double-blind, controlled trial in 674 centers in 33 countries, in which 13,199 patients with a nonsevere ischemic stroke or high-risk transient ischemic attack who had not received intravenous or intraarterial thrombolysis and were not considered to have had a cardioembolic stroke were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive either ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90). The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days.During the 90 days of treatment, a primary end-point event occurred in 442 of the 6589 patients (6.7%) treated with ticagrelor, versus 497 of the 6610 patients (7.5%) treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 to 1.01; P=0.07). Ischemic stroke occurred in 385 patients (5.8%) treated with ticagrelor and in 441 patients (6.7%) treated with aspirin (hazard ratio, 0.87; 95% CI, 0.76 to 1.00). Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin, intracranial hemorrhage in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%.In our trial involving patients with acute ischemic stroke or transient ischemic attack, ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01994720.).
Delphinidin, a major anthocyanidin in pigmented fruits and vegetables inhibits HGF/Met- mediated proliferation and invasion in immortalized MCF10A cells
Authors: Deeba Syed, Farrukh Afaq, Sami Sarfaraz, Naghma Khan, Rajendra Kedlaya, Vijayasaradhi Setaluri, Hasan Mukhtar
Journal: Cancer Research (2007)

4203   Hepatocyte growth factor (HGF) is a pleiotropic cytokine that promotes survival and proliferation in a wide variety of cells. Increased expression of HGF and its receptor Met has been linked to invasive human cancer and metastasis.  Delphinidin ,  an anthocyanidin present in pigmented fruits and vegetables possesses potent anti-oxidant, anti-inflammatory and anti-angiogenic properties. We have recently shown that  ‘ delphinidin protects against UVB-mediated oxidative stress and apoptosis in immortalized HaCaT cells’ (J Invest Dermatol.; 2006, In press). Here, we assessed the anti-proliferative and anti-invasive effect of delphinidin on HGF-mediated responses in the immortalized, nontumorigenic breast cell line, MCF10A. Exposure of MCF10A cells to exogenous HGF (40 nM; 30 min) resulted in tyrosyl-phosphorylation and increased expression of the Met receptor that was completely abolished by treatment of cells with delphinidin (5-40 μM; 3h). The functional involvement of PI3/AKT and Raf/MAPK pathway in HGF activation plays an important role in carcinogenesis. Immunoblot analysis shows that delphinidin treatment completely inhibited HGF-mediated activation of Raf/ MEK/ ERK pathway in MCF10A cells resulting in decreased phosphorylation of (i) Raf-1, MEK-1 and ERK1/2 MAPKs, (ii) JNK and p38 MAPKs; and (iii) increased expression of RasGap protein. Delphinidin treatment further resulted in the downregulation of HGF-mediated (i) activation of PI3K/AKT, (ii) phosphorylation of mTOR and its downstream target p70S6Kinase, and (iii) increased expression of MMPs 2 and 9. Oncogenic signals involve activation of kinases that transduce signals, leading to cell proliferation or inhibition of apoptosis by activating NFκB family of transcription factors. Our studies show that HGF-activated NFκB transcription in MCF10A cells was repressed by delphinidin treatement resulting in a decrease in HGF-mediated (i) phosphorylation of IKKα/β and IκBα, and (ii) activation and nuclear translocation of NFκB/p65. Delphinidin treatment to MCF10A cells resulted in nuclear translocation of PKCα, a serine/threonine kinase central to a variety of cellular functions including proliferation, motility, and inflammation. Cell invasion studies showed that delphinidin treatment resulted in attenuation of HGF-mediated enhanced migration of cells across the matrigel in a dose-dependent manner. A requirement of STAT3 signaling for HGF/Met mediated tumorigenesis has been reported. HGF stimulation of MCF10A cells resulted in activation of STAT3, and delphinidin-mediated ablation of STAT3 expression may in part be responsible for a reduction of Met-driven invasiveness. In conclusion, our results strongly suggest a potential inhibitory role of delphinidin in preventing HGF-mediated activation of various signaling pathways implicated in breast cancer.