tbuckley/cabot-search huggingface dataset:
An Antibody Delivery System for Regulated Expression of Therapeutic Levels of Monoclonal Antibodies In Vivo
Authors: Jianmin Fang, Saili Yi, Andrew Simmons, Guang Huan Tu, Minh Nguyen, Thomas C Harding, Melinda VanRoey, Karin Jooss
Journal: Molecular Therapy (2007)

Monoclonal antibody (mAb) delivery by gene transfer in vivo may be an attractive alternative to current mAb therapies for applications that require long-term therapy. This article describes a transfer system that allows inducible high-level expression of unmodified mAbs in vivo. A recombinant adeno-associated viral (rAAV) vector is used that comprises an expression cassette consisting of a dimerizer-regulated promoter that drives expression of the antibody heavy and light chains linked by a 2A self-processing peptide and a furin cleavage site. Following intravenous injection of the rAAV vector, serum mAb levels >1 mg/ml were attained by administration of the inducer, rapamycin. Antibody expression could be rapidly shut off by discontinuing treatment with rapamycin. By optimizing the furin cleavage sequence, this system generated native antibody in vivo, decreasing the likelihood of a host immune response to foreign sequences. In summary, this optimized mAb expression system allows regulated high-level expression of native full-length mAbs in vivo and may offer a new opportunity for delivery of therapeutic mAbs in the clinic.
Definitive proof for direct reprogramming of hematopoietic cells to pluripotency
Authors: Motohito Okabe, Makoto Otsu, Dong Hyuck Ahn, Toshihiro Kobayashi, Yohei Morita, Yukiko Wakiyama, Masafumi Onodera, Koji Eto, Hideo Ema, Hiromitsu Nakauchi
Journal: Blood (2009)
Biochemical determinants of 5-fluorouracil response in vivo. The role of deoxyuridylate pool expansion.
Authors: C E Myers, R C Young, B A Chabner
Journal: Journal of Clinical Investigation (1975)

5-Fluorodeoxyuridine monophosphate (FdUMP), the active metabolite of 5-fluorouracil (5-FU), is a tight-binding inhibitor of thymidylate synthetase, the enzyme which converts dUMP to TMP. Newly developed assays for FdUMP and dUMP were utilized to assess the competitive roles played by these nucleotides in determining the inhibition of TMP synthesis in mice bearing the P1534 ascites tumor. After 5-FU administration, levels of FdUMP reached a dose-dependent peak within 6 h in the ascites tumor and in bone marrow, and declined thereafter in a biphasic manner with an initial t 1/2 of 6 h and a final t 1/2 of 7-9 days. In duodenal mucosa, FdUMP levels were 1.8-2-fold higher than in the other tissues, but elimination was much more rapid. Simultaneous with the fall in FdUMP a progressive accumulation of the competitive substrate dUMP was observed in each tissue after 5-FU; and peak dUMP levels coincided with recovery of thymidylate synthesis, as determined by the incorporation of [3H]deoxyuridine into DNA. In vitro experiments with partially purifed thymidylate synthetase revealed and initial competitive interaction of dUMP and FdUMP, which, at high concentrations of dUMP was capable of markedly slowing the rate of irreversible inactivation of enzyme by FdUMP. These studies were found to be quantitatively consistent with a two-phase model of enzyme inactivation involving an initial competition between dUMP and FdUMP, with subsequent irreversible inactivation of enzyme by covalent linkage to the inhibitor. Recovery of thymidylate synthesis after 5-FU appears to result from both a fall in intracellular levels of inhibitor and a progressive accumulation of the competitive substrate dUMP.
Relationship between Coronary Collateral Circulation and Left Ventricular End Diastolic Pressure and Plasma Levels of N-Terminal Pro-B-Type Natriuretic Peptide in Patients with Chronic Total Occlusion
Authors: Fuad Samadov, Aysel Akhundova, Dursun Akaslan, Halil Ataş, İbrahim Sarı, Osman Yeşildağ
Journal: Journal of the American College of Cardiology (2013)
Low molecular weight heparins could be important in cancer
Authors: S. Siragusa
Journal: BMJ (1999)

EDITOR—Kakkar and Williamson clearly state the need for well conducted prospective clinical trials to evaluate the potential role of low molecular weight heparins in improving survival in cancer patients.1

In the absence of properly designed trials, indirect data can be extrapolated from trials comparing low molecular weight heparins and unfractionated heparin in the treatment of venous thromboembolism. Reduced mortality in patients with venous thromboembolism who were treated with low molecular weight heparins seemed to be confined to patients with cancer.2 …
Diabetes and Oesophageal Dysfunction
Authors: W. Silber
Journal: BMJ (1969)

Cineradiographic and manometric studies of oesophageal function were carried out in four different groups of patients (those suspected of having oesophageal disease, with and without symptoms; and in two groups of diabetes, with and without diabetic neuropathy). All groups were found to have abnormal oesophageal function, and this was not commoner in those with diabetic neuropathy.
Anatomy for Surgeons, vol 3: The Back and Limbs
Authors: Robert H. Cofield
Journal: JAMA (1982)

As a subject, anatomy does not lend itself to casual involvement by the reader. Studying anatomy, although perhaps pleasant, is work requiring concentration, memorization, organization of material, and then relation of this material to the problem at hand.<i>Anatomy for Surgeons</i>offers the physician who uses anatomy for patient care an additional learning source that differs somewhat from the standard anatomy text. Certainly, the anatomy is present in this work as in others, but the author skews the material to relate it to surgical practice by introducing related physiology, by incorporating information from articles on anatomy that are relevant to surgical practice, and by explaining the anatomic basis of surgical treatment methods. This volume contains a section on general considerations, treating bone, cartilage, muscle, tendon, nerve, and skin as tissues, and reviews the current concepts on growth and repair. This general section also presents the structure of vessels and joints.
Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes
Authors: Frederik Damm, Olivier Kosmider, Véronique Gelsi-Boyer, Aline Renneville, Nadine Carbuccia, Claire Hidalgo-Curtis, Véronique Della Valle, Lucile Couronné, Laurianne Scourzic, Virginie Chesnais, Agnes Guerci-Bresler, Bohrane Slama, Odile Beyne-Rauzy, Aline Schmidt-Tanguy, Aspasia Stamatoullas-Bastard, François Dreyfus, Thomas Prébet, Stéphane de Botton, Norbert Vey, Michael A. Morgan, Nicholas C. P. Cross, Claude Preudhomme, Daniel Birnbaum, Olivier A. Bernard, Michaela Fontenay
Journal: Blood (2012)
FOLLOW-UP STUDY OF FORMERLY HOSPITALIZED VOLUNTARY PSYCHIATRIC PATIENTS: THE FIRST TWO YEARS
Authors: SIDNEY LEVENSTEIN, DONALD F. KLEIN, MAX POLLACK
Journal: American Journal of Psychiatry (1966)

Of 173 voluntary patients followed after discharge, data were obtained regarding outcome patterns during the first two years on 156. Nine postdischarge patterns were isolated. Over-all, 29 percent had outcomes considered good, 29 percent were equivocal and 41 percent poor. Concentrating on the differences within large diagnostic categories, this study demonstrates the increased predictive value of amplifying diagnoses by statements concerning age of onset and course of illness in schizophrenia. Schizophrenic patients with definite childhood asociality had the poorest outcome while those with cyclic or affective features and adult onset did best. Among the nonschizophrenics the periodic depressives did best, while hysterical and passive-aggressive character disorders approximated the outcomes of the schizophrenics. Longitudinal rather than cross-sectional follow-ups provide more useful information regarding evaluation of both treatment effects and the ideal treatment model. Refined outcome measures improve the usefulness of outcome categories. Preliminary findings of third and fourth year experience postdischarge indicate the cyclic nature of certain illnesses, with some having short periods and others having long periods.
OspC facilitates Borrelia burgdorferi invasion of Ixodes scapularis salivary glands
Authors: Utpal Pal, Xiaofeng Yang, Manchuan Chen, Linda K. Bockenstedt, John F. Anderson, Richard A. Flavell, Michael V. Norgard, Erol Fikrig
Journal: Journal of Clinical Investigation (2004)

Outer surface protein C (OspC) is a differentially expressed major surface lipoprotein of Borrelia burgdorferi. ospC is swiftly upregulated when spirochetes leave the Ixodes scapularis tick gut, migrate to the salivary gland, and exit the arthropod vector. Here we show that OspC strongly binds to the tick salivary gland, suggesting a role for OspC in spirochete adherence to this tissue. In vivo studies using a murine model of Lyme borreliosis showed that while OspC F(ab)2 fragments did not influence either the viability of spirochetes or ospC gene expression, they did interfere with B. burgdorferi invasion of tick salivary glands. We then generated ospC knockout spirochetes in an infectious clone of B. burgdorferi and examined them within the vector. OspC-deficient or wild-type spirochetes persisted equally within the gut of unfed ticks and multiplied during the tick engorgement; however, unlike wild-type B. burgdorferi, the mutants were unable to invade salivary glands. Salivary gland colonization of OspC-deficient spirochetes was completely restored when this mutant was complemented in trans with a plasmid harboring the wild-type ospC gene. These studies conclusively demonstrate the importance of OspC in the invasion of tick salivary glands by B. burgdorferi, a critical step in the transmission of spirochetes from the arthropod vector to the mammalian host.
Combination B7-Fc Fusion Protein Treatment and Treg Cell Depletion Therapy
Authors: Aihong Liu, Peisheng Hu, Leslie A. Khawli, Alan L. Epstein
Journal: Clinical Cancer Research (2005)

A B7.1 fusion protein consisting of the extracellular domains of human B7.1 and the Fc portion of human IgG1, called B7.1-Fc, was generated and evaluated for its antitumor potential when used alone or in combination with regulatory T (Treg) cell depletion.A human B7.1-Fc fusion protein was constructed, expressed, purified, and examined for its antitumor activity in experimental mouse tumor models.Soluble B7.1-Fc showed costimulatory activity of T-cell proliferation in vitro, and when given in vivo, it induced complete regression of Colon 26 tumors after a 5-day treatment regimen. Parallel studies with human B7.2-Fc gave very similar results in the Colon 26 tumor model. Even in mice with established RENCA and Madison 109 tumors, which are poorly immunogenic, B7.1-Fc treatment slowed tumor growth dramatically. In these models, more potent antitumor activity was achieved when B7.1-Fc was used in combination with Treg depletion by i.p. administration of antibody PC61. Rechallenge experiments done with mice that had sustained complete tumor regressions showed that these mice had immunologic memory by their ability to reject subsequent implants. Histologically, B7.1-Fc treatment induced multiple areas of necrosis and infiltration of CD4+ and CD8+ T cells in tumors along with a concomitant dramatic increase in T-cell proliferation in tumor-draining lymph nodes.The B7.1-Fc fusion protein seems to be an effective antitumor agent especially in combination with Treg depletion. Its potency in stimulating immune responses and its human origin suggest that clinical studies may be warranted in the future.
The evolutionarily conserved TSC/Rheb pathway activates Notch in tuberous sclerosis complex and Drosophila external sensory organ development
Authors: Magdalena Karbowniczek, Diana Zitserman, Damir Khabibullin, Tiffiney Hartman, Jane Yu, Tasha Morrison, Emmanuelle Nicolas, Rachel Squillace, Fabrice Roegiers, Elizabeth Petri Henske
Journal: Journal of Clinical Investigation (2010)

Mutations in either of the genes encoding the tuberous sclerosis complex (TSC), TSC1 and TSC2, result in a multisystem tumor disorder characterized by lesions with unusual lineage expression patterns. How these unusual cell-fate determination patterns are generated is unclear. We therefore investigated the role of the TSC in the Drosophila external sensory organ (ESO), a classic model of asymmetric cell division. In normal development, the sensory organ precursor cell divides asymmetrically through differential regulation of Notch signaling to produce a pIIa and a pIIb cell. We report here that inactivation of Tsc1 and overexpression of the Ras homolog Rheb each resulted in duplication of the bristle and socket cells, progeny of the pIIa cell, and loss of the neuronal cell, a product of pIIb cell division. Live imaging of ESO development revealed this cell-fate switch occurred at the pIIa-pIIb 2-cell stage. In human angiomyolipomas, benign renal neoplasms often found in tuberous sclerosis patients, we found evidence of Notch receptor cleavage and Notch target gene activation. Further, an angiomyolipoma-derived cell line carrying biallelic TSC2 mutations exhibited TSC2- and Rheb-dependent Notch activation. Finally, inhibition of Notch signaling using a γ-secretase inhibitor suppressed proliferation of Tsc2-null rat cells in a xenograft model. Together, these data indicate that the TSC and Rheb regulate Notch-dependent cell-fate decision in Drosophila and Notch activity in mammalian cells and that Notch dysregulation may underlie some of the distinctive clinical and pathologic features of TSC.
Enhanced hindlimb collateralization induced by acidic fibroblast growth factor is dependent upon femoral artery extraction
Authors: J Hershey
Journal: Cardiovascular Research (2003)

Recent investigations have established the feasibility of using exogenously delivered angiogenic growth factors to increase collateral artery development in animal models of myocardial and hindlimb ischemia.Our aim was to evaluate the ability of a stabilized form of acidic fibroblast growth factor (aFGF-S117) to stimulate collateralization and arteriogenesis in the rabbit hindlimb following the surgical induction of ischemia by femoral artery extraction. A secondary objective was to examine angiogenic and arteriogenic effects of aFGF-S117 in the absence of a peripheral blood flow deficit.Five days after femoral artery removal, aFGF-S117 (1, 3, or 30 microg/kg) was intramuscularly delivered into the hindlimb, three times per week for 2 consecutive weeks. End-point measurements performed on day 20 found that hindlimb reserve blood flow was significantly improved in rabbits that received 3 or 30 microg/kg of aFGF-S117, with no difference in efficacy between these two doses. These hemodynamic results were supported by angiographic evidence showing enhanced density of collateral vessels in the medial thigh region and histological findings of increased capillary density within the gastrocnemius muscle from rabbits treated with aFGF-S117. When an efficacious dose of 3 microg/kg of aFGF-S117 was administered to sham-operated rabbits with intact femoral arteries, there was no change in any of the blood flow, angiographic or histological parameters measured.These findings demonstrate that a stabilized form of aFGF stimulated the development of functional collateral arteries in the rabbit hindlimb, an effect which was dependent upon removal of the femoral artery. These results suggest that aFGF-S117 may have therapeutic potential for the treatment of arterial occlusive disorders.
ABC of Computing
Authors: James M. Blackwood
Journal: JAMA (1986)

<i>ABC of Computing</i>is a collection of articles that appeared in the<i>British Medical Journal</i>in 1983. The first four chapters provide an introduction to the subject for those with very little "computer literacy." The material is general, but with an orientation toward microcomputers. Fourteen additional chapters cover computer applications in the intensive care unit, the laboratory, patient administration, medical education, and so on. This book has three flaws that limit its usefulness, at least for physicians in this country. First, it is dated. The sophistication of hardware and software has increased dramatically since 1983. Then, too, the systems described were developed several years prior to the publication of the articles. The statement that "the software presently generally available is still in its infancy" does not give the reader a realistic view of what may be available in the marketplace. Second, there are no references. Someone who becomes interested in
P4-02-01: Bis(2-Ethylhexyl) Phthalate: A Potential Endocrine Disruptor Confer Letrozole Insensitivity and Induction of Aromatase Activity in Breast Cancer Cells.
Authors: HB Nair, SS Bhaskaran, NK Krishnegowda, RR Tekmal, JL VandeBerg
Journal: Cancer Research (2011)

Abstract Exposure to endocrine disrupting compounds (EDC's) is an important determinant of mammary gland development and mammary tumor pathogenesis. The risk of breast cancer in adulthood is known to be influenced by environmental factors experienced as a fetus. Fetal exposure to dietary factors or certain pharmaceuticals and environmental chemicals that affect or mimic steroid hormones increase predisposition to breast cancer. The mechanisms by which EDC's alter epigenetic programming, differentiation and deregulation of ductal branching of mammary glands are poorly understood. A high ratio of estrogen receptor a (ERα) to ERβ has been recently found to be associated with poor prognosis and aggressive disease in breast cancer patients. Preliminary studies from our laboratory revealed that bis(2-ethylhexyl) phthalate (DEHP) is a possible EDC which induces cell proliferation in T47D, MCF7, MCF7/Aro breast cancer cells in vitro and confers insensitivity to letrozole, a third generation aromatase inhibitor. DEHP increased cell proliferation (MTT assay) in a dose dependent manner and was non toxic to T47D, MCF7 and MCF 7 Aro cells. 1, 10 and 100 nM concentrations of DEHP up regulated ERα and down regulated ERβ at the mRNA level. Hypermethylation in the estrogen receptor beta (ERβ) promoter was observed after treatment with 1nM DEHP for 24 h, suggesting that DEHP alter epigenetic programming through changes in the DNA methylation to modify the chromatin structure and change the accessibility of DNA to transcription factors. When breast cancer cells were treated with letrozole (200nM and DEHP (1nM) together, they survived, whereas those treated with letrozole alone did not survive. Aromatase mRNA and enzyme levels were higher in the DEHP treated cells by comparison with sham control MCF7/Aro cells. Nonmalignant MCF-10A breast epithelial cells showed a proliferation advantage (MTT assay) by up regulation of ERα as well as aromatase expression when treated with 1nM DEHP. Aromatase transgenic mice treated with 10mg/Kg b.wt of DEHP over a period of 30 days resulted in the excessive ductal branching density and epithelial outgrowth in the mammary gland. The present data suggest that dietary accumulation of DEHP through plastic food containers, water bottles, etc. may contribute to risk of hormone sensitive breast cancer in women and chemoinsensitivity and or drug resistance in breast cancer patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-01.
Can IT lead to radical redesign of health care?
Authors: Richard Smith
Journal: BMJ (2004)

network for people working in health care), Russell and colleagues (p 1174) found that members were able to improve cross-professional contact and share innovation, good practice, and research ideas.Soft networking enables knowledge for evidence based health care to be personalised and made meaningful through informal social interaction, say the authors, and skilled staff can encourage a strong culture of support and reciprocity.
Detection of inhibin α and βA subunits (inhibin A, B, activin A,AB) in the human pituitary gland and in pituitary adenomas by immunohistochemistry and nonradioisotopicin situ hybridization
Authors: Makoto Sugiyama, Naoko Sanno, Akira Teramoto, R. Yoshiyuki Osamura
Journal: Endocrine Pathology (1998)
Aspirin as an Antithrombotic Medication
Authors: Aaron J. Marcus
Journal: New England Journal of Medicine (1983)

IN 1977 an article in the Journal 1 reported that aspirin prophylaxis (600 mg twice daily) was effective against the development of postoperative venous thrombosis and pulmonary embolism in patients who had undergone total hip replacement. Postoperative venous thrombosis occurred in 23 of 51 patients given a placebo but in only 11 of 44 receiving aspirin. Treatment was initiated one day before surgery and was continued until radiographic phlebography — the diagnostic end point — had been completed (usually two weeks).The therapeutic use of aspirin in venous thrombosis seemed unorthodox, since venous thrombi consist mainly of a heterogeneous mass of . . .
Loss of Fhit Expression in Head and Neck Squamous Cell Carcinoma and Its Potential Clinical Implication
Authors: Shyh-Kuan Tai, Janet I. Lee, K. Kian Ang, Adel K. El-Naggar, Khaled A. Hassan, Diane Liu, J. Jack Lee, Hening Ren, Waun K. Hong, Li Mao
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Abnormalities of FHIT, a candidate tumor suppressor gene, have frequently been found in multiple malignancies, including head and neck squamous cell carcinoma (HNSCC). To define its role in HNSCC treated with surgery and postoperative radiotherapy (PORT), the Fhit protein expression status was investigated in 80 patients enrolled in a prospective Phase III clinical trial addressing the dose and fractionation regimen of PORT. Experimental Design: Immunohistochemical staining of HNSCC tissue sections for Fhit expression was performed. The Fhit expression status was correlated with the clinicopathological characteristics and clinical course. The median follow-up duration was 4.9 years. Results: Loss of Fhit expression was found in 52 of the 80 study patients (65%). There was not a significant association between Fhit expression and clinical characteristics. Patients whose tumor exhibited negative Fhit expression had a significantly worse 5-year overall survival duration [hazard ratio = 0.49; 95% confidence interval, 0.23–1.03; P = 0.05 (log-rank test)] than did those whose tumor exhibited positive Fhit expression. One third of the patients with a Fhit-negative tumor had distant metastasis during the follow-up period. Paradoxically, patients classified as high risk who had a Fhit-negative tumor experienced locoregional recurrence less often (18%) than did high-risk patients who had a Fhit-positive tumor (33%). Conclusions: Loss of Fhit expression is a poor prognostic indicator in patients with HNSCC. However, tumors lacking Fhit expression may be more sensitive to PORT and therefore more susceptible to locoregional control.
National smoking cessation services at risk
Authors: M. Raw, A. McNeill, J. Watt, D. Raw
Journal: BMJ (2001)

Twenty two years ago Russell and his colleagues showed the effectiveness of brief advice from doctors in persuading smokers to stop,1 but only in the past few years has treatment for dependent smokers finally been taken seriously. Treatment services have been established throughout the NHS and are an integral part of the government's plans to reduce deaths from coronary heart disease and cancer.2 Smokers are now offered behavioural support to stop plus NHS prescriptions of nicotine replacement therapy or bupropion, treatments shown to be effective by a huge body of research and based on national clinical guidelines.3 These services have achieved impressive throughput and success rates, but they are now under threat because of the government's failure to confirm their future funding.

In England between April 2000 and March 2001 about 127 000 smokers set a quit date and 48% of these stopped at one month. This has …