tbuckley/cabot-search huggingface dataset:
The Physician-Scientist Career Pipeline in 2005
Authors: Timothy J. Ley, Leon E. Rosenberg
Journal: JAMA (2005)

Context Physician-scientists play a unique and critical role in medical research.Nonetheless, a number of trends followed during the 1980s and 1990s revealed that this career pathway was in serious jeopardy.Physician-scientists were declining in number and were getting older.A variety of factors were thought to contribute to this problem, including increasing indebtedness of medical school graduates caused by rapidly rising medical school tuition costs.Objective To evaluate the impact of recently initiated programs from the National Institutes of Health (NIH) and several not-for-profit institutions designed to revitalize the physician-scientist career pipeline. DesignWe assessed recent trends in the physician-scientist career pipeline using data obtained from the NIH, the American Medical Association, the Association of American Medical Colleges, and other sources. Main Outcome MeasuresTotal numbers of physicians performing research, grant application numbers and success rates for MDs, MD-PhDs, and PhDs at various stages in their careers, interest in research among medical students, medical school tuitions and postgraduate salaries, numbers and composition of applicants for NIH loan repayment programs, and gender distribution of young physician-scientists. ResultsThe number of physician-scientists in the United States has been in a steady state for the past decade, but funded physician-scientists are significantly older than they were 2 decades ago.However, the study of early career markers over the past 7 to 10 years has demonstrated increasing interest in research careers by medical students, steady growth of the MD-PhD pool, and a new burst of activity in the "late bloomer" pool of MDs (individuals who choose research careers in medical school or in residency training), fueled by loan repayment programs that were created by the NIH in 2002.Several recent trends for more established physician-scientists have also suggested improvement. ConclusionsAlthough it is too early to assess the impact of these indicators on the long-term career pathway, the recent growth in activity in the physician-scientist career pipeline is an encouraging development.Continued funding of these new programs, coupled with sustained support for physician-scientists committed to the pathway, will be required to maintain these positive trends.
Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease
Authors: Jinghua Liu, Nancy M. Walker, Akifumi Ootani, Ashlee M. Strubberg, Lane L. Clarke
Journal: Journal of Clinical Investigation (2015)

Cystic fibrosis (CF) intestinal disease is associated with the pathological manifestation mucoviscidosis, which is the secretion of tenacious, viscid mucus that plugs ducts and glands of epithelial-lined organs. Goblet cells are the principal cell type involved in exocytosis of mucin granules; however, little is known about the exocytotic process of goblet cells in the CF intestine. Using intestinal organoids from a CF mouse model, we determined that CF goblet cells have altered exocytotic dynamics, which involved intrathecal granule swelling that was abruptly followed by incomplete release of partially decondensated mucus. Some CF goblet cells exhibited an ectopic granule location and distorted cellular morphology, a phenotype that is consistent with retrograde intracellular granule movement during exocytosis. Increasing the luminal concentration of bicarbonate, which mimics CF transmembrane conductance regulator–mediated anion secretion, increased spontaneous degranulation in WT goblet cells and improved exocytotic dynamics in CF goblet cells; however, there was still an apparent incoordination between granule decondensation and exocytosis in the CF goblet cells. Compared with those within WT goblet cells, mucin granules within CF goblet cells had an alkaline pH, which may adversely affect the polyionic composition of the mucins. Together, these findings indicate that goblet cell dysfunction is an epithelial-autonomous defect in the CF intestine that likely contributes to the pathology of mucoviscidosis and the intestinal manifestations of obstruction and inflammation.
Efficient neuronal differentiation and maturation of human pluripotent stem cells encapsulated in 3D microfibrous scaffolds
Authors: Hong Fang Lu, Sze-Xian Lim, Meng Fatt Leong, Karthikeyan Narayanan, Rebecca P.K. Toh, Shujun Gao, Andrew C.A. Wan
Journal: Biomaterials (2012)
Dll4 Blockade in Stromal Cells Mediates Antitumor Effects in Preclinical Models of Ovarian Cancer
Authors: Frank Kuhnert, Guoying Chen, Sandra Coetzee, Nithya Thambi, Carlos Hickey, Jing Shan, Pavel Kovalenko, Irene Noguera-Troise, Eric Smith, Jeanette Fairhurst, Julian Andreev, Jessica R. Kirshner, Nicholas Papadopoulos, Gavin Thurston
Journal: Cancer Research (2015)

Abstract The Notch ligand delta-like 4 (Dll4) has been identified as a promising target in tumor angiogenesis in preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. In this study, we report the development of REGN421 (enoticumab), a fully human IgG1 monoclonal antibody that binds human Dll4 with sub-nanomolar affinity and inhibits Notch signaling. Administering REGN421 to immunodeficient mice engineered to express human Dll4 inhibited the growth of several human tumor xenografts in association with the formation of nonfunctional tumor blood vessels. In ovarian tumor xenograft models, Dll4 was expressed specifically by the tumor endothelium, and Dll4 blockade by human-specific or mouse-specific Dll4 antibodies exerted potent antitumor activity, which relied entirely on targeting Dll4 expressed by tumor stromal cells but not by the tumor cells themselves. However, Dll4 blockade reduced Notch signaling in both blood vessels and tumor cells surrounding the blood vessels, suggesting that endothelial-expressed Dll4 might induce Notch signaling in adjacent ovarian tumor cells. The antitumor effects of targeting Dll4 were augmented significantly by simultaneous inhibition of VEGF signaling, whereas this combined blockade reversed normal organ vascular changes induced by Dll4 blockade alone. Overall, our findings deepen the rationale for antibody-based strategies to target Dll4 in ovarian cancers, especially in combination with VEGF blockade. Cancer Res; 75(19); 4086–96. ©2015 AACR.
Towards a better understanding of RNA carriage by ejaculate spermatozoa
Authors: David Miller, G.Charles Ostermeier
Journal: Human Reproduction Update (2006)

Research on spermatozoal RNA has made considerable progress since the original reports on its presence appeared in the late 1950s and early 1960s. Through the use of stringent procedures aimed at eliminating contamination artefacts, we now appreciate that a complex cohort of mRNAs persists in the ejaculate cell but that 80S (cytoplasmic) ribosomal complexes are not present in sufficient quantities to support cytoplasmic mRNA translation. Despite this, under certain conditions, at least some cytoplasmic mRNAs can apparently be translated de novo, possibly on mitochondrial polysomes. The detection of mRNA translation by mature spermatozoa essentially supports the earliest research reports on spermatozoal gene expression although the suggested relationship with protein turnover and capacitation is wholly unexpected. We also examine some alternative explanations and roles for RNA carriage, including the RNAs passive retention as a consequence of nuclear shutdown and a more active role in chromatin repackaging, genomic imprinting, gene silencing and post-fertilization requirements of essential paternal RNAs. The recent report of an RNA-mediated epigenetic alteration to phenotype that is likely to be sperm derived is of particular interest in this regard. We finally show that regardless of the biological role(s) of spermatozoal RNA, its utility in infertility studies, particularly when coupled with modern techniques in gene-expression analysis (e.g. microarrays), is obvious. As a wholly non-invasive proxy for the testis, this RNA offers considerable potential as a marker for fertility status and the genetic and environmental influences that could make all the difference between a fertile and an infertile phenotype.
Use of a special inhaler attachment in asthmatic children.
Authors: R Ellul-Micallef, F Moren, K Wetterlin, K C Hidinger
Journal: Thorax (1980)

Asthmatics often find difficulties in using an aerosol inhaler correctly as they are unable to co-ordinate the release of a bolus of drug to coincide with an inspiratory effort. This is especially the case with children. The addition of a special attachment to an ordinary inhaler overcame this problem. Twelve asthmatic children produced significantly better PEFR measurements when 0.25 mg terbutaline sulphate was administered via an inhaler with the attachment than when an ordinary inhaler was used alone.
Potent and Specific Antitumor Efficacy of CMC-544, a CD22-Targeted Immunoconjugate of Calicheamicin, against Systemically Disseminated B-Cell Lymphoma
Authors: John F. DiJoseph, Mary E. Goad, Maureen M. Dougher, Erwin R. Boghaert, Arthur Kunz, Philip R. Hamann, Nitin K. Damle
Journal: Clinical Cancer Research (2004)

Abstract Purpose: CMC-544 is a CD22-targeted immunoconjugate of calicheamicin and exerts a potent cytotoxic effect against CD22+ B-cell lymphoma. This study evaluated antitumor efficacy of CMC-544 against systemically disseminated B-cell lymphoma. Experimental Design: Scid mice received i.v. injections of CD22+ Ramos B-cell lymphoma cells for their systemic dissemination. CMC-544, G5/44, CD33-targeted CMA-676 (control conjugate) or rituximab were given i.p. 3, 9, 15, or 21 days after B-cell lymphoma dissemination. Diseased mice were monitored daily for hind-limb paralysis and death. Histopathological examination of CMC-544-treated and vehicle-treated diseased mice was also performed. Results: Mice with disseminated B-cell lymphoma developed hind-limb paralysis within 35 days. When given up to 15 days after B-cell lymphoma dissemination, CMC-544 extended survival of the diseased mice to &amp;gt;100 days, and these mice were considered cured. CMC-544 was efficacious when given during both the early initiation phase and the late established phase of the disease. A single dose of CMC-544 was effective in delaying the occurrence of hind-limb paralysis. In contrast, neither CMA-676 nor unconjugated G5/44 was effective. Rituximab was effective when given early in the disease process but not when the disease was established. Histopathological analysis revealed B-cell lymphoma infiltration in brain, spinal cord, bone marrow, and kidney in vehicle-treated but not in CMC-544–treated diseased mice. Consistent with its efficacy against the disseminated B-cell lymphoma, CMC-544 also caused regression of established Ramos B-cell lymphoma xenografts in scid mice. Conclusions: CMC-544 confers strong therapeutic activity against systemic disseminated B-cell lymphoma and protects mice from hind-limb paralysis and death. These results support clinical evaluation of CMC-544 in the treatment of CD22+ lymphoid malignancies.
Alterations in gene expression in hamster diaphragm after emphysema and lung volume reduction surgery
Authors: V. Reynders, E. Marchand, G. Gayan-Ramirez, P. De Leyn, G. Verhoeven, M. Decramer
Journal: European Respiratory Journal (2002)

The authors have demonstrated previously that emphysema and lung volume reduction surgery (LVRS) resulted in a significant shift of type IIx/b to type IIa fibres in the diaphragm of hamsters with elastase-induced emphysema. To explore the mechanisms leading to this fibre switching, the mRNA expression of the myogenic regulatory factors, the inhibitors of DNA binding proteins (Id-proteins) and insulin-like growth factor-I were examined. Ribonucleic acid was extracted from the diaphragm of control, emphysematous, emphysematous and sham operated and LVRS hamsters and subjected to reverse transcriptase polymerase chain reaction. Compared to control, the ratio MyoD to myogenin declined with emphysema, sham and even more after LVRS, due to a decrease in MyoD mRNA and an increase in myogenin mRNA. Similarly, compared to control, Id-1 protein mRNA levels decreased significantly in sham and even more in LVRS. Id-2 protein mRNA levels decreased in all groups, but reached statistical significance in LVRS only, compared to control. In conclusion: 1) the reduced MyoD/myogenin ratio may be the mechanism of the shift to a slower fibre type, 2) the decreased MyoD/myogenin ratio in lung volume reduction surgery animals suggests that lung volume reduction surgery enhances rather than decreases the load placed on the diaphragm and 3) the observed down-regulation of the inhibiting factors may facilitate the diaphragm adaptation to overload.
Strategic approach to the management of Hodgkin’s disease incorporating salvage therapy with high-dose ifosfamide, etoposide and epirubicin: a Northern Region Lymphoma Group study (UK)
Authors: S.J. Proctor, G.H. Jackson, A. Lennard, B. Angus, K. Wood, H.L. Lucraft, J. White, K. Windebank, P.R.A. Taylor
Journal: Annals of Oncology (2003)
Effects of Testosterone and Progressive Resistance Training in Eugonadal Men with AIDS Wasting
Authors: Steven Grinspoon
Journal: Annals of Internal Medicine (2000)

Background: Substantial loss of muscle mass occurs among men with AIDS wasting. Objective: To investigate the independent effects of testosterone therapy and progressive resistance training in eugonadal men with AIDS wasting. Design: Randomized, controlled trial. Setting: University hospital. Patients: 54 eugonadal men with AIDS wasting (weight < 90% ideal body weight or weight loss > 10%). Intervention: In a 2 × 2 factorial design, patients were assigned to receive testosterone enanthate (200 mg/wk) or placebo injections and progressive resistance training (three times weekly) or no training for 12 weeks. Measurements: Cross-sectional muscle area and other indices of muscle mass. Results: Cross-sectional muscle area increased in response to training compared with nontraining (change in arm muscle mass, 499 ± 349 mm2 vs. 206 ± 264 mm2 [P = 0.004]; change in leg muscle mass, 1106 ± 854 mm2 vs. 523 ± 872 mm2 [P = 0.045]) and in response to testosterone therapy compared with placebo (change in arm muscle mass, 512 ± 371 mm2 vs. 194 ± 215 mm2 [P < 0.001]; change in leg muscle mass, 1236 ± 881 mm2 vs. 399 ± 729 mm2 [P = 0.002]). Levels of high-density lipoprotein cholesterol decreased in response to testosterone therapy compared with placebo (−0.03 ± 0.13 mmol/L vs. 0.05 ± 0.13 mmol/L [−1 ± 5 mg/dL vs. 2 ± 5 mg/dL]; P = 0.011) and increased in response to training compared with nontraining (0.05 ± 0.13 mmol/L vs. 0.00 ± 0.16 mmol/L [2 ± 5 mg/dL vs. 0 ± 6 mg/dL]; P = 0.052). Conclusions: In contrast to anabolic therapies that may have adverse effects on metabolic variables, supervised exercise effectively increases muscle mass and is associated with significant positive health benefits in eugonadal men with AIDS wasting.
Role of PECAM-1 in Arteriogenesis and Specification of Preexisting Collaterals
Authors: Zhongming Chen, Janet Rubin, Ellie Tzima
Journal: Circulation Research (2010)

Rationale: Hemodynamic forces caused by the altered blood flow in response to an occlusion lead to the induction of collateral remodeling and arteriogenesis. Previous work showed that platelet endothelial cell adhesion molecule (PECAM)-1 is a component of a mechanosensory complex that mediates endothelial cell responses to shear stress. Objective: We hypothesized that PECAM-1 plays an important role in arteriogenesis and collateral remodeling. Methods and Results: PECAM-1 knockout (KO) and wild-type littermates underwent femoral artery ligation. Surprisingly, tissue perfusion and collateral-dependent blood flow were significantly increased in the KO mice immediately after surgery. Histology confirmed larger caliber of preexisting collaterals in the KO mice. Additionally, KO mice showed blunted recovery of perfusion from hindlimb ischemia and reduced collateral remodeling, because of deficits in shear stress–induced signaling, including activation of the nuclear factor κB pathway and inflammatory cell accumulation. Partial recovery was associated with normal responses to circumferential wall tension in the absence of PECAM-1, as evidenced by the upregulation of ephrin B2 and monocyte chemoattractant protein-1, which are 2 stretch-induced regulators of arteriogenesis, both in vitro and in vivo. Conclusions: Our findings suggest a novel role for PECAM-1 in arteriogenesis and collateral remodeling. Furthermore, we identify PECAM-1 as the first molecule that determines preexisting collateral diameter.
Feigning introspective blindness for thought
Authors: Robert W. Lurz
Journal: Behavioral and Brain Sciences (2009)

Abstract I argue that the very reasons Carruthers gives for why the “mindreading is prior” account should allow introspective access to perceptual/quasi-perceptual states, can be given for thought, as well. I also argue that we have good subjectively accessible grounds for the intuition in introspective thoughts, notwithstanding Carruthers' argument to the contrary and his attempt to explain the intuition away.
The Extracellular Calcium-Sensing Receptor: Its Role in Health and Disease
Authors: Edward M. Brown, MD, Martin Pollak, MD, Steven C. Hebert, MD
Journal: Annual Review of Medicine (1998)

The recent cloning of an extracellular calcium (Ca 2+ o )-sensing receptor (CaR) from parathyroid, kidney and other cell types has clarified the mechanisms through which Ca 2+ o exerts its direct actions on various cells and tissues. In the parathyroid, the CaR mediates the inhibitory effects of Ca 2+ o on parathyroid hormone (PTH) secretion and likely on expression of the PTH gene and parathyroid cellular proliferation. In the kidney, the receptor mediates direct inhibition of the reabsorption of divalent cations in the cortical thick ascending limb, and it likely underlies the inhibitory actions of hypercalcemia on the urinary-concentrating mechanism in the medullary thick ascending limb and inner medullary collecting duct. The identification of inherited diseases of Ca 2+ o -sensing that arise from mutations in the CaR gene has proven, by genetic means, the central role of the CaR in mineral ion homeostasis and the importance of the receptor in regulating the parathyroid and kidney. An allosteric CaR agonist (“calcimimetic”) is currently being tested for the treatment of primary hyperparathyroidism, and CaR-based therapeutics will likely be applicable to other disorders in which CaRs are under- or overactive. Thus the discovery of the CaR and its associated diseases has documented that Ca 2+ o plays an essential role as an extracellular first messenger, in addition to serving its better recognized role as an intracellular second messenger.
Dormancy of Mammary Carcinoma After Mastectomy
Authors: T. G. Karrison, D. J. Ferguson, P. Meier
Journal: JNCI Journal of the National Cancer Institute (1999)

The longest interval between primary treatment of breast cancer and tumor recurrence, i.e., the limit of breast cancer dormancy, defines the appropriate length of follow-up, the effectiveness of treatment, and curability (no excess mortality risk for patients relative to the general population) for the disease. To determine this limit, we analyzed long-term follow-up data from patients who underwent a radical mastectomy during a four-decade period at the University of Chicago Hospitals.For 1547 patients operated on during the period from 1945 through mid-1987, the number of recurrences and deaths occurring within each postoperative year were tabulated, and the hazard rate for first recurrence or death from breast cancer was estimated by use of the actuarial method. The excess mortality rate was calculated for successive 5-year intervals, beginning at the time of mastectomy, by use of U.S. life tables and matching on the basis of age, race, and sex.Most recurrences occurred within the first 10 years after mastectomy. Recurrences were rare after 20 years; only one recurrence was reported among 192 patients followed for 26-45 years. Patients who had a recurrence within 5 years following mastectomy had shorter subsequent survival times than those whose recurrence appeared after 5 years (two-sided P = .0001). The excess death rate increased with pathologic stage of the primary tumor. Overall, there was evidence of excess mortality up to 20 years postsurgery (two-sided P = .009).The limit of breast cancer dormancy in this patient population appears to be between 20 and 25 years. After this time, recurrences were rare, and the mortality rate was no longer statistically significantly different from that of the general population. Patients surviving to this time without evidence of recurrence or contralateral breast cancer are probably cured.
Imaging Plaques to Predict and Better Manage Patients With Acute Coronary Events
Authors: Hector M. Garcia-Garcia, Ik-Kyung Jang, Patrick W. Serruys, Jason C. Kovacic, Jagat Narula, Zahi A. Fayad
Journal: Circulation Research (2014)

Culprit lesions of patients, who have had an acute coronary syndrome commonly, are ruptured coronary plaques with superimposed thrombus. The precursor of such lesions is an inflamed thin-capped fibroatheroma. These plaques can be imaged by means of invasive techniques, such as intravascular ultrasound (and derived techniques), optical coherence tomography, and near-infrared spectroscopy. Often these patients exhibit similar (multiple) plaques beyond the culprit lesion. These remote plaques can be assessed noninvasively by computed tomographic angiography and MRI and also using invasive imaging. The detection of these remote plaques is not only feasible but also in natural history studies have been associated with clinical coronary events. Different systemic pharmacological treatments have been studied (mostly statins) with modest success and, therefore, newer approaches are being tested. Local treatment for such lesions is in its infancy and larger, prospective, and randomized trials are needed. This review will describe the pathological and imaging findings in culprit lesions of patients with acute coronary syndrome and the assessment of remote plaques. In addition, the pharmacological and local treatment options will be reviewed.
Remarks on the Electrical Treatment of Diseases of the Uterus
Authors: T. S. Wells
Journal: BMJ (1888)

the Queen's liousehol(l.I HAVE had, perhaps, a longer and more varied experience tlhan dealing with diseases, especially those which are characterised by overgrowth.I lhave so constantly had to regret the inefficacy of medical treatment; and the results of surgical operations, though sometimes brilliant, have often come so short of my desires that I have for many years past fallen into a frame of mind readily disposedl to listen to any suggestion of a which offere?d reasonable chance of success, perils attending the bolder practice.So, reports reaclhed me from Paris of what Dr. Apostoli was teaching doing, they came with a welcome ring.Electro-therapeutics were no novelty to me.Mfore than thirty years ago put galvanism to the test, and had gathered in