tbuckley/cabot-search huggingface dataset:
Chemopreventive and Chemotherapeutic Actions of mTOR Inhibitor in Genetically Defined Head and Neck Squamous Cell Carcinoma Mouse Model
Authors: Zhi-Jun Sun, Lu Zhang, Bradford Hall, Yansong Bian, J. Silvio Gutkind, Ashok B. Kulkarni
Journal: Clinical Cancer Research (2012)

Abstract Purpose: To assess the efficacy of rapamycin treatment in chemoprevention and chemotherapy of tumorigenesis in a genetically defined mouse model of head and neck squamous cell carcinoma (HNSCC). Experimental design: Knockdown of Tgfbr1 and/or Pten using siRNA-mediated RNA interference was carried out in human HNSCC cell lines to analyze molecular changes in the mTOR pathway. Tgfbr1flox/flox; Ptenflox/flox; K14-CreERtam mice were treated with oral gavage of tamoxifen for the conditional deletion of Tgfbr1 and Pten in oral mucosa, resulting in HNSCC. Tgfbr1 and Pten conditonal deletion (2cKO) mice were treated with rapamycin before or after the onset of HNSCC, and the efficacy of this treatment was assessed by determining tumor burden, longevity, and molecular analysis of the mTOR pathway. Molecular changes observed in human HNSCC cell lines and 2cKO mice were compared to identify key alterations in the mTOR pathway. Results: Knockdown of Tgfbr1 and/or Pten in human HNSCC cell lines resulted in activation of mTOR activity complex 1 and increased levels of survivin. Furthermore, we observed similar changes in HNSCC of the 2cKO mouse. In the human HNSCC tissue array, a loss of Tgfbr1 expression correlated with increased survivin levels. Chemopreventive rapamycin treatment significantly delayed the onset of the HNSCC tumors and prolonged survival in 2cKO mice. In addition, we also found that rapamycin had a therapeutic effect on squamous cell carcinomas in these mice. In 2cKO HNSCC tongue tumors, rapamycin treatment induced apoptosis, inhibited cell proliferation and phosphorylation of Akt and S6, and decreased survivin expression. Conclusions: These findings indicate that tumorigenesis in 2cKO HNSCC is associated with activation of the Akt/mTOR/survivin pathway, and inhibition of this pathway by rapamycin treatment successfully ameliorates the onset and progression of tumorigenesis. Clin Cancer Res; 18(19); 5304–13. ©2012 AACR.
Polymorphisms of the core, NS3, and NS5A proteins of hepatitis C virus genotype 1b associate With development of hepatocellular carcinoma
Authors: Ahmed El-Shamy, Michiko Shindo, Ikuo Shoji, Lin Deng, Tadao Okuno, Hak Hotta
Journal: Hepatology (2012)

Hepatocellular carcinoma (HCC) is one of the common sequelae of hepatitis C virus (HCV) infection. It remains controversial, however, whether HCV itself plays a direct role in the development of HCC. Although HCV core, NS3, and NS5A proteins were reported to display tumorigenic activities in cell culture and experimental animal systems, their clinical impact on HCC development in humans is still unclear. In this study we investigated sequence polymorphisms in the core protein, NS3, and NS5A of HCV genotype 1b (HCV-1b) in 49 patients who later developed HCC during a follow-up of an average of 6.5 years and in 100 patients who did not develop HCC after a 15-year follow-up. Sequence analysis revealed that Gln at position 70 of the core protein (core-Gln(70) ), Tyr at position 1082 plus Gln at 1112 of NS3 (NS3-Tyr(1082) /Gln(1112) ), and six or more mutations in the interferon/ribavirin resistance-determining region of NS5A (NS5A-IRRDR≥6) were significantly associated with development of HCC. Multivariate analysis identified core-Gln(70) , NS3-Tyr(1082) /Gln(1112) , and α-fetoprotein (AFP) levels (>20 ng/L) as independent factors associated with HCC. Kaplan-Meier analysis revealed a higher cumulative incidence of HCC for patients infected with HCV isolates with core-Gln(70) , NS3-Tyr(1082) /Gln(1112) or both than for those with non-(Gln(70) plus NS3-Tyr(1082) /Gln(1112) ). In most cases, neither the residues at position 70 of the core protein nor positions 1082 and 1112 of the NS3 protein changed during the observation period.HCV isolates with core-Gln(70) and/or NS3-Tyr(1082) /Gln(1112) are more closely associated with HCC development compared to those with non-(Gln(70) plus NS3-Tyr(1082) /Gln(1112) ).
Doctors "end of life" decisions vary across Europe
Authors: T. Sheldon
Journal: BMJ (2003)

Religion, culture, and geography all influence decisions by European doctors on limiting “life sustaining treatment” in intensive care, says a major study comparing practices in different countries.

The Ethicus study into end of life practices in European intensive care units looked at aspects such as religion and culture. It examined more than 30 000 patients admitted to 37 intensive care units in 17 European countries over an 18 month period up to June 2000, concluding that limiting life sustaining treatment is common but that the practice varies among countries ( JAMA 2003;290:790-7).

The researchers, from Israel, classified countries as northern (for example, Denmark and Finland), central(Germany and Austria), or …
P22 Factors associated with refractoriness to repeat exercise challenge in adults with asthma
Authors: N. Martin, I. Pavord
Journal: Thorax (2010)

<h3>Introduction</h3> A proportion of patients with asthma develops a refractory period, during which the bronchoconstrictor response to a second indirect challenge is reduced. A better understanding of factors associated with the development of refractoriness is potentially important as the refractory period may be the vestigial expression of a bronchoprotective pathway that may be pathogenically important and could be manipulated for therapeutic effect. We investigated factors associated with refractoriness in 10 subjects with mild to moderate asthma. <h3>Methods</h3> Subjects were recruited from primary care, had mild to moderate (Step 1 or 2 BTS guideline) asthma and were aged 18–50 years. Subjects underwent a standardised laboratory exercise challenge test breathing cold dry air. Those who had a positive test (&gt;15% fall in FEV1) were observed until lung function returned to within 5% of baseline and then underwent a further standardised exercise challenge test. The refractory index was calculated on the % reduction in the maximum percent fall in FEV<sub>1</sub> between the first and second challenge. On a separate occasion the subjects undertook a sodium metabisulphite challenge test (a known, indirectly acting bronchoconstrictor) and a PD20 (MBS PD20) was calculated for this from interpolation of the log-dose response curve. <h3>Results</h3> 22 individuals were screened to find 10 (1F; 9M) with a positive exercise test; these then went on to have a second challenge test. The mean (SEM) fall in FEV1 was 24.9% (2.4) and 13.7% (2.5) with first and second challenge respectively. The mean (SEM) refractory index was 50.1% (6.5). There was no correlation between the refractory index and age, sex, FEV1 % predicted, FVC, FEV1/FVC ratio, MBS PD20, or % fall in FEV1 on first challenge. <h3>Conclusions</h3> Our findings suggest that refractoriness is independent of baseline lung function and the magnitude of the response to the initial challenge. Further studies are required to determine whether other demographic factors are associated with this phenomenon.
Reporting Results From Chemotherapy Trials
Authors: Daniel M. Lane
Journal: JAMA (1985)

<h3>To the Editor.—</h3> The article by Oye and Shapiro<sup>1</sup>on the evaluation of cancer chemotherapy trials reflects the usual short-sighted view of retrospective statistical analyses evaluating earlier studies for response and survival. The main defect is that the authors attempt to take other people's data as published and evaluate those data without having made the observations themselves. Just as many errors in regard to the evaluation of cancer chemotherapy trials result from this approach as do the techniques criticized by the authors. Those errors in evaluation are the product of several factors, including the following. 1. Using survival as the only end point of response to therapy denies the importance of life quality despite the authors' comment that adequate criteria for evaluating quality of life do not exist. Problems of evaluating objective vs subjective responses are part of clinical research trials no matter what area is studied. This dilemma is
Anti-immunoglobulin M activates nuclear calcium/calmodulin-dependent protein kinase II in human B lymphocytes.
Authors: M A Valentine, A J Czernik, N Rachie, H Hidaka, C L Fisher, J C Cambier, K Bomsztyk
Journal: The Journal of Experimental Medicine (1995)

We and others have previously shown that the nuclear protein, Ets-1, is phosphorylated in a calcium-dependent manner after ligation of immunoglobulin (Ig) M on B lymphocytes. As this phosphorylation was independent of protein kinase C activity, we tested whether a calcium/calmodulin-dependent protein kinase (CaM kinase) might phosphorylate the Ets-1 protein after elevation of intracellular free calcium concentrations. The dephosphorylated form of Ets-1 has been shown to bind to chromatin, suggesting that the operative kinase should be detectable in the nucleus. We prepared nuclear extracts from two human B cell lines in which increased intracellular free calcium levels correlated with increased phosphorylation of the Ets-1 protein. Activity of the CaM kinases was determined using a synthetic peptide substrate both in the absence and presence of an inhibitor specific for the CaM kinase family, KN-62. Stimulation of cells with anti-IgM led to increased activity of a nuclear kinase that could phosphorylate the peptide, and this activity was reduced by 10 microM KN-62. Kinase activity was reduced in lysates preadsorbed using an antibody specific for CaM kinase II. Two-dimensional phosphopeptide maps of the Ets-1 protein from cells incubated with ionomycin or anti-IgM contained two unique phosphopeptides that were absent in untreated cells. Incubation of isolated Ets-1 protein with purified CaM kinase II produced phosphorylation of peptides that migrated identically to those found in cells incubated with either anti-IgM or ionomycin. These data suggest a model of signal transduction by the antigen receptor on B lymphocytes in which increased intracellular free calcium can rapidly activate nuclear CaM kinase II, potentially resulting in phosphorylation and regulation of DNA-binding proteins.
Current role of catheter ablative procedures in patients with cardiac arrhythmias. A report for health professionals from the Subcommittee on Electrocardiography and Electrophysiology, American Heart Association.
Authors: M M Scheinman, M M Laks, J DiMarco, V Plumb
Journal: Circulation (1991)

Catheter ablative techniques have assumed an increasingly important role in the treatment of patients with drug-refractory cardiac arrhythmias. Catheter ablation of the AV junction is considered the procedure of choice for management of patients without bypass tracts with drug-resistant supraventricular arrhythmias. Catheter techniques have been used with increasing frequency in attempts to ablate accessory AV tracts. These techniques currently appear to be less effective than surgical techniques but involve less morbidity and expense. In some centers, accessory pathway ablation using catheter techniques is the procedure of first choice in selected patients with drug-refractory tachycardia mediated by an accessory pathway. Catheter ablation of ventricular tachycardia should be reserved for patients with mappable ventricular tachycardia who are not candidates for cardiac electrosurgery or insertion of an automatic defibrillator. The development of more flexible catheters and more manageable energy delivery systems holds promise for more effective catheter techniques.
Urinary Concentrating Ability in Women with Asymptomatic Bacteriuria in Pregnancy
Authors: G. L. Williams, H. Campbell, K. J. Davies
Journal: BMJ (1969)

The incidence of impaired renal concentrating ability in pregnant women with asymptomatic significant bacteriuria is significantly less than previously reported when osmolality readings are performed on every urine specimen obtained during the 24 hours9 deprivation of fluids. The concentrating defect is more considerable as pregnancy progresses. The lower the maximum urinary osmolality the more difficult is the treatment of the patient, and the higher the incidence of acute pyelonephritis.
Barriers to Clinical Trial Participation by Older Women With Breast Cancer
Authors: M. Margaret Kemeny, Bercedis L. Peterson, Alice B. Kornblith, Hyman B. Muss, Judith Wheeler, Ellis Levine, Nancy Bartlett, Gini Fleming, Harvey J. Cohen
Journal: Journal of Clinical Oncology (2003)

Purpose: Although 48% of breast cancer patients are 65 years old or older, these older patients are severely underrepresented in breast cancer clinical trials. This study tested whether older patients were offered trials significantly less often than younger patients and whether older patients who were offered trials were more likely to refuse participation than younger patients. Patients and Methods: In 10 Cancer and Leukemia Group B institutions, using a retrospective case-control design, breast cancer patients eligible for an open treatment trial were paired: less than 65 years old and ≥ 65 years old. Each of the 77 pairs were matched by disease stage and treating physician. Patients were interviewed as to their reasons for participating or refusing to participate in a trial. The treating physicians were also given questionnaires about their reasons for offering or not offering a trial. Results: Sixty-eight percent of younger stage II patients were offered a trial compared with 34% of the older patients (P = .0004). In multivariate analyses, disease stage and age remained highly significant in predicting trial offering (P = .0008), when controlling for physical functioning and comorbidity. Of those offered a trial, there was no significant difference in participation between younger (56%) and older (50%) patients (P = .67). Conclusion: In a multivariate analysis including comorbid conditions, age and stage were the only predictors of whether a patient was offered a trial. The greatest impediment to enrolling older women onto trials in the setting of this study was the physicians’ perceptions about age and tolerance of toxicity.
Imaging of Olfactory Neuroblastoma by In-111 Bleomycin Complex
Authors: ANTTI P. JEKUNEN, KALEVI J.A. KAIREMO, HANS A. RAMSAY, MIKAEL J. KAJANTI
Journal: Clinical Nuclear Medicine (1996)

No other successful nuclear method, besides bone scanning, has been reported in the literature for in vivo imaging of olfactory neuroblastoma. In this article, excellent uptake is reported by an In-111 labeled bleomycin complex (BLMC) in the ethmoid region of a histologically confirmed olfactory neuroblastoma. The uptake of BLMC was 0.7 × 10-3% ID/g at 48 hours after injection, and tumor-to-muscle and tumor-to-fat ratios were 6:1 and 11:1, respectively. The authors conclude that BLMC should be considered as a useful imaging agent, and that BLMC has potential as a radiochemotherapeutic agent against an olfactory neuroblastoma.
The Effect of the Separate Isomers of Sodium Lactate on Uremic Acidosis.
Authors: Robert L. Scheer
Journal: Annals of Internal Medicine (1969)

s1 May 1969The Effect of the Separate Isomers of Sodium Lactate on Uremic Acidosis.Robert L. Scheer, M.D., F.A.C.P., Myron Brin, Ph.D.Robert L. Scheer, M.D., F.A.C.P.Search for more papers by this author, Myron Brin, Ph.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-70-5-1096_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe use of sodium lactate solutions for the treatment of uremic acidosis has been challenged for theoretical reasons and because of the observation that many of the patients who develop lactic acidosis are uremic. Since commercial parenteral sodium lactate is a racemic solution, we studied the effect of L-Na lactate and D-Na lactate given separately to five patients with uremic acidosis and three normal subjects. One hundred sixty-seven mEq of one isomer in 500 ml water were given intravenously in 30 min. Blood concentrations of lactate, pyruvate, electrolytes, and pH were done serially for up to 2 hr. Not less... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: Robert L. Scheer, M.D., F.A.C.P.; Myron Brin, Ph.D.Affiliations: Syracuse, New York PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1969Volume 70, Issue 5Page: 1096-1096KeywordsAttentionBloodLactatesLactic acidosisPyruvateSaltsSodium ePublished: 1 December 2008 Issue Published: 1 May 1969 PDF downloadLoading ...
Epidemic Infective Hepatitis in Gloucestershire
Authors: J. S. Cookson
Journal: BMJ (1944)

MEDITI'Sli 687Case 1.-This patient, aged 41, was diagnosed as having a frac- tured scaphoid five months after injury.Two and a half years' immobilization in plaster was employed, during which three unsuccessful bone-graft operations were performed at an E.M.S. ortho- paedic hospital.Advanced osteo-arthritis and severe disability resulted.Case 2.-The patient, aged 37, was first seen five years after injurty.There was then a good deal of sclerosis, and non-union had resulted.The wrist was immobilized for 40 weeks with no improvement, and osteo-arthritis and severe disability resulted.In three cascs of non-union the men were Cischarged to full duty.These were all late cases, but had been fortunate in having a good range of movement and no osteo-arthritic -~~~~~~~~~~~~~~~~~. . . . . . ..1. FIG. 4.-Established non-union with marked sclerosis of both fragments and early osteo-arthritic change.chadges.In 12 cases of established non-union which had no other treatment than prolonged immobilization the men were discharged to light duty.Most of these cases showed some degree of osteo-arthritis and disability of the wrist: these patients were all men who were especially valuable to the Service by reason of technical knowledge and experience.Twelve cases of non-union received operative treatment.These operations were performed at various hospitals; the results are set out in Table II.It will be noted that union was obtained in a further five of these cases; two had osteo- arthritic changes.Three of the five returned to duty; one was invalided owing to the severity of the 'disability; and the disposal of the fifth is unknown.The two cases of excision of the proximal fragment developed osteo-arthritis, but were fit for further service.Of the remaining five, two had to be invalided with non-union and arthritis and three went to light duty with non-union and arthritis.TABLE II.-12 Operation Cases Typertf No.
Alpha1-Antitrypsin Deficiency Carriers, Serum Alpha 1-Antitrypsin Concentration, and Non-small Cell Lung Cancer Survival
Authors: Yan Li, Michael J. Krowka, Yingwei Qi, Jerry A. Katzmann, Yong Song, Yafei Li, Sumithra J. Mandrekar, Ping Yang
Journal: Journal of Thoracic Oncology (2010)
Sequencing of Breast Cancer Genomes.
Authors: M. Stratton
Journal: Cancer Research (2009)

Abstract All cancer genomes carry somatic mutations. The recent advent of second generation sequencing technologies has brought closer the prospect of sequencing large numbers of cancer genomes. Early studies in breast cancer have investigated the prevalence and nature of rearrangements. These studies have shown that there are many more rearrangements in breast cancer than have previously been appreciated, some of which have distinctive patterns suggesting underlying DNA repair defects. These studies are now leading into the sequencing of complete breast cancer genomes which aim to generate comprehensive catalogues of somatic mutations. These will include point mutations, rearrangements and copy number changes and most of the driver and passenger mutations operative in individual cancers. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr ES3-2.
Intraocular Tissue Plasminogen Activator Concentrations after Subconjunctival Delivery
Authors: Jennifer I. Lim, Albert M. Maguire, George John, Margie A. Mohler, Richard G. Fiscella
Journal: Ophthalmology (1993)

Topical application of recombinant tissue plasminogen activator (tPA) results in detectable intraocular tPA levels. The authors sought to determine whether subconjunctival delivery of recombinant tPA results in enhanced intraocular drug levels.One week after first performing a gas vitrectomy in each eye, the authors injected 0.4 ml of a tPA solution (1 or 10 mg/ml) subconjunctivally in one eye of 16 rabbits and 0.4 ml of sterile water in the fellow control eye. Vitreous taps were performed to obtain vitreous samples for measuring tPA concentrations. An anterior chamber paracentesis was then done for each concentration at 15, 30, and 60 minutes. Aqueous and vitreous tPA concentrations were determined using a two-site enzyme-linked immunosorbent assay (ELISA).Vitreous tPA levels were higher than aqueous levels in the treated eyes. Vitreous levels averaged 7 +/- 7 ng/ml for the 1-mg/ml group (n = 7/7) and 202 +/- 230 ng/ml for the 10-mg/ml group (n = 7/8). Aqueous levels were positive in 8 of 16 samples. The authors conclude that subconjunctival delivery of tPA results in both vitreous and aqueous tPA levels.
Clear-Cell Adenocarcinoma of the Genital Tract in Young Females
Authors: Arthur L. Herbst, Robert J. Kurman, Robert E. Scully, David C. Poskanzer
Journal: New England Journal of Medicine (1972)

Among 91 Registry cases of vaginal and cervical adenocarcinoma predominantly of the clear-cell type, the patients, eight to 25 years of age, were born throughout the United States and in three foreign countries. Pregnancy histories of 66 of the patients' mothers have been obtained; 49 received stilbestrol or related drugs, nine received unidentified drugs administered because of bleeding or prior pregnancy loss, and eight had a negative history. The dosage and duration of therapy varied widely. The frequent coexistence of vaginal adenosis and occasional presence of transverse vaginal or cervical ridges suggested abnormal development of müllerian epithelium in utero. Seventeen of 65 patients have died or had recurrences despite brief follow-up periods in many cases. Although these cancers are rare, the frequency of asymptomatic cases and the unreliability of vaginal cytology for detection support the value of screening postmenarchal females who have been exposed prenatally to stilbestrol or related drugs.
Lead-Glass Cloth Shields
Authors: Hans Pollak
Journal: JAMA (1968)

<h3>To the Editor:—</h3> One treatment of cancer of the cervix is insertion of radium. Unfortunately, this produces almost always a more or less severe cystitis and proctitis which is most distressing to the patient and can cause prolonged disability. The conventional method of "protecting" the bladder and cervix by insertion of tampons is apparently ineffective to a large degree due to the proximity of these structures to the vagina and cervix uteri. I have long thought it might be possible to produce a better shield for bladder and rectum, and since lead is the outstanding shield metal against radiation, it has occurred to me to use<i>leaded glass-fibers</i>which can be spun into soft pliable cloth and used for vaginal tampons, among other uses. In this connection I wrote to the Corning Glass Works and received a reply assuring me that glass fibers can be made of high-lead glasses which