tbuckley/cabot-search huggingface dataset:
Abstract 2607: Antitumor activity of the selective RAF inhibitor HM95573 in solid tumors and hematologic malignancies
Authors: Young-Mi Lee, InHwan Bae, Namgoong Gwang Mo, Jae Ho Lee, Suhyeon Kim, Ji Yeon Song, Kyu Hang Lee, Tae Hun Song, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh
Journal: Cancer Research (2015)

Abstract The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of tumor cells. Activation of the MAPK pathway due to mutations in BRAF, NRAS and KRAS is considered one of the causes of solid tumors (NSCLC, CRC,HCC, andthyroid cancers) and hematologic malignancies. HM95573 is a novel, highly potent RAF kinase inhibitor. Biochemically assayed for over 120 kinases, HM95573 showed the high selectivity toward BRAF mutant and CRAF kinases. The half maximal inhibition concentrations (IC50) of HM95573 against BRAFWT, BRAFV600E and CRAF kinases were 41nM, 7nM and 2nM, respectively. The strongly inhibited kinases subsequent to RAF kinases appeared to be CSF1R (44nM), DDR1 (77nM) and DDR2 (182 nM). HM95573 potently inhibited the growth of BRAFmutation CRC cell lines (e.g. IC50: 118nM for Colo-205) and thyroid cancer cell lines (43nM for B-CPAP); KRAS mutation NSCLC cell lines(297nM for Calu-6),CRC cell lines(65nM for HCT-116) and thyroid cancer cell lines(479nM for CAL-62); and NRAS mutation HCC cell lines(28nM for HepG2) andleukemia cell lines (39nM for HL-60). HM95573 effectively inhibited the phosphorylations of MEK and ERK, downstream kinases associated with cell proliferation in tumor cell lines mutated in BRAF, KRAS and NRAS. In addition, the phosphorylation of downstream kinases of RAF such as MEK and ERK was effectively inhibited with treatment of HM95573 in mutant KRAS NSCLC and CRC cells. HM95573 showed the excellent antitumor activity in mouse models xenografted with BRAF mutation cell line (Colo-205), KRAS mutation cell lines (Calu-6 and HCT-116)and NRAS mutation cell line (HepG2)two RAF inhibitors approved in melanoma which were effective to only BRAF mutation cell lines under conditions tested. The in vivo antitumor activity of HM95573 was potentiated with MEK inhibitors. Now, HM95573 is currently in phase I development in patients with advanced solid tumors including KRAS mutation NSCLC in Korea. Citation Format: Young-Mi Lee, InHwan Bae, Namgoong Gwang Mo, Jae Ho Lee, Suhyeon Kim, Ji Yeon Song, Kyu Hang Lee, Tae Hun Song, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. Antitumor activity of the selective RAF inhibitor HM95573 in solid tumors and hematologic malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2607. doi:10.1158/1538-7445.AM2015-2607
Soundings: Healthism and eugenics
Authors: Imre Loefler
Journal: BMJ (2005)

Healthism resembles moral rearmament. It wishes to change mankind by controlling people's lifestyles. As healthism gets increasingly coercive, eugenic considerations may crowd out reproductive choice.

Versions of healthism have surfaced before. Two examples are Sparta and the Third Reich, both of which practised genetic selection. In Sparta, if an infant was considered to be defective it was discarded—taken to Taygetos, the mountain where hyenas lurked. Under Hitler, genetic selection was administered at many levels and according to multiple criteria: race, mental disease, congenital anomalies, and criminal tendencies.

Contemporary healthism employs eugenic manipulations of the Spartan kind, except that, thanks to sonography and tissue sampling, the selection and the discarding do not have to wait until birth.

Prenatal genetic selection has become an important branch of health care—the term eugenics is eschewed because of Hitler. However, it is quite likely that such squeamishness will soon be a thing of the past.

Hitler's methods—the elimination of “bad” genes through the extermination of people carrying those genes—are unlikely to be employed. Instead, the modern armamentarium will include screening for undesirable genetic combinations, to be followed by compulsory genetic counselling. Soon coercive practices—such as denying insurance to those who do not comply—will be introduced.

People will forfeit their reproductive rights if the cost of letting them wantonly broadcast bad genes will further burden health budgets. The logic of healthism is likely to mean that the practice of risk avoidance will begin before conception.

The moral objections to eugenics focus on the coerciveness. Liberals do not object to eugenic manipulations as long as parental choice is upheld. But it is unlikely that this notion can hold out against the diktats of healthism, for healthism is anti-liberal, anti-choice, anti-risk, and, ultimately, anti-human—one cannot have a healthy society if people are allowed to eat what they want, drink as much as they like, smoke, engage themselves in risky behaviour, and then produce children with bad genes.
Case 37-1992
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely
Journal: New England Journal of Medicine (1992)

Presentation of Case A 68-year-old woman was admitted to the hospital because of pleuritic chest pain and increasing dyspnea. The patient was in stable health until two weeks earlier, when she awoke with right lateral pleuritic chest pain accompanied by a dry cough, which interfered with her sleep for several hours and resolved in the next day or two. She subsequently experienced progressive exertional dyspnea and orthopnea. On the day of entry right lateral chest pain recurred, and the dyspnea worsened; she was admitted to the hospital. The patient was a widow with four healthy adult children. There was a . . .
Changes in perceived health status of depressed elderly patients treated until remission
Authors: M D Miller, R Schulz, C Paradis, P R Houck, S Mazumdar, E Frank, M A Dew, C F Reynolds
Journal: American Journal of Psychiatry (1996)

The authors predicted that depressed elderly patients who responded to treatment would rate their baseline health more positively than nonresponders, that responders would again rate their health more positively once they were in remission, and that lower baseline self-ratings of health would predict lack of response to protocol treatment.The Perception of Illness Scale was administered to 61 depressed elderly patients at baseline and again upon completion of the acute phase of a depression treatment protocol. A logistic regression was performed to ascertain whether Perception of Illness Scale scores predicted response to protocol treatment.Baseline Perception of Illness Scale scores were poorer among the nonresponders, accurately predicted response or lack of response in 75% of the subjects, and showed before-to after-treatment improvement among the responders.Patients who initially rated their health as fair to poor were less likely to recover from depression in a standardized treatment protocol. Self-ratings of health improved with resolution of depression.
P244 The impact of “Seven Day working” on Respiratory inpatient activity at St Helens and Knowsley NHS trust. – “The slow drift model”
Authors: S Twite, P Stockton, V Sreeguru Lakshman, P Malhotra, S Alapati, S Koduri, J Naveed, J Howard
Journal: Thorax (2015)

<h3></h3> St Helens and Knowsley NHS trust (STHK) have re designed the acute pathway for medical admissions. Investment in Consultant numbers has allowed the Acute Medical Admissions (MAU) team and the speciality teams to provide robust Consultant input to their areas Monday to Sunday. Speciality Consultants have been released from the acute medical take and traditional Physician of the day (POD) activities. Advantages of a Consultant led seven day service include: Greater parity of service across seven days a week; high level of clinical competence ensuring rapid and appropriate decision making; improved outcomes for patients; skilled judgement and performance leading to the most effective working and more efficient use of resources; and GP access to the opinion of a fully trained doctor. Respiratory Consultant numbers have increased from 5 to 8 (7.5 WTE). 90 PA’s have been invested in the service. The inpatient service is resourced with 64 inpatient beds. General principles have been applied to the inpatient service. These include: Each Consultant provides daily review, in the form of 3 ward rounds and 2 board rounds, to their allocated patients; rounds are performed in the first half of the day to aid patient flows and discharges; Consultants provide cross cover during leave; and weekends are covered on a 1 in 8 basis. Alteration to outpatient and elective services has also occurred. <h3>Results</h3> 160% increase in weekend Respiratory discharges and 48% increase in overall Respiratory discharges, with no increase in bed base. Significant fall in Respiratory length of stay. 50% improvement in MET calls per discharge reflecting improved quality of care. Significant fall in readmissions. Positive feedback from patients, relatives and staff. Additional benefits include improved elective and outpatient productivity due to less clinic cancellations enforced by the traditional POD model of acute medical activity. Outpatient activity has increased by 50% and elective (Bronchoscopy) activity by 35%. Improved junior doctor support and education are also achieved. Significant decrease in departmental complaints. <h3>Discussion</h3> The “slow drift” model presented here offers significant advantages over traditional working practices for both efficiency and outcome. The return on investment contributes to cost improvement programs.
Herpesvirus Infections of the Human Central Nervous System
Authors: Lloyd C. Olson, Edward L. Buescher, Malcolm S. Artenstein, Paul D. Parkman
Journal: New England Journal of Medicine (1967)

HUMAN Central-nervous-system infection with Herpesvirus hominis (herpes-simplex virus), first described in 1941,1 is by no means rare. A number of reports describe the clinical, pathological and epidemiological aspects of encephalitis caused by this virus and its frequency in nonbacterial Central-nervous-system infections.2 3 4 5 Because of its sporadic occurrence and difficulties in establishing diagnoses during life, knowledge of the disease has been based upon histologic study. However, accurate and rapid diagnosis during life is required if treatment with 5-iodo 2′-deoxyuridine (IUDR) is contemplated. This report reviews 49 patients with Central-nervous-system disease associated with herpes-simplex virus studied in this laboratory in the past twenty-five . . .
Efficacy of “Hong Kong” Vaccine in Preventing “England” Variant Influenza a in 1972
Authors: H. Grant Stiver, Patricia Graves, Theodore C. Eickhoff, Gordon Meiklejohn
Journal: New England Journal of Medicine (1973)

Abstract The antigenic drift that occurs among influenza A viruses may impair the effectiveness of available vaccines containing older antigens. We therefore studied the efficacy of such a vaccine containing Hong Kong virus antigen (A2/Aichi/2/68) during an outbreak of A2/England/72 influenza in a population of 979 vaccinated and 2955 unvaccinated men. Attack rates for laboratory-confirmed febrile influenza were 18.4 and 46.0 per 1000, respectively. One dose of the vaccine thus reduced the frequency of influenza in those vaccinated by 60 per cent (p<0.01). Of 171 men studied before the outbreak, 84 per cent had hemagglutination-inhibition titers of ≤1:8 against the epidemic strain, but only 22 per cent had such low titers two weeks after vaccination. A significantly greater attack rate was found in men with acute-phase hemagglutination-inhibition titers of ≤1:8 than among those with titers of ≥1:16. There was a direct relation between the clinical effectiveness of the vaccine and its ability to produce ...
Declaring the Sodium Content of Drug Products
Authors: Ana Szarfman, Thomas Kuchenberg, Janice Soreth, Simon Lajmanovich
Journal: New England Journal of Medicine (1995)

culture was inhibited by 74 percent with a combination of interferon alfa (1 U per milliliter) and zidovudine (0.1 mM); these agents had a strong synergistic effect (combination index, 0.116; values of less than 1 indicate synergy). 4 Zidovudine inhibits replication of EBV, 5 but the antiviral effect probably did not contribute to the cellular inhibitory effect, since the EBV-immortalized cells were latently infected.These results suggest that the effect of the combination was neither virusspecific nor T-cell-specific.Even more striking inhibitory effects on EBV-induced cell immortalization were produced by a combination of very low doses (0.05 to 1 U per milliliter) of interferon alfa and interferon gamma, which yielded combination indexes of 0.01 to 0.02 -approximately 10 times better than the index for interferon alfa plus zidovudine. 4 It may be worth determining whether these results in cell culture with what appear to be nontoxic levels of interferon alfa and interferon gamma can be applied to the treatment of adult T-cell leukemia-lymphoma and EBV-induced lymphoproliferative syndromes.
Mutations in the Gene for the Granulocyte Colony-Stimulating–Factor Receptor in Patients with Acute Myeloid Leukemia Preceded by Severe Congenital Neutropenia
Authors: Fan Dong, Russell K. Brynes, Nicola Tidow, Karl Welte, Bob Löwenberg, Ivo P. Touw
Journal: New England Journal of Medicine (1995)

In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction pathways for granulocyte colony-stimulating factor (G-CSF) may play a part in the progression to acute myeloid leukemia.
Epstein–Barr Virus in Smooth-Muscle Tumors
Authors: T. van Gelder, V.D. Vuzevski, W. Weimar
Journal: New England Journal of Medicine (1995)

To the Editor: Lee et al. (Jan. 5 issue)1 described three young liver-transplant recipients in whom smooth-muscle tumors containing the Epstein–Barr virus (EBV) genome developed. In the same issue ...
Hyperlysinemia Associated with Retardation
Authors: H. Ghadimi, V. I. Binnington, P. Pecora
Journal: New England Journal of Medicine (1965)

TWO unrelated patients, mentally and physically retarded, were found to have persistent hyperlysinemia and hyperlysinuria. Both patients had lax ligaments and hypotonie muscles. The metabolic anomaly was investigated through repeated quantitative analysis of biologic fluids for amino acids, administration of a loading dose of lysine and its metabolite and studies of the subsidiary pathway of lysine. The results suggested that both patients had a heretofore undescribed inborn error of lysine metabolism. This paper amplifies our previous report1 on this condition. Another case, in many respects similar to ours, was reported by Woody.2 Case ReportsCase 1. This patient was 27 . . .
Diagnostic and substance specificity of carbon-dioxide-induced panic
Authors: L A Papp, D F Klein, J Martinez, F Schneier, R Cole, M R Liebowitz, E Hollander, A J Fyer, F Jordan, J M Gorman
Journal: American Journal of Psychiatry (1993)

The authors assessed the substance and diagnostic specificity of carbon-dioxide-induced panic since, in addition to the specific biochemical effects of inhaled carbon dioxide (CO2), simple physiologic distress is also frequently implicated as a panicogenic factor during respiratory challenge studies with CO2 in patients with anxiety disorders.Eighteen patients with panic disorder, 20 with social phobia, and 23 psychiatrically normal subjects inhaled a mixture of 35% CO2 and 65% O2 for 30 seconds through a face mask. They also breathed for 30 seconds through a valve reducing the diameter of the airway. A double-blind, counterbalanced, randomized design was used.In spite of important similarities between the two interventions, including the induction of equal amounts of subjective respiratory distress, carbon dioxide inhalation was significantly more potent than increased airway resistance in provoking panic in the anxiety disorder patients. The patients with panic disorder were significantly more sensitive to CO2 than were the patients with social phobia or the normal subjects.Carbon dioxide inhalation appears to have a specific panicogenic effect in panic patients that goes beyond simple breathlessness.
Peanut Allergen Thresholds in Israel – a “Low Peanut Allergy” Prevalence Area
Authors: Tamar Yichie, Michael R. Goldberg, Michael B. Levy, Liat Nachshon, Keren Golobov, Arnon Elizur, Yitzhak Katz
Journal: Journal of Allergy and Clinical Immunology (2016)
Case 28-1995
Authors: J.G. Petros, L.R. Zukerberg
Journal: New England Journal of Medicine (1995)

Presentation of CaseA 69-year-old woman was admitted to the hospital because of recurrent pain in the right lower abdominal quadrant and radiographic evidence of a cecal abnormality.The patient had been well until 44 days earlier, when fever and pain in the right lower quadrant developed, without nausea, vomiting, or diarrhea. Two days later she was admitted to another hospital. The white-cell count was 16,600 per cubic millimeter; the bilirubin level was 2.4 mg per deciliter (41 μmol per liter); other tests of liver function were negative. A Gastrografin-enema examination showed that the colon was normal except for considerable . . .
Effect of Psychoprophylaxis (Lamaze Preparation) on Labor and Delivery in Primiparas
Authors: James R. Scott, Nancy B. Rose
Journal: New England Journal of Medicine (1976)

To investigate whether "prepared-childbirth" courses offer measurable physical advantages, we compared the labor and delivery characteristics of 129 primiparas who had completed ante-partum Lamaze-training psychoprophylaxis classes with an equal number of matched controls who had not. The former were given narcotics less frequently during labor (P<0.001), received conduction anesthesia less often (P<0.001), and had a higher frequency of spontaneous vaginal deliveries (P<0.001) than the control patients. However, these differences had no apparent effects on the length of labor, number or type of maternal complications, frequency of fetal distress, mean Apgar scores, or neonatal problems. (N Engl J Med 294:1205–1207, 1976)
Case 13-2011
Authors: Lawrence S. Blaszkowsky, James C. Cusack, Theodore S. Hong, Daniel C. Chung, Michael A. Blake, Jochen K. Lennerz
Journal: New England Journal of Medicine (2011)

A 49-year-old man came to this hospital for management of adenocarcinoma of the rectum, associated with adenomatous polyps. Imaging showed a large tumor with extension beyond the muscularis propria and multiple enlarged lymph nodes.
Purpura Fulminans in <i>Neisseria meningitidis</i> Sepsis
Authors: L M de la Maza, M Pezzlo
Journal: New England Journal of Medicine (1996)

Figure 1. A 26-year-old man with a one-day history of mild headache and fever was admitted to the hospital after having a seizure at home. He had had no contact with other sick people. On admission the patient's consciousness was impaired (score on the Glasgow coma scale, 10), but he had no neck stiffness. He was febrile (temperature, 41°C), with hypotension, leukopenia, and thrombocytopenia. Shortly after admission he had another seizure. The cerebrospinal fluid contained 165 red cells and 18 white cells per cubic millimeter, with 60 percent neutrophils, 5 percent band forms, 29 percent lymphocytes, and 6 percent monocytes. . . .
Professional golfers’ hips: prevalence and predictors of hip pain with clinical and MR examinations
Authors: Edward Dickenson, Imran Ahmed, Miguel Fernandez, Philip O'Connor, Philip Robinson, Robert Campbell, Andrew Murray, Martin Warner, Charles Hutchinson, Roger Hawkes, Damian Griffin
Journal: British Journal of Sports Medicine (2016)

Aims This study aimed to determine the prevalence of hip pain in professional golfers, comparing the lead (left hip in right-handed golfer) and trail hips, and to establish what player characteristics predicted hip symptoms. Methods Male elite professional golf players were invited to complete questionnaires and undergo clinical and MR examinations while attending the Scottish Hydro Challenge 2015. Questionnaires determined player demographics, self-reported hip pain and an International Hip Outcome Tool 12 (iHOT12) score (hip-related quality of life). Clinical examinations determined hip range of motion and the presence of a positive impingement test. MR scans determined the presence of labral pathology and player hip morphology with measures of α angle (cam), acetabular depth (pincer) and femoral neck antetorsion. Results A total of 109 (70% of tournament field) of players completed questionnaires, 73 (47%) underwent clinical examination and 55 (35%) underwent MR examination. 19.3% of players reported of hip pain. 11.9% of lead and 9.1% of trail hips were painful (p=0.378), iHOT12 scores were lower in the lead (94.1) compared to the trail hip (95.3) (p=0.007). Stepwise multiple linear regression modelling was able to predict 20.7% of the variance in iHOT12 scores with mean α angles between 12 and 3 o'clock, and increasing age-significant variables (R 2 =0.207, p&lt;0.001; β=−0.502, p&lt;0.001 and β=−0.399, p=0.031, respectively). Conclusions 19.3% of male professional golfers reported hip pain. The presence of an increasing α angle and increasing age were significant predictors of reduced hip-related quality of life.
Preclinical studies with dihydronaphthalene monophenol (NSC D725087), a vascular targeting agent, and its monophosphate prodrug (NSC D725088).
Authors: Hui Wang, Mao Li, Joseph M. Covey, Ruiwen Zhang, Donald L. Hill
Journal: Cancer Research (2004)

2044  CDDO (2-cyano,3,12-dioxoolean-1,9 (11)-dien-28-oic acid; NSC-711193) is a synthetic oleanane triterpenoid that has been shown to have potent differentiating, anti-proliferative, and anti-inflammatory activities both in vitro and in vivo. In preparation for clinical trials, the pharmacokinetics and toxicity of CDDO were investigated in groups of male Fischer rats (4 rats/dose group) and male and female beagle dogs (1 dog/sex/dose group) given single bolus iv doses or 120-hour continuous iv (civ) infusion doses. For rats given single bolus iv doses of 19.8 or 39.6 mg/m2, mean plasma concentrations of CDDO at 5 minutes after dosing increased proportional to the size of the dose and were 17.9 and 32.7 μM, respectively. CDDO was subsequently eliminated from plasma in two apparent phases with mean half-lives of 0.06 hours (α-phase) and 1.95 hours (β-phase). The total body clearance of CDDO was 9.1 L/m2/hr for rats given 19.8 mg/m2 and 9.5 L/m2/hr for rats given 39.6 mg/m2. The steady state volume of distribution (Vdss) was 13.3 or 15.8 L/m2 for rats given 19.8 or 39.6 mg/m2, respectively. For two dogs administered a single iv bolus dose of 60 mg/m2, CDDO was eliminated from plasma with mean half-lives of 0.02 and 0.65 hours. The mean clearance and steady state volume of distribution of CDDO in these dogs were 44.6 L/m2/hr and 26.8 L/m2, respectively. For rats given 120-hour civ doses of 0, 6, 18, 54, or 108 mg/m2/hr, mortality was observed within 24 hours after the start of the infusion of doses ≥18 mg/m2/hr. Drug-related toxicity included adverse clinical signs (diarrhea, hunched posture, piloerection), body weight loss, clinical pathology changes (including increases in BUN, AST, and ALT, and decreases in ALP), and histopathological changes (including lesions in the liver). No toxicity, as indicated by the absence of adverse clinical signs, changes in body weight, or changes in clinical chemistry parameters, was observed for dogs given 120-hr civ doses of CDDO of 20 or 50 mg/m2/hr. Mean steady state plasma concentrations of CDDO observed during the 120-hr infusion period were 0.886 μuM for dogs given 20 mg/m2/hr and 2.46 μM for dogs given 50 mg/m2/hr. The results of these studies indicated that, at the doses given, CDDO exhibited linear pharmacokinetics in rats and dogs. When given as 120-hr civ infusion doses, the maximum tolerated dose of CDDO was