tbuckley/cabot-search huggingface dataset:
Abstract 1792: Radiation-induced downregulation of GLT-1 glutamate transporter mRNA expression is reversed by renin-angiotensin system inhibitors
Authors: Mitra Kooshki, Christine Naczki, Michael E. Robbins, Linda J. Metheny-Barlow
Journal: Cancer Research (2015)

Abstract Fractionated partial or whole brain irradiation (fWBI) is often required to treat metastatic brain cancer. Unfortunately, fWBI can lead to the development of a progressive, irreversible cognitive impairment in patients who survive longer than six months following treatment. Prior studies suggest that neuroinflammation and alterations in neuronal plasticity may play a role in this treatment-related side effect. In the current study we determined that radiation-induced inflammatory activation of primary rat cortical astrocytes results in downregulation of mRNA and protein for the GLT-1 glutamate transporter, which functions to regulate glutamate signaling at excitatory synapses. Furthermore, we show that delivery of clinically-relevant fWBI (40Gy, 5Gy/fraction, 2x/week) to young adult male rats results in 51% decrease in Glt-1 mRNA in the cortex at 48 hours. Two months after completion of fWBI, cortical GLT-1 mRNA is further decreased to 25% the levels observed in sham controls, while at six months following fWBI GLT-1 levels remain 43% decreased compared to controls. We have previously identified two classes of compounds, the renin-angiotensin system inhibitors and PPAR agonists, which ameliorate the fWBI-induced cognitive impairment in this rodent model, although the full mechanisms by which these compounds protect cognition remain unknown. We found that dietary administration of the angiotensin receptor blocker L-158-809, but not the ACE inhibitor Ramipril, prevents fWBI-induced loss of cortical GLT-1 mRNA at 48 hours, while both cognition-sparing compounds restored GLT-1 expression at 2 months post-fWBI. Similarly, administration of the PPARδ agonist GW0742 prevented the fWBI-induced decrease of GLT-1 mRNA observed 6 months post-fWBI. Together these data suggest that radiation-induced downregulation of GLT-1 is a potential mechanism contributing to the development of radiation-induced brain injury, including cognitive impairment, and that GLT-1 may represent a druggable target to prevent this treatment-related cognitive decline. (Supported by NIH CA112593) Citation Format: Mitra Kooshki, Christine Naczki, Michael E. Robbins, Linda J. Metheny-Barlow. Radiation-induced downregulation of GLT-1 glutamate transporter mRNA expression is reversed by renin-angiotensin system inhibitors. [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 1792. doi:10.1158/1538-7445.AM2015-1792
Efficacy of Live, Attenuated Measles-Virus Vaccine Given with Human Immune Globulin
Authors: J. Stokes, M. R. Hilleman, R. E. Weibel, E. B. Buynak, R. Halenda, H. Goldner
Journal: New England Journal of Medicine (1961)

MEASLES, with its serious complications, remains A one of the important diseases of childhood. Numerous past investigations have been carried out with the purpose of developing a vaccine against this disease. Most significant progress in this endeavor was made by Enders et al.,1 who grew measles virus in tissue cultures of animal cells and who attenuated the virulence of the virus for man by passage in human cell cultures, in embryonated hen's eggs and in tissue cultures of chick embryo.In susceptible children given Enders's attenuated, live measles-virus vaccine neutralizing and complement-fixing antibodies against the virus uniformly developed.2 Krugman, Giles . . .
Cytokinetic and Cytotoxic Effects of Urea on HeLa Cells in Suspension Cultures
Authors: A D Glinos, G N Bardi, K C Dermitzaki, S A Perez, M J Talieri
Journal: JNCI Journal of the National Cancer Institute (1983)

Total and viable cell counts, differential mitotic cell counts, and incorporation of tritiated thymidine were used to study the kinetics of suspension cultures of HeLa cells exposed to urea concentrations of 0.5-1.5%. Aside from any nonspecific osmotic effects, urea concentrations of 1.0-1.4% exhibited significant cytokinetic and cytotoxic effects. Most characteristically, mitotic cells arrested in metaphase began to accumulate 4-6 hours after addition of urea and reached a peak at 15-18 hours. Thus when the cells were in the S-phase or at the S/G2 boundary at the time of addition of urea, they exhibited metaphase arrest. Subsequently, cultures continuously exposed to urea showed a decline in the mitotic index, indicating that the entry rate of cells into mitosis is lower than the rate at which cells escape from the mitotic block. Such cultures exhibited numerous abnormal and abortive mitoses and a decrease in growth and viability of the cell populations. In contrast to the initial single wave of arrested mitosis seen with continuous exposure to urea, intermittent exposure on alternate days resulted in successive waves of arrested metaphases and had considerably more pronounced effects on the growth and viability of the cultures.
Heart in the Heart
Authors: J Schuler, M Dissmann
Journal: New England Journal of Medicine (1999)

Figure 1. A 65-year-old man with a five-year history of uncontrolled hypertension was admitted to the emergency department with pulmonary edema. On admission his blood pressure was 180/110 mm Hg. A chest film showed bilateral pleural effusions as well as pulmonary edema. The electrocardiogram demonstrated left bundle-branch block. Hypertension and pulmonary edema resolved rapidly after treatment with nitroglycerin, furosemide, and morphine. During the first 24 hours of treatment, the levels of cardiac enzymes increased (creatine kinase, 370 U per liter; creatine kinase MB, 31 U per liter; and troponin I, 15.6 U per liter). The electrocardiographic findings remained unchanged. The . . .
A Rare Case of a Postoperative Submandibular Exophytic Goiter in a Patient With a Recurrent Normotopic Nodular Goiter
Authors: Jie-Hua Xu, Pei-Qiang Cai, Zi-Dong Zhou, Jie Qin, Xiao-Ping Lin
Journal: Clinical Nuclear Medicine (2016)

A 50-year-old woman presented a painless left submandibular mass. She had history of partial thyroidectomy for nodular goiter. A radioiodine whole-body scan showed tracer accumulation in the mass, which connected with the thyroid remnant. The left submandibular mass was resected, and the pathological examination demonstrated exophytic and normotopic nodular goiter.
Effect of Renal Disease on the Schilling Test
Authors: Charles E. Rath, Paul R. McCurdy, Benedict J. Duffy, John R. Howley
Journal: New England Journal of Medicine (1957)

THE diagnosis of pernicious anemia has become increasingly difficult with the widespread use of "panhematinics" containing folic acid. These preparations may correct the hematologic picture and yet allow the progression of combined-system disease.1 Conley et al.2 showed that large doses of parenterally injected B12 are almost quantitatively excreted in the urine during the first twenty-four hours after injection. Schilling3 utilized this observation to simplify the test of fecal excretion of cobalt60-labeled vitamin B12 introduced by Heinle and his associates.4 The Schilling test, which is simple, practical and useful, has now been widely used and reported5 6 7 8 9 in various . . .
Weak Reasoning: Diagnosis by Drug Reaction
Authors: Stephen G. Pauker, Richard I. Kopelman
Journal: New England Journal of Medicine (1993)

A 40-year-old Haitian woman who had never smoked had respiratory distress at work and was taken to the emergency department by ambulance.The first things that come to mind are the usual causes of respiratory distress, such as pneumonia, congestive heart failure, or a pulmonary embolus.Two days before admission she noticed chest congestion, a cough productive of yellow sputum, and shortness of breath, which progressed until she could no longer talk. While receiving oxygen in the emergency department, she could communicate with difficulty, but she said that she had not previously had any similar symptoms, chest . . .
Cancer and Fertility Program Improves Patient Satisfaction With Information Received
Authors: Joanne F. Kelvin, Bridgette Thom, Catherine Benedict, Jeanne Carter, Stacie Corcoran, Maura N. Dickler, Karyn A. Goodman, Allison Margolies, Matthew J. Matasar, Ariela Noy, Shari B. Goldfarb
Journal: Journal of Clinical Oncology (2016)

A cancer and fertility program was established at a large cancer center to support clinicians in discussing treatment-related fertility risks and fertility preservation (FP) options with patients and in referring patients to reproductive specialists. The program provides resources, clinician education, and fertility clinical nurse specialist consultation. This study evaluated the program's impact on patient satisfaction with information received.Retrospective cross-sectional surveys assessed satisfaction before (cohort 1 [C1]) and after (cohort 2 [C2]) program initiation. Questionnaires were investigator-designed, gender-specific, and anonymous.Most C1 (150 males, 271 females) and C2 (120 males, 320 females) respondents were 2 years postdiagnosis; the most frequently reported cancers were testicular, breast, and lymphoma. A significant difference in satisfaction with the amount of information received was seen between C1 and C2. For males, satisfaction with information on fertility risks was high in both cohorts but significantly greater in C2 for information on sperm banking (χ(2) = 9.3, P = .01) and finding a sperm bank (χ(2) = 13.3, P = .001). For females, satisfaction with information was significantly greater in C2 for information on fertility risks (χ(2) = 62.1, P < .001), FP options (χ(2) = 71.9, P < .001), help with decision making (χ(2) = 80.2, P < .001), and finding a reproductive endocrinologist (χ(2) = 60.5, P < .001). Among patients who received and read information materials, 96% of males and 99% of females found them helpful. Among C2 females, fertility clinical nurse specialist consultation was associated with significantly greater satisfaction with information on FP options (χ(2) = 11.2, P = .004), help with decision making (χ(2) = 10.4, P = .006), and finding a reproductive endocrinologist (χ(2) = 22.6, P < .001), with 10% reporting lack of knowledge as a reason for not pursuing FP.Improvements in patient satisfaction with information received demonstrate the potential for fertility programs in cancer care settings to improve the quality of clinician-patient discussions about fertility.
PET imaging of [<sup>11</sup>C]docetaxel uptake and tumor perfusion in lung cancer.
Authors: A. A. van der Veldt, M. Lubberink, E. F. Comans, H. N. Greuter, A. van Lingen, S. Rizvi, A. D. Windhorst, E. Smit, N. Hendrikse, A. A. Lammertsma
Journal: Journal of Clinical Oncology (2010)

2543 Background: Although docetaxel is an effective treatment of lung cancer, a number of patients do not benefit from this therapy due to tumor resistance. Positron emission tomography (PET) is a noninvasive imaging technique that allows for quantification of radiolabeled docetaxel ([11C]docetaxel) kinetics and might be useful for predicting response to treatment. The aim of the present study was to determine the feasibility and reproducibility of [11C]docetaxel PET scans in lung cancer and to investigate whether [11C]docetaxel uptake was related to tumor perfusion. Methods: Fourteen patients with advanced lung cancer underwent a dynamic PET-CT scan with [11C]docetaxel (60 min) and H215O (10 min). In addition, patients underwent a second [11C]docetaxel PET scan to assess test-retest reproducibility. Lesions were delineated on the CT scan and projected onto the dynamic PET frames. [11C]docetaxel uptake in tumors was quantified using the net influx rate (Ki). Tumor perfusion was quantified by applying the standard single tissue compartment model to the H215O data. Results: In total, 24 lesions were defined, including both primary tumors and metastases. Clearance of [11C]docetaxel from plasma was rapid and later PET frames suffered from high liver uptake. Therefore, only the first 10 min of data were used for further analysis. The median net influx rate of [11C]docetaxel was 0.009 min-1 (range, 0.000-0.022). [11C]docetaxel PET scans showed good reproducibility (intraclass correlation coefficient, 0.89). The inter- and intra-individual variability of [11C]docetaxel uptake in lesions was high. [11C]docetaxel uptake was correlated with tumor perfusion (r=0.853, p<0.001). Conclusions: Measurement of [11C]docetaxel uptake in lung cancer is feasible with good reproducibility. [11C]docetaxel uptake depends on tumor perfusion. The variability of [11C]docetaxel uptake in lung cancer lesions may reflect differential sensitivity to docetaxel treatment, suggesting that PET scans with [11C]docetaxel may be useful for personalized treatment planning. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Philips Healthcare
Improved Mineral Balance and Skeletal Metabolism in Postmenopausal Women Treated with Potassium Bicarbonate
Authors: Anthony Sebastian, Steven T. Harris, Joan H. Ottaway, Karen M. Todd, R. Curtis Morris
Journal: New England Journal of Medicine (1994)

In normal subjects, a low level of metabolic acidosis and positive acid balance (the production of more acid than is excreted) are typically present and correlate in degree with the amount of endogenous acid produced by the metabolism of foods in ordinary diets abundant in protein. Over a lifetime, the counteraction of retained endogenous acid by base mobilized from the skeleton may contribute to the decrease in bone mass that occurs normally with aging.To test that possibility, we administered potassium bicarbonate to 18 postmenopausal women who were given a constant diet (652 mg [16 mmol] of calcium and 96 g of protein per 60 kg of body weight). The potassium bicarbonate was given orally for 18 days in doses (60 to 120 mmol per day) that nearly completely neutralized the endogenous acid.During the administration of potassium bicarbonate, the calcium and phosphorus balance became less negative or more positive--that is, less was excreted in comparison with the amount ingested (mean [+/- SD] change in calcium balance, +56 +/- 76 mg [1.4 +/- 1.9 mmol] per day per 60 kg; P = 0.009; change in phosphorus balance, +47 +/- 64 mg [1.5 +/- 2.1 mmol] per day per 60 kg; P = 0.007) because of reductions in urinary calcium and phosphorus excretion. The changes in calcium and phosphorus balance were positively correlated (P < 0.001). Serum osteocalcin concentrations increased from 5.5 +/- 2.8 to 6.1 +/- 2.8 ng per milliliter (P < 0.001), and urinary hydroxyproline excretion decreased from 28.9 +/- 12.3 to 26.7 +/- 10.8 mg per day (220 +/- 94 to 204 +/- 82 mumol per day; P = 0.05). Net renal acid excretion decreased from 70.9 +/- 10.1 to 12.8 +/- 21.8 mmol per day, indicating nearly complete neutralization of endogenous acid.In postmenopausal women, the oral administration of potassium bicarbonate at a dose sufficient to neutralize endogenous acid improves calcium and phosphorus balance, reduces bone resorption, and increases the rate of bone formation.
Sleep Apnea Syndrome
Authors: Jeffrey M. Drazen
Journal: New England Journal of Medicine (2002)

Breathing and sleeping are two very basic processes. If you stop breathing for more than a few minutes, life itself stops. Sleep is a little more forgiving, but if you stop sleeping, or fail to achieve a truly rejuvenating sleep, it is not long before life is pretty miserable. Since these two physiologic processes are so important, it has been somewhat surprising to discover over the past 25 years that disordered, even disrupted, breathing during sleep is a substantial medical problem.The most common disorder of breathing during sleep, affecting more than 10 percent of the population over the age . . .
Can streptomycin prevent the selection of isoniazid-resistant mutants in nude mice infected with M. tuberculosis?
Authors: Claire Andrejak, Sandeep Tyagi, Eric Nuermberger, Jacques Grosset
Journal: European Respiratory Journal (2011)

Rationale:  In a previous study, the treatment of  M.tuberculosis  infected athymic nu/nu (nude) mice with the bactericidal drug isoniazid (H) combined with the two sterilizing drugs, rifampicin (R) and pyrazinamide (Z) failed and selected H-resistant mutants. We investigated whether the combination of H with the bactericidal drug, streptomycin (S) would be able to prevent that selection.   Methods:  A total of 80 nude mice were aerosol infected with 3.67±0.13 log10 of  M. tuberculosis  H37Rv. Two weeks later, at treatment initiation, mice were randomized in the following subgroups: untreated and treated with RZH + ethambutol (E) as controls; treated with SH or RH, as tests, Treatment was given five days/week for 12 weeks. Drug doses (mg/kg) were 10 for R and H, 150 for Z and 100 for S and E. Lung CFU counts were done the day after infection, on treatment initiation, and after 4, 8 and 12 weeks of treatment on plain and H 0.2 μg/ml-containing 7H11 selective plates.   Results:  Lung CFU counts were 7.40±0.28 log10 on treatment initiation. After 4, 8 and 12 weeks of treatment, they were 5.82±0.35, 4.05±0.55 and 2.30±0.25, respectively for RHZE; 5.00±0.09, 5.32±0.6 and 6.57±0.29, respectively for SH; and 6.00±0.39, 6.24±0.28, 7.68±0.49, respectively for RH. H resistance was prevented in RHZE treated mice but not in SH and RH treated mice.   Conclusion:  Despite its bactericidal activity, S alone cannot prevent selection of H-resistant mutants in nude mice.
A phase I pharmacokinetic (PK) study of vorinostat (V) in combination with irinotecan (I), 5-fluorouracil (5FU), and leucovorin (FOLFIRI) in advanced upper gastrointestinal cancers (AGC)
Authors: G. J. Fetterly, W. E. Brady, C. M. LeVea, A. M. Litwin, P. D. Zagst, J. D. Prey, M. Tarquini, M. K. Giardina, R. V. Iyer, N. I. Khushalani
Journal: Journal of Clinical Oncology (2009)

e15540 Background: Currently, advanced AGC has no clear standard regimen. The loss of transforming growth factor-β (TGFβ) response contributes to oncogenesis and has been described in gastric cancer. V, an inhibitor of histone deacetylase (HDAC) can restore TGFβ activity. We hypothesize that the addition of V to a standard chemotherapy regimen, FOLFIRI will result in improved therapeutic efficacy. Methods: AGC (esophagus, gastric, hepatocellular) patients (pts) with adequate organ function, performance status (ECOG 0–1), and 0–1 prior chemotherapy regimens are eligible for this phase 1 study to determine the MTD of V. Treatment consists of standard FOLFIRI (I 180mg/m 2 , leucovorin 400mg/m 2 , 5FU 400mg/m 2 followed by 46-hr infusion 5FU 2400 mg/m 2 q2w) with escalating doses of V given orally daily starting on day 2 (doses 200mg, 300mg, 400mg) in part 1 of the study. Per pre-specified design, initial intra- and inter-patient dose escalation was permitted, but then changed to a standard 3+3 design after observed toxicities. Tumor biopsy pre-Rx and at D13 are being done for TGFβ and survivin expression. PKs for I, SN-38 &amp; SN-38G are being evaluated in part 1. Part 2 examines PK of V at the highest V dose tolerated. Results: 10 pts (7 M, 3 F), with a median age of 52 yr have been treated at 3 dose levels of V in part 1 (2 at 200mg, 5 at 300mg, 3 at 400mg). 2 pts have been given 400mg V in part 2. Major toxicities included neutropenia, leukopenia, fatigue, diarrhea, anemia, and hypoalbunemia. No DLT was noted at any dose level. Of the 8 pts evaluable for response, 2 pts experienced a partial response and 5 pts had stable disease. SN-38 exposure was similar prior to (316–395 ng-hr/mL) and in combination with escalating doses of V (426–469 ng-hr/mL), with a terminal half-life ranging from 7.5–14 hr. Conclusions: V continuously at 400mg/d with FOLFIRI was tolerable in AGC pts. Drug exposure of SN-38 is not affected by V coadministration. The expansion cohort will determine the recommended phase 2 dose. Correlative studies of survivin and TGFβ expression are ongoing. Part 3 will examine intermittent V dosing. This study is supported by an IISP research grant from Merck &amp; Co., Inc. [Table: see text]
BMET-34DRUG REPURPOSING DISCOVERS BETA-SITOSTEROL AS AN EFFECTIVE THERAPEUTIC AGENT AGAINST MELANOMA BRAIN METASTASES IN VIVO
Authors: Terje Sundstrøm, Jobin Varughese, Lars Prestegarden, Francisco Azuaje, Gro Vatne Røsland, Kai Ove Skaftnesmo, Elizabeth S. Ingham, Lisa Even, Sarah Tam, Clifford Tepper, Kjell Petersen, Katherine W. Ferrara, Karl Johan Tronstad, Morten Lund-Johansen, Rolf Bjerkvig, Frits Thorsen
Journal: Neuro-Oncology (2015)

Despite major therapeutic advances in the management of patients with metastatic melanoma, brain metastases remain an intractable problem. It has proven difficult to identify and target single genes or pathways critical to brain metastasis formation. Here, we explore a more global and preventive treatment approach to melanoma brain metastases within an established xenograft model of human melanoma. Mice were injected intracardially and followed for six weeks with whole-body BLI and brain MRI. Tumor-bearing brains, adrenals, ovaries, and femurs were harvested and enzymatically dissociated before three tumor cell samples from each organ were flow-sorted and subjected to RNA sequencing. We were able to define a 108-gene brain metastasis gene signature, and queried the Connectivity Map database for candidate drugs, i.e. drugs that induce an opposite gene expression profile in various cancer cell lines. We found the cholesterol analogue beta-sitosterol to effectively inhibit brain metastases and improve survival, both in established and preventive therapeutic settings. Beta-sitosterol extensively suppressed the MAPK pathway, and effectively reduced mitochondrial respiration through Complex I inhibition. This novel mechanistic synergy may open new avenues of systemic therapy against metastatic melanoma, as increased mitochondrial respiration is a key mediator of resistance to MAPK-targeted drugs.
Type-Specific and Cross-Reactive Antibodies in Gram-Negative Bacteremia
Authors: William R. McCabe, Bernard E. Kreger, Margaret Johns
Journal: New England Journal of Medicine (1972)

Antibody titers to O-specific and two shared cross-reactive antigens (common entero-bacterial antigen [CA] and a determinant [Re] of rough bacilli) were related to the frequency of shock or a fatal outcome in 175 patients with gram-negative bacteremia. High titers of O antibody did not prevent development of bacteremia and were associated with only a very slight decrease in the frequency of shock and death. The height of antibody titers to CA also did not correlate with the frequency of shock or a fatal outcome. In contrast, both shock and death were 1/3 as frequent among patients with high titers (1:80 or above) of Re antibody. The apparent protective effect of Re antibody was independent of any contribution of O antibody. These observations, coupled with prior animal studies, suggest that enhancement of resistance to enterobacteria might be accomplished by immunization with shared cross-reactive antigens.
Case 30-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, T.H. Ebert, R.T. McCluskey
Journal: New England Journal of Medicine (1986)

Presentation of CaseA 74-year-old man was admitted to the hospital because of weakness and incontinence.There was a 13-year history of bronchial asthma. Several years after its onset he was treated at another hospital for a carcinoma of the urinary bladder. Three years before admission edema and exertional dyspnea developed, followed by pulmonary edema. He was admitted to another hospital, where no evidence of a myocardial infarct was found. Fever developed and resolved after the discontinuation of hydralazine. He was discharged but returned several weeks later with recurrence of pulmonary edema. Further studies showed evidence of mitral-valve prolapse, without . . .