tbuckley/cabot-search huggingface dataset:
The<i>Journal</i>'s New Look
Authors: Jerome P. Kassirer
Journal: New England Journal of Medicine (1996)

Competing philosophies about the desirability of change confront managers, business leaders, politicians, and even medical editors. The common-sense advice of Bert Lance, President Carter's director of the Office of Management and Budget — “If it ain't broke, don't fix it” — stands in dramatic contrast to the modern tenets of quality improvement. These ideas about quality, introduced into medicine in the past decade but familiar in business circles for more than 30 years, reject the status quo and promote ideas such as ongoing product assessment, the identification of features that might be enhanced, and continuous improvement.1 At the Journal, we . . .
Abstract 3338: Pharmacological inhibition of MRK/ZAK kinase for the treatment of medulloblastoma
Authors: Rosamaria Ruggieri, Daniel Markowitz, Caitlin Powell, Nhan Tran, Magimairajanissai Vanan, Mingzu He, Yousef Al-Abed, Marc Symons
Journal: Cancer Research (2015)

Abstract Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiation therapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell cycle arrest after ionizing radiation. Here we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radio-sensitizes UW228 medulloblastoma cells as well as IMB226 patient-derived primary cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell cycle arrest. We also tested the effect of M443 in an animal model of medulloblastoma that employs orthotopic implantation of IMB226 medulloblastoma cells in nude mice. Intra-tumoral delivery of M443 alone significantly extended animal survival by 5 days compared to vehicle treatment. Combination treatment of M443 with radiation at 2 × 3 Gy, that is not effective on its own (1 day of additional survival over control), achieved a synergistic increase in survival (15 days over the control survival time). Western blotting of tumor lysates demonstrated strong inhibition of MRK activity. In conclusion, we have developed a new small molecule inhibitor of MRK/ZAK that radio-sensitizes medulloblastoma cells. We hypothesize that combining radio-therapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Citation Format: Rosamaria Ruggieri, Daniel Markowitz, Caitlin Powell, Nhan Tran, Magimairajanissai Vanan, Mingzu He, Yousef Al-Abed, Marc Symons. Pharmacological inhibition of MRK/ZAK kinase for the treatment of medulloblastoma. [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 3338. doi:10.1158/1538-7445.AM2015-3338
Marine ω-3 polyunsaturated fatty acid intake and survival after colorectal cancer diagnosis
Authors: Mingyang Song, Xuehong Zhang, Jeffrey A Meyerhardt, Edward L Giovannucci, Shuji Ogino, Charles S Fuchs, Andrew T Chan
Journal: Gut (2016)

<h3>Objective</h3> Experimental evidence supports an antineoplastic activity of marine ω-3 polyunsaturated fatty acids (ω-3 PUFAs; including eicosapentaenoic acid, docosahexaenoic acid and docosapentaenoic acid). However, the influence of ω-3 PUFAs on colorectal cancer (CRC) survival is unknown. <h3>Design</h3> Within the Nurses9 Health Study and Health Professionals Follow-up Study, we prospectively studied CRC-specific and overall mortality in a cohort of 1659 patients with CRC according to intake of marine ω-3 PUFAs and its change after diagnosis. <h3>Results</h3> Higher intake of marine ω-3 PUFAs after CRC diagnosis was associated with lower risk of CRC-specific mortality (p for trend=0.03). Compared with patients who consumed &lt;0.10 g/day of marine ω-3 PUFAs, those consuming at least 0.30 g/day had an adjusted HR for CRC-specific mortality of 0.59 (95% CI 0.35 to 1.01). Patients who increased their marine ω-3 PUFA intake by at least 0.15 g/day after diagnosis had an HR of 0.30 (95% CI 0.14 to 0.64, p for trend &lt;0.001) for CRC deaths, compared with those who did not change or changed their intake by &lt;0.02 g/day. No association was found between postdiagnostic marine ω-3 PUFA intake and all-cause mortality (p for trend=0.47). <h3>Conclusions</h3> High marine ω-3 PUFA intake after CRC diagnosis is associated with lower risk of CRC-specific mortality. Increasing consumption of marine ω-3 PUFAs after diagnosis may confer additional benefits to patients with CRC.
Case 7-2007
Authors: Hasan Bazari, Michael R. Jaff, Michael Mannstadt, Shaofeng Yan
Journal: New England Journal of Medicine (2007)

A 59-year-old woman with diabetic renal disease was admitted to the hospital because of nonhealing painful ulcers on the right leg and foot. An ulcer on the heel had developed 6 years earlier and persisted despite local treatment, with development of osteomyelitis refractory to antibiotic therapy. A few months before admission, new painful ulcers developed on the right hip and thigh. A procedure was performed.
rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System
Authors: Seemin Seher Ahmed, Stefan A Schattgen, Ashley E Frakes, Elif M Sikoglu, Qin Su, Jia Li, Thomas G Hampton, Andrew R Denninger, Daniel A Kirschner, Brian Kaspar, Reuben Matalon, Guangping Gao
Journal: Molecular Therapy (2016)

Aspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD. Interestingly, central nervous system (CNS)-restricted therapy prolonged survival over systemic therapy in CD mice but failed to sustain motor functions seen in systemically treated mice. Importantly, we reveal through histological and functional examination of untreated CD mice that AspA deficiency in peripheral tissues causes morphological and functional abnormalities in this heretofore CNS-defined disorder. We demonstrate for the first time that AspA deficiency, possibly through excessive N-acetyl aspartic acid accumulation, elicits both a peripheral and CNS immune response in CD mice. Our data establish a role for peripheral tissues in CD pathology and serve to aid the development of more efficacious and sustained gene therapy for this disease.
Peroral Duodenal Biopsy in Progressive Systemic Sclerosis
Authors: Robert S. Rosson, Raymond Yesner
Journal: New England Journal of Medicine (1965)

INVOLVEMENT of the small bowel in progressive systemic sclerosis (scleroderma) has received increasing attention since the classic description of Hale and Schatzki1 in 1944. The subject has recently been well reviewed.2,3 We are aware of only three reports of peroral biopsy of the small intestine in patients with scleroderma. In the case reported by McBrien and Mummery4 the biopsy is said to have shown "a normal mucosal pattern." The site of biopsy is not stated, and no mention of Brunner's glands is made. Yesner et al.,5 in a report on the diagnostic value of peroral duodenal biopsy, included a . . .
Treatment of Muscular Dystrophy with Steroids
Authors: Robert M. Dowben
Journal: New England Journal of Medicine (1963)

THE muscular dystrophies are a group of hereditary diseases characterized by painless, symmetrical, progressive, unremitting weakness and wasting of muscle1 for which there is no specific treatment. There are several distinct forms, progressive facioscapulohumeral, limb-girdle and myotonic, which differ in the age at onset, sex distribution, distribution of involved muscles and course of progression.The appearance of a mutant strain of mice afflicted with a hereditary malady closely resembling human muscular dystrophy2 made possible a systematic study of the effects of drugs in this disease. The administration of certain anabolic steroids or cardiac glycosides to dystrophic mice was found to . . .
Individual patient data (IPD) analysis of progression-free survival (PFS) versus overall survival (OS) as an endpoint for metastatic colorectal cancer (mCRC) in modern trials: Findings from the 16,700 patients (pts) ARCAD database.
Authors: Qian Shi, Aimery De Gramont, Marc E. Buyse, Axel Grothey, Hans-Joachim Schmoll, Matthew T. Seymour, Richard A. Adams, Leonard Saltz, Richard M. Goldberg, Cornelis J. A. Punt, Jean-Yves Douillard, J. Randolph Hecht, Herbert Hurwitz, Eduardo Diaz-Rubio, Rainer Porschen, Niall C. Tebbutt, Charles S. Fuchs, John Souglakos, Alfredo Falcone, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2013)

3533 Background: PFS has previously been established as a surrogate for OS based on IPD from first-line mCRC trials conducted before 1999. As mCRC treatment (trt) has advanced in the last decade and OS has increased from 1 to 2 years, this surrogacy required re-examination. Methods: IPD from 16,762 pts, median age 62, 62% male, 53% ECOG PS 0 were available from 22 1st line mCRC studies conducted from 1997-2006; 12 tested targeted (anti-angiogenic and/or anti-EGFR) regimens. The relationship between PFS (first event of progression or death) and OS was evaluated at patient-, trt-arm-, and trial-levels using correlation (corr.) coefficients and R 2 (closer to 1 the better) from weighted least square (WLS) regression of arm-specific survival rates and trial-specific hazard ratios (HRs), estimated using Cox and Copula bivariate models. The concordance of significance (CoS) of the treatment effects (TEs) on both endpoints was calculated. Results: 44% pts received a targeted regimen. Median PFS was 8 and OS was18 months. The corr. between PFS and OS was modest at all three levels with low CoS in TE comparisons (see Table). Analyses limited to trials testing targeted trts, non-strategy trials, or superiority trials did not improve surrogacy. Conclusions: In modern mCRC trials, where survival post-first progression exceeds time to first progression, PFS TEs do not reliably predict TEs on OS. Nonetheless, until alternative endpoints of clinical benefit can be validated, PFS remains a relevant primary endpoint for 1st line mCRC trials, as our data demonstrate that the ability for any agent to produce an OS benefit from a single line of therapy is challenging. [Table: see text]
Serum Migration-Inhibitory Activity in Patients with Lymphoproliferative Diseases
Authors: Stanley Cohen, Ben Fisher, Takeshi Yoshida, Richard E. Bettigole
Journal: New England Journal of Medicine (1974)

Macrophage migration-inhibitory activity can be detected in the serums of the majority of patients with lymphoproliferative disease, but in less than 3 per cent of controls. This activity was found in 14 of 16 patients with non-Hodgkin's lymphoma, 10 of 13 with Hodgkin's disease, and four of five with chronic lymphocytic leukemia. In addition, two of three patients with multiple myeloma had low but detectable serum activity. The presence of such substances in the serums of these patients did not seem to be related to any of the clinical or laboratory measurements available, with the possible exception of duration of disease. No distinction was observed for diseases presumed to be dependent upon abnormalities of either T or B lymphocytes. Thus, in addition to immunologic activation, possible stimuli for the production of migration-inhibition factors in these patients included virus infection, the presence of nonspecific mitogenic factors and the proliferative response of the neoplastic cells itself. (N Engl J Med 290:882–886, 1974)
Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity
Authors: Krystyna M. Wozniak, James J. Vornov, Ying Wu, Kenichi Nomoto, Bruce A. Littlefield, Christopher DesJardins, Yanke Yu, George Lai, Larisa Reyderman, Nancy Wong, Barbara S. Slusher
Journal: Cancer Research (2016)

Abstract Chemotherapy-induced peripheral neuropathy is a dose-limiting side effect of many antineoplastic agents, but the mechanisms underlying the toxicities are unclear. At their MTDs, the microtubule-binding drugs paclitaxel and ixabepilone induce more severe neuropathy in mice relative to eribulin mesylate, paralleling their toxicity profiles in clinic. We hypothesized that the severity of their neurotoxic effects might be explained by the levels at which they accumulate in the peripheral nervous system. To test this hypothesis, we compared their pharmacokinetics and distribution in peripheral nerve tissue. After administration of a single intravenous dose, each drug was rapidly cleared from plasma but all persisted in the dorsal root ganglia (DRG) and sciatic nerve (SN) for up to 72 hours. Focusing on paclitaxel and eribulin, we performed a 2-week MTD-dosing regimen, followed by a determination of drug pharmacokinetics, tissue distribution, and multiple functional measures of peripheral nerve toxicity for 4 weeks. Consistent with the acute dosing study, both drugs persisted in peripheral nervous tissues for weeks, in contrast to their rapid clearance from plasma. Notably, although eribulin exhibited greater DRG and SN penetration than paclitaxel, the neurotoxicity observed functionally was consistently more severe with paclitaxel. Overall, our results argue that sustained exposure of microtubule-binding chemotherapeutic agents in peripheral nerve tissues cannot by itself account for their associated neurotoxicity. Cancer Res; 76(11); 3332–9. ©2016 AACR.
Hepatitis C Virus–Associated Fulminant Hepatic Failure
Authors: Patrizia Farci, Harvey J. Alter, Atsushi Shimoda, Sugantha Govindarajan, Ling C. Cheung, Jacqueline C. Melpolder, Ronald A. Sacher, James W. Shih, Robert H. Purcell
Journal: New England Journal of Medicine (1996)

ULMINANT hepatic failure is a dramatic clinical syndrome characterized by massive necrosis of liver cells. 1 It is most often caused by hepatitis A virus and hepatitis B virus (HBV) 2 ; whether hepatitis C virus (HCV) can cause it is still controversial. 3,4Among patients with non-A, non-B fulminant hepatitis, antibodies against HCV (anti-HCV) or serum HCV RNA were found in 40 to 60 percent in Japan 5,6 and Taiwan, 7 but in only 2 percent (range, 0 to 12 percent) in Western countries, [8][9][10][11][12][13] with one exception: a recent study conducted in California reported a prevalence of 60 percent associated with low socioeconomic status and Hispanic ethnicity. 14Whether these discrepancies reflect geographic differences in the epidemiology of HCV infection or the pathogenicity of the prevalent viral strains is not known.Furthermore, because of the dramatic course of fulminant hepatic failure, in most patients only a single serum sample, often obtained late in the course of the disease, was studied.In this report, we describe a patient with HCVassociated fulminant hepatitis in whom serial studies were done that provided a unique opportunity to establish a temporal association between the acquisition of HCV infection and the development of fulminant hepatitis and to define the clinical, virologic, and histologic profile of fulminant hepatitis C.
Case 10-1973
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, George R. Prout, James J. Galdabini
Journal: New England Journal of Medicine (1973)

Presentation of CaseA 26-year-old man was admitted to the hospital because of back pain.He was well until two months previously, when gross hematuria occurred and persisted for two days, accompanied by low-back pain. Physical examination in the hospital was negative. The urine gave a + + + test for protein; the sediment contained 10 white cells and innumerable red cells per high-power field. An x-ray film of the chest revealed a rounded calcification, 1 cm in diameter, at the apex of the left lung and calcified right hilar lymph nodes; there was a question of scarring at the . . .
Transfusion reactions: prevention, diagnosis, and treatment
Authors: Meghan Delaney, Silvano Wendel, Rachel S Bercovitz, Joan Cid, Claudia Cohn, Nancy M Dunbar, Torunn O Apelseth, Mark Popovsky, Simon J Stanworth, Alan Tinmouth, Leo Van De Watering, Jonathan H Waters, Mark Yazer, Alyssa Ziman
Journal: The Lancet (2016)
Abstract A44: p53 protects against MG132-induced apoptosis in a cell state-dependent manner.
Authors: Aster Legesse-Miller, Jacky Ho Wa Cheng
Journal: Clinical Cancer Research (2015)

Abstract Proteasome inhibition is an important strategy for treating many types of cancer. While proteasome inhibitors induce apoptosis in certain rapidly proliferating cancer cells, some cells enters quiescence and survives. The mechanism by which quiescent cells become resistant to proteasome inhibitors is unknown. The tumor suppressor protein p53 plays an essential role in establishing and maintaining quiescence in human cells. It also regulates several cell survival mechanisms, such as cell cycle arrest, autophagy, and activation of detoxifying enzymes. Here, we investigate the role of p53 in establishing resistance against proteasome inhibitors in quiescent cells. We found that MG132 (a known proteasome inhibitor) treatment induces the accumulation of p53 and its downstream target p21 more in quiescent than in proliferating primary human fibroblasts. shRNA-mediated down-regulation of p53 sensitizes both proliferating and quiescent fibroblasts to MG132-mediated apoptosis and cell death, suggesting that p53 plays a protective role in all cell states. Additional experiments demonstrated that proliferating fibroblasts are susceptible to inhibition of cytoplasmic p53 activity, whereas quiescent fibroblasts are sensitive to inhibition of either nuclear or cytoplasmic p53 activity. These findings suggest that proliferating and quiescent cells depend on different p53-induced survival mechanisms to be protected from proteasome inhibition. Autophagy, an alternative degradation pathway regulated by p53, is also induced in both cell states upon MG132 treatment. Identification of p53-mediated regulatory mechanisms that are activated in quiescent cells in response to proteasome inhibition may help to suggest strategies for improving the effectiveness of proteasome inhibitors in treating cancer. Citation Format: Aster Legesse-Miller, Jacky Ho Wa Cheng. p53 protects against MG132-induced apoptosis in a cell state-dependent manner. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A44.
Altered expression of PPAR and its interacting partners in human colon adenocarcinoma
Authors: Delphine Bouancheau, Anne Jarry, Claire Toquet, Damien Masson, Christian L. Laboisse, Marc G. Denis
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

136 

Peroxisome proliferator-activated receptor (PPAR) agonists have been demonstrated to exert an inhibitory effect on cell growth, and to induce cell differentiation and apoptosis of colorectal cancer cells. PPAR was therefore proposed as a therapeutic target. In an effort to evaluate the significance of alterations in the expression of PPAR and its co-activators in colon cancer, we have determined the expression level of PPAR, RXRα and 6 co-activators in a series of 18 human colon tumors by real-time PCR. PPAR expression was found to be heterogeneous between tumors. RXRα, PGC-1α, and SRC1 were often down-regulated. In contrast, PRIP, p300, PBP and CBP were up-regulated in most tumors. We have also measured the expression level of a recently described variant of PPAR that functions as a dominant negative (ORF4), and found it to be over-expressed in the majority of these tumors. We propose that prospects for treatment of colon cancer by selective PPAR modulators should take into account the deregulation and aberrant expression of PPAR and of its co-activators.
Use of Methyl Scopolamine Nitrate in the Treatment of Paroxysmal Fussing (Colic) in Infancy
Authors: Morris A. Wessel
Journal: New England Journal of Medicine (1957)

PAROXYSMAL fussing, or "irritable crying," "compulsive crying" and "infantile colic," describes a variable complaint of early infancy. The pediatrician attempting to relieve these distressing symptoms is faced with the choice of a variety of pharmacologic preparations, some of which offer relief in one situation and not in another. A recent paper from Sweden reports the value of methyl scopolamine nitrate in the treatment of this syndrome.1 In a previous study, data dealing with the incidence, duration of symptoms and etiology of "paroxysmal fussing" in a group of infants observed in the rooming-in project are presented.2 In summary, this condition was . . .
Soundings: The basics
Authors: Colin Douglas
Journal: BMJ (2002)

Once, a long time ago, I was buttonholed quite politely in the hospital dining room by a young anaesthetist I vaguely knew. He asked me to come and see an old man in intensive care who was very frail and very ill: but for where he was, he would have been dead already. No doubt there are excellent protocols now, and these things are well ordered within clinical governance, but what my young colleague needed then was someone already labelled consultant to say enough was enough. We agreed what was needed: comfort, dignity, and peace at the last.

More recently, in a ward where my responsibilities are far better defined, a frail and muddled elderly lady became quite unwell. A neurosurgical problem was suspected, though not by me. Some ambitious investigations were being planned in a hospital an uncomfortable ambulance journey away. The diagnosis was unclear but infection seemed more probable. We investigated lightly and treated vigorously. She did well.

Our trainees come to us highly skilled in diagnosis and intervention. For some, the most difficult lessons of the first few months are those of restraint: when not to do all the wonderful things they have spent the last three or four years honing to perfection. It takes time, but the dawning of compassionate realism is wonderful to watch.

Each month our students are asked to identify from their various attachments cases for discussion that demonstrate social and ethical issues arising in relation to the care of the elderly. From time to time the debate focuses on activism towards the end of life. Yes, even the frailest patients can benefit from the most sophisticated investigations and interventions; but occasionally our students seem to suspect that zeal goes untempered by judgment. In discussion both hawks and doves fly free. So we revert to the basic principles: beneficence, non-maleficence, autonomy, justice. Sometimes they help. Difficult cases remain difficult.

But only up to a point. Once, a long time ago and as a distinctly underdone registrar, I was left with unusual responsibilities when the unit's two consultants headed for a specialty meeting on the other side of Scotland. As they set off, the senior man wound down his window. “Colin, my boy,” he said—for that is how juniors were addressed in those days. “Heal the sick . . . Comfort the dying . . .” His blue eyes narrowed a little as the car drew away. “And don't get them mixed up.”