tbuckley/cabot-search huggingface dataset:
Abstract 2070: XBP-1 promotes cell survival by activating the unfolded protein response (UPR) in antiestrogen resistance in breast cancer
Authors: Ayesha N. Shajahan, F. Edward Hickman, Katherine Cook, Robert Clarke
Journal: Cancer Research (2011)

Abstract Most of the 192,000 newly diagnosed cases of invasive breast cancer in 2011 will be estrogen receptor positive alpha positive (ER+). Endocrine therapy, administered as an antiestrogen, e.g., Tamoxifen (TAM) or Faslodex (Fulvestrant; ICI 182,780) or an aromatase inhibitor (AI), e.g., Letrozole (LET), is the least toxic and most effective means to manage the hormone-dependent breast cancer in such patients. However, resistance to endocrine therapy remains a significant clinical problem. Our group has shown that antiestrogen resistant breast cancer cells over-express X-Box Binding Protein 1 (XBP1), a transcription factor that belongs to the basic region/leucine zipper (bZIP) family. XBP1(U) and XBP1(S) variants result from an unconventional splicing of the XBP1 mRNA by IRE1alpha. In the unfolded protein response (UPR), endoplasmic reticulum proteins (IRE1alpha, ATF6 and PERK) sense cellular stress to regulate the accumulation of unfolded proteins. Initially a compensatory mechanism allowing cells to recover normal endoplasmic reticulum function, prolonged UPR may induce cell death; this is often dependent upon which arm of the UPR predominates. XBP1 is an obligate component in both the IRE1alpha and ATF6 arms of the UPR. Our study shows that antiestrogen resistant breast cancer cells survive by activating pro-survival autophagy through XBP1-mediated UPR. MCF7/LCC9 [Faslodex resistant; TAM cross-resistant; high level of XBP1(S)] cells showed an increase in UPR signaling as detected by increased expression of BiP/GRP78. Antiestrogen-sensitive cells that over-express XBP1(S) show decreased sensitivity to Faslodex and show increased levels of basal and Faslodex-induced autophagy as measured by cleaved LC3BII protein fragment, GFP-LC3 activity, and reduced expression of p62/SQSTM1. Thus, we conclude that antiestrogen resistant breast cancer cells evade cell death by activating the XBP1-regulated arms of the UPR that results in prosurvival autophagy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2070. doi:10.1158/1538-7445.AM2011-2070
Industry influence moved focus of US dental research away from sugar, documents indicate
Authors: M. McCarthy
Journal: BMJ (2015)

The sugar industry successfully shifted the focus of a major US initiative to reduce tooth decay from research into the role of dietary sugar towards interventions that would not require a reduction in sugar consumption, concludes a new study of government and industry documents.1

The analysis of the documents by Cristin Kearns, Stanton Glantz, and Laura Schmidt of the University of California in San Francisco appears in the 10 March issue of PLOS Medicine .

“The documents show that the sugar industry knew that sugar caused dental caries as early as 1950 and did not attempt to deny the causative role of sucrose in tooth decay,” Kearns and her colleagues wrote. “Instead, through trade associations, the sugar industry adopted a strategy to deflect attention to public health interventions that would reduce the harm of sugar consumption, rather than restricting intake.” Among the interventions the industry promoted were enzyme containing food additives to reduce plaque and vaccines against cariogenic bacteria.

In the study the researchers analyzed internal sugar …
Effect of short-term ethanol treatment on voltage-dependent calcium channels in kupffer cells
Authors: Taizo Hijioka, Moritaka Goto, John J. Lemasters, Ronald G. Thurma
Journal: Hepatology (1993)

Kupffer cells, the resident hepatic macrophages, are activated by calcium, and several reports indicate that their function (e.g., phagocytosis and cytokine production) is altered by ethanol. We recently found that Kupffer cells contain L-type voltage-dependent Ca2+ channels. The purpose of this study, therefore, was to evaluate the effect of short-term ethanol treatment on voltage-dependent Ca2+ channels in Kupffer cells. Kupffer cells were isolated from rats 2 hr after intragastric administration of ethanol (5 gm/kg intragastrically). Cytosolic free calcium concentration of cultured Kupffer cells was measured with the fluorescent Ca2+ indicator fura-2. In Kupffer cells isolated from control rats, partial replacement of extracellular Na+ by K+ caused an increase in cytosolic free calcium concentration in a concentration-dependent manner (half-maximal effect was observed with 81 mmol/L K+), presumably because of membrane depolarization. Acute ethanol treatment in vivo shifted the concentration-response curve for K+ to the right (half-maximal effect was observed with 94 mmol/L K+) and reduced the maximal elevation of cytosolic free calcium concentration by means of K+. Significantly, the dihydropyridine-type calcium channel agonist BAY K 8644 (1 mumol/L) shifted the concentration-response curve for K+ to the left in control and ethanol-treated groups (half-maximal effect was observed with 61 and 77 mmol/L K+, respectively). Moreover, the dihydropyridine-type calcium channel blocker nitrendipine (10 mumol/L) prevented the increase in cytosolic free calcium concentration in both groups. When extracellular Ca2+ was omitted from the incubation medium, the increases in cytosolic free calcium concentration due to depolarization were prevented completely. However, direct addition of ethanol to the cell cultures was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Lipid-Lowering Therapy With Statins in High-Risk Elderly Patients
Authors: Dennis T. Ko, Muhammad Mamdani, David A. Alter
Journal: JAMA (2004)

The benefits of cardiovascular therapies such as statins for secondary prevention have been well documented, although they may not be optimally used in patients most likely to benefit. Ideally, aggressiveness in the use of these beneficial therapies should correlate with baseline cardiovascular risk.To examine the association between physicians' treatment aggressiveness and baseline cardiovascular risk.Retrospective cohort study incorporating the use of multiple linked health care administrative databases covering more than 1.4 million elderly residents of Ontario. We included 396,077 patients aged 66 years or older who had a history of cardiovascular disease or diabetes while undergoing medical treatment and who were alive on April 1, 1998. Baseline cardiovascular risk was derived using a risk-adjustment index in which we modeled probability of death after 3 years of follow-up.Likelihood of statin use, stratified by baseline cardiovascular risk, after adjusting for age, sex, socioeconomic status, and rural or urban residence.Only 75,617 patients (19.1%) in this secondary prevention cohort were prescribed statins. In patients 66 to 74 years old, the adjusted probabilities of statin prescription were 37.7%, 26.7%, and 23.4% in the categories of low, intermediate, and high baseline risk, respectively. The likelihood of statin prescription was 6.4% lower (adjusted odds ratio, 0.94; 95% confidence interval, 0.93-0.95) for each year of increase in age and each 1% increase in predicted 3-year mortality risk. The influence of age also interacted synergistically with baseline risk on the prescription of statins (P<.001).We found that prescription of statins diminished progressively as baseline cardiovascular risk and future probability of death increased. Since the benefits of a therapy are dependent on the baseline risk, the maximum benefits of statins may not be fully realized until implementation of therapy includes patients at highest risk.
Safety of single-balloon enteroscopy: our experience of 72 procedures
Authors: M. Manno, C. Barbera, E. Dabizzi, A. Mussetto, R. Conigliaro
Journal: Endoscopy (2010)

We read with great interest the article by Aktas et al. [1] on the complications of single-balloon enteroscopy (SBE). The authors performed 166 SBE procedures (105 by the oral approach and 61 by the anal approach) in 105 patients. No complications were reported in the 145 diagnostic SBE procedures. There was only one perforation in the 21 therapeutic SBE procedures, which occurred during dilation of a stricture in the distal ileum and was not related to the SBE technique. Moreover, although 13 patients had post-SBE hyperamylasemia, none had clinical acute pancreatitis.
Abstract 2733: LJM716: an anti-HER3 antibody that inhibits both HER2 and NRG driven tumor growth by trapping HER3 in the inactive conformation.
Authors: Andrew Garner, Qing Sheng, Uli Bialucha, Dongshu Chen, Yan Chen, Rita Das, Winfried Elis, Analeah Heidt, Christian Kunz, Sharon Li, Jinsheng Liang, Joshua Murtie, Parmita Saxena, Alwin Schuller, Olga Sineshchekova, Elizabeth Sprague, Hui Qin Wang, Alan Huang, Seth Ettenberg
Journal: Cancer Research (2012)

Abstract HER3 (ErbB3) is a member of the ErbB family of receptor tyrosine kinases (RTK). Inappropriate HER2/ HER3 dimerization as a result of HER2 or neuregulin (NRG) over-expression in cancer results in HER3 mediated activation of PI3K signaling. Consequently, HER3 is a mediator of oncogenic transformation. Although, ligand blocking HER3 antibodies inhibit growth of neuregulin driven xenograft models they are ineffective in models of HER2 amplified cancer as HER2 mediated activation of HER3 occurs in a ligand- independent manner. LJM716 is a high affinity HER3- targeted antibody selected from a Human Combinatorial Antibody Library (HuCAL) specifically for its ability to neutralize multiple modes of HER3 activation. LJM716 is a potent inhibitor of HER3/ AKT phosphorylation and proliferation in a range of HER2 amplified and NRG expressing cell lines in vitro. LJM716 induced tumor regression in Fadu (NRG expressing, HNSCC) tumor xenografts and significant tumor growth inhibition (&amp;gt;80%) in a variety of xenograft models including BT474 (HER2 amplified breast). Furthermore, the combination of LJM716 with trastuzumab, cetuximab or PI3K- targeted agents was synergistic in a panel of in vitro cell lines while the in vivo combination of LJM716 with trastuzumab or erlotinib was efficacious in BT474 and L3.3 (pancreatic) tumor xenografts respectively. To further understand the mechanism by which LJM716 inhibits multiple modes of HER3 activation we solved the crystal structure of LJM716 bound to the HER3 extra-cellular domain. This data revealed that LJM716 binds to a novel conformational epitope contained within domains 2 and 4 and appears to trap HER3 in the inactive conformation. Interestingly, LJM716 does not block NRG binding to HER3 nor does it affect the binding affinity of the HER3/ NRG interaction. LJM716 therefore possesses a novel mechanism of action; it prevents the structural rearrangements required for HER3 activation induced by either HER2 or NRG. Thus LJM716 is the first HER3 antibody to display efficacy in both HER2 and ligand driven xenograft models. Based on preclinical data, combining LJM716 with either trastuzumab, cetuximab or PI3K- targeted agents may lead to greater and more sustained clinical efficacy in ErbB driven cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2733. doi:1538-7445.AM2012-2733
PRODUCTION OF A SCURVY-LIKE CONDITION BY FEEDING OF A COMPOUND STRUCTURALLY RELATED TO ASCORBIC ACID
Authors: D. W. Woolley, L. O. Krampitz
Journal: The Journal of Experimental Medicine (1943)

The feeding of glucoascorbic acid, an analog of ascorbic acid, to mice and cotton rats caused the production of a condition exhibiting many of the changes characteristic of scurvy as seen in susceptible species. The condition was not prevented or cured by ascorbic acid, but was cured by removal of the glucoascorbic acid from the ration. The condition was produced in mice fed a highly purified ration. It was not produced in mice fed a natural ration. The presence of a substance in certain plant products which prevented the production of the condition was demonstrated.
Histological features and clinical course of large regenerative nodules: Evaluation of their precancerous potentiality
Authors: Fukuo Kondo, Masaaki Ebara, Nobuyuki Sugiura, Katsunori Wada, Kazuhiko Kita, Noboru Hirooka, Yoshinobu Nagato, Yoichiro Kondo, Masao Ohto, Kunio Okuda
Journal: Hepatology (1990)

Seventeen patients with cirrhosis and histologically defined, ultrasonically detected, large regenerative nodules of the liver were followed without treatment for more than 1 yr (range = 13 to 51 mo). During the follow-up period, none of the nodules were demonstrated sonographically to have enlarged. Computed tomography and/or hepatic angiography were also performed in 14 patients, but there was no evidence of malignant transformation in these lesions. None of the 17 patients showed acute elevation of serum α-fetoprotein levels. Furthermore, four nodules became undetectable by these imaging procedures. Follow-up biopsy performed in seven patients revealed no significant histological changes from the first biopsy sample. However, HCCs developed apart from these large regenerative nodules in four patients. These HCCs suddenly appeared and did not seem to have been derived from preexisting large regenerative nodules. From these observations, it was not possible to regard a large regenerative nodule having no cytological atypia as a high-potential premalignant lesion. Their precancerous potentiality needs to be compared with that of ordinary pseudolobules. (Hepatology 1990;12:592-598).
Community Health Specialists
Authors: H. Gordon
Journal: BMJ (1975)

<b>Background:</b> Allergy management in primary care is currently not optimal in most European countries which is attributed to educational gaps as reported by general practitioners (GPs). <b>Aim:</b> The aim of the logograms is to provide clarity and to facilitate the diagnostic process of 5 common allergic problems encountered in primary care (asthma, anaphylaxis, food allergy, drug allergy and urticaria). This abstract focuses on food allergy. <b>Methods:</b> Existing (inter)national guidelines and questionnaires on the diagnosis of food allergy were identified. The resulting food allergy logogram was based on a pragmatic primary care interpretation of existing literature. The food allergy logogram evolved during 5 in-depth interdisciplinary discussions with the international Task Force including GPs, allergy specialists, researchers and clinical fellows. <b>Results:</b> The food allergy logogram consists of 3 schematic flow diagrams: 1)differentiating food allergy from food intolerances, 2)determining the likelihood of food allergy, 3)risk-assessment of food allergy. If desired by the GP, more information behind the food allergy logogram is available in two layers about key terms in the food allergy logogram and background information. <b>Conclusion:</b> Based on existing mainly specialist guidelines, we developed a simple and pragmatic food allergy logogram for primary care in order to support GPs in making a (provisional) allergy diagnosis. Further steps are peer validation and computerization of the logograms. Ultimately, a trial should be undertaken to confirm the utility of the logograms in primary care. This may in future facilitate improved integrated care in allergy and improvement of both patient outcomes and experience of services.
Prevalence and Clinical Correlates of Residual Depressive Symptoms in Bipolar II Disorder
Authors: Franco Benazzi
Journal: Psychotherapy and Psychosomatics (2001)

Most patients with unipolar and bipolar I disorder have residual symptoms, despite successful treatment. The appraisal of subsyndromal symptomatology has important implications for pathophysiological models of disease and relapse prevention. Residual symptoms in bipolar II disorder were studied insufficiently. The study of residual symptoms in bipolar II disorder is important, because many depressed outpatients may suffer from it and because bipolar II disorder may be distinct from type I. The study aims were to assess the prevalence and clinical correlates of persistent residual depressive symptoms in bipolar II disorder.138 consecutive patients with bipolar II disorder and 83 unipolar disorder outpatients, presenting for major depressive episode treatment in private practice, were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders - Clinician's Version. Study variables were persistent (more than 2 years) residual depressive symptoms, age, gender, age at onset, illness duration, recurrences, axis I comorbidity, severity, psychotic, melancholic and atypical features.The prevalence of residual depressive symptoms was 44.9% in bipolar II disorder and 43.3% in unipolar disorder. Residual depressive symptoms in bipolar II and unipolar disorders were significantly and positively associated with illness duration and recurrences.Persistent residual depressive symptoms were common in bipolar II disorder. Residual unipolar and bipolar II depressive symptoms were related to duration of illness and number of recurrences. Reducing these variables could reduce and prevent residual symptoms. A mechanism of kindling (more mood episodes leading to worse outcome) could be that of leaving a larger and larger amount of residual symptoms after the acute episode has subsided.
A man with absolute dysphagia after eating a steak
Authors: M. S. Osborne, T. Saunders, F. Fuerstenberg, D. Costello, B. Dhesi
Journal: BMJ (2014)

A 52 year old man presented to the emergency department with a complete inability to swallow (absolute dysphagia) and pain in his throat. He described an acute onset of pain while eating “a nice piece of steak” three hours earlier. After this time he could not swallow without pain in the middle of his throat and was unable to manage fluids without regurgitation. He arrived in the emergency department carrying a bowl and was spitting out his own saliva. He reported no changes to his voice and no difficulty with breathing. He was otherwise fit and well, with no recent trauma, weight loss, or history of a similar presentation. Neck examination in the emergency department was unremarkable except that he regurgitated test drinks of water. Radiography was performed (fig 1⇓).





### 1. What radiographic view is shown?

#### Short answer 

A lateral soft tissue radiograph of the neck.

#### Long answer

Figure 1 shows a lateral soft tissue radiograph of the neck.

### 2. What does the radiograph show?

#### Short answer

An opacity consistent with soft tissue in the upper oesophagus measuring about 2 cm in width, lying anterior to the C5-C6 vertebrae with air below. There is also mild loss of lordosis.

#### Long answer

Within the distal pharynx-proximal oesophagus at the level of C5-C6, there is a soft tissue opacity measuring 2 cm in width (fig 2), which may represent a wedged food bolus at about the level of the cricopharyngeus muscle. There is mild loss of lordosis (due to muscular spasm) and air below the mass in the oesophagus. No prevertebral soft tissue swelling or surgical emphysema (suggestive of perforation) is visible.



Fig …
MEDICAL EDUCATIONAL INTERESTS.
Authors: J. N. McCormack
Journal: JAMA (1891)

and to present the same general chemical reac¬ tions.As the writer points out, urethane belongs to the class of narcotic poisons, and he suggests that uraemic symptoms may be due to the pres¬ ence and retention of this toxine.Whether in this discovery we have at least cleared up the doubtful pathology of uraemic coma, remains for further observation and study.Certain it is that it suggests a new line of inquiry that apriori is full of promise, and one which, apparently, is capable of reconciling the wide variation in the observed symptoms in acute urinary suppression and Bright's disease.
<sup>31</sup>P Nuclear Magnetic Resonance Spectroscopic Investigation of Human Neuroblastoma in Situ
Authors: John M. Maris, Audrey E. Evans, Alan C. McLaughlin, Giulio J. D'Angio, Lizanne Bolinger, Helen Manos, Britton Chance
Journal: New England Journal of Medicine (1985)

Neuroblastoma is a unique tumor of childhood that has a wide range of malignant expression. The prognoses range from excellent, with minimal treatment required, for patients with localized tumors or a special pattern of widespread disease to very poor for those with skeletal metastases. In some patients, the tumor regresses spontaneously. Spontaneous regression is predictable in infants who have small primary tumors and a particular distribution of disseminated disease with neuroblastoma in the liver, skin, bone marrow, or any combination of the three sites. Such infants, with disease classified as Stage IV-S, have a different prognosis from those with Stage . . .
Lung Cancer Among White South Africans
Authors: G. Dean
Journal: BMJ (1959)

MENTAL DEFICIENCYto the conception, and stage C because the extent of neonatal jaundice is modified by external factors like exchange transfusion.Since the development of the human mind is a continuous process to which all three stages make their contribution, it is evident that in the final analysis each will modify the outcome in any given case of mental defect.We can merely express an opinion on which of these stages in the history of the individual is of decisive importance in order to focus attention on that stage when seeking preventive measures.Summary Aetiological problems are considered in high-grade (feebleminded and educationally subnormal) and low-grade (idiot and imbecile) mental defectives.Psychological, educational, and social factors are generally of greater aetiological significance in the former group and gross brain pathology more often operative in the latter.However, such brain pathology, in " diluted " form, also produces minor degrees of mental defect, while environmental influences have a bearing on severe defect.This is illustrated with reference to phenylketonuria, kernicterus, tuberous sclerosis, and the Sturge-Weber syndrome.Of 44 educationally subnormal children, 32 (73%) had clinical abnormalities which could at least partially account for, or be related to, their mental retardation.In another 12 high-grade patients who came to necropsy, only 3 had no gross pathological lesions in the brain.Nearly all low-grade mental defectives show brain abnormalities at necropsy.The cause of these is elucidated in a small minority only.In 200 consecutive hospital admissions of low-grade cases, a known cause operated in 19 (9.5%) and a probable cause in another 8 (4%).Other factors were implicated in 111 (55.5%) and none in the remaining 62 (31%).Of the 200 cases 46 (23 %) were instances of mongolism.The condition is tentatively attributed to a biochemical error in the mother, which becomes more manifest with increasing age and leads to faulty organogenesis in a predisposed foetus.Metabolic studies of mothers should be undertaken in this connexion.Of the remaining 154 admissions in our series, 122 (79%) had gross physical signs.Factors productive of mental deficiency are briefly considered in terms of their operation before conception, during pregnancy, and post-natally.We are grateful to all our colleagues at the Fountain Hospital for help and advice.Dr. E. A. Brown had done some preliminary work on the data which we presented from our records during the period