tbuckley/cabot-search huggingface dataset:
Abstract 3686: Activation of signal transducer and activator of transcription 3 fails to confer resistance against withaferin A-induced apoptosis in human breast cancer cells
Authors: Joomin Lee, Eun-Ryeong Hahm, Shivendra V. Singh
Journal: Cancer Research (2011)

Abstract We have shown previously that withaferin A (WA), a constituent of Indian Ayurvedic medicine plant Withania somnifera that has been used safely for thousands of years for treatment of different ailments, inhibits growth of cultured MDA-MB-231 (an estrogen receptor negative cell line with mutant p53) and MCF-7 (an estrogen-responsive cell line with wild-type p53) human breast cancer cells. Moreover, the WA administration significantly inhibits growth of MDA-MB-231 xenografts in female athymic mice without causing any side effects. The WA-mediated inhibition of breast cancer cell growth in culture and xenografts correlates with apoptosis induction. However, the mechanism underlying proapoptotic effect of WA is not fully understood. The present study was designed to study the role of signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor activated in many human malignancies including breast cancer, in proapoptotic response to WA using MDA-MB-231 and MCF-7 cells. Growth suppressive and proapoptotic concentrations of WA (2 and 4 μM) decreased constitutive (MDA-MB-231) or interleukin-6 (IL-6)-inducible (MDA-MB-231 and MCF-7) phosphorylation of STAT3 (Tyr705) and its upstream regulator Janus-activated kinase 2 (JAK2; Tyr1007/1008) in MDA-MB-231, which was accompanied by suppression of their protein levels especially at the higher concentration. Exposure of MDA-MB-231 or MCF-7 cells to WA also resulted in suppression of (a) transcriptional activity of STAT3 with or without IL-6 stimulation in both cells; (b) dimerization of STAT3 (MDA-MB-231); and (c) nuclear translocation of Tyr705 phosphorylated STAT3 in both cells. To our surprise, the IL-6-stimulation, either before or after WA treatment, did not have an appreciable effect on WA-mediated apoptosis in MDA-MB-231 or MCF-7 cell line. The IL-6-stimulated activation of STAT3 conferred only a modest protection against WA-mediated suppression of MDA-MB-231 cell invasion. General implication of these findings is that WA can trigger apoptosis and largely inhibit cell migration/invasion of breast cancer cells even after IL-6-induced activation of STAT3, which should be viewed as a therapeutic advantage for this agent. This investigation was supported by the USPHS grant CA142604-01, awarded by the National Cancer Institute. 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 3686. doi:10.1158/1538-7445.AM2011-3686
EGFR expression using immunohistochemistry (IHC) testing as a tool for selecting patients (pts) for treatment with cetuximab
Authors: A. L. Ervin-Haynes, R. M. Schinagl, M. R. Dalesandro, J. Roecker, H. Youssoufian, E. Rowinsky
Journal: Journal of Clinical Oncology (2006)

13000 Background: EGFR expression, as determined by IHC, is currently used to select patients for cetuximab therapy. Based on prior studies in colorectal cancer patients, approximately 60 to 75% of patients express EGFR. There is increasing evidence that EGFR expression is not predictive of response to cetuximab therapy, and does not properly select patients who might benefit from such therapy (Chung et al 2005, Saltz et al 2005, Scartozi et al 2004, NCCN 2005). Such selection limits access to a considerable number of patients who might otherwise benefit. Methods: A clinical trial of cetuximab (Erbitux ® ) monotherapy is being conducted in 60 EGFR-undetectable patients with metastatic colorectal cancer at 14 sites in the US and Canada to explore the relationship between EGFR expression and cetuximab activity. Results: As of January 5, 2006, 112 patients have been screened. Of these patients, 33 (29%) were EGFR-undetectable and continued screening for study enrollment; 52 (46%) tested positive for EGFR expression; and 2 (2%) did not have enough tissue to evaluate EGFR status and were not enrolled onto the trial. The remaining 25 pts (22%), were initially found to be EGFR-undetectable by IHC testing at local labs, but were subsequently identified as EGFR-positive after reevaluation at a highly experienced, centralized laboratory. Conclusion: The majority of patients tested for EGFR expression are tested using the EGFR pharmDx™ IHC assay. Results of the IHC-based assay for EGFR expression are highly dependent upon sample preparation and the methods used in conducting the assay. Variability in methods among labs may result in poor identification of pts expressing EGFR. This finding, together with the growing evidence that EGFR expression is not predictive of response to cetuximab therapy, indicate that the current routine practice of tumor IHC EGFR testing for the purpose of selecting cetuximab therapy may be inappropriate and pts who could potentially benefit from cetuximab therapy are being excluded from a treatment option. [Table: see text]
GENETIC AND ENVIRONMENTAL INFLUENCES ON HUMAN BEHAVIORAL DIFFERENCES
Authors: Matt McGue, Thomas J. Bouchard
Journal: Annual Review of Neuroscience (1998)

▪ Abstract Human behavioral genetic research aimed at characterizing the existence and nature of genetic and environmental influences on individual differences in cognitive ability, personality and interests, and psychopathology is reviewed. Twin and adoption studies indicate that most behavioral characteristics are heritable. Nonetheless, efforts to identify the genes influencing behavior have produced a limited number of confirmed linkages or associations. Behavioral genetic research also documents the importance of environmental factors, but contrary to the expectations of many behavioral scientists, the relevant environmental factors appear to be those that are not shared by reared together relatives. The observation of genotype-environment correlational processes and the hypothesized existence of genotype-environment interaction effects serve to distinguish behavioral traits from the medical and physiological phenotypes studied by human geneticists. Behavioral genetic research supports the heritability, not the genetic determination, of behavior.
Delayed prescribing of antibiotics for upper respiratory tract infection
Authors: Paul Little
Journal: BMJ (2005)

With clear guidance to patients and parents it seems to be safe 

T he use of antibiotics by children with upper respiratory tract infection halved in the last decade in the United Kingdom, according to a paper in this week's BMJ (p 328).1 Sharland and colleagues attribute this decline to an initially sharp reduction in prescribing by general practitioners and, since 1997, to a reduction in the proportion of prescriptions taken by parents to a pharmacist. Widespread adoption of delayed prescribing, a strategy tested in a randomised controlled trial published in 1997, may well explain this pattern.1 2

Whether patients fill prescriptions depends, however, on the method of delayed prescribing. Retrospective data and historical comparisons—albeit limited scientifically—suggest that giving a prescription and asking the patient or parent to redeem it only if symptoms persist is more likely to result in antibiotic use than is asking the patient to return to the doctor for a prescription. This is the policy we used in our trials and, when patients were given clear guidance and were asked to return to collect prescriptions, only a few ended up taking antibiotics.2 3

Should doctors completely avoid prescribing antibiotics for patients with uncomplicated upper respiratory tract infections? The answer is no. Firstly, we do not yet know who is …
Reply to W. Hollingworth et al
Authors: Linda E. Carlson
Journal: Journal of Clinical Oncology (2014)

provided ongoing support and advice to staff using the DT&PL; nevertheless, we accept Carlson's general point that limited staff training and support might be one factor contributing to our finding that needs assessment using the DT&PL did not improve psychological morbidity.We disagree with the assertion made by Carlson 1 that our intervention amounted to screening without further assessment or evidence-based treatment.On average, needs assessment using the DT&PL took 25.5 minutes and, for some patients, more than 1 hour.The duration of the assessment was positively correlated with the levels of distress reported by patients, and further actions discussed included pharmacotherapy (36%), general practitioner, oncologist, or nurse contacts (10% to 22%), and clinical psychologist (7%), counseling (6%), and support groups (7%).The intervention was more than simply screening and fits the definition of needs assessment as ". . .a strategy that focuses on identifying the unresolved concerns that patients are experiencing and determines if they require further assistance as well as the level of assistance they require." 3(p1161) We also strongly disagree with Carlson's statement that "staff members were expected to manage all arising patient concerns." 1(p3616) Staff reported that they frequently used the resource directory to guide patients in self-care and to sources of support that were available in the community.The range of support available from other members of the clinical team (eg, general practitioner, oncologist, nurse, and clinical psychologist contacts previously described) also indicates that staff administering the DT&PL were not left to manage everything.Consulting a psychologist or attending counseling was discussed in 13 patients (12%; both options were discussed with one patient), not the 8 patients stated by Carlson.Carlson's statement that the difference between this and the 37% of patients who report high levels of distress indicates a departure from evidence-based treatment assumes that the high distress has a predominantly psychological cause.Distress caused by physical problems might be better addressed without referral for psychological therapy.However, again, we accept Carlson's general point that clearer referral pathways and more robust follow-up for patients with psychosocial support needs might have resulted in a more effective intervention.Trials of needs assessment and individualized management plans among patients diagnosed with cancer have produced mixed results. [4]5][6][7] Our trial is one of several to find no effect on patient healthrelated quality of life.It is vital that we use these trials to better understand these complex interventions, how they work, and in which circumstances.
Abstract 2440: RNF5 mediates ER stress-induced degradation of SLC1A5 in breast cancer
Authors: Young Joo Jeon, Sihem Khelifa, Yongmei Feng, Eric Lau, Robert Cardiff, Hyungsoo Kim, David L. Rimm, Yuval Kluger, Ze'ev Ronai
Journal: Cancer Research (2014)

Abstract Tumor cells have an altered metabolism that distinguishes it from their normal counterpart. Intriguingly, tumor cells show increased use of glutamine to fuel catabolic processes. Therefore, altered metabolic tumors have been considered as a good target for anticancer therapy. Ring finger protein 5 (RNF5) is an ER membrane-associated ubiquitin E3 ligase. RNF5 expression has been associated with breast cancer progression. We identified solute carrier family 1 member 5 (SLC1A5) as a possible RNF5 regulated protein using a MS analysis of breast cancer cells. SLC1A5 is a high affinity L-glutamine transporter, which is highly expressed in tumors such as breast, liver and lung. RNF5 promotes ubiquitination-mediated degradation of SLC1A5 in response to chemotherapeutic drugs known to induce ER stress. RNF5-mediated SLC1A5 instability attenuated mTOR signaling, leading to inhibition of tumor cell proliferation and promotion of apoptosis/autophagy. The loss of RNF5 in PyMT-MMTV crossed with RNF5 mutant animals developed less differentiated mammary tumors, which exhibit increased levels of SLC1A5. TMA analysis of human breast cancer tumors identified a fraction that exhibited an inverse correlation between RNF5 and SLC1A5 expression. Notably, reduced expression of SLC1A5 exhibited a strong association with improved prognosis of breast cancer. Taken together, our observations identify mechanisms underlying the control of SLC1A5 stability, and the implications of such regulation for mTOR signaling and breast cancer survival in response to therapy. Citation Format: Young Joo Jeon, Sihem Khelifa, Yongmei Feng, Eric Lau, Robert Cardiff, Hyungsoo Kim, David L. Rimm, Yuval Kluger, Ze'ev Ronai. RNF5 mediates ER stress-induced degradation of SLC1A5 in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2440. doi:10.1158/1538-7445.AM2014-2440
Tumor necrosis factor-α is required in the protective immune response against mycobacterium tuberculosis in mice
Authors: JoAnne L. Flynn, Marsha M. Goldstein, John Chan, Karla J. Triebold, Klaus Pfeffer, Charles J. Lowenstein, Robert Schrelber, Tak W. Mak, Barry R. Bloom
Journal: Immunity (1995)

Understanding the immunological mechanisms of protection and pathogenesis in tuberculosis remains problematic. We have examined the extent to which tumor necrosis factor-alpha (TNF alpha) contributes to this disease using murine models in which the action of TNF alpha is inhibited. TNF alpha was neutralized in vivo by monoclonal antibody; in addition, a mouse strain with a disruption in the gene for the 55 kDa TNF receptor was used. The data from both models established that TNF alpha and the 55 kDa TNF receptor are essential for protection against tuberculosis in mice, and for reactive nitrogen production by macrophages early in infection. Granulomas were formed in equal numbers in control and experimental mice, but necrosis was observed only in mice deficient in TNF alpha or TNF receptor. TNF alpha and the 55 kDa TNF receptor are necessary conditions for protection against murine M. tuberculosis infection, but are not solely responsible for the tissue damage observed.
BCR-ABL fusion regions as a source of multiple leukemia-specific CD8+ T-cell epitopes
Authors: J H Kessler, S A Bres-Vloemans, P A van Veelen, A de Ru, I J G Huijbers, M Camps, A Mulder, R Offringa, J W Drijfhout, O C Leeksma, F Ossendorp, C J M Melief
Journal: Leukemia (2006)
Schizophrenia: A Critical Review of the Developmental Hypothesis
Authors: D. Lewis
Journal: Annual Review of Neuroscience (2001)

▪ Abstract A combination of genetic susceptibility and environmental perturbations appear to be necessary for the expression of schizophrenia. In addition, the pathogenesis of the disease is hypothesized to be neurodevelopmental in nature based on reports of an excess of adverse events during the pre- and perinatal periods, the presence of cognitive and behavioral signs during childhood and adolescence, and the lack of evidence of a neurodegenerative process in most individuals with schizophrenia. Recent studies of neurodevelopmental mechanisms strongly suggest that no single gene or factor is responsible for driving a highly complex biological process. Together, these findings suggest that combinatorial genetic and environmental factors, which disturb a normal developmental course early in life, result in molecular and histogenic responses that cumulatively lead to different developmental trajectories and the clinical phenotype recognized as schizophrenia.
A Rational Approach to Corticosteroid Therapy for Asthma in Children
Authors: Jacqueline R. Jorgensen
Journal: JAMA (1966)

A lthough adrenal-corticosteroid preparations have been available for more than 15 years, there is still no consensus about their use for asthma. Some physicians prescribe corticosteroids freely for relatively minor indications, while others never give them. It is important in every situation where the use of these compounds is considered to weigh the advantages of this most effective and potent form of therapy against the well-known risks entailed. Equally important, the physician should always control the amount of medication taken and not allow the patient or his parents to decide when and how to make changes in therapy. Following is a presentation of the corticosteroid management of children institutionalized at the Children's Asthma Research Institute and Hospital (CARIH) because of severe, intractable asthma. More than 50% of these children are receiving corticosteroids in some form on admission, and approximately half of these continue to require steroids continuously or intermittently during
Strategy of acne therapy with long-term antibiotics
Authors: BRONWYN R. HUGHES, CLAIRE E. MURPHY, JULIA BARNETT, W.J. CUNLIFFE
Journal: British Journal of Dermatology (1989)

A study of the outcome of conventional antibiotic treatment in 543 patients with acne was performed. All were treated initially with erythromycin 1 g/day and topical 5% benzoyl peroxide. The median improvement at 6 months was 78%, with an interquartile range of 67-90%. Four-hundred and eight of the 492 who completed 6 months' treatment showed over 50% improvement and 247 of the 279 patients treated for a subsequent 6 months with benzoyl peroxide alone, continued to do well. Another subgroup of 174 patients, was continued for 6 months with systemic antibiotic and 5% benozyl peroxide. No significant benefit was gained, however, by maintaining successfully treated patients on a further 6 months of systemic antibiotics. Of the 84 patients who did less well, 18 were given alternative treatment (Diane, isotretinoin). The other 60, subsequently referred to as slow responders, were continued on antibiotics (erythromycin, 31; minocin, 29; cotrimoxazole, 4; trimethoprim, 2) and benzoyl peroxide. Those prescribed minocycline for the second 6 months appeared to have greater benefit (64%) than those receiving erythromycin (57%). This level of improvement was still lower than that seen in those who responded well within 6 months (78%). Of the risk factors analysed, the poorest response occurred in males with truncal acne. Age at presentation, duration and severity did not adversely affect therapeutic outcome. Side-effects were minimal.
Hemodialysis Fistula Infections Caused by Legionella pneumophila
Authors: WILHELM H. KALWEIT
Journal: Annals of Internal Medicine (1982)

Legionella pneumophila was found in the infected hemodialysis fistulas of two patients. The first patient developed an infection of the fistula during acute illness with Legionnaires' pneumonia. Legionella organisms were shown to be present in the graft by direct immunofluorescent staining. The second patient developed an infection of the hemodialysis fistula 3 weeks after completing a course of erythromycin therapy for Legionnaires' pneumonia. Legionella organisms were found by direct immunofluorescence in purulent material that was obtained from the graft, and serogroup 1 L. pneumophila was isolated from the pus. The frequency with which the organism causes infection of hemodialysis access sites is unknown. Increased awareness by physicians that L. pneumophila produces extrapulmonary disease may result in more frequent detection of these infections.
529. Development of Novel Systemic Gene Delivery System for Cancer Therapy with Tumor-Specifically Cleavable PEG-Lipid
Authors: Hiroto Hatakeyama, Hidetaka Akita, Kentaro Kogure, Motoi Oishi, Yukio Nagasaki, Hideo Kobayashi, Hiroshi Kikuchi, Hideyoshi Harashima
Journal: Molecular Therapy (2006)

Top of pageAbstract
[Purpose]

For the success in developing systemic gene carriers, it is essential to optimize the pharmacokinetics and intracellular trafficking to deliver the pDNA to the nucleus. To achieve this purpose, a Multifunctional Envelope-type Nano Device (MEND) was recently developed, in which the core of plasmid DNA, condensed by a polycation, was encapsulated by a lipid envelope. PEGylation and controlling the size of MEND are useful for stability of systemic circulation and tumor targeting by EPR effect. However, PEGylation results in a significant loss in transfection activity. In order to resolve this dilemma, a cleavable PEG-lipid composed of PEG/Matrix Metalloproteinase (MMP)-substrate peptide/DOPE (PPD) was synthesized, which is specifically cleaved by MMP in the extracellular space in tumor tissues. The function of PPD-modified MEND (PPD-MEND) as non-viral gene vector for cancer was evaluated in in vitro and in vivo.

[Methods]

N-terminal region of the peptide was reacted with MeO-PEG- CONHS. The C-terminal of the PEG-Peptide was conjugated with DOPE. The synthesis was confirmed by TOF-MS and 1H-NMR. MEND composed of DOTAP, DOPE, Cholesterol including a certain amount of PPD or PEG-DSPE were transfected in HT1080 and HEK293 cells, in which MMP is highly and poorly expressed, respectively. At 48 h after transfection, the transfection activity was assayed. The ability of PPD to improve the stability of the MEND in the systemic circulation was confirmed after i.v. administration. For measurement of blood concentrations, the lipid bilayers of MEND, PEG-MEND and PPD-MEND were labeled with 3H-Cholesteryl hexadecyl ether (CHE), and administered to mice via the tail vein. At 6 h post-injection, blood was collected and the radioactivity measured by liquid scintillation counting.

[Results]

TOF-MS and 1H-NMR analysis showed correct synthesis of PPD. The non-PEG-modified MEND (MEND) exhibited a high transfection activity in both cell lines. The transfection activity of PEG-MEND drastically decreased in both cell lines to less than 1% compared to MEND. The transfection activity of the PPD-MEND was enhanced by 35-fold compared to that of the PEG-MEND at 5% of PEG density. The blood concentration of PPD-MEND with 5% and 15% density of PEG was 10-fold and 35-fold higher than that of MEND, respectively, whereas it was slightly lower than that of PEG-MEND at the same PEG density. These results show that the PPD on MEND potently prolongs its systemic circulation.

[Conclusion]

The use of PPD provides a valuable function for in vitro transfection activity by virtue of its cleavable nature in response to a MMP-rich environment and for the stability of the MEND in the systemic circulation.
NASAL DISEASE AS A CAUSE OF HEADACHE
Authors: A. L. Whitehead
Journal: BMJ (1905)

TM a; '79 morning and worse in the evening.A diffuse headache is often due to nasal obstruction or rhinitis, but it can also be caused by disease of the accessory cavities.We all know the distressing symptoms which follow a so-called cold in the head (acute rhinitis).Professor Guye, of Amsterdam, calls the complex of symptoms which follow nasal obstruc- tion or rhinitis " aprosexia," the inability to concentrate the thoughts on any one subject.These symptoms-diminished capacity -for work, loss of energy, dislike to go anywlhere or do anything, forgetfulness, loss of memory, general mental depression, etc.-have is some cases been so severe as to cause patients to commit suicide. OVER-ZZEAL.In conclusion, I should like most strongly to dissociate myself from those enthusiastic practitioners who think that every little spur or deviation of the nasal septum, or slight hypertrophy of the mucous membrane of the nares, is most dangerous and harmful, and must always be removed.Nor do I believe that all diseases are of nasal origin.But I do think that in all cases of asthma, hay fever, laryngitis, bronchitis, deafness, headache, gastritis, etc., the nares should be carefully examined, and, if necessary, treated.Every patient who suffers from nasal obstruction or nasal discharge should be thoroughly treated, especially in child- hood.In fact, it should be part of the routine examination on the part of the physician, to ask the patient if he can breathe with his mouth shut, if one or both sides of the nostril are not occasionally blocked, if he can smell and taste, and if there is any discharge from the nares.If this were done thoroughly, a good many mistakes in diagnosis would be prevented, and many patients saved from much unnecessary suffering.