tbuckley/cabot-search huggingface dataset:
Combined Transductional Untargeting/Retargeting and Transcriptional Restriction Enhances Adenovirus Gene Targeting and Therapy for Hepatic Colorectal Cancer Tumors
Authors: Hua-Jung Li, Maaike Everts, Masato Yamamoto, David T. Curiel, Harvey R. Herschman
Journal: Cancer Research (2009)

Abstract Unresectable hepatic colorectal cancer (CRC) metastases are a leading cause of cancer mortality. These tumors and other epithelial tumors often express both cyclooxygenase-2 (COX-2) and carcinoembryonic antigen (CEA). Because adenovirus (Ad) vectors infect the liver and lack tumor tropism, they cannot be used for systemic therapy of hepatic metastases. We used COX-2 transcriptional restriction, in combination with transductional Ad hepatic untargeting and tumor retargeting by a bispecific adapter, sCARhMFE, composed of sCAR [the coxsackie/Ad receptor (CAR) ectodomain] and MFE-23 (a single-chain anti-CEA antibody), to untarget liver after i.v. administration of Ad vectors expressing firefly luciferase and to retarget virus to hepatic colorectal tumor xenografts and non–small cell lung tumor xenografts. To improve both liver untargeting and tumor retargeting, we developed sCARfMFE, a trimerized sCARhMFE adapter. Trimerization greatly improves both untargeting of CAR-dependent Ad infection and CEA-dependent virus retargeting in culture and in vivo. Combining sCARfMFE bispecific adapter transductional liver untargeting and transductional tumor retargeting with COX-2 transcriptional tumor-restricted transgene expression increases systemically administered Ad therapeutic efficacy for hepatic CRC tumors, using herpes virus type 1 thymidine kinase (HSV1-tk) as a therapeutic gene in conjunction with the prodrug ganciclovir (GCV). Both transductional untargeting and COX-2 transcriptional restriction also reduce HSV1-tk/GCV hepatic toxicity. In addition, transductional sCARfMFE untargeting reduces the innate immune response to systemic Ad administration. Combined transductional liver Ad untargeting, transductional tumor retargeting, and transcriptional transgene restriction suggests a means to engineer practical, effective therapeutic agents for hepatic CRC metastases in particular, as well as hepatic metastases of other epithelial cancers. [Cancer Res 2009;69(2):554–64]
Toward a Universal Influenza Virus Vaccine: Prospects and Challenges
Authors: Natalie Pica, Peter Palese
Journal: Annual Review of Medicine (2013)

Current influenza virus vaccines are annually reformulated to elicit protection by generating an immune response toward the virus strains that are predicted to circulate in the upcoming influenza season. These vaccines provide limited protection in cases of antigenic mismatch, when the vaccine and the circulating viral strains differ. The emergence of unexpected pandemic viruses presents an additional challenge to vaccine production. To increase influenza virus preparedness, much work has been dedicated to the development of a universal vaccine. Focusing on regions of viral proteins that are highly conserved across virus subtypes, vaccine strategies involving the matrix 2 protein, stalk domain of the hemagglutinin, and multivalent approaches have provided broad-based protection in animal models and show much promise. This review summarizes the most encouraging advances in the field with a focus on novel vaccine designs that have yielded promising preclinical and clinical data.
Down-Regulation of Insular Cortex Responses to Dyspnea and Pain in Asthma
Authors: Andreas von Leupoldt, Tobias Sommer, Sarah Kegat, Falk Eippert, Hans Jörg Baumann, Hans Klose, Bernhard Dahme, Christian Büchel
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Dyspnea is the impairing cardinal symptom of asthma but its accurate perception is also crucial for timely initiation of treatment. However, the underlying brain mechanisms of perceived dyspnea in patients with asthma are unknown.Objectives: To study brain mechanisms of dyspnea in asthma.Methods: By using functional magnetic resonance imaging we compared the neuronal responses to experimentally induced dyspnea in patients with asthma and healthy controls. These brain activations were compared with neuronal responses evoked by pain to study neuronal generalization processes to another, similarly unpleasant, physiological sensation.Measurements and Main Results: While lying in the scanner, fourteen patients with mild-to-moderate asthma and fourteen matched healthy controls repeatedly underwent conditions of mild dyspnea, severe dyspnea, mild pain and severe pain. Dyspnea was induced by resistive loaded breathing. Heat pain of similar intensity was induced by a contact thermode.Whereas the sensory intensity of both sensations was rated similar by patients and controls, ratings of the affective unpleasantness of dyspnea and pain were reduced in patients. This perceptual difference was mirrored by reduced insular cortex activity, but increased activity in the periaqueductal gray (PAG) in patients during both increased dyspnea and pain. Connectivity analyses showed that asthma-specific down-regulation of the insular cortex during dyspnea and pain was moderated by increased PAG activity.Conclusions: The results suggest a down-regulation of affect-related insular cortex activity by the PAG during perceived dyspnea and pain in patients with asthma. This might represent a neuronal habituation mechanism reducing the affective unpleasantness of dyspnea in asthma, which generalizes to other unpleasant physiological sensations such as pain.
Yield of Acid-fast Smear and Mycobacterial Culture for Tuberculosis Diagnosis in People with Human Immunodeficiency Virus
Authors: Patama Monkongdee, Kimberly D. McCarthy, Kevin P. Cain, Theerawit Tasaneeyapan, Nguyen H. Dung, Nguyen T. N. Lan, Nguyen T. B. Yen, Nipat Teeratakulpisarn, Nibondh Udomsantisuk, Charles Heilig, Jay K. Varma
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: The World Health Organization recently revised its recommendations for tuberculosis (TB) diagnosis in people with HIV. Most studies cited to support these policies involved HIV-uninfected patients and only evaluated sputum specimens.Objectives: To evaluate the performance of acid-fast bacilli smear and mycobacterial culture on sputum and nonsputum specimens for TB diagnosis in a cross-sectional survey of HIV-infected patients.Methods: In Thailand and Vietnam, we enrolled people with HIV regardless of signs or symptoms. Enrolled patients provided three sputum, one urine, one stool, one blood, and, for patients with palpable peripheral adenopathy, one lymph node aspirate specimen for acid-fast bacilli microscopy and mycobacterial culture on solid and broth-based media. We classified any patient with at least one specimen culture positive for Mycobacterium tuberculosis as having TB.Measurements and Main Results: Of 1,060 patients enrolled, 147 (14%) had TB. Of 126 with pulmonary TB, the incremental yield of performing a third sputum smear over two smears was 2% (95% confidence interval, 0–6), 90 (71%) patients were detected on broth-based culture of the first sputum specimen, and an additional 21 (17%) and 12 (10%) patients were diagnosed with the second and third specimens cultured. Of 82 lymph nodes cultured, 34 (42%) grew M. tuberculosis. In patients with two negative sputum smears, broth-based culture of three sputum specimens had the highest yield of any testing strategy.Conclusions: In people with HIV living in settings where mycobacterial culture is not routinely available to all patients, a third sputum smear adds little to the diagnosis of TB. Broth-based culture of three sputum specimens diagnoses most TB cases, and lymph node aspiration provides the highest incremental yield of any nonpulmonary specimen test for TB.
Glomerular Involvement in Adults with Sickle Cell Hemoglobinopathies
Authors: Antonio Guasch, Jose Navarrete, Kaleed Nass, Carlos F. Zayas
Journal: Journal of the American Society of Nephrology (2006)

Patients with sickle cell anemia (SCA) may develop a glomerulopathy with proteinuria and progressive renal insufficiency, leading to ESRD. Albuminuria is a sensitive marker of glomerular damage in this population and precedes the development of renal insufficiency. For determination of the prevalence of glomerular damage in SCA and the clinical correlates of renal insufficiency, 300 adult patients with SCA were studied (hemoglobin SS = 184; and 116 with other sickling hemoglobinopathies: SC, SD, and S-beta thalassemia); albumin excretion rates (AER) and renal function (Cockroft-Gault formula) were determined, and clinical and hematologic evaluations were conducted. In hemoglobin SS disease, increased AER (micro- and macroalbuminuria) occurred in 68% of adult patients, and macroalbuminuria occurred in 26%. In other sickling disorders, increased AER occurs in 32% of adults, and macroalbuminuria occurs in 10%. The development of graded albuminuria was age dependent, so at 40 yr, 40% of patients with SS disease had macroalbuminuria. There were no differences in hematologic parameters (hemoglobin levels, white blood cell count, percentage of reticulocytes, platelet counts, or lactate dehydrogenase levels) between patients with normoalbuminuria and those with micro- or macroalbuminuria. By multivariate analysis, albuminuria correlated with age and serum creatinine in SS disease but not with BP or hemoglobin levels. In other sickling disorders, albuminuria tended to be associated with age but not with hemoglobin or BP levels. The diastolic BP was lower in patients with SCA than in African American control subjects, and the development of renal insufficiency, which was present in 21% of adults with SS disease, was not accompanied by significant hypertension. It is concluded that glomerular damage in adults with SCA is very common, and a majority of patients with SS disease are at risk for the development of progressive renal failure. The development of micro- and macroalbuminuria is not related to the degree of anemia, suggesting that sickle cell glomerulopathy is not solely related to hemodynamic adaptations to chronic anemia. In contrast to other glomerulopathies, the development of systemic hypertension is uncommon in SS disease with renal insufficiency.
Multiple Colorectal Neoplasms in X-Linked Agammaglobulinemia
Authors: Lodewijk A.A. Brosens, Kristien M.A.J. Tytgat, Folkert H.M. Morsink, Richard J. Sinke, Ineke J.M. Ten Berge, Francis M. Giardiello, G. Johan A. Offerhaus, Josbert J. Keller
Journal: Clinical Gastroenterology and Hepatology (2007)
Patients are still bewildered by NHS complaints system, say experts
Authors: A. O'Dowd
Journal: BMJ (2015)

Patients are still overwhelmed and often intimated by the prospect of making a complaint about NHS treatment, MPs have been told.

Experts representing patients and their families appeared before the parliamentary Public Administration Select Committee, describing the current NHS complaints system as “mind boggling” for the public and in need of extensive reform.

During an evidence session on 10 February for the committee’s inquiry into NHS complaints and clinical failure, MPs asked how effective the NHS was in its approach to investigating untoward medical incidents.

Katherine Murphy, chief executive of the Patients Association, giving evidence, said, “Patients and their relatives tell us that the complaints system is too bureaucratic, complex, confusing—and very often it adds to the pain and grief …
LRRK2 in Parkinson's disease and dementia with Lewy bodies.
Authors: Xiongwei Zhu, Asim Babar, Sandra L Siedlak, Qiwei Yang, Genta Ito, Takeshi Iwatsubo, Mark A Smith, George Perry, Shu G Chen
Journal: Molecular Neurodegeneration (2006)

Mutations in LRRK2 encoding leucine-rich repeat kinase 2 are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic Parkinson's disease (PD). To examine whether LRRK2 is directly associated with neuropathology of PD and other related disorders, we analyzed LRRK2 in brains of patients affected by PD and dementia with Lewy bodies (DLB) using highly specific antibodies to LRRK2.We demonstrated that anti-LRRK2 antibodies strongly labelled brainstem and cortical Lewy bodies, the pathological hallmarks of PD and DLB, respectively. In addition, anti-LRRK2 also labelled brain vasculature, axons, and neuronal cell bodies. Interestingly, the immunocytochemical profile of LRRK2 varied with different antibodies depending upon specific antigenic sites along the LRRK2 protein. All anti-LRRK2 antibodies tested that were raised against various regions of LRRK2, were found to be immunoreactive to recombinant LRRK2 on Western blots. However, only the antibodies raised against the N-terminal and C-terminal regions of LRRK2, but not the regions containing folded protein domains, were positive in immunolabeling of Lewy bodies, suggesting a differential exposure of specific antigenic sites of LRRK2 on tissue sections.We conclude that LRRK2 is a component of Lewy bodies in both PD and DLB, and therefore plays an important role in the Lewy body formation and disease pathogenesis. Information on the cellular localization of LRRK2 under normal and pathological conditions will deepen our understanding of its functions and molecular pathways relevant to the progression of PD and related disorders.
A REVIEW OF ONE HUNDRED AND FIFTEEN CASES
Authors: HARVEY GORDON
Journal: British Journal of Dermatology (1961)

Journal Article A REVIEW OF ONE HUNDRED AND FIFTEEN CASES Get access HARVEY GORDON, M.B., Ch.B., D.P.H. HARVEY GORDON, M.B., Ch.B., D.P.H. Assistant Medical Officer of Health, Southport; late Senior House Officer, Department of Dermatology, Newsham General Hospital, Liverpool Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 73, Issue 11, 1 November 1961, Pages 393–409, https://doi.org/10.1111/j.1365-2133.1961.tb14987.x Published: 01 November 1961
Smad7 Inhibits Fibrotic Effect of TGF-β on Renal Tubular Epithelial Cells by Blocking Smad2 Activation
Authors: Jin H. Li, Hong-Jian Zhu, Xiao R. Huang, Kar N. Lai, Richard J. Johnson, Hui Y. Lan
Journal: Journal of the American Society of Nephrology (2002)

It has been shown that transforming growth factor-beta (TGF-beta) is a potent mediator in renal fibrosis and that Smad proteins are critical intracellular mediators in TGF-beta signaling. It is here reported that TGF-beta mediates renal fibrogenesis in tubular epithelial cells (TEC) in association with the activation of Smad2 and that overexpression of Smad7 blocks this fibrotic process. Using a normal rat kidney tubular epithelial cell line (NRK52E), it was determined that TGF-beta1 induces Smad2 phosphorylation and nuclear localization in both a dose- and time-dependent manner. The activation of Smad2 was evident at 5 min (20%), peaked at 15 to 30 min (85%), and declined to baseline levels by 2 h (5 to 10%). This was associated with de novo expression of collagens I, III, and IV and the transformation of TEC into a "myofibroblast" phenotype with de novo expression of alpha-smooth muscle actin (alpha-SMA) and with the loss of E-cadherin (>50%). To investigate a negative regulatory role of Smad7 in renal fibrosis, the Smad 7 gene was stably transfected and its expression was tightly controlled by doxycycline into NRK52E cells. Overexpression of Smad7 induced by doxycycline results in marked inhibition of TGF-beta-induced Smad2 activation (90% downward arrow) with the prevention of collagen synthesis and myofibroblast transformation. Thus, Smad2 activation occurs in the fibrogenic response of TEC to TGF-beta, and this process is blocked by overexpression of Smad7. This indicates that Smad signaling is a key pathway of TGF-beta-mediated renal fibrosis and suggests that treatments targeting the inactivation of Smad2 by overexpression of Smad7 may provide a new therapeutic strategy for renal fibrosis.
Absorptive and motor components of the antidiarrhoeal action of loperamide: an in vivo study in pigs.
Authors: V Theodorou, J Fioramonti, T Hachet, L Bueno
Journal: Gut (1991)

The effects of loperamide (0.1 mg/kg orally) on net colonic water absorption, orocolonic transit time, and intestinal motility were investigated in pigs chronically fitted either with two cannulas in the proximal colon and a catheter in the duodenum and the ileum or with intraparietal electrodes on the duodenum, jejunum, caecum, and proximal colon and a duodenal catheter. Loperamide, given 20 minutes before a meal reduced significantly colonic net water absorption for 10 hours after eating. It also reduced colonic flow rate, increased orocolonic transit time, modified the postprandial intestinal motility by inducing supplementary phase 3 motor complexes and did not affect caecocolonic motility. Intraduodenal infusion of a hypertonic solution of mannitol (900 mOsm/l; 0.6 ml/minute) for the first postprandial hour strongly reduced or reversed net colonic water absorption, increased the colonic flow rate, accelerated the orocolonic transit, and induced profuse diarrhoea. After loperamide administration, all these effects were blocked and the relative colonic water absorption, expressed as the fraction of flow entering the colon, was strongly increased. Mannitol did not modify motility of the small and large intestine, and supplementary phase 3 motor complexes were observed when mannitol infusion was preceded by loperamide administration. It is concluded that in experimental osmotic diarrhoea loperamide causes a reduction in digesta flow entering into the colon, mediated by its action on small intestinal motility, and an increase in colonic water absorption.
AN EXPERIMENTAL ANALYSIS OF THE CURATIVE ACTION OF PENICILLIN IN ACUTE BACTERIAL INFECTIONS
Authors: W. Barry Wood, Mary Ruth Smith
Journal: The Journal of Experimental Medicine (1956)

Three strains of pneumococcus (types I and III), equally sensitive to penicillin, have been shown to be killed by the antibiotic in vitro when grown either in enriched beef infusion broth or in a thin serous exudate. Killing of the bacteria resulted promptly when the penicillin was added during the logarithmic phase of growth but failed to occur if addition of the antibiotic was delayed until the later "stationary" growth phase. In analogous experiments with thick purulent exudates from established subcutaneous abscesses, the pneumococci failed to grow rapidly, and added penicillin exerted only a relatively slow bactericidal effect. The relevance of these in vitro observations to the curative action of penicillin was demonstrated in a systematic histologic study of the antimicrobial effect of the drug in experimental (type I) pneumococcal pneumonia. Evidence was obtained that at least two distinct processes are involved. The first, the direct bactericidal effect of the penicillin itself, was shown to operate in the outer edema zone of the spreading pneumonic lesion where the micro-organisms multiply rapidly in the thin serous exudate. The second, which predominates in the older more central portions of the lesion, was demonstrated to depend upon destruction of the pneumococci by phagocytosis. Here the bacteria, having presumably reached a relatively stationary phase of growth in the alveolar exudate, are resistant to the bactericidal action of the penicillin but are readily destroyed by the phagocytes.
Vasectomy and Risk of Prostate Cancer
Authors: Brian Cox
Journal: JAMA (2002)

Vasectomy is a common method of contraception, but concern exists about a reported association with risk of prostate cancer.To examine whether vasectomy increases risk of prostate cancer.National population-based case-control study of 923 new cases of prostate cancer among men aged 40 to 74 years from the New Zealand Cancer Registry who were on the general electoral roll. Controls (n = 1224) were randomly selected from the general electoral roll, with frequency matching to cases in 5-year age groups. Cases (3-15 months after diagnosis) and controls were interviewed by telephone between January 1997 and November 1999.Relative risk (RR) of prostate cancer for men who had had a vasectomy vs those who had not.There was no association between prostate cancer and vasectomy (RR, 0.92; 95% confidence interval [CI], 0.75-1.14) nor with time since vasectomy (RR, 0.92; 95% CI, 0.68-1.23 for > or = 25 years since vasectomy). Adjustment for social class, geographic region, religious affiliation, and a family history of prostate cancer did not affect these RRs.Vasectomy does not increase the risk of prostate cancer, even after 25 years or more.
The SJL/J T cell response to both spontaneous and transplantable syngeneic reticulum cell sarcoma is mediated predominantly by the V beta 17a+ T cell clonotype.
Authors: J D Katz, K Ohnishi, L T Lebow, B Bonavida
Journal: The Journal of Experimental Medicine (1988)

Previous studies have revealed that the reticulum cell sarcoma (RCS) of SJL/J (H-2s, IE-) mice express an "IE-like" stimulatory tumor-associated antigen, the expression of which is requisite for stimulating host T cells necessary for tumor growth. Herein, we present evidence that the predominant T cells raised in the syngeneic response to both spontaneous and transplantable RCS tumors are of the V beta 17a TCR clonotype. The V beta 17a+ clonotype of T cells has been shown to interact with IE allogeneic specificities. We demonstrate that all four characterized RCS-specific T cell hybridomas stained positively for the anti-V beta 17a mAb, KJ23a. Additionally, KJ23a, when added to cocultures of the T cell hybridomas and RCS tumors, inhibited the release of IL-2 by the hybridomas. Further, KJ23a was shown to markedly inhibit the proliferation of SJL/J T cells when cocultured with either spontaneous or transplantable RCS tumor cells. When analyzed by flow cytometry, the T cell blast population raised in response to both spontaneous and transplantable RCS were greater than 80% KJ23a+. These T cells were brightly stained by the anti-CD4 mAb, Gk1.5, and, therefore, represent class II-responsive T cells. In corroboration of the in vitro data, T cells derived from mesenteric lymph nodes of RCS tumor-bearing mice had likewise undergone a similar expansion of V beta 17a+, CD4+ T cells. Together, these results indicate that KJ23a+ T cells play an important and predominant role in the response of SJL/J mice to spontaneous RCS tumors and provide further suggestive evidence that the stimulatory antigen(s) on the RCS tumor is IE or an "IE-like" molecule. Significantly, the important role V beta 17a+ T cells play in the response to RCS suggests a potential therapeutic role for KJ23a mAb in the intervention and prevention of RCS tumors in SJL/J mice.