tbuckley/cabot-search huggingface dataset:
Cowden Syndrome and the PTEN Hamartoma Tumor Syndrome: Systematic Review and Revised Diagnostic Criteria
Authors: R. Pilarski, R. Burt, W. Kohlman, L. Pho, K. M. Shannon, E. Swisher
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundPTEN hamartoma tumor syndrome (PHTS) refers to a spectrum of disorders caused by mutations in the phosphatase and tensin homolog ( PTEN) gene. Diagnostic criteria for Cowden syndrome, the principal PTEN -related disorder, were first established in 1996 before the identification of the PTEN gene and the ability to molecularly confirm a clinical diagnosis. These consortium criteria were based on clinical experience and case reports in the existing literature, with their inherent selection biases. Although it was initially reported that approximately 80% of patients with Cowden syndrome had an identifiable germline PTEN mutation, more recent work has shown these diagnostic criteria to be far less specific. In addition, increasing evidence has documented the association of a broader spectrum of clinical features with PTEN mutations. Our goal was to develop revised, evidence-based diagnostic criteria and to include features of the broader spectrum of PTEN -related clinical syndromes.
Understanding self and other
Authors: R. Peter Hobson
Journal: Behavioral and Brain Sciences (2004)

Interpersonal understanding is rooted in social engagement. The question is: How? What features of intersubjective coordination are essential for the growth of concepts about the mind, and how does development proceed on this basis? Carpendale &amp; Lewis (C&amp;L) offer many telling insights, but their account begs questions about the earliest forms of self-other linkage and differentiation, especially as mediated by processes of identification.
Age-related 4,977 bp deletion in human lung mitochondrial DNA.
Authors: H J Fahn, L S Wang, R H Hsieh, S C Chang, S H Kao, M H Huang, Y H Wei
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

The accumulation of mitochondrial DNA (mtDNA) mutations has been suggested to be an important contributor to human aging and degenerative diseases. The lung is exposed to ambient air and makes direct contact with the external environment. Numerous potentially noxious agents may damage lung tissues directly or indirectly through free-radical-mediated reactions. In previous studies, we demonstrated an age-dependent increase of mtDNA mutations in various human tissues. We hypothesize that the accumulation of the 4,977 bp (base pairs) deleted mtDNA in human lung tissues is also age-dependent. Using the polymerase chain reaction technique, we determined the incidence of the 4,977 bp-deleted mtDNA in 127 human lung specimens from 34-wk gestation to 79 yr of age. The results showed that 77 lung biopsies (60.6%) contained the 4,977 bp-deleted mtDNA, which started to appear in lung tissues after the fourth decade of life. The incidence apparently increased from 14.3% (one of seven) of the subjects in the 30- to 39-yr age group to 77.8% (two of 27) of the subjects in the 70- to 79-yr age group (p < 0.0001). The mean (+/- SEM) proportion of the 4,977 bp-deleted mtDNA in lung tissues significantly increased from 0.007 +/- 0.007% of the subjects in the 30- to 39-yr age group to 0.833 +/- 0.330% of those in the 70- to 79-yr age group (p < 0.005). Other factors such as sex, pulmonary function indices, and smoking status did not have statistically significant impact on the amount of the deleted mtDNA. These findings suggest that the accumulation of the 4,977 bp-deleted mtDNA is associated with aging human lung.
Regulation of anaphylactic responses by phosphatidylinositol phosphate kinase type I α
Authors: Junko Sasaki, Takehiko Sasaki, Masakazu Yamazaki, Kunie Matsuoka, Choji Taya, Hiroshi Shitara, Shunsuke Takasuga, Miki Nishio, Katsunori Mizuno, Teiji Wada, Hideyuki Miyazaki, Hiroshi Watanabe, Ryota Iizuka, Shuichi Kubo, Shigeo Murata, Tomoki Chiba, Tomohiko Maehama, Koichi Hamada, Hiroyuki Kishimoto, Michael A. Frohman, Keiji Tanaka, Josef M. Penninger, Hiromichi Yonekawa, Akira Suzuki, Yasunori Kanaho
Journal: The Journal of Experimental Medicine (2005)

The membrane phospholipid phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P2] is a critical signal transducer in eukaryotic cells. However, the physiological roles of the type I phosphatidylinositol phosphate kinases (PIPKIs) that synthesize PI(4,5)P2 are largely unknown. Here, we show that the α isozyme of PIPKI (PIPKIα) negatively regulates mast cell functions and anaphylactic responses. In vitro, PIPKIα-deficient mast cells exhibited increased degranulation and cytokine production after Fcε receptor-I cross-linking. In vivo, PIPKIα−/− mice displayed enhanced passive cutaneous and systemic anaphylaxis. Filamentous actin was diminished in PIPKIα−/− mast cells, and enhanced degranulation observed in the absence of PIPKIα was also seen in wild-type mast cells treated with latrunculin, a pharmacological inhibitor of actin polymerization. Moreover, the association of FcεRI with lipid rafts and FcεRI-mediated activation of signaling proteins was augmented in PIPKIα−/− mast cells. Thus, PIPKIα is a negative regulator of FcεRI-mediated cellular responses and anaphylaxis, which functions by controlling the actin cytoskeleton and dynamics of FcεRI signaling. Our results indicate that the different PIPKI isoforms might be functionally specialized.
Cytokine production in the infrapatellar fat pad: another source of cytokines in knee synovial fluids
Authors: T Ushiyama
Journal: Annals of the Rheumatic Diseases (2003)

<b>Background:</b> Recent studies have shown that adipose tissue is an endocrine organ that releases various cytokines. <b>Objective:</b> To investigate the production of growth factors and proinflammatory cytokines in infrapatellar fat pad specimens. <b>Methods:</b> Infrapatellar fat pad tissues were obtained from patients during knee surgery. Protein levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)α, and interleukin (IL)6 in homogenised tissues were measured by an enzyme immunoassay. Gene expressions for those cytokines were examined by reverse transcription-polymerase chain reaction (RT-PCR). Localisation of bFGF and VEGF was evaluated by immunohistochemistry and in situ hybridisation. <b>Results:</b> Infrapatellar fat pads were found to contain various protein levels of bFGF, VEGF, TNFα, and IL6. Further, gene expressions for these cytokines were detected by RT-PCR. Immunohistochemistry and in situ hybridisation showed that the expressions of both bFGF and VEGF were localised in immature adipocytes, interstitial undifferentiated mesenchymal cells, and vascular endothelial cells. <b>Conclusion:</b> The production of bFGF, VEGF, TNFα, and IL6 in the infrapatellar fat pad was demonstrated. Although synovial cells and articular chondrocytes are thought to be primary sources of cytokines found in knee synovial fluids, the results suggest that they may also originate from this fat pad.
The vertebrate genome: isochores and evolution.
Authors: G Bernardi
Journal: Molecular Biology and Evolution (1993)

Vertebrate genomes are mosaics of isochores--namely, of long (> 300 kb), compositionally homogeneous DNA segments that can be subdivided into a small number of families characterized by different GC levels. In the human genome (which is representative of a number of mammalian genomes, and, more broadly, of the genomes of warm-blooded vertebrates), the compositional range of isochores is 30%-60% GC, and five families of isochores have been identified: two GC-poor families, L1 and L2, together representing 62% of the genome, and three GC-rich families, H1, H2, and H3, representing 22%, 9%, and 3%, respectively (the remaining 4% of the genome is formed by satellite and ribosomal DNA). Gene concentration is strikingly nonuniform, being highest in the H3 isochore family, lowest in the L1 + L2 families, and intermediate in the H1 + H2 families. The H3 family corresponds to T(elomeric) bands of metaphase chromosomes, and the L1 + L2 families correspond to G(iemsa) bands, whereas R(everse) bands comprise both GC-poor and GC-rich isochores. The compositional distributions of large genome fragments, of exons (and their codon positions), and of introns are correlated with each other. They represent compositional patterns and are very different between the genomes of cold- and warm-blooded vertebrates, mainly in that the former are much less heterogeneous in base composition and never reach the highest GC levels attained by the latter. Only relatively small compositional differences are found among the genomes of either cold- or warm-blooded vertebrates. Compositional patterns allow one to define two modes in genome evolution: a conservative mode, with no compositional change, and a transitional (or shifting) mode, with compositional changes. The conservative mode can be observed among either cold- or warm-blooded vertebrates. The transitional mode comprises both major and minor compositional changes. In vertebrate genomes, the major changes are associated with the appearance of GC-rich and very GC-rich isochores in mammalian and avian genomes. Mutational biases play a role in both modes of compositional evolution. According to one viewpoint, the fixation of compositionally biased mutations is responsible for the transitional mode of evolution of bacterial genomes; in the conservative mode of evolution of vertebrates, they accomplish their role in conjunction with differences either in chromatin structures that modulate replication errors or in chromatin transcriptional activities that may lead to various extents of repair-DNA synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)
Points: Animal experiments
Authors: D. FitzSimons
Journal: BMJ (1982)

p 4), I discussed this with the authors.In view of the fact that neither microscopic nor the earliest lymph node invasion is demonstrated by computed tomography, it appeared essential to define the track or volume within which malignant disease spread up the lym- phatics.This has been demonstrated in a series of 35-mm slides covering the lymphatic volume from the pelvis up through the abdomen and thorax to the root of the neck.This surprisingly small volume was agreed for surgical and radiotherapy planning for "cur- able" cancer with around 100 experienced consultants in surgery, radiology, and radio- therapy, on an extensive tour of Europe, Canada, and the United States.
Local government leaders almost walked away from Better Care Fund deal, MPs hear
Authors: A. O'Dowd
Journal: BMJ (2014)

The controversial Better Care Fund, designed to shift care from hospitals in England to the community by encouraging integrated health and social care, almost collapsed as local government leaders considered walking away from the agreement, MPs have been told.

The balance of the fund’s priorities tipped towards the NHS too much at one point, and local government had to be persuaded that it was not being unfairly dealt with, witnesses have admitted to MPs on the parliamentary Public Accounts Committee.

The Better Care Fund aims to help older and disabled people be cared for more in the community than in hospitals by creating a single pooled budget to incentivise the NHS and local government to work more closely together. It is now intended …
Durable Long-Term Remission With Chemotherapy Alone for Stage II to IV Laryngeal Cancer
Authors: F. Christopher Holsinger, Merrill S. Kies, Eduardo M. Diaz, Ann M. Gillenwater, Jan S. Lewin, Lawrence E. Ginsberg, Bonnie S. Glisson, Adam S. Garden, Nebil Ark, Heather Y. Lin, J. Jack Lee, Adel K. El-Naggar, Waun Ki Hong, Dong M. Shin, Fadlo R. Khuri
Journal: Journal of Clinical Oncology (2009)

For patients with stage II to IV laryngeal cancer, radiation therapy (RT) either alone or with concurrent chemotherapy provides the highest rate of organ preservation but can be associated with functional impairment. Thus, we studied the use of induction chemotherapy with or without conservation laryngeal surgery (CLS). Our objectives were to study the sensitivity of laryngeal cancer to platinum-based chemotherapy alone and to highlight the efficacy of CLS in this setting.Thirty-one previously untreated patients with laryngeal cancer (T2-4, N0-1, M0), who were resectable with CLS, were enrolled. Patients received three to four cycles of paclitaxel, ifosfamide, and cisplatin (TIP) chemotherapy, and response was assessed histologically. Patients with partial response (PR) proceeded to CLS. Patients achieving pathologic complete response (pCR) received an additional three cycles of TIP and no other treatment.Thirty patients were assessable for response. With TIP chemotherapy alone, 11 patients (37%) achieved pCR, 10 of whom (33%) remain alive with durable disease remission and no evidence of recurrence over a median follow-up time of 5 years. Nineteen patients (63%) treated with TIP alone achieved PR. The overall laryngeal preservation (LP) rate was 83%, and only five patients (16%) required postoperative RT. No patient required a gastrostomy tube or tracheotomy.Chemotherapy alone in selected patients with T2-4, N0-1 laryngeal cancer can provide durable disease remission at 5 years. For patients with PR, CLS provides a high rate of LP. This prospective study suggests that chemotherapy alone may cure selected patients with laryngeal cancer, warranting further prospective investigation.
Author response—vitamin D deficiency and systemic inflammation in bronchiectasis
Authors: James D Chalmers
Journal: Thorax (2013)

Dr Charles Shee raises a further possible explanation for our finding of an association between vitamin D status and disease severity in bronchiectasis, that low vitamin D status represents a negative acute phase response to acute inflammation.1

Our study was cross-sectional and was unable to establish whether vitamin D deficiency is a cause or consequence of bronchiectasis.2 Possible explanations that have been previously suggested are failed bacterial …
Interpreting Adverse Signals in Diabetes Drug Development Programs
Authors: Clifford J. Bailey
Journal: Diabetes Care (2013)

Detection and interpretation of adverse signals during preclinical and clinical stages of drug development inform the benefit-risk assessment that determines suitability for use in real-world situations. This review considers some recent signals associated with diabetes therapies, illustrating the difficulties in ascribing causality and evaluating absolute risk, predictability, prevention, and containment. Individual clinical trials are necessarily restricted for patient selection, number, and duration; they can introduce allocation and ascertainment bias and they often rely on biomarkers to estimate long-term clinical outcomes. In diabetes, the risk perspective is inevitably confounded by emergent comorbid conditions and potential interactions that limit therapeutic choice, hence the need for new therapies and better use of existing therapies to address the consequences of protracted glucotoxicity. However, for some therapies, the adverse effects may take several years to emerge, and it is evident that faint initial signals under trial conditions cannot be expected to foretell all eventualities. Thus, as information and experience accumulate with time, it should be accepted that benefit-risk deliberations will be refined, and adjustments to prescribing indications may become appropriate.
Airborne contact dermatitis from Compositae oleoresins simulating photodermatitis
Authors: Niels Hjorth, Jytte Roed‐Petersen, Kristian Thomsen
Journal: British Journal of Dermatology (1976)

American ragweed (Ambrosia) dermatitis has an airborne pattern and is caused by lipid soluble oleoresins of pollens. A similar weed dermatitis has been described in India and Australia. The weeds involved were all of the Compositae family and contain sesquiterpene lactones with one common antigenic determinant. This study reports seven Danish patients treated for many years under the diagnosis of photodermatitis, who eventually proved to suffer from Compsoitae oleoresin dermatitis. Probably, Compsitae dermatitis is a world-wide disease, although aften misdiagnosed as has happened in Scandinavia.
Genome-wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica
Authors: C. P Hersh, M. E Soto-Quiros, L. Avila, S. L Lake, C. Liang, E. Fournier, M. Spesny, J. S Sylvia, R. Lazarus, T. Hudson, A. Verner, B. J Klanderman, N. B Freimer, E. K Silverman, J. C Celedon
Journal: Thorax (2006)

<b>Background:</b> Although asthma is highly prevalent among certain Hispanic subgroups, genetic determinants of asthma and asthma-related traits have not been conclusively identified in Hispanic populations. A study was undertaken to identify genomic regions containing susceptibility loci for pulmonary function and bronchodilator responsiveness (BDR) in Costa Ricans. <b>Methods:</b> Eight extended pedigrees were ascertained through schoolchildren with asthma in the Central Valley of Costa Rica. Short tandem repeat (STR) markers were genotyped throughout the genome at an average spacing of 8.2 cM. Multipoint variance component linkage analyses of forced expiratory volume in 1 second (FEV<sub>1</sub>) and FEV<sub>1</sub>/ forced vital capacity (FVC; both pre-bronchodilator and post-bronchodilator) and BDR were performed in these eight families (pre-bronchodilator spirometry, n = 640; post-bronchodilator spirometry and BDR, n = 624). Nine additional STR markers were genotyped on chromosome 7. Secondary analyses were repeated after stratification by cigarette smoking. <b>Results:</b> Among all subjects, the highest logarithm of the odds of linkage (LOD) score for FEV<sub>1</sub> (post-bronchodilator) was found on chromosome 7q34–35 (LOD = 2.45, including the additional markers). The highest LOD scores for FEV<sub>1</sub>/FVC (pre-bronchodilator) and BDR were found on chromosomes 2q (LOD = 1.53) and 9p (LOD = 1.53), respectively. Among former and current smokers there was near-significant evidence of linkage to FEV<sub>1</sub>/FVC (post-bronchodilator) on chromosome 5p (LOD = 3.27) and suggestive evidence of linkage to FEV<sub>1</sub> on chromosomes 3q (pre-bronchodilator, LOD = 2.74) and 4q (post-bronchodilator, LOD = 2.66). <b>Conclusions:</b> In eight families of children with asthma in Costa Rica, there is suggestive evidence of linkage to FEV<sub>1</sub> on chromosome 7q34–35. In these families, FEV<sub>1</sub>/FVC may be influenced by an interaction between cigarette smoking and a locus (loci) on chromosome 5p.
IgE‐mediated anaphylactoid reactions to rubber
Authors: J. G. K. Axelsson, S. G. O. Johansson, K. Wrangsjö
Journal: Allergy (1987)

Delayed hypersensitivity to rubber chemicals is well known, but there are only a limited number of case reports on an immediate type of hypersensitivity inducing contact urticaria. We have recently seen several patients with rubber glove‐induced contact urticaria who have had both positive skin prick tests and positive RAST tests to natural latex from the rubber tree ( Hevea brasiliensis ). We now report on five patients who also developed systemic reactions. It is clear that sensitized subjects are at risk of developing anaphylaxis during medical examination or surgery when rubber gloves are used. The occurrence of IgE‐mediated allergy to rubber is probably underestimated.
Knockout mouse models of sperm flagellum anomalies
Authors: Denise Escalier
Journal: Human Reproduction Update (2006)

To date, 21 knockout mouse models are known to bear specific anomalies of the sperm flagellum structures leading to motility disorders. In addition, genes responsible for flagellar defects of two well-known spontaneous mutant mice have recently been identified. These models reveal genetic factors, which are required for the proper assembly of the axoneme, the annulus, the mitochondrial sheath and the fibrous sheath. Many of these genetic factors follow unexpected cellular pathways to act on sperm flagellum morphogenesis. These mouse models may bear anomalies which are restricted to the spermatozoa or display more complex phenotypes that often include neuropathies and/or cilia-related diseases. In human, several structural disorders of the sperm flagellum found in brothers or consanguineous men probably have a genetic origin, but the genes involved have not yet been identified. The mutant mice we present in this review are invaluable models, which can be used to identify potential candidate genes for infertile men with specific sperm flagellum anomalies.
Cartilage and bone macromolecules in knee joint synovial fluid in rheumatoid arthritis: relation to development of knee or hip joint destruction
Authors: B. Mansson, P. Geborek, T. Saxne
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVE</h3> To examine the hypothesis that aggrecan, cartilage oligomeric matrix protein (COMP), and bone sialoprotein (BSP) concentrations in synovial fluid could provide information on variations of progression of joint destruction in rheumatoid arthritis. <h3>METHODS</h3> Aggrecan, COMP, and BSP were quantified by enzyme linked immunosorbent assays in longitudinally collected knee joint synovial fluid samples of patients rapidly developing destruction in knees or hips, the “destructive” group, n = 18, and in patients slowly developing destruction, the “non-destructive” group, n = 25. <h3>RESULTS</h3> The aggrecan concentrations decreased from initially high levels (P &lt;&lt; 0.001), and the BSP concentrations increased (P &lt;&lt; 0.001) over time in the destructive group, whereas levels of both markers were low and did not change in the non-destructive group. The COMP levels did not change in any of the groups. The aggrecan concentrations were initially highest in the group developing destructions (P &lt;&lt; 0.001), whereas no difference between the groups was found regarding levels of COMP or BSP in the first sample. <h3>CONCLUSIONS</h3> A destructive group was characterised by higher initial aggrecan concentrations and rising BSP concentrations in synovial fluid with time. Quantification of cartilage and bone derived macromolecules contributes to the assessment of extent of tissue destruction and may help in the early identification of patients at risk of rapidly progressing destruction.
MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype.
Authors: D K Ways, C A Kukoly, J deVente, J L Hooker, W O Bryant, K J Posekany, D J Fletcher, P P Cook, P J Parker
Journal: Journal of Clinical Investigation (1995)

Increased protein kinase C (PKC) activity in malignant breast tissue and positive correlations between PKC activity and expression of a more aggressive phenotype in breast cancer cell lines suggest a role for this signal transduction pathway in the pathogenesis and/or progression of breast cancer. To examine the role of PKC in the progression of breast cancer, human MCF-7 breast cancer cells were transfected with PKC-alpha, and a group of heterogenous cells stably overexpressing PKC-alpha were isolated (MCF-7-PKC-alpha). MCF-7-PKC-alpha cells expressed fivefold higher levels of PKC-alpha as compared to parental or vector-transfected MCF-7 cells. MCF-7-PKC-alpha cells also displayed a substantial increase in endogenous expression of PKC-beta and decreases in expression of the novel delta- and eta-PKC isoforms. MCF-7-PKC-alpha cells displayed an enhanced proliferative rate, anchorage-independent growth, dramatic morphologic alterations including loss of an epithelioid appearance, and increased tumorigenicity in nude mice. MCF-7-PKC-alpha cells exhibited a significant reduction in estrogen receptor expression and decreases in estrogen-dependent gene expression. These findings suggest that the PKC pathway may modulate progression of breast cancer to a more aggressive neoplastic process.