tbuckley/cabot-search huggingface dataset:
Short telomere length is associated with <i>NOTCH1/SF3B1/TP53</i> aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients
Authors: Larry Mansouri, Pawel Grabowski, Sofie Degerman, Ulrika Svenson, Rebeqa Gunnarsson, Nicola Cahill, Karin Ekström Smedby, Christian Geisler, Gunnar Juliusson, Göran Roos, Richard Rosenquist
Journal: American Journal of Hematology (2013)

Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n = 265) and in relation to other prognostic markers. Short telomeres were particularly associated with high-risk genetic markers, such as NOTCH1, SF3B1, or TP53 aberrations, and predicted a short time to treatment (TTT) and overall survival (OS) (both P < 0.0001). TL was an independent prognostic factor and subdivided patients with otherwise good-prognostic features (e.g., mutated IGHV genes, favorable cytogenetics) into subgroups with different outcome. Furthermore, in follow-up samples (n = 119) taken 5-8 years after diagnosis, TL correlated well with TL at diagnosis and remained unaffected by treatment. Altogether, these novel data indicate that short TL already at diagnosis is associated with poor outcome in CLL and that TL can be measured at later stages of the disease.
Altered White Matter/Gray Matter Proportions in the Striatum of Patients With Schizophrenia: A Volumetric MRI Study
Authors: Chiharu Tamagaki, Göran C Sedvall, Erik G Jönsson, Gaku Okugawa, Håkan Hall, Stefan Pauli, Ingrid Agartz
Journal: American Journal of Psychiatry (2005)

Anatomical structures of the striatum were studied in 58 patients with schizophrenia and 56 healthy comparison subjects of both genders matched for age and handedness.Magnetic resonance imaging scans were used to measure gray matter, white matter, and CSF volumes of the caudate, putamen, and nucleus accumbens in the left and the right hemispheres.White matter/gray matter ratios of the striatal structures were significantly lower in patients than in healthy subjects. In patients, relative white matter volumes in the caudate and nucleus accumbens were reduced, whereas gray matter in the putamen was increased. The total accumbens volume did not differ by diagnosis, but left side accumbens was larger than right in the healthy subjects. The proportion of white matter was greater in women in both the patient and healthy comparison groups. Total caudate and putamen volumes demonstrated no differences due to diagnosis or laterality, but a negative correlation was found in patients between white matter volumes and increasing age. There were no significant correlations among total striatal volumes, white matter/gray matter ratios, age at onset of illness, or illness duration. An estimate of lifetime neuroleptic consumption was positively correlated with right gray matter volume of the putamen in male schizophrenia patients who received typical neuroleptics.The proportion of white matter to gray matter tissue volumes of the caudate, putamen, and nucleus accumbens is altered in medicated chronic schizophrenia patients, but the total volumes are unchanged.
THE HURLER SYNDROME: A STUDY OF CULTURED LYMPHOID CELL LINES
Authors: B. Shannon Danes, T. H. Hütteroth, H. Cleve, Alexander G. Bearn
Journal: The Journal of Experimental Medicine (1972)

Lymphoid suspension lines have been established from three patients with the Hurler syndrome and four normals. The Hurler lines can be distinguished from normals by (a) staining characteristics, (b) increase in total cellular mucopolysaccharide content, and (c) increase in dermatan sulfate. Hyaluronic acid is absent in cultured lymphoid cells from normal persons and patients with the Hurler syndrome. The availability of biochemically marked suspension cultures should prove useful for enzymatic studies as well as for further elucidation of this clinical syndrome.
Targeted Photothermal Ablation of Murine Melanomas with Melanocyte-Stimulating Hormone Analog–Conjugated Hollow Gold Nanospheres
Authors: Wei Lu, Chiyi Xiong, Guodong Zhang, Qian Huang, Rui Zhang, Jin Z. Zhang, Chun Li
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To develop melanoma-targeted hollow gold nanospheres (HAuNS) and evaluate their potential utility for selective photothermal ablation in melanoma. Experimental Design: A new class of photothermal coupling agents based on HAuNS was synthesized. HAuNS were stabilized with polyethylene glycol (PEG) coating and attached with α–melanocyte-stimulating hormone (MSH) analog, [Nle4,D-Phe7]α-MSH (NDP-MSH), which is a potent agonist of melanocortin type-1 receptor overexpressed in melanoma. The intracellular uptake of the NDP-MSH–conjugated PEGylated HAuNS (NDP-MSH-PEG-HAuNS) and the distribution of β-arrestin were examined in murine B16/F10 melanoma cells. The biodistribution of NDP-MSH-PEG-HAuNS was assessed at 4 hours post i.v. injection in tumor-bearing nude mice. Photothermal ablation effect of the nanoparticles was evaluated both histologically using excised tissue and functionally by [18F]fluorodeoxyglucose positron emission tomography. Results: NDP-MSH-PEG-HAuNS consist only of a thin gold wall with hollow interior (outer diameter, 43.5 ± 2.3 nm; shell thickness, 3-4 nm), which displays strong and tunable resonance absorption in near-IR region (peak, 808 nm). The nanoparticles were specifically taken up by melanoma cells, which initiated the recruitment of β-arrestins, the adapters to link the activated G-protein–coupled receptors to clathrin, indicating the involvement of receptor-mediated endocytosis. This resulted in enhanced extravasation of NDP-MSH-PEG-HAuNS from tumor blood vessels and their dispersion into tumor matrix compared with nonspecific PEGylated HAuNS. Successful selective photothermal ablation of B16/F10 melanoma with targeted HAuNS was confirmed by histologic and [18F]fluorodeoxyglucose positron emission tomography evaluation at 24 hours post near IR–region laser irradiation at a low-dose energy of 30 J/cm2. Conclusion: NDP-MSH-PEG-HAuNS have the potentials to mediate targeted photothermal ablation of melanoma.
Research identifies the most common cancers in teenagers and young adults
Authors: Adrian O'Dowd
Journal: BMJ (2006)

Cancers that disproportionately affect teenagers and young adults and their possible causes have been identified in new research. An analysis of 1.6 million cases of cancer in people aged up to 79 in England, in an eight year period, showed that cancers of the bone and specific types of ovarian and testicular cancers disproportionately affected young people aged between 13 and 24.

The research, presented at last week's international conference on …
Ayurvedic herbal medicine and lead poisoning
Authors: Krishna S Gunturu, Priyadharsini Nagarajan, Peter McPhedran, Thomas R Goodman, Michael E Hodsdon, Matthew P Strout
Journal: Journal of Hematology & Oncology (2011)

Abstract Although the majority of published cases of lead poisoning come from occupational exposures, some traditional remedies may also contain toxic amounts of lead. Ayurveda is a system of traditional medicine that is native to India and is used in many parts of world as an alternative to standard treatment regimens. Here, we report the case of a 58-year-old woman who presented with abdominal pain, anemia, liver function abnormalities, and an elevated blood lead level. The patient was found to have been taking the Ayurvedic medicine Jambrulin prior to presentation. Chemical analysis of the medication showed high levels of lead. Following treatment with an oral chelating agent, the patient's symptoms resolved and laboratory abnormalities normalized. This case highlights the need for increased awareness that some Ayurvedic medicines may contain potentially harmful levels of heavy metals and people who use them are at risk of developing associated toxicities.
Diagnosis and management of thyrotoxicosis
Authors: Elizabeth N Pearce
Journal: BMJ (2006)

Thyrotoxicosis occurs in approximately 2% of women and 0.2% of men.w1 Thyrotoxicosis due to Graves' disease most commonly develops between the second and fourth decades of life, whereas the prevalence of toxic nodular goitre increases with age. Autoimmune forms of thyrotoxicosis are more prevalent among smokers.w2 w3 Toxic nodular goitre is most common in regions where dietary iodine is insufficient.

I searched Medline for English language papers with the topics “thyrotoxicosis”, “Graves' disease”, and “goitre”, searched the Cochrane Database of Systematic Reviews by using the keyword “thyroid”, and used a personal archive of references.

Symptoms of overt thyrotoxicosis include heat intolerance, palpitations, anxiety, fatigue, weight loss, muscle weakness, and, in women, irregular menses. Clinical findings may include tremor, tachycardia, lid lag, and warm moist skin.1 Symptoms and signs of subclinical hyperthyroidism, if present, are usually vague and nonspecific.

To treat thyrotoxicosis appropriately, determining the cause is essential. The most common causes of thyrotoxicosis are discussed below; other causes are listed in the table.

View this table:

Causes of thyrotoxicosis



### Graves' disease

Graves' disease is an autoimmune disorder in which thyroid stimulating immunoglobulin (TSI) binds to and stimulates the thyroid stimulating hormone (TSH) receptor on the thyroid cell membrane, resulting in excessive synthesis and secretion of thyroid hormone.2 Patients with Graves' disease usually have diffuse, nontender, symmetrical enlargement of the thyroid gland. Ophthalmopathy, consisting of protrusion of the eyes with periorbital soft tissue swelling and inflammation, and inflammatory changes in the extraocular muscles resulting in diplopia and muscle imbalance, is clinically evident in 30% of patients with Graves' disease.1

### Toxic nodular goitre

Toxic adenomas are benign monoclonal thyroid tumours that secrete excess thyroid hormone autonomously. Thyrotoxicosis may develop in patients with a single autonomous thyroid nodule or in those with multiple autonomous nodules (toxic multinodular goitre, also known as Plummer's disease). Nodular autonomy typically …
Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia
Authors: Helen M. Marriott, Laura E. Jackson, Thomas S. Wilkinson, A. John Simpson, Tim J. Mitchell, David J. Buttle, Simon S. Cross, Paul G. Ince, Paul G. Hellewell, Moira K. B. Whyte, David H. Dockrell
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: The role of NADPH oxidase activation in pneumonia is complex because reactive oxygen species contribute to both microbial killing and regulation of the acute pulmonary infiltrate. The relative importance of each role remains poorly defined in community-acquired pneumonia.Objectives: We evaluated the contribution of NADPH oxidase–derived reactive oxygen species to the pathogenesis of pneumococcal pneumonia, addressing both the contribution to microbial killing and regulation of the inflammatory response.Methods: Mice deficient in the gp91phox component of the phagocyte NADPH oxidase were studied after pneumococcal challenge.Measurements and Main Results: gp91phox−/− mice demonstrated no defect in microbial clearance as compared with wild-type C57BL/6 mice. A significant increase in bacterial clearance from the lungs of gp91phox−/− mice was associated with increased numbers of neutrophils in the lung, lower rates of neutrophil apoptosis, and enhanced activation. Marked alterations in pulmonary cytokine/chemokine expression were also noted in the lungs of gp91phox−/− mice, characterized by elevated levels of tumor necrosis factor-α, KC, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and IL-6. The greater numbers of neutrophils in gp91phox−/− mice were not associated with increased lung injury. Levels of neutrophil elastase in bronchoalveolar lavage were not decreased in gp91phox−/− mice.Conclusions: During pneumococcal pneumonia, NADPH oxidase–derived reactive oxygen species are redundant for host defense but limit neutrophil recruitment and survival. Decreased NADPH oxidase–dependent reactive oxygen species production is well tolerated and improves disease outcome during pneumococcal pneumonia by removing neutrophils from the tight constraints of reactive oxygen species–mediated regulation.
Functional constraint and small insertions and deletions in the ENCODE regions of the human genome
Authors: Taane G Clark, Toby Andrew, Gregory M Cooper, Elliott H Margulies, James C Mullikin, David J Balding
Journal: Genome biology (2007)

We describe the distribution of indels in the 44 Encyclopedia of DNA Elements (ENCODE) regions (about 1% of the human genome) and evaluate the potential contributions of small insertion and deletion polymorphisms (indels) to human genetic variation. We relate indels to known genomic annotation features and measures of evolutionary constraint. Indel rates are observed to be reduced approximately 20-fold to 60-fold in exonic regions, 5-fold to 10-fold in sequence that exhibits high evolutionary constraint in mammals, and up to 2-fold in some classes of regulatory elements (for instance, formaldehyde assisted isolation of regulatory elements [FAIRE] and hypersensitive sites). In addition, some noncoding transcription and other chromatin mediated regulatory sites also have reduced indel rates. Overall indel rates for these data are estimated to be smaller than single nucleotide polymorphism (SNP) rates by a factor of approximately 2, with both rates measured as base pairs per 100 kilobases to facilitate comparison. Indel rates exhibit a broadly similar distribution across genomic features compared with SNP density rates, with a reduction in rates in coding transcription and evolutionarily constrained sequence. However, unlike indels, SNP rates do not appear to be reduced in some noncoding functional sequences, such as pseudo-exons, and FAIRE and hypersensitive sites. We conclude that indel rates are greatly reduced in transcribed and evolutionarily constrained DNA, and discuss why indel (but not SNP) rates appear to be constrained at some regulatory sites.
Expression of Wilms' tumor suppressor in the liver with cirrhosis: Relation to hepatocyte nuclear factor 4 and hepatocellular function
Authors: Carmen Berasain, José-Ignacio Herrero, Elena R. García-Trevijano, Matías A. Avila, Juan Ignacio Esteban, José M. Mato, Jesús Prieto
Journal: Hepatology (2003)

The Wilms' tumor suppressor WT1 is a transcriptional regulator present in the fetal but not in the mature liver. Its expression and functional role in liver diseases remains unexplored. In this study, we analyzed WT1 expression by reverse–transcription polymerase chain reaction (RT–PCR) and by immunohistochemistry in normal and diseased livers. In addition, we performed in vitro studies in isolated rat hepatocytes to investigate WT1 regulation and function. We detected WT1 messenger RNA (mRNA) in 18% of normal livers, 17% of chronic hepatitis with minimal fibrosis, 49% of chronic hepatitis with bridging fibrosis, and 71% of cirrhotic livers. In cirrhosis, WT1 immunoreactivity was localized to the nucleus of hepatocytes. WT1 mRNA abundance correlated inversely with prothrombin time ( P = .04) and directly with serum bilirubin ( P = .002) and with the MELD score ( P = .001) of disease severity. In rats, WT1 expression was present in fetal hepatocytes and in the cirrhotic liver but not in normal hepatic tissue. In vitro studies showed that isolated primary hepatocytes express WT1 when stimulated with transforming growth factor β (TGF–β) or when the cells undergo dedifferentiation in culture. Moreover, we found that WT1 down–regulates hepatocyte nuclear factor 4 (HNF–4), a factor that is essential to maintain liver function and metabolic regulation in the mature organ. Hepatic expression of HNF–4 was impaired in advanced human cirrhosis and negatively correlated with WT1 mRNA levels ( P = .001). In conclusion, we show that WT1 is induced by TGF–β and down–regulates HNF–4 in liver cells. WT1 is reexpressed in the cirrhotic liver in relation to disease progression and may play a role in the development of hepatic insufficiency in cirrhosis.
Abstract LB-188: Positive regulation of the Ras oncogene by ubiquitination
Authors: Atsuo T. Sasaki, Lewis C. Cantley
Journal: Cancer Research (2010)

Abstract Discussion Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-188.
Autosomal Dominant Progressive Nephropathy with Deafness
Authors: Sunil Prakash, Ki Wha Chung, Srish Sinha, Michael Barmada, Demetrius Ellis, Robert E Ferrell, David N Finegold, Parmjeet Singh Randhawa, Amit Dinda, Abhay Vats
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Focal segmental glomerulosclerosis (FSGS) and Alport syndrome (AS) are two major causes of end-stage renal disease (ESRD). A few families with autosomal dominant FSGS have been reported with linkage to chromosome 19q13 or 11q22, while AS is usually linked to mutations in type IV collagen (COL4) subunit genes. A phenotype resembling AS may also be seen with myosin heavy chain-9 (MYH9) gene mutations. This study ascertained a multigeneration family (CHP-177) with clinical aspects of both FSGS and AS where we identified a new locus for the trait. A genome-wide scan was performed with 400 markers, and fine mapping was performed for chromosome 11 markers. Data were analyzed by GENEHUNTER and VITESSE under various models. CHP-177 is a 39-member kindred residing near New Delhi, India, with seven affecteds and showed male-to-male transmission. Two members had ESRD. Renal biopsies showed both FSGS lesions and thin glomerular basement membranes. Five of the affecteds also had sensorineural deafness, which involved both low and high frequency in some members. The AS loci, <i>i.e.</i>, COL4A3/COL4A4 and MYH9 (LOD scores: −6.1 and −4.3, respectively) and FSGS loci, on 19q13 and 11q22, were excluded from linkage. A significant evidence of linkage was observed for 11q24 region, with a multipoint LOD (z-score) of 3.2 for marker D11S4464 at θ = 0. The z-1 confidence interval for the linked region spans a genetic distance of 7 cM. This study thus reports an autosomal dominant nephropathy with features of both FSGS and AS in which linkage to currently known loci for such phenotypes was excluded and a new locus on 11q24 was identified. The findings suggest further locus heterogeneity for the autosomal dominant nephropathy phenotype. E-mail: abhay.vats@chp.edu
Pharmacogenetic profiling across the doxorubicin pathway in Asian breast cancer patients
Authors: Edwin Sandanaraj, Suman Lal, Xiaoqiang Xiang, Edmund Lee, Balram Chowbay
Journal: Clinical Cancer Research (2007)

A60   The objective of this study was to investigate the influence of genetic variations in genes encoding doxorubicin metabolizing enzymes carbonyl reductases 1 and 3 ( CBR1  and  CBR3 ) and ATP-binding cassette transporters ( ABCB1  and  ABCC5 ) on the pharmacokinetics of doxorubicin in Asian breast cancer patients receiving adjuvant chemotherapy (N=48). Patients received doxorubicin (range: 56-61 mg/m 2 ) as a 20 minutes intravenous infusion and blood samples were collected at 0, 0.5, 1, 4, 8 and 24hrs. Non-linear mixed effect modeling was applied for the analysis of concentration-time profile of doxorubicin (NONMEM version 6). Doxorubicin pharmacokinetics was best described by a two-compartmental model, which included inter-individual variability (IIV) in terms of the fixed effect parameters [total plasma clearance (CL), the inter-compartmental clearance (Q) and the volume of distribution in central and peripheral compartments (V1 and V2)]. IIV was modeled based on an exponential relationship with fixed effect parameters and residual error model was described by the combination of additive and proportional equations. Model estimate for doxorubicin clearance (CL) was 44.7 L/h and inter-compartmental clearance (Q) was 46.8 L/h. The apparent volume of distribution in central compartment (V1) and peripheral compartment (V2) was 18.2 L and 537 L, respectively. Among the genetic and non-genetic covariates investigated, patient weight and  CBR1 . 219G>C  genotype showed significant associations with pharmacokinetics of doxorubicin.  CBR3  which has minimal relative tissue expression compared to  CBR1  did not show any influence on pharmacokinetics of doxorubicin. Weight alone explained 5.2% of inter-individual variability on doxorubicin clearance. The patients harbouring  CBR1 . 219G>C  observed 9% less clearance than the wild type (CL Lhr - 1: GG vs GC+CC: 48.2 ± 10.4 vs 41.8 ± 7.2; P = 0.03) and the exposure level was significantly higher in patients homozygous for the  CBR1 . 219C  allele (AUC μg hr L -1 : GG vs GC+CC: 1987 ± 376 vs 2275 ± 348.5; P = 0.045). The proposed population pharmacokinetic model incorporating patient weight and  CBR1  genotype status explained 22% of total variability in the clearance of doxorubicin in Asian breast cancer patients. No significant association of genetic and non genetic covariates on the pharmacokinetic parameters of doxorubicinol was observed.
Nucleosomes, ProGRP, NSE, CYFRA 21-1, and CEA in Monitoring First-Line Chemotherapy of Small Cell Lung Cancer
Authors: Stefan Holdenrieder, Joachim von Pawel, Elke Dankelmann, Thomas Duell, Bernhard Faderl, Andreas Markus, Maria Siakavara, Horst Wagner, Knut Feldmann, Harald Hoffmann, Hannelore Raith, Dorothea Nagel, Petra Stieber
Journal: Clinical Cancer Research (2008)

Besides new therapeutic drugs, effective diagnostic tools indicating early the efficacy of therapy are required to improve the individual management of patients with nonoperable cancer diseases.In prospectively collected sera of 128 patients with newly diagnosed small cell lung cancer receiving first-line chemotherapy, the courses of nucleosomes, progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), cytokeratin-19 fragments (CYFRA 21-1), and carcinoembryonic antigen were investigated and correlated with therapy response objectified by computed tomography before start of the third treatment course.In univariate analyses, high levels and insufficient decreases of nucleosomes, ProGRP, NSE, and CYFRA 21-1 during the first and second cycles of therapy correlated with poor outcome. Insufficient response to therapy was most efficiently indicated by the baseline values of nucleosomes, ProGRP, and CYFRA 21-1 before the second therapy cycle reaching areas under the curve (AUC) of 81.8%, 71.3%, and 74.9% in receiver operating characteristic curves, respectively. Combinations of nucleosomes with ProGRP (AUC 84.1%), CYFRA 21-1 (AUC 82.5%), and NSE (AUC 83.6%) further improved the diagnostic power in the high specificity range and yielded sensitivities of 47.1%, 35.3%, and 35.3% at 95% specificity, respectively. In multivariate analyses, including clinical and biochemical variables, only performance score and nucleosomes before cycle 2 were found to independently indicate therapy response.Biochemical markers specifically identified patients with insufficient therapy response at the early treatment phase and showed to be valuable for diseases management of small cell lung cancer.