tbuckley/cabot-search huggingface dataset:
Expansion of a CD8+PD-1+ Replicative Senescence Phenotype in Early Stage CLL Patients Is Associated with Inverted CD4:CD8 Ratios and Disease Progression
Authors: Claudia Nunes, Ryan Wong, Malcolm Mason, Chris Fegan, Stephen Man, Chris Pepper
Journal: Clinical Cancer Research (2011)

Patients with chronic lymphocytic leukemia (CLL) display immune deficiency that is most obvious in advanced stage disease. Here we investigated whether this immune dysfunction plays a pathologic role in the progression of early stage disease patients.We carried out eight-color immunophenotyping analysis in a cohort of 110 untreated early stage CLL patients and 22 age-matched healthy donors and correlated our findings with clinical outcome data.We found a significant reduction in naive CD4(+) and CD8(+) T cells in CLL patients. Only the CD4(+) subset showed significantly increased effector memory cells (T(EM) and T(EMRA)) in the whole cohort (P = 0.004 and P = 0.04, respectively). However, patients with inverted CD4:CD8 ratios (52 of 110) showed preferential expansion of the CD8 compartment, with a skewing of CD8(+) T(EMRA) (P = 0.03) coupled with increased percentage of CD57(+)CD28(-)CD27(-) T cells (P = 0.008) and PD-1 positivity (P = 0.027), consistent with a replicative senescence phenotype. Furthermore, inverted CD4:CD8 ratios were associated with shorter lymphocyte doubling time (P = 0.03), shorter time to first treatment (P = 0.03), and reduced progression-free survival (P = 0.005).Our data show that the emergence of CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with more aggressive clinical disease. Importantly, these findings were independent of tumor cell prognostic markers and could not be accounted for by patient age, changes in regulatory T-cell frequency, or cytomegalovirus serostatus (n = 217).
Impact of Metabolic Syndrome Compared With Impaired Fasting Glucose on the Development of Type 2 Diabetes in a General Japanese Population
Authors: Naoko Mukai, Yasufumi Doi, Toshiharu Ninomiya, Jun Hata, Koji Yonemoto, Masanori Iwase, Mitsuo Iida, Yutaka Kiyohara
Journal: Diabetes Care (2009)

OBJECTIVE We examined whether metabolic syndrome predicts incident type 2 diabetes more effectively than impaired fasting glucose (IFG) in a general Japanese population. RESEARCH DESIGN AND METHODS A total of 1,935 nondiabetic subjects aged 40–79 years were followed-up prospectively for a mean of 11.8 years. RESULTS During the follow-up, 286 subjects developed type 2 diabetes. Compared with those without metabolic syndrome, the multivariate-adjusted hazard ratio (HR) for incident type 2 diabetes was significantly higher in subjects of both sexes with metabolic syndrome, even after adjustment for confounding factors, age, family history of diabetes, total cholesterol, alcohol intake, smoking habits, and regular exercise (men: HR 2.58 [95% CI 1.85–3.59]; women: 3.69 [2.58–5.27]). The multivariate-adjusted HR of metabolic syndrome for type 2 diabetes was slightly lower in men and similar in women compared with that of IFG. The multivariate-adjusted HR for type 2 diabetes rose progressively as the number of metabolic syndrome components increased in both subjects with and without IFG. In stratified analysis, the multivariate-adjusted risk of type 2 diabetes was significantly higher in subjects with metabolic syndrome alone (2.37 [1.45–3.88]) or IFG alone (3.49 [2.57–4.74]) and markedly increased in subjects with both metabolic syndrome and IFG (6.76 [4.75–9.61]) than in subjects with neither metabolic syndrome nor IFG. Furthermore, the multivariate-adjusted risk for type 2 diabetes was also significantly higher in subjects with both metabolic syndrome and IFG than in those with either one alone (both P &amp;lt; 0.001). CONCLUSIONS Our findings suggest that metabolic syndrome significantly increases the risk of incident type 2 diabetes, independent of IFG, and is therefore a valuable tool to identify individuals at high risk of type 2 diabetes.
miR-2909-mediated regulation of KLF4: a novel molecular mechanism for differentiating between B-cell and T-cell pediatric acute lymphoblastic leukemias
Authors: Deepti Malik, Deepak Kaul, Nalini Chauhan, Ram Kumar Marwaha
Journal: Molecular Cancer (2014)

microRNAs (miRNAs) play both oncogenic and oncostatic roles in leukemia. However, the molecular details underlying miRNA-mediated regulation of their target genes in pediatric B- and T-cell acute lymphoblastic leukemias (ALLs) remain unclear. The present study investigated the relationship between miR-2909 and Kruppel-like factor 4 (KLF4), and its functional relevance to cell cycle progression and immortalization in patients with pediatric ALL. Elevated levels of miR-2909 targeted the tumor suppressor gene KLF4 in pediatric B-cell, but not pediatric T-cell ALL, as detected by pMIR-GFP reporter assay. Expression levels of genes including apoptosis-antagonizing transcription factor (AATF), MYC, B-cell lymphoma (BCL3), P21 CIP , CCND1 and SP1 in B- and T-cells from patients with pediatric ALL were compared with control levels using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and reporter assays. We identified two novel mutations in KLF4 in pediatric T-ALL. A mutation in the 3′ untranslated region of the KLF4 gene resulted in loss of miR-2909-mediated regulation, while mutation in its first or third zinc-finger motif (Zf1/Zf3) rendered KLF4 transcriptionally inactive. This mutation was a frameshift mutation resulting in alteration of the Zf3 motif sequence in the mutant KLF4 protein in all pediatric T-ALL samples. Homology models, docking studies and promoter activity of its target gene P21 CIP confirmed the lack of function of the mutant KLF4 protein in pediatric T-ALL. Moreover, the inability of miR-2909 to regulate KLF4 and its downstream genes controlling cell cycle and apoptosis in T-cell but not in B-ALL was verified by antagomiR-2909 transfection. Comprehensive sequence analysis of KLF4 identified the predominance of isoform 1 (~55 kDa) in most patients with pediatric B-ALL, while those with pediatric T-ALL expressed isoform 2 (~51 kDa). This study identified a novel miR-2909-KLF4 molecular axis able to differentiate between the pathogeneses of pediatric B- and T-cell ALLs, and which may represent a new diagnostic/prognostic marker.
Alteration of the Pulmonary Surfactant System in Full-Term Infants with Hereditary ABCA3 Deficiency
Authors: Frank Brasch, Sven Schimanski, Christian Mühlfeld, Stefan Barlage, Thomas Langmann, Charalampos Aslanidis, Alfred Boettcher, Ashraf Dada, Horst Schroten, Eva Mildenberger, Eric Prueter, Manfred Ballmann, Matthias Ochs, Georg Johnen, Matthias Griese, Gerd Schmitz
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

ABCA3 mutations are known to cause fatal surfactant deficiency.We studied ABCA3 protein expression in full-term newborns with unexplained respiratory distress syndrome (URDS) as well as the relevance of ABCA3 mutations for surfactant homeostasis.Lung tissue of infants with URDS was analyzed for the expression of ABCA3 in type II pneumocytes. Coding exons of the ABCA3 gene were sequenced. Surfactant protein expression was studied by immunohistochemistry, immunoelectron microscopy, and Western blotting.ABCA3 protein expression was found to be greatly reduced or absent in 10 of 14 infants with URDS. Direct sequencing revealed distinct ABCA3 mutations clustering within vulnerable domains of the ABCA3 protein. A strong expression of precursors of surfactant protein B (pro-SP-B) but only low levels and aggregates of mature surfactant protein B (SP-B) within electron-dense bodies in type II pneumocytes were found. Within the matrix of electron-dense bodies, we detected precursors of SP-C (pro-SP-C) and cathepsin D. SP-A was localized in small intracellular vesicles, but not in electron-dense bodies. SP-A and pro-SP-B were shown to accumulate in the intraalveolar space, whereas mature SP-B and SP-C were reduced or absent, respectively.Our data provide evidence that ABCA3 mutations are associated not only with a deficiency of ABCA3 but also with an abnormal processing and routing of SP-B and SP-C, leading to severe alterations of surfactant homeostasis and respiratory distress syndrome. To identify infants with hereditary ABCA3 deficiency, we suggest a combined diagnostic approach including immunohistochemical, ultrastructural, and mutation analysis.
THE TALKING PICTURES IN PSYCHIATRIC TEACHING AND RESEARCH
Authors: ALEXANDER H. LEIGHTON, THEODORE LIDZ
Journal: American Journal of Psychiatry (1942)

1. The sound film has a number of definite advantages as an adjunct to psychiatric teaching. Selection of case material can be improved, waste of time in teaching hours reduced, discussion can be free without harm to the patient, significant points can be driven home by captions, cutting and reprojecting the film, the whole course of an illness with the changing phases may be telescoped into half an hour, and the sound film can readily be used for instruction at places where the actual clinical material is not available. This may be of special value in military psychiatry, particularly for the instruction of non-commissioned officers at induction stations, and for teaching doctors about war neurosis before their arrival in combat zones. 2. In clinical research sound films are a means of preserving transient behavior and talk for analysis on the screen, for comparison of different phases of illness and for comparison of different patients. Selected segments of a patient's life and test situations can be recorded in a wholly objective manner. Some particular benefits derived in a study of aphasia are noted. It is suggested that very important advances can be made in the knowledge of brain function by using sound movies for the exact recording of behavior and speech disorders resulting from cranial injuries occurring in war.
Role of Vitamin K&lt;SUB&gt;2&lt;/SUB&gt; in the Development of Hepatocellular Carcinoma in Women With Viral Cirrhosis of the Liver
Authors: Daiki Habu
Journal: JAMA (2004)

a 2-year study showing that vitamin K 2 (menaquinone) helps to prevent bone loss in women with viral cirrhosis of the liver. 1 Most of the women agreed to participate in a longer study to clarify the long-term effects of vitamin K 2 on bone loss associated with cirrhosis.The incidence of hepatocellular carcinoma was found to differ between women who received vitamin K 2 and those who did not.
Diltiazem inhibits hKv1.5 and Kv4.3 currents at therapeutic concentrations
Authors: R CABALLERO, R GOMEZ, L NUNEZ, I MORENO, J TAMARGO, E DELPON
Journal: Cardiovascular Research (2004)

In the present study we examined the effects of diltiazem, an L-type Ca(2+) channel blocker widely used for the control of the ventricular rate in patients with supraventricular arrhythmias, on hKv1.5 and Kv4.3 channels that generate the cardiac ultrarapid delayed rectifier (I(Kur)) and the 4-aminopyridine sensitive transient outward (I(to)) K(+) currents, respectively.hKv1.5 and Kv4.3 channels were stably and transiently expressed in mouse fibroblast and Chinese hamster ovary cells, respectively. Currents were recorded using the whole-cell patch clamp.Diltiazem (0.01 nM-500 muM) blocked hKv1.5 channels, in a frequency-dependent manner exhibiting a biphasic dose-response curve (IC(50)=4.8+/-1.5 nM and 42.3+/-3.6 muM). Diltiazem delayed the initial phase of the tail current decline and shifted the midpoint of the activation (Vh=-16.5+/-2.1 mV vs -20.4+/-2.6 mV, P<0.001) and inactivation (Vh=-22.4+/-0.7 mV vs. -28.2+/-1.9 mV, P<0.001) curves to more negative potentials. The analysis of the development of the diltiazem-induced block yielded apparent association (k) and dissociation (P) rate constants of (1.6+/-0.2) x 10(6) M(-1)s(-1) and 46.8+/-4.8 s(-1), respectively. Diltiazem (0.1 nM-100 muM) also blocked Kv4.3 channels in a frequency-dependent manner exhibiting a biphasic dose-response curve (IC(50)=62.6+/-11.1 nM and 109.9+/-12.8 muM). Diltiazem decreased the peak current and, at concentrations > or =0.1 microM, accelerated the inactivation time course. The apparent association and dissociation rate constants resulted (1.7+/-0.2) x 10(6) M(-1)s(-1) and 258.6+/-38.1 s(-1), respectively. Diltiazem, 10 nM, shifted to more negative potentials the voltage-dependence of Kv4.3 channel inactivation (Vh=-33.1+/-2.3 mV vs -38.2+/-3.5 mV, n=6, Plt;0.05) the blockade increasing at potentials at which the amount of inactivated channels increased.The results demonstrated for the first time that diltiazem, at therapeutic concentrations, decreased hKv1.5 and Kv4.3 currents by binding to the open and the inactivated state of the channels.
Altered instantaneous and calcium-modulated oscillatory PTH secretion patterns in patients with secondary hyperparathyroidism.
Authors: C P Schmitt, D Huber, O Mehls, J Maiwald, G Stein, J D Veldhuis, E Ritz, F Schaefer
Journal: Journal of the American Society of Nephrology (1998)

The relative contributions of increased parathyroid cell mass and altered control mechanisms of parathyroid hormone (PTH) secretion in secondary hyperparathyroidism are still controversial. In this study, endogenous pulsatile PTH secretion was analyzed by the multiparameter deconvolution technique to differentiate alterations in cell mass-dependent (PTH burst mass) and regulation-dependent (frequency, synchrony, calcium responsiveness) PTH release in uremic patients. PTH concentration versus time profiles were obtained in 13 uremic and 16 healthy adults under baseline conditions and during acute hypo- and hypercalcemia. Plasma PTH half-life was increased in patients compared with control subjects (4.7+/-1.9 versus 2.6+/-0.1 min, P < 0.005). The baseline PTH secretion rate was elevated eightfold in the patients as a result of an increased PTH mass secreted per burst (17.1+/-4.7 versus 2.0+/-0.4 pM, P = 0.0001), higher burst frequency (8.0+/-0.3 versus 6.8+/-0.3 h(-1), P < 0.01), and a higher tonic secretion rate (343+/-99 versus 30+/-4 pM/h, P = 0.0001). Acute hypocalcemia elicited an immediate, frequency- and amplitude-mediated selective increase in the pulsatile secretory component, which was fractionally weaker in patients (+595%) than control subjects (+1755%, P < 0.001). The acceleration and the amplification of PTH bursts were 35 and 60% lower in the patient group. Acute hypercalcemia suppressed total PTH secretion by 79% in control subjects but only by 63% in patients (P < 0.002). PTH burst frequency was reduced during hypercalcemia by 30% in control subjects, but remained unchanged in patients. In conclusion, uremic hyperparathyroidism is mediated by a marked increase in glandular secretion, but also by reduced PTH elimination. The increased spontaneous PTH burst frequency and the blunted responsiveness to changes in Ca2+ indicate partial uncoupling of hyperplastic parathyroid glands from the physiologic regulatory mechanisms that direct pulsatile PTH release.
Angiogenin Regulation by Estradiol in Breast Tissue: Tamoxifen Inhibits Angiogenin Nuclear Translocation and Antiangiogenin Therapy Reduces Breast Cancer Growth <i>In vivo</i>
Authors: Ulrika W. Nilsson, Annelie Abrahamsson, Charlotta Dabrosin
Journal: Clinical Cancer Research (2010)

Angiogenin, a 14.2-kDa polypeptide member of the RNase A superfamily, has potent angiogenic effects. Nuclear accumulation of angiogenin is essential for its angiogenic activity. Increased angiogenin expression has been associated with the transition of normal breast tissue into invasive breast carcinoma. In this article, we investigated whether estradiol (E(2)) affected angiogenin in breast tissue.We used microdialysis for sampling of extracellular angiogenin in vivo. In vitro cultures of whole normal breast tissue, breast cancer cells, and endothelial cells were used.We show that extracellular angiogenin correlated significantly with E(2) in normal human breast tissue in vivo and that exposure of normal breast tissue biopsies to E(2) stimulated angiogenin secretion. In breast cancer patients, the in vivo angiogenin levels were significantly higher in tumors compared with the adjacent normal breast tissue. In estrogen receptor-positive breast cancer cells, E(2) increased and tamoxifen decreased angiogenin secretion. Moreover, E(2)-induced angiogenin derived from cancer cells significantly increased endothelial cell proliferation. Tamoxifen reversed this increase as well as inhibited nuclear translocation of angiogenin. In vivo, in experimental breast cancer, tamoxifen decreased angiogenin levels and decreased angiogenesis. Additionally, treating tumor-bearing mice with an antiangiogenin antibody resulted in tumor stasis, suggesting a role for angiogenin in estrogen-dependent breast cancer growth.Our results suggest previously unknown mechanisms by which estrogen and antiestrogen regulate angiogenesis in normal human breast tissue and breast cancer. This may be important for estrogen-driven breast cancer progression and a molecular target for therapeutic interventions.
On Some Recent Results in Pathological Histology, and on Scientific Therapeutics
Authors: E. L. Fox
Journal: BMJ (1873)

India, where so many circumstances combine to favour its occurrence ?The answer to this question I must leave to others who have had larger Indian experience than myself; and we must only hope that, now that more attention is being shown to the analysis of drinking-water in India, under the auspices of Dr. Macnamara and others, and that special inquiries as to the nature and spread of cholera are being systematically carried out by Dr.
Durable Carcinoembryonic Antigen (CEA)-Specific Humoral and Cellular Immune Responses in Colorectal Carcinoma Patients Vaccinated with Recombinant CEA and Granulocyte/Macrophage Colony-Stimulating Factor
Authors: Gustav J. Ullenhag, Jan-Erik Frödin, Mahmood Jeddi-Tehrani, Karin Strigård, Emma Eriksson, Ali Samanci, Aniruddha Choudhury, Bo Nilsson, Eva D. Rossmann, Szilvia Mosolits, Håkan Mellstedt
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Previous studies have indicated that carcinoembryonic antigen (CEA) might be a suitable immunotherapeutic target in colorectal carcinoma (CRC). The aim of the present study was to analyze the immunological and clinical effects of vaccination with CEA together with the adjuvant granulocyte/macrophage colony-stimulating factor (GM-CSF). Experimental Design: Twenty-four resected CRC patients without macroscopic disease were immunized seven times with recombinant CEA at four different dose levels over a 12-month period. Half of the patients received GM-CSF (80 μg/day for 4 consecutive days) at each immunization. Patients were monitored immunologically for 36 months and clinically for 76 months. T-cell response was evaluated by a [3H]thymidine incorporation assay, and IgG response was determined by ELISA. Results: Minor local side effects were common. All 12 patients (100%) in the GM-CSF group developed a CEA-specific T-cell as well as an IgG response. The corresponding figures in the CEA alone group were 9 of 12 (75%) and 8 of 12 (66%), respectively. GM-CSF significantly augmented the amplitude of the T-cell response and the IgG titers. No dose–response relationship was noted. The immune responses at 12 months persisted 24 months after the last vaccination. Anti-CEA IgG titers were associated with increased survival (P &amp;lt; 0.05), whereas standard prognostic factors had no relationship, with the exception of serum CEA value. Conclusions: Vaccination with recombinant CEA and GM-CSF appears to be a nontoxic regimen inducing potent and durable antigen-specific IgG and T-cell response. The results of this study justify more extensive trials with recombinant CEA protein for immunotherapy of CRC.
Hyperglycemic Crises in Adult Patients With Diabetes
Authors: Abbas E. Kitabchi, Guillermo E. Umpierrez, Mary Beth Murphy, Robert A. Kreisberg
Journal: Diabetes Care (2006)

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are the two most serious acute metabolic complications of diabetes. Most patients with DKA have autoimmune type 1 diabetes; however, patients with type 2 diabetes are also at risk during the catabolic stress of acute illness such as trauma, surgery, or infection. Table 1 outlines the diagnostic criteria and electrolyte and fluid deficits for both disorders. The mortality rate in patients with DKA is <5% in experienced centers, whereas the mortality rate of patients with HHS still remains high at ∼11% (1–8). Death in these conditions is rarely due to the metabolic complications of hyperglycemia or ketoacidosis but rather relates to the underlying precipitating illness. The prognosis of both conditions is substantially worsened at the extremes of age and in the presence of coma and hypotension (7,9–11)

This consensus statement will outline precipitating factors and recommendations for the diagnosis, treatment, and prevention of DKA and HHS in adult subjects. It is based on a previous technical review and more recently published peer-reviewed articles since 2001, which should be consulted for further information.

Although the pathogenesis of DKA is better understood than that of HHS, the basic underlying mechanism for both disorders is a reduction in the net effective action of circulating insulin coupled with a concomitant elevation of counterregulatory hormones, such as glucagon, catecholamines, cortisol, and growth hormone (1,3,4,8–13). DKA and HHS can fall anywhere along the disease continuum of diabetic metabolic derangements. At one extreme, pure DKA without significant hyperosmolarity typically indicates the total or relative absence of insulin (seen in type 1 diabetes). At the other extreme, HHS without ketoacidosis typically occurs with lesser degrees of insulin deficiency, as seen in type 2 diabetes. However, …
Combined suicide and cytokine gene therapy for peritoneal carcinomatosis
Authors: C Lechanteur, P Delvenne, F Princen, M Lopez, G Fillet, J Gielen, M P Merville, V Bours
Journal: Gut (2000)

<h3>BACKGROUND</h3> Gene therapy is a novel approach for the treatment of cancers, and tumours disseminated in the peritoneal cavity are suitable for in situ delivery of a therapeutic gene. <h3>AIMS</h3> The efficacy of a therapy combining a suicide gene (herpes simplex virus type I thymidine kinase (HSV-TK)) and cytokine genes was investigated in a model of peritoneal carcinomatosis induced by colon carcinoma cells in syngeneic rats. <h3>MATERIAL AND METHODS</h3> Pre-established macroscopic tumours in BDIX rats were treated by intraperitoneal injections of retrovirus producing cells (FLYA13 TK, FLYA13 granulocyte macrophage-colony stimulating factor (GM-CSF), FLYA13 interleukin 12 (IL-12)) and ganciclovir (GCV). <h3>RESULTS</h3> TK/GCV treated animals showed a slight increase in survival time (72 days) compared with the control group (63 days) while the association of cytokine and TK/GCV gene therapy resulted in significantly improved survival, with a large proportion of animals remaining tumour free on day 480 (60% and 40% for TK/GCV/GM-CSF and TK/GCV/IL-12 treated animals, respectively). Histological analysis of treated animals showed that the remaining tumour nodes were infiltrated by mononuclear cells but no major differences were observed between the various treatments. Immunohistochemical analysis revealed that lymphoid CD4<sup>+</sup>and CD8<sup>+</sup> T cells as well as macrophages accumulated outside untreated tumour nodes while CD8<sup>+</sup> and CD25<sup>+</sup>activated T cells and macrophages heavily infiltrated the tumours after the different treatments. <h3>CONCLUSIONS</h3> Our data indicate that combined suicide and cytokine gene therapy is a powerful approach for the treatment of macroscopic peritoneal carcinomatosis.