Miracle-dz/UniFAR-FTUs huggingface dataset:
Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo

Lithium has been demonstrated to increase neurogenesis in the dentate gyrus of rodent hippocampus. The present study was undertaken to investigate the effects of lithium on the proliferation and differentiation of rat neural progenitor cells in hippocampus both in vitro and in vivo. Lithium chloride (1–3 mm) produced a significant increase in the number of bromodeoxyuridine (BrdU)‐positive cells in high‐density cultures, but did not increase clonal size in low‐density cultures. Lithium chloride at 1 mm (within the therapeutic range) also increased the number of cells double‐labeled with BrdU antibody and TuJ1 (a class III β‐tubulin antibody) in high‐density cultures and the number of TuJ1‐positive cells in a clone of low‐density cultures, whereas it decreased the number of glial fibrillary acidic protein‐positive cells in both cultures. These results suggest that lithium selectively increased differentiation of neuronal progenitors. These actions of lithium appeared to enhance a neuronal subtype, calbindinD28k‐positive cells, and involved a phosphorylated extracellular signal‐regulated kinase and phosphorylated cyclic AMP response element‐binding protein‐dependent pathway both in vitro and in vivo. These findings suggest that lithium in therapeutic amounts may elicit its beneficial effects via facilitation of neural progenitor differentiation toward a calbindinD28k‐positive neuronal cell type.
Synchronized overproduction of AMPA, kainate, and NMDA glutamate receptors during human spinal cord development

Quantitative receptor autoradiography was used to map the distribution in the developing human spinal cord of the three types of ionotropic glutamate receptors. N‐methyl‐D‐Aspartate (NMDA) receptors were labeled with [3H]glutamate, kainic acid (KA) receptors were labeled with [3H]KA, and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole proprionate (AMPA) receptors were labeled with [3H]AMPA. In the adult, labeling of all three receptor subtypes is largely restricted to the substantia gelatinosa (SG) in the dorsal horn, with very low level labeling elsewhere in the spinal gray matter. In marked distinction, in late fetal life, high level ligand binding is seen throughout the spinal gray matter. In early postnatal life, binding sites diminish in all regions, but least so in the SG, until the adult pattern emerges. Thus a coordinated transient high level of ionotropic glutamate receptor expression occurs within the developing spinal cord. Saturation analysis of ligand binding shows that the affinity of [3H]KA and [3H]AMPA binding is not developmentally regulated. In contrast, the affinity of [3H]glutamate binding to the NMDA receptor in the fetal ventral horn is three‐fold greater than in the adult ventral horn. Thus, in addition to quantitative changes in glutamate receptor expression, qualitative changes occur in the expression of NMDA receptors during development. The distinct glutamate receptor phenotype of fetal and early postnatal spinal cord cells suggests that alterations in the excitable properties of these cells plays an important role in activity‐dependent development and in susceptibility to excitotoxic injury. J. Comp. Neurol. 384:200‐210, 1997. © 1997 Wiley‐Liss, Inc.
Does the Surgical Apgar Score Measure Intraoperative Performance?

Objective:To evaluate whether Surgical Apgar Scores measure the relationship between intraoperative care and surgical outcomes. Summary Background Data:With preoperative risk-adjustment now well-developed, the role of intraoperative performance in surgical outcomes may be considered. We previously derived and validated a 10-point Surgical Apgar Score—based on intraoperative blood loss, heart rate, and blood pressure—that effectively predicts major postoperative complications within 30 days of general and vascular surgery. This study evaluates whether the predictive value of this score comes solely from patients’ preoperative risk or also measures care in the operating room. Methods:Among a systematic sample of 4119 general and vascular surgery patients at a major academic hospital, we constructed a detailed risk-prediction model including 27 patient-comorbidity and procedure-complexity variables, and computed patients’ propensity to suffer a major postoperative complication. We evaluated the prognostic value of patients’ Surgical Apgar Scores before and after adjustment for this preoperative risk. Results:After risk-adjustment, the Surgical Apgar Score remained strongly correlated with postoperative outcomes (P < 0.0001). Odds of major complications among average-scoring patients (scores 7–8) were equivalent to preoperative predictions (likelihood ratio (LR) 1.05, 95% CI 0.78–1.41), significantly decreased for those who achieved the best scores of 9–10 (LR 0.52, 95% CI 0.35–0.78), and were significantly poorer for those with low scores—LRs 1.60 (1.12–2.28) for scores 5–6, and 2.80 (1.50–5.21) for scores 0–4. Conclusions:Even after accounting for fixed preoperative risk—due to patients’ acute condition, comorbidities and/or operative complexity—the Surgical Apgar Score appears to detect differences in intraoperative management that reduce odds of major complications by half or increase them by nearly 3-fold.
Role of the texture features of images in the diagnosis of solitary pulmonary nodules in different sizes.

OBJECTIVE To explore the role of the texture features of images in the diagnosis of solitary pulmonary nodules (SPNs) in different sizes. MATERIALS AND METHODS A total of 379 patients with pathologically confirmed SPNs were enrolled in this study. They were divided into three groups based on the SPN sizes: ≤10, 11-20, and >20 mm. Their texture features were segmented and extracted. The differences in the image features between benign and malignant SPNs were compared. The SPNs in these three groups were determined and analyzed with the texture features of images. RESULTS These 379 SPNs were successfully segmented using the 2D Otsu threshold method and the self-adaptive threshold segmentation method. The texture features of these SPNs were obtained using the method of grey level co-occurrence matrix (GLCM). Of these 379 patients, 120 had benign SPNs and 259 had malignant SPNs. The entropy, contrast, energy, homogeneity, and correlation were 3.5597±0.6470, 0.5384±0.2561, 0.1921±0.1256, 0.8281±0.0604, and 0.8748±0.0740 in the benign SPNs and 3.8007±0.6235, 0.6088±0.2961, 0.1673±0.1070, 0.7980±0.0555, and 0.8550±0.0869 in the malignant SPNs (all P<0.05). The sensitivity, specificity, and accuracy of the texture features of images were 83.3%, 90.0%, and 86.8%, respectively, for SPNs sized ≤10 mm, and were 86.6%, 88.2%, and 87.1%, respectively, for SPNs sized 11-20 mm and 94.7%, 91.8%, and 93.9%, respectively, for SPNs sized >20 mm. CONCLUSIONS The entropy and contrast of malignant pulmonary nodules have been demonstrated to be higher in comparison to those of benign pulmonary nodules, while the energy, homogeneity correlation of malignant pulmonary nodules are lower than those of benign pulmonary nodules. The texture features of images can reflect the tissue features and have high sensitivity, specificity, and accuracy in differentiating SPNs. The sensitivity and accuracy increase for larger SPNs.
Conjugal transfer from Streptococcus lactis ME2 of plasmids encoding phage resistance, nisin resistance and lactose-fermenting ability: evidence for a high-frequency conjugative plasmid responsible for abortive infection of virulent bacteriophage.

Streptococcus lactis ME2 exhibits at least three mechanisms which confer resistance to virulent bacteriophage. These include plasmid-induced interference with phage adsorption, host-controlled restriction and modification activities, and a heat-sensitive mechanism which suppresses development of virulent phage. Conjugal mating experiments were done with S. lactis ME2 to determine if phage-defence mechanisms present in this strain could be mobilized, associated with plasmid DNA elements and phenotypically characterized in transconjugants. Agar-surface matings of S. lactis ME2 with S. lactis LM0230 demonstrated that lactose-fermenting ability (Lac+) was transferred in a conjugation-like process at frequencies of 10(-6) per donor cell and was associated with a 40 MDal plasmid designated pTR1040. Resistance to nisin (Nisr) was acquired or lost simultaneously with Lac+, indicating that pTR1040 carried determinants for both phenotypes. Lac+ Nisr transconjugants that carried a 30 MDal plasmid (pTR2030) exhibited a heat-sensitive phage-defence mechanism (Hsp+) which limited the burst size and plaque size of phage c2 without altering the efficiency of plaquing (e.o.p.) or the level of adsorption. The ability of phage c2 to initiate plaquing at an e.o. p. of 1.0 indicated that DNA injection and early viral gene expression are not affected in the Hsp+ transconjugants. We suggest, therefore, that the Hsp+ phenotype may result from plasmid-induced abortive infection of phage dependent on the presence of pTR2030. Hsp+ transconjugants carrying pTR2030 also promoted high-frequency conjugal transfer of Lac+ Nisr associated with pTR1040 (greater than 10(-1) per donor cell). It was concluded that Hsp+ and determinants for conjugal transfer ability (Tra+) are located on pTR2030.
Natural history of attempts to stop smoking.

INTRODUCTION This study provides a prospective fine-grain description of the incidence and pattern of intentions to quit, quit attempts, abstinence, and reduction in order to address several clinical questions about self-quitting. METHODS A total of 152 smokers who planned to quit in the next 3 months called nightly for 12 weeks to an Interactive Voice Response system to report cigarettes/day, quit attempts, intentions to smoke or not in the next day, and so forth. No treatment was provided. RESULTS Most smokers (60%) made multiple transitions among smoking, reduction, and abstinence. Intention to not smoke or quit often did not result in a quit attempt but were still strong predictors of a quit attempt and eventual abstinence. Most quit attempts (79%) lasted less than 1 day; about one fifth (18%) of the participants were abstinent at 12 weeks. The majority of quit attempts (72%) were not preceded by an intention to quit. Such quit attempts were shorter than quit attempts preceded by an intention to quit (<1 day vs. 25 days). Most smokers (67%) used a treatment, and use of a treatment was nonsignificantly associated with greater abstinence (14 days vs. 3 days). Making a quit attempt and failing early predicted an increased probability of a later quit attempt compared to not making a quit attempt early (86% vs. 67%). Smokers often (17%) failed to report brief quit attempts on an end-of-study survey. CONCLUSIONS Cessation is a more chronic, complex, and dynamic process than many theories or treatments assume.
APM2 is a novel mediator of cisplatin resistance in a variety of cancer cell types regardless of p53 or MMR status

Cisplatin is one of the most widely used chemotherapeutics in the world today. Unfortunately, chemoresistance often develops hindering the effectiveness of the drug. Mismatch‐repair (MMR) and p53 have previously been shown to be important determinants of cisplatin resistance and can contribute to cisplatin resistance clinically. Here, we have used cDNA microarray to identify several genes as up or downregulated in a previously described, cisplatin resistant, clone of the HCT116 cell line (HCT116‐K). On follow‐up, one gene, APM2, was found to promote cisplatin resistance when overexpressed in sensitive HCT116 clones. Furthermore, silencing APM2 in a panel of cell lines encompassing all combinations of p53 status and MMR proficiency (HCT116‐K, HCT116, SW620, MCF7, PC‐3 and OV2008) resulted in sensitization regardless of these 2 factors. In addition, silencing APM2 stably using shRNA also resulted in the sensitization of cells to cisplatin. More importantly, cisplatin inhibited the growth of APM2 silenced tumor xenografts (HCT116‐K or OV2008 cells) significantly better than it inhibited the growth of xenografts carrying nontargeting control shRNAs. These findings represent a novel strategy that could be exploited to overcome cisplatin resistance in patients regardless of p53 status or ability to perform MMR. © 2009 UICC
The intention-to-treat approach in randomized controlled trials: Are authors saying what they do and doing what they say?

Background Intention-to-treat (ITT) is an approach to the analysis of randomized controlled trials (RCT) in which patients are analyzed as randomized regardless of the treatment actually received. Purpose To ascertain the proportion of RCT reporting the use of intention-to-treat and the accuracy of that report and to examine the distribution and analysis of missing data for the studies reporting an ITT analysis. Method We conducted a cross-sectional literature review of RCTs reported in 10 medical journals in 2002. All articles were assessed using a standardized form. Two evaluators independently reviewed a 10% sample of articles to assess reliability. Subsequently, one evaluator reviewed the remaining articles. The proportion of articles reporting the use of ITT was calculated. Among these, the proportion of articles that `analyzed patients as randomized' and the proportion and analysis of missing data were evaluated using standardized definitions. Results Of the 403 articles, 249 (62%) reported the use of ITT. Among these, available patients were clearly analyzed as randomized in 192 (77%). Authors used a modified ITT in 23 (9%); clearly violated a major component of ITT in 17 (7%), and the approach used was unclear in 17 (7%). More than 60% of articles had missing data in their primary analysis. Few articles reported a strategy for missing data. The main reason for missing data was loss to follow-up. Limitations A single evaluator evaluated most articles, but the high concordance obtained during the inter-rater evaluation suggests that the assessments were consistent. In addition, the small spectrum of journals limits generalizability. Finally, there could be a difference between what was reported and what was performed. Conclusions This study emphasizes that authors use the label `intention-to-treat' quite differently. The most common use refers to the analysis of all available subjects as randomized regardless of the missing data aspect. Clinical Trials 2007; 4: 350—356. http://ctj.sagepub. com
Activation of Toll-Like Receptor 2 (TLR2) and TLR4/MD2 by Neisseria Is Independent of Capsule and Lipooligosaccharide (LOS) Sialylation but Varies Widely among LOS from Different Strains

ABSTRACT Lipooligosaccharide (LOS) structure and capsular polysaccharide of Neisseria meningitidis each greatly influence the virulence of the organism and the quality of host innate immune responses. In this study, we found that production of the proinflammatory cytokine tumor necrosis factor (TNF) by a human monocyte-derived cell line (THP-1) exposed to strains of N. meningitidis lacking capsule and/or with truncated LOS was similar to that elicited by the isogenic wild-type strain. These mutants also exhibited no difference in induction of the interleukin-8 (IL-8) promoter in a transfected HeLa cell system of Toll-like receptor 2 (TLR2) and TLR4/MD2 signaling. However, purified LOS from diverse strains of Neisseria (both N. meningitidis and N. gonorrhoeae) caused widely variant levels of IL-8 promoter induction in cells expressing MD2 that correlated with the production of TNF from THP-1 cells. These data suggest that although modification of the oligosaccharide chain of LOS and/or absence of capsule do not affect cell signaling mediated by TLR4/MD2, fine-structural differences in the LOS do influence signaling through TLR4/MD2 and, through this pathway, influence some of the proinflammatory responses elicited by Neisseria.
Effects of cyclopiazonic acid on contractility and ecto‐ATPase activity in guinea‐pig urinary bladder and vas deferens

1 Cyclopiazonic acid (CPA), an inhibitor of sarcoplasmic ATPase, was tested on guinea‐pig urinary bladder and vas deferens for its ability: (1) to modify contractile responses to electrical field stimulation (EFS), exogenous ATP, α,β‐methylene ATP (α,β‐meATP), carbachol, noradrenaline (NA), histamine, and KCl; (2) to affect ecto‐ATPase activity; (3) to modify the release of ATP evoked by EFS. 2 In the urinary bladder, CPA (10 μm) potentiated contractile responses to EFS, exogenous ATP (100 μm), α,β‐meATP (1 μm), carbachol (0.5 μm), histamine (30 μm) and KCl (30 μm). In the vas deferens, CPA (10 μm) potentiated responses to EFS, ATP, α,β‐meATP, NA (100 μm) and KCl. CPA at a concentration of 1 μm had no effect on ATP‐induced relaxation of carbachol‐precontracted guinea‐pig taenia coli, and at a concentration of 10 μm it markedly increased spontaneous contractile activity of taenia. 3 Ecto‐ATPase was estimated to have Vmax and Km values of 0.98 nmol Pi 30 min−1 mg−1 wet tissue and 881 μm ATP in the urinary bladder, and 0.75 nmol Pi 30 min−1 mg−1 wet tissue and 914 μm ATP in the vas deferens, respectively. CPA at a concentration of 10 μm significantly inhibited ecto‐ATPase activity by 18% in the urinary bladder and by 24% in the vas deferens. 4 In the guinea‐pig vas deferens, CPA significantly potentiated ATP release evoked by EFS from 2.2 ± 0.8 (6) pmol ATP min−1 g−1 wet tissue to 35.2 ± 4.8 (6) pmol ATP min−1 g−1 wet tissue (P < 0.01). 5 In conclusion, the potentiation of contractile responses of the guinea‐pig urinary bladder and vas deferens by CPA has a non‐specific character. CPA inhibited ecto‐ATPase activity and increased ATP release, but these effects do not appear to contribute to the potentiation of P2x‐purinoceptor‐mediated responses since the contractile actions of all the agonists studied were potentiated to the same extent.
Phosphatase of regenerating liver‐3 as a convergent therapeutic target for lymph node metastasis in esophageal squamous cell carcinoma

Phosphatase of regenerating liver‐3 (PRL‐3) is a molecule associated with metastasis in a diverse of cancers, which, however, remains largely unknown in esophageal squamous cell carcinoma (ESCC). We examined both the clinical significance of PRL‐3 expression and its biological roles, and assessed possibilities as a therapeutic target in ESCC. PRL‐3 expression was found in 78% (69 of 88) of the primary ESCC on immunohistochemistry; it was the strong independent predictor for lymph node metastasis (LNM) on a multivariate logistic regression model (p = 0.0014, relative risk =15.20). Additionally, gene amplification was found in 3 (7.9%) of the 38 primary tumors with PRL‐3 overexpression by fluorescence in situ hybridization, but in none of the 19 tumors without it. PRL‐3 small interfering RNA robustly repressed cell proliferation, anchorage‐independent colony formation and invasion and augmented 5‐FU‐induced apoptosis in all the tested ESCC cell lines with PRL‐3 overexpression, irrespective of its gene amplification status. PRL‐3 inhibitor (1‐4‐bromo‐2‐benzylidene rhodanine) also suppressed such metastatic properties in the cell lines with PRL‐3 overexpression, but not with its low expression. Inverse effects were observed by PRL‐3 forced expression. Collectively, PRL‐3 overexpression is a frequent event associated with LNM and plays a causative role in promoting cancer progression. Moreover, the expression status may be a landmark to select patients with benefit from PRL‐3‐targeted therapy. Thus, PRL‐3 could be a convergent therapeutic target against ESCC with LNM.
Telomere Length in Human Natural Killer Cell Subsets

Abstract: Natural killer (NK) cells are cytotoxic cells that play a critical role in the innate immune response against infections and tumors. In the elderly, the cytotoxic function of NK cells is often compromised. Telomeres progressively shorten with each cell division and with age in most somatic cells eventually leading to chromosomal instability and cellular senescence. We studied the telomere length in NK cell subsets isolated from peripheral blood using “flow FISH,” a method in which the hybridization of telomere probe in cells of interest is measured relative to internal controls in the same tube. We found that the average telomere length in human NK cells decreased with age as was previously found for human T lymphocytes. Separation of adult NK cells based on CD56 and CD16 expression revealed that the telomere length was significantly shorter in CD56dimCD16+ (mature) NK cells compared to CD56brightCD16− (immature) NK cells from the same donor. Furthermore, sorting of NK cells based on expression of activation markers, such as NKG2D and LFA‐1, revealed that NK cells expressing these markers have significantly shorter telomeres. Telomere fluorescence was very heterogeneous in NK cells expressing CD94, killer inhibitory receptor (KIR), NKG2A, or CD161. Our observations indicate that telomeric DNA in NK cells is lost with cell division and with age similar to what has been observed for most other hematopoietic cells. Telomere attrition in NK cells is a plausible cause for diminished NK cell function in the elderly.
Hematopoietic Stem Cell Origin of BRAFV600E Mutations in Hairy Cell Leukemia

The cell of origin for the chronic lymphoproliferative disorder hairy cell leukemia is a long-term hematopoietic stem cell, as shown through human genetic data and murine genetic models. Finding the Origin Story for a Leukemia The cells that give rise to a cancer called hairy cell leukemia are hematopoietic stem cells, the precursors for all the types of normal blood cells, according to a new study by Chung et al. Although hairy cell leukemia is usually thought to be derived from mature B cells, it has not previously been matched with any specific stage of normal B cell development. Now, the authors performed detailed genetic analysis of human leukemia samples and also modeled this cancer in mice with different types of mutations, thus revealing the origin for hairy cell leukemia. Understanding the causes of this leukemia should help guide the design of effective treatments and may improve our understanding of similar cancers. Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder characterized by somatic BRAFV600E mutations. The malignant cell in HCL has immunophenotypic features of a mature B cell, but no normal counterpart along the continuum of developing B lymphocytes has been delineated as the cell of origin. We find that the BRAFV600E mutation is present in hematopoietic stem cells (HSCs) in HCL patients, and that these patients exhibit marked alterations in hematopoietic stem/progenitor cell (HSPC) frequencies. Quantitative sequencing analysis revealed a mean BRAFV600E-mutant allele frequency of 4.97% in HSCs from HCL patients. Moreover, transplantation of BRAFV600E-mutant HSCs from an HCL patient into immunodeficient mice resulted in stable engraftment of BRAFV600E-mutant human hematopoietic cells, revealing the functional self-renewal capacity of HCL HSCs. Consistent with the human genetic data, expression of BRafV600E in murine HSPCs resulted in a lethal hematopoietic disorder characterized by splenomegaly, anemia, thrombocytopenia, increased circulating soluble CD25, and increased clonogenic capacity of B lineage cells—all classic features of human HCL. In contrast, restricting expression of BRafV600E to the mature B cell compartment did not result in disease. Treatment of HCL patients with vemurafenib, an inhibitor of mutated BRAF, resulted in normalization of HSPC frequencies and increased myeloid and erythroid output from HSPCs. These findings link the pathogenesis of HCL to somatic mutations that arise in HSPCs and further suggest that chronic lymphoid malignancies may be initiated by aberrant HSCs.