To assess in children with optic nerve hypoplasia (ONH) whether newborn screening (NBS) thyroid-stimulating hormone (TSH) measurements can detect central hypothyroidism and whether newborn TSH or subsequent thyroidal status is associated with visual function.
A subset of patients in the registry of children with ONH at Children’s Hospital Los Angeles who were born in California was used to make a retrospective comparison of NBS TSH levels and subsequent postnatal thyroid status. Another subset of registry subjects with vision and thyroid status data at age 5 years was assessed for the relationship of vision to NBS TSH levels and ultimate thyroidal status.
A total of 135 subjects from the ONH registry were included in this study. Approximately 50% of subjects in each analysis were hypothyroid. Those diagnosed with hypothyroidism had lower median NBS TSH levels than did euthyroid subjects (3.2 vs 4.5 μIU/mL; P = 0.006) and significantly worse quantitative vision outcomes (median visual acuity, logMAR 3.0 vs 1.0; P = 0.039). Receiver operating characteristic analysis suggested an optimal NBS TSH cut-point of 3.3 μIU/mL. Serum TSH over this level (30/43) was associated with relatively better vision outcomes (median visual acuity, logMAR 1.2 vs 3.3; P = 0.04).
Children with ONH and lower NBS TSH levels are more likely to have central hypothyroidism and less likely to experience good vision than those with higher NBS TSH levels.
Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specific-promoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy.
Progression Elevated Gene-3; Sabutoclax; Apogossypol; BI-97C1; Gossypol; AP-1; PEA3; ETV4; E1AF; c-fos; c-jun; Cancer Terminator Virus
Dickkopf 1 (DKK1) is a secreted inhibitor of the Wnt signaling pathway and a critical modulator of tumor promotion and the tumor microenvironment. However, mechanisms regulating DKK1 expression are understudied. DNAJB6 is an HSP40 family member whose expression is compromised during progression of breast cancer and melanoma. Inhibition of Wnt/β-catenin signaling pathway, by up-regulation of DKK1, is one of the key mechanisms by which DNAJB6 suppresses tumor, metastasis and epithelial-mesenchymal transition (EMT). Analysis of the DKK1 promoter to define the cis-site responsible for its up regulation by DNAJB6 revealed the presence of two binding sites for a transcriptional repressor, MSX1 (muscle segment homeobox gene). Our investigations showed that MSX1 binds the DKK1 promoter and inhibits DKK1 transcription. Interestingly, silencing DNAJB6 resulted in up-regulation of MSX1 concomitant with increased stabilization of β-catenin. ChIP studies revealed that β-catenin binds MSX1 promoter and stabilization of β-catenin elevates MSX1 transcription, indicating that β-catenin works as a transcription co-activator for MSX1. Functionally, exogenous expression of MSX1 in DNAJB6 expressing cells promotes the mesenchymal phenotype by suppression of DKK1. Thus we have identified a novel regulatory mechanism of DNAJB6 mediated DKK1 transcription up-regulation that can influence epithelial-mesenchymal transition. DKK1 is a feedback regulator of β-catenin levels. Thus our studies also define an additional negative control of this β-catenin-DKK1 feedback loop by MSX1, which may potentially contribute to excessive stabilization of β-catenin.
DNAJB6; EMT; MSX1; DKK1; Wnt
High fever and/or rash prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥13.2Gy)-based myeloablative conditioning. Tacrolimus (n=35) or cyclosporine (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥38.5°C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% CI) of PES was 77% (66%–88%). The incidence of PES was significantly higher in patients who received cyclosporine as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact overall survival or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of cyclosporine for GVHD prophylaxis increases the risk of PES following dual umbilical cord blood transplantation.
pre-engraftment syndrome; dual umbilical cord blood transplantation; myeloablative
HSP40 family member MRJ (DNAJB6) has been in the spot light for its relevance to Huntington’s, Parkinson’s diseases, limb-girdle muscular dystrophy, placental development, neural stem cells, cell cycle and malignancies such as breast cancer and melanoma. This gene has two spliced variants coding for 2 distinct proteins with significant homology. However, MRJ(L) (large variant) is predominantly localized to the nucleus whereas MRJ(S) (small variant) is predominantly cytoplasmic. Interestingly MRJ(S) translocates to the nucleus in response to heat shock. The classical heat shock proteins respond to crises (stress) by increasing the number of molecules, usually by transcriptional up-regulation. Our studies imply that a quick increase in the molar concentration of MRJ in the nuclear compartment is a novel method by which MRJ responds to stress. We found that MRJ(S) shows NLS (nuclear localization signal) independent nuclear localization in response to heat shock and hypoxia. The specificity of this response is realized due to lack of such response by MRJ(S) when challenged by other stressors, such as some cytokines or UV light. Deletion analysis has allowed us to narrow down on a 20 amino acid stretch at the C-terminal region of MRJ(S) as a potential stress sensing region. Functional studies indicated that constitutive nuclear localization of MRJ(S) promoted attributes of malignancy such as proliferation and invasiveness overall indicating distinct phenotypic characteristics of nuclear MRJ(S).
MRJ; DnaJB6; NLS; Heat Shock
Current American Thyroid Association (ATA) guidelines recommend routine cervical ultrasound (US) in thyroid nodule evaluation. Specific US characteristics can help diagnose papillary thyroid carcinoma (PTC). The aim of this blinded cohort study was to determine whether these specific US characteristics can also reliably detect the more aggressive variants of PTC that are often associated with the BRAFV600E mutation.
After Institutional Review Board approval, we identified a cohort of patients from January 2007 to December 2009 with histologic PTC≥1 cm who had cervical US, initial thyroid surgery, and molecular testing for BRAFV600E on fine-needle aspiration biopsy or histology. Preoperative US images were evaluated by a single radiologist, who was blinded to BRAF status, for nodule size and the presence or absence of the following suspicious US features: taller-than-wide shape, ill-defined margins, hypoechogenicity, calcifications, noncystic composition, and absent halo.
BRAF-positivity was associated with most known suspicious US findings, including taller-than-wide shape (47% vs. 7%, p<0.001), ill-defined margins (42% vs. 9%, p<0.001), hypoechogenicity (83% vs. 36%, p<0.001), micro/macrocalcifications (87% vs. 24%, p<0.001), and absent halo (85% vs. 27%, p<0.001) but was not associated with noncystic composition. When ≥3 suspicious US features were present, BRAF-positivity was predicted with a positive predictive value of 82%. The absence of suspicious US features together with negative BRAF testing predicted PTC without extrathyroidal extension or lymph node metastasis (negative predictive value 88%).
With routine preoperative cervical US and molecular testing, a trained radiologist or surgeon can improve the preoperative characterization of PTC, potentially impacting risk stratification and initial surgical management.
Human immunodeficiency virus (HIV)-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction among HIV-infected children with and without hyperlipidemia to HIV-exposed, uninfected children (HEU) enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers.
Prospective cohort study
Biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP1)); coagulant dysfunction (fibrinogen and P-selectin); endothelial dysfunction (soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), and E-selectin); and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded.
The median ages were 12.3 y (HIV-infected) and 10.1 y (HEU). Body mass index (BMI) Z-scores, waist and hip circumference, and percent body fat were lower among HIV-infected. Total and non-HDL cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children had higher MCP-1, fibrinogen, sICAM, and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavorable lipid profiles were positively associated with IL6, MCP1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP1 and CRP) and endothelial dysfunction (sICAM and sVCAM).
HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavorable lipid levels and active HIV replication.
Children; HIV/AIDS; vascular dysfunction; cardiovascular risk factors; biomarkers
Impact of activating (aKIR) and inhibitory (iKIR) on overall survival (OS), relapse-related mortality (RRM), and acute graft-vs.-host disease (aGVHD) were studied in 84 adults with high risk hematologic malignancies receiving reduced intensity conditioning (RIC) T-cell depleted hematopoietic stem cell transplantation (HSCT) from haploidentical related donors. In this clinical model, freedom from RRM was more dependent on graft-vs-leukemia (GVL) effect. Patients were divided into myeloid (n=49) and lymphoid (n=35) malignancy groups. KIR-ligand and ligand-ligand models were studied in both directions and statistically correlated with outcome measures. In the myeloid group, OS was higher (p=0.009) and RRM lower (p=0.036) in patients missing HLA-C group2 ligand to donor inhibitory KIR. OS was higher if patients had >1 missing ligand (p=0.018). In lymphoid malignancy, missing ligand to donor KIR had no impact on OS or RRM. However, OS was longer with donor activating KIR 2DS2 (p=0.028). There was a trend toward shorter OS in recipient with KIR 2DS1, 2DS5 and 3DS1, although sample sizes are too small to provide inferential statistics. These results suggest that absence of appropriate HLA ligands in the recipient to donor iKIR may induce GVL without aGVHD in myeloid malignancy patients undergoing TCD-RIC transplants.
KIR; Activating KIR; Inhibitory KIR; Haploidentical; Reduced Intensity Conditioning (RIC); Hematopoietic Stem Cell Transplantation (HSCT)
Dickkopf1 (DKK1), a secreted inhibitor of the Wnt/β-catenin pathway, is a negative regulator of bone formation. DKK1 acts as a switch that transitions prostate cancer bone metastases from osteolytic to osteoblastic and also is an active indicator of poor outcome for multiple myeloma. However, in other tumor types, DKK1 up-regulation or over-expression suppresses tumor growth. Thus, the role of DKK1 in cancer appears to be diverse. This raises a question: Could the increased levels of DKK1 still be tumor protective when observed in high levels in the serum of patients? Here, we summarize the diverse, seemingly contradicting roles of DKK1 and attempt to explain the apparent dichotomy in its activity. We propose that DKK1 is a critical secreted factor that modulates microenvironment. Based on the location and components of the microenvironment DKK1 will support different outcomes.
Accelerated central arterial stiffening as represented by progression of aortic pulse-wave velocity (PWV) may be influenced by cardiovascular disease (CVD) risk factors. Little is known about the relationships between CVD risk factors and PWV progression among women transitioning through the menopause, or whether these relationships vary by ethnicity. To address this knowledge gap, we conducted a subgroup analysis of 303 African American and Caucasian participants in the Study of Women's Health Across the Nation (SWAN) Heart Study received PWV scans at baseline examination and at a follow-up examination an average of 2.3 years later. CVD risk factors were also assessed at baseline.
Methods and Results
Systolic blood pressure (SBP) and waist circumference were the strongest predictors of PWV progression, after adjustment for age, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), diastolic blood pressure (DBP), glucose, and triglyceride levels. The magnitude of the influence of SBP, DBP, LDL-C, and glucose on PWV progression varied by ethnicity (difference in slopes: p=0.02 for SBP, p=0.0009 for DBP, p=0.005 for LDL-C, and p=0.02 for glucose). The positive relationship between SBP and PWV progression was significant among women of both ethnicities. LDL-C, DBP, and, to a lesser extent, glucose levels were positively associated with PWV progression only among African Americans.
Blood pressure, LDL-C, glucose, and excess body size may be important targets for improving vascular health and preventing clinical outcomes related to arterial stiffening, particularly among African American women.
arteriosclerosis; risk factors; aging; ethnicity; pulse wave velocity; atherosclerosis
Purpose of review
Congenital adrenal hyperplasia (CAH) can present management challenges to the pediatric clinician. Glucocorticoid replacement remains the cornerstone of treatment; however, there are new formulations and delivery mechanisms being studied. Clinicians continue to discuss the optimal treatment of patients from the prenatal stage, through infancy to adulthood. As well, the role of genetics in the clinical care of patients with CAH, and screening for complications, remain topics of discussion. This review will highlight advances made in the past year, as they pertain to the management of pediatric patients with CAH.
This article covers recent studies pertaining to optimal medication regimens, including prenatal dexamethasone treatment; medication delivery; monitoring of hormonal control; and the role of genotyping and genetics in the management of children with CAH.
Much remains to be learned about the optimal management of children with CAH, including fludrocortisone replacement in simple-virilizing patients, frequency of and specific monitoring strategies (e.g., electrolytes, bone age, etc.), catecholamine status, stress-dosing in non-classical adrenal hyperplasia, and early screening for complications or metabolic sequelae. Further randomized, prospective studies are needed to address these issues.
Congenital adrenal hyperplasia; CAH; NCAH; childhood; treatment
An 18-month-old female status post-orthotopic liver transplant for biliary atresia presented nine months after transplant with severe diarrhea and intolerance of feeds. She was found to have a PLE as evidenced by a low serum albumin and a persistent elevation of fecal A1AT. Investigation eventually revealed that the cause of the PLE was a stricture at the anastomosis site between the hepatic vein and inferior cava, supported by resolution of the PLE after venoplasty of the stricture. The patient has subsequently required several repeat venoplasties for recurrence of her symptoms correlating with recurrence of the stricture. This is a very rare presentation of hepatic venous outflow obstruction. Moreover, normal duplex ultrasound imaging of liver vasculature and her unusual presentation led to a delay in her diagnosis highlighting the need for an increased index of suspicion.
diarrhea; infant; liver transplant
Many important experiments in cancer research are initiated with cell line data analysis due to the ease of accessibility and utilization. Recently, the ability to capture and characterize circulating tumor cells (CTCs) has become more prevalent in the research setting. This ability to detect, isolate, and analyze CTCs allows us to directly compare specific protein expression levels found in patient CTCs to cell lines. In this study, we use immunocytochemistry to compare the protein expression levels of total cytokeratin (CK) and androgen receptor (AR) in CTCs and cell lines from patients with prostate cancer to determine what translational insights might be gained through the use of cell line data. A non-enrichment CTC detection assay enables us to compare cytometric features and relative expression levels of CK and AR by indirect immunofluorescence from prostate cancer patients against the prostate cancer cell line LNCaP. We measured physical characteristics of these two groups and observed significant differences in cell size, fluorescence intensity, and nuclear to cytoplasmic (N/C) ratio. We hope that these experiments will initiate a foundation to allow cell line data to be compared against characteristics of primary cells from patients.
As important as the events that influence selection for specific chromosome types in the derivation of novel karyotypes, are the events that initiate the changes in chromosome number and structure between species, and likewise polymorphisms, variants and disease states within species. Although once thought of as transcriptional ‘noise', noncoding RNAs (ncRNAs) are now recognized as important mediators of epigenetic regulation and chromosome stability. Here we highlight recent work that illustrates the influence short and long ncRNAs have as participants in the function and stability of chromosome regions such as centromeres, telomeres, evolutionary breakpoints and fragile sites. We summarize recent evidence that ncRNAs can facilitate chromosome change and present mechanisms by which ncRNAs create DNA breaks. Finally, we present hypotheses on how they may create novel karyotypes and thus affect chromosome evolution.
non-coding; ncRNA; small RNA; chromosome; evolution; karyotype
Integrins are involved in prostate cancer metastasis by regulating cell adhesion, migration, invasion, motility, angiogenesis and bone metabolism. We evaluated the efficacy of two dose levels of cilengitide in patients (pts) with castrate resistant prostate cancer (CRPC).
Chemotherapy-naïve, asymptomatic metastatic CRPC pts were randomized to cilengitide 500mg or 2000mg IV twice weekly using parallel 2-stage design. The primary endpoint was rate of objective clinical progression at six-months. Secondary endpoints included clinical and PSA response rates, safety and effects of cilengitide treatment on circulating tumor cells (CTCs) and bone remodeling markers.
Forty-four pts were accrued to first stage (22/arm). Median number of cycles was three in both arms (500mg arm: 1–8; 2000 mg arm: 1–15). At six months, two pts (9%) on the 500mg arm and five pts (23%) on the 2000mg arm had not progressed. Best objective response was stable disease (SD) in seven pts for 9.9[8.1,20.9] months. There were three grade 3 and no grade 4 toxicities. At 12 weeks, analysis of bone markers did not reveal significant trends. At progression, bone specific alkaline phosphatase and N-telopeptide increased in all pts, less so in pts on the 2000mg arm and in pts on both arms who obtained SD at 6 months. CTCs increased over time in both arms.
Cilengitide was well tolerated with modest clinical effect in favor of the higher dose. The unique trial design including a shift from response rate to objective progression as the endpoint, and not acting on PSA increases was feasible.
prostate cancer; metastatic disease; integrins; angiogenesis; cilengitide; bone biomarkers
Primary graft failure after allogeneic hematopoietic cell transplantation is a life-threatening complication. A shortened conditioning regimen may reduce the risk of infection and increase the chance of survival. Here, we report the outcome of 11 patients with hematologic diseases (median age, 44; range, 25–67 years, 7 males) who received a 1-day reduced-intensity preparative regimen given as a re-transplantation for primary graft failure. The salvage regimen consisted of fludarabine, cyclophosphamide, alemtuzumab, and total-body irradiation, all administered 1 day before re-transplantation. All patients received T-cell replete peripheral blood stem cells from the same or different haploidentical donor (n = 10) or from the same matched sibling donor (n = 1). Neutrophil counts promptly increased to >500/µL for 10 of the 11 patients at a median of 13 days. Of these, none developed Grade III/IV acute graft-versus-host disease. At present, 8 of the 11 patients are alive with a median follow-up of 11.2 months from re-transplantation and 5 of the 8 are in remission. In conclusion, this series suggests that our 1-day preparative regimen is feasible, leads to successful engraftment in a high proportion of patients, and is appropriate for patients requiring immediate re-transplantation after primary graft failure following reduced-intensity transplantation.
allogeneic hematopoietic cell transplantation; primary graft failure; re-transplantation
Because of prior inconsistent findings, we studied a large cohort of HIV-infected children to determine: (1) prevalence of insulin resistance (IR); (2) anthropometric and clinical correlates of IR, and (3) concomitant abnormalities of glucose tolerance.
The study population consisted of 451 children from the Pediatric HIV/AIDS Cohort Study. The outcome of interest was HOMA-IR. Covariates included demographic, metabolic, growth, body composition, HIV laboratory tests, and treatment characteristics. Children meeting triggers for IR underwent oral glucose tolerance tests and hemoglobin A1c (HbA1c) measurements.
Among 402 children with glucose and insulin measurements, 15.2% had IR of whom 79% were pubertal. IR was associated with higher alanine aminotransferase, body mass index, and nadir CD4%, Tanner stage 5, and ever having received amprenavir. Of those with IR, three had impaired fasting glucose (IFG), three impaired glucose tolerance (IGT), one IFG and IGT, none diabetic glucose tolerance, and three HbA1c between 6.1 and 6.5%.
In our cohort of HIV-infected adolescents, we observed a 15.2% prevalence of IR more closely linked to obesity than any other variable. This finding mirrors the high prevalence of obesity-mediated IR in American youth. However, associations with CD4 count and use of protease inhibitors may indicate some effect of HIV and/or its treatment.
Insulin resistance; HIV; Highly active antiretroviral therapy; Homeostatic model assessment of insulin resistance
We report a scrotal epidermal inclusion cyst located outside the median raphe which a rare entity in the absence of trauma and few cases have been reported. 47 year old male presents with a complaint of right sided testicular swelling and discomfort. On examination a 3 cm mass was palpated between the scrotum and the medial thigh on the subcutaneous tissue with a positive slip sign. Complete surgical excision of the cyst was performed. Histopathology confirmed epidermal inclusion cyst with no evidence of malignancy.
The rationale for the use of epothilones in patients with castration-resistant prostate cancer is highlighted and the clinical data concerning epothilones in this setting are summarized.
The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostate-specific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first- and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC.
Epothilones; Castration-resistant prostate cancer; Chemotherapy; Taxanes
This article presents a novel method for small-scale lipidomics of bacterial cells by integrating extraction of glycerophospholipids on microchip with a nanoelectrospray ionization quadrupole time-of-flight tandem mass spectrometer (nanoESI-Q-TOF MS/MS). The standard starting point for typical macroscale lipid analysis is a multiphase liquid-liquid extraction. Working with small populations of cells (1 to about 1000) requires a scaled down process in order to minimize dilution and facilitate the interface with microscale separation methods for sample cleanup and introduction to mass spectrometry. We have developed a microfluidic system that allows for lysis of bacterial cells, capture of lipids, and elution of captured lipids from a solid phase for microscale purification of lipids. The best on-chip extraction efficiency for glycerophospholipids was as high as 83.3% by integrating silica beads as the packing material with methanol as the eluent. Ten successive measurements were evaluated indicating that the microchip packed with fresh silica beads is capable of being reused for four times without any loss in lipid extraction process. The initial screening based on high-resolution tandem mass spectrometry data along with discovery profiling approach revealed the presence of 173 identified phospholipid species from microfluidic cell extracts. This work demonstrates the potential of incorporating microchip-based lipid extraction into cellular lipidomics research.
lipid extraction; lipidomics; microchip; solid phase extraction
Multivariate analysis of functional magnetic resonance imaging (fMRI) data allows investigations into network behavior beyond simple activations of individual regions. We apply group independent component analysis to fMRI data collected in a previous study looking at the sustained neuromodulatory effects of electrical tongue stimulation in balance-impaired individuals. Twelve subjects with balance disorders viewed optic flow in an fMRI scanner before and after 5 days of electrical tongue stimulation. Nine healthy controls also viewed the visual stimuli but did not receive any stimulation. Multiple regression of the 47 estimated components found two that were modulated by the visual stimuli. Component 7, comprised primarily of the primary visual cortex (V1), responded to all visual stimuli and showed no difference in task-related activity between the healthy controls and the balance-impaired subjects before or after stimulation. Component 11 responded only to motion in the visual field and contained multiple cortical and subcortical regions involved in processing information pertinent to balance. Two-sample t-tests of the calculated signal change revealed that the task-related activity of this network is greater in balance-impaired subjects compared with controls before stimulation (p=0.02), but that this network hypersensitivity decreases after electrical tongue stimulation (p=0.001).
brain plasticity; CN-NINM; ICA; movement disorders; tongue; visual system
Background and objective
The presence of β-cell antibodies is associated with a high risk of type 1 diabetes. With increasing rates of obesity, the distinction between obese T1DM and T2DM has become difficult. Moreover, increasing body mass index (BMI) in at-risk children has been proposed not only as a possible contributor to T1DM by increasing insulin resistance, but also as exerting an effect via the immunomodulatory properties of certain adipokines. This study aimed to determine prevalence of β-cell autoantibodies (AA) in overweight non-diabetic children and assess insulin sensitivity and secretion derived from an oral glucose tolerance test (OGTT) in those with vs. without β-cell AA.
Research design and methods
A total of 357 overweight (BMI > 85%) youths underwent OGTTs, dual energy X-ray absorptiometry (DEXA) and measurement of GAD65 and IA-2 AA according to the NIDDK harmonization assay. Using the same methodology, AA were measured in 90 normal weight, non-diabetic individuals.
About 1.9% of overweight and 4.4% of control normal weight children had evidence of β-cell autoimmunity, with GAD65 AA detected in all subjects but none with IA-2. Youth with positive vs. those with negative AA had higher leptin/adiponectin ratio, glucose at 60 min and C-peptide at 90 min.
These findings suggest that the prevalence of β-cell AA in overweight youth may be similar to that in non-overweight children. Further studies using standardized methods are required.
autoimmunity; β-cell antibodies; children; obesity
To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC.
Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate-specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase).
The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by ≥40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3–4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (≥20%) were fatigue, nausea, diarrhea, headache, and anorexia.
Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC.