University of Texas Health Science Center at Houston

About: University of Texas Health Science Center at Houston is a education organization based out in Houston, Texas, United States. It is known for research contribution in the topics: Population & Poison control. The organization has 27309 authors who have published 42520 publications receiving 2151596 citations. The organization is also known as: UTHealth & The UT Health Science Center at Houston.

ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1

Abstract: Epithelial-mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo. Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.

Etanercept treatment for children and adolescents with plaque psoriasis.

Abstract: A B S T R AC T Background Etanercept, a soluble tumor necrosis factor receptor, has been shown to lessen disease severity in adult patients with psoriasis. We assessed the efficacy and safety of etanercept in children and adolescents with moderate-to-severe plaque psoriasis. Methods In this 48-week study, 211 patients with psoriasis (4 to 17 years of age) were initially randomly assigned to a double-blind trial of 12 once-weekly subcutaneous injections of placebo or 0.8 mg of etanercept per kilogram of body weight (to a maximum of 50 mg), followed by 24 weeks of once-weekly open-label etanercept. At week 36, 138 patients underwent a second randomization to placebo or etanercept to investigate the effects of withdrawal and retreatment. The primary end point was 75% or greater improvement from baseline in the psoriasis area-and-severity index (PASI 75) at week 12. Secondary end points included PASI 50, PASI 90, physician’s global assessment of clear or almost clear of disease, and safety assessments. Results At week 12, 57% of patients receiving etanercept achieved PASI 75, as compared with 11% of those receiving placebo (P<0.001). A significantly higher proportion of patients in the etanercept group than in the placebo group had PASI 50 (75% vs. 23%), PASI 90 (27% vs. 7%), and a physician’s global assessment of clear or almost clear (53% vs. 13%) at week 12 (P<0.001). At week 36, after 24 weeks of open-label etanercept, rates of PASI 75 were 68% and 65% for patients initially assigned to etanercept and placebo, respectively. During the withdrawal period from week 36 to week 48, response was lost by 29 of 69 patients (42%) assigned to placebo at the second randomization. Four serious adverse events (including three infections) occurred in three patients during treatment with open-label etanercept; all resolved without sequelae. Conclusions Etanercept significantly reduced disease severity in children and adolescents with moderate-to-severe plaque psoriasis. (ClinicalTrials.gov number, NCT00078819.)

Chemoimmunotherapy With a Modified Hyper-CVAD and Rituximab Regimen Improves Outcome in De Novo Philadelphia Chromosome–Negative Precursor B-Lineage Acute Lymphoblastic Leukemia

Abstract: Purpose The adverse prognosis of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia (ALL) prompted incorporation of monoclonal antibody therapy with rituximab into the intensive chemotherapy regimen hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone). Other modifications (irrespective of CD20 expression) included early anthracycline intensification, alterations in number of risk-adapted intrathecal chemotherapy treatments for CNS prophylaxis, additional early and late intensifications, and extension of maintenance phase chemotherapy by 6 months. Patients and Methods Two hundred eighty-two adolescents and adults with de novo Philadelphia chromosome (Ph)–negative precursor B-lineage ALL were treated with standard or modified hyper-CVAD regimens. The latter incorporated standard-dose rituximab if CD20 expression ≥ 20%. Results The complete remission (CR) rate was 95% with 3-year rates of CR duration (CRD) and survival (OS) of 60% and 50%, r...

Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy.

Abstract: Objective To determine the incidence and prognostic significance of documented eradication of breast cancer axillary lymph node (ALN) metastases after neoadjuvant chemotherapy. Summary Background Data Neoadjuvant chemotherapy is the standard of care for patients with locally advanced breast cancer and is being evaluated in patients with earlier-stage operable disease. Methods One hundred ninety-one patients with locally advanced breast cancer and cytologically documented ALN metastases were treated in two prospective trials of doxorubicin-based neoadjuvant chemotherapy. Patients had breast surgery with level I and II axillary dissection followed by additional chemotherapy and radiation treatment. Nodal sections from 43 patients who were originally identified as having negative ALNs at surgery were reevaluated and histologically confirmed to be without metastases. An additional 1112 sections from these lymph node blocks were obtained; half were stained with an anticytokeratin antibody cocktail and analyzed. Survival was calculated using the Kaplan‐Meier method. Results Of 191 patients with positive ALNs at diagnosis, 23% (43 patients) were converted to a negative axillary nodal status on histologic examination (median number of nodes removed 5 16). Of the 43 patients with complete axillary conversion, 26% (n 5 11) had N1 disease and 74% (n 5 32) had N2 disease. On univariate analysis, patients with complete versus incomplete histologic axillary conversion were more likely to have initial estrogenreceptor‐negative tumors, smaller primary tumors, and a complete pathologic response in the primary tumor. The 5-year disease-free survival rates were 87% in patients with preoperative eradication of axillary metastases and 51% for patients with residual nodal disease after neoadjuvant chemotherapy. Of the 39 patients with complete histologic conversion for whom nodal blocks were available, occult nodal metastases were found in additional nodal sections in 4 patients (10%). At a median follow-up of 61 months, the 5-year disease-free survival rates were 87% in patients without occult nodal metastases and 75% in patients with occult nodal metastases. Conclusions Neoadjuvant chemotherapy can completely clear the axilla of microscopic disease before surgery, and occult metastases are found in only 10% of patients with a histologically negative axilla. The results of this study have implications for the potential use of sentinel lymph node biopsy as an alternative to axillary dissection in patients treated with neoadjuvant chemotherapy.

Proteome-wide Analysis and CXCL4 as a Biomarker in Systemic Sclerosis

Abstract: Methods We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. Results Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 downregulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. Conclusions Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.)