The extracellular matrix (ECM) and its receptors make diverse contributions to development. The ECM comes in a variety of forms, including the more "standard" ECM that is internal to the animal and ...on the basal side of epithelial sheets, as well as the apical ECM, which is especially elaborated in the invertebrates to form the exoskeleton. ECM proteins accumulate adjacent to particular target tissues in the developing animal by a variety of mechanisms: local synthesis in the target tissue; local synthesis by migrating cells; and secretion from a distant source and capture by the target tissue. The diverse developmental functions of the ECM are discussed, including the generation of a road for cell migration, creation of morphogenetic checkpoints for differentiation, modulation of morphogen gradients, insulation of organs, gluing together cell layers, and providing structure for the organism.
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease, in which the role of inflammation is not well established. Innate and adaptive immunity were ...investigated in the CNS of the Superoxide Dismutase 1 (SOD1)G⁹³A transgenic mouse model of ALS. CD4⁺ and CD8+ T cells infiltrated SOD1G⁹³A spinal cords during disease progression. Cell-specific flow cytometry and gene expression profiling showed significant phenotypic changes in microglia, including dendritic cell receptor acquisition, and expression of genes linked to neuroprotection, cholesterol metabolism and tissue remodeling. Microglia dramatically up-regulated IGF-1 and down-regulated IL-6 expression. When mutant SOD1 mice were bred onto a TCRβ deficient background, disease progression was significantly accelerated at the symptomatic stage. In addition, microglia reactivity and IGF-1 levels were reduced in spinal cords of SOD1G⁹³A (TCRβ-/-) mice. These results indicate that T cells play an endogenous neuroprotective role in ALS by modulating a beneficial inflammatory response to neuronal injury.
Genomic profiling studies suggest that triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study, we sought to define TNBC subtypes and identify subtype-specific markers and ...targets.
RNA and DNA profiling analyses were conducted on 198 TNBC tumors estrogen receptor (ER) negativity defined as Allred scale value ≤ 2 with >50% cellularity (discovery set: n = 84; validation set: n = 114) collected at Baylor College of Medicine (Houston, TX). An external dataset of seven publically accessible TNBC studies was used to confirm results. DNA copy number, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed independently using these datasets.
We identified and confirmed four distinct TNBC subtypes: (i) luminal androgen receptor (AR; LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS), and (iv) basal-like immune-activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (log-rank test: P = 0.042 and 0.041, respectively) and DSS (log-rank test: P = 0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA) and suggested that gene amplification drives gene expression in some cases FGFR2 (BLIS). Putative subtype-specific targets were identified: (i) LAR: androgen receptor and the cell surface mucin MUC1, (ii) MES: growth factor receptors platelet-derived growth factor (PDGF) receptor A; c-Kit, (iii) BLIS: an immunosuppressing molecule (VTCN1), and (iv) BLIA: Stat signal transduction molecules and cytokines.
There are four stable TNBC subtypes characterized by the expression of distinct molecular profiles that have distinct prognoses. These studies identify novel subtype-specific targets that can be targeted in the future for the effective treatment of TNBCs.
The aberrant activation of oncogenic signaling pathways is a universal phenomenon in cancer and drives tumorigenesis and malignant transformation. This abnormal activation of signaling pathways in ...cancer is due to the altered expression of protein kinases and phosphatases. In response to extracellular signals, protein kinases activate downstream signaling pathways through a series of protein phosphorylation events, ultimately producing a signal response. Protein tyrosine phosphatases (PTP) are a family of enzymes that hydrolytically remove phosphate groups from proteins. Initially, PTPs were shown to act as tumor suppressor genes by terminating signal responses through the dephosphorylation of oncogenic kinases. More recently, it has become clear that several PTPs overexpressed in human cancers do not suppress tumor growth; instead, they positively regulate signaling pathways and promote tumor development and progression. In this review, we discuss both types of PTPs: those that have tumor suppressor activities as well as those that act as oncogenes. We also discuss the potential of PTP inhibitors for cancer therapy.
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The somatotropic signaling pathway has been implicated in aging and longevity studies in mice and other species. The physiology and lifespans of a variety of mutant mice, both spontaneous and ...genetically engineered, have contributed to our current understanding of the role of growth hormone and insulin-like growth factor I on aging-related processes. Several other mice discovered to live longer than their wild-type control counterparts also exhibit differences in growth factor levels; however, the complex nature of the phenotypic changes in these animals may also impact lifespan. The somatotropic axis impacts several pathways that dictate insulin sensitivity, nutrient sensing, mitochondrial function, and stress resistance as well as others that are thought to be involved in lifespan regulation.
Delirium is a common complication after cardiac surgical procedures and is associated with increased morbidity and mortality. However, whether rigorously assessed postoperative delirium is associated ...with an increased length of stay in the intensive care unit (LOS-ICU), length of stay (LOS), and hospital charges is not clear.
Patients (n = 66) undergoing coronary artery bypass or valve operations, or both, were enrolled in a nested cohort study. Rigorous delirium assessments were conducted using the Confusion Assessment Method. LOS-ICU and LOS were obtained from the medical record, and hospital charges were obtained from administrative data reported to the state. Because of the skewed distribution of outcome variables, outcomes were compared using rank-sum tests, as well as median regression incorporating propensity scores.
Patients who developed delirium (56%) versus no delirium (43%) had increased median LOS-ICU (75.6 hours interquartile range (IQR): 43.6 to 136.8 vs. 29.7 hours IQR: 21.7 to 46.0; p = 0.002), increased median LOS (9 days IQR: 6 to 16 vs. 7 days IQR: 5 to 8; p = 0.006), and increased median hospital charges ($51,805 IQR: $44,041 to $80,238 vs. $41,576 IQR: $35,748 to $43,660; p = 0.002). In propensity score models adjusted for patient-related and surgical characteristics and complications, the results for LOS-ICU and cost remained highly significant, although the results for LOS were attenuated on the basis of the specific statistical model. Increased severity of delirium was associated with both increased LOS-ICU and increased charges in a dose-response manner.
Delirium after cardiac surgical procedures is independently associated with both increased LOS-ICU and higher hospital charges. Because delirium is potentially preventable, targeted delirium-prevention protocols for high-risk patients may represent an important strategy for quality improvement.
The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation ...(EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations.
We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy.
A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval CI, 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients.
AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).
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