Vascular endothelial growth factor-A (VEGF), a potent angiogenic factor, is also implicated in self-renewal in several normal tissue types. VEGF has been shown to drive malignant stem cells but ...mechanisms thereof and tumor types affected are not fully characterized. Here, we show VEGF promotes breast and lung cancer stem cell (CSC) self-renewal via VEGF receptor-2 (VEGFR-2)/STAT3-mediated upregulation of Myc and Sox2. VEGF increased tumor spheres and aldehyde dehydrogenase activity, both proxies for stem cell function in vitro, in triple-negative breast cancer (TNBC) lines and dissociated primary cancers, and in lung cancer lines. VEGF exposure before injection increased breast cancer-initiating cell abundance in vivo yielding increased orthotopic tumors, and increased metastasis from orthotopic primaries and following tail vein injection without further VEGF treatment. VEGF rapidly stimulated VEGFR-2/JAK2/STAT3 binding and activated STAT3 to bind MYC and SOX2 promoters and induce their expression. VEGFR-2 knockdown or inhibition abrogated VEGF-mediated STAT3 activation, MYC and SOX2 induction and sphere formation. Notably, knockdown of either STAT3, MYC or SOX2 impaired VEGF-upregulation of pSTAT3, MYC and SOX2 expression and sphere formation. Each transcription factor, once upregulated, appears to promote sustained activation of the others, creating a feed-forward loop to drive self-renewal. Thus, in addition to angiogenic effects, VEGF promotes tumor-initiating cell self-renewal through VEGFR-2/STAT3 signaling. Analysis of primary breast and lung cancers (>1300 each) showed high VEGF expression, was prognostic of poor outcome and strongly associated with STAT3 and MYC expression, supporting the link between VEGF and CSC self-renewal. High-VEGF tumors may be most likely to escape anti-angiogenics by upregulating VEGF, driving CSC self-renewal to re-populate post-treatment. Our work highlights the need to better define VEGF-driven cancer subsets and supports further investigation of combined therapeutic blockade of VEGF or VEGFR-2 and JAK2/STAT3.
Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours in vivo. These cancer stem cells (CSCs) ...represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour relapse. Despite this realization and great interest in CSCs, it has been difficult to develop CSC-targeted treatments due to our limited understanding of CSC biology. Here, we present evidence that specific histone deacetylases (HDACs) play essential roles in the CSC phenotype. Utilizing a novel CSC model, we discovered that the HDACs, HDAC1 and HDAC7, are specifically over-expressed in CSCs when compared to non-stem-tumour-cells (nsTCs). Furthermore, we determine that HDAC1 and HDAC7 are necessary to maintain CSCs, and that over-expression of HDAC7 is sufficient to augment the CSC phenotype. We also demonstrate that clinically available HDAC inhibitors (HDACi) targeting HDAC1 and HDAC7 can be used to preferentially target CSCs. These results provide actionable insights that can be rapidly translated into CSC-specific therapies.
Abstract Background The efficacy and costs of indwelling interscalene catheter (ISC) and liposomal bupivacaine (LBC), with and without adjunctive medications, in patients with primary shoulder ...arthroplasty are a source of current debate. Methods In 214 arthroplasties, 156 patients had ISC and 58 had LBC injections that were mixed with morphine, ketorolac, and 0.5% bupivacaine with epinephrine. Charts were reviewed for visual analog scale pain scores, oral morphine equivalent (OME) usage, major complications, and costs. Results Visual analog scale scores were not significantly different at 24 hours or at 2, 6, and 12 weeks. Average OME consumption at 24 hours was significantly more with LBC, but was not significantly different at 12 weeks. Relative risk of a major complication was nearly 4 times higher with ISC than with LBC. The average cost for the LBC mixture was $289.04, and for ISC, including equipment and anesthesia fees, was $1559.42. Conclusion The intraoperative LBC mixture provided equivalent pain relief with significantly fewer major complications and at markedly lower cost than ISC. LBC required almost twice as much OME to attain the same level of pain relief at 24 hours, but there was no significant difference in the cumulative amount of outpatient narcotic use.
Background The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described ...wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined. Objective We sought to define the relationship of APOε4 to the human innate immune response. Methods We evaluated APOε4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APOε4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. Results Whole blood from healthy APOε3 / APOε4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APOε3 / APOε3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3 / APOε3 and APOε3 / APOε4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe -deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APOε3/APOε4 patients had higher hyperthermia and plasma TNF-α levels and earlier plasma IL-6 than APOε3/APOε3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APOε4 was associated with increased coagulation system failure among European American patients. Conclusions APOε4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.
Abstract Irrigation and debridement (I and D) is a procedure commonly used for the treatment of acute periprosthetic infection. This study retrospectively reviewed clinical records of patients with ...periprosthetic infection of the hip or knee who underwent I and D with retention of their prostheses between 1997 and 2005 at a single institution. One hundred four patients (44 males and 60 females) were identified. Mean age at time of initial debridement was 65 years. Average follow-up was 5.7 years. Treatment failure was defined as the need for resection arthroplasty or recurrent microbiologically proven infection. According to these criteria, I and D was successful in 46 patients (44%). Patients with staphylococcal infection, elevated American Society of Anesthesiologists score, and purulence around the prosthesis were more likely to fail. The high failure rate of this procedure implies that it should be preferably limited to select healthy patients with low virulence organisms and equivocal intraoperative findings.
Analgesic design and evaluation have been driven by the desire to create high-affinity high-selectivity mu (μ)-opioid peptide (MOP) receptor agonists. Such ligands are the mainstay of current ...clinical practice, and include morphine and fentanyl. Advances in this sphere have come from designing pharmacokinetic advantage, as in rapid metabolism for remifentanil. These produce analgesia, but also the adverse-effect profile that currently defines this drug class: ventilatory depression, tolerance, and abuse liability. The MOP receptor is part of a family, and there are significant functional interactions between other members of the family (delta δ-opioid peptide DOP, kappa κ-opioid peptide KOP, and nociceptin/orphanin FQ receptor NOP). Experimentally, MOP agonism and DOP antagonism produce anti-nociception (animals) with no tolerance, and low doses of MOP and NOP ligands synergise to antinociceptive advantage. In this latter context, the lack of effect of NOP agonists on ventilation is an additional advantage. Recent development has been to move towards low-selectivity multifunctional ‘mixed ligands’, such as cebranopadol, or ligand mixtures, such as Targinact®. Moreover, the observation that β-arrestin coupling underlies the side-effect profile for MOP ligands (from knockout animal studies) led to the discovery of biased (to G-protein and away from β-arrestin intracellular signalling) MOP ligands, such as oliceridine. There is sufficient excitement in the opioid field to suggest that opioid analgesics without significant side-effects may be on the horizon, and the ‘opioid Holy Grail’ might be in reach.
The estimation of the distance from the skin to the thoracic epidural space or skin to epidural depth (SED) may increase the success rate and decrease the incidence of complications during placement ...of a thoracic epidural catheter. Magnetic resonance imaging (MRI) is the most comprehensive imaging modality of the spine, allowing for the accurate determination of tissue spaces and distances. The present study uses MRI-derived measurements to measure the SED and define the ratio between the straight and inclined SEDs at two thoracic levels (T
and T
) in children.
The T
-weighed sagittal MRI images of 109 children, ranging in age from 1 month to 8 years, undergoing radiological evaluation unrelated to spine pathology were assessed. The SEDs (inclined and straight) were determined, and a comparison between the SEDs at two thoracic levels (T
and T
) was made. Univariate and multivariate linear regression models were used to assess the relationship of the inclined thoracic T
and T
SED measurements with age, height, and weight.
Body weight demonstrated a stronger association with the SED than did the age or height with
values of 0.6 for T
and 0.5 for T
. The formulae describing the relationship between the weight and the inclined SED were T
inclined (mm) = 7 + 0.9 × kg and T
inclined (mm) = 7 + 0.8 × kg.
The depth of the pediatric thoracic epidural space shows a stronger correlation with weight than with age or height. Based on the MRI data, the predictive weight-based formulas can serve as guide to clinicians for placement of thoracic epidural catheters.
The authors designed an automated electronic system that incorporates data from multiple hospital information systems to screen for acute lung injury (ALI) in mechanically ventilated patients. The ...authors evaluated the accuracy of this system in diagnosing ALI in a cohort of patients with major trauma, but excluding patients with congestive heart failure (CHF).
Single-center validation study. Arterial blood gas (ABG) data and chest radiograph (CXR) reports for a cohort of intensive care unit (ICU) patients with major trauma but excluding patients with CHF were screened prospectively for ALI requiring intubation by an automated electronic system. The system was compared to a reference standard established through consensus of two blinded physician reviewers who independently screened the same population for ALI using all available ABG data and CXR images. The system's performance was evaluated (1) by measuring the sensitivity and overall accuracy, and (2) by measuring concordance with respect to the date of ALI identification (vs. reference standard).
One hundred ninety-nine trauma patients admitted to our level 1 trauma center with an initial injury severity score (ISS) ≥ 16 were evaluated for development of ALI in the first five days in an ICU after trauma.
The system demonstrated 87% sensitivity (95% confidence interval CI 82.3–91.7) and 89% specificity (95% CI 84.7–93.4). It identified ALI before or within the 24-hour period during which ALI was identified by the two reviewers in 87% of cases.
An automated electronic system that screens intubated ICU trauma patients, excluding patients with CHF, for ALI based on CXR reports and results of ABGs is sufficiently accurate to identify many early cases of ALI.
Restoration Potential of the Mesopotamian Marshes of Iraq Richardson, Curtis J; Reiss, Peter; Hussain, Najah A ...
Science (American Association for the Advancement of Science),
02/2005, Letnik:
307, Številka:
5713
Journal Article
Recenzirano
Uncontrolled releases of Tigris and Euphrates River waters after the 2003 war have partially restored some former marsh areas in southern Iraq, but restoration is failing in others because of high ...soil and water salinities. Nearly 20% of the original 15,000-square-kilometer marsh area was reflooded by March 2004, but the extent of marsh restoration is unknown. High-quality water, nonsaline soils, and the densest native vegetation were found in the only remaining natural marsh, the Al-Hawizeh, located on the Iranian border. Although substantially reduced in area and under current threat of an Iranian dike, it has the potential to be a native repopulation center for the region. Rapid reestablishment, high productivity, and reproduction of native flora and fauna in reflooded former marsh areas indicate a high probability for successful restoration, provided the restored wetlands are hydraulically designed to allow sufficient flow of noncontaminated water and flushing of salts through the ecosystem.
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