Phase II study of the dual EGFR/HER3 inhibitor duligotuzumab (MEHD7945A) vs. cetuximab in combination with FOLFIRI in RAS wild-type metastatic colorectal cancer

PURPOSE: Duligotuzumab is a dual-action antibody directed against EGFR and HER3. EXPERIMENTAL DESIGN: mCRC patients with KRAS ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with RAS exon 2/3 wild-type tumors. RESULTS: Of 134 randomized patients, 98 were RAS ex2/3 wild-type. Duligotuzumab provided no PFS or OR benefit compared to cetuximab; though there was a trend for lower ORR in the duligotuzumab arm. No relationship was seen between PFS or ORR and ERBB3, NRG1, or AREG expression. There were fewer skin rash events for duligotuzumab but more diarrhea. Although the incidence of grade ≥ 3 AEs was similar, the frequency of serious AEs was higher for duligotuzumab. CONCLUSIONS: Duligotuzumab plus FOLFIRI did not appear to improve the outcomes in patients with RAS exon 2/3 wild-type mCRC compared to cetuximab + FOLFIRI

Microtubular Stability Affects pVHL-Mediated Regulation of HIF-1alpha via the p38/MAPK Pathway in Hypoxic Cardiomyocytes

BACKGROUND: Our previous research found that structural changes of the microtubule network influence glycolysis in cardiomyocytes by regulating the hypoxia-inducible factor (HIF)-1α during the early stages of hypoxia. However, little is known about the underlying regulatory mechanism of the changes of HIF-1α caused by microtubule network alternation. The von Hippel-Lindau tumor suppressor protein (pVHL), as a ubiquitin ligase, is best understood as a negative regulator of HIF-1α. METHODOLOGY/PRINCIPAL FINDINGS: In primary rat cardiomyocytes and H9c2 cardiac cells, microtubule-stabilization was achieved by pretreating with paclitaxel or transfection of microtubule-associated protein 4 (MAP4) overexpression plasmids and microtubule-depolymerization was achieved by pretreating with colchicine or transfection of MAP4 siRNA before hypoxia treatment. Recombinant adenovirus vectors for overexpressing pVHL or silencing of pVHL expression were constructed and transfected in primary rat cardiomyocytes and H9c2 cells. With different microtubule-stabilizing and -depolymerizing treaments, we demonstrated that the protein levels of HIF-1α were down-regulated through overexpression of pVHL and were up-regulated through knockdown of pVHL in hypoxic cardiomyocytes. Importantly, microtubular structure breakdown activated p38/MAPK pathway, accompanied with the upregulation of pVHL. In coincidence, we found that SB203580, a p38/MAPK inhibitor decreased pVHL while MKK6 (Glu) overexpression increased pVHL in the microtubule network altered-hypoxic cardiomyocytes and H9c2 cells. CONCLUSIONS/SIGNIFICANCE: This study suggests that pVHL plays an important role in the regulation of HIF-1α caused by the changes of microtubular structure and the p38/MAPK pathway participates in the process of pVHL change following microtubule network alteration in hypoxic cardiomyocytes

Cuidados generales en el manejo del traumatismo craneoencefálico grave: consenso latinoamericano

Severe traumatic brain injury (sTBI) remains prevalent in the young adult population. Indeed, far from descending, the incidence of sTBI remains high. One of the key bases of treatment is to avoid, detect and correct secondary injuries of systemic origin, which aggravate the primary lesion. Much of this can be achieved by maintaining an adequate physiological microenvironment allowing recovery of the damaged brain tissue. General care measures are nonspecific actions designed to meet that objective. The available guidelines on the management of sTBI have not included the topics contemplated in this consensus. In this regard, a group of members of the Latin American Brain Injury Consortium (LABIC), involved in the different aspects of the acute management of sTBI (neurosurgeons, intensivists, anesthesiologists, neurologists, nurses and physiotherapists) were gathered. An exhaustive literature search was made of selected topics in the LILACS, PubMed, Embase, Scopus, Cochrane Controlled Register of Trials and Web of Science databases. To establish recommendations or suggestions with their respective strength or weakness, the GRADE methodology (Grading of Recommendations, Assessment, Development and Evaluation) was applied. Additionally, certain recommendations (included in complementary material) were not assessed by GRADE, because they constitute a set of therapeutic actions of effective compliance, in which it was not possible to apply the said methodology. Thirty-two recommendations were established, 16 strong and 16 weak, with their respective levels of evidence. This consensus attempts to standardize and establish basic general care measures in this particular patient population. © 2020 Elsevier España, S.L.U. y SEMICYU

General care in the management of severe traumatic brain injury: Latin American consensus.

Severe traumatic brain injury (sTBI) remains prevalent in the young adult population. Indeed, far from descending, the incidence of sTBI remains high. One of the key bases of treatment is to avoid, detect and correct secondary injuries of systemic origin, which aggravate the primary lesion. Much of this can be achieved by maintaining an adequate physiological microenvironment allowing recovery of the damaged brain tissue. General care measures are nonspecific actions designed to meet that objective. The available guidelines on the management of sTBI have not included the topics contemplated in this consensus. In this regard, a group of members of the Latin American Brain Injury Consortium (LABIC), involved in the different aspects of the acute management of sTBI (neurosurgeons, intensivists, anesthesiologists, neurologists, nurses and physiotherapists) were gathered. An exhaustive literature search was made of selected topics in the LILACS, PubMed, Embase, Scopus, Cochrane Controlled Register of Trials and Web of Science databases. To establish recommendations or suggestions with their respective strength or weakness, the GRADE methodology (Grading of Recommendations, Assessment, Development and Evaluation) was applied. Additionally, certain recommendations (included in complementary material) were not assessed by GRADE, because they constitute a set of therapeutic actions of effective compliance, in which it was not possible to apply the said methodology. Thirty-two recommendations were established, 16 strong and 16 weak, with their respective levels of evidence. This consensus attempts to standardize and establish basic general care measures in this particular patient population

Reologia de polietileno de alta densidade tenacificado com polietileno elastomérico Rheology of high density polyethylene toughened with elastomeric polyethylene

Neste trabalho foram estudadas as propriedades reológicas de polietileno de alta densidade (HDPE) tenacificado com dois tipos de elastômeros metalocênicos à base de poli(etileno-co-octeno) (EOC). Estes elastômeros são polímeros comerciais com diferenças quanto ao peso molecular, índice de fluidez e índice Dow de reologia (DRI). Misturas físicas de HDPE e EOC foram processadas em extrusora monorosca Wortex (L/D=32), à 230 &deg;C e 50 rpm, utilizando percentagem mássica dos EOCs de 5% a 80%. As propriedades reológicas foram avaliadas em experimentos estacionários e dinâmicos a 190 &deg;C e taxas de cisalhamento na faixa de 90 s-1 a 1500 s-1 e freqüências na faixa de 10-1 rad/s a 10² rad/s. As misturas HDPE/EOC exibiram pseudoplasticidade e comportamento reológico complexo. A complexidade do comportamento reológico foi acentuada com o aumento do peso molecular e da concentração de ramificações de cadeia longa (DRI) do EOC.<br>In this work rheological properties of high density polyethylene toughened with two different grades of metallocene elastomers based on poly(ethylene-co-octene) were studied. These elastomers were commercial polymers differing in molecular weight, and Dow Rheology Index (DRI). Blends were processed in a Wortex single screw extruder (L/D=32), at 230 &deg;C and 50 rpm, using mass fractions of EOC in the range from 5% to 80%. The rheological properties were evaluated in steady and dynamic experiments at 190 &deg;C and shear rates in the range from 90 s-1 to 1500 s-1 with frequencies from 10-1 s-1 to 10-2 s-1. The blends exhibited pseudoplasticity and complex rheological behavior. The complex rheological behavior was intensified with increasing molecular weight and long chain branching proportion (DRI) in the EOC elastomers

VHL Promotes E2 Box-Dependent E-Cadherin Transcription by HIF-Mediated Regulation of SIP1 and Snail

The product of the von Hippel-Lindau gene (VHL) acts as the substrate-recognition component of an E3 ubiquitin ligase complex that ubiquitylates the catalytic α subunit of hypoxia-inducible factor (HIF) for oxygen-dependent destruction. Although emerging evidence supports the notion that deregulated accumulation of HIF upon the loss of VHL is crucial for the development of clear-cell renal cell carcinoma (CC-RCC), the molecular events downstream of HIF governing renal oncogenesis remain unclear. Here, we show that the expression of a homophilic adhesion molecule, E-cadherin, a major constituent of epithelial cell junctions whose loss is associated with the progression of epithelial cancers, is significantly down-regulated in primary CC-RCC and CC-RCC cell lines devoid of VHL. Reintroduction of wild-type VHL in CC-RCC (VHL(−/−)) cells markedly reduced the expression of E2 box-dependent E-cadherin-specific transcriptional repressors Snail and SIP1 and concomitantly restored E-cadherin expression. RNA interference-mediated knockdown of HIFα in CC-RCC (VHL(−/−)) cells likewise increased E-cadherin expression, while functional hypoxia or expression of VHL mutants incapable of promoting HIFα degradation attenuated E-cadherin expression, correlating with the disengagement of RNA polymerase II from the endogenous E-cadherin promoter/gene. These findings reveal a critical HIF-dependent molecular pathway connecting VHL, an established “gatekeeper” of the renal epithelium, with a major epithelial tumor suppressor, E-cadherin