Anti-tumor effect of inhibition of IL-6 signaling in mucoepidermoid carcinoma

Mucoepidermoid carcinoma (MEC) is the most frequent malignant salivary gland cancer. Response to chemoradiotherapy is modest, and therefore radical surgery remains the standard-of-care. Emerging evidence suggests that Interleukin (IL)-6 signaling correlates with the survival of cancer stem cells and resistance to therapy. Here, we investigated whether inhibition of IL-6 receptor (IL-6R) signaling with tocilizumab (humanized anti-human IL-6R antibody) sensitizes MEC to chemotherapy using human mucoepidermoid carcinoma cell lines (UM-HMC) and correspondent xenograft models. In vitro, we observed that tocilizumab inhibited STAT3 phosphorylation but had no measurable effect in MEC cell viability (UM-HMC-1,-3A,-3B). In contrast, the anti-tumor effect of single agent tocilizumab on MEC xenografts was comparable to paclitaxel or cisplatin. Combination of tocilizumab with cisplatin or paclitaxel enhanced the inhibitory effect of chemotherapy on xenograft growth (P < 0.05), time to failure (P < 0.01), decreased vascular endothelial growth factor (VEGF) expression and tumor microvessel density (P < 0.05) without added systemic toxicities. Notably, tocilizumab decreased the fraction of MEC cancer stem cells (ALDH^highCD44^high) in vitro, and prevented paclitaxel-induced increase in the fraction of cancer stem cells in vivo (P < 0.05). Collectively, these findings demonstrate that tocilizumab enhances the anti-tumor effect of conventional chemotherapy in preclinical models of mucoepidermoid carcinoma, and suggest that patients might benefit from combination therapy with an inhibitor of IL-6R signaling and chemotherapeutic agent such as paclitaxel.     

La prééclampsie: Physiopathologie et perspectives de dépistage précoce

Preeclampsia is a complication of pregnancy characterized by hypertension, edema and proteinuria, beginning after 20 weeks of gestation. Six percent of the pregnant women in North America develop this disease, which is associated with increased morbidity and mortality for the mother and her baby. The physiopathology remains uncertain despite many research efforts. Actual hypotheses seek to explain the vasospasm that characterizes the disease. Among the many factors influencing vascular reactivity and possibly implicated are: the renin-angiotensin system, prostaglandins, progesterone and its metabolites, calcium, magnesium, digoxin-like immunoreactive substance(s), auricular natriuretic factor, substances secreted by platelets and leukotrienes. Prevention of the disease is limited by the absence of a biological or clinical marker with good sensitivity and appropriate specificity. Many biochemical or hematological parameters have been reported: uric acid, calcium, magnesium, proteinuria, blood iron, hematocrit, platelet count, antithrombin III, estrogen and progesterone. The combination of several tests could be superior to the use of each test individually, providing a better sensitivity and improving the positive predictive value. With early detection, new therapies for the prevention of the disease could be experimented on the higher risk women before the apparition of clinical symptoms or signs. Furthermore, those tests could be used in the study of the pathophysiology and in the choice of the best therapy.     

Genetic and Biochemical Characterization of the First Extended-Spectrum CARB-Type ?-Lactamase,RTG-4, from Acinetobacter baumannii

Acinetobacter baumannii isolate KAR was uncommonly more resistant to cefepime and cefpirome than to ceftazidime and cefotaxime. Cloning and expression of the β-lactamase gene content of this isolate into Escherichia coli TOP10 identified ß-lactamase RTG-4 (or CARB-10), which corresponds to the first reported extended-spectrum CARB-type enzyme. RTG-4 is a plasmid-encoded Ambler class A β-lactamase whose sequence differs by 4 amino acid substitutions from the narrow-spectrum β-lactamase RTG-3. RTG-4 hydrolyzes cefepime and cefpirome and weakly hydrolyzes ceftazidime due to the single Ser-to-Thr substitution at Ambler position 69. RTG-4 is less susceptible to inhibition by tazobactam and sulbactam than RTG-3. Expression of β-lactamase RTG-4 in a wild-type A. baumannii reference strain showed that it conferred resistance to cefepime and cefpirome. The genetic environment of the bla_RTG-4 gene was made of a peculiar transposon located on a ca. 50-kb plasmid. ISAba9, located upstream of bla_RTG-4, may be responsible for its acquisition by recognizing a secondary right inverted repeat sequence, thus acting by a one-ended transposition process.Acinetobacter baumannii is an opportunistic pathogen that is an important source of nosocomial infections such as pneumonia, septicemia, urinary tract infections, and wound infections (2). Treatment of infections due to this microorganism is becoming a serious clinical concern since A. baumannii is frequently resistant to multiple classes of antibiotics (23, 37). The main mechanism of resistance to β-lactam molecules in A. baumannii is the production of β-lactamases. Resistance to carbapenems is mostly related to the production of metallo-β-lactamases or carbapenem-hydrolyzing oxacillinases (33), whereas resistance to expanded-spectrum cephalosporins mostly results from the overexpression of the natural AmpC-type enzyme (3) or from the acquisition of extended-spectrum β-lactamases (ESBLs). Those ESBLs may correspond to TEM or SHV derivatives but mostly correspond to β-lactamases of the VEB or PER type in A. baumannii (21). Carbenicillin-hydrolyzing β-lactamases (also named CARB enzymes) are narrow-spectrum class A penicillinases that share less than 50% amino acid identity with SHV and TEM β-lactamases (7). The 10 ß-lactamase variants of this family show similar hydrolytic properties but are divided into two subgroups, named the CARB and RTG subgroups, according to their amino acid sequences. The CARB subgroup includes CARB-1 (formerly PSE-4) (18), CARB-2 (formerly PSE-1) (18), CARB-3 (14), CARB-4 (26), Proteus mirabilis N29 β-lactamase (11), CARB-6 (6), CARB-7 (20), and CARB-9 (25). The RTG subgroup includes RTG-1 (P. mirabilis GN79 enzyme) (34), RTG-2 (CARB-5; described in Acinetobacter calcoaceticus var. anitratus [24]), and RTG-3 (CARB-8; identified from an Oligella urethralis clinical isolate [17]). Although those three RTG-type ß-lactamases possess low levels of amino acid identity with members of the CARB family (44%), they might be considered the ancestors of that enzymatic group, as proposed by Choury et al. (7).The carbenicillin-hydrolyzing enzymes belonging to the CARB group were first identified from Pseudomonas aeruginosa clinical isolates (38). The bla_CARB genes are now widespread among distantly related bacteria, including Vibrio spp. (19), because of their location on mobile genetic structures. Indeed, bla_CARB genes such as bla_CARB-1 (22), bla_CARB-2 (28), and bla_CARB-4 (36) were found as a form of gene cassettes of class 1 integrons. In contrast, little is known about the genetic environment of the bla_RTG genes.Analysis of the β-lactamase content of an A. baumannii clinical isolate exhibiting an atypical higher level of resistance to cefepime and cefpirome than to ceftazidime and cefotaxime allowed us to identify a novel plasmid-encoded ESBL-encoding gene belonging to the bla_RTG group.     

The role of therapist adherence,therapist competence,and alliance in predicting outcome of individual drug counseling: Results from the National Institute Drug Abuse Collaborative Cocaine Treatment Study

Abstract

This study tested hypotheses related to linear and curvilinear relations among adherence, competence, and outcome and interactions of these effects with the quality of the therapeutic alliance among patients (N=95) who received individual drug counseling as part of the National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Results support a hypothesized curvilinear relation between adherence and outcome as well as an interaction between this curvilinear effect and alliance early in treatment. For patients with a strong therapeutic alliance, counselor adherence to the treatment model was essentially irrelevant to treatment outcome. When the alliance was weaker, by contrast, a moderate (vs. high or low) level of counselor adherence was associated with the best outcome. The current results suggest that studies of the relation between therapist's adherence to models of treatment and outcome may need to take into account the complex moderating effect of therapeutic alliance.

Diese Studie testete Hypothesen bezüglich linearer und kurvilinearer Beziehungen zwischen vorgabegetreuem Vorgehen, Kompetenz und Erfolg, sowie der Interaktion zwischen diesen Variablen und der Qualität der therapeutischen Allianz bei Patienten (n?=?95), die individuelle Drogenberatung im Rahmen der gemeinsamen Drogenabhängigkeits-Behandlungs-Studie des Nationalen Instituts zur Kokain-Abhängigkeit erhielten. Die Ergebnisse unterstützten die vorhergesagte kurvilineare Beziehung zwischen vorgabegetreuem Vorgehen und dem Ergebnis, sowie einer Interaktion dieses kurvilinearen Effekts und der Allianz zu einem frühen Zeitpunkt der Behandlung. Für Patienten mit einer starken therapeutischen Allianz war das vorgabengetreue Vorgehen des Beraters zum Behandlungsmodell für das Behandlungsergebnis ohne Einfluss. Dagegen zeigte ein moderat vorgabengetreues Vorgehen des Beraters (im Vergleich zu einem hohen oder niedrigen Festhalten an den Vorgaben) den besten Erfolg, wenn die Allianz schwächer war. Die vorliegenden Ergebnisse legen nahe, dass Studien zur Beziehung zwischen einem Vorgehen des Therapeuten konform zu den Behandlungsrichtlinien und dem Ergebnis den komplexen Moderatoreffekt der therapeutischen Allianz berücksichtigen müssen.

Cette étude a testé des hypothèses au sujet de relations linéaires et curvilinéaires entre adhérence, compétence et résultat, et des interactions de ces effets avec la qualité de l'alliance thérapeutique chez des patients (N?=?95) qui avaient reçu du counseling individuel pour abus de drogues dans le cadre de l'Etude en Collaboration de l'Institut National pour l'Abus de Drogues sur le Traitement de la Cocaïne. Les résultats apportent du soutien à l'hypothèse d'une relation curvilinéaire entre adhérence et résultat ainsi que d'une interaction entre cet effet curvilinéaire et l'alliance en phase précoce du traitement. Pour les patients avec une alliance thérapeutique forte, l'adhérence du conseiller au modèle de traitement ne jouait pas de rôle essentiel pour le résultat du traitement. En cas d'alliance plus faible, par contre, un niveau modéré (versus haut ou bas) d'adhérence du conseiller était associé avec le meilleur résultat. Ces résultats suggèrent que des études de la relation entre l'adhérence du thérapeute à un modèle de traitement et le résultat devraient tenir compte l'effet de modération complexe de l'alliance thérapeutique.

Este estudio testeó hipótesis vinculadas con las relaciones lineales y curvilíneas entre adherencia, competencia y resultado así también como interacciones de estos efectos con la calidad de la alianza terapéutica entre pacientes (n?=?95) que recibieron Cunseling individual por drogas como parte del Estudio Colaborativo del tratamiento por cocaína del Instituto Nacional para el Abuso de Drogas. Los resultados apoyaron la hipótesis de la relación curvilineal entre adherencia y resultado, así también como la interacción entre este efecto curvilineal y la alianza temprana. Para los pacientes con una fuerte alianza terapéutica, la adherencia del consejero al modelo de tratamiento fue totalmente irrelevante al resultado. En los casos en los que la alianza fue más débil, en cambio, un nivel de adherencia del consejero (ni alta ni baja) estuvo asociada con el resultado mejor. Estos resultados sugieren que los estudios de la relación entre la adherencia del terapeuta a los modelos de tratamiento y resultado han de tener en cuenta el efecto moderador de la alianza terapéutica.

Let me know pls if this is all. Best, Beatriz

Il ruolo dell'adesione e della competenza del terapeuta ed il ruolo dell'alleanza nella previsione dell'esito del counseling individuale per le droghe: i risultati dall'Istituto Nazionale sull'abuso di droghe in equipe con lo Studio di trattamento della cocaina. Questo studio ha valutato le ipotesi collegate alle relazioni lineari e curvilinee tra adesione, competenza ed esito e le interazioni tra questi effetti con la qualità dell'alleanza terapeutica in pazienti (N: 95) che hanno ricevuto un counseling individuale sulle droghe come parte dello Studio di trattamento della cocaina in collaborazione con l'Istituto Nazionale di abuso di droghe.

I risultati supportano un'ipotizzata relazione curvilinea tra adesione ed esito, così come un'interazione tra questo effetto curvilineo e l'alleanza all'inizio del trattamento.

Per i pazienti con una forte alleanza terapeutica, l'adesione del counselor al modello di trattamento è stata essenzialmente irrilevante rispetto all'esito del trattamento. Quando l'alleanza era pi[ugrave] debole, al contrario, un moderato (verso l'alto o il basso) livello di adesione del counselor è stato associato con un miglior esito.

I risultati attuali suggeriscono che gli studi sulla relazione tra l'adesione del terapeuta ai modelli di trattamento e l'esito potrebbero aver bisogno di considerare il complesso effetto moderatore dell'alleanza terapeutica.

Este estudo estudou as hipóteses de relação linear e curvilínea entre adesão, competência e resultado e as interacç[otilde]es destes efeitos com a qualidade da aliança terapêutica em pacientes (N=95) que receberam aconselhamento individual para toxicodependência como parte do Estudo Colaborativo do Tratamento da Dependência da Cocaína do Instituto Nacional para o Abuso de Drogas. Os resultados apoiaram a relação curvilínea entre adesão e resultado, bem como uma interacção entre este efeito curvilíneo e aliança inicial. Para pacientes com uma forte aliança terapêutica, a adesão do terapeuta ao modelo terapêutico era, essencialmente, irrelevante para os resultados do tratamento. Quando a aliança era mais fraca, em contrate, um nível moderado (vs. baixo ou elevado) de adesão do terapeuta estava associado a melhores resultados. Estes resultados sugerem que estudos da relação entre adesão do terapeuta a modelos de tratamento e resultados terapêuticos podem necessitar de ter em consideração o efeito moderador complexo da aliança terapêutica.

     

Client resistance predicts outcomes in cognitive–behavioral therapy for panic disorder

Abstract

Objective: Little is known about how therapy processes relate to outcome in cognitive–behavioral therapy (CBT) for panic disorder (PD). This study examined whether client resistance predicts CBT for PD outcomes beyond the effects of established pre-treatment predictors. A secondary aim was to assess the consistency of resistance over treatment. Method: Data were from 71 adults participating in up to 24 biweekly sessions of CBT in a randomized controlled trial. Panic severity was assessed before, during (at Weeks 1, 5, and 9), and at termination of treatment (Week 12) using the Panic Disorder Severity Scale. Trained coders reliably rated resistance in videos of Sessions 2 and 10 using the Client Resistance Code. Results: Resistance was found to be moderately consistent (r?=?.64). Although overall resistance was unrelated to outcomes, hierarchical linear modeling revealed that openly hostile resistance at Session 10 predicted significantly diminished symptom change (r?=?.28, CI_95%?=?[.01, .51]), beyond the effects of pretreatment predictors. Hostile resistance at Session 2 predicted attrition (r_rb?=??.30, p?=?.001), even after established predictors were controlled. Conclusions: Although some forms of resistance may be benign, openly hostile resistance is an important therapy marker that warrants increased clinical and research attention.