Citalopram plus low-dose pipamperone versus citalopram plus placebo in patients with major depressive disorder: an 8-week, double-blind, randomized study on magnitude and timing of clinical response

Background: Selective serotonin reuptake inhibitors take several weeks to achieve their full antidepressant effects. Post-synaptic 5-HT<sub>2A</sub> receptor activation is thought to be involved in this delayed therapeutic effect. Pipamperone acts as a highly selective 5-HT<sub>2A</sub>/D<sub>4</sub> antagonist when administered in low doses. The purpose of this study was to compare citalopram 40 mg once daily plus pipamperone 5 mg twice daily (PipCit) versus citalopram plus placebo twice daily for magnitude and onset of therapeutic effect. Method: An 8-week, randomized, double-blind study in patients with major depressive disorder was carried out. Results: The study population comprised 165 patients (citalopram and placebo, n=82; PipCit, n=83) with a mean baseline Montgomery–Asberg Depression Rating Scale (MADRS) score of 32.6 (S.D.=5.5). In the first 4 weeks, more citalopram and placebo than PipCit patients discontinued treatment (18% v. 4%, respectively, p=0.003). PipCit patients had significantly greater improvement in MADRS score at week 1 [observed cases (OC), p=0.021; last observation carried forward (LOCF), p=0.007] and week 4 (LOCF, p=0.025) but not at week 8 compared with citalopram and placebo patients. Significant differences in MADRS scores favoured PipCit in reduced sleep, reduced appetite, concentration difficulties and pessimistic thoughts. Mean Clinical Global Impression–Improvement scores were significantly improved after 1 week of PipCit compared with citalopram and placebo (OC and LOCF, p=0.002). Conclusions: Although the MADRS score from baseline to 8 weeks did not differ between groups, PipCit provided superior antidepressant effects and fewer discontinuations compared with citalopram and placebo during the first 4 weeks of treatment, especially in the first week

Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression.

Vascular cell adhesion molecule-1 (VCAM-1) plays important roles in development and inflammation. Tumor necrosis factor-α (TNF-α) and focal adhesion kinase (FAK) are key regulators of inflammatory and integrin-matrix signaling, respectively. Integrin costimulatory signals modulate inflammatory gene expression, but the important control points between these pathways remain unresolved. We report that pharmacological FAK inhibition prevented TNF-α-induced VCAM-1 expression within heart vessel-associated endothelial cells in vivo, and genetic or pharmacological FAK inhibition blocked VCAM-1 expression during development. FAK signaling facilitated TNF-α-induced, mitogen-activated protein kinase activation, and, surprisingly, FAK inhibition resulted in the loss of the GATA4 transcription factor required for TNF-α-induced VCAM-1 production. FAK inhibition also triggered FAK nuclear localization. In the nucleus, the FAK-FERM (band 4.1, ezrin, radixin, moesin homology) domain bound directly to GATA4 and enhanced its CHIP (C terminus of Hsp70-interacting protein) E3 ligase-dependent polyubiquitination and degradation. These studies reveal new developmental and anti-inflammatory roles for kinase-inhibited FAK in limiting VCAM-1 production via nuclear localization and promotion of GATA4 turnover

Hemispheric asymmetry in visuospatial attention assessed with transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) was used to study visuospatial attention processing in ten healthy volunteers. In a forced choice recognition task the subjects were confronted with two symbols simultaneously presented during 120ms at random positions, one in the left and the other in the right visual field. The subject had to identify the presented pattern out of four possible combinations and to press the corresponding response key within 2 s. Double-pulse TMS (dTMS) with a 100-ms interstimulus interval (ISI) and an intensity of 80% of the stimulator output (corresponding to 110-120% of the motor threshold) was applied by a nonfocal coil over the right or left posterior parietal cortex (PPC, corresponding to P3/P4 of the international 10-20 system) at different time intervals after onset of the visual stimulus (starting at 120ms, 270ms and 520ms). Double-pulse TMS over the right PPC starting at 270ms led to a significant increase in percentage of errors in the contralateral, left visual field (median: 23% with TMS vs 13% without TMS, P=0.0025). TMS applied earlier or later showed no effect. Furthermore, no significant increase in contra- or ipsilateral percentage of errors was found when the left parietal cortex was stimulated with the same timing. These data indicate that: (1) parietal influence on visuospatial attention is mainly controlled by the right lobe since the same stimulation over the left parietal cortex had no significant effect, and (2) there is a vulnerable time window to disturb this cortical process, since dTMS had a significant effect on the percentage of errors in the contralateral visual hemifield only when applied 270ms after visual stimulus presentatio

Enhancement of antibody-dependent cellular cytotoxicity is associated with treatment response to extracorporeal photopheresis in Sézary syndrome.

Sézary syndrome (SS) is a rare, leukemic type of cutaneous T-cell lymphoma (CTCL), for which extracorporeal photopheresis (ECP) is a first-line therapy. Reliable biomarkers to objectively monitor the response to ECP in patients with SS are missing. We examined the quantitative and qualitative impact of ECP on natural killer (NK) cell activity in SS patients, and especially their functional ability for antibody-dependent cell-mediated cytotoxicity (ADCC). Further, we addressed the question whether the magnitude of the effect on ADCC can be associated with the anti-cancer efficacy of ECP in SS patients. We assessed numbers of NK cells, ADCC activity, and treatment response based on blood tumor staging in a cohort of 13 SS patients (8 women, 5 men) treated with ECP as a first-line therapy. Blood samples were collected before treatment start and after an average of 9 months of uninterrupted ECP treatment. NK cell numbers were reduced in SS patients compared to healthy individuals and showed a tendency of recovery after long-term ECP treatment, independent of the clinical response to treatment. Patients with marginal increase (≤1.5 AU-fold) or lack of increase in ADCC activity failed to respond clinically to treatment, while patients with an increased ADCC activity showed a reduction in blood tumor burden. NK-mediated ADCC is selectively enhanced and might be a mechanism underlying the effect of ECP while in addition it can possibly serve as a reliable biomarker to objectively monitor response to ECP in patients with SS

Consensus on guidelines for stereotactic neurosurgery for psychiatric disorders

Background For patients with psychiatric illnesses remaining refractory to \u27tandard\u27 therapies, neurosurgical procedures may be considered. Guidelines for safe and ethical conduct of such procedures have previously and independently been proposed by various local and regional expert groups. Methods To expand on these earlier documents, representative members of continental and international psychiatric and neurosurgical societies, joined efforts to further elaborate and adopt a pragmatic worldwide set of guidelines. These are intended to address a broad range of neuropsychiatric disorders, brain targets and neurosurgical techniques, taking into account cultural and social heterogeneities of healthcare environments. Findings The proposed consensus document highlights that, while stereotactic ablative procedures such as cingulotomy and capsulotomy for depression and obsessive-compulsive disorder are considered \u27stablished\u27 in some countries, they still lack level I evidence. Further, it is noted that deep brain stimulation in any brain target hitherto tried, and for any psychiatric or behavioural disorder, still remains at an investigational stage. Researchers are encouraged to design randomised controlled trials, based on scientific and data-driven rationales for disease and brain target selection. Experienced multidisciplinary teams are a mandatory requirement for the safe and ethical conduct of any psychiatric neurosurgery, ensuring documented refractoriness of patients, proper consent procedures that respect patient\u27s capacity and autonomy, multifaceted preoperative as well as postoperative long-term follow-p evaluation, and reporting of effects and side effects for all patients. Interpretation This consensus document on ethical and scientific conduct of psychiatric surgery worldwide is designed to enhance patient safety

Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis

Caspase-8 is a proapoptotic protease that suppresses neuroblastoma metastasis by inducing programmed cell death. Paradoxically, caspase-8 can also promote cell migration among nonapoptotic cells; here, we show that caspase-8 can promote metastasis when apoptosis is compromised. Migration is enhanced by caspase-8 recruitment to the cellular migration machinery following integrin ligation. Caspase-8 catalytic activity is not required for caspase-8-enhanced cell migration; rather, caspase-8 interacts with a multiprotein complex that can include focal adhesion kinase and calpain 2 (CPN2), enhancing cleavage of focal adhesion substrates and cell migration. Caspase-8 association with CPN2/calpastatin disrupts calpastatin-mediated inhibition of CPN2. In vivo, knockdown of either caspase-8 or CPN2 disrupts metastasis among apoptosis-resistant tumors. This unexpected molecular collaboration provides an explanation for the continued or elevated expression of caspase-8 observed in many tumors

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance

Inhibition of lipid oxidation increases glucose metabolism and enhances 2-deoxy-2-[¹⁸F]fluoro-D-glucose uptake in prostate cancer mouse xenografts

Includes bibliographic references.PURPOSE: Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of Pca, imaging with 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) is suboptimal, since tumors tend to have low avidity for glucose. PROCEDURES: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [¹⁸F]FDG-positron emission tomography ([¹⁸F]FDG-PET) imaging in PCa xenograft mouse models in 24 h. RESULTS: PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [¹⁸F]FDG signal in PCa mouse models. CONCLUSIONS: Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers

Anti-HIV Activity Mediated by Natural Killer and CD8+ Cells after Toll-Like Receptor 7/8 Triggering

We previously found that triggering TLR7/8 either by single stranded HIV RNA or synthetic compounds induced changes in the lymphoid microenvironment unfavorable to HIV. In this study, we used selective TLR7 and 8 agonists to dissect their contribution to the anti-HIV effects. While triggering TLR7 inhibited efficiently HIV replication in lymphoid suspension cells from tonsillar origin, its effect was inconsistent in peripheral blood mononuclear cells (PBMC). In contrast, triggering TLR8 showed a very prominent and overall very consistent effect in PBMC and tonsillar lymphoid suspension cells. Depletion of dendritic cells (DC), Natural killer cells (NK) and CD8+ T-cells from PBMC resulted in the reversal of TLR8 induced anti-HIV effects. Especially noteworthy, depletion of either NK or CD8+ T-cells alone was only partially effective. We interpret these findings that DC are the initiator of complex changes in the microenvironment that culminates in the anti-HIV active NK and CD8+ effector cells. The near lack of NK and the low number of CD8+ T-cells in tonsillar lymphoid suspension cells may explain the lower TLR8 agonist's anti-HIV effects in that tissue. However, additional cell-type specific differences must exist since the TLR7 agonists had a very strong inhibitory effect in tonsillar lymphoid suspension cells. Separation of effector from the CD4+ target cells did not abolish the anti-HIV effects pointing to the critical role of soluble factors. Triggering TLR7 or 8 were accompanied by major changes in the cytokine milieu; however, it appeared that not a single soluble factor could be assigned for the potent effects

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours