Two phase I studies of BI 836880, a vascular endothelial growth factor/angiopoietin-2 inhibitor, administered once every 3 weeks or once weekly in patients with advanced solid tumors.

BACKGROUND: BI 836880 is a humanized bispecific nanobody® that inhibits vascular endothelial growth factor and angiopoietin-2. Here, we report results from two phase I, nonrandomized, dose-escalation studies (NCT02674152 and NCT02689505; funded by Boehringer Ingelheim) evaluating BI 836880 in patients with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy, or for which standard therapy was ineffective. PATIENTS AND METHODS: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function received escalating intravenous doses of BI 836880 once every 3 weeks (Q3W; Study 1336.1) or once weekly (QW; Study 1336.6). Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose of BI 836880, based on dose-limiting toxicities (DLTs) during the first cycle. RESULTS: Patients received one of five dosages of 40-1000 mg Q3W (29 patients) or 40-240 mg QW (24 patients). One DLT occurred with Q3W treatment [Grade (G) 3 pulmonary embolism (1000 mg)]. Five DLTs occurred in four patients treated QW [G2 proteinuria (120 mg); G3 hypertension (180 mg); G3 proteinuria and G3 hypertension (240 mg); and G4 respiratory distress (240 mg)]. All patients experienced adverse events, most commonly hypertension with Q3W treatment (89.7%; G3 41.4%), and asthenia with QW treatment (62.5%). Two patients treated Q3W (both 1000 mg) and three patients treated QW (120 mg, 2 patients; 180 mg, 1 patient) experienced partial response. CONCLUSIONS: The MTD of BI 836880 was 720 mg Q3W and 180 mg QW. BI 836880 was generally manageable and demonstrated preliminary efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02674152; https://clinicaltrials.gov/ct2/show/NCT02674152 and NCT02689505; https://clinicaltrials.gov/ct2/show/NCT02689505.

MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): an open randomized, multicentric, parallel group clinical trial (MASPAC).

BACKGROUND: Pain symptoms in the upper abdomen and back are prevalent in 80% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), where the current standard treatment is a systemic therapy consisting of at least doublet-chemotherapy for fit patients. Palliative low-dose radiotherapy is a well-established local treatment option but there is some evidence for a better and longer pain response after a dose-intensified radiotherapy of the primary pancreatic cancer (pPCa). Stereotactic body radiation therapy (SBRT) can deliver high radiation doses in few fractions, therefore reducing chemotherapy-free intervals. However, prospective data on pain control after SBRT of pPCa is very limited. Therefore, we aim to investigate the impact of SBRT on pain control in patients with mPDAC in a prospective trial. METHODS: This is a prospective, double-arm, randomized controlled, international multicenter study testing the added benefit of MR-guided adaptive SBRT of the pPca embedded between standard of care-chemotherapy (SoC-CT) cycles for pain control and prevention of pain in patients with mPDAC. 92 patients with histologically proven mPDAC and at least stable disease after initial 8 weeks of SoC-CT will be eligible for the trial and 1:1 randomized in 3 centers in Germany and Switzerland to either experimental arm A, receiving MR-guided SBRT of the pPCa with 5 × 6.6 Gy at 80% isodose with continuation of SoC-CT thereafter, or control arm B, continuing SoC-CT without SBRT. Daily MR-guided plan adaptation intents to achieve good target coverage, while simultaneously minimizing dose to organs at risk. Patients will be followed up for minimum 6 and maximum of 18 months. The primary endpoint of the study is the "mean cumulative pain index" rated every 4 weeks until death or end of study using numeric rating scale. DISCUSSION: An adequate long-term control of pain symptoms in patients with mPDAC is an unmet clinical need. Despite improvements in systemic treatment, local complications due to pPCa remain a clinical challenge. We hypothesize that patients with mPDAC will benefit from a local treatment of the pPCa by MR-guided SBRT in terms of a durable pain control with a simultaneously favorable safe toxicity profile translating into an improvement of quality-of-life. TRIAL REGISTRATION: German Registry for Clinical Trials (DRKS): DRKS00025801. Meanwhile the study is also registered at ClinicalTrials.gov with the Identifier: NCT05114213.

Prevalence of mental disorders at admission to the penal justice system in emerging countries: a study from Chile.

BACKGROUND: Previous mental health surveys conducted in prisons within emerging countries recruited samples of all prisoners at any single point in time. However, this sampling strategy results in an overrepresentation of long-term prisoners as compared with those studies recruiting from all admissions over time. This study aimed to assess mental disorders in consecutively admitted prisoners soon after admission, in order to address service needs of people with short-term imprisonments and people at early stages of imprisonment. METHOD: Disorders were assessed in a sample of 229 male and 198 female prisoners, consecutively committed to the penal justice system in Santiago de Chile, using the structured Mini-Neuropsychiatric interview. Prevalence rates were calculated as per cent values. Ninety-five per cent confidence intervals were calculated for the proportions. RESULTS: Illicit drug and/or alcohol use disorders in the year prior to admission were present in 173 (76%) male and 64 (32%) female prisoners. The substances most frequently causing addiction were cocaine-based products in 108 (47%) male and 42 (21%) female prisoners. Current major depression was present in 124 (54%) male and 86 (43%) female prisoners, and current non-affective psychotic disorders in 18 (8%) male and in 10 (5%) female prisoners. High suicidal risk was present in 64 (28%) male prisoners and in 29 (15%) female prisoners. CONCLUSION: When consecutive prisoners are assessed at admission, rates of mental health and substance use disorders were higher than in previous studies in emerging countries that had sampled from all existing prisoners at a time. Affective disorders and suicide risk appear more prevalent than in admission studies conducted in Western high-income countries. Previous research may have systematically underestimated the extent of mental health problems in prisoners, which poses a major public health challenge in emerging countries.

Recent progress on STIM1 domains controlling Orai activation.

Ca(2+) entry in non-excitable cells is mainly carried by store-operated channels among which the CRAC channel is best characterized. Its two limiting molecular components are represented by the Ca(2+) sensor protein STIM1 located in the endoplasmic reticulum and Orai1 in the plasma membrane. STIM1 senses a decrease of the Ca(2+) content in internal stores and triggers its accumulation into puncta like structures resulting in coupling to as well as activation of Orai1 channels. The STIM1-Orai coupling process is determined by an interaction via their C-termini. This review highlights recent developments on domains particularly within the cytosolic part of STIM1 that govern this interaction.

Characterisation of cellular and humoral autoimmune responses to histone H1 and core histones in human systemic lupus erythaematosus.

OBJECTIVE: To address key aspects of anti-histone autoimmunity in systemic lupus erythaematosus (SLE), we performed a detailed characterisation of cellular and humoral autoreactivity to histone H1 and the four core histones H2A, H2B, H3, H4 in patients with SLE and healthy controls. METHODS: Peripheral blood mononuclear cells of 41 patients with SLE and 28 healthy controls were exposed to individual histones and proliferation was measured by [(3)H]-thymidine incorporation. H1-reactive T cell clones were obtained by limiting dilution. Cytokines and total IgG in culture supernatants was measured by ELISA, and autoantibodies to histones were determined by ELISA and immunoblotting. RESULTS: Proliferative responses to H1 were more frequent and more pronounced in cell cultures from patients with SLE (p<0.002), while among the core histones only the response to H2A was increased in patient cultures (p<0.01). All histones elicited a Th1-like cytokine response in patients and controls (high interferon (IFN)gamma and tumour necrosis factor (TNF)alpha, no interleukin (IL)4) with H1 inducing the highest levels of TNFalpha. However, H1 stimulated production of IgG and anti-histone antibodies only in cell cultures derived from patients with SLE. H1-specific T cell clones from patients and controls showed a CD4+CD28+ phenotype and a Th1 cytokine profile. Anti-histone antibodies were detected in 51% of patients with SLE, were primarily directed to H1, H3 and H4, and predominantly of the IgG2 subtype. CONCLUSIONS: Histone H1 constitutes a major B cell and T cell autoantigen in SLE, triggering a proinflammatory Th1 response and driving autoantibody production. This suggests that histone H1 may be of considerable relevance for the pathogenesis of SLE.

HDAC3 is linked to cell cycle machinery in MiaPaCa2 cells by regulating transcription of skp2.

OBJECTIVE: Histone deacetylases (HDACs) have been linked to cell cycle control in various models, involving regulation of the cyclin-dependent kinase inhibitor p27(Kip1). RESULTS: Here, we demonstrate that HDAC inhibition by trichostatin A reduces S-phase kinase-associated protein 2 mRNA and protein abundance. Furthermore, in contrast to HDAC1, recruited to the skp2 promoter in the G(0) phase, HDAC3 is bound in early S phase. Activating function of HDAC3 towards the skp2 gene has been validated using RNA interference techniques. siRNAs, targeting HDAC3 specifically, reduced skp2 transcription. CONCLUSION: These findings propose that the skp2 gene is a novel target of HDAC3, mediating cell cycle control and oncogenesis.

Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance.

Renal cell carcinoma (RCC) is resistant to chemotherapy, and this resistance is mirrored by a high apoptosis resistance of many RCC lines in vitro. Here, we report the loss of the pro-apoptotic BH3-only protein Bim in a large part of clinical RCC cases and provide evidence for a functional relevance of this loss. Immunohistochemistry of clear cell renal cell carcinoma cases and corresponding normal kidney showed strong Bim reactivity in renal tubules of all cases but loss of Bim in 35 of 45 RCC samples. Out of nine RCC cell lines investigated, six showed strongly diminished or undetectable levels of Bim protein by western blotting. Four RCC lines of varying apoptosis sensitivity were analysed further. Bcl-2, Bcl-x(L), Mcl-1, Bax and Bak expression did not correlate with apoptosis sensitivity. All cell lines underwent apoptosis upon forced expression of Bax and Bim, suggesting an upstream difference. In all four lines, adriamycin induced p53 but not its targets Puma or Noxa. However, apoptosis sensitivity correlated with levels of Bim protein. Bim siRNA reduced apoptosis sensitivity in a susceptible cell line. Furthermore, inhibition of histone deacetylation restored Bim expression in cell lines. These data suggest that Bim has a function as a tumor suppressor in RCC.

Early response to venlafaxine antidepressant correlates with lower ACTH levels prior to pharmacological treatment.

A link between stressful life events and development or exacerbation of depression has been established via a large body of evidence. An alteration in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis in depression has also been associated with an increase in cortisol secretion. As arginine-vasopressin (AVP) plays an important role in the activation of HPA axis during stress, the present study investigated ACTH and cortisol secretory response induced by an AVP-related peptide desmopressin (ddAVP) in patients with major depression. Prior to antidepressant treatment, endocrinological parameters were evaluated and correlated with the clinical response to venlafaxine treatment, which offers a dual antidepressant action. Depressive patients with no other psychiatric pathology were evaluated with 17-item Hamilton Depression Scale (HAM-D) in order to follow-up the response to venlafaxine. After 1 wk of treatment, 60% of patients reduced their initial HAM-D score to at least 25%; this group was classified as early responders. The other group (40%) started to reduce significantly their HAM-D score after 3 wk of treatment and was classified as late responders. After 6 wk of treatment both groups have reduced HAM-D score to at least 25% of the baseline score. Prior to the pharmacological treatment, both early and late responders showed salivary cortisol rhythm and urinary free cortisol (UFC) in 24-h similar to healthy subjects. However, we did observe differences in basal ACTH secretion, showing that the late responder group had higher basal ACTH than both early responders and controls. The ddAVP challenge promoted a robust secretion of ACTH only in late responders, suggesting a different sensitivity of pituitary vasopressin receptor. The differences in clinical response to venlafaxine among depressive patients seem to be related to endocrinological parameters.

Tabaquismo y salud mental / Tobacco smoking and mental health

BACKGROUND: Smoking continues to be one of the most important health burdens worldwide. AIM: To describe smoking habits and associated risk factors in the population of Santiago, Chile. MATERIAL AND METHODS: A cross sectional study of a representative sample of the population, from 16 to 64 years old, residents of Santiago, Chile (total population: 3,237,286). A structured interview that included questions about use of tobacco, the CIS-R interviews, used for common mental disorders, were applied. RESULTS: From the sample of 4,693 households, 3,870 people were interviewed (52.2 per cent women, 47.8 men) and 10 per cent refused. Forty percent of per cent the population currently smoked (52.5 per cent men, 47.8 per cent women). Being a current smoker was associated with being younger than 55, male sex, and having a common mental disorder. DISCUSSION: Smoking is highly prevalent in Chile, as compared with developed countries and with some developing countries. Gender differences in use of tobacco have decreased. A higher risk of smoking for people with mental disorders is confirmed.

Education and income: which is more important for mental health?

STUDY OBJECTIVE: To assess which indicators of socioeconomic status are associated with an increased prevalence of common mental disorders. DESIGN: Cross sectional household survey. SETTING: Santiago, Chile. PARTICIPANTS: Random sample of adults aged 16-65 residing in private households. MAIN RESULTS: Less education (odds ratio 2.44, 95% confidence intervals 1.50 to 3.97), a recent income decrease (odds ratio 2.14, 1.70 to 2.70), and poor housing (odds ratio 1.53, 1.05 to 2.23), were the only socioeconomic status variables that remained significantly associated with an increased prevalence of common mental disorders after adjustments. The prevalence of common mental disorders was also higher among people with manual unskilled occupations, overcrowded housing, and lower per capita income but these associations disappeared after adjustment for other explanatory and confounding variables. CONCLUSIONS: There is a strong, inverse, and independent association between education and common mental disorders. However, income was not associated with the prevalence of common mental disorders, after adjusting for other socioeconomic variables. Similar results have been found in other Latin American studies but British studies tend to find the opposite, that income but not education is associated with common mental disorders. Understanding the impact of socioeconomic factors on mental health requires research in poor as well as rich countries.

Endoscopic treatment of a Zenker's diverticulum using argon plasma coagulation in a patient with massive cachexia and esophageal obstruction: a case report and review of literature.

A case report is presented of an 86-year-old man in a very poor general condition with a 10-year history of a Zenker's diverticulum as a cause of a complete obstruction of the esophagus with subsequent aphagia and massive cachexia. Because of high surgical risk and contraindications to general anesthesia, an approach with the flexible endoscope to perform cricopharyngeal myotomy was undertaken. Several attempts with the flexible endoscope by experienced investigators had been performed until the esophageal inlet was intubated and argon plasma coagulation could be applied in several sessions to divide the tissue bridge between the esophagus and the Zenker diverticulum to successfully restore the pharyngoesophageal passage.

Functional coupling between nitric oxide synthesis and VIP release within enteric nerve terminals of the rat: involvement of protein kinase G and phosphodiesterase 5.

1. The subcellular mechanisms involved in the effect of nitric oxide (NO) on the release of vasoactive intestinal polypeptide (VIP) were examined in synaptosomes isolated from rat small intestine. 2. VIP release was stimulated by the NO donor SNAP (10(-7)-10(-4) M) in an oxyhaemoglobin-sensitive manner. The presence of the guanylate cyclase inhibitor ODQ (10(-5) M), or inhibition of protein kinase G (PKG) by KT 5823 (3 x 10(-6) M) or Rp-8Br-PET-cGMPS (5 x 10(-7) M), antagonized the SNAP-induced VIP release, suggesting a regulatory role of PKG, confirming previously published data from enteric ganglia. This finding was further supported by the fact that direct PKG activation by the stable cGMP analogue 8-pCPT-cGMP stimulated VIP secretion to the same extent as SNAP. 3. Basal VIP secretion was enhanced in the presence of zaprinast, an inhibitor of cGMP-dependent phosphodiesterase 5 (PDE 5), suggesting a functional role of PDE 5 in NO-cGMP signalling. Supportive evidence for this finding was obtained by demonstration of the presence of PDE 5 using RT-PCR. 4. Stimulation of endogenous NO production by L-arginine was also effective in releasing VIP. The effect was abolished in the presence of KT 5823, but was insensitive to oxyhaemoglobin (10(-3) M), suggesting that an interaction between NO and VIP is likely to occur within the same nerve terminal rather than between terminals. 5. NO synthesis was not affected by VIP (10(-8)-10(-5) M), suggesting that there is no feedback regulation between the NO and the VIP pathways. 6. These findings support the notion that an anatomical and functional interrelationship exists between NO and VIP in enteric nerve terminals and that complex signalling mechanisms involving PKG and PDE 5 contribute to NO-induced VIP release.

Common mental disorders in Santiago, Chile: prevalence and socio-demographic correlates.

BACKGROUND: There have been relatively few surveys in Latin America that have attempted to estimate the prevalence of psychiatric morbidity in private households. AIMS: To determine the prevalence of common mental disorders and socio-demographic correlates among adults from Santiago, Chile. METHOD: Cross-sectional survey of private households with a probabilistic sampling design was used. Common mental disorders were measured using the Clinical Interview Schedule-Revised (CIS-R). RESULTS: Three thousand eight hundred and seventy adults were interviewed. Twenty-five per cent were CIS-R cases and 13% met criteria for an ICD-10 diagnosis. Low education, female gender, unemployment, separation, low social status and lone parenthood were associated with a higher prevalence. CONCLUSIONS: Prevalence rates were higher than those found in urban areas of Great Britain, both for ICD-10 diagnoses and 'non-specific neurotic disorders'. Similar socio-demographic factors were associated with an increased prevalence of common mental disorders in Chile as in the UK. There is a need to unify methodologies to be able to compare results internationally.

Molecular and morphological evidence for an origin of the aberrant genus Milula within himalayan species of Allium (Alliacae).

Phylogenetic relationships between Allium and the monotypic Himalayan genus Milula were analyzed using sequences of the nuclear ribosomal DNA internal transcribed spacer (ITS) region and of the intergenic spacers from the chloroplast trnD(GUC)-trnT(GGU) region. Both marker systems unambiguously placed Milula spicata within Allium subgenus Rhizirideum, close to A. cyathophorum. Morphologically, the main difference between Allium and Milula is the conspicuous spicate inflorescence of Milula vs the mostly capitate or umbellate inflorescences in Allium. Anatomical investigations of leaf characters support a close relationship of Milula with A. cyathophorum and A. mairei, whereas root characters are distinctive from other species of section Cyathophora. To maintain Allium as monophyletic, Milula has been included as A. spicatum in Allium subgenus Rhizirideum.

NO releases bombesin-like immunoreactivity from enteric synaptosomes by cross-activation of protein kinase A.

The effect of nitric oxide (NO) on the release of bombesin-like immunoreactivity (BLI) was examined in synaptosomes of rat small intestine. The NO donor S-nitroso-N-acetylpenicillamine (SNAP; 10(-7) to 10(-4) M) significantly stimulated BLI release. In the presence of the NO scavenger oxyhemoglobin (10(-3) M) or the guanylate cyclase inhibitor ODQ (10(-5) M), SNAP-induced BLI release was antagonized. In addition, SNAP increased the synaptosomal cGMP content and elevation of cGMP levels by zaprinast (3 x 10(-5) M), an inhibitor of the cGMP-specific phosphodiesterase (PDE) type 5, and increased basal and SNAP-induced BLI release. NO-induced BLI release was blocked by Rp-adenosine 3',5'-cyclic monophosphorothioate (3 x 10(-5) M and 10(-4) M), an inhibitor of the cAMP-dependent protein kinase A, whereas KT-5823 (3 x 10(-6) M) and Rp-8-(4-chlorophenylthio)-cGMP (5 x 10(-5) M), inhibitors of the cGMP-dependent protein kinase G, had no effect. Because cGMP inhibits the cAMP-specific PDE3, thereby increasing cAMP levels, the role of PDE3 was investigated. Trequinsin (10(-8) M), a specific blocker of PDE3, stimulated basal BLI release but had no additive effect on NO-induced release, suggesting a similar mechanism of action. These data demonstrate that because of a cross-activation of cAMP-dependent protein kinase A by endogenous cGMP BLI can be released by NO from enteric synaptosomes.

Design and realization of an on-line database for multidimensional microscopic images of biological specimens.

The BioImage database is a new scientific database for multidimensional microscopic images of biological specimens, which is available through the World Wide Web (WWW). The development of this database has followed an iterative approach, in which requirements and functionality have been revised and extended. The complexity and innovative use of the data meant that technical and biological expertise has been crucial in the initial design of the data model. A controlled vocabulary was introduced to ensure data consistency. Pointers are used to reference information stored in other databases. The data model was built using InfoModeler as a database design tool. The database management system is the Informix Dynamic Server with Universal Data Option. This object-relational system allows the handling of complex data using features such as collection types, inheritance, and user-defined data types. Informix datablades are used to provide additional functionality: the Web Integration Option enables WWW access to the database; the Video Foundation Blade provides functionality for video handling.

Evolution of the chloroplast genome and polymorphic ITS regions in Allium subg. Melanocrommyum.

Relationships based on PCR-RFLPs of non-coding regions of cpDNA indicate that some of the largest subgenera of the genus Allium and five of the largest sections of the Central Asian subg. Melanocrommyum are artificial. Internested synapomorphic mutations without homoplasy were found only in the chloroplast genomes of plants of subg. Melanocrommyum that occur in the border region of Tajikistan, Uzbekistan, Afghanistan, and Kyrgyzstan. Eighteen of 49 plants surveyed were polymorphic for their ITS regions. Even plants that had identical chloroplast genomes were polymorphic for nuclear ribosomal regions. These individuals had markedly different frequencies of ITS variants that were detected with various restriction enzymes. The geographic partitioning of chloroplast haplotypes and the fact that the ITS variants could not be ordered hierarchically can readily be envisioned to result from gene flow. Processes such as concerted evolution and parallel morphological evolution may also be partly responsible for the disconcordance of mutations in the chloroplast and nuclear genome. However, the chimeric nature of the nuclear ribosomal regions indicates that concerted evolution is not the dominating process in Allium subg. Melanocrommyum.

Organising multi-dimensional biological image information: the BioImage Database.

Nowadays it is possible to unravel complex information at all levels of cellular organization by obtaining multi-dimensional image information. At the macromolecular level, three-dimensional (3D) electron microscopy, together with other techniques, is able to reach resolutions at the nanometer or subnanometer level. The information is delivered in the form of 3D volumes containing samples of a given function, for example, the electron density distribution within a given macromolecule. The same situation happens at the cellular level with the new forms of light microscopy, particularly confocal microscopy, all of which produce biological 3D volume information. Furthermore, it is possible to record sequences of images over time (videos), as well as sequences of volumes, bringing key information on the dynamics of living biological systems. It is in this context that work on BioImage started two years ago, and that its first version is now presented here. In essence, BioImage is a database specifically designed to contain multi-dimensional images, perform queries and interactively work with the resulting multi-dimensional information on the World Wide Web, as well as accomplish the required cross-database links. Two sister home pages of BioImage can be accessed at http://www. bioimage.org and http://www-embl.bioimage.org