Cadherin13 (CDH13) is a glycosylphosphatidylinositol-anchored cell adhesion molecule that plays a crucial role in morphogenesis and the maintenance of neuronal circuitry. CDH13 has been implicated in ...the susceptibility to a variety of psychiatric diseases. A recent genome-wide association study using Danish samples showed, for the first time, the involvement of a single nucleotide polymorphism (SNP) of CDH13 (intronic SNP rs8057927) in schizophrenia. Here, we investigated the association between other SNPs of CDH13 and schizophrenia and tried to replicate the association for the SNP of rs8057927, in the Japanese population.
Using TaqMan(®) SNP genotyping assays, five tag SNPs (rs12925602, rs7193788, rs736719, rs6565051, and rs7204454) in the promoter region of CDH13 were examined for their association with schizophrenia in two independent samples. The first sample comprised 665 patients and 760 controls, and the second sample comprised 677 patients and 667 controls. One tag SNP for rs8057927 was also examined for the association with schizophrenia in the first sample set.
A GACAG haplotype of the five SNPs in the promoter region of CDH13 was significantly associated with schizophrenia in the first sample set (P=0.016 and corrected P=0.098). A combined analysis of the GACAG haplotype with the second sample set enhanced the significance (P=0.0026 and corrected P=0.021). We found no association between rs8057927 and schizophrenia in the first sample set.
Our results suggest that CDH13 may contribute to the genetic risk of schizophrenia. Further replication on the association of CDH13 with schizophrenia and functional studies are required to confirm the current findings.
Numerous studies suggest that inflammation plays a key role in suicidal behavior. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has received increasing attention in ...depression research. However, no study has investigated whether
has genetic involvement in completed suicide. In this study, we sought to explore the relationship between two functional polymorphisms on the
gene promoter (
-794CATT
microsatellite and
-173G/C single-nucleotide polymorphism SNP) and completed suicide by using one of the largest samples of suicide completers ever reported.
The subjects comprised 602 suicide completers and 728 healthy controls. We genotyped
-794CATT
microsatellite by polymerase chain reaction-based size discrimination assay and
-173G/C SNP by TaqMan
SNP genotyping assay. The allele-, genotype-, or haplotype-based association analyses between the suicide completers and the controls were carried out with the
test, the Cochran-Armitage trend test, or Fisher's exact test.
Analyses of allele or genotype frequency distributions of the polymorphisms studied here did not reveal any significant differences between the suicide completers and the controls. Haplotype analysis also revealed no association with completed suicide.
To our knowledge, this is the first study that has examined the genetic association between MIF and completed suicide. Our results suggest that the effects of
-794CATT
microsatellite and
-173G/C SNP on the
gene promoter might not contribute to the genetic risk of completed suicide in the Japanese population.
Karstic caves are created by water eroding and corroding rocks that can be dissolved. Since both the spring areas of caves (normally at the valley bottom) as well as the recharge is controlled by ...superficial processes, the morphology of the cave bears strong links to these influences. Lowering of local base levels promotes the development of horizontal phreatic cave passages at progressively lower elevations, resulting in the formation of multi-level karst systems. Upon the next lowering of base level, these upper systems become fossilized, and sediment trapped within them may remain preserved for millions of years. Dating these sediments gives clues regarding the time when the passages were last active, and thus may yield age information for old valley floors. The present paper presents cosmogenic nuclide datings of twelve samples from eight caves in the central part of the Northern Calcareous Alps of Austria. Besides three samples that gave no results, most of the obtained ages are at the Mio-Pliocene boundary or within the Pliocene, as was expected before sampling. No multi-level caves could be sampled at different elevations, thus, the obtained valley deepening rates are averages between the age of sediment deposition and the present-day valley floor. However, the valley deepening rates of 0.12 to 0.21 km/Ma are in accordance to previous findings and corroborate a comparatively slow evolution of base level lowering in the Eastern Alps compared to the fast (Late Quaternary) evolution in the Central and Western Alps.
Up to 30% of depressed patients are partially or totally resistant to antidepressant therapy. The administration of triiodothyronine (T(3)) to antidepressant nonresponders can be an effective ...augmentation strategy, although the mechanism is not fully understood.
In vivo microdialysis was used to examine the effect of T(3) augmentation of the antidepressant, milnacipran. Basal extracellular serotonin, norepinephrine, and dopamine levels were measured before and after acute milnacipran administration in the medial prefrontal cortex and amygdala of rats which had received subchronic (7 days) T(3) treatment or control saline.
Subchronic administration of T(3) at 0.1 mg/kg significantly increased basal extracellular levels of serotonin in the medial prefrontal cortex, but not in the amygdala. In contrast, subchronic administration of T(3) at 0.2 mg/kg did not alter basal extracellular serotonin levels in the medial prefrontal cortex. Basal extracellular levels of norepinephrine and dopamine were not modified by either dose of T(3) in either region. Acute administration of milnacipran, a serotonin-norepinephrine reuptake inhibitor, to control animals resulted in a significant increase of extracellular levels of serotonin, norepinephrine, and dopamine. When administered to animals treated subchronically with T(3) at 0.1 mg/kg, milnacipran produced an additional increase in extracellular serotonin levels but not in levels of norepinephrine or dopamine in the medial prefrontal cortex of rats.
These results suggest that the mechanism of the augmentation effect of milnacipran by T(3) administration occurs via enhancement of serotonergic neurotransmission, but not through noradrenergic or dopaminergic neurotransmission.
Oxidative folding of secretory proteins in the endoplasmic reticulum (ER) is a redox active process, which also impacts the redox conditions in the cytosol. As the transcription factor Yap1 is ...involved in the transcriptional response to oxidative stress, we investigate its role upon the production of secretory proteins, using the yeast
as model, and report a novel important role of Yap1 during oxidative protein folding. Yap1 is needed for the detoxification of reactive oxygen species (ROS) caused by increased oxidative protein folding. Constitutive co-overexpression of
leads to increased levels of secreted recombinant protein, while a lowered Yap1 function leads to accumulation of ROS and strong flocculation. Transcriptional analysis revealed that more than 150 genes were affected by overexpression of
, in particular genes coding for antioxidant enzymes or involved in oxidation-reduction processes. By monitoring intracellular redox conditions within the cytosol and the ER using redox-sensitive roGFP1 variants, we could show that overexpression of
restores cellular redox conditions of protein-secreting
by reoxidizing the cytosolic redox state to the levels of the wild type. These alterations are also reflected by increased levels of oxidized intracellular glutathione (GSSG) in the
co-overexpressing strain. Taken together, these data indicate a strong impact of intracellular redox balance on the secretion of (recombinant) proteins without affecting protein folding per se. Re-establishing suitable redox conditions by tuning the antioxidant capacity of the cell reduces metabolic load and cell stress caused by high oxidative protein folding load, thereby increasing the secretion capacity.
Opiorphin (Oph) is a naturally produced endogenous peptide with a strong analgesic effect, superior to that of morphine, and without the severe side effects that morphine and morphine-like drugs ...exert. However, despite its strong therapeutic potential, the short duration of action, probably due to its low chemical stability and rapid degradation by the peptidases in the bloodstream, represents a serious obstacle to the Oph use into clinical practice. In this work a novel approach to construct Oph-loaded particles as a platform for its delivery has been developed. Gel beads loaded with Oph were synthesized from alginate, a naturally occurring biodegradable anionic polysaccharide, and coated with polyelectrolyte multilayers (from natural polyelectrolytes (chitosan and hyaluronic acid) and synthetic polyelectrolytes (poly(allylamine hydrochloride) and poly(styrene sulfonate)) or hybrid polyelectrolyte-graphene oxide multilayers. All coated Oph-loaded alginate beads show prolonged drug release compared to the non-coated ones, but the extent of the prolongation depends on the type of the coating. We expect that the successful encapsulation of opiorphin in biodegradable particles will provide an opportunity for the development of adequate drug delivery system with effective and prolonged analgesic activity and will offer a new alternative for pain management.
While the triplet combination of encorafenib (ENCO), binimetinib (BINI), plus cetuximab (CET) yielded a higher response rate compared with the doublet combination of ENCO plus CET, no significant ...survival benefits of the triplet combination were observed in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC), according to the BEACON CRC study. Although ENCO plus CET is the standard second-line therapy, poor prognoses are expected after disease progression.
BAYONET is a single-arm multicenter phase II trial designed to evaluate the efficacy and safety of staged combination with ENCO, BINI, plus CET for patients with BRAF V600E-mutant mCRC refractory to ENCO plus CET. The main inclusion criteria are as follows: RAS wild-type/BRAF V600E-mutant mCRC; <4 weeks from the last administration of previous ENCO or CET; no administration of other systemic therapy after refractoriness to ENCO plus CET; and complete response, partial response, or ≥4 months of stable disease in the previous ENCO plus CET. The primary endpoint of this trial is the 12-week progression-free survival rate. As a translational analysis, circulating tumor DNA for next-generation sequencing using Guardant360 is collected at two time points (before and after study treatment) to investigate potential mechanisms of resistance.
Specifications tableSubject areaMedicine and DentistryMore specific subject areaBRAF V600E-mutant colorectal cancerName of your trial in progressBAYONET trialReagents/toolsEligible patients who participated in this study received the combination treatment of encorafenib (ENCO; 300 mg once a day), binimetinib (BINI; 45 mg twice a day), plus cetuximab (CET; 400 mg/m2 initial dose and then 250 mg/m2 once a week) in a 28-day cycle as a study treatment until disease progression, death, patient’s withdrawal, or investigator’s decision (whichever comes first).Trial designBAYONET is a single-arm multicenter phase II trial designed to evaluate the efficacy and safety of staged combination with ENCO, BINI, plus CET for patients with BRAF V600E-mutant mCRC refractory to ENCO plus CET. The main inclusion criteria are as follows: RAS wild-type/BRAF V600E-mutant mCRC; <4 weeks from the last administration of previous ENCO or CET; no administration of other systemic therapy after refractoriness to ENCO plus CET; and complete response, partial response, or ≥4 months of stable disease observed in the previous ENCO plus CET. Included patients receive ENCO (300 mg once a day), BINI (45 mg twice a day), plus CET (400 mg/m2 initial dose and then 250 mg/m2 once a week) in a 28-day cycle as a study treatment. The planned sample size is 30. The primary endpoint of this trial is the 12-week progression-free survival (PFS) rate. The secondary endpoints are PFS, overall survival, objective response rate, disease control rate, time to treatment failure, and the incidence of adverse events. As a translational analysis, circulating tumor DNA for next-generation sequencing using Guardant360 is collected at two time points (before and after study treatment) to investigate potential mechanisms of resistance.Trial registrationjRCTs031210510EthicsThe current study has been approved by the Certified Institutional Review Board of National Cancer Center Hospital East (K2021006), and permission for conducting the study has been obtained from the management of all participating facilities. All patients are required to sign written informed consent. All experiments were carried out in accordance with the Declaration of Helsinki.Value of the trial in progress•A staged combination of ENCO, BINI, plus CET may overcome resistance to ENCO plus CET and has the potential to be an effective treatment strategy for patients with BRAF V600E-mutant mCRC.•A prospective, translational analysis using circulating tumor DNA is expected to reveal potential mechanisms underlying resistance to BRAF inhibitor plus anti-epidermal growth factor receptor (EGFR) antibody, contributing to the development of future promising treatments.
•BRAF-V600E mutant mCRC exhibits poor outcomes after treatment with ENCO plus CET.•BAYONET is a single-arm, multicenter phase II trial designed to evaluate ENCO, BINI, plus CET for BRAF V600E-mutant mCRC refractory to ENCO plus CET.•The primary endpoint is the 12-week progression-free survival rate.
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