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Charge-transfer states have been observed extensively in heterojunctions of organic semiconductors, which are also referred to as exciplexes in polymer blends. Such mechanisms have been well understood in the conventional material systems. However, electromer states may be produced only in some polymeric molecules with folded chains. We report here the interaction between exciplex and electromer states, which facilitates the formation of a new electrically excited state that we define as a secondary exciplex. This is an indirect process understood as an electromer-mediated heterojunction. We discovered such an optoelectronic mechanism in the blend film of poly(9,9'-dioctylfluorene

Background: Multiple myeloma (MM) is incurable in spite of recent treatment improvements, highlighting the development of new therapies. Chimeric antigen receptor (CAR) T-cell therapy has dramatically changed the therapeutic effectiveness in high-risk B-cell malignancies. For relapsed/refractory multiple myeloma (RRMM), preclinical evaluations of CAR-T therapy have shown promising efficacy, thus various active clinical trials are under way. Herein, we conducted this review to summarize efficacy and safety of CAR-T therapy and provide more evidence to guide clinical treatments. Method: We systematically searched literature based on databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials), and conference abstracts reported from American Society of Hematology (ASH), European Hematology Association (EHA) and American Society of Clinical Oncology (ASCO), in addition to other sources (www.clinicaltrials.gov, article citations). Data assessed efficacy and safety of CAR-T therapy in patients with RRMM were extracted and evaluated, and then systematically analyzed by Comprehensive Meta-analysis 3.0 (CMA 3.0). Results: A total of 23 studies including 350 participants from different countries, diagnosed as RRMM and treated with CAR-T therapy (containing 7 antigens targeted by CARs) were combined. In summary, we discovered the pooled overall response rate (77%), complete response rate (37%) and minimal residual disease (MRD) negativity rate within responders (78%). Furthermore, the pooled relapse rate of responders was 38% and median progression-free survival was 8 months. The pooled survival rate was 87% at last follow-up (median, 12 months). In addition, the pooled grade 3-4 rates of cytokine release syndrome (CRS) and neurologic toxicities (NT) were 14% and 13%, respectively. Conclusion: Our study suggests that CAR-T therapy has demonstrated efficacy and safety in RRMM patients. BCMA-targeted CAR-T and anti-BCMA contained regimen have shown better efficacy.

Hematological malignancies are diverse, with high malignancy characteristics, poor prognoses, and high mortality rates. The development of hematological malignancies is driven by genetic factors, tumor microenvironment factors, or metabolic factors; however, even when considering all of these factors, one still cannot fully estimate the risk of hematological malignancies. Several recent studies have demonstrated an intimate connection between intestinal microbes and the progression of hematological malignancies, and gut microbes play a primary role in the initiation and progression of hematological tumors through direct and indirect mechanisms. Thus, we summarize the correlation between intestinal microbes and hematological malignancies’ onset, progression, and therapeutic effect in order to better understand how intestinal microbes affect their initiation and progression, especially in leukemia, lymphoma, and multiple myeloma, which may provide potential therapeutic targets for improving the survival of patients with hematological malignancies.

Docetaxel (DTX) is a highly effective anti-tumor drug frequently used in clinical practice. Previous reports indicated that complications after DTX therapy could be related to retinal pigment epithelial (RPE) cell dysfunction, although no direct reports of this relationship have been published. In this study, human embryonic stem cell-derived RPE (hESC-RPE) cells were used to explore the effects of DTX on their morphology, viability, apoptosis, proliferation, and cell cycle. We also searched for DTX residue in these cells. DTX had a time- and concentration-dependent inhibitory effect on hESC-RPE cell viability, and the cells only survived after 24 h of stimulation with 0.1 mg/mL of DTX. Following drug withdrawal, the cell morphology continued to change, and hESC-RPE cell damage was observed. High-performance liquid chromatography/mass spectrometry showed that some unmetabolized DTX remained in hESC-RPE cells after the 48 and 120 h DTX treatments. Flow cytometry and immunofluorescence revealed that DTX significantly enhanced apoptosis, and the Cell Counting Kit-8 assay and flow cytometry indicated that DTX inhibited cell proliferation and blocked the cell cycle. These results suggest that DTX has a direct cytotoxic effect on hESC-RPE cells. Thus, RPE cell damage after DTX treatment may present an important safety problem that could potentially limit the application of this drug in clinical practice. The findings of this study suggest that clinicians should weigh the benefits of DTX versus the risks of ocular adverse reactions rationally. Timely diagnostic evaluation and drug withdrawal will be conducive to the recovery of patients' visual acuity.

Endometrial cancer (EC) is the most common gynecological tumor arising from the endometrium. In this study, we use a published single-cell transcriptome profile of endometrial carcinoma (EC) to reveal the composition of immune cells and found an immunosuppressive environment since the presence of macrophage subtype M2 and exhausted CD8+ T cell markers. We focused on ZEB2 (Zinc finger E-box binding homeobox 2), a well-known player in epithelial to mesenchymal transition process, and we showed that ZEB2 is exclusively expressed in immune cells in single-cell transcriptome and, at the same time, downregulated in TCGA-UCEC (The Cancer Genome Atlas—Uterine Corpus Endometrial Carcinoma) bulk RNA-seq data and negatively associated with tumor purity. Loss of ZEB2 protein in EC in normal endometrium and EC samples was validated in samples using immunohistochemistry (IHC) from HPA (Human Protein Atlas) database. Furthermore, we found ZEB2 was associated with immune infiltrations especially for macrophage using TIMER 2.0. Interestingly, ZEB2 prognostic significance differed under various macrophage and Th2 helper cell content using Kaplan–Meier Plotter analysis. More importantly, we showed that over 11% EC patients have somatic mutations of ZEB2 in EC samples collected from cBioportal and they have a lower body weight, earlier diagnosis age, and better overall survival and disease-free survival status compared with the unaltered group. Analysis in TIMER2.0 suggested that ZEB2 mutation would possibly change the composition of tumor-infiltrating lymphocytes. Taken together, by combining the results from single-cell data, bulk TCGA RNA-seq, and other online bioinformatic tools, we provided evidence that ZEB2 might have a unique role in the immune environment of EC. These results would provide a better insight into the pathogenetic process and ZEB2 might further be used an immunotherapeutic target of EC.

Many neuroimaging studies have demonstrated structural changes in the superior temporal gyrus (STG) in patients with schizophrenia. Several postmortem studies have reported on the pathogenesis of schizophrenia, but few reports have investigated alterations in molecules in the STG. In addition, several studies have suggested that calcineurin (CaN) inadequacy may be a risk factor for schizophrenia, but no reports about CaN expression in the STG in schizophrenia have been published. We compared the density of CaN-immunoreactive (CaN-IR) neurons in the STG from 11 patients with schizophrenia with that of 11 sex- and age-matched controls. We used immunohistochemical analysis with rabbit polyclonal antibodies against human CaN. In the STG, the density of CaN-IR neurons in layers II - VI in the group with schizophrenia was significantly higher than that in the control group. Our results confirmed pathological changes in the STG in patients with schizophrenia, suggesting that alterations in the CaN pathway play a role in the pathogenesis of schizophrenia.

Calcineurin (CaN) has been investigated extensively in numerous biochemical, behavioral, and genetic studies in schizophrenia because its function is closely related to dopamine–glutamate signal transduction, which is thought to be associated with pathophysiological changes in schizophrenia. Although evidence has suggested that dysfunction of CaN may be a risk factor for schizophrenia, there have been few reports focusing on the expression of CaN mRNA and CaN protein levels in the brains of schizophrenic patients. In addition, findings on CaN expression in postmortem brains from patients with schizophrenia have been inconsistent. Here, we conducted immunohistochemical examinations of several regions in postmortem brains, including the dorsolateral prefrontal cortex (DLPFC), hippocampus, caudate nucleus, and putamen, using specific antibodies, and compared the results from the brains of nine schizophrenic subjects to nine age- and sex-matched control subjects. There was no significant difference in the ratio of CaN immunoreactive (IR) neurons between schizophrenia and control groups in the DLPFC or hippocampus, and a significantly increased ratio of CaN-IR neurons was seen in the caudate nucleus in the brains from schizophrenia patients. As the striatum contains most of the brain dopamine, the results of the present study have critical implications and suggest that alterations in CaN signaling in the caudate contribute to the pathogenesis of schizophrenia. This is the first report of caudate CaN abnormalities in schizophrenia.

The Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene could be related to the response to antipsychotics. We examined the effects of the Taq1A polymorphism on the plasma monoamine metabolites during the treatment of schizophrenia with aripiprazole, a DRD2 partial agonist. Thirty Japanese patients with schizophrenia were treated with aripiprazole for 6 weeks. We measured plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol (pMHPG) before and after treatment. The Taq1A polymorphism was genotyped with polymerase chain reaction. Aripiprazole improved the acute symptoms of schizophrenia and decreased pHVA in responders (P = 0.023) but not in nonresponders (P = 0.28). Although A1 allele carriers showed a tendency to respond to aripiprazole (61.5%) compared to A1 allele noncarriers (29.4%) (P = 0.078), there was not statistically significant difference in the response between the 2 genotype groups. There were significant effect for response (P = 0.013) and genotype × response interaction (P = 0.043) on the change of pHVA. The changes of pHVA differ between responders and nonresponders in A1 allele carriers but not in A1 allele noncarriers. There were no genotype or response effects or genotype × response interaction on the changes of the plasma levels of 3-methoxy-4hydroxyphenylglycol. Our preliminary results suggest that Taq1A polymorphism may be partly associated with changes in pHVA during acute schizophrenia.

Aims: We focused on DNA methylation of the promoter regions of the Monoamine Oxidase (MAO) A and B genes from postmortem brains of subjects with schizophrenia. Methods: We determined levels of DNA methylation using genomic DNA samples purified from four brain areas: prefrontal cortex (PFC), hippocampus, occipital cortex and nucleus accumbens (NAc), by a bisulfite sequencing method from seven normal subjects and six subjects with schizophrenia. Results: Although very few methylated CpGs of the MAOA and MAOB genes were detected in male samples, various DNA methylation patterns were present in female samples, and some differences were found in such patterns between normal subjects and subjects with schizophrenia. In the PFC, the average level of methylation of both genes was significantly higher in subjects with schizophrenia than in normal subjects. The content of highly methylated alleles of the MAOA gene in the NAc was significantly associated with schizophrenia, with similar results obtained for the MAOB gene in both the NAc and PFC. Some CpG sites showed higher levels of methylation in schizophrenia than in normal subjects. Conclusions: Levels of methylation were quite high in NAc and PFC in female subjects with schizophrenia compared with those in female normal subjects.

In patients with schizophrenia, various physical disorders are sometimes discovered only when they have reached a later and more severe stage. This phenomenon is believed to be caused, at least in part, by an increase in pain threshold. The gamma-aminobutyric acid (GABA)-ergic and glutamatergic systems in the rostral agranular insular cortex (RAIC) are thought to be involved in the regulation of pain threshold. However, no postmortem studies of the cerebral cortex have previously been published. Dopamine and cAMP-regulated phosphoprotein 32 kD (DARPP-32), which is involved in the GABAergic and glutamatergic systems, is considered to be crucial for elucidating the pathogenesis of schizophrenia. Using specific antibodies, we conducted immunohistochemical examinations of the RAIC in 10 subjects from a healthy control group, and 11 subjects from a schizophrenia group. The sex, age, and postmortem interval (PMI) of the schizophrenia group were matched to those of the healthy control group. We revealed that the density of DARPP-32-immunoreactive (IR) neurons in the II and III layers of the RAIC was significantly decreased (p0.05) in the schizophrenia group compared with the healthy control group. Our findings could partially explain the molecular basis of the pain threshold abnormalities found in patients with schizophrenia.

The prevalence of dopamine and cAMP-regulated phosphoprotein 32kD (DARPP-32) is associated with the pathogenesis of schizophrenia. To date, the findings on DARPP-32 cellular expression and distribution in postmortem brains from patients with schizophrenia have been inconsistent. To clarify the detailed cellular expression of DARPP-32 in patients with schizophrenia, we immunohistochemically stained sections from postmortem brains using specific antibodies. We measured the density of immunopositive cells in various brain regions including the prefrontal cortex and compared the data from nine schizophrenia subjects with those of nine age- and sex-matched control subjects. The density of DARPP-32-immunoreactive (IR) neurons was significantly lower in layers II-V of the dorsolateral prefrontal cortex (DLPFC) from subjects with schizophrenia. In contrast, there were no marked differences in DARPP-32 expression in other brain regions. In addition, the density of threonine (Thr34)-phosphorylated DARPP-32-IR neurons was significantly higher in layer V of DLPFC from subjects with schizophrenia. These results suggest that the decrease in DARPP-32 in schizophrenia was more marked in neurons of DLPFC than in other cells or other brain regions, and that this decrease might be partly compensated for by an increase in expression of Thr34-phosphorylated DARPP-32 in DLPFC.

Protein substrates of a novel secretion system of Porphyromonas gingivalis contain a conserved C-terminal domain (CTD) essential for secretion and attachment to the cell surface. Inactivation of lptO (PG0027) or porT produced mutants that lacked surface protease activity and an electron-dense surface layer. Both mutants showed co-accumulation of A-LPS and unmodified CTD proteins in the periplasm. Lipid profiling by mass spectrometry showed the presence of both tetra- and penta-acylated forms of mono-phosphorylated lipid A in the wild-type and porT mutant, while only the penta-acylated forms of mono-phosphorylated lipid A were found in the lptO mutant, indicating a specific role of LptO in the O-deacylation of mono-phosphorylated lipid A. Increased levels of non-phosphorylated lipid A and the presence of novel phospholipids in the lptO mutant were also observed that may compensate for the missing mono-phosphorylated tetra-acylated lipid A in the outer membrane (OM). Molecular modelling predicted LptO to adopt a β-barrel structure characteristic of an OM protein, supported by the enrichment of LptO in OM vesicles. The results suggest that LPS deacylation by LptO is linked to the co-ordinated secretion of A-LPS and CTD proteins by a novel secretion and attachment system to form a structured surface layer.

The measurement of plasma concentrations of monoamine metabolites is a useful method for inferring the dynamics of monoamine metabolites in the brain. To clarify effects of age and sex on plasma monoamine metabolites levels, we used high-performance liquid chromatography to measure plasma levels of homovanillic acid (HVA), free and total 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) in healthy men and women of various ages (n=214). In all plasma monoamine metabolites, there were significant differences across the age groups, and multiple comparisons revealed that older subjects had higher levels than younger subjects. Moreover, significant positive correlations were found between age and plasma levels of HVA, free MHPG, total MHPG, and 5-HIAA. On the other hand, plasma concentrations of monoamine metabolites were not influenced by sex, except for total MHPG for which the plasma levels were significantly higher in men than in women. Age-related changes in monoamine oxidase and renal function might affect our results. This large cohort survey provides further evidence to be cautiously aware of age effects when regarding plasma monoamine metabolites levels as reflections of central activity.

Protein substrates of a novel secretion system of Porphyromonas gingivalis contain a conserved C-terminal domain (CTD) of ∼70–80 amino acid residues that is essential for their secretion and attachment to the cell surface. The CTD itself has not been detected in mature substrates, suggesting that it may be removed by a novel signal peptidase. More than 10 proteins have been shown to be essential for the proper functioning of the secretion system, and one of these, PG0026, is a predicted cysteine proteinase that also contains a CTD, suggesting that it may be a secreted component of the secretion system and a candidate for being the CTD signal peptidase. A PG0026 deletion mutant was constructed along with a PG0026C690A targeted mutant encoding an altered catalytic Cys residue. Analysis of clarified culture fluid fractions by SDS-PAGE and mass spectrometry revealed that the CTD was released intact into the surrounding medium in the wild type strain, but not in the PG0026 mutant strains. Western blot experiments revealed that the maturation of a model substrate was stalled at the CTD-removal step specifically in the PG0026 mutants, and whole cell ELISA experiments demonstrated partial secretion of substrates to the cell surface. The CTD was also shown to be accessible at the cell surface in the PG0026 mutants, suggesting that the CTD was secreted but could not be cleaved. The data indicate that PG0026 is responsible for the cleavage of the CTD signal after substrates are secreted across the OM. Background: Several virulence factors of Porphyromonas gingivalis have a novel C-terminal signal that directs secretion across the outer membrane. Results: The predicted catalytic amino acid of PG0026 was essential for the removal of this signal. Conclusion: PG0026 is a novel C-terminal signal peptidase. Significance: We have identified a novel signal peptidase of a new type of secretion system.

Protein substrates of a novel secretion system of Porphyromonas gingivalis contain a conserved C-terminal domain (CTD) essential for secretion and attachment to the cell surface. Inactivation of lptO (PG0027) or porT produced mutants that lacked surface protease activity and an electron-dense surface layer. Both mutants showed co-accumulation of A-LPS and unmodified CTD proteins in the periplasm. Lipid profiling by mass spectrometry showed the presence of both tetra- and penta-acylated forms of mono-phosphorylated lipid A in the wild-type and porT mutant, while only the penta-acylated forms of mono-phosphorylated lipid A were found in the lptO mutant, indicating a specific role of LptO in the O-deacylation of mono-phosphorylated lipid A. Increased levels of non-phosphorylated lipid A and the presence of novel phospholipids in the lptO mutant were also observed that may compensate for the missing mono-phosphorylated tetra-acylated lipid A in the outer membrane (OM). Molecular modelling predicted LptO to adopt a β-barrel structure characteristic of an OM protein, supported by the enrichment of LptO in OM vesicles. The results suggest that LPS deacylation by LptO is linked to the co-ordinated secretion of A-LPS and CTD proteins by a novel secretion and attachment system to form a structured surface layer.

Many neuroimaging studies have revealed structural abnormalities in the superior temporal gyrus (STG) in schizophrenia (Kasai et al., 2003a, 2003b; Sun et al., 2009). Neurophysiological studies of mismatch negativities (MMN) generated in the STG have suggested impaired function of N-methyl-d-aspartate (NMDA) receptors (Javitt et al., 1996). Although many postmortem studies have been conducted on the pathogenesis of schizophrenia, relatively few reports have studied molecular alterations in the STG (Bowden et al., 2008; Deng and Huang, 2006; Kang et al., 2009; Katsel et al., 2005; Le Corre et al., 2000; Nudmamud and Reynolds, 2001; Sokolov et al., 2000). The STG shows pronounced changes in gene expression when compared to other regions implicated in schizophrenia (Katsel et al., 2005). Dopamine and a cAMP-regulated phosphoprotein of molecular weight 32kDa (DARPP-32) is thought to be closely associated with pathophysiological changes in the dopamine and glutamate systems in schizophrenia because, when activated by phosphorylation, DARPP-32 acts as a critical regulator of D1 dopamine receptor and NMDA receptor activity (Greengard et al., 1999). The molecular pathways involving DARPP-32 appear important in the pathogenesis of schizophrenia. Here, we show dramatic alterations in DARPP-32 expression in the STG of postmortem brains from patients with schizophrenia. To clarify the detailed histological and cellular expression of DARPP-32 in the STG in schizophrenia, we immunohistochemically examined postmortem brains by using specific antibodies. We compared the density of immunoreactive cells of the STG (BA22) from 11 schizophrenia patients with those from 11 age- and sex-matched controls, and found significantly lower densities of DARPP-32-immunoreactive (IR) cells and threonine (Thr) 34-phosphorylated DARPP-32-IR cells in the STG in the schizophrenia group. Thus, the DARPP-32-related pathogenesis in schizophrenia may be more severe in the STG than previously found in the prefrontal cortex.

Studies on autopsy brains of mental illnesses are essential for psychiatric research. Brain materials from forensic autopsy cases have been valuable research resource. We introduced some characteristic neuronal structures of schizophrenic post-mortem brains and normal controls detected using both forensic and pathological autopsy cases and immunohistochemical method. Dopamine-related neuronal structures in schizophrenic cases were investigated by using immunohistochemistry for tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC) and phenylethanolamine- N -methyltransferase (PNMT). At the level of the striatum, the number of AADC-positive, but TH-negative neurons (d-neurons) reduced in schizophrenics compared with controls. In the brainstem structures, we described some morphological findings characteristic to catecholaminergic neurons of the ventral tegmental area of schizophrenic cases and reduction of the number of medullary catecholaminergic neurons. These results might be in accordance with recent reports describing neural stem cell dysfunction in schizophrenic brains. The authors also introduced the first systematic psychiatric brain bank in Japan, the Fukushima Psychiatric Brain Bank, constructed in 1997, and mentioned the necessity for arrangement of brain bank systems to further promote the psychiatric brain research.

Monoclonal IgG at pH 3.5 expressed a tendency to self-associate and associate non-specifically with surfaces, including the surfaces of precipitated chromatin heteroaggregates. The tendency was elevated with protein A-eluted IgG still in elution buffer (100mM acetate, pH 3.5). Association of IgG with chromatin elements under protein A elution conditions amplified host protein contamination of the elution fraction about 15-fold, caused formation of aggregates that persisted after pH neutralization, and imposed an approximate 5% loss on IgG recovery. Neutralization released eluted IgG from its low pH associations with chromatin and caused heteroaggregate remnants to associate into large particles easily removed by microfiltration. Most effective host contaminant clearance was achieved by filtration after neutralization to pH 5.5. All chromatin-mediated liabilities were suspended by extraction of chromatin heteroaggregates in advance of protein A.

Schizophrenia is one of the major psychiatric disorders, and lipids have focused on the important roles in this disorder. In fact, lipids related to various functions in the brain. Previous studies have indicated that phospholipids, particularly ones containing polyunsaturated fatty acyl residues, are deficient in postmortem brains from patients with schizophrenia. However, due to the difficulties in handling human postmortem brains, particularly the large size and complex structures of the human brain, there is little agreement regarding the qualitative and quantitative abnormalities of phospholipids in brains from patients with schizophrenia, particularly if corresponding brain regions are not used. In this study, to overcome these problems, we employed matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS), enabling direct microregion analysis of phospholipids in the postmortem brain of a patient with schizophrenia via brain sections prepared on glass slides. With integration of traditional histochemical examination, we could analyze regions of interest in the brain at the micrometric level. We found abnormal phospholipid distributions within internal brain structures, namely, the frontal cortex and occipital cortex. IMS revealed abnormal distributions of phosphatidylcholine molecular species particularly in the cortical layer of frontal cortex region. In addition, the combined use of liquid chromatography/electrospray ionization tandem mass spectrometry strengthened the capability for identification of numerous lipid molecular species. Our results are expected to further elucidate various metabolic processes in the neural system. Electronic supplementary material The online version of this article (doi:10.1007/s00216-011-4909-3) contains supplementary material, which is available to authorized users.