Patient-derived castration-resistant prostate cancer model revealed CTBP2 upregulation mediated by OCT1 and androgen receptor.

BACKGROUND: Prostate cancer is dependent on androgen receptor (AR) signaling, and androgen deprivation therapy (ADT) has proven effective in targeting prostate cancer. However, castration-resistant prostate cancer (CRPC) eventually emerges. AR signaling inhibitors (ARSI) have been also used, but resistance to these agents develops due to genetic AR alterations and epigenetic dysregulation. METHODS: In this study, we investigated the role of OCT1, a member of the OCT family, in an AR-positive CRPC patient-derived xenograft established from a patient with resistance to ARSI and chemotherapy. We conducted a genome-wide analysis chromatin immunoprecipitation followed by sequencing and bioinformatic analyses using public database. RESULTS: Genome-wide analysis of OCT1 target genes in PDX 201.1 A revealed distinct OCT1 binding sites compared to treatment-naïve cells. Bioinformatic analyses revealed that OCT1-regulated genes were associated with cell migration and immune system regulation. In particular, C-terminal Binding Protein 2 (CTBP2), an OCT1/AR target gene, was correlated with poor prognosis and immunosuppressive effects in the tumor microenvironment. Metascape revealed that CTBP2 knockdown affects genes related to the immune response to bacteria. Furthermore, TISIDB analysis suggested the relationship between CTBP2 expression and immune cell infiltration in prostate cancer, suggesting that it may contribute to immune evasion in CRPC. CONCLUSIONS: Our findings shed light on the genome-wide network of OCT1 and AR in AR-positive CRPC and highlight the potential role of CTBP2 in immune response and tumor progression. Targeting CTBP2 may represent a promising therapeutic approach for aggressive AR-positive CRPC. Further validation will be required to explore novel therapeutic strategies for CRPC management.

[A case of severe alcoholic hepatitis successfully treated with granulocytapheresis].

A 46-year-old male patient with a drinking history presented at our hospital with jaundice. He was diagnosed with moderate alcoholic hepatitis based on laboratory data. The white blood cell (WBC) counts were gradually increased and the prothrombin time was prolonged after hospitalization. Methylprednisolone (1000mg/day for 3 days) followed by oral prednisolone (40mg/day) was administered. However, the liver function was not improved and the patient progressed to severe alcoholic hepatitis. Therefore, we performed granulocytapheresis (GCAP). The WBC counts and interleukin-6 decreased and the liver function improved after 3 GCAP sessions.

[A case of fascioliasis].

A 38-year-old rice farmer visited a hospital for abdominal pain. Computed tomography (CT) showed a liver tumor and magnetic resonance imaging (MRI) revealed a hypovascular tumor, both in segment 4. Thus, he was diagnosed with liver abscess. Ten days later, CT showed a new liver tumor in segment 8, but the size of the liver tumor in segment 4 had decreased. He was suspected with parasitic disease because of eosinophilia. Enzyme-linked immunosorbent assay showed a high level of serum Fasciola antibody. The patient was diagnosed with fascioliasis and was treated with triclabendazole. Post-treatment, CT revealed that the liver tumors had shrunk. Eosinophilia and multiple lesions were characteristic findings of parasitic disease.

Antitumor effects of pyrrole-imidazole polyamide modified with alkylating agent on prostate cancer cells.

Androgens and androgen receptor (AR) have a central role in prostate cancer progression by regulating its downstream signaling. Although androgen depletion therapy (ADT) is the primary treatment for most prostate cancers, they acquires resistance to ADT and become castration resistant prostate cancers (CRPC). AR complex formation with multiple transcription factors is important for enhancer activity and transcriptional regulation, which can contribute to cancer progression and resistance to ADT. We previously demonstrated that OCT1 collaborates with AR in prostate cancer, and that a pyrrole-imidazole (PI) polyamide (PIP) targeting OCT1 inhibits cell and castration-resistant tumor growth (Obinata D et al. Oncogene 2016). PIP can bind to DNA non-covalently without a drug delivery system unlike most DNA targeted therapeutics. In the present study, we developed a PIP modified with a DNA alkylating agent, chlorambucil (ChB) (OCT1-PIP-ChB). Then its effect on the growth of prostate cancer LNCaP, 22Rv1, and PC3 cells, pancreatic cancer BxPC3 cells, and colon cancer HCT116 cells, as well as non-cancerous MCF-10A epithelial cells, were analyzed. It was shown that the IC50s of OCT1-PIP-ChB for 22Rv1 and LNCaP were markedly lower compared to other cells, including non-cancerous MCF-10A cells. Comprehensive gene expression analysis of CRPC model 22Rv1 cells treated with IC50 concentrations of OCT1-PIP-ChB revealed that the gene group involved in DNA double-strand break repair was the most enriched among gene sets repressed by OCT1-PIP-ChB treatment. Importantly, in vivo study using 22Rv1 xenografts, we showed that OCT1-PIP-ChB significantly reduced tumor growth compared to the control group without showing obvious adverse effects. Thus, the PIP combined with ChB can exert a significant inhibitory effect on prostate cancer cell proliferation and castration-resistant tumor growth, suggesting a potential role as a therapeutic agent.

Relationship between Nutritional Scales and Prognosis in Elderly Patients after Acute Ischemic Stroke: Comparison of Controlling Nutritional Status Score and Geriatric Nutritional Risk Index.

BACKGROUND/AIMS: Undernutrition is common in patients after acute ischemic stroke (AIS) and predicts poor clinical outcomes. We assessed the relationship between undernutrition and prognosis after AIS. METHODS: We retrospectively assessed consecutively hospitalized AIS patients aged ≥65 years. A poor prognosis for patients after AIS was defined as a modified Rankin Scale (mRS) score of ≥3 at discharge. Nutritional status was evaluated based on the degree and risk of undernutrition as determined by the Controlling Nutritional Status (UND-CONUT) and Geriatric Nutritional Risk Index (UNR-GNRI) scores. RESULTS: Among 218 patients (male, 62.8%; median age, 77 years), 81 had a poor prognosis. A significant correlation was found between UND-CONUT and UNR-GNRI scores (p < 0.001, r = 0.433). Patients with a poor prognosis showed significant undernutrition based on UND-CONUT (p = 0.003) but not on UNR-GNRI (p = 0.218). Patients with undernutrition based on UND-CONUT showed poor outcomes: higher mRS scores at discharge, higher percentages of mRS scores of ≥2 and ≥3, and more complications associated with pneumonia. No significant differences were seen between cases with and without undernutrition risk based on UNR-GNRI. CONCLUSION: UND-CONUT appeared to be more useful than UNR-GNRI for predicting the prognosis of elderly patients with AIS at discharge.

Clinical Study of Cerebral Ischemia in Moyamoya Disease from the View of Development of the Anterior Choroidal Artery.

OBJECTIVES: The anterior choroidal artery (AchA) is one of the collateral vessels in moyamoya disease (MMD). The incidence of cerebral ischemia in MMD was analyzed through the association between development of the AchA and advancement of MMD stage. MATERIALS AND METHODS: Twelve patients of MMD with cerebral ischemia (infarction; 9 patients, transient ischemic attack; 3 patients) were enrolled. Advancement of MMD was evaluated using Suzuki's stage. The grades in Suzuki's stage were subclassified into a non-progressive stage for grades 1 and 2, and a progressive stage for grades 4 and 5. Dilatation of the AchA was judged as the presence of development of this artery. Development of the AchA was grouped into proximal type and proximal and distal type. RESULTS: Most frequent locations of infarcts were the anterior and parietal lobes in 6 patients each. Development of the AchA was confirmed on the ischemic side in all patients and on the non-ischemic side in 9 patients. Development of the AchA in the progressive stage was limited in the proximal and distal type on both sides. Development of the AchA in the non-progressive stage was the proximal type on the ischemic side. CONCLUSIONS: The cause of cerebral ischemia was possibly associated with inadequate blood supply of the AchA in the non-progressive stage, and the lower blood flow from the internal carotid artery (ICA) in the progressive stage. Disparity between collateral blood flow from the AchA and the blood flow from the ICA was considered to relate to incidence of cerebral ischemia in MMD.

Late-onset MELAS syndrome with mtDNA 14453G→A mutation masquerading as an acute encephalitis: a case report.

BACKGROUND: A unique patient with MELAS syndrome, who initially masqueraded as having acute encephalitis and was eventually diagnosed with MELAS syndrome harboring a mtDNA 14453G → A mutation, is described. CASE PRESENTATION: A 74-year-old Japanese man was admitted to another hospital due to acute onset of cognitive impairment and psychosis. After 7 days he was transferred to our hospital with seizures and deteriorating psychosis. The results of primary ancillary tests that included EEG, CSF findings, and brain MRI supported the diagnosis of an acute encephalitis. HSV-DNA and antibodies against neuronal surface antigens in the CSF were all negative. With the assistance of the lactate peak on the brain lesions in the magnetic resonance spectroscopy image and genetic analysis of the biopsied muscle, he was eventually diagnosed with MELAS syndrome harboring mtDNA 14453G → A mutation in the ND6 gene. CONCLUSIONS: This case provides a caveat that MELAS syndrome can manifest in the symptoms and ancillary tests masquerading as an acute encephalitis caused by infection or autoimmunity. This is the first adult patient seen to harbor the mtDNA14453G → A with a unique onset, which broadens the phenotypic spectrum of MELAS syndrome associated with ND6 gene mutation.

A case of prosopometamorphopsia caused by infarction of the splenium of the corpus callosum and major forceps.

An adult female complained of enlargement of right eyes in other people. Diffusion-weighted imaging detected an abnormal high-intensity area in the region from the splenium of the corpus callosum to the major forceps on the right side. The patient reported that right eyes appeared larger in size, which suggested prosopometamorphopsia. Adichotic listening test identified left-ear deficit. Acombination of prosopometamorphopsia and left-ear deficit was not identified in the reported patients. Prosopometamorphopsia in most of the reported patients included the eye as did that in our patient. This result suggested the importance of information on the eye in recognizing faces.

Second nationwide surveillance of bacterial pathogens in patients with acute uncomplicated cystitis conducted by Japanese Surveillance Committee from 2015 to 2016: antimicrobial susceptibility of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus saprophyticus.

The Japanese Surveillance Committee conducted a second nationwide surveillance of antimicrobial susceptibility patterns of uropathogens responsible for acute uncomplicated cystitis (AUC) in premenopausal patients aged 16-40 years old at 31 hospitals throughout Japan from March 2015 to February 2016. In this study, the susceptibility of causative bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus) for various antimicrobial agents was investigated by isolation and culturing of organisms obtained from urine samples. In total, 324 strains were isolated from 361 patients, including E. coli (n = 220, 67.9%), S. saprophyticus (n = 36, 11.1%), and K. pneumoniae (n = 7, 2.2%). The minimum inhibitory concentrations (MICs) of 20 antibacterial agents for these strains were determined according to the Clinical and Laboratory Standards Institute (CLSI) manual. At least 93% of the E. coli isolates showed susceptibility to fluoroquinolones and cephalosporins, whereas 100% of the S. saprophyticus isolates showed susceptibility to fluoroquinolones and aminoglycosides. The proportions of fluoroquinolone-resistant and extended-spectrum ß-lactamase (ESBL)-producing E. coli strains were 6.4% (13/220) and 4.1% (9/220), respectively. The antimicrobial susceptibility of K. pneumoniae was retained during the surveillance period, while no multidrug-resistant strains were identified. In summary, antimicrobial susceptibility results of our second nationwide surveillance did not differ significantly from those of the first surveillance. Especially the numbers of fluoroquinolone-resistant and ESBL-producing E. coli strains were not increased in premenopausal patients with AUC in Japan.

Clinical Study of Thirteen Patients with Spinal Cord Infarction.

BACKGROUND: A concept of sensory tracts in the spinal cord has been established in relation to a dorsolateral pathway which is located in the posterior part of the lateral column and conveys the deep sense. METHODS: The clinical status at onset, neurological symptoms, and magnetic resonance imaging (MRI) findings in 13 patients of spinal cord infarction were studied. RESULTS: The clinical status was acute in 11 patients and subacute in 2 patients. Palsy of the extremities was noted in 11 patients. Segmental sensory disturbance was shown in all patients. One patient showed disturbance of all senses and paraplegia, which indicated transverse myelopathy. In the other 12 patients, 11 patients showed impairment of pain sense although joint position sense was preserved, excluding 1 patient whose sensory disturbance showed dysesthesia alone. In these 11 patients, soft touch and vibration senses were impaired in 7 patients. Abnormality of spinal cord MRI was detected 7 patients. The lesions were located in the cervical cord in 3 patients, cervical to thoracic cord in 1 patient, and thoracic cord in 3 patients. CONCLUSIONS: In the 11 patients in whom pain sense was impaired and joint position sense was preserved, involvement of the anterior spinal cord artery (ASCA) was the mainstay. Impairment of vibration sense was accompanied in 7 patients in patients of ASCA infarction. It was speculated that impairment of vibration sense can occur in patients with ASCA infarction whose ischemia spread to the dorsolateral pathway in the posterior part of the lateral column.

Clinical Study on 3 Patients with Infarction of the Vermis/Tonsil in the Cerebellum.

BACKGROUND: Infarction of the vermis and the tonsil in the cerebellum presents as truncal and gait ataxia. Acute rotatory vertigo is often present in infarction of the nodulus in the caudal vermis, which is closely associated with the vestibular pathway, but is minor in infarction of the rostral vermis. The rostral vermis receives input from the dorsal spinocerebellar tract (DSCT) which conveys unconsciousness proprioceptive signals from the ipsilateral lower trunk and leg. The present study investigated the characteristics of infarction of the vermis and the tonsil. PATIENTS AND METHODS: Neuroradiological findings of 3 patients whose lesions were located in the vermis or the tonsil were analyzed. RESULTS: All lesions were located in the anterior lobe in the rostral vermis, the nodulus in the caudal vermis, or the tonsil. Truncal and gait ataxia were exhibited by 3 patients. Rotatory vertigo was exhibited by 2 patients whose lesions were located in the nodulus and the tonsil, but absent in a patient with infarction of the anterior lobe. Lateropulsion opposite the lesion was apparent in a patient with infarction of the tonsil. Gaze-evoked nystagmus was observed in 2 patients with infarction of the nodulus and the tonsil. CONCLUSIONS: The tonsil and the nodulus were considered to have a close relationship with the vestibular pathway. Absence of rotatory vertigo indicated impairment of the DSCT. Our data suggested that the cause of truncal and gait ataxia differed between the rostral vermis and the caudal vermis/tonsil.

A stress response pathway regulates DNA damage through ß2-adrenoreceptors and ß-arrestin-1.

The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is generally transient because its accompanying effects (for example, immunosuppression, growth inhibition and enhanced catabolism) can be harmful in the long term. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders, and epidemiological studies strongly indicate that chronic stress leads to DNA damage. This stress-induced DNA damage may promote ageing, tumorigenesis, neuropsychiatric conditions and miscarriages. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates ß(2)-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos. Activated ß(2)-adrenoreceptors promote Gs-protein-dependent activation of protein kinase A (PKA), followed by the recruitment of ß-arrestins, which desensitize G-protein signalling and function as signal transducers in their own right. Here we elucidate a molecular mechanism by which ß-adrenergic catecholamines, acting through both Gs-PKA and ß-arrestin-mediated signalling pathways, trigger DNA damage and suppress p53 levels respectively, thus synergistically leading to the accumulation of DNA damage. In mice and in human cell lines, ß-arrestin-1 (ARRB1), activated via ß(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. Catecholamine-induced DNA damage is abrogated in Arrb1-knockout (Arrb1(-/-)) mice, which show preserved p53 levels in both the thymus, an organ that responds prominently to acute or chronic stress, and in the testes, in which paternal stress may affect the offspring's genome. Our results highlight the emerging role of ARRB1 as an E3-ligase adaptor in the nucleus, and reveal how DNA damage may accumulate in response to chronic stress.

Perirhinal accumulation of neuronal alpha-synuclein in a multiple system atrophy patient with dementia.

We report the case of a 79-year-old Japanese woman who developed cerebellar ataxia followed by rigidity, dysautonomia and cognitive disorders, and was thus clinically diagnosed as having possible MSA with dementia. Neuropathological findings demonstrated not only olivopontocerebellar and striatonigral degeneration with frequent glial cytoplasmic inclusions (GCIs), but also degenerative changes in the parahippocampal region, accentuated in the anterior portion of perirhinal cortex, where neuronal cytoplasmic inclusions (NCIs) and NFTs were numerous while GCIs were limited. NCIs were frequent in the deep layer, whereas NFTs were more frequent in superficial cortical layers. Other hippocampal subregions including subiculum, dentate fascia and cornu ammonis were minimally involved. NCIs in the perirhinal cortex showed intense argyrophilia with the Campbell-Switzer silver impregnation method, but not argyrophilic with the Gallyas method. Most neuronal alpha-synuclein aggregates in dendrosomatic fraction formed globular/tadpole-like, and ultrastructurally comprised granular-coated fine fibrils 12-24 nm in diameter. To the best of our knowledge, alpha-synuclein-related neuronal pathology localized in the perirhinal region without hippocampal involvement has not been previously reported in MSA, and may provide clues to elucidate how neuronal pathology evolves in the hippocampal/parahippocampal regions in MSA, particularly in cases with dementia.

Cultural evolution of hinoeuma superstition controlling human mate choice: The role of half-believer.

In this study, we used a cultural dynamic model to explain the persistence of the hinoeuma superstition in traditional Japan. Men with this superstition avoid marrying women born in a hinoeuma year (or hinoeuma-women). Parents avoided childbirth during the last hinoeuma year out of the concern that their daughter would have trouble finding a husband in the future, and this resulted in a large drop in the number of babies born in 1966. A previous theoretical analysis of the hinoeuma superstition considered two alternative cultural factors: believers and nonbelievers. In the present study, we considered a third cultural factor, the half-believer. A man that is a half-believer accepts a hinoeuma-woman as his wife, but parents that are half-believers avoid childbirth during hinoeuma years. With these three cultural factors, there are two possible outcomes for the population. In the first outcome, [1] non-believers become extinct, with the population consisting of believers and half-believers; some men refuse hinoeuma-women as their mate choice, and most parents attempt to avoid childbirth during hinoeuma years. In the second outcome, [2] believers become extinct, and the remaining population consists of non-believers and half-believers; no man refuses hinoeuma-women, and some parents avoid childbirth in hinoeuma years to prevent potential harm to their daughters. If birth control fails at a steady rate, believers will become extinct eventually. The superstition is more likely to be maintained if the mother has a stronger influence on the beliefs of her children than the father.

[Undifferentiated carcinoma of the jejunum producing granulocyte colony-stimulating factor].

An 80-year-old man presented with abdominal fullness and vomiting. Laboratory data revealed severe anemia, an inflammatory response, and elevated white blood cell counts. Abdominal computed tomography indicated ileus caused by a jejunal tumor measuring 8cm in diameter. Although small-bowel endoscopy enabled visualization of the tumor, adequate biopsy specimens could not be obtained for accurate diagnosis. The patient's condition rapidly deteriorated, because of which surgical treatment could not be initiated. The patient died approximately 3 weeks after admission. High serum granulocyte colony-stimulating factor (G-CSF) levels were detected at autopsy. Immunohistochemical staining of the autopsy specimen indicated positive G-CSF levels in the jejunal tumor. On the basis of these findings, a final diagnosis of undifferentiated carcinoma of the jejunum producing G-CSF was made.

Association of Body Water Balance, Nutritional Risk, and Sarcopenia with Outcome in Patients with Acute Ischemic Stroke: A Single-Center Prospective Study.

In the present study, we examined the inter-relationships between body water balance, nutritional risk, sarcopenia, and outcome after acute ischemic stroke (AIS) in patients who were living independently. We defined abnormal body water balance as overhydration, with an extracellular fluid/total body water ratio > 0.390. A geriatric nutritional risk index (GNRI) < 98 was considered low GNRI. Sarcopenia was defined according to the 2019 Asian Working Group for sarcopenia criteria. Poor outcome was defined as a modified Rankin scale (mRS) score ≥ 3 at discharge. Among 111 eligible patients (40 females, median age: 77 years), 43 had a poor prognosis, 31 exhibited overhydration, 25 had low GNRI, and 44 experienced sarcopenia. Patients with poor outcomes had significantly higher National Institutes of Health Stroke Scale (NIHSS) scores, which were significantly more common with overhydration, low GNRI, and sarcopenia (p < 0.001 for all). Concomitant overhydration, low GNRI, and sarcopenia were associated with poorer outcomes. In multivariate analysis, overhydration [odds ratio (OR) 5.504, 95% confidence interval (CI) 1.717-17.648; p = 0.004], age (OR 1.062, 95%CI 1.010-1.117; p = 0.020), and NIHSS score (OR 1.790, 95%CI 1.307-2.451; p < 0.001) were independent prognostic factors for poor outcome. The results indicated that the combination of overhydration, low GNRI, and sarcopenia predict poor outcomes following AIS. Overhydration was particularly associated with poor outcomes.

Isoform transition from four-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology.

Regional progression of neurofibrillary tangles (NFTs) around the hippocampus was traced on thick sections double immunofluorolabeled with RD3 and RD4 antibodies, specific for three- and four-repeat tau, respectively. As reported, the cubic density of all tau-positive neurons was predominant in the entorhinal cortex and cornu ammonis (CA)1, and decreased progressively to the CA2-4 subregions. Among the three isoform profiles (RD3+/4-, RD3+/4+, and RD3-/4+), this regional gradient was replicated with RD3+/4- and RD3+/4+ neurons, while RD3-/4+ neurons exhibited the reverse gradient. Comparison of the subregion pairs confirmed a consistent profile shift along this gradient in every case regardless of the abundance of NFTs. To clarify the underlying mechanism of this regional profile shift, intraneuronal intensity of RD3 and RD4 immunoreactivity (IR) was quantified. Although their intensities were both lower in dendrites than in the soma, this gradient was steeper with RD4, leaving RD3 IR in dendrites. Dendritic arborization was abundant in RD3-/4+ pretangles, attenuated in RD3+/4+ neurons, and further attenuated in RD3+/4- ghost tangles. These findings suggest that dendritic RD4 IR retracts first, leaving RD3 IR in the dendrites. Taken together, this dendrite-oriented retraction initiates the gradual shift from RD3-/4+ pretangle neurons to RD3+/4- ghost tangles by way of RD3+/4+ NFTs. This intraneuronal profile shift may be a basis for the regional gradation featured by the similar profile shift during progression of NFT pathology.

Global phosphorylation analysis of beta-arrestin-mediated signaling downstream of a seven transmembrane receptor (7TMR).

beta-Arrestin-mediated signaling downstream of seven transmembrane receptors (7TMRs) is a relatively new paradigm for signaling by these receptors. We examined changes in protein phosphorylation occurring when HEK293 cells expressing the angiotensin II type 1A receptor (AT1aR) were stimulated with the beta-arrestin-biased ligand Sar(1), Ile(4), Ile(8)-angiotensin (SII), a ligand previously found to signal through beta-arrestin-dependent, G protein-independent mechanisms. Using a phospho-antibody array containing 46 antibodies against signaling molecules, we found that phosphorylation of 35 proteins increased upon SII stimulation. These SII-mediated phosphorylation events were abrogated after depletion of beta-arrestin 2 through siRNA-mediated knockdown. We also performed an MS-based quantitative phosphoproteome analysis after SII stimulation using a strategy of stable isotope labeling of amino acids in cell culture (SILAC). We identified 1,555 phosphoproteins (4,552 unique phosphopeptides), of which 171 proteins (222 phosphopeptides) showed increased phosphorylation, and 53 (66 phosphopeptides) showed decreased phosphorylation upon SII stimulation of the AT1aR. This study identified 38 protein kinases and three phosphatases whose phosphorylation status changed upon SII treatment. Using computational approaches, we performed system-based analyses examining the beta-arrestin-mediated phosphoproteome including construction of a kinase-substrate network for beta-arrestin-mediated AT1aR signaling. Our analysis demonstrates that beta-arrestin-dependent signaling processes are more diverse than previously appreciated. Notably, our analysis identifies an AT1aR-mediated cytoskeletal reorganization network whereby beta-arrestin regulates phosphorylation of several key proteins, including cofilin and slingshot. This study provides a system-based view of beta-arrestin-mediated phosphorylation events downstream of a 7TMR and opens avenues for research in a rapidly evolving area of 7TMR signaling.

[Main Syndrome and Antibody Effects of Autoimmune Encephalitis Caused by Antineuronal Surface Antibodies: An Update].

Since the discovery of a series of antineuronal surface antibodies (NSAs), the diagnostic approach and management of patients with autoimmune encephalitis (AE) and related disorders have undergone a "paradigm shift." However, recent topics described below are also announcing the dawn of the next era in the practice of patients with AE. As the clinical spectrum of NSA-associated AE expands, some types of AE (e.g., anti-DPPX antibody-associated and anti-IgLON5 antibody-associated disorders) can be misclassified into reconsider diagnosis when using the previously published diagnostic criteria. Nobel active immunization animal models of NSA-associated disorders (e.g., anti-NMDAR encephalitis model) can remarkably emphasize the understanding of the pathophysiological effects and main syndrome induced by NSAs. Additionally, several international clinical trials (e.g., rituximab, inebilizumab, ocrelizumab, bortezomib, and rozanolixizumab) for AE treatments, including anti-NMDAR encephalitis, have been implemented. Data from these clinical trials can be used to establish the best treatment of AE.

Long-term outcomes and health-related quality of life in patients with autoimmune encephalitis: An observational study.

Autoimmune encephalitis (AE) subacutely causes severe and multiple symptoms; however, most patients achieve neurologically favorable outcomes. Despite the substantial recovery in motor function, persistent impairments in mental/social aspects lasting for several years have been recognized, and its potential effect on health-related quality of life (HRQOL) has been argued. To urgently evaluate the long-term effects of AE on patients' HRQOL, we investigated patient-oriented long-term outcomes and assessed the HRQOL of patients with AE. Data of patients who were diagnosed with probable/definite AE, defined by Graus AE criteria 2016, and treated at our hospital between January 2011 and October 2020 were retrospectively retrieved. Their long-term (≥2 years) outcomes, which included various sequelae and handicaps in social activities such as returning to previous work/school life through structured interview forms, were evaluated, and the HRQOL was assessed using Neuro-QOL battery. We identified 32 patients who met the Graus AE criteria 2016 and eventually enrolled 21 patients in the study. The median interval between disease onset and survey period was 63 (25-156) months, and 43% of the patients had persistent neuropsychiatric symptoms, including memory disorders, personality changes, and seizures. No more than 71% returned to their previous work/school life. Although most of the patients had global QOL within normal limits, 48% had social QOL under normal limits. Patients with sequelae were significantly less likely to return to previous work/school and had worse global/social quality of life than patients without sequelae. In conclusion, nearly half of patients with AE had social QOL under normal limits 5 years after onset. The difficulty in returning to work/school and a worse HRQOL were notable in patients with sequelae.