Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis.

Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.

Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders.

Recently discovered genome-wide rare copy number variants (CNVs) have unprecedented levels of statistical association with many developmental neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, intellectual disability and attention deficit hyperactivity disorder. However, as CNVs often include multiple genes, causal genes responsible for CNV-associated diagnoses and traits are still poorly understood. Mouse models of CNVs are in use to delve into the precise mechanisms through which CNVs contribute to disorders and associated traits. Based on human and mouse model studies on rare CNVs within human chromosome 22q11.2, we propose that alterations of a distinct set of multiple, noncontiguous genes encoded in this chromosomal region, in concert with modulatory impacts of genetic background and environmental factors, variably shift the probabilities of phenotypes along a predetermined developmental trajectory. This model can be further extended to the study of other CNVs and may serve as a guide to help characterize the impact of genes in developmental neuropsychiatric disorders.

A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody.

BACKGROUND: An important unmet need for new treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-programmed cell death protein 1 (PD-1) antibody. Retrospective studies suggest that previous treatment with immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. Here, we conducted a phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab for patients in this setting. PATIENTS AND METHODS: This was a single-arm, multicenter, phase II trial. Key eligibility criteria were R/M-HNSCC, and previous treatment with both platinum-based chemotherapy and PD-1 antibody. Paclitaxel plus biweekly cetuximab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (Common Terminology Criteria for Adverse Events version 5.0). RESULTS: Between August 2020 and August 2022, 35 patients were enrolled, of whom 33 were assessable for response. ORR was 69.6% (95% confidence interval 51.2% to 84.4%). With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.5 and 13.3 months, respectively. DCR was 93.7%. Twenty-three patients (65%) experienced grade 3 or 4 AEs, including neutropenia (34%), infection (14%), leukopenia (11%), mucositis (8%), and pneumonitis (8%). Eight patients discontinued study treatment due to treatment-related AEs, and no treatment-related death was observed. CONCLUSIONS: Paclitaxel plus biweekly cetuximab showed highly encouraging efficacy and manageable toxicities in R/M-HNSCC patients previously treated with both platinum-based chemotherapy and PD-1 antibody. This combination therapy warrants further investigation in this setting.

Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase.

The actin cytoskeleton undergoes extensive remodeling during cell morphogenesis and motility. The small guanosine triphosphatase Rho regulates such remodeling, but the underlying mechanisms of this regulation remain unclear. Cofilin exhibits actin-depolymerizing activity that is inhibited as a result of its phosphorylation by LIM-kinase. Cofilin was phosphorylated in N1E-115 neuroblastoma cells during lysophosphatidic acid-induced, Rho-mediated neurite retraction. This phosphorylation was sensitive to Y-27632, a specific inhibitor of the Rho-associated kinase ROCK. ROCK, which is a downstream effector of Rho, did not phosphorylate cofilin directly but phosphorylated LIM-kinase, which in turn was activated to phosphorylate cofilin. Overexpression of LIM-kinase in HeLa cells induced the formation of actin stress fibers in a Y-27632-sensitive manner. These results indicate that phosphorylation of LIM-kinase by ROCK and consequently increased phosphorylation of cofilin by LIM-kinase contribute to Rho-induced reorganization of the actin cytoskeleton.

Preliminary studies on streoid-binding proteins in human testes of testicular feminization syndrome.

This study was designed to detect either 5alpha-dihydrotestosterone (DHT) or 17beta-estradiol (E2)-binding protein in the testes of a 1-year-old patient with testicular feminization syndrome (TFS) and in the testes of patients with prostatic cancer. Sucrose gradient analyses revealed E27S protein binding (but no such 7S protein binding of DHT) in the testes of the patient with TFS, but both E2 and DHT 7 S protein binding was observed in normal senile testes. The dissociation constants (Kd) were measured by charcoal adsorption. The Kd of E2 protein binding in both testes of different status was approximately 1.3 x 10(-9) M, and the Kd of DHT protein binding was 2.0 x 10(-9) M in the senile testes. A ligand specificty study indicated characteristics of both E2 and DHT receptors in the senile testes. It is speculated that a deficiency of androgen receptor and the presence of estrogen receptor in the testes of patients with TFS lead to insensitivity to androgen as a result of the androgen receptor deficiency and to sensitivity to estrogen as a result of the presence of the estrogen receptor.

The clinical effect of bifemelane hydrochloride on dementia in aged patients.

The effect of bifemelane hydrochloride on dementia in the elderly was studied in thirty-one patients having cerebrovascular disorders. Alzheimer's disease, Parkinsonism and related diseases. The drug (150 mg) was administered orally three times daily for 10 weeks. The final global improvement rating was 77.4% for all patients. The rates of improvement for Alzheimer's disease were higher than those for cerebrovascular disorders, suggesting that this drug affects Alzheimer's disease through a cholinergic potentiating action. Psychotic, neurological and subjective symptoms, and the activity of daily life, were rated before, during and after treatment. All mean rates of improvement were based on observations made in the 4th week after the start of treatment. Improvement rates for global symptoms were more than 80% for emotional incontinence and prejudice or querulous attitudes toward the nurses, and in headache, tinnitus and dizziness among the subjective symptoms. The improvement in intellectual function was evaluated by the dementia rating scale for the elderly (DRSE), and a significant increase was found in DRSE after treatment with this drug. Side effects attributable to the drug were noted in one patient developing urticaria. It is thus suggested that bifemelane hydrochloride is useful in the treatment of different symptoms of dementia.

Evaluation of alaryngeal voice quality by nonparametric procedures.

Alaryngeal voice quality was evaluated based on nonparametric statistics. Twenty voice samples of the vowel /e/ were recorded from sixteen alaryngeal and four normal speakers, and were randomized and presented to twenty normal listeners. The listeners rated the voices using seven-point scales consisting of twelve pairs of polar-opposite adjectives. By means of nonparametric procedures such as the Wilcoxon signed rank test, significant differences in the rating scores were detected for certain combinations of the voice samples, the classes of voicing methods, the listeners and the rating scales. Quality of the alaryngeal voices differed significantly from that of the normal voices on some of the rating scales. The results suggest the nonparametric procedures are useful to evaluate alaryngeal voice quality.

[Two cases of renovascular hypertension detected by 2-D Doppler method].

Renovascular hypertension is most frequent causes of secondary hypertension. Although angiography of renal artery is reliable procedure for the diagnosis of the renovascular hypertension, it is expensive and invasive. We report two cases which become possible to make diagnosis of the renovascular hypertension by measurement of velocity of segmental or interlobar artery using 2-D color Doppler method. Case 1: 39 year-old male was hospitalized because of hypertension (200/130 mmHg). Ccr was 82 ml/min. 2-D Doppler test demonstrated that the Vmax, the Vmin and the Vmin/Vmax of the right segmental artery were 40 cm/sec., 24 cm/sec. and 0.60, respectively. The Vmax, the Vmin, and the Vmin/Vmax of the left segmental artery were 42 cm/sec., 22 cm/sec. and 0.52, respectively. Renal angiography shows right renovascular stenosis. After percutaneous transluminal angioplasty, the blood pressure became normal and Vmin/Vmax ratio of the right segmental artery was down to 0.52. Case 2: 46 year-old male was hospitalized because of chronic renal failure (Ccr: 14.6 ml/min) and uncontrollable hypertension. 2-D Doppler test demonstrated that the Vmax, the Vmin, the Vmin/Vmax ratio and the acceleration of the right segmental artery were 10 cm/sec., 6 cm/sec., 0.62 and 1.7 m/sec.2, respectively. The Vmax, the Vmin, the Vmin/Vmax ratio and the acceleration of the left interlobar artery were 8 cm/sec., 5 cm/sec., 0.63 and 0.8 m/sec.2, respectively. Renal angiography shows bilateral renovascular stenosis. Thus, the elevated value of Vmin/Vmax ratio (over 0.6) (mean value: 0.43 +/- 0.08, when Ccr is over 70 ml/min, whereas 0.32 +/- 0.11, when Ccr is under 30 ml/min) and decreased acceleration (under 2.0 m/sec. 2) of the segmental or the interlobar artery seems to be helpful for the diagnosis of renovascular hypertension.

[Involvement of allergic mechanism in minimal change nephrotic syndrome (MCNS)].

In this study we evaluated the involvement of allergic mechanisms in patients with adult onset MCNS (17 cases) by measuring serum IgE levels and RAST scores to house dust 1 (H.D.1), house dust 2 (H.D.2), Dermatophagoides farinae (D.f.), Dermatophagoides ptenonyssinus (D.p.). Out of the 17 cases, three cases showed high levels of IgE (more than 1000 IU/ml) and the mean level of serum IgE was 877 IU/ml before treatment. All cases were treated with steroid and/or cyclophosphamide. After the treatment, all cases returned to remission. The level of IgE decreased to the normal range in four out of seven cases which had shown high levels of IgE before treatment. RAST was carried out on seven of the 17 cases. RAST scores for D.f. and D.f. were found to be positive in three cases, but these became negative in two cases after treatment. In five cases relapsed, the all cases showed to have the increased level of serum IgE and two of four cases which were examined RAST score showed to have the increased RAST score for D.f. and D.p. Thus, the data indicated that allergic mechanism, especially against D.f. and D.p. antigen, seemed to play one of the factors in the pathogenesis of MCNS.

[Clinicopathological significance of immune complex (IC) along the tubular basement membrane (TBM) in lupus nephritis].

This paper reports on the clinicopathological significance of IC along the TBM in lupus nephritis. Renal biopsies were performed on 60 patients with SLE. All of the patients demonstrated immunoglobulin deposits in the glomeruli, and 16 of them also showed immune deposits along the TBM. The IgG in the glomeruli or along the TBM completely disappeared after incubation with human IgG, IgG Fc fragments, but not with human F(ab')2, rabbit or rat IgG. These results suggest that IgG along the TBM are similar in nature to IC in the glomeruli and that the IC are composed of IgG rheumatoid factor. The square of tubulointerstitial lesions was more severe in the group with IgG along the TBM than in the group with no IgG along the TBM (5.85 +/- 9.88% vs 1.29 +/- 3.72%). In addition of this, the group with IgG deposits along the TBM frequently demonstrated type IV lupus nephritis. Although the renal function was not significantly different in the both groups, the serum complement level was lower in the cases with IC deposits in the TBM. From these results, it is suggested that IC deposits along the TBM as one of the important inflammatory agents lead to the severe forms of tubulointerstitial injury and show the active stage of the disease in SLE patients.

[A role of platelet activating factor in experimental hemorrhagic enteritis induced by Clostridium difficile toxin].

Clostridium difficile is thought to be an important causative agent of antibiotics associated colitis. However its mechanisms are not fully understood. The present study was designed to elucidate the effect of PAF and free radicals on experimental hemorrhagic enteritis induced by Clostridium difficile toxin. PAF concentration in the portal blood and accumulated fluid, disturbance of the vascular endothelial cells in the ligated jejunal loops and chemiluminescence activity of WBC in the control group's rats increased from 4 hrs over 10 hrs after the administration of Clostridium difficile toxin. On the other hand, the amount of fluid accumulation, protein concentrations in the accumulated fluids, histological changes in the ligated jejunal loops of toxin administered rats and chemiluminescence activity of WBC were significantly suppressed by PAF antagonist (CV6209:TAKEDA). These results suggest that PAF and free radicals may have some role in microcirculatory disturbance and hyperpermeability of the blood vessels in the intestine of hemorrhagic enteritis induced by Clostridium difficile toxin.

Zymogram analyses of various organs, glands and tissues from spontaneously hypertensive rats (SHR) and DOCA hypertensive rats.

Esterase and Acid phosphatase isozymes were examined in a number of organs, glands and tissues from Spontaneously Hypertensive Rats (SHR) and kidney and liver from DOCA hypertensive rats at various stages in comparison with those of normotensive rats (CR). In SHR, the abnormalities in the patterns of esterase isozyme were demonstrated in endocrine glands and respiratory tracts as well as in the kidney, liver and digestive tracts throughout the whole life span, and abnormalities in the patterns of acid phosphatase isozyme was also demonstrated in the liver after seven days of age. Moreover, in DOCA hypertensive Rats, minute alterations in esterase isozyme were demonstrated in the kidney and liver after seventh month of the duration of hypertension.

[The effect of enzymes on progesterone-receptor binding and chromatin binding of the complex in the estrogen-primed rabbit uterus (author's transl)].

The present study was designed to determine the characteristics of the progesterone receptor and chromatin binding site ("acceptor") of the progesterone-receptor complex in the rabbit uterus. The uterus was obtained from an estrogen-primed immature female rabbit. The binding of progesterone to the uterine receptor was examined in vitro. The progesterone-receptor binding was reduced only by proteases, and phosphorus moiety may not be related for progesterone-receptor binding. The effects of enzymes on the acceptor of the chromatin were investigated. The progesterone-receptor complex was bound to the dehistonized chromatin. The dehistonized chromatins, which were pretreated with enzymes at 4 degrees C or 37 degrees C for 30 minutes, were incubated with 3H-progesterone prelabeled uterine cytosol at 4 degrees C for 30 minutes, and the radioactivity in the chromatin pellet was counted. Proteases effectively decreased the receptor binding capacity to the dehistonized chromatin in the following order: pronase greater than trypsin greater than papain greater alpha-chymotrypsin. DNAse moderately and phospholipase A slightly decreased its binding capacity. The results may indicate that the acceptor site of the progesterone receptor is nonhistone protein over DNA of chromatin and may contain phosphorus moiety.