Inhibitory Roles of Apolipoprotein E Christchurch Astrocytes in Curbing Tau Propagation Using Human Pluripotent Stem Cell-Derived Models.

Genetic variants in the apolipoprotein E (APOE) gene affect the onset and progression of Alzheimer's disease (AD). The APOE Christchurch (APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3Ch/3Ch human-induced pluripotent stem cells (iPSCs) from APOE3/3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3Ch/3Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3/3 astrocytes, but not in APOE3Ch/3Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3Ch/3Ch astrocytes reduced complexity compared with APOE3/3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3Ch/3Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research.

Combined hepatocellular-cholangiocarcinoma with angiosarcomatoid change: A case report with immunohistochemical study.

Sarcomatoid combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare condition, with only 16 cases reported to date; however, there have been no reports of hepatic sarcomatoid carcinoma with angiosarcomatous features. Here, we report a rare case of cHCC-CCA with angiosarcomatoid changes in a 77-year-old man. The tumor was biphasic with malignant epithelial and mesenchymal components. Histologically, the epithelial component was concordant with classical type cHCC-CCA. The mesenchymal component included angiosarcomatoid cells growing in a vasoformative structure and undifferentiated spindle cells. Immunohistochemical analyses showed that angiosarcomatoid cells were positive for CD31, factor VIII-related antigen, and other angiosarcoma markers. Characteristically diffuse and strong expression of p53 protein was observed in the nuclei of angiosarcomatoid cells but not in carcinoma cells, suggesting that TP53 gene mutations commonly occur in these cells. Transitional zones were observed between HCC and spindle cells and between HCC and angiosarcomatoid cells. A small portion of undifferentiated spindle cells expressed pan-cytokeratin. These findings suggested that this extremely rare tumor developed from dedifferentiation or metaplastic changes of cHCC-CCA.

Time to castration resistance is a novel prognostic factor of cancer-specific survival in patients with nonmetastatic castration-resistant prostate cancer.

We aimed to identify prognostic factors of cancer-specific survival (CSS) in non-metastatic castration-resistant prostate cancer (M0CRPC) patients. The final analysis of this retrospective cohort included 82 patients who were diagnosed as M0CRPC between 1998 and 2018 at the University of Tokyo Hospital. CRPC was defined as prostate-specific antigen (PSA) progression (increased PSA ≥ 25% and ≥ 2 ng/mL above the nadir or detection of a metastatic lesion). The median value of age and PSA at the time of CRPC were 76 (range 55-94) years and 2.84 (range 2.04-22.5) ng/mL, respectively. The median follow-up time from CRPC diagnosis was 38 (range 3-188) months. The prognostic factors of CSS were 'PSA doubling time (PSADT) ≤ 3 months', 'time to CRPC diagnosis from the start of androgen deprivation therapy (TTCRPC) ≤ 12 months', of which TTCRPC was a novel risk factor of CSS. In the multivariate analysis, 'PSADT ≤ 3 months' and TTCRPC ≤ 12 months' remained as statistically significant predictors of CSS. Novel risk stratification was developed based on the number of these risk factors. The high-risk group showed a hazard ratio of 4.416 (95% confidence interval 1.701-11.47, C-index = 0.727).

Collagenous Alzheimer amyloid plaque component impacts on the compaction of amyloid-ß plaques.

Massive deposition of amyloid ß peptides (Aß) as senile plaques (SP) characterizes the brain pathology of Alzheimer's disease (AD). SPs exhibit a variety of morphologies, although little is known about the SP components that determine their morphology. Collagenous Alzheimer amyloid plaque component (CLAC) is one of the major non-Aß proteinaceous components of SP amyloid in AD brains. Here we show that overexpression of CLAC precursor (CLAC-P) in the brains of APP transgenic mice results in a significant remodeling of amyloid pathology, i.e., reduction in diffuse-type amyloid plaques and an increase in compact plaques laden with thioflavin S-positive amyloid cores. In vivo microdialysis revealed a significant decrease in Aß in the brain interstitial fluid of CLAC-P/APP double transgenic mice compared with APP transgenic mice. These findings implicate CLAC in the compaction of Aß in amyloid plaques and the brain dynamics of Aß.