GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer's disease mouse model.

GV1001 protects neural cells from amyloid-ß (Aß) toxicity and other stressors in in vitro studies and demonstrates clinically beneficial effects in patients with moderate to severe Alzheimer's disease (AD). Here, we investigated the protective effects and mechanism of action of GV1001 in triple transgenic AD (3xTg-AD) mice. We found that GV1001 improved memory and cognition in middle- and old-aged 3xTg-AD mice. Additionally, it reduced Aß oligomer and phospho-tau (Ser202 and Thr205) levels in the brain, and mitigated neuroinflammation by promoting a neuroprotective microglial and astrocyte phenotype while diminishing the neurotoxic ones. In vitro, GV1001 bound to gonadotropin releasing hormone receptors (GnRHRs) with high affinity. Levels of cyclic adenosine monophosphate, a direct downstream effector of activated GnRHRs, increased after GV1001 treatment. Furthermore, inhibition of GnRHRs blocked GV1001-induced effects. Thus, GV1001 might improve cognitive and memory functions of 3xTg-AD mice by suppressing neuroinflammation and reducing Aß oligomers levels and phospho-tau by activating GnRHRs and their downstream signaling pathways.

DKK3 expression is associated with immunosuppression and poor prognosis in glioblastoma, in contrast to lower-grade gliomas.

PURPOSE: We previously reported that expression of dickkopf-3 (DKK3), which is involved in the Wnt/ß-catenin pathway, is significantly associated with prognosis in patients with glioblastoma multiforme (GBM). The aim of this study was to compare the association of DKK3 with other Wnt/ß-catenin pathway-related genes and immune responses between lower grade glioma (LGG) and GBM. METHODS: We obtained the clinicopathological data of 515 patients with LGG (World Health Organization [WHO] grade II and III glioma) and 525 patients with GBM from the Cancer Genome Atlas (TCGA) database. We performed Pearson's correlation analysis to investigate the relationships between Wnt/ß-catenin-related gene expression in LGG and GBM. Linear regression analysis was performed to identify the association between DKK3 expression and immune cell fractions in all grade II to IV gliomas. RESULTS: A total of 1,040 patients with WHO grade II to IV gliomas were included in the study. As the grade of glioma increased, DKK3 showed a tendency to be more strongly positively correlated with the expression of other Wnt/ß-catenin pathway-related genes. DKK3 was not associated with immunosuppression in LGG but was associated with downregulation of immune responses in GBM. We hypothesized that the role of DKK3 in the Wnt/ß-catenin pathway might be different between LGG and GBM. CONCLUSION: According to our findings, DKK3 expression had a weak effect on LGG but a significant effect on immunosuppression and poor prognosis in GBM. Therefore, DKK3 expression seems to play different roles, through the Wnt/ß-catenin pathway, between LGG and GBM.

Predicting cognitive stage transition using p-tau181, Centiloid, and other measures.

BACKGROUND: A combination of plasma phospho-tau (p-tau), amyloid beta (Aß)-positron emission tomography (PET), brain magnetic resonance imaging, cognitive function tests, and other biomarkers might predict future cognitive decline. This study aimed to investigate the efficacy of combining these biomarkers in predicting future cognitive stage transitions within 3 years. METHODS: Among the participants in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE-V) study, 49 mild cognitive impairment (MCI) and 113 cognitively unimpaired (CU) participants with Aß-PET and brain imaging data were analyzed. RESULTS: Older age, increased plasma p-tau181, Aß-PET positivity, and decreased semantic fluency were independently associated with cognitive stage transitions. Combining age, p-tau181, the Centiloid scale, semantic fluency, and hippocampal volume produced high predictive value in predicting future cognitive stage transition (area under the curve = 0.879). CONCLUSIONS: Plasma p-tau181 and Centiloid scale alone or in combination with other biomarkers, might predict future cognitive stage transition in non-dementia patients. HIGHLIGHTS: -Plasma p-tau181 and Centiloid scale might predict future cognitive stage transition. -Combining them or adding other biomarkers increased the predictive value. -Factors that independently associated with cognitive stage transition were demonstrated.

High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach.

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/ß-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/ß-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM. METHODS: We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/ß-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression. RESULTS: In analyses of 31 genes related to Wnt/ß-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression. CONCLUSIONS: These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM.

Effect of Osteoporotic Condition on Ventriculomegaly and Shunt-Dependent Hydrocephalus After Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Hydrocephalus is a common complication in aneurysmal rupture subarachnoid hemorrhage (SAH). As both the bone and arachnoid trabeculae are composed of type 1 collagen, we identified the possible relationship between bone mineral density and ventriculomegaly and shunt-dependent hydrocephalus (SDHC) development after aneurysmal rupture SAH in younger patients. METHODS: We measured frontal skull Hounsfield unit (HU) values on brain computed tomography upon admission, and mean frontal skull HU values were used instead of T-score value. Hazard ratios were calculated using Cox regression analysis to identify whether osteoporotic condition is an independent predictor for ventriculomegaly and SDHC after surgical clipping for SAH in younger patients. RESULTS: Altogether, 412 patients (≤65 years) who underwent surgical clipping for primary spontaneous SAH from a ruptured aneurysm were enrolled in this 11-year analysis in 2 hospitals. We observed that the first tertile group of skull HU was an independent predictor of SDHC after SAH compared with the third tertile of skull HU values (hazard ratio, 2.55 [95% CI, 1.25-5.20]; P=0.010). There were no significant interactions between age and skull HU with respect to ventriculomegaly and SDHC in younger patients. CONCLUSIONS: Our study suggests a relationship between possible osteoporotic conditions and ventriculomegaly and SDHC development after SAH in younger patients. Our findings may be useful in predicting hydrocephalus in young SAH patients using a convenient method of measuring skull HU value on brain computed tomography upon admission.

Relationship between the atlantodental interval and T1 slope after atlantoaxial fusion in patients with rheumatoid arthritis.

BACKGROUND: Atlantoaxial fusion has been widely used for the treatment of atlantoaxial instability (AAI). However, atlantoaxial fusion sacrifices the motion of atlantoaxial articulation, and postoperative loss of cervical lordosis and aggravation of cervical kyphosis are observed. We investigated various factors under the hypothesis that the atlantodental interval (ADI) and T1 slope may be associated with sagittal alignment after atlantoaxial fusion in patients with rheumatoid arthritis (RA). METHODS: We retrospectively investigated 64 patients with RA who underwent atlantoaxial fusion due to AAI. Radiological factors, including the ADI, T1 slope, Oc-C2 angle, cervical sagittal vertical axis, and C2-C7 angle, were measured before and after surgery. RESULTS: The various factors associated with atlantoaxial fusion before and after surgery were compared according to the upper and lower preoperative ADIs. There was a significant difference in the T1 slope 1 year after surgery (p = 0.044) among the patients with lower preoperative ADI values. The multivariate logistic regression analysis showed that the preoperative ADI (> 7.92 mm) defined in the receiver-operating characteristic curve analysis was an independent predictive factor for the increase in the T1 slope 1 year after atlantoaxial fusion (odds ratio, 4.59; 95% confidence interval, 1.34-15.73; p = 0.015). CONCLUSION: We found an association between the preoperative ADI and difference in the T1 slope after atlantoaxial fusion in the patients with RA. A preoperative ADI (> 7.92 mm) was an independent predictor for the increase in the T1 slope after atlantoaxial fusion. Therefore, performing surgical treatment when the ADI is low would lead to better cervical sagittal alignment.

Association Between Possible Osteoporosis and Shunt-Dependent Hydrocephalus After Subarachnoid Hemorrhage.

Background and Purpose- Pathological obstruction in arachnoid granulations after subarachnoid hemorrhage (SAH) can impede cerebrospinal fluid flow outward to the venous sinus and causing hydrocephalus. Because bone and arachnoid granulations share the same collagen type, we evaluated the possible relation between bone mineral density and shunt-dependent hydrocephalus after SAH. Methods- We measured Hounsfield units of the frontal skull on admission brain computed tomography in patients with SAH. Receiver operating characteristic curve analysis was performed to determine the optimal cutoff Hounsfield unit in skull to predict osteopenia and osteoporosis in a large sample registry. According to the optimal cutoff skull Hounsfield unit values, study patients were then categorized as hypothetical normal, osteopenia, and osteoporosis. Odds ratios were estimated using logistic regression to determine whether the osteoporotic conditions are independent predictive factors for the development of shunt-dependent hydrocephalus after clipping for SAH. Results- A total of 447 patients (alive ≥14 days) with ruptured aneurysm SAH who underwent surgical clipping were retrospectively enrolled in this study during a 9-year period from 2 hospitals. We found that hypothetical osteoporosis was an independent predictor for shunt-dependent hydrocephalus after aneurysmal clipping for SAH after full adjustment for other predictive factors, including age (odds ratio, 2.08; 95% confidence interval, 1.06-4.08; P=0.032). Conclusions- Our study demonstrates a possible relation between possible osteoporosis and hydrocephalus after SAH. Hounsfield unit measurement on admission brain computed tomography may be helpful for predicting hydrocephalus during the clinical course of SAH in patients with osteoporosis or suspected osteoporosis.

Nature of intrinsic uncertainties in equilibrium molecular dynamics estimation of shear viscosity for simple and complex fluids.

We study two types of intrinsic uncertainties, statistical errors and system size effects, in estimating shear viscosity via equilibrium molecular dynamics simulations, and compare them with the corresponding uncertainties in evaluating the self-diffusion coefficient. Uncertainty quantification formulas for the statistical errors in the shear-stress autocorrelation function and shear viscosity are obtained under the assumption that shear stress follows a Gaussian process. Analyses of simulation results for simple and complex fluids reveal that the Gaussianity is more pronounced in the shear-stress process (related to shear viscosity estimation) compared with the velocity process of an individual molecule (related to self-diffusion coefficient). At relatively high densities corresponding to a liquid state, we observe that the shear viscosity exhibits complex size-dependent behavior unless the system is larger than a certain length scale, and beyond which, reliable shear viscosity values are obtained without any noticeable scaling behavior with respect to the system size. We verify that this size-dependent behavior is configurational and relate the characteristic length scale to the shear-stress correlation length.

Predictors of Supratentorial Deep Intracerebral Hemorrhage Volume and Their Effect on Short-Term Mortality in Asians.

BACKGROUND: The volume of intracerebral hemorrhage (ICH) measured at hospital admission is the strongest predictor of clinical outcomes in patients with ICH. Despite the high incidence rate of ICH in Asians, there is lack of data regarding predictors of ICH volume in this ethnic group. The purpose of this study was to determine predictors of deep ICH volume and examine their effect on short-term mortality in Asians. METHODS: Hematoma volume was measured using the ABC/2 method. ICH volume was transformed to the natural log scale to normalize distributions for all analyses. We estimated the coefficients of ICH volume based on relevant predictors using multivariable linear regression. We also determined the association between body mass index (BMI) and ICH volume using a regression line and a line determined by a locally weighted scatter plot smoothing. RESULTS: A total of 1,039 patients from 2 twin hospitals in Korea who were admitted with primary spontaneous supratentorial deep ICH over a 12-year period were enrolled in this study. The median ICH volume was 19.7 ml. The average patient age was 59.2, and 62.4% of patients were men. The mean ICH volume showed a gradual, approximately 2% decrease per 1 BMI increase in the current study, after adjusting for all relevant variables (ß = -0.024; SE 0.004; p < 0.001). In addition, patients with frequent alcohol consumption showed a 10% increase in mean ICH volume (ß = 0.098; SE 0.041; p = 0.016), and patients undergoing warfarin treatment showed a 30% increase in mean ICH volume after full adjustment of all relevant variables (ß = 0.296; SE 0.050; p < 0.001). Relative to overweight patients, there was a 47, 11, and 18% increase in admission mean ICH volume in underweight, normal weight and obese patients, respectively. Patients in the first quartile and underweight BMI groups had 1.45-fold (hazard ratio (HR) 1.45; 95% CI 1.03-2.03; p = 0.035) and 1.77-fold (HR 1.77; 95% CI 1.10-2.84; p = 0.019) higher increased risk of death during the first 3 months after ICH, retrospectively. In addition, patients in groups with frequent alcohol consumption and warfarin use both showed a significant association with mortality 90 days after ICH. CONCLUSIONS: We demonstrated the association between various predictors and admission ICH volume with short-term mortality in Asians. Further studies are needed to account for these observations and determine their underlying mechanisms.

Association between hemorrhagic stroke occurrence and meteorological factors and pollutants.

BACKGROUND: The purpose of this study is to determine whether intracerebral hemorrhage and subarachnoid hemorrhage have different incidence patterns based on monthly variations in meteorological and air pollution parameters in the Seongdong district of Seoul, South Korea. METHODS: From January 1, 2004 to December 31, 2014, 1,477 consecutive hemorrhagic stroke events (>19 years old) were registered among residents of the Seongdong district, Seoul, South Korea. The authors calculated the relative risk of hemorrhagic stroke and its subtype incidence based on meteorological and air pollution factors. We also estimated relative risk with 95 % confidence intervals using a multivariate Poisson regression model to identify potential independent variables among meteorological factors and pollutants associated with either intracerebral hemorrhage or subarachnoid hemorrhage occurrence. RESULTS: We observed a negative correlation between intracerebral hemorrhage and mean temperature. In the multivariate Poisson model, particulate matter with an aerodynamic diameter < 10 µm showed positive correlations with intracerebral hemorrhage (relative risk, 1.09; 95 % confidence interval, 1.02 to 1.15; P = 0.012). In contrast, ozone correlated significantly with subarachnoid hemorrhage occurrence (relative risk, 1.32; 95 % confidence interval, 1.10 to 1.58; P = 0.003). CONCLUSIONS: Our findings show the relationship between hemorrhagic stroke and meteorological parameters and pollutants under similar weather and environmental conditions in a small area. Among meteorological and pollutant variables, only higher particulate matter concentrations correlated independently with intracerebral hemorrhage occurrence, while only ozone was independently associated with subarachnoid hemorrhage occurrence. These findings suggest the possibility that there are pathogenic associations between hemorrhagic stroke and meteorological factors and pollutants.

Effect of seasonal and monthly variation in weather and air pollution factors on stroke incidence in Seoul, Korea.

BACKGROUND AND PURPOSE: The purpose of the present study was to determine whether seasonal and monthly variations in stroke incidence exist and whether they are related to meteorologic and air pollution parameters under similar weather and environmental conditions in selected areas of Seongdong district, Seoul, South Korea. METHODS: From January 1, 2004, to December 31, 2013, 3001 consecutive stroke events were registered in residents of selected areas of Seongdong district, Seoul, South Korea. The authors calculated the stroke attack rate per 100,000 people per month and the relative risk of stroke incidence associated with meteorologic and air pollution parameters. We also analyzed odds ratios with a 95% confidence interval for seasonal and monthly stroke incidence. RESULTS: The incidence of stroke in September was significantly higher (odds ratio, 1.233; 95% confidence interval, 1.042-1.468) compared with January. The seasonal ischemic stroke incidence in summer (odds ratio, 1.183; 95% confidence interval, 1.056-1.345) was significantly higher than in winter, whereas the seasonal incidence of intracerebral hemorrhage relative to winter was not significant. The mean temperature was positively correlated with ischemic stroke (relative risk, 1.006; P=0.003), and nitrogen dioxide (relative risk, 1.262; P=0.001) showed a strong positive correlation with intracerebral hemorrhage incidence among the older age group. CONCLUSIONS: We demonstrated distinct patterns of seasonal and monthly variation in the incidence of stroke and its subtypes through consideration of the meteorologic and air pollution parameters. We therefore expect that these findings may enhance our understanding of the relationships between stroke and weather and pollutants.

Changes in Disc Height as a Prognostic Factor in Patients Undergoing Microscopic Discectomy.

OBJECTIVE: Some patients with disc herniation who underwent discectomy complain of back pain after surgery and are unsatisfied with the surgical results. This study aimed to evaluate the relationship between preoperative disc height (DH), postoperative DH, and pain score 12 months after surgery in patients who underwent microdiscectomy for herniated lumbar disc. METHODS: This study enrolled patients who underwent microdiscectomy at a medical center between January 2012 and December 2020. Patients with X-ray or computed tomography and pain score assessment (visual analog scale score) prior to surgery, immediately post-op, and at 1, 6, and 12 months after surgery were included. The DH index was defined as DH/overlying vertebral width. The DH ratio was defined as the postoperative DH/preoperative DH. Simple linear regression and multivariate linear regression analyses were applied to assess the correlation between DHs and leg pain scores 12 months after surgery. RESULTS: A total of 118 patients who underwent microdiscectomy were included. DH decreased up to 12 months after surgery. The DH ratio at 1, 6, and 12 months after discectomy showed a significant positive correlation with the pain scores at 12 months after discectomy (1 month : p=0.045, B=0.52; 6 months : p=0.008, B=0.78; 12 months : p=0.005, B=0.69). Multivariate linear regression analysis revealed that the level of surgery, sex, age, and body mass index had no significant relationship with back pain scores after 12 months. CONCLUSION: In patients who underwent microdiscectomy, the DH ratios at 1, 6, and 12 months after surgery were prognostic factors for back pain scores at 12 months after surgery. Aggressive discectomy is recommended for lower postoperative DH ratios and Visual analog scale scores, leading to improved patient satisfaction.

Significant Genes Associated with Mortality and Disease Progression in Grade II and III Glioma.

BACKGROUND: The Wnt/ß-catenin pathway plays a critical role in the tumorigenesis and maintenance of glioma stem cells. This study aimed to evaluate significant genes associated with the Wnt/ß-catenin pathway involved in mortality and disease progression in patients with grade II and III glioma, using the Cancer Genome Atlas (TCGA) database. METHODS: We obtained clinicopathological information and mRNA expression data from 515 patients with grade II and III gliomas from the TCGA database. We performed a multivariate Cox regression analysis to identify genes independently associated with glioma prognosis. RESULTS: The analysis of 34 genes involved in Wnt/ß-catenin signaling demonstrated that four genes (CER1, FRAT1, FSTL1, and RPSA) related to the Wnt/ß-catenin pathway were significantly associated with mortality and disease progression in patients with grade II and III glioma. We also identified additional genes related to the four significant genes of the Wnt/ß-catenin pathway mentioned above. The higher expression of BMP2, RPL18A, RPL19, and RPS12 is associated with better outcomes in patients with glioma. CONCLUSIONS: Using a large-scale open database, we identified significant genes related to the Wnt/ß-catenin signaling pathway associated with mortality and disease progression in patients with grade II and III gliomas.

Stroke recurrence and osteoporotic conditions in postmenopausal patients with atherosclerotic ischemic stroke.

Recurrence after stroke is common, and associated with a high mortality rate. Degradation of the elastic tissue in the arterial wall has been shown to aggravate atherosclerosis in blood vessels. Considering that type 1 collagen is present in both bone and vascular smooth muscle cells, we explored whether osteoporotic conditions affect the likelihood of stroke recurrence in postmenopausal women following atherosclerotic ischemic stroke. To determine actual bone mineral density (BMD), the Hounsfield unit values in the frontal skull were evaluated using brain computed tomography (CT) scans taken at admission. A multivariate Cox regression analysis was also performed to examine if osteoporosis could independently predict stroke recurrence in postmenopausal patients with large artery atherosclerosis (LAA) or small vessel occlusion (SVO) stroke. This study included 2130 consecutive patients (both males and females aged 50 and older) with acute LAA or SVO strokes. After adjusting for all covariates, hypothetical osteoporosis was identified as an independent predictor of stroke recurrence in female patients ≥50 years with acute LAA or SVO stroke (hazard ratio, 1.84; 95 % confidence interval, 1.05 to 3.24; p = 0.034). Our findings showed that osteoporosis could potentially affect the recurrence of ischemic stroke in postmenopausal patients with LAA or SVO stroke.

Identification of predictive factors for better outcomes in LINAC-based radiation treatment for cerebral cavernous malformation.

The effectiveness of radiation therapy in the treatment of cerebral cavernous malformations (CCM) remains debatable. However, numerous studies have shown a reduction in hemorrhage risk following radiotherapy for CCM. Therefore, herein, we share our experiences utilizing linear accelerator (LINAC)-based radiation for treating CCMs, with the aim of identifying the key factors influencing the therapeutic outcomes. We conducted a retrospective review of all patients with non-brainstem CCMs who underwent radiation treatment, as recorded in the NOVALIS registry at our institution. T2-weighted MR images were used for volumetric assessments using the iPlan radiotherapy planning software. To determine the independent predictors of nidus volume reduction and perilesional brain edema (PBE), we performed multivariate Cox regression analysis to calculate hazard ratios. Twenty patients with 31 non-brainstem CCMs were enrolled in this study. Analysis revealed age as an independent predictive factor for both nidus volume reduction and PBE after radiation treatment for CCM. Furthermore, a single fraction dose of 17 Gy or more was identified as an independent predictor of nidus volume decrease, while a single fraction dose of 18 Gy or more was found to be an independent risk factor for PBE in patients with CCM following LINAC-based radiation therapy. LINAC-based radiation therapy for non-brainstem CCMs with a single fraction radiation dose between 16.5 and 17.5 Gy, or a biologically equivalent dose of approximately 120 Gy, may be the most effective at reducing nidus volume and limiting side effects, particularly in patients under the age of 55 years. We further observed that the risk of PBE increased as the maximum radiation dose delivered to a 1 cc volume of the surrounding normal brain exceeded approximately 17.3 Gy. Therefore, we believe that calculating the D1cc of the normal brain may help to predict the occurrence of PBE when radiotherapy is administered to non-brainstem CCMs.

Coil embolization of the middle cerebral artery bifurcation aneurysms: Feasibility and durability.

OBJECTIVE: To evaluate the feasibility and durability of coil embolization for MCAB aneurysms by analyzing clinical and radiological results. METHODS: From January of 2008 to June of 2018, we treated a total of 1785 aneurysms using coil embolization. The aneurysms were treated by both coiling and stent-assisted coiling. Among these cases, 223 MCAB aneurysms were analyzed retrospectively. Clinical and radiological assessments were conducted at admission, after treatment, at discharge, and at last clinical follow-up. RESULTS: Coil embolization was performed on 223 MCAB aneurysms in 217 patients. Peri-procedural ischemic, hemorrhagic, and other complications within 30 days after coil embolization occurred at rates of 8.0 %, 8.0 %, and 2.0 %, respectively, in the ruptured group and at 2.9 %, 1.2 %, and 0 %, respectively, in the unruptured group. The overall morbidity and mortality rates associated with complications were 2.3 % and 2.0 %. The cumulative major recurrence rates were 5.1 % at 12 months, 7.1 % at 18 months, and 11.9 % at three years after coil embolization. The mean follow-up period was 33.27 ± 25.48 months. Independent risk factors for major recurrence after coil embolization for MCAB aneurysms were a ruptured aneurysm, initial incomplete occlusion, the aneurysm size, and the neck size. CONCLUSION: Coil embolization is a good alternative treatment option for MCAB aneurysms compared to surgical clipping. Considering the risk factors for major recurrence, the follow-up angiography should continue up to three years after coil embolization.

p27 Cell Cycle Inhibitor and Survival in Luminal-Type Breast Cancer: Gene Ontology, Machine Learning, and Drug Screening Analysis.

PURPOSE: A widely distributed cell cycle inhibitor, p27, regulates cyclin-dependent kinase-cyclin complexes. Although the prognostic value of p27 has been established for various types of carcinomas, its role in luminal breast cancer remains poorly understood. This study aimed to explore the functional enrichment of p27 and identify potential drug targets in patients with luminal-type breast cancer. METHODS: Clinicopathological data were collected from 868 patients with luminal-type breast cancer. Additionally, publicly available data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (1,500 patients) and the Gene Expression Omnibus database (855 patients) were included in the analysis. Immunohistochemical staining for p27, differential gene expression analysis, disease ontology analysis, survival prediction modeling using machine learning (ML), and in vitro drug screening were also performed. RESULTS: Low p27 expression correlated with younger age, advanced tumor stage, estrogen receptor/progesterone receptor negativity, decreased cluster of differentiation 8+ T cell count, and poorer survival outcomes in luminal-type breast cancer. The METABRIC data revealed that reduced cyclin-dependent kinase inhibitor 1B (CDKN1B) expression (encoding p27) was associated with cell proliferation-related pathways and epigenetic polycomb repressive complex 2. Using ML, p27 emerged as the second most significant survival factor after N stage, thereby enhancing survival model performance. Additionally, luminal-type breast cancer cell lines with low CDKN1B expression demonstrated increased sensitivity to specific anticancer drugs such as voxtalisib and serdemetan, implying a potential therapeutic synergy between CDKN1B-targeted approaches and these drugs. CONCLUSION: The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer.

GV1001 reduces neurodegeneration and prolongs lifespan in 3xTg-AD mouse model through anti-aging effects.

GV1001, which mimics the activity of human telomerase reverse transcriptase, protects neural cells from amyloid beta (Aß) toxicity and other stressors through extra-telomeric function, as noted in our prior in vitro studies. As per a recent phase II clinical trial, it improves cognitive function in patients with moderate to severe dementia. However, the underlying protective mechanisms remain unclear. This study aimed to investigate the effects of GV1001 on neurodegeneration, senescence, and survival in triple transgenic Alzheimer's disease (3xTg-AD) mice. GV1001 (1 mg/kg) was subcutaneously injected into old 3xTg-AD mice thrice a week until the endpoint for sacrifice, and survival was analysed. Magnetic resonance imaging (MRI) and Prussian blue staining (PBS) were performed to evaluate entry of GV1001 entrance into the brain. Diverse molecular studies were performed to investigate the effect of GV1001 on neurodegeneration and cellular senescence in AD model mice, with a particular focus on BACE, amyloid beta1-42 (Aß1-42), phosphorylated tau, volume of dentate gyrus, ß-galactosidase positive cells, telomere length, telomerase activity, and ageing-associated proteins. GV1001 crossed the blood-brain barrier, as confirmed by assessing the status of ferrocenecarboxylic acid-conjugated GV1001 using magnetic resonance imaging and PBS. GV1001 increased the survival of 3xTg-AD mice. It decreased BACE and Aß1-42 levels, neurodegeneration (i.e., reduced CA1, CA3 and dentate gyrus volume, decreased levels of senescence-associated ß-galactosidase positive cells, and increased telomere length and telomerase activity), and levels of ageing-associated proteins. We suggest that GV1001 exerts anti-ageing effects in 3xTg-AD mice by reducing neurodegeneration and senescence, which contributes to improved survival.

Association between osteoporosis and the rate of telomere shortening.

A shorter leukocyte telomere length (LTL) is reported to be associated with age-related diseases, including osteoporosis. Many studies have tried identifying the association between LTL and osteoporosis, although it remains controversial. This study aimed to determine whether osteoporosis is independently associated with LTL shortening in a prospective longitudinal cohort. The KBASE study is an independent multicenter prospective cohort in South Korea, which began in 2014. We compared the LTL values for each participant at baseline and over a 2-year follow-up period. Boxplots were used to demonstrate the differences in the change in LTL over a 2-year follow-up according to osteoporosis. Multivariable linear regression was conducted to identify whether osteoporosis is independently associated with the rate of telomere shortening. A total of 233 subjects (from 55 to 88 years) from the KBASE cohort were finally enrolled in the study. We observed that the LTL decreased by approximately 1.2 kbp over 2 years. While the LTL decreased as age increased, the rate of LTL shortening did not increase with age. Multivariable linear regression analysis indicated that only osteoporosis was independently associated with rapid LTL shortening over 2 years (B, -8.08; p = 0.038). We sought to identify an association between osteoporosis and LTL shortening in an independent prospective cohort. We found that participants with osteoporosis had significantly faster LTL shortening over 2 years than those without osteoporosis. We hope this study will help elucidate the underlying mechanisms in the relationship between LTL and osteoporosis in the future.

Relationship between telomere shortening and early subjective depressive symptoms and cognitive complaints in older adults.

Telomere length (TL) has been reported to be associated with depression and cognitive impairment in elderly. Early detection of depression and cognitive impairment is important to delay disease progression. Therefore, we aimed to identify whether TL is associated with early subjective depressive symptoms and cognitive complaints among healthy elderly subjects. This study was a multicenter, outcome assessor-blinded, 24-week, randomized controlled trial (RCT). Measurement of questionnaire and physical activity scores and blood sample analyses were performed at baseline and after six months of follow-up in all study participants. Linear regression analyses were performed to identify whether early subjective depressive symptoms, cognitive complaints, and several blood biomarkers are associated with TL. Altogether, 137 relatively healthy elderly individuals (60-79 years old) were enrolled in this prospective RCT. We observed an approximate decrease of 0.06 and 0.11-0.14 kbps of TL per one point increase in the geriatric depression scale and cognitive complaint interview scores, respectively, at baseline and after six months of follow-up. We also found an approximate decrease of 0.08-0.09 kbps of TL per one point increase in interleukin (IL)-6 levels at baseline and after six months of follow-up. Our study showed that both early subjective depressive symptoms and cognitive complaints were associated with a relatively shorter TL in relatively healthy elderly individuals. In addition, based on our findings, we believe that IL-6 plays an important role in the relationship between shortening TL and early subjective depressive symptoms and cognitive complaints.