Nevin Manimala

J Alzheimers Dis. 2023 Jan 11. doi: 10.3233/JAD-221044. Online ahead of print.

ABSTRACT

BACKGROUND: Alzheimer’s disease (AD) is the most common dementia syndrome in the elderly characterized by synaptic failure and unique brain pathology. De novo protein synthesis is required for the maintenance of memory and synaptic plasticity. Mounting evidence links impaired neuronal protein synthesis capacity and overall protein synthesis deficits to AD pathogenesis. Meanwhile, identities of AD-associated dysregulation of “newly synthesized proteome” remain elusive.

OBJECTIVE: To investigate de novo proteome alterations in the hippocampus of aged Tg19959 AD model mice.

METHODS: In this study, we combined the bioorthogonal noncanonical amino acid tagging (BONCAT) method with the unbiased large-scale proteomic analysis in acute living brain slices (we name it “BONSPEC”) to investigate de novo proteome alterations in the hippocampus of Tg19959 AD model mice. We further applied multiple bioinformatics methods to analyze in-depth the proteomics data.

RESULTS: In total, 1,742 proteins were detected across the 10 samples with the BONSPEC method. After exclusion of those only detected in less than half of the samples in both groups, 1,362 proteins were kept for further analysis. 37 proteins were differentially expressed (based on statistical analysis) between the WT and Tg19959 groups. Among them, 19 proteins were significantly decreased while 18 proteins were significantly increased in the hippocampi of Tg19959 mice compared to WT mice. The results suggest that proteins involved in synaptic function were enriched in de novo proteome of AD mice.

CONCLUSION: Our study could provide insights into the future investigation into the molecular signaling mechanisms underlying AD and related dementias (ADRDs).

PMID:36641677 | DOI:10.3233/JAD-221044

J Alzheimers Dis. 2023 Jan 12. doi: 10.3233/JAD-220770. Online ahead of print.

ABSTRACT

BACKGROUND: The fecal immunochemical test (FIT) is widely used in screening for colorectal cancer (CRC), but FIT results can be positive for diseases other than CRC.

OBJECTIVE: We investigated the association between positive results of FIT and the incidence of dementia using a nationwide database.

METHODS: FIT-positive participants were collected from a database provided by the Korean National Health Insurance Service.

RESULTS: The incidence of all kinds of dementia was higher in FIT-positive than FIT-negative subjects (p < 0.0001). FIT-positive participants had a higher risk of Alzheimer’s disease (AD) (p < 0.0001) and vascular dementia (p = 0.0002), compared to participants with FIT negativity. The risk of all kinds of dementia or AD in FIT-positive participants was higher in younger (age < 65 years) than older participants (p < 0.0001 for all kinds of dementia; p = 0.0002 for AD).

CONCLUSION: FIT positivity was correlated with an increased risk of dementia, especially in participants under 65 years of age. The study suggests that clinicians can consider dementia when FIT-positive participants fail to show any malignancies.

PMID:36641669 | DOI:10.3233/JAD-220770

Breast Dis. 2022;41(1):489-493. doi: 10.3233/BD-229007.

ABSTRACT

INTRODUCTION: The relationship between increased platelet count and cancer classification stage has long been established. The prevalence of thrombocytosis varies from 10% to 57% in cancer patients. The pathogenesis of thrombocytosis in malignancy is uncertain. However, there is evidence that tumor cells secrete humoral factors that can cause thrombocytosis. Preoperative thrombocytosis is a poor prognostic variable in malignancies. This study investigated the correlation between platelet count and breast cancer stage.

METHODS: This cross-sectional study was conducted from February 2020 to January 2021. Patient data were collected from medical records. The study population comprised breast cancer patients at Dr. Wahidin Sudirohusodo Makassar. The staging examinations were based on the tumor, node, metastasis (TNM) classification according to the American Joint Committee on Cancer (AJCC) 8th Edition.

RESULTS: The study group comprised 171 breast cancer patients of varying ages. Metastasis was present in five (2.92%) patients and absent in 166 (97.8%) patients. Analyses found no statistically significant differences between the three staging groups based on the platelet count (p = 0.952).

CONCLUSION: There was no statistically significant relationship between increased platelet count and staging according to the TNM classification in breast cancer patients.

PMID:36641658 | DOI:10.3233/BD-229007

Breast Dis. 2022;41(1):481-487. doi: 10.3233/BD-229004.

ABSTRACT

BACKGROUND: Breast cancer (BC) is the most common cancer among women worldwide and a leading cause of death in Indonesia. The primary treatment of locally advanced BC is neoadjuvant chemotherapy (NAC). The rapid proliferation of tumor cells in a neoplastic microenvironment is largely due to hypoxia, which also encourages the development of chemoresistant BC. The master regulator of the hypoxia response is hypoxia-inducible factor-1α (HIF-1α). The response evaluation criteria in solid tumors (RECIST) is an objective response metric that demonstrates the efficacy of a NAC based mostly on the size of the tumor. Ca15-3 is the protein product of the MUC1 gene and is the most widely used serum marker in BC. The purpose of this study is to investigate the relationship between HIF-1α and RECIST and between Ca15-3 and RECIST and to assess the relationship among all of them in BC.

METHODS: This observational study used the prospective cohort method included 11 patients with histopathologically confirmed BC, specifically invasive ductal carcinoma. We evaluated the changes in HIF-1α and Ca15-3 serum levels using ELISA and measured tumor lesions with RECIST. The procedure was carried out twice. Serum levels were measured at baseline, and after receiving two cycles of NAC (5 weeks).

RESULTS: Among the 11 patients included in this study, HIF-1α, Ca15-3, and RECIST decreased significantly after NAC. The changes in RECIST correlated with Ca15-3: each unit decrease in RECIST score was associated with a 0.3-unit decrease in Ca15-3 levels (p = 0.019).

CONCLUSIONS: There was a decrease in HIF-1α, followed by a decrease in Ca15-3 and RECIST in response to chemotherapy. There was a statistically significant correlation between Ca15-3 and response to chemotherapy. This study evidences the relationship between factors that shape the local tumor microenvironment.

PMID:36641657 | DOI:10.3233/BD-229004

Breast Dis. 2022;41(1):471-480. doi: 10.3233/BD-220023.

ABSTRACT

OBJECTIVE: In this study, the profiling of the expression of major histocompatibility complex (MHC) class I-related chain A and B (MICA/B) in human breast cancer tumor tissue, saliva, and urine samples of breast cancer patients and control is carried out. MICA/B is ligand of NKG2D receptor expressed on malignant cells. The release of MICA/B from tumor tissue comprises an immune escape mechanism that impairs antitumor immunity. Based on this literature we explored the potential of soluble MICA (sMICA) as a marker in breast cancer (BC).

METHODS: The expression was profiled by using immunohistochemistry (MICA/B), western blot (MICA/B) and ELISA (MICA).

RESULTS: The optical density of western blot of MICA/B in different stages of BC illustrated significant difference as per one way analysis of variance and significant difference with stage III and IV by Dunnett’s multiple comparisons test respectively. Analysis of sMICA in serum, saliva and urine of BC patients revealed significantly higher levels (median 41.0 ± 4.1 pg/ml in pre-treatment sera, 181.9 ± 1.6 pg/ml in saliva and 90.7 ± 1.7 pg/ml in urine) than in control (median <1.2 pg/ml). The elevated levels of sMICA were related to the cancer stage.

CONCLUSIONS: The elevated levels of sMICA were observed in patients with well differentiated cancer while the poor expression of sMICA was observed in patients with poorly differentiated tumors. Tumor immunity is impaired by the release of MICA in the biofluids and may be useful for detection and diagnosis of the stage of BC.

PMID:36641654 | DOI:10.3233/BD-220023

J Prev Alzheimers Dis. 2023;10(1):133-136. doi: 10.14283/jpad.2022.91.

ABSTRACT

OBJECTIVES: Whole grains (WG) have been widely recognized as healthy foods but few prospective studies have examined WG foods consumption and all-cause dementia and Alzheimer’s disease (AD) dementia. This pilot study aimed to investigate the relationship between WG and dementia.

METHODS: 2958 subjects from the Framingham Offspring cohort were included with the Food Frequency Questionnaire (FFQ) to assess their diet intake. And multivariate Cox proportional regression was conducted to examine the relations.

RESULTS: After an average follow-up of 12.6 years, 322 all-cause dementia were documented, including 247 AD dementia. In the fully adjusted model, participants in the highest vs. the lowest quintiles of WG consumption had lower risks of all-cause dementia (HR, 0.72; 95% CI, 0.53-0.84; P for trend <0.001) and AD dementia (HR, 0.64; 95% CI, 0.47-0.80; P for trend <0.001).

CONCLUSIONS: High consumption of WG foods is associated with decreased risks of all-cause dementia and AD dementia.t disease mortality. Our findings are from a preliminary study and need to be confirmed in comprehensive settings and integrated statistical methods.

PMID:36641618 | DOI:10.14283/jpad.2022.91

J Prev Alzheimers Dis. 2023;10(1):25-33. doi: 10.14283/jpad.2022.84.

ABSTRACT

BACKGROUND: Previously we reported the clinical safety and pharmacological activity of buntanetap (known as Posiphen or ANVS401) in healthy volunteers and mild cognitive impaired (MCI) patients (21). The data supported continued clinical evaluation of buntanetap for treating Alzheimer’s Disease (AD). Neurodegenerative diseases such as AD and Parkinson’s disease (PD) share several pathological manifestations, including increased levels of multiple neurotoxic protein aggregates. Therefore, a treatment strategy that targets toxic species common to both disorders can potentially provide better clinical outcomes than attacking one neurotoxic protein alone. To test this hypothesis, we recently completed a clinical study in early AD and early PD participants and report the data here.

OBJECTIVES: We evaluated safety, pharmacokinetics, biomarkers, and efficacy of buntanetap in treating early AD and PD patients.

DESIGN: Double-blind, placebo-controlled, multi-center study.

SETTING: 13 sites in the US participated in this clinical trial. The registration number is NCT04524351 at ClinicalTrials.gov.

PARTICIPANTS: 14 early AD patients and 54 early PD patients.

INTERVENTION: AD patients were given either 80mg buntanetap or placebo QD. PD patients were given 5mg, 10mg, 20mg, 40mg, 80mg buntanetap or placebo QD.

MEASUREMENTS: Primary endpoint is safety and tolerability; secondary endpoint is pharmacokinetics of buntanetap in plasma; exploratory endpoints are 1) biomarkers in cerebrospinal fluid (CSF) in both AD and PD patients 2) psychometric tests specific for AD (ADAS-Cogs and WAIS coding test) or PD (MDS-UPDRS and WAIS coding test).

RESULTS: Buntanetap was safe and well tolerated. Biomarker data indicated a trend in lowering levels of neurotoxic proteins and inflammatory factors and improving axonal integrity and synaptic function in both AD and PD cohorts. Psychometric tests showed statistically significant improvements in ADAS-Cog11 and WAIS coding in AD patients and MDS-UPDRS and WAIS coding in PD patients.

CONCLUSIONS: Buntanetap is well tolerated and safe at doses up to 80mg QD in both AD and PD patients. Cmax and AUC increase with dose without evidence for a plateau up to 80mg QD. The drug shows promising evidence in exploratory biomarker and efficacy measures. Further evaluation of buntanetap in larger, longer-term clinical trials for the treatment of AD and PD are warranted.

PMID:36641607 | DOI:10.14283/jpad.2022.84

J Prev Alzheimers Dis. 2023;10(1):7-8. doi: 10.14283/jpad.2022.104.

NO ABSTRACT

PMID:36641604 | DOI:10.14283/jpad.2022.104

BMC Health Serv Res. 2023 Jan 14;23(1):33. doi: 10.1186/s12913-023-09025-2.

ABSTRACT

BACKGROUND: Equity and efficiency are basic value dimensions to evaluate the effectiveness of China’s medical and health service system (MHS) reform and development. Coordinated development of equity and efficiency is necessary to realize high-quality development of medical and health services. This study aims to evaluate the equity, efficiency, and combined efforts in coordinating the MHS during 1991-2020 reform.

METHODS: Data on China’s MHS were obtained from the China Statistical Yearbook 1992-2021. Ratios of urban to rural residents’ medical expenditure and number of medical professionals per 10,000 people were employed to evaluate MHS’s equity. The data envelopment analysis-Malmquist model was employed to evaluate MHS’s efficiency. We constructed a combined-efforts-in-coordination model to examine the coordination degree between equity and efficiency.

RESULTS: Equity of medical expenditure burden significantly improved from during 1991-2007. Urban residents’ 1991 medical expenditure burden was 87.8% of that of rural residents, which increased to 100.1% in 2007. Urban areas’ mean medical expenditure burden was 105.94% of that in rural areas during 1991-2007. The gap in equity of medical expenditure burden between urban and rural areas slowly widened after 2007, with urban areas’ mean burden being 68.52% of that in rural areas during 2007-2020. Medical and health resources allocation shows an alarming inequity during this period, with mean number of medical professionals per 10,000 people in urban areas being 238.30% of that in rural areas. Efficiency experienced several fluctuations before 2008. Since 2008, efficiency was high (0.915) and remained stable, except in 2020. The combined-efforts-in-coordination score for medical expenditure burden was less than 0.2 for 80% of the years, while that for in medical and health resources was more than 0.5 for 99.67% of the years.

CONCLUSIONS: MHS inequity remains between urban and rural China, primarily because of disproportionate allocation of medical and health resources. The government should enhance rural medical professionals’ salary and welfare and provide medical subsidies for rural residents to adjust resource allocation levels in urban and rural areas, control differences in medical expenditure burden between urban and rural residents to a reasonable range, and continuously improve urban and rural residents’ equity level.

PMID:36641525 | DOI:10.1186/s12913-023-09025-2

Commun Biol. 2023 Jan 14;6(1):49. doi: 10.1038/s42003-023-04443-8.

ABSTRACT

Pulmonary function is an indicator of well-being, and pulmonary pathologies are the third major cause of death worldwide. We analysed the UK Biobank genome-wide association summary statistics of pulmonary function for Europeans and individuals of recent African descent to identify variants associated with the trait in the two ancestries. Here, we show 627 variants in Europeans and 3 in Africans associated with three pulmonary function parameters. In addition to the 110 variants in Europeans previously reported to be associated with phenotypes related to pulmonary function, we identify 279 novel loci, including an ISX intergenic variant rs369476290 on chromosome 22 in Africans. Remarkably, we find no shared variants among Africans and Europeans. Furthermore, enrichment analyses of variants separately for each ancestry background reveal significant enrichment for terms related to pulmonary phenotypes in Europeans but not Africans. Further analysis of studies of pulmonary phenotypes reveals that individuals of European background are disproportionally overrepresented in datasets compared to Africans, with the gap widening over the past five years. Our findings extend our understanding of the different variants that modify the pulmonary function in Africans and Europeans, a promising finding for future GWASs and medical studies.

PMID:36641522 | DOI:10.1038/s42003-023-04443-8