Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo?

Many neurodegenerative diseases are characterized by abnormal protein aggregates, including the two most common neurodegenerative diseases Alzheimer’s disease (AD) and Parkinson’s disease (PD). In the global search to prevent and treat diseases, most research has been focused on the early stages of the diseases, including how these pathogenic protein aggregates are initially formed. We argue, however, that an equally important aspect of disease etiology is the characteristic spread of protein aggregates throughout the nervous system, a key process in disease progression. Growing evidence suggests that both alterations in lipid metabolism and dysregulation of extracellular vesicles (EVs) accelerate the spread of protein aggregation and progression of neurodegeneration, both in neurons and potentially in surrounding glia. We will review how these two pathways are intertwined and accelerate the progression of AD and PD. Understanding how lipid metabolism, EV biogenesis, and EV uptake regulate the spread of pathogenic protein aggregation could reveal novel therapeutic targets to slow or halt neurodegenerative disease progression.

The Prognostic Impact of Abnormal Protein Bands in Multiple Myeloma: A Systematic Review and Meta-Analysis

Introduction: The detection of abnormal protein bands (APB) different from the original monoclonal protein in patients with multiple myeloma (MM) who underwent stem cell transplantation and/or chemotherapy has been reported. These atypical serum immunofixation patterns may be monoclonal (also termed secondary monoclonal gammopathy of undetermined significance) or oligoclonal bands (OB). The prognostic significance of this phenomenon remains controversial. This systematic review and meta-analysis aimed to summarize and analyze the evidence for the association between APB with survival in MM patients. Methods: A systematic search of PubMed, Cochrane, Google Scholar, Medline-Ovid, CINAHL, and ERIC, was conducted using relevant search terms. All studies were screened using predefined selection criteria and critically appraised for quality assessment following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All studies that described the presence of APB, defined as monoclonal spike with heavy or light chain immunoglobulin distinct from the original paraprotein at initial diagnosis of MM, and its associations with survival were included. Studies that reported multivariate adjusted hazard ratios (HR) were further included for meta-analysis. Random-effects model was used to synthesize the pooled HR estimate for the association of APB with survival. Cochran's Q statistics and I2 tests were used to evaluate statistical heterogeneity. Results: A total of 24 out of 181 eligible studies were included for qualitative synthesis. Four studies (including 1115 patients) that reported HR estimates were included in the final meta-analysis. The random-effect summary HR for the progression-free survival among patients with APB was 0.44 (95% CI, 0.31-0.65) with no statistical heterogeneity (I2=0%, p=0.93). The pooled HR for the association with overall survival was 0.31 (95% CI, 0.14-0.66) with moderate statistical heterogeneity (I2=45%; p=0.16) for patients with APB. One study (Silva et al, 2017) only included patients with at least very good partial response while the other three studies reported similar findings of higher occurrence of APB with complete response (Tovar et al, 2013; Jo et al, 2014; Zou et al, 2014). These results are also consistent with the presumed association of APB with complete response as suggested in other studies included in qualitative review. Conclusions: This study indicated a potential prognostic value of APB for favorable outcomes in the context of both overall and progression-free survival in MM patients after treatment. Further research is needed to evaluate the prognostic impact of the sole emergence of APB irrespective of treatment response. Figure 1 Figure 1. Disclosures Jamshed: Takeda: Honoraria.

Preoperative Tumor Abnormal Protein as a Promising Biomarker to Predict Oncological Outcome of Hepatocellular Carcinoma After Curative Resection

Background: TAP (tumor abnormal protein) has been used as an important indicator in the early diagnosis of cancers, and some literatures showed that TAP can act as a prognostic factor in different kinds of cancer. The objective of this study was to explore the potential relationship between TAP and the prognosis of HCC after radical hepatectomy, and attempted to construct a robustly predictive nomogram on the strength of TAP and other prognostic variables of HCC patients.Methods: This retrospective study included 168 HCC patients (tumor recurrence occurred in 78 patients) who had undergone curative resection during January 2018 to June 2020 at the Department of Hepatopancreatobiliary Surgery of Liaoning Cancer Hospital & Institute. Serum TAP was detected by Abnormal Sugar Chain Structure of Glycoproteins, and according to the area of condensation particle, the whole population was categorized into the TAP high group (TAP≥225μm2) and TAP low group (TAP<225μm2).Results: There was no correlation between maximum tumor size and TAP. In the whole population or subgroups stratified by maximum tumor size, the recurrence-free survival (RFS) rate of the TAP low group was distinctly higher than TAP high group (P<0.05 for all). The multivariate analysis revealed that TAP (hazard ratio [HR], 3.47; 95% CI, 2.18-5.51; P<0.001), large tumor size (HR, 2.18; 95% CI, 1.36-3.49; P<0.001), poor tumor differentiation (HR, 0.53; 95% CI, 0.33-0.84; P=0.007) and presence of microvascular invasion (MVI) (HR, 2.03; 95% CI, 1.28-3.22; P=0.003) were independently associated with RFS. The prognostic implication of nomogram incorporating TAP, maximun tumor diameter, tumor differentiation and MVI was stronger than the model that integrated maximun tumor diameter, degree of tumor differentiation and MVI only.Conclusion: The present study suggested that higher preoperative TAP was correlated with undesirable prognosis in HCC patients who had undergone radical hepatectomy,and on the strength of prognostic variables identified by multivariate analysis, we constructed a robust nomogram for RFS of postoperative HCC patients.

The Evolution of the Hallmarks of Aging

The evolutionary theory of aging has set the foundations for a comprehensive understanding of aging. The biology of aging has listed and described the “hallmarks of aging,” i.e., cellular and molecular mechanisms involved in human aging. The present paper is the first to infer the order of appearance of the hallmarks of bilaterian and thereby human aging throughout evolution from their presence in progressively narrower clades. Its first result is that all organisms, even non-senescent, have to deal with at least one mechanism of aging – the progressive accumulation of misfolded or unstable proteins. Due to their cumulation, these mechanisms are called “layers of aging.” A difference should be made between the first four layers of unicellular aging, present in some unicellular organisms and in all multicellular opisthokonts, that stem and strike “from the inside” of individual cells and span from increasingly abnormal protein folding to deregulated nutrient sensing, and the last four layers of metacellular aging, progressively appearing in metazoans, that strike the cells of a multicellular organism “from the outside,” i.e., because of other cells, and span from transcriptional alterations to the disruption of intercellular communication. The evolution of metazoans and eumetazoans probably solved the problem of aging along with the problem of unicellular aging. However, metacellular aging originates in the mechanisms by which the effects of unicellular aging are kept under control – e.g., the exhaustion of stem cells that contribute to replace damaged somatic cells. In bilaterians, additional functions have taken a toll on generally useless potentially limited lifespan to increase the fitness of organisms at the price of a progressively less efficient containment of the damage of unicellular aging. In the end, this picture suggests that geroscience should be more efficient in targeting conditions of metacellular aging rather than unicellular aging itself.

The Potential Effects of Oxidative Stress-Related Plasma Abnormal Protein Aggregate Levels on Brain Volume and Its Neuropsychiatric Consequences in Parkinson’s Disease

Background. Oxidative stress has been implicated in the pathogenesis of many diseases, including Parkinson’s disease. Large protein aggregates may be produced after the breakdown of the proteostasis network due to overt oxidative stress. Meanwhile, brain volume loss and neuropsychiatric deficits are common comorbidities in Parkinson’s disease patients. In this study, we applied a mediation model to determine the potential influences of oxidative stress-related plasma abnormal protein aggregate levels on brain volume and neuropsychiatric consequences in Parkinson’s disease. Method. 31 patients with PD and 24 healthy controls participated in this study. The PD patients were further grouped according to the presentation of cognitive decline or not. All participants received complete examinations to determine plasma abnormal protein aggregates levels, brain volume, and neuropsychiatric performance. The results were collected and analyzed in a single-level three-variable mediation model. Results. Patients with PD cognitive decline exhibited higher plasma NfL levels, decreased regional brain volume, and poor neuropsychiatric subtest results compared with PD patients with normal cognition, with several correlations among these clinical presentations. The mediation model showed that the superior temporal gyrus completely mediated the effects of elevated plasma NfL levels due to the poor psychiatric performance of picture completion and digit span. Conclusion. This study provides insight into the effects of oxidative stress-related plasma abnormal protein aggregate levels on regional brain volume and neuropsychiatric consequences in Parkinson’s disease patients.

The characteristics of host lipid body biogenesis during coral-dinoflagellate endosymbiosis

Intracellular lipid body (LB) biogenesis depends on the symbiosis between coral hosts and their Symbiodinaceae. Therefore, understanding the mechanism(s) behind LB biosynthesis in corals can portentially elucide the drivers of cellular regulation during endosymbiosis. This study assessed LB formation in the gastrodermal tissue layer of the hermatypic coral Euphyllia glabrescens. Diel rhythmicity in LB size and distribution was observed; solar irradiation onset at sunrise initiated an increase in LB formation, which continued throughout the day and peaked after sunset at 18:00. The LBs migrated from the area near the mesoglea to the gastrodermal cell border near the coelenteron. Micro-LB biogenesis occurred in the endoplasmic reticulum (ER) of the host gastrodermal cells. A transcriptomic analysis of genes related to lipogenesis indicated that binding immunoglobulin protein (BiP) plays a key role in metabolic signaling pathways. The diel rhythmicity of LB biogenesis was correlated with ER-localized BiP expression. BiP expression peaked during the period with the largest increase in LB formation, thereby indicating that the chaperoning reaction of abnormal protein folding inside the host ER is likely involved in LB biosynthesis. These findings suggest that the host ER, central to LB formation, potentially facilitates the regulation of endosymbiosis between coral hosts and Symbiodiniaceae.

High Expression of Tumor Abnormal Protein Preoperatively Predicts Poor Prognosis of Patients With Esophageal Squamous Cell Carcinoma

Background: Esophageal squamous cell carcinoma (ESCC) acts as a fatal malignant tumor among human beings and is marked by late-stage diagnosis, frequent recurrence, metastasis, and therapy resistance. Tumor abnormal protein (TAP) remarkably affects cancer development and progression of human cancers. TAP has been shown to be a biomarker for gastric and lung cancer progression. Nevertheless, the clinical value exhibited by TAP for ESCC has not been well-explained in the current literature.Methods: The present study included 183 ESCC cases who received surgical resection and 183 cases who had normal physical checkup from March 2013 to January 2015 at the People's Hospital of Chizhou, and used the TAP detection agent for evaluating the TAP relative level.Results: As found, ESCC patients presented an obviously higher TAP expression relative to cases who had normal physical checkup. Moreover, TAP expression was significantly downregulated after surgery. Furthermore, the TAP expression was correlated with gender, smoking, pathologic differentiation, and pN stage, but not with age, tumor location, surgical type, pT stage, and vascular invasion. High expression of TAP was significantly correlated with poorer overall survival (OS) rate in ESCC patients. TAP was an independent prognostic predictor in ESCC patients, based on the multivariate survival analysis.Conclusion: The study reveals how TAP upregulation promotes ESCC malignant progression, and concludes that TAP acts as the therapeutic target and potential biomarker specific to ESCC.