Machine Learning Classification of Alzheimer's Disease Pathology Reveals Diffuse Amyloid as a Major Predictor of Cognitive Impairment in Human Hippocampal Subregions.

Analyzing Alzheimer's disease (AD) pathology within anatomical subregions is a significant challenge, often carried out by pathologists using a standardized, semi-quantitative approach. To augment traditional methods, a high-throughput, high-resolution pipeline was created to classify the distribution of AD pathology within hippocampal subregions. USC ADRC post-mortem tissue sections from 51 patients were stained with 4G8 for amyloid, Gallyas for neurofibrillary tangles (NFTs) and Iba1 for microglia. Machine learning (ML) techniques were utilized to identify and classify amyloid pathology (dense, diffuse and APP (amyloid precursor protein)), NFTs, neuritic plaques and microglia. These classifications were overlaid within manually segmented regions (aligned with the Allen Human Brain Atlas) to create detailed pathology maps. Cases were separated into low, intermediate, or high AD stages. Further data extraction enabled quantification of plaque size and pathology density alongside ApoE genotype, sex, and cognitive status. Our findings revealed that the increase in pathology burden across AD stages was driven mainly by diffuse amyloid. The pre and para-subiculum had the highest levels of diffuse amyloid while NFTs were highest in the A36 region in high AD cases. Moreover, different pathology types had distinct trajectories across disease stages. In a subset of AD cases, microglia were elevated in intermediate and high compared to low AD. Microglia also correlated with amyloid pathology in the Dentate Gyrus. The size of dense plaques, which may represent microglial function, was lower in ApoE4 carriers. In addition, individuals with memory impairment had higher levels of both dense and diffuse amyloid. Taken together, our findings integrating ML classification approaches with anatomical segmentation maps provide new insights on the complexity of disease pathology in AD progression. Specifically, we identified diffuse amyloid pathology as being a major driver of AD in our cohort, regions of interest and microglial responses that might advance AD diagnosis and treatment.

RNA in extracellular vesicles during adolescence reveal immune, energetic and microbial imprints of early life adversity.

Exposure to early life adversity (ELA), including childhood maltreatment, is one of the most significant risk factors for the emergence of neuropsychiatric disorders in adolescence and adulthood. Despite this relationship being well established, the underlying mechanisms remain unclear. One way to achieve this understanding is to identify molecular pathways and processes that are perturbed as a consequence of childhood maltreatment. Ideally, these perturbations would be evident as changes in DNA, RNA or protein profiles in easily accessible biological samples collected in the shadow of childhood maltreatment. In this study, we isolated circulating extracellular vesicles (EVs) from plasma collected from adolescent rhesus macaques that had either experienced nurturing maternal care (CONT) or maternal maltreatment (MALT) in infancy. RNA sequencing of RNA in plasma EVs and gene enrichment analysis revealed that genes related to translation, ATP synthesis, mitochondrial function and immune response were downregulated in MALT samples, while genes involved in ion transport, metabolism and cell differentiation were upregulated. Interestingly, we found that a significant proportion of EV RNA aligned to the microbiome and that MALT altered the diversity of microbiome-associated RNA signatures found in EVs. Part of this altered diversity suggested differences in prevalence of bacterial species in CONT and MALT animals noted in the RNA signatures of the circulating EVs. Our findings provide evidence that immune function, cellular energetics and the microbiome may be important conduits via which infant maltreatment exerts effects on physiology and behavior in adolescence and adulthood. As a corollary, perturbations of RNA profiles related to immune function, cellular energetics and the microbiome may serve as biomarkers of responsiveness to ELA. Our results demonstrate that RNA profiles in EVs can serve as a powerful proxy to identify biological processes that might be perturbed by ELA and that may contribute to the etiology of neuropsychiatric disorders in the aftermath of ELA.

[Studies of YB-1 protein in breast tumors].

The multifunctional mammalian protein YB-1 is involved in multiple DNA- and mRNA-dependent events in the cell and regulates gene expression at different levels. The intracellular localization and relative mRNA content of YB-1 in the breast tumors were studied. The presence of cells with nuclear YB-1 localization in the tumor cell population is a poor predictor that correlates with larger tumors (more than 5 cm). The high YB-1 mRNA content in the breast tumors promotes metastasis of small neoplasms and patients with breast cancer who have high tumor tissue YB-1 mRNA levels may referred to as an early distant metastasis risk group. The findings suggest that combined determination of YB-1 intercellular localization and mRNA levels can ensure a more reliable prognosis of breast cancer.

[Galavit-induced change of immunologic parameters in patients with non-small lung cancer].

Administration of an immunomodulator, galavit, for stage II-III non-small lung cancer along with standard therapy was followed by immunological vigor improvement by the end of the course. CD3, CD4, IgA, IgM and IgG indices were normal in more than 80% of the study group by day 51 after surgery; CD8, CD20 and HLA-DR--in more than 50%; CD16--in 45.2%. In control, by day 51, normal IgG and HLA-DR levels were reported in 60%. The remaining indices were normal in less than 50%. Our results point to immunological vigor improvement due to use of galavit. The drug is well tolerated, has neither side effects nor toxicity.

[Protective action of leukinferin during radiotherapy of oncologic patients]. / Zashchitnoe deistvie leikinferona pri luchevom lechenii onkologicheskikh bol'nykh.

In clinical observation on 248 patients with breast cancer IIb-III-b stages given radiotherapy on breast gland, parasternal and axillary-subclavian regions (total doses 40 Gr for each) before mastectomy was shown, that use LF im 2-3 times a week through the course of therapy decreases statistically significant pancytopenia, induced by radiation. Quantity leukocytes was even increase in a process of therapy. Frequency of anemia and lyphopenia was decreased almost 3 times. E-RFC were depressed also more slight, then in the group without immunocorrection and after mastectomy practically, restored. IFN-gamma production by T-lymphocytes was not changed and essentially more high then in the comparative group. The presented data are shown, that LF provides a defensive action on hematological indices and immune effectors function in oncological patients during radiotherapy.

[Experience of immunotherapy with leukinferon in the comprehensive therapy of breast cancer]. / Opyt primeneniia immunoterapii leikinferonom v kompleksnom lechenii raka molochnoi zhelezy.

Patients with breast tumors, stage IIb-IIIb, received complex treatment including radiation therapy, radical surgery and polychemotherapy. Some of them were also injected 4-40 doses of leukinferon, im, for immunocorrection. The latter treatment carried out during radiotherapy and preparation for surgery prevented lymphopenia development. Leukinferon administered during 6-8 courses of cytostatic polychemotherapy was followed by a significant rise in lymphocyte concentration. Leukinferon-treated patients, on the whole, revealed higher rates of postoperative rehabilitation, improved tolerance of rigorous treatment and lower frequency of metastatic development. A correlation was established between preoperative lymphocyte level and risk of metastasis development at later stages. No metastasis or recurrence was detected within 15-42 months in 16 patients who received leukinferon throughout the entire period of treatment.