In-silico generation of high-dimensional immune response data in patients using a deep neural network.

Technologies for single-cell profiling of the immune system have enabled researchers to extract rich interconnected networks of cellular abundance, phenotypical and functional cellular parameters. These studies can power machine learning approaches to understand the role of the immune system in various diseases. However, the performance of these approaches and the generalizability of the findings have been hindered by limited cohort sizes in translational studies, partially due to logistical demands and costs associated with longitudinal data collection in sufficiently large patient cohorts. An evolving challenge is the requirement for ever-increasing cohort sizes as the dimensionality of datasets grows. We propose a deep learning model derived from a novel pipeline of optimal temporal cell matching and overcomplete autoencoders that uses data from a small subset of patients to learn to forecast an entire patient's immune response in a high dimensional space from one timepoint to another. In our analysis of 1.08 million cells from patients pre- and post-surgical intervention, we demonstrate that the generated patient-specific data are qualitatively and quantitatively similar to real patient data by demonstrating fidelity, diversity, and usefulness.

Machine learning models of plasma proteomic data predict mood in chronic stroke and tie it to aberrant peripheral immune responses.

Post-stroke depression is common, long-lasting and associated with severe morbidity and death, but mechanisms are not well-understood. We used a broad proteomics panel and developed a machine learning algorithm to determine whether plasma protein data can predict mood in people with chronic stroke, and to identify proteins and pathways associated with mood. We used Olink to measure 1,196 plasma proteins in 85 participants aged 25 and older who were between 5 months and 9 years after ischemic stroke. Mood was assessed with the Stroke Impact Scale mood questionnaire (SIS3). Machine learning multivariable regression models were constructed to estimate SIS3 using proteomics data, age, and time since stroke. We also dichotomized participants into better mood (SIS3 > 63) or worse mood (SIS3 ≤ 63) and analyzed candidate proteins. Machine learning models verified that there is indeed a relationship between plasma proteomic data and mood in chronic stroke, with the most accurate prediction of mood occurring when we add age and time since stroke. At the individual protein level, no single protein or set of proteins predicts mood. But by using univariate analyses of the proteins most highly associated with mood we produced a model of chronic post-stroke depression. We utilized the fact that this list contained many proteins that are also implicated in major depression. Also, over 80% of immune proteins that correlate with mood were higher with worse mood, implicating a broadly overactive immune system in chronic post-stroke depression. Finally, we used a comprehensive literature review of major depression and acute post-stroke depression. We propose that in chronic post-stroke depression there is over-activation of the immune response that then triggers changes in serotonin activity and neuronal plasticity leading to depressed mood.

Depression, Anxiety and Stress Among Indians in Times of Covid-19 Lockdown.

Covid-19 has caused significant distress around the globe. Apart from the evident physical symptoms in infected cases, it has caused serious damage to public mental health. India, like other countries, implemented a nationwide lockdown to contain and curb the transmission of the virus. The current research is an attempt to explore psychological distress among people residing in India during the lockdown. Four hundred and three participants were asked to complete a questionnaire with questions around symptoms of depression, anxiety, stress, and family affluence. The results indicated that people who do not have enough supplies to sustain the lockdown were most affected, and family affluence was found to be negatively correlated with stress, anxiety, and depression. Among different professions, students and healthcare professionals were found to experience stress, anxiety, and depression more than others. Despite the current situation, stress, anxiety, and depression were found to be in normal ranges for mental health professionals highlighting their capabilities to remain normal in times of distress. Policymakers and other authorities may take the assistance of mental health professionals to help overcome psychological issues related to Covid-19.

Illuminating Perspectives: Navigating Eye Care Access in Sub-Saharan Africa Through the Social Determinants of Health.

Ensuring access to proper eye health services is not only a fundamental human right but also crucial for preserving an individual's quality of life, preventing blindness, and promoting overall well-being. This is especially true in low-income countries like Sub-Saharan Africa (SSA) where recognizing the intricate relationship between access to healthcare and social determinants of health (SDOH ) is crucial to addressing health disparities. The goal of this study was to elucidate and highlight not only the barriers millions face in obtaining eye care but also pave the way for interventions and policies aimed at creating equitable access across diverse populations. To do this, a scoping review was conducted across the Cumulated Index to Nursing and Allied Health Literature (CINAHL), Embase, and PubMed databases for studies meeting the search terms and inclusion criteria. The results show that intervention strategies that increase vision care must extend beyond the healthcare sector to address the multifaceted challenges. Collaborating with stakeholders involved in addressing broader livelihood issues, such as food security, education, and SDOH, becomes imperative to ensure comprehensive and sustainable improvements in vision care accessibility in SSA.

Large-scale correlation network construction for unraveling the coordination of complex biological systems.

Advanced measurement and data storage technologies have enabled high-dimensional profiling of complex biological systems. For this, modern multiomics studies regularly produce datasets with hundreds of thousands of measurements per sample, enabling a new era of precision medicine. Correlation analysis is an important first step to gain deeper insights into the coordination and underlying processes of such complex systems. However, the construction of large correlation networks in modern high-dimensional datasets remains a major computational challenge owing to rapidly growing runtime and memory requirements. Here we address this challenge by introducing CorALS (Correlation Analysis of Large-scale (biological) Systems), an open-source framework for the construction and analysis of large-scale parametric as well as non-parametric correlation networks for high-dimensional biological data. It features off-the-shelf algorithms suitable for both personal and high-performance computers, enabling workflows and downstream analysis approaches. We illustrate the broad scope and potential of CorALS by exploring perspectives on complex biological processes in large-scale multiomics and single-cell studies.

A data-driven health index for neonatal morbidities.

Whereas prematurity is a major cause of neonatal mortality, morbidity, and lifelong impairment, the degree of prematurity is usually defined by the gestational age (GA) at delivery rather than by neonatal morbidity. Here we propose a multi-task deep neural network model that simultaneously predicts twelve neonatal morbidities, as the basis for a new data-driven approach to define prematurity. Maternal demographics, medical history, obstetrical complications, and prenatal fetal findings were obtained from linked birth certificates and maternal/infant hospitalization records for 11,594,786 livebirths in California from 1991 to 2012. Overall, our model outperformed traditional models to assess prematurity which are based on GA and/or birthweight (area under the precision-recall curve was 0.326 for our model, 0.229 for GA, and 0.156 for small for GA). These findings highlight the potential of using machine learning techniques to predict multiple prematurity phenotypes and inform clinical decisions to prevent, diagnose and treat neonatal morbidities.

The Expression and Functional Roles of miRNAs in Embryonic and Lineage-Specific Stem Cells.

The discovery of small non-coding RNAs began an interesting era in cellular and molecular biology. To date, miRNAs are the best recognized non-coding RNAs for maintenance and differentiation of pluripotent stem cells including embryonic stem cells (ES), induced pluripotent stem cells (iPSC), and cancer stem cells. ES cells are defined by their ability to self-renew, teratoma formation, and to produce numerous types of differentiated cells. Dual capacity of ES cells for self-renewal and differentiation is controlled by specific interaction with the neighboring cells and intrinsic signaling pathways from the level of transcription to translation. The ES cells have been the suitable model for evaluating the function of non-coding RNAs and in specific miRNAs. So far, the general function of the miRNAs in ES cells has been assessed in mammalian and non-mammalian stem cells. Nowadays, the evolution of sequencing technology led to the discovery of numerous miRNAs in human and mouse ES cells that their expression levels significantly changes during proliferation and differentiation. Several miRNAs have been identified in ectoderm, mesoderm, and endoderm cells, as well. This review would focus on recent knowledge about the expression and functional roles of miRNAs in embryonic and lineage-specific stem cells. It also describes that miRNAs might have essential roles in orchestrating the Waddington's landscape structure during development.

Intracellular hydroxyl radical production induced by recombinant human tumor necrosis factor and its implication in the killing of tumor cells in vitro.

This study investigated the effect of recombinant human tumor necrosis factor (rhTNF) on hydroxyl radical production by established cell lines in vitro, and its implication in the killing of tumor cells by rhTNF. During incubation of TNF sensitive mouse tumorigenic fibroblast L-M cells (2 X 10(7) cells) in the presence of rhTNF (100 U), hydroxyl radical production as detected by the evolution of methane gas from dimethyl sulfoxide increased gradually, at 18 h reaching 1.8 times that in the absence of rhTNF. This increase was dependent on the concentration of rhTNF and was effectively prevented by the simultaneous addition of anti-rhTNF monoclonal antibody III 2F3, which inhibited both the binding of rhTNF to its receptor and the cytotoxic activity of rhTNF. The addition of iron chelator 2,2'-bipyridine, which inhibits iron-catalized Fenton reaction and so inhibits hydroxyl radical generation, suppressed both the increase of hydroxyl radical production and the cytotoxicity induced by rhTNF. A similar increase in hydroxyl radical production in the presence of rhTNF was also detected with TNF-sensitive human myosarcoma-derived KYM cells, but no such increase was detected with TNF insensitive human embryonic lung fibroblast HEL cells. The results show that rhTNF induces increased hydroxyl radical production in TNF-sensitive cells, and suggest that this plays an important role in the mechanism of tumor cell killing by rhTNF.

Synergistic effects of recombinant human tumor necrosis factor and hyperthermia on in vitro cytotoxicity and artificial metastasis.

Synergy in cytotoxic effect between recombinant human tumor necrosis factor and hyperthermia (incubation at 38.5 degrees C or 40 degrees C) was observed to occur against L-M (mouse tumorigenic fibroblast) cells and shown to be related to an accelerated turnover rate of recombinant human tumor necrosis factor-receptor complex under elevated temperatures rather than to changes in number of cell receptors or binding strength. However, no synergy in cytotoxic effect was observed to occur against human embryonic lung (HEL) cells. A clearly synergistic inhibition of metastatic tumor growth by combined administration of recombinant human tumor necrosis factor (300 units) and whole-body hyperthermia (40 degrees C, 30 min) was also observed in BALB/c mice previously given injections of 1 x 10(6) Meth-A (MH) cells/mouse via tail vein, neither of which alone resulted in significant inhibition.

Synergistic cytotoxic and antitumor effects of recombinant human tumor necrosis factor and hyperthermia.

A synergistic increase in the cytotoxic effects of recombinant human tumor necrosis factor (rH-TNF) and hyperthermia was demonstrated both in vitro and in vivo. The cytotoxicity of rH-TNF against L-M cells in incubation for 12 h at 38.5 and 40 degrees C based on the concentration necessary for 50% cytotoxicity was, respectively, 125 and more than 500 times as high as in similar incubation at 37 degrees C. As observed 18 days after implantation of Meth-A fibrosarcoma cells in mice, single i.v. administration of rH-TNF at 1000 units/mouse resulted in complete cures in five mice when performed in combination with hyperthermia (40 degrees C), whereas rH-TNF alone in the same dose resulted in 27.1% inhibition of tumor growth and hyperthermia alone had no appreciable effect on tumor growth. The i.v. administration of rH-TNF three times at 100 or 300 units/mouse together with hyperthermia (40 degrees C) resulted in 41.2 and 89.0% tumor growth inhibition, respectively; similar administration without hyperthermia appeared to have little or no appreciable effect on tumor growth. The results suggest that combination therapy including rH-TNF and hyperthermia may be of value in the treatment of malignancy in human patients.

Toxic effect of tumor necrosis factor on tumor vasculature in mice.

Stereoscopic observation via an implanted sight glass in mice bearing transplanted methylcholanthrene-induced A-cells showed tumorivascular hemorrhage at 1-2 h after tumor necrosis factor (TNF) administration, congestion at 4-6 h, and hemorrhage, congestion, and blood circulation blockage at 24 h. Histological examination after TNF administration to mice bearing similar methylcholanthrene-induced A-cell transplants showed thrombus formation in the tumor vasculature at 4 h and thereafter. Suppression of this thrombus formation with heparin had no apparent influence on the necrotic response, tumor growth inhibition or complete cure rate following TNF administration to mice bearing the methylcholanthrene-induced A-cell tumors. The results suggest that direct toxicity of TNF on tumor vasculature is a factor in the overall antitumor mechanism of TNF.

Induction of synthesis of tumor necrosis factor in human and murine cell lines by exogenous recombinant human tumor necrosis factor.

Treatment of sensitive human myosarcoma cells (KYM-S) with exogenous tumor necrosis factor (r-TNF) resulted in the production of TNF by the cells. The newly synthesized cellular TNF was identified immunologically on Western blots and as a single 1.8-kilobase band on Northern blots. TNF synthesis began within 2 h of administration of the exogenous TNF in a dose-dependent manner. r-TNF also induced TNF synthesis in mouse tumorigenic fibroblasts (L-M). Resistant sublines of these cells as well as TNF nonsensitive human diploid fibroblasts possessed TNF mRNA without pretreatment, indicating an inverse correlation between levels of TNF expressed and sensitivity to the cytotoxic effects of exogenous TNF. It is conceivable that the newly synthesized cellular TNF functions in some protective manner to block cytolytic effects of exogenous TNF.

Expression of endogenous tumor necrosis factor as a protective protein against the cytotoxicity of exogenous tumor necrosis factor.

Based on the finding that expression of endogenous tumor necrosis factor (TNF) which is not detected in TNF-susceptible cells was observed in TNF-resistant cells, the assumption was made that endogenous TNF may be a protective protein against the cytotoxic activity of TNF. In order to confirm this possibility, we investigated the relationship between expression of endogenous TNF and TNF susceptibility by using the gene transfection method. When L-M, TNF-highly sensitive murine fibrosarcoma cells were transfected with a human TNF gene, the stable transfectants expressed endogenous TNF and acquired resistance to TNF. Conversely, when endogenous TNF synthesis was inhibited by introducing an antisense TNF gene into HeLa, TNF-less sensitive human cervical cancer cells, the sensitivity was enhanced. These findings indicate that endogenous TNF is one of the protective factors against the cytotoxic activity of TNF.

Endogenous tumor necrosis factor exerts its protective function intracellularly against the cytotoxicity of exogenous tumor necrosis factor.

Based on the findings that expression of endogenous tumor necrosis factor (enTNF), which is not present in TNF-susceptible cells, was generally observed in TNF-resistant cells and that TNF gene transfection gives rise to TNF resistance, the assumption was made that enTNF may be a protective protein against the cytotoxicity of exogenous TNF. However, it remains unknown whether the protection by enTNF is exerted in an intracellular or extracellular (autocrine) manner. We therefore transfected a nonsecretory human TNF gene (pTNF delta pro) into highly TNF-sensitive mouse tumorigenic fibroblasts (L-M cells) and investigated their TNF susceptibility. The transfectants expressed enTNF which was not secreted into the medium and acquired an appreciable degree of resistance to exogenous TNF. A significant increase in the manganous superoxide dismutase level was also noted in the transfectants. These findings suggest that enTNF exerts its protective function intracellularly by inducing manganous superoxide dismutase production.

Treatment of cerebral radiation necrosis with bevacizumab: the Cleveland clinic experience.

BACKGROUND: Cerebral radiation necrosis (RN) is a devastating complication of radiation therapy for brain tumors. Recent studies have explored the role of bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor in the treatment of RN of the brain. We report 24 patients with cerebral RN who were treated with bevacizumab. MATERIALS AND METHODS: Twenty-four patients diagnosed with cerebral RN and treated with different schedules of bevacizumab between July 2007 and June 2012, were identified from the Cleveland Clinic Brain Tumor and Neuro-Oncology Center's database. Pretreatment and posttreatment magnetic resonance imaging (MRI) studies were compared to evaluate bevacizumab efficacy. RESULTS: Posttreatment MRI demonstrated a radiographic improvement in 23 of 24 patients on the postcontrast T1-weighted MRI and fluid-attenuated inversion-recovery sequences. Using the McDonald criteria, the average change in the T1-weighted postcontrast MRI was a decrease of 48.1%, and the average change in the fluid-attenuated inversion-recovery images was a decrease of 53.7%. There was a mean daily dose reduction of 9.4 mg of dexamethasone after initiation of bevacizumab in patients who were on steroids at the start of bevaciuzmab therapy for RN. Treatment with bevacizumab was well tolerated with only 1 grade 3 adverse event. CONCLUSIONS: The current study demonstrates that bevacizumab treatment results in excellent clinical and radiologic response in patients with RN caused by common forms of radiation therapy. The safety profile of bevacizumab use in RN is acceptable. In the current study, we found no difference between different schedules of bevacizumab in treatment outcomes.

Ectopic choroidal calcification of the eyes of a patient with parathyroid adenoma.

A 39-year-old man was admitted to our hospital complaining of general malaise, polyuria, disturbance of ocular movement and right cervical tumor. Blood examination revealed increased parathyroid hormone, hypercalcemia and hypophosphatemia, suggestive of hyperparathyroidism. Histology of the resected tumor revealed a benign parathyroid adenoma. Ectopic calcifications in the choroid and sclera were noted by computed tomography and further ophthalmological examination. Although ocular calcification in conjunctiva and cornea associated with hyperthyroidism is not unusual, sclerochoroidal calcification has not been reported previously in Japan. The possible cause of this unusual condition in this patient is discussed.

[Mechanisms of production of tumor necrosis factor (TNF)--reconstitution experiment white nude mice].

In order to investigate the role of T cells in the production of tumor necrosis factor (TNF), a reconstitution experiment was performed with nude mice (Balb/c, nu/nu). The results obtained were as follows: The cytotoxic activity of tumor necrosis serum (TNS) from Balb/c, nu/nu mice treated with P. acnes-LPS was 1/22 against that from Balb/c, nu/+ mice. TNF activity increased 14 times in reconstituted nude mice against Balb/c, nu/nu mice. Investigation of the production of the cytotoxic activity per cell was carried out using T cell and macrophage fractions separated from the spleens of both Balb/c, nu/nu and Balb/c, nu/+ mice treated with P. acnes as a priming agent. Elicitation employing LPS was done in vitro. Cytotoxic activity released into culture medium was observed in the macrophage fraction, but not in the T cell fraction. However, no significant difference was shown in species. With P. acnes treatment, the population of macrophages in the spleens from Balb/c, nu/+ mice increased 25.5 times, whereas that from Balb/c, nu/nu mice only increased 6.8 times. The above results suggest that the mechanism of the incremental effect of T cells on TNF production was due to the promotion of macrophage proliferation during the priming period after injection of P. acnes.

[Continuous internalization of TNF receptors in a human myosarcoma cell line].

The cell dynamics of the receptor on tumor necrosis factor (TNF) were studied with the use of TNF-sensitive KYM cells derived from human myosarcoma. With receptor synthesis inhibited by cycloheximide, the half-life of the surface TNF receptor was 2h in the absence of TNF and 30min in its presence, suggesting that the TNF receptor was non-recycling and that its internalization was accelerated by TNF. During cell incubation with suppression of TNF receptor degradation by chloroquine, the number of surface TNF receptors remained approximately constants, but the total number of surface and internal TNF receptors increased gradually, at 3h reaching 1.5 times of the initial number, thus suggesting continuous synthesis, externalization, internalization, and degradation of the TNF receptor in the absence of cycloheximide. When the cells were incubated with 125I-TNF, the intracellular quantity of the pulse-labeled TNF-receptor complex promptly increased, reaching a maximum at 20 min, and then declining gradually. Thus, it was confirmed that the TNF receptor is internalized as a TNF-receptor complex in the presence of TNF. In incubation with suppression of protein synthesis by cycloheximide following surface TNF receptor digestion by trypsin, TNF receptors reappeared on the cell surface, increasing in the number to a peak level at 60 min and gradually decreasing. The cells previously exposed to cycloheximide with or without TNF showed no recurrence of surface TNF receptors, suggesting that the TNF receptor is non-recycling. The results thus suggest that the TNF receptor is continuously internalized and degraded intracellularly by lysosomes without being recycled regardless of the presence or absence of TNF, and further that its internalization is accelerated when it is part of the TNF-receptor complex.

[Anti-tumor effect of human recombinant TNF].

In this article, the clinical effects of rH-TNF on various cancer patients and the mechanism of self-induction of defense against rH-TNF cytotoxicity in tumor cells and the counter measures against this are reviewed. 1) Clinical effects of rH-TNF Intratumoral administration of rH-TNF was performed in 7 patients and clinical efficacy (PR + MR) was observed in 3/7 (42.9%). Also a reduction of leukemia cells in peripheral blood was observed in all 4 leukemia patients following intravenous (i.v.) administration of rH-TNF. Furthermore, in 2 multiple myeloma patients, the myeloma protein and plasma cells in bone marrow were reduced by i.v. administration of rH-TNF. 2) Self-induction of defense against rH-TNF cytotoxicity Investigation of the effect of TNF on RNA and protein synthesis by tumorigenic and normal cell lines showed that their synthesis in tumor cells was increased at 12 h and peaked at 24 h of incubation with TNF, while that in normal diploid fibroblast (HEL) cells was apparently unaffected by the presence of TNF. Artificial inhibition of either RNA or protein synthesis by L-M cells, upon addition of Act D or CHI increased the cytotoxic effect of TNF, thus suggesting that the elevated RNA and protein synthesis is related not to the cytotoxic reaction itself but rather to a defense mechanism. Similar incubation of HEL cells with TNF in the presence of either inhibitor resulted in the occurrence of cytotoxicity not observed with TNF alone, thus suggesting the existence of a defense mechanism in normal, TNF-resistant cells which is absent or greatly weakened in tumor cells. 3) Combination therapy of rH-TNF with various anticancer drugs. A synergistic increase in the cytotoxic effects of rH-TNF and anti-cancer drugs was demonstrated in vitro The cytotoxicity of rH-TNF against L-M cells in combination with MMC, ADM, Ara-C, ACD, DM, CDDP, VCR and 5-FU was 4 to 347 times as high as that of rH-TNF alone. These results suggest that combination therapy including rH-TNF and anti-cancer drugs may be of value in the treatment of malignancy in human patients.

[Analysis of the TNF receptor in KYM cells by affinity cross-linking].

We investigated the identity of the TNF receptor on the KYM cell membrane by cross-linking 125I-TNF and the presumed receptor site with DSS, and subjecting the TNF-receptor complex to electrophoresis. Four specific bands were observed at 145 K, 50 K, 35 K, and 17 K, and those at 50 K, 35 K and 17 K being consistent with trimers, dimers and monomers of TNF, respectively. The 145 K band disappeared after addition of excess unlabelled TNF or anti-human recombinant TNF monoclonal antibody (IV3-E), which quenched the cytotoxic activity of TNF and inhibited the TNF binding to the receptor. The molecular weight of native TNF as estimated by gel filtration was 45 K and this observation showed that native TNF existed only as the TNF trimer. These results confirmed that 95K, i.e., the difference between 145 K and 50 K, is the molecular size of the TNF receptor.