Placental Exosomes Trigger Maternal Inflammation and Vascular Dysfunction in Preeclampsia

Preeclampsia is a pregnancy-specific disease associated with inadequate placental formation, chronic inflammation, and maternal vascular dysfunction. Preeclampsia affects about 5-8% of pregnant women and it is a prevalent cause of maternal mortality. The level and composition of exosomes in the maternal circulation are altered in preeclampsia, and studies have shown that the major source of this greater level of exosomes is the placenta. We propose that exosomal contents from the placenta trigger maternal inflammation and vascular dysfunction, thereby exacerbating the disease progression. This mini-review will focus on the content of placental exosomes and how they could contribute to the development of preeclampsia.

Cell Therapy for Neurological Disorders: The Perspective of Promising Cells

Neurological disorders are big public health challenges that are afflicting hundreds of millions of people around the world. Although many conventional pharmacological therapies have been tested in patients, their therapeutic efficacies to alleviate their symptoms and slow down the course of the diseases are usually limited. Cell therapy has attracted the interest of many researchers in the last several decades and has brought new hope for treating neurological disorders. Moreover, numerous studies have shown promising results. However, none of the studies has led to a promising therapy for patients with neurological disorders, despite the ongoing and completed clinical trials. There are many factors that may affect the outcome of cell therapy for neurological disorders due to the complexity of the nervous system, especially cell types for transplantation and the specific disease for treatment. This paper provides a review of the various cell types from humans that may be clinically used for neurological disorders, based on their characteristics and current progress in related studies.

Biosimulation Using the Cellworks Computational Omics Biology Model (CBM) Identifies Genomic and Molecular Markers for Decitabine (DAC) Plus Valproic-Acid (VPA) Treatment Response in Patients with Myelodysplastic Syndromes (MDS)

Background: DNA methyltransferase inhibition (DNMTi) with hypomethylating agents (HMA), azacitidine (AZA) or decitabine (DAC), remains the mainstay of therapy for most high-risk Myelodysplastic syndrome (MDS) patients. However, only 40-50% of MDS patients achieve clinical improvement with DNMTi. Previously, combinations of HMA and histone deacetylase (HDAC) inhibitors have been explored in MDS with varying clinical outcomes. However, the heterogeneity of genomic aberrations in MDS portend widely divergent responses from HDAC inhibition, implying that a predictive clinical decision support tool could select patients most likely to benefit from this combination. We explored the molecular basis of observed clinical response in a group of patients treated with DAC and Valproic-Acid (VPA). Method: 16 MDS patients with known clinical responses to DAC + VPA were selected for study from the Cellworks patient repository. The aberration and copy number variations from individual cases served as input into the Computational Omics Biology Model, a computational multi-omic biology software model largely created using literature sourced from PubMed, to generate a patient-specific protein network map. Disease biomarkers unique to each patient were identified within these maps. The Cellworks Biosimulation Platform has the capacity to biosimulate disease phenotypic behavior and was used to create a patient-specific disease model. Biosimulations were then conducted on each patient-specific disease model to measure the effect of DAC + VPA according to a cell growth score. This score was comprised of a composite of cell proliferation, viability, apoptosis, metastasis, and other cancer hallmarks. Biosimulation of drug response was conducted to identify and predict therapeutic efficacy. Results: In the biosimulation, VPA is a relatively weak HDAC inhibitor, but it also inhibits GSK3B and in turn increases beta-catenin (CTNNB1) levels. Additionally, monosomy 7 associated with loss of CAV1, HIPK2, and TRRAP also causes high CTNNB1, thereby further contributing to drug resistance. Biosimulation correctly identified that 7 of 8 patients with these genomic findings were clinical non-responders (NR) to VPA, indicating that CTNNB1 status is likely to predict treatment failure from the VPA + HMA combination in this disease. Notably, CTNNB1 levels have been reported to foster an immune-evasive tumor microenvironment resistant to CTL activation. By contrast, high levels of c-MYC predict response to VPA + HMA combination. VPA inhibits MYC transcription and thereby reduces MYC-induced downregulation of p21 through CKS1B. Additionally MYC is a transcriptional regulator of DNMT1 which is degraded after hyperacetylation induced by HDAC3 inhibition suggesting that VPA also enhances DNMT1 turnover. One patient analyzed had trisomy 8 resulting in c-MYC over-expression and responded to HMA + VPA. Additionally, other aberrations enhancing c-MYC transcription such as copy number variant (CNV) loss of MXI1, HHEX, FBXW7, SMAD7 or CNV gain of BRD4, BCL7B led to high clinical response to the combination (Table 1). By comparison to the CTNNB1-driven subset, the impact of VPA on CTNNB1 in the MYC-dominant disease network did not negate the benefit of VPA for these patients. Additionally, the inhibition of GSK3B by VPA leading to diminished FBXW7 and less ubiquitin-mediated turnover of c-MYC was not sufficient to overcome the inhibition of MYC transcription and HDAC3i-mediated turnover. Immune activation has become a recognized mechanism of responsiveness to HMA. However, among patients with upregulated CTNNB1, VPA is likely to further decrease response to treatment. By contrast, among MYC-driven cancers that are typically immune-evasive, VPA appears to be a vital mechanism of overcoming MYC-driven immune evasion. Conclusion: Signaling pathway consequences related to CTNNB1 and c-MYC upregulation predict response to DAC + VPA. Although HMA plus HDAC inhibition can be generally beneficial for MDS, variable mechanisms of action among various HDAC inhibitors and unique patient disease characteristics should be considered for optimal treatment selection. Finally, CTNNB1 emerged from the Cellworks biosimulations as a therapeutically relevant target in MDS that determines whether VPA synergizes or antagonizes the effect of other agents in this challenging subtype of MDS. Figure 1 Figure 1. Disclosures Castro: Caris Life Sciences Inc.: Consultancy; Omicure Inc: Consultancy; Cellworks Group Inc.: Current Employment; Exact sciences Inc.: Consultancy; Guardant Health Inc.: Speakers Bureau; Bugworks: Consultancy. Kumar: Cellworks Group Inc.: Current Employment. Grover: Cellworks Group Inc.: Current Employment. Patil: Cellworks Group Inc.: Current Employment. Kapoor: Cellworks Group Inc.: Current Employment. Agrawal: Cellworks Group Inc.: Current Employment. Sauban: Cellworks Group Inc.: Current Employment. Prasad: Cellworks Group Inc.: Current Employment. Basu: Cellworks Group Inc.: Current Employment. Suseela: Cellworks Group Inc.: Current Employment. Kumar: Cellworks Group Inc.: Current Employment. Nair: Cellworks Group Inc.: Current Employment. Kumari: Cellworks Group Inc.: Current Employment. Pampana: Cellworks Group Inc.: Current Employment. Ullal: Cellworks Group Inc.: Current Employment. Azam: Cellworks Group Inc.: Current Employment. Prasad: Cellworks Group Inc.: Current Employment. Amara: Cellworks Group Inc.: Current Employment. Sahu: Cellworks Group Inc.: Current Employment. Raveendaran: Cellworks Group Inc.: Current Employment. Veedu: Cellworks Group Inc.: Current Employment. Mundkur: Cellworks Group Inc: Current Employment. Patel: Cellworks Group Inc.: Current Employment. Christie: Cellworks Group Inc.: Current Employment. Macpherson: Cellworks Group Inc.: Current Employment. Howard: Servier: Consultancy; Cellworks Group Inc.: Consultancy; Sanofi: Consultancy, Other: Speaker fees.

Acute Liver Failure due to Hepatitis A Virus

Acute liver failure (ALF) is a syndrome, rather than a specific disease, with several possible causes, and viral hepatitis is a major cause. The relationship between self-limited and ALF hepatitis A is still poorly understood. A 45-year-old woman presented to our hospital with ALF diagnosis (from another hospital). She suffered from hospital-acquired pneumonia. The patient recovered within 4 weeks and returned to her normal life after 6 months of follow-up.

Personalized Drug-Disease prediction using Multiple Linear Regression with ReLU

Predicting models for personalized Drugs related to specific disease are essential, as traditional methods are expensive and time consuming. The most challenging task in personalized medicine is predicting the status of disease from high dimensionality data. In the biomedical domain the association between drugs and disease plays a vital role as the same drug may treat similar diseases. For the good adaptability to complex and nonlinear behaviour data, Multiple Linear Regression method with ReLU Activation function is used for calculation and to fit the model with Drug –Disease dataset. Based on the results the drug or combination of drugs that treat a specific disease is predicted efficiently.

Mesenchymal stem/stromal cell therapy in atopic dermatitis and chronic urticaria: immunological and clinical viewpoints

Allergic diseases are immune-mediated diseases. Allergies share a common immunopathogenesis, with specific differences according to the specific disease. Mesenchymal stem/stromal cells (MSCs) have been applied to people suffering from allergic and many other diseases. In this review, the immunologic roles of MSCs are systemically reviewed according to disease immunopathogenesis from a clinical viewpoint. MSCs seem to be a promising therapeutic modality not only as symptomatic treatments but also as causative and even preventive treatments for allergic diseases, including atopic dermatitis and chronic urticaria.

A literary study of purvarupa (prodromal features ) w. s. r. to prameha vyadhi purvarupa.

In Ayurvedic science, diagnosis of the disease is done with help of Nidan Panchakaaa. In five-fold examination, Purvarupa is one of the component parts of Nidan Panchaka. Purvarupa means Prodromal features of diseases. Any disease does not appear suddenly. Time taken between etiological factors intake to the appearance of specific disease is of Purvarupa. They are premonitory features that manifest before the actual emergence of disease. These symptoms could be doshik or adoshik. Purvarupa are of two types, general and specific. Careful understanding of Purvarupa helps in the differential diagnosis of diseases. Purvarupa also helps to determine the prognosis of any disease. The appearance of all Purvarupa of any disease is considered a bad prognosis because it means the disease is incurable. At Purvarupa stage, treatment modalities for any disease are simpler or easier. So the knowledge of Purvarupa is essential. In samhitas the Purvarupa (Prodromal features )of Prameha vyadhi is described very well. As the Prameha vyadhi is asadhya in its chronic stage as well as it may cause many serious complications if it is not treated and controlled in the early stage, it is very important to know the disease in very primary stage.This is possible by detecting the prameha Purvarupas in patient earlier. So that we can diagnose this stage and can prevent developing it further in vyaktavastha. So in this review study, an attempt is made to elaborate on the importance of Purvarupas and to compile the Purvarupas of Prameha from all ayurvedic samhitas.

The diverse bioactivity of α-mangostin and its therapeutic implications

α-Mangostin is a xanthone natural product isolated as a secondary metabolite from the mangosteen tree. It has attracted a great deal of attention due to its wide-ranging effects on certain biological activity, such as apoptosis, tumorigenesis, proliferation, metastasis, inflammation, oxidation, bacterial growth and metabolism. This review focuses on the key pathways directly affected by α-mangostin and how this varies between disease states. Insight is also provided, where investigated, into the key structural features of α-mangostin that produce these biological effects. The review then sheds light on the utility of α-mangostin as a investigational tool for certain diseases and demonstrate how future derivatives may increase selectivity and potency for specific disease states.

Quantitative Analysis of Knee Radiography

The most common orthopedic illness in the worldwide, osteoarthritis (OA), affects mainly hand, hip, and knee joints. OA invariably leads to surgical intervention, which is a huge burden on both the individual and the society. There are numerous risk factors that contribute to OA, although the pathogenesis of OA and the molecular basis of through such are unknown at this time. OA is presently identified with an analyses were used to examine and, if required, corroborated through imaging - a radiography study. These traditional methods, on the other hand, are not susceptible to sense the beginning phases of OA, making the creation of precautionary interventions for specific disease problematic. As a result, other approaches which might permit for the timely identification of OA are needed. As a result, computerized perception algorithms give measurable indicators that may be used to determine the severity of OA from photographs in an automated and systematic manner. The study of Knee radiography and its quantitative analysis is analyzed in this paper.