Reduced gene dosage of ribosomal protein subunits has been implicated in 5q؊ myelodysplastic syndrome and Diamond Blackfan anemia, but the cellular and pathophysiologic defects associated with these conditions are enigmatic. Using conditional inactivation of the ribosomal protein S6 gene in laboratory mice, we found that reduced ribosomal protein gene dosage recapitulates cardinal features of the 5q؊ syndrome, including macrocytic anemia, erythroid hypoplasia, and megakaryocytic dysplasia with thrombocytosis, and that p53 plays a critical role in manifestation of these phenotypes. The blood cell abnormalities are accompanied by a reduction in the number of HSCs, a specific defect in late erythrocyte development, and suggest a disease-specific ontogenetic pathway for megakaryocyte development. Further studies of highly purified HSCs from healthy patients and from those with myelodysplastic syndrome link reduced expression of ribosomal protein genes to decreased RBC maturation and suggest an underlying and common pathophysiologic pathway for additional subtypes of myelodysplastic syndrome. (Blood. 2011;118(13):3622-3633) IntroductionMyelodysplastic syndrome (MDS) is a heterogeneous group of blood cell disorders characterized by defective hematopoiesis and increased susceptibility to leukemia; it is thought to involve abnormalities in HSCs. Approximately 50% of affected patients have blood cell cytogenetic abnormalities, of which deletions of chromosome 5q are the most common and portend a favorable prognosis. 1 Identification of causal genes in 5qϪ and other MDS subtypes has been challenging, but recent advances in genetics and genomics have enhanced our understanding of how specific chromosomal alterations and their molecular consequences contribute to the pathogenesis of MDS. 2,3 On the basis of a large-scale RNAi screen, Ebert et al identified RPS14 as a critical gene on 5q whose hemizygosity in BM cells recapitulates many of the features in 5qϪ MDS. 2 Intriguingly, erythroid abnormalities in 5qϪ MDS are similar to those in Diamond Blackfan anemia (DBA), a dominantly inherited disorder in which germline mutations in one allele of either a 40S (encoded by RPS genes) or a 60S (encoded by the RPL genes) ribosomal protein gene have been identified. 4,5 However, there are also important differences between the blood cell phenotypes of the 2 conditions; thrombocytosis and megakaryocytic dysplasia are cardinal features of 5qϪ MDS but not of DBA. Furthermore, recent work from Starczynowski et al suggests that 2 microRNAs are critical mediators of the 5qϪ phenotype because knockdown of these genes in immature hematopoietic cells leads to megakaryocytic dysplasia and thrombocytosis after transplantation in mice. 6 Increased understanding of how ribosomal protein mutations cause disease might provide additional insight into the pathogenesis of MDS and DBA.Spontaneous and induced ribosomal protein mutations have been studied in many model organisms, including yeast, flies, plants, fish, and mice. [7][8][9][10][11][12][13] ...

The myelodysplastic syndromes (MDS) represent a group of clonal disorders that result in ineffective hematopoiesis and are associated with an increased risk of transformation into acute leukemia. MDS arises from hematopoietic stem cells (HSCs); therefore, successful elimination of MDS HSCs is an important part of any curative therapy. However, current treatment options, including allogeneic hematopoietic cell transplantation (HCT), often fail to ablate disease-initiating MDS HSCs, and thus have low curative potential and high relapse rates. Here, we demonstrate that human HSCs can be targeted and eliminated by monoclonal antibodies (mAbs) that bind cell-surface CD117 (c-Kit). We show that an anti-human CD117 mAb, SR-1, inhibits normal cord blood and bone marrow HSCs in vitro. Furthermore, SR-1 and clinical-grade humanized anti-human CD117 mAb, AMG 191, deplete normal and MDS HSCs in vivo in xenograft mouse models. Anti-CD117 mAbs also facilitate the engraftment of normal donor human HSCs in MDS xenograft mouse models, restoring normal human hematopoiesis and eradicating aggressive pathologic MDS cells. This study is the first to demonstrate that anti-human CD117 mAbs have potential as novel therapeutics to eradicate MDS HSCs and augment the curative effect of allogeneic HCT for this disease. Moreover, we establish the foundation for use of these antibody agents not only in the treatment of MDS but also for the multitude of other HSC-driven blood and immune disorders for which transplant can be disease-altering.

The severe acute respiratory syndrome-novel coronavirus mediated COVID-19 has been recently declared a pandemic by the World Health Organization. The primary target of the SARS-CoV-2 virus is the human lungs governed by the ACE-2 receptor of epithelial type II cells/endothelial cells, which promote modulation of the immune response of host cells through generating cytokine storm, inflammation, severe pneumonia symptoms, and secondary complications such as acute respiratory distress syndrome. Although numerous antiviral and anti-parasitic drugs are under clinical trials to combat this pandemic, to date, neither a specific treatment nor any successful vaccine has been established, urging researchers to identify any potential candidate for combating the disease. Mesenchymal stem cells own self-renewal, differentiation, homing, immunomodulation and remains unaffected by the coronavirus on the virtue of the absence of ACE-2 receptors, indicating that MSC's could be used an ameliorative approach for COVID-19. MSCs have shown to combat the disease via various pathways such as repairing the lung epithelial and endothelial cells, reducing hyperimmune response, maintaining the renin-angiotensin system. Although MSCs-based treatment approaches for COVID-19 is still under consideration with limited data, many human clinical trials of MSC's has been initiated to explore their potential for COVID 19 treatment. The current review summarizes and emphasizes on how MSC's modulate the immune response, can repair the lungs from the impact of the virus, and various aspects of MSC's as a remedial source for COVID-19, to provide better insight for biomedical researchers and for those who are fascinated by stem cells as a therapeutic approach.

Ageratum conyzoides L. (Family—Asteraceae) is an annual aromatic invasive herb, mainly distributed over the tropical and subtropical regions of the world. It owns a reputed history of indigenous remedial uses, including as a wound dressing, an antimicrobial, and mouthwash as well as in treatment of dysentery, diarrhea, skin diseases, etc. In this review, the core idea is to present the antifungal potential of the selected medicinal plant and its secondary metabolites against different fungal pathogens. Additionally, toxicological studies (safety profile) conducted on the amazing plant A. conyzoides L. are discussed for the possible clinical development of this medicinal herb. Articles available from 2000 to 2020 were reviewed in detail to exhibit recent appraisals of the antifungal properties of A. conyzoides. Efforts were aimed at delivering evidences for the medicinal application of A. conyzoides by using globally recognized scientific search engines and databases so that an efficient approach for filling the lacunae in the research and development of antifungal drugs can be adopted. After analyzing the literature, it can be reported that the selected medicinal plant effectively suppressed the growth of numerous fungal species, such as Aspergillus, Alternaria, Candida, Fusarium, Phytophthora, and Pythium, owing to the presence of various secondary metabolites, particularly chromenes, terpenoids, flavonoids and coumarins. The possible mechanism of action of different secondary metabolites of the plant against fungal pathogens is also discussed briefly. However, it was found that only a few studies have been performed to demonstrate the plant’s dosage and safety profile in humans. Considered all together, A. conyzoides extract and its constituents may act as a promising biosource for the development of effective antifungal formulations for clinical use. However, in order to establish safety and efficacy, additional scientific research is required to explore chronic toxicological effects of ageratum, to determine the probability of interactions when used with different herbs, and to identify safe dosage. The particulars presented here not only bridge this gap but also furnish future research strategies for the investigators in microbiology, ethno-pharmacology, and drug discovery.

Introduction: Central nervous system (CNS) neoplasms, in India, constitute 1.9% of all cancers and in U.S. adults-2% of all cancers. Many of the non-neoplastic CNS lesions can clinically & radiologically simulate brain tumours. In such cases, histopathological examination (HPE) can be helpful in differentiating between neoplastic and non-neoplastic etiologies. Materials and Methods: This retrospective descriptive study of histopathological analysis of brain tumours was carried out in TMMC&RC, Department of Pathology from January 2015 to December 2018. The biopsies were processed by routine histological techniques and H&E stained sections were analyzed. Special stains and IHC were performed wherever appropriate. The diagnosed brain tumours were classified according to WHO 2016 classification system. Results: A total of 96 CNS biopsies were studied. The neoplasms constituted 62 (64.6%) cases, which included 60 (96.8%) primary, 1 (1.6%) metastatic and 1 miscellaneous lesion (1.6%). The 3 most common primary tumours were Astrocytic tumours, Schwannomas and Meningiomas. About 34(35.4%) cases were non neoplastic out of which the 2 most common lesions were: Cystic Lesions and non-specific inflammation. Patients' age ranged from 5 days to 80 years. The ratio of number of male and female patients was 1:1.67. IHC for Glial Fibrillary Acidic Protein (GFAP) was positive in astrocytomas and mixed neuronal-glial tumours. Conclusion: The present study provides information regarding the spectrum and frequency of various CNS lesions in our area and concludes that histological examination of biopsies is gold standard for accurate diagnosis of various lesions of CNS when coupled with radiological and clinical data.