The Role of N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies

Epigenetics is identified as the study of heritable modifications in gene expression and regulation that do not involve DNA sequence alterations, such as DNA methylation, histone modifications, etc. Importantly, N6-methyladenosine (m6A) methylation modification is one of the most common epigenetic modifications of eukaryotic messenger RNA (mRNA), which plays a key role in various cellular processes. It can not only mediate various RNA metabolic processes such as RNA splicing, translation, and decay under the catalytic regulation of related enzymes but can also affect the normal development of bone marrow hematopoiesis by regulating the self-renewal, proliferation, and differentiation of pluripotent stem cells in the hematopoietic microenvironment of bone marrow. In recent years, numerous studies have demonstrated that m6A methylation modifications play an important role in the development and progression of hematologic malignancies (e.g., leukemia, lymphoma, myelodysplastic syndromes [MDS], multiple myeloma [MM], etc.). Targeting the inhibition of m6A-associated factors can contribute to increased susceptibility of patients with hematologic malignancies to therapeutic agents. Therefore, this review elaborates on the biological characteristics and normal hematopoietic regulatory functions of m6A methylation modifications and their role in the pathogenesis of hematologic malignancies.

Experimenter sex modulates mouse biobehavioural and pharmacological responses

Differential rodent responses to the sex of human experimenters could have far reaching consequences in preclinical studies. Here, we show that the sex of human experimenters affects mouse behaviours and responses to the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. We found that mice manifest aversion to human male odours, preference to female odours, and increased susceptibility to stress when handled by male experimenters. This male induced aversion and stress susceptibility is mediated by the activation of brain corticotropin-releasing factor (CRF) neurons projecting from the entorhinal cortrex to hippocampal area CA1. We further establish that exposure to male scent prior to ketamine administration activates CRF neurons projecting from the entorhinal cortex to hippocampus, and that CRF is necessary and sufficient for the in vivo and in vitro actions of ketamine. Further understanding of the specific and quantitative contributions of the sex of human experimenters to different experimental outcomes in rodents may lead not only to reduced heterogeneity between studies, but also increased capability to uncover novel biological mechanisms.

A literature review on osteoporosis risk factors and prevention: the importance of an early approach

Osteoporosis is a condition characterized by deterioration of bone microarchitecture resulting in loss of total bone mass, decreased tissue resistance and increased susceptibility to fractures. The study in question aimed to analyze and debate the risk factors and the effectiveness of forms of prevention related to osteoporosis, given their implication for the general population and the need to disseminate safe and effective forms of behavioral management that can contribute to the decrease in the condition, mainly in the most susceptible individual. For this, 42 articles indexed in Bireme, PubMed, Scielo and UpToDate platforms were selected for discussion of the topic. Thus, it was concluded that the need for active investigation of risk factors by health professionals, as well as the encouragement of preventive practices, especially in the population with higher incidence of the disease.

Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

HAS2 is a member of the gene family encoding the hyaluronan synthase 2, which can generate high-molecular-weight hyaluronan (HMW-HA). Our previous study identified HAS2 as a candidate gene for increased susceptibility to adult asthma. However, whether HAS2 dysfunction affects airway remodeling and steroid insensitivity is still limited. Therefore, this study aimed to clarify the Has2 dysfunction, triggering severe airway remodeling and steroid insensitivity in a murine model of asthma. Has2 heterozygous-deficient (Has2+/−) mice and their wild-type littermates have been evaluated in a model of chronic ovalbumin (OVA) sensitization and challenge. Mice present a higher sensitivity to OVA and higher IL-17 release as well as eosinophilic infiltration. RNA sequencing demonstrated the downregulation of EIF2 signaling pathways, TGF-β signaling pathways, and heat shock proteins with Th17 bias in Has2+/−-OVA mice. The combined treatment with anti-IL-17A antibody and dexamethasone reduces steroid insensitivity in Has2+/−-OVA mice. Has2 attenuation worsens eosinophilic airway inflammation, airway remodeling, and steroid insensitivity. These data highlight that HAS2 and HMW-HA are important for controlling intractable eosinophilic airway inflammation and remodeling and could potentially be exploited for their therapeutic benefits in patients with asthma.

Acute Rhino-orbital-cerebral Mucormycosis in a Patient with COVID – 19

COVID-19 patients are known to have immunosuppression due to decreased lymphocytes and increased susceptibility to co-infections (Bacterial and fungal). We present a case of 61-year-old patient who had diabetes, hypertension and ischemic heart disease with COVID-19 infection admitted after RT-PCR positive result. He developed rhino-orbital Mucormycosis during treatment. He received Remdesivir with parenteral Methylprednisolone and Meropenem. While admitted in the ward, he developed signs of orbital cellulitis. Magnetic resonance imaging (MRI) of the brain, orbits, and paranasal sinuses revealed right frontal, ethmoidal, and maxillary sinusitis with the extension of the sinisuidal disease to the orbit. A nasal biopsy revealed broad aseptate filamentous fungal hyphae suggestive of Mucormycosis. Long-term use of steroids/monoclonal antibodies/broad-spectrum antibiotics may contribute to the predisposition to fungal disease. Early diagnosis and prompt management are warranted to avoid morbidity. Key Words: Mucormycosis, COVID – 19, Orbital Cellulitis.

Human leukocyte antigen Class II alleles associated with acral lentiginous melanoma in Mexican Mestizo patients: A case-control study

Background: Melanoma is an aggressive cutaneous cancer. Acral lentiginous melanoma is a melanoma subtype arising on palms, soles, and nail-units. The incidence, prevalence and prognosis differ among populations. The link between expression of major histocompatibility complex Class II alleles and melanoma progression is known. However, available studies report variable results regarding the association of melanoma with specific HLA Class II loci. Aims: The aim of the study was to determine HLA Class II allele frequencies in acral lentiginous melanoma patients and healthy Mexican Mestizo individuals. Methods: Eighteen patients with acral lentiginous melanoma and 99 healthy controls were recruited. HLA Class II typing was performed based on the sequence-specific oligonucleotide method. Results: Three alleles were associated with increased susceptibility to develop acral lentiginous melanoma, namely: HLA-DRB1*13:01; pC = 0.02, odds ratio = 6.1, IC95% = 1.4–25.5, HLA-DQA1*01:03; pC = 0.001, odds ratio = 9.3, IC95% = 2.7–31.3 and HLA-DQB1*02:02; pC = 0.01, odds ratio = 3.7, IC95% = 1.4–10.3. Limitations: The small sample size was a major limitation, although it included all acral lentiginous melanoma patients seen at the dermatology department of Dr. Manuel Gea González General Hospital during the study period. Conclusion: HLA-DRB1*13:01, HLA-DQB1*02:02 and HLA-DQA*01:03 alleles are associated with increased susceptibility to develop acral lentiginous melanoma in Mexican Mestizo patients.

Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora

Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates—the so-called Lafora Bodies (LBs)—in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain.

Bone Marrow Harbors a Unique Population of Dendritic Cells with the Potential to Boost Neutrophil Formation upon Exposure to Fungal Antigen

Apart from controlling hematopoiesis, the bone marrow (BM) also serves as a secondary lymphoid organ, as it can induce naïve T cell priming by resident dendritic cells (DC). When analyzing DCs in murine BM, we uncovered that they are localized around sinusoids, can (cross)-present antigens, become activated upon intravenous LPS-injection, and for the most part belong to the cDC2 subtype which is associated with Th2/Th17 immunity. Gene-expression profiling revealed that BM-resident DCs are enriched for several c-type lectins, including Dectin-1, which can bind beta-glucans expressed on fungi and yeast. Indeed, DCs in BM were much more efficient in phagocytosis of both yeast-derived zymosan-particles and Aspergillus conidiae than their splenic counterparts, which was highly dependent on Dectin-1. DCs in human BM could also phagocytose zymosan, which was dependent on β1-integrins. Moreover, zymosan-stimulated BM-resident DCs enhanced the differentiation of hematopoietic stem and progenitor cells towards neutrophils, while also boosting the maintenance of these progenitors. Our findings signify an important role for BM DCs as translators between infection and hematopoiesis, particularly in anti-fungal immunity. The ability of BM-resident DCs to boost neutrophil formation is relevant from a clinical perspective and contributes to our understanding of the increased susceptibility for fungal infections following BM damage.

Examining the Executioners, Influenza Associated Secondary Bacterial Pneumonia

Influenza infections typically present mild to moderate morbidities in immunocompetent host and are often resolved within 14 days of infection onset. Death from influenza infection alone is uncommon; however, antecedent influenza infection often leads to an increased susceptibility to secondary bacterial pneumonia. Bacterial pneumonia following viral infection exhibits mortality rates greater than 10-fold of those of influenza alone. Furthermore, bacterial pneumonia has been identified as the major contributor to mortality during each of the previous four influenza pandemics. Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pyogenes are the most prevalent participants in this pathology. Of note, these lung pathogens are frequently found as commensals of the upper respiratory tract. Herein we describe influenza-induced host-changes that lead to increased susceptibility to bacterial pneumonia, review virulence strategies employed by the most prevalent secondary bacterial pneumonia species, and highlight recent findings of bacterial sensing and responding to the influenza infected environment.

Implications of Vitamins in COVID-19 Prevention and Treatment through Immunomodulatory and Anti-Oxidative Mechanisms

Since the appearance of the coronavirus disease 2019 (COVID-19) and its announcement as a global pandemic, the search for prophylactic and therapeutic options have become a priority for governments and the scientific community. The approval of several vaccines against SARS-CoV-2 is being crucial to overcome this situation, although the victory will not be achieved while the whole population worldwide is not protected against the virus. This is why alternatives should be studied in order to successfully support the immune system before and during a possible infection. An optimal inflammatory and oxidative stress status depends on an adequate diet. Poor levels of several nutrients could be related to an impaired immune response and, therefore, an increased susceptibility to infection and serious outcomes. Vitamins exert a number of anti-microbial, immunomodulatory, anti-inflammatory, and antioxidant activities, which can be of use to fight against this and several other diseases (especially vitamin D and C). Even though they cannot be considered as a definitive therapeutic option, in part owing to the lack of solid conclusions from well-designed clinical trials, currently available evidence from similar respiratory diseases may indicate that it would be rational to deeply explore the use of vitamins during this global pandemic.