Interferon-gamma plasma levels and presence of mouse mammary tumor virus-like env gene: Implications on the pathogenesis of breast cancer.

Mouse mammary tumor virus (MMTV) is a retrovirus that has been associated with the development of breast cancer (BC) in mice. The identification of a 95% homologous gene sequence to MMTV in human BC samples has increased interest in this hypothesis. This virus in humans received the name of mouse mammary tumor virus-like (MMTV-like). Several cytokines may be involved in the interactions between MMTV and the immune system, such as interferon-gamma (IFN-γ), which can enhance Th1-mediated antitumor immune response but it can also play a protumorigenic role by transmitting antiapoptotic and proliferative signals. Little is known about the antiviral immune response in a microenvironment with the presence of MMTV-like in BC patients. Therefore, the purpose of the present study was to quantify the plasma levels of IFN-γ in the peripheral blood of 123 neoplasia-free donors and 98 BC patients of different molecular subtypes, by enzyme-linked immunosorbent assay (ELISA), and evaluate the association of these plasma levels with the detection of the MMTV-like env gene in tumor tissue. Correlation analyzes involving IFN-γ plasma levels and clinical-pathological parameters were performed by Kendall Tau-c test. In our study, a decrease in IFN-γ levels was observed in the group of BC patients (30.85 ± 57.49 pg/ml) compared to the control group (115.00 ± 176.80 pg/ml) (p < 0.0001). In the analysis by stratified BC molecular subtypes, Luminal-A (30.79 ± 61.04 pg/ml; p < 0.0001), Luminal-B (24.74 ± 25.78 pg/ml; p = 0.0188) and triple-negative (23.95 ± 40.45 pg/ml; p = 0.0005) had a lower plasma level compared to control group. There was no significant difference between IFN-γ plasma levels of MMTV-like DNA positive samples compared to MMTV-negative samples (p = 0.2056). In general BC, patients with larger tumor size had higher IFN-γ plasma levels (Tau-c = 0.202; p = 0.019). By analyzing the MMTV-like env negative samples, we could identify that IFN-γ plasma levels were higher in larger tumor size (Tau-c = 0.222; p = 0.020) and with greater lymph node involvement (Tau-c = 0.258; p = 0.042). Also, higher IFN-γ plasma levels were observed in patients with higher histopathological grades (Tau-c = 0.384; p = 0.019) in MMTV-like env positive samples. For the first time, we assessed the association between plasma levels of IFN-γ and the presence of the MMTV-like env gene in BC samples. However, more studies are needed to clarify whether the high levels of IFN-γ in MMTV-like env positive samples are reflecting a possible antiviral immune response or whether this cytokine is promoting tumor growth.

Involvement of CXCL12/CXCR4 axis in colorectal cancer: a mini-review.

Migration of metastatic tumor cells is similar to the traffic of leukocytes and has been reported that can be guided by chemokines and their receptors, through the circulation to distant organs. The chemokine CXCL12 and its receptor CXCR4 play an essential role in hematopoietic stem cell homing and the activation of this axis supports malignant events. Binding of CXCL12 to CXCR4 activates signal transduction pathways, with broad effects on chemotaxis, cell proliferation, migration and gene expression. Thus, this axis serves as a bridge for tumor-stromal cell communication, creating a permissive microenvironment for tumor development, survival, angiogenesis and metastasis. Evidence suggests that this axis may be involved in the colorectal cancer (CRC) carcinogenesis. Therefore, we review emerging data and correlations between CXCL12/CXCR4 axis in CRC, the implications for cancer progression and possible therapeutic strategies that exploit this system.

Acute lymphoid leukemia etiopathogenesis.

Acute lymphoid leukemia (ALL) is a type of hematological neoplasm that affects the precursor cells of strains B, T  and NK, with a higher incidence in the pediatric range. The pathophysiology of ALL is characterized by chromosomal abnormalities and genetic alterations involved in the differentiation and proliferation of lymphoid precursor cells. Despite the lack of information in the literature, it is believed that leukemogenesis originates from a complex interaction between environmental and genetic factors, which combined lead to cellular modifications. Environmental factors have been evaluated as possible predisposing factors in the development of ALL but there are still conflicting results in the world literature. In this context, the aim of the present review is to discuss the major exogenous factors regarding ALL.

Effects of GSTT1 and GSTM1 polymorphisms in glutathione levels and breast cancer development in Brazilian patients.

Polymorphisms in the glutathione transferase enzymes (GSTs) genes have been associated with susceptibility to develop breast cancer (BC), but few are known regarding its role on this disease prognosis and impact on antioxidant status. This study evaluated the polymorphisms of GSTM1 and GSTT1 genes and their relationship with BC susceptibility and prognostic, as well as its impact on plasma reduced glutathione (GSH) levels. The present study included 121 women with invasive ductal BC and 151 healthy controls. Polymorphisms analyses were performed using the polymerase chain reaction (PCR) technique and GSH levels were measured with the Ellman's reagent. GSTT1 (OR 1.29; p = 0.39) and GSTM1 (OR 1.03; p = 0.91) polymorphisms did not show any association with BC susceptibility. The mean concentration values in nmol/L of GSH were 20.37 ± 5.82 for patients with null genotypes for both genes, 19.75 ± 3.47 for null GSTT1, 17.22 ± 1.35 for active GSTT1, 18.82 ± 1.96 for absent GSTM1, and 16.59 ± 1.66 for active GSTM1, but no significance was found. Therefore, it can be concluded that the behavior of these polymorphisms concerning BC might be not only related to the absence of enzymatic expression but may also be related to the body's response with its antioxidant mechanisms and it should be further studied.

COVID-19: The question of genetic diversity and therapeutic intervention approaches.

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), is the largest pandemic in modern history with very high infection rates and considerable mortality. The disease, which emerged in China's Wuhan province, had its first reported case on December 29, 2019, and spread rapidly worldwide. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic and global health emergency. Since the outbreak, efforts to develop COVID-19 vaccines, engineer new drugs, and evaluate existing ones for drug repurposing have been intensively undertaken to find ways to control this pandemic. COVID-19 therapeutic strategies aim to impair molecular pathways involved in the virus entrance and replication or interfere in the patients' overreaction and immunopathology. Moreover, nanotechnology could be an approach to boost the activity of new drugs. Several COVID-19 vaccine candidates have received emergency-use or full authorization in one or more countries, and others are being developed and tested. This review assesses the different strategies currently proposed to control COVID-19 and the issues or limitations imposed on some approaches by the human and viral genetic variability.

Transforming growth factor beta 1 (TGFß1) plasmatic levels in breast cancer and neoplasia-free women: Association with patients' characteristics and TGFB1 haplotypes.

Transforming growth factor beta 1 (TGFß1) is a pleiotropic cytokine that acts in a context-dependent manner. In breast cancer (BC) this cytokine exerts subtype- and stage-specific roles, inhibiting poorly aggressive tumors while enhances the invasive potential of highly aggressive cancers. Single-nucleotide polymorphisms (SNPs) affecting TGFß1 production largely reflect this pattern of association, but studies investigating systemic TGFß1 levels in BC patients and their association with clinical features or SNPs produced conflicting conclusions. Therefore, the present work investigated plasmatic TGFß1 levels through enzyme linked immunosorbent assay (ELISA) in 341 individuals previously genotyped for four TGFB1 SNPs [G-800A (rs1800468), C-509T (rs1800469), T29C (rs1800470) and G74C (rs1800471)], encompassing 184 neoplasia-free women with clinical information regarding health status, 113 treatment-free pre-surgery BC patients and 44 treated BC patients. Results have shown that TGFß1 levels varied greatly in function of health status in neoplasia-free women, and disease-free individuals had higher TGFß1 levels than both treatment-free or treated BC patients. There was no correlation between TGFß1 with clinicopathological features in treatment-free BC general group, but it was negatively correlated with tumor size in luminal-B-HER2+ patients and with histopathological grade in triple-negative group. Also, TGFB1 ACTG haplotype (from G-800A to G74C) was associated with decreased TGFß1 levels compared to the reference GCTG haplotype, and regression analyses showed that this association was independent of age, health status or BC diagnosis. In conclusion, several factors may influence TGFß1 levels, and ACTG haplotype seems to be an important factor regulating TGFß1 production.

Polymorphisms in GSTT1 and GSTM1 genes as possible risk factors for susceptibility to breast cancer development and their influence in chemotherapy response: a systematic review.

Breast cancer (BC) is a heterogeneous and multifactorial disease. The system formed by glutathione-S-transferases (GSTs) acts to protect the organism against the oxidative stress generated by xenobiotics and their active products. Glutathione transferase mu 1 (GSTM1) and glutathione transferase theta 1 (GSTT1) present null polymorphic variants by complete deletion. The absence of these enzymes may influence the susceptibility to several diseases such as BC. This study aimed to systematically review and investigate the existence of a possible correlation between the presence/absence of these genetic variants and the development of BC and their influence in chemotherapy response. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol was used, and the searches were performed in the portal of the Virtual Health Library (VHL) and the PubMed, resulting in 21 articles. It is clear that most studies revealed a risk association between the deletion of GSTM1 and/or GSTT1 and the development and/or prognosis of BC.Moreover, it should be noted that these results of risk association were found in large part in the populations of the Americas and Europe, followed by Asians. Regarding the response to treatment, protective associations were found in the presence of GSTM1 deletion. However, due to the inconclusive results of many studies, further analysis in this area is required.

Transforming growth factor beta receptor II (TGFBR2) promoter region polymorphism in Brazilian breast cancer patients: association with susceptibility, clinicopathological features, and interaction with TGFB1 haplotypes.

PURPOSE: Transforming growth factor beta (TGFß) has paradoxical effects in breast cancer (BC), inhibiting initial tumors while promoting aggressive ones. A polymorphism on TGFBR2 promoter region (G-875A, rs3087465) increases TGFß type II receptor expression and is protective against cancer. Previously, we have shown that TGFB1 variants have subtype-specific roles in BC. This work sought to investigate the association between TGFBR2 and susceptibility and clinicopathological features in BC subgroups. METHODS: TGFBR2 G-875A was analyzed through PCR-RFLP in 388 BC patients and 405 neoplasia-free women. Case-control analyses as well as interaction with TGFB1 haplotypes previously associated with BC were tested through age-adjusted logistic regression. Correlations between G-875A and clinicopathological parameters were assessed through Kendall's Tau-b test. All statistical tests were two-tailed (α = 0.05). RESULTS: TGFBR2 G-875A was protective against BC in additive, genotypic, and dominant models. In subgroup-stratified analyses, these effects were greater in hormonal receptor-positive and luminal-A tumors, but were not significant in other subgroups. Logistic models including TGFB1 variants showed that in luminal-A tumors, G-875A retained its significance while TGFB1 haplotype showed a trend towards significance; otherwise, in HER2+ tumors TGFB1 variants remained significant while TGFBR2 showed a trend for association. There was no interaction between these genes. In correlation analyses, G-875A positively correlated with histopathological grade in total sample, and a trend towards significance was observed in triple-negative BCs. CONCLUSION: These results indicate that G-875A is a protective factor against BC, especially from luminal-A subtype, but may promote anaplasia in established tumors, consistent with TGFß signaling roles in BC.

Involvement of a mouse mammary tumor virus (MMTV) homologue in human breast cancer: Evidence for, against and possible causes of controversies.

Breast cancer (BC) is a complex and heterogeneous disease whose evolution depends on the tumor-host interaction. This type of cancer occurs when the mammary cells begin to grow wildly and become able to invade nearby tissues and/or promote metastases. Mouse mammary tumor virus (MMTV) is the accepted etiological agent of mammary tumors in mice. The identification of MMTV-like sequences and antigens in human mammary carcinoma has supported the theory that a virus homologous to MMTV (namely, HMTV) may be involved in human BC, but the role of retroviral elements in this disease remains elusive, as results from different research groups were contradictory. In the present review we present works for and against the involvement of HMTV in BC and discuss possible causes of divergences among studies. In the final section we fit current data regarding this issue to stablished causality criteria. We conclude that there is convincing data supporting the association of HMTV with BC, however there is still a need for epidemiological and basic research studies focusing on carcinogenic mechanisms for this virus in humans to fully understand its role in BC. This knowledge may open the way for the development of new preventive and therapeutic approaches in human BC.

An overview of the immune response and Arginase I on CHIKV immunopathogenesis.

Chikungunya virus (CHIKV) is mosquito-borne alphavirus that has caused epidemics around the world. Many individuals affected by the disease may experience joint pain that persists for months after the acute phase. The pathophysiology of viral arthritis is not completely elucidated. And it is important to emphasize that the effects of the viral infection in each host may depend on host factors that include immune response, as well as factors specific to the virus as tissue tropism. The main pathway for the response against viral infection is through induction of type I interferon (IFN-I), whose function is important to control viral replication. Beside this, T cell and macrophage mediated immunopathology in CHIKV infections has been reported. It has been demonstrated that some association with the Arginase I and macrophages type II are involved in the infection profile along with myeloid-derived suppressor cells (MDSC) that are responsible for T cell suppression. Therefore, in this review, will be discuss an overview on CHIKV immunopathogenesis and the importance of Arginase I.

CCL5 protein level: influence on breast cancer staging and lymph nodes commitment.

Many tumor cells express chemokines and chemokine receptors, and these molecules can contribute to distinct modes of metastasis processes. It is known that they play a crucial role in breast cancer (BC) tumorigenesis and progression. Considering this, it was investigated a possible role for C-Chemokine receptor type 5(CCR5) polymorphism (rs333/delta32) by conventional polymerase chain reaction (PCR) and CCL5 (C-C motif chemokine ligand 5) protein level by immunosorbent assay (ELISA) in 47 BC patients (resulting in 47 tumoral tissue samples and 47 adjacent normal tissue samples). There was a significant difference between CCL5 level in tumoral and adjacent normal tissues for the same BC patients (p < 0.0001). A significant association was also found for CCL5 level in relation to lymph nodes commitment (p = 0.03). Likewise, there was a significant difference in CCL5 level from tumor tissue of stage III in relation to stage I (p < 0.02). On the other hand, it was verified that CCR5-delta32 polymorphism presented no significant association in relation to CCL5 protein level. Considering the present findings, we suggest that CCL5 may be involved in BC staging and metastasis process.

Interleukin 7 receptor alpha Thr244Ile genetic polymorphism is associated with susceptibility and prognostic markers in breast cancer subgroups.

Interleukin-7 (IL-7) exerts crucial functions on lymphoid cells' development and maintenance. In breast cancer (BC), IL-7 promotes growth of tumor cells in culture through the activation of JAK1/3-STAT5 and PI3K/AKT pathways, and expression of IL-7 signaling components was associated with worst prognosis. AC>T polymorphism (rs6897932; Thr244Ile) at exon 6 of IL-7 receptor alpha (IL-7Rα) gene (IL7RA) shifts the balance between the membrane-bound and soluble IL-7Rα splicing variants and was previously associated with autoimmune diseases, but has not been studied in cancer, including BC, so far. Therefore, the present study aimed to investigate the possible association of this polymorphism with the susceptibility and clinicopathological parameters of BC subgroups. IL7RA Thr244Ile was genotyped through PCR-RFLP in 403 women without neoplasia, no personal history of malignancy or family history of BC and in 338 BC patients with clinicopathological data available. BC patients were stratified according to their positivity for estrogen (ER) and/or progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Age-adjusted logistic regression was performed for case-control analyses, and correlations with clinicopathological parameters were assessed through Kendall's Tau-b coefficient. All analyses were two-tailed and had 95% confidence interval. In ER-PR-HER2- BCs, TT genotype was associated with increased susceptibility both in genotypic (TT vs. CC: OR=3.07; CI=1.01-9.38; p=0.05) and recessive (TT vs. CC+CT: OR=3.59; CI=1.19-10.85; p=0.02) models and negatively correlated with disease stage (Tau-b=-0.27; p=0.05). Whereas T allele was positively correlated with histopathological grade (Tau-b=0.29; p=0.03) and lymph node metastasis (Tau-b=0.35; p=0.02) in ER/PR+HER2+BCs and with Ki67 (Tau-b=0.51; p=0.008) in ER-PR-HER2+ subgroup. These data indicate that IL-7Rα is involved in BC, and that IL7RA polymorphism may play distinct roles in breast carcinogenesis according to BC subtype, pointing this genetic variant as an interesting marker for breast carcinogenesis to be validated by further mechanistic and prospective studies with larger samples.

Potential use of CXCL12/CXCR4 and sonic hedgehog pathways as therapeutic targets in medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor occurring in children, and although high long-term survival rates have been reached with current therapeutic protocols, several neurological injuries are still observed among survivors. It has been shown that the development of MB is highly dependent on the microenvironment surrounding it and that the CXCL12 chemokine and its receptor, CXCR4 and the Sonic Hedgehog (SHH) pathway are crucial for cerebellar development, coordinating proliferation and migration of embryonic cells and malfunctions in these axes can lead to MB development. Indeed, the concomitant overactivation of these axes was suggested to define a new MB molecular subgroup. New molecules are being studied, aiming to inhibit either CXCR4 or the SHH pathways and have been tested in preclinical settings for the treatment of cancers. The use of these molecules could improve MB treatment and save patients from aggressive surgery, chemotherapy and radiotherapy regimens, which are responsible for severe neurological consequences. This review aims to summarize current data about the experimental inhibition of CXCR4 and SHH pathways in MB and its potential implications in treatment of this cancer.

CXCL12/CXCR4 axis in the pathogenesis of acute lymphoblastic leukemia (ALL): a possible therapeutic target.

Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy, accounting for approximately 80 % of leukemia in the pediatric group, and its etiology is unknown. This neoplasia is characterized by male predominance, high-risk features and poor outcome, mainly in recurrence patients and adults. In recent years, advances in the success of childhood ALL treatment were verified, and the rate of cure is over 80 % of individuals. However, there is a considerable scope for improving therapeutic outcome in this neoplasia. Improvements in ALL therapy might readily be achieved by developing additional biomarkers that can predict and refine prognosis in patients with ALL. In normal hematopoietic cells, cytokines provide the stimulus for proliferation, survival, self-renewal, differentiation and functional activation. Abnormalities of cytokines are characteristic in all forms of leukemia, including ALL. The stromal cell-derived factor-1 (SDF-1 or CXCL12) is a member of the CXC chemokine family that binds to CXC chemokine receptor 4 (CXCR4). The CXCL12/CXCR4 axis appears to play a role in dissemination of solid tumors and hematopoietic diseases. Understanding the mechanisms by which ALL cells are disseminated will provide additional information to expand therapeutic approach. Therefore, this review summarizes information relating to ALL cell biology, focusing specifically in a cytokine receptor important axis, CXCL12/CXCR4, that may have implications for novel treatment strategies to improve life expectancy of patients with this neoplasia.

IL-10 gene polymorphism and influence of chemotherapy on cytokine plasma levels in childhood acute lymphoblastic leukemia patients: IL-10 polymorphism and plasma levels in leukemia patients.

Acute Lymphoblastic Leukemia is the leading form of cancer in infancy, and compelling evidences suggest an involvement of altered immune competence on this malignancy pathogenesis. Interleukin 10 (IL-10) is a pleiotropic cytokine designated as an immunosuppressive molecule, but may act as an immunostimulant factor in cancer development and progression. An IL-10 single nucleotide polymorphism (SNP) rs1800896 has been associated with disease progression to ALL, and might influence cytokine expression. This study analyzed the IL-10 rs1800896 polymorphism and performed a case-control study to determine the significant associations with ALL susceptibility and prognosis. IL-10 plasma levels were determined and associated with genotypes and disease phase. The study consisted of 67 childhood ALL patients and 75 age-related healthy controls. The rs1800896 was not associated with ALL susceptibility or risk of relapse. No significant association was observed between different genotypes of the rs1800896 and plasma levels of IL-10. Cytokine plasma levels were significantly higher in the diagnosis group (9.71 pg/mL ± 3.7), comparing to the treatment (3.48 pg/mL ± 1.3; p=0.01) and remission phase (0.12 pg/mL ± 0.1; p=0.0001) groups. This work indicates that the IL-10 plasma expression is altered from ALL disease diagnosis and remission. Moreover, prospective studies will establish the functional role of IL-10 in immune modulation in childhood ALL.

Changes in gene expression in PBMCs profiles of PPARα target genes in obese and non-obese individuals during fasting.

BACKGROUND: The prevalence of obesity has risen dramatically and the World Health Organization estimates that 700 million people will be obese worldwide by 2015. Approximately, 50% of the Brazilian population above 20 years of age is overweight, and 16% is obese. AIM: This study aimed to evaluate the differences in the expression of PPARα target genes in human peripheral blood mononuclear cells (PBMCs) and free fatty acids (FFA) in obese and non-obese individuals after 24 h of fasting. We first presented evidence that Brazilian people exhibit expression changes in PPARα target genes in PBMCs under fasting conditions. METHODS: Q-PCR was utilized to assess the mRNA expression levels of target genes. RESULTS: In both groups, the FFA concentrations increased significantly after 24 h of fasting. The basal FFA mean concentration was two-fold higher in the obese group compared with the non-obese group. After fasting, all genes evaluated in this study showed increased expression levels compared with basal expression in both groups. CONCLUSION: However, our results reveal no differences in gene expression between the obese and non-obese, more studies are necessary to precisely delineate the associated mechanisms, particularly those that include groups with different degrees of obesity and patients with diabetes mellitus type 2 because the expression of the main genes that are involved in ß-oxidation and glucose level maintenance are affected by these factors.

CXCL12 and TP53 genetic polymorphisms as markers of susceptibility in a Brazilian children population with acute lymphoblastic leukemia (ALL).

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Genetic polymorphisms in the 3'UTR region of the CXCL12 (rs1801157) and TP53 codon 72 (rs1042522) genes may contribute to susceptibility to childhood ALL because they affect some important processes, such as metastasis regulation and tumor suppression. Thus the objective of the present study was to detect the frequency of two genetic polymorphisms in ALL patients and controls and to add information their impact on genetic susceptibility and prognosis. The CXCL12 and TP53 polymorphisms were tested in 54 ALL child patients and in 58 controls by restriction fragment length polymerase chain reaction and allelic specific chain reaction techniques, respectively. The frequencies of both allelic variants were higher in ALL patients than in the controls and indicated a positive association: OR = 2.44; 95 % CI 1.05-5.64 for CXCL12 and OR = 2.20; 95 % CI 1.03-4.70 for TP53. Furthermore, when the two genetic variants were analyzed together, they increased significantly more than fivefold the risk of this neoplasia development (OR = 5.24; 95 % CI 1.39-19.75), indicating their potential as susceptibility markers for ALL disease and the relevance of the allelic variant combination to increased risk of developing malignant tumors. Future studies may indicate a larger panel of genes involved in susceptibility of childhood ALL and other hematological neoplasias.

Involvement of APOBEC3A/B Deletion in Mouse Mammary Tumor Virus (MMTV)-like Positive Human Breast Cancer.

The association between mouse mammary tumor virus (MMTV)-like sequences and human breast cancer (BC) is largely documented in the literature, but further research is needed to determine how they influence carcinogenesis. APOBEC3 cytidine deaminases are viral restriction factors that have been implicated in cancer mutagenesis, and a germline deletion that results in the fusion of the APOBEC3A coding region with the APOBEC3B 3'-UTR has been linked to increased mutagenic potential, enhanced risk of BC development, and poor prognosis. However, little is known about factors influencing APOBEC3 family activation in cancer. Thus, we hypothesized that MMTV infection and APOBEC3-mediated mutagenesis may be linked in the pathogenesis of BC. We investigated APOBEC3A/B genotyping, MMTV-like positivity, and clinicopathological parameters of 209 BC patients. We show evidence for active APOBEC3-mediated mutagenesis in human-derived MMTV sequences and comparatively investigate the impact of APOBEC3A/B germline deletion in MMTV-like env positive and negative BC in a Brazilian cohort. In MMTV-like negative samples, APOBEC3A/B deletion was negatively correlated with tumor stage while being positively correlated with estrogen receptor expression. Although APOBEC3A/B was not associated with MMTV-like positivity, samples carrying both MMTV-like positivity and APOBEC3A/B deletion had the lowest age-at-diagnosis of all study groups, with all patients being less than 50 years old. These results indicate that APOBEC3 mutagenesis is active against MMTV-like sequences, and that APOBEC3A/B deletion might act along with the MMTV-like presence to predispose people to early-onset BC.

Dermatological Manifestations in COVID-19: A Case Study of SARS-CoV-2 Infection in a Genetic Thrombophilic Patient with Mthfr Mutation.

The present case study describes the dermatological manifestations of COVID-19 in a patient with genetic thrombophilia (MTHFR-C677T mutation) and the identification of a SARS-CoV-2 variant of interest (VOI). A female patient, 47 years old, unvaccinated, with thrombophilia, was diagnosed with COVID-19. She presented with urticarial and maculopapular eruptions from the seventh day of symptoms, which progressed to multiple lesions with dark centers (D-dimer value > 1450 ng/mL). The dermatological manifestations disappeared after 30 days, corroborating the reduction in D-dimer levels. Viral genome sequencing revealed infection by the VOI Zeta (P.2). Antibody testing, performed 30 days after the onset of symptoms, detected only IgG. The virus neutralization test showed the highest neutralizing titer for a P.2 strain, validating the genotypic identification. Lesions were suggested to be due to infection in skin cells causing a direct cytopathic effect or release of pro-inflammatory cytokines triggering erythematous and urticarial eruptions. In addition, vascular complications are also proposed to be due to the MTHFR mutation and increased D-dimer values. This case report is an alert about COVID-19 in patients with pre-existing vascular diseases, especially in unvaccinated patients, by VOI.