A Novel Constitutional t(3;8)(p26;q21) and ANKRD26 and SRP72 Variants in a Child with Myelodysplastic Neoplasm: Clinical Implications.

BACKGROUND: Childhood myelodysplastic neoplasm (cMDS) often raises concerns about an underlying germline predisposition, and its verification is necessary to guide therapeutic choice and allow family counseling. Here, we report a novel constitutional t(3;8)(p26;q21) in a child with MDS, inherited from the father, the ANKRD26 and SRP72 variants from the maternal origin, and the acquisition of molecular alterations during MDS evolution. CASE PRESENTATION: A 4-year-old girl showed repeated infections and severe neutropenia. Bone marrow presented hypocellularity with dysplastic features. The patient had a t(3;8)(p26;q21)c identified by G-banding and FISH analysis. The family nucleus investigation identified the paternal origin of the chromosomal translocation. The NGS study identified ANKRD26 and SRP72 variants of maternal origin. CGH-array analysis detected alterations in PRSS3P2 and KANSL genes. Immunohistochemistry showed abnormal p53 expression during the MDS evolution. CONCLUSION: This study shows for the first time, cytogenetic and genomic abnormalities inherited from the father and mother, respectively, and their clinical implications. It also shows the importance of investigating patients with constitutional cytogenetic alterations and/or germline variants to provide information to their family nucleus for genetic counseling and understanding of the pathogenesis of childhood MDS.

Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service.

Several studies have demonstrated the cost-effectiveness of genetic testing for surveillance and treatment of carriers of germline pathogenic variants associated with hereditary breast/ovarian cancer syndrome (HBOC). In Brazil, seventy percent of the population is assisted by the public Unified Health System (SUS), where genetic testing is still unavailable. And few studies were performed regarding the prevalence of HBOC pathogenic variants in this context. Here, we estimated the prevalence of germline pathogenic variants in BRCA1, BRCA2 and TP53 genes in Brazilian patients suspected of HBOC and referred to public healthcare service. Predictive power of risk prediction models for detecting mutation carriers was also evaluated. We found that 41 out of 257 tested patients (15.9%) were carriers of pathogenic variants in the analyzed genes. Most frequent pathogenic variant was the founder Brazilian mutation TP53 c.1010G > A (p.Arg337His), adding to the accumulated evidence that supports inclusion of TP53 in routine testing of Brazilian HBOC patients. Surprisingly, BRCA1 c.5266dupC (p.Gln1756fs), a frequently reported pathogenic variant in Brazilian HBOC patients, was not observed. Regarding the use of predictive models, we found that familial history of cancer might be used to improve selection or prioritization of patients for genetic testing, especially in a context of limited resources.

Can torque teno virus be a predictor of SARS-CoV-2 disease progression in cancer patients?

INTRODUCTION: Cancer patients with SARS-CoV-2 infection can experience a broad range of clinical manifestations and outcomes. Previous studies have demonstrated an association between torque teno virus (TTV) load and deficiencies of the immune system. The impact of SARS-CoV-2 and TTV viral loads in cancer patients is unknown. METHODS: In this retrospective study, 157 cancer patients and 191 noncancer controls were analysed for SARS-CoV-2 RNA and TTV DNA presence. RESULTS: SARS-CoV-2 RNA was detected in 66.2% of cancer patients and in 68.6% of noncancer control subjects. In SARS-CoV-2-positive patients, TTV was detectable in 79.8% of cancer patients, while in controls, TTV was detected in 71.7% of subjects. No statistically significant correlation was found between TTV and SARS-CoV-2 loads in cancer patients. However, the 100-day survival rate in cancer patients who died from COVID-19 was significantly lower in the TTV-positive group than in the TTV-negative group (P = 0.0475). In the cancer TTV-positive group, those who died also had a higher load of TTV than those who did not die (P = 0.0097). CONCLUSIONS: Our findings indicated that the presence of TTV in nasopharyngeal swabs from cancer patients was related to a higher number of deaths from COVID-19 and to a higher TTV DNA load.

KMT2A-MLLT1 and the Novel SEC16A-KMT2A in a Cryptic 3-Way Translocation t(9;11;19) Present in an Infant With Acute Lymphoblastic Leukemia.

About 25% of the patients with the translocation t(11;19)(q23;p13.3)/KMT2A-MLLT1 present three-way or more complex fusions, associated with a worse prognosis, suggesting that a particular mechanism creates functional KMT2A fusions for this condition. In this work, we show a cryptic three-way translocation t(9;11;19). Interestingly, long-distance inverse polymerase chain reaction sequencing revealed a KMT2A-MLLT1 and the yet unreported out-of-frame SEC16A-KMT2A fusion, associated with low SEC16A expression and KMT2A overexpression, in an infant with B-acute lymphoblastic leukemia presenting a poor prognosis. Our case illustrates the importance of molecular cytogenetic tests in selecting cases for further investigations, which could open perspectives regarding novel therapeutic approaches for poor prognosis childhood leukemias.

Twist1 Influences the Expression of Leading Members of the IL-17 Signaling Pathway in HER2-Positive Breast Cancer Cells.

Breast cancer (BC) is a heterogeneous disease composed of multiple subtypes with different molecular characteristics and clinical outcomes. The metastatic process in BC depends on the transcription factors (TFs) related to epithelial-mesenchymal transition (EMT), including the master regulator Twist1. However, its role beyond EMT in BC subtypes remains unclear. Our study aimed to investigate the role of Twist1, beyond EMT, in the molecular subtypes of BC. In patients, we observed the overexpression of TWIST1 in the HER2+ group. The silencing of TWIST1 in HER2+ BC cells resulted in the upregulation of 138 genes and the downregulation of 174 genes compared to control cells in a microarray assay. In silico analysis revealed correlations between Twist1 and important biological processes such as the Th17-mediated immune response, suggesting that Twist1 could be relevant for IL-17 signaling in HER2+ BC. IL-17 signaling was then examined, and it was shown that TWIST1 knockdown caused the downregulation of leading members of IL-17 signaling pathway. Taken together, our findings suggest that Twist1 plays a role on IL-17 signaling in HER2+ BC.

NRIP1 is activated by C-JUN/C-FOS and activates the expression of PGR, ESR1 and CCND1 in luminal A breast cancer.

Using chip array assays, we identified differentially expressed genes via a comparison between luminal A breast cancer subtype and normal mammary ductal cells from healthy donors. In silico analysis confirmed by western blot and immunohistochemistry revealed that C-JUN and C-FOS transcription factors are activated in luminal A patients as potential upstream regulators of these differentially expressed genes. Using a chip-on-chip assay, we identified potential C-JUN and C-FOS targets. Among these genes, the NRIP1 gene was revealed to be targeted by C-JUN and C-FOS. This was confirmed after identification and validation with transfection assays specific binding of C-JUN and C-FOS at consensus binding sites. NRIP1 is not only upregulated in luminal A patients and cell lines but also regulates breast cancer-related genes, including PR, ESR1 and CCND1. These results were confirmed by NRIP1 siRNA knockdown and chip array assays, thus highlighting the putative role of NRIP1 in PGR, ESR1 and CCND1 transcriptional regulation and suggesting that NRIP1 could play an important role in breast cancer ductal cell initiation.

Perfil clínico epidemiológico de pacientes com glaucoma atendidos em um serviço de referência em oftalmologia do estado de Minas Gerais / Epidemiological clinical profile of glaucoma patients attended in a ophthalmology reference service in the state of Minas Gerais

Introdução: O glaucoma é uma neuropatia óptica progressiva que pode acarretar defeitos progressivos do campo visual e perda da visão. É a principal causa de cegueira irreversível no mundo, sendo o aumento da pressão intraocular (PIO) o principal fator de risco. Objetivos: Identificar o perfil dos usuários do SUS no Estado de Minas Gerais, especificamente do Departamento de Glaucoma do Instituto de Olhos Ciências Médicas (IOCM). Métodos: Realizou-se um estudo clínico observacional, transversal e de caráter retrospectivo com 1484 pacientes. Foram incluídos pacientes do sexo feminino e masculino, acima de 18 anos de idade, encaminhados ao setor de glaucoma do IOCM para o primeiro atendimento, com suspeita ou doença confirmada. Os diagnósticos considerados foram: suspeita de glaucoma; hipertenso ocular; glaucoma primário de ângulo aberto; glaucoma primário de ângulo fechado; glaucoma de pressão normal; glaucoma congênito; glaucoma secundário; glaucoma neovascular e glaucoma maligno. Resultados: Houve predomínio do sexo feminino e o diagnóstico mais frequente foi "glaucoma primário de ângulo aberto". Os fatores de risco mais prevalentes foram idade avançada e hipertensão arterial sistêmica. Conclusões: O perfil clínico demográfico dos pacientes em tratamento de glaucoma em Minas Gerais são semelhantes ao encontrado em alguns trabalhos realizados em outros países do mundo.

Introduction: Glaucoma is a progressive optic neuropathy that can lead to progressive visual field defects and loss of vision. It is the main cause of irreversible blindness in the world, with increased intraocular pressure (IOP) being the main risk factor. Objectives: Identify the profile of the Brazilian Public Health System (SUS) users, specifically in the Department of Glaucoma at the Instituto de Olhos Ciencias Medicas (IOCM), State of Minas Gerais, Brazil. Methods: An observational, cross-sectional, retrospective study enrolled 1484 patients. Were inclueded female and male patients, over 18 years of age, referred to the glaucoma sector of the IOCM for the first visit, with suspected or confirmed disease. The diagnoses considered were: suspected glaucoma; ocular hypertension; primary open-angle glaucoma; primary closedangle glaucoma; normal-pressure glaucoma; congenital glaucoma; secondary glaucoma; neovascular glaucoma. Results: There was a predominance of females and the most frequent diagnosis was "Primary Open-angle Glaucoma". The most prevalent risk factors were advanced age and hypertension. Conclusions: The demographics and clinical profile of patients undergoing glaucoma treatment at IOCM are similar to those found in some studies performed in other countries.

Topological flat band, Dirac fermions and quantum spin Hall phase in 2D Archimedean lattices.

Materials with properties designed on-demand arise in a synergy between theoretical and experimental approaches. Here, we explore a set of Archimedean lattices, providing a guide to their electronic properties and topological phases. Within these lattices, a rich electronic structure emerges forming type-I and II Dirac fermions, topological flat bands and high-degeneracy points with linear and flat dispersions. Employing a tight-binding model with spin-orbit coupling, we characterize quantum spin Hall (QSH) phases in all Archimedean lattices. Our discussions are validated within density functional theory calculations, where we show the characteristic bands of the studied lattices arising in 2D carbon allotropes.

A New Complex Karyotype Involving a KMT2A-r Variant Three-Way Translocation in a Rare Clinical Presentation of a Pediatric Patient with Acute Myeloid Leukemia.

Patients with childhood acute myeloid leukemia (AML) with complex karyotypes (CKs) have a dismal outcome. However, for patients with a KMT2A rearrangement (KMT2A-r), the prognosis appears to depend on the fusion partner gene rather than the karyotype structure. Thus, a precise characterization of KMT2A-r and the fusion partner genes, especially in CKs, is of interest for managing AML. We describe the clinical and molecular features of a child who presented with a large abdominal mass, AML, and a new CK, involving chromosomes 11, 16, and 19 leading to a KMT2A-MLLT1 fusion and 2 extra copies of the ELL gene, thus resulting in the concurrent overexpression of MLLT1 and ELL. Molecular cytogenetic studies defined the karyotype as 47,XY,der(11)t(11;16)(q23.3;p11.2),der(16)t(16;19)(p11.2;p13.3),der(19)t(11;19)(q23.3;p13.3),+der(19)t(16;19)(16pter→p11.2::19p13.3→19q11::19p11→19p13.3::16p11.2→16pter). Array CGH revealed a gain of 30.5 Mb in the 16p13.3p11.2 region and a gain of 18.1 Mb in the 19p13.3p12 region. LDI-PCR demonstrated the KMT2A-MLLT1 fusion. Reverse sequence analysis showed that the MLLT1 gene was fused to the 16p11.2 region. RT-qPCR quantification revealed that ELL and MLLT1 were overexpressed (4- and 10-fold, respectively). In summary, this is a pediatric case of AML presenting a novel complex t(11;16;19) variant with overexpression of ELL and MLLT1.

Quantum anomalous Hall effect in metal-bis(dithiolene), magnetic properties, doping and interfacing graphene.

The realization of the Quantum anomalous Hall effect (QAHE) in two dimensional (2D) metal organic frameworks (MOFs), (MC4S4)3 with M = Mn, Fe, Co, Ru and Rh, has been investigated based on a combination of first-principles calculations and tight binding models. Our analysis of the magnetic anisotropy energy (MAE) reveals that the out-of-plane (in-plane) magnetization is favored for M = Mn, Fe, and Ru (Co, and Rh). Therefore, we predict that the structural symmetry of (MC4S4)3 yields the QAHE only for M = Mn, Fe and Ru. Such a quantum anomalous Hall phase has been confirmed through the calculation of the Chern number, and examining the formation of topologically protected (metallic) edge states. Furthermore, we show that viable electron (n-type) doping of the MOFs can be used to place the Fermi level within the non-trivial energy gap; where we find that in (RuC4S4)3, in addition to the up-shift of the Fermi level, the MAE energy increases by 40%. Finally, we show that in MOF/graphene (vdW) interfaces, the Fermi level tuning can be done with an external electric field, which controls the charge transfer at the MOF/graphene interface, giving rise to switchable topologically protected edge currents in the MOFs.

NF-kappaB Regulates Redox Status in Breast Cancer Subtypes.

Oxidative stress (OS) is an indispensable condition to ensure genomic instability in cancer cells. In breast cancer (BC), redox alterations have been widely characterized, but since this process results from a chain of inflammatory events, the causal molecular triggers remain to be identified. In this context, we used a microarray approach to investigate the role of the main pro-oxidant transcription factor, nuclear factor-kappa B (NF-κB), in gene profiles of BC subtypes. Our results showed that NF-κB knockdown in distinct BC subtypes led to differential expression of relevant factors involved in glutathione metabolism, prostaglandins, cytochrome P450 and cyclooxygenase, suggesting a relationship between the redox balance and NF-κB in such cells. In addition, we performed biochemical analyses to validate the microarray dataset focusing on OS and correlated these parameters with normal expression or NF-κB inhibition. Our data showed a distinct oxidative status pattern for each of the three studied BC subtype models, consistent with the intrinsic characteristics of each BC subtype. Thus, our findings suggest that NF-κB may represent an additional mechanism related to OS maintenance in BC, operating in various forms to mediate other important predominant signaling components of each BC subtype.

Suppressed topological phase transitions due to nonsymmorphism in SnTe stacking.

We combine first principles calculations with a group theory analysis to investigate topological phase transitions in the stacking of SnTe monolayers. We show that distinct finite stacking yields different symmetry-imposed degeneracy, which dictates the hybridization properties of opposite surface states. For SnTe aligned along the [001] direction, an (even) odd number of monolayers yields a (non)symmorphic space group. For the symmorphic case, the hybridization of surface states lead to band inversions and topological phase transitions as the sample height is reduced. In contrast, for a nonsymmorphic stacking, an extra degeneracy is guaranteed by symmetry, thus avoiding the hybridization and topological phase transitions, even in the limit of a few monolayers. Our group theory analysis provide a clear picture for this phenomenology and matches well the first principles calculations.

Molecular approaches identify a cryptic MECOM rearrangement in a child with a rapidly progressive myeloid neoplasm.

Myeloid neoplasms are a heterogeneous group of hematologic disorders with divergent patterns of cell differentiation and proliferation, as well as divergent clinical courses. Rare recurrent genetic abnormalities related to this group of cancers are associated with poor outcomes. One such abnormality is the MECOM gene rearrangement that typically occurs in cases with chromosome 7 abnormalities. MECOM encodes a transcription factor that plays an essential role in cell proliferation and maintenance and also in epigenetic regulation. Aberrant expression of this gene is associated with reduced survival. Hence, its detailed characterization provides biological and clinical information relevant to the management of pediatric myeloid neoplasms. In this work, we describe a rare karyotype harboring three copies of MECOM with overexpression of the gene in a child with a very aggressive myeloid neoplasm. Cytogenetic studies defined the karyotype as 46,XX,der(7)t(3;7)(q26.2;q21.2). Array comparative genomic hybridization (aCGH) revealed a gain of 26.04 Mb in the 3q26.2-3qter region and a loss of 66.6 Mb in the 7q21.2-7qter region. RT-qPCR analysis detected elevated expression of the MECOM and CDK6 genes (458.5-fold and 35.2-fold, respectively). Overall, we show the importance of performing detailed molecular cytogenetic analysis of MECOM to enable appropriate management of high-risk pediatric myeloid neoplasms.

NF-kappaB: Two Sides of the Same Coin.

Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer. In addition, microorganisms, such as viruses and bacteria, cooperate in the activation of NF-κB in tumors, confirming the multifactorial role of this transcription factor as a cancer driver. Recent reports have shown that the NF-κB signaling pathway should receive attention for the development of therapies. In addition to the direct effects of NF-κB in cancer cells, it might also impact immune cells that can both promote or prevent tumor development. Currently, with the rise of cancer immunotherapy, the link among immune cells, inflammation, and cancer is a major focus, and NF-κB could be an important regulator for the success of these therapies. This review discusses the contrasting roles of NF-κB as a regulator of pro- and antitumor processes and its potential as a therapeutic target.

Conductance and Kondo Interference beyond Proportional Coupling.

The transport properties of nanostructured systems are deeply affected by the geometry of the effective connections to metallic leads. In this work we derive a conductance expression for a class of interacting systems whose connectivity geometries do not meet the Meir-Wingreen proportional coupling condition. As an interesting application, we consider a quantum dot connected coherently to tunable electronic cavity modes. The structure is shown to exhibit a well-defined Kondo effect over a wide range of coupling strengths between the two subsystems. In agreement with recent experimental results, the calculated conductance curves exhibit strong modulations and asymmetric behavior as different cavity modes are swept through the Fermi level. These conductance modulations occur, however, while maintaining robust Kondo singlet correlations of the dot with the electronic reservoir, a direct consequence of the lopsided nature of the device.

Is there a role for epithelial-mesenchymal transition in adrenocortical tumors?

PURPOSE: Epithelial-mesenchymal transition (EMT) is a biological dynamic process by which epithelial cells lose their epithelial phenotype and acquire mesenchymal invasive and migratory characteristics. This has been postulated as an essential step during cancer progression and metastasis. Although this is well described in other tumors, the role of EMT in adrenocortical tumors (ACT) has yet to be addressed. METHODS: The aim of this study was to evaluate the expression of EMT markers e-cadherin, vimentin, and fibronectin, along with EMT-transcription factors (EMT-TFs), TWIST1, SIP1, and SNAIL in 24 adrenocortical carcinoma (ACC), 19 adrenocortical adenomas (ACA), 27 childhood-onset adrenocortical tumors (CAT), and 12 normal adrenal glands. The association of EMT and EMT-TFs with clinical outcomes and pathology features were also evaluated. RESULTS: Cytoplasmic vimentin expression was increased among CAT samples when compared to ACC, ACA, and normal adrenal samples (p < 0.001). There was no difference in e-cadherin and fibronectin expression observed between groups. Nuclear and cytoplasmic expression of TWIST1 and SIP1 was stronger in CAT and ACC vs. ACA and normal tissue samples (all, p < 0.05). ACT, regardless of classification, exhibited increased SNAIL expression when compared to normal tissue (p < 0.05). A significant correlation was observed between vimentin and TWIST1 (r s = 0.44, p < 0.001); SIP1 (r s = 0.51, p < 0.001); and SNAIL (r s = 0.23, p < 0.05). TWIST1 and SIP1 expressions demonstrated a significant correlation (r s = 0.56, p < 0.001). High SIP1 expression was associated with a lower survival rate among ACC cases (p < 0.05). CONCLUSIONS: Vimentin, TWIST1, and SIP1 expressions are increased in aggressive ACT. Therefore, EMT may play a relevant role in adrenal tumorigenesis.

GAS6 Oncogene and Reverse MLLT3-KMT2A Duplications in an Infant with Acute Myeloid Leukemia and a Novel Complex Hyperdiploid Karyotype: Detailed High-Resolution Molecular Cytogenetic Studies.

Pediatric acute myeloid leukemia (AML) is a highly heterogeneous disease, presenting cytogenetic and molecular abnormalities which turned out to be critical prognostic factors. Ploidy changes as gain or loss of individual chromosomes are rare in AML, occurring only in about 1-2% of the affected children. Hyperdiploid karyotypes are exceedingly rare in infants less than 12 months of age. In this age group, structural rearrangements involving the KMT2A gene occur in about 58% of the cases. Among them, the translocation t(9;11)(p22;q23), KMT2A-MLLT3, is the most common abnormality accounting for approximately 22% of KMT2A rearrangements in infant AML cases. Here, we describe a 7- month-old girl with a history of fever and severe diarrhea, and a physical examination remarkable for pallor and hepatosplenomegaly. A novel complex hyperdiploid karyotype 53,XX,+X,+6,t(9;11)(p21.3;q23.3),+der(9)t(9;11)(p21.3;q23.3),dup(13)(q31q34),+14,+19,+21,+22 was characterized by high-resolution molecular cytogenetic approaches. Fluorescence in situ hybridization, multiplex-FISH, and multicolor chromosome banding were applied, revealing 2 reverse MLLT3-KMT2A fusions and a duplication of the GAS6 oncogene. Our work suggests that molecular cytogenetic studies are crucial for the planning of a proper strategy for risk therapy in AML infants with hyperdiploid karyotypes.