The Biology, Impact, and Management of Xyleborus Beetles: A Comprehensive Review.

Xyleborus beetles, a diverse group of ambrosia beetles, present challenges to forestry and agriculture due to their damaging burrowing behavior and symbiotic relationships with fungi. This review synthesizes current knowledge on the biology, ecology, and management of Xyleborus. We explore the beetles' life cycle, reproductive strategies, habitat preferences, and feeding habits, emphasizing their ecological and economic impacts. Control and management strategies, including preventive measures, chemical and biological control, and integrated pest management (IPM), are critically evaluated. Recent advances in molecular genetics and behavioral studies offer insights into genetic diversity, population structure, and host selection mechanisms. Despite progress, managing Xyleborus effectively remains challenging. This review identifies future research needs and highlights innovative control methods, such as biopesticides and pheromone-based trapping systems.

Integrating Genetic and Cytogenetic Data: A Diversity Study of Astyanax and Psalidodon (Characidae) Species from the Paraná River Basin.

Astyanax is one of the most specious fish groups in the Neotropical region, with many cryptic species, which represents a challenge for correct identification through traditional taxonomic methods. Psalidodon is a recently resurrected genus group of species previously belonging to Astyanax, specifically those with extensive chromosomal variation of the A. scabripinnis and fasciatus complexes. In the present study, the mitochondrial genes cytochrome c oxidase subunit 1 (COI), mitochondrial ATP synthase 6 and 8 (ATPase 6/8), and NADH dehydrogenase subunit 2 (ND2) were used in conjunction with chromosomal data to characterize molecularly and cytogenetically populations of Astyanax and Psalidodon from rivers and streams of the Ivaí River Basin (Paraná Basin). The results demonstrated the effectiveness of the integrative use of molecular and cytogenetic techniques, with the confirmation of at least three species for the sampled sites: A. lacustris, P. paranae, and P. fasciatus, which showed inter- and intrapopulation karyotype variations. In addition, extensive haplotypic variation can be observed for these species within the Ivaí River Basin and throughout the Paraná River Basin. The data demonstrate a hidden diversity among the species analyzed, enrich the ichthyofaunistic knowledge of small rivers and streams, and contribute to future conservation projects in these areas.

Exome Sequencing Reveals Biallelic Mutations in MBTPS1 Gene in a Girl with a Very Rare Skeletal Dysplasia.

The Kondo-Fu type of spondyloepiphyseal dysplasia (SEDKF) is a rare skeletal dysplasia caused by homozygous or compound heterozygous mutations in the MBTPS1 gene. The MBTPS1 gene encodes a protein that is involved in the regulation of cholesterol and fatty acid metabolism. Mutations in MBTPS1 can lead to reduced levels of these lipids, which can have a number of effects on development, including skeletal anomalies, growth retardation, and elevated levels of blood lysosomal enzymes. This work reports the case of a 5-year-old girl with SEDKF. The patient had a severely short stature and a number of skeletal anomalies, including kyphosis, pectus carinatum, and reduced bone mineral density. She also had early onset cataracts and inguinal hernias. Genetic testing revealed two novel compound heterozygous variants in the MBTPS1 gene. These variants are predicted to disrupt the function of the MBTPS1 protein, which is consistent with the patient's clinical presentation. This case report adds to the growing body of evidence that mutations in the MBTPS1 gene are causal of SEDKF. We summarized the features of previous reported cases (with age ranges from 4 to 24 years) and identified that 80% had low stature, 70% low weight, 80% had bilateral cataracts and 70% showed Spondyloepiphyseal dysplasia on X-rays. The findings of this study suggest that SEDKF is a clinically heterogeneous disorder that can present with a variety of features. Further studies are needed to better understand the underlying mechanisms of SEDKF and to develop more effective treatments.

A new insight into the pathway behind spontaneous recurrent pregnancy loss: decreased CYR61 gene expression

ABSTRACT OBJECTIVE: Investigating the potential role of CYR61 in recurrent pregnancy loss is critical for developing diagnostic approaches and treatments for recurrent pregnancy loss. METHODS: In this prospective case-control study, we have investigated the expression patterns of CYR61 in blood samples from participants with recurrent pregnancy loss in their medical history and control group (n=20 vs n=10). Peripheral blood mononuclear cells from study and control groups were isolated and the expression patterns of the CYR61 gene were determined by real-time semi-quantitative reverse transcriptase PCR. RESULTS: A significant decrease in CYR61 gene expression was demonstrated in patients with two or more clinically recognized miscarriages compared with patients without miscarriages or with a history of miscarriage (p<0.01), which may make the CYR61 gene a potential candidate for predicting the risk of recurrent pregnancy loss. DISCUSSION: This study provides a basis for a detailed investigation of candidate biomarkers and molecular players involved in the development of recurrent pregnancy loss and for the development of potential treatment approaches to prevent recurrent pregnancy loss.

Methods in molecular biology and genetics: looking to the future.

In recent decades, advances in methods in molecular biology and genetics have revolutionized multiple areas of the life and health sciences. However, there remains a global need for the development of more refined and effective methods across these fields of research. In this current Collection, we aim to showcase articles presenting novel molecular biology and genetics techniques developed by scientists from around the world.

Comprehensive Landscape of Cyclin Pathway Gene Alterations and Co-occurrence with FGF/FGFR Aberrations Across Urinary Tract Tumors.

BACKGROUND: Cyclin pathway gene alterations are frequent in urothelial tumors and may co-exist with other important aberrations, leading to therapeutic opportunities. We characterized the landscape of cyclin gene alterations in urothelial and non-urothelial urinary tract (UT) malignancies. PATIENTS AND METHODS: Overall, 6842 urothelial and 897 non-urothelial UT cancers were analyzed (hybrid-capture-based comprehensive genomic profile (Foundation Medicine)). Alteration frequency in cyclin-sensitizing and -resistance genes, and co-occurrence with fibroblast growth factor receptor (FGFR) gene abnormalities were evaluated. RESULTS: Cyclin-activating gene alterations were detected in 47.3% of urothelial and 37.9% of non-urothelial UT cancers. Frequency varied by histology and tumor site. CDKN2A and CDKN2B loss were the most frequent alterations in urothelial tumors (present in 38.5% and 30.4% of patients, respectively). Both genes were less frequently altered in adenocarcinomas (15.2% and 8.9%), but commonly altered in squamous cell carcinomas (74.4% and 39%). Tumors of neuroendocrine origin were relatively silent in activating cyclin alterations, but frequently displayed Rb1 alterations (86% and 83.7% of neuroendocrines and small cell carcinomas). Urachal tumors (n = 79) presented a distinct landscape of cyclin alterations relative to other UT cancers, with less frequent alterations overall. FGF/FGFR genes were altered in 34.9% of urothelial (22.1% in FGFR3), and 19.4% of non-urothelial urinary tract tumors (6.8% FGFR3). Cyclin-activating alterations frequently co-occurred with FGF/FGFR alterations but were in general mutually exclusively with cyclin resistance alterations (RB1/CCNE1). CONCLUSIONS: Cyclin pathway activating alterations are common in urinary tract tumors, but frequency varies with histology and tumors sites. Co-occurrence of cyclin and FGFR pathway alterations may inform therapeutic opportunities.

Molecular Genetic Epidemiology of an Emerging Antimicrobial-Resistant Klebsiella pneumoniae Clone (ST307) Obtained from Clinical Isolates in Central Panama.

Klebsiella pneumoniae has been among the main pathogens contributing to the burden of antimicrobial resistance (AMR) in the last decade, and K. pneumoniae AMR strains predominantly cluster in the ST258 clonal complex. However, ST307 is emerging as an important high-risk clone. In Central America, there have been few studies on the molecular epidemiology of the K. pneumoniae strains involved in infections. MATERIALS AND METHODS: We conducted an epidemiological study in three reference hospitals in the central region of Panama, using isolates of K. pneumoniae involved in infections, and identifying their AMR profile, associated clinical risk factors, and molecular typing using a multilocus sequence typing (ST) scheme. RESULTS: Six STs were detected: 307 (55%), 152, 18, 29, 405, and 207. CTX-M-15- and TEM-type beta-lactamases were identified in 100% of ESBL-producing strains; substitutions in gyrA Ser83Ile and parC Ser80Ile were identified in all ST307s; and in ST152 gyrA Ser83Phe, Asp87Ala, and parC Ser80Ile, the qnrB gene was detected in all strains resistant to ciprofloxacin. CONCLUSIONS: We present the first report on ST307 in three reference hospitals in the central region of Panama, which is a high-risk emerging clone and represents a public health alert for potential difficulties in managing K. pneumoniae infections in Panama, and which may extend to other Central American countries.

How adaptive laboratory evolution can boost yeast tolerance to lignocellulosic hydrolyses.

The yeast Saccharomyces cerevisiae is an excellent candidate for establishing cell factories to convert lignocellulosic biomass into chemicals and fuels. To enable this technology, yeast robustness must be improved to withstand the fermentation inhibitors (e.g., weak organic acids, phenols, and furan aldehydes) resulting from biomass pretreatment and hydrolysis. Here, we discuss how evolution experiments performed in the lab, a method commonly known as adaptive laboratory evolution (ALE), may contribute to lifting yeast tolerance against the inhibitors of lignocellulosic hydrolysates (LCHs). The key is that, through the combination of whole-genome sequencing and reverse engineering, ALE provides a robust platform for discovering and testing adaptive alleles, allowing to explore the genetic underpinnings of yeast responses to LCHs. We review the insights gained from past evolution experiments with S. cerevisiae in LCH inhibitors and propose experimental designs to optimise the discovery of genetic variants adaptive to biomass toxicity. The knowledge gathered through ALE projects is envisaged as a roadmap to engineer superior yeast strains for biomass-based bioprocesses.

Consensus Statement: Importance of Timely Access to Multiple Myeloma Diagnosis and Treatment in Central America and the Caribbean.

Background: In Central America and the Caribbean, multiple myeloma (MM) patients face significant barriers to diagnosis and treatment. The aim of this study is to describe the current situation of MM in the region, discuss the current barriers to timely diagnosis and proper treatment, and develop consensus recommendations to address these issues. Methods: Nine experts from five countries took part in a virtual consensus meeting on MM in Central America and the Caribbean. During the meeting, experts analyzed the disease burden, the current conditions for disease management, and access to treatment in the region. The participants reached a consensus on the extent of the problem and the necessary measures. Results: Hard evidence on the incidence and prevalence of MM in the region is scarce, but the experts perceive an increase in MM cases. The lack of data on the direct and indirect costs at the local and regional levels obscures the impact of the disease and limits awareness among decision-makers. Most patients are diagnosed late and face long waiting times and geographical barriers to access treatment. Access to efficacious innovative therapies that increase survival time is limited due to access barriers within health systems. Conclusions: There was consensus on five recommendations: 1) to generate evidence; 2) to educate the public; 3) to increase timely diagnosis and facilitate access to treatment; 4) to promote interaction, collaboration, and participation among all sectors involved in the decision-making process; and 5) to guarantee timely access to new therapies.

Interplay of Oxidative Stress and Nitric Oxide Synthase Gene Expression on Cardiovascular Responses in Preeclampsia / Interação do estresse oxidativo e da expressão dos genes das óxido nítrico sintases nas respostas cardiovasculares na pré-eclâmpsia

Abstract Objective To assess the influence of oxidative stress on the gene expression of nitric oxide synthases (NOS 3 and NOS 2) and, hence, the cardiovascular responses in preeclampsia. Methods This was a case control study in which patients with preeclampsia (PE group) and normal pregnancy controls (NP group) were included according to the guidelines of the American College of Obstetricians and Gynecologists (ACOG). The serum levels of malondialdehyde (MDA), total antioxidant capacity, and nitric oxide (NO) were estimated, and the heart rate andmean arterial pressure were recorded. The gene profiling of NOS3 and NOS2 was performed through real-time polymerase chain reaction (RT-PCR). The statistical analysis was performed using the Student t-test, and values of p<0.05 were considered statistically significant. Results The serum levels of malondialdehyde were increased (p<0.0001), and the total antioxidant capacity was reduced in the PE group (p=0.034), indicating oxidative stress. In the PE group, themean arterial pressure was significantly higher (p<0.0001), but the serum levels of NO did not show a statistically significant reduction (p=0.20). The gene expression profiling of NOS3 and NOS2 revealed a down regulation in the PE group by 8.49 and 51.05 times respectively. Conclusion Oxidative stress may lead to endothelial dysfunction, which could result in increased mean arterial pressure. Nitric oxide may play a role in this mechanism, but interactions with other vasoactive /biological substances cannot be overlooked, as the gene expression of NOS3 and NOS2 has been reduced.

Resumo Objetivo Avaliar a influência do estresse oxidativo na expressão genética das óxido nítrico sintases (nitric oxide synthases, NOS, em inglês; NOS 3 e NOS 2) e, consequentemente, nas respostas cardiovasculares na pré-eclâmpsia. Métodos Este foi um estudo caso-controle no qual pacientes com pré-eclâmpsia (grupo PE) e controles comgravidez normal (grupo GN) foramincluídos de acordo com as diretrizes do American College of Obstetricians and Gynecologists (ACOG). Foram estimados os níveis séricos de malondialdeído (MDA) da capacidade antioxidante total, e de óxido nítrico (nitric oxide, NO, em inglês). A frequência cardíaca e a pressão arterial média foram registradas. O perfil genético da NOS3 e da NOS2 foi feito por reação em cadeia de polimerase em tempo real (real-time polymerase chain reaction, RT-PCR, em inglês). A análise estatística foi feita utilizando-se o teste t de Student, e valores de p<0,05 foram considerados estatisticamente significativos. Resultados Os níveis séricos de malondialdeído sérico estavam aumentados (p<0,0001), e a capacidade antioxidante total, reduzida no grupo PE (p=0,034), o que indicava estresse oxidativo. No grupo PE, a pressão arterial média era significativamente maior (p<0,0001), mas os níveis séricos de NO não demostraram redução estatisticamente significativa (p=0,20). O perfil de expressão genética da NOS3 e da NOS2 revelou uma regulação negativa no grupo PE de 8,49 e 51,05 vezes, respectivamente. Conclusão O estresse oxidativo pode levar à disfunção endotelial, o que pode resultar em aumento da pressão arterialmédia. O NO pode desempenhar umpapel neste mecanismo, mas as interações com outras substâncias vasoativas/biológicas não podem ser negligenciadas, uma vez que a expressão genética da NOS3 e da NOS2 foi reduzida.

Association between somatotropic axis gene polymorphisms and reproductive efficiency of bovine females: a review / Associação entre polimorfismos de genes do eixo somatotrópico e eficiência reprodutiva de fêmeas bovinas: revisão de literatura

Reproductive characteristics directly reflect on productive performance, as they determine the number of calves born annually and the interval between generations, thereby affecting the selection intensity. This allows for the determination of the most important economic variables that directly affect the production system. The present study is a literature review of somatotropic axis gene polymorphisms that are associated with reproductive functions in heifers and cows (Bos taurus taurus and Bos taurus indicus). The following characteristics were analyzed from the various studies reviewed: number of services per pregnancy (Nº services/ pregnancy), age at first calving (AFC), calving interval (CI), and period of service calving conception interval (CCI). The research was conducted during the period from 2011 to 2021, and associations were found among all indicators of reproductive efficiency evaluated in heifers and cows, with 27 single nucleotide polymorphisms (SNPs): 18 in GHR, 5 in IGF-I, and 4 in STAT5A. This study revealed the relationships between SNPs and the reproductive efficiency indicators and demonstrated that molecular genetic techniques enhance the animal selection process, resulting in more profitable systems that are sustainable in the long term.

Características reprodutivas refletem diretamente no desempenho produtivo visto que são capazes de determinar o número de bezerros nascidos anualmente, além de afetar o intervalo entre gerações e, consequentemente, a intensidade de seleção, fazendo com o que tais atributos sejam apontados como variáveis econômicas das mais importantes que afetam diretamente o sistema de produção. O presente estudo propõe realizar uma revisão de literatura de polimorfismos de genes do eixo somatotrópico associados a funções reprodutivas em novilhas e vacas (Bos taurus taurus e Bos taurus indicus), indicadas pelos índices: número de serviços por gestação (Nº serviços/gestação), idade ao primeiro parto (IPP), intervalo de partos (IP) e período de serviço, como também denominado de intervalo parto-concepção (IPC). As pesquisas encontradas durante o período de 2011 a 2021 demonstraram associações entre todos os indicadores de eficiência reprodutiva analisados de novilhas e vacas com 27 polimorfismos de nucleotídeo único (SNPs), sendo 18 em GHR, 5 em IGF-I e 4 em STAT5A. Dessa forma, este estudo mostrou relação entre os SNPs e os indicadores de eficiência reprodutiva, demonstrando que técnicas de genética molecular potencializam o processo de seleção dos animais, resultando em sistemas mais lucrativos e que se sustentam a longo prazo.

EPSP Synthase-Depleted Cells Are Aromatic Amino Acid Auxotrophs in Mycobacterium smegmatis.

The epidemiological importance of mycobacterial species is indisputable, and the necessity to find new molecules that can inhibit their growth is urgent. The shikimate pathway, required for the synthesis of important bacterial metabolites, represents a set of targets for inhibitors of Mycobacterium tuberculosis growth. The aroA-encoded 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) enzyme catalyzes the sixth step of the shikimate pathway. In this study, we combined gene disruption, gene knockdown, point mutations (D61W, R134A, E321N), and kinetic analysis to evaluate aroA gene essentiality and vulnerability of its protein product, EPSPS, from Mycolicibacterium (Mycobacterium) smegmatis (MsEPSPS). We demonstrate that aroA-deficient cells are auxotrophic for aromatic amino acids (AroAAs) and that the growth impairment observed for aroA-knockdown cells grown on defined medium can be rescued by AroAA supplementation. We also evaluated the essentiality of selected MsEPSPS residues in bacterial cells grown without AroAA supplementation. We found that the catalytic residues R134 and E321 are essential, while D61, presumably important for protein dynamics and suggested to have an indirect role in catalysis, is not essential under the growth conditions evaluated. We have also determined the catalytic efficiencies (Kcat/Km) of recombinant wild-type (WT) and mutated versions of MsEPSPS (D61W, R134A, E321N). Our results suggest that drug development efforts toward EPSPS inhibition may be ineffective if bacilli have access to external sources of AroAAs in the context of infection, which should be evaluated further. In the absence of AroAA supplementation, aroA from M. smegmatis is essential, its essentiality is dependent on MsEPSPS activity, and MsEPSPS is vulnerable. IMPORTANCE We found that cells from Mycobacterium smegmatis, a model organism safer and easier to study than the disease-causing mycobacterial species, when depleted of an enzyme from the shikimate pathway, are auxotrophic for the three aromatic amino acids (AroAAs) that serve as building blocks of cellular proteins: l-tryptophan, l-phenylalanine, and l-tyrosine. That supplementation with only AroAAs is sufficient to rescue viable cells with the shikimate pathway inactivated was unexpected, since this pathway produces an end product, chorismate, that is the starting compound of essential pathways other than the ones that produce AroAAs. The depleted enzyme, the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), catalyzes the sixth step of shikimate pathway. Depletion of this enzyme inside cells was performed by disrupting or silencing the EPSPS-encoding aroA gene. Finally, we evaluated the essentiality of specific residues from EPSPS that are important for its catalytic activity, determined with experiments of enzyme kinetics using recombinant EPSPS mutants.

Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large-Scale Data to Inform Therapeutic Directions.

BACKGROUND: We describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors. METHODS: Using comprehensive genomic profiling (315 genes, >500× coverage), samples were analyzed for alterations in activating/sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), hormone genes (estrogen receptor 1 [ESR1], androgen receptor [AR]), and co-alterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1). RESULTS: Alterations in at least one cyclin activating/sensitizing gene occurred in 24% of malignancies. Tumors that frequently harbored at least one cyclin alteration were brain gliomas (47.1%), esophageal (40.3%) and bladder cancer (37.9%), and mesotheliomas (37.9%). The most frequent alterations included CDKN2A (13.9%) and CDKN2B loss (12.5%). Examples of unique patterns of alterations included CCND1 amplification in breast cancer (17.3%); CDK4 alterations in sarcomas (12%); CCND2 in testicular cancer (23.4%), and SMARCB1 mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors). Alterations in resistance genes RB1 and CCNE1 affected 7.2% and 3.6% of samples. Co-occurrence analysis demonstrated a lower likelihood of concomitant versus isolated alterations in cyclin activating/sensitizing and resistance genes (odds ratio [OR], 0.35; p < .001), except in colorectal, cervical, and small intestine cancers. AR and cyclin activating/sensitizing alterations in prostate cancer co-occurred more frequently (vs. AR alterations and wild-type cyclin activating/sensitizing alterations) (OR, 1.79; p < .001) as did ESR1 and cyclin activating/sensitizing alterations in breast (OR, 1.62; p < .001) and cervical cancer (OR, 4.08; p = .04) (vs. ESR1 and cyclin wild-type activating/sensitizing alterations). CONCLUSION: Cyclin pathway alterations vary according to tumor type/histology, informing opportunities for targeted therapy, including for rare cancers. IMPLICATIONS FOR PRACTICE: Cyclin pathway genomic abnormalities are frequent in human solid tumors, with substantial variation according to tumor site and histology. Opportunities for targeted therapy emerge with comprehensive profiling of this pathway.

Dento-osseous anomalies in patients with familial adenomatous polyposis: A follow-up study.

OBJECTIVE: The aim of this longitudinal study was to characterize the dento-osseous phenotype of eleven familial adenomatous polyposis (FAP) patients and twenty-two family members from four Brazilian families who were followed over nine years and to investigate adenomatous polyposis coli (APC) gene variants using a targeted next-generation sequencing approach. MATERIALS AND METHODS: Medical and dental history, oral examination, and panoramic radiography were performed to diagnose and follow up the dento-osseous anomalies. The anomalies were evaluated following the validated diagnostic tool dental panoramic radiographic score (DPRS), a system developed for high-risk FAP patients. Patients diagnosed with dento-osseous anomalies underwent cone-beam computed tomography. For genetic analysis, DNA was isolated from patients' saliva. RESULTS: Dento-osseous anomalies were identified in ten of the eleven FAP patients by panoramic radiograph evaluation. DPRS ≥ 7 (significant changes) was found in 81.8% (9/11) of FAP patients. The follow-up showed an increase in osseous jaw lesions in two young patients during adolescence. Dento-osseous anomalies were not found in non-FAP patients. A novel heterozygous nonsense pathogenic variant in APC exon 5 (c.481C > T; p.Gln161*) was identified in family 2, and a heterozygous splice-site pathogenic variant was identified in family 1 (c.532-1G > A). CONCLUSION: Our study expands the mutation spectrum of the APC gene and provides evidence that dento-osseous screening by imaging is a putative tool for early diagnosis of FAP. Also, the detection of dento-osseous anomalies in young patients with increasing osseous lesions during adolescence highlights the need for dental follow-up of high-risk FAP children. CLINICAL RELEVANCE: Dental radiographs are important for the screening and the follow-up of dento-osseous anomalies associated with FAP. It can also contribute to the early diagnosis of the disease.

miRNAs as biomarkers of orofacial clefts: A systematic review.

Orofacial clefts are facial malformations caused by the improper development of the lips and palate. Many genetic and epigenetic molecules have been involved in the mechanisms of orofacial clefts, one of which are miRNAs. This systematic review aimed to identify miRNAs associated to non-syndromic orofacial clefts in humans. After applying a series of criteria, four studies were selected for analysis. In total, one hundred miRNAs were observed in the literature, of which 57 were reported as upregulated and 43 as downregulated in all orofacial cleft classifications. Moreover, nine miRNAs were differentially expressed only in cleft palate patients, which might suggest distinct regulatory mechanisms for the etiology of cleft lips and palates. We suggest broader population sampling in order to include diverse ethnic groups in the future, as well as analyses toward identifying miRNA target genes and pathways. We highlight the need for experimental validation and of these results to allow further translational approaches and clinical applications.

Mutations in renal cell carcinoma.

Renal cell carcinoma (RCC) is a commonly diagnosed and histologically diverse urologic malignancy. Clear cell RCC (ccRCC) is by far the most common, followed by the papillary and chromophobe subtypes. Sarcomatoid differentiation is a morphologic change that can be seen in all subtypes that typically portends a poor prognosis. In the past, treatment options for RCC were limited to cytokine-based therapy with a high-toxicity profile and low response rate. An increased understanding of the molecular basis of RCC has led to substantial improvement in treatment options in the form of targeted therapy and immunotherapy. A significant early discovery in RCC was frequent inactivation of the Von Hippel Lindau gene in ccRCC, which ultimately led to the development of vascular endothelial growth factor and mammalian target of rapamycin inhibitors. Further genomic sequencing of ccRCC tumors has identified other common mutations including BAP-1, PBRM1, SETD2, and PIK3CA. Many recent studies have explored how these mutations can affect prognosis and response to treatment. Likewise, papillary RCC has also been studied at the molecular level, which has shown a high level of mutations in the MET gene; early clinical data suggest the utility of MET targeted therapy. Finally, regarding the rarer sarcomatoid tumors, mutations in TP53 and NF2 may be important to their development. As we continue to learn more about what drives RCC at the molecular level, treatment options for RCC patients are diversifying.

El paciente hemofílico: consideraciones clínicas y moleculares de importancia para el odontólogo / Hemophilic patients: clinical and molecular considerations of interest to dentists

RESUMEN Introducción: La hemofilia es una enfermedad genética poco frecuente en la consulta odontológica. En algunas situaciones se presenta como una urgencia odonto-estomatológica, en la que el profesional debe relacionar las manifestaciones clínicas generales de la enfermedad, con una correcta semiología, paraclínicos y análisis genético-molecular, para diagnosticar y aplicar pertinentes terapéuticas dirigidas a resolver el motivo de consulta del paciente así como el manejo y control de sus complicaciones. Objetivo: Describir los principales aspectos fisiopatológicos generales y de importancia odontológica de la hemofilia, así como las herramientas diagnósticas desde el punto de vista clínico, paraclínico y genético-molecular. Métodos: Búsqueda bibliográfica en las bases de datos Pubmed, Proquest, Scielo y Elsevier, en idioma inglés y español, en las que se seleccionaron artículos publicados en un periodo de 13 años para un total de 50 (2005-2018), empleando los descriptores "hemophilia A, hemophilia B, diagnostic criteria, genetic, molecular, oral health, clinical diagnosis". Análisis e integración de la información: Los estudios han demostrado que la hemofilia, una condición genética y sistémica, tiene repercusiones bucales en el contexto de sus manifestaciones y complicaciones, lo que la hace importante para el odontólogo, debido a que debe ser diagnosticada desde el punto de vista genético-molecular y manejada interdisciplinariamente. Conclusiones: La implicación del diagnóstico genético-molecular por parte del genetista soporta la integración del hematólogo y el odontólogo para el manejo y control de la interconsulta cuando se trata de pautar procedimientos en pacientes con hemofilia(AU)

ABSTRACT Introduction: Hemophilia is a genetic disease scarcely found in dental practice. On occasion it presents as a dental emergency in face of which the professional should relate the general clinical manifestations of the disease to an appropriate semiological, paraclinical and genetic-molecular analysis to diagnose the condition and apply relevant therapies aimed at solving the patient's main concern as well as managing and controlling its complications. Objective: Describe the main general pathophysiological features and aspects of dental interest of hemophilia, as well as the diagnostic tools related to the condition from a clinical, paraclinical and genetic-molecular perspective. Methods: A bibliographic search was conducted in the databases Pubmed, Proquest, Scielo and Elsevier of papers published in English and Spanish in a period of 13 years (2005-2018), using the search terms "hemophilia A", "hemophilia B", "diagnostic criteria", "genetic", "molecular", "oral health", "clinical diagnosis". A total 50 papers were selected. Data analysis and integration: Studies have shown that hemophilia, a genetic systemic condition, may have oral manifestations and complications. This makes it important to dentists, since the disease should be diagnosed from a genetic-molecular point of view and managed in an interdisciplinary manner. Conclusions: Genetic-molecular diagnosis by geneticists implies involvement of hematologists and dentists in the management and control of the condition via interconsultation, when it comes to deciding on procedures for hemophilic patients(AU)

Genetic Screening of the Usher Syndrome in Cuba.

BACKGROUND: Usher syndrome (USH) is a recessive inherited disease characterized by sensorineural hearing loss, retinitis pigmentosa, and sometimes, vestibular dysfunction. Although the molecular epidemiology of Usher syndrome has been well studied in Europe and United States, there is a lack of studies in other regions like Africa or Central and South America. METHODS: We designed a NGS panel that included the 10 USH causative genes (MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, ADGRV1, WHRN, and CLRN1), four USH associated genes (HARS, PDZD7, CEP250, and C2orf71), and the region comprising the deep-intronic c.7595-2144A>G mutation in USH2A. RESULTS: NGS sequencing was performed in 11 USH patients from Cuba. All the cases were solved. We found the responsible mutations in the USH2A, ADGRV1, CDH23, PCDH15, and CLRN1 genes. Four mutations have not been previously reported. Two mutations are recurrent in this study: c.619C>T (p.Arg207∗) in CLRN1, previously reported in two unrelated Spanish families of Basque origin, and c.4488G>C (p.Gln1496His) in CDH23, first described in a large Cuban family. Additionally, c.4488G>C has been reported two more times in the literature in two unrelated families of Spanish origin. CONCLUSION: Although the sample size is very small, it is tempting to speculate that the gene frequencies in Cuba are distinct from other populations mainly due to an "island effect" and genetic drift. The two recurrent mutations appear to be of Spanish origin. Further studies with a larger cohort are needed to elucidate the real genetic landscape of Usher syndrome in the Cuban population.

10q23.31 microduplication encompassing PTEN decreases mTOR signalling activity and is associated with autosomal dominant primary microcephaly.

BACKGROUND: Hereditary primary microcephaly (MCPH) is mainly characterised by decreased occipitofrontal circumference and variable degree of intellectual disability. MCPH with a dominant pattern of inheritance is a rare condition, so far causally linked to pathogenic variants in the ALFY, DPP6, KIF11 and DYRK1A genes. OBJECTIVE: This study aimed at identifying the causative variant of the autosomal dominant form of MCPH in a Brazilian family with three affected members. METHODS: Following clinical evaluation of two sibs and their mother presenting with autosomal dominant MCPH, array comparative genome hybridisation was performed using genomic DNA from peripheral blood of the family members. Gene and protein expression studies were carried out in cultured skin fibroblasts. RESULTS: A 382 kb microduplication at 10q23.31 was detected, encompassing the entire PTEN, KLLN and ATAD1 genes. PTEN haploinsufficiency has been causally associated with macrocephaly and autism spectrum disorder and, therefore, was considered the most likely candidate gene to be involved in this autosomal dominant form of MCPH. In the patients' fibroblasts, PTEN mRNA and protein were found to be overexpressed, and the phosphorylation patterns of upstream and downstream components of the mammalian target of rapamycin (mTOR) signalling pathway were dysregulated. CONCLUSIONS: Taken together, our results demonstrate that the identified submicroscopic 10q23.31 duplication in a family with MCPH leads to markedly increased expression of PTEN and reduced activity of the mTOR signalling pathway. These results suggest that the most probable pathomechanism underlying the microcephaly phenotype in this family involves downregulation of the mTOR pathway through overexpression of PTEN.

CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures.

BACKGROUND: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is an autosomal recessive disorder caused by pathogenic variants of the conserved telomere maintenance component 1 (CTC1) gene. The CTC1 forms the telomeric capping complex, CST, which functions in telomere homeostasis and replication. METHODS: A Brazilian pedigree and an Australian pedigree were referred to the International Registry of Werner Syndrome (Seattle, WA, USA), with clinical features of accelerated aging and recurrent bone fractures. Whole exome sequencing was performed to identify the genetic causes. RESULTS: Whole exome sequencing of the Brazilian pedigree revealed compound heterozygous pathogenic variants in CTC1: a missense mutation (c.2959C>T, p.Arg987Trp) and a novel stop codon change (c.322C>T, p.Arg108*). The Australian patient carried two novel heterozygous CTC1 variants, c.2916G>T, p.Val972Gly and c.2926G>T, p.Val976Phe within the same allele. Both heterozygous variants were inherited from the unaffected father, excluding the diagnosis of CRMCC in this pedigree. Cell biological studies demonstrated accumulation of double strand break foci in lymphoblastoid cell lines derived from the patients. Increased DSB foci were extended to non-telomeric regions of the genome, in agreement with previous biochemical studies showing a preferential binding of CTC1 protein to GC-rich sequences. CONCLUSION: CTC1 pathogenic variants can present with unusual manifestations of progeria accompanied with recurrent bone fractures. Further studies are needed to elucidate the disease mechanism leading to the clinical presentation with intra-familial variations of CRMCC.