Homologous recombination deficiency gene panel analysis results in synchronous endometrial and ovarian cancers

SUMMARY OBJECTIVE: The objective of this study was to analyze the genetic alterations of tumors within the scope of the homologous recombination deficiency gene panel in patients diagnosed with synchronous endometrial ovarian cancer who have been followed for over 5 years using next-generation sequencing. METHODS: DNA was isolated from the patient's formalin-fixed, paraffin-embedded tissue blocks. Next-generation sequencing was performed using the Illumina capture-based sequencing method. Samples were sequenced using the Sophia HR Solution DNA Kit. RESULTS: Seven patients were included in this study. The ratios of likely pathogenic (LP)/pathogenic (P) somatic mutations in ATM (serine/threonine kinase or Ataxia-telangiectasia mutated gene), BRCA2 (breast cancer type 2 susceptibility gene), BARD1 (BRCA1 associated RING domain 1), TP53 (tumor protein p53), BIRP1 (BRCA1-interacting helicase 1 gene), PALB2 (partner and localizer of BRCA2), and CHECK2 were 21 (48.8%), 8 (18.6%), 5 (11.6%), 3 (6.9%), 2 (4.6%), 2 (4.6%), and 2 (4.6%), respectively, in endometrium, and the ratios of somatic mutations in ATM, BRCA2, TP53, BARD1, RAD54L (DNA repair/recombination protein like), BIRP1, and RAD51D (RAD51 recombinase paralog D) were 24 (60%), 6 (15%), 5 (12.5%), 2 (5%), 2 (5%), 1 (2.5%), and 1 (2.5%), respectively, in ovary. In endometrioid-synchronous endometrial ovarian cancer cases, P/LP mutations were observed in ATM and CHECK2 genes in endometrium and ATM, BRCA2, and TP53 genes in ovary. In two non-endometrioid-synchronous endometrial ovarian cancer cases, CHEK2 (checkpoint kinase 2) mutations were observed in endometrium and ATM and TP53 mutations in ovary, whereas in one case, P/LP mutations in ATM and TP53 genes were common in both tissues. CONCLUSION: Pathogenic variations confirming the diagnosis of synchronous endometrial ovarian cancer with genetic alterations were identified in all but one case. ATM gene mutation emerged as the most common alteration and has a potential association with a favorable prognosis.

Oromandibular dystonia as a cause of temporomandibular disorder (Case report) / Distonia oromandibular como causa de disfunção temporomandibular (Relato de caso)

Temporomandibular disorders (TMD) can have multiple etiologies, including oromandibular dystonia (OMD). However, in a few cases, the OMD can evolve from cervical dystonia (CD), leading to severe bone degeneration. The purpose of this case report of a 64-year-old woman presenting to the Outpatient Neurology Clinic of the Federal University of Bahia is to illustrate the development of oromandibular dystonia with temporomandibular joint (TMJ) dysfunction after 10 years of cervical dystonia. Clinical examination showed bone degeneration of the mandibular ramus and right TMJ click, a prevalent sound in patients with temporomandibular disorders when they open their mouths or chew. After onabotulinum toxin type A injections in the right lateral pterygoid muscle, the patient improved in swallowing and pain. This case highlights the importance of close follow-up of cervical dystonia patients to identify new dystonic muscles. In our patient, lateral pterygoid muscle involvement was followed by several comorbidities, such as dysphagia and jawbone abnormalities.

Os distúrbios temporomandibulares (DTM) podem ter múltiplas etiologias, incluindo a distonia oromandibular (DO). No entanto, em raros casos, a DO pode evoluir a partir da distonia cervical (DC) e raramente pode levar a degeneração óssea. O objetivo deste relato de caso de uma mulher de 64 anos atendida no Ambulatório de Neurologia da universidade Federal da Bahia é ilustrar o desenvolvimento de distonia oromandibular com disfunção da articulação temporomandibular (ATM) após 10 anos de distonia cervical. O exame clínico mostrou degeneração óssea do ramo mandibular e clique na ATM direita, um som prevalente em pacientes com distúrbios temporomandibulares quando abrem a boca ou mastigam. Após injeções de toxina botulínica tipo A no músculo pterigoideo lateral direito, a paciente apresentou melhora na deglutição e na dor. Este caso destaca a importância do acompanhamento próximo de pacientes com distonia cervical para identificar novos músculos distônicos. Em nossa paciente, o envolvimento do músculo pterigoide lateral foi seguido por várias comorbidades, como disfagia e anormalidades ósseas da mandíbula.

Contribuições ao uso coerente da artroscopia em distúrbios temporomandibular / Contributions to the coherent use of arthroscopy in temporomandibular disorders

A artroscopia temporomandibular representa um importante procedimento para o diagnóstico e tratamento de distúrbios na articulação temporomandibular. É indicada quando diagnósticos menos invasivos não são conclusivos, proporcionando uma abordagem direta para examinar a articulação e permitindo uma visualização detalhada das estruturas internas. Além disso, a artroscopia temporomandibular representa uma alternativa menos invasiva em comparação com procedimentos cirúrgicos mais tradicionais. Com incisões menores e uma abordagem mais direta, ela oferece aos pacientes a possibilidade de uma recuperação mais rápida e menos desconfortável, tornando-a uma opção atraente para aqueles que buscam alívio dos sintomas da DTM com menor tempo de inatividade e menor impacto na qualidade de vida. Uma visão holística da doença é de fundamental importância para o sucesso do tratamento... (AU)

Multilocus inherited neoplasia allele syndrome: report of uncommon combinations between CHEK2/ATM and BRCA1/CDKN2A genes.

Background: Multilocus inherited neoplasia allelic syndrome (MINAS) is a recently coined term that describes the coexistence of two or more pathogenic variants (PVs) in cancer susceptibility genes (CSGs) in a single individual. Case presentation: This article presents two cases of MINAS due to rare CSG combinations. The first was a 37-year-old woman carrying PVs in the mutated ataxia telangiectasia (ATM) and CHEK2 genes, with HER-2 positive unilateral breast cancer at 29. The second was a 53-year-old woman carrying PVs in the BRCA1 and CDKN2A genes, who presented with triple-negative breast cancer at 51. We describe their family history and treatment, where the lack of evidence for personalised management becomes evident. Conclusion: Predicting the phenotypic effect of harbouring two variants in CSG is challenging. It is essential to encourage the notification of other cases and carry out functional studies to establish specific risks for affected individuals to develop personalised follow-up guidelines to reduce the associated morbimortality.

Signos y Síntomas en 3557 Pacientes con Trastornos Temporomandibulares

Los trastornos temporomandibulares (TTM) tienen una alta frecuencia en la población y pueden presentar síntomas en la región de la cabeza, el oído y la región cervical. Este estudio evalúa la presencia de signos y síntomas en la región de la cabeza y el cuello, incluyendo: cefalea, trastornos del oído, y de la columna vertebral, en una población de 3557 pacientes con TTM. Para este estudio los datos consistieron en los registros de 3557 pacientes consecutivos de TTM referidos a una clínica privada de trastornos temporomandibulares y dolor craneofacial, en Santiago de Chile entre 1998 y 2019. El examen y los registros fueron efectuados por uno los autores (RW), en un programa computacional previamente diseñado. Los resultados fueron analizaron utilizando la distribución de la frecuencia de los datos para evaluar la prevalencia. En esta serie 72.67 % correspondieron a pacientes de sexo femenino. Los síntomas más prevalentes reportados por los 3557 pacientes estudiados fueron rigidez en el cuello 65,25 %, cefaleas 61,01 % y dolor lumbar 57,16 %. Los síntomas relacionados con el oído fueron: mareos en el 46,70 %, dolor de oídos en 32,64 % y tinnitus en el 33,60 % de los pacientes. La asimetría facial estuvo presente en el 74.08 % de los 3557 pacientes. Se observó desviación mandibular en apertura bucal, en el 74.44 % de los 3557 pacientes. Se presentó dolor a la palpación muscular en un alto porcentaje de los pacientes, en los músculos temporales, maseteros, esternocleidomastoideo y trapecio, Este estudio nos permite describir la frecuencia de los signos y síntomas que presentan los pacientes con TTM en una amplia casuística.

Temporomandibular disorders (TMD) are frequently associated with other conditions in the head, ear and neck region, including cervical spine disorders and headache. This study evaluates the presence of signs and symptoms in the head and neck region, including headache, ear disorders, cervical and spine disorders, on a population of 3557 patients with TMD. For this study data consisted of the records of 3557 consecutive TMD patients referred to a temporomandibular disorder and craniofacial pain private clinic in Santiago, Chile between 1998 and 2019. The examination and recordings were made by all the authors. The results were analyzed using the distribution of frequency of the data to asses prevalence. The most prevalent symptoms reported by the 3557 subjects were neck stiffness 65.25 %, headaches 61.01 % and low back pain 57.16 %, the most frequent ear symptom was dizziness 46.70 %. The present study analize the frecuency of signs and symptons presented in a big casuistic of patients with TMD.

Comparación de sistemas de evaluación diagnóstica de la severidad de la osteoartrosis en imágenes de TAC de las ATM / comparison of diagnostic systems for the assessment of the severity of osteoarthrosis in CT images of the TMJ

Objetivo: Comparar y validar sistemas diagnósticos de severidad de Osteoartrosis (OA) de las articulaciones temporomandibulares (ATM) en imágenes de tomografía computada (TAC). Método: Se efectuó un estudio observacional, retrospectivo, analítico y ciego. Se evaluaron 99 pacientes (198TAC-ATM), aplicando los criterios de siete diferentes sistemas diagnósticos. Un clínico calibrado (K=0,7) efectuó las evaluaciones. La validez de contenido se efectuó bajo los criterios Ahmad. La consistencia interna se determinó con Alpha de Cronbach. Se correlacionaron los datos con Rho de Spearman. Resultados: La severidad de la erosión condilar presenta alta correlación positiva entre las clasificaciones Alexiou/Arayasantiparb (rho=0,986) y baja entre Cömert/Alexiou (rho=0,421) y Cömert/Arayasantiparb (rho=0,422). La esclerosis condilar presentó fuerte correlación entre las clasificaciones de Cömert/Alexiou, Masilla/Alexiou y Cömert/Masilla (rho=857;rho=0,853;rho=0,998). Los datos presentaron alta consistencia interna (Alfa Cronbach=0,897) y baja validación de contenido (36,2%). Conclusiones: Las mediciones de los 7 sistemas presentan alta fiabilidad. La erosión ósea, esclerosis y osteofitos son medidos en cuatro niveles de severidad y con similar escala en tres sistemas de diagnóstico (Alexiou, Arayasantiparb y Cömert), sugiriendose complementar con determinación del espacio articular y movilidad condilar, como propone RDC/TMD para TTM. La validación de contenido fue baja, solo los sistemas diagnósticos de Cömert y Alexiou superaron el 50%.

Objective: To compare and validate diagnostic systems for the severity of Osteoarthrosis (OA) of the temporomandibular joints (TMJ) in computed tomography (CT) images. Method: An observational, retrospective, analytical, blinded, retrospective study was performed. Ninety-nine patients (198MSCT-ATM) were evaluated, applying the criteria of seven different diagnostic systems. A calibrated clinician (K=0.7) performed the evaluations. Content validity was performed under the Ahmad criteria. Internal consistency was determined with Cronbach's Alpha. Data were correlated with Spearman's Rho. Results: For condylar erosion severity, there was a high positive correlation between Alexiou/Arayasantiparb (rho=0.986) and a low one between Cömert/Alexiou (rho=0.421) and Cömert/Arayasantiparb (rho=0.422) classifications. For condylar sclerosis, we found a strong correlation between Cömert/Alexiou, Masilla/Alexiou and Cömert/Masilla classifications (rho=857; rho=0.853; rho=0.998). The data presented high internal consistency (Cronbach's alpha=0.897) and low content validation (36.2%). Conclusions: The measurements of the 7 systems have a high reliability. Bone erosion, sclerosis and osteophytes are measured at four levels of severity and with a similar scale in three diagnostic systems (Alexiou, Arayasantiparb and Cömert). We suggest to complement it with the determination of joint space and condylar mobility, as proposed by RDC/TMD. Content validity was low, only the Cömert and Alexiou diagnostic systems were higher than 50%.

Somatic and germline ATM variants in non-small-cell lung cancer: Therapeutic implications.

ATM is an apical kinase of the DNA damage response involved in the repair of DNA double-strand breaks. Germline ATM variants (gATM) have been associated with an increased risk of developing lung adenocarcinoma (LUAD), and approximately 9% of LUAD tumors harbor somatic ATM mutations (sATM). Biallelic carriers of pathogenic gATM exhibit a plethora of immunological abnormalities, but few studies have evaluated the contribution of immune dysfunction to lung cancer susceptibility. Indeed, little is known about the clinicopathological characteristics of lung cancer patients with sATM or gATM alterations. The introduction of targeted therapies and immunotherapies, and the increasing number of clinical trials evaluating treatment combinations, warrants a careful reexamination of the benefits and harms that different therapeutic approaches have had in lung cancer patients with sATM or gATM. This review will discuss the role of ATM in the pathogenesis of lung cancer, highlighting potential therapeutic approaches to manage ATM-deficient lung cancers.

Effectiveness of the therapeutic laser in the syndrome of dysfunction of the temporomandibular joint of arthrogenic origin / Eficacia del láser terapéutico en el síndrome de disfunción de la articulación temporomandibular de origen artrogénico

Abstract Temporomandibular joint dysfunction syndrome (TMD), is a collective term characterized by symptoms involving chewing muscles, temporomandibular joint and orofacial structures. The efficacy of low intensity laser (LLLT) Gallium arsenide, in combination with a non-steroidal anti-inflammatory drug (NSAID) was evaluated. The main objective was to evaluate the maximum mouth opening without pain (ABM), arthralgia in the joint capsule through visual analog scale (VAS), laterality, protrusion, joint noises and count of tablets ingested per group. A controlled clinical trial (double-blind-randomized) was carried out in 30 subjects, who presented DTM of arthrogenic etiology; 5 applications of LLLT were made with wavelength of 810 nm, output optical power of 100-200 mw, emission PW=Pulsed (1-10,000Hz), dose of 10 jouls-cm², time of 1.44 minutes in mouth closed and with the mouth half open. One more follow-up appointment per month. There were two groups: experimental and control group, where different variables were analyzed (ABM, laterality, protrusion, VAS and sociodemographic). In the control group, a supposed LT application (not active) was made, for later comparison. Pain-free ABM was assessed in all appointments in addition to the other clinical parameters. Repeated measures analysis was performed with mixed models. Thirty patients were included of which 28 finished the treatment, two of them were lost during follow-up. The groups were similar in all their baseline variables. There were no statistically significant differences when applying the final multiple regression analysis, in the ABM, or in any other of the clinical parameters analyzed. LT was not effective in treating arthrogenic DTM.

Resumen El síndrome de disfunción de la articulación temporomandibular (DTM) es un término colectivo caracterizado por síntomas que involucran músculos de la masticación, articulación temporomandibular y estructuras orofaciales. Se evaluó la eficacia del láser de baja intensidad (LLLT) Arseniuro de galio, en combinación con un antiinflamatorio no esteroideo (AINE). El objetivo principal fue evaluar la apertura bucal máxima sin dolor (ABM), la artralgia en cápsula articular a través de escala visual análoga (EVA), lateralidades, protrusión, ruidos articulares y conteo de tabletas ingeridas por grupo. Se realizó un ensayo clínico controlado (doble ciego-aleatorizado) en 30 sujetos, que presentaban DTM de etiología artrogénica; se les realizaron 5 aplicaciones de LLLT con longitud de onda de 810 nm, potencia óptica de salida de 100-200 mw, emisión PW=Pulsed (1-10,000Hz), dosis de10 jouls-cm², tiempo de1.44 minutos a boca cerrada y con la boca semiabierta. Una cita más de seguimiento al mes. Se tuvieron dos grupos: experimental y grupo control, donde se analizaron diferentes variables (ABM, lateralidades, protrusión, EVA y sociodemográficas). En el grupo control se hizo una supuesta aplicación LT (no activo), para posterior comparación. En todas las citas se valoró la ABM sin dolor además de los otros parámetros clínicos. Se realizó análisis de medidas repetidas con modelos mixtos. Se incluyeron 30 pacientes de los cuales 28 finalizaron el tratamiento, dos de ellos se perdieron en el seguimiento. Los grupos fueron similares en todas sus variables basales. No hubo diferencias estadísticas significativas al aplicar los análisis de regresión múltiple finales, en la ABM, ni tampoco en ningún otro de los parámetros clínicos analizados. El LT no fue eficaz en el tratamiento de la DTM de origen artrogénico.

Hereditary Breast Cancer in the Brazilian State of Ceará (The CHANCE Cohort): Higher-Than-Expected Prevalence of Recurrent Germline Pathogenic Variants.

Purpose: There is a significant lack of epidemiological data on hereditary cancer in Northeast Brazil. This is the largest study on the prevalence and mutational spectrum of cancer predisposition genes conducted in this region and the first in the State of Ceará. Methods: Patients ≥18 years of age that were referred to CHANCE (Grupo de Câncer Hereditário do Ceará) from March 2014 to December 2020 with testing criteria for breast cancer susceptibility genes according to NCCN v.1.2021 were eligible to participate. The inclusion of patients was limited to one individual per family and to those born in the State of Ceará. All patients underwent a hereditary cancer panel testing with at least 30 genes. Results: A total of 355 patients were included, and 97 (27.3%) carried a P/LP germline variant in 18 different genes. Among the 97 P/LP carriers, BRCA1 (31, 31.9%) and BRCA2 (25, 25.7%) were the most frequently mutated genes, followed by PALB2 (10, 10.3%), CHEK2 (7, 7.2%) and ATM (4, 4.1%). A small number of recurrent variants (detected in three or more individuals) in BRCA1, BRCA2, CHEK2 and ATM represented the majority of the P/LP variants described in this cohort. Conclusion: In this cohort, the prevalence of L/PL was high, particularly involving the BRCA1, BRCA2, PALB2, CHEK2 and ATM genes and, to a lesser extent than expected, the TP53 gene. A high frequency of recurrent variants was also observed, for which further and larger analyses should clarify the presence of any possible founder effect. Characterizing the mutational profile of cancer predisposition genes in diverse populations may contribute to cancer prevention and therapeutic management.

ATM Pathway Is Essential for HPV-Positive Human Cervical Cancer-Derived Cell Lines Viability and Proliferation.

Infection with some mucosal human papillomavirus (HPV) types is the etiological cause of cervical cancer and of a significant fraction of vaginal, vulvar, anal, penile, and head and neck carcinomas. DNA repair machinery is essential for both HPV replication and tumor cells survival suggesting that cellular DNA repair machinery may play a dual role in HPV biology and pathogenesis. Here, we silenced genes involved in DNA Repair pathways to identify genes that are essential for the survival of HPV-transformed cells. We identified that inhibition of the ATM/CHK2/BRCA1 axis selectively affects the proliferation of cervical cancer-derived cell lines, without altering normal primary human keratinocytes (PHK) growth. Silencing or chemical inhibition of ATM/CHK2 reduced the clonogenic and proliferative capacity of cervical cancer-derived cells. Using PHK transduced with HPV16 oncogenes we observed that the effect of ATM/CHK2 silencing depends on the expression of the oncogene E6 and on its ability to induce p53 degradation. Our results show that inhibition of components of the ATM/CHK2 signaling axis reduces p53-deficient cells proliferation potential, suggesting the existence of a synthetic lethal association between CHK2 and p53. Altogether, we present evidence that synthetic lethality using ATM/CHK2 inhibitors can be exploited to treat cervical cancer and other HPV-associated tumors.

Alternative end-joining originates stable chromosome aberrations induced by etoposide during targeted inhibition of DNA-PKcs in ATM-deficient tumor cells.

ATM and DNA-PKcs coordinate the DNA damage response at multiple levels following the exposure to chemotherapy. The Topoisomerase II poison etoposide (ETO) is an effective chemotherapeutic agent that induces DNA double-strand breaks (DSB), but it is responsible from the chromosomal rearrangements frequently found in therapy-related secondary tumors. Targeted inhibition of DNA-PKcs in ATM-defective tumors combined with radio- or chemotherapy has been proposed as relevant therapies. Here, we explored the DNA repair mechanisms and the genetic consequences of targeting the non-oncogenic addiction to DNA-PKcs of ATM-defective tumor cells after exposure to ETO. We demonstrated that chemical inhibition of DNA-PKcs followed by treatment with ETO resulted in the accumulation of chromatid breaks and decreased mitotic index in both A-T cells and ATM-knocked-down (ATMkd) tumor cells. The HR repair process in DNA-PKcs-inhibited ATMkd cells amplified the RAD51 foci number, with no correlated increase in sister chromatid exchanges. The analysis of post-mitotic DNA lesions presented an augmented number of persistent unresolved DSB, without alterations in the cell cycle progression. Long-term examination of chromosome aberrations revealed a strikingly high number of chromatid and chromosome exchanges. By using genetic and pharmacological abrogation of PARP-1, we demonstrated that alternative end-joining (alt-EJ) repair pathway is responsible for those chromosome abnormalities generated by limiting c-NHEJ activities during directed inhibition of DNA-PKcs in ATM-deficient cells. Targeting the non-oncogenic addiction to DNA-PKcs of ATM-defective tumors stimulates the DSB repair by alt-EJ, which is liable for the origin of cells carrying stable chromosome aberrations that may eventually restrict the therapeutic strategy.

Profile of explosives's use in ATMs/cash safes robberies in Brazil.

This retrospective study reports data obtained by the Federal Police's National Institute of Criminalistics (INC-PF) relating to chemical analysis aimed at identifying explosives used in Automated teller machines (ATMs)/cash safes robberies between 2014 and 2020 in Brazil. 93 Real cases were studied and, based on the analysis carried out on the materials related to these cases, focusing on the type of explosive used, the following distribution profile was obtained: I) explosive mixtures based on chlorates and/or perchlorates (53%); explosive emulsion (22%); black gunpowder (13%); negative/inconclusive (11%) and organic - pentaerythritol tetranitrate (PETN) (1%). These results can contribute to investigations related to diversion/loss of explosives for criminal purposes, indicating, for example, through relationships between prevalence in the use of a certain type of explosive with a certain location, its possible origin (mining industry, explosive industries, fireworks factories, among others). The profile observed in the results can guide the selection of explosives to be studied in future research, as the possibilities are vast. Furthermore, despite the expressive number of occurrences in Brazil in the period of interest of this study, only a small fraction of samples was sent to the forensic chemistry laboratory to identify the explosive involved, which suggests that expanding chemical analysis should be encouraged in this field. In combination with an increase in professional training and collaboration trials between the laboratories, these activities can improve the chemical explosive's profile in Brazil, enabling the search for correlations between occurrences and contributing to the growth and development of this area.

Low-power infrared laser modulates mRNA levels from genes of base excision repair and genomic stabilization in heart tissue from an experimental model of acute lung injury.

The aim of this study was to evaluate photobiomodulation effects on mRNA relative levels from genes of base excision repair and genomic stabilization in heart tissue from an experimental model of acute lung injury by sepsis. For experimental procedure, animals were randomly assigned to six main groups: (1) control group was animals treated with intraperitoneal saline solution; (2) LASER-10 was animals treated with intraperitoneal saline solution and exposed to an infrared laser at 10 J cm-2; (3) LASER-20 was animals treated with intraperitoneal saline solution and exposed to an infrared laser at 20 J cm-2; (4) acute lung injury (ALI) was animals treated with intraperitoneal LPS (10 mg kg-1); (5) ALI-LASER10 was animals treated with intraperitoneal LPS (10 mg kg-1) and, after 4 h, exposed to an infrared laser at 10 J cm-2 and (6) ALI-LASER20 was animals treated with intraperitoneal LPS (10 mg kg-1) and, after 4 h, exposed to an infrared laser at 20 J cm-2. Irradiation was performed only once and animal euthanasias for analysis of mRNA relative levels by RT-qPCR. Our results showed that there was a reduction of mRNA relative levels from ATM gene and an increase of mRNA relative levels from P53 gene in the heart of animals with ALI when compared to the control group. In addition, there was an increase of mRNA relative levels from OGG1 and APE1 gene in hearts from animals with ALI when compared to the control group. After irradiation, an increase of mRNA relative levels from ATM and OGG1 gene was observed at 20 J cm-2. In conclusion, low-power laser modulates the mRNA relative levels from genes of base excision repair and genomic stabilization in the experimental model of acute lung injury evaluated.

Biomarcadores inflamatorios en líquido sinovial de trastornos intraarticulares de la articulación temporomandibular. Revisión sistemática / Inflammatory biomarkers in synovial fluid of intra-articular disorders of the temporomandibular joint. Systematic review

RESUMEN Objetivo: Determinar los biomarcadores inflamatorios del líquido sinovial (LS) de pacientes adultos con trastornos intraarticulares (TI) de la articulación temporomandibular (ATM) y su capacidad diagnóstica. Métodos: Se realizó búsqueda electrónica/manual de artículos (2010-2019) en paralelo por dos investigadores. La calidad de los estudios, se determinó por medio de CONSORT y STROBE y el sesgo según criterios Cochrane RoB 2 en ensayos clínicos aleatorizados y Escala Newcastle-Ottawa en estudios observacionales. Se estudiaron pacientes con TI de la ATM y determinación de biomarcadores del LS. Resultados: De 264 artículos encontrados, 6 cumplieron los criterios inclusión-exclusión, incluyendo 262 pacientes, [OA=153, 93 con desplazamientos discales (DD) y 16 con OA+DD]. Todas las muestras fueron obtenidas por artrocentesis y detectadas por ELISA. Se determinaron 19 biomarcadores en pacientes con OA; 9 en DD y 2 en diagnosticados con OA+DD. El incremento de biomarcadores en el LS de la ATM se asocia con TI. Conclusión: Los biomarcadores detectados con mayor frecuencia en LS de pacientes con TI de ATM fueron IL-1β, IL-6 y TNF-α y en segunda frecuencia TGF-β1, MMP-3 e IFN-γ. Dada la inconsistencia de los protocolos utilizados la evidencia fue débil, imposibilitando asociar biomarcadores con diagnóstico de TI determinado, ni efectuar análisis estadístico.

ABSTRACT: Objective: To determine the evidence of inflammatory biomarkers present in the synovial fluid (SF) of adult patients with intra-articular disorders (ID) of the temporomandibular joint (TMJ) and their diagnostic ability. Methods: Electronic/manual search of articles (2010-2019) was performed. Data were extracted in duplicate. The quality of the studies was determined by CONSORT, STROBE and risk of bias was determined by Cochrane RoB 2 and Newcastle-Ottawa Scale. The populations studied were patients with TMJ ID and with studies of SF biomarkers. Results: Out of 264 articles found, 6 met the inclusion-exclusion criteria, including 262 patients, 93 with disc displacements (DD) and 16 with OA+DD. All samples were obtained by arthrocentesis and detected by ELISA. Nineteen biomarkers were evaluated in patients with OA, 9 in patients with DD and 2 in those diagnosed with OA+DD. Increased inflammatory biomarkers in the SF of TMJ are associated with ID. Conclusion: The most frequent biomarkers detected in SF of patients with TMJ ID were IL-1β, IL-6 and TNF-α and in second frequency TGF-β1, MMP-3 and IFN-γ. Given the inconsistency of the protocols used, the evidence was weak, making it impossible to associate biomarkers with a given IT diagnosis, or to perform statistical analysis.

PIMREG expression level predicts glioblastoma patient survival and affects temozolomide resistance and DNA damage response.

PIMREG expression strongly correlates with cellular proliferation in both malignant and normal cells. Throughout embryo development, PIMREG expression is prominent in the central nervous system. Recent studies have described elevated PIMREG expression in different types of tumors, which correlates with patient survival and tumor aggressiveness. Given the emerging significance of PIMREG in carcinogenesis and its putative role in the context of the nervous system, we investigated the expression and function of PIMREG in gliomas, the most common primary brain tumors. We performed an extensive analysis of PIMREG expression in tumors samples from glioma patients. We then assessed the effects of PIMREG silencing and overexpression on the sensitivity of glioblastoma cell lines treated with genotoxic agents commonly used for treating patients and assessed for treatment response, proliferation and migration. Our analysis shows that glioblastoma exhibits the highest levels of PIMREG expression among all cancers analyzed and that elevated PIMREG expression is a biomarker for glioma progression and patient outcome. Moreover, PIMREG is induced by genotoxic agents, and its silencing renders glioblastoma cells sensitive to temozolomide treatment and affects ATR- and ATM-dependent signaling. Our data demonstrate that PIMREG is involved in DNA damage response and temozolomide resistance of glioblastoma cells and further supports a role for PIMREG in tumorigenesis.

Thyroid and Breast Cancer in 2 Sisters With Monoallelic Mutations in the Ataxia Telangiectasia Mutated (ATM) Gene.

The presence of a bidirectional risk for metachronous carcinomas among women with thyroid and breast cancer is well established. However, the underlying risk factors remain poorly understood. Two sisters developed papillary thyroid cancer (PTC) at age 32 and 34 years, followed by ductal carcinoma of the breast at 44 and 42 years. The 2 children of the younger sister developed ataxia-telangiectasia; the son also developed lymphoblastic lymphoma and his sister died secondary to acute lymphoblastic leukemia (ALL). They were found to be compound heterozygous for ataxia telangiectasia mutated (ATM) gene mutations (c.3848T>C, p.L1283P; and c.802C>T, p.Q268X). Exome sequencing of the 2 sisters (mother and aunt of the children with ataxia-telangiectasia) led to the detection of the pathogenic monoallelic ATM mutation in both of them (c.3848T>C; minor allele frequency [MAF] < 0.01) but detected no other variants known to confer a risk for PTC or breast cancer. The findings suggest that monoallelic ATM mutations, presumably in conjunction with additional genetic and/or nongenetic factors, can confer a risk for developing PTC and breast cancer.

Factores Asociados a Trastornos Temporomandibulares en el Servicio de Estomatología Quirúrgica de un Hospital Peruano / Factors Associated with Temporomandibular Joint Disorder in the Surgical Stomatology Service of a Peruvian Hospital

RESUMEN: El objetivo de este estudio fue determinar los factores asociados a Trastornos Temporomandibulares (TTM) en pacientes del servicio de Estomatología Quirúrgica de un Hospital Peruano. La muestra del estudio estuvo conformado por 132 pacientes diagnosticados con Trastornos Temporomandibulares por cirujanos dentistas especialistas en Cirugía Bucal y Maxilofacial del servicio de Estomatología Quirúrgica. Se realizó una anamnesis complementaria y una evaluación clínica. Del total de pacientes evaluados, se encontró que el 84,09 % pertenecía al sexo femenino y el 20,45 % tenía entre 50-59 años. Además, el 72,73 % refirieron haber recibido atención previa por otro servicio, el 52,27 % presentaron hábito parafuncional de bruxismo, el 58,33 % presentaron patrón oclusal alterado, el 25,76 % presentaron pérdida de 5 dientes o más por arcada con prevalencia en ambas arcadas y el 54,55 % presentaron atrición. Se concluyó que el sexo predominante fue el femenino y el grupo etario prevalente en pacientes con diagnóstico de TTM, se ubicó en el rango de edad de 50-59 años. Respecto a la sintomatología dolorosa en pacientes con diagnóstico de TTM del servicio de Estomatología Quirúrgica del HNAL fue prevalente el dolor al masticar o hablar.

ABSTRACT: The objective of this study was to determine the factors associated with Temporomandibular Disorders (TMD) in patients of the Surgical Stomatology service of a Peruvian Hospital. The study sample consisted of 132 patients diagnosed with Temporomandibular Disorders by dental surgeons specializing in Oral and Maxillofacial Surgery of the Surgical Stomatology service. A complementary anamnesis and a clinical evaluation were carried out. Of the total of patients evaluated, it was found that 84.09 % belonged to the females and 20.45 % were between 50-59 years old. In addition, 72.73 % reported having received prior care from another service, 52.27 % had a parafunctional habit of bruxism, 58.33 % had an altered occlusal pattern, 25.76 % had loss of 5 or more teeth due to arch with prevalence in both arches and 54.55 % presented attrition. It was concluded that the predominant sex was female and the prevalent age group in patients diagnosed with TMD was in the age range of 50-59 years. Regarding the painful symptoms in patients with a diagnosis of TMD from the Surgical Stomatology Service of the HNAL, pain when chewing or speaking was prevalent.

Relación entre contactos mediotrusivos con la articulación temporomandibular y la oclusión / Relationship between mediotrusive contacs, the temporomandibular joint and occlusion

Los contactos mediotrusivos son aquellos contactos oclusales que se encuentran entre las vertientes in- ternas de las cúspides linguales maxilares y las inter- nas de las cúspides bucales mandibulares del lado de no trabajo durante los movimientos de lateralidad. Estos contactos mediotrusivos podría desencadenar trastornos temporomandibulares, afectando la oclu- sión y la articulación temporomandibular. El objetivo de este estudio es analizar las caracterís- ticas y la relación entre los contactos mediotrusivos con la articulación temporomandibular y la oclusión en pacientes que consultan al Servicio de Oclusión y ATM del Hospital Odontológico de la Facultad de Odontología de la Universidad Nacional del Nordeste (AU)

Mediotrusive contacts are those occlusal contacts that are found between the internal slopes of the maxillary lingual cusps and the internal slopes of the mandibular buccal cusps on the non-working side during laterality movements. These mediotrusive contacts could trigger temporomandibular disorders affecting occlusion and temporomandibular joint. The objective of this study was to analyze the characteristics and relationship of mediotrusive contacts with occlusion and the temporomandibular joint, in patients who consult the Occlusion and TMJ Service of the Dental Hospital of the Faculty of Dentistry of the National University of the Northeast (AU)

Modelo lineal vs. vectorial: estimación del movimiento mandibular y trabajo mecánico / Linear vs. vector model: estimation of mandible motion and mechanical work

Objetivo: Determinar los momentos de fuerza del haz superficial del masetero (SMH) obtenidos por modelos lineal y vectorial. Métodos: Investigación comparati-va in silico. Se obtuvo la fuerza del SMH con dinamó-metro en 12 pacientes varones adultos jóvenes para calcular el momento de la fuerza y trabajo mecánico a través de simulaciones en JAVA+ con NetBeans8.2. La descomposición de la fuerza fue F.cos α(x,y) y F.cos α(x,y,z) en el modelo lineal y vectorial respectivamen-te. Los momentos de fuerza fueron comparados por ANOVA (p<0,05). Resultados: La fuerza del SMH unila-teral obtenida con dinamómetro (2,5±0,1N) no difirió significativamente del modelo lineal (2,6±0,05N), pero difirió (p<0,001) del vectorial: 1,7, 2,2, 4,2N en x,y,z (general 2,7±0,02N). El momento medio de la fuerza en el modelo vectorial fue -17,9, -15,5, +14,3N.m-2, apuntando a la inclinación mandibular en el eje lateral en dirección caudal anterior, movimiento de inclina-ción en el eje lateral en la dirección cráneo-medial, e inclinación en el eje craneal en la dirección lateral-an-terior. El modelo lineal mostró momento de fuerza de 13,5N.m-2 apuntando un movimiento traslacional en dirección caudal-craneal en el eje anterior-posterior y menor trabajo mecánico del SMH (p=0,012). Con-clusión: Los modelos vectoriales son más eficientes proporcionando datos detallados para estimar los momentos de fuerza y el trabajo mecánico del SMH, y deben incluirse en los algoritmos de cálculo utilizados por dinamómetros (AU)

Objective: to determine the moments of force exerted by the superficial masseter head (SMH) obtained through linear models and vector ones. Methods: comparative in silico research. Data of SMH force obtained with dynamometer in 12 young adult male patients was used to calculate the moment of the force and mechanical work through simulations in JAVA+ performed with NetBeans8.2. Force decomposition was F.cos α(x,y) and F.cos α(x,y,z) in the linear and vector model respectively. The moments of force were compared by ANOVA (p<0.05). Results: Dynamometrical unilateral SMH force (2.5±0.1N) did not differ significantly from the linear model (2.6±0.05N), but differed (p<0.001) from the vector model: 1.7, 2.2, 4.2N on x,y,z (overall 2.7±0.02N). The mean moment of the force in the vector model was -17.9, -15.5, +14.3N.m-2, pointing to mandible's inclination on the lateral axis in anterior-caudal direction, inclination movement on the lateral axis in the cranio-medial direction and inclination on the cranial axis in the lateral-anterior direction. The linear model showed a moment of force of 13.5N.m-2 pointing to translational motion on caudal-cranial direction on the anterior-posterior axis and lower SMH mechanical work (p=0,012). Conclusion: Vector models are more efficient to provide detailed data to estimate the moments of force and mechanical work of SMH and should be included in the calculation algorithms used by dynamometers (AU)

Novel Compound Heterozygous Mutation c.3955_3958dup and c.5825C>T in the ATM Gene: Clinical Evidence of Ataxia-Telangiectasia and Cancer in a Peruvian Family.

Pathogenic and likely pathogenic variants in the ATM gene are associated both with Ataxia-telangiectasia disease or ATM syndrome and an increased cancer risk for heterozygous carriers. We identified a novel compound heterozygous mutation c.3955_3958dup (p.Asp1320delinsValTer) and c.5825C>T (p.Ala1942Val) in the ATM gene in a Peruvian patient with progressive ataxia combined with other movement disorders, mild conjunctival telangiectasia and increased alpha-fetoprotein, without history of recurrent infection or immunodeficiency. We also determined the carrier status of the family members, and we were able to detect gastric and breast cancer at an early stage during the cancer risk assessment in the mother (c.3955_3958dup). Here, we describe clinical evidence for the novel compound heterozygous mutation and c.3955_3958dup not previously reported.