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OBJECTIVES: Guidelines recommend risk-reducing bilateral salpingo-oophorectomy (RRSO) for women with pathogenic variants of non-BRCA and Lynch syndrome-associated ovarian cancer susceptibility genes. Optimal timing and findings at the time of RRSO for these women remains unclear. We sought to characterize practice patterns and frequency of occult gynecologic cancers for these women at our two institutions. METHODS: Women with germline ovarian cancer susceptibility gene pathogenic variants who underwent RRSO between 1/2000-9/2019 were reviewed in an IRB-approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. RESULTS: 26 Non-BRCA (9 BRIP1, 9 RAD51C, and 8 RAD51D) and 75 Lynch (36 MLH1, 18 MSH2, 21 MSH6) pathogenic variants carriers were identified. Median age at time of RRSO was 47. There were no occurrences of occult ovarian or fallopian tube cancer in either group. Two patients (3%) in the Lynch group had occult endometrial cancer. Median follow up was 18 and 35 months for non-BRCA and Lynch patients, respectively. No patient developed primary peritoneal cancer upon follow up. Post-surgical complications occurred in 9/101 (9%) of patients. Hormone replacement therapy (HRT) was rarely used despite reported post-menopausal symptoms in 6/25 (23%) and 7/75 (37%) patients, respectively. CONCLUSIONS: No occult ovarian or tubal cancers were observed in either group. No recurrent or primary gynecologic-related cancers occurred upon follow-up. Despite frequent menopausal symptoms, HRT use was rare. Both groups experienced surgical complications when hysterectomy and/or concurrent colon surgery was performed suggesting concurrent surgeries should only be performed when indicated.
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Neoplasias de la Mama , Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Primarias Desconocidas , Neoplasias Ováricas , Femenino , Humanos , Ovariectomía , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/cirugía , Genes BRCA2 , Neoplasias Ováricas/genética , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/patología , Genes BRCA1 , Mutación , Factores de Riesgo , Neoplasias Primarias Desconocidas/genética , Neoplasias de la Mama/genética , Predisposición Genética a la EnfermedadRESUMEN
AIM: Evaluate the expression of exomiRs-126, -146, and -155 in urinary exosomes of patients with T2DM and diabetic kidney disease to establish a predictive classification model with exomiRs and clinical variables in order to determine their contribution to DKD. METHODS: The study group included 92 subjects: 64 patients diagnosed with T2DM subclassified into two groups with albuminuria (T2DM with albuminuria, n = 30) and without albuminuria (TD2M, n = 34) as well as 28 healthy, non-diabetic participants. Exosomes were isolated from urine and identified by TEM and flow cytometry. Profile expression of exomiRs-126, -146 and -155 was evaluated by RT-qPCR. Data were analysed by permutational multivariate analysis of variance (PERMANOVA), similarity percentage (SIMPER), principal coordinate analysis (PCO), and canonical analysis of principal coordinates (CAP). RESULTS: T2DM patients with and without albuminuria showed higher levels of miR-155 and miR-146 compared with controls. In addition, T2DM patients with albuminuria presented a significant increase in miR-126 contrasted to controls and patients without albuminuria. PCO analysis explained 34.6% of the total variability of the data (PERMANOVA; p < .0001). Subsequently, SIMPER analysis showed that miR-146, miR-155, and miR-126 together, with some clinical parameters, contributed to 50% of the between-group significance. Finally, the CAP analysis developed showed a correct classification of 89.01% with the analysed parameters. CONCLUSION: A platform using a combination of clinical variables and exomiRs could be used to classify individuals with T2D as risk for developing DKD.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , MicroARNs , Albuminuria/etiología , Albuminuria/genética , Biomarcadores , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/genética , Femenino , Humanos , Masculino , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Type 2 diabetes mellitus (T2D) is a risk factor for the development of tuberculosis (TB) through mechanisms poorly understood. Monocytes and macrophages are key effector cells to control TB, but they are also subverted by Mycobacterium tuberculosis (Mtb). Specifically, Mtb can induce a bystander effect that skews monocyte differentiation towards macrophages with a permissive phenotype to infection. Here, we evaluated whether T2D impacts this TB aspect. Our approach was to differentiate monocytes from healthy control (HC) subjects and T2D patients into macrophages (MDM), and then assess their response to Mtb infection, including their secretome content and bystander effect capacity. Through flow cytometric analyses, we found a lower level of activation markers in MDM from T2D patients than from HC in response to mock (HLA-DR, CD86 and CD163) or Mtb challenge (CD14 and CD80). In spite of high TGF-ß1 levels in mock-infected MDM from T2D patients, cytometric bead arrays indicated that there were no major differences in the secretome cytokine content in these cells relative to HC-MDM, even in response to Mtb. Mimicking a bystander effect, the secretome of Mtb-infected HC-MDM drove HC monocytes towards MDM with a permissive phenotype for Mtb intracellular growth. However, the secretome from Mtb-infected T2D-MDM did not exacerbate the Mtb load compared to secretome from Mtb-infected HC-MDM, possibly due to the high IL-1ß production relative to Mtb-infected HC-MDM. Collectively, despite T2D affecting the basal MDM activation, our approach revealed that it has no major consequence on their response to Mtb or capacity to generate a bystander effect influencing monocyte differentiation.
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Diabetes Mellitus Tipo 2 , Mycobacterium tuberculosis , Efecto Espectador , Diferenciación Celular , Humanos , Macrófagos , Monocitos , SecretomaRESUMEN
OBJECTIVE: We assessed the feasibility, patient acceptability of and compliance of a new surveillance strategy for ovarian cancer surveillance in women with BRCA mutations, based on assessments of serum CA125 and HE4 every 4 months (Risk of Ovarian Cancer Algorithm (ROCA) arm), compared to Standard of Care (SOC) surveillance with CA125 blood tests and pelvic ultrasounds every 6 months. METHODS: Women were recruited 6/13/16-9/11/17 from an integrated health care system in California for this non-randomized prospective cohort study. Women were invited to participate in a novel serum biomarker surveillance strategy using ROCA or they could opt to be in the standard of care control arm with ultrasound and CA 125 every 6 months. Outcomes assessed included compliance, self-reported distress using the Impact of Event Scale (IES) and cancer anxiety using the Cancer Worry Scale. RESULTS: There were 159 women in the ROCA arm and 43 in the SOC arm. Overall, compliance was higher in the ROCA arm (83.2%) than in SOC (51.9%), p < 0.0001. Based on the IES, ROCA arm women reported less feelings about intrusion and avoidance at 12 months compared to baseline; the difference approached significance for intrusion (7.6% vs 4.1% severe, p = 0.057) and was statistically significant for avoidance (20.8% vs 9.9% severe, p = 0.034). CONCLUSIONS: This pilot demonstrated that compliance was high with blood tests performed every four months for ovarian cancer surveillance. Moreover, ROCA women had lower stress scores over time than SOC women. Given the lack of clinical utility and poor compliance shown with traditional ultrasound and CA125 tests, further investigation is warranted of longitudinal biomarker surveillance for early detection of ovarian cancer.
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Antígeno Ca-125/sangre , Proteínas de la Membrana/sangre , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico por imagen , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Adulto , Algoritmos , Biomarcadores de Tumor/sangre , Estudios de Factibilidad , Femenino , Humanos , Cooperación del Paciente , Proyectos Piloto , Riesgo , Ultrasonografía , Espera Vigilante/métodosRESUMEN
OBJECTIVE: To develop a longitudinal algorithm combining two biomarkers, CA125 and HE4, for early detection of ovarian cancer in women with BRCA mutations. METHODS: Women with BRCA mutations and intact ovaries were invited to participate in a novel ovarian cancer early detection prospective study. The Risk of Ovarian Cancer Algorithm (ROCA) identifying significant increases above each woman's baseline in serum CA125 and HE4 was performed every four months; abnormal risks triggered a subsequent ultrasound. The study first used a risk algorithm for only CA125, a second algorithm was developed for HE4 and finally a risk algorithm combining the two biomarkers was implemented. The ROCA strategy was compared to Standard of Care (SOC) surveillance strategy. RESULTS: A total of 149 women enrolled in the ROCA arm while 43 women enrolled in the SOC arm. Abnormal scores were found in 24% of ROCA CA125 tests, 16% if ROCA CA125 or the novel ROCA HE4 were used independently and reduced to 8% using the new two-marker ROCA, significantly lower than the 15% of abnormal tests seen in the SOC arm (p = 0.042). The average false positive rate among women without ovarian cancer for two-marker ROCA for referral to ultrasound was 6.6% (specificity 93.4%), and for the two-marker ROCA plus ultrasound for referral to surgical consultation was 1.7% (specificity 98.3%). CONCLUSION: A newly developed two-marker ROCA administered every 4 months had lower call-back rates than SOC surveillance. Having established high specificity, the two-marker ROCA score deserves further evaluation for sensitivity in a larger trial.
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Antígeno Ca-125/sangre , Detección Precoz del Cáncer/métodos , Proteínas de la Membrana/sangre , Neoplasias Ováricas/diagnóstico , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Adulto , Anciano , Algoritmos , Proteína BRCA1/genética , Proteína BRCA2/genética , Femenino , Estudios de Seguimiento , Heterocigoto , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/sangre , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Ovario/diagnóstico por imagen , Estudios Prospectivos , Medición de Riesgo/métodos , Sensibilidad y Especificidad , UltrasonografíaRESUMEN
OBJECTIVE: Compare detection of Lynch syndrome in endometrial cancer between regions of a health care system with different screening strategies. METHODS: A retrospective study of endometrial cancer (EC) cases from 2 regions of an integrated health care system (Kaiser Permanente Northern (KPNC) and Southern (KPSC) California). Within KPNC, immunohistochemistry tumor screening (IHC) was physician ordered and risk-based; within KPSC, IHC was universal and automated. Clinical risk factors associated with abnormal IHC and Lynch Syndrome (LS) were identified. RESULTS: During the study, there were 2045 endometrial cancers: 1399 in the physician-order group and 646 in the universal testing group. In the physician-order group: among women < age 60, 34% underwent IHC; 9.6% were abnormal, and 3% were possible LS after methylation testing; among women ≥60, 11% underwent IHC, 3% were abnormal and <1% were possible LS. In the universal group, 87% of women age <60 had IHC, 19.4% were abnormal, and 6% were possible LS; Among women age ≥60, 82% underwent IHC, 26% were abnormal, and 2% were possible LS. There were no differences in LS cases between the physician-order group and the universal group in either age strata (<60: 3% vs. 3.6%, p=0.62; ≥60: <1% vs. 1%, p=0.63) Factors associated with LS were younger age (odds ratio (OR) 0.11, 95% confidence interval (CI) 0.04-0.29) and lower body mass index (BMI), (OR 0.38 95% CI 0.18-0.80). CONCLUSIONS: Universal IHC screening did not result in increased LS detection in EC.
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Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/metabolismo , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/metabolismo , California , Estudios de Cohortes , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Detección Precoz del Cáncer/métodos , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Asesoramiento Genético , Pruebas Genéticas , Humanos , Inmunohistoquímica/métodos , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios RetrospectivosRESUMEN
Genetic testing has increased over the last decade due to growth in the number of clinical and direct-to-consumer (DTC) tests. However, there is uncertainty about how increased DTC genetic testing affects disparities. Between November 2017 and February 2018, a nationwide electronic survey on experiences with genetic testing was conducted among adult Kaiser Permanente members. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals comparing receipt of clinical and DTC genetic testing between groups by race and ethnicity. Invitations were sent to 57,331 members, and 10,369 surveys were completed. 22% of respondents had received genetic testing (17% DTC and 5% provider-ordered). Non-Hispanic Whites were more likely than other groups to have clinical genetic testing but were similar to Hispanics and non-Hispanic Blacks in rates of DTC genetic testing. Among those who received any health-related genetic test, 10% reported abnormal results. Of these, non-Hispanic Whites were more likely than other racial/ethnic groups to speak to a medical professional about abnormal results. Results suggest that racial/ethnic disparities in the use of clinical genetic services persist. Additional research is needed to identify lessons learned from DTC genetic testing that may increase equity in the use of clinical genetic services.
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Demografía , Pruebas Dirigidas al Consumidor , Pruebas Genéticas/estadística & datos numéricos , Adolescente , Adulto , Anciano , Etnicidad , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Estados Unidos , Población BlancaRESUMEN
Metabolomics is a potential tool for the discovery of new biomarkers in the early diagnosis of diseases. An ultra-fast gas chromatography system equipped to an electronic nose detector (FGC eNose) was used to identify the metabolomic profile of Volatile Organic Compounds (VOCs) in type 2 diabetes (T2D) urine from Mexican population. A cross-sectional, comparative, and clinical study with translational approach was performed. We recruited twenty T2D patients and twenty-one healthy subjects. Urine samples were taken and analyzed by FGC eNose. Eighty-eight compounds were identified through Kovats's indexes. A natural variation of 30% between the metabolites, expressed by study groups, was observed in Principal Component 1 and 2 with a significant difference (p < 0.001). The model, performed through a Canonical Analysis of Principal coordinated (CAP), allowed a correct classification of 84.6% between healthy and T2D patients, with a 15.4% error. The metabolites 2-propenal, 2-propanol, butane- 2,3-dione and 2-methylpropanal, were increased in patients with T2D, and they were strongly correlated with discrimination between clinically healthy people and T2D patients. This study identified metabolites in urine through FGC eNose that can be used as biomarkers in the identification of T2D patients. However, more studies are needed for its implementation in clinical practice.
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Cromatografía de Gases/métodos , Diabetes Mellitus Tipo 2/metabolismo , Nariz Electrónica , Metabolómica/métodos , Compuestos Orgánicos Volátiles/orina , Adulto , Anciano , Biomarcadores/orina , Estudios Transversales , Humanos , Persona de Mediana Edad , Proyectos PilotoRESUMEN
We designed and implemented a novel automated negative non-invasive prenatal test (NIPT) result disclosure process using a proprietary, HIPAA-compliant web-based portal. High-risk pregnant patients who opted for NIPT from 04/2017 to 12/2018 were given the option to receive their negative result through the automated process. Patients were required to watch a brief educational video and answer evaluative questions before downloading their result. After completing the process, patients completed a survey regarding their opinion of the efficiency and convenience of the process and their satisfaction. A total of 10,170 women registered online during the study period, and 8,965 completed the automated process (88%). Out of 8,965 women, 2,121 women responded to the survey (24%). Most (2,030 of 2,101) strongly agreed/agreed that they could easily navigate the patient portal (97%); 1,852 of 1,966 strongly agreed/agreed that disclosure was efficient and convenient (94%); 1,852 of 1,960 strongly agreed/agreed that they felt informed after watching a short educational video (94%); and 1,903 of 1,967 strongly agreed/agreed that they preferred downloading results rather than waiting for their next doctor's appointment (97%). This study demonstrates high patient satisfaction with this automated and scalable solution in a high-volume health system. As the utilization of genetic testing increases, we predict greater need for innovative healthcare delivery models.
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Revelación , Pruebas Genéticas/métodos , Diagnóstico Prenatal/métodos , Adulto , Automatización , Femenino , Humanos , Persona de Mediana Edad , Satisfacción del Paciente , Embarazo , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Once in the pulmonary alveoli, Mycobacterium tuberculosis (Mtb) enters into contact with alveolar macrophages and dendritic cells (DCs). DCs represent the link between the innate and adaptive immune system owing to their capacity to be both a sentinel and an orchestrator of the antigen-specific immune responses against Mtb. The effect that the virulence of Mtb has on the interaction between the bacilli and human DCs has not been fully explored. OBJECTIVE: To evaluate the effect of Mtb virulence on human monocyte-derived DCs. METHODS: We exposed human monocyte-derived DCs to Mtb clinical strains (isolated from an epidemiological Mtb diversity study in Mexico) bearing different degrees of virulence and evaluated the capacity of DCs to internalise the bacilli, control intracellular growth, engage cell death pathways, express markers for activation and antigen presentation, and expand to stimulate autologous CD4+ T cells proliferation. FINDINGS: In the case of the hypervirulent Mtb strain (Phenotype 1, strain 9005186, lineage 3), we report that DCs internalise and neutralise intracellular growth of the bacilli, undergo low rates of apoptosis, and contribute poorly to T-cell expansion, as compared to the H37Rv reference strain. In the case of the hypovirulent Mtb strain (Phenotype 4, strain 9985449, lineage 4), although DCs internalise and preclude proliferation of the bacilli, the DCs also display a high level of apoptosis, massive levels of apoptosis that prevent them from maintaining autologous CD4+ T cells in a co-culture system, as compared to H37Rv. MAIN CONCLUSIONS: Our findings suggest that variability in virulence among Mtb clinical strains affects the capacity of DCs to respond to pathogenic challenge and mount an immune response against it, highlighting important parallels to studies previously done in mouse models.
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Células Dendríticas/virología , Activación de Linfocitos , Mycobacterium tuberculosis/patogenicidad , Linfocitos T Reguladores/parasitología , Animales , Humanos , Ratones , Transducción de Señal , VirulenciaRESUMEN
BACKGROUND: Type 2 diabetes (T2D) is a risk factor for the development of tuberculosis (TB), although the associated mechanisms are not known. OBJECTIVES: To study the association between T2D and the basal phenotype of macrophages, and their immune response to Mycobacterium tuberculosis (Mtb) infection. METHODS: We evaluated the influence of T2D on the response of monocyte-derived macrophages (MDM) to Mtb in patients with T2D (n = 10) compared to healthy subjects (n = 9), before and after infection with Mtb clinical isolates bearing different degrees of virulence. The levels of cell surface markers for activation secreted cytokines and chemokines, bacterial association, and intracellular bacterial growth were evaluated. FINDINGS: The expression levels of HLA-DR, CD80, and CD86 were low while those of of PD-L1 were high in uninfected MDMs derived from patients with diabetes; as a result of Mtb infection, changes were only observed in the expression levels of PD-L1. The levels of cytokines (e.g., IL-6, IL-1ß, IL-10, and IL-12) and chemokines (e.g., MCP-1, MIG, and RANTES) are perturbed in MDMs derived from patients with diabetes, both before infection and in response to Mtb infection. In response to the more virulent Mtb strains, the levels of association and bacterial clearance were diminished in MDMs derived from patients with diabetes. CONCLUSIONS: T2D affects the basal activation state of the macrophages and its capacity to respond and control Mtb infection.
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Diabetes Mellitus Tipo 2/inmunología , Macrófagos/inmunología , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/patogenicidad , Fenotipo , Tuberculosis/inmunología , Adulto , Anciano , Análisis de Varianza , Glucemia/análisis , Estudios de Casos y Controles , Quimiocinas/análisis , Recuento de Colonia Microbiana , Citocinas/análisis , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Valores de Referencia , Factores de Riesgo , Estadísticas no Paramétricas , VirulenciaRESUMEN
INTRODUCTION: Screening for pancreatic cancer (PC) is suggested for high-risk individuals. Additional risk factors may enhance early detection in this population. METHODS: Retrospective cohort study among patients with germline variants and/or familial pancreatic cancer in an integrated healthcare system between 2003 and 2019. We calculated the incidence rate (IR) by risk category and performed a nested case-control study to evaluate the relationship between HbA1C and PC within 3 years before diagnosis (cases) or match date (controls). Cases were matched 1:4 by age, sex, and timing of HbA1c. Logistic regression was performed to assess an independent association with PC. RESULTS: We identified 5,931 high-risk individuals: 1,175(19.8%) familial PC, 45(0.8%) high-risk germline variants ( STK11, CDKN2A ), 4,097(69.1%) had other germline variants ( ATM, BRCA 1, BRCA 2, CASR, CDKN2A, CFTR, EPCAM, MLH1, MSH2, MSH6, PALB2, PRSS1, STK11, and TP53 ), and 614(10.4%) had both germline variants and family history. Sixty-eight patients (1.1%) developed PC; 50% were metastatic at diagnosis. High-risk variant was associated with greatest risk of PC, IR = 85.1(95% confidence interval: 36.7-197.6)/10,000 person-years; other germline variants and first-degree relative had IR = 33 (18.4, 59.3), whereas IR among ≥2 first-degree relative alone was 10.7 (6.1, 18.8). HbA1c was significantly higher among cases vs controls (median = 7.0% vs 6.4%, P = 0.02). In multivariable analysis, every 1% increase in HbA1c was associated with 36% increase in odds of PC (odds ratio 1.36, 95% confidence interval: 1.08-1.72). Pancreatitis was independently associated with a risk of PC (odds ratio 3.93, 95% confidence limit 1.19, 12.91). DISCUSSION: Risk of PC varies among high-risk individuals. HbA1c and history of pancreatitis may be useful additional markers for early detection in this patient population.
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Carcinoma , Neoplasias Pancreáticas , Pancreatitis , Humanos , Hemoglobina Glucada , Estudios Retrospectivos , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/genéticaRESUMEN
Bariatric surgery (BS) is considered the most effective intervention for patients with severe obesity and is used to maintain long-term weight loss and glycemic control. The aim of this study was to analyze the effects of genotypes and haplotypes of the fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes on total body weight loss (TBWL), post-surgery weight, and post-BMI after bariatric surgery. We retrospectively selected 101 patients from Bajio High Specialty Regional Hospital, León Guanajuato, México, who underwent Roux-en-Y gastric bypass (RYGB) to determine their body mass index (BMI), blood pressure, biochemical characteristics, and comorbidities. Post-surgery, patients were referred for registered anthropometry and blood pressure. Glucose, lipid and hepatic profiles, and insulin, leptin, and ghrelin levels were measured, and rs9939609, rs9930506, and rs1421085 FTO and rs17782313 MC4R polymorphisms were genotyped. Six (4-8) years after BS, post-surgery weight was greater in carriers of the rs9939609 and rs1421085 risk genotypes. TBWL was lower for the rs9930506 and rs1421085 risk genotypes. Insulin and HOMA-IR were greater in patients with the three FTO polymorphisms. There were significant interaction effects of the rs9930506 and rs1421085 FTO risk genotypes on weight and BMI in response to BS. No association was found with the MC4R polymorphism. The genotypes and haplotypes of the FTO gene influence post-surgery weight, TBWL, insulin levels, and HOMA-IR.
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Cirugía Bariátrica , Índice de Masa Corporal , Polimorfismo de Nucleótido Simple , Receptor de Melanocortina Tipo 4 , Pérdida de Peso , Humanos , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Receptor de Melanocortina Tipo 4/genética , Masculino , Femenino , Adulto , Pérdida de Peso/genética , Persona de Mediana Edad , Obesidad Mórbida/cirugía , Obesidad Mórbida/genética , Estudios Retrospectivos , Haplotipos , GenotipoRESUMEN
In the South American Republic of Chile genetic counseling is not currently recognized as an independent clinical discipline, and in general is provided by physicians with training in clinical genetics. At present only one genetic counselor and 28 clinical geneticists practice in this country of over 16 million inhabitants. Pediatric dysmorphology constitutes the primary area of practice in clinical genetics. Although the country has a universal health care system and an adequate level of health care, genetic conditions are not considered a health care priority and there is a lack of clinical and laboratory resources designated for clinical genetics services. Multiple educational, cultural and financial barriers exist to the growth and development of genetic counseling services in Chile. However, during the last 10 years increased awareness of the importance of identifying individuals at risk for inherited cancer syndromes led to growing interest in the practice of cancer genetics.
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Asesoramiento Genético , Genética Médica , Chile , Atención a la Salud/organización & administración , HumanosRESUMEN
Variants in hereditary cancer risk genes are frequently identified following tumor-based DNA sequencing and represent an opportunity to diagnose hereditary cancer. We implemented an automated hereditary cancer screening program in a large HMO for all patients who underwent tumor-based DNA sequencing to identify patients with hereditary cancer and determine if this approach augmented existing genetic counseling approaches driven by personal/family history criteria. Regular automated searches of a centralized tumor DNA variant database were performed for ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6, PALB2, and/or PMS2 variants, and germline hereditary cancer gene panel testing was offered to patients with tumor variants who had never undergone germline testing. Patients completing germline testing due to their tumor DNA test results were considered part of the tumor DNA safety net. Patients previously completing germline testing via traditional genetic counseling and tumor DNA safety net were compared for demographics, tumor type, presence of germline pathogenic/likely pathogenic (P/LP) variant, and whether NCCN criteria were met for hereditary cancer genetic testing. Germline P/LP variants were common in both groups. Patients who received germline testing through traditional genetic counseling were more likely to have cardinal hereditary tumors than the tumor DNA safety net group. Patients identified with hereditary cancer through traditional genetic counseling were more likely to meet NCCN personal/family history criteria for germline testing than the tumor DNA safety net group (99% versus 34%). A universal tumor DNA safety net screen is an important diagnostic strategy which augments traditional genetic counseling approaches based on personal/family history.
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Predisposición Genética a la Enfermedad , Síndromes Neoplásicos Hereditarios , Humanos , Sistemas Prepagos de Salud , Detección Precoz del Cáncer , Pruebas Genéticas/métodos , Mutación de Línea Germinal , Síndromes Neoplásicos Hereditarios/genéticaRESUMEN
INTRODUCTION: A therapeutic approach to severe obesity is bariatric surgery (BS), which is considered an effective intervention for ameliorating comorbidities such as T2DM, hypertension, dyslipidemia, and cardiovascular diseases. Some polymorphisms are considered markers for addictive disorders and hedonic hunger. We analyzed factors associated with the outcomes of BS, including rs1800497 ANKK1 and rs1799732 DRD2 polymorphisms, eating behavior, hedonic hunger, and depressive symptoms. METHODS: We retrospectively selected 101 patients who underwent BS and agreed to participate. The previous conditions to BS, such as body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and comorbidities, were registered; the scholarship value was evaluated as the total number of years of scholarly education. To evaluate the post-surgery conditions of the participants, we took blood samples, anthropometric measures, and 3 questionnaires to evaluate eating behavior (TFEQ-R18), hedonic hunger (PFS), and depressive symptoms (PHQ-9). The ANKK1 rs1800497 and rs1799732 DRD2 polymorphisms were genotyped. RESULTS: The median total weight loss (TWL) was 34.7 kg, with a BMI of 33.8 kg/m2, 6 (4-8) years after BS. The TWL was positively associated with the TFEQ-R18 score (p = 0.006) and negatively associated with triglycerides (p = 0.011). rs1800497 ANKK1 was associated with TFEQ-R18 (OR = 1.13 (1.02-1.25), p = 0.009). We also found a negative correlation of pre-surgery BMI with scholarship (r = - 0.27, p < 0.05). CONCLUSION: The patients showed an improvement in metabolic and anthropometric parameters post-surgery. Interestingly, the ANKK1 Taq1A polymorphism was associated with eating behavior and scholarship with pre-surgery BMI, which may be considered predictors of BS outcomes.
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Cirugía Bariátrica , Depresión , Humanos , Depresión/genética , Hambre , Estudios Retrospectivos , Receptores de Dopamina D2/genética , Polimorfismo Genético , Conducta Alimentaria , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
9-fluorenylmethoxycarbonyl (Fmoc) and 4,4'-dimethoxytrityl (DMTr) are orthogonal hydroxyl protecting groups that have been used in conjunction to assemble oligonucleotide libraries whose variants contain wild-type and mutant codons randomly interspersed throughout a focused DNA region. Fmoc is labile to organic bases and stable to weak acids, whereas DMTr behaves oppositely. Based on these chemical characteristics, we have now devised TrimerDimer, a novel codon-based saturation mutagenesis approach that removes redundant and stop codons during the assembly of degenerate oligonucleotides. In this approach, five DMTr-protected trinucleotide phosphoramidites (dTGG, dATG, dTTT, dTAT and dTGC) and five Fmoc-protected dinucleotide phosphoramidites (dAA, dTT, dAT, dGC and dCG) react simultaneously with a starting oligonucleotide growing on a solid support. The Fmoc group is then removed and the incorporated dimers react with a mixture of three DMTr-protected monomer phosphoramidites (dC, dA and dG) to produce 15 trinucleotides: dCAA, dAAA, dGAA, dCTT, dATT, dGTT, dCAT, dAAT, dGAT, dCGC, dAGC, dGGC, dCCG, dACG and dGCG. After one mutagenic cycle, 20 codons are generated encoding the 20 natural amino acids. TrimerDimer was tested by randomizing the four contiguous codons that encode amino acids L64-G67 of an engineered, nonfluorescent GFP protein. Sequencing of 89 nonfluorescent mutant clones and isolation of two fluorescent mutants confirmed the principle.
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Codón de Terminación , Mutagénesis , Oligonucleótidos/química , Sustitución de Aminoácidos , Proteínas Fluorescentes Verdes/genética , Oligonucleótidos/síntesis química , Compuestos Organofosforados/químicaRESUMEN
Advances in gene sequencing of mutations related to hereditary cancers have enabled expansion of this testing to patients cared for in community clinics. Our goal was to report on the prevalence of pathogenic/likely pathogenic variants (PV/LPV) and the distribution of mutations by cancer history in a diverse cohort. We evaluated 3162 women in a large non-profit health plan who were referred for cancer genetic counseling and tested them via the same multigene cancer panel. We examined the pathogenic variant/likely pathogenic variant (PV/LPV) prevalence for 20 genes by clinical factors, demographics, and personal or family cancer history. We calculated adjusted odds ratios for the association between race/ethnicity and mutation results. The majority of women (65.4%) were referred post-breast or ovarian cancer diagnosis. The overall prevalence of any PV/LPV result was 11.7%. Overall, nearly 5.4% had BRCA1/2 mutations, while 6.3% had at least one mutation in non-BRCA genes. In the subset with any PV/LPV result, 55.0% of the total mutations were in non-BRCA genes. The distribution of mutations was similar in those with or without a personal cancer history. Latina women were somewhat less likely to have mutations in non-BRCA genes implicated with breast cancer (OR = 0.55, 95% CI 0.36-0.87). Given that 55.0% of the PV/LPV results were in genes other than BRCA1/2, regardless personal or family cancer history, the study suggests that multigene cancer panel testing may be appropriate for detecting germline mutations in a high-risk cohort in a managed care or public health setting.
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BACKGROUND: Most genetics studies lack the diversity necessary to ensure that all groups benefit from genetic research. OBJECTIVES: To explore facilitators and barriers to genetic research participation. METHODS: We conducted a survey on genetics in research and healthcare from November 15, 2017 to February 28, 2018 among adult Kaiser Permanente (KP) members who had been invited to participate in the KP biobank (KP Research Bank). We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing the willingness to participate in genetic research under different return of results scenarios and genetic discrimination concerns between groups, according to their demographic characteristics. RESULTS: A total of 57,331 KP members were invited to participate, and 10,369 completed the survey (18% response rate). Respondents were 65% female, 44% non-Hispanic White (NH White), 22% Asian/Native Hawaiian or other Pacific Islander (Asian/PI), 19% non-Hispanic Black (NH Black), and 16% Hispanic. Respondents willing to participate in genetic research ranged from 22% with no results returned to 87% if health-related genetic results were returned. We also found variation by race/ethnicity; when no results were to be returned, Asian/PIs, Hispanics, and NH Blacks were less likely to want to participate than NH Whites (p < 0.05). However, when results were returned, disparities in the willingness to participate disappeared for NH Blacks and Hispanics. Genetic discrimination concerns were more prevalent in Asian/PIs, Hispanics, and NH Blacks than in NH Whites (p < 0.05). CONCLUSIONS: Policies that prohibit the return of results and do not address genetic discrimination concerns may contribute to a greater underrepresentation of diverse groups in genetic research.
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Actitud/etnología , Etnicidad , Investigación Genética/ética , Participación del Paciente , Sujetos de Investigación , Encuestas y Cuestionarios/estadística & datos numéricos , Etnicidad/psicología , Etnicidad/estadística & datos numéricos , Femenino , Pruebas Genéticas/ética , Pruebas Genéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Participación del Paciente/psicología , Participación del Paciente/estadística & datos numéricos , Formulación de Políticas , Sujetos de Investigación/psicología , Sujetos de Investigación/estadística & datos numéricos , Estados UnidosRESUMEN
INTRODUCTION: Quibdó, the capital of Chocó Province, is one of the poorest cities in Colombia. Enteric viruses such as rotavirus and hepatitis A virus was found to occur commonly in city drinking water and indicated poor water quality and high risk of becoming infected. The source of these viruses was unknown, but humans and cattle were suspect sources. OBJECTIVE: City water was assessed to determine source and persistence of diarrhea and hepatitis among the human populations in the environs of Quibdó. MATERIAL AND METHODS: Four thousand liters of water were collected, filtered by tangential ultrafiltration and centrifuged in Centriprep Ultracel YM-50 tubes. Sixty samples of untreated and 20 of treated water were probed by RT-PCR. RESULTS: Six samples were positive for rotavirus and 2 for hepatitis A virus in both, treated and non treated water. DNA sequence analysis identified the presence of human G2 rotavirus and human hepatitis A virus. CONCLUSION: The evidence indicated a high level of contamination with pathogenic viruses in consumable water sources in Quibdó, Colombia.