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BACKGROUND: Incomplete resolution of T cell-mediated rejection (TCMR) after treatment may not be detected with serum creatinine monitoring and is associated with donor-specific antibodies and chronic rejection. We evaluate the utility of follow-up biopsies (FUB) to identify and characterize rates of persistent TCMR after treatment in pediatric kidney transplant patients. METHODS: Patients from two pediatric transplant centers performing standard of care FUB at 1.5-2 months after treatment for TCMR were included. FUB were evaluated for extent of rejection resolution (complete vs. incomplete) and grade. Clinical data at time of FUB and later were reported, where available. RESULTS: Fifty-eight patients underwent FUB, at mean of 1.7 months (SD 0.7) post-index biopsy. Rejection grade on index biopsy was Banff borderline (≥i1t1 and Asunto(s)
Trasplante de Riñón
, Humanos
, Niño
, Trasplante de Riñón/efectos adversos
, Linfocitos T
, Estudios de Seguimiento
, Biopsia
, Resultado del Tratamiento
, Receptores de Trasplantes
, Rechazo de Injerto
, Riñón/patología
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Salivary duct carcinoma (SDC) is aggressive with limited therapeutic options. A subset of SDC display human epidermal growth factor receptor 2 (HER2) protein overexpression by immunohistochemistry, and some show ERBB2 gene amplification. Guidelines for HER2 scoring are not firmly established. Recent advances in breast carcinoma have established a role for anti-HER2 therapies in lesions with low HER2 expression lacking ERBB2 amplification. Delineating HER2 staining patterns in SDC is critical for evaluating anti-HER2 treatments. In total, 53 cases of SDC resected at our institution between 2004 and 2020 were identified. Androgen receptor (AR) and HER2 immunohistochemistry and ERBB2 fluorescence in situ hybridization were performed in all cases. AR expression was scored for percentage positive cells and categorized as positive (>10% of cells), low positive (1%-10%), or negative (<1%). HER2 staining levels and patterns were recorded, scored using 2018 ASCO/CAP guidelines, and categorized into HER2-positive (3+ or 2+ with ERBB2 amplification), HER2-low (1+ or 2+ without ERBB2 amplification), HER2-very low (faint staining in <10% of cells), or HER2-absent types. Clinical parameters and vital status were recorded. Median age was 70 years, with a male predominance. ERBB2-amplified tumors (11/53; 20.8%) presented at lower pT stages (pTis/pT1/pT2; P = .005, Fisher exact test) and more frequently had perineural invasion (P = .007, Fisher exact test) compared with ERBB2 nonamplified tumors; no other pathologic features differed significantly by gene amplification status. In addition, 2+ HER2 staining by 2018 ASCO/CAP criteria was most common (26/53; 49%); only 4 cases (8%) were HER2-absent status; 3+ HER2 staining was found in 9 tumors, and all were ERBB2 amplified. Six patients with HER2-expressing tumors received trastuzumab therapy, including 2 with ERBB2-amplified tumors. Overall survival and recurrence-free survival did not differ significantly based on ERBB2 status. This work suggests that 2018 ASCO/CAP guidelines for HER2 evaluation in breast carcinoma could be applied to SDC. Our findings also show broad overexpression of HER2 in SDC raising the possibility that more patients may benefit from anti-HER2-directed therapies.
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AIMS: Due to its rarity and non-specific clinical and pathological features, low-grade adenosquamous carcinoma (LGASC) of the breast continues to pose diagnostic challenges. Unlike other triple-negative breast carcinomas, LGASC tends to have an indolent clinical behaviour. It is essential to recognise this lesion for accurate diagnosis and appropriate management. METHODS AND RESULTS: Twenty-five cases of LGASC were identified in our archives and collaborating institutes. Cases of LGASC with dominant coexisting other type carcinomas were excluded. We studied the clinical presentation, morphological features, patterns of the commonly used immunohistochemical stains and follow-up. In our cohort, LGASC was commonly located at the outer aspect of the breast and associated with intraductal papilloma. The morphology of LGASC is characterised by infiltrating small glands and nests with variable squamous differentiation. We also found cuffing desmoplastic (fibrolamellar) stromal change in 75% of patients and peripheral lymphocytic aggregates in 87.5% of patients. P63 and smooth muscle myosin (SMM) were the most common myoepithelial markers used to assist in diagnosis. P63 often stained peripheral tumour cells surrounding invasive glands (circumferential staining in 80% of the cases), mimicking myoepithelial cells. It also stained the small nests with squamous differentiation. However, SMM was negative in 63% of the cases. The vast majority of our cases were triple-negative; only a few had focal and weak expressions of ER and PR. One patient who did not have excision developed lymph node metastasis. Most patients underwent excision or mastectomy with negative margins as surgical treatment; there were no recurrences or metastases in these patients with clinical follow-ups up to 108 months. CONCLUSIONS: LGASC has some unique, although not entirely specific, morphological features and immunohistochemical staining patterns. Fibrolamellar stromal change, peripheral lymphocytic aggregates and variable staining of p63 and SMM are valuable features to facilitate the diagnosis.
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Neoplasias de la Mama , Carcinoma Adenoescamoso , Carcinoma de Células Escamosas , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Carcinoma Adenoescamoso/diagnóstico , Carcinoma Adenoescamoso/patología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Mastectomía , Mama/patología , Neoplasias de la Mama Triple Negativas/patología , Carcinoma de Células Escamosas/patología , Biomarcadores de Tumor/análisisRESUMEN
The International Cardio-Metabolic Forum held a plenary session to establish a multinational consensus on the challenges faced in diabetes management within lower-middle-income countries (LMICs) and their potential solutions. Stakeholders, including patients, family/caretakers, healthcare professionals, and healthcare policymakers & organizations, participated in discussions. The audience of 280 doctors from 15 different countries (Pakistan, Qatar, Sri Lanka, Kenya, Myanmar, Georgia, Nigeria, Philippines, Uzbekistan, Iraq, Tanzania, Cambodia, Kazakhstan, South Sudan and Libya) was divided into 4 groups led by Group Leaders to represent each stakeholder group. Questionnaires addressing key challenges and solutions specific to each group were used to facilitate consensus development. Participants voted on relevant options based on their clinical experience. SLIDO software was used for polling, generating separate results for each group. The insights shared by healthcare professionals highlighted the importance of improving medication accessibility and cost-effectiveness for patients, emphasizing the need for adherence to treatment plans and lifestyle modifications. The significance of balanced nutrition with low glycemic index food for enhancing quality of life was recognized. Caregivers of diabetic patients with comorbidities face increasing demands for care, particularly in relation to age-related milestones. Healthcare professionals emphasized the challenges posed by cultural beliefs and health awareness, underscoring the importance of teamwork and early referral for managing comorbidities. Healthcare policymakers need to focus on disease education, awareness programs, screening guidelines, and advocacy for community and clinical screening. By addressing these challenges, a more comprehensive and effective approach to diabetes management can be achieved in LMICs, ultimately improving outcomes for individuals with diabetes.
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Immunohistochemistry techniques have been incorporated into surgical pathology for nearly a half-century and have since become intimately intertwined with its practice. In the realm of breast pathology, immunohistochemistry serves several purposes, including providing crucial prognostic and predictive data. Among its other applications, assessment of stromal invasion and establishment of mammary origin are crucial from a diagnostic standpoint. In these regards, sole reliance on immunohistochemistry may lead to misdiagnosis. In this review, we highlight pitfalls of immunohistochemistry commonly encountered in the practice of breast pathology and emphasize the importance of careful histopathological evaluation.
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Neoplasias de la Mama , Patología Quirúrgica , Biomarcadores de Tumor , Mama , Neoplasias de la Mama/diagnóstico , Femenino , Humanos , Inmunohistoquímica , Patología Quirúrgica/métodosRESUMEN
The impact of the COVID-19 pandemic upon care of malignant melanoma (MM) remains as yet poorly understood. We undertook a UK-wide national survey, in conjunction with a patient support group (Melanoma UK), to explore patient perceptions of the impact of the pandemic upon treatment and outpatient care of their MM. Our findings suggest that following the onset of COVID-19, a significant minority of treatments and appointments have been delayed, there has been a shift from face-to-face to virtual outpatient consultations and there may be a rise in psychological comorbidities in patients with MM. We would urge clinicians to consider mental health interventions as part of a holistic care package.
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Ansiedad/etiología , COVID-19/prevención & control , Melanoma/terapia , Neoplasias Cutáneas/terapia , Estrés Psicológico/etiología , Adulto , Anciano , Anciano de 80 o más Años , Atención Ambulatoria , Citas y Horarios , Control de Enfermedades Transmisibles/métodos , Estudios Transversales , Femenino , Encuestas de Atención de la Salud , Accesibilidad a los Servicios de Salud , Humanos , Masculino , Melanoma/psicología , Persona de Mediana Edad , SARS-CoV-2 , Neoplasias Cutáneas/psicología , Telemedicina , Reino Unido , Adulto JovenRESUMEN
AIMS: The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) updated the testing guideline in 2018 to address issues arising from uncommon human epidermal growth factor receptor 2 (HER2) fluorescence in-situ hybridisation (FISH) results according to the 2013 guideline. Next-generation sequencing (NGS) may be used to better classify patients. The aim of this study was to assess the ERBB2 amplification status of invasive breast carcinoma with equivocal HER2 immunohistochemistry (IHC) results by using NGS, focusing on Group 4 (HER2/CEP17 ratio of <2.0; average HER2 signals/cell of ≥4.0 and <6.0). METHODS AND RESULTS: We retrospectively reviewed HER2 FISH and NGS data of HER2 IHC-equivocal breast carcinomas at our centre between January 2009 and September 2019, wherein all three assays were performed on the same tissue block, and compared HER2 FISH results, according to the 2018 ASCO/CAP guideline, and the ERBB2 amplification status determined with NGS. A total of 52 HER2 FISH and NGS results from 51 patients with HER2 IHC-equivocal breast carcinomas were reviewed. The cohort included eight cases classified as 2018 ASCO/CAP in-situ hybridisation Group 1, three classified as Group 2, three classified as Group 3, 14 classified as Group 4, and 24 classified as Group 5. Thirteen of 14 (92.9%) Group 4 (HER2-negative) cases were classified as ERBB2-non-amplified by the use of NGS; the discordant case was later classified as Group 1 with alternative sample FISH testing. NGS revealed no significant difference in somatic mutations or copy number alterations between Groups 4 and 5. CONCLUSIONS: Our NGS findings support the reclassification of HER2 FISH-equivocal cases as HER2-negative under the 2018 ASCO/CAP guideline.
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Neoplasias de la Mama/clasificación , Variaciones en el Número de Copia de ADN , Receptor ErbB-2/genética , American Medical Association , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Estudios de Cohortes , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Oncología Médica , Clasificación del Tumor , Patólogos , Guías de Práctica Clínica como Asunto , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , Estados UnidosRESUMEN
Diabetes is a pandemic which is becoming endemic to society. Primary care physicians should be able to offer basic diabetes prevention and care services, to ensure timely detection and management of the condition. This expert opinion shares suggestions to help primary care physicians introduce and integrate diabetes care in their routine practice. It identifies and focuses on four pillars: improving oneself, strengthening the health care team, empowering the person living with diabetes, and sensitizing the public at large.
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Diabetes Mellitus , Atención Primaria de Salud , Diabetes Mellitus/epidemiología , Diabetes Mellitus/terapia , Humanos , Grupo de Atención al PacienteRESUMEN
BACKGROUND AND PURPOSE: Basilar artery occlusion (BAO) leads to high rates of morbidity and mortality, despite successful recanalization. The discordance between flow restoration and long-term functional status clouds clinical decision-making regarding further aggressive care. We sought to develop and validate a practical, prognostic tool for the prediction of 3-month favorable outcome after acute reperfusion therapy for BAO. METHODS: This retrospective, multicenter, observational study was conducted at four high-volume stroke centers in the USA and Europe. Multivariate regression analysis was performed to identify predictors of favorable outcome (90-day modified Rankin scale scores 0-2) and derive a clinically applicable prognostic model (the Pittsburgh Outcomes after Stroke Thrombectomy-Vertebrobasilar (POST-VB) score). The POST-VB score was evaluated and internally validated with regard to calibration and discriminatory ability. External validity was assessed in patient cohorts at three separate centers. RESULTS: In the derivation cohort of 59 patients, independent predictors of favorable outcome included smaller brainstem infarct volume on post-procedure magnetic resonance imaging (P < 0.01) and younger age (P = 0.01). POST-VB score was calculated as: age + (10 × brainstem infarct volume). POST-VB score demonstrated excellent discriminatory ability [area under the receiver-operating characteristic curve (AUC) = 0.91] and adequate calibration (P = 0.88) in the derivation cohort (Center A). It performed equally well across the three external validation cohorts (Center B, AUC = 0.89; Center C, AUC = 0.78; Center D, AUC = 0.80). Overall, a POST-VB score < 49 was associated with an 88% likelihood of favorable outcome, as compared to 4% with a score ≥ 125. CONCLUSIONS: The POST-VB score effectively predicts 3-month functional outcome following acute reperfusion therapy for BAO and may aid in guiding post-procedural care.
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Procedimientos Endovasculares , Accidente Cerebrovascular , Insuficiencia Vertebrobasilar , Arteria Basilar/diagnóstico por imagen , Europa (Continente) , Humanos , Reperfusión , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Optical materials with a high refractive index enable effective manipulation of light at the nanoscale through strong light confinement. However, the optical near field, which is mainly confined inside such high-index nanostructures, is difficult to probe with existing measurement techniques. Here, we exploit the connection between Raman scattering and the stored electric energy to detect resonance-induced near-field enhancements in silicon nanostructures. We introduce a Raman setup with a wavelength-tunable laser, which allows us to tune the Raman excitation wavelength and thereby identify Fabry-Pérot and Mie type resonances in silicon thin films and nanodisk arrays, respectively. We measure the optical near-field enhancement by comparing the Raman response on and off resonance. Our results show that tunable-excitation Raman spectroscopy can be used as a complimentary far-field technique to reflection measurements for nanoscale characterization and quality control. As proof-of-principle for the latter, we demonstrate that Raman spectroscopy captures fabrication imperfections in the silicon nanodisk arrays, enabling an all-optical quality control of metasurfaces.
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AIMS: Secretory carcinoma of the breast (SCB) is a rare histological type of breast carcinoma with a generally indolent clinical behaviour. We aim to elucidate the clinical, pathological and molecular findings of SCB cases and identify characteristics associated with aggressive clinical courses. METHODS AND RESULTS: Fourteen patients with SCB were identified, including 12 women and two men, with a median age of 56 years (range = 8-81 years). Clinical data, histological diagnosis, molecular findings and follow-up were reviewed. Eight patients presented with palpable masses and four patients with radiographic abnormalities. All cases were unilateral. Surgical procedures included excisional biopsies and ipsilateral mastectomies. In 10 cases, oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) results were obtained, with six cases positive for ER and three positive for PR. All cases lacked HER2 overexpression. Sentinel lymph node biopsy was performed in 10 cases, and two patients had axillary lymph node metastasis. Follow-up ranged from 21 to 212 months (median = 70 months). Two patients developed distant metastasis of SCB. Molecular analysis of these aggressive tumours revealed amplification of the 16p13.3 locus, a TERT promotor mutation and loss of 9p21.3 locus. Review of the literature for SCB cases with distant metastasis was performed. CONCLUSIONS: Although SCBs are generally associated with a favourable prognosis, our study and review demonstrate that a subset of SCBs may develop distant metastases. Further studies are warranted to identify markers predictive of more aggressive clinical behaviour in this rare breast cancer subtype.
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Neoplasias de la Mama/patología , Carcinoma/patología , Metástasis de la Neoplasia/patología , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenAsunto(s)
Miocitos Cardíacos , Transcriptoma , Animales , Animales Recién Nacidos , Proliferación Celular , Corazón , Humanos , Regeneración , PorcinosRESUMEN
BACKGROUND: The gut is becoming increasingly recognized as the source of various systemic diseases, and recently, it has been linked to bone metabolism via the so-called gut-bone axis. The microbiome and gut-derived mediators are thought to impact upon bone metabolism, and administration of probiotics has been shown to have beneficial effects in bone. The gut brush border enzyme intestinal alkaline phosphatase (IAP) plays an important role in controlling calcium absorption, inhibiting lipopolysaccharides, and other inflammatory mediators responsible for endotoxemia and appears to preserve the normal gut microbiota. Interestingly, IAP-deficient mice (AKP3-/-) also display a significant decrease in fecal Lactobacillus, the genus shown to be beneficial to bone. MATERIALS AND METHODS: IAP mRNA levels in mouse bone were measured using quantitative real-time polymerase chain reaction. Femurs of IAP-knockout (KO) and wild-type (WT) mice were analyzed by microcomputed tomography and histopathology. Serum levels of alkaline phosphatase, calcium, and phosphorus were measured. Target cell response upon exposure to serum from IAP-KO and WT mice was quantified using primary bone marrow macrophages. RESULTS: IAP was not significantly expressed in bones of WT or KO animals. IAP (alkaline phosphatase 3) expression in bone was vanishingly low compared to the duodenum (bone versus duodenum, 56.9 ± 17.7 versus 25,430.3 ± 10,884.5 relative expression, P = 0.01). Bone histology of younger IAP-KO and WT animals was indistinguishable, whereas older IAP-deficient mice showed a distinctly altered phenotype on histology and computed tomography scan. Younger KO mice did not display any abnormal levels in blood chemistry. Older IAP-KO animals showed an isolated increase in serum alkaline phosphatase levels reflecting an environment of active bone formation (IAP-WT versus IAP-KO, 80 ± 27.4 U/I versus 453 ± 107.5 U/I, P = 0.004). There was no significant difference in serum calcium or phosphorus levels between KO and WT mice. Serum from IAP-KO mice induced a significantly higher inflammatory target cell response. CONCLUSIONS: Through its multiple functions, IAP seems to play a crucial role in connecting the gut to the bone. IAP deficiency leads to chronic changes in bone formation, most likely through dysbiosis and systemic dissemination of proinflammatory mediators.
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Fosfatasa Alcalina/deficiencia , Remodelación Ósea/fisiología , Duodeno/metabolismo , Fémur/patología , Mucosa Intestinal/metabolismo , Fosfatasa Alcalina/sangre , Fosfatasa Alcalina/genética , Animales , Células Cultivadas , Disbiosis/metabolismo , Femenino , Fémur/diagnóstico por imagen , Fémur/metabolismo , Microbioma Gastrointestinal/fisiología , Macrófagos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Cultivo Primario de Células , ARN Mensajero/aislamiento & purificación , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Organismos Libres de Patógenos Específicos , Microtomografía por Rayos XRESUMEN
INTRODUCTION: Conservative management of penetrating renal trauma is emerging, with data originating from centers with variable level of trauma care. This study reviews the outcomes of renal salvage after penetrating trauma at a level I trauma center. MATERIALS AND METHODS: An institutional review board approved trauma registry at Saint Louis University Hospital was retrospectively analyzed, for patients with penetrating renal trauma from 2009 to 2014. Patients were divided into nephrectomy group (NG) or non-nephrectomy group (non-NG), and compared. A multi-variable analysis was performed to determine predictors of nephrectomy, with cross validation to evaluate the performance of the multi-variable model. Data was analyzed using R version 3.3.2. A p value of < 0.05 was considered as significant. RESULTS: A total of 121 patients were identified with penetrating renal trauma. Gunshot injury was the leading cause of injury (87%). Eighteen (15%) patients required nephrectomy. The overall mean injury severity score (ISS). was 20. High grade (grade 4-5) renal injuries were noted in 41 patients (34%). Among these, 14 patients (34%) underwent a nephrectomy, while 27 patients (66%) were managed conservatively to salvage renal units. CT grade of renal injury was the only predictor of nephrectomy, on multi-variable analysis (OR 17.09 CI 2.75-105.99, p = 0.002). CT grade of injury and injury severity score were predictors of endoscopic intervention on a sub group analysis of non-NG. CONCLUSIONS: CT grade of injury predicts nephrectomy after penetrating renal trauma. Conservative management is a feasible option in penetrating renal trauma even with a higher grade of injury.
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Tratamiento Conservador/métodos , Riñón/lesiones , Tratamientos Conservadores del Órgano/métodos , Sistema de Registros , Heridas Penetrantes/cirugía , Adulto , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Hospitales Universitarios , Humanos , Puntaje de Gravedad del Traumatismo , Riñón/cirugía , Masculino , Missouri , Análisis Multivariante , Nefrectomía/métodos , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Medición de Riesgo , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Heridas Penetrantes/diagnósticoRESUMEN
Background Type 2 diabetes mellitus (T2DM) is a global major health problem resulting from interaction of environmental and genetic factors, examples of the latter being KCNJ11 (coding for part of the ATP-sensitive potassium channel) and SDF-1ß (coding for chemokine CXCL12). Our case-control study was conducted to assess whether recessive, dominant or additive genotype model associations of KCNJ11 (E23K, rs5219) and SDF-1ß (G801A, rs1801157) were more strongly linked to type 2 diabetes. Subjects & Methods Genetic polymorphism analysis was performed by polymerase chain reaction-restriction fragment length polymorphism. Alleles and genotype frequencies between 200 cases and 200 controls were determined and compared. Results The dominant (EE v EK + KK, p = 0.022) and additive (EK v EE + KK, p = 0.021) models, but not the recessive model (KK v EE + EK, p = 0.727) of KCNJ11 were linked to diabetes. Similarly, the dominant (GG v GA + AA, p < 0.001) and additive (AG v GG + AA, p=<0.001) models, but not the recessive model (AA v AG + GG, p = 0.430) of SDF-1ß were linked to diabetes. The A allele (p = 0.006) of SDF-1ß was protective against the risk of T2DM. Conclusion Both dominant and additive models in both KCNJ11 (E23K, rs5219) and SDF-1ß (G801A, rs1801157) genetic polymorphisms are significantly associated with type 2 diabetes.
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Quimiocina CXCL12/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Canales de Potasio de Rectificación Interna/genética , Alelos , Diabetes Mellitus Tipo 2/patología , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción/genética , Factores de RiesgoRESUMEN
BACKGROUND: Certain forms of chemoradiotherapy generate toxic reactive oxygen species, which may be ameliorated by antioxidant enzymes such as glutathione S-transferase (GST). Genetic polymorphisms of GST may predict treatment outcomes and can be used as genetic marker to screen patients before treatment. We hypothesised an effect of GST polymorphisms on the response and toxicities produced by chemoradiation therapy. MATERIALS AND METHODS: GST polymorphisms were determined by multiplex polymerase chain reaction and PCR-restriction fragment length polymorphism (PCR-RFLP) in 227 women with cervical cancer receiving cisplatin based chemoradiotherapy. Treatment response and toxicities were evaluated by standard internationally recognised criteria (RECIST and RTOG). RESULTS: Severe (grade 3-4) gastrointestinal and haematological toxicities were present in 22 (9.4%) and 16 (7.0%) patients, respectively. GSTM1 null, GSTT1 null and GSTP1 AG genotypes brought marginally better non-significant associations. In single locus analysis GSTP1 AG and GG was linked to greatest risk of severe (grade 3-4) gastrointestinal toxicity (OR = 3.12, P = 0.035 and OR = 6.99, P = 0.01, respectively). In gene-gene interaction analysis, GSTM1 null-GSTP1 GG showed 4.2-fold higher risk of severe gastrointestinal toxicity (P = 0.014). GSTT1 null-GSTP1 AG reached statistical significance with a 3.9-fold higher risk of high grade gastrointestinal toxicity (P = 0.038). CONCLUSIONS: Although no significant links were found between GST polymorphism and treatment response, null genotypes of GSTM1, GSTT1 and 'G' allele of GSTP1 bring a higher risk of severe gastrointestinal toxicity due to chemoradiation therapy in cervical cancer.
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Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Neoplasias del Cuello Uterino/genética , Anciano , Quimioradioterapia/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/genética , Enfermedades Gastrointestinales/patología , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/efectos de la radiación , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
BACKGROUND: Type 2 diabetes mellitus describes a metabolic disorder characterised by prolonged elevated blood glucose that brings a risk of developing microvascular and macrovascular disease. Several factors, such as dysregulation of the Toll-like receptor 4 (TLR-4), are reputed to contribute to the multiple pathophysiological disturbances responsible for impaired glucose homeostasis. We hypothesised that variants rs5030717 and rs5030718 of TLR4 are associated with diabetic nephropathy, hypertension and dyslipidaemia. MATERIAL & METHODS: We recruited 370 diabetics (122 with nephropathy, 119 with hypertension and 129 with dyslipidaemia) and 120 ethnicity matched healthy controls. TLR4 polymorphisms were evaluated using polymerase chain reaction followed by restriction fragment length polymorphism analysis. The genotyping data were compared between cases and controls using chi-square test and logistic regression analysis. RESULTS: Although there was no overall difference in the genotype frequencies of TLR4 rs5030717 in diabetes v controls, the genotype frequencies of diabetic dyslipidaemia cases compared with controls were different (p = 0.001). Overall, the rs5030718 GA and GG genotype frequencies in the entire diabetes cohort were different from those of the controls (p = 0.037), and the frequencies of diabetic nephropathy cases (p = 0.03) and diabetic dyslipidaemia cases were different (p = 0.001) compared with controls. There were no links with diabetic hypertension. CONCLUSION: TLR4 polymorphisms rs5030717 and rs5030718 may be useful in predicting those type 2 diabetics who are at risk of hypertension, nephropathy and/or dyslipidaemia.
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Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Dislipidemias/genética , Hipertensión/genética , Receptor Toll-Like 4/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/patología , Dislipidemias/etiología , Dislipidemias/patología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Hipertensión/etiología , Hipertensión/patología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de RiesgoRESUMEN
Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034-429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co-segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub-isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID.
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Predisposición Genética a la Enfermedad/genética , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Consanguinidad , Exoma/genética , Salud de la Familia , Femenino , Finlandia , Efecto Fundador , Genes Recesivos , Genotipo , Geografía , Humanos , Masculino , Países Bajos , Linaje , Análisis de Secuencia de ADN/métodos , Homología de Secuencia de AminoácidoRESUMEN
AIMS: Lanthanum carbonate is used as an alternative to calcium-based phosphate binders to manage hyperphosphataemia in patients with renal failure. The deposition of lanthanum within gastroduodenal mucosa of patients treated with the medication has been described, but given the relative novelty of this entity, the histiocytic deposits in the gastroduodenal mucosa can be confused with a variety of other processes, including infections and other drug-induced forms of injury. METHODS AND RESULTS: We describe five cases of lanthanum phosphate deposition in upper gastrointestinal (GI) tract biopsies. Three cases were confirmed with scanning electron microscopy and energy dispersive X-ray analysis, including one unique patient, status post-renal transplant for polycystic kidney disease, who had last taken lanthanum 7 years prior to biopsy. CONCLUSION: Lanthanum deposition in the upper GI tract is a mimic of other drug-related forms of GI injury, including iron pill-related gastropathy. The key to making this diagnosis is a thorough drug history and awareness of the histological features.