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BACKGROUND: Findings from observational studies suggest that dietary patterns may offer protective benefits against cognitive decline, but data from clinical trials are limited. The Mediterranean-DASH Intervention for Neurodegenerative Delay, known as the MIND diet, is a hybrid of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet, with modifications to include foods that have been putatively associated with a decreased risk of dementia. METHODS: We performed a two-site, randomized, controlled trial involving older adults without cognitive impairment but with a family history of dementia, a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 25, and a suboptimal diet, as determined by means of a 14-item questionnaire, to test the cognitive effects of the MIND diet with mild caloric restriction as compared with a control diet with mild caloric restriction. We assigned the participants in a 1:1 ratio to follow the intervention or the control diet for 3 years. All the participants received counseling regarding adherence to their assigned diet plus support to promote weight loss. The primary end point was the change from baseline in a global cognition score and four cognitive domain scores, all of which were derived from a 12-test battery. The raw scores from each test were converted to z scores, which were averaged across all tests to create the global cognition score and across component tests to create the four domain scores; higher scores indicate better cognitive performance. The secondary outcome was the change from baseline in magnetic resonance imaging (MRI)-derived measures of brain characteristics in a nonrandom sample of participants. RESULTS: A total of 1929 persons underwent screening, and 604 were enrolled; 301 were assigned to the MIND-diet group and 303 to the control-diet group. The trial was completed by 93.4% of the participants. From baseline to year 3, improvements in global cognition scores were observed in both groups, with increases of 0.205 standardized units in the MIND-diet group and 0.170 standardized units in the control-diet group (mean difference, 0.035 standardized units; 95% confidence interval, -0.022 to 0.092; P = 0.23). Changes in white-matter hyperintensities, hippocampal volumes, and total gray- and white-matter volumes on MRI were similar in the two groups. CONCLUSIONS: Among cognitively unimpaired participants with a family history of dementia, changes in cognition and brain MRI outcomes from baseline to year 3 did not differ significantly between those who followed the MIND diet and those who followed the control diet with mild caloric restriction. (Funded by the National Institute on Aging; ClinicalTrials.gov number, NCT02817074.).
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Disfunção Cognitiva , Demência , Dieta Mediterrânea , Idoso , Idoso de 80 Anos ou mais , Humanos , Encéfalo/diagnóstico por imagem , Cognição , Disfunção Cognitiva/prevenção & controle , Demência/prevenção & controle , Dieta Hipossódica , Restrição CalóricaRESUMO
BACKGROUND: The contradictory role of CD8 + CD28- T cells in tumour immunity has been reported, while their biological and clinical significance in HER2-positive metastatic breast cancer (MBC) is still unknown. METHODS: HER2-positive MBC patients with no prior therapy in the metastatic setting were retrospectively recruited at two medical centres. Peripheral CD8 + CD28- T cells (pTCD8+CD28-) were detected at baseline and following therapeutic intervals. Progression-free survival (PFS) was compared according to pTCD8+CD28- levels. The molecular features of pTCD8+CD28- and its correlation with tumour immunity were also investigated. RESULTS: A total of 252 patients were enrolled, and the median follow-up time was 29.6 months. pTCD8+CD28- high at baseline has prolonged PFS compared to pTCD8+CD28- low (P = 0.001). Patients who maintained pTCD8+CD28- high had a longer PFS than those who kept pTCD8+CD28- low (P < 0.001). The enhanced pTCD8+CD28- level also indicates a longer PFS compared to pTCD8+CD28- low (P = 0.025). Here, pTCD8+CD28- was demonstrated as an antigen-experienced effector T cell. Higher IL-2 level (P = 0.034) and lower TGF-ß level (P = 0.016) in the serum and highly infiltrated CD8 + CD28- T cells (P = 0.037) were also connected to pTCD8+CD28- high. CONCLUSIONS: High pTCD8+CD28- level is associated with a favourable tumour immunity and a better PFS of HER2-targeting therapy in MBC patients.
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Neoplasias da Mama , Antígenos CD28 , Linfócitos T CD8-Positivos , Receptor ErbB-2 , Adulto , Feminino , Humanos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/imunologia , Metástase Neoplásica , Intervalo Livre de Progressão , Receptor ErbB-2/metabolismo , Estudos RetrospectivosRESUMO
Tetraspanins, including CD53 and CD81, regulate a multitude of cellular processes through organizing an interaction network on cell membranes. Here, we report the crystal structure of CD53 in an open conformation poised for partner interaction. The large extracellular domain (EC2) of CD53 protrudes away from the membrane surface and exposes a variable region, which is identified by hydrogen-deuterium exchange as the common interface for CD53 and CD81 to bind partners. The EC2 orientation in CD53 is supported by an extracellular loop (EC1). At the closed conformation of CD81, however, EC2 disengages from EC1 and rotates toward the membrane, thereby preventing partner interaction. Structural simulation shows that EC1-EC2 interaction also supports the open conformation of CD81. Disrupting this interaction in CD81 impairs the accurate glycosylation of its CD19 partner, the target for leukemia immunotherapies. Moreover, EC1 mutations in CD53 prevent the chemotaxis of pre-B cells toward a chemokine that supports B-cell trafficking and homing within the bone marrow, a major CD53 function identified here. Overall, an open conformation is required for tetraspanin-partner interactions to support myriad cellular processes.
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Movimento Celular , Células Precursoras de Linfócitos B/metabolismo , Tetraspanina 25 , Tetraspanina 28 , Animais , Antígenos CD19/química , Antígenos CD19/genética , Antígenos CD19/metabolismo , Humanos , Camundongos , Camundongos Knockout , Domínios Proteicos , Tetraspanina 25/química , Tetraspanina 25/genética , Tetraspanina 25/metabolismo , Tetraspanina 28/química , Tetraspanina 28/genética , Tetraspanina 28/metabolismoRESUMO
BACKGROUND: Pyrotinib is currently approved for the treatment of HER2-positive advanced breast cancer in China. Data on the overall survival (OS) and efficacy in patients with brain metastasis (BM) remain scarce. This study evaluated the effectiveness of pyrotinib in a real-world setting, especially in patients with BM. METHODS: We reviewed patients with metastatic breast cancer treated with pyrotinib-based therapy between June 2018 and June 2022. Progression-free survival (PFS), OS, objective response rate, and safety were analyzed following the administration of pyrotinib. RESULTS: A total of 239 patients were included. The median PFS in patients who received pyrotinib-based therapy as first-line (15/239), second-line (115/239), or third-or-higher-line (109/239) treatment was 14.00, 9.33, and 8.20 months, respectively, and the median OS was not reached, 29.07 and 22.23 months, respectively. The median PFS in patients who pretreated with trastuzumab (214/239), trastuzumab plus pertuzumab (22/239), lapatinib (68/239), or trastuzumab emtansine (14/239) was 9.33, 6.87, 7.20, and 7.20 months, respectively. In 61 patients with BM, the median PFS was 7.50 months, the median central nervous system (CNS)-PFS was 11.17 months, and the median OS was 21.27 months. Furthermore, 19 patients with concomitant brain radiotherapy tended to achieve a longer OS than 42 patients without radiation (34.17 vs. 20.70 months, Pâ =â .112). CONCLUSIONS: Long-term outcomes of pyrotinib-based therapy are promising for patients with HER2-positive metastatic breast cancer in real world and in patients with BM, regardless of the treatment lines and prior anti-HER2 therapies.
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Acrilamidas , Aminoquinolinas , Neoplasias Encefálicas , Neoplasias da Mama , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêuticoRESUMO
PURPOSE: In patients with first-line advanced breast cancer (ABC), the correlation between ctDNA variant allele frequency (VAF) and tumor disease burden, and its prognostic value remains poorly investigated. METHODS: This study included patients with ABC diagnosed at Peking University Cancer Hospital who performed ctDNA test before receiving first-line treatment. Baseline plasma samples were collected for assessing ctDNA alterations and VAF with next-generation sequencing. The sum of tumor target lesion diameters (SLD) was measured with imaging methods according to RECIST 1.1 criteria. RESULTS: The final cohort included 184 patients. The median age of the cohort was 49.4 (IQR: 42.3-56.8) years. The median VAF was 15.6% (IQR: 5.4%-33.7%). VAF showed positive correlation with SLD in patients with relatively large tumor lesions (r = 0.314, p = 0.003), but not in patients with small tumor lesions (p = 0.226). VAF was associated with multiple metastasis sites (p = 0.001). Multivariate Cox regression analysis showed that high VAF was associated with shorter overall survival (OS) (HR: 3.519, 95% confidence interval (CI): 2.149-5.761), and first-line progression-free survival (PFS) (HR: 2.352, 95%CI: 1.462-3.782). Combined VAF and SLD improved prediction performance, both median OS and PFS of patients in VAF(H)/SLD(H) group were significantly longer than VAF(L)/SLD(L) group (mOS: 49.3 vs. 174.1 months; mPFS: 9.6 vs. 25.3 months). CONCLUSION: ctDNA VAF associated with tumor disease burden, and was a prognostic factor for patients with ABC. A combination of ctDNA test and radiographic imaging might enhance tumor burden evaluation, and improve prognosis stratification in patients with ABC.
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Neoplasias da Mama , DNA Tumoral Circulante , Neoplasias Pulmonares , Humanos , Adulto , Pessoa de Meia-Idade , Feminino , DNA Tumoral Circulante/genética , Carga Tumoral , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Biomarcadores Tumorais/genética , Prognóstico , Neoplasias Pulmonares/genética , Frequência do Gene , MutaçãoRESUMO
INTRODUCTION: Isolated partial anomalous pulmonary venous connection (PAPVC) is difficult to diagnose, and surgical indications remain controversial. We reviewed 10 y of isolated PAPVC cases. METHODS: The data of patients with isolated PAPVC admitted to the Anzhen Congenital Heart Disease Department from 2010 to 2019 were reviewed retrospectively. RESULTS: Thirty patients, aged between 4 mo and 32 y, were included in this study. Significant correlations were found between the right ventricle (RV), end-diastolic dimension Z-score (RVED-z) and age (r = 0.398, P = 0.03), and between estimated pulmonary pressure and age (r = 0.423, P = 0.02). However, no significant correlations were found between the RVED-z and the number of anomalous pulmonary veins (r = 0.347, P = 0.061), between estimated pulmonary pressure and the RVED-z (r = 0.218, P = 0.248), and between estimated pulmonary pressure and the number of anomalous veins (r = 0.225, P = 0.232). Transthoracic echocardiography (TTE) confirmed 90% of isolated PAPVC cases. Surgical repair was performed in 29 patients with RV enlargement, persistent low weight, pulmonary hypertension, or respiratory symptoms. Among the surgical patients, nine had elevated pulmonary pressure before surgery, which decreased postoperatively; no mortality or reintervention was observed. The mean duration of echocardiographic follow-up was 1.9 y. CONCLUSIONS: TTE is recommended for routine assessments, and further clarification can be obtained with computed tomography when TTE proves inconclusive for diagnosis. Transesophageal echocardiography and computed tomography are further recommended for adult patients if TTE fails to provide clear results. PAPVC should be considered as an underlying cause when unexplained RV enlargement is observed. Surgery is recommended for patients with RV enlargement, pulmonary hypertension, or respiratory symptoms.
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Veias Pulmonares , Síndrome de Cimitarra , Humanos , Estudos Retrospectivos , Masculino , Adulto , Feminino , Adolescente , Criança , Pré-Escolar , Adulto Jovem , Lactente , Síndrome de Cimitarra/cirurgia , Síndrome de Cimitarra/diagnóstico por imagem , Síndrome de Cimitarra/diagnóstico , Veias Pulmonares/anormalidades , Veias Pulmonares/cirurgia , Veias Pulmonares/diagnóstico por imagem , EcocardiografiaRESUMO
Background: Paraquat (PQ) plays an important role in agricultural production due to its highly effective herbicidal effect. However, it has led to multiple organ failure in those who have been poisoned, with damage most notable in the lungs and ultimately leading to death. Because of little research has been performed at the genetic level, and therefore, the specific genetic changes caused by PQ exposure are unclear.Methods: Paraquat poisoning model was constructed in Sprague Dawley (SD) rats, and SD rats were randomly divided into Control group, paraquat (PQ) poisoning group and Anthrahydroquinone-2,6-disulfonate (AH2QDS) treatment group. Then, the data was screened and quality controlled, compared with reference genes, optimized gene structure, enriched at the gene expression level, and finally, signal pathways with significantly different gene enrichment were screened.Results: This review reports on lung tissues from paraquat-intoxicated Sprague Dawley (SD) rats that were subjected to RNA-seq, the differentially expressed genes were mainly enriched in PI3K-AKT, cGMP-PKG, MAPK, Focal adhesion and other signaling pathways.Conclusion: The signaling pathways enriched with these differentially expressed genes are summarized, and the important mechanisms mediated through these pathways in acute lung injury during paraquat poisoning are outlined to identify important targets for AH2QDS treatment of acute lung injury due to paraquat exposure, information that will be used to support a subsequent in-depth study on the mechanism of PQ action.
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Lesão Pulmonar Aguda , Paraquat , Ratos , Animais , Ratos Sprague-Dawley , Paraquat/toxicidade , RNA-Seq , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Pulmão , Transdução de Sinais , TecnologiaRESUMO
BACKGROUND: Current animal models of sensitive skin do not adequately reflect the objective symptoms or physiological manifestations observed in human sensitive skin. OBJECTIVE: To construct and validate a sensitive skin model in mice. METHODS: Tape stripping (TS) was used to induce partial mechanical disruption of the lipid film and stratum corneum. Subsequently, propylene glycol (PG) was applied to disrupt the lipid structure in the skin barrier, and capsaicin (CS) activate transient receptor potential vanilloid 1 (TRPV1) receptors of keratinocytes to simulate the formation of sensitive skin. Evident itching and tingling sensations, scaly skin, vasodilation, local congestion, increased transepidermal water loss (TEWL), elevated TRPV1 expression, and inflammatory symptoms were subsequently evaluated. RESULTS: TS combined with PG and CS application resulted in skin flakes; skin barrier disruption; vascular dilation; increased itching, stinging, and inflammation; TRPV1 upregulation in the epidermis; and a significant increase in lactic acid-induced itching and stinging. CONCLUSION: Using a combination of TS and PG, and CS application, a mouse model of sensitive skin was successfully established involving various skin phenotypes and physiological manifestations, including skin flakes, vasodilation, increased blood flow and TEWL, itching and stinging sensations, inflammation, and elevated TRPV1 expression.
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PURPOSE: To evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) heavily pretreated with anthracycline and taxanes. METHODS: In this single-arm, phase II study, patients with HER2-negative MBC previously treated with anthracycline and taxanes as second- to fifth chemotherapy received PLD (Duomeisu®, generic doxorubicin hydrochloride liposome) 40 mg/m2 every 4 weeks until disease progression, unacceptable toxicity, or completion of six cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety. RESULTS: Of 44 enrolled patients (median age, 53.5 years; range, 34-69), 41 and 36 were evaluable for safety and efficacy, respectively. In total, 59.1% (26/44) of patients had ≥ 3 metastatic sites, 86.4% (38/44) had visceral disease, and 63.6% (28/44) had liver metastases. Median PFS was 3.7 months (95% confidence interval [CI] 3.3-4.1) and median OS was 15.0 months (95% CI 12.1-17.9). ORR, DCR, and CBR were 16.7%, 63.9%, and 36.1%, respectively. The most common adverse events (AEs) were leukopenia (53.7%), fatigue (46.3%), and neutropenia (41.5%), with no grade 4/5 AEs. The most common grade 3 AEs were neutropenia (7.3%) and fatigue (4.9%). Patients experienced palmar-plantar-erythrodysesthesia (24.4%, 2.4% grade 3), stomatitis (19.5%, 7.3% grade 2), and alopecia (7.3%). One patient displayed a left ventricular ejection fraction decline of 11.4% from baseline after five cycles of PLD therapy. CONCLUSION: PLD (Duomeisu®) 40 mg/m2 every 4 weeks was effective and well-tolerated in patients with HER2-negative MBC heavily pretreated with anthracycline and taxanes, revealing a potentially viable treatment option for this population. Trial registration Chinese Clinical Trial Registry: ChiCTR1900022568.
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Neoplasias da Mama , Neutropenia , Humanos , Pessoa de Meia-Idade , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Antraciclinas/uso terapêutico , Antraciclinas/farmacologia , Volume Sistólico , Taxoides/uso terapêutico , Função Ventricular Esquerda , Doxorrubicina/efeitos adversos , Antibióticos Antineoplásicos/farmacologia , Polietilenoglicóis/efeitos adversos , Neutropenia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento , Metástase Neoplásica/tratamento farmacológicoRESUMO
This study aimed to analyze the correlation between the microdeletion of different regions of the azoospermia factor (AZF) gene and semen parameters, sex hormone levels, and karyotypes in infertile males by retrospective study. This was performed to obtain a comprehensive understanding of the clinical data of AZF microdeletion in infertile males, to guide clinical diagnoses and treatments, and to improve the efficacy and safety of assisted reproductive technology. For this purpose, Fifty-seven patients with AZF microdeletions and complete data were selected from 1916 patients with AZF microdeletions in our hospital from January 2020 to August 2022. The correlation between semen parameters, sex hormone levels, and chromosome karyotypes of these 57 patients was analyzed. Results showed that among the 57 patients with AZF microdeletions, the region with the highest microdeletion rate was AZFc with 57.89%; single or combined deletions in AZFa and AZFb regions resulted in azoospermia. The deletion frequency of AZFc in the oligospermia group was significantly higher than that in the azoospermia group, and the deletion frequencies of AZFb and AZFb + c in the azoospermia group were significantly higher than those in the oligospermia group (P<0.05). There were statistically significant differences in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and chromosome karyotypes between patients with azoospermia and oligospermia (P<0.05). Statistically significant differences were observed in prolactin (PRL), FSH, testosterone (T), LH levels, and chromosome karyotypes of patients in different AZF microdeletion regions (P<0.05). In conclusion, AZF microdeletions can lead to a decline in semen quality in men, and different types of deletions have different effects on semen parameters, sex hormone levels, and karyotype analysis. Further treatments should be selected based on the AZF microdeletion area.
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Azoospermia , Infertilidade Masculina , Oligospermia , Masculino , Humanos , Azoospermia/genética , Azoospermia/diagnóstico , Oligospermia/genética , Oligospermia/diagnóstico , Análise do Sêmen , Sêmen , Estudos Retrospectivos , Deleção Cromossômica , Cromossomos Humanos Y/genética , Infertilidade Masculina/genética , Cariótipo , Hormônios Esteroides Gonadais , Hormônio FoliculoestimulanteRESUMO
Loxostege turbidalis, Loxostege aeruginalis, Pyrausta despicata, and Crambus perlellus belong to Crambidae, Pyraloidea. Their mitochondrial genomes (mitogenomes) were successfully sequenced. The mitogenomes of L. turbidalis, L. aeruginalis, P. despicata, and C. perlellus are 15 240 bp, 15 339 bp, 15 389 bp, and 15 440 bp. The four mitogenomes all have a typical insect mitochondrial gene order, including 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes, and one A + T rich region (control region). The PCGs are initiated by the typical ATN codons, except CGA for the cox1 gene. Most PCGs terminate with common codon TAA or TAG, the incomplete codon T is found as the stop codon for cox2, nad4, and nad5. Most tRNA genes exhibit typical cloverleaf structure, except trnS1 (AGN) lacking the dihydrouridine (DHU) arm. The secondary structure of rRNA of four mitogenomes were predicted. Poly-T structure and micro-satellite regions are conserved in control regions. The phylogenetic analyses based on 13 PCGs showed the relationships of subfamilies in Pyraloidea. Pyralidae, and Crambidae are monophyletic, respectively. Pyralidae comprises four subfamilies, which form the following topology with high support values: (Galleriinae + ((Pyralinae + Epipaschiinae)+ Phycitinae)). Crambidae includes seven subfamilies and is divided into two lineages. Pyraustinae and Spilomelinae are sister groups of each other, and form the "PS clade." Other five subfamilies (Crambinae, Acentropinae, Scopariinae, Schoenobiinae, and Glaphyriinae) form the "non-PS clade" in the Bayesian inference tree. However, Schoenobiinae is not grouped with the other four subfamilies and located at the base of Crambidae in two maximum likelihood trees.
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Genoma Mitocondrial , Lepidópteros , Mariposas , Animais , Lepidópteros/genética , Filogenia , Teorema de Bayes , Mariposas/genética , RNA de Transferência/genética , CódonRESUMO
INTRODUCTION: To determine the role of vitamin D intake on cognitive decline among Blacks and Whites. METHODS: Using data from the population-based Chicago Health and Aging Project, we studied 2061 Blacks and 1329 Whites with dietary vitamin D data and cognitive testing over 12 years of follow-up. Multivariable linear mixed-effects models were used to determine the association of vitamin D intake with cognitive decline. RESULTS: Vitamin D intake, particularly dietary vitamin D, was associated with a slower rate of decline in cognitive function among Blacks. In Blacks, comparing individuals in the lowest tertile of dietary intake, those in the highest tertile had a slower cognitive decline of 0.017 units/year (95% confidence interval 0.006, 0.027), independently of supplementation use. In Whites, vitamin D intake was not associated with cognitive decline. DISCUSSION: Dietary vitamin D may help to slow the decline in cognitive abilities among Blacks as they age.
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Disfunção Cognitiva , Vitamina D , Humanos , Dieta , Suplementos Nutricionais , Vitamina D/administração & dosagem , Vitaminas , Negro ou Afro-Americano , BrancosRESUMO
This study aimed to design a novel mouse model of chronic photoaging. We used three different species of mice (C57BL/6J, ICR, and KM) to create a chronic photoaging model of the skin. The irradiation time was gradually increased for 40 consecutive days. The skins of the mice were removed on day 41 and subjected to staining to observe them for morphological changes. Immunohistochemistry was used to detect tumor necrosis factor-α (TNF-α) and p53 expression; superoxide dismutase (SOD) and malondialdehyde (MDA) were measured as well. Compared with C57BL/J mice, which showed hyperpigmentation, the irradiated skin of ICR and KM mice showed more obvious skin thickening and photoaging changes of the collagen and elastic fibers. KM mice had higher levels of inflammation, oxidative stress, and senescent cells. Compared with the 5-month-old KM mice, the photoaging changes of the 9-month-old KM mice were more pronounced, the SOD values were lower, and the MDA values were higher. In summary, KM mice have higher levels of abnormal elastic fibers, inflammation, cellular senescence, and oxidative stress than ICR mice, and are more suitable for studies related to chronic skin photoaging. C57BL/6J mice were found to be suitable for studies related to skin pigmentation due to photoaging.
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Envelhecimento da Pele , Camundongos , Animais , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Pele/metabolismo , Superóxido Dismutase/metabolismo , Raios Ultravioleta/efeitos adversosRESUMO
A 51-year-old man was admitted to the hospital with a history of hematochezia for the previous 16 hours. Abdominal computed tomography with contrast enhancement showed only slight punctate and linear high density in the ascending colon. Colonic curved plannar reconstruction with maximum intensity projection showed an accumulation of remarkable high-density material in the ascending colon. A colonoscopy revealed a polypoid eminence lesion with bleeding in the same location, 4 cm in the diameter. The patient underwent endoscopic mucosal resection and was discharged 2 days after surgery.
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Colo , Colonoscopia , Masculino , Humanos , Pessoa de Meia-Idade , Colonoscopia/métodos , Tomografia Computadorizada por Raios X , Hemorragia Gastrointestinal/diagnóstico por imagem , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/cirurgiaRESUMO
A 32-year-old man was referred to us for further therapy of diffuse large B-cell lymphoma. He had suffered from abdominal pain due to perforation of small intestine 1 month ago and had received partial small bowel resection. Pathological examination of tissue obtained by means of partial small bowel resection indicated diffuse large B-cell lymphoma. Abdominal CT showed prominent diffuse small intestinal wall thickening and lumen stenosis (blue arrows). Multiple enlarged mesenteric lymph nodes were also demonstrated. The abdominal cavity volume was relatively full with bladder compression. The patient underwent rituximab chemotherapy and autologous stem cell transplantation. Repeat abdominal CT 5 months later showed marked improvement, with position of bilateral abdominal wall and bladder returned to normal. He was feeling well at 6 months of follow-up.
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Neoplasias Duodenais , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Masculino , Humanos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante Autólogo , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/terapia , Intestino Delgado/diagnóstico por imagem , Intestino Delgado/cirurgia , Intestino Delgado/patologia , Neoplasias Duodenais/patologiaRESUMO
BACKGROUND: The correlations between circulating tumour DNA (ctDNA)-derived genomic markers and treatment response and survival outcome in Chinese patients with advanced breast cancer (ABC) have not been extensively characterized. METHODS: Blood samples from 141 ABC patients who underwent first-line standard treatment in Peking University Cancer Hospital were collected. A next-generation sequencing based liquid biopsy assay (PredicineCARE) was used to detect somatic mutations and copy number variations (CNVs) in ctDNA. A subset of matched blood samples and tumour tissue biopsies were compared to evaluate the concordance. RESULTS: Overall, TP53 (44.0%) and PIK3CA (28.4%) were the top two altered genes. Frequent CNVs included amplifications of ERBB2 (24.8%) and FGFR1 (8.5%) and deletions of CDKN2A (3.5%). PIK3CA/TP53 and FGFR1/2/3 variants were associated with drug resistance in hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-positive (HER2 +) patients. The comparison of genomic variants across matched tumour tissue and ctDNA samples revealed a moderate to high concordance that was gene dependent. Triple-negative breast cancer (TNBC) patients harbouring TP53 or PIK3CA alterations had a shorter overall survival than those without corresponding mutations (P = 0.03 and 0.008). A high ctDNA fraction was correlated with a shorter progression-free survival (PFS) (P = 0.005) in TNBC patients. High blood-based tumor mutation burden (bTMB) was associated with a shorter PFS for HER2 + and TNBC patients (P = 0.009 and 0.05). Moreover, disease monitoring revealed several acquired genomic variants such as ESR1 mutations, CDKN2A deletions, and FGFR1 amplifications. CONCLUSIONS: This study revealed the molecular profiles of Chinese patients with ABC and the clinical validity of ctDNA-derived markers, including the ctDNA fraction and bTMB, for predicting treatment response, prognosis, and disease progression. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03792529. Registered January 3rd 2019, https://clinicaltrials.gov/ct2/show/NCT03792529 .
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Neoplasias da Mama , DNA Tumoral Circulante , Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , DNA Tumoral Circulante/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Variações do Número de Cópias de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação/genética , PrognósticoRESUMO
PURPOSE OF REVIEW: Recent inconsistencies in nutrition research studies examining the influence of saturated fat (SFA) on cardiovascular disease (CVD) risk have led to substantial scientific debate and increased public confusion. This review will summarize metabolic characteristics and food-based factors that underlie interindividual responsiveness to SFA consumption. RECENT FINDINGS: The magnitude of postprandial blood lipid responses to SFA intake is dependent on a number of individual factors including age, sex, and adiposity status. Further, the metabolic effects of SFA intake are influenced by the specific types of SFAs and the food matrix within which they are contained. Importantly, results from research examining the effects of SFA on CVD risk should be interpreted with consideration of the comparator nutrient (i.e., carbohydrate, monounsaturated fat, polyunsaturated fat). A more nuanced understanding of the multitude of factors mediating the influence of SFA on lipid metabolism and CVD risk might help resolve the current controversy and inform more precise personalized recommendations for future dietary guidelines.
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Doenças Cardiovasculares , Gorduras na Dieta , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Gorduras na Dieta/efeitos adversos , Ácidos Graxos , Humanos , Política Nutricional , FenótipoRESUMO
Proteins adopt different higher-order structures (HOS) to enable their unique biological functions. Understanding the complexities of protein higher-order structures and dynamics requires integrated approaches, where mass spectrometry (MS) is now positioned to play a key role. One of those approaches is protein footprinting. Although the initial demonstration of footprinting was for the HOS determination of protein/nucleic acid binding, the concept was later adapted to MS-based protein HOS analysis, through which different covalent labeling approaches "mark" the solvent accessible surface area (SASA) of proteins to reflect protein HOS. Hydrogen-deuterium exchange (HDX), where deuterium in D2O replaces hydrogen of the backbone amides, is the most common example of footprinting. Its advantage is that the footprint reflects SASA and hydrogen bonding, whereas one drawback is the labeling is reversible. Another example of footprinting is slow irreversible labeling of functional groups on amino acid side chains by targeted reagents with high specificity, probing structural changes at selected sites. A third footprinting approach is by reactions with fast, irreversible labeling species that are highly reactive and footprint broadly several amino acid residue side chains on the time scale of submilliseconds. All of these covalent labeling approaches combine to constitute a problem-solving toolbox that enables mass spectrometry as a valuable tool for HOS elucidation. As there has been a growing need for MS-based protein footprinting in both academia and industry owing to its high throughput capability, prompt availability, and high spatial resolution, we present a summary of the history, descriptions, principles, mechanisms, and applications of these covalent labeling approaches. Moreover, their applications are highlighted according to the biological questions they can answer. This review is intended as a tutorial for MS-based protein HOS elucidation and as a reference for investigators seeking a MS-based tool to address structural questions in protein science.
Assuntos
Proteínas/química , Medição da Troca de Deutério , Espectrometria de Massas , Conformação ProteicaRESUMO
We investigate [Formula: see text]/[Formula: see text] superlattices in which we observe a full electron transfer at the interface from Ir to Ni, triggering a massive structural and electronic reconstruction. Through experimental characterization and first-principles calculations, we determine that a large crystal field splitting from the distorted interfacial [Formula: see text] octahedra surprisingly dominates over the spin-orbit coupling and together with the Hund's coupling results in the high-spin (S = 1) configurations on both the Ir and Ni sites. This demonstrates the power of interfacial charge transfer in coupling lattice, charge, orbital, and spin degrees of freedom, opening fresh avenues of investigation of quantum states in oxide superlattices.
RESUMO
PURPOSE: To investigate the potential genetic cause in a primary infertility patient with multiple morphological abnormalities of sperm flagella (MMAF). METHODS: The patient's sperm was observed by light and electron microscopy. Whole-exome sequencing (WES) was carried out to identify candidate genes. Then, the mutation found by WES was verified by Sanger sequencing. The proteins interacting with ARMC2 were revealed by co-immunoprecipitation (co-IP) and mass spectrometry. Intracytoplasmic sperm injection (ICSI) was carried out to achieve successful pregnancy. RESULTS: Typical MMAF phenotype (absent, short, coiled, bent irregular flagella) was shown in the patient's sperm. A novel homozygous mutation in ARMC2 (c.1264C > T) was identified. The proteins interacting with ARMC2 we found were CEP78, PGAM5, RHOA, FXR1, and SKIV2L2. The ICSI therapy was successful, and boy-girl twins were given birth. CONCLUSION: We found a novel mutation in ARMC2 which led to MMAF and male infertility. This is the first report of ICSI outcome of patient harboring ARMC2 mutation. The interacting proteins indicated that ARMC2 might be involved in multiple processes of spermatogenesis.