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1.
Blood ; 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38838300

RESUMO

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by ADAMTS13 deficiency. Caplacizumab, an anti-VWF nanobody, is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet count recovery and survival. We conducted a retrospective study on 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased after the first caplacizumab dose. Baseline characteristics and patient outcomes were compared with a control group of 59 patients with iTTP, receiving frontline treatment with TPE, caplacizumab, and immunosuppression. The main outcome was the time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractory iTTP, iTTP-related deaths, and the time to platelet count doubling. The median time to platelet count normalization was similar between the two cohorts (3 and 4 days; P = 0.31). There were no significant differences in clinical response, exacerbations, refractoriness, iTTP-related deaths, or time to platelet count doubling reflecting the short-term treatment response. Four patients did not respond to the first caplacizumab dose and TPE was subsequently initiated. Cytomegalovirus infection, HIV/hepatitis B co-infection, an ovarian teratoma with associated anti-platelet antibodies, and multiple platelet transfusion before the correct diagnosis may have impeded immediate treatment response in these patients. In conclusion, caplacizumab and immunosuppression alone, without TPE, rapidly controlled thrombotic microangiopathy and achieved a sustained clinical response in iTTP. Our study provides a basis for TPE-free iTTP management in experienced centers via shared decision-making between patients and treating physicians.

2.
Proc Natl Acad Sci U S A ; 120(22): e2211087120, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37216524

RESUMO

Mutations in genes encoding molecular chaperones can lead to chaperonopathies, but none have so far been identified causing congenital disorders of glycosylation. Here we identified two maternal half-brothers with a novel chaperonopathy, causing impaired protein O-glycosylation. The patients have a decreased activity of T-synthase (C1GALT1), an enzyme that exclusively synthesizes the T-antigen, a ubiquitous O-glycan core structure and precursor for all extended O-glycans. The T-synthase function is dependent on its specific molecular chaperone Cosmc, which is encoded by X-chromosomal C1GALT1C1. Both patients carry the hemizygous variant c.59C>A (p.Ala20Asp; A20D-Cosmc) in C1GALT1C1. They exhibit developmental delay, immunodeficiency, short stature, thrombocytopenia, and acute kidney injury (AKI) resembling atypical hemolytic uremic syndrome. Their heterozygous mother and maternal grandmother show an attenuated phenotype with skewed X-inactivation in blood. AKI in the male patients proved fully responsive to treatment with the complement inhibitor Eculizumab. This germline variant occurs within the transmembrane domain of Cosmc, resulting in dramatically reduced expression of the Cosmc protein. Although A20D-Cosmc is functional, its decreased expression, though in a cell or tissue-specific manner, causes a large reduction of T-synthase protein and activity, which accordingly leads to expression of varied amounts of pathological Tn-antigen (GalNAcα1-O-Ser/Thr/Tyr) on multiple glycoproteins. Transient transfection of patient lymphoblastoid cells with wild-type C1GALT1C1 partially rescued the T-synthase and glycosylation defect. Interestingly, all four affected individuals have high levels of galactose-deficient IgA1 in sera. These results demonstrate that the A20D-Cosmc mutation defines a novel O-glycan chaperonopathy and causes the altered O-glycosylation status in these patients.


Assuntos
Injúria Renal Aguda , Chaperonas Moleculares , Masculino , Humanos , Chaperonas Moleculares/metabolismo , Mutação , Polissacarídeos/metabolismo , Células Germinativas/metabolismo
3.
Proc Natl Acad Sci U S A ; 119(44): e2203150119, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36306328

RESUMO

This study explores how researchers' analytical choices affect the reliability of scientific findings. Most discussions of reliability problems in science focus on systematic biases. We broaden the lens to emphasize the idiosyncrasy of conscious and unconscious decisions that researchers make during data analysis. We coordinated 161 researchers in 73 research teams and observed their research decisions as they used the same data to independently test the same prominent social science hypothesis: that greater immigration reduces support for social policies among the public. In this typical case of social science research, research teams reported both widely diverging numerical findings and substantive conclusions despite identical start conditions. Researchers' expertise, prior beliefs, and expectations barely predict the wide variation in research outcomes. More than 95% of the total variance in numerical results remains unexplained even after qualitative coding of all identifiable decisions in each team's workflow. This reveals a universe of uncertainty that remains hidden when considering a single study in isolation. The idiosyncratic nature of how researchers' results and conclusions varied is a previously underappreciated explanation for why many scientific hypotheses remain contested. These results call for greater epistemic humility and clarity in reporting scientific findings.


Assuntos
Análise de Dados , Pesquisadores , Humanos , Incerteza , Reprodutibilidade dos Testes
4.
Gut ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834297

RESUMO

OBJECTIVE: Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant immunosuppressive and fibrotic tumour microenvironment (TME). Future therapeutic attempts will therefore demand the targeting of tumours and stromal compartments in order to be effective. Here we investigate whether dual specificity and tyrosine phosphorylation-regulated kinase 1B (DYRK1B) fulfil these criteria and represent a promising anticancer target in PDAC. DESIGN: We used transplantation and autochthonous mouse models of PDAC with either genetic Dyrk1b loss or pharmacological DYRK1B inhibition, respectively. Mechanistic interactions between tumour cells and macrophages were studied in direct or indirect co-culture experiments. Histological analyses used tissue microarrays from patients with PDAC. Additional methodological approaches included bulk mRNA sequencing (transcriptomics) and proteomics (secretomics). RESULTS: We found that DYRK1B is mainly expressed by pancreatic epithelial cancer cells and modulates the influx and activity of TME-associated macrophages through effects on the cancer cells themselves as well as through the tumour secretome. Mechanistically, genetic ablation or pharmacological inhibition of DYRK1B strongly attracts tumoricidal macrophages and, in addition, downregulates the phagocytosis checkpoint and 'don't eat me' signal CD24 on cancer cells, resulting in enhanced tumour cell phagocytosis. Consequently, tumour cells lacking DYRK1B hardly expand in transplantation experiments, despite their rapid growth in culture. Furthermore, combining a small-molecule DYRK1B-directed therapy with mammalian target of rapamycin inhibition and conventional chemotherapy stalls the growth of established tumours and results in a significant extension of life span in a highly aggressive autochthonous model of PDAC. CONCLUSION: In light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting both the cancer cell compartment and its microenvironment.

5.
Stroke ; 55(4): 1015-1024, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38275117

RESUMO

BACKGROUND: The dynamics of blood clot (combination of Hb [hemoglobin], fibrin, and a higher concentration of aggregated red blood cells) formation within the hematoma of an intracerebral hemorrhage is not well understood. A quantitative neuroimaging method of localized coagulated blood volume/distribution within the hematoma might improve clinical decision-making. METHODS: The deoxyhemoglobin of aggregated red blood cells within extravasated blood exhibits a higher magnetic susceptibility due to unpaired heme iron electrons. We propose that coagulated blood, with higher aggregated red blood cell content, will exhibit (1) a higher positive susceptibility than noncoagulated blood and (2) increase in fibrin polymerization-restricted localized diffusion, which can be measured noninvasively using quantitative susceptibility mapping and diffusion tensor imaging. In this serial magnetic resonance imaging study, we enrolled 24 patients with acute intracerebral hemorrhage between October 2021 to May 2022 at a stroke center. Patients were 30 to 70 years of age and had a hematoma volume >15 cm3 and National Institutes of Health Stroke Scale score >1. The patients underwent imaging 3×: within 12 to 24 (T1), 36 to 48 (T2), and 60 to 72 (T3) hours of last seen well on a 3T magnetic resonance imaging system. Three-dimensional anatomic, multigradient echo and 2-dimensional diffusion tensor images were obtained. Hematoma and edema volumes were calculated, and the distribution of coagulation was measured by dynamic changes in the susceptibilities and fractional anisotropy within the hematoma. RESULTS: Using a coagulated blood phantom, we demonstrated a linear relationship between the percentage coagulation and susceptibility (R2=0.91) with a positive red blood cell stain of the clot. The quantitative susceptibility maps showed a significant increase in hematoma susceptibility (T1, 0.29±0.04 parts per millions; T2, 0.36±0.04 parts per millions; T3, 0.45±0.04 parts per millions; P<0.0001). A concomitant increase in fractional anisotropy was also observed with time (T1, 0.40±0.02; T2, 0.45±0.02; T3, 0.47±0.02; P<0.05). CONCLUSIONS: This quantitative neuroimaging study of coagulation within the hematoma has the potential to improve patient management, such as safe resumption of anticoagulants, the need for reversal agents, the administration of alteplase to resolve the clot, and the need for surgery.


Assuntos
Acidente Vascular Cerebral Hemorrágico , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral Hemorrágico/complicações , Imagem de Tensor de Difusão , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/complicações , Hemorragia Cerebral/complicações , Imageamento por Ressonância Magnética/métodos , Hematoma/complicações , Coagulação Sanguínea , Hemoglobinas , Fibrina
6.
Soft Matter ; 20(6): 1347-1360, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38252016

RESUMO

Despite the long history of investigations of polyelectrolyte multilayer formation on solid or liquid surfaces, important questions remain open concerning the construction of the first set of layers. These are generally deposited on a first anchoring layer of different chemistry, influencing their construction and properties. We propose here an in-depth investigation of the formation of NaPSS/PAH multilayers at the air/water interface in the absence of a chemically different anchoring layer, profiting from the surface activity of NaPSS. To analyse the mechanical properties of the different layers, we combine recently established analysis techniques of an inflating/deflating bubble exploiting simultaneous shape and pressure measurement: bubble shape elastometry, general stress decomposition and capillary meniscus dynanometry. We complement these measurements by interfacial shear rheology. The obtained results allow us to confirm, first of all, the strength of the aforementioned techniques to characterize complex interfaces with non-linear viscoelastic properties. Furthermore, their sensitivity allows us to show that the multilayer properties are highly sensitive to the temporal and mechanical conditions under which they are constructed and manipulated. We nevertheless identify a robust trend showing a clear transition from a liquid-like viscoelastic membrane to a solid-like viscoelastic membrane after the deposition of 5 layers. We interpret this as the number of layers required to create a fully connected multilayer, which is consistent with previous results obtained on solid or liquid interfaces.

7.
BMC Infect Dis ; 24(1): 637, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38926682

RESUMO

INTRODUCTION: Chronic lung disease is a major cause of morbidity in African children with HIV infection; however, the microbial determinants of HIV-associated chronic lung disease (HCLD) remain poorly understood. We conducted a case-control study to investigate the prevalence and densities of respiratory microbes among pneumococcal conjugate vaccine (PCV)-naive children with (HCLD +) and without HCLD (HCLD-) established on antiretroviral treatment (ART). METHODS: Nasopharyngeal swabs collected from HCLD + (defined as forced-expiratory-volume/second < -1.0 without reversibility postbronchodilation) and age-, site-, and duration-of-ART-matched HCLD- participants aged between 6-19 years enrolled in Zimbabwe and Malawi (BREATHE trial-NCT02426112) were tested for 94 pneumococcal serotypes together with twelve bacteria, including Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), Moraxella catarrhalis (MC), and eight viruses, including human rhinovirus (HRV), respiratory syncytial virus A or B, and human metapneumovirus, using nanofluidic qPCR (Standard BioTools formerly known as Fluidigm). Fisher's exact test and logistic regression analysis were used for between-group comparisons and risk factors associated with common respiratory microbes, respectively. RESULTS: A total of 345 participants (287 HCLD + , 58 HCLD-; median age, 15.5 years [IQR = 12.8-18], females, 52%) were included in the final analysis. The prevalence of SP (40%[116/287] vs. 21%[12/58], p = 0.005) and HRV (7%[21/287] vs. 0%[0/58], p = 0.032) were higher in HCLD + participants compared to HCLD- participants. Of the participants positive for SP (116 HCLD + & 12 HCLD-), 66% [85/128] had non-PCV-13 serotypes detected. Overall, PCV-13 serotypes (4, 19A, 19F: 16% [7/43] each) and NVT 13 and 21 (9% [8/85] each) predominated. The densities of HI (2 × 104 genomic equivalents [GE/ml] vs. 3 × 102 GE/ml, p = 0.006) and MC (1 × 104 GE/ml vs. 1 × 103 GE/ml, p = 0.031) were higher in HCLD + compared to HCLD-. Bacterial codetection (≥ any 2 bacteria) was higher in the HCLD + group (36% [114/287] vs. (19% [11/58]), (p = 0.014), with SP and HI codetection (HCLD + : 30% [86/287] vs. HCLD-: 12% [7/58], p = 0.005) predominating. Viruses (predominantly HRV) were detected only in HCLD + participants. Lastly, participants with a history of previous tuberculosis treatment were more likely to carry SP (adjusted odds ratio (aOR): 1.9 [1.1 -3.2], p = 0.021) or HI (aOR: 2.0 [1.2 - 3.3], p = 0.011), while those who used ART for ≥ 2 years were less likely to carry HI (aOR: 0.3 [0.1 - 0.8], p = 0.005) and MC (aOR: 0.4 [0.1 - 0.9], p = 0.039). CONCLUSION: Children with HCLD + were more likely to be colonized by SP and HRV and had higher HI and MC bacterial loads in their nasopharynx. The role of SP, HI, and HRV in the pathogenesis of CLD, including how they influence the risk of acute exacerbations, should be studied further. TRIAL REGISTRATION: The BREATHE trial (ClinicalTrials.gov Identifier: NCT02426112 , registered date: 24 April 2015).


Assuntos
Infecções por HIV , Humanos , Estudos de Casos e Controles , Adolescente , Criança , Masculino , Feminino , Infecções por HIV/complicações , Infecções por HIV/microbiologia , Infecções por HIV/epidemiologia , Zimbábue/epidemiologia , Malaui/epidemiologia , Pneumopatias/microbiologia , Pneumopatias/virologia , Pneumopatias/epidemiologia , Adulto Jovem , Doença Crônica , Bactérias/isolamento & purificação , Bactérias/classificação , Bactérias/genética , Vírus/isolamento & purificação , Vírus/classificação , Vírus/genética , Infecções Respiratórias/microbiologia , Infecções Respiratórias/virologia , Infecções Respiratórias/epidemiologia , Streptococcus pneumoniae/isolamento & purificação , Sistema Respiratório/microbiologia , Sistema Respiratório/virologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-38934146

RESUMO

The aim of the presented prospective observational study was to evaluate the effect of fistula flow on peripheral wave morphology and pulse wave velocity by means of the oscillometric Vicorder®-device with the purpose of fistula surveillance. METHODS: Digitized and normalized curves of 53 haemodialysis patients at the fistula and non-fistula arm were analyzed. Slope parameters and the areas under the curve of characteristic sections of pulse waves as well as the power spectrum of the pulse waves and their first and second derivatives were computed. Furthermore, the amplitude of volumetric change (AMP) was assessed. Duplex-sonography served as a reference method. RESULTS: In the comprehensive set of novel pulse wave parameters significant inter-arm differences were demonstrated and a significant delay of the systolic maximum at the fistula arm in comparison to the non-fistula arm (204 ± 3.4 versus 162 ± 5.3 ms, p<0.001) was proven. Unexpectedly, pulse wave velocity apparently did not differ between both arms (7.85 versus 8.05 m/sec at the fistula/non-fistula side, p=0.942). The inter-arm differences of the slope parameters were more pronounced in forearm than in upper arm fistulas. Finally, we showed that the inter-arm difference of AMP correlated with volume-flow (r= 0.326 with p=0.017). CONCLUSION: Pulse waves as assessed by oscillometric pulse wave analysis have distinct features at fistula and non-fistula arms. This is due to enhanced arteriovenous flow, i.e. in both the brachial artery and the fistula vein. The analysis of those alterations has the potential to assess fistula function.

9.
Mol Cell Proteomics ; 21(8): 100268, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35839996

RESUMO

Active mutations in the RAS genes are found in ∼30% of human cancers. Although thought to have overlapping functions, RAS isoforms show preferential activation in human tumors, which prompted us to employ a comparative and quantitative proteomics approach to generate isoform-specific and nucleotide-dependent interactomes of the four RAS isoforms, KRAS4A, KRAS4B, HRAS, and NRAS. Many isoform-specific interacting proteins were identified, including HRAS-specific CARM1 and CHK1 and KRAS-specific PIP4K2C and IPO7. Comparing the interactomes of WT and constitutively active G12D mutant of RAS isoforms, we identified several potential previously unknown effector proteins of RAS, one of which was recently reported while this article was in preparation, RADIL. These interacting proteins play important roles as knockdown or pharmacological inhibition leads to potent inhibition of cancer cells. The HRAS-specific interacting protein CARM1 plays a role in HRAS-induced senescence, with CARM1 knockdown or inhibition selectively increasing senescence in HRAS-transformed cells but not in KRAS4B-transformed cells. By revealing new isoform-specific and nucleotide-dependent RAS interactors, the study here provides insights to help understand the overlapping functions of the RAS isoforms.


Assuntos
Neoplasias , Proteômica , Humanos , Mutação , Nucleotídeos , Isoformas de Proteínas , Proteínas Proto-Oncogênicas p21(ras)
10.
Eur Heart J ; 44(47): 4935-4949, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-37941454

RESUMO

BACKGROUND AND AIMS: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. METHODS: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. RESULTS: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. CONCLUSIONS: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.


Assuntos
Autoanticorpos , Doenças Cardiovasculares , Receptores CXCR3 , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Apolipoproteínas E , Aterosclerose , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doenças Autoimunes , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Espessura Intima-Media Carotídea , Fatores de Risco de Doenças Cardíacas , Insuficiência Cardíaca , Receptores de Quimiocinas , Fatores de Risco , Receptores CXCR3/imunologia
11.
Biophys J ; 122(17): 3489-3505, 2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37525464

RESUMO

Traction patterns of adherent cells provide important information on their interaction with the environment, cell migration, or tissue patterns and morphogenesis. Traction force microscopy is a method aimed at revealing these traction patterns for adherent cells on engineered substrates with known constitutive elastic properties from deformation information obtained from substrate images. Conventionally, the substrate deformation information is processed by numerical algorithms of varying complexity to give the corresponding traction field via solution of an ill-posed inverse elastic problem. We explore the capabilities of a deep convolutional neural network as a computationally more efficient and robust approach to solve this inversion problem. We develop a general purpose training process based on collections of circular force patches as synthetic training data, which can be subjected to different noise levels for additional robustness. The performance and the robustness of our approach against noise is systematically characterized for synthetic data, artificial cell models, and real cell images, which are subjected to different noise levels. A comparison with state-of-the-art Bayesian Fourier transform traction cytometry reveals the precision, robustness, and speed improvements achieved by our approach, leading to an acceleration of traction force microscopy methods in practical applications.


Assuntos
Aprendizado de Máquina , Tração , Microscopia de Força Atômica/métodos , Teorema de Bayes , Movimento Celular
12.
J Urol ; 209(3): 600-610, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36475807

RESUMO

PURPOSE: Varicocele is a common condition in adolescence and the most common correctable cause of infertility. This study aimed to analyze and compare the outcomes of scrotal antegrade sclerotherapy and laparoscopic Palomo surgery in a tertiary referral center. MATERIALS AND METHODS: Patients with left grade 3 varicocele indicated for surgery were prospectively enrolled and randomly allocated to the scrotal antegrade sclerotherapy and laparoscopic Palomo surgery groups, with their respective contralateral normal testes taken as controls. The primary outcome measures were clinical varicocele recurrence, testicular catch-up growth, and postoperative hydrocele. All patients were evaluated clinically and using Doppler ultrasound by radiologists. RESULTS: From 2015 to 2020, 113 patients completed the study and were statistically analyzed (scrotal antegrade sclerotherapy, n = 57; laparoscopic Palomo surgery, n = 56). All patients had significantly smaller testes preoperatively; the testicular volume differences with control testes were -23% in scrotal antegrade sclerotherapy and -19% in laparoscopic Palomo surgery. At 12-month follow-up, there were no statistically significant differences in clinical recurrences between the 2 groups (scrotal antegrade sclerotherapy = 5.3% vs laparoscopic Palomo surgery = 5.4%, P > .05, noninferiority test). Testicular catch-up growths were observed in both groups; the mean testicular volume difference between the treatment and control testes decreased from -23% to -8.1% in scrotal antegrade sclerotherapy (P < .001) and from -19% to -9.3% in laparoscopic Palomo surgery (P < .001) at 12-month follow-up. There was no postoperative hydrocele in the scrotal antegrade sclerotherapy group compared to 7 cases in the laparoscopic Palomo surgery group (0% vs 13%, P = .006). CONCLUSIONS: Both scrotal antegrade sclerotherapy and laparoscopic Palomo surgery are safe and effective procedures for treatment of adolescent varicocele with significant positive effect on testicular catch-up growth. Scrotal antegrade sclerotherapy is not inferior to laparoscopic Palomo surgery in terms of clinical recurrence rate and has significantly less postoperative hydrocele.


Assuntos
Laparoscopia , Varicocele , Masculino , Humanos , Adolescente , Varicocele/cirurgia , Escleroterapia/métodos , Estudos Prospectivos , Estudos Retrospectivos , Laparoscopia/métodos
13.
Blood ; 138(25): 2655-2669, 2021 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-34280257

RESUMO

Antibody-based immunotherapy is a promising strategy for targeting chemoresistant leukemic cells. However, classical antibody-based approaches are restricted to targeting lineage-specific cell surface antigens. By targeting intracellular antigens, a large number of other leukemia-associated targets would become accessible. In this study, we evaluated a novel T-cell bispecific (TCB) antibody, generated by using CrossMAb and knob-into-holes technology, containing a bivalent T-cell receptor-like binding domain that recognizes the RMFPNAPYL peptide derived from the intracellular tumor antigen Wilms tumor protein (WT1) in the context of HLA-A*02. Binding to CD3ε recruits T cells irrespective of their T-cell receptor specificity. WT1-TCB elicited antibody-mediated T-cell cytotoxicity against AML cell lines in a WT1- and HLA-restricted manner. Specific lysis of primary acute myeloid leukemia (AML) cells was mediated in ex vivo long-term cocultures by using allogeneic (mean ± standard error of the mean [SEM] specific lysis, 67 ± 6% after 13-14 days; n = 18) or autologous, patient-derived T cells (mean ± SEM specific lysis, 54 ± 12% after 11-14 days; n = 8). WT1-TCB-treated T cells exhibited higher cytotoxicity against primary AML cells than an HLA-A*02 RMF-specific T-cell clone. Combining WT1-TCB with the immunomodulatory drug lenalidomide further enhanced antibody-mediated T-cell cytotoxicity against primary AML cells (mean ± SEM specific lysis on days 3-4, 45.4 ± 9.0% vs 70.8 ± 8.3%; P = .015; n = 9-10). In vivo, WT1-TCB-treated humanized mice bearing SKM-1 tumors exhibited a significant and dose-dependent reduction in tumor growth. In summary, we show that WT1-TCB facilitates potent in vitro, ex vivo, and in vivo killing of AML cell lines and primary AML cells; these results led to the initiation of a phase 1 trial in patients with relapsed/refractory AML (#NCT04580121).


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Peptídeos/uso terapêutico , Proteínas WT1/imunologia , Animais , Anticorpos Biespecíficos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Antígeno HLA-A2/imunologia , Humanos , Leucemia Mieloide Aguda/imunologia , Camundongos , Peptídeos/farmacologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Células Tumorais Cultivadas
14.
Langmuir ; 39(46): 16303-16314, 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-37939256

RESUMO

Oil/water interfaces are ubiquitous in nature. Opposing polarities at these interfaces attract surface-active molecules, which can seed complex viscoelastic or even solid interfacial structure. Biorelevant proteins such as hydrophobin, polymers such as PNIPAM, and the asphaltenes in crude oil (CRO) are examples of some systems where such layers can occur. When a pendant drop of CRO is aged in brine, it can form an interfacial elastic membrane of asphaltenes so stiff that it wrinkles and crumples upon retraction. Most of the work studying CRO/brine interfaces focuses on the viscoelastic liquid regime, leaving a wide range of fully solidified, elastic interfaces largely unexplored. In this work, we quantitatively measure elasticity in all phases of drop retraction. In early retraction, the interface shows a fluid viscoelasticity measurable using a Gibbs isotherm or dilatational rheology. Further retraction causes a phase transition to a 2D elastic solid with nonisotropic, nonhomogeneous surface stresses. In this regime, we use new techniques in the elastic membrane theory to fit for the elasticities of these solid capsules. These elastic measurements can help us develop a deeper understanding not only of CRO interfaces but also of the myriad fluid systems with solid interfacial layers.

15.
Pediatr Res ; 94(3): 1172-1179, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37061642

RESUMO

BACKGROUND: Energy drinks (EDs) are popular beverages among minors. To date, clinical studies investigating ED-induced effects on the pediatric cardiovascular system are sparse. This study aimed to investigate the effects of a single, bodyweight-adjusted ED dosage on 24-h ambulatory blood pressure monitoring (ABPM) in healthy children and adolescents. METHODS: This study was a randomized, single-blind, placebo-controlled, crossover clinical trial. Study participants received a single, bodyweight-adjusted ED amount or a placebo drink on 2 consecutive days at similar morning hours. Twenty-four-hour ABPM was assessed via an automated oscillometric blood pressure device after beverage consumption on both study days. RESULTS: A total of 17 healthy children and teenagers (13.90 (12.29-17.89) years) were included in the final analysis. The ED consumption led, compared to the placebo intake, to a significantly higher 24-h systolic (115.90 (110.22-118.04) vs. 110.64 (108.09-115.45) mmHg, p = 0.013) and diastolic blood pressure (66.08 (64.20-68.32) vs. 62.63 (61.40-66.46) mmHg, p = 0.005). CONCLUSIONS: The single, bodyweight-adjusted ED consumption is linked with a significantly higher systolic as well as diastolic 24-h blood pressure in healthy children and adolescents. Minors, particularly those with an increased cardiovascular morbidity, should be discouraged from drinking EDs. IMPACT: Energy drinks (EDs) are consumed by many children and teenagers. While adverse cardiovascular events after ED consumption were reported in the literature, the effects of these beverages on the pediatric 24-h blood pressure profile have not been systematically evaluated yet. In our manuscript, we demonstrate for the first time that acute ED consumption is associated with a significantly higher 24-h systolic blood pressure and diastolic blood pressure in healthy minors.


Assuntos
Sistema Cardiovascular , Bebidas Energéticas , Adolescente , Humanos , Criança , Bebidas Energéticas/efeitos adversos , Monitorização Ambulatorial da Pressão Arterial , Método Simples-Cego , Pressão Sanguínea , Peso Corporal
16.
Int J Gynecol Pathol ; 42(4): 421-425, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-36044308

RESUMO

We report an unusual case of a pelvic extraovarian moderately differentiated Sertoli-Leydig cell tumor arising in a 4-yr-old female. The tumor contained a DICER1 pathogenic variant which was absent in the germline ruling out DICER1 syndrome. In reporting this case, we discuss the differential diagnosis and possible histogenesis and review reported cases of extraovarian Sertoli-Leydig cell tumor.


Assuntos
Síndromes Neoplásicas Hereditárias , Neoplasias Ovarianas , Tumor de Células de Sertoli-Leydig , Tumores do Estroma Gonadal e dos Cordões Sexuais , Masculino , Humanos , Feminino , Tumor de Células de Sertoli-Leydig/diagnóstico , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patologia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Ribonuclease III/genética , Diagnóstico Diferencial , Síndromes Neoplásicas Hereditárias/diagnóstico , RNA Helicases DEAD-box/genética
17.
Clin Nephrol ; 99(4): 161-171, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36683554

RESUMO

INTRODUCTION: Acute kidney injury (AKI) is a frequent condition in patients hospitalized for COVID-19. There are only a few reports on the use of urinary biomarkers in COVID-19 and no data so far comparing the prognostic use of individual biomarkers in the prediction of adverse outcomes. MATERIALS AND METHODS: We performed a prospective mono-centric study on the value of urinary biomarkers in predicting the composite endpoint of a transfer to the intensive care unit, the need for renal replacement therapy, mechanical ventilation, and in-hospital mortality. 41 patients hospitalized for COVID-19 were enrolled in this study. Urine samples were obtained shortly after admission to assess neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), calprotectin, and vascular non-inflammatory molecule-1 (vanin-1). RESULTS: We identified calprotectin as a predictor of a severe course of the disease requiring intensive care treatment (AUC 0.728, p = 0.016). Positive and negative predictive values were 78.6% and 76.9%, respectively, using a cut-off concentration of 127.8 ng/mL. NGAL tended to predict COVID-19-associated AKI without reaching statistical significance (AUC 0.669, p = 0.053). The best parameter in the prediction of in-hospital mortality was NGAL as well (AUC 0.674, p = 0.077). KIM-1 and vanin-1 did not reach significance for any of the investigated endpoints. CONCLUSION: While KIM-1 and vanin-1 did not provide prognostic clinical information in the context of COVID-19, the present study shows that urinary calprotectin is moderately predictive of the need for intensive care unit (ICU) admission, and NGAL may be modestly predictive of AKI in COVID-19. Calprotectin and NGAL show promise as potential helpful adjuncts in the identification of patients at increased risk of poor outcomes or complications in COVID-19.


Assuntos
Injúria Renal Aguda , COVID-19 , Doenças Ureterais , Humanos , Lipocalina-2 , Estudos Prospectivos , COVID-19/complicações , Biomarcadores , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Rim , Complexo Antígeno L1 Leucocitário
18.
Biochem J ; 479(5): 701-717, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35234841

RESUMO

The photosystem II reaction centre (RCII) protein subunit D1 is the main target of light-induced damage in the thylakoid membrane. As such, it is constantly replaced with newly synthesised proteins, in a process dubbed the 'D1 repair cycle'. The mechanism of relief of excitation energy pressure on RCII, non-photochemical quenching (NPQ), is activated to prevent damage. The contribution of the D1 repair cycle and NPQ in preserving the photochemical efficiency of RCII is currently unclear. In this work, we seek to (1) quantify the relative long-term effectiveness of photoprotection offered by NPQ and the D1 repair cycle, and (2) determine the fraction of sustained decrease in RCII activity that is due to long-term protective processes. We found that while under short-term, sunfleck-mimicking illumination, NPQ is substantially more effective in preserving RCII activity than the D1 repair cycle (Plant. Cell Environ.41, 1098-1112, 2018). Under prolonged constant illumination, its contribution is less pronounced, accounting only for up to 30% of RCII protection, while D1 repair assumes a predominant role. Exposure to a wide range of light intensities yields comparable results, highlighting the crucial role of a constant and rapid D1 turnover for the maintenance of RCII efficiency. The interplay between NPQ and D1 repair cycle is crucial to grant complete phototolerance to plants under low and moderate light intensities, and limit damage to photosystem II under high light. Additionally, we disentangled and quantified the contribution of a slowly reversible NPQ component that does not impair RCII activity, and is therefore protective.


Assuntos
Complexo de Proteína do Fotossistema II , Tilacoides , Luz , Células Vegetais , Subunidades Proteicas
19.
BMC Nephrol ; 24(1): 186, 2023 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-37355570

RESUMO

BACKGROUND: Pulse wave analysis may be useful to assess fistula function. We aimed to prospectively evaluate if convenient oscillometric devices are applicable to detect flow below 500 ml/min in a real life clinical setting. METHODS: Pulse waves were recorded ambilaterally with the vicorder® device at the brachial artery in 53 patients on haemodialysis with native fistula. Primary variables consisted of the mean slope between the systolic maximum and the diacrotic notch (Slope2), the sum of the mean slopes in the four characteristic sections of pulse waves (Slope∑) and the amplitude of relative volumetric change in the measuring cuff at the upper arm (AMP). Fistula flow was measured with the use of duplex sonography using a standardized approach. RESULTS: Parameter values above or below the median indicated measurement at the non-fistula side, with sensitivities/specificities of 0.79/0.79 (p < 0.001) for Slope 2, 0.64/0.64 (p = 0.003) for Slope∑ and 0.81/0.81 (p < 0.001) for AMP if measurements at the fistula and non-fistula arm were considered. ROC-analyses of parameter values measured at the fistula to detect low flow demonstrated AUCs (with CI) of 0.652 (0.437-0.866, p = 0.167) for Slope2, 0.732 (0.566-0.899, p = 0.006) for Slope∑ and 0.775 (0.56-0.991, p = 0.012) for AMP. The point with maximal youden's index was regarded as optimal cut-off, which corresponded to sensitivities and specificities of 0.8/0.56 for slope2, 0.86/ 0.56 for Slope∑ and 0.93/0.78 for AMP. CONCLUSION: Functional surveillance with oscillometry is a promising clinical application to detect a low fistula flow. Among all investigated pulse wave parameters AMP revealed the highest diagnostic accuracy.


Assuntos
Fístula Arteriovenosa , Artéria Braquial , Humanos , Oscilometria , Artéria Braquial/diagnóstico por imagem , Sensibilidade e Especificidade , Análise de Onda de Pulso
20.
Proc Natl Acad Sci U S A ; 117(29): 17260-17268, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632007

RESUMO

Understanding how a network of interconnected neurons receives, stores, and processes information in the human brain is one of the outstanding scientific challenges of our time. The ability to reliably detect neuroelectric activities is essential to addressing this challenge. Optical recording using voltage-sensitive fluorescent probes has provided unprecedented flexibility for choosing regions of interest in recording neuronal activities. However, when recording at a high frame rate such as 500 to 1,000 Hz, fluorescence-based voltage sensors often suffer from photobleaching and phototoxicity, which limit the recording duration. Here, we report an approach called electrochromic optical recording (ECORE) that achieves label-free optical recording of spontaneous neuroelectrical activities. ECORE utilizes the electrochromism of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) thin films, whose optical absorption can be modulated by an applied voltage. Being based on optical reflection instead of fluorescence, ECORE offers the flexibility of an optical probe without suffering from photobleaching or phototoxicity. Using ECORE, we optically recorded spontaneous action potentials in cardiomyocytes, cultured hippocampal and dorsal root ganglion neurons, and brain slices. With minimal perturbation to cells, ECORE allows long-term optical recording over multiple days.


Assuntos
Eletrofisiologia/métodos , Neurônios/fisiologia , Poliestirenos , Tiofenos , Potenciais de Ação/fisiologia , Encéfalo/citologia , Encéfalo/fisiologia , Técnicas Eletroquímicas/métodos , Fenômenos Eletrofisiológicos , Corantes Fluorescentes , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Humanos , Imagem Óptica , Óptica e Fotônica/métodos
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