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1.
J Am Chem Soc ; 146(17): 12100-12112, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38635878

ABSTRACT

Two (BE)8-[16]annulenes were prepared and fully characterized by experimental and quantum-chemical means (1, E = N; 2, E = O). The 1,8-naphthalenediyl-bridged diborane(6) 3 served as their common starting material, which was treated with [Al(NH3)6]Cl3 to form 1 (91% yield) or with 1,8-naphthalenediboronic acid anhydride to form 2 (93% yield). As a result, the heteroannulenes 1 and 2 are supported by four aromatic "clamps" and may also be viewed as NH- or O-bridged cyclic tetramers of BNB- or BOB-doped phenalenyls. X-ray crystallography on mono-, di-, and tetraadducts 2·thf, 2·py2, and 2·py4 showed that 2 is an oligotopic Lewis acid (thf/py: tetrahydrofuran/pyridine donor). The applicability of 2 also as a Lewis basic ligand in coordination chemistry was demonstrated by the synthesis of the mononuclear Ag+ complex [Ag(py)2(2·py4)]+ and the dinuclear Pb2+ complex 6. During the assembly of 6, the rearrangement of 2 led to the formation of two (BO)9-macrocycles linked by two BOB-phenalenyls to form a nanometer-sized cage with four negatively charged, tetracoordinated B atoms. Both 1 and 2 show several redox waves in the cathodic regions of the cyclic voltammograms. An in-depth assessment of the consequences of electron injection on the aromaticity of 1 and 2 was achieved by electronic structure calculations. 1 and 2 are proposed to exhibit aromatic switching capabilities in the [16]annulene motif.

2.
Chemistry ; 30(27): e202400320, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38426580

ABSTRACT

NBN- and BNB-doped phenalenyls are isoelectronic to phenalenyl anions and cations, respectively. They represent a pair of complementary molecules that have essentially identical structures but opposite properties as electron donors and acceptors. The NBN-phenalenyls 1-4 considered here were prepared from N,N'-dimethyl-1,8-diaminonaphthalene and readily available boron-containing building blocks (i. e., BH3⋅SMe2 (1), p-CF3-C6H4B(OH)2 (2), C6H5B(OH)2 (3), or MesBCl2/iPr2NEt (4)). Treatment of 1 with 4-Me2N-2,6-Me2-C6H2Li gave the corresponding NBN derivative 5. The BNB-phenalenyl 6 was synthesized from 1,8-naphthalenediyl-bridged diborane(6), PhNH2, and MesMgBr. A computational study reveals that the photoemission of 1, 4, and 5 originates from locally excited (LE) states at the NBN-phenalenyl fragments, while that of 2 is dominated by charge transfer (CT) from the NBN-phenalenyl to the p-CF3-C6H4 fragment. Depending on the dihedral angle θ between its Ph and NBN planes, compound 3 emits mainly from a less polar LE (θ >55°) or more polar CT state (θ <55°). In turn, the energetic preference for either state is governed by the polarity of the solvent used. An equimolar aggregate of the NBN- and BNB-phenalenyls 3 and 6 (in THF/H2O) shows a distinct red-shifted emission compared to that of the individual components, which originates from an intermolecular CT state.

3.
Nat Commun ; 14(1): 1103, 2023 Feb 27.
Article in English | MEDLINE | ID: mdl-36843156

ABSTRACT

Printed organic and inorganic electronics continue to be of large interest for sensors, bioelectronics, and security applications. Many printing techniques have been investigated, albeit often with typical minimum feature sizes in the tens of micrometer range and requiring post-processing procedures at elevated temperatures to enhance the performance of functional materials. Herein, we introduce laser printing with three different inks, for the semiconductor ZnO and the metals Pt and Ag, as a facile process for fabricating printed functional electronic devices with minimum feature sizes below 1 µm. The ZnO printing is based on laser-induced hydrothermal synthesis. Importantly, no sintering of any sort needs to be performed after laser printing for any of the three materials. To demonstrate the versatility of our approach, we show functional diodes, memristors, and a physically unclonable function based on a 6 × 6 memristor crossbar architecture. In addition, we realize functional transistors by combining laser printing and inkjet printing.

4.
Int J Mol Sci ; 23(17)2022 Aug 24.
Article in English | MEDLINE | ID: mdl-36076983

ABSTRACT

Acute kidney injury (AKI) is commonly associated with severe human diseases, and often worsens the outcome in hospitalized patients. The mammalian kidney has the ability to recover spontaneously from AKI; however, little progress has been made in the development of supportive treatments. Increasing evidence suggest that histone deacetylases (HDAC) and NF-κB promote the pathogenesis of AKI, and inhibition of Hdac activity has a protective effect in murine models of AKI. However, the role of HDAC at the early stages of recovery is unknown. We used the zebrafish pronephros model to study the role of epigenetic modifiers in the immediate repair response after injury to the tubular epithelium. Using specific inhibitors, we found that the histone deacetylase Hdac2, Hdac6, and Hdac8 activities are required for the repair via collective cell migration. We found that hdac6, hdac8, and nfkbiaa expression levels were upregulated in the repairing epithelial cells shortly after injury. Depletion of hdac6, hdac8, or nfkbiaa with morpholino oligonucleotides impaired the repair process, whereas the combined depletion of all three genes synergistically suppressed the recovery process. Furthermore, time-lapse video microscopy revealed that the lamellipodia and filopodia formation in the flanking cells was strongly reduced in hdac6-depleted embryos. Our findings suggest that Hdac activity and NF-κB are synergistically required for the immediate repair response in the zebrafish pronephros model of AKI, and the timing of HDAC inhibition might be important in developing supportive protocols in the human disease.


Subject(s)
Acute Kidney Injury , Histone Deacetylase 6/metabolism , Histone Deacetylases/metabolism , Pronephros , Zebrafish Proteins/metabolism , Acute Kidney Injury/genetics , Acute Kidney Injury/pathology , Animals , Histone Deacetylase Inhibitors/pharmacology , Humans , Mice , NF-kappa B , Pronephros/metabolism , Pronephros/pathology , Repressor Proteins , Zebrafish/metabolism
5.
Front Med (Lausanne) ; 9: 874307, 2022.
Article in English | MEDLINE | ID: mdl-35872778

ABSTRACT

Background: Autopsies can shed light on the pathogenesis of new and emerging diseases. Aim: To describe needle core necropsy findings of the lung, heart, and liver in decedents with COVID-19. Material: Cross-sectional study of needle core necropsies in patients who died with virologically confirmed COVID-19. Histopathological analyses were performed, and clinical data and patient course evaluated. Results: Chest core necropsies were performed in 71 decedents with a median age of 81 years (range 52-97); 47 (65.3%) were men. The median interval from symptoms onset to death was 17.5 days (range 1-84). Samples of lung (n = 62, 87.3%), heart (n = 48, 67.6%) and liver (n = 39, 54.9%) were obtained. Fifty-one lung samples (82.3%) were abnormal: 19 (30.6%) showed proliferative diffuse alveolar damage (DAD), 12 (19.4%) presented exudative DAD, and 10 (16.1%) exhibited proliferative plus exudative DAD. Of the 46 lung samples tested for SARS-CoV-19 by RT-PCR, 39 (84.8%) were positive. DAD was associated with premortem values of lactate dehydrogenase of 400 U/L or higher [adjusted odds ratio (AOR) 21.73; 95% confidence interval (CI) 3.22-146] and treatment with tocilizumab (AOR 6.91; 95% CI 1.14-41.7). Proliferative DAD was associated with an onset-to-death interval of over 15 days (AOR 7.85, 95% CI 1.29-47.80). Twenty-three of the 48 (47.9%) heart samples were abnormal: all showed fiber hypertrophy, while 9 (18.8%) presented fibrosis. Of the liver samples, 29/39 (74.4%) were abnormal, due to steatosis (n = 12, 30.8%), cholestasis (n = 6, 15.4%) and lobular central necrosis (n = 5, 12.8%). Conclusion: Proliferative DAD was the main finding on lung core needle necropsy in people who died from COVID-19; this finding was related to a longer disease course. Changes in the liver and heart were common.

6.
Proc Natl Acad Sci U S A ; 119(19): e2123483119, 2022 05 10.
Article in English | MEDLINE | ID: mdl-35507878

ABSTRACT

Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC-101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses.


Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Neoplasms , Adaptive Immunity , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Immunity, Innate , Mice , Neoplasms/pathology
7.
Micromachines (Basel) ; 13(4)2022 Apr 08.
Article in English | MEDLINE | ID: mdl-35457888

ABSTRACT

Printing technology and mounting technology enable the novel field of hybrid printed electronics. To establish a hybrid printed system, one challenge is that the applied mounting process meets the requirements of functional inks and substrates. One of the most common requirements is low process temperature. Many functional inks and substrates cannot withstand the high temperatures required by traditional mounting processes. In this work, a standardized interconnection and an automated bump-less flip-chip mounting process using a room temperature curing conductive adhesive are realised. With the proposed process, the conductive adhesive selected for the standardized interconnection can be dispensed uniformly, despite its increase of viscosity already during pot time. Electrical and mechanical performance of the interconnection are characterized by four terminal resistance measurement and shear test. The herein proposed automated process allows for fabrication of hybrid printed devices in larger batch sizes than manual assembly processes used beforehand and thus, more comprehensive evaluation of device parameters. This is successfully demonstrated in a first application, a novel hybrid printed security device. The room temperature mounting process eliminates any potentially damaging thermal influence on the performance of the printed circuits that might result from other assembly techniques like soldering.

8.
J Infect ; 82(3): 378-383, 2021 03.
Article in English | MEDLINE | ID: mdl-33450302

ABSTRACT

OBJECTIVES: This study aims to analyze the incidence of Post-acute COVID-19 syndrome (PCS) and its components, and to evaluate the acute infection phase associated risk factors. METHODS: A prospective cohort study of adult patients who had recovered from COVID-19 (27th February to 29th April 2020) confirmed by PCR or subsequent seroconversion, with a systematic assessment 10-14 weeks after disease onset. PCS was defined as the persistence of at least one clinically relevant symptom, or abnormalities in spirometry or chest radiology. Outcome predictors were analyzed by multiple logistic regression (OR; 95%CI). RESULTS: Two hundred seventy seven patients recovered from mild (34.3%) or severe (65.7%) forms of SARS-CoV-2 infection were evaluated 77 days (IQR 72-85) after disease onset. PCS was detected in 141 patients (50.9%; 95%CI 45.0-56.7%). Symptoms were mostly mild. Alterations in spirometry were noted in 25/269 (9.3%), while in radiographs in 51/277 (18.9%). No baseline clinical features behaved as independent predictors of PCS development. CONCLUSIONS: A Post-acute COVID-19 syndrome was detected in a half of COVID19 survivors. Radiological and spirometric changes were mild and observed in less than 25% of patients. No baseline clinical features behaved as independent predictors of Post-acute COVID-19 syndrome development.


Subject(s)
COVID-19 , Adult , Cohort Studies , Humans , Incidence , Prospective Studies , Risk Factors , SARS-CoV-2
9.
Front Cell Infect Microbiol ; 11: 795026, 2021.
Article in English | MEDLINE | ID: mdl-35141170

ABSTRACT

Objective: To develop and validate a prognostic model for in-hospital mortality after four days based on age, fever at admission and five haematological parameters routinely measured in hospitalized Covid-19 patients during the first four days after admission. Methods: Haematological parameters measured during the first 4 days after admission were subjected to a linear mixed model to obtain patient-specific intercepts and slopes for each parameter. A prediction model was built using logistic regression with variable selection and shrinkage factor estimation supported by bootstrapping. Model development was based on 481 survivors and 97 non-survivors, hospitalized before the occurrence of mutations. Internal validation was done by 10-fold cross-validation. The model was temporally-externally validated in 299 survivors and 42 non-survivors hospitalized when the Alpha variant (B.1.1.7) was prevalent. Results: The final model included age, fever on admission as well as the slope or intercept of lactate dehydrogenase, platelet count, C-reactive protein, and creatinine. Tenfold cross validation resulted in a mean area under the receiver operating characteristic curve (AUROC) of 0.92, a mean calibration slope of 1.0023 and a Brier score of 0.076. At temporal-external validation, application of the previously developed model showed an AUROC of 0.88, a calibration slope of 0.95 and a Brier score of 0.073. Regarding the relative importance of the variables, the (apparent) variation in mortality explained by the six variables deduced from the haematological parameters measured during the first four days is higher (explained variation 0.295) than that of age (0.210). Conclusions: The presented model requires only variables routinely acquired in hospitals, which allows immediate and wide-spread use as a decision support for earlier discharge of low-risk patients to reduce the burden on the health care system. Clinical Trial Registration: Austrian Coronavirus Adaptive Clinical Trial (ACOVACT); ClinicalTrials.gov, identifier NCT04351724.


Subject(s)
COVID-19 , SARS-CoV-2 , Hospital Mortality , Hospitalization , Humans , Retrospective Studies
10.
Nat Commun ; 11(1): 5543, 2020 Nov 02.
Article in English | MEDLINE | ID: mdl-33139711

ABSTRACT

Modern society is striving for digital connectivity that demands information security. As an emerging technology, printed electronics is a key enabler for novel device types with free form factors, customizability, and the potential for large-area fabrication while being seamlessly integrated into our everyday environment. At present, information security is mainly based on software algorithms that use pseudo random numbers. In this regard, hardware-intrinsic security primitives, such as physical unclonable functions, are very promising to provide inherent security features comparable to biometrical data. Device-specific, random intrinsic variations are exploited to generate unique secure identifiers. Here, we introduce a hybrid physical unclonable function, combining silicon and printed electronics technologies, based on metal oxide thin film devices. Our system exploits the inherent randomness of printed materials due to surface roughness, film morphology and the resulting electrical characteristics. The security primitive provides high intrinsic variation, is non-volatile, scalable and exhibits nearly ideal uniqueness.

11.
ACS Nano ; 14(8): 9972-9978, 2020 08 25.
Article in English | MEDLINE | ID: mdl-32589396

ABSTRACT

Transmission electron cryo-microscopy (cryoEM) of vitrified biological specimens is a powerful tool for structural biology. Current preparation of vitrified biological samples starts off with sample isolation and purification, followed by the fixation in a freestanding layer of amorphous ice. Here, we demonstrate that ultrathin (∼10 nm) smart molecular nanosheets having specific biorecognition sites embedded in a biorepulsive layer covalently bound to a mechanically stable carbon nanomembrane allow for a much simpler isolation and structural analysis. We characterize in detail the engineering of these nanosheets and their biorecognition properties employing complementary methods such as X-ray photoelectron and infrared spectroscopy, atomic force microscopy as well as surface plasmon resonance measurements. The desired functionality of the developed nanosheets is demonstrated by in situ selection of a His-tagged protein from a mixture and its subsequent structural analysis by cryoEM.


Subject(s)
Carbon , Electrons , Cryoelectron Microscopy , Microscopy, Atomic Force , Microscopy, Electron, Transmission
12.
J Am Chem Soc ; 142(25): 11072-11083, 2020 06 24.
Article in English | MEDLINE | ID: mdl-32464052

ABSTRACT

A highly modular synthesis of BNB- and BOB-doped phenalenyls is presented. Treatment of the 1,8-naphthalenediyl-bridged boronic acid anhydride 1 with LiAlH4/Me3SiCl afforded the corresponding 1,8-naphthalenediyl-supported diborane(6) 2, which served as the starting material for all subsequent transformations. Upon addition of MesMgBr/Me3SiCl, 2 was readily converted to the tetraorganyl diborane(6) 5. The further heteroatoms were finally introduced through the reaction of 2 with (Me3Si)2NR' or 5 with H2NR' or H2O (R' = H, Me, p-Tol). A helically twisted, fully BNB-embedded PAH 11 was prepared by combining 2 with a dibrominated m-terphenylamine, followed by a Grignard-mediated double ring-closure reaction. All compounds devoid of B-H bonds show favorable optoelectronic properties, such as luminescence and reversible reduction behavior. In the case of the BNB-phenalenyl 7 (BMes, NMe), the radical-anion salt K[7•] was generated through chemical reduction with K metal and characterized by EPR spectroscopy. K[7•] is not long-term stable in a THF/c-hexane solution, but abstracts an H atom with formation of the diamagnetic BNB-doped 1H-phenalene K[7H].

13.
BMC Bioinformatics ; 20(1): 664, 2019 Dec 12.
Article in English | MEDLINE | ID: mdl-31830916

ABSTRACT

BACKGROUND: A lack of reproducibility has been repeatedly criticized in computational research. High throughput sequencing (HTS) data analysis is a complex multi-step process. For most of the steps a range of bioinformatic tools is available and for most tools manifold parameters need to be set. Due to this complexity, HTS data analysis is particularly prone to reproducibility and consistency issues. We have defined four criteria that in our opinion ensure a minimal degree of reproducible research for HTS data analysis. A series of workflow management systems is available for assisting complex multi-step data analyses. However, to the best of our knowledge, none of the currently available work flow management systems satisfies all four criteria for reproducible HTS analysis. RESULTS: Here we present uap, a workflow management system dedicated to robust, consistent, and reproducible HTS data analysis. uap is optimized for the application to omics data, but can be easily extended to other complex analyses. It is available under the GNU GPL v3 license at https://github.com/yigbt/uap. CONCLUSIONS: uap is a freely available tool that enables researchers to easily adhere to reproducible research principles for HTS data analyses.


Subject(s)
Data Analysis , High-Throughput Nucleotide Sequencing , Software , Algorithms , Computational Biology , Genome , Reproducibility of Results , Transcriptome/genetics
14.
Pediatr Obes ; 14(9): e12528, 2019 09.
Article in English | MEDLINE | ID: mdl-30957427

ABSTRACT

BACKGROUND: Trans fatty acid (TFA) intake has been positively associated with obesity in adults, although the evidence in children is scarce. There is growing evidence that TFA of industrial or natural origin may have different effects. OBJECTIVES: We aimed to explore the association between total, industrial, and natural TFA intake and overweight including obesity in 4 to 5-year-old Spanish children. METHODS: We cross-sectionally analyzed data of 1744 children aged 4 to 5 from the INMA study, a prospective mother-child cohort study in Spain. We estimated the intake of total, industrial, and natural TFA in grams per day (g/day) using a validated food frequency questionnaire and expressed it as quartiles. Overweight including obesity was defined according to the International Obesity Task Force criteria. We used multiple logistic regression to estimate adjusted odds ratios (OR) and confidence intervals (95%CI). RESULTS: After adjusting for major risk factors, the highest quartile of industrial TFA intake (>0.7 g/day) was positively associated with overweight including obesity (OR 1.57, 95%CI 1.13-2.21, P trend for quartiles 0.01). No significant associations were observed between natural TFA intake and overweight including obesity. CONCLUSIONS: In 4 to 5-year-old Spanish children, higher intake of industrial but not natural TFA was positively associated with overweight including obesity.


Subject(s)
Dietary Fats/administration & dosage , Pediatric Obesity/epidemiology , Trans Fatty Acids/administration & dosage , Child, Preschool , Cohort Studies , Cross-Sectional Studies , Energy Intake , Female , Humans , Prospective Studies , Spain/epidemiology
15.
Nat Commun ; 9(1): 3660, 2018 09 10.
Article in English | MEDLINE | ID: mdl-30202007

ABSTRACT

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.


Subject(s)
Chemokine CXCL12/metabolism , Gene Expression Regulation, Developmental , Kidney Diseases/metabolism , Proto-Oncogene Proteins/metabolism , Zebrafish Proteins/metabolism , Zebrafish/genetics , Animals , Animals, Genetically Modified , Cell Movement , Energy Metabolism , Gene Deletion , Gene Expression Profiling , Glycolysis , Homeostasis , Kidney/injuries , Kidney/metabolism , Male , Mice , Mice, Inbred C57BL , Signal Transduction , Tretinoin/chemistry
16.
Mol Ther ; 26(5): 1354-1365, 2018 05 02.
Article in English | MEDLINE | ID: mdl-29606504

ABSTRACT

Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels. High tumor expression of ACKR3 correlates with poor prognosis and potential treatment resistance, making it an attractive therapeutic target. We engineered a single chain FV-human FC-immunoglobulin G1 (IgG1) antibody, X7Ab, to target ACKR3 in human and mouse GBM cells. We used hydrodynamic gene transfer to overexpress the antibody, with efficacy in vivo. X7Ab kills GBM tumor cells and ACKR3-expressing vascular endothelial cells by engaging the cytotoxic activity of natural killer (NK) cells and complement and the phagocytic activity of macrophages. Combining X7Ab with TMZ allows the TMZ dosage to be lowered, without compromising therapeutic efficacy. Mice treated with X7Ab and in combination with TMZ showed significant tumor reduction by MRI and longer survival overall. Brain-tumor-infiltrating leukocyte analysis revealed that X7Ab enhances the activation of M1 macrophages to support anti-tumor immune response in vivo. Targeting ACKR3 with immunotherapeutic monoclonal antibodies (mAbs) in combination with standard of care therapies may prove effective in treating GBM.


Subject(s)
Antibodies, Monoclonal/pharmacology , Glioblastoma/immunology , Glioblastoma/metabolism , Receptors, CXCR/antagonists & inhibitors , Temozolomide/pharmacology , Animals , Antibodies, Monoclonal/metabolism , Antibody Affinity/immunology , Antineoplastic Agents, Immunological/pharmacology , Cell Line, Tumor , Cytotoxicity, Immunologic/drug effects , Disease Models, Animal , Drug Synergism , Glioblastoma/diagnosis , Glioblastoma/mortality , Humans , Magnetic Resonance Imaging , Mice , Mortality , Protein Binding/immunology , Receptors, CXCR/metabolism , Xenograft Model Antitumor Assays
17.
Clin Immunol ; 187: 37-45, 2018 02.
Article in English | MEDLINE | ID: mdl-29031828

ABSTRACT

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.


Subject(s)
Antigens, Neoplasm/immunology , B-Lymphocytes/immunology , Neoplasms/immunology , Adenocarcinoma of Lung/immunology , Adenocarcinoma of Lung/secondary , Adult , Aged , Aged, 80 and over , Antibodies , Binding Sites, Antibody/immunology , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/secondary , Disease Progression , Female , Humans , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Male , Melanoma/immunology , Melanoma/secondary , Middle Aged , Neoplasm Metastasis , Plasma Cells/immunology , Precursor Cells, B-Lymphoid , Skin Neoplasms/immunology , Skin Neoplasms/pathology
18.
Nutrients ; 8(10)2016 Oct 10.
Article in English | MEDLINE | ID: mdl-27735864

ABSTRACT

Trans fatty acid (TFA) intake has been identified as a health hazard in adults, but data on preschool children are scarce. We analyzed the data from the Spanish INMA Project to determine the intake of total, industrial and natural TFA, their main sources and the associated socio-demographic and lifestyle factors in children aged 4-5 (n = 1793). TFA intake was estimated using a validated Food Frequency Questionnaire, and multiple linear regression was used to explore associated factors. The mean daily intakes of total, industrial and natural TFA were 1.36, 0.60, and 0.71 g/day, respectively. Ten percent of the children obtained >1% of their energy intake from TFA. The main sources of industrial TFA were fast food, white bread and processed baked goods. Milk, red and processed meat and processed baked goods were the main sources of natural TFA. Having parents from countries other than Spain was significantly associated with higher natural TFA (in mg/day) intake (ß 45.5) and television viewing was significantly associated with higher industrial TFA intake (ß 18.3). Higher fruits and vegetables intake was significantly associated with lower intakes of all TFAs, whereas higher sweetened beverages intake was significantly associated with lower total and natural TFA intake. Thus, total and industrial TFA intake was associated with less healthy food patterns and lifestyles in Spanish preschool children.


Subject(s)
Dietary Fats/administration & dosage , Trans Fatty Acids/administration & dosage , Animals , Beverages , Child, Preschool , Cohort Studies , Diet Records , Diet Surveys , Dietary Carbohydrates/administration & dosage , Energy Intake , Fruit , Humans , Life Style , Meat , Milk , Red Meat , Risk Factors , Spain , Surveys and Questionnaires , Vegetables
19.
Blood ; 128(1): 104-9, 2016 07 07.
Article in English | MEDLINE | ID: mdl-27207787

ABSTRACT

UNLABELLED: Circulating factor VIII (FVIII) is derived from liver and from extrahepatic sources probably of endothelial origin, but the vascular sites of FVIII production remain unclear. Among organs profiled, only liver and lymph nodes (LNs) show abundant expression of F8 messenger RNA (mRNA). Transcriptomic profiling of subsets of stromal cells, including endothelial cells (ECs) from mouse LNs and other tissues, showed that F8 mRNA is expressed by lymphatic ECs (LECs) but not by capillary ECs (capECs), fibroblastic reticular cells, or hematopoietic cells. Among blood ECs profiled, F8 expression was seen only in fenestrated ECs (liver sinusoidal and renal glomerular ECs) and some high endothelial venules. In contrast, von Willebrand factor mRNA was expressed in capECs but not in LECs; it was coexpressed with F8 mRNA in postcapillary high endothelial venules. Purified LECs and liver sinusoidal ECs but not capECs from LNs secrete active FVIII in culture, and human and mouse lymph contained substantial FVIII: C activity. Our results revealed localized vascular expression of FVIII and von Willebrand factor and identified LECs as a major cellular source of FVIII in extrahepatic tissues.


Subject(s)
Endothelial Cells/metabolism , Endothelium, Lymphatic/metabolism , Endothelium, Vascular/metabolism , Factor VIII/biosynthesis , Gene Expression Regulation/physiology , von Willebrand Factor/biosynthesis , Animals , Capillaries/cytology , Capillaries/metabolism , Endothelial Cells/cytology , Endothelium, Lymphatic/cytology , Endothelium, Vascular/cytology , Female , Humans , Kidney Glomerulus/blood supply , Kidney Glomerulus/cytology , Kidney Glomerulus/metabolism , Liver/blood supply , Liver/cytology , Liver/metabolism , Male , Mice , Mice, Inbred BALB C , Organ Specificity , Venules/cytology , Venules/metabolism
20.
Gac. sanit. (Barc., Ed. impr.) ; 30(2): 126-132, mar.-abr. 2016. tab
Article in English | IBECS | ID: ibc-151044

ABSTRACT

Objective: To describe the association between consumption of different alcoholic beverages and adherence to the Mediterranean diet. Methods: A cross-sectional analysis was conducted of the baseline data of the DiSA-UMH study, an ongoing cohort study with Spanish health science students (n=1098) aged 17-35 years. Dietary information was collected by a validated 84-item food frequency questionnaire. Participants were grouped into non-drinkers, exclusive beer and/or wine drinkers and drinkers of all types of alcoholic beverages. Mediterranean diet adherence was determined by using a modification of the relative Mediterranean Diet Score (rMED; score range: 0-16) according to consumption of 8 dietary components. We performed multiple linear and multinomial regression analyses. Results: The mean alcohol consumption was 4.3g/day (SD: 6.1). A total of 19.5%, 18.9% and 61.6% of the participants were non-drinkers, exclusive beer and/or wine drinkers and drinkers of all types of alcoholic beverages, respectively. Participants who consumed beer and/or wine exclusively had higher rMED scores than non-drinkers (β: 0.76, 95%CI: 0.25-1.27). Drinkers of all types of alcoholic beverages had similar rMED scores to non-drinkers. Non-drinkers consumed less fish and more meat, whereas drinkers of all types of alcoholic beverages consumed fewer fruits, vegetables and more meat than exclusive beer and/or wine drinkers. Conclusions: The overall alcohol consumption among the students in our study was low-to-moderate. Exclusive beer and/or wine drinkers differed regarding the Mediterranean diet pattern from non-drinkers and drinkers of all types of alcohol. These results show the need to properly adjust for diet in studies of the effects of alcohol consumption (AU)


Objetivo: Explorar la asociación entre el consumo de diferentes bebidas alcohólicas y la adherencia a la dieta Mediterránea. Métodos: Se analizaron transversalmente los datos basales del estudio DiSA-UMH (n=1098) de 17-35 años. Para recoger información dietética se utilizó un cuestionario de frecuencia de alimentos de 84 ítems validado previamente. Se agrupó a los participantes en no bebedores, bebedores exclusivos de cerveza o vino (o ambos), y bebedores de todo tipo de bebidas. La adherencia a la dieta mediterránea se determinó usando una modificación de la relative Mediterranean Diet Score (rMED). Se utilizó regresión lineal múltiple y multinomial. Resultados: La media de alcohol fue de 4,3 (6,1) g/día. El 19,5%, el 18,9% y el 61,6% de los participantes fueron clasificados en no bebedores, bebedores exclusivos de cerveza o vino, y bebedores de todo tipo de bebida, respectivamente. Los participantes clasificados en bebedores exclusivos de cerveza o vino tuvieron una mayor rMED que los no bebedores (β: 0,76; intervalo de confianza del 95%: 0,25-1,27). Los participantes clasificados en bebedores de todo tipo de bebidas tuvieron una rMED similar a los no bebedores. En comparación con los bebedores exclusivos de cerveza o vino, los no bebedores consumían menos pescado y más carne, mientras que los bebedores de todo tipo consumían menos frutas, vegetales y más carne. Conclusiones: La ingesta de alcohol entre los estudiantes de nuestro estudio fue en general baja-moderada. Los bebedores exclusivos de cerveza o vino presentaron un patrón dietético mediterráneo diferenciado del de los no bebedores y los bebedores de todo tipo de bebidas, lo que justificaría ajustar correctamente por la dieta en estudios sobre los efectos del consumo de alcohol (AU)


Subject(s)
Humans , Male , Female , Adolescent , Young Adult , Adult , Diet, Mediterranean/statistics & numerical data , Alcohol Drinking/epidemiology , Students, Health Occupations/statistics & numerical data , Cross-Sectional Studies , Feeding Behavior
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