RESUMO
The adaptive immune receptor repertoire (AIRR), consisting of T- and B-cell receptors, is the core component of the immune system. The AIRR sequencing is commonly used in cancer immunotherapy and minimal residual disease (MRD) detection of leukemia and lymphoma. The AIRR is captured by primers and sequenced to yield paired-end (PE) reads. The PE reads could be merged into one sequence by the overlapped region between them. However, the wide range of AIRR data raises the difficulty, so a special tool is required. We developed a software package for IMmune PE reads merger of sequencing data, named IMperm. We used the k-mer-and-vote strategy to pin down the overlapped region rapidly. IMperm could handle all types of PE reads, eliminate adapter contamination and successfully merge low-quality and minor/non-overlapping reads. Compared with existing tools, IMperm performed better in both simulated and sequencing data. Notably, IMperm was well suited to processing the data of MRD detection in leukemia and lymphoma and detected 19 novel MRD clones in 14 patients with leukemia from previously published data. Additionally, IMperm can handle PE reads from other sources, and we demonstrated its effectiveness on two genomic and one cell-free deoxyribonucleic acid datasets. IMperm is implemented in the C programming language and consumes little runtime and memory. It is freely available at https://github.com/zhangwei2015/IMperm.
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Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Análise de Sequência de DNA , Software , Genoma , AlgoritmosRESUMO
Both DNA damage response and methylation play a crucial role in antigen receptor recombination by creating a diverse repertoire in developing lymphocytes, but how their defects relate to T cell repertoire and phenotypic heterogeneity of immunodeficiency remains obscure. We studied the TCR repertoire in patients with the mutation in different genes (ATM, DNMT3B, ZBTB24, RAG1, DCLRE1C, and JAK3) and uncovered distinct characteristics of repertoire diversity. We propose that early aberrancies in thymus T cell development predispose to the heterogeneous phenotypes of the immunodeficiency spectrum. Shorter CDR3 lengths in ATM-deficient patients, resulting from a decreased number of nucleotide insertions during VDJ recombination in the pre-selected TCR repertoire, as well as the increment of CDR3 tyrosine residues, lead to the enrichment of pathology-associated TCRs, which may contribute to the phenotypes of ATM deficiency. Furthermore, patients with DNMT3B and ZBTB24 mutations who exhibit discrepant phenotypes present longer CDR3 lengths and reduced number of known pathology-associated TCRs.
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Síndromes de Imunodeficiência , Linfócitos T , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/genética , Reparo do DNA/genética , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Metilação , Proteínas Repressoras/genéticaRESUMO
MOTIVATION: T and B cell receptors (TCRs and BCRs) play a pivotal role in the adaptive immune system by recognizing an enormous variety of external and internal antigens. Understanding these receptors is critical for exploring the process of immunoreaction and exploiting potential applications in immunotherapy and antibody drug design. Although a large number of samples have had their TCR and BCR repertoires sequenced using high-throughput sequencing in recent years, very few databases have been constructed to store these kinds of data. To resolve this issue, we developed a database. RESULTS: We developed a database, the Pan Immune Repertoire Database (PIRD), located in China National GeneBank (CNGBdb), to collect and store annotated TCR and BCR sequencing data, including from Homo sapiens and other species. In addition to data storage, PIRD also provides functions of data visualization and interactive online analysis. Additionally, a manually curated database of TCRs and BCRs targeting known antigens (TBAdb) was also deposited in PIRD. AVAILABILITY AND IMPLEMENTATION: PIRD can be freely accessed at https://db.cngb.org/pird.
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Sequenciamento de Nucleotídeos em Larga Escala , Receptores de Antígenos de Linfócitos T/genética , Antígenos , Bases de Dados Factuais , Humanos , ImunoterapiaRESUMO
The rhesus macaque is a valuable preclinical animal model to estimate vaccine effectiveness and is also important for understanding Ab maturation and B cell repertoire evolution responding to vaccination. However, incomplete mapping of rhesus Ig germline genes hinders the research efforts. To address this deficiency, we sequenced the BCR repertoires of 75 Indian rhesus macaques. Using a bioinformatic method that has been validated with BCR repertoire analysis of three human donors, we were able to infer rhesus variable (V) and joint (J) germline alleles. We identified a total of 122 V and 20 J germline alleles, of which 91 V and 13 J alleles were novel, with 40 V novel genes, of which 8 were located at a novel genomic region not, to our knowledge, previously recorded. The novelty of these newly identified alleles was supported by two observations. First, the 50 V and 5 J novel alleles were observed in the whole genome sequencing data of 10 rhesus macaques. Second, using alignment reference including the novel alleles, the mutation rate of the rearranged repertoires significantly declined in nine other irrelevant samples, and all our identified novel V and J alleles were 100%-identity mapped by rearranged repertoire data. These identified novel alleles, along with the previously reported alleles, provide an important reference for future investigations of rhesus immune repertoire evolution in response to vaccination or infection. In addition, the method outlined in our study offers a powerful foundation for the identification of novel Ig alleles in the future.
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Alelos , Região de Junção de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Receptores de Antígenos de Linfócitos B/genética , Animais , Biologia Computacional , Humanos , Região de Junção de Imunoglobulinas/imunologia , Região Variável de Imunoglobulina/imunologia , Macaca mulatta , Receptores de Antígenos de Linfócitos B/imunologiaRESUMO
BACKGROUND & AIMS: The presence of multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy. METHODS: We combined whole-exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 patients with HCC and multifocal lesions. RESULTS: IM and MO demonstrated distinct clonal architecture, mutational spectrum and genetic susceptibility. The immune microenvironment also displayed spatiotemporal heterogeneity, such as less T cell and more M2 macrophage infiltration in IM and higher expression of inhibitory immune checkpoints in MO. Similar to mutational profiles, shared neoantigens and TCR repertoires among tumors from the same patients were abundant in IM but scarce in MO. Combining neoantigen prediction and immunopeptidomes identified T cell-specific neoepitopes and achieved a high verification rate in vitro. Immunoediting mainly occurred in MO but not IM, due to the relatively low immune infiltration. Loss of heterozygosity of human leukocyte antigen (HLA) alleles, identified in 17% of multifocal HCC, hampered the ability of major histocompatibility complex to present neoantigens, especially in IM. An integrated analysis of Immunoscore, immunoediting, TCR clonality and HLA loss of heterozygosity in each tumor could stratify patients into 2 groups based on whether they have a high or low risk of recurrence (p = 0.038). CONCLUSION: Our study comprehensively characterized the genetic structure, neoepitope landscape, T cell profile and immunoediting status that collectively shape tumor evolution and could be used to optimize personalized immunotherapies for multifocal HCC. LAY SUMMARY: Immunogenomic features of multifocal hepatocellular carcinoma (HCC) are important for understanding immune-escape mechanisms and developing more effective immunotherapy. Herein, comprehensive immunogenomic characterization showed that diverse genomic structures within multifocal HCC would leave footprints on the immune landscape. Only a few tumors were under the control of immunosurveillance, while others evaded the immune system through multiple mechanisms that led to poor prognosis. Our study revealed heterogeneous immunogenomic landscapes and immune-constrained tumor evolution, the understanding of which could be used to optimize personalized immunotherapies for multifocal HCC.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/imunologia , Evasão Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/imunologia , Feminino , Predisposição Genética para Doença , Antígenos HLA/genética , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Receptores de Antígenos de Linfócitos T/genética , Transcriptoma , Sequenciamento do ExomaRESUMO
The pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis. Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor ß chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells of RA patients, with highly similar TCR repertoires. Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Notably, we showed that TCR diversity and abundance of differentiated T cells of Th17 were significantly correlated with RA disease activity. Based on these observations, we propose that abnormal differentiation from EMT to Th17 and expansion of Th17 play pivotal role in RA pathogenesis.
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Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Artrite Reumatoide/patologia , Biomarcadores , Linfócitos T CD4-Positivos/patologia , Células Cultivadas , Suscetibilidade a Doenças , Humanos , Ativação Linfocitária , Subpopulações de Linfócitos T/patologiaRESUMO
OBJECTIVE: T cell receptor (TCR) diversity determines the autoimmune responses in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and is closely associated with autoimmune diseases prognosis and prevention. However, the characteristics of variations in TCR diversity and their clinical significance is still unknown. Large series of patients must be studied in order to elucidate the effects of these variations. METHODS: Peripheral blood from 877 SLE patients, 206 RA patients and 439 healthy controls (HC) were amplified for the TCR repertoire and sequenced using a high-throughput sequencer. We have developed a statistical model to identify disease-associated TCR clones and diagnose autoimmune diseases. RESULTS: Significant differences were identified in variable (V), joining (J) and V-J pairing between the SLE or RA and HC groups. These differences can be utilised to discriminate the three groups with perfect accuracy (V: area under receiver operating curve > 0.99). One hundred ninety-eight SLE-associated and 53 RA-associated TCRs were identified and used for diseases classification by cross validation with high specificity and sensitivity. Disease-associated clones showed common features and high similarity between both autoimmune diseases. SLE displayed higher TCR heterogeneity than RA with several organ specific properties. Furthermore, the association between clonal expansion and the concentration of disease-associated clones with disease severity were identified, and pathogen-related TCRs were enriched in both diseases. CONCLUSIONS: These characteristics of the TCR repertoire, particularly the disease-associated clones, can potentially serve as biomarkers and provide novel insights for disease status and therapeutical targets in autoimmune diseases.
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Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Adulto , Análise de Variância , Artrite Reumatoide/sangue , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Autoimunidade , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/metabolismo , Valores de Referência , Medição de Risco , Estatísticas não ParamétricasRESUMO
Immunoglobulin A Nephropathy (IgAN) is the most common glomerulonephritis worldwide. The pathologic hallmark of IgAN is immune complex deposited in glomerular mesangium, which induces inflammation and affects the kidney's normal functions. The exact pathogenesis of IgAN, however, remains obscure. Further, in current clinical practice, the diagnosis relies on needle biopsy of renal tissue. Therefore, a non-invasive method for diagnosis and prognosis surveillance of the disease is highly desirable. To this end, we investigated the T cell receptor beta chain (TCRB) and immunoglobulin heavy chain (IGH) repertoire in circulating lymphocytes and compared them with kidney infiltrating lymphocytes using immune repertoire high throughput sequencing. We found that some features of TCRB and IGH in renal tissues were remarkably different from that in the blood, including decreased repertoire diversity, increased IgA and IgG frequency, and more antigen-experienced B cells. The complementarity-determining region 3 (CDR3) length of circulating TCRB and IGH in IgAN patients was significantly shorter than that in healthy controls, which is the result of both VDJ rearrangement and clonal selection. The IgA1 frequency in the blood of IgAN patients is significantly higher than that in other Nephropathy (NIgAN) patients and healthy control. Importantly we identified a set of TCRB and IGH clones, which can be used to distinguish IgAN from NIgAN and healthy controls with high accuracy. These results indicated that the TCRB and IGH repertoire can potentially serve as non-invasive biomarkers for the diagnosis of IgAN. The characteristics of the kidney infiltrating and circulating lymphocytes repertoires shed light on IgAN detection, treatment and surveillance.
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Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/etiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adolescente , Adulto , Idoso , Regiões Determinantes de Complementaridade/imunologia , Regiões Determinantes de Complementaridade/metabolismo , Biologia Computacional/métodos , Suscetibilidade a Doenças , Feminino , Glomerulonefrite por IGA/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Imunoglobulina G/imunologia , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The B cells inhabited in mucosa play a vital role in mediating homeostasis with autoantigens and external Ags. Tumor-infiltrating lymphocytes are potential prognostic markers and therapeutic agents for cancer. However, the spatial heterogeneity of the B cell repertoire in intestinal mucosa and the tumor-infiltrating lymphocytes in colorectal cancer (CRC) remain poorly understood. In this study, we developed an unbiased method to amplify the IgH repertoire, as well as a bioinformatic pipeline to process these high-throughput sequencing data. With biopsies from seven intestinal mucosal segments, we uncovered their strong spatial homogeneity among the large intestine, where the clone overlap rate was up to 62.21%. The heterogeneity between terminal ileum and large intestine was also observed, including discrepant isotype distribution and low clone overlap rate. With tumor and adjacent normal mucosal tissues from CRC and colorectal advanced adenoma (AD) patients, we observed a similar IgH profile between tumor and adjacent normal mucosal tissues in AD, as well as a slight difference in CRC. Interestingly, we found distinct repertoire properties in the CRC tumor from AD and normal mucosa. Finally, we identified 1445 public clones for the normal mucosa, and 22 public clones for the CRC tumor with characteristic features. These data may be of potential use in clinical prognosis, diagnosis, and treatment of CRC.
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Adenoma/imunologia , Linfócitos B/fisiologia , Neoplasias do Colo/imunologia , Neoplasias Colorretais/imunologia , Mucosa Intestinal/imunologia , Linfócitos do Interstício Tumoral/fisiologia , Receptores de Antígenos de Linfócitos B/genética , Adenoma/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Biologia Computacional , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
BACKGROUND: The disease-causing effects of genetic variations often depend on their location within a gene. Exonic changes generally lead to alterations in protein production, secretion, activity, or clearance. However, owing to the overlap between proteins and splicing codes, missense variants can also affect messenger RNA splicing, thus adding a layer of complexity and influencing disease phenotypes. OBJECTIVES: To extensively characterize a panel of 13 exonic variants in the F9 gene occurring at 6 different factor IX positions and associated with varying severities of hemophilia B (HB). METHODS: Computational predictions, splicing analysis, and recombinant factor IX assays were exploited to characterize F9 variants. RESULTS: We demonstrated that 5 (38%) of 13 selected F9 exonic variants have pleiotropic effects. Although bioinformatic approaches accurately classified effects, extensive experimental assays were required to elucidate and deepen the molecular mechanisms underlying the pleiotropic effects. Importantly, their characterization was instrumental in developing tailored RNA therapeutics based on engineered U7 small nuclear RNA to mask cryptic splice sites and compensatory U1 small nuclear RNA to enhance exon definition. CONCLUSION: Overall, albeit a multitool bioinformatic approach suggested the molecular effects of multiple HB variants, the deep investigation of molecular mechanisms revealed insights into the HB phenotype-genotype relationship, enabling accurate classification of HB variants. Importantly, knowledge of molecular mechanisms allowed the development of tailored RNA therapeutics, which can also be translated to other genetic diseases.
Assuntos
Hemofilia B , Humanos , Hemofilia B/genética , Fator IX/genética , Mutação , Nucleotídeos , Splicing de RNA , Sítios de Splice de RNA , ÉxonsRESUMO
Smart sensing and excellent actuation abilities of natural organisms have driven scientists to develop bionic soft-bodied robots. However, most conventional robots suffer from poor electrical conductivity, limiting their application in real-time sensing and actuation. Here, we report a novel strategy to enhance the electrical conductivity of hydrogels that integrated actuation and strain-sensing functions for bioinspired self-sensing soft actuators. Conductive hydrogels were synthesized in situ by copolymerizing MXene nanosheets with thermosensitive N-isopropylacrylamide and acrylamide under a direct current electric field. The resulting hydrogels exhibited high electrical conductivity (2.11 mS/cm), good sensitivity with a gauge factor of 4.79 and long-term stability. The developed hydrogels demonstrated remarkable capabilities in detecting human motions at subtle strains such as facial expressions and large strains such as knee bending. Additionally, the hydrogel electrode patch was capable of monitoring physiological signals. Furthermore, the developed hydrogel showed good thermally induced actuation effects when the temperature was higher than 30 °C. Overall, this work provided new insights for the design of sensory materials with integrated self-sensing and actuation capabilities, which would pave the way for the development of high-performance conductive soft materials for intelligent soft robots and automated machinery.
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Skull fracture and brain injury are frequent head injuries in electric two-wheeler (ETW) accidents, and the type of helmet and impact conditions affect the effectiveness of the helmet in protecting the rider's head. The purpose of this study was to conduct in-depth reconstructions of rider's head-to-ground impacts in ten ETW accidents by using a multi-body system combined with a finite element approach and to evaluate the effect of two typical full-face helmets (FFH) and one half-coverage helmet (HCH) through head accelerations and intracranial biomechanics injury metrics in ground impacts. The results showed that all three helmets reduced the risk of skull fracture in most cases, however, FFH performed better due to its wider protection area. In addition, three helmets showed varying degrees of overall reduction in measuring all indicators of brain injury. Although the effectiveness of the helmets on angular acceleration was largely influenced by the angle and location of impact, it was certain that wearing an FFH was more likely to reduce rotational head movements than an HCH, and that the FFH also offered the better advantage in reducing diffuse axonal injury (DAI) risk due to its better resistance to ejection in a crash.
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Lesões Encefálicas , Traumatismos Craniocerebrais , Fraturas Cranianas , Humanos , Dispositivos de Proteção da Cabeça , Acidentes de Trânsito , Traumatismos Craniocerebrais/prevenção & controle , Lesões Encefálicas/prevenção & controle , AceleraçãoRESUMO
RATIONALE: Since the introduction of the aldosterone-to-renin ratio (ARR) as a screening tool for primary aldosteronism (PA), there has been a marked increase in the reported prevalence of this condition among hypertensive, even normotensive, subjects. PATIENT CONCERNS: But ARR as a spot blood draw for estimating a patient's aldosterone secretory status is influenced by many factors. DIAGNOSES: Here, we describe a series of patients with biochemically confirmed PA, whose diagnosis was delayed by the initial ARR assessment with non-suppressed renin. INTERVENTIONS: Patient 1 had a history of resistant hypertension for many years and had a negative initial screening for secondary hypertension (including ARR). At the reevaluation, ARR was close to cutoff still with normal renin after strict and extended drug washout, and the further workup for PA demonstrated a unilateral aldosterone producing adenoma that was surgically removed, with subsequent complete biochemical remission and partial clinical success. Patient 2 was diagnosed with idiopathic hyperaldosteronism combined with obstructive sleep apnea syndrome, which could increase renin resulting in a negative ARR, and finally got a better treatment effect with PA-specific spironolactone, as well as continuous positive airway pressure. Patient 3 with hypokalemia as the main presentation was finally diagnosed with PA after excluding other diseases, and proceeded to laparoscopic adrenalectomy and histologically confirmed an aldosterone producing adenoma. Postoperatively, patient 3 achieved complete biochemical success without any medicine. OUTCOMES: The clinical status of all three patients was effectively managed, resulting in either complete resolution or notable improvement of their respective conditions. LESSONS: After rigorous standardized diagnostic evaluation, there are still many reasons for ARR negative in PA, but they all basically occur in the background of normal or normal-high renin without suppression. A negative screening test result should be repeated and analyzed carefully if this is not consistent with the clinical picture. If, despite a repeatedly negative ARR, clinical suspicion remains high, we recommend consideration of further evaluation, including confirmatory tests and adrenal venous blood sampling (AVS) or even 68Ga-pentixafor PET/CT to better confirm the diagnosis and improve patient outcomes.
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Adenoma , Adenoma Adrenocortical , Hiperaldosteronismo , Hipertensão , Humanos , Aldosterona , Hiperaldosteronismo/complicações , Renina , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Hipertensão/complicações , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/diagnóstico , Adenoma Adrenocortical/cirurgia , Adenoma/complicaçõesRESUMO
The aim of this study was to investigate the peak running, mechanical, and physiological demands of players of different positions in professional men's field hockey matches. Eighteen professional male field hockey players participated in the study, and data were collected in eleven official matches. Players wore GPS units (Vector S7, Catapult Sports) and heart rate (HR) monitors (Polar H1, Polar Electros) to collect physical and physiological data. Physical and physiological output of forwards, midfielders, and defenders in full matches and during 1-min peak periods was analysed. For all metrics and positions, the values identified for the 1-min peak periods were greater than the average values of match play (p < 0.05). In terms of 1-min peak period Player Load, all three positions were significantly different from each other. Forwards achieved the highest Player Load per minute, while defenders the lowest. The distance per minute, high-speed distance per minute, and the relative average heart rate of defenders were significantly lower than of midfielders and forwards (p < 0.05). The current study revealed the peak running, mechanical, and physiological demands of professional men's field hockey matches. It is recommended when prescribing training programmes, to consider not only match average demands, but also peak demands. Forwards and midfielders displayed similar peak demands, while defenders had the lowest demands in all metrics except the number of accelerations and decelerations per minute. Player Load per minute can be used to identify the differences in peak mechanical demands between forwards and midfielders.
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OBJECTIVES: The aim of this study was to examine the effects of emergency avoidance behaviors on the kinematics and injuries of electric two-wheeler (ETW) riders. METHODS: Four typical riding postures of ETW riders before collisions, including one normal posture and three avoidance postures, were identified through analysis of 298 videos of vehicle to ETW accidents. Crash simulations were then performed using the Total Human Model of Safety (THUMS) occupant model, ETW and a sedan finite element (FE) model, and the kinematics of ETW riders were compared. The risk of head injury and lower extremity injury was also investigated. RESULTS: When the struck foot position of the ETW rider was lower than the ETW pedal, the lower extremity was struck by the sedan bumper and ETW frame from the right and left side respectively, and the upper body of the rider rotated around the hood leading edge. At a car velocity of 40 km/h, the rider was at high risk of head injury and the tibia was fractured. The medial cruciate ligament (MCL) was ruptured in both the 20 km/h and 40 km/h collisions. When the struck foot position of the ETW rider was higher than the pedal, the lower extremity was hit by the bumper and then rebounded. In this situation, the bending moments of the femur and tibia, as well as the bending angle and shear displacement of the knee joint were less than the injury threshold in all crash simulations. Furthermore, when the head was turned toward the colliding car, the risk of head injury varied with the emergency avoidance posture. CONCLUSIONS: The height of the struck foot relative to the ETW pedal influenced the rider's global kinematics, and head and lower extremity injuries risk. In the struck side foot landing and both feet landing postures, the lower extremity was restrained and compressed by the ETW frame, resulting in a high risk of tibia fracture and MCL rupture. Reducing the impact velocities could effectively mitigate the injury risk of the ETW riders; however, loading patterns remain an important factor influencing the risk of lower extremity injury.
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Traumatismos Craniocerebrais , Traumatismos da Perna , Acidentes de Trânsito/prevenção & controle , Aprendizagem da Esquiva , Fenômenos Biomecânicos , Humanos , Extremidade Inferior/lesõesRESUMO
Doege-Potter syndrome is a rare paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. Doege-Potter syndrome always presents with recurrent fasting hypoglycemia, which can occasionally be life-threatening. The best choice of treatment for Doege-Potter syndrome and solitary fibrous tumor is complete resection. However, when it is unfeasible, local-regional treatment can be used as a palliative therapy. Herein, we report a case of a 46-year-old man with Doege-Potter syndrome that occurred secondary to the liver and pancreatic metastatic solitary fibrous tumors. After he received six rounds of targeting-intratumoral-lactic-acidosis transcatheter-arterial-chemoembolization (TILA-TACE) treatment in our hospital, his hypoglycemia was clinically cured, and the liver metastatic tumor was well controlled. We suggest that TILA-TACE can be considered when curative resection is unfeasible for metastatic liver solitary fibrous tumors to help a patient obtain further surgery opportunities.
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Acidose , Neoplasias Gastrointestinais , Hipoglicemia , Neoplasias de Tecidos Moles , Tumores Fibrosos Solitários , Anormalidades Congênitas , Humanos , Rim/anormalidades , Nefropatias/congênito , Fígado , Masculino , Pessoa de Meia-Idade , Anormalidades UrogenitaisRESUMO
BACKGROUND: Immune checkpoint inhibitor therapy has revolutionized lung adenocarcinoma therapy. Treatment with antibodies against the immune checkpoint molecules programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) can induce a durable response in a subset of patients. Immunohistochemistry characterization of tumor PD-L1 expression using either a histopathology specimen or a cytopathology specimen has been shown to correlate with treatment response. However, the current practice relies on pathologists' visual estimation of tumor PD-L1 staining, which can be variable in certain conditions. Highlighting tumor cells via double immunostaining with PD-L1 and thyroid transcription factor-1 (TTF-1) may improve estimation accuracy. METHODS: We performed PD-L1 single staining and PD-L1/TTF-1 double staining in 42 pairs of cytopathology and histopathology specimens from lung adenocarcinoma patients. An experienced pathologist visually estimated PD-L1 expression in each case and placed tumor PD-L1 expression into 1 of 3 categories: <1%, 1%-49%, or ≥50%. A medical technologist also performed estimations of the same cases based on a count of 200 tumor cells, and the results were compared. RESULTS: PD-L1/TTF-1 double immunohistochemistry could better identify the PD-L1-positive tumor cells in cytopathology specimens compared with PD-L1 single staining. The concordance of PD-L1 expression categorization between the pathologist's visual estimation and the medical technologist's counting was increased by double staining in cytopathology specimens (Cohen's weighted kappa: single stain, 0.784; double stain, 0.880). Double staining reduced possible error in the pathologist's visual estimation of PD-L1 expression from 9.5% to 4.8%. The benefit was not observed in histopathology specimens. CONCLUSION: A simple PD-L1/TTF-1 double immunohistochemistry technique can be applied successfully to cytopathology specimens in better identifying patients who can potentially benefit from immune checkpoint blockade treatment.
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Adenocarcinoma/metabolismo , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/metabolismo , Fator Nuclear 1 de Tireoide/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Diabetic nephropathy (DN) is a chronic inflammatory complication of diabetes mellitus, which becomes the most common cause of end-stage renal disease (ESRD). Recently, bone marrow mesenchymal stem cells (BMSCs) are considered as a promising therapy for DN. However, the protective mechanism of BMSCs on DN remains unclear. This study was done to explore the effect of a bone marrow stromal cell (BMSCs) transplant on DN rats and rat glomerular mesangial cells in high-glucose concentration. Diabetic rats were induced by a single intraperitoneal injection of streptozotocin (STZ) 65 mg/kg, then 4 × 106 BMSCs were transplanted in diabetic rats as the treatment group. Six weeks after BMSCs transplantation, blood serum creatinine (Scr) and blood urea nitrogen (BUN) were used to test renal function. Renal pathological examination was observed by HE staining, Masson staining, PAS staining and immunohistochemistry. The results demonstrated that BMSCs could dramatically improve renal function and collagen accumulation by reducing Scr, BUN, collagen I and IV expression and histopathological abnormalities in the diabetic kidneys. Furthermore, BMSCs could significantly attenuate the expression of TLR4/NF-κB and MCP-1 in vitro and in vivo (P < 0.05, vs diabetic groups). This study reported a novel finding that BMSCs play a protective role in inhibition of inflammatory and fibrotic cytokines by down-regulating TLR-4/NF-κB expression under diabetic condition.
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Diabetes Mellitus Experimental/terapia , Nefropatias Diabéticas/prevenção & controle , Transplante de Células-Tronco Mesenquimais/métodos , Animais , Nitrogênio da Ureia Sanguínea , Células Cultivadas , Creatinina/sangue , Citocinas/metabolismo , Diabetes Mellitus Experimental/complicações , Feminino , Fibrose , Glucose/metabolismo , Células Mesangiais/metabolismo , NF-kappa B/genética , Ratos , Ratos Sprague-Dawley , Estreptozocina , Receptor 4 Toll-Like/genéticaRESUMO
[This corrects the article DOI: 10.3389/fimmu.2019.02064.].