Research on fluorescent semiconductor nanocrystals (also known as quantum dots or qdots) has evolved over the past two decades from electronic materials science to biological applications. We review ...current approaches to the synthesis, solubilization, and functionalization of qdots and their applications to cell and animal biology. Recent examples of their experimental use include the observation of diffusion of individual glycine receptors in living neurons and the identification of lymph nodes in live animals by near-infrared emission during surgery. The new generations of qdots have far-reaching potential for the study of intracellular processes at the single-molecule level, high-resolution cellular imaging, long-term in vivo observation of cell trafficking, tumor targeting, and diagnostics.
In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and
models support that some of these bacteria can trigger host transcriptomic signatures associated ...with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB-IV tumor-node-metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB-IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified
as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with
led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGNIFICANCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.
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To establish a novel panel of cancer-specific methylated genes for cancer detection and prognostic stratification of early-stage non-small cell lung cancer (NSCLC).
Identification of differentially ...methylated regions (DMR) was performed with bumphunter on "The Cancer Genome Atlas (TCGA)" dataset, and clinical utility was assessed using quantitative methylation-specific PCR assay in multiple sets of primary NSCLC and body fluids that included serum, pleural effusion, and ascites samples.
A methylation panel of 6 genes (
, and
) was selected from TCGA dataset. Promoter methylation of the gene panel was detected in 92.2% (83/90) of the training cohort with a specificity of 72.0% (18/25) and in 93.0% (40/43) of an independent cohort of stage IA primary NSCLC. In serum samples from the later 43 stage IA subjects and population-matched 42 control subjects, the gene panel yielded a sensitivity of 72.1% (31/41) and specificity of 71.4% (30/42). Similar diagnostic accuracy was observed in pleural effusion and ascites samples. A prognostic risk category based on the methylation status of
, and
refined the risk stratification for outcomes as an independent prognostic factor for an early-stage disease. Moreover, the paralog group for HOXA9, predominantly overexpressed in subjects with
methylation, showed poor outcomes.
Promoter methylation of a panel of 6 genes has potential for use as a biomarker for early cancer detection and to predict prognosis at the time of diagnosis.
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Transient mitochondrial stress can promote beneficial physiological responses and longevity, termed “mitohormesis.” To interrogate mitohormetic pathways in mammals, we generated mice in which ...mitochondrial superoxide dismutase 2 (SOD2) can be knocked down in an inducible and reversible manner (iSOD2-KD mice). Depleting SOD2 only during embryonic development did not cause post-natal lethality, allowing us to probe adaptive responses to mitochondrial oxidant stress in adult mice. Liver from adapted mice had increased mitochondrial biogenesis and antioxidant gene expression and fewer reactive oxygen species. Gene expression analysis implicated non-canonical activation of the Nrf2 antioxidant and PPARγ/PGC-1α mitochondrial signaling pathways in this response. Transient SOD2 knockdown in embryonic fibroblasts from iSOD2-KD mice also resulted in adaptive mitochondrial changes, enhanced antioxidant capacity, and resistance to a subsequent oxidant challenge. We propose that mitohormesis in response to mitochondrial oxidative stress in mice involves sustained activation of mitochondrial and antioxidant signaling pathways to establish a heightened basal antioxidant state.
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•Inducible and reversible SOD2 knockdown mice (iSOD2-KD) have been developed•Embryonic mitochondrial oxidant stress results in adaptive changes in adult liver•Mitohormesis in adapted liver involves basal activation of PPARγ, PGC-1α, and Nrf2•Mitohormesis in iSOD2-KD embryonic fibroblasts provides resistance to oxidative stress
A mouse model of inducible SOD2 gene knockdown reveals the existence of stable, adaptive responses in adult liver to mitochondrial oxidant stress during embryogenesis and in primary embryonic fibroblasts. These mitohormetic responses involve mitochondrial remodeling and priming of antioxidant pathways via basal activation of PPARγ, PGC-1α, and Nrf2 signaling.
Studies performed in animal models and in humans indicate that the innate arm of the immune system provides an essential role in the initial protection against potential insults and in maintaining ...tolerance to self-antigens. In the B cell compartment, several subsets engage in both adaptive and innate functions. Whereas B cell subsets are recognized to play important roles in autoimmune diseases, understanding the intricacies of their effector functions remains challenging. In addition to B-1a cells and marginal zone B cells, the B cell compartment comprises other B cells with innate-like functions, including innate response activator B cells, T-bet positive B cells, natural killer-like B cells, IL-17-producing B cells, and human self-reactive V
4-34-expressing B cells. Herein, we summarize the functions of recently described B cell populations that can exert innate-like roles in both animal models and humans. We also highlight the importance of the cross talk between innate-like B cells and other adaptive and innate branches of the immune system in various autoimmune and inflammatory diseases. In as much as innate immunity seems to be important in resolving inflammation, it is possible that targeting certain innate-like B cell subsets could represent a novel therapeutic approach for inducing resolution of inflammation of autoimmune and inflammatory responses.
The sensory origins of human position sense Tsay, A. J.; Giummarra, M. J.; Allen, T. J. ...
The Journal of physiology,
15 February 2016, Letnik:
594, Številka:
4
Journal Article
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Key points
Position sense at the human forearm can be measured in blindfolded subjects by matching positions of the arms or by a subject pointing to the perceived position of an unseen arm.
Effects ...on position sense tested were: elbow muscle conditioning with a voluntary contraction, muscle vibration, loading the arm and elbow skin stretch.
Conditioning contractions and vibration produced errors in a matching task, consistent with the action of muscle spindles as position sensors. Position errors in a pointing task were not consistent with the action of muscle spindles. Loading the arm or skin stretch had no effect in either matching or pointing tasks.
It is proposed that there are two kinds of position sense: (i) indicating positions of different body parts relative to one another, using signals from muscle spindles; and (ii) indicating position of the body in extrapersonal space, using signals from exteroceptors, vision, touch and hearing.
Human limb position sense can be measured in two ways: in a blindfolded matching task, position of one limb is indicated with the other limb. Alternatively, position of a limb, hidden from view, is indicated with a pointer, moved by pressing a lever. These experiments examined the sensory basis of position sense measured in these two ways. Position errors were measured in 14 subjects after elbow flexors or extensors had been conditioned with a half‐maximum voluntary contraction. In agreement with previous studies, in the matching trials, position errors were distributed according to a pattern consistent with the action of muscle spindles as the position sensors. In the pointing trials, all errors lay in the direction of extension of the true position of the hidden arm and their distribution was inconsistent with influences arising in muscle spindles. Vibration of elbow muscles produced an illusion of muscle lengthening during a matching task, while during the pointing task no illusion was present. Finally, the matching–pointing error difference was preserved, even when one arm was loaded with a weight or skin over the elbow was stretched. It is proposed that there are two kinds of position sense. One is signalled by muscle spindles, indicating position of one part of the body relative to another. A second provides information about the position of the body in extrapersonal space and here we hypothesise that exteroceptors, including vision, touch and hearing, acting via a central map of the body, provide the spatial information.
Key points
Position sense at the human forearm can be measured in blindfolded subjects by matching positions of the arms or by a subject pointing to the perceived position of an unseen arm.
Effects on position sense tested were: elbow muscle conditioning with a voluntary contraction, muscle vibration, loading the arm and elbow skin stretch.
Conditioning contractions and vibration produced errors in a matching task, consistent with the action of muscle spindles as position sensors. Position errors in a pointing task were not consistent with the action of muscle spindles. Loading the arm or skin stretch had no effect in either matching or pointing tasks.
It is proposed that there are two kinds of position sense: (i) indicating positions of different body parts relative to one another, using signals from muscle spindles; and (ii) indicating position of the body in extrapersonal space, using signals from exteroceptors, vision, touch and hearing.
Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been ...limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
Cancer recurrence after tumor resection in early-stage non-small cell lung cancer (NSCLC) is common, yet difficult to predict. The lung microbiota and systemic immunity may be important modulators of ...risk for lung cancer recurrence, yet biomarkers from the lung microbiome and peripheral immune environment are understudied. Such markers may hold promise for prediction as well as improved etiologic understanding of lung cancer recurrence.
In tumor and distant normal lung samples from 46 stage II NSCLC patients with curative resection (39 tumor samples, 41 normal lung samples), we conducted 16S rRNA gene sequencing. We also measured peripheral blood immune gene expression with nanoString®. We examined associations of lung microbiota and peripheral gene expression with recurrence-free survival (RFS) and disease-free survival (DFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression, and examined predictive accuracy using time-dependent receiver operating characteristic (ROC) curves.
Over a median of 4.8 years of follow-up (range 0.2-12.2 years), 43% of patients experienced a recurrence, and 50% died. In normal lung tissue, a higher abundance of classes Bacteroidia and Clostridia, and orders Bacteroidales and Clostridiales, were associated with worse RFS, while a higher abundance of classes Alphaproteobacteria and Betaproteobacteria, and orders Burkholderiales and Neisseriales, were associated with better RFS. In tumor tissue, a higher abundance of orders Actinomycetales and Pseudomonadales were associated with worse DFS. Among these taxa, normal lung Clostridiales and Bacteroidales were also related to worse survival in a previous small pilot study and an additional independent validation cohort. In peripheral blood, higher expression of genes TAP1, TAPBP, CSF2RB, and IFITM2 were associated with better DFS. Analysis of ROC curves revealed that lung microbiome and peripheral gene expression biomarkers provided significant additional recurrence risk discrimination over standard demographic and clinical covariates, with microbiome biomarkers contributing more to short-term (1-year) prediction and gene biomarkers contributing to longer-term (2-5-year) prediction.
We identified compelling biomarkers in under-explored data types, the lung microbiome, and peripheral blood gene expression, which may improve risk prediction of recurrence in early-stage NSCLC patients. These findings will require validation in a larger cohort.
Malignant pleural effusions (MPE) complicate malignancies and portend worse outcomes. MPE is comprised of various components, including immune cells, cancer cells, and cell-free DNA/RNA. There have ...been investigations into using these components to diagnose and prognosticate MPE. We hypothesize that the microbiome of MPE is unique and may be associated with diagnosis and prognosis. We compared the microbiota of MPE against microbiota of pleural effusions from non-malignant and paramalignant states. We collected a total of 165 pleural fluid samples from 165 subjects; Benign (n = 16), Paramalignant (n = 21), MPE-Lung (n = 57), MPE-Other (n = 22), and Mesothelioma (n = 49). We performed high throughput 16S rRNA gene sequencing on pleural fluid samples and controls. We showed that there are compositional differences among pleural effusions related to non-malignant, paramalignant, and malignant disease. Furthermore, we showed differential enrichment of bacterial taxa within MPE depending on the site of primary malignancy. Pleural fluid of MPE-Lung and Mesothelioma were associated with enrichment with oral and gut bacteria that are commonly thought to be commensals, including Rickettsiella, Ruminococcus, Enterococcus, and Lactobacillales. Mortality in MPE-Lung is associated with enrichment in Methylobacterium, Blattabacterium, and Deinococcus. These observations lay the groundwork for future studies that explore host-microbiome interactions and their influence on carcinogenesis.
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