Background Perforin-1 (Prf1) is the predominant cytolytic protein secreted by natural killer (NK) cells. For a rapid immune response, resting NK cells contain high Prf1 mRNA concentrations while ...exhibiting minimal cytotoxicity caused by a blockage of Prf1 protein synthesis, implying that an unknown posttranscriptional regulatory mechanism exists. Objective We sought to determine whether microRNA-150 (miR-150) posttranscriptionally regulates Prf1 translation in both mouse and human NK cells at rest and at various time points after activation. Methods Mouse NK cells with a targeted deletion of miR-150 (miR-150−/− NK cells), primary human NK cells, and NK92 MI cells were used to investigate the role of miR-150 in NK cells. NK cell cytotoxicity assays and Western blotting proved that activated miR-150−/− NK cells expressed upregulated Prf1, augmenting NK cell cytotoxicity. When immunodeficient mice were injected with miR-150−/− NK cells, there was a significant reduction in tumor growth and metastasis of B16F10 melanoma. Results We report that miR-150 binds to 3′ untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. Mouse wild-type NK cells displayed downregulated miR-150 expression in response to IL-15, which led to corresponding repression and induction of Prf1 during rest and after IL-15 activation, respectively. Conclusion Our results indicate that miR-150 is a common posttranscriptional regulator for Prf1 in mouse and human NK cells that represses NK cell lytic activity. Thus the therapeutic control of miR-150 in NK cells could enhance NK cell–based immunotherapy against cancer, providing a better clinical outcome.
Generalized anxiety disorder (GAD) is marked by uncontrollable, persistent worry and exaggerated response to uncertainty. Here, we review and summarize the findings from the GAD literature that ...employs functional neuroimaging methods. In particular, the present review focuses on task-based blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. We find that select brain regions often regarded as a part of a corticolimbic circuit (e.g., amygdala, anterior cingulate cortex, prefrontal cortex) are consistently targeted for a priori hypothesis-driven analyses, which, in turn, shows varying degrees of abnormal BOLD responsivity in GAD. Data-driven whole-brain analyses show the insula and the hippocampus, among other regions, to be affected by GAD, depending on the task used in each individual study. Overall, while the heterogeneity of the tasks and sample size limits the generalizability of the findings thus far, some promising convergence can be observed in the form of the altered BOLD responsivity of the corticolimbic circuitry in GAD.
•A–T should be considered in undiagnosed dystonia, even without typical phenotype of A–T.•Generalized dystonia from childhood or adolescence is characteristic in dystonic A–T.•Cerebellar involvement ...is associated with telangiectasia and oculomotor apraxia in dystonic A–T.•Dystonic A–T without cerebellar involvement is related with combined choreoathetosis and malignancy.
Besides cerebellar ataxia, various other movement disorders, including dystonia, could manifest as main clinical symptoms in ataxia-telangiectasia (A–T). However, the clinical characteristics of dystonic A–T patients are not clearly elucidated.
To investigate the characteristics of dystonic A–T, we screened previous reports with A–T patients presenting dystonia as a main manifestation, and included 38 dystonic A–T patients from 16 previous studies and our 2 cases. We reviewed clinical and demographic data of dystonic A–T patients. Additionally, to figure out clinical meaning of cerebellar involvement in dystonic A–T, we divided them into two groups based on the presence of cerebellar involvement, and compared clinical features between two groups.
In the patients with dystonic A–T, dystonia tended to appear during childhood or adolescence and became generalized over time. Choreoathetosis and myoclonus accompanied more frequently than the typical clinical features, including cerebellar ataxia or atrophy, telangiectasia, or oculomotor apraxia. Additionally, alpha-fetoprotein level was also elevated in the patients with dystonic A–T. When we compared dystonic A–T with and without cerebellar involvement, the former was related with more chance for telangiectasia and oculomotor apraxia, while the latter with that for choreoathetosis and malignancy.
Even without ataxia, telangiectasia, or oculomotor apraxia, A–T should be considered in undiagnosed dystonia, especially generalized dystonia which started from childhood or adolescence period, and alpha-fetoprotein level can be a useful screening tool. In addition, cerebellar involvement is important considering different phenotype in dystonic A–T patients with and without cerebellar sign.
Label-free surface-enhanced Raman spectroscopy (SERS) can interrogate systems by directly fingerprinting their components' unique physicochemical properties. In complex biological systems however, ...this can yield highly overlapping spectra that hinder sample identification. Here, we present an artificial-nose inspired SERS fingerprinting approach where spectral data is obtained as a function of sensor surface chemical functionality. Supported by molecular dynamics modeling, we show that mildly selective self-assembled monolayers can influence the strength and configuration in which analytes interact with plasmonic surfaces, diversifying the resulting SERS fingerprints. Since each sensor generates a modulated signature, the implicit value of increasing the dimensionality of datasets is shown using cell lysates for all possible combinations of up to 9 fingerprints. Reliable improvements in mean discriminatory accuracy towards 100% are achieved with each additional surface functionality. This arrayed label-free platform illustrates the wide-ranging potential of high-dimensionality artificial-nose based sensing systems for more reliable assessment of complex biological matrices.
Colorectal cancer (CRC) is one of the most common causes of cancer morbidity in both sexes but shows sex differences. First, sex-specific differences in tumor recurrence and survival rates have been ...reported. For example, the development of CRC is found about 1.5 times higher and 4-8 years earlier in males compared to females, suggesting the protective role of estrogen in the disease. Furthermore, female patients have a higher risk of developing right-sided (proximal) colon cancer than male patients, which is known to have more aggressive clinical character compared to left-sided (distal) colon cancer. That is, left and right CRCs show differences in carcinogenic mechanism, that the chromosomal instability pathway is more common in left colon cancer while the microsatellite instability and serrated pathways are more common in right colon cancer. It is thought that there are sex-based differences on the background of carcinogenesis of CRC. Sex differences of CRC have two aspects, sexual dimorphism (biological differences in hormones and genes) and gender differences (non-biological differences in societal attitudes and behavior). Recently, sex difference of colon adenoma pathway and sexual dimorphism in the biology of gene and protein expression, and in endocrine cellular signaling in the CRC carcinogenesis have been accumulated. In addition, behavioral patterns can lead to differences in exposure to risk factors such as drinking or smoking, diet and physical activity. Therefore, understanding sex/gender-related biological and sociocultural differences in CRC risk will help in providing strategies for screening, treatment and prevention protocols to reduce the mortality and improve the quality of life. In this review, sex/gender differences in colon adenoma pathway and various aspects such as clinicopathological, biological, molecular, and socio-cultural aspects of CRC were described.
Owing to rapid advancements in NGS (next generation sequencing), genomic alteration is now considered an essential predictive biomarkers that impact the treatment decision in many cases of cancer. ...Among the various predictive biomarkers, tumor mutation burden (TMB) was identified by NGS and was considered to be useful in predicting a clinical response in cancer cases treated by immunotherapy. In this study, we directly compared the lab-developed-test (LDT) results by target sequencing panel, K-MASTER panel v3.0 and whole-exome sequencing (WES) to evaluate the concordance of TMB. As an initial step, the reference materials (n = 3) with known TMB status were used as an exploratory test. To validate and evaluate TMB, we used one hundred samples that were acquired from surgically resected tissues of non-small cell lung cancer (NSCLC) patients. The TMB of each sample was tested by using both LDT and WES methods, which extracted the DNA from samples at the same time. In addition, we evaluated the impact of capture region, which might lead to different values of TMB; the evaluation of capture region was based on the size of NGS and target sequencing panels. In this pilot study, TMB was evaluated by LDT and WES by using duplicated reference samples; the results of TMB showed high concordance rate (R2 = 0.887). This was also reflected in clinical samples (n = 100), which showed R2 of 0.71. The difference between the coding sequence ratio (3.49%) and the ratio of mutations (4.8%) indicated that the LDT panel identified a relatively higher number of mutations. It was feasible to calculate TMB with LDT panel, which can be useful in clinical practice. Furthermore, a customized approach must be developed for calculating TMB, which differs according to cancer types and specific clinical settings. BMB Reports 2021; 54(7): 386-391.
Urachal cancer is a rare cancer that develops in the urachus. Because of its rarity, standard treatment therapies for urachal cancer are not established, and chemotherapeutic regimens for bladder ...cancer have been unsuccessful for patients with urachal cancer. Hence, we aim to understand a systematic molecular characterisation of urachal cancer.
We identified somatic single-nucleotide variations (SNVs)/indels and somatic copy number aberrations (SCNAs) in the 17 patients by using whole-exome sequencing (WES) and OncoScan platform (Affymetrix) as follows: tumour-normal paired sequencing (WES, n=10), tumour-only sequencing (WES, n=1; targeted deep sequencing, n=16), and OncoScan (n=17).
Our analyses identified 27 genes with somatic SNVs and indels, as well as six genes (APC, COL5A1, KIF26B, LRP1B, SMAD4 and TP53) that were recurrent in at least two patients. By analysing the SCNAs, we found that the extent of chromosomal amplification was highly associated with the patient's cancer stage. Interestingly, 35% (6/17) of the patients had focal DNA amplifications in fibroblast growth factor receptor family genes. The integration of somatic SNVs, indels and SCNAs revealed significant alterations in the mitogen-activated protein kinase signalling pathways.
Our genome-wide analysis of urachal cancer suggests that molecular characteristics may be important for the treatment of urachal cancer.
Abstract
Despite remarkable advances in the design and synthesis of hollow inorganic spheres (HISs), the harsh synthetic conditions have precluded the applications of HISs to biochemical and ...biological fields. Herein we report a biocompatible strategy for synthesizing metal hydroxide HISs (MH-HISs) by simply mixing CaCO
3
particles with metal ions in water. The ion-exchange reaction between Ca
2+
and metal ions leads to the structural and chemical evolution from solid CaCO
3
particles to hollow MH-HISs via core-shell and yolk-shell structures, while enabling the encapsulation of enzymes to the shells without loss of catalytic activities. The biocompatible protocol makes multienzymatic cascade reactions achievable, with great recyclability due to mechanical durability of MH-HISs.
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