Extracellular vesicles (EVs) are nano-sized lipid bilayer vesicles released by virtually every cell type. EVs have diverse biological activities, ranging from roles in development and homeostasis to ...cancer progression, which has spurred the development of EVs as disease biomarkers and drug nanovehicles. Owing to the small size of EVs, however, most studies have relied on isolation and biochemical analysis of bulk EVs separated from biofluids. Although informative, these approaches do not capture the dynamics of EV release, biodistribution, and other contributions to pathophysiology. Recent advances in live and high-resolution microscopy techniques, combined with innovative EV labeling strategies and reporter systems, provide new tools to study EVs in vivo in their physiological environment and at the single-vesicle level. Here we critically review the latest advances and challenges in EV imaging, and identify urgent, outstanding questions in our quest to unravel EV biology and therapeutic applications.
The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this ...inhibitory axis in the suppression of tumour-specific T-cell responses. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 protein is limited. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane protein of previously unknown function, as a regulator of the PD-L1 protein. Interference with CMTM6 expression results in impaired PD-L1 protein expression in all human tumour cell types tested and in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6-deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member, CMTM4, but not by any of the other CMTM members tested. Notably, CMTM6 increases the PD-L1 protein pool without affecting PD-L1 (also known as CD274) transcription levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with the PD-L1 protein, reduces its ubiquitination and increases PD-L1 protein half-life. Consistent with its role in PD-L1 protein regulation, CMTM6 enhances the ability of PD-L1-expressing tumour cells to inhibit T cells. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway.
Summary
Immune checkpoint inhibitors are a new and effective class of cancer therapy, with ipilimumab being the most established drug in this category. The drugs’ mechanism of action includes ...promoting the effector T cell response to tumours and therefore increased autoimmunity is a predictable side effect. The endocrine effects of these drugs include hypophysitis and thyroid dysfunction, with rare reports of adrenalitis. The overall incidence of hypophysitis with these medications is up to 9%. Primary thyroid dysfunction occurs in up to 15% of patients, with adrenalitis reported in approximately 1%. The mean onset of endocrine side effects is 9 weeks after initiation (range 5–36 weeks). Investigation and/or screening for hypophysitis requires biochemical and radiological assessment. Hypopituitarism is treated with replacement doses of deficient hormones. Since the endocrine effects of immune checkpoint inhibitors are classed as toxic adverse events, most authors recommend both discontinuation of the immune checkpoint inhibiting medication and ‘high‐dose’ glucocorticoid treatment. However, this has been challenged by some authors, particularly if the endocrine effects can be managed (e.g. pituitary hormone deficiency), and the therapy is proving effective as an anticancer agent. This review describes the mechanism of action of immune checkpoint inhibitors and details the key clinical endocrine‐related consequences of this novel class of immunotherapies.
Background Frailty is a state of increased vulnerability to health-related stressors and can be measured by summing the number of frailty characteristics present in an individual. Discharge ...institutionalization (rather than discharge to home) represents disease burden and functional dependence after hospitalization. Our aim was to determine the relationship between frailty and need for postoperative discharge institutionalization. Study Design Subjects ≥65 years undergoing major elective operations requiring postoperative ICU admission were enrolled. Discharge institutionalization was defined as need for institutionalized care at hospital discharge. Fourteen preoperative frailty characteristics were measured in 6 domains: comorbidity burden, function, nutrition, cognition, geriatric syndromes, and extrinsic frailty. Results A total of 223 subjects (mean age 73 ± 6 years) were studied. Discharge institutionalization occurred in 30% (n = 66). Frailty characteristics related to need for postoperative discharge institutionalization included: older age, Charlson index ≥3, hematocrit <35%, any functional dependence, up-and-go ≥15 seconds, albumin <3.4 mg/dL, Mini-Cog score ≤3, and having fallen within 6 months (p < 0.0001 for all comparisons). Multivariate logistic regression retained prolonged timed up-and-go (p < 0.0001) and any functional dependence (p < 0.0001) as the variables most closely related to need for discharge institutionalization. An increased number of frailty characteristics present in any one subject resulted in increased rate of discharge institutionalization. Conclusions Nearly 1 in 3 geriatric patients required discharge to an institutional care facility after major surgery. The frailty characteristics of prolonged up-and-go and any functional dependence were most closely related to the need for discharge institutionalization. Accumulation of a higher number of frailty characteristics in any one geriatric patient increased their risk of discharge institutionalization.
We report on a statistical tool based on partial least-squares regression (PLSR) able to retrieve single-component concentrations in a multiple-gas mixture characterized by spectrally overlapping ...absorption features. Absorption spectra of mixtures of CO–N2O and mixtures of C2H2–CH4–N2O, both diluted in N2, were detected in the mid-IR range by exploiting quartz-enhanced photoacoustic spectroscopy (QEPAS) and using two quantum cascade lasers as light sources. Single-gas reference spectra of each target molecule were acquired and used as PLSR-based algorithm training data set. The concentration range explored in the analysis varies from a few parts-per-million (ppm) to thousands of ppm. Within this concentration range, the influence of the gas matrix on nonradiative relaxation processes can be neglected. Exploiting the ability of PLSR to deal with correlated data, these spectra were used to generate new simulated spectra, i.e., linear combinations of the reference ones. A Gaussian noise distribution was added to the created data set, simulating the real QEPAS signal fluctuations around the peak value. Compared with standard multilinear regression, PLSR predicted gas concentrations with a calibration error up to 5 times better, even with absorption features with spectral overlap greater than 97%.
Lineage plasticity is a prominent feature of pancreatic ductal adenocarcinoma (PDA) cells, which can occur via deregulation of lineage-specifying transcription factors. Here, we show that the zinc ...finger protein ZBED2 is aberrantly expressed in PDA and alters tumor cell identity in this disease. Unexpectedly, our epigenomic experiments reveal that ZBED2 is a sequence-specific transcriptional repressor of IFN-stimulated genes, which occurs through antagonism of IFN regulatory factor 1 (IRF1)-mediated transcriptional activation at cooccupied promoter elements. Consequently, ZBED2 attenuates the transcriptional output and growth arrest phenotypes downstream of IFN signaling in multiple PDA cell line models. We also found that ZBED2 is preferentially expressed in the squamous molecular subtype of human PDA, in association with inferior patient survival outcomes. Consistent with this observation, we show that ZBED2 can repress the pancreatic progenitor transcriptional program, enhance motility, and promote invasion in PDA cells. Collectively, our findings suggest that high ZBED2 expression is acquired during PDA progression to suppress the IFN response pathway and to promote lineage plasticity in this disease.
Abstract
The heavy fermion paramagnet UTe
2
exhibits numerous characteristics of spin-triplet superconductivity. Efforts to understand the microscopic details of this exotic superconductivity have ...been impeded by uncertainty regarding the underlying electronic structure. Here we directly probe the Fermi surface of UTe
2
by measuring magnetic quantum oscillations in pristine quality crystals. We find an angular profile of quantum oscillatory frequency and amplitude that is characteristic of a quasi-2D Fermi surface, which we find is well described by two cylindrical Fermi sheets of electron- and hole-type respectively. Additionally, we find that both cylindrical Fermi sheets possess considerable undulation but negligible small-scale corrugation, which may allow for their near-nesting and therefore promote magnetic fluctuations that enhance the triplet pairing mechanism. Importantly, we find no evidence for the presence of any 3D Fermi surface sections. Our results place strong constraints on the possible symmetry of the superconducting order parameter in UTe
2
.
The rich phenomena in the FeSe and related compounds have attracted great interests as it provides fertile material to gain further insight into the mechanism of high temperature superconductivity. A ...natural follow-up work was to look into the possibility of superconductivity in MnSe. We demonstrated in this work that high pressure can effectively suppress the complex magnetic characters of MnSe, and induce superconductivity with T
~ 5 K at pressure ~12 GPa confirmed by both magnetic and resistive measurements. The highest T
is ~ 9 K (magnetic result) at ~35 GPa. Our observations suggest the observed superconductivity may closely relate to the pressure-induced structural change. However, the interface between the metallic and insulating boundaries may also play an important role to the pressure induced superconductivity in MnSe.
Background & Aims Inflammatory bowel diseases (IBD) are becoming more common in Asia, but epidemiologic data are lacking. The Asia-Pacific Crohn’s and Colitis Epidemiology Study aimed to determine ...the incidence and phenotype of IBD in 8 countries across Asia and in Australia. Methods We performed a prospective, population-based study of IBD incidence in predefined catchment areas, collecting data for 1 year, starting on April 1, 2011. New cases were ascertained from multiple overlapping sources and entered into a Web-based database. Cases were confirmed using standard criteria. Local endoscopy, pathology, and pharmacy records were searched to ensure completeness of case capture. Results We identified 419 new cases of IBD (232 of ulcerative colitis UC, 166 of Crohn’s disease CD, and 21 IBD-undetermined). The crude annual overall incidence values per 100,000 individuals were 1.37 for IBD in Asia (95% confidence interval: 1.25−1.51; 0.76 for UC, 0.54 for CD, and 0.07 for IBD-undetermined) and 23.67 in Australia (95% confidence interval: 18.46−29.85; 7.33 for UC, 14.00 for CD, and 2.33 for IBD-undetermined). China had the highest incidence of IBD in Asia (3.44 per 100,000 individuals). The ratios of UC to CD were 2.0 in Asia and 0.5 in Australia. Median time from symptom onset to diagnosis was 5.5 months (interquartile range, 1.4−15 months). Complicated CD (stricturing, penetrating, or perianal disease) was more common in Asia than Australia (52% vs 24%; P = .001), and a family history of IBD was less common in Asia (3% vs 17%; P < .001). Conclusions We performed a large-scale population-based study and found that although the incidence of IBD varies throughout Asia, it is still lower than in the West. IBD can be as severe or more severe in Asia than in the West. The emergence of IBD in Asia will result in the need for specific health care resources, and offers a unique opportunity to study etiologic factors in developing nations.
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