•TAMs are involved in tumor progression via multiple mechanisms.•TAMs serve as angiogenesis promoting cells in cancer.•TAMs play vital roles in tumor metastasis.•TAMs are the promising candidate in ...cancer therapy.
Tumor associated macrophages (TAMs) are the most frequent immune cells within tumor microenvironment (TME). There is growing evidence that TAMs are involved in tumor progression via multiple mechanisms. TAMs create an immunosuppressive TME by producing growth factors, chemokines, and cytokines which modulate recruitment of immune cells and inhibit anti-tumor responses. They also serve as angiogenesis promoting cells by production of pro-angiogenic factors and matrix metalloproteinases (MMPs) and vascular constructing which guarantee supplying oxygen and nutrients to solid tumor cells. Furthermore, TAMs play important functions in tumor metastasis through contributing to invasion, extravasation, survival, intravasation, and colonization of tumor cells. In this review, we summarized macrophage classification, TAMs polarization, and mechanisms underlying TAM-promoting angiogenesis and metastasis.
Designing materials capable of adapting their mechanical properties in response to external stimuli is the key to preventing failure and extending their service life. However, existing mechanically ...adaptive polymers are hindered by limitations such as inadequate load‐bearing capacity, difficulty in achieving reversible changes, high cost, and a lack of multiple responsiveness. Herein, we address these challenges using dynamic coordination bonds. A new type of mechanically adaptive material with both rate‐ and temperature‐responsiveness was developed. Owing to the stimuli‐responsiveness of the coordination equilibria, the prepared polymers, PBMBD‐Fe and PBMBD‐Co, exhibit mechanically adaptive properties, including temperature‐sensitive strength modulation and rate‐dependent impact hardening. Benefitting from the dynamic nature of the coordination bonds, the polymers exhibited impressive energy dissipation, damping capacity (loss factors of 1.15 and 2.09 at 1.0 Hz), self‐healing, and 3D printing abilities, offering durable and customizable impact resistance and protective performance. The development of impact‐resistant materials with comprehensive properties has potential applications in the sustainable and intelligent protection fields.
This work proposes a novel strategy with reversible coordination equilibria for fabricating rate‐ and temperature‐responsive mechanically adaptive materials. Based on dynamic coordination interactions, the developed polymers demonstrate excellent energy dissipation, damping, self‐healing and 3D printing properties, providing potential applications in durable and customizable impact protection fields.
Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab ...(VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome.
VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18–75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology EULAR Sjögren's Syndrome Disease Activity Index ESSDAI score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895.
Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline −1·92 points (95% CI −4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia n=1 and gastroenteritis n=1 in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group).
The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future.
Novartis.
The “macrotrabecular-massive” (MTM) pattern of hepatocellular carcinoma (HCC) has been suggested to represent a distinct HCC subtype and is associated with specific molecular features. Since the ...immune microenvironment is heterogenous in HCC, it is important to evaluate the immune microenvironment of this novel variant. CMTM6, a key regulator of PD-L1, is an important immunocheckpoint inhibitor. This study aimed to evaluate the prognostic effect of CMTM6/PD-L1 coexpression and its relationship with inflammatory cells in HCC. We analyzed 619 HCC patients and tumors were classified into MTM and non-MTM HCC subtypes. The expression levels of CMTM6 and PD-L1 in tumor and inflammatory cells were evaluated by immunohistochemistry. The density of inflammatory cells in the cancer cell nest was calculated. Tumoral PD-L1 expression and inflammatory cell density were higher in the MTM type than in the non-MTM type. CMTM6-high expression was significantly associated with shorter OS and DFS than CMTM6-low expression in the whole HCC patient population and the MTM HCC patient population. Moreover, MTM HCC patients with CMTM6/PD-L1 coexpression experienced a higher risk of HCC progression and death. In addition, CMTM6/PD-L1 coexpression was shown to be related to a high density of inflammatory cells. Notably, a new immune classification, based on CMTM6/PD-L1 coexpression and inflammatory cells, successfully stratified OS and DFS in MTM HCC. CMTM6/PD-L1 coexpression has an adverse effect on the prognosis of HCC patients, especially MTM HCC patients. Our study provides evidence for the combination of immune status assessment with anti-CMTM6 and anti-PD-L1 therapy in MTM HCC patients.
Maize/peanut intercropping system shows the significant yield advantage. Soil microbes play major roles in soil nutrient cycling and were affected by intercropping plants. This experiment was carried ...out to evaluate the changing of rhizosphere microbial community composition, and the relationship between microbial community and soil enzymatic activities, soil nutrients in maize/peanut intercropping system under the following three treatments： maize （Zea mays L.） and peanut （Arachis hypogaea L.） were intercropped without any separation （NS）, by half separation （HS） using a nylon net （50 μm） and complete separation （CS） by using a plastic sheet, respectively. The soil microbial communities were assessed by phospholipid fatty acid （PLFA）. We found that soil available nutrients （available nitrogen （Avail N） and available phosphorus （Avail P）） and enzymatic activities （soil urase and phosphomonoesterase） in both crops were improved in NS and HS treatments as compared to CS. Both bacterial and fungal biomasses in both crops were increased in NS followed by HS. Furthermore, Gram-positive bacteria （G＋） in maize soils were significant higher in NS and HS than CS, while the Gram-negative （G-） was significant higher in peanut soil. The ratio of normal saturated to monounsaturated PLFAs was significantly higher in rhizosphere of peanut under CS treatment than in any other treatments, which is an indicator of nutrient stress. Redundancy analysis and cluster analysis of PLFA showed rhizospheric microbial community of NS and HS of both plants tended to be consistent. The urase and Avail N were higher in NS and HS of both plants and positively correlated with bacteria, fungi （F） and total PLFAs, while negatively correlated with G＋/G- and NS/MS. The findings suggest that belowground interactions in maize/peanut intercropping system play important roles in changing the soil microbial composition and the dominant microbial species, which was closely related with the improving of soil available nutrients （N and P） and enzymatic activities.
In a post-hoc subgroup analysis on disease duration, we have found that participants with a short disease duration might show improved differentiation for EULAR Sjögren's Syndrome Disease Activity ...Index change from baseline improvements on active treatment versus placebo treatment (unpublished data). ...we have seen evidence of a correlation in cross-sectional cohort analysis.4Patient stratification by clinical features could be an important consideration in primary Sjögren's syndrome trials.5 In addition to TWINSS (NCT03905525), NECESSITY-IMI2 also includes a group of patients with high symptom burden alongside a group with systemic disease. ...NECESSITY-IMI2 is aiming to validate a novel composite outcome measure, the Sjögren's Tool for Assessing Response, with similar domains to the Composite of Relevant Endpoints for Sjögren's Syndrome.6 Both of these closely related measures include the EULAR Sjögren's Syndrome Disease Activity Index and EULAR Sjögren's Syndrome Patient Reported Index, potentially allowing for an improvement in either systemic disease or patient-reported outcomes to deliver a positive trial outcome.
Valuation of the EQ-5D-5L in Taiwan Lin, Hsiang-Wen; Li, Chia-Ing; Lin, Fang-Ju ...
PloS one,
12/2018, Letnik:
13, Številka:
12
Journal Article
Recenzirano
Odprti dostop
To date, a value set for the EQ-5D-5L based on the health state preferences of the general Taiwanese population has not been available. This study aimed to develop a Taiwanese value set for EQ-5D-5L ...to facilitate health technology assessment for medical products and services.
An international standardized protocol for EQ-5D-5L valuation studies developed by the EuroQol group was adopted. Adult members of the general public were recruited from six geographic regions in Taiwan. In computer-based face-to-face interviews, each participant completed 10 composite time trade-off (C-TTO) tasks and 7 discrete choice experiment (DCE) tasks. The C-TTO and DCE data were modeled alone or in combination (using hybrid models) with additive models containing 20 dummy variables as main effects. The model performance was assessed both quantitatively and qualitatively (mainly logical consistency and prediction patterns).
Of 1,073 recruited participants, 1,000 completed the study. Approximately 13% of observed utility values were -1 in the C-TTO tasks. The hybrid model, using all available data that assumed C-TTO response values left-censored at -1 and with main effects coefficients with logical consistency (monotonicity), was considered as the most appropriate model. The predicted utility ranged from -1.0259 to 1.
An EQ-5D-5L value set was developed for Taiwan using an established study protocol and a representative sample of the general population. This may facilitate health economic evaluations and decision making on resource allocation under Taiwan's national health insurance program in the future.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We propose that the use of tightly stacked three-dimensional (3D) diamond-shaped Ge nanowire (NW) gate-all-around field-effect transistor (Ge-NW GAAFET) is a feasible approach to continuous scaling. ...The proposed devices with the Al 2 O 3 dielectric exhibit high I SAT of 1200 <inline-formula> <tex-math notation="LaTeX">\boldsymbol {\mu } \text{A}/\boldsymbol {\mu } \text{m} </tex-math></inline-formula> (pFET) and 1100 <inline-formula> <tex-math notation="LaTeX">\boldsymbol {\mu } \text{A}/\boldsymbol {\mu } \text{m} </tex-math></inline-formula> (nFET), high I ON /I OFF ratio of approximately <inline-formula> <tex-math notation="LaTeX">{1} \times {10}^{{5}} </tex-math></inline-formula>, and steep subthreshold swing (SS) close to 70mV/dec. Superior gate control of the Ge-NW GAAFET was confirmed by the 3D TCAD simulation for the sub-3nm node applications. The formation of the tightly stacked Ge NWs is fully compatible with the complementary metal oxide semiconductor (CMOS) technology platform using only alternating isotropic and anisotropic dry etching, thus showing promising potential for extending CMOS scaling in the vertical direction.
Summary
The acetylation level of histones on lysine residues regulated by histone acetyltransferases and histone deacetylases plays an important but under‐studied role in the control of gene ...expression in plants. With the aim of characterizing the Arabidopsis RPD3/HDA1 family histone deacetylase HDA5, we present evidence showing that HDA5 displays deacetylase activity. Mutants defective in the expression of HDA5 displayed a late‐flowering phenotype. Expression of the flowering repressor genes FLC and MAF1 was up‐regulated in hda5 mutants. Furthermore, the gene activation markers, histone H3 acetylation and H3K4 trimethylation on FLC and MAF1 chromatin were increased in hda5‐1 mutants. Chromatin immunoprecipitation analysis showed that HDA5 binds to the chromatin of FLC and MAF1. Bimolecular fluorescence complementation assays and co‐immunoprecipitation assays showed that HDA5 interacts with FVE, FLD and HDA6, indicating that these proteins are present in a protein complex involved in the regulation of flowering time. Comparing gene expression profiles of hda5 and hda6 mutants by RNA‐seq revealed that HDA5 and HDA6 co‐regulate gene expression in multiple development processes and pathways.
Significance Statement
We found that HISTONE DEACETYLASE 5 (HDA5) and HDA6 form a HDAC repression complex with FVE and FLD involved in the regulation of flowering time in Arabidopsis.
Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.
In a multicenter noninferiority ...trial, we randomized 2037
kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m
at post-transplant month 12 using a 10% noninferiority margin.
In the intent-to-treat population (everolimus
=1022, MPA
=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%).
donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.
In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.
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