The photolysis of acetaminophen, a widely used pharmaceutical, in simulated natural organic matter solutions was investigated. The triplet states of natural organic matter (3NOM*) were found to play ...the dominant role in its photodegradation, while the contributions from hydroxyl radicals and singlet oxygen were negligible. Dissolved oxygen (DO) plays a dual role. From anaerobic to microaerobic (0.5 mg/L DO) conditions, the degradation rate of acetaminophen increased by 4–fold. That suggests the involvement of DO in reactions with the degradation intermediates. With increasing oxygen levels to saturated conditions (26 mg/L DO), the degradation rate became slower, mainly due to DO's quenching effect on 3NOM*. Superoxide radical (O2-) did not react with acetaminophen directly, but possibly quenched the intermediates to reverse the degradation process. The main photochemical pathways were shown to involve phenoxyl radical and N-radical cations, finally yielding hydroxylated derivatives, dimers and nitrosophenol. A reaction mechanism involving 3NOM*, oxygen and O2- is proposed.
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•3NOM* was the major specie accounting for indirect photolysis of acetaminophen.•Dissolved oxygen played dual roles in acetaminophen photodegradation.•O2- suppressed the photodegradation by transferring electrons to the oxidative intermediates.•The photodegradation mechanism involving 3NOM*, oxygen and O2- was proposed.
Abstract Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are playing critical roles in tumorgenesis. LncRNA ANRIL has been reported to promote tumor progression in types of ...cancers. However, the expression and function of ANRIL in cervical cancer are still largely unclear. We measured the expression of ANRIL in cervical cancer tissues and cell lines and analyzed its association with clinicopathological features and prognosis. Loss-of-function experiments were used to identify the biological function of ANRIL. Our results showed that the expression of lncRNA ANRIL was significantly increased both in cervical cancer tissues and cell lines. Patients with high ANRIL expression had advanced FIGO stage, lymph node metastasis and poor overall survival than those with low ANRIL expression. Multivariable Cox proportional hazards regression analysis suggested that high ANRIL expression was an independent prognostic factor of prognosis. Loss-of-function experiments showed that decreased expression of ANRIL inhibited cell proliferation, migration and invasion of cervical cancer. Finally, western blot indicated that the PI3K/Akt pathway was found to be inactivated in cervical cancer cells after ANRIL inhibition. These results indicated that lncRNA ANRIL might play an important role in cervical cancer progression and could serve as a novel prognostic biomarker and therapeutic target in cervical cancer.
Effective extraction is an essential step in the sensitive and accurate analysis of sulfonamides (SAs) in complex samples. In this study, based on the chemical properties of SAs, a novel ...monolith-based adsorbent using 4-vinylbenzoic acid and 4-vinylphenylboronic acid as dual-functional monomers was tailored and employed as efficient extraction phase of solid-phase microextraction. Various characterized techniques were applied to investigate the structure and morphology of the obtained adsorbent. Due to the abundant functional groups, the synthetic adsorbent displayed satisfying extraction performance for target SAs through multiple interactions including ion-exchange, B–N coordination, π-π and hydrophobic interactions. Following elution with the desorption solution of methanol/formic acid (98.5/1.5, v/v), the extractive SAs were measured by HPLC-MS/MS. Under the optimized conditions, the proposed approach exhibited wide linear ranges (0.005–10.0 μg/L for most of analytes), low limits of detection (in the range of 0.31–2.3 ng/L) and good precision (RSDs were lower than 8.0%). In the analysis of target SAs in environment waters and honey samples, the recoveries at low, medium and high spiked concentrations were in the range of 83.5–119%, and the RSDs (n = 3) varied from 0.6% to 9.6%. Compared with existing approaches, the current method presents some merits such as high sensitivity, good reproducibility, low consumptions of sample and organic solvent.
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•A novel porous monolith-based adsorbent for MMF-SPME was prepared.•Multiply interactions contributed to the effective extraction of SAs.•Various parameters affecting the extraction performance were optimized.•Highly sensitive method for the quantification of trace SAs was developed.
In a comparison of tumors from patients with melanoma who benefitted from blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) with tumors from patients who did not benefit, tumor neoantigens were ...detected that were strongly associated with a response.
Immune checkpoint blockade has led to durable antitumor effects in patients with metastatic melanoma, non–small-cell lung cancer, and other tumor types, but the factors determining whether a patient will have a response remain elusive.
1
,
2
The fully human monoclonal antibodies ipilimumab and tremelimumab block cytotoxic T-lymphocyte antigen 4 (CTLA-4), resulting in T-cell activation. Some studies have established correlations between outcomes with ipilimumab and peripheral-blood lymphocyte count, markers of T-cell activation,
3
an “inflammatory” microenvironment,
4
,
5
and maintenance of high-frequency T-cell receptor clonotypes.
6
The relationship among the genomic landscape of the tumor, the mutational load, and the benefit from treatment remains obscure. . . .
Indoleamine 2,3-dioxygenase (IDO) has been described as a major mechanism of immunosuppression in tumors, though the mechanisms of this are poorly understood. Here, we find that expression of IDO by ...tumor cells results in aggressive tumor growth and resistance to T-cell-targeting immunotherapies. We demonstrate that IDO orchestrates local and systemic immunosuppressive effects through recruitment and activation of myeloid-derived suppressor cells (MDSCs), through a mechanism dependent on regulatory T cells (Tregs). Supporting these findings, we find that IDO expression in human melanoma tumors is strongly associated with MDSC infiltration. Treatment with a selective IDO inhibitor in vivo reversed tumor-associated immunosuppression by decreasing numbers of tumor-infiltrating MDSCs and Tregs and abolishing their suppressive function. These findings establish an important link between IDO and multiple immunosuppressive mechanisms active in the tumor microenvironment, providing a strong rationale for therapeutic targeting of IDO as one of the central regulators of immune suppression.
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•Tumor IDO mediates local/systemic immunosuppression and resistance to immunotherapy•IDO expression in human and mouse tumors is associated with MDSC infiltration•Tumor IDO induces immunosuppression by expanding, recruiting, and activating MDSCs•Tumor-IDO-mediated recruitment and activation of MDSCs are Treg dependent
IDO mediates immune inhibition in tumors, though the mechanisms of this are poorly understood. Holmgaard et al. demonstrate that tumor IDO is a central regulator of both local and systemic immunosuppression and resistance to immunotherapy, which is orchestrated through expansion, recruitment, and activation of MDSCs in a Treg-dependent manner.
Rose Bengal dye has been successfully integrated into the skeleton of a conjugated microporous polymer via palladium-catalyzed Sonogashira–Hagihara cross-coupling polycondensation. These polymers are ...stable in various solvents, including concentrated hydrochloric acid, and are thermally stable. The resulting polymers show substantial porosity and are highly active for heterogeneous photocatalytic aza-Henry reactions at room temperature for a wide range of substrates. Moreover, this noble-metal-free photocatalyst shows robust recycling capability with good retention of photoactivity over 10 cycles without significant loss of conversion (<10%). These data show that dye-functionalized conjugated microporous polymers are stable, highly active, and reusable noble-metal-free heterogeneous photo-organocatalysts.
•Viral recombination is common and contributes to genetic heterogeneity and integrity.•Phylogeny incongruence exists in papillomavirus and hints recombination.•Unbalance of theoretical support and ...actual evidence exists on recombination in HPV.•Recombination in HPV may impact genotyping and vaccination.
Papillomaviruses (PV) have a wide distribution of hosts, among which human papillomavirus (HPV) has been recognized as the major cause of cervical cancer. HPV is characterized by its high genetic variability with more than 200 genotypes identified, and numerous variants exist within the same genotype. Though phylogenetic incongruence between early gene and late gene of PVs was observed, the recombination in HPV was not taken seriously until the last two decades. The first report of evidence on HPV recombination was published in 2006, in which only intertypic ancient recombination events were identified. Since then, several publications on recombination in HPV provided evidence for intertypic as well as intratypic recombination. Recombination may create challenges on HPV genotyping and vaccination that could cause a great impact in screening and prevention of cervical cancer. Here, we review the literature on recombination and summarize the reasons underlying the difficulties for detecting recombination in HPV. In addition, we analyze the potential consequences of HPV recombination and make further prospects for clinical practice in the future.
Modulating T cell homeostatic mechanisms with checkpoint blockade can efficiently promote endogenous anti-tumor T cell responses
. However, many patients still do not benefit from checkpoint blockade
..., highlighting the need for targeting of alternative immune pathways
. Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is an attractive target for immunotherapy, owing to its capacity to promote effector T cell (T
) functions
and hamper regulatory T cell (T
) suppression
. On the basis of the potent preclinical anti-tumor activity of agonist anti-GITR antibodies, reported by us and others
, we initiated the first in-human phase 1 trial of GITR agonism with the anti-GITR antibody TRX518 ( NCT01239134 ). Here, we report the safety profile and immune effects of TRX518 monotherapy in patients with advanced cancer and provide mechanistic preclinical evidence to rationally combine GITR agonism with checkpoint blockade in future clinical trials. We demonstrate that TRX518 reduces circulating and intratumoral T
cells to similar extents, providing an easily assessable biomarker of anti-GITR activity. Despite T
reductions and increased T
:T
ratios, substantial clinical responses were not seen. Similarly, in mice with advanced tumors, GITR agonism was not sufficient to activate cytolytic T cells due to persistent exhaustion. We demonstrate that T cell reinvigoration with PD-1 blockade can overcome resistance of advanced tumors to anti-GITR monotherapy. These findings led us to start investigating TRX518 with PD-1 pathway blockade in patients with advanced refractory tumors ( NCT02628574 ).
Plastid-to-nucleus retrograde signaling is critical for normal growth and development in plants. The dualfunction and dual-located ssDNA binding protein WHIRLY1 （WHY1） has been proposed to coordinate ...the retrograde signaling from plastids to the nucleus. However, the regulatory mechanism governing the functional switch of WHY1 for mediating plastid-to-nucleus retrograde signaling remains unknown. Here, we report that the Calcineurin B-Like-Interacting Protein Kinase14 （CIPK14） interacts with and phosphorylates WHY1 in Arabidopsis. Phosphorylation of WHY1 results in increased accumulation in the nucleus and enhanced binding with the promoter of WRKY53, which encodes a key transcription factor regulating leaf senescence in Arabidopsis. Transgenic plants overexpressing CIPK14 showed an increased nuclear isoform but decreased plastid isoform of WHY1, among which 95% of transgenic lines showed the stay-green phenotype and 5% of lines showed the variegated pale-green phenotype. Interestingly, the phenotypes of both types of transgenic plants could be recovered by overexpression of plastid-form WHY1. In contrast, knockdown of ClPK14 caused early senescence and even seedling-lethal phenotypes along with elevated expression of senescence-related genes such as WRKY53, SAG12, and NDHF but decreased expression of MER11, RAD50, and POR genes, which could be rescued by overexpression of CIPK14 but not by overexpressing plastid-form or nuclear-form WHY1; the stay-green plants overexpressing ClPK14 showed reduced expression of WRKY53, SAG12, NDHF, and large plastid rRNA. Consistently, the accu- mulation of nuclear-form WHY1 was significantly reduced in the CIPK14 knockdown lines, resulting in a low ratio of nuclear-/plastid-form WHY1. Taken together, our results demonstrate that CIPK14 regu- lates the phosphorylation and organeUar distributions of WHY1 and pinpoint that ClPK14 may function as a cellular switch between leaf senescence and plastid development for coordinating the intercellular signaling in Arabidopsis.
Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the ...heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.
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•Most small cell lung cancer (SCLC) tumors share a small PLCG2-high subpopulation•This PLCG2-high SCLC subpopulation is linked to metastasis and poor prognosis•SCLC is enriched in profibrotic and immunosuppressive monocytes/macrophages•The presence of myeloid cells is associated with the PLCG2-high SCLC subpopulation
Chan et al. use single-cell transcriptome sequencing and imaging techniques to study the heterogeneity and tumor microenvironment of clinical small cell lung cancer specimens. This analysis identifies a PLCG2-high-expressing subpopulation linked to metastasis and poor prognosis, and an enrichment of a monocyte/macrophage population with a profibrotic, immunosuppressive phenotype.
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