PD-1 blockade plus COX inhibitors in dMMR metastatic colorectal cancer: Clinical, genomic, and immunologic analyses from the PCOX trial.

BACKGROUND: Approximately 20% of patients with DNA mismatch repair deficiency (dMMR) metastatic colorectal cancer do not respond to anti-programmed death-1 (PD-1) ligand therapy, and baseline biomarkers of response are lacking. METHODS: We conducted a phase 2 study to evaluate the efficacy of cyclooxygenase (COX) inhibitors in combination with anti-PD-1 therapy in patients with dMMR metastatic colorectal cancer. The primary endpoint was objective response rate. The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate, duration of response, and safety. FINDINGS: A total of 30 patients were enrolled, and the objective response rate was 73.3%, meeting the predefined endpoint of 68%. The median PFS and median OS were not reached at a median follow-up period of 50.8 months. Disease control was achieved in 28 patients (93.3%). The median duration of response was not reached. The combination was well tolerated. Multiomics analysis revealed that the antigen processing and presentation pathway was positively associated with treatment response and PFS. Higher TAPBP expression was predictive of better PFS (log-rank p = 0.003), and this prognostic significance was confirmed in an immunotherapy validation cohort. CONCLUSIONS: Thus, COX inhibitors combined with PD-1 blockade may be effective and safe treatment options for patients with dMMR metastatic colorectal cancer, and TAPBP may serve as a biomarker for immune checkpoint inhibitor therapy (this study was registered at ClinicalTrials.gov: NCT03638297). FUNDING: Funded by the National Natural Science Foundation of China (81974369) and the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004).

RNA-binding protein QKI promotes the progression of HCC by interacting with long non-coding RNA EGOT.

BACKGROUND: RNA-binding proteins are revealed to play important roles during the progression of hepatocellular carcinoma (HCC). However, the regulatory mechanisms of RNA-binding protein Quaking (QKI) in the expression and role of long non-coding RNAs (lncRNAs) in HCC cells remain not well understood. METHODS: Cell Counting Kit-8, wound-healing, Transwell and colony-forming assays were performed to evaluate the effects of QKI and lncRNA EGOT on proliferation and migration of HCC cells. Tumor growth of HCC was analyzed using a mouse xenograft model. Immunoprecipitation (RIP) assay was used to investigate the interaction between QKI and EGOT. RESULTS: The expression of QKI was significantly upregulated in HCC tissues and the higher QKI level was significantly associated with a poorer prognosis. Overexpression of QKI promoted the proliferation, migration, and colony-forming ability of HCC cells in vitro and tumor growth of HCC in vivo. Mechanistically, QKI protein could bind to EGOT RNA and increase its expression. Inhibition of EGOT attenuated the effects of QKI on the malignant phenotypes of HCC cells. In addition, both QKI and EGOT could activate the SAPK/JNK signaling pathway in HCC cells. CONCLUSIONS: Our findings indicated that QKI exerted promotive effects on the malignant phenotypes of HCC through its interaction with EGOT.

Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

Near-Infrared Perylenecarboximide Fluorophores for Live-Cell Super-Resolution Imaging.

Organic near-infrared (NIR) photoblinking fluorophores are highly desirable for live-cell super-resolution imaging based on single-molecule localization microscopy (SMLM). Herein we introduce a novel small chromophore, PMIP, through the fusion of perylenecarboximide with 2,2-dimetheylpyrimidine. PMIP exhibits an emission maximum at 732 nm with a high fluorescence quantum yield of 60% in the wavelength range of 700-1000 nm and excellent photoblinking without any additives. With resorcinol-functionalized PMIP (PMIP-OH), NIR SMLM imaging of lysosomes is demonstrated for the first time in living mammalian cells under physiological conditions. Moreover, metabolically labeled nascent DNA is site-specifically detected using azido-functionalized PMIP (PMIP-N3) via click chemistry, thereby enabling the super-resolution imaging of nascent DNA in phosphate-buffered saline with a 9-fold improvement in spatial resolution. These results indicate the potential of PMIP-based NIR blinking fluorophores for biological applications of SMLM.

Stable π-Extended Thio[7]helicene-Based Diradical with Predominant Through-Space Spin-Spin Coupling.

In this work, a novel π-extended thio[7]helicene scaffold was synthesized, where the α-position of the thiophene unit could be functionalized with bulky phenoxy radicals after considerable synthetic attempts. This open-shell helical diradical, ET7H-R, possesses high stability in the air, nontrivial π conjugation, persistent chirality, and a high diradical character (y0 of 0.998). The key feature is a predominant through-space spin-spin coupling (TSC) between two radicals at the helical terminals. Variable-temperature continuous-wave electron spin resonance (cw-ESR) and superconducting quantum interference device (SQUID) magnetometry in the solid state reveal a singlet ground state with a nearly degenerate triplet state of ET7H-R. These results highlight the significance of a stable helical diradicaloid as a promising platform for investigating intramolecular TSCs.

Function and mechanism of TREM2 in bacterial infection.

Triggering receptor expressed on myeloid cells 2 (TREM2), which is a lipid sensing and phagocytosis receptor, plays a key role in immunity and inflammation in response to pathogens. Here, we review the function and signaling of TREM2 in microbial binding, engulfment and removal, and describe TREM2-mediated inhibition of inflammation by negatively regulating the Toll-like receptor (TLR) response. We further illustrate the role of TREM2 in restoring organ homeostasis in sepsis and soluble TREM2 (sTREM2) as a diagnostic marker for sepsis-associated encephalopathy (SAE). Finally, we discuss the prospect of TREM2 as an interesting therapeutic target for sepsis.

Targeting the NAT10/NPM1 axis abrogates PD-L1 expression and improves the response to immune checkpoint blockade therapy.

BACKGROUND: PD-1/PD-L1 play a crucial role as immune checkpoint inhibitors in various types of cancer. Although our previous study revealed that NPM1 was a novel transcriptional regulator of PD-L1 and stimulated the transcription of PD-L1, the underlying regulatory mechanism remains incompletely characterized. METHODS: Various human cancer cell lines were used to validate the role of NPM1 in regulating the transcription of PD-L1. The acetyltransferase NAT10 was identified as a facilitator of NPM1 acetylation by coimmunoprecipitation and mass spectrometry. The potential application of combined NAT10 inhibitor and anti-CTLA4 treatment was evaluated by an animal model. RESULTS: We demonstrated that NPM1 enhanced the transcription of PD-L1 in various types of cancer, and the acetylation of NPM1 played a vital role in this process. In particular, NAT10 facilitated the acetylation of NPM1, leading to enhanced transcription and increased expression of PD-L1. Moreover, our findings demonstrated that Remodelin, a compound that inhibits NAT10, effectively reduced NPM1 acetylation, leading to a subsequent decrease in PD-L1 expression. In vivo experiments indicated that Remodelin combined with anti-CTLA-4 therapy had a superior therapeutic effect compared with either treatment alone. Ultimately, we verified that the expression of NAT10 exhibited a positive correlation with the expression of PD-L1 in various types of tumors, serving as an indicator of unfavorable prognosis. CONCLUSION: This study suggests that the NAT10/NPM1 axis is a promising therapeutic target in malignant tumors.

Biomarkers of Pathologic Complete Response to Neoadjuvant Immunotherapy in Mismatch Repair-Deficient Colorectal Cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) have become the standard of care for patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer. However, biomarkers of response to ICI are still lacking. EXPERIMENTAL DESIGN: Forty-two patients with dMMR colorectal cancer treated with neoadjuvant PD-1 blockade were prospectively enrolled. To identify biomarkers of pathologic complete response (pCR) to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles based on next-generation sequencing, and immune cell density based on multiplex immunofluorescence (mIF) staining. An integrated analysis of single-cell RNA sequencing from our previous study and GSE178341, as well as mIF was performed to further explore the significance of the tumor microenvironment (TME) on pCR response. RESULTS: The tumor mutation burden of both tumor tissue and plasma blood samples was comparable between the pCR and non-pCR groups, while HLA-DQA1 and HLA-DQB1 were significantly overexpressed in the pCR group. Gene signature enrichment analysis showed that pathways including T-cell receptor pathway, antigen presentation pathway were significantly enriched in the pCR group. In addition, higher pre-existing CD8+ T-cell density was associated with pCR response (767.47 per.mm2 vs. 326.64 per.mm2, P = 0.013 Wilcoxon test). Further integrated analysis showed that CD8+ T cells with low PD-1 expression (PD-1lo CD8+ T cells) expressing high levels of TRGC2, CD160, and KLRB1 and low levels of proliferated and exhausted genes were significantly associated with pCR response. CONCLUSIONS: Immune-associated transcriptomic features, particularly CD8+ T cells were associated with pCR response to ICI in dMMR colorectal cancer. Heterogeneity of TME within dMMR colorectal cancer may help to discriminate patients with complete response to neoadjuvant ICI.

High-Performance Near-Infrared Chlorinated Rylenecarboximide Fluorophores via Consecutive C-N and C-C Bond Formation.

A new class of near-infrared (NIR) fluorophores, PAI, is obtained by consecutive C-N/C-C bond formation between diphenylamines and 9,10-dibromoperylenecarboximide. Owing to the rigid structure, extended π-conjugation and pronounced push-pull substitution, these fluorophores show emission maxima up to 804 nm and large Stokes shifts. The extraordinarily high fluorescence quantum yields from 47 % to 70 % are attributed to chloro substitution in the bay positions of the perylene core. These characteristics, together with high photostability, qualify them as useful NIR emitters for applications as biomarkers and security inks.

A Terrylene-Anthraquinone Dyad as a Chromophore for Photothermal Therapy in the NIR-II Window.

A terrylenedicarboximide-anthraquinone dyad, FTQ, with absorption in the second near-infrared region (NIR-II) is obtained as a high-performance chromophore for photothermal therapy (PTT). The synthetic route proceeds by C-N coupling of amino-substituted terrylenedicarboximide (TMI) and 1,4-dichloroanthraquinone followed by alkaline-promoted dehydrocyclization. FTQ with extended π-conjugation exhibits an optical absorption band peaking at 1140 nm and extending into the 1500 nm range. Moreover, as determined by dielectric spectroscopy in dilute solutions, FTQ achieves an ultrastrong dipole moment of 14.4 ± 0.4 Debye due to intense intramolecular charge transfer. After encapsulation in a biodegradable polyethylene glycol (DSPE-mPEG2000), FTQ nanoparticles (NPs) deliver a high photothermal conversion efficiency of 49% under 1064 nm laser irradiation combined with excellent biocompatibility, photostability, and photoacoustic imaging capability. In vitro and in vivo studies reveal the great potential of FTQ NPs in photoacoustic-imaging-guided photothermal therapy for orthotopic liver cancer treatment in the NIR-II window.

Self-engineered binary nanoassembly enabling closed-loop glutathione depletion-amplified tumor ferroptosis.

Ferroptosis has emerged as a promising target for anticancer treatment, comprising iron-dependent lipid peroxidation and excessive accumulation of reactive oxygen species. Given that glutathione (GSH) overproduced in tumor cells antagonizes the cellular oxidation system, the reduction of GSH production has been extensively explored to induce ferroptosis. However, reducing GSH production alone is insufficient to trigger an intense lipid peroxidation storm. It is highly desirable to achieve systemic GSH depletion through simultaneous production and consumption intervention. Herein, we propose a bidirectional blockage strategy for closed-loop GSH depletion-amplified tumor ferroptosis. Sorafenib (Sor) and gambogic acid (GA) were elaborately fabricated as a self-engineered carrier-free nanoassembly without any nanocarrier materials. The PEGylated dual-drug nanoassembly enables favorable co-delivery and tumor-specific release of Sor and GA. Notably, a closed-loop GSH depletion is observed as a result of a Sor-induced decrease in GSH production and GA-accelerated GSH consumption in vitro and in vivo. As expected, this uniquely engineered dual-drug nanoassembly demonstrates vigorous antitumor activity in 4T1 breast tumor-bearing mice. This study presents a novel nanotherapeutic modality for ferroptosis-driven cancer treatment.

Adsorption properties of corn starch modified by malt amylases and crosslinking agents: A comparison between sodium trimetaphosphate and organic acids.

In order to investigate the effects of different crosslinking agents on physicochemical properties and adsorption properties of porous starch. Native corn starch was hydrolyzed by maltase and crosslinked with different crosslinking agents. Sodium trimetaphosphate crosslinked porous starch (STMP-MPS), malic acid cross-linked porous starch (MA-MPS) and citric acid cross-linked porous starch (CA-MPS) were prepared. After crosslinking, MA-MPS and CA-MPS showed a new CO stretching absorption peak at 1738 cm-1, and the crosslinking degree was much higher than that of STMP-MPS. The surface area of MA-MPS was 36 % higher than that of STMP-MPS. Compared with the average pore size of 12.43 nm of STMP-MPS, CA-MPS (14.02 nm) and MA-MPS (14.79 nm) were increased more significantly. The degradation temperature of MA-MPS and CA-MPS was increased by the introduction of ester bond, which indicates that the organic acid cross-linking strengthens the starch granules and hence more energy is required for disruption. Compared with STMP-MPS, the water absorption of MA-MPS and CA-MPS increased by 64 % and 32 %, respectively. Furthermore, the adsorption capacity of MA-MPS to essential oil was the strongest, about 4 times that of STMP-MPS. Overall, it is feasible to modify porous starch by crosslinking reaction to improve its heat resistance and adsorption properties.

Tespa1 deficiency reduces the antitumour immune response by decreasing CD8+T cell activity in a mouse Lewis lung cancer model.

Thymocyte-expressed, positive selection-associated 1 (Tespa1) is a key molecule in T-cell development and has been linked to immune diseases. However, its role in antitumour CD8+T cell immunity remains unclear. Here, we demonstrated that Tespa1 plays an important role in antitumour CD8+T cell immunity. First, compared with wild-type (WT) mice, Lewis lung cancer cells grew faster in Tespa1 knockout (Tespa1-/-) mice, with reduced apoptosis, and decreased CD8+T cells in peripheral blood and tumor tissues. Second, the proportion of CD8+T and Th1 cells in the splenocytes of Tespa1-/- mice was lower than that in WT mice. Third, Tespa1-/- CD8+ tumor-infiltrating lymphocytes (TILs) showed weakened proliferation, invasion, cytotoxicity, and protein expression of IL-2 signalling pathway components compared to WT CD8+TILs. Furthermore, PD-1 expression in CD8+TILs was higher in Tespa1-/- than in WT mice. Lastly, CD8+TILs in WT mice improved the antitumour ability of Tespa1-/- mice. In conclusion, these findings suggest that Tespa1 plays a critical role in the tumor immune system by regulating CD8+T cells.

Effects of polyols with different hydroxyl numbers on the structure and properties of starch straws.

To study the relationship between the number of hydroxyl groups of polyols and the plasticizing effect, the effects of different polyols including ethylene glycol, glycerol, erythritol, xylitol and sorbitol on the structure and properties of corn starch straws were analyzed and compared. The results showed that the addition of plasticizer significantly improved the performance of starch straws, which greatly improved the mechanical properties, water absorption rate (WAR) and thermal stability. However, there was no linear relationship between the plasticizing effect on starch straws and the number of hydroxyl groups in plasticizers. Fourier transform infrared (FTIR) results showed that erythritol formed the strongest intermolecular interaction with starch. Starch straws with erythritol (S-ERY) had the highest bending force (Fb = 25.78 N) and the lowest WAR. Starch straws with glycerol (S-GLY) showed the lowest relative crystallinity (RC = 12.87 %) and the highest temperature of the maximum degradation (Tdmax = 302.1 °C). In addition, after storing for 180 days, S-GLY showed higher modulus of elasticity in bending (Eb = 4.26 N/cm) and a uniform surface.

Prior Knowledge Uses Prestimulus Alpha Band Oscillations and Persistent Poststimulus Neural Templates for Conscious Perception.

Prior knowledge has a profound impact on the way we perceive the world. However, it remains unclear how the prior knowledge is maintained in our brains and thereby influences the subsequent conscious perception. The Dalmatian dog illusion is a perfect tool to study prior knowledge, where the picture is initially perceived as noise. Once the prior knowledge was introduced, a Dalmatian dog could be consciously seen, and the picture immediately became meaningful. Using pictures with hidden objects as standard stimuli and similar pictures without hidden objects as deviant stimuli, we investigated the neural representation of prior knowledge and its impact on conscious perception in an oddball paradigm using electroencephalogram (EEG) in both male and female human subjects. We found that the neural patterns between the prestimulus alpha band oscillations and poststimulus EEG activity were significantly more similar for the standard stimuli than for the deviant stimuli after prior knowledge was provided. Furthermore, decoding analysis revealed that persistent neural templates were evoked after the introduction of prior knowledge, similar to that evoked in the early stages of visual processing. In conclusion, the current study suggests that prior knowledge uses alpha band oscillations in a multivariate manner in the prestimulus period and induces specific persistent neural templates in the poststimulus period, enabling the conscious perception of the hidden objects.SIGNIFICANCE STATEMENT The visual world we live in is not always optimal. In dark or noisy environments, prior knowledge can help us interpret imperfect sensory signals and enable us to consciously perceive hidden objects. However, we still know very little about how prior knowledge works at the neural level. Using the Dalmatian dog illusion and multivariate methods, we found that prior knowledge uses prestimulus alpha band oscillations to carry information about the hidden object and exerts a persistent influence in the poststimulus period by inducing specific neural templates. Our findings provide a window into the neural underpinnings of prior knowledge and offer new insights into the role of alpha band oscillations and neural templates associated with conscious perception.

The association of targets modulates the search efficiency in multitarget searches.

Previous studies have found that distractors can affect visual search efficiency when associated with the target in a single-target search. However, multitarget searches are frequently necessary in daily life. In the present study, we examined how the association of targets in a multitarget search affected performance when searching for two targets simultaneously (Experiment 1). In addition, we explored whether the association affected switch cost (Experiment 2) and preparation cost (Experiment 3). Participants were required to learn associations between different colors or shapes and then performed feature search and conjunction search tasks. For all experiments, the results of search efficiency showed that for conjunction search, the search efficiency under the associated condition was significantly higher than that under the neutral condition. Similarly, the response times in the associated condition were significantly faster than those in the neutral condition under the conjunction search condition in Experiments 1 and 2. However, in Experiment 3, the response times in the associated condition were longer than those in the neutral condition. These results indicate that the association between targets can improve the efficiency of multitarget searches. Furthermore, associations can reduce the time spent searching for individual targets and the switch cost; however, the preparation cost increases.

The speed and temporal frequency of visual apparent motion modulate auditory duration perception.

In the present study, we investigated how the perception of auditory duration could be modulated by a task-irrelevant, concurrent visual apparent motion, induced by visual bars alternating between left and right sides. Moreover, we examined the influence of the speed and temporal frequency of visual apparent motion on the perception of auditory duration. In each trial, the standard visual stimuli (two vertical bars) were presented sequentially, except that visual apparent motion was included in the fourth stimulus. A tone was presented simultaneously with each visual stimulus, while the fourth tone was presented with varied duration. Participants judged whether the fourth tone lasted longer than the other four tones. In Experiment 1, the speed of visual apparent motion (Fast vs. Slow) was manipulated by changing the interval between two bars. The mean point of subjective equality (PSE) in the Slow apparent motion condition was larger than that in the Static condition. Moreover, participants tended to overestimate the duration only in the Static condition, i.e., time dilation effect, which disappeared under apparent motion conditions. In Experiment 2, in addition to speed, we controlled the temporal frequency of apparent motion by manipulating the number of bars, generating four conditions of visual apparent motion (Physical-fast, Perceived-fast, Perceived-slow, vs. Static). The mean PSE was significantly smaller in the Physical-fast condition than in the Static and Perceived-slow conditions. Moreover, we found a time compression effect in both the Perceived-slow and Static conditions but not in the Perceived-fast and Physical-fast conditions. These results suggest that the auditory duration could be modulated by the concurrent, contextual visual apparent motion, and both the speed and temporal frequency of the task-irrelevant visual apparent motion contribute to the bias in perceiving the auditory duration.

Twisted Diindeno-Fused Dibenzo[a,h]anthracene Derivatives and their Dianions.

We report a facile synthesis of diindeno-fused dibenzo[a,h]anthracene derivatives (DIDBA-2Cl, DIDBA-2Ph, and DIDBA-2H) with different degrees of non-planarity using three substituents (chloro, phenyl, and hydrogen) of various sizes. The planarization of their cores, as evidenced by the decreased end-to-end torsional angles, was confirmed by X-ray crystallography. Their enhanced energy gaps with twisting were investigated by a combination of spectroscopic and electrochemical methods with density functional theory, which showed a transition from singlet open-shell to closed-shell configuration. Moreover, their doubly reduced states, DIDBA-2Ph2- and DIDBA-2H2- , were achieved by chemical reduction. The structures of dianions were identified by X-ray crystallographic analysis, which elucidated that the electron charging further distorted the backbones. The electronic structure of the dianions was demonstrated by experimental and theoretical approaches, suggesting decreased energy gaps with larger non-planarity, different from the neutral species.

Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer.

Immune checkpoint inhibitor (ICI) therapy can induce complete responses in mismatch repair-deficient and microsatellite instability-high (d-MMR/MSI-H) colorectal cancers (CRCs). However, the underlying mechanism for pathological complete response (pCR) to immunotherapy has not been completely understood. We utilize single-cell RNA sequencing (scRNA-seq) to investigate the dynamics of immune and stromal cells in 19 patients with d-MMR/MSI-H CRC who received neoadjuvant PD-1 blockade. We found that in tumors with pCR, there is a concerted decrease in CD8+ Trm-mitotic, CD4+ Tregs, proinflammatory IL1B+ Mono and CCL2+ Fibroblast following treatment, while the proportions of CD8+ Tem, CD4+ Th, CD20+ B, and HLA-DRA+ Endothelial cells increase. Proinflammatory features in the tumor microenvironment mediate the persistence of residual tumors by modulating CD8+ T cells and other response-associated immune cell populations. Our study provides valuable resources and biological insights into the mechanism of successful ICI therapy and potential targets for improving treatment efficacy.