Abstract
The immediate processing of whole blood specimen is required in circulating tumor cell-based liquid biopsy. Reliable blood specimen stabilization towards preserving circulating tumor cells ...can enable more extensive geographic sharing for precise rare-cell technology, but remains challenging due to the fragility and rarity of circulating tumor cells. Herein, we establish a zwitterionic magnetic microgel platform to stabilize whole blood specimen for long-term hypothermic preservation of model circulating tumor cells. We show in a cohort study of 20 cancer patients that blood samples can be preserved for up to 7 days without compromising circulating tumor cell viability and RNA integrity, thereby doubling the viable preservation duration. We demonstrate that the 7-day microgel-preserved blood specimen is able to reliably detect cancer-specific transcripts, similar to fresh blood specimens, while there are up/down expression regulation of 1243 genes in model circulating tumor cells that are preserved by commercial protectant. Mechanistically, we find that the zwitterionic microgel assembly counters the cold-induced excessive reactive oxygen species and platelet activation, as well as extracellular matrix loss-induced cell anoikis, to prevent circulating tumor cell loss in the whole blood sample. The present work could prove useful for the development of blood-based noninvasive diagnostics.
Helicobacter pylori (H. pylori) is the predominant etiological agent of gastritis and disrupts the integrity of the gastric mucosal barrier through various pathogenic mechanisms. After H. pylori ...invades the gastric mucosa, it interacts with immune cells in the lamina propria. Macrophages are central players in the inflammatory response, and H. pylori stimulates them to secrete a variety of inflammatory factors, leading to the chronic damage of the gastric mucosa. Therefore, the study aims to explore the mechanism of gastric mucosal injury caused by inflammatory factors secreted by macrophages, which may provide a new mechanism for the development of H. pylori-related gastritis.
The expression and secretion of CCL3 from H. pylori infected macrophages were detected by RT-qPCR, Western blot and ELISA. The effect of H. pylori-infected macrophage culture medium and CCL3 on gastric epithelial cells tight junctions were analyzed by Western blot, immunofluorescence and transepithelial electrical resistance. EdU and apoptotic flow cytometry assays were used to detect cell proliferation and apoptosis levels. Dual-luciferase reporter assays and chromatin immunoprecipitation assays were used to study CCL3 transcription factors. Finally, gastric mucosal tissue inflammation and CCL3 expression were analyzed by hematoxylin and eosin staining and immunohistochemistry.
After H. pylori infection, CCL3 expressed and secreted from macrophages were increased. H. pylori-infected macrophage culture medium and CCL3 disrupted gastric epithelial cells tight junctions, while CCL3 neutralizing antibody and receptor inhibitor of CCL3 improved the disruption of tight junctions between cells. In addition, H. pylori-infected macrophage culture medium and CCL3 recombinant proteins stimulated P38 phosphorylation, and P38 phosphorylation inhibitor improved the disruption of tight junctions between cells. Besides, it was identified that STAT1 was a transcription factor of CCL3 and H. pylori stimulated macrophage to secret CCL3 through the JAK1-STAT1 pathway. Finally, after mice were injected with murine CCL3 recombinant protein, the gastric mucosal injury and inflammation were aggravated, and the phosphorylation level of P38 was increased.
In summary, our findings demonstrate that H. pylori infection stimulates macrophages to secrete CCL3 via the JAK1-STAT1 pathway. Subsequently, CCL3 damages gastric epithelial tight junctions through the phosphorylation of P38. This may be a novel mechanism of gastric mucosal injury in H. pylori-associated gastritis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: Hepatocellular carcinoma (HCC) (about 85–90% of primary liver cancer) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. HCC is the fourth ...most common malignancy and the third leading cause of tumor-related deaths in China. It poses a significant threat to the life and health of Chinese people. Summary: This guideline presents official recommendations of the National Health and Family Planning Commission of the People’s Republic of China on the surveillance, diagnosis, staging, and treatment of HCC occurring in China. The guideline was written by more than 50 experts in the field of HCC in China (including liver surgeons, medical oncologists, hepatologists, interventional radiologists, and diagnostic radiologists) on the basis of recent evidence and expert opinions, balance of benefits and harms, cost-benefit strategies, and other clinical considerations. Key Messages: The guideline presents the Chinese staging system, and recommendations regarding patients with HCC in China to ensure optimum patient outcomes.
Two metal‐free radical annulation‐hydrofunctionalization cascades of 1,6‐enynes have been established, enabling the complete stereoselectivity to access a wide range of functionalized (E)‐1‐indanones ...with moderate to good yields. The reaction pathways involve in situ‐generated P‐ or S‐centered radical‐triggered α,β‐conjugated addition/5‐exo‐dig cyclization/H‐ion sequence, allowing direct and versatile protocols for stereoselective construction of 1‐indanone scaffolds with high functional group tolerance and wide substrate scope.
Two metal‐free radical annulation‐hydrofunctionalization cascades of 1,6‐enynes have been established, enabling the complete stereoselectivity to access a wide range of functionalized (E)‐1‐indanones with moderate to good yields.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Forging and welding are common necessary procedures for AA6××× alloys, and recrystallization is an inevitable process. However, it is still difficult to realize the control of the recrystallization ...behavior, while realizing the strengthening of mechanical properties of the base metal and welded joint. In this study, we overcome this problem through 0.5 wt% TiC–TiB2 nanoparticles, and fully reveal the influence of the nanoparticles on the recrystallization behavior of the base metal and nugget zone of a friction-stir-welded (FSW)-ed joint from the perspectives of dislocation rearrangement and grain boundary motion. The strengthening mechanisms of the base metal and FSW-ed joint are clarified. The recrystallization driving force of the base metal and nugget zone was increased. Dislocations with a higher density rearranged and formed more grain boundaries in the nugget zone. Besides, nanoparticles distributed on the grain boundaries restrained the vanishing of low-angle grain boundaries. The nugget zone microstructures were refined from 3.1 to 2.3 μm, and the recrystallization ratio was increased from 7.2% to 10.4% at 800 rpm. The grains in the nugget zone were refined from 2.2 to 1.9 μm, and the recrystallization ratio was increased from 16.1% to 18.4% at 1200 rpm. The promoted recrystallization in the nugget zone accelerated the release of stress. Nanoparticles weakened the precipitate coarsening in the nugget zone. After strengthening, the ultimate tensile strength and plastic strain of the FSW-ed joint at 800 rpm were increased by 4.7% and 18.8%, respectively. This study provides new approaches for a systematic microstructure evolution control in FSW-ed 6061 Al alloys.
•Trace nanoparticles double the recrystallization driving force of base metal.•More dislocation tangles promoted recrystallization of nugget zone.•Nanoparticle also inhibited grain coarsening of nugget zone.•Precipitate coarsening in the nugget zone was weakened.•FSW-ed joint softening was alleviated and the mechanical properties were enhanced.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Substrate-controlled generation of 3-sulfonylated 1-indenones and 3-arylated (Z)-indenes through radical cyclization cascades of o-alkynylbenzonitriles with sulfonyl hydrazides was established by ...combining copper(II) with tert-butyl hydroperoxide (TBHP) as a catalytic oxidative system. With the installation of the aryl group (R1) into the alkynyl unit, sulfonyl radicals triggered addition–cyclization cascades to access 3-sulfonylated 1-indenones with good yields by using a Cu/TBHP system, whereas a series of new functionalized 3-arylated (Z)-indenes were obtained in good yields when o-alkynylbenzonitriles bearing the alkyl group in the alkynyl unit were subjected with arylsulfonyl hydrazides with an electron-rich nature under the above conditions.
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IJS, KILJ, NUK, PNG, UL, UM
It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) ...patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM.
This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio OR 0.70; 95% confidence intervals CI 0.30, 1.67, Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI 0.37, 1.83, Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range IQR, 50.0, 69.7 versus 55.0%, IQR 42.8, 63.8, Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR 12.8, 40.5), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio HR 0.74, 95% CI 0.50, 1.11, Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection.
The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity.
ClinicalTrials.gov Identifier: NCT03493048.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Oxidative stress is an early event in the development of Alzheimer's disease (AD) and maybe a pivotal point of interaction governing AD pathogenesis; oxidative stress contributes to ...metabolism imbalance, protein misfolding, neuroinflammation and apoptosis. Excess reactive oxygen species (ROS) are a major contributor to oxidative stress. As vital sources of ROS, mitochondria are also the primary targets of ROS attack. Seeking effective avenues to reduce oxidative stress has attracted increasing attention for AD intervention.
Methods
We developed liposome‐packaged Ligustilide (LIG) and investigated its effects on mitochondrial function and AD‐like pathology in the APPswe/PS1dE9 (APP/PS1) mouse model of AD, and analyzed possible mechanisms.
Results
We observed that LIG‐loaded liposome (LIG‐LPs) treatment reduced oxidative stress and β‐amyloid (Aβ) deposition and mitigated cognitive impairment in APP/PS1 mice. LIG management alleviated the destruction of the inner structure in the hippocampal mitochondria and ameliorated the imbalance between mitochondrial fission and fusion in the APP/PS1 mouse brain. We showed that the decline in cAMP‐dependent protein kinase A (PKA) and A‐kinase anchor protein 1 for PKA (AKAP1) was associated with oxidative stress and AD‐like pathology. We confirmed that LIG‐mediated antioxidant properties and neuroprotection were involved in upregulating the PKA/AKAP1 signaling in APPswe cells in vitro.
Conclusion
Liposome packaging for LIG is relatively biosafe and can overcome the instability of LIG. LIG alleviates mitochondrial dysfunctions and cognitive impairment via the PKA/AKAP1 signaling pathway. Our results provide experimental evidence that LIG‐LPs may be a promising agent for AD therapy.
Ligustilide‐mediated interactions of protein kinase A (PKA) and AKAP1 ameliorate the imbalance between mitochondrial fission and fusion in the brains of AD mouse model, alleviate oxidative stress injury and inhibit apoptosis. The increases in ATP triggered by Ligustilide treatment activate PKA and enhance the transcription of AKAP1, facilitating the upregulation of PKA/AKAP1 signaling.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Cancer cells induce the infiltration of various immune cells that are located or distributed in different sites and play multiple roles, which have recently been proposed to predict clinical ...outcomes. We therefore studied the prognostic significance of the presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different types of immune cells in hypopharyngeal squamous cell carcinoma (HPSCC).
We retrospectively analysed 132 consecutive patients diagnosed with advanced HPSCC in 2013-2017. Tumoural parenchyma was immunohistochemically counted manually for the number of CD8, CD4 and Foxp3 cells. The ratios of CD8/Foxp3 and CD8/CD4 ratios were calculated for each specimen and analyzed with respect to patient clinicopathological variables and prognosis.
HPSCC patients with high levels of TILs showed evident correlations with well differentiated tumors (P < 0.05). Moreover, Foxp3+ TIL is also associated with overall staging group and T category (P = 0.048 and P = 0.046, respectively). Kaplan-Meier analysis showed that high CD8 and FoxP3 infiltration correlated with favourable overall survival (OS, P = 0.019 and P = 0.001), disease-free survival (DFS, P = 0.045 and P = 0.028) and distant metastasis-free survival (DMFS, P = 0.034 and P = 0.009), respectively, but only Foxp3 displayed prognostic significance for DMFS in multivariate analysis (MVA). In the lymphocyte ratio analysis, CD8/Foxp3 appeared to play a pivotal role, and patients with a high CD8/Foxp3 ratio had a superior 3-year DFS and DMFS compared with those a low CD8/Foxp3 ratio in both univariate analysis (UVA) and MVA (P = 0.015 and P = 0.011). A high CD8/CD4 ratio was associated with better DFS and local relapse-free survival (LRFS) in UVA, and was an independent prognostic factor for improved LRFS in MVA (P = 0.040).
Although high TILs levels were determined to be prognostically significant in advanced HPSCC, the ratios of these subsets may be more informative. Particularly, a higher ratio of CD8/Foxp3 accurately predicts prognosis for improved DFS and DMFS, and an increased CD8/CD4 ratio is an independent predictor for favourable LRFS.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An efficient synthetic approach for the synthesis of cyclopentenones containing a C–C stereocenter that relies on gold(I)-catalyzed Nazarov-type cyclization/1,6-addition of 1,3-enyne esters with ...p-quinone methides (p-QMs) is described. This tandem transformation exhibited a satisfactory substrate scope and passable functional group compatibility, providing a novel protocol for rapid assembly cyclopentenones in good to excellent yields under mild reaction conditions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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