Bladder cancer (BLCA) is one of the most common urological cancer with increasing cases and deaths every year. In the present study, we aim to construct an immune‐related prognostic lncRNA signature ...(IRPLS) in bladder cancer (BLCA) patients and explore its immunogenomic implications in pan‐cancers. First, the immune‐related differentially expressed lncRNAs (IRDELs) were identified by ‘limma’ R package and the score of IRPLS in every patient were evaluated by Cox regression. The dysregulation of IRDELs expression between cancer and para‐cancer normal tissues was validated through RT‐qPCR. Then, we further explore the biological functions of a novel lncRNA from IRPLS, RP11‐89 in BLCA using CCK8 assay, Transwell assay and Apoptosis analysis, which indicated that RP11‐89 was able to promote cell proliferation and invasive capacity while inhibits cell apoptosis in BLCA. In addition, we performed bioinformatic methods and RIP to investigate and validate the RP11‐89/miR‐27a‐3p/PPARγ pathway in order to explore the mechanism. Next, CIBERSORT and ESTIMATE algorithm were used to evaluate abundance of tumour‐infiltrating immune cells and scores of tumour environment elements in BLCA with different level of IRPLS risk scores. Finally, multiple bioinformatic methods were performed to show us the immune landscape of these four lncRNAs for pan‐cancers. In conclusion, this study first constructed an immune‐related prognostic lncRNA signature, which consists of RP11‐89, PSORS1C3, LINC02672 and MIR100HG and might shed lights on novel targets for individualized immunotherapy for BLCA patients.
Patients with N2–3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin–fluorouracil regimen. We aimed to ...compare the efficacy and safety of concurrent adjuvant cisplatin–gemcitabine with cisplatin–fluorouracil in N2–3 nasopharyngeal carcinoma.
We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18–65 years with untreated, non-keratinising, stage T1–4 N2–3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0–1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up.
From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years IQR 36–52; 175 73% male and 65 27% female) were randomly assigned to the cisplatin–fluorouracil group (n=120) or cisplatin–gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32–48). 3-year progression-free survival was 83·9% (95% CI 75·9–89·4; 19 disease progressions and 11 deaths) in the cisplatin–gemcitabine group and 71·5% (62·5–78·7; 34 disease progressions and seven deaths) in the cisplatin–fluorouracil group (stratified hazard ratio 0·54 95% CI 0·32–0·93; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 52% of 117 in the cisplatin–gemcitabine group vs 34 29% of 116 in the cisplatin–fluorouracil group; p=0·00039), neutropenia (37 32% vs 19 16%; p=0·010), and mucositis (27 23% vs 32 28%; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six 5% vs ten 9%). One (1%) patient in the cisplatin–gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin–fluorouracil group had treatment-related deaths.
Our findings suggest that concurrent adjuvant cisplatin–gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2–3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio.
National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.
In the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) ...and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models.
We analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and
knockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC.
The numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPN
tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8
T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC.
OPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.
Background
The tumor‐stromal ratio (TSR) has been verified to be a prognostic factor in many solid tumors. In most studies, it was manually assessed on routinely stained H&E slides. This study aimed ...to assess the TSR using image analysis algorithms developed by the Qupath software, and integrate the TSR into a nomogram for prediction of the survival in invasive breast cancer (BC) patients.
Methods
A modified TSR assessment algorithm based on the recognition of tumor and stroma tissues was developed using the Qupath software. The TSR of 234 invasive BC specimens in H&E‐stained tissue microarrays (TMAs) were assessed with the algorithm and categorized as stroma‐low or stroma‐high. The consistency of TSR estimation between Qupath prediction and pathologist annotation was analyzed. Univariable and multivariable analyses were applied to select potential risk factors and a nomogram for predicting survival in invasive BC patients was constructed and validated. An extra TMA containing 110 specimens was obtained to validate the conclusion as an independent cohort.
Results
In the discovery cohort, stroma‐low and stroma‐high were identified in 43.6% and 56.4% cases, respectively. Good concordance was observed between the pathologist annotated and Qupath predicted TSR. The Kaplan–Meier curve showed that stroma‐high patients were associated with worse 5‐DFS compared to stroma‐low patients (p = 0.007). Multivariable analysis identified age, T stage, N status, histological grade, ER status, HER‐2 gene, and TSR as potential risk predictors, which were included in the nomogram. The nomogram was well calibrated and showed a favorable predictive value for the recurrence of BC. Kaplan–Meier curves showed that the nomogram had a better risk stratification capability than the TNM staging system. In the external validation of the nomogram, the results were further validated.
Conclusions
Based on H&E‐stained TMAs, this study successfully developed image analysis algorithms for TSR assessment and constructed a nomogram for predicting survival in invasive BC.
This study aimed to assess the TSR using image analysis algorithms developed by the Qupath software, and include the TSR into a nomogram for prediction of the survival in invasive breast cancer (BC) patients.
Utilizing aggregation‐induced emission luminogens (AIEgens) as ligands has proven to be an effective strategy for constructing metal–organic frameworks (MOFs) with intense luminescent properties. ...However, highly luminescent AIEgen‐based MOFs with adjustable emission properties are rarely achieved because of the rigid conformation of AIEgens in the crystalline state. Here, a dual‐node 3D silver chalcogenolate cluster MOF (1) is designed and synthesized, where the AIE ligand shows relatively flexible and rotatable conformations. The conformations of AIE ligands in 1 are switchable by the absorption/desorption of guest molecules. As a result, 1 exhibited not only intense but also guest molecule switched luminescent properties. More importantly, the switching rate is tunable by using different guest molecules. 1 provides a unique visualized prototype to understand the mechanism of guest‐triggered aggregation‐induced emission in MOFs.
A dual‐node 3D silver chalcogenolate cluster metal–organic framework is designed and synthesized, which provides a unique visualized prototype to understand the mechanism of guest‐triggered aggregation‐induced emission in metal–organic frameworks.
Alzheimer's disease (AD) is currently ranked as the third leading cause of death for eldly people, just behind heart disease and cancer. Autophagy is declined with aging. Our study determined the ...biphasic changes of miR-331-3p and miR-9-5p associated with AD progression in APPswe/PS1dE9 mouse model and demonstrated inhibiting miR-331-3p and miR-9-5p treatment prevented AD progression by promoting the autophagic clearance of amyloid beta (Aβ).
The biphasic changes of microRNAs were obtained from RNA-seq data and verified by qRT-PCR in early-stage (6 months) and late-stage (12 months) APPswe/PS1dE9 mice (hereinafter referred to as AD mice). The AD progression was determined by analyzing Aβ levels, neuron numbers (MAP2
) and activated microglia (CD68
IBA1
) in brain tissues using immunohistological and immunofluorescent staining. MRNA and protein levels of autophagic-associated genes (
) were tested to determine the autophagic activity. Morris water maze and object location test were employed to evaluate the memory and learning after antagomirs treatments in AD mice and the Aβ in the brain tissues were determined.
MiR-331-3p and miR-9-5p are down-regulated in early-stage of AD mice, whereas up-regulated in late-stage of AD mice. We demonstrated that miR-331-3p and miR-9-5p target autophagy receptors Sequestosome 1 (
) and Optineurin (
), respectively. Overexpression of miR-331-3p and miR-9-5p in SH-SY5Y cell line impaired autophagic activity and promoted amyloid plaques formation. Moreover, AD mice had enhanced Aβ clearance, improved cognition and mobility when treated with miR-331-3p and miR-9-5p antagomirs at late-stage.
Our study suggests that using miR-331-3p and miR-9-5p, along with autophagic activity and amyloid plaques may distinguish early versus late stage of AD for more accurate and timely diagnosis. Additionally, we further provide a possible new therapeutic strategy for AD patients by inhibiting miR-331-3p and miR-9-5p and enhancing autophagy.
A series of phenanthroline‐based ligands have been synthesised and their influence as bidentate nitrogen ligands in heteroleptic Cu(P^P)(N^N)+ photosensitisers in light‐driven water reduction has ...been studied. In this noble‐metal‐free Cu–Fe‐based photocatalytic water reduction system, the structural effects of the nitrogen ligands have been explored, including the steric and electronic effects of substituents at the 2,9‐ and 4,7‐positions of phenanthroline. Ligands were prepared that led to increased hydrogen generation, with turnover numbers (TONCu) of up to 1388 being observed. All the new complexes were electrochemically and photophysically characterised. We demonstrate for the first time that the presence of fluorine in nitrogen ligands increases the efficacy of copper complexes in photocatalytic hydrogen production.
Hydrogen production: A series of phenanthroline‐based ligands have been synthesised and the photosensitising ability of their heteroleptic Cu(P^P)(N^N)+ complexes in light‐driven Cu–Fe‐based water reduction has been studied (see scheme). In this noble‐metal‐free system, the steric and electronic effects of the substituents at the 2,9‐ and 4,7‐positions of phenanthroline have been explored. It is shown for the first time that the presence of fluorine in nitrogen ligands increases the efficacy of copper complexes in photocatalytic hydrogen production.
Although hepatocellular carcinoma (HCC) is one of the deadliest health burdens worldwide, few drugs are available for its clinical treatment. However, in recent years, major breakthroughs have been ...made in the development of new drugs due to intensive fundamental research and numerous clinical trials in HCC. Traditional systemic therapy schemes and emerging immunotherapy strategies have both advanced. Between 2017 and 2020, the United States Food and Drug Administration (FDA) approved a variety of drugs for the treatment of HCC, including multikinase inhibitors (regorafenib, lenvatinib, cabozantinib, and ramucirumab), immune checkpoint inhibitors (nivolumab and pembrolizumab), and bevacizumab combined with atezolizumab. Currently, there are more than 1000 ongoing clinical trials involving HCC, which represents a vibrant atmosphere in the HCC drug research and development field. Additionally, traditional Chinese medicine approaches are being gradually optimized. This review summarizes FDA-approved agents for HCC, elucidates promising agents evaluated in clinical phase I/II/III trials and identifies emerging targets for HCC treatment. In addition, we introduce the development of HCC drugs in China. Finally, we discuss potential problems in HCC drug therapy and possible future solutions and indicate future directions for the development of drugs for HCC treatment.
Hierarchical heterostructures with large surface areas and multiple interfaces as photoanode materials, are holding great promise for photoelectrochemical (PEC) water splitting toward efficient solar ...energy utilization. In this work, the cactus-like WO3@ZnWO4@ZnO-ZnO (i.e. W@WZ@Z-Z) arrays compromising the first-order W@WZ@Z core-shell nanosheets and the second-order ZnO nanosheets, have been fabricated by combining atomic layer deposition (ALD) technique and hydrothermal process. The modification of ZnO nanosheets on the surface of WO3 and the simultaneous formation of ZnWO4 in-between buffer layer have endowed the photoanode a drastic enhancement in both ultraviolet light absorption and charge separation via the favorable band alignment at the WO3-ZnWO4-ZnO interfaces. Particularly, the W@WZ@Z-Z nanocactus (NC) array photoanode with a 30nm ZnO layer on WO3 precisely controlled by ALD, exhibited around 3.8 times higher photocurrent density (~ 1.57mA/cm2) at 1.23V vs. RHE than pristine WO3 photoanode (~ 0.41mA/cm2), with little loss after long-term continuous illumination as well. Overall, the novel combination of WO3 with ZnO and the ZnWO4 buffer layer, and construction of hierarchical heterostructures, along with the resulted improvement in light absorption and charge separation which have been confirmed by spectroscopic characterizations and finite-difference time-domain simulation, suggest many exciting opportunities for further development of high-performance PEC devices for solar energy conversion.
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•A large-scale array of 3D heterostructured hierarchical WO3@ZnWO4@ZnO-ZnO nanoacatus was formed.•The nanocactus array shows an improvement of light absorption and the transfer of charge carriers.•The proposed photoanode has an efficent PEC performance.
No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.
We conducted a randomized, controlled, open-label trial involving hospitalized adult patients ...with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao
) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao
) to the fraction of inspired oxygen (Fio
) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.
A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval CI, 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.
In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
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