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Abstract Integrin αvβ6 holds promise as a therapeutic target for organ fibrosis, yet targeted therapies are hampered by concerns over inflammatory-related side effects. The role of αvβ6 in renal inflammation remains unknown, and clarifying this issue is crucial for αvβ6-targeted treatment of chronic kidney disease (CKD). Here, we revealed a remarkable positive correlation between overexpressed αvβ6 in proximal tubule cells (PTCs) and renal inflammation in CKD patients and mouse models. Notably, knockout of αvβ6 not only significantly alleviated renal fibrosis but also reduced inflammatory responses in mice, especially the infiltration of pro-inflammatory macrophages. Furthermore, conditional knockout of αvβ6 in PTCs in vivo and co-culture of PTCs with macrophages in vitro showed that depleting αvβ6 in PTCs suppressed the migration and pro-inflammatory differentiation of macrophages. Screening of macrophage activators showed that αvβ6 in PTCs activates macrophages via secreting IL-34. IL-34 produced by PTCs was significantly diminished by αvβ6 silencing, and reintroduction of IL-34 restored macrophage activities, while anti-IL-34 antibody restrained macrophage activities enhanced by αvβ6 overexpression. Moreover, RNA-sequencing of PTCs and verification experiments demonstrated that silencing αvβ6 in PTCs blocked hypoxia-stimulated IL-34 upregulation and secretion by inhibiting YAP expression, dephosphorylation, and nuclear translocation, which resulted in the activation of Hippo signaling. While application of a YAP agonist effectively recurred IL-34 production by PTCs, enhancing the subsequent macrophage migration and activation. Besides, reduced IL-34 expression and YAP activation were also observed in global or PTCs-specific αvβ6-deficient injured kidneys. Collectively, our research elucidates the pro-inflammatory function and YAP/IL-34/macrophage axis-mediated mechanism of αvβ6 in renal inflammation, providing a solid rationale for the use of αvβ6 inhibition to treat kidney inflammation and fibrosis.

Abstract Background Unresectable intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis despite treatment with standard combination chemotherapy. We aimed to evaluate the efficacy and safety of radiotherapy in combination with an anti-PD-1 antibody in unresectable iCCA without distant metastases. Methods In this phase II study, patients with histopathologically confirmed unresectable primary or postoperative recurrent iCCA without distant metastases were enrolled. Patients received external radiotherapy with a dose of ≥45 Gy (2-2.5 Gy per fraction), followed by anti-PD-1 immunotherapy (camrelizumab 200 mg once, every 3 weeks) initiated within 7 days after completion of radiotherapy as first-line therapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The secondary end points included safety, objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results From December 2019 to March 2021, 36 patients completed radiotherapy and at least one cycle of immunotherapy and were included in efficacy and safety analyses. The median follow-up was 19.0 months (IQR 12.0-24.0), and the one-year PFS rate was 44.4% (95% CI, 30.8-64.0). The median PFS was 12.0 months (95% CI, 7.5-not estimable); the median OS was 22.0 months (95% CI, 15.0-not estimable). The ORR was 61.1% and the DCR was 86.1%. Seventeen of 36 (47.2%) patients experienced treatment-related adverse effects (AEs) of any grade. The most common AE was reactive cutaneous capillary endothelial proliferation (25.0%). Five (13.9%) patients experienced grade ≥3 treatment-related AEs, including decreased lymphocyte (5.6%), bullous dermatitis (2.8%), decreased platelet count (2.8%), and deep-vein thrombosis (2.8%). Conclusions External radiotherapy plus camrelizumab, as first-line therapy, met its primary endpoint and showed antitumor activity and low toxicity levels in patients with unresectable iCCA without distant metastases, warranting further investigation. Trial registration NCT03898895. Registered 2 April 2019.

Abstract Background Hotspot mutations in the promoter of telomerase reverse transcriptase (TERT) gene are the most common genetic variants in hepatocellular carcinoma (HCC) and associated with poor prognosis of the disease. However, no drug was currently approved for treating TERT promoter mutation positive HCC patients. Here, we aim to explore the potential therapeutic strategy for targeting TERT promoter mutation in HCC. Methods The Liver Cancer Model Repository database was used for screening potential drugs to selectively suppress the growth of TERT promoter mutant HCC cells. RNA‐seq, CRISPR‐Cas9 technology and siRNA transfection were performed for mechanistic studies. Cell counting kit‐8 (CCK8) assay and the xenograft tumour models were used for cell growth detection in vitro and in vivo, respectively. Cell apoptosis and cell cycle arrest were analysed by Annexin V‐FITC staining and/or propidium iodide staining. Results PLK1 inhibitors were remarkably more sensitive to HCC cells harbouring TERT promoter mutation than wild‐type cells in vitro and in vivo, which were diminished after TERT promoter mutation was edited to the wild‐type nucleotide. Comparing the HCC cells with wild‐type promoter of TERT, PLK1 inhibitors specifically downregulated Smad3 to regulate TERT for inducing apoptosis and G2/M arrest in TERT mutant HCC cells. Moreover, knockout of Smad3 counteracted the effects of PLK1 inhibitors in TERT mutant HCC cells. Finally, a cooperative effect of PLK1 and Smad3 inhibition was observed in TERT mutant cells. Conclusions PLK1 inhibition selectively suppressed the growth of TERT mutant HCC cells through Smad3, thus contributed to discover a novel therapeutic strategy to treat HCC patients harbouring TERT promoter mutations. Key points TERT promoter mutation confers sensitivity to PLK1 inhibitors in HCC. The selective growth inhibition of TERT mutant HCC cells induced by PLK1 inhibitor was mediated by Smad3. Combined inhibition of PLK1 and Smad3 showed a cooperative anti‐tumor effect in TERT mutant HCC cells.

Background: Radiotherapy is an effective treatment for hepatocellular carcinoma (HCC). Recent studies indicated that N7-methylguanosine (m7G)-associated genes are involved in radioresistance and prognosis of HCC. However, the prognostic value and underlying mechanism of m7G-and radiosensitivity-associated genes are still lacking. Methods: The related statistics of HCC were downloaded from The Cancer Genome Atlas (TCGA). M7G- and radiosensitivity-associated genes were screened and evaluated using correlation, differential, univariate, and multivariate analysis. The least absolute shrinkage and selection operator (LASSO) algorithm was used to establish a prognostic model. Prognostic efficacy, functional analysis, immune cell infiltration,and drug sensitivity of the prognostic model were assessed. The ceRNA network was predicted and evaluated through the StarBase database, correlation analysis, expression analysis, and survival analysis. Result: METTL1, EIF3D, NCBP2, and WDR4 participated in prognosis model construction. The favorable prediction efficiency has been verified in both the training and verification sets. Different risk groups have differences in prognosis outcome, function analysis, immune cell infiltration, and drug sensitivity. NCBP2 can be used to predict the prognosis and has excellent potential in immunotherapy. A prognostic ceRNA network based on the NCBP2/miR-122-5p axis was established. Conclusion: The prognosis model of m7G- and radiosensitivity-related genes is constructed, and widely used in clinical prognosis, immunotherapy, and drug therapy. NCBP2, as a hub gene, may be a prognostic biomarker for HCC and is related to immunotherapy. Establishing the NCBP2/miR-122-5p axis helps study the mechanism of ceRNA and provides new ideas for finding a new candidate biomarker.

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1–BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination–deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

Shrinking cities suffer from a decreased level of resident activities. As a result, areas with low levels of resident activities may become breeding grounds for social issues. To ease and prevent social issues, it is important to deploy physical space optimisation strategies to effectively guide the distribution of resident activities in shrinking cities. To support the development of such spatial strategies, this paper introduces machine learning-based methods for analysing the nuanced non-linear relationship between resident activities and physical space in shrinking cities. Utilising dual-scale grids, this study calculates multi-source spatial elements, which are subsequently integrated with resident activity data to construct a gradient boosting decision tree model. It then analyses the weight of different spatial elements’ impacts on resident activities and their nonlinear relationships. The model proposed in this study demonstrates good precision in construing the relationship between resident activities and physical space. Based on the research findings, strategies for different types of spatial development in shrinking cities are drawn out. This paper advocates for the application of this analytical approach before conducting spatial planning in shrinking cities to maximise the effectiveness of spatial development in guiding resident activities.

Introduction: Reducing the protein adsorption of nanoparticles (NPs) as drug carriers to slow their rapid clearance by macrophages uptake is a critical challenge for NPs clinical translational applications. Despite extensive research efforts to inhibit cellular uptake, including covering biological agents or surface chemical coatings to impart “stealth” properties to NPs, their stability remains insufficient. Objectives: Developed a novel surface modification technology based on a physical infusion engineering approach to achieve persistent inhibition of protein adhesion and cellular uptake by nanocarriers. Methods: The nanoparticles were prepared based on conventional drug carrier mesoporous silica NPs through a two-step process. A functional nanoscale slippery surface was formed by grafting “liquid-like” brushes on the particles surface, and then a lubricant-entrenched slippery surfaces (LESS) was formed by infusing silicone oil lubricant into the entire surface. Co-incubation with macrophages (in vitro and in vivo) was used to examine the anti-uptake properties of modified NPs. The anti-adhesion properties of LESS coating surfaces to various liquids, proteins and cells were used to analyze the anti-uptake mechanism. Loaded with drugs, combined with tumor models, to evaluate the drug utilization of modified NPs. Results: Relying on the stable and slippery LESS coating, the modified surface could prevent the adhesion of various liquids and effectively shield against the adhesion of proteins and cells, as well as remarkably reduce macrophage cellular uptake in vitro and in vivo. In addition, the LESS coating does not affect cell activity and allows NPs to be loaded with drugs, significantly improving the utilization of drugs in vitro and in vivo. This allows the NPs to reach to the target tumor site for drug delivery without active clearance by macrophages. Conclusion: Our research introduces a new nanocarrier technology to improve anti-biofouling performance and stealth efficiency that will facilitate the development of nanomedicines for clinical transformation applications.

BackgroundWe aimed to investigate the efficacy of a novel regimen, external beam radiation (RT) combined with trans arterial chemoembolization (TACE) and lenvatinib (LEN), in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus.MethodsWe prospectively observed 102 participants from three tertiary medical centers in China between October 2018 and October 2020, who chose either RT plus TACE and LEN (RT-TACE-LEN) or TACE and LEN (TACE-LEN). LEN (12 mg or 8 mg daily) was administrated orally and continued until progression or intolerable side effects were noted. TACE was given one day after administration of LEN, and RT began within 4 weeks after the first TACE. The median dose/fraction of RT was 50 Gy/25 fractions (range: 45-60 Gy/25 fractions). Overall survival and progression free survival were compared between two groups, and complications were assessed.ResultsBoth 51 patients received RT-TACE-LEN and TACE-LEN, respectively. Most patients had tumor size> 5 cm (73.8%) and tumor number≥ 2 (69.9%). The overall incidence of toxicities was significantly higher in RT-TACE-LEN group than TACE-LEN group (100% vs. 64.7%, p< 0.001), but incidences of grade 3-4 toxicities were comparable (54.9% vs. 49.0%, p= 0.552). Both median overall survival (22.8 vs. 17.1 months, p= 0.031) and median progression-free survival (12.8 vs. 10.5 months, p= 0.035) were significantly longer after RT-TACE-LEN treatment than TACE-LEN.ConclusionsThe addition of RT to TACE and LEN was safe, and might improve clinical outcomes of patients with advanced HCC, which needs conformation from further studies.

Abstract Treatment options specifically for patients with locally advanced pancreatic adenocarcinoma (LAPC) are scare and chemotherapy alone delivers limited efficacy. Immunotherapy and radiotherapy are potential effective treatments for LAPC, and both of them may synergize with chemotherapy. Therefore, in this prospective cohort study, we compared the efficacy and safety of nab-paclitaxel plus gemcitabine combined with anti-programmed cell death (PD-1) immunotherapy and radiotherapy (hereafter, combination treatment) versus nab-paclitaxel plus gemcitabine (chemotherapy alone) in the treatment of LAPC. In the combination group, participants received conventional fractionated radiotherapy with doses ranging from 54 to 63 Gy in 28 fractions, intravenous camrelizumab 200 mg once every 3 weeks, and intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death or unacceptable toxicity. In the chemotherapy group, participants received intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles. From April, 2020 to December, 2021, 96 participants with LAPC were prospectively enrolled with 32 received combination treatment and 64 received chemotherapy alone at a single center. The combination treatment yielded significantly longer median overall-survival (22.3 months vs. 18.6 months, P = 0.031) and progression-free survival (12.0 months vs. 10.5 months, P = 0.043) than chemotherapy alone did. And the incidence of severe adverse events was not significantly different between the combination group and chemotherapy group (P = 0.856). In conclusion, nab-paclitaxel plus gemcitabine combined with anti-PD-1 immunotherapy and radiotherapy was effective and safe for LAPC patients, and it warrants further investigation in larger randomized trials.

While a significant number of studies have focused on elucidating the functioning mechanisms of the Hepatocellular carcinoma (HCC) microenvironment, the intercellular crosstalk between multiple cells in the tumor microenvironment remains unclear. Here we co-cultured spheroids of HCC cells, hepatic stellate cells (HSCs), and hepatocytes in a biomimetic composite hydrogel to construct a 3D model of the HCC microenvironment in vitro. The model reproduced the major cellular components of early HCC in a biomimetic 3D microenvironment, realizing the visualization of the cellular interplay between cells and the microenvironment. Using this model, we showed that the HSCs were activated when co-cultured with HCC cells and deposed collagen to remodel the microenvironment, which in turn triggered higher EMT levels in HCC cells. The hepatocytes also responded to the existence of HCC cells and the activation of HSCs in co-culture, showing the downregulated expression level of ALB, AFP, and HNF4A. This model recapitulated the activation of HSCs in the HCC microenvironment and enabled visualization of multicellular interplay in 3D, providing a biomimetic platform to investigate mechanisms of HCC and related hepatic fibrosis.

Objectives Recurrent hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI)-positive primary tumor is at high risk of re-recurrence while treated with radiofrequency ablation (RFA). We aimed to investigate whether neoadjuvant conventional transarterial chemoembolization (cTACE) was effective in reducing re-recurrence after RFA for recurrent HCC patients with MVI-positive primary tumors.Methods In this retrospective multicenter study, 468 patients with solitary small recurrent HCC (≤3.0cm) underwent RFA alone (n = 322) or with neoadjuvant cTACE (n = 146) between June 2007 and December 2017 were included. Overall survival (OS) and recurrence-free survival (RFS) were compared.Results The 1-, 5-year OS rates were 74.8%, 42.5% for RFA with neoadjuvant cTACE group, and 53.5%, 28.7% for RFA group (P 2cm (HR = 0.52, 95% CI: 0.36–0.77; HR = 0.49, 95% CI: 0.36–0.67) or not (HR = 0.53, 95% CI: 0.32–0.88; HR = 0.65, 95% CI: 0.42–0.98), or the time interval of recurrence from initial treatment ≤ 1 year (HR = 0.53, 95% CI: 0.36–0.77; HR = 0.70, 95% CI: 0.52–0.94) or not (HR = 0.56, 95% CI: 0.34–0.95; HR = 0.39, 95% CI: 0.25–0.62). Multivariable analyses showed that RFA alone (HR = 1.329, P = 0.031; HR = 1.764, P = 0.004) and interval of recurrence from initial treatment > 1 year(HR = 0.642, P = 0.001; HR = 0.298, P = 0.037) were independent prognostic factors of OS and RFS.Conclusions Neoadjuvant cTACE could effectively reduce re-recurrence after RFA, and improve the long-term survivals for patients with solitary small recurrent HCC whose primary tumor was MVI-positive. Key pointsFor recurrent hepatocellular carcinoma (HCC) patients whose primary tumor was positive for microvascular invasion, neoadjuvant conventional transarterial chemoembolization (cTACE) with radiofrequency ablation (RFA) achieved better efficacy.Multivariable analyses showed that the interval of recurrence from initial treatment > 1 year and RFA alone were independent prognostic factors of overall survival and recurrence-free survival, respectively.

The use of radiotherapy for hypopharyngeal cancer (HC) treatment is increasing, and it is currently the primary treatment option for this cancer. However, radioresistance occurs in a proportion of patients. Here, we found that radiation increased proteasomal gene expression and that proteasome assembly was dependent on the induction of transcription factor NRF1 in HC. Through screening assays, we identified a mechanism by which proteasome-mediated degradation of DEP domain-containing mTOR-interacting protein (DEPTOR) contributes to the elevation of mTORC1 signaling after radiation. Therefore, after treatment with proteasome inhibitors (PIs), stabilization of DEPTOR inhibited mTORC1 signaling elevated by radiation and ultimately sensitized HC to radiotherapy. Mechanically, PIs not only interrupted the deubiquitination and degradation of DEPTOR but also suppressed the ubiquitination of DEPTOR mediated by β-TrCP. Clinically, the high levels of DEPTOR in HC cells were associated with sensitivity to radiotherapy and favorable prognosis. Stabilizing DEPTOR through targeting proteasome-mediated degradation is a potential strategy for sensitizing HC to radiotherapy.

Although radiotherapy has become indispensable for tumor treatment in recent years, the inevitable side effects of high-dose radiation on the normal tissue and deficiency of appropriate radiosensitizers without long-term body retention that do not cause potential toxicity limit further clinical applications to a certain extent. Herein, we rationally synthesized BiOI nanodots coated with M1 macrophage membrane (BiOI@M) by utilizing their coordination interaction. With two high-atomic-number elements and ultrasmall size, the prepared BiOI nanodots not only enhanced radiosensitivity by reactive oxygen species under X-ray irradiation in vitro, but also could be excreted quickly by kidneys. Meanwhile, the M1 macrophage membrane functioned as a highly desirable carrier with long-circulating and tumor-targeting capability. As a result, treatment with as-prepared BiOI@M could improve the therapeutic outcome of radiotherapy in a xenograft mouse model and reduce the potential toxicity of nanoparticles. Simultaneously, BiOI nanodots exhibited excellent CT imaging ability as contrast agents to visualize biodistribution in vivo and to monitor tumor growth. Therefore, our work demonstrated the preparation of a tumor targeting and renal clearable radiosensitizer and offered a potential approach to enhance the radiotherapy efficacy of hepatocellular carcinoma.

Patients with cancer are considered at high risk of COVID-19 related complications with higher mortality rates than healthy individuals. This study investigated the perception, acceptance, and influencing factors of COVID-19 vaccination among cancer patients in Guangzhou, China. A cross-sectional survey was conducted in Guangzhou, China from August to November 2021 in two tertiary medical centers. Outpatients were recruited through hospital posters to complete a questionnaire including demographics, medical history, knowledge, and attitude toward COVID-19 vaccines and COVID-19 vaccination status. Chi-square tests and multivariable logistic regression were used to analyze predictors for acceptance of COVID-19 vaccination. In total, only 75 out of 343 patients (21.87%) had received at least one dose of COVID-19 vaccine. Twenty-one patients (6.12%) had received a recommendation about COVID-19 vaccination from their physicians. Patients who were recommended by physicians to get vaccinated (aOR = 11.71 95% CI: 2.71–50.66), with a monthly income of more than CNY 5000 (aOR = 3.94, 95% CI: 1.88–8.26) were more likely to have received COVID-19 vaccination. Cancer patients who had been diagnosed for more than one year (aOR = 0.21, 95% CI: 0.09–0.51), had received multiple cancer treatment strategies (aOR = 0.34, 95% CI: 0.16–0.74), worried about the safety of COVID-19 vaccines (aOR = 0.21, 95% CI: 0.11–0.40), were less likely to have received COVID-19 vaccination. COVID-19 vaccination uptake among cancer patients was insufficient. The proportion of cancer patients receiving vaccination recommendations from physicians remains inadequate. Physicians are expected to play an essential role in patients’ knowledge of the safety and effectiveness of COVID-19 vaccines.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Local ablation, such as radiofrequency ablation, microwave ablation, cryoablation and irreversible electroporation, etc., are well established in elimination and control of HCC. However, high recurrence rate after local ablation remains the biggest challenge for HCC management. Novel and effective therapeutic strategies to improve long-term survival are urgently needed. Accumulating studies have reported the role of ablation in modulating the tumor signaling pathway and the immune microenvironment to both eliminate residual/metastatic tumor and promote tumor progression. Ablation has been shown to elicit tumor-specific immune responses by inducing massive cell death and releasing tumor antigen. Immunotherapies that unleash the immune system have the potential to enhance the anti-tumor immunity induced by ablation. Multiple combinatory strategies have been explored in preclinical and clinical studies. In this review, we comprehensively summarize the latest progress on different mechanisms underlying the effects of ablation on tumor cells and tumor microenvironment. We further analyze the clinical trials testing the combination of ablation and immunotherapies, and discuss the possible role of immunomodulation to boost the anti-tumor effects of ablation and prevent HCC recurrence.

Summary: Background: Induction chemotherapy regimens of docetaxel and cisplatin plus fluorouracil (TPF) are currently clinically used for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) but have well-known side effects, such as myelosuppression and diarrhea. A docetaxel plus cisplatin (TP) regimen was developed to decrease the toxic effects induced by fluorouracil. In this trial, we assessed whether the TP induction chemotherapy regimen was noninferior to the TPF regimen. Methods: We performed an open-label, noninferiority, phase 3, multicentre, randomised, controlled trial at six centres in China. Eligible patients with NPC (stage III-IVA (excluding T3-4N0), Karnofsky's Performance Scoring ≥70) were randomly assigned (1:1) to receive either TP (docetaxel (75 mg per square meter, d1, intravenous infusion) and cisplatin (75 mg per square meter of body-surface area, d1, intravenous infusion)) or TPF (docetaxel (60 mg per square meter, d1, intravenous infusion) plus cisplatin (60 mg per square meter, d1, intravenous infusion) and 5-fluorouracil (600 mg per square meter, d1-d5, intravenous 120-hour infusion)) administered every 3 weeks for 3 cycles followed by concurrent chemoradiotherapy. The primary endpoint was failure-free survival at 2 years. Secondary endpoints included overall survival, safety, and treatment compliance. The trial was stopped early because of strong evidence for noninferiority (margin was -10%) of TP in failure-free survival. Efficacy analyses were performed in both the intention-to-treat and per-protocol trial populations and we included the patients who started treatment in each group for the safety analysis. The study was registered with chictr.org.cn, ChiCTR1800016337. Findings: Between June 1, 2018 and October 31, 2021, we randomly assigned 361 patients to the TP (n = 181) or TPF (n = 180) induction chemotherapy group. The 2-year failure-free survival was 91·3% (95% CI 86·2-96·4) in the TP group and 82·4% (84·8-88·9) in the TPF group (P = 0·029). Patients in the TPF group had a higher frequency of grade 1 or 2 neutropenia (53 (30·0%) vs. 28 (15·7%); P = 0·0010), grade 1 or 2 diarrhea (20 (11·3%) vs. 9 (5·1%); P = 0·032), and grade 3 or 4 neutropenia (43 (24·3%) vs. 25 (14·0%); P = 0·014) in the induction chemotherapy period. There was no treatment-related death. Interpretation: The preliminary results revealed that TP induction chemotherapy regimen was found to be clearly non-inferior compared to the TPF regimen in failure-free survival, with a lower frequency of neutropenia, anaemia and diarrhoea. The more convenient and beneficial survival regimen of the TP regimen should be recommended in patients with LA-NPC. Funding: This study was supported by grants from the Natural Science Foundation of Guangdong Province, China [grant number 2021A1515011182], Natural Science Foundation of Guangdong Province, China [grant number 2022A1515012272], National Natural Science Foundation of China [grant number 82072029] and National Natural Science Foundation of China [grant number 81903037].

A distributed optical fiber refractive index sensor based on etched Ge-doped SMF in optical frequency domain reflection (OFDR) was proposed and demonstrated. The etched Ge-doped SMF was obtained by only using wet-etching, i.e., hydrofluoric acid solution. The distributed refractive index sensing is achieved by measuring the spectral shift of the local RBS spectra using OFDR. The sensing length of 10 cm and the spatial resolution of 5.25 mm are achieved in the experiment. The refractive index sensing range is as wide as 1.33–1.44 refractive index units (RIU), where the average sensitivity was about 757 GHz/RIU. Moreover, the maximum sensitivity of 2396.9 GHZ/RIU is obtained between 1.43 and 1.44 RIU.

Abstract Cancer is one of the leading causes of human death, despite enormous efforts to explore cancer biology and develop anticancer therapies. The main challenges in cancer research are establishing an efficient tumor microenvironment in vitro and exploring efficient means for screening anticancer drugs to reveal the nature of cancer and develop treatments. The tumor microenvironment possesses human-specific biophysical and biochemical factors that are difficult to recapitulate in conventional in vitro planar cell models and in vivo animal models. Therefore, model limitations have hindered the translation of basic research findings to clinical applications. In this review, we introduce the recent progress in tumor-on-a-chip devices for cancer biology research, medicine assessment, and biomedical applications in detail. The emerging tumor-on-a-chip platforms integrating 3D cell culture, microfluidic technology, and tissue engineering have successfully mimicked the pivotal structural and functional characteristics of the in vivo tumor microenvironment. The recent advances in tumor-on-a-chip platforms for cancer biology studies and biomedical applications are detailed and analyzed in this review. This review should be valuable for further understanding the mechanisms of the tumor evolution process, screening anticancer drugs, and developing cancer therapies, and it addresses the challenges and potential opportunities in predicting drug screening and cancer treatment.

Abstract Background Limited effective intervention for advanced hepatocellular carcinoma (HCC) is available. This study aimed to investigate the potential clinical utility of apatinib, a highly selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, as a radiosensitizer in the treatment of HCC. Methods Four human HCC cell lines SMMC-7721, MHCC-97H, HCCLM3 and Hep-3B were treated with apatinib, irradiation or combination treatment. Colony formation assay, flow cytometry and nuclear γ-H2AX foci immunofluorescence staining were performed to evaluate the efficacy of combination treatment. RNA sequencing was conducted to explore the potential mechanism. The impact of combination treatment on tumor growth was assessed by xenograft mice models. Results Colony formation assay revealed that apatinib enhanced the radiosensitivity of HCC cell lines. Apatinib suppressed repair of radiation-induced DNA double-strand breaks. Flow cytometry analysis showed that apatinib increased radiation-induced apoptosis. Apatinib radiosensitized HCC via suppression of radiation-induced PI3K/AKT pathway. Moreover, an in vivo study indicated apatinib combined with irradiation significantly decreased xenograft tumor growth. Conclusions Our results indicate that apatinib has therapeutic potential as a radiosensitizer in HCC, and PI3K/AKT signaling pathway plays a critical role in mediating radiosensitization of apatinib.

IntroductionRole of response to antiviral therapies on survival of patients with intermediate-stage hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) undergoing transarterial chemoembolization (TACE) remains unknown. We aimed to determine whether virological response (VR) or prolonged maintained virological response (MVR) to nucelos(t)ide analogues (NA) therapy could result in improved survival in HBV-HCC patients receiving TACE.MethodsBetween January 2012 and October 2018, data of patients with intermediate HBV-HCC who underwent TACE and started NA therapy within one week prior to TACE treatment at our institution were reviewed. Overall survival (OS) was compared using the Kaplan-Meier method with log-rank test between different VR status groups. Univariable and multivariable Cox regression analyses were used to determine the association between achievement of VR or MVR and OS. VR was defined as an undetectable HBV DNA level (

A high-spatial-resolution OFDR distributed temperature sensor based on Au-SMF was experimentally demonstrated by using step-by-step and image wavelet denoising methods (IWDM). The measured temperature between 50 and 600 °C could be successfully demodulated by using SM-IWDM at a spatial resolution of 3.2 mm. The temperature sensitivity coefficient of the Au-SMF was 3.18 GHz/°C. The accuracy of the demodulated temperature was approximately 0.24 °C. Such a method has great potential to expand the temperature measurement range, which is very useful for high-temperature applications.

miR-101–3p may play a therapeutic role in various tumours. However, its anti-tumour mechanism remains unclear, and a definitive strategy to treat tumour cells in vivo is lacking. The objective of this study was to investigate the inhibitory mechanism of miR-101–3p on tumour cells and to develop relevant nanomedicines for in vivo therapy. The expression levels of miR-101–3p and its target protein TBLR1 in tumour tissues and cells were detected, and their relationship with ferroptosis was clarified. Furthermore, the efficacy of nanocarriers in achieving in vivo therapeutic gene delivery was evaluated. Nanomedicine was further developed, with the anti-proliferative in vivo therapeutic effect validated using a subcutaneous xenograft cancer model. The expression level of miR-101–3p negatively correlated with clinical tumour size and TNM stage. miR-101–3p restores ferroptosis in tumour cells by directly targeting TBLR1, which in turn promotes apoptosis and inhibits proliferation. We developed nanomedicine that can deliver miR-101–3p to tumour cells in vivo to achieve ferroptosis recovery, as well as to inhibit in vivo tumour proliferation. The miR-101–3p/TBLR1 axis plays an important role in tumour ferroptosis. Nanopharmaceuticals that increase miR-101–3p levels may be effective therapies to inhibit tumour proliferation.

Abstract Background The role of transarterial chemoembolization (TACE) as the standard treatment for intermediate‐stage hepatocellular carcinoma (HCC) is being challenged by increasing studies supporting liver resection (LR); but evidence of survival benefits of LR is lacking. We aimed to compare the overall survival (OS) of LR with that of TACE for the treatment of intermediate‐stage HCC in cirrhotic patients. Methods A Markov model, comparing LR with TACE over 15 years, was developed based on the data from 31 literatures. Additionally, external validation of the model was performed using a data set (n = 1735; LR: 701; TACE: 1034) from a tertiary center with propensity score matching method. We conducted one‐way and two‐way sensitivity analyses, in addition to a Monte Carlo analysis with 10 000 patients allocated into each arm. Results The mean expected survival times and survival rates at 5 years were 77.8 months and 47.1% in LR group, and 48.6 months and 25.7% in TACE group, respectively. Sensitivity analyses found that initial LR was the most favorable treatment. The 95% CI for the difference in OS was 2.42‐2.46 years between the two groups (P

With the implementation of China’s rural revitalization strategy, the social economy of villages is expected to fully develop; however, their carbon emissions must be controlled within a reasonable range. Realization of this goal is part of the guidance and control of village planning. Clarifying the coupling relationship between village land uses and rural carbon emissions is fundamental for low-carbon village planning. In this study, by exploring the relationships between carbon emissions factors, land-use types, and human activities, the reference range of carbon emissions coefficients for various land-use types in rural areas is obtained. Then, based on the interval values of carbon emissions coefficients, a two-stage optimization model for village carbon emissions analysis is established, which is used to generate the minimal value of village carbon emissions and planning schemes to achieve different carbon emissions target values. First, the smallest carbon emissions value for a certain village is obtained based on a linear programming model. Then, to analyze the planning scheme possibilities under different carbon emissions targets, an objective planning model (including various parameters) is constructed. Through this two-stage optimization model, the optimal planning scheme is set and corresponding planning indicators under different scenarios are obtained through a sensitivity analysis. Combined with a case study in Dongzhuang Village, Shanghai, the results indicate that, with continuous improvement of the basic national carbon emissions database, the range of carbon emissions coefficients for typical local land uses can be determined, and the carbon emissions and land-use types of villages can be co-planned using the two-stage optimization model. With the proposed model, the range of carbon emissions for villages and scenario analysis results considering carbon emissions values associated with various land-use planning schemes can be obtained, contributing greatly to low-carbon village planning.

Abstract Background To compare the efficacy of low dose (27 mg) Bacillus Calmette-Guérin (BCG) and a full dose (81 mg) BCG immunotherapy for patients with intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) after a typical transurethral bladder resection. Methods We constructed a Markov model for a 20-year simulation of the disease to compare the overall survival of patients with intermediate and high-risk of NMIBC between the full-dose therapy (FD group) and the low-dose therapy (LD group). Base case analysis, one-way and two-way sensitivity analysis and a second-order Monte Carlo analysis were performed based on data from 15 published articles. Results The expected overall survivals were 9.56 (9.55–9.57) years for FD group and 9.63 (9.61–9.64) years for LD group(P

Limited data reported the synergistic anti-tumor effect of anti-PD-1 (programmed death 1) therapy and radiotherapy on melanoma BM (brain metastasis). And the efficacy in the Chinese population is unclear. This study aimed to evaluate the efficacy of anti-PD-1 therapy and radiotherapy in Chinese melanoma patients with BM. We retrospectively reviewed 96 consecutive melanoma patients with BM treated at Sun Yat-Sen University Cancer Center. Patient demographics, BM characteristics and treatment details were carefully collected. The intracranial PFS (progression free survival) and OS (overall survival) were estimated using the Kaplan-Meier method. Twenty-five patients were treated with anti-PD-1 therapy and radiotherapy. Eighteen (72.0%) patients had SBRT (stereotactic body radiation therapy) or SRS (stereotactic radiosurgery) for BM, 1 (4.0%) patient had WBRT (whole brain radiation therapy), 6 (24.0%) patients had SBRT/SRS and WBRT. The median treatment period of anti-PD-1 therapy was 10.77 months. Objective intracranial response was observed in 15 (60%) patients, and 5 (20%) patients achieved CR (complete response). After a median follow-up of 16 months, 11 (44%) patients experienced intracranial PD (progressive disease), and 15 (60%) patients died. The median intracranial PFS and OS were 10.73 months (range, 1.67–38.83 months) and 15.87 months (range, 2.47–41.50 months), respectively. The 1-year intracranial PFS and OS were 61.9% (95% CI, 44.1–86.9%) and 62.5% (95%CI, 45.8–85.2%), respectively. Patients with BM can benefit from a combination of anti-PD-1 therapy and radiotherapy. It merits further investigation in melanoma patients with BM.

This study aimed to develop and validate a risk score for early prediction of venous thromboembolism (VTE) in patients with lung cancer. A total of 827 patients with lung cancer from February 2013 to February 2018 in our hospital were retrospectively analyzed. Demographic and clinicopathological variables independently correlated to VTE were applied to develop the risk score in the development group while examined in the validation group. The regression coefficients of multivariable logistic regression test were applied to assign a risk score system. The incidence of VTE was 12.3%, 12.7%, and 11.8% in all patients, in the development and validation groups, respectively. The 496 patients in the development group were classified into 3 groups: low risk (scores ≤3), moderate risk (scores 4-5), and high risk (scores ≥6). The risk of VTE was significantly and positively related to the risk scores in both development and validation groups. The risk score system aided proper stratification of patients with either high or low risk of VTE in the development and validation groups ( c statistic = 0.819 and 0.827, respectively). This risk score system based on the factors with most significant correlation showed good predictive ability and is potentially useful for predicting VTE in patients with lung cancer. However, it was developed and validated by a retrospective analysis and has significant limitations, and a prospective validation with all the classic variables assessing the thrombotic risk is needed for a solid conclusion.

Abstract Background Sorafenib and transarterial chemoembolization (TACE) might both provide survival benefit for advanced hepatocellular carcinoma (HCC). Adopting either as a first-line therapy carries major cost and resource implications. We aimed to estimate the cost-effectiveness of sorafenib and TACE in advanced HCC. Methods A Markov model was constructed in a hypothetical cohort of patients aged 60 years with advanced HCC and Child-Pugh A/B cirrhosis over a 2-year time frame. Three strategies (full or dose-adjusted sorafenib and TACE) were compared in two cost settings: China and the USA. Transition probabilities, utility and costs were extracted from systematic review of 27 articles. Sensitivity analysis and Monte Carlo analysis were conducted. Results Full and dose-adjusted sorafenib respectively produced 0.435 and 0.482 quality-adjusted life years (QALYs) while TACE produced 0.375 QALYs. The incremental cost-effectiveness ratio (ICER) of full-dose sorafenib versus TACE was $101,028.83/QALY in China whereas full-dose sorafenib is a dominant strategy (ICER of -$1,014,507.20/ QALY) compared with TACE in the USA. Compared to full-dose sorafenib, dose-adjusted sorafenib was the dominant strategy with the negative ICERs in both China (−$132,238.94/QALY) and the USA (−$230,058.09/QALY). However, dose-adjusted sorafenib is not available currently, so full-dose sorafenib should be compared with TACE. As the acceptability curves shown, full-dose sorafenib was the optimal strategy at the accepted thresholds of WTP in these two countries. Specifically, full-dose sorafenib was the cost-effective treatment compared with TACE if a WTP was set above $21,670 in the USA, whereas in China, TACE could be more favorable than full-dose sorafenib if a WTP was set below $10,473. Conclusions Dose-adjusted sorafenib may be cost-effective compared to full-dose sorafenib or TACE for advanced HCC patients. However, when confining the comparisons between full-dose sorafenib and TACE, full-dose sorafenib was cost-effective for these patients, under the accepted thresholds of WTP.

BackgroundAn elevated preoperative neutrophil-to-lymphocyte ratio (NLR) has been reported to be a prognostic factor for hepatocellular carcinoma (HCC) patients after treatment. However, the clinical implication of postoperative NLR change remains unclear.Materials and methodsFrom May 2005 to Aug 2008, a cohort of consecutive 178 small HCC patients treated with radiofrequency ablation (RFA) was retrospectively reviewed. The NLR was recorded within 3 days before and 1 month after RFA. Baseline characteristics, overall survival (OS) and recurrence free survival (RFS) were compared according to preoperative NLR and/or postoperative NLR change. Prognostic factors were assessed by multivariate analysis.ResultsCompared with preoperative NLR level, postoperative NLR decreased in 87 patients and increased in 91 patients after RFA. No significant differences were identified between two groups in commonly used clinic-pathologic features. The 1, 3, 5 years OS was 98.8%, 78.6%, 67.1% for NLR decreased group, and 92.2%, 55.5%, 35.4% for NLR increased group respectively (PConclusionThe postoperative NLR change was an independent prognostic factor for small HCC patient undergoing RFA, and patients with decreased NLR indicated better survival than those with increased NLR.

Background: We aimed to investigate the efficacy of a novel regimen, external beam radiation (RT) combined with trans arterial chemoembolization (TACE) and lenvatinib (LEN), in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus. Methods: We prospectively observed 102 participants from three tertiary medical centers in China between October 2018 and October 2020, who chose either RT plus TACE and LEN (RT-TACE-LEN) or TACE and LEN (TACE-LEN). LEN (12 mg or 8 mg daily) was administrated orally and continued until progression or intolerable side effects were noted. TACE was given one day after administration of LEN, and RT began within 4 weeks after the first TACE. The median dose/fraction of RT was 50 Gy/25 fractions (range: 45-60 Gy/25 fractions). Overall survival and progression free survival were compared between two groups, and complications were assessed. Results: Both 51 patients received RT-TACE-LEN and TACE-LEN, respectively. Most patients had tumor size> 5 cm (73.8%) and tumor number≥ 2 (69.9%). The overall incidence of toxicities was significantly higher in RT-TACE-LEN group than TACE-LEN group (100% vs. 64.7%, p< 0.001), but incidences of grade 3-4 toxicities were comparable (54.9% vs. 49.0%, p= 0.552). Both median overall survival (22.8 vs. 17.1 months, p= 0.031) and median progression-free survival (12.8 vs. 10.5 months, p= 0.035) were significantly longer after RT-TACE-LEN treatment than TACE-LEN. Conclusions: The addition of RT to TACE and LEN was safe, and might improve clinical outcomes of patients with advanced HCC, which needs conformation from further studies. [ABSTRACT FROM AUTHOR]