Novel Optical Modulator Photonic Device Based on TiN/Ti3C2 Heterojunction.

Due to the ability of optical modulators to achieve rapid modulation of optical signals, meeting the demands of high-speed data transmission, modulators based on different novel nanomaterials have become one of the research hotspots over the past dacade. Recently, TiN/Ti3C2 heterojunction exhibits highly efficient thermo-optic performance and extremely strong stability. Therefore, we have demonstrated an all-optical modulator based on the principle of Michelson interference and the thermo-optic effect in this paper. The modulator employs a TiN/Ti3C2 heterojunction-coated microfiber (THM) and further demonstrates its ability to generate phase shifts through an ASE light source. The modulator, with a phase shift slope of 0.025π/mW, can also convert the phase shifts of signal light into amplitude modulation through Michelson interference. The fixed signal light wavelength is 1552.09 nm, and the modulation depth is stable at about 26.4 dB within a wavelength detuning range of -10 to 6 nm; The waveforms of signal light at modulation rates of 500 Hz, 1000 Hz, 2000 Hz, and 3000 Hz were tested, and a 3 dB modulation bandwidth of 2 kHz was measured. The all-optical modulator based on THM has the advantages of high efficiency and stability and has broad application prospects in the fields of all-optical signal processing and high-speed optical communication.

Optimized path planning and scheduling strategies for connected and automated vehicles at single-lane roundabouts.

This paper focuses on the cooperative driving challenges of connected and automated vehicles (CAVs) at single-lane roundabouts. First, a geometric path planning method is proposed for CAVs navigating a single-lane roundabout. Based on this method, a vehicle roundabout model is established. Four potential traffic scenarios for CAVs are established, and the optimal arrival times at conflict points are analyzed. By correlating the optimal arrival times at conflict points with the optimal entry times into the roundabout, the multi-vehicle coordination problem in complex intersections is simplified to a speed control issue during entry. Utilizing the principles of optimal control and Pontryagin minimization, two speed optimization strategies are proposed. Finally, MATLAB is employed for simulation analysis. The results indicate that the control strategy proposed in this paper enables the system to clearly identify potential conflicts between vehicles and implement an optimal control strategy, ensuring that vehicles can navigate the roundabout efficiently in terms of time and fuel without collisions. Additionally, the minimum time interval is established at 0.2 seconds to completely prevent vehicle collisions. In this study, the fusion problem involving two vehicles at a single conflict point is further expanded to encompass multiple vehicles at multiple conflict points. Thus, the efficient scheduling of multiple vehicles in single-lane roundabouts is realized.

NLRP3-mediated IL-1ß in regulating the imbalance between Th17 and Treg in experimental autoimmune prostatitis.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a urinary disorder that affects youthful to middle-aged men most frequently. It has been revealed that Th17/Treg imbalance is a crucial factor in the pathophysiological mechanisms behind this disease. However, this imbalance's mechanisms are unknown. In the experimental autoimmune prostatitis (EAP) mouse model, the NLRP3 inflammasome was turned on, IL-1ß levels went up. Moreover, there exists a discernible positive association between the upsurge in IL-1ß and the perturbation of Th17/Treg equilibrium. Additionally, we have revealed that IL-1ß plays a vital role in promoting the differentiation of Naïve CD4+ T cells into the Th17 cells and enhances the conversion of Treg cells into Th17 cells. Further studies revealed that IL-1ß promotes STAT3 phosphorylation, which is what causes Treg cells to become Th17 cells. All data strongly suggest that the NLRP3 inflammatory influence Th17 cell development and the conversion of Treg cells into Th17 cells through IL-1ß, disrupting the Th17/Treg balance and exacerbating EAP inflammation. In this article, we provide new theories for the pathogenesis of CP/CPPS and propose new prevention and therapy methods.

Efficacy and Safety of Re-Challenging PD-1 Inhibitors in Second-Line Treatment in Metastatic Nasopharyngeal Carcinoma Previously Treated with Chemotherapy and PD-1 Inhibitors.

Background: We aim to evaluate the efficacy and safety of anti-PD1 rechallenge in combination with chemotherapy in patients with metastatic nasopharyngeal carcinoma (mNPC) who have progressed on prior anti-PD1 therapy. Patients and Methods: We enrolled patients with mNPC who received chemotherapy combined with PD-1 immune-checkpoint inhibitors (ICIs) or chemotherapy alone after prior progression of anti-PD1 therapy. The primary endpoint was progress-free survival (PFS), and the secondary endpoints included overall survival (OS), disease control rate (DCR) and objective response rate (ORR). Results: A total of 96 patients were eligible between January 2015 and December 2020. Thirty-seven (38.5%) were in the PD-1 ICIs re-challenge group, while the remaining 59 patients (61.5%) were in the chemotherapy group. The ORR and DCR of PD-1 ICIs group and chemotherapy group were 37.8% vs 23.7% and 86.5% vs.74.5%, respectively. After a median follow-up period of 21.1 months (IQR 16.1-28.7), the log-rank analysis demonstrated a significantly improved PFS in the PD-1 ICIs re-challenge group compared to the chemotherapy group (8.4 months [95% CI 4.3-14.0] vs 5.0 months [95% CI 2.8-7.2], P = 0.03). However, no significant difference in OS was observed between the two groups (28.3 vs 24.1 months, P = 0.09). The two groups had similar adverse reactions, but the incidence of grade 3 or 4 thrombocytopenia was significantly higher in the PD-1 ICIs re-challenge group (18.9% vs 3.4%, P = 0.025). Conclusion: mNPC patients who progressed from prior anti-PD1 therapy could benefit from the anti-PD1 rechallenge in combination with chemotherapy. However, further validation is needed.

Effect of Online Clinic on Follow-Up Compliance and Survival Outcomes in Nasopharyngeal Carcinoma: Real-World Cohort Study from Endemic Area.

Nasopharyngeal carcinoma (NPC) requires regular follow-up to detect recurrence as early as possible. However, many patients are unable to regularly follow up due to the inconvenience of the conventional approach. Therefore, this study was designed to investigate the impact of the online clinic on follow-up compliance and prognosis in NPC patients. Patients who were first diagnosed with NPC between April 2019 and November 2019 were enrolled. Good follow-up compliance was defined as having at least one follow-up visit every 6 months within 2 years after treatment completion. Sensitivity analyses were performed using a propensity score matching model. A total of 539 (42%) patients used online follow-up while 731 (58%) used traditional follow-up. The median age of patients in the online cohort was lower than that in the traditional cohort (44 vs. 47, p < 0.001). Compared with the traditional cohort, the online cohort had significantly better follow-up compliance (57.3% vs. 17.1%, p < 0.001) and a higher 2-year PFS rate (98.1% vs. 94.4%, p = 0.003). Survival analysis showed that online follow-up was an independent factor for better survival prognosis (HR 0.39, 95%CI 0.20-0.74, p = 0.004). Sensitivity analysis further confirmed these results. Our study found that the online clinic increased follow-up compliance and improved prognosis in NPC patients.

Nab-paclitaxel, cisplatin, and capecitabine versus cisplatin and gemcitabine as first line chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma: randomised phase 3 clinical trial.

OBJECTIVE: To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma. DESIGN: Phase 3, open label, multicentre, randomised trial. SETTING: Four hospitals located in China between September 2019 and August 2022. PARTICIPANTS: Adults (≥18 years) with recurrent or metastatic nasopharyngeal carcinoma. INTERVENTIONS: Patients were randomised in a 1:1 ratio to treatment with either nab-paclitaxel (200 g/m2 on day 1), cisplatin (60 mg/m2 on day 1), and capecitabine (1000 mg/m2 twice on days 1-14) or gemcitabine (1 g/m2 on days 1 and 8) and cisplatin (80 mg/m2 on day 1). MAIN OUTCOME MEASURES: Progression-free survival was evaluated by the independent review committee as the primary endpoint in the intention-to-treat population. RESULTS: The median follow-up was 15.8 months in the prespecified interim analysis (31 October 2022). As assessed by the independent review committee, the median progression-free survival was 11.3 (95% confidence interval 9.7 to 12.9) months in the nab-TPC cohort compared with 7.7 (6.5 to 9.0) months in the gemcitabine and cisplatin cohort. The hazard ratio was 0.43 (95% confidence interval 0.25 to 0.73; P=0.002). The objective response rate in the nab-TPC cohort was 83% (34/41) versus 63% (25/40) in the gemcitabine and cisplatin cohort (P=0.05), and the duration of response was 10.8 months in the nab-TPC cohort compared with 6.9 months in the gemcitabine and cisplatin cohort (P=0.009). Treatment related grade 3 or 4 adverse events, including leukopenia (4/41 (10%) v 13/40 (33%); P=0.02), neutropenia (6/41 (15%) v 16/40 (40%); P=0.01), and anaemia (1/41 (2%) v 8/40 (20%); P=0.01), were higher in the gemcitabine and cisplatin cohort than in the nab-TPC cohort. No deaths related to treatment occurred in either treatment group. Survival and long term toxicity are still being evaluated with longer follow-up. CONCLUSION: The nab-TPC regimen showed a superior antitumoural efficacy and favourable safety profile compared with gemcitabine and cisplatin for recurrent or metastatic nasopharyngeal carcinoma. Nab-TPC should be considered the standard first line treatment for recurrent or metastatic nasopharyngeal carcinoma. Longer follow-up is needed to confirm the benefits for overall survival. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900027112.

GateView: A Multi-Omics Platform for Gene Feature Analysis of Virus Receptors within Human Normal Tissues and Tumors.

Viruses are obligate intracellular parasites that rely on cell surface receptor molecules to complete the first step of invading host cells. The experimental method for virus receptor screening is time-consuming, and receptor molecules have been identified for less than half of known viruses. This study collected known human viruses and their receptor molecules. Through bioinformatics analysis, common characteristics of virus receptor molecules (including sequence, expression, mutation, etc.) were obtained to study why these membrane proteins are more likely to become virus receptors. An in-depth analysis of the cataloged virus receptors revealed several noteworthy findings. Compared to other membrane proteins, human virus receptors generally exhibited higher expression levels and lower sequence conservation. These receptors were found in multiple tissues, with certain tissues and cell types displaying significantly higher expression levels. While most receptor molecules showed noticeable age-related variations in expression across different tissues, only a limited number of them exhibited gender-related differences in specific tissues. Interestingly, in contrast to normal tissues, virus receptors showed significant dysregulation in various types of tumors, particularly those associated with dsRNA and retrovirus receptors. Finally, GateView, a multi-omics platform, was established to analyze the gene features of virus receptors in human normal tissues and tumors. Serving as a valuable resource, it enables the exploration of common patterns among virus receptors and the investigation of virus tropism across different tissues, population preferences, virus pathogenicity, and oncolytic virus mechanisms.

Organic dye-loaded reduced titanium dioxide as a broadband saturable absorber for ultrafast fiber lasers.

As a rising star among metal oxide nanomaterials, titanium dioxide (TiO2) has been widely investigated and employed in optical applications because of its excellent optical properties. In this work, we demonstrate the efficient and broadband nonlinear photonic properties of methylene blue (MB)-loaded reduced TiO2 (TiO2-x-MB) and explore the performance of a TiO2-x-MB-microfiber photonic device in broadband ultrafast photonics. Within an erbium-doped fiber laser (EDFL) system, utilizing the TiO2-x-MB-microfiber photonic device as a saturable absorber (SA), steady mode-locked pulses together with chaotic pulses were successfully achieved at the wavelength of 1.55 µm. Furthermore, by incorporating the TiO2-x-MB SA into a thulium-doped fiber laser (TDFL) system, an ultrashort single pulse and multiple pulses were obtained at 2.0 µm. These results indicate that TiO2-x-MB is an excellent nanomaterial for use in mode-locked lasers, being an alternative candidate for ultrafast fiber lasers via exploiting the chemical and physical properties of oxide nanomaterials.

Molecular mechanism of Rhizoma Polygonati in the treatment of nephrolithiasis: network pharmacology analysis and in vivo experimental verification.

Rhizoma Polygonati (RP) is the dried rhizome of the liliaceous plant. It has anti-inflammatory and anti-apoptosis effects. But its role in kidney stones has not been studied. The purpose of this study was to verify the effect of RP in the treatment of nephrolithiasis through network pharmacological analysis and in vivo experiments. The active compounds and protein targets of RP, as well as the potential targets of the nephrolithiasis were searched from the database. The protein-protein interaction (PPI) network diagram and the drug-compounds-targets-disease network were constructed. The enrichment analysis was performed by Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, the effect of RP on the prevention and treatment of nephrolithiasis was experimentally validated in vivo. Animal experiments showed that RP ameliorates renal function and reduced crystal deposition in a mouse model. It may act through anti-inflammation and anti-apoptosis. Our study showed that RP could prevent and treat nephrolithiasis by inhibiting apoptosis and inflammation, which provided a new efficacy and clinical application for RP.

Camrelizumab and apatinib plus induction chemotherapy and concurrent chemoradiotherapy in stage N3 nasopharyngeal carcinoma: a phase 2 clinical trial.

The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Patients with N3 nasopharyngeal carcinoma have a high risk of distant metastasis, however, if the addition of immunotherapy to standard treatment could improve efficacy is unclear. In this phase II clinical trial (ChiCTR2000032317), 49 patients with stage TanyN3M0 nasopharyngeal carcinoma were enrolled and received the combination of three cycles of induction chemotherapy, camrelizumab and apatinib followed by chemoradiotherapy. Here we report on the primary outcome of distant metastasis-free survival and secondary end points of objective response rate, failure-free survival, locoregional recurrence-free survival, overall survival and toxicity profile. After induction therapy, all patients had objective response, including 13 patients (26.5%) with complete response. After a median follow-up of 28.7 months, the primary endpoint of 1-year distant metastasis-free survival was met for the cohort (1-year DMFS rate: 98%). Grade≥3 toxicity appeared in 32 (65.3%) patients, with the most common being mucositis (14[28.6%]) and nausea/vomiting (9[18.4%]). In this work, camrelizumab and apatinib in combination with induction chemotherapy show promising distant metastasis control with acceptable safety profile in patients with stage TanyN3M0 nasopharyngeal carcinoma.

Toripalimab plus capecitabine in the treatment of patients with residual nasopharyngeal carcinoma: a single-arm phase 2 trial.

Patients with residual nasopharyngeal carcinoma after receiving definitive treatment have poor prognoses. Although immune checkpoint therapies have achieved breakthroughs for treating recurrent and metastatic nasopharyngeal carcinoma, none of these strategies have been assessed for treating residual nasopharyngeal carcinoma. In this single-arm, phase 2 trial, we aimed to evaluate the antitumor efficacy and safety of toripalimab (anti-PD1 antibody) plus capecitabine in patients with residual nasopharyngeal carcinoma after definitive treatment (ChiCTR1900023710). Primary endpoint of this trial was the objective response rate assessed according to RECIST (version 1.1). Secondary endpoints included complete response rate, disease control rate, duration of response, progression-free survival, safety profile, and treatment compliance. Between June 1, 2020, and May 31, 2021, 23 patients were recruited and received six cycles of toripalimab plus capecitabine every 3 weeks. In efficacy analyses, 13 patients (56.5%) had complete response, and 9 patients (39.1%) had partial response, with an objective response rate of 95.7% (95% CI 78.1-99.9). The trial met its prespecified primary endpoint. In safety analyses, 21 of (91.3%) 23 patients had treatment-related adverse events. The most frequently reported adverse event was hand-foot syndrome (11 patients [47.8%]). The most common grade 3 adverse event was hand-foot syndrome (two patients [8.7%]). No grades 4-5 treatment-related adverse events were recorded. This phase 2 trial shows that combining toripalimab with capecitabine has promising antitumour activity and a manageable safety profile for patients with residual nasopharyngeal carcinoma.

Combination strategy exploration for prior treated recurrent or metastatic nasopharyngeal carcinoma in the era of immunotherapy.

To assess the efficacy and safety of the combination of immune checkpoint inhibitors (ICIs) and target therapy (anti-angiogenesis or EGFR inhibitors) as a second-line or subsequent treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M NPC), we conducted a retrospective study. In this study, previously treated R/M NPC patients were administered one of the following treatment: ICIs combined with target therapy and chemotherapy (ITC), ICIs combined with target therapy alone (IT), ICIs combined with chemotherapy (IC), or chemotherapy alone (C). The primary endpoint under consideration was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety measures. A total of 226 patients participated in this study, with 70 receiving the ITC regimen, 48 receiving IT, 48 treated with IC, and 60 undergoing C alone. The median PFS for the four cohorts was 20.67, 13.63, 12.47, and 7.93 months respectively. Notably, ITC regimen yielded the most favorable PFS among these cohorts. The ITC cohort exhibited a comparable tumor response and safety profile to the IT and IC cohorts (p > 0.05), but superior tumor response compared to the C cohort (p < 0.05). The ITC regimen also conferred a significant improvement in OS when comparing to C alone (HR 0.336, 95%CI 0.123-0.915, p = 0.033). The IT and IC regimens achieved a nearly identical PFS (HR 0.955, 95%CI 0.515-1.77, p = 0.884), although the IT regimen was associated with a lower occurrence of SAEs in contrast to the IC regimen (p < 0.05). In addition, the IT regimen demonstrated superior PFS (HR 0.583, 95%CI 0.345-0.985, p = 0.044) and fewer SAEs when compared to C alone (p < 0.05). These findings collectively support the notion that the combination of ICIs, target and chemotherapy exhibits robust antitumor activity in previously treated R/M NPC patients, without a significant increase in adverse events.

Effect of lumbar bone marrow composition on bone marrow diffusion signal intensity and apparent diffusion coefficient in healthy adult women / 重庆医学

Objective To analyze the effect of lumbar bone marrow composition on bone marrow diffu-sion-weighted imaging(DWI)in healthy adult women.Methods Retrospective analysis was performed on up-per abdominal MRI of 103 adult women.Bone marrow fat fraction of lumbar vertebra was measured according to two-point water-lipid separation technique,and apparent diffusion coefficient(ADC)value of lumbar verte-bra was measured according to DWI image(b=800 s/mm2).The subjects were divided into the high-signal group and the equal-low-signal group according to the signal intensity of lumbar vertebra and adjacent erector spine muscles.The effects of age,lumbar bone marrow fat fraction and menstrual status on the signal intensity and ADC value of lumbar bone marrow diffusion were analyzed.Finally,the correlation between lumbar bone marrow fat fraction and ADC value was analyzed.Results Univariate analysis showed that the lumbar bone marrow diffusion signal intensity and ADC value were affected by age,lumbar bone marrow fat fraction and menstrual status(P＜0.001).Multivariate analysis showed that age(P=0.046)and lumbar bone marrow fat fraction(P=0.005)were the influencing factors of lumbar bone marrow diffusion signal intensity,but men-strual status(P=0.242)was not the influencing factor.In addition,lumbar bone marrow fat fraction(P＜0.001)was the factor influencing the ADC value of lumbar bone marrow,and the two were negatively correla-ted(r=-0.607,P＜0.001),but age(P=0.497)and menstrual status(P=0.082)were not the influencing factors.Conclusion The bone marrow composition of lumbar vertebrae in healthy adult women has significant effects on the signal intensity and ADC value of bone marrow diffusion.

Quercetin Alleviates Lipopolysaccharide-Induced Cardiac Inflammation via Inhibiting Autophagy and Programmed Cell Death / 生物医学与环境科学（英文）

OBJECTIVE@#The aim of this study is to explore the potential modulatory role of quercetin against Endotoxin or lipopolysaccharide (LPS) induced septic cardiac dysfunction.@*METHODS@#Specific pathogen-free chicken embryos ( n = 120) were allocated untreated control, phosphate buffer solution (PBS) vehicle, PBS with ethanol vehicle, LPS (500 ng/egg), LPS with quercetin treatment (10, 20, or 40 nmol/egg, respectively), Quercetin groups (10, 20, or 40 nmol/egg). Fifteen-day-old embryonated eggs were inoculated with abovementioned solutions via the allantoic cavity. At embryonic day 19, the hearts of the embryos were collected for histopathological examination, RNA extraction, real-time polymerase chain reaction, immunohistochemical investigations, and Western blotting.@*RESULTS@#They demonstrated that the heart presented inflammatory responses after LPS induction. The LPS-induced higher mRNA expressions of inflammation-related factors (TLR4, TNFα, MYD88, NF-κB1, IFNγ, IL-1β, IL-8, IL-6, IL-10, p38, MMP3, and MMP9) were blocked by quercetin with three dosages. Quercetin significantly decreased immunopositivity to TLR4 and MMP9 in the treatment group when compared with the LPS group. Quercetin significantly decreased protein expressions of TLR4, IFNγ, MMP3, and MMP9 when compared with the LPS group. Quercetin treatment prevented LPS-induced increase in the mRNA expression of Claudin 1 and ZO-1, and significantly decreased protein expression of claudin 1 when compared with the LPS group. Quercetin significantly downregulated autophagy-related gene expressions (PPARα, SGLT1, APOA4, AMPKα1, AMPKα2, ATG5, ATG7, Beclin-1, and LC3B) and programmed cell death (Fas, Bcl-2, CASP1, CASP12, CASP3, and RIPK1) after LPS induction. Quercetin significantly decreased immunopositivity to APOA4, AMPKα2, and LC3-II/LC3-I in the treatment group when compared with the LPS group. Quercetin significantly decreased protein expressions of AMPKα1, LC3-I, and LC3-II. Quercetin significantly decreased the protein expression to CASP1 and CASP3 by immunohistochemical investigation or Western blotting in treatment group when compared with LPS group.@*CONCLUSION@#Quercetin alleviates cardiac inflammation induced by LPS through modulating autophagy, programmed cell death, and myocardiocytes permeability.

A human-specific insertion promotes cell proliferation and migration by enhancing TBC1D8B expression.

Human-specific insertions play important roles in human phenotypes and diseases. Here we reported a 446-bp insertion (Insert-446) in intron 11 of the TBC1D8B gene, located on chromosome X, and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5. Interestingly, Insert-446 was present in the human Neanderthal and Denisovans genomes, and was fixed in humans after human-chimpanzee divergence. We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques. In addition, over-expression TBC1D8B promoted cell proliferation and migration through "a dual finger" catalytic mechanism (Arg538 and Gln573) in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo. Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells. Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene. These findings provide a significant insight into the effects of human-specific insertions on evolution.

Efficacy and safety of sintilimab plus bevacizumab in metastatic nasopharyngeal carcinoma after failure of platinum-based chemotherapy: an open-label phase 2 study.

Background: There are limited treatment options for patients with metastatic nasopharyngeal carcinoma (mNPC) after failure of platinum-based chemotherapy. In this trial, we assessed the efficacy and safety of sintilimab plus bevacizumab in patients with mNPC where platinum-based chemotherapy has been ineffective. Methods: This was a single-centre, open-label, single-arm, phase 2 trial in Guangzhou, China for patients with mNPC progressed after at least one line of systemic therapy. Eligible patients were between 18 and 75 years old, were histologically confirmed differentiated or undifferentiated non-keratinized NPC, were ineffective after platinum-based chemotherapy, and they had at least one measurable metastatic lesion assessed with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST V.1.1) by investigators and unsuitable for local surgery or radiotherapy. Key exclusion criterion was previous treatment with anti-PD-1/PD-L1 antibodies plus anti-VEGF antibodies and high risk of hemorrhage or nasopharyngeal necrosis. Patients were enrolled and received sintilimab (200 mg) plus bevacizumab (7.5 mg/kg) intravenously every 3 weeks. Intention-to-treat population was included in primary endpoint analyses and safety analyses. The primary endpoint was objective response rate (ORR) assessed by investigators following the guidelines of RECIST V1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. This trial is registered with ClinicalTrials.gov (NCT04872582). Findings: Between July 29, 2021 and August 16, 2022, 33 patients were enrolled. Median age was 46 years (range, 18-64 years), and 63.6% of patients had previously received two or more lines of chemotherapy for metastatic disease. Median follow-up was 7.6 months (range, 4.1-17.5 months). ORR was 54.5% (95% CI, 36.4-71.9%) with 3 complete responses (9.1%) and 15 partial responses (45.5%). Median PFS was 6.8 months (95% CI, 5.2 months to not estimable). Median DOR was 7.2 months (95% CI, 4.4 months to not estimable). Median OS was not reached. The most common potential immune-related adverse event (AE) was Grade 1-2 hypothyroidism (42.4%). Treatment-related grade 3 or 4 AEs occurred in 7 patients (21.2%), including nasal necrosis (3/33), hypertension (1/33), pruritus (1/33), total bilirubin increased (1/33) and anaphylactic shock (1/33). No treatment-related deaths and severe epistaxis occurred. Interpretation: This phase 2 trial showed that sintilimab plus bevacizumab demonstrated promising antitumour activity and manageable toxicities in patients with mNPC after failure of platinum-based chemotherapy. Further trials are warranted, and the detailed mechanisms need to be elucidated. Funding: The Guangdong Basic and Applied Basic Research Foundation, the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, and the Science and Technology Planning Project of International Cooperation of Guangdong Province.

Anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR treatment beyond progression in recurrent/metastatic nasopharyngeal carcinoma patients.

We aim to evaluate the efficacy and safety of anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR treatment in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) patients who progressed to previous anti-PD1 therapy. Enrolled patients were divided into a combination group and a chemotherapy only group. A total of 145 patients were enrolled. The median progress-free survival (mPFS) was 7.9 months and 4.4 months, respectively for the two groups. The combination group exhibited significantly longer PFS (HR=0.363, p < 0.001), and better disease control ratio (DCR, p = 0.022) compared with the chemotherapy group. Among the combination group, longer PFS was found in those patients who received different PD1 inhibitor from prior therapy, reached object response rate (ORR) from prior anti-PD1 therapy, and EBV DNA ≤ 1500 copy/ml before therapy, comparing to the corresponding other patients. R/M NPC patients who progressed from prior anti-PD1 therapy could benefit from the anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR agents.

Evaluation of the efficacy of ureteroscopic lithotripsy for proximal impacted ureter stones based on a new scoring standard: a bicentric matched-pair analysis.

OBJECTIVE: To evaluate the clinical efficacy of ureteroscopic lithotripsy (URSL) in the treatment of proximal impacted ureter stones (PIUS) based on a new scoring standard in two medical centers. METHODS: The data of 45 patients with Complicated PIUS (total stone score ≥ 3) and 350 with Simple PIUS (total stone score < 3) who underwent URSL were collected in this retrospective study between January 2015 and June 2022. The definition and scoring standards for preoperative high-risk factors associated with stones included whether the diameter of the stone was > 2 cm, stone density was > 1000 HU, there was a history of lithotripsy, the degree of hydronephrosis was greater than moderate, and there was an infection. Scores for stones were then assigned (yes = 1, no = 0), and the Complicated stone case was defined as a total stone score ≥ 3; the Simple stone case was defined as a total stone score < 3. During the same period, 45 patients were selected from the patients with Simple stone cases as the control group, matched at a 1:1 ratio to index Complicated stone cases with regard to age, sex, and BMI. Perioperative data were compared between the two groups. RESULTS: All 90 operations were successfully completed. Compared to the Simple cases group, the surgical duration of the Complicated group was significantly longer (59.69 ± 28.06 min vs. 73.46 ± 27.12 min, p < 0.05), and stone-free rate (SFR) was significantly lower (88.89 vs. 68.9%, p < 0.05). There was a significant difference in complication rate between the two groups regarding Clavien grade I, II, or III complications (20.0% in Complicated cases group vs. 8.9% in Simple cases group, p = 0.037). As for the length of the hospital stay and the total treatment cost, the two groups have no difference. CONCLUSION: For Simple stone cases, URSL had a better SFR and higher surgical efficacy, whereas complicated stone cases had a high complication rate and long operation time. Thus, we suggest that URSL is the preferred choice for Simple stone cases rather than complicated stone cases.

Epstein-Barr virus DNA seropositivity links distinct tumoral heterogeneity and immune landscape in nasopharyngeal carcinoma.

Background: Epstein-Barr virus (EBV) DNA seronegative (Sero-) and seropositive (Sero+) nasopharyngeal carcinoma (NPC) are distinctly different disease subtypes. Patients with higher baseline EBV DNA titers seem to benefit less from anti-PD1 immunotherapy, but underlying mechanisms remain unclear. Tumor microenvironment (TME) characteristics could be the important factor affecting the efficacy of immunotherapy. Here, we illuminated the distinct multicellular ecosystems of EBV DNA Sero- and Sero+ NPCs from cellular compositional and functional perspectives at single-cell resolution. Method: We performed single-cell RNA sequencing analyses of 28,423 cells from ten NPC samples and one non-tumor nasopharyngeal tissue. The markers, function, and dynamics of related cells were analyzed. Results: We found that tumor cells from EBV DNA Sero+ samples exhibit low-differentiation potential, stronger stemness signature, and upregulated signaling pathways associated with cancer hallmarks than that of EBV DNA Sero- samples. Transcriptional heterogeneity and dynamics in T cells were associated with EBV DNA seropositivity status, indicating different immunoinhibitory mechanisms employed by malignant cells depending on EBV DNA seropositivity status. The low expression of classical immune checkpoints, early-triggered cytotoxic T-lymphocyte response, global activation of IFN-mediated signatures, and enhanced cell-cell interplays cooperatively tend to form a specific immune context in EBV DNA Sero+ NPC. Conclusions: Collectively, we illuminated the distinct multicellular ecosystems of EBV DNA Sero- and Sero+ NPCs from single-cell perspective. Our study provides insights into the altered tumor microenvironment of NPC associated with EBV DNA seropositivity, which will help direct the development of rational immunotherapy strategies.

The NF-κB pathway plays a vital role in rat salivary gland atrophy model.

Objective: The aim of this study was to explore the histopathological and genetic changes in the submandibular glands after duct ligation and provide important clues to functional regeneration. Design: We established a rat salivary gland duct ligation model and observed pathological changes in the rat submandibular gland on day 1 and weeks 1, 2, 3, and 4 using hematoxylin and eosin staining, Alcian blue-periodic acid Schiff staining, Masson staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), and immunohistochemical staining. RNA sequencing was performed on normal salivary glands and those from the ligation model after 1 week. Significantly differentially expressed genes were selected, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Results: Apoptosis levels and histological and functional KEGG pathway analyses showed that injury to the salivary gland after ligation gradually increased. The TGF-ß pathway was activated and promoted fibrosis. RNA sequencing results and further verification of samples at week 1 showed that the NF-κB pathway plays a vital role in salivary gland atrophy. Conclusions: Our results detailed the pathological changes in the submandibular gland after ligation and the important functions of the NF-κB pathway.