A single-arm, multicenter, phase 2 clinical study of recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate (MRG002) in HER2-positive unresectable locally advanced or metastatic urothelial carcinoma.

BACKGROUND: MRG002 is a novel HER2-targeted antibody-drug conjugate being investigated in the MRG002-006 trial to evaluate the efficacy and safety in HER2-positive urothelial carcinoma patients. METHODS: This is an open-label, single-arm, multicenter phase II study. Eligibility criteria included: histologically confirmed HER2 IHC 2 + or 3 + UC, prior received ≥ 1 standard treatment. Patients in this study received MRG002 every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was confirmed ORR per RECIST 1.1. RESULTS: As of February 24, 2023, a total of 43 patients were enrolled. The median age was 60. 9 patients were dosed at 2.6 mg/kg and 34 patients were dosed at 2.2 mg/kg. At baseline, most patients (29/43) received ≥ 2 lines of treatment and 35 (81.4%) patients had prior ICI therapy. FISH test was performed in 41 patients and 9 (22.0%) were positive. By the cut-off date, 41 patients were evaluable and the ORR was 53% (95%CI：38.9%-67.5%), with 6.9% CR, and the DCR was 83.7% (95%CI：70.0%-91.9%). The median PFS and OS for the 43 patients were 7.0 months (95%CI：5.4-NE) and 14.9 months (95%CI：11.9-NE), respectively. The ORR was 77.8% in 9 patients with positive HER2 FISH results. Most common treatment-related AEs were anemia (51.2%), alopecia (44.2%) and neutropenia (39.5%); most were grade 1 or 2. CONCLUSION: Preliminary results of MRG002 demonstrated a clinically meaningful response in pretreated HER-2 positive unresectable locally advanced or metastatic UC patients. MRG002 at 2.2 mg/kg was well tolerated with a manageable toxicity.

Emergence of decadal linkage between Western Australian coast and Western-central tropical Pacific.

The impact of interbasin linkage on the weather/climate and ecosystems is significantly broader and profounder than that of only appearing in an individual basin. Here, we reveal that a decadal linkage of sea surface temperature (SST) has emerged between western Australian coast and western-central tropical Pacific since 1985, associated with continuous intensification of decadal variabilities (8-16 years). The rapid SST changes in both tropical Indian Ocean and Indo-Pacific warm pool in association to greenhouse gases and volcanoes are emerging factors resulting in enhanced decadal co-variabilities between these two regions since 1985. These SST changes induce enhanced convection variability over the Maritime Continent, leading to stronger easterlies in the western-central tropical Pacific during the warm phase off western Australian coast. The above changes bring about cooling in the western-central tropical Pacific and strengthened Leeuwin Current and anomalous cyclonic wind off western Australian coast, and ultimately resulting in enhanced coupling between these two regions. Our results suggest that enhanced decadal interbasin connections can offer further understanding of decadal changes under future warmer conditions.

Prognostic analysis of lung squamous cell carcinoma patients with second primary malignancies: a SEER database study.

Background: As lung squamous cell carcinoma (LUSC) patients are at increased risk of developing a second primary cancer, this complicates the patient's condition and thus makes prognostic assessment more difficult, posing a significant prognostic challenge for clinicians. Our goal was to assess the prognosis of LUSC patients with a second primary tumor, and provide insights into appropriate therapy and monitoring strategies. Methods: Data was obtained for LUSC patients from the Surveillance, Epidemiology, and End Results (SEER) database. The LUSC patients were divided into three groups (LS-SPM, OT-LUSC and LUSC-only). Univariate and stratified analyses were performed for the baseline and clinical characteristics of the participants. Multiple regression and Kaplan-Meier survival analyses were also performed, followed by a final life table analysis. Results: In our sample of 101,626 patients, the HR for OS in the LS-SPM group was 0.40 in univariate analysis. Kaplan-Meier survival curves showed that LS-SPM patients had considerably longer lifespans compared to the other groups. The LS-SPM patients had median and mean survival times of 64 months and 89.11 months. Unadjusted and adjusted multiple regression analyses showed that LS-SPM patients had a superior survival compared to LUSC-only and OT-LUSC groups. Conclusion: LS-SPM patients have a good prognosis with aggressive therapy and immune monitoring. The present study offers novel insights into the pathophysiological causes and treatments for LS-SPM.

2D-Like Catalyst with a Micro-nanolinked Functional Surface for Water Purification.

In water purification, the performance of heterogeneous advanced oxidation processes significantly relies upon the utilization of the catalyst's specific surface area (SSA). However, the presence of the structural "dead volume" and pore-size-induced diffusion-reaction trade-off limitation restricts the functioning of the SSA. Here, we reported an effective approach to make the best SSA by changing the traditional 3D spherule catalyst into a 2D-like form and creating an in situ micro-nanolinked structure. Thus, a 2D-like catalyst was obtained which was characterized by a mini "paddy field" surface, and it exhibited a sharply decreased dead volume, a highly available SSA and oriented flexibility. Given its paddy-field-like mass-transfer routine, the organic capture capability was 7.5-fold higher than that of the catalyst with mesopores only. Moreover, such a catalyst exhibited a record-high O3-to-·OH transition rate of 2.86 × 10-8 compared with reported millimetric catalysts (metal base), which contributed to a 6.12-fold higher total organic removal per catalyst mass than traditional 3D catalysts. The facile scale preparation, performance stability, and significant material savings with the 2D-like catalyst were also beneficial for practical applications. Our findings provide a unique and general approach for designing potential catalysts with excellent performance in water purification.

Electric field-enhanced heterogeneous catalytic ozonation (EHCO) process for sulfadiazine removal: The role of cathodic reduction.

In this work, an electric field-enhanced heterogeneous catalytic ozonation (EHCO) was systematically investigated using a prepared FeOx/PAC catalyst. The EHCO process exhibited high sulfadiazine (SDZ) and TOC removal efficiency compared with electrocatalysis (EC) and heterogeneous catalytic ozonation (HCO) process. Almost 100% of SDZ was removed within 2 min, and the TOC removal reached approximately 85% within 60 min. Quenching experiments and EPR analysis suggested that the prominent SDZ and TOC removal performance is supported by the enhanced ·OH generation ability. Further study proved that H2O2 formed by O2 electrochemical reduction, peroxone reaction and electrochemical reduction of ozone contributed to improving ·OH generation. Furthermore, the EHCO system showed satisfactory stability and recyclability compared to conventional HCO systems, and the SDZ and TOC removal rates were maintained at ≥95% and ≥70% in 16 consecutive recycles, respectively. Meanwhile, XPS analysis and Boehm's titration for the FeOx/PAC catalyst used in HCO and EHCO process confirmed that the external electron supply could restrain the oxidation of surface functional groups of PAC and maintain a balance of the Fe(II)/Fe(III) ratio, which proved the critical role of cathode reduction in catalyst in situ regeneration during long consecutive recycles. In addition, the EHCO system could achieve more than 80% SDZ removal within 2 min in different water matrices. These results confirmed that the EHCO process has a wide application perspective for refractory organics removal in actual wastewater.

Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2-Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials.

PURPOSE: To evaluate the efficacy and safety of disitamab vedotin (DV, RC48-ADC), a novel humanized anti-human epidermal growth factor receptor 2 (HER2) antibody conjugated with monomethyl auristatin E, in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (UC) refractory to standard or regular therapies. PATIENTS AND METHODS: The data analyzed and reported are from two phase II, open-label, multicenter, single-arm studies (RC48-C005 and RC48-C009) in patients with HER2-positive (immunohistochemistry 3+ or 2+) locally advanced or metastatic UC who have progressed on at least one previous line of systemic chemotherapy. Patients received DV treatment (2 mg/kg IV infusion, once every 2 weeks). The primary end point was objective response rate (ORR) assessed by a blinded independent review committee (BIRC). Progression-free survival (PFS), overall survival (OS), and safety were also assessed. RESULTS: One hundred and seven patients were enrolled in total. The overall confirmed ORR by BIRC was 50.5% (95% CI, 40.6 to 60.3). Consistent results were observed in prespecified subgroups including patients with liver metastasis and patients previously treated with anti-PD-1/L1 therapies. By the cutoff date of May 10, 2022, the median duration of response was 7.3 months (95% CI, 5.7 to 10.8). The median PFS and OS were 5.9 months (95% CI, 4.3 to 7.2) and 14.2 months (95% CI, 9.7 to 18.8), respectively. The most common treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (68.2%), leukopenia (50.5%), AST increased (42.1%), and neutropenia (42.1%). Fifty-eight (54.2%) patients experienced grade ≥3 TRAEs, including peripheral sensory neuropathy (18.7%) and neutropenia (12.1%). CONCLUSION: DV demonstrated a promising efficacy with a manageable safety profile in patients with HER2-positive locally advanced or metastatic UC who had progressed on at least one line of systemic chemotherapy.

Emergence of the Central Atlantic Niño.

The Atlantic Niño is characterized by sea surface warming in the equatorial Atlantic, which can trigger La Niña, the cold phase of El Niño-Southern Oscillation (ENSO). Although observations show that the Atlantic Niño has weakened by approximately 30% since the 1970s, its remote influence on ENSO remains strong. Here, we show that this apparent discrepancy is due to the existence of two types of Atlantic Niño with distinct patterns and climatic impacts, which we refer to as the central and eastern Atlantic Niño. Our results show that with equal strength, the central Atlantic Niño has a stronger influence on tropical climate than its eastern counterpart. Meanwhile, the eastern Atlantic Niño has weakened by approximately 50% in recent decades, allowing the central Atlantic Niño to emerge and dominate the remote impact on ENSO. Given the distinct climatic impacts of the two types, it is necessary to distinguish between them and investigate their behaviors and influences on climate in future studies.

An extra-chelator-free fenton process assisted by electrocatalytic-induced in-situ pollutant carboxylation for target refractory organic efficient treatment in chemical-industrial wastewater.

For traditional Fenton processes, the quenching behavior of radical contenders (e.g., most aliphatic hydrocarbons) on hydroxyl radicals (·OH) usually hinders the removal of target refractory pollutants (aromatic/heterocyclic hydrocarbons) in chemical industrial wastewater, leading to excess energy consumption. Herein, we proposed an electrocatalytic-assisted chelation-Fenton (EACF) process, with no extra-chelator addition, to significantly enhance target refractory pollutant (pyrazole as a representative) removal under high ·OH contender (glyoxal) levels. Experiments and theoretical calculations proved that superoxide radical (·O2-) and anodic direct electron transfer (DET) effectively converted the strong ·OH-quenching substance (glyoxal) to a weak radical competitor (oxalate) during the electrocatalytic oxidation process, promoting Fe2+ chelation and therefore increasing radical utilization for pyrazole degradation (reached maximum of ∼43-fold value upon traditional Fenton), which appeared more obviously in neutral/alkaline Fenton conditions. For actual pharmaceutical tailwater treatment, the EACF achieved 2-folds higher oriented-oxidation capability and ∼78% lower operation cost per pyrazole removal than the traditional Fenton process, demonstrating promising potential for future practical applications.

Efficacy and safety of LY01005 versus goserelin implant in Chinese patients with prostate cancer: A multicenter, randomized, open-label, phase III, non-inferiority trial.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04563936.

A single-centre, open-label, single-arm, fixed-sequence pharmacokinetic study of SHR3680 on repaglinide and bupropion in prostate cancer patients.

To evaluate the pharmacokinetic effects of SHR3680 on repaglinide and bupropion and its metabolite hydroxybupropion. METHODS: A single-centre, open-label, single-arm, fixed-sequence clinical trial in 18 patients with prostate cancer. RESULTS: After a single oral dose of 0.5 mg repaglinide and SHR3680, geometric mean peak plasma concentration (Cmax ) of plasma repaglinide was 14.240 and 5.887 ng/mL, geometric mean area under the concentration-time curve (AUC0-t )was 20.577 and 7.320 h ng/mL, geometric mean AUC0-∞ was 20.949 and 7.451 h ng/mL, mean half-life (t1/2 ) was 1.629 and 1.195 hours, and geometric mean oral clearance (CL/F) was 23.867 and 67.107 L/h, respectively. After a single oral administration of 150 mg bupropion and SHR3680, geometric mean Cmax of plasma bupropion was 85.430 and 33.747 ng/mL, geometric mean AUC0-t was 1003.896 and 380.158 h ng/mL, geometric mean AUC0-∞ was 1038.054 and 401.387 h ng/mL, mean t1/2 was 22.533 and 17.733 hours, and geometric mean CL/F was 144.501 and 373.705 L/h, respectively. The plasma geometric mean Cmax of its main active metabolic hydroxybupropion was 268.113 and 177.318 ng/mL, geometric mean AUC0-t was 14 283.087 and 5420.219 h ng/mL, geometric mean AUC0-∞ was 15 218.158 and 5364.625 h ng/mL, mean t1/2 were 36.069 and 16.688 hours, and geometric mean CL/F was 8.623 L/h and 27.961 L/h, respectively. CONCLUSION: Coadministration of SHR3680 with repaglinide or bupropion significantly shortened the elimination half-lives, significantly increased the apparent clearance rate, and significantly decreased the in vivo exposure of repaglinide, bupropion and hydroxybupropion compared with single administration of repaglinide or bupropion.

Integrated electro-Fenton system based on embedded U-tube GDE for efficient degradation of ibuprofen.

Ibuprofen (IBP) is a carcinogenic non-steroidal anti-inflammatory drug (NSAID). It is of certain hazard to aquatic animals and may cause potential harm to human health. As traditional methods cannot effectively remove such a pollutant, many advanced oxidation processes (AOPs) have been developed for its degradation. The electro-Fenton process has the advantages of strong oxidative ability, a synergistic effect of various degradation processes, and a wide application range. This study developed a high-performance gas diffusion electrode (GDE) for electrochemical hydrogen peroxide (H2O2) production. The optimum system performance was found at the current density of 10 mA cm-2, pH of 7.0, and air flow rate at 0.6 L min-1, where the accumulation of H2O2 could reach as high as 769.82 mg L-1. The computational fluid dynamics (CFD) simulation results revealed a fast mass-transfer property in this electro-Fenton system with U-tube GDEs, which resulted in a deep-level degradation (∼100%) of the pollutant (IBP) and a low-concentration degradation of 10 mg L-1 within a 120-min reaction period. The high-performance liquid chromatography-mass spectrometry (LC-MS) studies demonstrated that the hydroxyl radicals were the primary active species in the electro-Fenton system and that the degradation intermediates of IBP were mainly 1-(4-isobutylphenyl) ethanol and 2-hydroxy-2-(4-isobutyl phenyl) propanoic acid through four probable electro-Fenton degradation pathways. This report provides a facile and efficient way to construct a high-performance electro-Fenton reactor, which could be effectively used in advanced oxidation processes (AOPs) to remove emerging contaminants in wastewater and natural water.

Oxidative Phosphorylation-Related Signature Participates in Cancer Development, and PTPRG Overexpression Suppresses the Cancer Progression in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) was a common cancer type diagnosed with frequent metastases, harboring an unfavorable therapeutic response, and results in a poor prognosis. More promising therapeutic targets are urgently required for treating ccRCC. This study was conducted to explore the role of oxidative phosphorylation in ccRCC development and reveal its clinical potential. We first identified oxidative phosphorylation-related clusters based on consensus clustering and validated their diversity in the genome instability, environmental infiltration, and immunosuppression by Gistic, ESTIMATE, GSVA, and TIDE web tools. We also compared their prognostic and clinical feature differences and predicted the IC50 level between the clusters using pRRophetic. Subsequently, we performed weighted gene coexpression network analysis to select cluster-related genes and performed functional analysis for them. The cluster-related genes were adopted to construct a risk score and nomogram for predicting patient prognosis with predictive accuracy evaluated. Finally, we performed lentivirus to induce ccRCC cell PTPRG overexpression and conducted western blot experiments to detect the critical protein expression of oxidative phosphorylation, apoptosis, cell cycle, and epithelial-mesenchymal transition processes. Also, the cell cycle and apoptosis level were evaluated by flow cytometry. As a result, we discovered that both the C1 cluster and high-risk group predicted patient survival with high accuracy and characterized lower survival rates, lower oxidative phosphorylation levels, higher immune infiltration, and malignant clinical features. Besides, we observed that overexpression of PTPRG activated oxidative phosphorylation and inhibited apoptosis. Its overexpression also depressed the epithelial-mesenchymal transition and promoted G1/S cell cycle arrest. Comprehensively, we confirmed the anticancer role of oxidative phosphorylation in ccRCC cells and discovered its association with immune and immunosuppression. PTPRG was also identified as a potential therapeutic target due to its multiple anticancer effects. We believe this study discovered a novel mechanism of ccRCC pathological progression and will provide promising targets for therapeutic strategy development.

Bifunctional anti-PD-L1/TGF-ßRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.

BACKGROUND: Dual inhibition of PD-1/PD-L1 and TGF-ß pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-ß receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. METHODS: This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). RESULTS: In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. CONCLUSIONS: SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03710265.

Sea level extremes and compounding marine heatwaves in coastal Indonesia.

Low-lying island nations like Indonesia are vulnerable to sea level Height EXtremes (HEXs). When compounded by marine heatwaves, HEXs have larger ecological and societal impact. Here we combine observations with model simulations, to investigate the HEXs and Compound Height-Heat Extremes (CHHEXs) along the Indian Ocean coast of Indonesia in recent decades. We find that anthropogenic sea level rise combined with decadal climate variability causes increased occurrence of HEXs during 2010-2017. Both HEXs and CHHEXs are driven by equatorial westerly and longshore northwesterly wind anomalies. For most HEXs, which occur during December-March, downwelling favorable northwest monsoon winds are enhanced but enhanced vertical mixing limits surface warming. For most CHHEXs, wind anomalies associated with a negative Indian Ocean Dipole (IOD) and co-occurring La Niña weaken the southeasterlies and cooling from coastal upwelling during May-June and November-December. Our findings emphasize the important interplay between anthropogenic warming and climate variability in affecting regional extremes.

Rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy in patients with high-volume, metastatic, hormone-sensitive prostate cancer (CHART): a randomised, open-label, phase 3 trial.

BACKGROUND: Rezvilutamide, a novel androgen-receptor inhibitor with low blood-brain barrier penetration, has shown potent antitumour activity against metastatic castration-resistant prostate cancer. In this study, we aimed to evaluate the efficacy and safety of rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy (ADT) for high-volume, metastatic, hormone-sensitive prostate cancer. METHODS: CHART is a randomised, open-label, phase 3 study done at 72 hospitals in China, Poland, Czech Republic, and Bulgaria. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had high-volume metastatic, hormone-sensitive prostate cancer. Previous chemotherapy or other localised treatment for prostate cancer were not allowed. Patients were randomly assigned (1:1) to receive ADT plus either rezvilutamide (240 mg) or bicalutamide (50 mg) orally once daily. Randomisation was done via an interactive response technology system (block size of four) and stratified according to ECOG performance status and presence of visceral metastasis (excluding lymph nodes). Herein, we present the results of the preplanned interim analyses for the two co-primary endpoints of radiographic progression-free survival assessed by a blinded independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study medication. This study is ongoing, but is closed to recruitment. This trial is registered with ClinicalTrials.gov, NCT03520478. FINDINGS: Between June 28, 2018, and Aug 6, 2020, 792 patients were screened and 654 patients were randomly assigned to receive rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328). At the preplanned interim analysis for radiographic progression-free survival (data cutoff May 16, 2021), the median follow-up duration was 21·2 months (IQR 16·6-25·8). Rezvilutamide significantly improved radiographic progression-free survival compared with bicalutamide (median radiographic progression-free survival not reached [95% CI not reached-not reached] vs 25·1 months [95% CI 15·7-not reached]; hazard ratio [HR] 0·44 [95% CI 0·33-0·58]; p<0·0001). At the preplanned interim analysis for overall survival (data cutoff Feb 28, 2022), the median follow-up duration was 29·3 months (IQR 21·0-33·3). Rezvilutamide significantly improved overall survival compared with bicalutamide (HR 0·58 [95% CI 0·44-0·77]; p=0·0001; median overall survival was not reached [95% CI not reached-not reached] vs not reached [36·2-not reached]). The most common grade 3 or worse adverse events of any cause in the safety population were hypertension (26 [8%] of 323 patients in the rezvilutamide group vs 24 [7%] of 324 patients in the bicalutamide group), hypertriglyceridaemia (24 [7%] vs seven [2%]), increased weight (20 [6%] vs 12 [4%]), anaemia (12 [4%] vs 16 [5%]), and hypokalaemia (11 [3%] vs four [1%]). Serious adverse events were reported in 90 (28%) of 323 patients in the rezvilutamide group and 69 (21%) of 324 patients in the bicalutamide group. No treatment-related deaths occurred in patients in the rezvilutamide group; one treatment-related death of unknown specific cause (<1%) occurred in the bicalutamide group. INTERPRETATION: In the two interim analyses, rezvilutamide plus ADT significantly improved radiographic progression-free survival and overall survival compared with bicalutamide plus ADT in patients with high-volume, metastatic, hormone-sensitive prostate cancer, with a tolerable safety profile. FUNDING: Jiangsu Hengrui Pharmaceuticals.

Membrane Fouling and Electrochemical Regeneration at a PbO2-Reactive Electrochemical Membrane: Study on Experiment and Mechanism.

Membrane fouling and regeneration are the key issues for the application of membrane separation (MS) technology. Reactive electrochemical membranes (REMs) exhibited high, stable permeate flux and the function of chemical-free electrochemical regeneration. This study fabricated a micro-filtration REM characterized by a PbO2 layer (PbO2-REM) to investigate the electro-triggered anti-fouling and regeneration progress within REMs. The PbO2-REM exhibited a three-dimensional porous structure with a few branch-like micro-pores. The PbO2-REM could alleviate Humic acid (HA) and Bisphenol A (BPA) fouling through electrochemical degradation combined with bubble migration, which achieved the best anti-fouling performance at current density of 4 mA cm-2 with 99.2% BPA removal. Regeneration in the electro-backwash (e-BW) mode was found as eight times that in the forward wash and full flux recovery was achieved at a current density of 3 mA cm-2. EIS and simulation study also confirmed complete regeneration by e-BW, which was ascribed to the air-water wash formed by bubble migration and flow. Repeated regeneration tests showed that PbO2-REM was stable for more than five cycles, indicating its high durability for practical uses. Mechanism analysis assisted by finite element simulation illustrated that the high catalytic PbO2 layer plays an important role in antifouling and regeneration.

Removal performance and mechanisms of Pb(II) and Sb(V) from water by iron-doped phosphogypsum: single and coexisting systems.

The serious environmental risks caused by Pb(II) and Sb(V) co-contamination increase the need for their efficient and simultaneous removal. In this study, the remediation feasibility by Fe-doped phosphogypsum (FPG) was elucidated for single systems with Pb or Sb pollutant and coexisting systems with both from water. As for single systems, Fe doping effectively enhanced the Pb(II) removal performance by phosphogypsum (PG) at low Pb(II) concentrations of below 100 mg/L via the combination of precipitation and complexation. The optimal removal rate of Sb(V) by FPG increased by 2.08-3.31 times as compared to that of by PG (10-120 mg/L), mainly due to the strong affinity of iron hydroxyl (≡Fe-O-H) towards Sb(V). Compared with the single systems, the coexistence greatly enhanced the Pb(II) and Sb(V) removal performance by FPG, and the interaction behavior between Pb(II) and Sb(V) on the FPG was concentration dependent. Briefly, the sorption of FPG controlled the elimination of low coexisting concentrations of Pb(II) and Sb(V), whereas the co-precipitation process between Pb(II) and Sb(V) predominated with high ions concentration. The significant synergistic effects were found during the removal of Pb(II) and Sb(V) on FPG in the coexisting system, which mainly attributed to precipitation, bridging complexation and electrostatic attraction. Considering the advantages such as facile preparation, low cost and high removal capacity, FPG is a promising material to uptake Pb(II) and/or Sb(V) from contaminated water.

Clinical Effect of Retroperitoneal Laparoscopic Radical Nephrectomy on Renal Cell Carcinoma, the Influence of Renal Function, and the Influencing Factors of Recurrence.

Renal cell carcinoma is abbreviated as renal carcinoma, and its clinical symptoms are basically hematuria, lumbago, and abdomen bump. As people's lifestyles change, the incidence of renal carcinoma continues to rise due to factors such as smoking and obesity. At present, surgical treatment is mostly used in clinical practice. Traditional open radical nephrectomy (ORN) is one of the main methods for clinical treatment of renal carcinoma. However, due to its large wound and large amount of intraoperative blood loss, the renal function of patients after surgery is poor, which is not conducive to the postoperative recovery of patients. Retroperitoneal laparoscopic radical nephrectomy (RLRN) has been widely used in the surgical treatment of renal cancer due to its advantages of small wound, less bleeding, and rapid recovery. The purpose of this study was to investigate the efficacy of RLRN in the treatment of renal cancer patients and its effect on renal function and to analyze the related factors affecting postoperative recurrence of patients. We adopt ORN and RLRN, two kinds of treatment, in patients with renal cancer surgery way, contrast analysis of the two groups of operation time, intraoperative blood loss, postoperative intestinal function recovery time, drainage tube indwelling time, length of hospital stay, and other clinical indicators and renal function indexes and use the single factor analysis and multifactor analysis, the relevant factors that affect kidney cancer patients with postoperative recurrence. The results showed that, compared with ORN treatment, RLRN treatment of renal cancer patients has a short operation time, less trauma, quick recovery after surgery, and fewer complications and can effectively alleviate the renal function injury and the body's inflammatory response, which is worthy of promotion. Postoperative recurrence was related to age, tumor diameter, TNM stage, surgical method, and postoperative immunotherapy.

Camrelizumab plus famitinib for advanced or metastatic urothelial carcinoma after platinum-based therapy: data from a multicohort phase 2 study.

BACKGROUND: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. Camrelizumab is a monoclonal antibody against PD-1, and famitinib is a multitargeted receptor tyrosine kinase inhibitor with antiangiogenesis and antiproliferation activities against tumor cells. We conducted an open-label, multicenter phase 2 basket study of camrelizumab and famitinib in eight cohorts of genitourinary or gynecological cancers. Here, findings in cohort of advanced or metastatic urothelial carcinoma with platinum-progressive disease (cohort 2) are presented. METHODS: Patients who had progressed after platinum-based chemotherapy for advanced or metastatic disease or had progressed within 12 months after completion of platinum-based (neo)adjuvant therapy were given camrelizumab (200 mg intravenously every 3 weeks) plus famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Totally, 36 patients were recruited. With a median duration from enrollment to data cut-off of 11.9 months (range 6.1-28.5), ORR was 30.6% (95% CI 16.3% to 48.1%). Median duration of response (DoR) was 6.3 months (95% CI 2.1 to not reached). Median progression-free survival (PFS) was 4.1 months (95% CI 2.2 to 8.2), and median overall survival (OS) was 12.9 months (95% CI 8.8 to not reached). Patients with bladder cancer (n=18) had numerically better outcomes, with an ORR of 38.9% (95% CI 17.3% to 64.3%) and a median PFS of 8.3 months (95% CI 4.1 to not reached). Median DoR and OS in this subpopulation had not been reached with lower limit of 95% CI of 4.2 months for DoR and 11.3 months for OS, respectively. Of 36 patients, 22 (61.1%) had grade 3 or 4 treatment-related adverse events, mainly decreased platelet count and hypertension. CONCLUSIONS: Camrelizumab plus famitinib showed potent antitumor activity in advanced or metastatic urothelial carcinoma patients after platinum-based chemotherapy. Patients with bladder cancer seemed to have better response to this combination. TRIAL REGISTRATION NUMBER: NCT03827837.

Active-chlorine-mediated oxidation of 5-fluorouracil on a hierarchically ordered macroporous RuO2 electrode.

A hierarchically ordered macroporous RuO2 electrode (HOM-RuO2) was fabricated to enhance in situ active chlorine production in an electrochemical system intended for treatment of pharmaceutical active compounds (PhACs). The unique structure of HOM-RuO2 resulted in a decrease of the chlorine evolution potential, a large electro-active area available for in situ conversion of Cl- to active chlorine, and hence improved the active chlorine production by 40%. 5-Fluorouracil (5-FU) was used as a target pollutant to explore the performance of the HOM-RuO2 for PhACs degradation based on the in situ generated active chlorine. The results showed that the reaction rate of active-chlorine-mediated oxidation of 5-FU produced using the HOM-RuO2 was 18.4 times higher than that in the case of hydroxyl radicals (OH)-initiated oxidation using a PbO2 electrode at 30 mA cm-2. The effects of current density and initial solution pH on the 5-FU removal were investigated. The mechanism of 5-FU degradation was proposed taking into accounts both active chlorine production, and change of the speciation of 5-FU caused by pH variations. The dominant degradation products observed for the degradation of 5-FU using the HOM-RuO2 were lactic acid, propanol, acetic acid, urea and other small molecules, but no chlorinated products were detected. These study demonstrates the promise of the HOM-RuO2-based electrochemical systems for the active-chlorine-mediated treatment of recalcitrant pharmaceuticals found in wastewater.