Long-term survival and post-hoc analysis of toripalimab plus definitive chemoradiotherapy for oesophageal squamous cell carcinoma: insights from the EC-CRT-001 phase II trial.

Background: In the EC-CRT-001 phase II study, the combination of toripalimab (an anti-programmed death-1 antibody) and definitive chemoradiotherapy (CRT) has shown promising efficacy in patients with locally advanced oesophageal squamous cell carcinoma (ESCC). Here, we reported the long-term outcomes and post-hoc exploratory analyses. Methods: This single-arm, phase II trial enrolled 42 patients diagnosed with unresectable stage I-IVA ESCC was conducted at Sun Yat-sen University Cancer Center between November 2019 and January 2021. Treatment consisted of chemotherapy (weekly 50 mg/m2 of paclitaxel and 25 mg/m2 of cisplatin for five cycles), concurrent radiotherapy (50.4 Gy in 28 fractions), and toripalimab (240 mg every 3 weeks for up to 1 year). The primary endpoint was clinical complete response (CR) rate at 3 months after CRT completion. The 3-year overall survival (OS) and progression-free survival (PFS) rates were evaluated. Additionally, the exploratory objectives included analysing recurrence patterns, assessing the associations between immune-related adverse events (irAEs) and efficacy, and identifying potential predictors for irAEs. The trial was registered with ClinicalTrials.gov (NCT04005170). Findings: With a median follow-up of 44.3 months (IQR 40.8-46.1), the 3-year OS and PFS rates were 44.8% (95% CI 31.9-62.8) and 35.7% (95% CI 23.8-53.6), respectively. Patients who failed to achieve a clinical complete response (CR) demonstrated significantly worse OS (hazard ratio [HR] = 13.73, 95% CI 4.43-42.54, P < 0.0001) and PFS (HR = 32.08, 95% CI 8.57-120.10, P < 0.0001). Disease recurrence occurred in 23 of 42 patients (55%), with recurrences being earlier and more frequent in the non-CR group compared to the CR group. Patients experiencing irAEs showed a significantly higher CR rate (72% vs. 39%, P = 0.082) and better PFS (HR = 0.43, 95% CI 0.19-0.93, P = 0.027) than those without irAEs. GON4L mutation was associated with a lower incidence of irAEs (P = 0.036). Interpretation: The updated survival outcomes confirmed the efficacy of toripalimab plus definitive CRT in locally advanced ESCC. Moreover, the development of irAEs may predict a more favourable prognosis. Funding: National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Sci-Tech Project Foundation of Guangzhou.

Efficacy and safety of methotrexate plus hydroxychloroquine combination therapy vs. methotrexate monotherapy in the treatment of rheumatoid arthritis: A randomized controlled clinical trial.

OBJECTIVE: To explore the efficacy and safety of combination therapy with methotrexate (MTX) plus hydroxychloroquine (HCQ) vs. MTX monotherapy in patients with rheumatoid arthritis (RA). METHODS: Sixty patients without prior RA treatments were randomly allocated in a 1:1 ratio to two groups: one receiving MTX plus HCQ, and the other receiving MTX monotherapy. We conducted a comparative analysis before and after the 12-week trial, evaluating the visual analogue scale (VAS), the disease activity score in 28 joints (DAS), serum inflammatory factor (including serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), as well as the outcome of the World Health Organization Quality of Life Brief Version questionnaire (WHOQOL-BREF) and the treatment-emergent adverse events (TEAEs) for all the participants in the study. RESULTS: At the 12th week of the trial, a more remarkable decrease in pain score (VAS), disease activity score (DAS), and serum inflammatory factor levels could be noticed in individuals on the combination therapy. The quality of life score was as well found to be higher in the MTX + HCQ group than the MTX monotherapy group. The incidence of adverse reactions in the MTX + HCQ and the MTX monotherapy groups were 10.00% and 6.67%, respectively. However, no statistical significance could be observed (p > .05). CONCLUSION: In our study, both the MTX + HCQ combination therapy and MTX monotherapy demonstrated improvements in symptoms, conditions and quality of life for patients with RA. Notably, the combination therapy could achieve better outcomes across all indices compared to MTX monotherapy, highlighting its potential as the optimal first-line treatment for RA. © 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Whole-genome sequencing and pathogenicity analysis of Rhodococcus equi isolated in horses.

BACKGROUND: Rhodococcus equi (R. equi) is a Gram-positive zoonotic pathogen that frequently leads to illness and death in young horses (foals). This study presents the complete genome sequence of R. equi strain BJ13, which was isolated from a thoroughbred racehorse breeding farm in Beijing, China. RESULTS: The BJ13 genome has a length of 5.30 Mb and consists of a complete chromosome and a plasmid measuring 5.22 Mb and 0.08 Mb, respectively. We predicted 4,929 coding gene open reading frames, along with 52 tRNAs and 12 rRNAs. Through analysis of mobile genetic elements, we identified 6 gene islands and 1 prophage gene. Pathogenic system analysis predicted the presence of 418 virulence factors and 225 drug resistance genes. Secretion system analysis revealed the prediction of 297 secreted proteins and 1,106 transmembrane proteins. BJ13 exhibits genomic features, virulence-associated genes, potential drug resistance, and a virulence plasmid structure that may contribute to the evolution of its pathogenicity. Lastly, the pathogenicity of the isolated strain was assessed through animal experiments, which resulted in inflammatory reactions or damage in the lungs, liver, and spleen of mice. Moreover, by the 7th day post-infection, the mortality rate of the mice reached 50.0%, indicating complex immune regulatory mechanisms, including overexpression of IL-10 and increased production of pro-inflammatory cytokines like TNF-α. These findings validate the strong pathogenicity of the isolated strain and provide insights for studying the pathogenic mechanisms of Rhodococcus equi infection. CONCLUSIONS: The complete genome sequence of R. equi strain BJ13 provides valuable insights into its genomic characteristics, virulence potential, drug resistance, and secretion systems. The strong pathogenicity observed in animal experiments underscores the need for further investigation into the pathogenic mechanisms of R. equi infection.

Ti3O MOenes: Quantum Spin Hall Effect and Promising Semiconductors for Light-Harvesting.

The continuous pursuit of novel two-dimensional (2D) materials with intriguing properties has been a driving force in advancing various scientific and technological frontiers. Here, based on a wide range of first-principles calculations, we predicted the existence of a novel family of 2D transition-metal oxides, the Ti3O MOenes (MXene-like 2D transition oxides), and determined its distinctive electronic and topological properties. A pair of 2D antiferromagnetic (AFM) Dirac points precisely located at the Fermi level in the absence of spin-orbit coupling (SOC) is observed in the 1T-Ti3O monolayer. Moreover, upon halogenation on a bare monolayer, 1T-Ti3OCl3 and 1T-Ti3OBr3 monolayers display the quantum spin Hall (QSH) effect with nontrivial helical edge states within the gapless bulk states. Specifically, single layer 1T-Ti3OF3 behaves as an indirect semiconductor with a gap of 0.81 eV, exhibiting a strong light-harvesting capability. The indirect-gap feature can be switched to a direct one by only exerting a small tensile strain of 1.5%. These findings broaden emerging phenomena in a rich family of MOenes, suggesting a novel platform for the development of next-generation nanodevices.

Biomedical potentials of alginate via physical, chemical, and biological modifications.

Alginate is a linear polysaccharide with a modifiable structure and abundant functional groups, offers immense potential for tailoring diverse alginate-based materials to meet the demands of biomedical applications. Given the advancements in modification techniques, it is significant to analyze and summarize the modification of alginate by physical, chemical and biological methods. These approaches provide plentiful information on the preparation, characterization and application of alginate-based materials. Physical modification generally involves blending and physical crosslinking, while chemical modification relies on chemical reactions, mainly including acylation, sulfation, phosphorylation, carbodiimide coupling, nucleophilic substitution, graft copolymerization, terminal modification, and degradation. Chemical modified alginate contains chemically crosslinked alginate, grafted alginate and oligo-alginate. Biological modification associated with various enzymes to realize the hydrolysis or grafting. These diverse modifications hold great promise in fully harnessing the potential of alginate for its burgeoning biomedical applications in the future. In summary, this review provides a comprehensive discussion and summary of different modification methods applied to improve the properties of alginate while expanding its biomedical potentials.

Epidemiological investigation of Trichomonas gallinae in beijing, China.

Trichomonas gallinae is a globally distributed protozoan parasite that causes avian trichomoniasis, leading to significant morbidity and mortality in birds. The present study aims to investigate the prevalence, genetic diversity, and phylogenetic relationship of T. gallinae in various bird species in Beijing. A total of 413 oropharyngeal swab samples were collected from domestic pigeons, wild pigeons, and other bird species. The overall prevalence of T. gallinae infection was 32.0% (132/413). The infection was detected in domestic pigeons, wild pigeons, and red-necked turtledoves, but not in other wild birds. Molecular analysis identified two predominant genotypes, A and B, with genotype A found in wild pigeons and genotype B found in domestic pigeons. The present study provides valuable insights on the prevalence and genetic diversity of T. gallinae in Beijing. This can be useful for understanding its pathogen distribution and host range, and the development of strategies for the prevention and control of avian trichomoniasis.

Relationship between cathepsins and cardiovascular diseases: a Mendelian randomized study.

Background: Cardiovascular diseases (CVDs) are the leading age-related disorders worldwide, with their prevalence increasing annually. Cathepsins are protein-degrading enzymes essential for processes such as intracellular protein breakdown, apoptosis, and immune responses. Recent studies suggest a potential link between cathepsins and CVDs, yet the exact causal relationship remains to be elucidated. To address this, we propose using Mendelian randomization (MR) to explore the causal relationships between cathepsins and CVDs. Methods: We obtained single nucleotide polymorphism (SNP) data for cathepsins from the INTERVAL study, a publicly accessible genome-wide association study (GWAS) dataset. Outcome SNP data were sourced from seven distinct GWAS datasets, ensuring a comprehensive analysis across multiple cardiovascular outcomes. For MR analysis, we primarily employed the inverse variance weighted (IVW) method, known for its efficiency when all SNPs are valid instruments. This was supplemented by the weighted median and MR-Egger methods to provide robustness against potential violations of MR assumptions, such as pleiotropy. The IVW method offers precision and efficiency, the weighted median method adds robustness against invalid instruments, and the MR-Egger method helps identify and correct for pleiotropic biases. Cochran's Q test was utilized to assess heterogeneity, and sensitivity analyses were conducted using MR-PRESSO and the leave-one-out approach. Results: The strength of the associations between exposure and outcome was measured using odds ratios (ORs), and results were presented with 95% confidence intervals (CIs). The cathepsin E increases the risk of myocardial infarction (MI) (OR = 1.053%, 95% CI: 1.007-1.101, p = 0.024) and ischemic stroke (IS) (OR = 1.06%, 95% CI: 1.019-1.103, p = 0.004). Conversely, cathepsin L2 decreases the risk of chronic heart failure (CHF) (OR = 0.922%, 95% CI: 0.859-0.99, p = 0.025) and atrial fibrillation (AF) (OR = 0.956%, 95% CI: 0.918-0.996, p = 0.033). Cathepsin O was associated with an increased risk of IS (OR = 1.054%, 95% CI: 1.008-1.102, p = 0.021) and AF (OR = 1.058%, 95% CI: 1.02-1.098, p = 0.002). Conclusion: Our MR analysis reveals that cathepsin E is a risk factor for MI and IS, cathepsin L2 offers protective effects against CHF and AF, and cathepsin O increases the risk for IS and AF.

Extending the Charge Carrier Recombination Lifetime by Octahedral Rotations in Ruddlesden-Popper Ba3Zr2S7 Perovskites.

Intentional distortions of [BX6] octahedra within perovskite structures have been recognized as a potent strategy for precise band gap adjustments and optimization of their photovoltaic properties, yet information regarding charge carrier dynamics linked to octahedral distortion under ambient conditions for chalcogenide perovskites remains limited. In this study, we utilize ab initio nonadiabatic molecular dynamics to explore the dynamics of photogenerated carriers in a representative two-dimensional Ba3Zr2S7 material in the Ruddlesden-Popper phase. The theoretical results highlight the influence of octahedral rotation on the materials' stability and carrier recombination lifetime of the system. Specifically, the octahedrally rotating P42/mnm phase exhibits a prolonged nonradiative carrier recombination lifetime attributed to the stabilized electron-phonon coupling. These findings offer valuable insights into the fundamental physical characteristics of imposed octahedral distortion and its potential for optimizing the optoelectronic performance of 2D Ruddlesden-Popper Ba-Zr-S chalcogenide materials.

Comparison of Efficacy and Safety of Combined Chemoimmunotherapy With or Without Radiation Therapy for Stage IVB Esophageal Squamous Cell Carcinoma: A Multicenter Propensity Score Matching Analysis.

PURPOSE: This study aimed to compare the efficacy and safety of combining first-line chemoimmunotherapy with radiation therapy versus chemoimmunotherapy alone in patients with stage IVB esophageal squamous cell carcinoma (ESCC). METHODS AND MATERIALS: We retrospectively examined 409 patients with stage IVB ESCC who received first-line chemotherapy and anti-PD-1 antibody, with or without radiation therapy of ≥40 Gy radiation dose to primary lesion, from 4 academic cancer centers between October 2018 and December 2022. Propensity score matching was conducted to minimize the potential confounding effects. RESULTS: In the overall cohort of 409 patients, the group that received additional radiation therapy had superior overall survival (OS) (hazard ratio [HR], 0.51; 95% CI, 0.39-0.66; P < .001) and progression-free survival (PFS) (HR, 0.52; 95% CI, 0.40-0.66; P < .001) compared to the group that received chemoimmunotherapy alone. After 1:1 propensity score matching, matching age, tumor location, and metastatic sites, a total of 250 patients were selected for further analysis. The results remained consistent and showed that the addition of radiation therapy significantly improved OS and PFS (median OS, 24.9 vs 14.6 months; P = .003; median PFS, 14.2 vs 10.6 months; P = .002). Multivariate Cox analysis including tumor location, T stage, metastatic sites, and treatment modality, revealed that radiation therapy was an independent prognostic factor for both OS (HR, 0.57; 95% CI, 0.41-0.81) and PFS (HR, 0.63, 95% CI, 0.47-0.86). Subgroup analyses revealed significant OS prolongation in patients with nonregional lymph node metastases only who received radiation therapy (HR, 0.49; 95% CI, 0.34-0.70). No OS survival benefit was observed in those with distant organ metastases (HR, 0.72; 95% CI, 0.46-1.13). Regarding safety, the group receiving additional radiation therapy had higher incidences of grade 3 to 4 lymphopenia (74.4% vs 17.7%, P < .001) and esophagitis (11.2% vs 2.4%, P = .006). CONCLUSIONS: The addition of radiation therapy to chemoimmunotherapy improved the survival of stage IVB ESCC patients with nonregional lymph node metastasis.

Prognostic significance of PET/CT and its association with immuno-genomic profiling in oesophageal squamous cell carcinoma treated with immunotherapy plus chemoradiotherapy: results from a phase II study.

BACKGROUND: A phase II trial (EC-CRT-001) demonstrated the promising efficacy of combining toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) for locally advanced oesophageal squamous cell carcinoma (ESCC). Biomarkers are key to identifying patients who may benefit from this therapeutic approach. METHODS: Of the 42 patients with ESCC who received toripalimab combined with definitive CRT, 37 were included in this analysis. Baseline assessments included PET/CT metabolic parameters (SUVmax, SUVmean, SUVpeak, MTV, and TLG), RNA sequencing of tumour biopsies to quantify the tissue mutational burden (TMB), and multiplex immunofluorescence staining to estimate immune cell infiltration in the tumour microenvironment (TME). Frozen neoplastic samples were procured for RNA sequencing to further explore the immune-related TME. RESULTS: Among the 37 patients, high baseline SUVmax (≥12.0; OR = 6.5, 95% CI 1.4-48.2, p = 0.032) and TLG (≥121.8; OR = 6.8, 95% CI 1.6-33.5, p = 0.012) were significantly correlated with lower complete response rates. All five PET/CT parameters were notably associated with overall survival; only SUVmax and TLG were associated with a significantly worse progression-free survival. A trend towards an inverse correlation was observed between SUVmax and TMB (R = -0.33, p = 0.062). PD-1 + CD8 + T cell infiltration was negatively correlated with MTV (R = -0.355, p = 0.034) and TLG (R = -0.385, p = 0.021). Moreover, RNA sequencing revealed that the high TLG subgroup exhibited low immune cell infiltration, indicating an immunosuppressive landscape. CONCLUSIONS: High baseline SUVmax and TLG might predict poorer treatment response and worse survival in patients with ESCC undergoing immunotherapy combined with CRT. In addition, high PET/CT metabolic parameters, particularly TLG, were correlated with an immunosuppressive TME, which warrants further exploration.

The First Report of Tritrichomonas Foetus and Tetratrichomonas Buttreyi in Raccoon Dogs (Nyctereutes Procyonoides) in China.

BACKGROUND: In recent years, the trichomonosis in raccoon dogs in China had occurred frequently. Pentatrichomonas hominis had been described in raccoon dogs in China in some previous studies. PURPOSE TO REVEAL: whether raccoon dogs can be infected by other trichomonad species besides P. hominis, and clarify the prevalence and species distribution of trichomonad in raccoon dogs. METHODS: Herein, the 389 fecal samples were collected from farm-raised raccoon dogs in Hebei Province, all the samples were detected using the microscopic examination and several fecal samples containing trichomonad-like organisms were processed, cultured, stained, and photographed. Meanwhile, all the samples were screened by the species-specific nested PCR based on the small subunit rRNA (SSU rRNA) gene of P. hominis,Tritrichomonas foetus and Tetratrichomonas buttreyi, respectively, and all positive secondary PCR amplications obtained in this study were sequenced, aligned and analysed. RESULTS: 62 fecal samples (15.9%,62/389) were trichomonad-positive under light microscopy, and the trichomonad-like cells were clearly observed in the culture contents. The PCR results showed that 100 samples were trichomonad-positive, including 45 P. hominis-positive samples (11.6%,45/389), 32 T. foetus-positive samples (8.2%,32/389), and 33 T. buttreyi-positive samples (8.5%,33/389), respectively. Double mixed infections were observed in 10 samples. The prevalence of T. foetus and P. hominis were both significantly higher in raccoon dogs with diarrhea (13.9%, and 25.0%) than that in raccoon dogs without diarrhea (7.6%, and 9.3%) (p < 0.05).All samples confirmed as trichomonad-positive under microscopy were also found to be trichomonad-positive by PCR analysis. The sequencing and phylogenetic analysis demonstrated the sequences obtained in this study belonged to P. hominis, T. foetus and T. buttreyi SSU rRNA, respectively. Among them, the T. buttreyi SSU rRNA sequences obtained in this study harbored the new sequence polymorphisms. Based on preliminary morphological and molecular analyses, raccoon dogs are considered as the new host of T. foetus and T. buttreyi. CONCLUSION: This is the first report about the identifcation and prevalence of T. foetus and T. buttreyi in raccoon dogs in China, and the results increase our knowledge about the host range and prevalence of trichomonad species.

A developed and validated centrifugal ultrafiltration coupled with high performance liquid chromatography-tandem mass spectrometry method for rapid quantification of unbound lenvatinib in human plasma.

In clinical practice, the determination of unbound drug concentration is very important for dose adjustment and toxicity prediction because only the unbound fraction can achieve a pharmacological effect. A fast, sensitive and accurate analytical method of centrifugal ultrafiltration coupled with high performance liquid chromatography-tandem mass spectrometry method was developed and applied to allow the quantification of unbound lenvatinib concentration. The application of linear regression analysis was used to examine the effects of centrifugal force, centrifugal time, and protein content on ultrafiltrate volume (Vu). The results indicated that the centrifugal force and centrifugal time have an influence on Vu that is significantly positive (P < 0.05). This developed method with good linearity (r2 = 0.9996), good accuracy (bias % ≤ 2.24 %), good precision (CV % ≤ 7.10 %), and good recovery (95.46 %-106.46 %) was suitable for routine clinical practice and studies. Particularly, the ultrafiltration membrane had no non-specific binding to lenvatinib. The unbound fractions can be separated in just 15 min. This method was applied to quantify clinical samples and to determine the plasma protein binding and unbound fraction of lenvatinib. This study provides a more effective and promising method for determination of unbound lenvatinib. It could be beneficial to measure the unbound concentration of lenvatinib in personalized medicine and therapeutic drug monitoring in routine clinical practice.

Family quality of life of parents of children with intellectual disability: Do psychological stress and parental involvement matter?

Background: The psychological stress of parents and improving family quality of life (FQoL) are continuing concerns for families of children with intellectual disability. We need to identify further ways to reduce their stress and improve their FQoL in China. Method: Examine the interrelations between psychological stress, parental involvement, and FQoL for parents with intellectual disability in mainland China. 467 parents of children with intellectual disability completed instruments measuring variables. Structural equation modelling (SEM) was employed to examine the interrelations. Results: Psychological stress, directly and indirectly, influenced parental involvement in FQoL. Physical and mental response (PMR) and risk awareness (RA) had a positive direct effect on FQoL, and optimistic hope (OH) had a negative effect on FQoL. Conclusions: Psychological stress affects FQoL of parents with children with intellectual disability in complex ways. Policies should be developed to help parents with children with disability decrease stress and develop scientific parental involvement.

Treatment for middle cerebral artery bifurcation aneurysms: in silico comparison of the novel Contour device and conventional flow-diverters.

Endovascular treatment has become the standard therapy for cerebral aneurysms, while the effective treatment for middle cerebral artery (MCA) bifurcation aneurysms remains a challenge. Current flow-diverting techniques with endovascular coils cover the aneurysm orifice as well as adjacent vessel branches, which may lead to branch occlusion. Novel endovascular flow disruptors, such as the Contour device (Cerus Endovascular), are of great potential to eliminate the risk of branch occlusion. However, there is a lack of valid comparison between novel flow disruptors and conventional (intraluminal) flow-diverters. In this study, two in silico MCA bifurcation aneurysm models were treated by specific Contour devices and flow-diverters using fast-deployment algorithms. Computational fluid dynamic simulations were used to examine the performance and efficiency of deployed devices. Hemodynamic parameters, including aneurysm inflow and wall shear stress, were compared among each Contour device, conventional flow-diverter, and untreated condition. Our results show that the placement of devices can effectively reduce the risk of aneurysm rupture, while the deployment of a Contour device causes more flow reduction than using flow-diverters (e.g. Silk Vista Baby). Besides, the Contour device presents the flow diversion capability of targeting the aneurysm neck without occluding the daughter vessel. In summary, the in silico aneurysm models presented in this study can serve as a powerful pre-planning tool for testing new treatment techniques, optimising device deployment, and predicting the performance in patient-specific aneurysm cases. Contour device is proved to be an effective treatment of MCA bifurcation aneurysms with less daughter vessel occlusion.

A case control study of vNOTES hysterectomy with the da Vinci surgical system and conventional vNOTES hysterectomy.

The aim of the case control study was to compare surgical outcomes of transvaginal natural orifice transluminal endoscopic surgery (vNOTES) hysterectomy with the da Vinci surgical system (dVSS) and conventional vNOTES. A case control study was performed on 25 cases in our hospital. Patients (n = 8) who underwent vNOTES hysterectomy with dVSS were selected to compare with the control group (n = 17) consisted of patients who underwent conventional vNOTES. Patients in the 2 groups underwent different operations respectively, and no case was transferred to transabdominal laparoscopy. In the conventional vNOTES group, 1 patient happened intraoperative hemorrhage of about 1000 mL, and was treated with blood transfusion, and the other one of vNOTES hysterectomy with dVSS had poor incision healing within 1 month after surgery. The other patients had no intraoperative and postoperative complications. The difference of pain scores on the first day (P = .006) and the third day (P = .045) after the 2 surgical methods differed significantly. No statistical differences were observed in operation time, median hospital stay, blood loss, decreased hemoglobin 3 days after surgery, and postoperative white blood cell count. vNOTES hysterectomy with dVSS is safe and feasible, and can achieve the same effect as the conventional vNOTES hysterectomy. And this method may alleviate the pain of patients.

Predictive role of ctDNA in esophageal squamous cell carcinoma receiving definitive chemoradiotherapy combined with toripalimab.

The combination of toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) demonstrated encouraging efficacy against locally advanced esophageal squamous cell carcinoma (ESCC) in the EC-CRT-001 phase II trial (NCT04005170). The primary endpoint of this trial was the clinical complete response rate (cCR), and the secondary endpoints included overall survival (OS), progression-free survival (PFS), duration of response, and quality of life. The exploratory analyses of EC-CRT-001 include exploring the role of circulating tumor DNA (ctDNA) and blood-based tumor mutational burden (bTMB) in predicting the response and survival. In total, 118 blood and 35 tissue samples from 42 enrolled patients were included in the analyses. We found that ctDNA-negative patients achieved a higher cCR compared to those with detectable ctDNA during CRT (83%, 19/23 vs. 39%, 7/18; p = 0.008) or post-CRT (78%, 21/27 vs. 30%, 3/10; p = 0.017). Patients with detectable ctDNA during CRT had shorter PFS (p = 0.014). Similarly, patients with post-CRT detectable ctDNA had a significantly shorter PFS (p = 0.012) and worse OS (p = 0.004). Moreover, patients with high bTMB levels during CRT had prolonged OS (p = 0.027). In conclusion, ctDNA and bTMB have the potential to predict treatment efficacy and survival in ESCC treated with CRT and immunotherapy.

Unraveling the photochemical behavior of dissolved organic matter derived from hydrothermal carbonization process water: Insights from molecular transformation and photoactive species.

Hydrothermal carbonization process water (HTPW) has been utilized as a substitute for chemical fertilizers in agricultural applications. However, the input of HTPW into paddy water, particularly the significant proportion of dissolved organic matter (DOM) in HTPW (DOM-HTPW), directly engages in photochemical transformations, a phenomenon often overlooked. This study observed a consistent decrease in humification (SUVA280, 7.7-53.9%) and aromaticity (SUVA254, 6.1-40.0%) of DOM-HTPW after irradiation. The primary active photobleaching components of DOM-HTPW varied depending on the feedstock, such as protein for chicken manure DOM-HTPW and lignin for rice straw DOM-HTPW. The photochemical activity of DOM-HTPW was augmented by its lower molecular weight and higher hydrophilic composition, particularly evident in chicken manure DOM-HTPW, which exhibited higher generation rates for 1O2 (35.1-37.1%), 3DOM* (32.8-43.9%), and O2•- (28.6-48.8%) as measured by molecular probes. DOM-HTPW effectively facilitated the phototransformation of tetracycline, with the contribution of O2•- being more significant than 3DOM* and 1O2. These findings shed new light on the understanding the photochemical processes of DOM-HTPW as exogenous DOM and the interconnected fate of contaminants in aquatic environments.

Integrating bioinformatics and experimental validation to unveil disulfidptosis-related lncRNAs as prognostic biomarker and therapeutic target in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) stands as a prevalent malignancy globally, characterized by significant morbidity and mortality. Despite continuous advancements in the treatment of HCC, the prognosis of patients with this cancer remains unsatisfactory. This study aims at constructing a disulfidoptosis­related long noncoding RNA (lncRNA) signature to probe the prognosis and personalized treatment of patients with HCC. METHODS: The data of patients with HCC were extracted from The Cancer Genome Atlas (TCGA) databases. Univariate, multivariate, and least absolute selection operator Cox regression analyses were performed to build a disulfidptosis-related lncRNAs (DRLs) signature. Kaplan-Meier plots were used to evaluate the prognosis of the patients with HCC. Functional enrichment analysis was used to identify key DRLs-associated signaling pathways. Spearman's rank correlation was used to elucidate the association between the DRLs signature and immune microenvironment. The function of TMCC1-AS1 in HCC was validated in two HCC cell lines (HEP3B and HEPG2). RESULTS: We identified 11 prognostic DRLs from the TCGA dataset, three of which were selected to construct the prognostic signature of DRLs. We found that the survival time of low-risk patients was considerably longer than that of high-risk patients. We further observed that the composition and the function of immune cell subpopulations were significantly different between high- and low-risk groups. Additionally, we identified that sorafenib, 5-Fluorouracil, and doxorubicin displayed better responses in the low-score group than those in the high-score group, based on IC50 values. Finally, we confirmed that inhibition of TMCC1-AS1 impeded the proliferation, migration, and invasion of hepatocellular carcinoma cells. CONCLUSIONS: The DRL signatures have been shown to be a reliable prognostic and treatment response indicator in HCC patients. TMCC1-AS1 showed potential as a novel prognostic biomarker and therapeutic target for HCC.

A 3-Year Survival Update from a Phase 2 Study of Paclitaxel Plus Cisplatin and 5-Fuorouracil Induction Chemotherapy for Locally Advanced Borderline-Resectable Esophageal Squamous Cell Carcinoma: The NEOCRTEC-1601 Clinical Trial.

BACKGROUND: This study updated 3-year analyses to further characterize the impact of docetaxel, cisplatin, and fluorouracil (TPF) chemotherapy followed by surgery. METHODS: This study was a single-center phase 2 clinical trial. Patients with a diagnosis of borderline resectable esophageal squamous cell carcinoma (BR-ESCC) because of the primary tumor or bulky lymph node that potentially invaded adjacent organs were eligible. The treatment started with TPF chemotherapy followed by surgery if the cancer was resectable, or by concurrent chemoradiation if it was unresectable. This updated report presents the 3-year overall survival (OS) and progression-free survival (PFS) rates. RESULTS: Surgery was performed for 27 patients (57.4%), and R0 resection was confirmed in 25 patients (53.2%). Pathologic complete response was confirmed in four patients (8.5%). The median follow-up time for the surviving patients was 44.8 months (range, 3.4-74.6 months). The median OS for all the patients was 41.9 months (95% confidence interval [CI], 18.6-65.3 months), with a median PFS of 38.7 months (95% CI, 23.5-53.9 months). The 3-year survival rate for all the patients was 54.4%. The 3-year survival rate for the R0 patients was 65.4%. CONCLUSION: Long-term follow-up evaluation confirmed that TPF followed by surgery is feasible and promising in terms of survival for BR-ESCC patients. Trial Registration ClinicalTrials.gov identifer: NCT02976909.