Impact of thoracic radiotherapy on first-line treatment outcomes in ES-SCLC patients.

BACKGROUND: The therapeutic advantage of thoracic radiotherapy (tRT) as an adjunct to first-line immunotherapy and chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC) remains unclear. We sought to elucidate this in a retrospective cohort study comparing the effectiveness and safety of tRT in combination with first-line immunotherapy and chemotherapy. METHODS: Our retrospective study included patients with ES-SCLC, treated at the West China Hospital between January 2019 and December 2022. They received first-line immunotherapy and chemotherapy and were categorized into two cohorts based on the administration of tRT. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Cox regression analysis was utilized to identify potential independent predictors of prognosis and to compare the treatment outcomes across various patient subgroups. Treatment-related toxicities across both cohorts were compared using the Chi-squared test. RESULTS: A total of 99patients were eligible for the study, out of which 55 received tRT. The medianduration of follow-up was 39 months. Remarkably, patients who received tRTdemonstrated superior OS and PFS in comparison to those who did not (P < 0.05). Subgroup analysis further confirmed these findings. Multivariate analysisidentified treatment group and liver metastasis as independent prognosticfactors (P < 0.05). The incidence of grade 3-4 adverse events showed nostatistically significant difference between the two cohorts. CONCLUSIONS: Thus, weconfirmed that the addition of tRT to the conventional regimen of first-linechemotherapy and immunotherapy yields better survival outcomes without asignificant increase in toxicity.

Anoikis-Related Long Non-Coding RNA Signatures to Predict Prognosis and Immune Infiltration of Gastric Cancer.

Anoikis is a distinct type of programmed cell death and a unique mechanism for tumor progress. However, its exact function in gastric cancer (GC) remains unknown. This study aims to investigate the function of anoikis-related lncRNA (ar-lncRNA) in the prognosis of GC and its immunological infiltration. The ar-lncRNAs were derived from RNA sequencing data and associated clinical information obtained from The Cancer Genome Atlas. Pearson correlation analysis, differential screening, LASSO and Cox regression were utilized to identify the typical ar-lncRNAs with prognostic significance, and the corresponding risk model was constructed, respectively. Comprehensive methods were employed to assess the clinical characteristics of the prediction model, ensuring the accuracy of the prediction results. Further analysis was conducted on the relationship between immune microenvironment and risk features, and sensitivity predictions were made about anticancer medicines. A risk model was built according to seven selected ar-lncRNAs. The model was validated and the calibration plots were highly consistent in validating nomogram predictions. Further analyses revealed the great accuracy of the model and its ability to serve as a stand-alone GC prognostic factor. We subsequently disclosed that high-risk groups display significant enrichment in pathways related to tumors and the immune system. Additionally, in tumor immunoassays, notable variations in immune infiltrates and checkpoints were noted between different risk groups. This study proposes, for the first time, that prognostic signatures of ar-lncRNA can be established in GC. These signatures accurately predict the prognosis of GC and offer potential biomarkers, suggesting new avenues for basic research, prognosis prediction and personalized diagnosis and treatment of GC.

Efficacy and safety of RS plus bevacizumab versus RS plus fruquintinib as the third-line therapy in patients with refractory metastatic colorectal cancer: A real-world propensity score matching study.

BACKGROUND: This study aims to compare the effectiveness and safety of the combination of raltitrexed, S-1 (RS), and fruquintinib with the combination of RS and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). METHODS: This retrospective cohort included mCRC patients who received the RS plus fruquintinib or regorafenib as the third-line therapy from May 2019 to April 2023. A propensity score matching (PSM) analysis was used to balance the baseline characteristics of all patients. Overall survival (OS), progression-free survival (PFS), tumor response, and safety of the two regimens were evaluated. RESULTS: Of the 153 patients enrolled, 123 patients received the RS plus bevacizumab and 30 patients received the RS plus fruquintinib. After PSM, 30 pairs were analyzed. Patients treated with RS plus fruquintinib had a longer PFS than those treated with RS plus bevacizumab before PSM (5.0 months vs. 4.3 months, p = 0.008) and after PSM (5.0 months vs. 4.4 months, p = 0.012). A longer OS was also observed in RS plus fruquintinib group before PSM and after PSM, but there was no statistic difference between two groups after PSM. Both objective response rate and disease control rate were higher in the RS plus fruquintinib cohort than those in the RS plus bevacizumab cohort before PSM, and the difference in values between the two groups reduced after PSM. The adverse effects (AEs) of both groups were well tolerated. CONCLUSION: In patients with refractory mCRC, RS plus fruquintinib demonstrated a superior OS, PFS than RS plus bevacizumab and had manageable AEs.

Achieving an Ultralow-κ yet Strong and Transparent Film by Antisolvent-Confined Nanowelding of Electrospun Polyimide Nanofibers.

Developing ultralow-κ (dielectric constant) polyimides (PIs) that are mechanically robust while also being optically transparent is challenging. For the first time, we report a nanoporous PI film with an ultralow κ of 1.8 in combination with a tensile strength of up to 180 MPa, a Young's modulus of up to 6 GPa, and a transmittance of ∼88%. This is achieved by direct nanowelding of a porous electrospun PI nanofiber membrane using a simple mixture of ethanol-dominating DMAc. Benefiting from the effective evaporation of the antisolvent ethanol upon heating, the proposed nanowelding approach allows for the localized surface dissolution of the PI nanofibers, which enables the dissolved PI to "glue" the nanofibers and occupy vacant space in the membrane, resulting in the formation of a dense but nanoporous self-reinforced nanocomposite film. Our findings provide a renewed understanding of the potential of electrospun nanofibrous materials, and the underlying principle can hopefully be applied to other commodity polymers.

Nanoparticle-specific transformations dictate nanoparticle effects associated with plants and implications for nanotechnology use in agriculture.

Nanotechnology shows potential to promote sustainable and productive agriculture and address the growing population and food demand worldwide. However, the applications of nanotechnology are hindered by the lack of knowledge on nanoparticle (NP) transformations and the interactions between NPs and macromolecules within crops. In this Review, we discuss the beneficial and toxicity-relieving transformation products of NPs that provide agricultural benefits and the toxic and physiology-disturbing transformations that induce phytotoxicities. Based on knowledge related to the management of NP transformations and their long-term effects, we propose feasible design suggestions to attain nano-enabled efficient and sustainable agricultural applications.

Chromothripsis is a novel biomarker for prognosis and differentiation diagnosis of pancreatic neuroendocrine neoplasms.

This study aimed to identify the role of chromothripsis as a novel biomarker in the prognosis and differentiation diagnosis of pancreatic neuroendocrine neoplasms (pNENs). We conducted next-generation gene sequencing in a cohort of 30 patients with high-grade (G3) pNENs. As a reference, a similar analysis was also performed on 25 patients with low-grade (G1/G2) pancreatic neuroendocrine tumors (pNETs). Chromothripsis and its relationship with clinicopathological features and prognosis were investigated. The results showed that DNA damage response and repair gene alteration and TP53 mutation were found in 29 and 11 patients, respectively. A total of 14 out of 55 patients had chromothripsis involving different chromosomes. Chromothripsis had a close relationship with TP53 alteration and higher grade. In the entire cohort, chromothripsis was associated with a higher risk of distant metastasis; both chromothripsis and metastasis (ENETS Stage IV) suggested a significantly shorter overall survival (OS). Importantly, in the high-grade pNENs group, chromothripsis was the only independent prognostic indicator significantly associated with a shorter OS, other than TP53 alteration or pathological pancreatic neuroendocrine carcinomas (pNECs) diagnosis. Chromothripsis can guide worse prognosis in pNENs, and help differentiate pNECs from high-grade (G3) pNETs.

A machine learning radiomics based on enhanced computed tomography to predict neoadjuvant immunotherapy for resectable esophageal squamous cell carcinoma.

Background: Patients with resectable esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunotherapy (NIT) display variable treatment responses. The purpose of this study is to establish and validate a radiomics based on enhanced computed tomography (CT) and combined with clinical data to predict the major pathological response to NIT in ESCC patients. Methods: This retrospective study included 82 ESCC patients who were randomly divided into the training group (n = 57) and the validation group (n = 25). Radiomic features were derived from the tumor region in enhanced CT images obtained before treatment. After feature reduction and screening, radiomics was established. Logistic regression analysis was conducted to select clinical variables. The predictive model integrating radiomics and clinical data was constructed and presented as a nomogram. Area under curve (AUC) was applied to evaluate the predictive ability of the models, and decision curve analysis (DCA) and calibration curves were performed to test the application of the models. Results: One clinical data (radiotherapy) and 10 radiomic features were identified and applied for the predictive model. The radiomics integrated with clinical data could achieve excellent predictive performance, with AUC values of 0.93 (95% CI 0.87-0.99) and 0.85 (95% CI 0.69-1.00) in the training group and the validation group, respectively. DCA and calibration curves demonstrated a good clinical feasibility and utility of this model. Conclusion: Enhanced CT image-based radiomics could predict the response of ESCC patients to NIT with high accuracy and robustness. The developed predictive model offers a valuable tool for assessing treatment efficacy prior to initiating therapy, thus providing individualized treatment regimens for patients.

Case report: Disitamab vedotin combined with immunotherapy demonstrated excellent efficacy in scrotal Paget's disease with Her-2 overexpression.

Background: Extramammary Paget's disease (EMPD) is a rare epithelial malignancy, and approximately 30%-40% of EMPD patients overexpress human epidermal growth factor receptor 2 (Her-2). Currently, there are no established standard treatments for advanced EMPD while anti-Her-2 therapy is recommended for Her-2-positive cases. Case presentation: Here, we report a 51-year-old male diagnosed with advanced Her-2-positive EMPD, presenting with numerous lymph node metastases. This patient received disitamab vedotin (an antibody-drug conjugate, targeting Her-2) combined with serplulimab as first-line treatment. After seven cycles of combination therapy, the patient tolerated the treatment well and the lymph node lesions continued to shrink. However, the patient developed immunotherapy-related pneumonia following the eighth treatment. Hormone therapy was administered while all the anti-tumor therapies were halted. After the pneumonia improved, the patient underwent positron emission tomography-computed tomography, revealing a complete response to his tumor. To consolidate the effect, he received another five cycles of disitamab vedotin monotherapy as maintenance therapy, without experiencing any adverse events. To date, the patient has remained in good health without any recurrence 10 months after drug discontinuance. Conclusion: Disitamab vedotin combined with immunotherapy demonstrated a long-term clinical benefit in advanced Her-2-positive EMPD. For rare solid tumors with Her-2 overexpression, disitamab vedotin combined with immunotherapy might offer a viable therapeutic choice.

Occurrence and Distribution of Antibacterial Quaternary Ammonium Compounds in Chinese Estuaries Revealed by Machine Learning-Assisted Mass Spectrometric Analysis.

Antimicrobial resistance (AMR) undermines the United Nations Sustainable Development Goals of good health and well-being. Antibiotics are known to exacerbate AMR, but nonantibiotic antimicrobials, such as quaternary ammonium compounds (QACs), are now emerging as another significant driver of AMR. However, assessing the AMR risks of QACs in complex environmental matrices remains challenging due to the ambiguity in their chemical structures and antibacterial activity. By machine learning prediction and high-resolution mass spectrometric analysis, a list of antibacterial QACs (n = 856) from industrial chemical inventories is compiled, and it leads to the identification of 50 structurally diverse antibacterial QACs in sediments, including traditional hydrocarbon-based compounds and new subclasses that bear additional functional groups, such as choline, ester, betaine, aryl ether, and pyridine. Urban wastewater, aquaculture, and hospital discharges are the main factors influencing QAC distribution patterns in estuarine sediments. Toxic unit calculations and metagenomic analysis revealed that these QACs can influence antibiotic resistance genes (particularly sulfonamide resistance genes) through cross- and coresistances. The potential to influence the AMR is related to their environmental persistence. These results suggest that controlling the source, preventing the co-use of QACs and sulfonamides, and prioritizing control of highly persistent molecules will lead to global stewardship and sustainable use of QACs.

Clinicopathologic features and genomic profiling of female axillary lymph node metastases from adenocarcinoma or poorly differentiated carcinoma of unknown primary.

PURPOSE: Axillary lymph node metastases from adenocarcinoma or poorly differentiated carcinoma of unknown primary (CUPAx) is a rare disease in women. This retrospective study intended to examine the clinicopathological features of CUPAx and compared CUPAx genetically with axillary lymph node metastases from breast cancer (BCAx), investigating differences in their biological behavior. METHODS: We conducted the clinical and prognostic analysis of 58 CUPAx patients in West China Hospital spanning from 2009 to 2021. Gemonic profiling of 12 CUPAx patients and 16 BCAx patients was conducted by the FoundationOne CDx (F1CDx) platform. Moreover, we also compared the gene mutation spectrum and relevant pathways between the two groups and both TCGA and COSMIC databases. RESULTS: The majority of the 58 CUPAx patients were HR-/HER2- subtype. Most patients received mastectomy combined radiotherapy (50 Gy/25f). CUPAx patients who received mastectomy instead of breast-conserving surgery had a more favorable overall prognosis. Radiotherapy in chest wall/breast and supraclavicular/infraclavicular fossa was the independent prognostic factor (HR = 0.05, 95%CI = 0.00-0.93, P = 0.04). In 28 sequencing samples (CUPAx, n = 12, BCAx, n = 16) and 401 TCGA-BRCA patients, IRS2 only mutated in CUPAx (33.33%) but amplified in BCAx (11.11%) and TCGA-BRCA (1.5%). Pathway analysis revealed that BCAx had more NOTCH pathway mutations than CUPAx. Enrichment analysis showed that CUPAx enriched more in mammary development and PML bodies than BCAx, but less in the positive regulation of kinase activity. CONCLUSIONS: More active treatment methods, like chemotherapy, mastectomy and postoperative radiotherapy, could improve the prognosis of CUPAx. The differential mutation genes of CUPAx and BCAx might be associated with their respective biological behaviors like invasiveness and prognosis.

Ryegrass uptake behavior and forage risk assessment after exposing to soil with combined polycyclic aromatic hydrocarbons and cadmium.

Internalization of chemicals and the forage risks of ryegrass under the combined exposure to PAHs and Cd at environmental concentrations were studied here. The effect of soil pH was also concerned due to the widely occurred soil acidification and general alkali remediation for acidification soil. Unexpectedly, as same as the acid-treated group (pH 6.77), the alkali-treatment (pH 8.83) increased Cd uptake compared with original soil pH group (pH 7.92) for the reason of CdOH+ and CdHCO3+ formed in alkali-treated group. Co-exposure to PAHs induced more oxidative stress than Cd exposure alone due to PAHs aggregated in young root regions, such as root tips, and consequently, affecting the expression of Cd-transporters, destroying the basic structure of plant cells, inhibiting the energy supply for the transporters, even triggering programmed cell death, and finally resulting in decreased Cd uptake. Even under environmental concentrations, combined exposure caused potential risks derived from both PAHs and Cd. Especially, ryegrass grown in alkali-treated soil experienced an increased forage risks despite the soil meeting the national standards for Cd at safe levels. These comprehensive results reveal the mechanism of PAHs inhibiting Cd uptake, improve the understanding of bioavailability of Cd based on different forms, provide a theoretical basis to formulate the safety criteria, and guide the application of actual soil management.

Mechanism of tartaric acid mediated dissipation and biotransformation of tetrabromobisphenol A and its derivatives in soil.

Biotransformation is a major dissipation process of tetrabromobisphenol A and its derivatives (TBBPAs) in soil. The biotransformation and ultimate environmental fate of TBBPAs have been widely studied, yet the effect of root exudates (especially low-molecular weight organic acids (LMWOAs)) on the fate of TBBPAs is poorly documented. Herein, the biotransformation behavior and mechanism of TBBPAs in bacteriome driven by LMWOAs were comprehensively investigated. Tartaric acid (TTA) was found to be the main component of LMWOAs in root exudates of Helianthus annus in the presence of TBBPAs, and was identified to play a key role in driving shaping bacteriome. TTA promoted shift of the dominant genus in soil bacteriome from Saccharibacteria_genera_incertae_sedis to Gemmatimonas, with a noteworthy increase of 24.90-34.65% in relative abundance of Gemmatimonas. A total of 28 conversion products were successfully identified, and ß-scission was the principal biotransformation pathway for TBBPAs. TTA facilitated the emergence of novel conversion products, including 2,4-dibromophenol, 3,5-dibromo-4-hydroxyacetophenone, para-hydroxyacetophenone, and tribromobisphenol A. These products were formed via oxidative skeletal cleavage and debromination pathways. Additionally, bisphenol A was observed during the conversion of derivatives. This study provides a comprehensive understanding about biotransformation of TBBPAs driven by TTA in soil bacteriome, offering new insights into LMWOAs-driven biotransformation mechanisms.

Simultaneous determination of 19 bromophenols by gas chromatography-mass spectrometry (GC-MS) after derivatization.

Bromophenols (BPs) are a class of ubiquitous emerging halogenated pollutants. Their 19 congeners are problematically separated and detected. This work described the separation and detection of 19 BP congeners by gas chromatography-mass spectrometry (GC-MS). Investigations into the derivatization of bromophenols were carried out using two silylation reagents (N,O-bis(trimethylsilyl)trifluoroacetamide and N-methyl-N-(trimethylsily)trifluoroacetamide), two alkylation reagents (methyl iodide and trimethylsilyldiazomethane) and acetic anhydride prior to GC-MS analysis. Optimal chromatographic separation, sensitivity, and linearity were achieved after BP derivatization using acetic anhydride, featuring the equipment detection limits of 0.39-1.26 pg and correlation coefficients of 0.9948-0.9999 (linear range: 0.5-250 ng mL-1) for all 19 BP congeners. Furthermore, the simultaneous determination of 19 bromophenols and 19 bromoanisoles, common environmental transformation products of BPs, is also demonstrated. The improved analytical performance on GC-MS after derivatization would benefit investigations on the environmental origins, behaviors and fates of BPs and their environmental metabolites.

A phase II study of efficacy and safety of the MEK inhibitor tunlametinib in patients with advanced NRAS-mutant melanoma.

BACKGROUND: NRAS-mutant melanoma is an aggressive subtype with poor prognosis; however, there is no approved targeted therapy to date worldwide. METHODS: We conducted a multicenter, single-arm, phase II, pivotal registrational study that evaluated the efficacy and safety of the MEK inhibitor tunlametinib in patients with unresectable, stage III/IV, NRAS-mutant melanoma (NCT05217303). The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response(DOR), overall survival (OS) and safety. FINDINGS: Between November 2, 2020 and February 11, 2022, a total of 100 patients were enrolled. All (n = 100) patients received at least one dose of tunlametinib (safety analysis set [SAS]) and 95 had central laboratory-confirmed NRAS mutations (full analysis set [FAS]). In the FAS, NRAS mutations were observed at Q61 (78.9%), G12 (15.8%) and G13 (5.3%). The IRRC-assessed ORR was 35.8%, with a median DOR of 6.1 months. The median PFS was 4.2 months, DCR was 72.6% and median OS was 13.7 months. Subgroup analysis showed that in patients who had previously received immunotherapy, the ORR was 40.6%. No treatment-related deaths occurred. INTERPRETATION: Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.

Memory/Active T-Cell Activation Is Associated with Immunotherapeutic Response in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. RESULTS: In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.

Flame-Retardant Thermoplastic Polyether Ester/Aluminum Butylmethylphosphinate/Phenolphthalein Composites with Enhanced Mechanical Properties and Antidripping.

Aluminum butylmethylphosphinate AiBMP as a flame retardant and phenolphthalein as a synergistic agent were applied in a thermoplastic polyester elastomer (TPEE)) in the current study. The thermal properties, flame retardancy, crystallization and mechanical properties of TPEE/AiMBP with or without phenolphthalein were investigated using various characterizations, including the limiting oxygen index (LOI), vertical burning test (UL 94), thermogravimetric analysis TG, differential scanning calorimetry, microcombustion calorimeter (MCC), scanning electron microscopy (SEM), and mechanical tests. The results revealed that AiBMP alone is an efficient flame retardant of TPEE. Adding 15 wt.% AiBMP increases the LOI value of TPEE from 20% to 36%. The formula TPEE-15 AiBMP passed the UL 94 V-0 rating with no dripping occurring. The MCC test shows that AiBMP depresses the heat release of TPEE. In comparison with pure TPEE, the heat release rate at peak temperature and the heat release capacity of TPEE-15AiBMP are reduced by 46.1% and 55.5%, respectively. With the phenolphthalein added, the formula TPEE/13AiBMP/2Ph shows a higher char yield at high temperatures (>600 °C), and the char layer is stronger and more condensed than TPEE-15AiBMP.The tensile strength and elongation at break values of TPEE-13AiBMP-2Ph are increased by 29.63% and 4.8% in comparison with TPEE-15AiBMP. The SEM morphology of the fracture surface of the sample shows that phenolphthalein acts as a plasticizer to improve the dispersion of AiBMP within the matrix. The good char charming ability of phenolphthalein itself and improved dispersion of AiBMP make the TPEE composites achieve both satisfying flame retardancy and high mechanical properties.

Peripheral arterial rather than venous blood is a better source of circulating tumor cells in early lung cancer.

BACKGROUND: Circulating tumor cells (CTCs) play a crucial role in the early diagnosis and prognosis of lung cancer. Identification of a more suitable sample source could be a breakthrough towards enhancing CTC detectability in early-stage lung cancer. We investigated the differences in detectable CTCs between peripheral arterial and venous blood in early- and mid-stage lung cancer patients undergoing surgery and analyzed the association between clinicopathological factors and detectable CTCs in peripheral arterial and venous blood. METHODS: Peripheral arterial and venous blood was collected in 5-mL samples from 56 patients with surgically resected and pathologically clear at early- or mid-stage lung cancer. Blood specimens were enriched for CTCs based on isolation by size of epithelial tumor cells. The CTCs were identified using Swiss Giemsa staining and immunohistochemistry for CD45/CD31. RESULTS: In stage I lung cancer, CTC-positive rate was significantly higher in peripheral arterial than in venous blood (45.45% vs. 17.39%). There was no significant difference in the number of detectable CTCs between peripheral arterial and venous blood. A low degree of differentiation was associated with a high positive rate of CTCs in peripheral venous blood. The number of circulating tumor microemboli was significantly higher in patients with tumor size >3 cm compared with ≤3 cm. CONCLUSION: CTC levels in peripheral arterial and venous blood differed little in lung cancer patients.Compared to peripheral venous blood, peripheral arterial blood had a higher CTC positivity rate in early-stage lung cancer.This study was favorable for early detection and monitoring of lung cancer.

High dielectric transparent polymer composite with well-organized carboxymethyl cellulose microfibers in silicon elastomer fabricated under direct current electric field.

The combination of transparency, high dielectric permittivity, biocompatibility and flexibility is highly desired in the embedded capacitors. Herein, we show that assembling biodegradable sodium carboxymethyl cellulose (CMC) microfibers in biocompatible silicon elastomer (PDMS) under direct current (DC) electric field enables the production of high dielectric constant composite film with above desired properties. This process leads to the formation of columns of CMC microfibers spanning across the thickness direction, thus generating microfiber depleted regions in between fibers and polymer matrix. The as-prepared composite film with CMC (15 wt%) aligned exhibits a remarkable and an almost sevenfold higher dielectric permittivity as compared to that of the film with CMC randomly dispersed (72 vs 11.4, at 100 Hz). This high CMC loading does not compromise the flexibility and optical transmittance. Interestingly, the compression modulus along the thickness direction increases by >20 times from 16.4 MPa (CMC unaligned) to 339.9 MPa (CMC aligned). We demonstrate a facile strategy of fabricating high dielectric materials combining transparency, biocompatibility, flexibility and compression resistant, making the dielectric materials more versatile. This work shows that biomass derived CMC is a promising filler for high dielectric constant polymer composites benefiting from electric field driven construction of ordered micromorphology.

Genomic and Evolutionary Characterization of Concurrent Intraductal Carcinoma and Adenocarcinoma of the Prostate.

Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally coexists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared with concomitant adenocarcinoma. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathologic heterogeneity between IDC-P and PAC. Compared with coexisting PAC, IDC-P displayed increased expression of adverse prognosis-associated genes. Survival analysis based on an independent cohort of 505 patients with metastatic prostate cancer revealed that IDC-P carriers with lower risk International Society of Urological Pathology (ISUP) grade 1-4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation-associated master regulators and genes involved in intratumoral androgen biosynthesis. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P. SIGNIFICANCE: The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.

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.