RET rearrangement as a mechanism of resistance to ALK-TKI in non-small cell lung cancer patient with EML4-ALK fusion: A case report.

Patients with non-small cell lung cancer (NSCLC) and anaplastic lymphoma kinase (ALK) mutations have previously derived substantial benefits from ALK tyrosine kinase inhibitors (ALK-TKIs). However, resistance may develop in some patients. We present a case of co-mutation with anaplastic lymphoma kinase (ALK) and rearranged during transfection (RET)-rearranged NSCLC, representing a novel resistance mechanism to ALK-TKIs, in which the patient exhibited a favorable response to combination therapy with ensartinib and pralsetinib. Notably, the patient survived 12 months without experiencing adverse events, a rare occurrence in ALK-rearranged lung adenocarcinoma cases. This case provides further evidence for the existence of RET rearrangements in ALK-positive lung cancer and their potential treatment response to a combination of ALK inhibitors and pralsetinib. This case underscores that a dual-target therapy involving ALK inhibitors, specifically ensartinib and pralsetinib, could be a viable approach in cases of RET-rearranged lung cancer with concurrent targetable ALK mutations. We propose the consideration of this dual-target approach, specifically employing ensartinib and pralsetinib, in managing RET-rearranged lung cancer coexisting with targetable ALK mutations. Given the potential efficacy of these treatments, it is imperative to proactively conduct molecular profiling tests in NSCLC patients upon the emergence of resistance.

Iodoarene-directed photoredox ß-C(sp3)-H arylation of 1-(o-iodoaryl)alkan-1-ones with cyanoarenes via halogen atom transfer and hydrogen atom transfer.

Site selective functionalization of inert remote C(sp3)-H bonds to increase molecular complexity offers vital potential for chemical synthesis and new drug development, thus it has been attracting ongoing research interest. In particular, typical ß-C(sp3)-H arylation methods using chelation-assisted metal catalysis or metal-catalyzed oxidative/photochemical in situ generated allyl C(sp3)-H bond processes have been well developed. However, radical-mediated direct ß-C(sp3)-H arylation of carbonyls remains elusive. Herein, we describe an iodoarene-directed photoredox ß-C(sp3)-H arylation of 1-(o-iodoaryl)alkan-1-ones with cyanoarenes via halogen atom transfer (XAT) and hydrogen atom transfer (HAT). The method involves diethylaminoethyl radical-mediated generation of an aryl radical intermediate via XAT, then directed 1,5-HAT to form the remote alkyl radical intermediate and radical-radical coupling with cyanoarenes, and is applicable to a broad scope of unactivated remote C(sp3)-H bonds like ß-C(sp3)-H bonds of o-iodoaryl-substituted alkanones and α-C(sp3)-H bonds of o-iodoarylamides. Experimental findings are supported by computational studies (DFT calculations), revealing that this method operates via a radical-relay stepwise mechanism involving multiple SET, XAT, 1,5-HAT and radical-radical coupling processes.

IMPDH2 Positively Impacts the Proliferation Potential of Hepatoblastoma Cells by Activating JunB Signaling Pathway.

BACKGROUND: Amplification of inosine monophosphate dehydrogenase II, EC 1,1,1,205 (IMPDH2) has been reported in various cancers, which results in transformation and tumorigenicity. In our current work, we have explored the oncogenic properties and the underlying pathophysiology of IMPDH2 in hepatoblastoma (HB). METHODS: To investigate IMPDH2 expression in HB tissues and prognostic significance in HB patients, gene expression profiling interactive analysis (GEPIA) has been adopted. Immunohistochemistry has also helped to validate the protein expression of IMPDH2 in HB tissues. The effect of IMPDH2 overexpression or depletion on the proliferation of Hepatoblastoma cells in vitro has been evaluated by CCK8 assays and colony formation assays. Xenograft tumor growth of mice has been detected. Luciferase reporter assays have been conducted to determine the interaction of IMPDH2 and JunB, which was further asserted by pharmacological inhibition of JunB. RESULTS: IMPDH2 was highly expressed in HB tissues. Experimentally, the proliferation and colony formation of HuH6 cells were increased by IMPDH2 overexpression. Conversely, genetic inactivation of IMPDH2 impaired the proliferative efficiency and colony-forming rate of HepG2 cells. Besides, the luciferase reporter assay validated IMPDH2 overexpression to be associated with enhanced JunB transcriptional activity, while its activity was diminished in the case of IMPDH2 depletion. JunB inhibitor neutralized the IMPDH2-mediated increased phosphorylation of JunB. CONCLUSION: Our findings, thus, suggest that IMPDH2 exhibits its oncogenic role in HB partially via JunB-dependent proliferation.

MRI-Based Clinical-Imaging-Radiomics Nomogram Model for Discriminating Between Benign and Malignant Solid Pulmonary Nodules or Masses.

RATIONALE AND OBJECTIVES: Pulmonary nodules or masses are highly prevalent worldwide, and differential diagnosis of benign and malignant lesions remains difficult. Magnetic resonance imaging (MRI) can provide functional and metabolic information of pulmonary lesions. This study aimed to establish a nomogram model based on clinical features, imaging features, and multi-sequence MRI radiomics to identify benign and malignant solid pulmonary nodules or masses. MATERIALS AND METHODS: A total of 145 eligible patients (76 male; mean age, 58.4 years ± 13.7 [SD]) with solid pulmonary nodules or masses were retrospectively analyzed. The patients were randomized into two groups (training cohort, n = 102; validation cohort, n = 43). The nomogram was used for predicting malignant pulmonary lesions. The diagnostic performance of different models was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: Of these patients, 95 patients were diagnosed with benign lesions and 50 with malignant lesions. Multivariate analysis showed that age, DWI value, LSR value, and ADC value were independent predictors of malignant lesions. Among the radiomics models, the multi-sequence MRI-based model (T1WI+T2WI+ADC) achieved the best diagnosis performance with AUCs of 0.858 (95%CI: 0.775, 0.919) and 0.774 (95%CI: 0.621, 0.887) for the training and validation cohorts, respectively. Combining multi-sequence radiomics, clinical and imaging features, the predictive efficacy of the clinical-imaging-radiomics model was significantly better than the clinical model, imaging model and radiomics model (all P < 0.05). CONCLUSION: The MRI-based clinical-imaging-radiomics model is helpful to differentiate benign and malignant solid pulmonary nodules or masses, and may be useful for precision medicine of pulmonary diseases.

[Prediction of Ozone Pollution in Sichuan Basin Based on Random Forest Model].

To study the long-term variation in ozone (O3) pollution in Sichuan Basin,the spatiaotemporal distribution of O3 concentrations during 2017 to 2020 was analyzed using ground-level O3 concentration data and meteorological observation data from 18 cities in the basin. The dominant meteorological factors affecting the variation in O3 concentration were screened out,and a prediction model between meteorological factors and O3 concentration was constructed based on a random forest model. Finally,a prediction analysis of O3 pollution in the Sichuan Basin urban agglomeration during 2020 was carried out. The results showed that:① O3 concentrations displayed a fluctuating trend during the period from 2017 to 2020,with a downward trend in 2019 and a rebound in 2020. ② The fluctuating trend of O3 concentration was significantly influenced by relative humidity,daily maximum temperature,and sunshine hours,whereas wind speed,air pressure,and precipitation had less impact. The linear relationships between meteorological factors were different. Air pressure was negatively correlated with other meteorological factors,whereas the remaining meteorological factors had a positive correlation. ③ The goodness of fit statistics (R2) between the predicted and actual values of the O3 prediction model constructed based on random forest demonstrated a strong predictive performance and ability to accurately forecast the long-term daily variations in O3 concentration. The random forest O3 prediction model exhibited excellent stability and generalization capability. ④ The prediction analysis of O3 concentrations in 18 cities in the basin showed that the explanation rate of variables in the prediction model reached over 80% in all cities (except Ya'an),indicating that the random forest model predicted the trend of O3 concentration accurately.

Chaperones Hsc70 and Hsp70 play distinct roles in the replication of bocaparvovirus minute virus of canines.

Minute virus of canines (MVC) belongs to the genus Bocaparvovirus (formerly Bocavirus) within the Parvoviridae family and causes serious respiratory and gastrointestinal symptoms in neonatal canines worldwide. A productive viral infection relies on the successful recruitment of host factors for various stages of the viral life cycle. However, little is known about the MVC-host cell interactions. In this study, we identified that two cellular proteins (Hsc70 and Hsp70) interacted with NS1 and VP2 proteins of MVC, and both two domains of Hsc70/Hsp70 were mediated for their interactions. Functional studies revealed that Hsp70 was induced by MVC infection, knockdown of Hsc70 considerably suppressed MVC replication, whereas the replication was dramatically promoted by Hsp70 knockdown. It is interesting that low amounts of overexpressed Hsp70 enhanced viral protein expression and virus production, but high amounts of Hsp70 overexpression weakened them. Upon Hsp70 overexpressing, we observed that the ubiquitination of viral proteins changed with Hsp70 overexpression, and proteasome inhibitor (MG132) restored an accumulation of viral proteins. In addition, we verified that Hsp70 family inhibitors remarkably decreased MVC replication. Overall, we identified Hsc70 and Hsp70 as interactors of MVC NS1 and VP2 proteins and were involved in MVC replication, which may provide novel targets for anti-MVC approach.

Study on the mechanism of quercetin inducing mesenchymal stem cells to differentiate into fibroblasts through TGF-ß1 and IGF-1.

BACKGROUND: Stem cell differentiation has opened up new avenues for disease treatment, tissue repair, and drug development in the study of regenerative medicine, and has huge application prospects. This study aimed to explore the mechanism of quercetin on the differentiation of mesenchymal stem cells (MSCs) into fibroblasts. METHODS: In this study, cell differentiation experiments and flow cytometry were used to detect the successful isolation of bone marrow MSCs from SD rats. Quercetin at 5, 10, and 20 µM was used as low, medium, and high doses to intervene in MSCs. The cell viability changes of ligament fibroblasts at 24, 48, and 72 hours after quercetin treatment were detected using a CCK-8 cell counting kit. Cell proliferative capacity was determined by flow cytometry. RT-qPCR measured the relative expression levels of TGF-ß1, IGF-1, COL-Ⅰ, COL-Ⅲ, FN (fibronectin), and TNMD (Tenomodulin) in different experimental groups. Molecular docking experiments were conducted to explore the binding effect of quercetin on TGF-ß1 and IGF-1 proteins. RESULTS: Flow cytometry verified the successful isolation of MSCs, which had high expression of CD29 and CD73, while lower expression of CD90 and CD45. Experimental results show that low and medium doses of quercetin can enhance cell proliferation, while high doses have no significant effect on cells. Detection of cell proliferation through flow cytometry yielded similar results to CCK-8. Transwell experiments have shown that low and medium doses of quercetin can increase cell migration ability. In addition, RT-qPCR detection showed that quercetin can increase the mRNA expression of TGF-ß1 and IGF-1, and promote the expression of COL-Ⅰ, COL-Ⅲ, FN, and TNMD genes in ligament fibroblasts. Molecular docking results showed that quercetin can bind firmly to TGF-ß1 and IGF-1. CONCLUSION: Overall, this study revealed the morphological characteristics and identification of MSCs, as well as the regulatory mechanism of quercetin on the behavior of ligament fibroblasts. Quercetin affects the proliferation and gene expression of ligament fibroblasts by regulating the expression of TGF-ß1 and IGF-1, which may provide a new perspective for biomedical research on the skeletal system.

First-in-human phase I study of BEBT-109 in previously treated EGFR exon 20 insertion-mutated advanced non-small cell lung cancer.

BACKGROUND: BEBT-109 is an oral pan-mutant-selective inhibitor of epidermal growth factor receptor (EGFR) that demonstrated promising antitumor potency in preclinical models. METHODS: This first-in-human study was a single-arm, open-label, two-stage study. Phase Ia dose-escalation study evaluated the safety and pharmacokinetics of BEBT-109 in 11 patients with EGFR T790M-mutated advanced non-small cell lung cancer (aNSCLC). Phase Ib dose-expansion study evaluated the safety and efficacy of BEBT-109 in 18 patients with EGFR exon 20 insertion (ex20ins)-mutated treatment-refractory aNSCLC. The primary outcomes were adverse events and antitumor activity. Clinical trial registration number CTR20192575. FINDINGS: The phase Ia study demonstrated no dose-limiting toxicity, no observation of the maximum tolerated dose, and no new safety signals with BEBT-109 in the dose range of 20-180 mg/d, suggesting that BEBT-109 had an acceptable safety profile among patients with EGFR T790M-mutated aNSCLC. Plasma pharmacokinetics of BEBT-109 showed a dose-proportional increase in the area under the curve and maximal concentration, with no significant drug accumulation. The dose-expansion study demonstrated that BEBT-109 treatment was tolerable across the three dose levels. The three most common treatment-related adverse events were diarrhea (100%; 22.2% ≥Grade 3), rash (66.7%; 5.6% ≥Grade 3), and anemia (61.1%; 0% ≥Grade 3). The objective response rate was 44.4% (8 of 18). Median progression-free survival was 8.0 months (95% confidence intervals, 1.33-14.67). CONCLUSION: Preliminary findings showed that BEBT-109 had an acceptable safety profile and favorable antitumor activity in patients with refractory EGFR ex20ins-mutated aNSCLC. FUNDING: National Natural Science Foundation of China.

Single dual-specific anti-PD-L1/TGF-ß antibody synergizes with chemotherapy as neoadjuvant treatment for pancreatic ductal adenocarcinoma: a preclinical experimental study.

AIMS: Chemotherapy resistance is an important cause of neoadjuvant therapy failure in pancreatic ductal adenocarcinoma (PDAC). BiTP (anti-PD-L1/TGF-ß bispecific antibody) is a single antibody that can simultaneously and dually target transforming growth factor-beta (TGF-ß) and programmed cell death ligand 1 (PD-L1). We attempted in this study to investigate the efficacy of BiTP in combination with first-line chemotherapy in PDAC. METHODS: Preclinical assessments of BiTP plus gemcitabine and nab-paclitaxel were completed through a resectable KPC mouse model (C57BL/6J). Spectral flow cytometry, tissue section staining, enzyme-linked immunosorbent assays, Counting Kit-8, transwell, and Western blot assays were used to investigate the synergistic effects. RESULTS: BiTP combinatorial chemotherapy in neoadjuvant settings significantly downstaged PDAC tumors, enhanced survival, and had a higher resectability for mice with PDAC. BiTP was high affinity binding to targets and reverse chemotherapy resistance of PDAC cells. The combination overcame immune evasion through reprogramming tumor microenvironment via increasing penetration and function of T cells, natural killer cells, and dendritic cells and decreasing the function of immunosuppression-related cells as regulatory T cells, M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. CONCLUSION: Our results suggest that the BiTP combinatorial chemotherapy is a promising neoadjuvant therapy for PDAC.

Electroreductive Remote Benzylic C(sp3)-H Arylation of Aliphatic Ethers Using Cyanoarenes for the Synthesis of α-(Hetero)aryl Ethers.

An iodoarene-driven electroreductive remote C(sp3)-H arylation of unsymmetrical 1-(o-iodoaryl)alkyl ethers with cyanoarenes for the site selective synthesis of α-(hetero)aryl ethers is developed. With the introduction of cyanoarenes as both aryl sources and electron transfer mediators, this method includes an iodoarene-driven strategy to enable the regiocontrollable formation of two new bonds, one C(sp2)-H bond, and one C(sp2)-C(sp3) bond, in a single reaction step through the sequence of halogen atom transfer (XAT), hydrogen atom transfer (HAT), radical-radical coupling, and decyanation.

Stored white tea ameliorates DSS-induced ulcerative colitis in mice by modulating the composition of the gut microbiota and intestinal metabolites.

Changes in the chemical composition of white tea during storage have been studied extensively; however, whether such chemical changes impact the efficacy of white tea in ameliorating colitis remains unclear. In this study, we compared the effects of new (2021 WP) and 10-year-old (2011 WP) white tea on 3% dextrose sodium sulfate (DSS)-induced ulcerative colitis in mice by gavaging mice with the extracts at 200 mg kg-1 day-1. Chemical composition analysis showed that the levels of 50 compounds, such as flavanols, dimeric catechins, and amino acids, were significantly lower in the 2011 WP extract than in the 2021 WP extract, whereas the contents of 21 compounds, such as N-ethyl-2-pyrrolidinone-substituted flavan-3-ols, theobromine, and (-)-epigallocatechin-3-(3''-O-methyl) gallate, were significantly higher. Results of the animal experiments showed that 2011 WP ameliorated the pathological symptoms of colitis, which was superior to the activity of 2021 WP, and this effect was likely enhanced based on the decreasing of the relative abundance of the g_bacteroides and g_Escherichia-Shigella flora in mice with colitis and promoting the conversion of primary bile acids to secondary bile acids in the colon. These results will facilitate the development of novel functional products from white tea.

SCAC: A Semi-Supervised Learning Approach for Cervical Abnormal Cell Detection.

Cervical abnormal cell detection plays a crucial role in the early screening of cervical cancer. In recent years, some deep learning-based methods have been proposed. However, these methods rely heavily on large amounts of annotated images, which are time-consuming and laborintensive to acquire, thus limiting the detection performance. In this paper, we present a novel Semi-supervised Cervical Abnormal Cell detector (SCAC), which effectively utilizes the abundant unlabeled data. We utilize Transformer as the backbone of SCAC to capture long-range dependencies to mimic the diagnostic process of pathologists. In addition, in SCAC, we design a Unified Strong and Weak Augment strategy (USWA) that unifies two data augmentation pipelines, implementing consistent regularization in semisupervised learning and enhancing the diversity of the training data. We also develop a Global Attention Feature Pyramid Network (GAFPN), which utilizes the attention mechanism to better extract multi-scale features from cervical cytology images. Notably, we have created an unlabeled cervical cytology image dataset, which can be leveraged by semi-supervised learning to enhance detection accuracy. To the best of our knowledge, this is the first publicly available large unlabeled cervical cytology image dataset. By combining this dataset with two publicly available annotated datasets, we demonstrate that SCAC outperforms other existing methods, achieving state-of-theart performance. Additionally, comprehensive ablation studies are conducted to validate the effectiveness of USWA and GAFPN. These promising results highlight the capability of SCAC to achieve high diagnostic accuracy and extensive clinical applications. The code and dataset are publicly available at https://github.com/Lewisonez/cc_detection.

Uterine Commensal Peptostreptococcus Species Contribute to IDO1 Induction in Endometrial Cancer via Indoleacrylic Acid.

Microbial dysbiosis has an increasingly appreciated impact on carcinogenesis, and the cervicovaginal microbiome plays a critical role in microenvironmental inflammation. Here, we investigated the involvement of the female genital tract Peptostreptococcus species in gynecological cancer via indoleacrylic acid (IAA). IAA production from Peptostreptococcus species and the effect of bacterial culture on tumor growth in vivo were examined. The impact of IAA on cytokine production and indoleamine-2,3-dioxygenase 1 (IDO1) expression in an endometrial cancer (EC) cell line, as well as their effect on Treg and Teff cells, and M1 and M2 macrophage populations were examined in EC patients and tumor-grafted mice. Clinically, Peptostreptococcus species abundance, IAA, and IDO1 expression were verified in EC patients. The results showed that IAA production was induced in the uteri of BALB/c nude mice by Peptostreptococcus species transplantation, and the intratumoral injection of a conditioned medium from Peptostreptococcus cultures into tumor-grafted mice promoted tumor growth. IL-10 expression was upregulated by IAA; IFN-γ expression was increased by IL-10. IFN-γ induced IDO1 expression in the EC cell line. The co-culture of IDO1-expressing EC cells with peripheral blood mononuclear cells upregulated the Treg proportion and decreased the M1/M2 ratio. Clinically, P. anaerobius was more abundant amongst the uterine microbiota of EC patients than the control. The IAA, IDO1, and kynurenine/tryptophan ratios were all higher in EC tissue, and the M1/M2 ratio was lower. Our study sheds light on the link between IDO1 induction and uterine Peptostreptococcus dysbiosis and provides a potential rationale for the role of Peptostreptococcus species in immune tolerance induction in type I endometrial cancer.

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China.

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

The role of superoxide anion to Cr(VI) reduction by pine biochar.

It has been reported that Cr(VI) can be reduced by biochar because of its redox activity. Considering the anionic form of Cr(VI), we hypothesize that the reduction in aqueous phase is significant. However, the contribution of different reactive oxygen species in the biochar-Cr(VI) reaction system has not been distinguished. Herein, we quantitatively identified Cr(VI) adsorption and reduction in biochar systems. The reduction content of Cr(VI) was 1.5 times higher in untreated conditions than in anaerobic conditions. The disappearance of·O2- under anaerobic conditions illustrated that·O2- may be involved in the reduction of Cr(VI). Quenching of·O2- resulted in a decrease of Cr(VI) reduction by 34%, while 1O2 was negligible, probably due to the stronger electron-donating capacity of·O2-. The degradation of nitrotetrazolium blue chloride (quenching agent of·O2-) confirmed that the reduction process of·O2- mainly occurred in the liquid-phase. Boehm titration and quantification of·O2- further elucidated the significant correlation (P < 0.05) between phenolic groups and the formation of·O2-, which implied that phenolic groups acted as the primary electron donors in generating·O2-. This study highlights the importance of the liquid-phase reduction process in removing Cr(VI), which provides theoretical support for biochar conversion of Cr(VI).

Detection and localization of corrosion using the combination information of multiple Lamb wave modes.

Themulti-modeanddispersionnature of Lamb waves means that a variety of modes with individual mode structures and distinct dispersion behaviors would propagate in the structures simultaneously. The existence of a corrosion would result in thickness reduction, which means the frequency-thickness product under a specific excitation would also decrease. Due to dispersion diversity, the interaction of each individual Lamb mode at the corrosion may be distinct, i.e., the velocity varies in different extent and even in opposite trends. In this paper, the combination of multiple modes, rather than a single sensitive mode, is used for structure diagnosis. Specifically, two Lamb modes both sensitive to corrosion but with opposite variation trends are taken and the corrosion index is defined on the ratio of their time-of-flight, so as to enhance the sensitivity to corrosion and eliminate the influence of difference path lengths in the sensor network. On this basis, a probabilistic reconstruction algorithm is introduced for corrosion detection and localization. Since the two modes are extracted from the same wideband Lamb wave response, the proposed method is baseline-free. The influence of mode conversion on the effectiveness of the proposed method is discussed. Ultimately, the performance of the proposed method is demonstrated by an experimental example. The results show that the defect could be correctly identified and accurately localized.

Tethered Small-Molecule Acceptor Refines Hierarchical Morphology in Ternary Polymer Solar Cells: Enhanced Stability and 19% Efficiency.

Polymer solar cells (PSCs) are promising for efficient solar energy conversion, but achieving high efficiency and device longevity within a bulk-heterojunction (BHJ) structure remains a challenge. Traditional small-molecule acceptors (SMAs) in the BHJ blend show thermodynamic instability affecting the morphology. In contrast, tethered SMAs exhibit higher glass transition temperatures, mitigating these concerns. Yet, they might not integrate well with polymer donors, causing pronounced phase separation and overpurification of mixed domains. Herein, a novel ternary device is introduced that uses DY-P2EH, a tethered dimeric SMA with conjugated side-chains as host acceptor, and BTP-ec9, a monomeric SMA as secondary acceptor, which respectively possess hypomiscibility and hypermiscibility with the polymer donor PM6. This unique combination affords a parallel-connected ternary BHJ blend, leading to a hierarchical and stable morphology. The ternary device achieves a remarkable fill factor of 80.61% and an impressive power conversion efficiency of 19.09%. Furthermore, the ternary device exhibits exceptional stability, retaining over 85% of its initial efficiency even after enduring 1100 h of thermal stress at 85 °C. These findings highlight the potential advantage of tethered SMAs in the design of ternary devices with a refined hierarchical structure for more efficient and durable solar energy conversion technologies.

Adverse events and efficacy of second-round CAR-T cell therapy in relapsed pediatric B-ALL.

OBJECTIVE: Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment approach for pediatric patients suffering from relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, there was a paucity of data on the challenges associated with second-round CAR-T therapy in this population. METHODS: Medical records of nine pediatric patients who received second-round CAR-T therapy in a single center from June 2019 to May 2023 were analyzed. Throughout the course of the clinical trial, we evaluated adverse events including CRS, CRES, infections, hematologic toxicity, and organ injury, as well as CAR-T responses. RESULTS: Except for one patient who chose CART therapy due to testicular relapse, the remaining patients had indications for CAR-T therapy due to relapse with bone marrow alone or combined with other site. There were no difference between the transfusion dose of CART1 and CART2. No differences of incidence and grade of CRS was found between the first-round CAR-T therapy (CART1) and second-round CAR-T therapy (CART2). Additionally, we found that the incidence of CRES was higher for CART1(3/9,33.3%) than CART2(1/9,11.1%). Our findings revealed that there were no differences of IL-2, IL-4, IL-6, IL-10, IFN-γ, and TNF-α between CART1 and CART2, but the peak level of IL-17A was significantly higher in patients receiving CART1 compared to those receiving CART2 (p = .011). Early and late infection rates after CART1 were higher than CART2. Based on the dynamic changes of ANC, hemoglobin and platelet, ANC, and platelet were reduced obviously post CART. It seems that the incidences of severe thrombocytopenia and severe anemia were higher in the CART1 group compared to CART2. The MRD-negative CR rates for CART1 and CART2 are 100% and 44.4%, respectively (p = .029). All patients experienced events (relapse, chemotherapy, transplantation, or death) after receiving CART2, including one died, three discharged automatically, and the remaining five patients survived. CONCLUSION: Although the remission rate of CART2 is not as high as the CART1 due to the severity of the disease, its safety regarding CRS, CRES, infections, and organ injury is still excellent. Therefore, CART2 remains a viable option for treating pediatric relapsed B-ALL.

Elevation of H3K27me3 level contributes to the radioresistance of nasopharyngeal carcinoma by inhibiting OAS1 expression.

Radiotherapy has long been a main treatment option for nasopharyngeal carcinoma (NPC). However, during clinical treatment, NPC is prone to developing radioresistance, resulting in treatment failure. This study aims to examine the role of histone methylation in the induction of radioresistance. It was found that the radioresistance of NPC cells was related to the increase of the level of histone H3 lysine 27 trimethylation (H3K27me3). Treatment of cells with histone methyltransferase inhibitor GSK126 increased the radiosensitivity of NPC cells by triggering Bcl2 apoptosis regulator/BCL2-associated X, apoptosis regulator (Bcl2/BAX) signaling pathway. Bioinformatics analysis indicated that the expression of 2'-5'-oligoadenylate synthetase 1 (OAS1) was reduced in the radioresistant cells but increased in the GSK126-treated cells. Chromatin immunoprecipitation assay confirmed that the decrease of OAS1 expression in radioresistant cells was mainly due to the enrichment of H3K27me3 in its promoter region. Furthermore, downregulation of OAS1 reduced apoptosis due to the inhibition of Bcl2/BAX pathway after irradiation, while OAS1 overexpression increased radiosensitivity. Our findings revealed for the first time that the increase of H3K27me3 level was associated with the decrease of OAS1 expression, leading to the inhibition of apoptosis and ultimately contributing to the radioresistance of NPC cells. Moreover, the histone methyltransferase inhibitor GSK126 could overcome the radioresistance and thus might be a potential therapeutic strategy for NPC.NEW & NOTEWORTHY Our findings revealed for the first time that the increase of H3K27me3 level was associated with the decrease of OAS1 expression, leading to the inhibition of apoptosis and ultimately contributing to the radioresistance of NPC cells. Moreover, we demonstrated that the histone methyltransferase inhibitor GSK126 could be a promising therapeutic strategy for NPC by overcoming radioresistance, providing valuable insights into the clinical treatment of NPC.

Inundative practice for screening siRNA management candidates against a notorious predatory beetle using olfactory silencing.

Calosoma maximoviczi, a predatory pest beetle, poses a significant threat to wild silk farm production due to its predation on wild silkworms. Given the coexistence of this species with beneficial silkworms in the farm orchards, chemical pesticides are not an ideal solution for controlling its population. In this study, we employed a comprehensive multi-target RNA interference (RNAi) approach to disrupt the olfactory perception of C. maximoviczi through independently silencing 16 odorant receptors (ORs) in the respective genders. Specifically, gene-specific siRNAs were designed to target a panel of ORs, allowing us to investigate the specific interactions between odorant receptors and ligands within this species. Our investigation led to identifying four candidate siOR groups that effectively disrupted the beetle's olfactory tracking of various odorant ligands associated with different trophic levels. Furthermore, we observed sex-specific differences in innate RNAi responses reflected by subsequent gene expression, physiological and behavioral consequences, underscoring the complexity of olfactory signaling and emphasizing the significance of considering species/sex-specific traits when implementing pest control measures. These findings advance our understanding of olfactory coding patterns in C. maximoviczi beetles and establish a foundation for future research in the field of pest management strategies.