Deciphering the Prognostic Significance of MYD88 and CD79B Mutations in Diffuse Large B-Cell Lymphoma: Insights into Treatment Outcomes.

BACKGROUND: The clinical and genetic characteristics, as well as treatment outcomes, of diffuse large B-cell lymphoma (DLBCL) patients with different MYD88 and CD79B mutation status merit further investigation. OBJECTIVE: This study aims to investigate the distinctions in clinical manifestations, genetic characteristics, and treatment outcomes among MYD88-CD79Bco-mut, MYD88/CD79Bsingle-mut, and MYD88-CD79Bco-wt DLBCL patients. PATIENTS AND METHODS: Clinical and genetic characteristics, along with treatment outcomes among 2696 DLBCL patients bearing MYD88-CD79Bco-mut, MYD88/CD79Bsingle-mut, and MYD88-CD79Bco-wt treated with R-CHOP/R-CHOP-like regimens from the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and six external cohorts were analyzed. Potential molecular mechanisms were investigated through Gene Set Enrichment Analysis and xCell methodology. RESULTS: In the MCD subtype, patients with MYD88-CD79Bco-mut showed comparable progression-free survival (PFS) and overall survival (OS) compared to MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt. However, in the non-MCD subtype, patients with MYD88-CD79Bco-mut exhibited significantly inferior OS than MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt, while there was no significant OS difference between MYD88/CD79Bsingle-mut and MYD88-CD79Bco-wt (median OS: 68.8 [95% CI 22-NA] vs NA [95% CI 112-NA] vs 177.7 [95% CI 159-NA] months; MYD88-CD79Bco-mut vs MYD88/CD79Bsingle-mut: p = 0.02; MYD88-CD79Bco-mut vs MYD88-CD79Bco-wt: p = 0.03; MYD88/CD79Bsingle-mut vs MYD88-CD79Bco-wt: p = 0.33). Regarding patients with MYD88-CD79Bco-mut, there was no significant difference in PFS and OS between the MCD and non-MCD subtypes. Within the MYD88-CD79Bco-mut group, patients with PIM1mut had better PFS than PIM1wt (median PFS: 8.34 [95% CI 5.56-NA] vs 43.8 [95% CI 26.4-NA] months; p = 0.02). Possible mechanisms contributing to the superior PFS of PIM1mut patients may include activated lymphocyte-mediated immunity and interferon response, a higher proportion of natural killer T cells and plasmacytoid dendritic cells, as well as suppressed angiogenesis and epithelial-mesenchymal transition, along with lower fibroblast and stromal score. CONCLUSIONS: In the MCD subtype, patients with MYD88-CD79Bco-mut showed comparable PFS and OS compared to MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt, while in the non-MCD subtype, they exhibited significantly inferior OS. There was no significant disparity in PFS and OS of MYD88-CD79Bco-mut between the MCD and non-MCD subtypes. The presence of PIM1mut within the MYD88-CD79Bco-mut group correlated with better PFS, which may result from an intricate interplay of immune processes and tumor microenvironment alterations.

Genomic diversity of the pathogenic fungus Aspergillus fumigatus in Japan reveals the complex genomic basis of azole resistance.

Aspergillus fumigatus is a pathogenic fungus with a global distribution. The emergence of azole-resistant A. fumigatus (ARAf) other than the TR-mutants is a problem in Japan. Additionally, the genetic diversity of A. fumigatus strains in Japan remains relatively unknown. Here we show the diversity in the A. fumigatus strains isolated in Japan as well as the complexity in the global distribution of the pathogenic strains. First, we analyzed the genome sequences of 171 strains from Japan as well as the antifungal susceptibility of these strains. Next, we conducted a population analysis of 876 strains by combining the available genomic data for strains isolated worldwide, which were grouped in six clusters. Finally, a genome-wide association study identified the genomic loci associated with ARAf strains, but not the TR-mutants. These results highlight the complexity of the genomic mechanism underlying the emergence of ARAf strains other than the TR-mutants.

Construction of SU-102 for adsorption and photocatalytic synergistic removal of tetracycline.

Tetracycline (TC) is a significant group of broad-spectrum antibiotics that are frequently employed in medical health and animal husbandry. However, the problem of TC residues has been increasing globally with the large-scale production and widespread use, posing a serious threat to the human health and ecological environment. In this paper, a green plant-based MOF SU-102 was prepared, and the adsorption characteristics of SU-102 on TC were investigated. SU-102 was columnar crystal with considerable specific surface area and pore structure, and it could adsorb TC quickly and effectively. And compared to SU-102-a, the adsorption rate of TC by SU-102-b has increased by nearly four times. The adsorption reaction was a spontaneous, entropy-gaining, heat-absorbing process. The adsorption mechanisms between SU-102 and TC were π-π interaction and hydrogen bonding. In addition, SU-102 also had considerable photocatalytic properties, and its application in adsorbent desorption treatment effectively solved the problem of secondary pollution.

Tracking pairwise genomic loci by the ParB-ParS and Noc-NBS systems in living cells.

The dynamics of genomic loci pairs and their interactions are essential for transcriptional regulation and genome organization. However, a robust method for tracking pairwise genomic loci in living cells is lacking. Here we developed a multicolor DNA labeling system, mParSpot (multicolor ParSpot), to track pairs of genomic loci and their interactions in living cells. The mParSpot system is derived from the ParB/ParS in the parABS system and Noc/NBS in its paralogous nucleoid occlusion system. The insertion of 16 base-pair palindromic ParSs or NBSs into the genomic locus allows the cognate binding protein ParB or Noc to spread kilobases of DNA around ParSs or NBSs for loci-specific visualization. We tracked two loci with a genomic distance of 53 kilobases and measured their spatial distance over time. Using the mParSpot system, we labeled the promoter and terminator of the MSI2 gene span 423 kb and measured their spatial distance. We also tracked the promoter and terminator dynamics of the MUC4 gene in living cells. In sum, the mParSpot is a robust and sensitive DNA labeling system for tracking genomic interactions in space and time under physiological or pathological contexts.

Multi-Scale Attention Network for Building Extraction from High-Resolution Remote Sensing Images.

The precise building extraction from high-resolution remote sensing images holds significant application for urban planning, resource management, and environmental conservation. In recent years, deep neural networks (DNNs) have garnered substantial attention for their adeptness in learning and extracting features, becoming integral to building extraction methodologies and yielding noteworthy performance outcomes. Nonetheless, prevailing DNN-based models for building extraction often overlook spatial information during the feature extraction phase. Additionally, many existing models employ a simplistic and direct approach in the feature fusion stage, potentially leading to spurious target detection and the amplification of internal noise. To address these concerns, we present a multi-scale attention network (MSANet) tailored for building extraction from high-resolution remote sensing images. In our approach, we initially extracted multi-scale building feature information, leveraging the multi-scale channel attention mechanism and multi-scale spatial attention mechanism. Subsequently, we employed adaptive hierarchical weighting processes on the extracted building features. Concurrently, we introduced a gating mechanism to facilitate the effective fusion of multi-scale features. The efficacy of the proposed MSANet was evaluated using the WHU aerial image dataset and the WHU satellite image dataset. The experimental results demonstrate compelling performance metrics, with the F1 scores registering at 93.76% and 77.64% on the WHU aerial imagery dataset and WHU satellite dataset II, respectively. Furthermore, the intersection over union (IoU) values stood at 88.25% and 63.46%, surpassing benchmarks set by DeepLabV3 and GSMC.

Adsorption Behavior of Dissolved Gas Molecules in Transformer Oil on Rh Modified GeSe Monolayer.

Dissolved gas analysis in transformer oil is useful for detecting early transformer failures. The research on gas sensors for monitoring dissolved gas in transformer oil has attracted wide attention from academia and industry. In this study, Rh-doped GeSe monolayers were used as gas sensing materials based on the density functional theory (DFT). The potential of the Rh-GeSe monolayer as a gas sensor was evaluated by calculating the geometric structure, adsorption distance (dsub/gas), binding energy (Eb), adsorption energy (Eads), transfer charge (ΔQ), the density of states (DOS), band structure, electron localization function (ELF), charge difference density (CDD), and sensitivity (S) of Rh-GeSe monolayer with eight gas molecules (SO2, C2H2, NO2, H2, CH4, CO2, H2S, and CO). The results show that the Rh-GeSe monolayer has a prominent response to SO2, C2H2, and NO2 gas molecules and has great potential to become an excellent gas sensor. This study provides a theoretical basis for the application of Rh-GeSe monolayer in the field of gas sensing and provides a new way for the development of other gas sensors.

Antennal excision reveals disparate olfactory expression patterns within castes in Reticulitermes aculabialis (Isoptera: Rhinotermitidae).

In lower termites, which exhibit a high degree of compound eye degradation or absence, antennae play a pivotal role in information acquisition. This comprehensive study investigates the olfactory system of Reticulitermes aculabialis, spanning five developmental stages and three castes. Initially, we characterize the structures and distribution of antennal sensilla across different developmental stages. Results demonstrate variations in sensilla types and distributions among stages, aligning with caste-specific division of labor and suggesting their involvement in environmental sensitivity detection, signal differentiation, and nestmate recognition. Subsequently, we explore the impact of antennal excision on olfactory gene expression in various caste categories through transcriptomics, homology analysis, and expression profiling. Findings reveal that olfactory genes expression is influenced by antennal excision, with outcomes varying according to caste and the extent of excision. Finally, utilizing fluorescence in situ hybridization, we precisely localize the expression sites of olfactory genes within the antennae. This research reveals the intricate and adaptable nature of the termite olfactory system, highlighting its significance in adapting to diverse ecological roles and demands of social living.

Development and validation of a novel risk stratification model and a survival rate calculator for diffuse large B-cell lymphoma in the rituximab era: a multi-institutional cohort study.

BACKGROUND: This study aimed to develop and validate a novel risk stratification model and a web-based survival rate calculator to improve discriminative and predictive accuracy for diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: We retrospectively collected pre-treatment data from 873 primary DLBCL patients who received R-CHOP-based immunochemotherapy regimens at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 1, 2005, to December 31, 2018. An independent cohort of 175 DLBCL patients from Fujian Cancer Hospital was used for external validation. FINDINGS: Age, ECOG PS, number of extranodal sites, Ann Arbor stage, bulky disease, and LDH levels were screened to develop the nomogram and web-based survival rate calculator. The C-index of the nomogram in the training, internal validation, and external validation cohorts was 0.761, 0.758, and 0.768, respectively. The risk stratification model generated based on the nomogram effectively stratified patients into three distinct risk groups. K-M survival curves demonstrated that the novel risk stratification model exhibited a superior level of predictive accuracy compared to IPI, R-IPI, and NCCN-IPI both in training and two validation cohorts. Additionally, the area under the curve (AUC) value of the novel model (0.763) for predicting 5-year overall survival rates was higher than those of IPI (0.749), R-IPI (0.725), and NCCN-IPI (0.727) in the training cohort. Similar results were observed in both internal and external validation cohort. CONCLUSIONS: In conclusion, we have successfully developed and validated a novel risk stratification model and a web-based survival rate calculator that demonstrated superior discriminative and predictive accuracy compared to IPI, R-IPI, and NCCN-IPI in the rituximab era.

Boosting the Catalase-Like Activity of SAzymes via Facile Tuning of the Distances between Neighboring Atoms in Single-Iron Sites.

A nanozyme with neighboring single-iron sites (Fe2 -SAzyme) was introduced as a bioinspired catalase mimic, featuring excellent activity under varied conditions, twice as high as that of random Fe1 -SAzyme and ultrahigh H2 O2 affinity as that of bioenzymes. Surprisingly, the interatomic spacing tuning between adjacent iron sites also suppressed the competitive peroxidase pathway, remarkably increasing the catalase/peroxidase selectivity up to ~6 times compared to Fe1 -SAzyme. This dramatically switched the catalytic activity of Fe-SAzymes from generating (i.e. Fe1 -SAzymes, preferably mimicking peroxidase) to scavenging ROS (i.e. Fe2 -SAzymes, dominantly mimicking catalase). Theoretical and experimental investigations suggested that the pairwise single-iron sites may serve as a robust molecular tweezer to efficiently trap and decompose H2 O2 into O2 , via cooperative hydrogen-bonding induced end-bridge adsorption. The versatile mechano-assisted in situ MOF capsulation strategy enabled facile access to neighboring M2 -SAzyme (M=Fe, Ir, Pt), even up to a 1000 grams scale, but with no obvious scale-up effect for both structures and performances.

The Euphrates Poplar Responses to Abiotic Stress and Its Unique Traits in Dry Regions of China (Xinjiang and Inner Mongolia): What Should We Know?

At the moment, drought, salinity, and low-temperature stress are ubiquitous environmental issues. In arid regions including Xinjiang and Inner Mongolia and other areas worldwide, the area of tree plantations appears to be rising, triggering tree growth. Water is a vital resource in the agricultural systems of countries impacted by aridity and salinity. Worldwide efforts to reduce quantitative yield losses on Populus euphratica by adapting tree plant production to unfavorable environmental conditions have been made in response to the responsiveness of the increasing control of water stress. Although there has been much advancement in identifying the genes that resist abiotic stresses, little is known about how plants such as P. euphratica deal with numerous abiotic stresses. P. euphratica is a varied riparian plant that can tolerate drought, salinity, low temperatures, and climate change, and has a variety of water stress adaptability abilities. To conduct this review, we gathered all available information throughout the Web of Science, the Chinese National Knowledge Infrastructure, and the National Center for Biotechnology Information on the impact of abiotic stress on the molecular mechanism and evolution of gene families at the transcription level. The data demonstrated that P. euphratica might gradually adapt its stomatal aperture, photosynthesis, antioxidant activities, xylem architecture, and hydraulic conductivity to endure extreme drought and salt stress. Our analyses will give readers an understanding of how to manage a gene family in desert trees and the influence of abiotic stresses on the productivity of tree plants. They will also give readers the knowledge necessary to improve biotechnology-based tree plant stress tolerance for sustaining yield and quality trees in China's arid regions.

Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial.

Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. Design, Setting, and Participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Main Outcome: Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Results: Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. Conclusions and Relevance: The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT03581786.

Efficacy and safety of pembrolizumab with preoperative neoadjuvant chemotherapy in patients with resectable locally advanced head and neck squamous cell carcinomas.

Background: This study aimed to explore the efficacy and safety of pembrolizumab combined with chemotherapy as neoadjuvant therapy in patients with resectable locally advanced head and neck squamous cell carcinomas (LA-HNSCCs). Methods: In this prospective, single-arm, single-centre clinical trial, patients meeting the inclusion criteria were treated with preoperative neoadjuvant therapy with 200 mg pembrolizumab combined with 75 mg/m2 cisplatin and 175 mg/m2 paclitaxel. This was followed by surgery and postoperative adjuvant therapy. The primary endpoint was the postoperative pathological complete response (pCR) rate. All statistical analyses were performed using SPSS 26. Results: A total of 22 patients were enrolled. The location of primary lesion showed: hypopharynx were 15 (68.2%), oropharynx were 6 (27.3%) and oral cavity was 1 (4.5%). The postoperative pCR rate, was 36.4% (8/22), and there was no delay to surgery due to adverse drug reactions. The rate of laryngeal function preservation was 90.9% (20/22). Delayed wound healing was the main surgical complication, with an incidence of 22.7% (5/22). The median follow-up time was 9.5 months, and only 1 patient (4.55%) suffered a regional recurrence. Conclusion: Preoperative treatment with pembrolizumab and chemotherapy in resectable LA-HNSCC has a high pCR rate with no significant impact on surgical safety. This treatment was found to increase the rate of laryngeal function preservation. However, the effects of neoadjuvant immunotherapy on long-term prognosis in LA-HNSCCs require further study.

Obesity and head and neck cancer risk: a mendelian randomization study.

BACKGROUND: Observational studies have reported controversial results on the association between obesity and head and neck cancer risk. This study aimed to perform a two-sample Mendelian randomization (MR) analysis to assess the causal association between obesity and head and neck cancer risk using publicly available genome-wide association studies (GWAS) summary statistics. METHODS: Single-nucleotide polymorphisms (SNPs) for obesity [body mass index (BMI), waist-to-hip ratio (WHR), whole body fat mass, lean body mass, and trunk fat mass] and head and neck cancer (total head and neck cancer, oral cavity cancer, oropharyngeal cancer, and oral cavity and oropharyngeal cancer) were retrieved from published GWASs and used as genetic instrumental variables. Five methods including inverse-variance-weighted (IVW), weighted-median, MR-Egger, weighted mode, and MR-PRESSO were used to obtain reliable results, and odds ratio with 95% confidence interval (CI) were calculated. Tests for horizontal pleiotropy, heterogeneity, and sensitivity were performed separately. RESULTS: Genetically predicted BMI was negatively associated with the risk of total head and neck cancer, which was significant in the IVW [OR (95%CI), 0.990 (0.984-0.996), P = 0.0005], weighted-median [OR (95%CI), 0.984 (0.975-0.993), P = 0.0009], and MR-PRESSO [OR (95%CI), 0.990 (0.984-0.995), P = 0.0004] analyses, but suggestive significant in the MR-Egger [OR (95%CI), 0.9980 (0.9968-0.9991), P < 0.001] and weighted mode [OR (95%CI), 0.9980 (0.9968-0.9991), P < 0.001] analyses. Similar, genetically predicted BMI adjust for smoking may also be negatively associated with the risk of total head and neck cancer (P < 0.05). Genetically predicted BMI may be negatively related to the risk of oral cavity cancer, oropharyngeal cancer, and oral cavity and oropharyngeal cancer (P < 0.05), but no causal association was observed for BMI adjust for smoking (P > 0.05). In addition, no causal associations were observed for other exposures and outcomes (all P > 0.05). CONCLUSION: This MR analysis supported the causal association of BMI-related obesity with decreased risk of total head and neck cancer. However, the effect estimates from the MR analysis were close to 1, suggesting a slight protective effect of BMI-related obesity on head and neck cancer risk.

Water use strategies of Nitraria tangutorum in the lake-basin region of the Badain Jaran Desert.

Information regarding plant water-use strategies is essential for understanding the hydrological processes and plant survival adaptation mechanisms in desert lake basin regions. To examine the water use strategies of plants in desert lake basin areas, water uptake patterns, water use efficiency, and water potential of Nitraria tangutorum were investigated at different distances from the lake duringhe growing seasons in the lake basin regions of the Badain Jaran Desert. The results indicate that N. tangutorum primarily absorbed groundwater in May (63.8%) and August (53.5%), relied on deep soil water in June (75.1%), and uniformly absorbed soil water from different layers in July. These observations could be explained by periodic fluctuations in the groundwater level and the consequent decrease in soil water availability, as well as plant root adjustments. As soil water availability decreases, N. tangutorum adapts to water variation by increasing its water use efficiency (WUE) and reducing its leaf water potential (Ψ). With intensified water stress, N. tangutorum gradually shifted from adventurous anisohydric regulation to conservative isohydric regulation. Thus, N. tangutorum responds to diverse degrees of environmental changes by altering its water-use strategy. A better understanding of the adaptive water use strategies developed by desert plants under varying water availability conditions provides insight into the diversity of species' reactions to long-term drought and quantifies the hydrological cycle of desert ecosystems against the background of worldwide climate warming.

Catalyst-Controlled Direct Oxysulfonylation of Alkenes by Using Sulfonylazides as the Sulfonyl Radical.

A copper/cobalt-catalyzed difunctionalization of alkenes with sulfonylazides and tert-butyl hydroperoxide has been achieved. This protocol provides an efficient and direct oxysulfonylation approach to ß-ketosulfones and ß-sulfonyl peroxides in moderate to good yields under mild conditions. This methodology applies sulfonylazides as a new sulfonyl radical source and features a wide substrate scope and good functional group tolerance.

Efficacy and safety of PD-1 monoclonal antibody plus rituximab in relapsed/refractory diffuse large B cell lymphoma patients.

BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) have poor outcomes and few treatment options. We report the preliminary results of the efficacy and safety of PD-1 monoclonal antibody (mab) plus Rituximab for r/r DLBCL. METHODS: In this single-center, single-arm phase 2 and retrospective study, r/r DLBCL patients received PD-1 mab and Rituximab every 3 weeks. Immunohistochemistry, fluorescence in situ hybridization, and probe capture-based high-resolution sequencing were performed. Efficacy, safety and prognostic factors were analyzed. RESULTS: Between October 16th, 2018, and July 10th, 2022, 36 patients (10 patients in retrospective study and 26 patients in phase 2 study) were enrolled and received at least one dose of PD-1 mab combined with Rituximab. The objective response rate was 52.8%. The median progression free survival (PFS) and overall survival was 2.8 and 19.6 months, respectively. The median duration of response was 18.7 months. Rare grade 3 or 4 treatment related adverse events were observed. B2M mutations correlated with a significantly poor PFS (p = .013) and OS (p = .009) in DLBCL patients treated with this regimen. CONCLUSION: PD-1 mab combined with Rituximab could be a potential treatment option for r/r DLBCL with manageable safety profile.

SETDB1 confers colorectal cancer metastasis by regulation of WNT/ß-catenin signaling.

BACKGROUND: Metastasis is a critical step in tumor development; however, its specific molecular mechanism is still not fully understood. SETDB1 overexpression is associated with tumor progression and poor prognosis. Here, we explored a novel mechanism by which SETDB1 promotes tumor metastasis in colorectal cancer. METHODS: We conducted database and clinical specimen analysis to determine the expression level of SETDB1 in colorectal cancer, as well as the prognosis of colorectal cancer with overexpressed SETDB1. We used wound healing assays, Transwell assays, and animal studies to study the effect of SETDB1 on colorectal cancer. We performed western blotting, qRT-PCR, immunofluorescence, and co-immunoprecipitation to explore the underlying associations between SETDB1 and ß-catenin. We further used wound healing assays, Transwell assays, and animal studies to verify the relationship between SETDB1 and Wnt/ß-catenin. RESULTS: SETDB1 expression was upregulated in colorectal cancer and correlated with poor prognosis. Low expression of SETDB1 decreased invasion and metastasis in colorectal cancer. Low-expression of SETDB1 in colorectal tumor cells decreased ß-catenin expression and its nuclear import. We also found that SETDB1 can bind and directly methylate ß-catenin, Lastly, we discovered that this metastatic ability could be decreased by activating the Wnt/ß-catenin pathway with SETDB1 knock-down. CONCLUSION: SETDB1 is highly expressed in colorectal cancer and plays an important role in the invasion and metastasis through the Wnt/ß-catenin pathway. It does so by direct methylation of ß-catenin. This novel SETDB1/Wnt/ß-catenin pathway provides a new strategy for the treatment of colorectal cancer.

Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer.

PURPOSE: The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC. PATIENTS AND METHODS: This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. RESULTS: Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25-0.61; P < 0.0001] in Chinese patients with RAIR-DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand-foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation. CONCLUSIONS: Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.

Case report: Complete response of an anaplastic thyroid carcinoma patient with NRAS Q61R/BRAF D594N mutations to the triplet of dabrafenib, trametinib and PD-1 antibody.

Anaplastic thyroid carcinoma, BRAF non-V600, NRAS, combination immunotherapy and targeted therapy, case report. Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid cancer with a mortality rate near 100%. BRAF V600 and NRAS mutations are the most common drivers of ATC. While patients with BRAF V600-mutated ATC can be treated with BRAF-targeted therapy, there is no effective treatment for ATC driven by NRAS or non-V600 BRAF mutations. For patients with untargetable driver mutations, immunotherapy provides an alternative treatment option. Here, we present a metastatic ATC patient with PD-L1 positive (tumor proportion score of 60%) tumor and NRAS Q61R/BRAF D594N mutations, who progressed on PD-1 antibody sintilimab plus angiogenesis inhibitor anlotinib. The class 3 BRAF mutant D594N is sensitive to the inhibition of MEK inhibitor trametinib, and its oncogenic activity also depends on CRAF, which can be inhibited by BRAF inhibitor dabrafenib. For these reasons, the patient received a salvage treatment regime of dabrafenib, trametinib, and sintilimab, which resulted in a complete pathological response. To our best knowledge, this is the first report of successful treatment of ATC patients with concurrent NRAS/BRAF non-V600 mutations with the combination of immunotherapy and targeted therapy. Further investigation is required to decipher the mechanism by which the combination of dabrafenib/trametinib with PD-1 antibody overcomes initial immunotherapy resistance likely mediated by concurrent BRAF and NRAS mutations.

Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: A multicenter phase 3 trial (RATIONALE-309).

Checkpoint inhibitors are effective in recurrent/metastatic nasopharyngeal cancer (R/M NPC). RATIONALE-309 (NCT03924986) randomized 263 treatment-naive R/M NPC patients to tislelizumab or placebo every 3 weeks (Q3W), plus chemotherapy (Q3W for 4-6 cycles). At interim analysis, progression-free survival (PFS) was significantly longer with tislelizumab-chemotherapy versus placebo-chemotherapy (hazard ratio: 0.52; 95% confidence interval: 0.38, 0.73; p < 0.0001). PFS benefit for tislelizumab-chemotherapy versus placebo-chemotherapy was observed regardless of programmed death-ligand 1 expression. PFS after next line of treatment and overall survival showed favorable trends for tislelizumab-chemotherapy versus placebo-chemotherapy. The safety profile was similar between arms. Gene expression profiling (GEP) identified immunologically "hot" tumors, and showed an activated dendritic cell (DC) signature was associated with tislelizumab-chemotherapy PFS benefit. Our results support that tislelizumab-chemotherapy should be considered as first-line treatment for R/M NPC, and GEP and activated DC signature results may help identify patients who might benefit most from immunochemotherapy treatment. VIDEO ABSTRACT.