EBF1 nuclear repositioning instructs chromatin refolding to promote therapy resistance in T leukemic cells.

Chromatin misfolding has been implicated in cancer pathogenesis; yet, its role in therapy resistance remains unclear. Here, we systematically integrated sequencing and imaging data to examine the spatial and linear chromatin structures in targeted therapy-sensitive and -resistant human T cell acute lymphoblastic leukemia (T-ALL). We found widespread alterations in successive layers of chromatin organization including spatial compartments, contact domain boundaries, and enhancer positioning upon the emergence of targeted therapy resistance. The reorganization of genome folding structures closely coincides with the restructuring of chromatin activity and redistribution of architectural proteins. Mechanistically, the derepression and repositioning of the B-lineage-determining transcription factor EBF1 from the heterochromatic nuclear envelope to the euchromatic interior instructs widespread genome refolding and promotes therapy resistance in leukemic T cells. Together, our findings suggest that lineage-determining transcription factors can instruct changes in genome topology as a driving force for epigenetic adaptations in targeted therapy resistance.

[Diffuse Hepatoid Adenocarcinoma in the Peritoneal Cavity:Report of One Case].

Hepatoid adenocarcinoma is a rare and unique type of adenocarcinoma,resembling hepatocellular carcinoma in histopathology.Most cases occur in the stomach,lacking specific clinical and imaging manifestations,which leads to high rates of missed diagnosis and misdiagnosis.Hepatoid adenocarcinoma in the peritoneal cavity is even rarer.This article reports a case of hepatoid adenocarcinoma with the manifestation of diffuse peritoneal thickening,aiming to provide reference for clinical diagnosis and treatment.

Mutational analysis of microsatellite-stable gastrointestinal cancer with high tumour mutational burden: a retrospective cohort study.

BACKGROUND: Genomic signatures contributing to high tumour mutational burden (TMB-H) independent from mismatch-repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status are not well studied. We aimed to characterise molecular features of microsatellite stable (MSS) TMB-H gastrointestinal tumours. METHODS: Molecular alterations of 48 606 gastrointestinal tumours from Caris Life Sciences (CARIS) identified with next-generation sequencing were compared among MSS-TMB-H, dMMR/MSI-H, and MSS-TMB-low (L) tumours, using χ2 or Fisher's exact tests. Antitumour immune response within the tumour environment was predicted by analysing the infiltration of immune cells and immune signatures using The Cancer Genome Atlas database. The Kaplan-Meier method and the log-rank test were used to evaluate the impact of gene alterations on the efficacy of immune checkpoint inhibitors in MSS gastrointestinal cancers from the CARIS database, a Memorial Sloan Kettering Cancer Center cohort, and a Peking University Cancer Hospital cohort. FINDINGS: MSS-TMB-H was observed in 1600 (3·29%) of 48 606 tumours, dMMR/MSI-H in 2272 (4·67%), and MSS-TMB-L in 44 734 (92·03%). Gene mutations in SMAD2, MTOR, NFE2L2, RB1, KEAP1, TERT, and RASA1 might impair antitumour immune response despite TMB-H, while mutations in 16 other genes (CDC73, CTNNA1, ERBB4, EZH2, JAK2, MAP2K1, MAP2K4, PIK3R1, POLE, PPP2R1A, PPP2R2A, PTPN11, RAF1, RUNX1, STAG2, and XPO1) were related to TMB-H with enhanced antitumour immune response independent of dMMR/MSI-H, constructing a predictive model (modified TMB [mTMB]) for immune checkpoint inhibitor efficacy. Patients with any mutation in the mTMB gene signature, in comparison with patients with mTMB wildtype tumours, showed a superior survival benefit from immune checkpoint inhibitors in MSS gastrointestinal cancers in the CARIS cohort (n=95, median overall survival 18·77 months [95% CI 17·30-20·23] vs 7·03 months [5·73-8·34]; hazard ratio 0·55 [95% CI 0·31-0·99], p=0·044). In addition, copy number amplification in chromosome 11q13 (eg, CCND1, FGF genes) was more prevalent in MSS-TMB-H tumours than in the dMMR/MSI-H or MSS-TMB-L subgroups. INTERPRETATION: Not all mutations related to TMB-H can enhance antitumour immune response. More composite biomarkers should be investigated (eg, mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provide novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1 or FGFs. FUNDING: US National Cancer Institute, Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Gene Gregg Pancreas Research Fund, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong Research Project, Ming Hsieh Research Fund, Shanghai Sailing Program, China National Postdoctoral Program for Innovative Talents, China Postdoctoral Science Foundation, National Natural Science Foundation of China.

Construction and validation of risk model of EMT-related prognostic genes for kidney renal clear cell carcinoma.

BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is a prevalent type of urological malignancy. The present study aimed to predict biomarkers for KIRC. METHODS: We collected transcriptomic and clinical information for KIRC from The Cancer Genome Atlas and GSE22541 cohorts. RESULTS: Unsupervised clustering of 35 epithelial-mesenchymal transformation (EMT)-related differentially expressed gene profiles divided samples into two clusters with distinct immune characteristics. Six genes (IL20RB, DDC, ANKRD36BP2, F2RL1, TEK, and AMN) were found to construct a prognostic risk model using multivariate Cox regression analysis. Kaplan-Meier analysis suggested the better prognosis of the KIRC patients in the low-risk group than that in the high-risk group. Immune infiltration analyses was conducted using xCell and single-sample gene set enrichment analysis, indicating that the risk score was associated with the immune microenvironment of the KIRC. Prognostic marker gene-targeted medications with high drug sensitivity were predicted in KIRC patients. CONCLUSIONS: In summary, the present study identified IL20RB, DDC, ANKRD36BP2, F2RL1, TEK, and AMN as prognostic biomarkers, providing insight into immunotherapy and gene-targeted drugs of KIRC.

Rapidly Constructing Sodium Fluoride-Rich Interface by Pressure and Diglyme-Induced Defluorination Reaction for Stable Sodium Metal Anode.

Sodium (Na) metal is able to directly use as a battery anode but have a highly reductive ability of unavoidably occurring side reactions with organic electrolytes, resulting in interfacial instability as a primary factor in performance decay. Therefore, building stable Na metal anode is of utmost significance for both identifying the electrochemical performance of laboratory half-cells employed for quantifying samples and securing the success of room-temperature Na metal batteries. In this work, we propose an NaF-rich interface rapidly prepared by pressure and diglyme-induced defluorination reaction for stable Na metal anode. Once the electrolyte is dropped into the coin-type cells followed by a slight squeeze, the Na metal surface immediately forms a protective layer consisting of amorphous carbon and NaF, effectively inhibiting the dendrite growth and dead Na. The resultant Na metal anode exhibits a long-term cycling lifespan over 1800 h even under the area capacity of 3.0 mAh cm-2 . Furthermore, such a universal and facile method is readily applied in daily battery assembly regarding Na metal anode.

BP-based supervised learning algorithm for multilayer photonic spiking neural network and hardware implementation.

We introduce a supervised learning algorithm for photonic spiking neural network (SNN) based on back propagation. For the supervised learning algorithm, the information is encoded into spike trains with different strength, and the SNN is trained according to different patterns composed of different spike numbers of the output neurons. Furthermore, the classification task is performed numerically and experimentally based on the supervised learning algorithm in the SNN. The SNN is composed of photonic spiking neuron based on vertical-cavity surface-emitting laser which is functionally similar to leaky-integrate and fire neuron. The results prove the demonstration of the algorithm implementation on hardware. To seek ultra-low power consumption and ultra-low delay, it is great significance to design and implement a hardware-friendly learning algorithm of photonic neural networks and realize hardware-algorithm collaborative computing.

Fertilizing-induced alterations of microbial functional profiles in soil nitrogen cycling closely associate with crop yield.

Fertilization and rhizosphere selection are key regulators for soil nitrogen (N) cycling and microbiome. Thus, clarifying how the overall N cycling processes and soil microbiome respond to these factors is a prerequisite for understanding the consequences of high inputs of fertilizers, enhancing crop yields, and formulating reasonable nitrogen management strategies under agricultural intensification scenarios. To do this, we applied shotgun metagenomics sequencing to reconstruct N cycling pathways on the basis of abundance and distribution of related gene families, as well as explored the microbial diversity and interaction via high throughput sequencing based on a two-decade fertilization experiment in Loess Plateau of China semiarid area. We found that bacteria and fungi respond divergent to fertilization regimes and rhizosphere selection, in terms of community diversity, niche breadth, and microbial co-occurrence networks. Moreover, organic fertilization decreased the complexity of bacterial networks but increased the complexity and stability of fungal networks. Most importantly, rhizosphere selection exerted more strongly influences on the soil overall nitrogen cycling than the application of fertilizers, accompanied by the increase in the abundance of nifH, NIT-6, and narI genes and the decrease in the abundance of amoC, norC, and gdhA genes in the rhizosphere soil. Furthermore, keystone families screening from soil microbiome (e.g., Sphingomonadaceae, Sporichthyaceae, and Mortierellaceae), which were affected by the edaphic variables, contributed greatly to crop yield. Collectively, our findings emphasize the pivotal roles of rhizosphere selection interacting with fertilization regimes in sustaining soil nitrogen cycling processes in response to decades-long fertilization, as well as the potential importance of keystone taxa in maintaining crop yield. These findings significantly facilitate our understanding of nitrogen cycling in diverse agricultural soils and lay a foundation for manipulating specific microorganisms to regulate N cycling and promote agroecosystem sustainability.

RIG-I regulates myeloid differentiation by promoting TRIM25-mediated ISGylation.

Retinoic acid-inducible gene I (RIG-I) is up-regulated during granulocytic differentiation of acute promyelocytic leukemia (APL) cells induced by all-trans retinoic acid (ATRA). It has been reported that RIG-I recognizes virus-specific 5'-ppp-double-stranded RNA (dsRNA) and activates the type I interferons signaling pathways in innate immunity. However, the functions of RIG-I in hematopoiesis remain unclear, especially regarding its possible interaction with endogenous RNAs and the associated pathways that could contribute to the cellular differentiation and maturation. Herein, we identified a number of RIG-I-binding endogenous RNAs in APL cells following ATRA treatment, including the tripartite motif-containing protein 25 (TRIM25) messenger RNA (mRNA). TRIM25 encodes the protein known as an E3 ligase for ubiquitin/interferon (IFN)-induced 15-kDa protein (ISG15) that is involved in RIG-I-mediated antiviral signaling. We show that RIG-I could bind TRIM25 mRNA via its helicase domain and C-terminal regulatory domain, enhancing the stability of TRIM25 transcripts. RIG-I could increase the transcriptional expression of TRIM25 by caspase recruitment domain (CARD) domain through an IFN-stimulated response element. In addition, RIG-I activated other key genes in the ISGylation pathway by activating signal transducer and activator of transcription 1 (STAT1), including the modifier ISG15 and several enzymes responsible for the conjugation of ISG15 to protein substrates. RIG-I cooperated with STAT1/2 and interferon regulatory factor 1 (IRF1) to promote the activation of the ISGylation pathway. The integrity of ISGylation in ATRA or RIG-I-induced cell differentiation was essential given that knockdown of TRIM25 or ISG15 resulted in significant inhibition of this process. Our results provide insight into the role of the RIG-I-TRIM25-ISGylation axis in myeloid differentiation.

Stenocarpella chrysopogonis, a New Species Causing Leaf Streak Disease of Chrysopogon zizanioides in Southern China.

Vetiver grass (Chrysopogon zizanioides) has been widely used in recent years for ecological environment management, restoration of degraded ecosystems, and essential oil extraction. In 2019, a leaf streak disease of C. zizanioides was observed in Zhanjiang, Guangdong Province, China. The disease appeared as large streak lesions on the leaves, on which conidiomata were formed. A pathogenicity test with the fungus isolated from these lesions confirmed Koch's postulates and thus the fungus as the causal agent of this disease. A morphological resemblance of the pathogen to Stenocarpella was noted upon microscopic examination. Phylogenetic trees inferred from both individual and combined ITS, LSU, and tef1 sequences confirmed the pathogen as a species of the Diaporthaceae and revealed it to be closely related to Phaeocytostroma and Stenocarpella species. As morphological characters clearly placed the pathogen in the genus Stenocarpella, it was described as S. chrysopogonis.

First report of Neofusicoccum sinoeucalypti causing leaf spot on Terminalia catappa in China.

Terminalia catappa belonging to the family Combretaceae, spreads in tropical and subtropical coastal areas. It mainly serves as shading and decorative tree (Anand et al, 2015). It is planted as roadside tree in Southern China. A leaf spot disease of T. catappa was observed at Wencheng Town (110.805323°E, 19.524567°N), Wenchang City, Hainan province, China in June, 2022. The disease incidence of leaves reached 10%. The occurrence of this leaf spot would reduce the ornamental value of T. catappa. The early symptoms of infected leaves were small, round, dark brown spots surrounded by irregular light halos, developing to larger irregular necrotic lesions and leaves withered. Twelve diseased leaves were collected from three survey trees. Symptomatic leaf samples were collected and cut into small pieces (3×3 mm). The pieces were surface sterilized with 2.5% sodium hypochlorite for 1 min, rinsed with sterile distilled water three times, placed on potato dextrose agar (PDA) medium and incubated at 28 ℃ in the dark for 3 days. Three hyphal tip isolates (DYLR-1, DYLR-2 and DYLR-3) were cultured on PDA. Colonies on PDA reached the edge of the 90 mm plates after 3 d and had fluffy mycelia with an uneven margin, initially creamy white, becoming light grey (5 d) to mouse grey (10 d) at the surface with the black globular cavity. To induce sporulation, the isolates were transferred to 2% water agar media with sterilised pine needles placed on the surface of the media. Conidia was hyaline, unicellular, thin-walled, smooth with granular contents, aseptate, narrowly fusiform, base subtruncate to bluntly rounded, 11.1 to 16.7 (14.5±1.4) × 4.6 to 7.6 (6.2±0.7) µm (n=50). Spermatia was hyaline, unicellular, aseptate, allantoid to rod-shaped, 3.2 to 6.9 (5.1±0.9) µm × 2.0 to 3.8 (2.5±0.4) µm (n=50). Pathogenicity tests were performed both in vitro and in vivo, and replicated twice. All three isolates were used for pathogenicity tests, with 18 detached leaves used for pathogenicity tests in vitro and 3 seedlings used for pathogenicity tests in vivo. A 5-mm-diameter agar plug containing mycelia were placed on the leaves both without and with wound. Sterile PDA plugs were used as controls. The leaves were moisturized with a clear plastic bag for 24 hours in a greenhouse under 90% ± 5% RH at 25 ℃. Brown spot symptoms were observed at 1 day post-inoculation (dpi) in vitro and 3 dpi in vivo. The same strains were reisolated from lesions of inoculated leaves. Control plants were symptomless. For molecular identification, internal transcribed spacer region and intervening 5.8S nrRNA gene (ITS; ITS1/ITS4 primers; White et al. 1990), translation elongation factor 1-alpha gene (tef1-α; EF1-728F/EF1-986R primers; Carbone and Kohn 1999), beta-tubulin gene (tub2; Bt2a/Bt2b primers; Glass and Donaldson 1995) and DNA directed RNA polymerase II second largest subunit gene (rpb2; RPB2bot6F/RPB2bot7R; Sakalidis et al. 2011) regions were PCR amplified from genomic DNA. The sequences (GenBank accessions numbers: OP435357 to OP435359 of ITS; OP535354 to OP535356 of tef1-α; OP535351 to OP535353 of tub2; OP535348 to OP535350 of rpb2) had 100%, 99.7%, 100%, 100% similar to the type strain of Neofusicoccum sinoeucalypti CERC2005 (GenBank accessions numbers: KX278061, KX278166, KX278270 and KX278290), respectively. Multi-locus phylogenetic tree (ITS, tef1-α, tub2 and rpb2) of Neofusicoccum spp. (Zhang et al. 2021) showed that those three isolates were sister to N. sinoeucalypti based on the maximum likelihood and bayesian inference methods. N. sinoeucalypti was first reported pathogen causing from Eucalyptus plantations and adjacent plants in China (Li et al. 2018). To our knowledge, this is the first report of Neofusicoccum sinoeucalypti causing leaf spot disease on Terminalia catappa in China. Neofusicoccum species, commonly cause diseases in woody plants worldwide, and identification of this pathogen is important for effective disease management and control.

Occurrence of Anthracnose Caused by Colletotrichum fructicola on Ficus hirta in Southern China.

Ficus hirta Vahl. is a Moraceae plant, named for its palm-like leaves. It is a widely used traditional medicinal material with definite curative effect. At the same time, it is also a commonly used soup material among the folk in South China. In March 2022, a serious leaf spot disease with symptoms similar to anthracnose was observed on F. hirta in several plantations in Qinzhou and Zhanjiang City of China, with an incidence of 32~65%. The early symptoms of infected leaves were small, round, yellow spots that further expanded into larger, brown, irregular, necrotic lesions surrounded by dark brown edges, which eventually led to leaf wilt. Twenty symptomatic leaves were collected from three plantations with a total area of about 10 hm2. Fragments (2×2 mm) from the 20 infected leaves were surface sterilized, plated on potato dextrose agar (PDA) and incubated at 28°C. After 3 days, isolates with similar cultural morphology were obtained and three representative isolates (WZMT-1, WZMT-3 and WZMT-8) were randomly selected for following study. The colonies by single-spore purification on PDA were initially cottony, pale white and became grayish green with age. The conidia were hyaline, abundant, cylindrical, with rounded ends, 14.4~18.2 µm×4.6~6.0 µm (av. 16.2 µm×5.4 µm, n=100). Conidiogenous cells hyaline, cylindrical or ampulliform, 6.2~22.7 µm × 2.7~5.0 µm (av. 12.9 µm×3.8 µm, n=50). Appressoria were brown to dark brown, ovoid to clavate, elliptical or irregular, 7.9~13.4 µm × 5.6~9.2 µm (av. 10.6 µm×7.9 µm, n=50). The morphology of the fungus resembled Colletotrichum fructicola (Prihastuti et al. 2009). For molecular identification, the internal transcribed spacer (ITS) regions, glyceraldehyde-3-phosphatedehydrogenase (GAPDH), actin (ACT), beta-tubulin 2 (TUB2), calmodulin (CAL), partial manganese superoxide dismutase (sod2), partial Apn2-Mat1-2 intergenic spacer and partial mating type (Mat1-2) (ApMat) genes were amplified from genomic DNA for the isolates using the primers described by Silva et al. (2012) and Weir et al. (2012). The sequences of the above seven loci of the three isolates (accession nos. OQ121661 to OQ121663 and OQ133400 to OQ133417) were obtained and showed over 99% identity with the existing sequences of ex-type culture ICMP 18581 of Colletotrichum fructicola (Weir et al. 2012). A multilocus phylogenetic analysis of the seven loci concatenated sequences using the maximum likelihood method revealed that the isolates belong to C. fructicola. To confirm pathogenicity, five 3-month-old potted plants were used for inoculation with each representative isolate. Tested plants were sprayed with 10 ml of a conidial suspension (1 × 108 conidia/ml) , and the controls plants were sprayed with sterile water. All the plants were incubated in a growth chamber at 26 ± 2°C with 95% relative humidity. After 10 days, typical lesions like those observed on the field plants appeared on all inoculated plants, while the control remained healthy. The same fungal pathogen was reisolated and the identity was confirmed by morphological characterization and molecular analysis, confirming Koch's postulates. The pathogen has been reported as the causal agent of anthracnose on a wide range of plant hosts worldwide (Marquez-Zequera et al. 2018; Horfer et al. 2021; Jiang et al. 2022; Li et al. 2023). To our knowledge, this is the first report of anthracnose on F. hirta caused by C. fructicola in southern China.

[Identification and biological characteristics of violet root rot pathogen of Pseudostellaria heterophylla in Fujian province].

Violet root rot is one of the main root diseases in the production process of Pseudostellaria heterophylla. To clarify the pathogenic species that cause the violet root rot of P. heterophylla in Fujian province, the roots and the sclerotia with violet root rot symptoms were collected from the main producing areas of P. heterophylla(Fujian province) from 2017 to 2021, and the pathogens were isolated by tissue separation method and identified by morphology and multi-gene phylogenetic analysis. Additionally, the biological characteristics of the pathogens were studied and the fungicides were determined. The results showed that 78 strains of violet root rot were isolated from the collected root samples, which belonged to one type after preliminary morphological identification. Two represen-tative strains were selected from the pathogens for multi-gene phylogenetic analysis, and they were clustered with Helicobasidium mompa together. The suitable culture conditions for the mycelium were OA medium, 25 ℃, pH 6, and ammonium oxalate as the nitrogen source. The lethal temperature of the mycelium was 50 ℃ for 10 minutes. Moreover, 99.1% propiconazole and 98.7% azoxystrobin had the optimal bacteriostatic effect, and the concentrations with the 50% bacteriostatic rate were 16.85 and 12.24 µg·mL~(-1), respectively. On the basis of the above results, the pathogen causing violet root rot of P. heterophylla in Fujian province was H. mompa. The medium type, growth temperature, pH value, nitrogen source, etc. had significant effect on the growth of mycelium.

[Identification and biological characterization of pathogen causing black spot of Pseudostellaria heterophylla in Fujian province].

In Zherong county, Fujian province, the black spot of Pseudostellaria heterophylla often breaks out in the rainy season from April to June every year. As one of the main leaf diseases of P. heterophylla, black spot seriously affects the yield and quality of the medicinal material. To identify and characterize the pathogens causing black spot, we isolated the pathogens, identified them as a species of Alternaria according to Koch's postulates, and then tested their pathogenicity and biological characteristics. The results showed that the pathogens causing P. heterophylla black spot were A. gaisen, as evidenced by the similar colony morphology, spore characteristics, sporulation phenotype, and the same clade with A. gaisen on the phylogenetic tree(the maximum likelihood support rate of 100% and the Bayesian posterior probability of 1.00) built based on the tandem sequences of ITS, tef1, gapdh, endoPG, Alta1, OPA10-2, and KOG1077. The optimum conditions for mycelial growth of the pathogen were 25 ℃, pH 5-8, and 24 h dark culture. The lethal conditions for mycelia and spores were both treatment at 50 ℃ for 10 min. We reported for the first time the A. gaisen-caused black spot of P. heterophylla. The results could provide a theoretical basis for the diagnosis and control of P. heterophylla leaf spot diseases.

Enantioselective Ni/N-Heterocyclic Carbene-Catalyzed Redox-Economical Coupling of Aldehydes, Alkynes, and Enones for Rapid Construction of Acyclic All-Carbon Quaternary Stereocenters.

Acyclic quaternary carbon stereocenters exist widely in natural products and bioactive molecules, but their enantioselective construction remains a prominent challenge. In particular, multicomponent enantioselective couplings of simple precursors to acyclic all-carbon quaternary stereocenters are very rare. We describe herein an N-heterocyclic carbene (NHC)-Ni catalyzed redox-economical three-component reaction of aldehydes, alkynes, and enones that proceeds in a highly chemo-, regio-, and enantioselective manner. A wide variety of valuable acyclic α-quaternary chiral ketones were synthesized in a single step with 100% atom economy. This reaction proceeds through the formation of a transient cyclic enolate followed by an aldol reaction/ring-opening sequence. The strategy is expected to inspire new and efficient approaches to generate other acyclic quaternary stereocenters.

Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer.

BACKGROUND: The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC). METHODS: We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes. RESULTS: In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS. CONCLUSIONS: TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.

Liver transplantation for Hepatocellular Carcinoma: A prognostic model incorporating pretransplant inflammatory cytokines.

PURPOSE: Liver transplantation (LT) remains an optimal treatment for selected hepatocellular carcinoma (HCC). Cytokines can be obtained by minimally invasive techniques and are associated with the development of HCC. The purpose of our investigation was to explore the prognostic value of pretransplant serum inflammatory cytokine profiles in HCC patients for LT. METHODS: We detected forty inflammatory cytokines in pre-LT serum from 42 HCC patients by using an inflammation-related antibody array. A pretransplant serum inflammatory cytokine-associated risk assessment model (pre-SCRAM) was developed and was validated in an external cohort of 213 HCC patients who underwent LT and were then followed prospectively. RESULTS: The pre-LT factors independently associated with recurrence-free survival (RFS) were as follows: B-lymphocyte chemoattractant (BLC), interleukin (IL)-12p40 and maximum tumor diameter. High IL-12P40 level was associated with a significantly smaller maximum tumor diameter (p = 0.021), decreased proportion of nodules ≥ 3 (p = 0.001), lower platelet counts (p = 0.011) and lower portal vein tumor thrombus (p = 0.031). Conversely, recipients with poor BLC level had higher alpha-fetoprotein (AFP) levels (p = 0.016). Kaplan-Meier analyses revealed that high pre-LT BLC or IL-12p40 level was associated with superior RFS. The pre-SCRAM stratified recipients into three risk groups: high risk, intermediate risk and low risk. In the validation cohort, for patients in the high, intermediate, and low risk groups, the 3-year RFS rates were 29.3%, 58.7%, and 82.2%, respectively, the 3-year HCC-specific survival rates were 54.5%, 73.8%, and 86%, respectively, and the 3-year overall survival rates were 44.4%, 60.9%, and 79.9%, respectively. The pre-SCRAM model performed well and remained significant in optimizing the risk stratification of recurrence in patients beyond the Milan criteria or the AFP model. CONCLUSION: Pretransplant cytokine profiles can provide powerful prognostic information in the setting of LT for HCC. A pre-LT risk model incorporating cytokines showed excellent efficiency in recurrence prediction for HCC patients, which could ultimately stratify the prognosis in patients beyond the Milan criteria or the AFP model.

Identification of a Novel 15q21.1 Microdeletion in a Family with Marfan Syndrome.

Background: Marfan syndrome (MFS) is a connective tissue disease involving multiple systems, with thoracic aortic aneurysm (TAA) as the most common life-threatening manifestation. Method: A pedigree with TAA was investigated, and peripheral venous blood was extracted from six family members. After whole exome sequencing (WES) and chromosomal microarray analysis (CMA) in these individuals, bioinformatics and inheritance analyses were performed. Result: WES revealed a novel, small, 0.76 Mb microdeletion in 15q21.1, which cosegregated with the disease phenotype in the family and led to the haploinsufficiency of the fibrillin 1 (FBN1) gene, which is associated with MFS. This small copy number variant (CNV) was confirmed by CMA. Conclusion: Our study expands the phenotypic spectrum of the pathogenic CNV associated with MFS, thereby facilitating clinical genetic diagnosis and future genetic counseling for this family.

RIG-I modulates Src-mediated AKT activation to restrain leukemic stemness.

Retinoic acid (RA)-inducible gene I (RIG-I) is highly upregulated and functionally implicated in the RA-induced maturation of acute myeloid leukemia (AML) blasts. However, the underlying mechanism and the biological relevance of RIG-I expression to the maintenance of leukemogenic potential are poorly understood. Here, we show that RIG-I, without priming by foreign RNA, inhibits the Src-facilitated activation of AKT-mTOR in AML cells. Moreover, in a group of primary human AML blasts, RIG-I reduction renders the Src family kinases hyperactive in promoting AKT activation. Mechanistically, a PxxP motif in RIG-I, upon the N-terminal CARDs' association with the Src SH1 domain, competes with the AKT PxxP motif for recognizing the Src SH3 domain. In accordance, mutating PxxP motif prevents Rig-I from inhibiting AKT activation, cytokine-stimulated myeloid progenitor proliferation, and in vivo repopulating capacity of leukemia cells. Collectively, our data suggest an antileukemia activity of RIG-I via competitively inhibiting Src/AKT association.

Neoadjuvant chemotherapy endows CD9 with prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.

BACKGROUND: The selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient's prognosis remain controversial. METHODS: A total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9. RESULTS: The relationship between CD9 and prognostic indicators was not significant in the non-neoadjuvant group. Nevertheless, CD9 expression in both tumor (T-CD9) and stromal areas (S-CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T-CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S-CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The T&S-CD9 risk-level system was used to stratify patients with different survival levels. The combination of T&S-CD9 risk level and TNM stage were accurate predictors of OS (C-index: 0.676; AIC: 512.51) and RFS (C-index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1-year RFS. These results were verified using a validation cohort. CONCLUSION: Neoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.

Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma.

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.