Clonal Hematopoiesis and Therapy-Related Myeloid Neoplasms After Autologous Transplant for Hodgkin Lymphoma.

PURPOSE: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell transplantation (aPBSCT) for Hodgkin lymphoma (HL). Although previous studies have reported an association between clonal hematopoiesis (CH) in the infused PBSC product and subsequent post-aPBSCT risk of t-MN in patients with non-HL, information about patients with HL treated with aPBSCT is not available. METHODS: We constructed a retrospective cohort of 321 patients with HL transplanted at a median age of 34 years (range, 18-71). Targeted DNA sequencing of PBSC products performed for CH-associated or myeloid malignancy-associated genes identified pathogenic mutations in these patients. RESULTS: CH was identified in the PBSC product of 46 patients (14.3%) with most prominent representation of DNMT3A (n = 25), PPM1D (n = 7), TET2 (n = 7), and TP53 (n = 5) mutations. Presence of CH in the PBSC product was an independent predictor of t-MN (adjusted hazard ratio [aHR], 4.50 [95% CI, 1.54 to 13.19]). Notably all patients with TP53 mutations in the PBSC product developed t-MN, whereas none of the patients with DNMT3A mutations alone (without co-occurring TP53 or PPM1D mutations) did. Presence of TP53 and/or PPM1D mutations was associated with a 7.29-fold higher hazard of t-MN when compared with individuals carrying no CH mutations (95% CI, 1.72 to 30.94). The presence of TP53 and/or PPM1D mutations was also associated with a 4.17-fold higher hazard of nonrelapse mortality (95% CI, 1.25 to 13.87). There was no association between CH and relapse-related mortality. CONCLUSION: The presence of TP53 and/or PPM1D mutations in the PBSC product increases the risk of post-aPBSCT t-MN and nonrelapse mortality among patients with HL and may support alternative therapeutic strategies.

Theaflavin-3,3'-Digallate Protects Liver and Kidney Functions in Diabetic Rats by Up-Regulating Circ-ITCH and Nrf2 Signaling Pathway.

Theaflavin-3,3'-digallate (TFDG) in black tea has a strong antioxidant capacity. However, its effect on diabetic liver and kidney injury and the underlying mechanisms remain unclear. In the present study, our findings indicated that TFDG administration effectively lowers the fasting blood glucose and serum lipid concentrations and enhances the functionality and cellular architecture of the liver and kidney in rats with diabetes. The data also showed that TFDG mitigates oxidative harm in the liver and kidney of rats afflicted with diabetes. Additionally, metformin combined with TFDG was significantly more effective in reducing blood glucose and oxidative stress. Further studies suggested that TFDG upregulates the Nrf2 signal pathway and circ-ITCH (hsa_circ_0001141) expression. Silencing of circ-ITCH by transfection of the interfering plasmid apparently reduces the effects of TFDG on the Nrf2 signal pathway and oxidative stress in high-glucose-treated hepatic and renal cells. In conclusion, the present study highlights the great potential of TFDG in ameliorating diabetic liver and kidney injury by up-regulating circ-ITCH to promote the Nrf2 signal pathway and provides a potential option for the prevention and treatment of diabetic complications.

Flexible microfluidic colorimetric detection chip integrated with ABTS·+ and Co@MnO2 nanozyme catalyzed TMB reaction systems for bio-enzyme free detection of sweat uric acid.

BACKGROUND: The development of wearable detection devices that can achieve noninvasive, on-site and real-time monitoring of sweat metabolites is of great demand and practical significance for point-of-care testing and healthcare monitoring. Monitoring uric acid (UA) content in sweat provides a simple and promising way to reduce the risk of gout and hyperuricemia. Traditional bioenzyme based UA assays suffer from high cost, poor stability, inconvenience for storage and easy deactivation of bioenzymes. Wearable microfluidic colorimetric detection device for sweat UA detection has not been reported. The development of novel wearable microfluidic colorimetric detection chip with no requirement of bioenzymes for sweat UA detection is of great importance for health care monitoring. RESULTS: Firstly, Co@MnO2 nanozyme with high oxidase-like activity was synthesized and characterized. Co@MnO2 can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) directly to generate blue-green colored ox-TMB. Green colored 2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate) radical (ABTS·+) was produced by the oxidation of ABTS by potassium persulfate. UA exhibits distinct quenching effect on Co@MnO2 catalyzed TMB colorimetric reaction system and ABTS·+ based colorimetric system, leading to obvious color fading of the two colorimetric systems. Then, a flexible microfluidic colorimetric detection chip for UA detection was fabricated by assembling Co@MnO2/TMB modified paper chips and ABTS·+ modified paper chips into a polydimethylsiloxane (PDMS) microfluidic chip. The fabricated microfluidic colorimetric detection chip exhibits good linear relationship for sweat UA detection. The linear range is from 20 to 200 µmol/L with detection limit as low as 6.6 µmol/L. Good results were obtained for the detection of UA in actual sweat from three volunteers. SIGNIFICANCE: This work provides two bio-enzyme free colorimetric detection systems for UA detection. Furthermore, a simple, low-cost and selective flexible wearable microfluidic colorimetric detection chip was fabricated for noninvasive and on-site detection of sweat UA, which holds great application potential for personal health monitoring and point-of-care testing.

Prognostic impact of age in advanced non-small cell lung cancer patients undergoing first-line checkpoint inhibitor immunotherapy and chemotherapy treatment.

BACKGROUND: Research on the association between age and clinical outcome in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy combined with chemotherapy as first-line setting is limited. The aim of study is to determine the influence of age on the progress-free survival (PFS) and overall survival (OS) in those patients after adjusting for potential confounders. METHODS: A total of 207 advanced NSCLC patients treated with immunotherapy combined with chemotherapy in the first-line treatment in Guangxi Medical University Cancer Hospital from March 10, 2019, to December 31, 2022, was retrospectively analyzed. χ2 (categorical variables) was used to analyze the differences among the different age groups. Cox regression and Kaplan-Meier analyses were used to assess the association between age and clinical outcomes. P values < 0.05 (two-sided) were considered statistically significant. RESULTS: The mean age of the cohort was 58.8 ± 10.3 years. The percentages of patients < 65, 65-69, 70-74, and ≥ 75 years were 66.7 %, 19.3 %, 9.2 % and 4.8 %, respectively. Compared to the aged < 65 years group, the HR for the risk of disease progression for each group are 0.67 (95 %CI = 0.40-1.12, P = 0.125), 0.66 (95 %CI = 0.31, 1.43, P = 0.298), and 2.27 (95 %CI = 0.80, 6.45, P = 0.124), respectively, with no significant differences in the results. And the HR for risk of death for the 65-69 years and 70-74 years groups was 1.16 (95 %CI = 0.64-2.08, P = 0.628) and 0.93 (95 %CI = 0.39-2.23, P = 0.879), respectively. The difference has no statistical significance. Whereas in patients aged ≥ 75, there is an increased risk of death after adjusted confounders with HR = 4.83 (95 %CI = 2.06-11.35). The difference was statistically significant (P < 0.001). Trend test indicates that with advancing age, the patient's risk of death increases (HR = 1.33, 95 % CI = 1.02-1.75, P = 0.034). CONCLUSION: Age may not be the primary factor influencing the efficacy of immunotherapy combined with chemotherapy, but particular attention should be given to the elderly population.

Machine learning assisted discrimination and detection of antibiotics by using multicolor microfluidic chemiluminescence detection chip.

The fabrication of multicolor chemiluminescence (CL) sensing chip for the discrimination and detection of multianalytes remains a great challenge. Herein, machine learning assisted multicolor microfluidic CL detection chip for the identification and concentration prediction of antibiotics was presented. Firstly, a three-channel microfluidic CL detection chip was fabricated. The three detection zones of the microfluidic detection chip were modified with CL catalyst Co(II) and different CL reagents including luminol, luminol mixed with fluorescein, and luminol mixed with phloxine B, respectively. Strong blue, green and pink-purple colored light emissions can be generated from the three detection zones in the presence of H2O2 solution. The three multicolor CL emissions show different degrees of reduce in intensity and change in color in the presence of different antibiotics, including diethylstilbestro (DES), metronidazole (MNZ), kanamycin (KAN), isoniazide (INH), and ceftiofur sodium (CS), resulting in distinct fingerprint-like response patterns. The red (R), green (G), blue (B) and gray scale values of the three multicolor light emissions were extracted and ten characteristic sensing parameters were chosen to obtain multicolor CL response database. Then, machine learning assisted data analysis were carried out. The five antibiotics can be facilely classified by using principal component analysis (PCA) and hierarchical clustering analysis (HCA), and further quantified by using deep neural networks (DNN) algorithm. Good results were obtained for identification of binary antibiotic mixtures, spiked antibiotics in water samples, and unknown antibiotic samples. Satisfied results were obtained for concentration prediction of antibiotics. This work provides a simple machine learning assisted and multicolor microfluidic CL detection chip based CL sensing strategy for discrimination and quantitative detection of multiple analytes.

Prognostic Significance of Pretreatment Plasma D-dimer Levels in EGFR-Positive Advanced Non-Small Cell Lung Cancer Patients Receiving Osimertinib: A Multicentre Retrospective Study.

Purpose: This study examined the association between plasma D-dimer levels and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients treated with osimertinib. Methods: In this multicenter study, 88 patients with advanced non-small cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) mutations and receiving osimertinib were enrolled. The target independent and dependent variables were the D-dimer levels before osimertinib treatment and OS time, respectively. The t-test or chi-square test was utilized to analyze the variances among various groups. The predictive significance of D-dimer for overall survival (OS) was assessed using Kaplan-Meier survival analysis and the Cox proportional hazard regression model. Results: The selected patients had an average age of 58.01±10.72 years, with females comprising 54.55%. Based on their D-dimer levels, the patients were categorized into three groups: low-level (< 0.6 mg/L), middle-level (0.6 ~ 2 mg/L), and high-level (≥ 2 mg/L). After accounting for possible confounding variables, the Cox proportional hazard model showed that increased D-dimer levels were linked to a greater likelihood of death (HR 2.28, 95% CI = 1.09 ~ 4.76, p = 0.029). Importantly, there was a significant trend indicating that as D-dimer levels rose, the risk of mortality also increased (p for trend, HR 1.15, 95% CI = 1.03 ~ 1.28, p = 0.012). Consistently comparable outcomes were noted in the majority of subcategories. Patients with low-middle and high D dimer levels had a median OS of 28.6 and 17 months, respectively (p =0.014). Conclusion: In conclusion, elevated levels of D-dimer in the bloodstream were found to have a significant negative correlation with the overall survival (OS) of patients with EGFR-positive non-small cell lung cancer (NSCLC) who underwent treatment with osimertinib.

Association between Vitamin B6 and Risk of Gastric Cancer: A Systematic Review and Meta-Analysis of Epidemiological Studies.

Inconsistent findings have emerged from epidemiological research investigating the association between vitamin B6 and the risk of gastric cancer. To obtain a more precise assessment, we conducted a comprehensive search of published data and performed a meta-analysis. PubMed, Web of Science, EMBASE and Cochrane Library databases were systematically searched. A total of 12 studies (5 prospective cohort and 7 case-control studies) involving 5,692 cases and 814,157 participants were included in the meta-analysis. The results showed that high intake of vitamin B6 may reduce the odds of gastric cancer (OR = 0.83, 95% CI: 0.73-0.95, p = 0.006). However, this association was only observed in the case-control studies (OR = 0.68, 95% CI: 0.51-0.89, p = 0.006) but not in the cohort studies (RR = 1.01, 95% CI: 0.94-1.08, p = 0.819). Additionally, the negative association between vitamin B6 intake and gastric cancer risk was found in the United States of America (OR = 0.71, 95% CI: 0.62-0.82, p = 10-4), but not in Europe (OR = 0.88, 95% CI: 0.74-1.05, p = 0.169) or the other regions (OR = 0.86, 95% CI: 0.66-1.13, p = 0.280). In conclusion, there is not sufficient evidence to assume that vitamin B6 intake is associated with gastric cancer risk, which needs further confirmation.

VEGF signaling governs the initiation of biliary-mediated liver regeneration through the PI3K-mTORC1 axis.

Biliary epithelial cells (BECs) are a potential source to repair the damaged liver when hepatocyte proliferation is compromised. Promotion of BEC-to-hepatocyte transdifferentiation could be beneficial to the clinical therapeutics of patients with end-stage liver diseases. However, mechanisms underlying the initiation of BEC transdifferentiation remain largely unknown. Here, we show that upon extreme hepatocyte injury, vegfaa and vegfr2/kdrl are notably induced in hepatic stellate cells and BECs, respectively. Pharmacological and genetic inactivation of vascular endothelial growth factor (VEGF) signaling would disrupt BEC dedifferentiation and proliferation, thus restraining hepatocyte regeneration. Mechanically, VEGF signaling regulates the activation of the PI3K-mammalian target of rapamycin complex 1 (mTORC1) axis, which is essential for BEC-to-hepatocyte transdifferentiation. In mice, VEGF signaling exerts conserved roles in oval cell activation and BEC-to-hepatocyte differentiation. Taken together, this study shows VEGF signaling as an initiator of biliary-mediated liver regeneration through activating the PI3K-mTORC1 axis. Modulation of VEGF signaling in BECs could be a therapeutic approach for patients with end-stage liver diseases.

The XOR-IDH3α axis controls macrophage polarization in hepatocellular carcinoma.

BACKGROUND & AIMS: Tumor-associated macrophages (TAMs) are indispensable in the hepatocellular carcinoma (HCC) tumor microenvironment. Xanthine oxidoreductase (XOR), also known as xanthine dehydrogenase (XDH), participates in purine metabolism, uric acid production, and macrophage polarization to a pro-inflammatory phenotype. However, the role of XOR in HCC-associated TAMs is unclear. METHODS: We evaluated the XOR level in macrophages isolated from HCC tissues and paired adjacent tissues. We established diethylnitrosamine/carbon tetrachloride (CCl4)-induced and orthotopically implanted HCC mouse models using mice with Xdh-specific depletion in the myeloid cell lineage (Xdhf/fLyz2cre) or Kupffer cells (Xdhf/fClec4fcre). We determined metabolic differences using specific methodologies, including metabolomics and metabolic flux. RESULTS: We found that XOR expression was downregulated in HCC TAMs and positively correlated with patient survival, which was strongly related to the characteristics of the tumor microenvironment, especially hypoxia. Using HCC-inflicted mice (Xdhf/fLyz2cre and Xdhf/fClec4fcre), we revealed that XOR loss in monocyte-derived TAMs rather than Kupffer cells promoted their M2 polarization and CD8+ T-cell exhaustion, which exacerbated HCC progression. In addition, the tricarboxylic acid cycle was disturbed, and the generation of α-ketoglutarate was enhanced within XOR-depleted macrophages. XOR inhibited α-ketoglutarate production by interacting with IDH3α catalytic sites (K142 and Q139). The increased IDH3α activity caused increased adenosine and kynurenic acid production in TAMs, which enhanced the immunosuppressive effects of TAMs and CD8+ T cells. CONCLUSIONS: The XOR-IDH3α axis mediates TAM polarization and HCC progression and may be a small-molecule therapeutic or immunotherapeutic target against suppressive HCC TAMs. IMPACT AND IMPLICATIONS: Immunotherapies have been widely applied to the treatment of hepatocellular carcinoma (HCC), but to date they have been associated with unsatisfactory efficacy. The tumor microenvironment of HCC is full of different infiltrating immune cells. Tumor-associated macrophages (TAMs) are vital components in the tumor microenvironment and are involved in HCC progression. Herein, we confirm the downregulation of XOR expression in TAMs isolated from human HCC. The loss of XOR in monocyte-derived macrophages increases IDH3 activity and results in an increase in α-ketoglutarate production, which can promote M2-like polarization. Additionally, XOR-null TAMs derived from monocytes promote CD8+ T-cell exhaustion via the upregulation of immunosuppressive metabolites, including adenosine and kynurenic acid. Given the prevalence and high rate of incidence of HCC and the need for improved therapeutic options for patients, our findings identify potential therapeutic targets that may be further studied to develop improved therapies.

Extensive jejunal injury is repaired by migration and transdifferentiation of ileal enterocytes in zebrafish.

A major cause of intestinal failure (IF) is intestinal epithelium necrosis and massive loss of enterocytes, especially in the jejunum, the major intestinal segment in charge of nutrient absorption. However, mechanisms underlying jejunal epithelial regeneration after extensive loss of enterocytes remain elusive. Here, we apply a genetic ablation system to induce extensive damage to jejunal enterocytes in zebrafish, mimicking the jejunal epithelium necrosis that causes IF. In response to injury, proliferation and filopodia/lamellipodia drive anterior migration of the ileal enterocytes into the injured jejunum. The migrated fabp6+ ileal enterocytes transdifferentiate into fabp2+ jejunal enterocytes to fulfill the regeneration, consisting of dedifferentiation to precursor status followed by redifferentiation. The dedifferentiation is activated by the IL1ß-NFκB axis, whose agonist promotes regeneration. Extensive jejunal epithelial damage is repaired by the migration and transdifferentiation of ileal enterocytes, revealing an intersegmental migration mechanism of intestinal regeneration and providing potential therapeutic targets for IF caused by jejunal epithelium necrosis.

Gene-allele system of shade tolerance in southern China soybean germplasm revealed by genome-wide association study using gene-allele sequence as markers.

KEY MESSAGE: Fifty-three shade tolerance genes with 281 alleles in the SCSGP were identified directly using gene-allele sequence as markers in RTM GWAS, from which optimized crosses, evolutionary motivators, and gene-allele networks were explored. Shade tolerance is a key for optimal cultivation of soybean inter/relay-cropped with corn. To explore the shade tolerance gene-allele system in the southern China soybean germplasm, we proposed using gene-allele sequence markers (GASMs) in a restricted two-stage multi-locus model genome-wide association study (GASM-RTM-GWAS). A representative sample with 394 accessions was tested for their shade tolerance index (STI), in Nanning, China. Through whole-genome re-sequencing, 47,586 GASMs were assembled. From GASM-RTM-GWAS, 53 main-effect STI genes with 281 alleles (2-13 alleles/gene) (totally 63 genes with 308 alleles, including 38 G × E genes with 191 alleles) were identified and then organized into a gene-allele matrix composed of eight submatrices corresponding to geo-seasonal subpopulations. The population featured mild STI changes (1.69 → 1.56-1.82) and mild gene-allele changes (92.5% alleles inherited, 0% alleles excluded, 7.5% alleles emerged) from the primitive (SAIII) to the derived seven subpopulations, but large transgressive recombination potentials and optimal crosses were predicted. The 63 STI genes were annotated into six biological categories (metabolic process, catalytic activity, response to stresses, transcription and translation, signal transduction and transport and unknown functions), interacted as gene networks. From the STI gene-allele system, 38 important alleles of 22 genes were nominated for further in-depth study. GASM-RTM-GWAS performed powerful and efficient in germplasm population genetic study comparing to other procedures through facilitating direct and thorough identification of its gene-allele system, from which genome-wide breeding by design could be achieved, and evolutionary motivators and gene-allele networks could be explored.

An Improved Genome-Wide Association Procedure Explores Gene-Allele Constitutions and Evolutionary Drives of Growth Period Traits in the Global Soybean Germplasm Population.

In soybeans (Glycine max (L.) Merr.), their growth periods, DSF (days of sowing-to-flowering), and DFM (days of flowering-to-maturity) are determined by their required accumulative day-length (ADL) and active temperature (AAT). A sample of 354 soybean varieties from five world eco-regions was tested in four seasons in Nanjing, China. The ADL and AAT of DSF and DFM were calculated from daily day-lengths and temperatures provided by the Nanjing Meteorological Bureau. The improved restricted two-stage multi-locus genome-wide association study using gene-allele sequences as markers (coded GASM-RTM-GWAS) was performed. (i) For DSF and its related ADLDSF and AATDSF, 130-141 genes with 384-406 alleles were explored, and for DFM and its related ADLDFM and AATDFM, 124-135 genes with 362-384 alleles were explored, in a total of six gene-allele systems. DSF shared more ADL and AAT contributions than DFM. (ii) Comparisons between the eco-region gene-allele submatrices indicated that the genetic adaptation from the origin to the geographic sub-regions was characterized by allele emergence (mutation), while genetic expansion from primary maturity group (MG)-sets to early/late MG-sets featured allele exclusion (selection) without allele emergence in addition to inheritance (migration). (iii) Optimal crosses with transgressive segregations in both directions were predicted and recommended for breeding purposes, indicating that allele recombination in soybean is an important evolutionary drive. (iv) Genes of the six traits were mostly trait-specific involved in four categories of 10 groups of biological functions. GASM-RTM-GWAS showed potential in detecting directly causal genes with their alleles, identifying differential trait evolutionary drives, predicting recombination breeding potentials, and revealing population gene networks.

Correlation between KRAS mutation subtypes and prognosis in Chinese advanced non-squamous non-small cell lung cancer patients.

PURPOSE: The relationship between mutant KRAS and the risk of disease progression and death in advanced non-squamous non-small cell lung cancer (NSCLC) is still controversial among current studies, and the effects of distinct KRAS mutations on prognosis may be different. This study aimed to further investigate the association between them. PATIENTS AND METHODS: Of the 184 patients eventually included in the study, 108 had KRAS wild type (WT) and 76 had KRAS mutant type (MT). Kaplan-Meier curves were plotted to describe the survival for patients among groups, while log-rank tests were conducted to evaluate the survival differences. The univariate and multivariate Cox regression were performed to identify predictors, and subgroup analysis was used to verify the interaction effect. RESULTS: Similar efficacy of first-line therapy was observed for KRAS MT and WT patients (p = 0.830). The association between KRAS mutation and progression-free survival (PFS) was not significant in univariate analysis (hazard ratio [HR] = 0.94; 95% CI, 0.66-1.35), and no KRAS mutation subtype significantly affected PFS. However, KRAS mutation and KRAS non-G12C were associated with increased risk of death compared to KRAS WT in univariate and multivariate analysis. Univariate and multivariate analysis also confirmed that chemotherapy combined with antiangiogenesis or immunotherapy in the KRAS mutation group was associated with decreased risk of disease progression. However, the overall survival (OS) among KRAS mutant patients received different first-line treatments did not significantly differ. CONCLUSION: KRAS mutations and their subtypes are not independent negative predictors of PFS, while KRAS mutation and KRAS non-G12C were independent prognostic factors for OS. Chemotherapy combined with antiangiogenesis or immunotherapy conferred decreased risk of disease progression to KRAS mutation patients compared to single chemotherapy.

First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors.

BACKGROUND: QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. METHODS: In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. RESULTS: Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3-not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. CONCLUSIONS: QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Genetic basis of STEM occupational choice and regional economic performance: a UK biobank genome-wide association study.

BACKGROUND: Science, technology, engineering, and mathematics (STEM) professionals are regarded as the highly skilled labor force that fosters economic productivity, enterprise innovation, and international competitiveness of a country. This study aims to understand the genetic predisposition to STEM occupations and investigate its associations with regional economic performance. We conducted a genome-wide association study on the occupational choice of STEM jobs based on a sample of 178,976 participants from the UK Biobank database. RESULTS: We identified two genetic loci significantly associated with participants' STEM job choices: rs10048736 on chromosome 2 and rs12903858 on chromosome 15. The SNP heritability of STEM occupations was estimated to be 4.2%. We also found phenotypic and genetic evidence of assortative mating in STEM occupations. At the local authority level, we found that the average polygenic score of STEM is significantly and robustly associated with several metrics of regional economic performance. CONCLUSIONS: The current study expands our knowledge of the genetic basis of occupational choice and potential regional disparities in socioeconomic developments.

The MRN complex maintains the biliary-derived hepatocytes in liver regeneration through ATR-Chk1 pathway.

When the proliferation of residual hepatocytes is prohibited, biliary epithelial cells (BECs) transdifferentiate into nascent hepatocytes to accomplish liver regeneration. Despite significant interest in transdifferentiation, little is known about the maintenance of nascent hepatocytes in post-injured environments. Here, we perform an N-ethyl-N-nitrosourea (ENU) forward genetic screen and identify a mutant containing a nonsense mutation in the gene nibrin (nbn), which encodes a component of the Mre11-Rad50-Nbn (MRN) complex that activates DNA damage response (DDR). The regenerated hepatocytes cannot be maintained and exhibit apoptosis in the mutant. Mechanistically, the nbn mutation results in the abrogation of ATR-Chk1 signaling and accumulations of DNA damage in nascent hepatocytes, which eventually induces p53-mediated apoptosis. Furthermore, loss of rad50 or mre11a shows similar phenotypes. This study reveals that the activation of DDR by the MRN complex is essential for the survival of BEC-derived hepatocytes, addressing how to maintain nascent hepatocytes in the post-injured environments.

Prognostic value of CYFRA 21 - 1 and Ki67 in advanced NSCLC patients with wild-type EGFR.

BACKGROUND: The prognostic value of cytokeratin 19 fragment (CYFRA 21 - 1) and Ki67 in advanced non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) remains to be explored. METHODS: In this study, 983 primary NSCLC patients from January 2016 to December 2019 were retrospectively reviewed. Finally, 117 advanced NSCLC patients with wild-type EGFR and 37 patients with EGFR mutation were included and prognostic value of CYFRA 21 - 1 and Ki67 were also identified. RESULTS: The patients age, smoking history and the Eastern Corporative Oncology Group (ECOG) performance scores were significantly different between CYFRA21-1 positive and negative groups (p < 0.05), while no significant differences were found in Ki67 high and low groups. The results of over survival (OS) demonstrated that patients with CYFRA21-1 positive had markedly shorter survival time than CYFRA21-1 negative (p < 0.001, For whole cohorts; p = 0.002, For wild-type EGFR). Besides, patients with wild-type EGFR also had shorter survival times than Ki67 high group. Moreover, In CYFRA 21 - 1 positive group, patients with Ki67 high had obviously shorter survival time compared to patients with Ki67 low (median: 24vs23.5 months; p = 0.048). However, Ki67 could not be used as an adverse risk factor for patients with EGFR mutation. Multivariate cox analysis showed that age (HR, 1.031; 95%CI, 1.003 ~ 1.006; p = 0.028), Histopathology (HR, 1.760; 95%CI,1.152 ~ 2.690; p = 0.009), CYFRA 21 - 1 (HR, 2.304; 95%CI,1.224 ~ 4.335; p = 0.01) and Ki67 (HR, 2.130; 95%CI,1.242 ~ 3.652; p = 0.006) served as independent prognostic risk factor for advanced NSCLC patients. CONCLUSIONS: Our finding indicated that CYFRA 21 - 1 was an independent prognostic factor for advanced NSCLC patients and Ki67 status could be a risk stratification marker for CYFRA 21 - 1 positive NSCLC patients with wild-type EGFR.

Differential SW16.1 allelic effects and genetic backgrounds contributed to increased seed weight after soybean domestication.

Although seed weight has increased following domestication from wild soybean (Glycine soja) to cultivated soybean (Glycine max), the genetic basis underlying this change is unclear. Using mapping populations derived from chromosome segment substitution lines of wild soybean, we identified SW16.1 as the causative gene underlying a major quantitative trait locus controlling seed weight. SW16.1 encodes a nucleus-localized LIM domain-containing protein. Importantly, the GsSW16.1 allele from wild soybean accession N24852 had a negative effect on seed weight, whereas the GmSW16.1 allele from cultivar NN1138-2 had a positive effect. Gene expression network analysis, reverse-transcription quantitative polymerase chain reaction, and promoter-luciferase reporter transient expression assays suggested that SW16.1 regulates the transcription of MT4, a positive regulator of seed weight. The natural variations in SW16.1 and other known seed weight genes were analyzed in soybean germplasm. The SW16.1 polymorphism was associated with seed weight in 247 soybean accessions, showing much higher frequency of positive-effect alleles in cultivated soybean than in wild soybean. Interestingly, gene allele matrix analysis of the known seed weight genes revealed that G. max has lost 38.5% of the G. soja alleles and that most of the lost alleles had negative effects on seed weight. Our results suggest that eliminating negative alleles from G. soja led to a higher frequency of positive alleles and changed genetic backgrounds in G. max, which contributed to larger seeds in cultivated soybean after domestication from wild soybean. Our findings provide new insights regarding soybean domestication and should assist current soybean breeding programs.

Rngtt governs biliary-derived liver regeneration initiation by transcriptional regulation of mTORC1 and Dnmt1 in zebrafish.

In cases of end-stage liver diseases, the proliferation of existing hepatocytes is compromised, a feature of human chronic liver disease, in which most hepatocytes are dysfunctional. So far, liver transplantation represents the only curative therapeutic solution for advanced liver diseases, and the shortage of donor organs leads to high morbidity and mortality worldwide. The promising treatment is to prompt the biliary epithelial cells (BECs) transdifferentiation. However, the critical factors governing the initiation of BEC-derived liver regeneration are largely unknown. The zebrafish has advantages in large-scale genetic screens to identify the critical factors involved in liver regeneration. Here, we combined N-ethyl-N-nitrosourea screen, positional cloning, transgenic lines, antibody staining, and in situ hybridization methods and identified a liver regeneration defect mutant ( lrd ) using the zebrafish extensive liver injury model. Through positional cloning and genomic sequencing, we mapped the mutation site to rngtt . Loss of rngtt leads to the defects of BEC dedifferentiation, bipotential progenitor cell activation, and cell proliferation in the initiation stage of liver regeneration. The transdifferentiation from BECs to hepatocytes did not occur even at the late stage of liver regeneration. Mechanically, Rngtt transcriptionally regulates the attachment of mRNA cap to mTOR complex 1 (mTORC1) components and dnmt1 to maintain the activation of mTORC1 and DNA methylation in BECs after severe liver injury and prompt BEC to hepatocyte conversion. Furthermore, rptor and dnmt1 mutants displayed the same liver regeneration defects as rngtt mutation. In conclusion, our results suggest Rngtt is a new factor that initiates BEC-derived liver regeneration.

Genome-Wide Association Studies (GWAS).

Most of the breeding targets are quantitative traits. In exploring the quantitative trait locus (QTL) system of a trait, linkage mapping was established using sparse polymerase chain reaction (PCR) markers. With the genome-wide sequencing technology advanced, genome-wide association study (GWAS) was developed for natural (germplasm) populations using dense genomic markers, which facilitates the identification of the complete QTL system with their multiple alleles on genomic locations. GWAS makes use of the linkage disequilibrium (LD) due to historical saturate recombination and high-density genomic markers to detect QTLs through statistical test for the association between molecular markers and phenotypes. However, due to inbreeding and mixture of source populations, the germplasm population often has complex and unknown structure, which leads to false positives/negatives in GWAS. Various GWAS methods have been proposed to reduce false positives/negatives, including those of the general linear model and the mixed linear model, which focused mainly on finding a handful of major QTLs under single-locus model for major gene cloning and could not detect directly the multiple alleles using bi-allelic single-nucleotide polymorphism (SNP) marker. As a relatively thorough detection of QTLs with their multiple alleles is required for germplasm population, the restricted two-stage multi-locus multi-allele GWAS (RTM-GWAS) procedure was proposed for identifying the QTL system with varying multiple alleles. From the RTM-GWAS results, a QTL-allele matrix is constructed as a compact form of the population genetic constitution, which can be further used for crop genetic and breeding studies, including major gene mining, population evolution, and breeding by genetic design.