Sex-based Differences in Risk for Therapy-related Myeloid Neoplasms.

BACKGROUND: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell (PBSC) transplantation for non-Hodgkin lymphoma (NHL). Prior studies report an association between clonal hematopoiesis (CH) in PBSC and risk of t-MN, but small samples precluded examination of risk within specific sub-populations. METHODS: Targeted DNA sequencing was performed to identify CH mutations in PBSC from a retrospective cohort of 984 NHL patients (median age at transplant 57y; range: 18-78). Fine-Gray proportional subdistribution hazard regression models estimated association between number of CH mutations and t-MN, adjusting for demographic, clinical, and therapeutic variables. Secondary analyses evaluated association between CH and t-MN among males and females. RESULTS: CH was identified in PBSC from 366 patients (37.2%). t-MN developed in 60 patients after median follow-up of 5y. Presence of ≥2 mutations conferred increased t-MN risk (adjusted hazard ratio [aHR]=2.10, 95% confidence interval [CI]=1.08-4.11, p=0.029). CH was associated with increased t-MN risk among males (aHR=1.83, 95%CI=1.01-3.31) but not females (aHR=0.56, 95%CI=0.15-2.09). Although prevalence and type of CH mutations in PBSC was comparable, the 8y cumulative incidence of t-MN was higher among males vs. females with CH (12.4% vs. 3.6%) but was similar between males and females without CH (4.9% vs. 3.9%). Expansion of CH clones from PBSC to t-MN was seen only among males. CONCLUSIONS: Presence of CH mutations in PBSC confers increased risk of t-MN after autologous transplantation in male but not female patients with NHL. Factors underlying sex-based differences in risk of CH progression to t-MN merit further investigation.

Exploring the Potential Role of Dexmedetomidine in Reducing Postoperative Cognitive Dysfunction in Elderly Hip Fracture Patients.

BACKGROUND: Hip fractures are prevalent in the elderly; however, Postoperative Cognitive Dysfunction (POCD) is a possible complication of hip fracture surgery in elderly patients. This study examines the influence and the underlying mechanism of dexmedetomidine on POCD in elderly patients following hip fracture surgery. METHODS: The retrospective study involved elderly patients with hip fracture who were treated at the Fifth Affiliated Hospital of Xinjiang Medical University from October 2021 to August 2022. During the surgery procedures, dexmedetomidine was administrated and the peripheral blood samples were collected from the patients. Inflammatory factors were measured using Enzyme-linked immunosorbent assay (ELISA), while pyroptosis-related proteins were detected through quantitative reverse transcription PCR (RT-qPCR) and western blot. Additionally, the levels of CD4+T and CD8+T cells were assessed using flow cytometry. An aged rats hip fracture model was established to further investigate the impact of dexmedetomidine on postoperative mobility, cognition function, pyroptosis and immune cells in rats. RESULTS: Postoperative cognitive function in patients did not show significant alteration when compared with pre-operation levels (p > 0.05). There were notable reduction in the levels of interleukin-18 (IL-18), Caspase-3, Gasdermin-D (GSDMD) and NLR Family Pyrin Domain Containing 3 (NLRP3) (p < 0.001), accompanied by an increase in the proportion of CD4+T cells and an decrease in CD8+T cells after operation (p < 0.01). In aged rats, postoperative exploratory activities increased compared to their preoperative state. Compared with preoperative levels, the levels of interleukin-1ß (IL-1ß), IL-18, Caspase-3, GSDMD, and NLRP3 were significantly decreased (p < 0.001), the proportion of CD4+T cells was increased, and the proportion of CD8+T cells was decreased postoperatively (p < 0.01). CONCLUSIONS: Although there was no significant alteration in postoperative cognitive function in patients, dexmedetomidine may still play a role in mitigating POCD potentially due to its effects on reducing immune inflammation and pyroptosis markers. Further research is needed to fully understand the underlying mechanisms and its clinical implications.

Epidermal growth factor-like domain 7 drives brain lymphatic endothelial cell development through integrin αvß3.

In zebrafish, brain lymphatic endothelial cells (BLECs) are essential for meningeal angiogenesis and cerebrovascular regeneration. Although epidermal growth factor-like domain 7 (Egfl7) has been reported to act as a pro-angiogenic factor, its roles in lymphangiogenesis remain unclear. Here, we show that Egfl7 is expressed in both blood and lymphatic endothelial cells. We generate an egfl7 cq180 mutant with a 13-bp-deletion in exon 3 leading to reduced expression of Egfl7. The egfl7 cq180 mutant zebrafish exhibit defective formation of BLEC bilateral loop-like structures, although trunk and facial lymphatic development remains unaffected. Moreover, while the egfl7 cq180 mutant displays normal BLEC lineage specification, the migration and proliferation of these cells are impaired. Additionally, we identify integrin αvß3 as the receptor for Egfl7. αvß3 is expressed in the CVP and sprouting BLECs, and blocking this integrin inhibits the formation of BLEC bilateral loop-like structures. Thus, this study identifies a role for Egfl7 in BLEC development that is mediated through the integrin αvß3.

Electrochemiluminescence in Graphitic Carbon Nitride Decorated with Silver Nanoparticles for Dopamine Determination Using Machine Learning.

Electrochemiluminescence (ECL) luminophores with wavelength-tunable multicolor emissions are essential for multicolor ECL imaging detection and multiplexed analysis. In this work, silver nanoparticle (Ag NP)-decorated graphitic carbon nitride (g-CN@Ag) nanocomposites were synthesized. The morphology, chemical composition, structure, and ECL property of g-CN@Ag were investigated. The prepared g-CN, g-CN@Ag1, g-CN@Ag5, and g-CN@Ag10 can produce blue, blue-green, chartreuse, and yellow colored ECL emissions, respectively, by using K2S2O8 as the coreagent. The ECL emission wavelength of g-CN@Ag can be regulated from 460 to 565 nm by modulating the content of the immobilized Ag NPs. Then, a multicolor ECL detection array was fabricated by using g-CN, g-CN@Ag1, g-CN@Ag5, and g-CN@Ag10 as four ECL luminophores. Dopamine was detected based on its inhibition effect on the multicolor ECL emissions. The linear range is from 0.1 nM to 1 mM with the lowest detection limit of 44 pM. Then, machine learning-assisted multiparameter concentration prediction of dopamine was further carried out by combining the deep neural network (DNN) algorithm. This work provides a new avenue to regulate the ECL emission wavelength of g-CN by using the metal nanoparticle modification strategy and presents an effective machine learning-assisted multicolor ECL detection strategy for accurate multiparameter quantitative detection.

DCAF1 interacts with PARD3 to promote hepatocellular carcinoma progression and metastasis by activating the Akt signaling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is a fatal malignancy with poor prognosis due to lack of effective clinical interference. DCAF1 plays a vital role in regulating cell growth and proliferation, and is involved in the progression of various malignancies. However, the function of DCAF1 in HCC development and the underlying mechanism are still unknown. This study aimed to explore the effect of DCAF1 in HCC and the corresponding molecular mechanism. METHODS: Quantitative real-time PCR, Western blot and immunostaining were used to determine DCAF1 expression in tumor tissues and cell lines. Subsequently, in vitro and in vivo experiments were conducted to explore the function of DCAF1 in tumor growth and metastasis in HCC. Coimmunoprecipitation, mass spectrometry and RNA sequencing were performed to identify the underlying molecular mechanisms. RESULTS: In this study, we found that DCAF1 was observably upregulated and associated with poor prognosis in HCC. Knockdown of DCAF1 inhibited tumor proliferation and metastasis and promoted tumor apoptosis, whereas overexpressing DCAF1 yielded opposite effects. Mechanistically, DCAF1 could activate the Akt signaling pathway by binding to PARD3 and enhancing its expression. We also found that the combined application of DCAF1 knockdown and Akt inhibitor could significantly suppress subcutaneous xenograft tumor growth. CONCLUSIONS: Our study illustrates that DCAF1 plays a crucial role in HCC development and the DCAF1/PARD3/Akt axis presents a potentially effective therapeutic strategy for HCC.

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.

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.

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.

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.

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.

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.

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.