Transcriptomic analysis of hub genes regulating albinism in light- and temperature-sensitive albino tea cultivars 'Zhonghuang 1' and 'Zhonghuang 2'.

Albino tea cultivars have high economic value because their young leaves contain enhanced free amino acids that improve the quality and properties of tea. Zhonghuang 1 (ZH1) and Zhonghuang 2 (ZH2) are two such cultivars widely planted in China; however, the environmental factors and molecular mechanisms regulating their yellow-leaf phenotype remain unclear. In this study, we demonstrated that both ZH1 and ZH2 are light- and temperature-sensitive. Under natural sunlight and low-temperature conditions, their young shoots were yellow with decreased chlorophyll and an abnormal chloroplast ultrastructure. Conversely, young shoots were green with increased chlorophyll and a normal chloroplast ultrastructure under shading and high-temperature conditions. RNA-seq analysis was performed for high light and low light conditions, and pairwise comparisons identified genes exhibiting different light responses between albino and green-leaf cultivars, including transcription factors, cytochrome P450 genes, and heat shock proteins. Weighted gene coexpression network analyses of RNA-seq data identified the modules related to chlorophyll differences between cultivars. Genes involved in chloroplast biogenesis and development, light signaling, and JA biosynthesis and signaling were typically downregulated in albino cultivars, accompanied by a decrease in JA-ILE content in ZH2 during the albino period. Furthermore, we identified the hub genes that may regulate the yellow-leaf phenotype of ZH1 and ZH2, including CsGDC1, CsALB4, CsGUN4, and a TPR gene (TEA010575.1), which were related to chloroplast biogenesis. This study provides new insights into the molecular mechanisms underlying leaf color formation in albino tea cultivars.

Post-diagnostic multivitamin supplement use and colorectal cancer survival: A prospective cohort study.

BACKGROUND: Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown. METHODS: Among 2424 patients with stage I-III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow-up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all-cause and CRC-specific mortality according to post-diagnostic use and dose of multivitamin supplements. RESULTS: During a median follow-up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non-uses, post-diagnostic users of multivitamin supplements at a dose of 3-5 tablets/week had lower CRC-specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36-0.83, p = .005), and post-diagnostic users at doses of 3-5 and 6-9 tablets/week had lower all-cause mortality (HR, 0.81; 95% CI, 0.67-0.99, p = .04; HR, 0.79; 95% CI, 0.70-0.88), p < .001). The dose-response analysis showed a curvilinear relationship for both CRC-specific (pnonlinearity < .001) and all-cause mortality (pnonlinearity  = .004), with the maximum risk reduction observed at 3-5 tablets/week and no further reduction at higher doses. Compared to non-users in both pre- and post-diagnosis periods, new post-diagnostic users at dose of <10 tablets/week had a lower all-cause mortality (HR, 0.81; 95% CI, 0.71-0.94, p = .005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07-2.33) and discontinued users (HR, 1.35; 95% CI, 1.14-1.59) had a higher risk of mortality. CONCLUSIONS: Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC-specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC-specific mortality.

Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer.

The clinical implications of extrachromosomal DNA (ecDNA) in cancer therapy remain largely elusive. Here, we present a comprehensive analysis of ecDNA amplification spectra and their association with clinical and molecular features in multiple cohorts comprising over 13,000 pan-cancer patients. Using our developed computational framework, GCAP, and validating it with multifaceted approaches, we reveal a consistent pan-cancer pattern of mutual exclusivity between ecDNA amplification and microsatellite instability (MSI). In addition, we establish the role of ecDNA amplification as a risk factor and refine genomic subtypes in a cohort from 1015 colorectal cancer patients. Importantly, our investigation incorporates data from four clinical trials focused on anti-PD-1 immunotherapy, demonstrating the pivotal role of ecDNA amplification as a biomarker for guiding checkpoint blockade immunotherapy in gastrointestinal cancer. This finding represents clinical evidence linking ecDNA amplification to the effectiveness of immunotherapeutic interventions. Overall, our study provides a proof-of-concept of identifying ecDNA amplification from cancer whole-exome sequencing (WES) data, highlighting the potential of ecDNA amplification as a valuable biomarker for facilitating personalized cancer treatment.

CsLHY positively regulates cold tolerance by activating CsSWEET17 in tea plants.

Low temperature is one of the most important environmental factors limiting tea plants' geographic distribution and severely affects spring tea's yield and quality. Circadian components contribute to plant responses to low temperatures; however, comparatively little is known about these components in tea plants. In this study, we identified a core clock component the LATE ELONGATED HYPOCOTYL, CsLHY, which is mainly expressed in tea plants' mature leaves, flowers, and roots. Notably, CsLHY maintained its circadian rhythmicity of expression in summer, but was disrupted in winter and held a high expression level. Meanwhile, we found that CsLHY expression rhythm was not affected by different photoperiods but was quickly broken by cold, and the low temperature induced and kept CsLHY expression at a relatively high level. Yeast one-hybrid and dual-luciferase assays confirmed that CsLHY can bind to the promoter of Sugars Will Eventually be Exported Transporters 17 (CsSWEET17) and function as a transcriptional activator. Furthermore, suppression of CsLHY expression in tea leaves not only reduced CsSWEET17 expression but also impaired the freezing tolerance of leaves compared to the control. Our results demonstrate that CsLHY plays a positive role in the low-temperature response of tea plants by regulating CsSWEET17 when considered together.

Letrozole combined with rhGH treatment increases the adult height of short pubertal boys.

OBJECTIVES: This study was performed to investigate the effectiveness of the combination of letrozole and recombinant human growth hormone (rhGH) to improve the predicted adult height (PAH) and final adult height (FAH) of Chinese short pubertal boys. METHODS: In total, 171 Chinese short pubertal boys were recruited for this study. 96 of them received letrozole (2.5 mg/d) combined with rhGH (33.3-66.6 µg/kg.d), and the others received rhGH alone. Follow-up visits were conducted at 1, 3, 6, 9, and 12 months or regularly after the first treatment. During each visit, plasma samples were collected for clinical tests and biomedical analyses, all of which were performed according to standard protocols. This study was registered at www.chictr.org.cn under ID number ChiCTR1900026142. RESULTS: After receiving treatment for at least 3 months, 68 boys (91 %) in the rhGH therapy group and 90 (94 %) in the letrozole combined with rhGH (letrozole+rhGH) therapy group achieved an increase in PAH, with the latter treatment leading to a more effective slowing of bone age (BA) advancement. Moreover, the increased PAH showed a significant positive correlation with treatment time in both groups, and letrozole+rhGH increased the PAH to a greater degree than rhGH alone (p=0.0023). And letrozole+rhGH not only slowed the increase in BA more efficiently than rhGH therapy alone (p=0.0025), but also achieved a higher FAH (p=0.0078). CONCLUSIONS: Letrozole combined with rhGH treatment is a promising therapy to increase the PAH and FAH of Chinese short pubertal boys.

Unlocking Bimetallic Active Centers via Heterostructure Engineering for Exceptional Phosphate Electrosorption: Internal Electric Field-Induced Electronic Structure Reconstruction.

Development of electrode materials exhibiting exceptional phosphate removal performance represents a promising strategy to mitigate eutrophication and meet ever-stricter stringent emission standards. Herein, we precisely designed a novel LaCeOx heterostructure-decorated hierarchical carbon composite (L8C2PC) for high-efficiency phosphate electrosorption. This approach establishes an internal electric field within the LaCeOx heterostructure, where the electrons transfer from Ce atoms to neighboring La atoms through superexchange interactions in La-O-Ce coordination units. The modulatory heterostructure endows a positive shift of the d band of La sites and the increase of electron density at Fermi level, promoting stronger orbital overlap and binding interactions. The introduction of oxygen vacancies during the in situ nucleation process reduces the kinetic barrier for phosphate-ion migration and supplies additional active centers. Moreover, the hierarchical carbon framework ensures electrical double-layer capacitance for phosphate storage and interconnected ion migration channels. Such synergistically multiple active centers grant the L8C2PC electrode with high-efficiency record in phosphate electrosorption. As expected, the L8C2PC electrode demonstrates the highest removal capability among the reported electrode materials with a saturation capacity of 401.31 mg P g-1 and a dynamic capacity of 91.83 mg P g-1 at 1.2 V. This electrochemical system also performs well in the dephosphorization in natural water samples with low concentration that enable effluent concentration to meet the first-class discharge standard for China (0.5 mg P L-1). This study advances efficient dephosphorization techniques to a new level and offers a deep understanding of the internal electric field that regulates metal orbitals and electron densities in heterostructure engineering.

Non-linear relationship between sleep duration and blood pressure in children with short stature.

Background: Evidence regarding the relationship between sleep duration and blood pressure is controversial. Therefore, the aim of this study was to investigate the relationship between sleep duration and blood pressure in children with short stature. Methods: A total of 1,085 participants with short stature were enrolled from the Affiliated Hospital of Jining Medical University in China. The variables involved in this study included sleep duration, anthropometric indicators and biochemical parameters. Sleep duration was evaluated in a face-to-face interview. Results: The average age of the 1,085 selected participants was 10.2 ± 3.5 years old, and approximately 763 (70.32%) of them were male. The results of adjusted linear regression showed that sleep duration was negatively associated with systolic blood pressure z scores (SBP-Z) and diastolic blood pressure z scores (DBP-Z) after adjusting for confounders (ß -0.07, 95% CI -0.13, -0.01 P = 0.038; ß -0.05, 95% CI -0.10, -0.01 P = 0.035, respectively). A nonlinear relationship was detected between sleep duration and blood pressure, including SBP-Z, DBP-Z and mean arterial pressure z scores (MAP-Z). The inflection point of the nonlinear relationship between sleep duration and SBP-Z is 10 h, and the inflection point of DBP-Z and MAP-Z is 8 h. Conclusion: This study revealed a nonlinear relationship between sleep duration and blood pressure in children with short stature. The findings suggest that the optimal sleep duration in children with short stature was 8-10 h, and sleep durations either too short or too long were associated with increased blood pressure levels.

Comprehensive genomic characterization of sporadic synchronous colorectal cancer: Implications for treatment optimization and clinical outcome.

Sporadic synchronous colorectal cancer (SCRC) refers to multiple primary CRC tumors detected simultaneously in an individual without predisposing hereditary conditions, which accounts for the majority of multiple CRCs while lacking a profound understanding of the genomic landscape and evolutionary dynamics to optimize its treatment. In this study, 103 primary tumor samples from 51 patients with SCRC undergo whole-exome sequencing. The germline and somatic mutations and evolutionary and clinical features are comprehensively investigated. Somatic genetic events are largely inconsistent between paired tumors. Compared with solitary CRC, SCRCs have higher prevalence of tumor mutation burden high (TMB-H; 33.3%) and microsatellite-instability high (MSI-H; 29.4%) and different mutation frequencies in oncogenic signaling pathways. Moreover, neutrally evolving SCRC tumors are associated with higher intratumoral heterogeneity and better prognosis. These findings unveil special molecular features, carcinogenesis, and prognosis of sporadic SCRC. Strategies for targeted therapy and immunotherapy should be optimized accordingly.

Clinical Manifestations, Genetic Variants and Therapeutic Evaluation in Sporadic Chinese Patients with Idiopathic Hypogonadotropic Hypogonadism.

Purpose: Genetic factors account for a large proportion of idiopathic hypogonadotropic hypogonadism (IHH) etiologies, although not necessarily a complete genetic basis. This study aimed to characterize the clinical presentations, genetic variants, and therapeutic outcomes of patients with sporadic IHH, which may be helpful for genetic counseling and treatment decisions. Patients and Methods: Eleven Chinese patients with IHH were retrospectively analyzed. Rare genetic variants were evaluated using whole-exome sequencing and bioinformatics analysis and were further classified according to the ACMG-AMP guidelines. The therapeutic responses of patients were further evaluated. Results: Six heterozygous variants of SOX10, WDR11, PROKR2, CHD7 and FGF17 were detected in five Kallmann syndrome (KS) patients, whereas two heterozygous variants of CHD7 and PROKR2 were detected in two normosmic IHH (nIHH) patients. Among these variants, a novel likely pathogenic variant in the SOX10 (c.429-1G>C) was considered to cause the KS phenotype in patient 02, and two potential variants of uncertain significance (VUS) in CHD7 (c.3344G>A and c.7391A>G) possibly contributed to the KS phenotype in patient 05 and the nIHH phenotype in patient 07, which need to be confirmed by further evidence. Additionally, long-term testosterone or estradiol replacement treatment effectively improved the development of sexual characteristics in patients with IHH. Conclusion: Next-generation sequencing is a powerful tool for identifying the molecular etiology and early diagnosis of IHH. Efficient therapeutic outcomes strongly indicate a need for timely treatment.

In Utero and Childhood/Adolescence Exposure to Tobacco Smoke, Genetic Risk, and Cancer Incidence in Adulthood: A Prospective Cohort Study.

OBJECTIVE: To evaluate the association of early-life tobacco smoke exposure, especially interacting with cancer genetic variants, with adult cancer. PARTICIPANTS AND METHODS: We examined the associations of in utero tobacco smoke exposure, age of smoking initiation, and their interaction with genetic risk levels with cancer incidence in 393,081 participants from the UK Biobank. Information on tobacco exposure was obtained by self-reported questionnaires. A cancer polygenic risk score was constructed by weighting and integrating 702 genome-wide association studies-identified risk variants. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) for overall cancer and organ-specific cancer incidence. RESULTS: During 11.8 years of follow-up, 23,450 (5.97%) and 23,413 (6.03%) incident cancers were included in the analyses of in utero exposure and age of smoking initiation, respectively. The HR (95% CI) for incident cancer in participants with in utero exposure to tobacco smoke was 1.04 (1.01-1.07) for overall cancer, 1.59 (1.44-1.75) for respiratory cancer, and 1.09 (1.03-1.17) for gastrointestinal cancer. The relative risk of incident cancer increased with earlier smoking initiation (Ptrend<.001), with the HR (95% CI) of 1.44 (1.36-1.51) for overall cancer, 13.28 (11.39-15.48) for respiratory cancer, and 1.72 (1.54-1.91) for gastrointestinal cancer in smokers with initiation in childhood compared with never smokers. Importantly, a positive additive interaction between age of smoking initiation and genetic risk was observed for overall cancer (Padditive=.04) and respiratory cancer (Padditive=.003) incidence. CONCLUSION: In utero exposure and earlier smoking initiation are associated with overall and organ-specific cancer, and age of smoking initiation interaction with genetic risk is associated with respiratory cancer.

NeRF-Art: Text-Driven Neural Radiance Fields Stylization.

As a powerful representation of 3D scenes, the neural radiance field (NeRF) enables high-quality novel view synthesis from multi-view images. Stylizing NeRF, however, remains challenging, especially in simulating a text-guided style with both the appearance and the geometry altered simultaneously. In this paper, we present NeRF-Art, a text-guided NeRF stylization approach that manipulates the style of a pre-trained NeRF model with a simple text prompt. Unlike previous approaches that either lack sufficient geometry deformations and texture details or require meshes to guide the stylization, our method can shift a 3D scene to the target style characterized by desired geometry and appearance variations without any mesh guidance. This is achieved by introducing a novel global-local contrastive learning strategy, combined with the directional constraint to simultaneously control both the trajectory and the strength of the target style. Moreover, we adopt a weight regularization method to effectively suppress cloudy artifacts and geometry noises which arise easily when the density field is transformed during geometry stylization. Through extensive experiments on various styles, we demonstrate that our method is effective and robust regarding both single-view stylization quality and cross-view consistency. The code and more results can be found on our project page: https://cassiepython.github.io/nerfart/.

ABI5 promotes heat stress-induced chlorophyll degradation by modulating the stability of MYB44 in cucumber.

The yellowing of leaves caused by the decomposition of chlorophyll (Chl) is a characteristic event during senescence, which can be induced by various environmental stresses. However, the molecular mechanisms of high temperature-induced Chl degradation in horticultural plants remain poorly understood. Here, we found that heat stress induced Chl degradation and the expression of ABI5 and MYB44 in cucumber. Silencing of ABI5 compromised heat stress-induced Chl degradation, and the transcription of pheophytinase (PPH) and pheophorbide a oxygenase (PAO), two key genes in Chl catabolic pathway, but silencing of MYB44 exhibited the opposite results. Furthermore, ABI5 interacted with MYB44 in vitro and in vivo. ABI5 positively regulated heat stress-induced Chl degradation through two pathways. ABI5 directly bound to PPH and PAO promoters to promote their expression, leading to accelerating Chl degradation. On the other hand, the interaction between ABI5 and MYB44 reduced the binding of MYB44 to PPH and PAO promoters and led to the ubiquitination-depended protein degradation of MYB44, thereby alleviating the transcription inhibitory effect of MYB44 on PPH and PAO. Taken together, our findings propose a new regulatory network for ABI5 in regulating heat stress-induced Chl degradation.

Latent class analysis-derived classification improves the cancer-specific death stratification of molecular subtyping in colorectal cancer.

The molecular subtypes of colorectal cancer (CRC) represent a comprehensive dissection of CRC heterogeneity. However, molecular feature-based classification systems have limitations in accurately prognosticating stratification due to the inability to distinguish cancer-specific deaths. This study aims to establish a classification system that bridges clinical characteristics, cause-specific deaths, and molecular features. We adopted latent class analysis (LCA) on 491,107 first primary CRC patients from the Surveillance, Epidemiology, and End Results (SEER) database to reveal hidden profiles of CRC. The LCA-derived classification scheme was further applied to The Cancer Genome Atlas (TCGA) to assess its effectiveness in improving the accurate stratification of molecular-based subtypes of CRC. Four classes were identified based on latent class analysis integrating demographic and clinicopathological information of CRC patients. The LCA-derived Class 1 (LCAC1) and the LCAC2 showed a high risk of dying from non-CRC, while patients in LCAC3 had a risk of dying from CRC 1.41 times that of LCAC1 (95% confidence interval [CI] = 1.39-1.43). LCAC4 had the lowest probability to die from non-CRC (hazard ratio [HR] = 0.22, 95% CI = 0.21-0.24) compared with LCAC1. Since the LCA-derived classification can identify patients susceptible to CRC-specific death, adjusting for this classification allows molecular-based subtypes to achieve more accurate survival stratification. We provided a classification system capable of distinguish CRC-specific death, which will improve the accuracy of consensus molecular subtypes for CRC patients' survival stratification. Further studies are warranted to confirm the molecular features of LCA-derived classification to inform potential therapeutic strategies and treatment recommendations.

Development and validation of a nomogram to predict which patients with colorectal cancer liver metastases would benefit from primary tumor resection.

PURPOSE: The use of primary tumor resection (PTR) in the treatment of colorectal cancer liver metastases (CRLM) patients has become increasingly controversial. Our goal is to establish a nomogram to screen for the candidates that would benefit from PTR in CRLM patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was searched for 8366 patients with colorectal liver cancer metastases (CRLM) from 2010 to 2015. Overall survival (OS) rates were calculated using the Kaplan-Meier curve. After propensity score matching (PSM), predictors were analyzed by logistic regression analysis, and a nomogram was created to predict for survival benefit of PTR using R software. RESULTS: After PSM, there were 814 patients in both PTR group and non-PTR group, respectively. The median OS time in the PTR group was 26 months (95%CI = 23.33 ~ 28.67) and the median OS time in the non-PTR group was 15 months (95%CI = 13.36 ~ 16.64). The Cox regression analysis found that PTR was an independent predictive factor (HR = 0.46, 0.41 ~ 0.52) for OS. Additionally, logistic regression was used to study the factors impacting PTR benefit, and the results showed that CEA (P = 0.016), chemotherapy (P < 0.001), N stage (P < 0.001), histological grade (P < 0.001), and lung metastasis (P = 0.001) are independent predictive factors affecting the therapeutic outcome of PTR in patients with CRLM. The developed nomogram displayed good discriminative ability in predicting the beneficial probability of PTR surgery, with the area under the curve (AUC) values of 0.801 in training set and 0.739 in validation set respectively. CONCLUSION: We developed a nomogram that predicts the survival benefits of PTR in CRLM patients with relatively high accuracy, and quantifies the predictive factors for PTR-related benefits.

CsCIPK11-Regulated Metalloprotease CsFtsH5 Mediates the Cold Response of Tea Plants.

Photosystem II repair in chloroplasts is a critical process involved in maintaining a plant's photosynthetic activity under cold stress. FtsH (filamentation temperature-sensitive H) is an essential metalloprotease that is required for chloroplast photosystem II repair. However, the role of FtsH in tea plants and its regulatory mechanism under cold stress remains elusive. In this study, we cloned a FtsH homolog gene in tea plants, named CsFtsH5, and found that CsFtsH5 was located in the chloroplast and cytomembrane. RT-qPCR showed that the expression of CsFtsH5 was increased with leaf maturity and was significantly induced by light and cold stress. Transient knockdown CsFtsH5 expression in tea leaves using antisense oligonucleotides resulted in hypersensitivity to cold stress, along with higher relative electrolyte leakage and lower Fv/Fm values. To investigate the molecular mechanism underlying CsFtsH5 involvement in the cold stress, we focused on the calcineurin B-like-interacting protein kinase 11 (CsCIPK11), which had a tissue expression pattern similar to that of CsFtsH5 and was also upregulated by light and cold stress. Yeast two-hybrid and dual luciferase (Luc) complementation assays revealed that CsFtsH5 interacted with CsCIPK11. Furthermore, the Dual-Luc assay showed that CsCIPK11-CsFtsH5 interaction might enhance CsFtsH5 stability. Altogether, our study demonstrates that CsFtsH5 is associated with CsCIPK11 and plays a positive role in maintaining the photosynthetic activity of tea plants in response to low temperatures.

GSK-3ß/ß-catenin pathway plays crucial roles in the regulation of NK cell cytotoxicity against myeloma cells.

The plasma cell malignancy, multiple myeloma (MM), has significantly improved by the application of new drugs and autologous hematopoietic stem cell transplantation. However, MM remains incurable. A number of studies have revealed an anti-MM effect of natural killer (NK) cells; however, their clinical efficacy is limited. Furthermore, glycogen synthase kinase (GSK)-3ß inhibitors show an antitumor function. In this study, we aimed to evaluate the potential roles of a GSK-3ß inhibitor (TWS119) in the regulation of NK cell cytotoxicity against MM. Our results showed that, in the presence of TWS119, the NK cell line, NK-92, and in vitro-expanded primary NK cells exhibited a significantly higher degranulation activity, expression of activating receptors, cellular cytotoxicity, and cytokine secretion when they were exposed to MM cells. Mechanistic studies indicated that TWS119 treatment markedly upregulated RAB27A expression, a key molecule for NK cell degranulation, and induced the colocalization of ß-catenin with NF-κB in the nucleus of NK cells. More importantly, GSK-3ß inhibition combined with the adoptive transfer of TWS119-treated NK-92 cells significantly reduced tumor volume and prolonged the survival time of myeloma-bearing mice. In summary, our novel findings suggest that targeting GSK-3ß through the activation of ß-catenin/NF-κB pathway may be an important approach to improve therapeutic efficacy of NK cell transfusion for MM.

Safety and Clinical Activity of SHR7390 Monotherapy or Combined With Camrelizumab for Advanced Solid Tumor: Results From Two Phase I Trials.

BACKGROUND: SHR7390 is a novel, selective MEK1/2 inhibitor. Here, we report results from two phase I trials conducted to evaluate the tolerability, safety and antitumor activity of SHR7390 monotherapy for advanced solid tumors and SHR7390 plus camrelizumab for treatment-refractory advanced or metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients received SHR7390 alone or combined with fixed-dose camrelizumab (200 mg every 2 weeks) in an accelerated titration scheme to determine the maximum tolerated dose (MTD). A recommended dose for expansion was determined based on the safety and tolerability of the dose-escalation stage. The primary endpoints were dose limiting toxicity (DLT) and MTD. RESULTS: In the SHR7390 monotherapy trial, 16 patients were enrolled. DLTs were reported in the 1.0 mg cohort, and the MTD was 0.75 mg. Grade ≥3 treatment-related adverse events (TRAEs) were recorded in 4 patients (25.0%). No patients achieved objective response. In the SHR7390 combination trial, 22 patients with CRC were enrolled. One DLT was reported in the 0.5 mg cohort and the MTD was not reached. Grade ≥3 TRAEs were observed in 8 patients (36.4%), with the most common being rash (n=4). One grade 5 TRAE (increased intracranial pressure) occurred. Five patients (22.7%) achieved partial response, including one of 3 patients with MSS/MSI-L and BRAF mutant tumors, one of 15 patients with MSS/MSI-L and BRAF wild type tumors, and all 3 patients with MSI-H tumors. CONCLUSIONS: SHR7390 0.5 mg plus camrelizumab showed a manageable safety profile. Preliminary clinical activity was reported regardless of MSI and BRAF status.

In Utero and Childhood/Adolescence Exposure to Tobacco Smoke, Genetic Risk, and Lung Cancer Incidence and Mortality in Adulthood.

Rationale: The individual effects of early-life tobacco smoke exposure and its interactions with genetic factors on lung cancer in adulthood remain unclear. Objectives: To investigate the associations of early-life tobacco exposures as well as their interactions with polygenic risk scores (PRSs) with lung cancer incidence and mortality. Methods: A total of 432,831 participants from the UK Biobank study were included. We estimated the associations of in utero exposure to tobacco smoke, the age of smoking initiation and their interactions with PRSs with lung cancer incidence and mortality in adulthood using Cox proportional hazard models. Measurements and Main Results: Lung cancer incidence (hazard ratio [HR]: 1.59, 95% confidence interval [CI], 1.44-1.76) increased among participants with in utero tobacco exposure. Multivariable-adjusted HRs (with 95% CIs) of lung cancer incidence for smoking initiation in adulthood, adolescence, and childhood (versus never-smokers) were 6.10 (5.25-7.09), 9.56 (8.31-11.00), and 15.15 (12.90-17.79) (Ptrend < 0.001). Similar findings were observed in lung cancer mortality. Participants with high PRSs and in utero tobacco exposure (versus low PRSs participants without in utero exposure) had an HR of 2.35 for lung cancer incidence (95% CI, 1.97-2.80, Pinteraction = 0.089) and 2.43 for mortality (95% CI, 2.05-2.88, Pinteraction = 0.032). High PRSs with smoking initiation in childhood (versus never-smokers with low PRSs) had HRs of 18.71 for incidence (95% CI, 14.21-24.63, Pinteraction = 0.004) and 19.74 for mortality (95% CI, 14.98-26.01, Pinteraction = 0.033). Conclusions: In utero and childhood/adolescence exposure to tobacco smoke and its interaction with genetic factors may substantially increase the risks of lung cancer incidence and mortality in adulthood.

Exemplar-Based 3D Portrait Stylization.

Exemplar-based portrait stylization is widely attractive and highly desired. Despite recent successes, it remains challenging, especially when considering both texture and geometric styles. In this article, we present the first framework for one-shot 3D portrait style transfer, which can generate 3D face models with both the geometry exaggerated and the texture stylized while preserving the identity from the original content. It requires only one arbitrary style image instead of a large set of training examples for a particular style, provides geometry and texture outputs that are fully parameterized and disentangled, and enables further graphics applications with the 3D representations. The framework consists of two stages. In the first geometric style transfer stage, we use facial landmark translation to capture the coarse geometry style and guide the deformation of the dense 3D face geometry. In the second texture style transfer stage, we focus on performing style transfer on the canonical texture by adopting a differentiable renderer to optimize the texture in a multi-view framework. Experiments show that our method achieves robustly good results on different artistic styles and outperforms existing methods. We also demonstrate the advantages of our method via various 2D and 3D graphics applications.