Physiological and Structural Changes in Leaves of Platycrater arguta Seedlings Exposed to Increasing Light Intensities.

Understanding the light adaptation of plants is critical for conservation. Platycrater arguta, an endangered deciduous shrub endemic to East Asia, possesses high ornamental and phylogeographic value. However, the weak environmental adaptability of P. arguta species has limited its general growth and conservation. To obtain a deeper understanding of the P. arguta growth conditions, we examined the leaf morphology and physiology via anatomical and chloroplast ultrastructural analyses following exposure to different natural light intensities (full light, 40%, and 10%). The findings indicated that P. arguta seedings in the 10% light intensity had significantly improved leaf morphological characteristics and specific leaf area compared to those exposed to other intensities. The net photosynthetic rate, chlorophyll (Chl) content, photosynthetic nitrogen use efficiency (PNUE), and photosynthetic phosphorus use efficiency (PPUE) exhibited marked increases at a 10% light intensity compared to both 40% light and full light intensities, whereas the light compensation point and dark respiration levels reached their lowest values under the 10% light condition. With reduced light, leaf thickness, palisade tissue, spongy tissue, and stomatal density significantly decreased, whereas the stomatal length, stomatal width, and stomatal aperture were significantly elevated. When exposed to 10% light intensity, the ultrastructure of chloroplasts was well developed, chloroplasts and starch grain size, the number of grana, and thylakoids all increased significantly, while the number of plastoglobules was significantly reduced. Relative distance phenotypic plasticity index analysis exhibited that P. arguta adapts to varying light environments predominantly by adjusting PPUE, Chl b, PNUE, chloroplast area, and the activity of PSII reaction centers. We proposed that P. arguta efficiently utilizes low light to reconfigure its energy metabolism by regulating its leaf structure, photosynthetic capacity, nutrient use efficiency, and chloroplast development.

Shared genetic basis and causality between schizophrenia and inflammatory bowel disease: evidence from a comprehensive genetic analysis.

BACKGROUND: The comorbidity between schizophrenia (SCZ) and inflammatory bowel disease (IBD) observed in epidemiological studies is partially attributed to genetic overlap, but the magnitude of shared genetic components and the causality relationship between them remains unclear. METHODS: By leveraging large-scale genome-wide association study (GWAS) summary statistics for SCZ, IBD, ulcerative colitis (UC), and Crohn's disease (CD), we conducted a comprehensive genetic pleiotropic analysis to uncover shared loci, genes, or biological processes between SCZ and each of IBD, UC, and CD, independently. Univariable and multivariable Mendelian randomization (MR) analyses were applied to assess the causality across these two disorders. RESULTS: SCZ genetically correlated with IBD (rg = 0.14, p = 3.65 × 10−9), UC (rg = 0.15, p = 4.88 × 10−8), and CD (rg = 0.12, p = 2.27 × 10−6), all surpassed the Bonferroni correction. Cross-trait meta-analysis identified 64, 52, and 66 significantly independent loci associated with SCZ and IBD, UC, and CD, respectively. Follow-up gene-based analysis found 11 novel pleiotropic genes (KAT5, RABEP1, ELP5, CSNK1G1, etc) in all joint phenotypes. Co-expression and pathway enrichment analysis illustrated those novel genes were mainly involved in core immune-related signal transduction and cerebral disorder-related pathways. In univariable MR, genetic predisposition to SCZ was associated with an increased risk of IBD (OR 1.11, 95% CI 1.07­1.15, p = 1.85 × 10−6). Multivariable MR indicated a causal effect of genetic liability to SCZ on IBD risk independent of Actinobacteria (OR 1.11, 95% CI 1.06­1.16, p = 1.34 × 10−6) or BMI (OR 1.11, 95% CI 1.04­1.18, p = 1.84 × 10−3). CONCLUSIONS: We confirmed a shared genetic basis, pleiotropic loci/genes, and causal relationship between SCZ and IBD, providing novel insights into the biological mechanism and therapeutic targets underlying these two disorders.

MicroRNA1432 regulates rice drought stress tolerance by targeting the CALMODULIN-LIKE2 gene.

Due to climate change, drought has become a major threat to rice (Oryza sativa L.) growth and yield worldwide. Understanding the genetic basis of drought tolerance in rice is therefore of great importance. Here, we identified a microRNA, miR1432, which regulates rice drought tolerance by targeting the CALMODULIN-LIKE2 (OsCaML2) gene. Mutation of MIR1432 (Bhardwaj et al., 2014). Moreover, recent studies have demonstrated that some miRNAs, such as miR164 (Fang et al., 2014), miR166 (Zhang et al., 2018), miR319 (Zhou et al., 2013) and miR408 (Hang et al., 2021), play important roles in regulating plant drought resistance. An improved understanding of the miRNA-mediated regulatory mechanisms involved in drought resistance would help to elucidate the regulatory networks that control drought stress responses and adaptation to water deficiency and may facilitate the genetic engineering of drought-tolerant crop varieties.

A designer synthetic chromosome fragment functions in moss.

Rapid advances in DNA synthesis techniques have enabled the assembly and engineering of viral and microbial genomes, presenting new opportunities for synthetic genomics in multicellular eukaryotic organisms. These organisms, characterized by larger genomes, abundant transposons and extensive epigenetic regulation, pose unique challenges. Here we report the in vivo assembly of chromosomal fragments in the moss Physcomitrium patens, producing phenotypically virtually wild-type lines in which one-third of the coding region of a chromosomal arm is replaced by redesigned, chemically synthesized fragments. By eliminating 55.8% of a 155 kb endogenous chromosomal region, we substantially simplified the genome without discernible phenotypic effects, implying that many transposable elements may minimally impact growth. We also introduced other sequence modifications, such as PCRTag incorporation, gene locus swapping and stop codon substitution. Despite these substantial changes, the complex epigenetic landscape was normally established, albeit with some three-dimensional conformation alterations. The synthesis of a partial multicellular eukaryotic chromosome arm lays the foundation for the synthetic moss genome project (SynMoss) and paves the way for genome synthesis in multicellular organisms.

Intensive cycles of neoadjuvant camrelizumab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma: a single-arm, phase II trial.

BACKGROUND: Two cycles of neoadjuvant PD-1 blockade plus chemotherapy induced favorable pathological response and tolerant toxicity in patients with locally advanced esophageal squamous cell carcinoma (ESCC). However, approximately 25% of patients relapsed within 1 year after surgery, indicating that a short course of treatment may not be sufficient. Therefore, exploring the effects of intensive treatment is needed for optimal clinical outcomes. METHODS: Locally advanced ESCC patients were administered three cycles of camrelizumab plus nab-paclitaxel and capecitabine, followed by thoracoscopic esophagectomy. The primary endpoint was pathologic response. Secondary endpoints included safety, feasibility, radiologic response, survival outcomes, and immunologic/genomic correlates of efficacy. RESULTS: Forty-seven patients were enrolled in the study. Forty-two patients received surgery, and R0 resection was achieved in all cases. The complete and major pathological response rates were 33.3% and 64.3%, respectively, and the objective response rate was 80.0%. Three cycles of treatment significantly improved T down-staging compared to two cycles (P = 0.03). The most common treatment-related adverse events were grades 1-2, and no surgical delay was reported. With a median follow-up of 24.3 months, the 1-year disease-free survival and overall survival rates were both 97.6%, and the 2-year disease-free survival and overall survival rates were 92.3% and 97.6%, respectively. Three patients experienced disease recurrence or metastasis ranging from 12.5 to 25.8 months after surgery, and one patient died 6 months after surgery due to cardiovascular disease. Neither programmed death-ligand 1 expression nor tumor mutational burden was associated with pathological response. An increased infiltration of CD56dim natural killer cells in the pretreatment tumor was correlated with better pathological response in the primary tumor. CONCLUSIONS: It seems probable that intensive cycles of neoadjuvant camrelizumab plus nab-paclitaxel and capecitabine increased tumor regression and improved survival outcomes. Randomized controlled trials with larger sample sizes and longer follow-up periods are needed to validate these findings. Trial registration Chinese Clinical Trial Registry, ChiCTR2000029807, Registered February 14, 2020, https://www.chictr.org.cn/showproj.aspx?proj=49459 .

Nuclear DNA Amounts in Chinese Bryophytes Estimated by Flow Cytometry: Variation Patterns and Biological Significances.

There exists an obvious gap in our knowledge of the nuclear DNA amount of bryophytes, not only in terms of the low number of species represented, but also in systematic and geographic representation. In order to increase our knowledge of nuclear DNA amounts and variation patterns in bryophytes, and their potential phylogenetic significances and influences on phenotypes, we used flow cytometry to determine the DNA 1C values of 209 bryophyte accessions, which belong to 145 mosses and 18 liverworts collected from China, by using Physcomitrella patens as a standard. We quantified the differences in DNA 1C values among different orders and families and constructed a phylogenetic tree of 112 mosses with four gene sequences (nad5, rbcL, trnL-F, and 18S-ITS1-5.8S-ITS2-26S). DNA 1C values were mapped onto the phylogenetic tree to test a potential phylogenetic signal. We also evaluated the correlations of the DNA 1C value with the sizes of individuals, leaves, cells, and spores by using a phylogenetically controlled analysis. New estimates of nuclear DNA amounts were reported for 145 species. The DNA 1C values of 209 bryophyte accessions ranged from 0.422 pg to 0.860 pg, with an average value of 0.561 pg, and a 2.04-fold variation covered the extremes of all the accessions. Although the values are not significantly different (p = 0.355) between mosses (0.528 pg) and liverworts (0.542 pg), there are variations to varying extents between some families and orders. The DNA 1C value size exerts a positive effect on the sizes of plants, leaves, and cells, but a negative effect on spore size. A weak phylogenetic signal is detected across most moss species. Phylogenetic signals are comparatively strong for some lineages. Our findings show that bryophytes have very small and highly constrained nuclear DNA amounts. There are nucleotype effects of nuclear DNA amounts for bryophytes at the individual, organ, and cell levels. We speculate that smaller nuclear DNA amounts are advantageous for bryophytes in dry environments. Significant differences in the DNA 1C values among some moss families and orders, as well as phylogenetic signals for some lineages, imply that nuclear DNA amount evolution in mosses seems to be unidirectional.

Moderately hypo-fractionated radiotherapy combined with S-1 in inoperable locally advanced esophageal squamous cell carcinoma: A prospective, single-arm phase II study (GASTO-1045).

Purpose: We launched this prospective phase II single-arm trial on the combination of moderately hypo-fractionated radiotherapy and S-1, to explore the safety and efficacy of the new potent regimen in inoperable locally advanced esophageal squamous carcinoma (LA-ESCC) patients. Methods: Patients with unresectable stage II-IVB LA-ESCC (UICC 2002, IVB only with metastatic celiac or supraclavicular lymph nodes) were included. Moderately hypofractionated radiotherapy (60Gy in 24 fractions) concurrent with S-1 was delivered. Meanwhile, gastrostomy tube placement by percutaneous endoscopic gastrostomy (PEG) was performed to provide nutritional support. Nutritional supplements were prescribed to meet requirements. The study outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), failure pattern, toxicities, nutritional status and treatment compliance. Endoscopy was routinely performed during post-treatment follow-up. Results: Fifty-eight patients were included with a median follow-up of 24.4 months. The median age was 63 years (range 49-83 years) and 42 patients (72.4%) had stage III or IV diseases. The ORR was 91.3% and the CR rate was 60.3%. The estimated 2-year PFS rate and 2-year OS rate was 44.2% (95% confidence interval (CI), 31.3-57.1%) and 71.4% (95% CI, 59.4-83.4%), respectively. Radiation-induced esophagitis was the most common non-hematologic toxicity and 5 patients (8.6%) developed grade≥3 esophagitis. While, with PEG nutrition support, the nutrition-related indicators presented a clear trend toward a gradual improvement. Treatment-related death was not observed. Conclusions: The moderately hypo-fractionated radiotherapy combined with S-1 showed promising loco-regional disease control and survival benefit in inoperable LA-ESCC patients. Meanwhile, favorable nutritional status and low incidence of severe radiation-induced esophagitis were observed with PEG nutritional support. Moreover, endoscopy examination contributed to the early detection of recurrent esophageal lesions and timely salvage treatment. The efficacy and toxicity of the combined regimen deserved further evaluation. Trial registration: Clinicaltrials.gov, identifier NCT03660449.

Are more courses of immunochemotherapy beneficial for the short-term outcome of locally advanced esophageal squamous cell carcinoma?

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy and neoadjuvant immunochemotherapy have shown promising results in esophageal carcinoma. However, it is still unclear whether more courses of immunochemotherapy are therapeutically better. We aimed to investigate the safety and efficacy of three courses of neoadjuvant treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC received three courses of camrelizumab plus nab-paclitaxel and capecitabine before undergoing surgery. Additionally, patients received safety, computed tomography (CT), and endoscopy (with endoscopic ultrasonography and mucosal biopsy) assessments before and in the second and third courses of treatment. We used the CT and endoscopic assessment results from the second and third courses for comparison. RESULTS: From May 2020 to December 2021, 47 patients were enrolled at Sun Yat-sen University Cancer Center. In our study, 43 patients completed three courses of preoperative chemotherapy combined with anti-Programmed cell death-1 (PD-1) therapy and radical surgical resection. The toxicity of the third course of immunochemotherapy was mild and well tolerated without increased treatment-related adverse events (TRAEs) and mortality compared with that of the second course of treatment. In terms of efficacy, an additional course of treatment after the second course of treatment was effective, with increased CT and endoscopy T (clinical T stage) downstaging rates by 16.3% and 25.9%, N (clincial N stage) downstaging rates by 7.0% and 11.1%, and objective response rates (ORRs) by 13.6% and 22.0%, respectively. CONCLUSIONS: Regardless of downstaging or ORR, three courses of immunochemotherapy appear to be superior to two courses of treatment without increasing TRAEs.

Thresholds in the Species-Area-Habitat Model: Evidence from the Bryophytes on Continental Islands.

AIM: To clarify whether (1) there are thresholds in the species-area-habitat relationship for bryophytes and potential mechanisms, (2) such thresholds vary among different bryophyte groups, and (3) choros is better than area or habitat alone in the prediction of SR. LOCATION: Islands in central and southern Zhejiang, China. METHODS: We investigated the species richness (SR) of five bryophyte groups (total bryophytes, total mosses, liverworts, acrocarpous mosses, and pleurocarpous mosses) and habitat types on 66 islands. By using four threshold models, the logarithmic and the power models, we quantified their SR-choros relationships (SKRs), species-area relationships (SARs), and species-habitat relationships (SHRs). We also conducted path analyses to detect the direct effects of area per se and habitat per se on the SR. RESULTS: The AICc values of the SKR models were overall smaller than those of the respective SAR and SHR models. The left-horizontal two-threshold model was best for the SKRs. A phenomenon (the small-choros effect, SCE) in which SR independently varied choros below a given threshold was detected. The SCE thresholds were smaller in mosses than in liverworts and in acrocarpous mosses than in pleurocarpous mosses. No direct and positive effects of habitat per se on the SR were detected below choros thresholds for all five groups. MAIN CONCLUSIONS: There were two thresholds and SCEs in the SKRs of all five bryophyte groups. The SCEs likely resulted from the elimination of the direct and positive effects of habitat diversity on the SR of the bryophytes on small choros islands. The SCE thresholds were high for species groups sensitive to environments. Choros was better than area or habitat alone in determining the SR of the bryophytes on continental islands.

Taxon-dependent effects of dispersal limitation versus environmental filters on bryophyte assemblages-Multiple perspective studies in land-bridge islands.

To explore the taxon-dependent contribution of dispersal limitation versus environmental filters to bryophyte assemblages. We investigated bryophytes and six environmental variables on 168 islands in the Thousand Island Lake,China. We compared the observed beta diversity with the expected values based on six null models (EE, EF, FE, FF, PE, and PF), detected the partial correlation of beta diversity with geographical distances. We quantified the contributions of spatial versus environmental variables and island isolation per se to species composition (SC) using variance partitioning. We modeled the species-area relationships (SARs) for bryophytes and the other eight biotas. To explore the taxon-dependent effects of spatial versus environmental filters on bryophytes, 16 taxa including five categories (total bryophytes, total mosses, liverworts, acrocarpous, and pleurocarpous mosses) and 11 species-richest families were included in the analyses. The observed beta diversity values were significantly different from the predicted values for all 16 taxa. For all five categories, the observed partial correlations between beta diversity and geographical distance after controlling environmental effects were not only positive, but also significantly different from the predicted values based on the null models. Spatial eigenvectors are more important in shaping SC than environmental variables for all 16 taxa except Brachytheciaceae and Anomodontaceae. Spatial eigenvectors contributed more to SC variation in liverworts than in mosses and in pleurocarpous mosses than in acrocarpous mosses. The effects of island isolation on SC were significant for all five categories, highly varied at the family level. The z values of the SARs for the five bryophyte categories were all larger than those of the other eight biotas. In subtropical fragmented forests, dispersal limitation exerted significant, taxon-dependent effects on bryophyte assemblages. It was dispersal limitation rather than environmental filtering that predominantly regulated the SC patterns of bryophytes.

Study of preoperative diagnostic modalities in Chinese patients with superficial esophageal squamous cell carcinoma.

BACKGROUND: Endoscopic ultrasonography (EUS) and magnifying endoscopy (ME) reliably determine indications for endoscopic resection in patients with superficial esophageal squamous cell carcinoma (SESCC). ME is widely accepted for predicting the invasion depth of superficial esophageal cancer with satisfying accuracy. However, the addition of EUS is controversial. AIM: To evaluate the diagnostic efficiency of ME vs EUS for invasion depth prediction and investigate the influencing factors in patients with SESCC to determine the best diagnostic model in China. METHODS: We retrospectively analyzed patients with suspected SESCC who completed both ME and EUS and then underwent endoscopic or surgical resection at Sun Yat-Sen University Cancer Center between January 2018 and December 2021. We evaluated and compared the diagnostic efficiency of EUS and ME according to histological results, and investigated the influencing factors. RESULTS: We included 152 lesions from 144 patients in this study. The diagnostic accuracies of ME and EUS in differentiating invasion depth were not significantly different (73.0% and 66.4%, P = 0.24); both demonstrated moderate consistency with the pathological results (ME: kappa = 0.58, 95% confidence interval [CI]: 0.48-0.68, P < 0.01; EUS: kappa = 0.46, 95%CI: 0.34-0.57, P < 0.01). ME was significantly more accurate in the diagnosis of high-grade intraepithelial (HGIN) or carcinoma in situ (odds ratio [OR] = 3.62, 95%CI: 1.43-9.16, P = 0.007) subgroups. Using a miniature probe rather than conventional EUS can improve the accuracy of lesion depth determination (82.3% vs 49.3%, P < 0.01). Less than a quarter of circumferential occupation and application of a miniature probe were independent risk factors for the accuracy of tumor invasion depth as assessed by EUS (< 1/4 circumferential occupation: OR = 3.07, 95%CI: 1.04-9.10; application of a miniature probe: OR = 5.28, 95%CI: 2.41-11.59, P < 0.01). Of the 41 lesions (41/152, 27.0%) that were misdiagnosed by ME, 24 were corrected by EUS (24/41, 58.5%). CONCLUSION: Preoperative diagnosis of SESCC should be conducted endoscopically using white light and magnification. In China, EUS can be added after obtaining patient consent. Use of a high-frequency miniature probe or miniature probe combined with conventional EUS is preferable.

Photosynthesis, Nitrogen Allocation, Non-Structural Carbohydrate Allocation, and C:N:P Stoichiometry of Ulmus elongata Seedlings Exposed to Different Light Intensities.

The leaf photosynthetic capacity, leaf N partitioning, non-structural carbohydrate content, C, N, and P contents of endangered U. elongata seedlings exposed to different light intensities were compared in this study. The most favorable light condition for the survival and growth of U. elongata seedlings in the present study was 100% full sunlight, as this induced higher Pn, PNUE, PC, PR, PB, and NSC content relative to shade-treated seedlings. PNUE, PR, PC, and PB in U. elongata seedling leaves decreased under 40% and 10% full sunlight, while PL increased, indicating that shade increased the light capture efficiency of photosystem (PS) II but decreased electron transfer from PSII to PSI. Furthermore, leaf N content increased with shade intensity, revealing an adaptive strategy for poor light environments. Additionally, the smallest leaf biomass, Pn, WUE, and CE values and C:N and C:P ratios in stems and leaves were observed under 10% full sunlight. These results indicate that seedlings growing under 40% full sunlight will benefit U. elongata conservation.

A Static Area Coverage Algorithm for Heterogeneous AUV Group Based on Biological Competition Mechanism.

Static area coverage of the heterogeneous autonomous underwater vehicle (AUV) group is widely used in many fields. With the use of the centroidal Voronoi tessellation (CVT) algorithm, the coverage problem can be resolved. However, the CVT method, which is optimized with the location evaluation function, cannot consider the heterogeneity of AUVs when the group performs the static area coverage task and will cause a waste of resources. In this paper, considering different AUVs' task requirements and detection capabilities comprehensively, we propose a coverage control optimization algorithm based on a biological competition mechanism (BCM). By using BCM, the task load of each AUV can be distributed consistently. In addition, we provide strict proof of the consistency of the algorithm based on the Lyapunov method. Simulation results demonstrate that with the proposed algorithm, the location distribution of the heterogeneous AUV group for area coverage is close to the balanced value, and the performance is better than the CVT algorithm for static area coverage.

[Effects of arbuscular mycorrhizal fungi inoculation on non-structural carbohydrate contents and C:N:P stoichiometry of Heptacodium miconioides under drought stress]. / å¹²æ—±èƒè¿«ä¸‹æŽ¥ç§ä¸›æžèŒæ ¹çœŸèŒå¯¹ä¸ƒå­èŠ±éžç»“æž„æ€§ç¢³æ°´åŒ–åˆç‰©ç§¯ç´¯åŠC、N、P化学计量特征的影响.

A pot experiment was conducted to investigate the effects of drought stress and arbuscular mycorrhizal fungi (AMF) inoculation on C:N:P stoichiometry and non-structural carbohydrate (NSC) contents in two-year-old Heptacodium miconioides seedlings. There were four treatments, including control (CK), drought stress (D), AMF inoculation (AMF), and combined drought stress and AMF inoculation (D+AMF). The results showed that drought stress significantly reduced AMF colonization rate, whereas plant height and leaf number of inoculated treatment were significantly higher than the non-inoculated treatment. Inoculation with AMF significantly increased soluble sugar and NSC content in root and leaf, as well as starch content in stem and leaf. The inoculation significantly decreased the stem and leaf soluble sugar to starch ratio under drought stress. Drought stress caused a significant increase in C content in roots and leaves, and a significant decrease in P content in stems. Compared with no inoculation drought stress, P content in roots, stems, leaves, and C content in leaves of mycorrhizal seedlings were significantly increased by inoculation under drought stress, whereas root C and N content and stem C content were significantly reduced. Under drought stress, AMF inoculation significantly decreased C:N, C:P, and N:P ratios in roots and stems, and N:P ratios in leaves of H. miconioides. P content in roots and leaves were significantly positively correlated with soluble sugar and NSC content. Stem P content was significantly positively correlated with starch and NSC content. N:P ratios in each organ was significantly negatively correlated with NSC content. In all, inoculation with AMF can improve the drought tolerance of H. miconioides seedling by increasing soluble sugar content in roots and leaves and the soluble sugar/starch ratio in roots, improving starch content in above-ground organs, promoting the P absorption, and reducing N:P ratios in each organ. Therefore, AMF colonization could improve the survival rate of H. miconioides seedling in dry environments.

A Formation Control Method for AUV Group Under Communication Delay.

This article presents a consistency control algorithm for the autonomous underwater vehicle (AUV) group combined with the leader-follower approach under communication delay. First, the six-degree-of-freedom (DoF) model of AUV is represented, and the graph theory is used to describe the communication topology of the AUV group. Especially, a hybrid communication topology is introduced to adapt to large formation control. Second, the distributed control law is constructed by combining the consensus theory with the leader-follower method. The consistency control algorithms for homogeneous and heterogeneous AUV groups based on the leader-follower approach under communication delay are proposed. Stability criteria are established to guarantee the consensus based on the Gershgorin disk theorem and Nyquist law, respectively. Finally, numerous simulation experiments are carried out to show the effectiveness and superiority of the proposed algorithms.

A Prospective Phase II Study of Simultaneous Modulated Accelerated Radiotherapy Concurrently With CDDP/S1 for Esophageal Squamous Cell Carcinoma in the Elderly.

BACKGROUND: To explore the efficacy and toxicity of simultaneous modulated accelerated radiotherapy (SMART) concurrently with cisplatin (CDDP) and S1 (tegafur/gimeracil/oteracil) in elderly patients with esophageal squamous cell carcinoma (ESCC). METHODS: This single-arm, phase II study enrolled pathologically confirmed, stage II-IVa ESCC of 70-80 years old and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients received SMART (64 Gy to gross tumor volume and 48 Gy to clinical target volume in 30 fractions) with concurrent CDDP (day 1 of each week) and S1 (days 1-14, 22-35). The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicities. RESULTS: Thirty-seven eligible patients were analyzed with median follow-up of 25.7 months for all and 46.1 months for survivors. The ORR was 88.9%. Patients with baseline weight loss <5% (p=0.050) and nutritional risk index (NRI) ≥105.2 (p=0.023) had better tumor response. Median PFS was 13.8 months with 2-year PFS of 37.5%. Median OS was 27.7 months with 2-year OS of 57.5%. OS was significantly associated with ECOG PS (p=0.005), stage (p=0.014), gross tumor volume (p=0.004), baseline NRI (p=0.036), baseline C-reactive protein (CRP) level (p=0.003) and tumor response (p=0.000). CRP level (p=0.016) and tumor response (p=0.021) were independently prognostic of OS. ≥grade 3 anemia, neutropenia and thrombocytopenia occurred in 2.7%, 10.8% and 13.5% of patients; ≥grade 3 esophagitis and pneumonitis occurred in 18.9% and 2.7% of patient, respectively. CONCLUSION: SMART concurrently with CDDP/S1 yielded satisfactory response rate, survival outcome and tolerable treatment-related toxicities in elderly patients with ESCC. Further studies are warranted to validate the results.

Neoadjuvant programmed death-1 blockade plus chemotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Immunotherapy is effective in treating unresectable esophageal squamous cell carcinoma (ESCC), but little is known about its role in the preoperative setting. The aim of this study was to evaluate the safety, feasibility and efficacy of neoadjuvant treatment with camrelizumab plus chemotherapy in locally advanced ESCC. METHODS: Patients diagnosed with locally advanced ESCC were retrospectively included if they had received neoadjuvant camrelizumab plus nab-paclitaxel and S1 capsule followed by radical esophagectomy between November, 2019 and June, 2020 at Sun Yat-sen University Cancer Center. Primary endpoints were safety and feasibility. In addition, pathological response and the relationship between tumor immune microenvironment (TIME)/tumor mutational burden (TMB) and treatment response were also investigated. RESULTS: Twelve patients were included and they all received three courses of preoperative treatment with camrelizumab plus nab-paclitaxel/S1. No grade 3 or higher toxicities occurred. No surgical delay or perioperative death was reported. Nine patients (75%) responded to the treatment, four with a complete pathological response (pCR) and five with a major pathological response (MPR). Neither programmed death-ligand 1 (PD-L1) expression nor TMB was correlated with treatment response. TIME analysis revealed that a higher abundance of CD56dim natural killer cells was associated with better pathological response in the primary tumor, while lower density of M2-tumor-associated macrophages was associated with better pathological response in the lymph nodes (LNs). CONCLUSIONS: Neoadjuvant camrelizumab plus nab-paclitaxel and S1 is safe, feasible and effective in locally advanced ESCC and is worth further investigation.

Endobronchial Ultrasound Improves Evaluation of Recurrent Laryngeal Nerve Lymph Nodes in Esophageal Squamous Cell Carcinoma Patients.

BACKGROUND: The bilateral recurrent laryngeal nerve (RLN) lymph nodes are the most common metastatic site for esophageal squamous cell carcinoma (ESCC); however, the RLNs are susceptible to injury during dissection. Clinically, there is an urgent need to determine an effective diagnostic method for RLN nodes to help achieve selective nodal dissection and avoid potential serious complications by performing more conservative surgery for those with nonmetastatic nodes. Here, we innovatively applied endobronchial ultrasonography (EBUS) and investigated its diagnostic performance for preoperative evaluation of RLN nodes in ESCC patients. PATIENTS AND METHODS: All 81 enrolled ESCC patients underwent preoperative EBUS and CT examinations. The ability of EBUS and CT to detect RLN node metastasis was evaluated based on the resulting sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The diagnostic performance of EBUS was superior to that of CT; in particular, EBUS of the left RLN (L-RLN) nodes presented the best sensitivity, specificity, PPV, NPV, and accuracy compared with EBUS evaluations of the right RLN (R-RLN) nodes, CT of the L-RLN and R-RLN nodes. Moreover, EBUS combined with CT increased the NPV relative to that of EBUS or CT alone, promoting the ability to identify true-negative RLN nodes. In particular, the NPVs of the combined modality were 100% for both the L- and R-RLN nodes in early-T-stage (T1-T2) ESCC. CONCLUSIONS: EBUS is an efficient tool for RLN node evaluation, and the combination with CT may provide better guidance for selective RLN node dissection in ESCC patients.

SPT6 recruits SND1 to co-activate human telomerase reverse transcriptase to promote colon cancer progression.

Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional factor of hTERT in CRC and explored its role and the corresponding molecular mechanisms in regulating hTERT expression and CRC survival with an aim of developing mechanism-based combinational targeting therapy. The possible binding proteins at the hTERT promoter were uncovered using pull-down/mass spectrometry analysis. The regulation of SPT6 on hTERT expression and CRC survival was evaluated in human CRC cell lines and mouse models. Mechanistic studies focusing on the synergy between SPT6 and staphylococcal nuclease and Tudor domain containing 1 (SND1) in controlling hTERT expression and CRC progression were conducted also in the above two levels. The expression correlation and clinical significance of SPT6, SND1, and hTERT were investigated in tumor tissues from murine models and patients with CRC in situ. SPT6 was identified as a possible transcriptional factor to bind to the hTERT promoter. SPT6 knockdown decreased the activity of hTERT promoter, downregulated the protein expression level of hTERT, suppressed proliferation, invasion, and stem-like properties, promoted apoptosis induction, and enhanced chemotherapeutic drug sensitivity in vitro. SPT6 silencing also led to the delay of tumor growth and metastasis in mice carrying xenografts of human-derived colon cancer cells. Mechanistically, SND1 interacted with SPT6 to co-control hTERT expression and CRC cell proliferation, stemness, and growth in vitro and in vivo. SPT6, SND1, and hTERT were highly expressed simultaneously in CRC tissues, both from the murine model and patients with CRC in situ, and pairwise expression among these three factors showed a significant positive correlation. In brief, our research demonstrated that SPT6 synergized with SND1 to promote CRC development by targeting hTERT and put forward that inhibiting the SPT6-SND1-hTERT axis may create a therapeutic vulnerability in CRC.

High Diagnostic Accuracy and Safety of Endoscopic Ultrasound-Guided Fine-Needle Aspiration in Malignant Lymph Nodes: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is increasingly being used for diagnosing lymphadenopathy. We aim to systematically review the accuracy of EUS-FNA in differentiating benign and malignant mediastinal and abdominal lymph nodes (LNs). METHODS: A comprehensive literature search was performed on multiple electronic databases through February 2020. A random or fixed effect model generated the pooled sensitivity, specificity, likelihood ratio (LR), and diagnostic odds ratio (DOR) of EUS-FNA. Subgroup analyses and meta-regression were used to explore sources of heterogeneity. RESULTS: Twenty-six studies involving 2753 patients with 2833 LNs were included. In the differential diagnosis of benign and malignant LNs, EUS-FNA had a pooled sensitivity, specificity, positive LR, and negative LR of 87% (95% confidence interval [CI] 86-90%), 100% (95% CI 99-100%), 68.98 (95% CI 42.10-113.02), and 0.14 (95% CI 0.11-0.17), respectively. The pooled rate of adverse events associated with EUS-FNA was 1.57% (95% CI 1.06-2.24%). The summary receiver operating characteristic (SROC) yielded an area under the curve (AUC) of 0.9912. EUS-FNA performed in mediastinal LNs gained a sensitivity of 85% (95% CI 81-88%), while in abdominal LNs, it reached 87% (95% CI 82-91%). The sensitivity of the subgroup with rapid on-site evaluation (ROSE) was 91% (95% CI 89-93%), while non-ROSE was 85% (95% CI 82-87%). CONCLUSIONS: EUS-FNA is a sensitive, highly specific, and safe method for distinguishing benign and malignant mediastinal or abdominal LNs. However, the sensitivity of EUS-FNA still varies significantly among different centers.