Genomic conservation of crop wild relatives: A case study of citrus.

Conservation of crop wild relatives is critical for plant breeding and food security. The lack of clarity on the genetic factors that lead to endangered status or extinction create difficulties when attempting to develop concrete recommendations for conserving a citrus wild relative: the wild relatives of crops. Here, we evaluate the conservation of wild kumquat (Fortunella hindsii) using genomic, geographical, environmental, and phenotypic data, and forward simulations. Genome resequencing data from 73 accessions from the Fortunella genus were combined to investigate population structure, demography, inbreeding, introgression, and genetic load. Population structure was correlated with reproductive type (i.e., sexual and apomictic) and with a significant differentiation within the sexually reproducing population. The effective population size for one of the sexually reproducing subpopulations has recently declined to ~1,000, resulting in high levels of inbreeding. In particular, we found that 58% of the ecological niche overlapped between wild and cultivated populations and that there was extensive introgression into wild samples from cultivated populations. Interestingly, the introgression pattern and accumulation of genetic load may be influenced by the type of reproduction. In wild apomictic samples, the introgressed regions were primarily heterozygous, and genome-wide deleterious variants were hidden in the heterozygous state. In contrast, wild sexually reproducing samples carried a higher recessive deleterious burden. Furthermore, we also found that sexually reproducing samples were self-incompatible, which prevented the reduction of genetic diversity by selfing. Our population genomic analyses provide specific recommendations for distinct reproductive types and monitoring during conservation. This study highlights the genomic landscape of a wild relative of citrus and provides recommendations for the conservation of crop wild relatives.

Involvement of CgHSFB1 in the regulation of self-incompatibility in 'Shatian' pummelo.

As self-incompatibility is a major issue in pummelo breeding and production, its mechanism in citrus was analyzed to improve breeding efficiency and reduce production costs. Rutaceae belongs to S-RNase type of gametophytic self-incompatibility. While the function of S-RNase/SLF and the mechanism of self-incompatibility have been studied extensively, the transcriptional regulation of S-RNase has been less studied. We performed transcriptome sequencing with the styles of 'Shatian' pummelo on the day of anthesis and 1-5 days before anthesis, and found that the transcript level of S-RNase gradually decreased with flower development. By analyzing differentially expressed genes and correlation with the expression trend of S-RNase, we identified a candidate gene, CgHSFB1, and utilized biochemical experiments such as yeast one-hybrid assay, electrophoretic mobility shift assay and dual-luciferase assay, as well as transient transformation of citrus calli and Citrus microcarpa and demonstrated that CgHSFB1 could directly bind to the S1-RNase promoter and repress the expression of S1-RNase, which is involved in the pummelo self-incompatibility response. In contrast, CgHSFB1 did not bind to the promoter of S2-RNase, and there was specificity in the regulation of S-RNase.

Transposable elements cause the loss of self-incompatibility in citrus.

Self-incompatibility (SI) is a widespread prezygotic mechanism for flowering plants to avoid inbreeding depression and promote genetic diversity. Citrus has an S-RNase-based SI system, which was frequently lost during evolution. We previously identified a single nucleotide mutation in Sm-RNase, which is responsible for the loss of SI in mandarin and its hybrids. However, little is known about other mechanisms responsible for conversion of SI to self-compatibility (SC) and we identify a completely different mechanism widely utilized by citrus. Here, we found a 786-bp miniature inverted-repeat transposable element (MITE) insertion in the promoter region of the FhiS2-RNase in Fortunella hindsii Swingle (a model plant for citrus gene function), which does not contain the Sm-RNase allele but are still SC. We demonstrate that this MITE plays a pivotal role in the loss of SI in citrus, providing evidence that this MITE insertion prevents expression of the S-RNase; moreover, transgenic experiments show that deletion of this 786-bp MITE insertion recovers the expression of FhiS2-RNase and restores SI. This study identifies the first evidence for a role for MITEs at the S-locus affecting the SI phenotype. A family-wide survey of the S-locus revealed that MITE insertions occur frequently adjacent to S-RNase alleles in different citrus genera, but only certain MITEs appear to be responsible for the loss of SI. Our study provides evidence that insertion of MITEs into a promoter region can alter a breeding strategy and suggests that this phenomenon may be broadly responsible for SC in species with the S-RNase system.

ERF108 from Poncirus trifoliata (L.) Raf. functions in cold tolerance by modulating raffinose synthesis through transcriptional regulation of PtrRafS.

Ethylene-responsive factors (ERFs) are plant-specific transcription factors involved in cold stress response, and raffinose is known to accumulate in plants exposed to cold. However, it remains elusive whether ERFs function in cold tolerance by modulating raffinose synthesis. Here, we identified a cold-responsive PtrERF108 from trifoliate orange (Poncirus trifoliata (L.) Raf.), a cold-tolerant plant closely related to citrus. PtrERF108 is localized in the nucleus and has transcriptional activation activity. Overexpression of PtrERF108 conferred enhanced cold tolerance of transgenic lemon, whereas virus-induced gene silencing (VIGS)-mediated knockdown of PtrERF108 in trifoliate orange greatly elevated cold sensitivity. Transcriptome profiling showed that PtrERF108 overexpression caused extensive reprogramming of genes associated with signaling transduction, physiological processes and metabolic pathways. Among them, a raffinose synthase (RafS)-encoding gene, PtrRafS, was confirmed as a direct target of PtrERF108. RafS activity and raffinose content were significantly increased in PtrERF108-overexpressing transgenic plants, but prominently decreased in the VIGS plants under cold conditions. Meanwhile, exogenous replenishment of raffinose could recover the cold tolerance of PtrERF108-silenced plants, whereas VIGS-mediated knockdown of PtrRafS resulted in cold-sensitive phenotype. Taken together, the current results demonstrate that PtrERF108 plays a positive role in cold tolerance by modulation of raffinose synthesis via regulating PtrRafS. Our findings reveal a new transcriptional module composed of ERF108-RafS underlying cold-induced raffinose accumulation in plants.

Breaking of integrability and conservation leading to Hamiltonian chaotic system and its energy-based coexistence analysis.

In this paper, a four-dimensional conservative system of Euler equations producing the periodic orbit is constructed and studied. The reason that a conservative system often produces periodic orbit has rarely been studied. By analyzing the Hamiltonian and Casimir functions, three invariants of the conservative system are found. The complete integrability is proved to be the mechanism that the system generates the periodic orbits. The mechanism route from periodic orbit to conservative chaos is found by breaking the conservation of Casimir energy and the integrability through which a chaotic Hamiltonian system is built. The observed chaos is not excited by saddle or center equilibria, so the system has hidden dynamics. It is found that the upgrade in the Hamiltonian energy level violates the order of dynamical behavior and transitions from a low or regular state to a high or an irregular state. From the energy bifurcation associated with different energy levels, rich coexisting orbits are discovered, i.e., the coexistence of chaotic orbits, quasi-periodic orbits, and chaotic quasi-periodic orbits. The coincidence between the two-dimensional diagram of maximum Lyapunov exponents and the bifurcation diagram of Hamiltonian energy is observed. Finally, field programmable gate array implementation, a challenging task for the chaotic Hamiltonian conservative system, is designed to be a Hamiltonian pseudo-random number generator.

Modeling and staged assessments of the controllability of spread for repeated outbreaks of COVID-19.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has been causing an outbreak of a new type of pneumonia globally, and repeated outbreaks have already appeared. Among the studies on the spread of the COVID-19, few studies have investigated the repeated outbreaks in stages, and the quantitative condition of a controllable spread has not been revealed. In this paper, a brief compartmental model is developed. The effective reproduction number (ERN) of the model is interpreted by the ratio of net newly infectious individuals to net isolation infections to assess the controllability of the spread of COVID-19. It is found that the value of the ERN at the inflection point of the pandemic is equal to one. The effectiveness of the quarantine, even the treatment, is parametrized in various stages with Gompertz functions to increase modeling accuracy. The impacts of the vaccinations are discussed by adding a vaccinated compartment. The results show that the sufficient vaccinations can make the inflection point appear early and significantly reduce subsequent increases in newly confirmed cases. The analysis of the ERNs of COVID-19 in the United States, Spain, France, and Peru confirms that the condition of a repeated outbreak is to relax or lift the interventions related to isolation and quarantine interventions to a level where the ERN is greater than one.

Analysis of second outbreak of COVID-19 after relaxation of control measures in India.

At present, more and more countries have entered the parallel stage of fighting the epidemic and restoring the economy after reaching the inflection point. Due to economic pressure, the government of India had to implement a policy of relaxing control during the rising period of the epidemic. This paper proposes a compartment model to study the development of COVID-19 in India after relaxing control. The Sigmoid function reflecting the cumulative effect is used to characterize the model-based diagnosis rate, cure rate and mortality rate. Considering the influence of the lockdown on the model parameters, the data are fitted using the method of least squares before and after the lockdown. According to numerical simulation and model analysis, the impact of India's relaxation of control before and after the inflection point is studied. Research shows that adopting a relaxation policy prematurely will have disastrous consequences. Even if the degree of relaxation is only 5% before the inflection point, it will increase the number of deaths by 15.03%. If the control is relaxed after the inflection point, the higher degree of relaxation, the more likely a secondary outbreak will occur, which will extend the duration of the pandemic, leading to more deaths and put more pressure on the health care system. It is found that after the implementation of the relaxation policy, medical quarantine capability and public cooperation are two vital indicators. The results show that if the supply of kits and detection speed can be increased after the control is relaxed, the secondary outbreak can be effectively avoided. Meanwhile, the increase in public cooperation can significantly reduce the spread of the virus, suppress the second outbreak of the pandemic and reduce the death toll. It is of reference significance to the government's policy formulation.

[A multicenter, randomized, controlled, phase â ¢ clinical study of PEG-rhG-CSF for preventing chemotherapy-induced neutropenia in patients with breast cancer and non-small cell lung cancer].

OBJECTIVE: To explore the safety and efficacy of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing chemotherapy-induced neutropenia in patients with breast cancer and non-small cell lung cancer (NSCLC), and to provide the basis for clinical application. METHODS: According to the principle of open-label, randomized, parallel-group controlled clinical trial, all patients were randomized by 1∶1∶1 into three groups to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg, respectively. The patients with breast cancer received two chemotherapy cycles, and the NSCLC patients received 1-2 cycles of chemotherapy according to their condition. All patients were treated with the combination chemotherapy of TAC (docetaxel+ epirubicin+ cyclophosphamide) or TA (docetaxel+ epirubicin), or the chemotherapy of docetaxel combined with carboplatin, with a 21 day cycle. RESULTS: The duration of grade 3-4 neutropenia in the PEG-rhG-CSF 100 µg/kg and PEG-rhG-CSF 6 mg groups were similar with that in the rhG-CSF 5 µg/kg group (P>0.05 for all). The incidence rate of grade 3-4 neutropenia in the PEG-rhG-CSF 100 µg/kg group, PEG-rhG-CSF 6 mg group, and G-CSF 5 µg/kg group were 69.7%, 68.4%, and 69.5%, respectively, with a non-significant difference among the three groups (P=0.963). The incidence rate of febrile neutropenia in the PEG-rhG-CSF 100 µg/kg group, PEG-rhG-CSF 6 mg group and G-CSF 5 µg/kg group were 6.1%, 6.4%, and 5.5%, respectively, showing no significant difference among them (P=0.935). The incidence rate of adverse events in the PEG-rhG-CSF 100 µg/kg group, PEG-rhG-CSF 6 mg group and G-CSF 5 µg / kg group were 6.7%, 4.1%, and 5.5%, respectively, showing a non-significant difference among them (P=0.581). CONCLUSIONS: In patients with breast cancer and non-small cell lung cancer (NSCLC) undergoing TAC/TA chemotherapy, a single 100 µg/kg injection or a single fixed 6 mg dose of PEG-rhG-CSF at 48 hours after chemotherapy show definite therapeutic effect with a low incidence of adverse events and mild adverse reactions. Compared with the continuous daily injection of rhG-CSF 5 µg/kg/d, a single 100 µg/kg injection or a single fixed 6 mg dose of PEG-rhG-CSF has similar effect and is more advantageous in preventing chemotherapy-induced neutropenia.

FcWRKY70, a WRKY protein of Fortunella crassifolia, functions in drought tolerance and modulates putrescine synthesis by regulating arginine decarboxylase gene.

WRKY comprises a large family of transcription factors in plants, but most WRKY members are still poorly understood. In this study, we report functional characterization of a Group III WRKY gene (FcWRKY70) from Fortunella crassifolia. FcWRKY70 was greatly induced by drought and abscisic acid, but slightly or negligibly by salt and cold. Overexpression of FcWRKY70 in tobacco (Nicotiana nudicaulis) and lemon (Citrus lemon) conferred enhanced tolerance to dehydration and drought stresses. Transgenic tobacco and lemon exhibited higher expression levels of ADC (arginine decarboxylase), and accumulated larger amount of putrescine in comparison with wild type (WT). Treatment with D-arginine, an inhibitor of ADC, caused transgenic tobacco plants more sensitive to dehydration. Knock-down of FcWRKY70 in kumquat down-regulated ADC abundance and decreased putrescine level, accompanied by compromised dehydration tolerance. The promoter region of FcADC contained two W-box elements, which were shown to be interacted with FcWRKY70. Taken together, our data demonstrated that FcWRKY70 functions in drought tolerance by, at least partly, promoting production of putrescine via regulating ADC expression.

PtrABF of Poncirus trifoliata functions in dehydration tolerance by reducing stomatal density and maintaining reactive oxygen species homeostasis.

Abscisic acid-responsive element (ABRE)-binding factors (ABFs) play important roles in abiotic stress responses; however, the underlying mechanisms are poorly understood. In this study, it is reported that overexpression of Poncirus trifoliata PtrABF significantly enhanced dehydration tolerance. The transgenic lines displayed smaller stomatal apertures, reduced stomatal density/index, and lower expression levels of genes associated with stomatal development. PtrABF was found to interact with PtrICE1, a homologue of ICE1 (Inducer of CBF Expression 1) that has been shown to be critical for stomatal development. Microarray analysis revealed that a total of 70 genes were differentially expressed in the transgenic line, 42 induced and 28 repressed. At least two units of ABREs and coupling elements were present in the promoters of most of the induced genes, among which peroxidase and arginine decarboxylase were verified as bona fide targets of PtrABF. Transgenic plants exhibited higher antioxidant enzyme activities and free polyamine levels, but lower levels of reactive oxygen species (ROS) and malondialdehyde. Polyamines were revealed to be associated with ROS scavenging in the transgenic plants due to a modulation of antioxidant enzymes triggered by signalling mediated by H2O2 derived from polyamine oxidase (PAO)-mediated catabolism. Taken together, the results indicate that PtrABF functions positively in dehydration tolerance by limiting water loss through its influence on stomatal movement or formation and maintaining ROS homeostasis via modulation of antioxidant enzymes and polyamines through transcriptional regulation of relevant target genes.

Association between the CYP1A2-164 A/C polymorphism and colorectal cancer susceptibility: a meta-analysis.

To date, epidemiological studies have assessed the association between CYP1A2-164 A/C polymorphism and colorectal cancer susceptibility. However, the results of these studies remained controversial. We aimed to examine the associations by conducting a meta-analysis of case-control studies. A total of 11 studies including 5,093 cases and 5,941 controls evaluated the association between the CYP1A2-164 A/C polymorphism and colorectal cancer susceptibility. No significantly associations were found in all genetic models (CC vs. AA: OR = 1.14, 95 % CI = 0.93-1.40; AC vs. AA: OR = 1.05, 95 % CI = 0.91-1.20; dominant model: OR = 1.08, 95 % CI = 0.95-1.24; recessive model: OR = 1.10, 95 % CI = 0.95-1.28). In the subgroup analysis by ethnicity or source of controls, there were still no significant associations detected in all genetic models. This meta-analysis suggested the CYP1A2-164 A/C polymorphism was not a risk factor for increasing colorectal cancer, further large and well-designed studies are needed to confirm these conclusions.

Quantitative assessment of the association between XPG Asp1104His polymorphism and bladder cancer risk.

Published data regarding the association between XPG Asp1104His polymorphism and bladder cancer risk remained controversial. This meta-analysis of literatures was performed to draw a more precise estimation of the relationship. We systematically searched PubMed, Embase, and Web of Science with a time limit of June 22, 2013. Summary odds ratios (ORs) with 95 % CIs were used to assess the strength of the association between XPG Asp1104His polymorphism and bladder cancer risk using random effects model. A total of eight case-control studies including 2,613 cases and 2,934 controls were included for analysis. Overall, no significant association was found between XPG Asp1104His polymorphism and bladder cancer susceptibility for CC vs. GG (OR = 1.12, 95 % CI = 0.74-1.69), GC vs. GG (OR = 1.12, 95 % CI = 0.86-1.46), the dominant model CC + GC vs. GG (OR = 1.08, 95 % CI = 0.85-1.38), and the recessive model CC vs. GC + GG (OR = 0.92, 95 % CI = 0.66-1.29). In the subgroup analysis, no significant associations were found in either Asian or non-Asian population. This meta-analysis suggested that XPG Asp1104His polymorphism was not associated with bladder cancer risk.

The APE1 Asp148Glu polymorphism and colorectal cancer susceptibility: a meta-analysis.

BACKGROUND: Published data regarding the association between the APE1 Asp148Glu polymorphism and colorectal cancer susceptibility remained controversial. This meta-analysis of literatures was performed to draw a more precise estimation of the relationship. MATERIALS AND METHODS: We systematically searched PubMed, Embase, and Web of Science with a time limit of August 19, 2013. Summary odds ratios (ORs) with 95% CIs were used to assess the strength of association between the APE1 Asp148Glu polymorphism and colorectal cancer susceptibility using random-effects model. RESULTS: A total of eight case-control studies including 2,597 cases and 3,063 controls were included for analysis. Overall, no significant associations were found between the APE1 Asp148Glu polymorphism and colorectal cancer susceptibility for GG vs TT (OR = 1.00, 95% CI = 0.73-1.36, p = 0.00 for heterogeneity), TG vs TT (OR = 1.17, 95% CI = 0.88-1.55, p = 0.00 for heterogeneity), the dominant model GG + TG vs TT (OR = 1.21, 95% CI = 0.91-1.60, p = 0.00 for heterogeneity) nor the recessive model GG vs TG + TT(OR = 0.95, 95% CI = 0.75-1.20, p = 0.02 for heterogeneity). In subgroup analysis, no significant associations were found in the Asian or Caucasian populations. CONCLUSION: This meta-analysis suggested that the APE1 Asp148Glu polymorphism was not associated with colorectal cancer susceptibility among Asians or Caucasians.

Integral Compensation Function Observer and Its Application to Disturbance-Rejection Control of QUAV Attitude.

Observer-based disturbance rejection holds substantial theoretical and practical relevance in the field of control engineering, with numerous variants of disturbance observers already schemed. Nevertheless, the criteria for accuracy and avenues for enhancement remain areas warranting further investigation. This article introduces an integral compensation function observer (CFO) featuring a novel structure and efficient utilization of information for estimating disturbances in n th-order uncertain systems. This approach enhances estimation accuracy by addressing the inherent limitations of the linear extended state observer (LESO), such as low order, lacking usage of information, nonconvergence, and limited bandwidth. Through the derivation and quantification of the disturbance sensitivity transfer function (DSTF), this study examines the disturbance sensitivities of the CFO, LESO, and an improved ESO (IESO). The findings indicate that the CFO elevates the estimable order of disturbance and surpasses both LESO and IESO in bandwidth and disturbance estimation accuracy. In evaluating both the estimation accuracy of disturbance of the CFO and the disturbance-rejection performance (DRP) of CFO-based control, nonlinear pole assignment controls (NPACs) employing 2nd/3rd-order CFO, IESO, LESO, and 4th-order CFO are implemented in the context of attitude control for a quadrotor unmanned aerial vehicle (QUAV) that is exposed to prearranged disturbance torques. The results illustrate that the CFO outperforms the IESO and LESO in terms of accurately estimating the prearranged disturbing torques. Furthermore, the recorded magnitudes of attitude in response to disturbances underscore the superior DRP of CFO-NPAC relative to IESO-NPAC and LESO-NPAC.

Fabrication of bimetallic Ag@ZnO nanocomposite and its anti-cancer activity on cervical cancer via impeding PI3K/AKT/mTOR pathway.

INTRODUCTION: Bimetallic nanoparticles, specifically Zinc oxide (ZnO) and Silver (Ag), continue to much outperform other nanoparticles investigated for a variety of biological uses in the field of cancer therapy. This study introduces biosynthesis of bimetallic silver/zinc oxide nanocomposites (Ag@ZnO NCs) using the Crocus sativus extract and evaluates their anti-cancer properties against cervical cancer. METHODS: The process of generating bimetallic nanoparticles (NPs), namely Ag@ZnO NCs, through the utilization of Crocus sativus extract proved to be uncomplicated and eco-friendly. Various methods, such as UV-vis, DLS, FTIR, EDX, and SEM analyses, were utilized to characterize the generated Ag@ZnO NCs. The MTT assay was employed to assess the cytotoxic properties of biosynthesized bimetallic Ag@ZnO NCs against the HeLa cervical cancer cell line. Moreover, the impact of Ag@ZnO NCs on HeLa cells was assessed by examining cell survival, ROS production, MMP levels, and induced apoptosis. Through western blot analysis, the expression levels of the PI3K, AKT, mTOR, Cyclin D, and CDK proteins seemed to be ascertained. Using flow cytometry, the cancer cells' progression through necrosis and apoptosis, in addition to the cell cycle analysis, were investigated. RESULTS: Bimetallic Ag@ZnO NCs that were biosynthesized showed a high degree of stability, as demonstrated by the physicochemical assessments. The median size of the particles in these NCs was approximately 80-90 nm, and their zeta potential was -14.70 mV. AgNPs and ZnO were found, according to EDX data. Further, Ag@ZnO NCs hold promise as a potential treatment for cervical cancer. After 24 hours of treatment, a dosage of 5 µg/mL or higher resulted in a maximum inhibitory effect of 58 ± 2.9. The concurrent application of Ag/ZnO NPs to HeLa cells resulted in elevated apoptotic signals and a significant generation of reactive oxygen species (ROS). As a result, the bimettalic Ag@ZnO NCs treatment has been recognized as a chemotherapeutic intervention by inhibiting the production of PI3K, AKT, and mTOR-mediated regulation of propagation and cell cycle-regulating proteins. CONCLUSIONS: The research yielded important insights into the cytotoxic etiology of biosynthesized bimetallic Ag@ZnO NCs against HeLa cells. The biosynthesized bimetallic Ag@ZnO NCs have a significant antitumor potential, which appears to be associated with the development of oxidative stress, which inhibits the development of the cell cycle and the proliferation of cells. Therefore, in the future, biosynthesized bimetallic Ag@ZnO NCs may be used as a powerful anticancer drug to treat cervical cancer.

Sn0.1-Li4Ti5O12/C as a promising cathode material with a large capacity and high rate performance for Mg-Li hybrid batteries.

The development prospects of conventional Li-ion batteries are limited by the paucity of Li resources. Mg-Li hybrid batteries (MLIBs) combine the advantages of Li-ion batteries and magnesium batteries. Li+ can migrate rapidly in the cathode materials, and the Mg anode has the advantage of being dendrite-free. In this study, a type of Li4Ti5O12 composite material doped with Sn4+ and a conductive carbon skeleton (Li4Ti4.9Sn0.1O12/C, Sn0.1-LTO/C) was prepared by a simple one-pot sol-gel method. The doped Sn4+ replaces part of Ti4+ in the crystal lattice, which makes Ti3+ require charge compensation, thus improving the ionic conductivity. The intervention of the conductive carbon skeleton further improves the conductivity of the Sn0.1-LTO/C composite material. The performance of Sn0.1-LTO/C as the cathode of MLIBs is explored. The initial discharge capacity was 159.1 mA h g-1 at 0.5 C, and it was maintained at 105 mA h g-1 even after 500 cycles. The excellent electrochemical performance is attributed to a small amount of Sn doping and the involvement of the conductive carbon skeleton, which indicated that the Sn0.1-LTO/C composite material provides great potential application in MLIBs.

A meta-analysis of evidences on XPC polymorphisms and lung cancer susceptibility.

Published data regarding the association between the XPC polymorphisms and lung cancer susceptibility remained controversial. This meta-analysis was performed to draw a precise estimation of the relationship. We systematically searched PubMed, Embase, Elsevier, and Web of Science with a time limit of September 10, 2012. Summary odds ratios (ORs) with 95 % CIs were used to assess the strength of association between these polymorphisms and lung cancer susceptibility using random-effects model. This meta-analysis including 13 case-control studies evaluated the associations between three commonly XPC polymorphisms (Lys939Gln, Ala499Val, and PAT(-/+)) and lung cancer susceptibility. No significant associations were found between the three XPC polymorphisms and lung cancer susceptibility (for Lys939Gln polymorphism: CC vs AA, OR = 1.191, p = 0.033; AC vs AA, OR = 0.992, p = 0.762, the dominant model, OR = 1.028, p = 0.521; the recessive model, OR = 1.205, p = 0.022). For Ala499Val polymorphism: TT vs CC, OR = 1.195, p = 0.071; TC vs CC, OR = 1.146, p = 0.133; the dominant model, OR = 1.161, p = 0.086; the recessive model, OR = 1.123, p = 0.156. For PAT(-/+) polymorphism: +/+ vs -/-, OR = 1.094, p = 0.539; +/- vs -/-, OR = 0.925, p = 0.313; the dominant model, OR = 0.969, p = 0.725; the recessive model, OR = 1.135, p = 0.290. p = 0.004 for Bonferroni testing). Significant associations were also not found in the subgroup analysis for the three XPC polymorphisms. This meta-analysis suggested that the three XPC polymorphisms might not be risk factors for developing lung cancer.

A real-world study of anlotinib combined with GS regimen as first-line treatment for advanced pancreatic cancer.

Background: Anlotinib may boost the efficacy of pancreatic cancer (PC) treatment if timely added to the GS regimen (Gemcitabine, Tegafur-gimeracil-oteracil potassium); however, no data has been published. This study evaluated the safety and efficacy of anlotinib in combination with the GS regimen(hereafter referred to as the A+GS regimen) in the first-line treatment of patients with unresectable or metastatic PC. Methods: Patients with unresectable or metastatic PC treated at Yueyang Central Hospital and Yueyang People's Hospital between October 2018 and June 2022 were enrolled in this retrospective real-world investigation. Treatment efficacy was evaluated based on the overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and objective response rate (ORR), while the treatment safety was assessed by the frequency of major adverse events (AEs). Results: Seventy-one patients were included in this study, 41 in the GS group and 30 in the A+GS group. The A+GS group had a longer mPFS than the GS group (12.0 months (95% CI, 6.0-18.0) and 6.0 months (95% CI, 3.0-8.1)), respectively (P = 0.005). mOS was longer in the GS+A group) when compared with the GS group (17.0 months (95%CI, 14.0-20.0) and 10.0 months (95% CI, 7.5-12.5)), respectively (P = 0.018). The GS+A group had higher ORR (50.0% vs 26.8%, P = 0.045) and DCR (83.3% vs 58.5%, P = 0.026). Furthermore, there were no grade 4-5 AEs and no treatment-related deaths, and no discernible increase in AEs in the GS+A group when compared with the GS group. Conclusion: The A+GS regimen therapy holds great promise in managing treatment-naive advanced PC, except that future prospective studies with larger sample sizes and multiple centers are required to determine its efficacy and safety.

Structural variation and parallel evolution of apomixis in citrus during domestication and diversification.

Apomixis, or asexual seed formation, is prevalent in Citrinae via a mechanism termed nucellar or adventitious embryony. Here, multiple embryos of a maternal genotype form directly from nucellar cells in the ovule and can outcompete the developing zygotic embryo as they utilize the sexually derived endosperm for growth. Whilst nucellar embryony enables the propagation of clonal plants of maternal genetic constitution, it is also a barrier to effective breeding through hybridization. To address the genetics and evolution of apomixis in Citrinae, a chromosome-level genome of the Hongkong kumquat (Fortunella hindsii) was assembled following a genome-wide variation map including structural variants (SVs) based on 234 Citrinae accessions. This map revealed that hybrid citrus cultivars shelter genome-wide deleterious mutations and SVs into heterozygous states free from recessive selection, which may explain the capability of nucellar embryony in most cultivars during Citrinae diversification. Analyses revealed that parallel evolution may explain the repeated origin of apomixis in different genera of Citrinae. Within Fortunella, we found that apomixis of some varieties originated via introgression. In apomictic Fortunella, the locus associated with apomixis contains the FhRWP gene, encoding an RWP-RK domain-containing protein previously shown to be required for nucellar embryogenesis in Citrus. We found the heterozygous SV in the FhRWP and CitRWP promoters from apomictic Citrus and Fortunella, due to either two or three miniature inverted transposon element (MITE) insertions. A transcription factor, FhARID, encoding an AT-rich interaction domain-containing protein binds to the MITEs in the promoter of apomictic varieties, which facilitates induction of nucellar embryogenesis. This study provides evolutionary genomic and molecular insights into apomixis in Citrinae and has potential ramifications for citrus breeding.

Efficacy and Safety of Limertinib (ASK120067) in Patients With Locally Advanced or Metastatic EGFR Thr790Met-Mutated NSCLC: A Multicenter, Single-Arm, Phase 2b Study.

INTRODUCTION: Limertinib (ASK120067) is a newly developed third-generation EGFR tyrosine kinase inhibitor targeting both sensitizing EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to evaluate the efficacy and safety of limertinib in patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. METHODS: This is a single-arm, open-label, phase 2b study conducted at 62 hospitals across the People's Republic of China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumor tissue or blood plasma who progressed after first- or second-generation EGFR tyrosine kinase inhibitors or with primary EGFR T790M mutations were enrolled. Patients received limertinib 160 mg orally twice daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) assessed by independent review committee per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate, progression-free survival (PFS), duration of response (DoR), overall survival, and safety. Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. RESULTS: From July 16, 2019, to March 10, 2021, a total of 301 patients were enrolled and started the treatment of limertinib. All patients entered the full analysis set and safety set. By the data cutoff date on September 9, 2021, 76 (25.2%) remained on treatment. The median follow-up time was 10.4 months (range: 0.3-26.3). On the basis of full analysis set, the independent review committee-assessed ORR was 68.8% (95% confidence interval [CI]: 63.2%-74.0%) and disease control rate was 92.4% (95% CI: 88.8%-95.1%). The median PFS was 11.0 months (95% CI: 9.7-12.4), median DoR was 11.1 months (95% CI: 9.6-13.8), and median OS was not reached (95% CI 19.7 months-not evaluable). Objective responses were achieved across all prespecified subgroups. For 99 patients (32.9%) with central nervous system (CNS) metastases, the ORR was 64.6% (95% CI: 54.4%-74.0%), median PFS was 9.7 months (95% CI: 5.9-11.6), and median DoR was 9.6 months (95% CI: 8.1-15.2). For 41 patients who had assessable CNS lesion, the confirmed CNS-ORR was 56.1% (95% CI: 39.7%-71.5%) and median CNS-PFS was 10.6 months (95% CI: 5.6-not evaluable). In safety set, 289 patients (96.0%) experienced at least one treatment-related adverse event (TRAE), with the most common being diarrhea (81.7%), anemia (32.6%), rash (29.9%), and anorexia (28.2%). Grade ≥3 TRAEs occurred in 104 patients (34.6%), with the most common including diarrhea (13.0%), hypokalemia (4.3%), anemia (4.0%), and rash (3.3%). TRAEs leading to dose interruption and dose discontinuation occurred in 24.6% and 2% of patients, respectively. No TRAE leading to death occurred. CONCLUSIONS: Limertinib (ASK120067) was found to have promising efficacy and an acceptable safety profile for the treatment of patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. CLINICAL TRIAL INFORMATION: NCT03502850.