Regional consistency assessment in multiregional clinical trials.

Multiregional clinical trials (MRCTs) have become a favored strategy for new drug development. The accurate evaluation of treatment effects across different regions is crucial for interpreting the results of MRCTs. Consistency between regional and overall results ensures the extrapolability of the overall conclusions to individual regions. While numerous statistical methods have been proposed for consistency assessment, a notable proportion necessitate a substantial escalation in sample size, particularly in scenarios involving more than four regions within MRCTs. This, paradoxically, undermines the fundamental intent of MRCTs. In addition, standardized statistical criteria for concluding consistency are yet to be established. In this paper, we develop further consistency assessment approaches in the framework of two multivariate likelihood ratio test-based methods, namely mLRTa and mLRTb, wherein consistency is cast as the alternative and null hypotheses. Notably, our exploration unveils that qualitative methods such as the funnel approach and PMDA methods are special instances of mLRTa. Furthermore, our work underscores that these three qualitative methodologies roughly share the same level of assurance probability (AP). Intriguingly, when the number of regions in an MRCT surpasses five, even when the overall sample size guarantees a power of 90% or more and the true treatment effects remain uniform across regions, the AP remains below the 70% mark. Drawing from our meticulous examination of operational attributes, we recommend mLRTa with positive treatment effects in all regions in the alternative hypothesis with significance level 0.5 or mLRTb with all regional treatment effects being equal in the null and significance level of 0.2.

Genome-wide analysis and expression profiling of the HD-ZIP gene family in kiwifruit.

The homeodomain-leucine zipper (HD-Zip) gene family plays a pivotal role in plant development and stress responses. Nevertheless, a comprehensive characterization of the HD-Zip gene family in kiwifruit has been lacking. In this study, we have systematically identified 70 HD-Zip genes in the Actinidia chinensis (Ac) genome and 55 in the Actinidia eriantha (Ae) genome. These genes have been categorized into four subfamilies (HD-Zip I, II, III, and IV) through rigorous phylogenetic analysis. Analysis of synteny patterns and selection pressures has provided insights into how whole-genome duplication (WGD) or segmental may have contributed to the divergence in gene numbers between these two kiwifruit species, with duplicated gene pairs undergoing purifying selection. Furthermore, our study has unveiled tissue-specific expression patterns among kiwifruit HD-Zip genes, with some genes identified as key regulators of kiwifruit responses to bacterial canker disease and postharvest processes. These findings not only offer valuable insights into the evolutionary and functional characteristics of kiwifruit HD-Zips but also shed light on their potential roles in plant growth and development.

Side Chain Programming Synchronously Enhances the Photothermal Conversion Efficiency and Photodynamic Activity of A-D-A Photosensitizers.

Synchronously improving the photothermal conversion efficiency and photodynamic activity of organic small molecule photosensitizers is crucial for their further wide application in cancer treatment. Recently, the emerging A-D-A photosensitizer-based phototherapy systems have attracted great interest due to their plentiful inherent merits. Herein, we propose a design strategy for A-D-A photosensitizers with synchronously enhanced photothermal conversion and reactive oxygen species (ROS) generation efficiencies. Side chain programming is carried out to design three A-D-A photosensitizers (IDT-H, IDT-Br, IDT-I) containing hexyl, bromohexyl, and iodohexyl side chains, respectively. Theoretical calculations confirm that a bulky iodine atom could weaken the intermolecular π-π stacking and enhance spin-orbit coupling constants of IDT-I. These molecular mechanisms enable IDT-I nanoparticles (NPs) to exhibit 2.4-fold and 1.7-fold higher ROS generation efficiency than that of IDT-H NPs and IDT-Br NPs, respectively, as well as the highest photothermal conversion efficiency. Both the experimental results in vitro and in vivo verify that IDT-I NPs are perfectly qualified for the mission of photothermal and photodynamic synergistic therapy. Therefore, in this contribution, we provide a promising perspective for the design of A-D-A photosensitizers with simultaneously improved photothermal and photodynamic therapy ability.

Two-stage stratified designs with survival outcomes and adjustment for misclassification in predictive biomarkers.

Biomarker stratified clinical trial designs are versatile tools to assess biomarker clinical utility and address its relationship with clinical endpoints. Due to imperfect assays and/or classification rules, biomarker status is prone to errors. To account for biomarker misclassification, we consider a two-stage stratified design for survival outcomes with an adjustment for misclassification in predictive biomarkers. Compared to continuous and/or binary outcomes, the test statistics for survival outcomes with an adjustment for biomarker misclassification is much more complicated and needs to take special care. We propose to use the information from the observed biomarker status strata to construct adjusted log-rank statistics for true biomarker status strata. These adjusted log-rank statistics are then used to develop sequential tests for the global (composite) hypothesis and component-wise hypothesis. We discuss the power analysis with the control of the type-I error rate by using the correlations between the adjusted log-rank statistics within and between the design stages. Our method is illustrated with examples of the recent successful development of immunotherapy in nonsmall-cell lung cancer.

Genome assembly of autotetraploid Actinidia arguta highlights adaptive evolution and enables dissection of important economic traits.

Actinidia arguta, the most widely distributed Actinidia species and the second cultivated species in the genus, can be distinguished from the currently cultivated Actinidia chinensis on the basis of its small and smooth fruit, rapid softening, and excellent cold tolerance. Adaptive evolution of tetraploid Actinidia species and the genetic basis of their important agronomic traits are still unclear. Here, we generated a chromosome-scale genome assembly of an autotetraploid male A. arguta accession. The genome assembly was 2.77 Gb in length with a contig N50 of 9.97 Mb and was anchored onto 116 pseudo-chromosomes. Resequencing and clustering of 101 geographically representative accessions showed that they could be divided into two geographic groups, Southern and Northern, which first diverged 12.9 million years ago. A. arguta underwent two prominent expansions and one demographic bottleneck from the mid-Pleistocene climate transition to the late Pleistocene. Population genomics studies using paleoclimate data enabled us to discern the evolution of the species' adaptation to different historical environments. Three genes (AaCEL1, AaPME1, and AaDOF1) related to flesh softening were identified by multi-omics analysis, and their ability to accelerate flesh softening was verified through transient expression assays. A set of genes that characteristically regulate sexual dimorphism located on the sex chromosome (Chr3) or autosomal chromosomes showed biased expression during stamen or carpel development. This chromosome-level assembly of the autotetraploid A. arguta genome and the genes related to important agronomic traits will facilitate future functional genomics research and improvement of A. arguta.

A case study: Assessing the efficacy of the revised dosage regimen via prediction model for recurrent event rate using biomarker data.

In recently conducted phase III trials in a rare disease area, patients received monthly treatment at a high dose of the drug, which targets to lower a specific biomarker level, closely associated with the efficacy endpoint, to around 10% across patients. Although this high dose demonstrated strong efficacy, treatments were withheld due to the reports of serious adverse events. Dosing in these studies were later resumed at a reduced dosage which targets to lower the biomarker level to 15%-35% across patients. Two questions arose after this disruption. The first is whether the efficacy of this revised regimen as measured by the reduction in annualized event rate is adequate to support the continuation of the development and the second is whether the potential bias due to the loss of patients during this dosing gap process can be gauged. To address these questions, we built a prediction model that quantitatively characterizes biomarker vs. endpoint relationship and predicts efficacy at the 15%-35% range of the biomarker level using the available data from the original high dose. This model predicts favorable event rate in the target biomarker level and shows that the bias due to the loss of patients is limited. These results support the continued development of the revised regimen, however, given the limitation of the data available, this prediction is planned to be validated further when data under the revised regimen become available.

Design and monitoring of clinical trials with an interim analysis and a negative binomial endpoint.

There are very rich publications devoted to group sequential design, adaptive design and trial monitoring for continuous, binary and time to event endpoints. Many authors also discuss fixed design, blinded sample size re-estimation design and group sequential design for studies with a negative binomial outcome. Nonetheless, literature is sparse in adaptive design for a trial with a negative binomial endpoint. The features of such an endpoint in a flexible trial design setting remains inadequately understood. In this research, we seek to bridge this knowledge gap by offering a thorough examination of utilizing data components from a two-stage adaptive design for unblinded conditional power calculation and corresponding sample size re-estimation. We also provide expression for calculating the probability of meeting the futility criterion to determine the appropriate timing for the interim analysis. To evaluate the performance of the design, we conduct simulations to assess its operation characteristics. Finally, we provide a helpful and illustrative example to demonstrate the practical applications of the methods.

The Potential Application of Aloe Barbadensis Mill. as Chinese Medicine for Constipation: Mini-Review.

Aloe barbadensis Mill. has a long history of medicinal use in the annals of traditional Chinese medicine, wherein it has garnered considerable renown. Its multifaceted therapeutic properties, characterized by its anti-inflammatory and antibacterial attributes, alongside its established efficacy as a laxative agent, have been extensively documented. This review commences with an exploration of the nomenclature, fundamental characteristics, and principal constituents of Aloe barbadensis Mill. responsible for its laxative effects. Subsequently, we delve into an extensive examination of the molecular mechanisms underlying Aloe barbadensis Mill.'s laxative properties, types of constipation treatments, commercially available preparations, considerations pertaining to toxicity, and its clinical applications. This review aims to serve as a comprehensive reference point for healthcare professionals and researchers, fostering an enhanced understanding of the optimal utilization of Aloe barbadensis Mill. in the treatment of constipation.

Expression Significance of Estrogen Receptor ER-α36 in Breast Cancer Treated by Chemotherapy: A Meta-Analysis.

Estrogen receptor (ER) is a molecular marker and target for diagnosing and treating breast cancer (BC). ER-α36, a novel estrogen receptor subtype, involved in the proliferation, differentiation, metastasis, and invasion of tumor cells. It is closely linked to the progression of various cancers. Therefore, studying ER is of high significance in treating BC. In this study, we will investigate the changes in the expression level of ER-α36 in patients with BC treated by chemotherapy through meta-analysis, so as to evaluate the clinical value of ER-α36 in the prognosis of BC treated by chemotherapy. English databases such as PubMed, Web of Science, Embase, and The Cochrane Library were searched to retrieve the articles published from the establishment of the database to April 2023. The keywords included chemotherapy, neoadjuvant chemotherapy, breast cancer, estrogen receptor alpha, and ER-α36. Five suitable studies, encompassing 636 patients, were ultimately selected. The meta-analysis results revealed that, following the chemotherapy, the analysis of ER-α36 positive cases yielded an Odds Ratio (OR) of 0.42, a 95% confidence interval (CI) of 0.28-0.64 (Z = 4.00, P < 0.0001). Additionally, the analysis of cases exhibiting remission in BC demonstrated an OR of 2.22 (95% CI = 1.40-3.50, Z = 3.40, P = 0.0007). Compared to patients receiving single chemotherapy agents or those untreated with chemotherapy, the combined use of multiple chemotherapy drugs can significantly reduce the levels of ER-α36 in BC patients, enhancing the remission rate of BC. ER-α36 can serve as a critical indicator for assessing the prognosis of BC following chemotherapy.

Development and validation of a prognostic model for 90-day survival in patients with alcohol-associated cirrhosis and acute decompensation.

BACKGROUND/PURPOSE: Patients with alcohol-associated cirrhosis and acute decompensation are considered critically ill and have a higher risk of short-term mortality. This study aimed to establish a nomogram to evaluate their 90-day survival and identify factors that affect disease progression. METHODS: We included patients from September 2008 to December 2016 (n = 387 in the derivation group) and from January 2017 to August 2020 (n = 157 in the validation group). LASSO regression and Cox multivariate risk regression were used to analyze the influencing factors of the 90-day mortality risk, and a nomogram was constructed. The performance of a model was analyzed based on the C-index, area under the receiver operating curve, calibration curve, and decision curve analysis. RESULTS: Total bilirubin >10 upper limit of normal, high-density lipoprotein cholesterol, lymphocyte and monocyte ratios ≤2.33, white blood cells, and hemoglobin were identified as independent risk factors affecting the 90-day mortality risk of patients and the nomogram was developed. A nomogram demonstrated excellent model predictive accuracy in both the derivation and validation cohorts (C-index: 0.976 and 0.945), which was better than other commonly used liver scoring models (p < 0.05). The nomogram also performed good calibration ability and more clinical net benefit. According to the nomogram score, patients were divided into high- and low-risk groups. Mortality was significantly higher in the high-risk group than in the low-risk group (p < 0.0001). CONCLUSION: The nomogram could accurately predict the 90-day mortality risk in patients with alcohol-associated cirrhosis and acute decompensation, helping to identify high-risk patients and personalize treatment at their first admission.

End Group Engineering for Constructing A-D-A Fused-Ring Photosensitizers with Balanced Phototheranostics Performance.

Phototheranostics continues to flourish in cancer treatment. Due to the competitive relationships between these photophysical processes of fluorescence emission, photothermal conversion, and photodynamic action, it is critical to balance them through subtle photosensitizer designs. Herein, it is provided a useful guideline for constructing A-D-A photosensitizers with superior phototheranostics performance. Various cyanoacetate group-modified end groups containing ester side chains of different length are designed to construct a series of A-D-A photosensitizers (F8CA1 ∼ F8CA4) to study the structure-property relationships. It is surprising to find that the photophysical properties of A-D-A photosensitizers can be precisely regulated by these tiny structural changes. The results reveal that the increase in the steric hindrance of ester side chains has positive impacts on their photothermal conversion capabilities, but adverse impacts on the fluorescence emission and photodynamic activities. Notably, these tiny structural changes lead to their different aggregation behavior. The molecule mechanisms are detailedly explained by theoretical calculations. Finally, F8CA2 nanoparticles with more balanced photophysical properties perform well in fluorescence imaging-guided photothermal and type I&II photodynamic synergistic cancer therapy, even under hypoxic conditions. Therefore, this work provides a novel practicable construction strategy for desired A-D-A photosensitizers.

Mitochondria-Targeting Multimodal Phototheranostics Based on Triphenylphosphonium Cation Modified Amphiphilic Pillararenes and A-D-A Fused-Ring Photosensitizers.

Tumor-targeting phototheranostics has gradually developed as a powerful tool for the precise diagnosis and treatment of cancer. However, the designs of tumor-targeting phototheranostics agents with excellent multimodal phototherapy and fluorescence imaging (FLI) capability, as well as very few components, are still scarce and challenging for cancer treatment. Herein, a mitochondria-targeting multimodal phototheranostics system has been constructed by combining a designed amphiphilic pillararene WP5-2PEG-2TPP and the A-D-A fused-ring photosensitizer F8CA5. WP5-2PEG-2TPP is constructed by attaching the triphenylphosphonium cations to our previously reported dual PEG-functionalized amphiphilic pillararene, which can self-assemble into regular spherical nanocarriers with outstanding mitochondria targeting and water solubility. The A-D-A photosensitizer F8CA5 containing two methyl cyanoacetate group modified end groups displays superior photothermal conversion ability and dual type I/II photodynamic activity as well as strong NIR fluorescence emission. Through their strong union, multifunctional mitochondria-targeting phototheranostics agent F8CA5 NPs were obtained to be applied into FLI-guided synergistic photothermal and type I/II photodynamic therapy. As a result, F8CA5 NPs show good mitochondria-targeting and phototherapy effects in various tumor cells. Not only that, they can combat tumor hypoxia, which hinders the efficacy of photodynamic therapy. Therefore, this work provides a creative ideal for the construction of multifunctional tumor-targeting phototheranostic agents with excellent performance.

Eliminating Ferroelectric Hysteresis in All-Two-Dimensional Gate-Stack Negative-Capacitance Transistors.

Boltzmann distribution thermal tails of carriers restrain the subthreshold swing (SS) of field-effect transistors (FETs) to be lower than 60 mV/decade at room temperature, which restrains the reduction of operate-voltage and power consumption of transistors. The negative-capacitance FET (NC FET) is expected to break through this physical limit and obtain a steep SS by amplifying the gate voltage through the negative capacitance effect of the ferroelectric thin film, providing a new way to further reduce the power consumption of the transistor at the end of Moore's law. Here, we show a MoS2 NC FET with a CuInP2S6 ferroelectric, exhibiting a large on/off ratio of 108, a steep SS as low as 6 mV/decade, and a wide sub-60 mV/decade drain current range of more than 4 orders of magnitude while sacrificially inducing a huge hysteresis larger than 500 mV. Furthermore, we found that by inserting the h-phase boron nitride (h-BN) layer with suitable thickness, the dielectric capacitance matches the ferroelectric negative capacitance better, and thus the hysteresis on the transfer curve is reduced, and the ideal switching-behavior transistors with SS as low as 62 mV/decade and only 5 mV negligible hysteresis were obtained. Our work demonstrates that under the capacitance-matching condition, the hysteresis-free negative-capacitance transistors do not act as the predicted steep-slope transistors, but their voltage-saving still occurs instead as a type of effective transconductance booster with more than 20 times transconductance amplification.

Evaluating the impact of test-trace-isolate for COVID-19 management and alternative strategies.

There are many contrasting results concerning the effectiveness of Test-Trace-Isolate (TTI) strategies in mitigating SARS-CoV-2 spread. To shed light on this debate, we developed a novel static-temporal multiplex network characterizing both the regular (static) and random (temporal) contact patterns of individuals and a SARS-CoV-2 transmission model calibrated with historical COVID-19 epidemiological data. We estimated that the TTI strategy alone could not control the disease spread: assuming R0 = 2.5, the infection attack rate would be reduced by 24.5%. Increased test capacity and improved contact trace efficiency only slightly improved the effectiveness of the TTI. We thus investigated the effectiveness of the TTI strategy when coupled with reactive social distancing policies. Limiting contacts on the temporal contact layer would be insufficient to control an epidemic and contacts on both layers would need to be limited simultaneously. For example, the infection attack rate would be reduced by 68.1% when the reactive distancing policy disconnects 30% and 50% of contacts on static and temporal layers, respectively. Our findings highlight that, to reduce the overall transmission, it is important to limit contacts regardless of their types in addition to identifying infected individuals through contact tracing, given the substantial proportion of asymptomatic and pre-symptomatic SARS-CoV-2 transmission.

Integrating Pillar[5]arene and BODIPY for a Supramolecular Nanoplatform To Achieve Synergistic Photodynamic Therapy and Chemotherapy.

BODIPY photosensitizers have been integrated with a hypoxia-activated prodrug to achieve synergistic photodynamic therapy (PDT) and chemotherapy. A novel BODIPY derivative BDP-CN was designed and synthesized. It had two cyano groups to make it complex well with a water-soluble pillar[5]arene. Their association constant was calculated to be (6.8±0.9)×106  M-1 . After self-assembly in water, regular spherical nanocarriers can be formed; these were used to encapsulate the hypoxia-activated prodrug tirapazamine (TPZ). BDP-CN displayed excellent photodynamic activity to complete PDT. In this process, O2 can be continuously consumed to activate TPZ to allow it to be converted to a benzotriazinyl (BTZ) radical with high cytotoxicity to complete chemotherapy. As a result, the formed nanoparticles showed excellent synergistic photodynamic therapy and chemotherapy efficacy. The synergistic therapy mechanism is discussed in detail.

Full-length transcriptome sequencing and transgenic tobacco revealed the key genes in the chlorogenic acid synthesis pathway of Sambucus chinensis L.

Chlorogenic acid is a key chemical in antioxidation and antisepsis. Sambucus chinensis L. is an herbaceous plant rich in chlorogenic acid and a potential genetic resource for breeding high-chlorogenic acid plants. However, there are few studies on the synthesis pathway of chlorogenic acid in S. chinensis. Our study found chlorogenic acid accumulation in S. chinensis to be organ-specific, higher in leaves and buds but lower in roots, stems and fruits. A total number of 546,844 CCS (circular consensus sequence), including 402,767 full-length nonchimeric (FLNC) and 39 annotated sequences related to the synthesis of chlorogenic acid, was obtained by single-molecule real-time sequencing technology (SMRT). qRT-PCR showed that a number of key genes involved in chlorogenic acid synthesis were differentially expressed in various tissues of S. chinensis. Transgenic tobacco revealed that ectopic expression of the HCT homologous gene HCT-45178 increased the content of chlorogenic acid. Our results should be the first report of full-length transcriptome data of S. chinensis, which help to understand the basis of chlorogenic acid synthesis and provide a novel strategy for breeding tobacco cultivars with higher levels of chlorogenic acid.

A novel 7-chemokine-genes predictive signature for prognosis and therapeutic response in renal clear cell carcinoma.

Background: Renal clear cell carcinoma (ccRCC) is one of the most prevailing type of malignancies, which is affected by chemokines. Chemokines can form a local network to regulate the movement of immune cells and are essential for tumor proliferation and metastasis as well as for the interaction between tumor cells and mesenchymal cells. Establishing a chemokine genes signature to assess prognosis and therapy responsiveness in ccRCC is the goal of this effort. Methods: mRNA sequencing data and clinicopathological data on 526 individuals with ccRCC were gathered from the The Cancer Genome Atlas database for this investigation (263 training group samples and 263 validation group samples). Utilizing the LASSO algorithm in conjunction with univariate Cox analysis, the gene signature was constructed. The Gene Expression Omnibus (GEO) database provided the single cell RNA sequencing (scRNA-seq) data, and the R package "Seurat" was applied to analyze the scRNA-seq data. In addition, the enrichment scores of 28 immune cells in the tumor microenvironment (TME) were calculated using the "ssGSEA" algorithm. In order to develop possible medications for patients with high-risk ccRCC, the "pRRophetic" package is employed. Results: High-risk patients had lower overall survival in this model for predicting prognosis, which was supported by the validation cohort. In both cohorts, it served as an independent prognostic factor. Annotation of the predicted signature's biological function revealed that it was correlated with immune-related pathways, and the riskscore was positively correlated with immune cell infiltration and several immune checkpoints (ICs), including CD47, PDCD1, TIGIT, and LAG-3, while it was negatively correlated with TNFRSF14. The CXCL2, CXCL12, and CX3CL1 genes of this signature were shown to be significantly expressed in monocytes and cancer cells, according to scRNA-seq analysis. Furthermore, the high expression of CD47 in cancer cells suggested us that this could be a promising immune checkpoint. For patients who had high riskscore, we predicted 12 potential medications. Conclusion: Overall, our findings show that a putative 7-chemokine-gene signature might predict a patient's prognosis for ccRCC and reflect the disease's complicated immunological environment. Additionally, it offers suggestions on how to treat ccRCC using precision treatment and focused risk assessment.

Photobiomodulation provides neuroprotection through regulating mitochondrial fission imbalance in the subacute phase of spinal cord injury.

Increasing evidence indicates that mitochondrial fission imbalance plays an important role in delayed neuronal cell death. Our previous study found that photobiomodulation improved the motor function of rats with spinal cord injury. However, the precise mechanism remains unclear. To investigate the effect of photobiomodulation on mitochondrial fission imbalance after spinal cord injury, in this study, we treated rat models of spinal cord injury with 60-minute photobiomodulation (810 nm, 150 mW) every day for 14 consecutive days. Transmission electron microscopy results confirmed the swollen and fragmented alterations of mitochondrial morphology in neurons in acute (1 day) and subacute (7 and 14 days) phases. Photobiomodulation alleviated mitochondrial fission imbalance in spinal cord tissue in the subacute phase, reduced neuronal cell death, and improved rat posterior limb motor function in a time-dependent manner. These findings suggest that photobiomodulation targets neuronal mitochondria, alleviates mitochondrial fission imbalance-induced neuronal apoptosis, and thereby promotes the motor function recovery of rats with spinal cord injury.

Utilization of treatment effect on a surrogate endpoint for planning a study to evaluate treatment effect on a final endpoint.

To design a phase III study with a final endpoint and calculate the required sample size for the desired probability of success, we need a good estimate of the treatment effect on the endpoint. It is prudent to fully utilize all available information including the historical and phase II information of the treatment as well as external data of the other treatments. It is not uncommon that a phase II study may use a surrogate endpoint as the primary endpoint and has no or limited data for the final endpoint. On the other hand, external information from the other studies for the other treatments on the surrogate and final endpoints may be available to establish a relationship between the treatment effects on the two endpoints. Through this relationship, making full use of the surrogate information may enhance the estimate of the treatment effect on the final endpoint. In this research, we propose a bivariate Bayesian analysis approach to comprehensively deal with the problem. A dynamic borrowing approach is considered to regulate the amount of historical data and surrogate information borrowing based on the level of consistency. A much simpler frequentist method is also discussed. Simulations are conducted to compare the performances of different approaches. An example is used to illustrate the applications of the methods.

LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway.

LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients' tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.