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Circular RNAs (circRNAs) are a class of RNA molecules with closed loops and high stability. CircRNAs are abundantly expressed in eukaryotic organisms and exhibit both location- and step-specificity. In recent years, circRNAs are attracting considerable research attention attributed to their possible contributions to gene regulation through a variety of actions, including sponging microRNAs, interacting with RNA-binding proteins, regulating transcription and splicing, and protein translation. Growing evidence has revealed that circRNAs play critical roles in the development and progression of diseases, especially in cancers. Without doubt, expanding our understanding of circRNAs will enrich knowledge of cancer and provide new opportunities for cancer therapy. In this review, we provide an overview of the characteristics, functions and functional mechanisms of circRNAs. In particular, we summarize current knowledge regarding the functions of circRNAs in the hallmarks, stemness, resistance of cancer, as well as the possibility of circRNAs as biomarkers in cancer.

Multiple SARS-CoV-2 variants of concern (VOCs) have been emerging and some have been linked to an increase in case numbers globally. However, there is yet a lack of understanding of the molecular basis for the interactions between the human ACE2 (hACE2) receptor and these VOCs. Here we examined several VOCs including Alpha, Beta, and Gamma, and demonstrate that five variants receptor-binding domain (RBD) increased binding affinity for hACE2, and four variants pseudoviruses increased entry into susceptible cells. Crystal structures of hACE2-RBD complexes help identify the key residues facilitating changes in hACE2 binding affinity. Additionally, soluble hACE2 protein efficiently prevent most of the variants pseudoviruses. Our findings provide important molecular information and may help the development of novel therapeutic and prophylactic agents targeting these emerging mutants. The SARS-CoV-2 spike (S) protein mediates viral entry by binding of its receptor-binding domain (RBD) to the human angiotensin-converting enzyme 2 (ACE2) receptor and mutations of the S protein may have a great impact on virus transmissibility. Here, the authors characterize the interactions of six different SARS-CoV-2 RBD variants among them Alpha, Beta and Gamma and present crystal structures of these ACE2-RBD complexes.

The benefits of secondary cytoreduction for platinum-sensitive relapsed ovarian cancer are still widely debated. We aimed to assess the efficacy of secondary cytoreduction plus chemotherapy versus chemotherapy alone in this patient population. This multicentre, open-label, randomised, controlled, phase 3 trial (SOC-1), was done in four primarily academic centres in China (two in Shanghai, one in Hangzhou, and one in Guangzhou). Eligible patients were women aged 18 years and older with platinum-sensitive relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months after the end of first-line platinum-based chemotherapy and were predicted to have potentially resectable disease according to the international model (iMODEL) score and PET-CT imaging. iMODEL score was calculated using six variables: International Federation of Gynecology and Obstetrics stage, residual disease after primary surgery, platinum-free interval, Eastern Cooperative Oncology Group performance status, serum level of cancer antigen 125 at recurrence, and presence of ascites at recurrence. An iMODEL score of 4·7 or lower predicted a potentially complete resection. As per a protocol amendment, patients with an iMODEL score of more than 4·7 could only be included if the serum level of cancer antigen 125 was more than 105 U/mL, but the principal investigators assessed the disease to be resectable by PET-CT. Eligible participants were randomly assigned (1:1) via a permuted block design (block size of six) and stratified by study centre, iMODEL score, residual disease at primary surgery, and enrolment in the Shanghai Gynecologic Oncology Group SUNNY trial, to undergo secondary cytoreductive surgery followed by intravenous chemotherapy (six 3-weekly cycles of intravenous paclitaxel [175 mg/m2] or docetaxel [75 mg/m2] combined with intravenous carboplatin [area under the curve of 5 mg/mL per min]; surgery group) or intravenous chemotherapy alone (no surgery group). Primary endpoints were progression-free survival and overall survival, analysed in all participants randomly assigned to treatment, regardless of treatment received (intention-to-treat [ITT] population). Here, we report the final analysis of progression-free survival and the prespecified interim analysis of overall survival. Safety was assessed in all participants who received their assigned treatment and had available adverse event data. This study is registered with ClinicalTrials.gov, NCT01611766, and is ongoing but closed to accrual. Between July 19, 2012, and June 3, 2019, 357 patients were recruited and randomly assigned to the surgery group (182) or the no surgery group (175; ITT population). Median follow-up was 36·0 months (IQR 18·1–58·3). In the no surgery group, 11 (6%) of 175 participants had secondary cytoreduction during second-line therapy while 48 (37%) of 130 participants who had disease progression crossed-over and had surgery at a subsequent recurrence. Median progression-free survival was 17·4 months (95% CI 15·0–19·8) in the surgery group and 11·9 months (10·0–13·8) in the no surgery group (hazard ratio [HR] 0·58; 95% CI 0·45–0·74; p<0·0001). At the interim overall survival analysis, median overall survival was 58·1 months (95% CI not estimable to not estimable) in the surgery group and 53·9 months (42·2–65·5) in the no surgery group (HR 0·82, 95% CI 0·57–1·19). In the safety population, nine (5%) of 172 patients in the surgery group had grade 3–4 surgical morbidity at 30 days, and no patients in either group had died at 60 days after receiving assigned treatment. The most common grade 3–4 adverse events during chemotherapy were neutropenia (29 [17%] of 166 patients in the surgery group vs 19 [12%] of 156 patients in the no surgery group), leucopenia (14 [8%] vs eight [5%]), and anaemia (ten [6%] vs nine [6%]). Four serious adverse events occurred, all in the surgery group. No treatment-related deaths occurred in either group. Secondary cytoreduction followed by chemotherapy was associated with significantly longer progression-free survival than was chemotherapy alone in patients with platinum-sensitive relapsed ovarian cancer, and patients should be counselled about the option of secondary cytoreduction in specialised centres. Long-term survival outcomes will be assessed using mature data on overall survival. Zhongshan Development Program. For the Chinese translation of the abstract see Supplementary Materials section.

Background Genome-scale phylogenetic analysis based on core gene sets is routinely used in microbiological research. However, the techniques are still not approachable for individuals with little bioinformatics experience. Here, we present EasyCGTree, a user-friendly and cross-platform pipeline to reconstruct genome-scale maximum-likehood (ML) phylogenetic tree using supermatrix (SM) and supertree (ST) approaches. Results EasyCGTree was implemented in Perl programming languages and was built using a collection of published reputable programs. All the programs were precompiled as standalone executable files and contained in the EasyCGTree package. It can run after installing Perl language environment. Several profile hidden Markov models (HMMs) of core gene sets were prepared in advance to construct a profile HMM database (PHD) that was enclosed in the package and available for homolog searching. Customized gene sets can also be used to build profile HMM and added to the PHD via EasyCGTree. Taking 43 genomes of the genus Paracoccus as the testing data set, consensus (a variant of the typical SM), SM, and ST trees were inferred via EasyCGTree successfully, and the SM trees were compared with those inferred via the pipelines UBCG and bcgTree, using the metrics of cophenetic correlation coefficients (CCC) and Robinson–Foulds distance (topological distance). The results suggested that EasyCGTree can infer SM trees with nearly identical topology (distance < 0.1) and accuracy (CCC > 0.99) to those of trees inferred with the two pipelines. Conclusions EasyCGTree is an all-in-one automatic pipeline from input data to phylogenomic tree with guaranteed accuracy, and is much easier to install and use than the reference pipelines. In addition, ST is implemented in EasyCGTree conveniently and can be used to explore prokaryotic evolutionary signals from a different perspective. The EasyCGTree version 4 is freely available for Linux and Windows users at Github ( https://github.com/zdf1987/EasyCGTree4 ).

Background Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and tumor recurrence and metastasis are major factors that contribute to the poor outcome of patients with HCC. Long noncoding RNAs (lncRNAs) are known to regulate different tumorigenic processes, and a growing body of evidence indicates that Hippo kinase signaling is inactivated in many cancers. However, the upstream lncRNA regulators of Hippo kinase signaling in HCC are poorly understood. Methods Using a lncRNA microarray, we identified a novel lncRNA, uc.134, whose expression was significantly decreased in the highly aggressive HCC cell line HCCLM3 compared with MHCC97L cells. Furthermore, we evaluated uc.134 expression in clinical samples using in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The full-length transcript of uc.134 was confirmed using rapid amplification of cDNA ends (RACE) analyses. To investigate the biological function of uc.134, we performed gain-of-function and loss-of-function studies both in vitro and in vivo. The underlying mechanisms of uc.134 in HCC were investigated using RNA pulldown, RNA immunoprecipitation, ubiquitination assays, Western blotting, mRNA microarray analyses, and qRT-PCR analyses. Results The ISH assay revealed that uc.134 expression was significantly decreased in 170 paraffin-embedded samples from patients with HCC compared with adjacent tissues and uc.134 expression directly correlated with patient prognosis. Furthermore, we defined a 1867-bp full-length transcript of uc.134 using 5′- and 3′-RACE analysis. The overexpression of uc.134 inhibited HCC cell proliferation, invasion, and metastasis in vitro and in vivo, whereas the knockdown of uc.134 produced the opposite results. Furthermore, we confirmed that uc.134 (1408–1867 nt) binds to CUL4A (592–759 aa region) and inhibits its nuclear export. Moreover, we demonstrated that uc.134 inhibits the CUL4A-mediated ubiquitination of LATS1 and increases YAP S127 phosphorylation to silence the target genes of YAP. Finally, a positive correlation between uc.134, LATS1, and pYAP S127 was confirmed in 90 paraffin-embedded samples by ISH and immunohistochemical staining. Conclusions Our study identifies that a novel lncRNA, uc.134, represses hepatocellular carcinoma progression by inhibiting the CUL4A-mediated ubiquitination of LATS1 and increasing YAP S127 phosphorylation. The use of this lncRNA may offer a promising treatment approach by inhibiting YAP and activating Hippo kinase signaling.

Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is rare and often misdiagnosed as clear cell renal cell carcinoma (ccRCC). Therefore, a CT-based scoring system was developed to improve differential diagnosis. Retrospectively, 25 ESC-RCC and 176 ccRCC cases, were collected. The two groups were matched on a 1:2 basis using the propensity-score-matching (PSM) method, with matching factors including sex and age. Finally, 25 ESC-RCC and 50 ccRCC cases were included and randomly divided into a training cohort (52 cases) and a validation cohort (23 cases). Logistic regression identified significant factors, constructed the primary model, and assigned weights for the scoring model. Diagnostic performance was compared using receiver operating characteristic curves, dividing points into three intervals. Multifactorial logistic regression identified three independent factors: intra-tumour necrosis (3 points), degree of corticomedullary phase (CMP) enhancement (3 points), and pseudocapsule (2 points). The primary model’s area under the curve (AUC) value was 0.954 (95% confidence interval [CI]: 0.857–0.993, P  < 0.001), with 85.7% sensitivity and 94.1% specificity. The scoring model’s AUC value for the training cohort was 0.950 (95% CI: 0.852–0.991, P  < 0.001), with 77.1% sensitivity and 100% specificity at a cut-off of 4 points. The validation cohort’s AUC was 0.942 (95% CI: 0.759–0.997, P  < 0.001). The scoring system intervals were: ≥0 to < 2 points, ≥ 2 to ≤ 3 points, and > 3 to ≤ 8 points. Higher scores correlated with increased ccRCC incidence and decreased ESC-RCC incidence.The limitation of this study is the small sample size. A CT-based scoring system effectively differentiates ESC-RCC from ccRCC.

SARS-CoV-2 can infect many domestic animals, including dogs. Herein, we show that dog angiotensin-converting enzyme 2 (dACE2) can bind to the SARS-CoV-2 spike (S) protein receptor binding domain (RBD), and that both pseudotyped and authentic SARS-CoV-2 can infect dACE2-expressing cells. We solved the crystal structure of RBD in complex with dACE2 and found that the total number of contact residues, contact atoms, hydrogen bonds and salt bridges at the binding interface in this complex are slightly fewer than those in the complex of the RBD and human ACE2 (hACE2). This result is consistent with the fact that the binding affinity of RBD to dACE2 is lower than that of hACE2. We further show that a few important mutations in the RBD binding interface play a pivotal role in the binding affinity of RBD to both dACE2 and hACE2. Our work reveals a molecular basis for cross-species transmission and potential animal spread of SARS-CoV-2, and provides new clues to block the potential transmission chains of this virus. Many domestic animals, among them dogs, have been infected with SARS-CoV-2 during the COVID-19 pandemic. Here, the authors present the crystal structure of the SARS-CoV-2 spike protein receptor binding domain (RBD) bound to its receptor, dog angiotensin-converting enzyme 2 (dACE2), and show that the RBD N501Y mutation increases the infectivity and host range of SARS-CoV-2, which highlights the need to monitor emerging SARS-CoV-2 mutations in domestic animals.

Natural deep eutectic solvents (NADESs) coupled with microwave-assisted extraction (MAE) were applied to extract total flavonoid compounds from spent sweet potato (Ipomoea batatas L.) leaves. In this study, ten different NADESs were successfully synthesized for the MAE. Based on single-factor experiments, the response surface methodology (RSM) was applied, and the microwave power, extraction temperature, extraction time, and solid–liquid ratio were further evaluated in order to optimize the yields of total flavonoid compounds. Besides, the extracts were recovered by macroporous resin for the biological activity detection of flavonoid compounds. As a result, NADES-2, synthesized by choline chloride and malic acid (molar ratio 1:2), exhibited the highest extraction yield. After that, the NADES-2-based MAE process was optimized and the optimal conditions were as follows: microwave power of 470 W, extraction temperature of 54 °C, extraction time of 21 min, and solid–liquid ratio of 70 mg/mL. The extraction yield (40.21 ± 0.23 mg rutin equivalents/g sweet potato leaves) of the model validation experiment was demonstrated to be in accordance with the predicted value (40.49 mg rutin equivalents/g sweet potato leaves). In addition, flavonoid compounds were efficiently recovered from NADES-extracts with a high recovery yield (>85%) using AB-8 macroporous resin. The bioactivity experiments in vitro confirmed that total flavonoid compounds had good DPPH and O2−· radical-scavenging activity, as well as inhibitory effects on E. coli, S. aureus, E. carotovora, and B. subtilis. In conclusion, this study provides a green and efficient method to extract flavonoid compounds from spent sweet potato leaves, providing technical support for the development and utilization of sweet potato leaves’ waste.

Background and aimsCompared with tyrosine kinase inhibitor (TKI) monotherapy, TKI combined with PD1 can improve the therapeutic effect of liver cancer and has been widely used in clinical practice. However, there is a lack of effective biomarkers to identify patients who would benefit more from this combination therapy. Therefore, this study aimed to evaluate whether baseline lymphocyte counts can identify patients with liver cancer who would benefit from targeted immune combination therapy.MethodsData from patients with hepatocellular carcinoma (HCC) who received TKIs or TKIs in combination with PD1 between June 2018 and June 2020 were retrospectively collected. The patients were divided into high and low groups based on the median absolute count of peripheral lymphocytes before systemic therapy and differences in overall survival (OS) and progression-free survival (PFS) between TKI and TKI+PD1 were compared between the two groups.ResultsIn total, 72 patients were included in this study, with a median follow-up of 1.5 years. Both PFS and OS in the TKI+PD1 group showed a good prognostic trend (p = 0.058 and p = 0.077, respectively). Subgroup analyses based on peripheral blood lymphocyte counts showed that the combination regimen had a significant PFS and OS advantage only in patients with high peripheral blood lymphocyte counts (p = 0.036 and p = 0.031, respectively), but not in patients with low absolute peripheral blood lymphocyte counts (p = 0.819 and p = 0.913, respectively).ConclusionsPeripheral blood lymphocyte count is a simple and effective biomarker that can be used to identify patients with liver cancer who will benefit more from TKI+PD-1 combination therapy.

Genetic variance is vital for breeding programs and mutant screening, yet traditional mutagenesis methods wrestle with genetic redundancy and a lack of specificity in gene targeting. CRISPR-Cas9 offers precise, site-specific gene editing, but its application in crop improvement has been limited by scalability challenges. In this study, we develop genome-wide multi-targeted CRISPR libraries in tomato, enhancing the scalability of CRISPR gene editing in crops and addressing the challenges of redundancy while maintaining its precision. We design 15,804 unique single guide RNAs (sgRNAs), each targeting multiple genes within the same gene families. These sgRNAs are classified into 10 sub-libraries based on gene function. We generate approximately 1300 independent CRISPR lines and successfully identify mutants with distinct phenotypes related to fruit development, fruit flavor, nutrient uptake, and pathogen response. Additionally, we develop CRISPR-GuideMap, a double-barcode tagging system to enable large-scale sgRNA tracking in generated plants. Our results demonstrate that multi-targeted CRISPR libraries are scalable and effective for large-scale gene editing and offer an approach to overcome gene functional redundancy in basic plant research and crop breeding. Genetic variance is vital for breeding programs and mutant screening, yet traditional mutagenesis methods wrestle with genetic redundancy and a lack of specificity in gene targeting. Here the authors develop a scalable CRISPR system in tomato to edit multiple genes at once, overcoming genetic redundancy and revealing new traits related to fruit quality, nutrient use, and disease resistance.