Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Pd/IPrBIDEA-Catalyzed Hydrodefluorination of gem-Difluorocyclopropanes: Regioselective Synthesis of Terminal Fluoroalkenes.

Developing new strategies to enable chemo- and regioselective reductions is an important topic in chemical research. Herein, an efficient and regioselective Pd/IPrBIDEA-catalyzed ring-opening hydrodefluorination of gem-difluorocyclopropanes to access terminal fluoroalkenes is developed. The success of this transformation was attributed to the use of 3,3-dimethylallyl Bpin as a novel hydride donor. DFT calculations suggest that a direct 3,4'-hydride transfer via a 9-membered cyclic transition state is more favorable, which combined with the irreversibility of the reaction enables the unusual selectivity for the less thermodynamically stable terminal alkene isomer. This reaction mode is also applicable to a variety of regioselective allylic and propargyl reductions.

SMNN: batch effect correction for single-cell RNA-seq data via supervised mutual nearest neighbor detection.

Batch effect correction has been recognized to be indispensable when integrating single-cell RNA sequencing (scRNA-seq) data from multiple batches. State-of-the-art methods ignore single-cell cluster label information, but such information can improve the effectiveness of batch effect correction, particularly under realistic scenarios where biological differences are not orthogonal to batch effects. To address this issue, we propose SMNN for batch effect correction of scRNA-seq data via supervised mutual nearest neighbor detection. Our extensive evaluations in simulated and real datasets show that SMNN provides improved merging within the corresponding cell types across batches, leading to reduced differentiation across batches over MNN, Seurat v3 and LIGER. Furthermore, SMNN retains more cell-type-specific features, partially manifested by differentially expressed genes identified between cell types after SMNN correction being biologically more relevant, with precision improving by up to 841.0%.

Pd-IHept-Catalyzed Ring-Opening of gem-Difluorocyclopropanes with Malonates Via Selective C-C Bond Cleavage: Synthesis of Monofluoroalkenes.

Monofluoroalkene scaffolds are frequently found in various functional molecules. Herein, we report a Pd-IHept-catalyzed (NHC = N-heterocyclic carbene) defluorinative functionalization approach for the synthesis of monofluoroalkenes from gem-difluorocyclopropanes and malonates. The flexible yet sterically hindered N,N'-bis(2,6-di(4-heptyl)phenyl)imidazol-2-ylidene ligand plays a key role in ensuring the high reaction efficiency. In addition, sterically hindered 1,1- and 1,2-disubstituted gem-difluorocyclopropanes could also be used in this transformation.

Hysteroscopic Fenestration with Precise Incision of the Cavity Septum: A Novel Minimally Invasive Surgery of Complete Septate Uterus with Double Cervix.

STUDY OBJECTIVE: This study aimed to develop and describe a novel surgical procedure that involves hysteroscopic fenestration with precise incision of the complete uterine septum and double cervix preservation after magnetic resonance imaging (MRI) evaluation in patients and to evaluate its efficacy. DESIGN: A prospective consecutive clinical study. SETTING: A university teaching hospital. PATIENTS: Twenty-four patients with complete septate uterus and double cervix. INTERVENTIONS: Three-dimensional reconstruction of uterus was performed with pelvic MRI and three-dimensional SPACE sequence scanning. Hysteroscopic fenestration with precise incision of the cavity septum and double cervix preservation was performed in patients. Three months after operation, follow-up pelvic MRI and second-look hysteroscopy were performed conventionally. MEASUREMENTS AND MAIN RESULTS: Operating time, blood loss, operative complications, MRI and hysteroscopic changes of uterus, symptoms improvement, and reproductive outcomes were assessed. The surgery was successfully completed without any intraoperative complications in all patients. Operating time was 21.71 ± 8.28 minutes (range, 10-40 minutes) and blood loss was 9.92 ± 7.14 mL (range, 5-30 mL). Postoperative MRI showed the uterine anteroposterior diameter (3.66 cm vs 3.92 cm; p <.05) was increased. Postoperative MRI and the second-look hysteroscopy showed the cavity shape and uterine volume were expanded to the normal. Symptoms of dysmenorrhea, abnormal uterine bleeding, and dyspareunia were ameliorated after the surgery in 70% of patients (7 of 10), 60% of patients (3 of 5), and 1 patient, respectively. The preoperative spontaneous abortion rate was 80% (4 of 5) and the postoperative spontaneous abortion rate was 11.11% (1 of 9). After the surgery, there were 2 ongoing pregnancies and 6 pregnancies ended in term births. Two live births were delivered by cesarean section and 4 by vaginal delivery without cervical incompetence during pregnancy. CONCLUSIONS: Hysteroscopic fenestration with precise incision of the uterine septum and double cervix preservation is an effective surgical procedure.

Chemo-, Stereo- and Regioselective Fluoroallylation/Annulation of Hydrazones with gem-Difluorocyclopropanes via Tunable Palladium/NHC Catalysis.

Defluorinative manipulation of polyfluorinated molecules has shown great promise due to its granting of synthetic versatility to inert C-F bonds. The development of chemo-, stereo- and regioselective strategies to realize highly efficient formation of either the linear/branched or E/Z products from gem-difluorocyclopropanes (gem-F2 CPs) is a challenging task. Herein, we have realized palladium/NHC-catalyzed fluoroallylation/annulation of hydrazones with gem-F2 CPs that incorporate the hydrazone N2 moiety into the products. The thermodynamically unstable fluorinated E-allylation products with aryl ketone hydrazones were obtained for the first time, while the di-alkyl ketone hydrazones yielded the monofluorinated products with branched selectivity under similar reaction conditions. With aldehyde hydrazones, two kinds of pyrazoles were obtained via a defluorinative allylation/annulation cascade, in which different carbon atoms of gem-F2 CPs could be incorporated into the pyrazole rings regiospecifically. DFT calculations revealed that the divergent selectivity was kinetically controlled and the final C-C bond formation proceeded through a 7-membered TS.

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

MEG3 interacted with miR-494 to repress bladder cancer progression through targeting PTEN.

The long noncoding RNA MEG3 is a significant tumor-suppressive gene in various tumors. But its biological role in bladder cancer remains uninvestigated. Herein, the biological mechanism of MEG3 in bladder cancer pathogenesis was explored. First, the expression of MEG3 in bladder cancer cells was examined, and we found that it was significantly reduced. In addition, in bladder cancer cells, we observed htat miR-494 was increased. Then, MEG3 was overexpressed in UMUC3 and SW780 cells and it could negatively modulate miR-494 expression. Bladder cancer cell proliferation was repressed, cell apoptosis was triggered and meanwhile, the cell cycle was remarkably arrested by the overexpression of MEG3. Moreover, the increase of MEG3 suppressed bladder cancer cell migration and invasion capacity. MEG3 can sponge miR-494 and the binding sites between them were confirmed by carrying out a series of functional assays. Furthermore, PTEN was speculated as a putative target of miR-494. Meanwhile, we found that miR-494 inhibitors induced PTEN. Finally, in vivo assays were conducted to prove that MEG3 can restrain bladder tumor growth by modulating miR-494 and PTEN. In conclusion, it was suggested MEG3 can interact with miR-494 to regulate PTEN in bladder cancer development.

Analysis of the reproductive outcomes and the size of the unicornuate uterus measured by magnetic resonance imaging and their relationship.

PURPOSE: To evaluate the relationship between the uterine size measured by pelvic magnetic resonance and reproductive outcome in women with a unicornuate uterus. METHODS: This was a retrospective study including 140 patients affiliated with unicornuate uterus diagnosed by the pelvic MR prior to their first pregnancy in the Obstetrics and Gynecology Hospital of Fudan University from April 2010 to December 2017. All the length of the unicornuate uterus were re-measured and recorded by skilled radiologists during the study period. We divided all the 140 participants with complete pelvic MR imaging into four groups by the best reproductive outcomes, which refers to Group 1 (primary infertility, n = 21), Group 2 ( < 24 weeks' gestation, n = 34), Group 3 (preterm delivery, 24-35 weeks' gestation, n = 13), Group 4 ( ≥ 35 weeks' gestation, n = 72), followed them up and then analyzed the data. RESULTS: Measurements of 140 patients with hemi-uteri were retrieved for analysis. The mean length of the uterine was 4.90  ± 0.56 cm. There were no significant differences in the uterine cavity length, cervical length, endometrial thickness and uterine wall thickness between the four groups while the uterine length (P = 0.001) was statistically significant. Women with uterine lengths ≥  4.5 cm were more likely to experience full-term delivery compared with the other group (P = 0.001). Ordinal multiple logistic regression analysis showed that the uterine length [OR = 9.03 (95% CI: 2.90-28.13)] and uterine cavity length [OR = 0.32 (95% CI: 0.06-2.04)] were independent protective factors for better obstetric outcomes CONCLUSION: The uterine length is a reliable prognostic factor for the gestational week of delivery and an appropriate antenatal surveillance factor of women with unicornuate uterus.

Certain BCG-reactive responses are associated with bladder cancer prognosis.

A subset of bladder patients does not respond to BCG treatment effectively and the underlying reason behind this observation is currently unclear. CD4+ T cells are composed of various subsets that each expresses a distinctive set of cytokines and can potently shift the immune response toward various directions. In this study, we examined the CD4+ T-cell cytokine response in bladder cancer patients toward BCG stimulation. We found that bladder cancer patients presented a variety of responses toward BCG, with no uniform characteristics. Those patients with high IFN-γ and IL-21 expression in CD4+ T cells presented significantly better prognosis than patients with low cytokine secretion in CD4+ T cells. Tumor-infiltrating CD4+ T cells were significantly less potent in expressing IFN-γ, IL-4, and IL-17, and more potent in expressing IL-10 than circulating CD4+ T cells. In addition, we found no difference in CD80, CD86, or MHC II expression by macrophages from patients with different IFN-γ and IL-21 levels. However, the secretion of IL-12, a Th1-skewing cytokine, was released at significantly higher level by macrophages from patients with high IFN-γ or high IL-21 secretion. We also identified that modulating monocytes/macrophages by GM-CSF-mediated polarization resulted in significantly elevated expression of IFN-γ and IL-21 from CD4+ T cells. Overall, these results suggested that the specific types of responses mounted by CD4+ T cells were critical to the final outcome of bladder cancer patients and can be influenced by monocyte/macrophage polarization.

Downregulation of miR-193a-3p inhibits cell growth and migration in renal cell carcinoma by targeting PTEN.

Although miR-193a-3p has been found to be dysregulated in variety of human tumors, little is known about its role in renal cell carcinoma. This study was designed to investigate the function and underlying mechanism of miR-193a-3p in human renal cell carcinoma tissues and cell lines. Here, we demonstrated that the expression of miR-193-3p was increased in renal cell carcinoma tissues and cell lines. In addition, knockdown of miR-193a-3p significantly inhibited cell proliferation and colony formation and induced cells into G1 phase arrest. Meanwhile, the migration potential of 786-O cells was also decreased compared to control group. Furthermore, we identified PTEN as a direct and functional target of miR-193a-3p, at least partly responsible for promoting tumor effect of miR-193a-3p in renal cell carcinoma. Taken together, the findings indicated for the first time that miR-193a-3p functions as a tumor-promoting microRNA by directly targeting PTEN in renal cell carcinoma.

Role of microRNA-27a in down-regulation of angiogenic factor AGGF1 under hypoxia associated with high-grade bladder urothelial carcinoma.

Hypoxia stimulates angiogenesis under a variety of pathological conditions, including malignant tumors by inducing expression of angiogenic factors such as VEGFA. Surprisingly, here we report significant association between down-regulation of a new angiogenic factor AGGF1 and high-grade urothelial carcinoma. The proportion of strong AGGF1 expression cases was significantly lower in the high-grade urothelial carcinoma group than that in the low-grade urothelial carcinoma group (P=1.40×10(-5)) or than that in the normal urothelium tissue group (P=2.11×10(-4)). We hypothesized that tumor hypoxia was responsible for differential expression of the AGGF1 protein in low- and high-grade urothelial carcinomas, and therefore investigated the molecular regulatory mechanism for AGGF1 expression under hypoxia. Under hypoxic conditions, AGGF1 protein levels declined without any change in mRNA levels and protein stability. Hypoxia-induced down-regulation of AGGF1 was mediated by miR-27a. Overexpression of miR-27a suppressed AGGF1 expression through translational inhibition, but not by RNA degradation. Moreover, the hypoxia-induced decrease of AGGF1 expression disappeared after miR-27a expression was inhibited. Furthermore, down-regulation of AGGF1 reduced hypoxia-induced apoptosis in cancer cells. Taken together, the results of this study indicate that (1) hypoxia down-regulates expression of the AGGF1 protein, but not AGGF1 mRNA, by inducing expression of miR-27a; (2) Down-regulation of AGGF1 had an apparent protective role for cancer cells under hypoxia; (3) Down-regulation of the AGGF1 protein confers a significant risk of high-grade human urothelial bladder carcinoma.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

The growth and shape of the eyeball and crystalline lens in utero documented by fetal MR imaging.

Purpose: To study the growth model, shape, and developmental relationship of lens and eyeball, we used two-dimensional Magnetic Resonance (MR) imaging to investigate gestationally age-related changes in the selected ocular parameters in vivo. Materials and methods: We retrospectively reviewed the MR images from 126 fetuses ranging from 21 to 39 weeks' gestation. Ocular parameters on MR imaging of transverse plane were measured including lens diameter (LD), anteroposterior lens diameter (APLD), lens surface area (LS), globe diameter (GD), anteroposterior globe diameter (APGD), globe surface area (GS). The growth model of each biometric against gestational age (GA), aspect ratio of lens and globe (LD/APLD and GD/APGD), and growing relationship between the ratio of lens and globe surface area (LS/GS) were studied by statistical analysis. Results: The growth model of most biometry for gestational age is logarithmic, except for the diameter of the ocular globe (GD and APGD) showing a quadratic growth pattern. Our study showed that the lens was consistently larger in the transverse than the anteroposterior diameters during 21-39 weeks(P < 0.001). Besides, the ratio of surface area (LS/GS) was not significantly changing with GA(P = 0.4908), while the increase of LS was significantly accorded with that of GS(P < 0.001). Conclusion: The lens shape throughout fetal life may take part in the process, shape changing from vertical ellipsoid, spherical to transversal ellipsoid, based on the logarithmically increased ratio of lens transverse and anteroposterior diameters. In the meanwhile, the aspect ratio of eyeball in late fetal life may imply a gradually spherical shape during gestation. Nomogram data from this study may provide appropriate information about morphological changes in the fetal lens and the synchronous relationship between lens and eyeball.

The Effects of circ_000558/miR-1225-5p/ARL4C on Regulating the Proliferation of Renal Cell Carcinoma Cells.

Renal cell carcinoma (RCC) is one of the top ten tumors over the world. RCC is not sensitive to radiotherapy and chemotherapy. Therefore, it is necessary to find new targets for the treatment. CircRNAs are a special type of noncoding RNAs, which play important roles in many types of cancer. In this study, we found circ_000558 was upregulated in RCC cells, and it elevated the proliferation ability of RCC cells. The relationship between miR-1225-5p and circ_000558 or ARL4C was predicted via circBank and circular RNA interactome and confirmed by dual-luciferase reporter assay. Then, the effects of circ_000558/miR-1225-5p/ARL4C on RCC cell proliferation and apoptosis were assessed by CCK-8 assay. The results revealed that the knockdown of ARL4C significantly reduced RCC cell proliferation and overexpression of circ_000558 could significantly induce RCC cell proliferation after miR-1225-5p treatment further promoted the inhibitory ability of ARL4C knockdown. Overall, our study suggested that circ_000558/miR-1225-5p/ARL4C network was related to the RCC cell proliferation. This finding could provide new targets for the treatment and prognosis of RCC.

Transient Receptor Potential Channel 1 Potentially Serves as a Biomarker Indicating T/TNM Stages and Predicting Long-Term Prognosis in Patients With Renal Cell Carcinoma.

Background: Transient receptor potential channel 1 (TRPC1) regulates the progression of several cancers, but its clinical implication in renal cell carcinoma (RCC) has not been explored yet. This study aimed to investigate the correlation of TRPC1 with clinical characteristics and prognosis in patients with RCC. Methods: Totally, 177 patients with primary RCC who received surgical resection were retrospectively screened. Their tumor and paired adjacent tissue specimens were retrieved to assess TRPC1 mRNA expression using RT-qPCR and TRPC1 protein expression using immunohistochemistry (IHC). Results: Both TRPC1 IHC score and TRPC1 mRNA expression were elevated in RCC tissue than in adjacent tissue (both P < 0.001). Meanwhile, both TRPC1 IHC score and TRPC1 mRNA expression in tumor were associated with higher T stage (both P = 0.02) and TNM stage (P = 0.009, P = 0.003, respectively). However, no correlation was found in tumor TRPC1 IHC score or TRPC1 mRNA expression with other tumor properties (all P > 0.05). Besides, the 3-, 5-, and 7-year overall survival (OS) were 81.4, 68.6, and 60.2%, respectively in patients with high tumor TRPC1 protein, while they were 89.3, 82.7, and 76.7%, respectively in patients with low tumor TRPC1 protein. High (vs. low) TRPC1 protein in the tumor was associated with shorter OS (P = 0.017), while high (vs. low) TRPC1 mRNA in the tumor was not correlated with OS (P = 0.144). By the forward stepwise method, TRPC1 protein expression independently predicted poor OS (P = 0.01, hazard ratio = 2.052). Conclusion: TRPC1 serves as a potential biomarker reflecting tumor features and long-term survival profile in patients with RCC.

CTSV (cathepsin V) promotes bladder cancer progression by increasing NF-κB activity.

Chronic inflammation is positively associated with the development of urinary bladder cancer. However, its detailed regulatory mechanism remains elusive. The quantitative real-time polymerase chain reaction was used to measure mRNA levels of relative genes. The protein levels were monitored by western blotting. Cell proliferation and viability were evaluated by the cell counting Kit 8 (CCK8) and colony formation assays, respectively. The dual-luciferase reporter assay was performed to assay the transcriptional activity. In vivo experiments were implemented in nude mice as well. The TCGA database analysis suggested that the aberrant expression of cathepsin V (CTSV) was related to a poor outcome in bladder cancer patients. CTSV boosted the inflammation reaction, which facilitated the development of bladder cancer. The overexpression of CTSV increased the proliferation and viability of bladder cancer cells. On the contrary, the deletion of CTSV significantly inhibited the proliferation and viability of bladder cancer cells. The tumor repression resulting from CTSV deficiency in vitro was also verified in vivo. Moreover, multiple cancer-associated luciferase screening showed that the overexpression of CTSV triggered the inflammatory signaling pathway, which could be restored by introducing the NF-κB inhibitor. CTSV is upregulated and promotes proliferation through the NF-κB pathway in bladder cancer and may be a potential target in inflammation-associated bladder cancer.

CRMP4 CpG Hypermethylation Predicts Upgrading to Gleason Score ≥ 8 in Prostate Cancer.

Background: This study determined the predictive value of CRMP4 promoter methylation in prostate tissues collected by core needle biopsies for a postoperative upgrade of Gleason Score (GS) to ≥8 in patients with low-risk PCa. Method: A retrospective analysis of the clinical data was conducted from 631 patients diagnosed with low-risk PCa by core needle biopsy at multiple centers and then underwent Radical Prostatectomy (RP) from 2014-2019. Specimens were collected by core needle biopsy to detect CRMP4 promoter methylation. The pathologic factors correlated with the postoperative GS upgrade to ≥8 were analyzed by logistic regression. The cut-off value for CRMP4 promoter methylation in the prostate tissues collected by core needle biopsy was estimated from the ROC curve in patients with a postoperative GS upgrade to ≥8. Result: Multivariate logistic regression showed that prostate volume, number of positive cores, and CRMP4 promoter methylation were predictive factors for a GS upgrade to ≥8 (OR: 0.94, 95% CI: 0.91-0.98, P=0.003; OR: 3.16, 95% CI: 1.81-5.53, P<0.001; and OR: 1.43, 95% CI: 1.32-1.55, P<0.001, respectively). The positive predictive rate was 85.2%, the negative predictive rate was 99.3%, and the overall predictive rate was 97.9%. When the CRMP4 promoter methylation rate was >18.00%, the low-risk PCa patients were more likely to escalate to high-risk patients. The predictive sensitivity and specificity were 86.9% and 98.8%, respectively. The area under the ROC curve (AUC) was 0.929 (95% CI: 0.883-0.976; P<0.001). The biochemical recurrence (BCR)-free survival, progression-free survival (PFS), and cancer-specific survival (CSS) were worse in patients with CRMP4 methylation >18.0% and postoperative GS upgrade to ≥8 than in patients without an upgrade (P ≤ 0.002). Conclusion: A CRMP4 promoter methylation rate >18.00% in prostate cancer tissues indicated that patients were more likely to escalate from low-to-high risk after undergoing an RP. We recommend determining CRMP4 promoter methylation before RP for low-risk PCa patients.

Ligand-controlled regioselective and chemodivergent defluorinative functionalization of gem-difluorocyclopropanes with simple ketones.

Modulating the reaction selectivity is highly attractive and pivotal to the rational design of synthetic regimes. The defluorinative functionalization of gem-difluorocyclopropanes constitutes a promising route to construct ß-vinyl fluorine scaffolds, whereas chemo- and regioselective access to α-substitution patterns remains a formidable challenge. Presented herein is a robust Pd/NHC ligand synergistic strategy that could enable the C-F bond functionalization with exclusive α-regioselectivity with simple ketones. The key design adopted enolates as π-conjugated ambident nucleophiles that undergo inner-sphere 3,3'-reductive elimination warranted by the sterically hindered-yet-flexible Pd-PEPPSI complex. The excellent branched mono-defluorinative alkylation was achieved with a sterically highly demanding IHept ligand, while subtly less bulky SIPr acted as a bifunctional ligand that not only facilitated α-selective C(sp3)-F cleavage, but also rendered the newly-formed C(sp2)-F bond as the linchpin for subsequent C-O bond formation. These examples represented an unprecedented ligand-controlled regioselective and chemodivergent approach to various mono-fluorinated terminal alkenes and/or furans from the same readily available starting materials.