The synchronous upregulation of a specific protein cluster in the blood predicts both colorectal cancer risk and patient immune status.

BACKGROUND: Early detection and treatment of colorectal cancer (CRC) is crucial for improving patient survival rates. This study aims to identify signature molecules associated with CRC, which can serve as valuable indicators for clinical hematological screening. METHOD: We have systematically searched the Human Protein Atlas database and the relevant literature for blood protein-coding genes. The CRC dataset from TCGA was used to compare the acquired genes and identify differentially expressed molecules (DEMs). Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify modules of co-expressed molecules and key molecules within the DEMs. Signature molecules of CRC were then identified from the key molecules using machine learning. These findings were further validated in clinical samples. Finally, Logistic regression was used to create a predictive model that calculated the likelihood of CRC in both healthy individuals and CRC patients. We evaluated the model's sensitivity and specificity using the ROC curve. RESULT: By utilizing the CRC dataset, WGCNA analysis, and machine learning, we successfully identified seven signature molecules associated with CRC from 1478 blood protein-coding genes. These markers include S100A11, INHBA, QSOX2, MET, TGFBI, VEGFA and CD44. Analyzing the CRC dataset showed its potential to effectively discriminate between CRC and normal individuals. The up-regulated expression of these markers suggests the existence of an immune evasion mechanism in CRC patients and is strongly correlated with poor prognosis. CONCLUSION: The combined detection of the seven signature molecules in CRC can significantly enhance diagnostic efficiency and serve as a novel index for hematological screening of CRC.

Enhancing osteoporosis treatment using a targeted, sustained-release drug delivery system based on macrocyclic amphiphile.

Osteoporosis, a prevalent systemic bone metabolic disorder, primarily affects postmenopausal women and is characterized by increased bone fragility and a heightened risk of fractures. The efficacy of current osteoporosis treatments is often limited by non-specific drug targeting and undesirable off-target skeletal side effects. To address this challenge, we have developed a novel hydroxyapatite-responsive drug delivery system. This system utilizes a self-assembled p-phosphonatocalix[4]arene tetradodecyl ether (PC4A12C), engineered to specifically target and sustain the release of osteoporosis medication at sites of bone remodeling. Our focus centers on icariin (ICA), a drug known for its potent osteogenic properties and minimal adverse effects. In vitro, ICA-loaded PC4A12C (ICA@PC4A12C) demonstrated enhanced proliferation, differentiation, and mineralization in bone marrow mesenchymal stem cells (BMSCs). In vivo, ICA@PC4A12C exhibited superior efficacy in specifically targeting bone tissue, ensuring a controlled and slow release of icariin directly within the bone environment. In an osteoporosis mouse model, treatment with ICA@PC4A12C showed notable enhancement in osteogenic activity and a significant increase in bone density compared to ICA alone. These results demonstrate the potential of PC4A12C as an effective drug carrier in the development of advanced antiosteoporotic drug delivery systems.

KLF11 promotes the proliferation of breast cancer cells by inhibiting p53-MDM2 signaling.

Abnormal Krüppel-like factor 11 (KLF11) expression is frequently found in tumor tissues and is associated with cancer prognosis, but its biological functions and corresponding mechanisms remain elusive. Here, we demonstrated that KLF11 functions as an oncoprotein to promote tumor proliferation in breast cancer cells. Mechanistically, at the transcription level, KLF11 decreased TP53 mRNA expression. Notably, KLF11 also interacted with and stabilized MDM2 through inhibiting MDM2 ubiquitination and subsequent degradation. This increase in MDM2 in turn accelerated the ubiquitin-mediated proteolysis of p53, leading to the reduced expression of p53 and its target genes, including CDKN1A, BAX, and NOXA1. Accordingly, data from animals further confirmed that KLF11 significantly upregulated the growth of breast cancer cells and was inversely correlated with p53 expression. Taken together, our findings reveal a novel mechanism for breast cancer progression in which the function of the tumor suppressor p53 is dramatically weakened.

LRP1 in GABAergic neurons is a key link between obesity and memory function.

OBJECTIVE: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood. METHODS: Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age. RESULTS: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition. CONCLUSIONS: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.

Interface-induced dual-pinning mechanism enhances low-frequency electromagnetic wave loss.

Improving the absorption of electromagnetic waves at low-frequency bands (2-8 GHz) is crucial for the increasing electromagnetic (EM) pollution brought about by the innovation of the fifth generation (5G) communication technology. However, the poor impedance matching and intrinsic attenuation of material in low-frequency bands hinders the development of low-frequency electromagnetic wave absorbing (EMWA) materials. Here we propose an interface-induced dual-pinning mechanism and establish a magnetoelectric bias interface by constructing bilayer core-shell structures of NiFe2O4 (NFO)@BiFeO3 (BFO)@polypyrrole (PPy). Such heterogeneous interface could induce distinct magnetic pinning of the magnetic moment in the ferromagnetic NFO and dielectric pinning of the dipole rotation in PPy. The establishment of the dual-pinning effect resulted in optimized impedance and enhanced attenuation at low-frequency bands, leading to better EMWA performance. The minimum reflection loss (RLmin) at thickness of 4.43 mm reaches -65.30 dB (the optimal absorption efficiency of 99.99997%), and the effective absorption bandwidth (EAB) can almost cover C-band (4.72 ~ 7.04 GHz) with low filling of 15.0 wt.%. This work proposes a mechanism to optimize low-frequency impedance matching with electromagnetic wave (EMW) loss and pave an avenue for the research of high-performance low-frequency absorbers.

Whole genome identification, molecular docking and expression analysis of enzymes involved in the selenomethionine cycle in Cardamine hupingshanensis.

BACKGROUND: The selenomethionine cycle (SeMTC) is a crucial pathway for the metabolism of selenium. The basic bioinformatics and functions of four enzymes involved in the cycle including S-adenosyl-methionine synthase (MAT), SAM-dependent methyltransferase (MTase), S-adenosyl-homocysteine hydrolase (SAHH) and methionine synthase (MTR), have been extensively reported in many eukaryotes. The identification and functional analyses of SeMTC genes/proteins in Cardamine hupingshanensis and their response to selenium stress have not yet been reported. RESULTS: In this study, 45 genes involved in SeMTC were identified in the C. hupingshanensis genome. Phylogenetic analysis showed that seven genes from ChMAT were clustered into four branches, twenty-seven genes from ChCOMT were clustered into two branches, four genes from ChSAHH were clustered into two branches, and seven genes from ChMTR were clustered into three branches. These genes were resided on 16 chromosomes. Gene structure and homologous protein modeling analysis illustrated that proteins in the same family are relatively conserved and have similar functions. Molecular docking showed that the affinity of SeMTC enzymes for selenium metabolites was higher than that for sulfur metabolites. The key active site residues identified for ChMAT were Ala269 and Lys273, while Leu221/231 and Gly207/249 were determined as the crucial residues for ChCOMT. For ChSAHH, the essential active site residues were found to be Asn87, Asp139 and Thr206/207/208/325. Ile204, Ser111/329/377, Asp70/206/254, and His329/332/380 were identified as the critical active site residues for ChMTR. In addition, the results of the expression levels of four enzymes under selenium stress revealed that ChMAT3-1 genes were upregulated approximately 18-fold, ChCOMT9-1 was upregulated approximately 38.7-fold, ChSAHH1-2 was upregulated approximately 11.6-fold, and ChMTR3-2 genes were upregulated approximately 28-fold. These verified that SeMTC enzymes were involved in response to selenium stress to varying degrees. CONCLUSIONS: The results of this research are instrumental for further functional investigation of SeMTC in C. hupingshanensis. This also lays a solid foundation for deeper investigations into the physiological and biochemical mechanisms underlying selenium metabolism in plants.

[Progress on treatment of acetabular quadrilateral plate injury].

Acetabular quadrilateral plate injury has become a hot spot and focus in the field of orthopaedic trauma and pelvic floor function in recent years. Although there are five fracture types,they are all based on fracture morphology,without considering the pulling force of ligaments,joint capsular and muscles. A perfect classification needs to describe the displacement of bone mass in three-dimensional space to better guide reduction and fixation. The seven incision and exposure methods are still the traditional open-eye surgery,and how to protect the criss-crossing vascular neural network and pelvic organs is still the focus. Quadrilateral defect causes dislocation of artificial hip joint,and quantitative evaluation of quadrilateral defect volume and revision techniques are still a hot topic. In this paper,the viewpoints of three-dimensional network structure of acetabular pelvic vascular anatomy,anatomical surgical target channel and fixation anchor point of acetabular fracture reduction are proposed to design new techniques for accurate and minimally invasive surgical operations,in order to realize the requirements of rapid orthopedic rehabilitation.

Potential Role of Bmal1 in Lipopolysaccharide-Induced Depression-Like Behavior and its Associated "Inflammatory Storm".

Inflammation plays an important role in the pathogenesis of depression; however, the underlying mechanisms remain unclear. Apart from the disordered circadian rhythm in animal models and patients with depression, dysfunction of clock genes has been reported to be involved with the progress of inflammation. This study aimed to investigate the role of circadian clock genes, especially brain and muscle ARNT-like 1 (Bmal1), in the linkage between inflammation and depression. Lipopolysaccharide (LPS)-challenged rats and BV2 cells were used in the present study. Four intraperitoneal LPS injections of 0.5 mg/kg were administered once every other day to the rats, and BV2 cells were challenged with LPS for 24 h at the working concentration of 1 mg/L, with or without the suppression of Bmal1 via small interfering RNA. The results showed that LPS could successfully induce depression-like behaviors and an "inflammatory storm" in rats, as indicated by the increased immobility time in the forced swimming test and the decreased saccharin preference index in the saccharin preference test, together with hyperactivity of the hypothalamic-pituitary-adrenal axis, hyperactivation of astrocyte and microglia, and increased peripheral and central abundance of tumor necrosis factor-α, interleukin 6, and C-reactive protein. Moreover, the protein expression levels of brain-derived neurotrophic factor, triggering receptor expressed on myeloid cells 1, Copine6, and Synaptotagmin1 (Syt-1) decreased in the hippocampus and hypothalamus, whereas the expression of triggering receptor expressed on myeloid cells 2 increased. Interestingly, the fluctuation of temperature and serum concentration of melatonin and corticosterone was significantly different between the groups. Furthermore, protein expression levels of the circadian locomotor output cycles kaput, cryptochrome 2, and period 2 was significantly reduced in the hippocampus of LPS-challenged rats, whereas Bmal1 expression was significantly increased in the hippocampus but decreased in the hypothalamus, where it was co-located with neurons, microglia, and astrocytes. Consistently, apart from the reduced cell viability and increased phagocytic ability, LPS-challenged BV2 cells presented a similar trend with the changed protein expression in the hippocampus of the LPS model rats. However, the pathological changes in BV2 cells induced by LPS were reversed after the suppression of Bmal1. These results indicated that LPS could induce depression-like pathological changes, and the underlying mechanism might be partly associated with the imbalanced expression of Bmal1 and its regulated dysfunction of the circadian rhythm.

PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.

ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem or progenitor cells. AML prognosis remains poor owing to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is often dysregulated in AML. We found that although PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes nuclear factor erythroid 2-related factor 2 (NRF2) nuclear accumulation, which induces 6-phosphogluconate dehydrogenase (PGD) and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may, therefore, eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.

Tumor Necrosis Factor-Alpha (+489 G/A) Polymorphism Can Predict the Response to Adalimumab in Chinese Han Patients With Ankylosing Spondylitis.

BACKGROUND: Studies investigating the association between single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha (TNFα) and the efficacy of adalimumab (ADA) in ankylosing spondylitis (AS) therapy have reported conflicting results. We aimed to investigate the value of SNP typing of TNFα in predicting the efficacy of ADA in AS. MATERIALS AND METHODS: Eighty patients with active AS who received ADA treatment were followed up for 24 weeks. Six known SNPs of TNFα (+489G/A, -238G/A, -308G/A, -857C/T, -863C/A, and -1031C/T) were subjected to the SNaPshot SNP typing method, which has been proven to be a reliable, efficient, and cost-effective method for detecting SNPs. The relationship between each SNP genotype and the therapeutic efficacy of ADA was analyzed. RESULTS: At the end of the 24-week follow-up, 58.8% of the patients with AS achieved Assessment of SpondyloArthritis International Society (ASAS) partial remission (PR), 67.5% of the patients achieved the criteria of an ASAS40 response (40% improvement on indices), and 53.8% of the patients achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement (MI). The univariate analysis showed that patients with AS carrying the TNFα +489 A allele were more likely to achieve ASAS-PR, ASAS40 response criteria, and ASDAS-MI after ADA treatment. In the multivariate regression analysis, the TNFα +489 A allele was an independent factor influencing the efficacy of ADA in treating AS (ASAS-PR odds ratio (OR) = 2.66, 95% confidence interval (CI) = 1.01-7.01; ASAS40 OR = 4.56, 95% CI = 1.39-15.00; ASDAS-MI OR = 3.31, 95% CI = 1.02-10.69). CONCLUSIONS: The patients carrying the TNFα +489 A allele may be more likely to experience better therapeutic efficacy and achieve the treatment target (ASAS-PR, ASAS40 response, or ASDAS-MI) after receiving ADA treatment. Detection of TNFα +489 G/A may predict the therapeutic efficacy of ADA, which can be used in clinical practice to tailor treatment for individual patients with AS. Further studies with larger sample sizes and longer follow-up periods with imaging evaluation are needed to verify our findings.

[Research Progress of Next Generation Sequencing in Acute Leukemia --Review].

With the advent of precision medicine, next-generation sequencing (NGS) is playing an increasingly important role in clinical oncology diagnosis and treatment with its advantages of high sensitivity, high accuracy, high efficiency and operability. NGS reveals the genetic characteristics of acute leukemia(AL) patients by screening for specific disease-causing genes to identify occult as well as complex genetic mutations in patients with AL, leading to early diagnosis and targeted drug therapy for AL patients, as well as to predict disease recurrence by detecting mnimal residual disease (MRD) and analyzing mutated genes to determine patient prognosis. NGS plays an increasingly important role in the diagnosis, treatment and prognosis assessment in AL, providing a direction for the pursuit of precision medicine. This paper reviews the research progress of NGS in AL.

Prognostic impact of tumor deposits on overall survival in colorectal cancer: Based on Surveillance, Epidemiology, and End Results database.

BACKGROUND: In colorectal cancer, tumor deposits (TDs) are considered to be a prognostic factor in the current staging system, and are only considered in the absence of lymph node metastases (LNMs). However, this definition and the subsequent prognostic value based on it is controversial, with various hypotheses. TDs may play an independent role when it comes to survival and addition of TDs to LNM count may predict the prognosis of patients more accurately. AIM: To assess the prognostic impact of TDs and evaluate the effect of their addition to the LNM count. METHODS: The patients are derived from the Surveillance, Epidemiology, and End Results database. A prognostic analysis regarding impact of TDs on overall survival (OS) was performed using Cox regression model, and other covariates associating with OS were adjusted. The effect of addition of TDs to LNM count on N restaging was also evaluated. The subgroup analysis was performed to explore the different profile of risk factors between patients with and without TDs. RESULTS: Overall, 103755 patients were enrolled with 14131 (13.6%) TD-positive and 89624 (86.4%) TD-negative tumors. TD-positive patients had worse prognosis compared with TD-negative patients, with 3-year OS rates of 47.3% (95%CI, 46.5%-48.1%) and 77.5% (95%CI, 77.2%-77.8%, P < 0.0001), respectively. On multivariable analysis, TDs were associated poorer OS (hazard ratio, 1.35; 95%CI, 1.31-1.38; P < 0.0001). Among TD-positive patients, the number of TDs had a linear negative effect on disease-free survival and OS. After reclassifying patients by adding TDs to the LNM count, 885 of 19 965 (4.4%) N1 patients were restaged as pN2, with worse outcomes than patients restaged as pN1 (3-year OS rate: 78.5%, 95%CI, 77.9%-79.1% vs 63.2%, 95%CI, 60.1%-66.5%, respectively; P < 0.0001). CONCLUSION: TDs are an independent prognostic factor for OS in colorectal cancer. The addition of TDs to LNM count improved the prognostic accuracy of tumor, node and metastasis staging.

Acute toxicity of Zanthoxylum bungeanum against two stored product insects and synergistic interactions between two major compounds limonene and linalool.

In order to find and develop new botanical pesticides against storage pests, components of the essential oil (EO) from Zanthoxylum bungeanum were identified by GC-MS and their insecticidal activity against the stored product pests were studied. The EO was obtained by steam distillation. Results showed that EO was rich in limonene (23.67), linalool (21.76) and linalyl anthranilate (10.87). In contact assays, linalool exhibited strongest toxicity to red flour beetle adult (LD50 = 17.06 µg/adult) and larvae (LD50 = 16.42 µg/larvae), and linalool was the most active one against the Lasioderma serricorne (LD50 = 15.36 µg/larvae). Then limonene and linalool showed different levels of fumigant activities against the two insect species. Synergism effect existed in the proportion of contact assays against Tribolium castaneum adults, and additive was observed in the proportion of 7:1 against T. castaneum larvae. This work provides important information for the development and utilization of Z. bungeanum and suggests that the EO of Z. bungeanum has the potential to serve as bio-insecticides for controlling pest damage in stored products.

Median Effective Concentration of Ropivacaine for Femoral Nerve Block Maintaining Motor Function During Knee Arthroscopy in Two Age Groups.

Background: Femoral nerve block combined with general anesthesia is commonly used for patients undergoing knee arthroscopy in ambulatory care centers. An ideal analgesic agent would selectively (differentially) block sensory fibers, with little or no effect on motor nerves. Ropivacaine is considered to cause less motor block than others. This study investigated the median effective concentration (EC50) of ropivacaine for differential femoral nerve block in adults either younger or older than 60 years. Methods: Patients with American Society of Anesthesiologists physical status I-III and scheduled for knee arthroscopy were categorized as 18- to 60-years-old (Group 1), or older than 60 years (Group 2). Surgeries were performed under general anesthesia combined with femoral nerve block via 22 mL ropivacaine. The EC50 of ropivacaine for differential femoral nerve block was determined using the up-and-down method and probit regression. The primary outcome was the EC50 (95% confidence interval [CI]) of the 2 groups. Data on the sensory block, analgesic effect, complications, and hemodynamics during surgery were also recorded. Results: The EC50 of 22 mL ropivacaine for differential femoral nerve block of Group 1 (0.124%, 95% CI 0.097-0.143%) was significantly higher than that of Group 2 (0.088%, 95% CI 0.076-0.103%). The sensory block and hemodynamic data of the 2 groups were comparable. None of the patients experienced neurological complications. Conclusion: The EC50 of ropivacaine administered for differential femoral nerve block during knee arthroscopy was lower in patients older than 60 years, relative to younger adults.

Unstable plaques hide in heavily calcified coronary arteries.

Background: The napkin-ring sign (NRS) was accepted as unstable plaques at coronary computed tomography angiography (CCTA). However, the incidence is relatively low. We sought to assess whether the newly defined diamond-attenuation-sign [DAS, defined as a qualitative plaque feature in a mixed plaque (MP) on CCTA cross-section images by the presence of two features: a visual calcification (in the shape of a diamond) accompanied by an annular-shape lower attenuation plaque tissue surrounding the lumen like a ring], could be accurately identified as unstable atherosclerotic plaques. Methods: Eight heart transplant recipients (8 male; mean age, 48.5±11.6 years; range, 37-65 years) underwent CCTA exams prior to heart transplant surgery. Segment-based CCTA sections were independently evaluated for various plaque patterns including non-calcified plaque (NCP) with NRS (NCP-NRS), NCP without NRS (NCP-non-NRS), MP with DAS (MP-DAS), MP without DAS sign (MP-non-DAS), and calcified plaque (CP). Results: NCP-NRS plaques in 6.4% (23/358), NCP-non-NRS plaques in 24.0% (86/358), MP-DAS plaques in 18.2% (65/358), MP-non-DAS plaques in 20.1% (72/358), and calcified-plaques in 7.0% (25/358) of all cases. The specificity and positive predictive values of the MP-DAS and NCP-NRS signs to identify unstable plaque features were excellent (97.1% vs. 98.6%, 90.8% vs. 87.0%, respectively). DAS plaques were more frequently seen on CCTA exams than that of NRS (39.3% vs. 13.3%, respectively, P=0.001). The diagnostic performance of MP-DAS to identify unstable coronary lesions was superior compared to NCP-NRS [area under the receiver operating characteristic curve (ROC), 0.756; 95% CI: 0.717-0.791 vs. 0.558; 95% CI: 0.514-0.600, respectively, P<0.001]. Conclusions: Both the DAS and NRS had a high specificity and positive predictive value for the presence of unstable lesions. DAS was a better identification of unstable atherosclerotic plaques in the assessment of plaque-calcification-pattern (PCP).

Clinical practice guideline for transurethral plasmakinetic resection of prostate for benign prostatic hyperplasia (2021 Edition).

Benign prostatic hyperplasia (BPH) is highly prevalent among older men, impacting on their quality of life, sexual function, and genitourinary health, and has become an important global burden of disease. Transurethral plasmakinetic resection of prostate (TUPKP) is one of the foremost surgical procedures for the treatment of BPH. It has become well established in clinical practice with good efficacy and safety. In 2018, we issued the guideline "2018 Standard Edition". However much new direct evidence has now emerged and this may change some of previous recommendations. The time is ripe to develop new evidence-based guidelines, so we formed a working group of clinical experts and methodologists. The steering group members posed 31 questions relevant to the management of TUPKP for BPH covering the following areas: questions relevant to the perioperative period (preoperative, intraoperative, and postoperative) of TUPKP in the treatment of BPH, postoperative complications and the level of surgeons' surgical skill. We searched the literature for direct evidence on the management of TUPKP for BPH, and assessed its certainty generated recommendations using the grade criteria by the European Association of Urology. Recommendations were either strong or weak, or in the form of an ungraded consensus-based statement. Finally, we issued 36 statements. Among them, 23 carried strong recommendations, and 13 carried weak recommendations for the stated procedure. They covered questions relevant to the aforementioned three areas. The preoperative period for TUPKP in the treatment of BPH included indications and contraindications for TUPKP, precautions for preoperative preparation in patients with renal impairment and urinary tract infection due to urinary retention, and preoperative prophylactic use of antibiotics. Questions relevant to the intraoperative period incorporated surgical operation techniques and prevention and management of bladder explosion. The application to different populations incorporating the efficacy and safety of TUPKP in the treatment of normal volume (< 80 ml) and large-volume (≥ 80 ml) BPH compared with transurethral urethral resection prostate, transurethral plasmakinetic enucleation of prostate and open prostatectomy; the efficacy and safety of TUPKP in high-risk populations and among people taking anticoagulant (antithrombotic) drugs. Questions relevant to the postoperative period incorporated the time and speed of flushing, the time indwelling catheters are needed, principles of postoperative therapeutic use of antibiotics, follow-up time and follow-up content. Questions related to complications incorporated types of complications and their incidence, postoperative leukocyturia, the treatment measures for the perforation and extravasation of the capsule, transurethral resection syndrome, postoperative bleeding, urinary catheter blockage, bladder spasm, overactive bladder, urinary incontinence, urethral stricture, rectal injury during surgery, postoperative erectile dysfunction and retrograde ejaculation. Final questions were related to surgeons' skills when performing TUPKP for the treatment of BPH. We hope these recommendations can help support healthcare workers caring for patients having TUPKP for the treatment of BPH.

Progesterone Changes the Pregnancy-Induced Adaptation of Cardiomyocyte Kv2.1 Channels via MicroRNA-29b.

The cardiovascular system adaptation occurs during pregnancy to ensure adequate maternal circulation. Progesterone (P4) is widely used in hormone therapy to support pregnancy, but little is known about its effects on maternal cardiac function. In this study, we investigated the cardiac repolarization and ion channel expression in pregnant subjects and mice models and studied the effects of P4 administrations on these pregnancy-mediated adaptations. P4 administrations shortened the prolongation of QTC intervals and action potential duration (APD) that occurred during pregnancy, which was mainly attributable to the reduction in the voltage-gated potassium (Kv) current under basal conditions. In vitro studies indicated that P4 regulated the Kv2.1 channel in a bidirectional manner. At a low dose (1 µM), P4 induced upregulation of Kv2.1 through P4 receptor, while at a higher dose (5 µM), P4 downregulated Kv2.1 by targeting microRNA-29b (miR-29b). Our data showed that P4 modulated maternal cardiac repolarization by regulating Kv2.1 channel activity during pregnancy. Kv2.1, as well as miR-29b, might be used as potential therapeutic targets for adaptations of the maternal cardiovascular system or evaluation of progesterone medication during pregnancy.

RLL5, an F-box-containing protein, involved in preventing transgene silencing and in maintaining global DNA methylation in Arabidopsis.

RNA-directed DNA methylation (RdDM) and ROS1-dependent active DNA demethylation pathways are antagonistic processes that dynamically regulate site-specific methylation. In this study, we obtained a mutant with reduced luciferase (LUC) luminescence by genetic screening, which was named rll5-1 (for reduced LUC luminescence 5-1). The rll5-1 mutant showed narrower, frizzled and curly leaves, and the low-LUC-luminescence phenotype in the rll5-1 mutant can be largely restored by DNA methylation inhibitor 5-Aza-2'-deoxycytidine. Map-based cloning coupled with genome resequencing data revealed that a nucleotide substitution of G to A was found at the 124th bp of ORF of At4G10190, leading to an aspartate-to-asparagine change at position 42 in such a protein. Bisulfite sequencing data indicated that DNA methylation of 3' region of the double 35S promoter that drives the LUC expression was appreciably increased. Further analysis revealed that there were 4747 hypo-DMRs and 936 hyper-DMRs found in the rll5-1 genome, and the hypo-DMRs was predominantly distributed on TEs, which appeared to stem from the downregulation of a few RdDM pathway genes and DNA methyltransferase genes. Closer inspection demonstrated that there were 1229 hypo-DMRs commonly shared among rll5-1, nrpd1-3 and nrpe1-11, and a total of 1349 hypo-DMRs were common to rll5-1 and cmt2 mutants. Thus, these studies demonstrate the roles of RLL5 in preventing transgene silencing and in maintaining genome-wide DNA methylation in a direct/indirect or locus-specific manner.

Predictive value of serum alpha-fetoprotein for tumor regression after preoperative chemotherapy for rectal cancer.

BACKGROUND: Preoperative therapy is widely used in locally advanced rectal cancer. It can improve local control of rectal cancer. However, there are few indicators that can predict the effect of preoperative chemotherapy accurately. AIM: To investigate whether the increase in serum α-fetoprotein (AFP) can predict better efficacy of preoperative chemotherapy. METHODS: This was a retrospective study. We analyzed 125 patients admitted between 2017 and 2019 with locally advanced rectal cancer. All patients received six cycles of preoperative chemotherapy (mFOLFOX6 every 2 wk). Serum AFP of 26 patients rose slightly after three or four cycles of chemotherapy, and fell to normal again within 2 mo. The other 99 patients had a normal level of serum AFP during chemotherapy. Patients were divided into two groups (AFP risen and AFP normal). According to postoperative pathology, we compared tumor regression and complete response rate between the two groups. The primary outcome measure was the tumor regression grade (TRG) after chemotherapy. The difference in pathological complete response between the two groups was also investigated. RESULTS: There were no tumor progression and distant metastasis in both groups during preoperative chemotherapy. Patients in the AFP risen group achieved better TRG 0/1 than those in the AFP normal group (61.5% vs 39.4%). The increase in AFP was a significant predictor for better tumor regression [χ 2 = 4.144, odds ratio (OR) = 2.666, P = 0.04]. In the AFP risen group, the complete response rate was 30.8%, which was higher than in the AFP normal group (30.8% vs 12.1%, χ 2 = 4.542, OR = 3.251, P = 0.03). CONCLUSION: Patients with a slight increase in serum AFP can achieve better tumor regression during preoperative chemotherapy, and are more likely to achieve pathological complete response.