The control of the location and activity of stem cells depends on spatial regulation of gene activities in the stem cell niche. Using computational and experimental approaches, we have tested and found support for a hypothesis for gene interactions that specify the apical stem cell population. The hypothesis explains how the WUSCHEL gene product, synthesized basally in the meristem, induces-expressing stem cells in the meristem apex but, paradoxically, not in the basal domain where itself is expressed. The answer involves the activity of the small family of genes, which prevent the activation of and which are expressed basally in the shoot meristem.

Artificial intelligence (AI) has experienced rapid growth over the past few years, moving from the experimental to the implementation phase in various fields, including medicine. Advances in learning algorithms and theories, the availability of large datasets and improvements in computing power have contributed to breakthroughs in current AI applications. Machine learning (ML), a subset of AI, allows computers to detect patterns from large complex datasets automatically and uses these patterns to make predictions. AI is proving to be increasingly applicable to healthcare, and multiple machine learning techniques have been used to improve the performance of assisted reproductive technology (ART). Despite various challenges, the integration of AI and reproductive medicine is bound to give an essential direction to medical development in the future. In this review, we discuss the basic aspects of AI and machine learning, and we address the applications, potential limitations and challenges of AI. We also highlight the prospects and future directions in the context of reproductive medicine.

Multidrug resistance (MDR) has become a major impediment to a successful treatment for liver cancer patients, and one of the common reasons for MDR is the activation of ABCB1 gene, leading to the over-expression of P-glycoprotein (P-gp), which conferred cancer cells be resistant to a broad range of anticancer drugs. MicroRNAs (miRNAs) are a class of short, non-coding RNA moleculars that can regulate gene expression at the post-transcriptional level. In the current study, the aim is to explore whether miRNA participates in the regulation of MDR mediated by ABCB1. We found that the expression of ABCB1 was correlated with the doxorubicin IC50 dose in eight hepatocellular carcinoma (HCC) cell lines: Hep3B, HCC3, LM-6, SMMC7721, Huh-7, SK-Hep-1, HepG2 and BEL-7402. Using the bioinformatics, we discovered that there were several miRNAs that can bind to the 3'UTR of ABCB1 gene. Among these candidate miRNAs, miR-223 was chosen for further study. Then, EGFP reporter assay, real-time PCR and Western blot were performed to verify that miR-223 targeted ABCB1 3'UTR directly, and miR-223 downregulated ABCB1 at both mRNA and protein levels. Finally, we found that the over-expression of miR-223 increased the HCC cell sensitivity to anticancer drugs, and the inhibition of miR-223 had the opposite effect. Importantly, the over-expression or silencing of ABCB1 can rescue the cell response to the anticancer drugs mediated by miR-223 over-expression or inhibition, respectively. In conclusion, our findings indicated that miR-223 played an important role in the regulation of MDR mediated by ABCB1, and it suggests that miR-223 may be considered as a therapeutic biomarker for HCC patients who had MDR problems induced by high expression of ABCB1.

BackgroundTo update a previously published systematic review and meta-analysis on the efficacy and safety of tubeless percutaneous nephrolithotomy (PCNL).MethodsA systematic literature search of EMBASE, PubMed, Web of Science, and the Cochrane Library was performed to confirm relevant studies. The scientific literature was screened in accordance with the predetermined inclusion and exclusion criteria. After quality assessment and data extraction from the eligible studies, a meta-analysis was conducted using Stata SE 12.0.ResultsFourteen randomized controlled trials (RCTs) involving 1148 patients were included. Combined results demonstrated that tubeless PCNL was significantly associated with shorter operative time (weighted mean difference [WMD], −3.79 min; 95% confidence interval [CI], −6.73 to −0.85; P = 0.012; I2 = 53.8%), shorter hospital stay (WMD, −1.27 days; 95% CI, −1.65 to −0.90; P < 0.001; I2 = 98.7%), faster time to return to normal activity (WMD, −4.24 days; 95% CI, −5.76 to −2.71; P < 0.001; I2 = 97.5%), lower postoperative pain scores (WMD, −16.55 mm; 95% CI, −21.60 to −11.50; P < 0.001; I2 = 95.7%), less postoperative analgesia requirements (standard mean difference, −1.09 mg; 95% CI, −1.35 to −0.84; P < 0.001; I2 = 46.8%), and lower urine leakage (Relative risk [RR], 0.30; 95% CI 0.15 to 0.59; P = 0.001; I2 = 41.2%). There were no significant differences in postoperative hemoglobin reduction (WMD, −0.02 g/dL; 95% CI, −0.04 to 0.01; P = 0.172; I2 = 41.5%), stone-free rate (RR, 1.01; 95% CI, 0.97 to 1.05; P = 0.776; I2 = 0.0%), postoperative fever rate (RR, 1.05; 95% CI, 0.57 to 1.93; P = 0.867; I2 = 0.0%), or blood transfusion rate (RR, 0.79; 95% CI, 0.36 to 1.70; P = 0.538; I2 = 0.0%). The results of subgroup analysis were consistent with the overall findings. The sensitivity analysis indicated that most results remained constant when total tubeless or partial tubeless or mini-PCNL studies were excluded respectively.ConclusionsTubeless PCNL is an available and safe option in carefully evaluated and selected patients. It is significantly associated with the advantages of shorter hospital stay, shorter time to return to normal activity, lower postoperative pain scores, less analgesia requirement, and reduced urine leakage.

In clinical studies with time-to-event as a primary endpoint, one main interest is to find the best treatment strategy to maximize patients’ mean survival time. Due to patient’s heterogeneity in response to treatments, great efforts have been devoted to developing optimal treatment regimes by integrating individuals’ clinical and genetic information. A main challenge arises in the selection of important variables that can help to build reliable and interpretable optimal treatment regimes since the dimension of predictors may be high. In this paper, we propose a robust loss-based estimation framework that can be easily coupled with shrinkage penalties for both estimation of optimal treatment regimes and variable selection. The asymptotic properties of the proposed estimators are studied. Moreover, a model-free estimator of restricted mean survival time under the derived optimal treatment regime is developed and its asymptotic property is studied. Simulations are conducted to assess the empirical performance of the proposed method for parameter estimation, variable selection, and optimal treatment decision. An application to an AIDS clinical trial data set is given to illustrate the method.

BackgroundTreatment options are limited for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) following progression after first-line platinum-based therapy, particularly in Asian countries.Patients and methodsIn this randomised, open-label, phase III trial, we enrolled Asian patients aged ≥18 years, with histologically or cytologically confirmed recurrent/metastatic HNSCC following first-line platinum-based therapy who were not amenable for salvage surgery or radiotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1. Patients were randomised (2 : 1) to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week), stratified by ECOG performance status and prior EGFR-targeted antibody therapy. The primary end point was progression-free survival (PFS) assessed by an independent central review committee blinded to treatment allocation.ResultsA total of 340 patients were randomised (228 afatinib; 112 methotrexate). After a median follow-up of 6.4 months, afatinib significantly decreased the risk of progression/death by 37% versus methotrexate (hazard ratio 0.63; 95% confidence interval 0.48–0.82; P = 0.0005; median 2.9 versus 2.6 months; landmark analysis at 12 and 24 weeks, 58% versus 41%, 21% versus 9%). Improved PFS was complemented by quality of life benefits. Objective response rate was 28% with afatinib and 13% with methotrexate. There was no significant difference in overall survival. The most common grade ≥3 drug-related adverse events were rash/acne (4% with afatinib versus 0% with methotrexate), diarrhoea (4% versus 0%), fatigue (1% versus 5%), anaemia (<1% versus 5%) and leukopenia (0% versus 5%).ConclusionsConsistent with the phase III LUX-Head & Neck 1 trial, afatinib significantly improved PFS versus methotrexate, with a manageable safety profile. These results demonstrate the efficacy and feasibility of afatinib as a second-line treatment option for certain patients with recurrent or metastatic HNSCC.Clinical trial registrationClinicalTrials.gov identifier: NCT01856478.

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Rationale Mutations in ACTA2, encoding the smooth muscle isoform of α-actin (SM α-actin), cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. Objective We sought to identify the mechanism by which loss of SM α-actin causes aortic disease. Methods and Results Acta2−/− mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2−/− aortas or kidneys. Aortic tissue and explanted smooth muscle cells (SMCs) from Acta2−/− aortas show increased production of reactive oxygen radicals (ROS) and increased basal NF-κB signaling, leading to an increase in the expression of the AngII receptor type I (Agtr1a) and activation of signaling at 100-fold lower levels of AngII in the mutant compared to wild-type cells. Furthermore, disruption of SM α-actin filaments in wildtype SMCs by various mechanisms activates NF-κB signaling and increases expression of Agtr1a. Conclusions These findings reveal that disruption of SM α-actin filaments in SMCs increases ROS levels, activates NF-κB signaling and increases Agtr1a expression, thus potentiating AngII signaling in vascular SMCs without an increase in the exogenous levels of AngII.