Comparison of postoperative pulmonary complications and intraoperative safety in thoracoscopic surgery under non-intubated versus intubated anesthesia: a randomized, controlled, double-blind non-inferiority trial.

PURPOSE: Traditional anesthesia for video-assisted thoracoscopy (VATS) such as double-lumen tracheal intubation (DLT) and one-lung ventilation (OLV), may lead to post-operative pulmonary complications (PPCs). Non-intubation VATS (NIVATS) is an anesthetic technique that avoided DLT and OLV, maybe avoiding the PPCs. So we hypothesized that NIVATS would non-inferiority to intubation VATS (IVATS) in the risk of developing PPCs and some safety indicators. METHODS: This study is a randomised, controlled, double-blind, non-inferiority trial, 120 patients were randomly assigned to the NIVATS group and IVATS group according to 1:1. The primary outcome was the incidence of PPCs with a pre-defined non-inferiority margin of 10%. The second outcome was the safety indicators, including the incidence of cough/body movement, hypoxemia, malignant arrhythmia, regurgitation and aspiration, and transferring to endobronchial intubation intraoperatively (The malignant arrhythmia was defined as an arrhythmia that caused hemodynamic disturbances in a short period of time, resulting in persistent hypotension or even cardiac arrest in the patient). RESULTS: There was no significant difference in demographic indicators such as gender and age between the two groups. The incidence of PPCs in the NIVATS group was non-inferior to that in the IVATS group (1.67% vs. 3.33%, absolute difference: - 1.67%; 95%CI - 7.25 to 3.91). In additionan, no significant differences were found between the two groups for the incidence of cough/body movement (10.00% vs. 11.67%, p = 0.77), the incidence of hypoxemia (25% vs. 18.33%, p = 0.38), the incidence of malignant arrhythmia (1.67% vs. 6.67%, p = 0.36), the incidence of regurgitation and aspiration (0% vs. 0%, p > 0.999) and the incidence of transferring to endobronchial intubation intraoperatively (0% vs. 0%, p > 0.999). CONCLUSION: We conclude that when using the non-intubation anesthesia for VATS, the incidence of PPCs was not inferior to intubation anesthesia. Furthermore, NIVATS had little effect on perioperative safety.

An Automated Diagnosis Method for Lung Cancer Target Detection and Subtype Classification-Based CT Scans.

When dealing with small targets in lung cancer detection, the YOLO V8 algorithm may encounter false positives and misses. To address this issue, this study proposes an enhanced YOLO V8 detection model. The model integrates a large separable kernel attention mechanism into the C2f module to expand the information retrieval range, strengthens the extraction of lung cancer features in the Backbone section, and achieves effective interaction between multi-scale features in the Neck section, thereby enhancing feature representation and robustness. Additionally, depth-wise convolution and Coordinate Attention mechanisms are embedded in the Fast Spatial Pyramid Pooling module to reduce feature loss and improve detection accuracy. This study introduces a Minimum Point Distance-based IOU loss to enhance correlation between predicted and ground truth bounding boxes, improving adaptability and accuracy in small target detection. Experimental validation demonstrates that the improved network outperforms other mainstream detection networks in terms of average precision values and surpasses other classification networks in terms of accuracy. These findings validate the outstanding performance of the enhanced model in the localization and recognition aspects of lung cancer auxiliary diagnosis.

Glutathione dynamics in subcellular compartments and implications for drug development.

Glutathione (GSH) is a pivotal tripeptide antioxidant essential for maintaining cellular redox homeostasis and regulating diverse cellular processes. Subcellular compartmentalization of GSH underscores its multifaceted roles across various organelles including the cytosol, mitochondria, endoplasmic reticulum, and nucleus, each exhibiting distinct regulatory mechanisms. Perturbations in GSH dynamics contribute to pathophysiological conditions, emphasizing the clinical significance of understanding its intricate regulation. This review consolidates current knowledge on subcellular GSH dynamics, highlighting its implications in drug development, particularly in covalent drug design and antitumor strategies targeting intracellular GSH levels. Challenges and future directions in deciphering subcellular GSH dynamics are discussed, advocating for innovative methodologies to advance our comprehension and facilitate the development of precise therapeutic interventions based on GSH modulation.

Advances in research and utilization of botanical pesticides for agricultural pest management in Inner Mongolia, China.

Traditional Chinese herbal medicines not only cure human diseases, but also play an important role as insecticides. Compared with conventional chemical agents, traditional Chinese herbal medicines are characterized by low toxicity, low residues, and being eco-friendly, and they have become a research hotspot. Traditional Chinese herbal medicines have tremendous flexibility and indefinite potential. Therefore, this paper reviewed the types of insecticides belonging to traditional Chinese herbal medicines in Inner Mongolia, China, including their traditional uses, secondary metabolites, biological activities, action mechanisms, application methods, and development status. In addition, the most relevant issues involved in the development of traditional Chinese herbal medicines was discussed. We believe that traditional Chinese herbal medicines can be better implemented and developed; such that its other advantages, such as an insect repellent, can be promoted. Moreover, this study lays a solid foundation for further research on traditional Chinese herbal medicines in Inner Mongolia, China.

The Effect of Ciprofol on Postoperative Delirium in Elderly Patients Undergoing Thoracoscopic Surgery for Lung Cancer: A Prospective, Randomized, Controlled Trial.

Purpose: This study was conducted to assess whether ciprofol vs propofol could affect the incidence of postoperative delirium (POD) in elderly patients with lung cancer after thoracoscopic surgery. Patients and Methods: In this study, a total of 84 elderly patients undergoing thoracoscopic surgery for lung cancer were recruited and randomized into two groups to receive anesthesia with either ciprofol or propofol. The primary outcome was the incidence of POD within three days after surgery. Secondary outcomes included the Confusion Assessment Method (CAM) score, intraoperative indicators related to mean arterial pressure (MAP), and cerebral tissue oxygen saturation (SctO2). Moreover, MAP- and SctO2-related indicators associated with POD were analyzed. Results: The incidence of POD was 7.1% and 16.7%, respectively, in the ciprofol group and the propofol group (risk ratio [RR], 0.37; 95% confidence interval [CI], 0.07 to 2.03; risk difference [RD], -9.6%; 95% CI, -23.3% to 4.1%; p = 0.178). Compared with those in the propofol group, patients in the ciprofol group had lower CAM scores three days after surgery (13 (12, 15) vs 15 (14, 17); 12 (11, 13) vs 14 (13, 16); 12 (11, 12) vs 13 (12, 14), p<0.05). Besides, patients in the ciprofol group exhibited higher mean and minimum MAP (88.63 ± 6.7 vs 85 ± 8.3; 69.81 ± 9.59 vs 64.9 ± 9.43, p<0.05) and SctO2 (77.26 ± 3.96 vs 75.3 ± 4.49, 71.69 ± 4.51 vs 68.77 ± 6.46, p<0.05) and percentage of time for blood pressure stabilization (0.6 ± 0.14 vs 0.45 ± 0.14, p<0.05) than those in the propofol group. Furthermore, MAP and SctO2-related indicators were validated to correlate with POD. Conclusion: Anesthesia with ciprofol did not increase the incidence of POD compared with propofol. The results demonstrated that ciprofol could improve intraoperative MAP and SctO2 levels and diminish postoperative CAM scores.

A broad-spectrum gas sensor based on correlated two-dimensional electron gas.

Designing a broad-spectrum gas sensor capable of identifying gas components in complex environments, such as mixed atmospheres or extreme temperatures, is a significant concern for various technologies, including energy, geological science, and planetary exploration. The main challenge lies in finding materials that exhibit high chemical stability and wide working temperature range. Materials that amplify signals through non-chemical methods could open up new sensing avenues. Here, we present the discovery of a broad-spectrum gas sensor utilizing correlated two-dimensional electron gas at a delta-doped LaAlO3/SrTiO3 interface with LaFeO3. Our study reveals that a back-gating on this two-dimensional electron gas can induce a non-volatile metal to insulator transition, which consequently can activate the two-dimensional electron gas to sensitively and quantitatively probe very broad gas species, no matter whether they are polar, non-polar, or inert gases. Different gas species cause resistance change at their sublimation or boiling temperature and a well-defined phase transition angle can quantitatively determine their partial pressures. Such unique correlated two-dimensional electron gas sensor is not affected by gas mixtures and maintains a wide operating temperature range. Furthermore, its readout is a simple measurement of electric resistance change, thus providing a very low-cost and high-efficient broad-spectrum sensing technique.

Scoliosis due to scar contracture caused by infection after cyst-peritoneal shunt: a case report and literature review.

BACKGROUND: Cyst-peritoneal (CP) shunt is one of the most common methods for the treatment of intracranial arachnoid cysts (ACs). Infection is a common postoperative complication. We report a patient with scoliosis due to scar contracture caused by infection after CP shunt. CASE DESCRIPTION: A 12-year-old boy underwent CP shunt surgery for the left frontoparietotemporal AC when he was 2 years old. At the age of 7 years, he underwent a shunt catheter removal procedure because of the infection caused by the fistula leading from the subcutaneous tunnel to the body surface. However, contracture of the subcutaneous scar from fistula infection caused scoliosis and limited range of motion of the right arm. At the age of 12, the patient received scar lysis and his symptoms improved. CONCLUSION: We presented the first case of scoliosis due to scar contracture caused by infection after CP shunt. In this case, timely release of scar tissue can effectively correct scoliosis and limb movement limitation.

Effects of metformin on Sonic hedgehog subgroup medulloblastoma progression: In vitro and in vivo studies.

Metformin is a first-line drug for type 2 diabetes, and its anticancer effects have also been widely studied in recent years. The Sonic hedgehog (Shh) signaling pathway is involved in the initiation and progression of medulloblastoma. In order to develop a new treatment strategy for medulloblastoma (MB), this study investigated the inhibitory effect of metformin on MB and the underlying mechanism of metformin on the Shh signaling pathway. The effect of metformin on proliferation was evaluated by the cell counting kit-8 (CCK-8) test and colony formation experiment. The effect of metformin on metastasis was assessed by the scratch-wound assay and transwell invasion assay. Cell cycle and apoptosis were evaluated by flow cytometry, and the associated proteins were examined by western blotting. The mRNA and protein expression levels related to the Shh pathway were measured by quantitative PCR, western blotting, and immunofluorescence staining. The xenograft murine model was carried out to evaluate the anticancer effect of metformin on medulloblastoma in vivo. Metformin inhibited proliferation and metastasis of the Shh subgroup MB cell line, and the inhibitory effect on proliferation was related to apoptosis and the block of the cell cycle at the G0/G1 phase. Animal experiments showed that metformin inhibits medulloblastoma growth in vivo. Moreover, metformin decreased mRNA and protein expression levels of the Shh pathway, and this effect was reversed by the AMP-activated protein kinase (AMPK) siRNA. Furthermore, the pro-apoptotic and cell cycle arrest effects of metformin on Daoy cells could be reversed by the Shh pathway activators. Our findings demonstrated that metformin could inhibit medulloblastoma progression in vitro and in vivo, and this effect was associated with AMPK-mediated inhibition of the Shh signaling pathway in vitro studies.

Up-regulated FNDC1 accelerates stemness and chemoradiation resistance in colorectal cancer cells.

Neoadjuvant chemoradiation (nCRT) followed by radical surgery is the preferred option for locally advanced colorectal cancer (CRC) treatment. However, chemo/radio-resistance remains a main obstacle in CRC therapy. In the study, we analyzed the mRNA expression profiling of CRC patients and revealed that the aberrant expression of fibronectin type III domain containing 1 (FNDC1) was associated with disease progression and poor prognosis in CRC. FNDC1 expression was consistently increased in multiple independent cohorts of CRC. Upregulated FNDC1 in pretreated primary tumor tissues predicted a poor response to nCRT, recurrence, and poor disease-free survival in nCRT-treated CRC patients. FNDC1 overexpression accelerated CRC cell survival on 5-FU or radiation treatment both in vitro and in vivo, whereas FNDC1 inhibition sensitized CRC cells to chemoradiation. In addition, FNDC1 accelerated stem cell-like properties of CRC cells. Furthermore, tumor tissues from non-responders exhibited higher activation of PI3K/Akt signaling than those from responders. FNDC1 depletion repressed 5-FU or irradiation-induced activation of PI3K/AKT in CRC cells. More importantly, pharmacological inhibition of PI3K/Akt signaling effectively decreased the effect of FNDC1 on chemoradiation resistance. Taken together, our study reveals the potential function of FNDC1 as a biomarker to predict nCRT sensitivity in CRC and a therapeutic target in CRC treatment.

Rigid Neuroendoscopy Assisted Hematoma Resection Reduces the Recurrence Rate of Chronic Subdural Hematoma With Mixed Density: A Retrospective Analytic Cohort Study.

Background: The mixed density hematoma (MDH) has a high recurrence rate in chronic subdural hematoma (CSDH). This study adopted rigid neuroendoscopy assisted hematoma resection to evacuate CSDH and investigated its efficacy as compared with the traditional burr-hole craniostomy (BHC) in CSDH with mixed density. Methods: A retrospective cohort study was conducted at two centers between January 2015 and December 2020. The data of 124 patients who underwent BHC for CSDH with mixed density were collected and analyzed. A total of 41 patients underwent rigid neuroendoscopy assisted hematoma resection (neuroendoscopy group) and 83 patients were treated by the traditional BHC (control group). Follow-ups were conducted 6 months after the surgery. Results: There was no significant difference in the baseline characteristics and preoperative CT features between the two groups (p > 0.05). The neuroendoscopy group had a lower recurrence rate than the control group (p = 0.043). Besides the neuroendoscopy group had a higher rate of hematoma evacuation (p < 0.001), less pneumocephalus volume (p < 0.001), shorter hospital stay (p < 0.001) and better Markwalder score (p < 0.001) than the control group within 24-48 h after operation. However, there was no significant difference between the two groups in the incidence of pneumocephalus, Markwalder score (at discharge and 6 months after surgery) and mortality. Moreover, the operation time was longer in the neuroendoscopy group (p < 0.001). Conclusions: When compared with the traditional BHC, rigid neuroendoscopy assisted hematoma resection can better reduce the recurrence rate of CSDH with mixed density. Also, it surpassed the results obtained from BHC in reducing the volume of pneumocephalus, improving hematoma evacuation rate, promoting short-term neurological recovery, and shortening hospital stays.

Fluorescent Probes and Mass Spectrometry-Based Methods to Quantify Thiols in Biological Systems.

Significance: Fluorescent probes and mass spectrometry are the two most popular and complementary methods to quantify thiols in biological systems. In this review, we focus on the widely used and commercially available methods to detect and quantify thiols in living cells and the general approaches applied in mass spectrometry-based thiol quantification. We hope that this review can serve as a general guide for redox biologists who are interested in thiol species. Sulfur, one of the most important elements in living systems, contributes to every aspect of physiology and pathology. Thiols, including cysteine, homocysteine, glutathione, hydrogen sulfide, and hydropersulfides, are the main players in the redox biology system. Therefore, quantifying these thiol species in biological systems is one of the important steps to understand their roles in biology. Recent Advances: Fluorescent probes and mass spectrometry-based methods have been developed to detect and/or quantify thiols in biological systems. Mass spectrometry-based methods have been the gold standard for metabolite quantification in cells. Fluorescent probes can directly detect or quantify thiol species in living cells with spatial and temporal resolutions. Additionally, organelle-specific fluorescent probes have been widely developed. These two methods are complementary to each other. Critical Issues: Reliable quantification of thiol species using fluorescent probes remains challenging. Future Directions: When developing fluorescent probes, we suggest using both the fluorescent probes and mass spectrometry-based thiol quantification methods to cross-check the results. In addition, we call on chemical biologists to move beyond qualitative probes and focus on probes that can provide quantitative results in live cells. These quantitative measurements based on fluorescent probes should be validated with mass spectrometry-based methods. More importantly, chemical biologists should make their probes accessible to the biology end users. Regarding mass spectrometry-based methods, quantification of the derivatized thiol specifies should fit into the general metabolomics workflow. Antioxid. Redox Signal. 36, 354-365.

A Novel Mechanism of Endoplasmic Reticulum Stress- and c-Myc-Degradation-Mediated Therapeutic Benefits of Antineurokinin-1 Receptor Drugs in Colorectal Cancer.

The neurokinin-1 receptor (NK-1R) antagonists are approved as treatment for chemotherapy-associated nausea and vomiting in cancer patients. The emerging role of the substance P-NK-1R system in oncogenesis raises the possibility of repurposing well-tolerated NK-1R antagonists for cancer treatment. This study reports that human colorectal cancer (CRC) patients with high NK-1R expression have poor survival, and NK-1R antagonists SR140333 and aprepitant induce apoptotic cell death in CRC cells and inhibit CRC xenograft growth. This cytotoxicity induced by treatment with NK-1R antagonists is mediated by induction of endoplasmic reticulum (ER) stress. ER stress triggers calcium release, resulting in the suppression of prosurvival extracellular signal-regulated kinase (ERK)-c-Myc signaling. Along with ER calcium release, one ER stress pathway mediated by protein kinase RNA-like ER kinase (PERK) is specifically activated, leading to increased expression of proapoptotic C/EBP-homologous protein (CHOP). Moreover, NK-1R antagonists enhance the efficacy of chemotherapy by increasing the sensitivity and overcoming resistance to 5-fluorouracil in CRC cells through the induction of sustained ER stress and the consequent suppression of ERK-c-Myc signaling both in vitro and in vivo. Collectively, the findings provide novel mechanistic insights into the efficacy of NK-1R antagonists either as a single agent or in combination with chemotherapy for cancer treatment.

Synergistic antitumor effect of the anti-ErbB2 antibodies trastuzumab and H2-18 on trastuzumab-resistant gastric cancer cells.

Trastuzumab resistance is a severe problem in the treatment of ErbB2-amplified cancer. Although trastuzumab plus pertuzumab is able to partly overcome trastuzumab resistance in ErbB2-overexpressing cancer, its antitumor efficacy remains limited. The present study investigated the antitumor activity of the combination of trastuzumab with H2-18, which is an antibody targetinsg ErbB2 domain I. Cell proliferation and inhibition experiments indicated that H2-18 and trastuzumab synergistically inhibited the proliferation of both the trastuzumab-sensitive gastric cancer cell line, NCI-N87 and the trastuzumab-resistant gastric cancer cell line, NCI-N87-TraRT. Furthermore, H2-18 plus trastuzumab inhibited the growth of NCI-N87-TraRT cells more effectively than trastuzumab plus pertuzumab, both in vitro and in vivo. Compared with trastuzumab plus pertuzumab, H2-18 plus trastuzumab had a potent ability to inhibit NCI-N87-TraRT cells to form colonies. Notably, H2-18 plus trastuzumab was more effective in inducing cell death than trastuzumab plus pertuzumab. The in vivo studies demonstrated that H2-18 plus trastuzumab effectively inhibited the growth of both NCI-N87 and NCI-N87-TraRT xenograft tumors. Further experiments revealed that in NCI-N87-TraRT cells, H2-18 plus trastuzumab was comparable to trastuzumab plus pertuzumab in the inhibition of phosphorylated (p-)HER3, p-AKT and p-ERK. However, compared with trastuzumab plus pertuzumab, H2-18 plus trastuzumab effectively activated ROS production and the phosphorylation of JNK and c-jun in NCI-N87-TraRT cells. Therefore, the superior antitumor efficacy of H2-18 plus trastuzumab over trastuzumab plus pertuzumab may be mainly attributable to the potent cell death-inducing activity. In addition, the in vitro and in vivo antitumor effect of the combination of H2-18, trastuzumab and pertuzumab were further investigated. The results revealed that H2-18 plus trastuzumab plus pertuzumab exhibited a maximal antitumor effect among all the anti-ErbB2 monoclonal antibody combinations tested. In summary, H2-18 plus trastuzumab may have potential as an effective strategy to overcome the resistance to trastuzumab in ErbB2-amplified gastric cancer cell lines.

Resistance to Both Chemotherapy and EGFR-TKI in Small Cell Lung Cancer With EGFR 19-Del Mutation: A Case Report.

Epidermal growth factor receptor (EGFR) mutations are common in non-small cell lung cancers, but rare in small cell lung cancers (SCLCs). In previous reports, some SCLC patients with EGFR mutations could benefit from EGFR tyrosine kinase inhibitors (TKIs). In this study, we reported a case in which an SCLC patient with EGFR exon 19 deletion (19-Del) mutation did not benefit from EGFR-TKIs. Interestingly, the standard treatment strategies for SCLC also failed to control tumor progression. Moreover, we screened 43 SCLC patients in China and found that the frequency of EGFR mutations in Chinese SCLC patients was about 4.65% by next-generation sequencing (NGS). Collectively, this case illustrated a rare subtype of SCLCs which harbored EGFR mutations and was intrinsically resistant to standard treatments and EGFR-TKIs. We also tried to explore the mechanisms underlying drug resistance. The literature concerning SCLCs with EGFR mutations is reviewed.

Aprepitant Sensitizes Acute Myeloid Leukemia Cells to the Cytotoxic Effects of Cytosine Arabinoside in vitro and in vivo.

PURPOSE: Acute myeloid leukemia (AML) is a complex malignancy characterized by the clonal expansion of immature myeloid precursors. The standard treatment for newly diagnosed AML is chemotherapy consisting of cytosine arabinoside (Ara-C) and anthracyclines with disappointing clinical outcomes and severe adverse effects, such as symptomatic bradycardia, neurotoxicity. Thus, it is promising to treat AML through combination drug therapy to reduce the adverse effects of chemotherapeutics. In our recent published PNAS paper, we reported that NK-1R antagonists, both Aprepitant and SR140333, induce apoptosis of myeloid leukemia cells by inducing oxidative stress through mitochondrial calcium overload. We, therefore, tested the hypothesis of the combination Ara-C with NK-1R antagonist could enhance the efficacy of Ara-C. METHODS: MTT assay was employed to detect the cell proliferation. Flow cytometry was applied to detect the cell cycle and necrosis. PI uptake and LDH release assay were used to detect the disintegration of the plasma membrane. Xenograft model was constructed to explore the effect of combination Ara-C with Aprepitant in vivo. RESULTS: Our results showed that Aprepitant sensitizes HL60 cells to the cytotoxic effects of Ara-C more than 5-fold by enhancing G0/G1 cell cycle arrest and necrosis in vitro. Furthermore, Nec-1, a specific inhibitor of necroptosis, could recover the cell proliferative viability significantly. Attractively, once every 2-days regimen of Ara-C (5 mg/kg) and Aprepitant (10 mg/kg) via in situ injection dramatically reduced the tumor volume from 2175.0 ± 341.9 mm3 in the vehicle group to 828.4 ± 232.4 mm3 in the combination group without obvious toxicity in human myeloid leukemia xenograft mice. CONCLUSION: Taken together, reduced dose of Ara-C combination with moderate Aprepitant provides more effective therapeutical methods for AML treatment in vitro and in vivo with the elimination of the toxicity of Ara-C, which may pay new avenue for the usage of the routine chemotherapy drug Ara-C with low dose to enhance efficacy and reduce toxicity in clinical practice.

The function of SOX2 in breast cancer and relevant signaling pathway.

OBJECTIVE: The purpose of this study was to explore the functional roles of SOX2 in the progression of breast cancer and relevant molecular mechanism. METHODS: A total of 108 breast cancer patients were included, and breast cancer cell line MDA-MB-231 was selected for this research. Real time-qualitative polymerase chain reaction (RT-qPCR) was conducted to measure the expression level of SOX2 mRNA. MTT and Transwell assays were used to detected the proliferation, migration and invasion of breast cancer cells, respectively. Luciferase reporter assay was conducted to reveal the relationship of SOX2 with PTEN. Western blot was performed to detect the expressions of Wnt/ß-catenin pathway-related proteins. RESULTS: The expression of SOX2 mRNA was up-regulated in breast cancer tissues and cells (P < 0.001). SOX2 expression was significantly associated with TNM stage and lymph node metastasis of breast cancer patients (P < 0.05). SOX2 knockdown significantly inhibited the proliferation, migration and invasion of breast cancer cells (P < 0.05). PTEN was a direct target of SOX2. The inhibition of PTEN could significantly suppress the progression of breast cancer cells with SOX2 overexpression. SOX2 knockdown also inhibited the expressions of ß-catenin, TCP-4, FZD7, C-myc and MMP-7 proteins. Moreover, PTEN knockdown reversed the results caused by SOX2 overexpression, that is, increased expressions of ß-catenin, TCP-4, FZD7, C-myc and MMP-7 proteins (P < 0.05). CONCLUSION: SOX2 promotes the progression of breast cancer through activating Wnt/ß-catenin signaling pathway via regulating PTEN.

Downregulation of miR-423-5p Contributes to the Radioresistance in Colorectal Cancer Cells.

Resistance to radiotherapy is the main reason causing treatment failure in locally advanced rectal cancer. MicroRNAs (miRNAs) have been well demonstrated to regulate cancer development and progression. However, how miRNAs regulate radiotherapy resistance in colorectal cancer remains unknown. Herein, we established two human colorectal cancer cell lines resistant to radiotherapy, named HCT116-R and RKO-R, using the strategy of fractionated irradiation. The radioresistant phenotypical changes of the two cell lines were validated by cell viability assay, colony formation assay and apoptosis assay. The miRNA expression profilings of HCT116-R and RKO-R were determined using RNA-seq analyses, and further confirmed by quantitative real-time PCR. Multiple miRNAs, including miR-423-5p, miR-7-5p, miR-522-3p, miR-3184-3p, and miR-3529-3p, were identified with altered expression in both of the radiotherapy-resistant cells, compared to the parental cells. The downregulation of miR-423-5p was further validated in the rectal cancer tissues from radiotherapy-resistant patients. Silencing of miR-423-5p in parental HCT116 and RKO cells decreased the sensitivity to radiation treatment, and inhibited the radiation-induced apoptosis. In consistence, overexpression of miR-423-5p in HCT116-R and RKO-R cells partially rescued their sensitivity to radiotherapy, and promoted the radiation-induced apoptosis. Bcl-xL (Bcl-2-like protein 1) was predicted to be a potential target gene for miR-423-5p, and miR-423-5p/Bcl-xL axis could be a critical mediator of radiosensitivity in colorectal cancer cells. The current finding not only revealed a novel role of miR-423-5p in regulating the radiosensitivity in colorectal cancer, but also suggested miR-423-5p as a molecular candidate for combination therapy with radiation to treat colorectal cancer.

Accurate wisdom of the crowd from unsupervised dimension reduction.

Wisdom of the crowd, the collective intelligence from responses of multiple human or machine individuals to the same questions, can be more accurate than each individual and improve social decision-making and prediction accuracy. Crowd wisdom estimates each individual's error level and minimizes the overall error in the crowd consensus. However, with problem-specific models mostly concerning binary (yes/no) predictions, crowd wisdom remains overlooked in biomedical disciplines. Here we show, in real-world examples of transcription factor target prediction and skin cancer diagnosis, and with simulated data, that the crowd wisdom problem is analogous to one-dimensional unsupervised dimension reduction in machine learning. This provides a natural class of generalized, accurate and mature crowd wisdom solutions, such as PCA and Isomap, that can handle binary and also continuous responses, like confidence levels. They even outperform supervised-learning-based collective intelligence that is calibrated on historical performance of individuals, e.g. random forest. This study unifies crowd wisdom and unsupervised dimension reduction, and extends its applications to continuous data. As the scales of data acquisition and processing rapidly increase, especially in high-throughput sequencing and imaging, crowd wisdom can provide accurate predictions by combining multiple datasets and/or analytical methods.

Causal Transcription Regulatory Network Inference Using Enhancer Activity as a Causal Anchor.

Transcription control plays a crucial role in establishing a unique gene expression signature for each of the hundreds of mammalian cell types. Though gene expression data have been widely used to infer cellular regulatory networks, existing methods mainly infer correlations rather than causality. We developed statistical models and likelihood-ratio tests to infer causal gene regulatory networks using enhancer RNA (eRNA) expression information as a causal anchor and applied the framework to eRNA and transcript expression data from the FANTOM Consortium. Predicted causal targets of transcription factors (TFs) in mouse embryonic stem cells, macrophages and erythroblastic leukaemia overlapped significantly with experimentally-validated targets from ChIP-seq and perturbation data. We further improved the model by taking into account that some TFs might act in a quantitative, dosage-dependent manner, whereas others might act predominantly in a binary on/off fashion. We predicted TF targets from concerted variation of eRNA and TF and target promoter expression levels within a single cell type, as well as across multiple cell types. Importantly, TFs with high-confidence predictions were largely different between these two analyses, demonstrating that variability within a cell type is highly relevant for target prediction of cell type-specific factors. Finally, we generated a compendium of high-confidence TF targets across diverse human cell and tissue types.