NAD+ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis.

Rationale: In recent years, nicotinamide adenine dinucleotide (NAD+) precursors (Npre) have been widely employed to ameliorate female reproductive problems in both humans and animal models. However, whether and how Npre plays a role in the male reproductive disorder has not been fully clarified. Methods: In the present study, a busulfan-induced non-obstructive azoospermic mouse model was used, and Npre was administered for five weeks following the drug injection, with the objective of reinstating spermatogenesis and fertility. Initially, we assessed the NAD+ level, germ cell types, semen parameters and sperm fertilization capability. Subsequently, testis tissues were examined through RNA sequencing analysis, ELISA, H&E, immunofluorescence, quantitative real-time PCR, and Western blotting techniques. Results: The results indicated that Npre restored normal level of NAD+ in blood and significantly alleviated the deleterious effects of busulfan (BU) on spermatogenesis, thereby partially reestablishing fertilization capacity. Transcriptome analysis, along with recovery of testicular Fe2+, GSH, NADPH, and MDA levels, impaired by BU, and the fact that Fer-1, an inhibitor of ferroptosis, restored spermatogenesis and semen parameters close to CTRL values, supported such possibility. Interestingly, the reduction in SIRT2 protein level by the specific inhibitor AGK2 attenuated the beneficial effects of Npre on spermatogenesis and ferroptosis by affecting PGC-1α and ACLY protein levels, thus suggesting how these compounds might confer spermatogenesis protection. Conclusion: Collectively, these findings indicate that NAD+ protects spermatogenesis against ferroptosis, probably through SIRT2 dependent mechanisms. This underscores the considerable potential of Npre supplementation as a feasible strategy for preserving or restoring spermatogenesis in specific conditions of male infertility and as adjuvant therapy to preserve male fertility in cancer patients receiving sterilizing treatments.

Montelukast Sodium to Prevent and Treat Bronchopulmonary Dysplasia in Very Preterm Infants: A Quasi-Randomized Controlled Trial.

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in preterm infants and lacks effective methods for prevention and treatment. The aim of this study is to explore the efficacy and safety of montelukast in preventing or treating BPD in preterm infants. The preterm infants with BPD risk factors were divided randomly into a montelukast group and a control group. In the montelukast group, preterm infants were given 1 mg/kg of montelukast sodium daily. There was no placebo in the control group. There was no significant difference in the incidence of moderate or severe BPD between the two groups (31.8% vs. 35%). The duration of respiratory support in the montelukast group was shorter than that in the control group (36.4 ± 12.8 d vs. 43.1 ± 15.9 d, p = 0.037). The pulmonary severity score (PSS) at 21 days of life in the montelukast group was significantly lower than that in the control group (0.56 ± 0.13 vs. 0.62 ± 0.14, p = 0.048). There were no significant differences in the duration of mechanical ventilation, length of stay, hospitalization expenses, or incidence of adverse events. Although montelukast cannot alleviate the severity of BPD, it may shorten the duration of respiratory support and decrease the PSS in very preterm infants. There were no significant adverse drug events associated with montelukast treatment.

[Retrospective study on the modified Uhl technique of closed reduction and percutaneous pin in the treatment of Colles' fracture].

OBJECTIVE: To retrospectively assess the advantages of the modified Uhl technique in the treatment of Colles' fracture guided by the principles of Chinese osteosynthesis (CO) concept. METHODS: A retrospective study was conducted on 358 patients with Colles' fracture treated with the modified Uhl technique of closed reduction and percutaneous pin between January 2016 and June 2021. Out of these, 120 eligible cases were selected and categorized into two groups according to different surgical methods:the closed reduction and percutaneous pin group, and the open reduction group. Sixty-eight patients in the closed reduction and percutaneous pin group were treated with the modified Uhl technique, while fifty-two patients in the open reduction group were treated with open reduction and internal fixation using plates. The modified Sarmiento imaging score, Gartland-Werley wrist score, operation time, hospital stay, and treatment costs between the two groups were compared at a 6-month postoperative follow-up. RESULTS: There were no significant differences in terms of gender, age, affected side, injure factors, time of injury to surgery, Sarmiento imaging score, and Gartland-Werley wrist joint score (P>0.05). The closed reduction and percutaneous pin group exhibited an operation time of (35.88±14.11) minutes, hospitalization stay of (9.78±2.48) days, and treatment costs of (16 074.91±1 964.48) yuan, while the open reduction group demonstrated comparatively longer operation time of (65.48±14.26) minutes, hospitalization stay of (15.88±2.00) days, and treatment costs of (20 451.27±1 760.22) yuan (P<0.01). CONCLUSION: The modified Uhl technique presents notable advantages in the management of Colles' fracture, including reliable fixation, less trauma, shorter operation time, less pain, shorter hospital stay, and cost-effectiveness. This technique exhibits promising potential for broader clinical application. However, it is important to note that the pin could potentially damage tendons, and in cases of Colles' fractures with osteoporosis and comminuted fragments, additional techniques may be required for reliable fixation.

Antagonizing exosomal miR-18a-5p derived from prostate cancer cells ameliorates metastasis-induced osteoblastic lesions by targeting Hist1h2bc and activating Wnt/ß-catenin pathway.

More than 50% of prostate cancer (PCa) patients have bone metastasis with osteoblastic lesions. MiR-18a-5p is associated with the development and metastasis of PCa, but it remains unclear whether it is involved in osteoblastic lesions. We first found that miR-18a-5p was highly expressed in the bone microenvironment of patients with PCa bone metastases. To address how miR-18a-5p affects PCa osteoblastic lesions, antagonizing miR-18a-5p in PCa cells or pre-osteoblasts inhibited osteoblast differentiation in vitro. Moreover, injection of PCa cells with miR-18a-5p inhibition improved bone biomechanical properties and bone mineral mass in vivo. Furthermore, miR-18a-5p was transferred to osteoblasts by exosomes derived from PCa cells and targeted the Hist1h2bc gene, resulting in Ctnnb1 up-regulation in the Wnt/ß-catenin signaling pathway. Translationally, antagomir-18a-5p significantly improved bone biomechanical properties and alleviated sclerotic lesions from osteoblastic metastases in BALB/c nude mice. These data suggest that inhibition of exosome-delivered miR-18a-5p ameliorates PCa-induced osteoblastic lesions.

In Situ Enzymatic Reaction Generates Magnesium-Based Mineralized Microspheres with Superior Bioactivity for Enhanced Bone Regeneration.

Bone is a naturally mineralized tissue with a remarkable hierarchical structure, and the treatment of bone defects remains challenging. Microspheres with facile features of controllable size, diverse morphologies, and specific functions display amazing potentials for bone regeneration. Herein, inspired by natural biomineralization, a novel enzyme-catalyzed reaction is reported to prepare magnesium-based mineralized microspheres. First, silk fibroin methacryloyl (SilMA) microspheres are prepared using a combination of microfluidics and photo-crosslinking. Then, the alkaline phosphatase (ALP)-catalyzed hydrolysis of adenosine triphosphate (ATP) is successfully used to induce the formation of spherical magnesium phosphate (MgP) in the SilMA microspheres. These SilMA@MgP microspheres display uniform size, rough surface structure, good degradability, and sustained Mg2+ release properties. Moreover, the in vitro studies demonstrate the high bioactivities of SilMA@MgP microspehres in promoting the proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Transcriptomic analysis shows that the osteoinductivity of SilMA@MgP microspheres may be related to the activation of the PI3K/Akt signaling pathway. Finally, the bone regeneration enhancement units (BREUs) are designed and constructed by inoculating BMSCs onto SilMA@MgP microspheres. In summary, this study demonstrates a new biomineralization strategy for designing biomimetic bone repair materials with defined structures and combination functions.

Comparison of clinical effects of percutaneous vertebroplasty with two different puncture approaches on the treatment of thoracolumbar osteoporotic vertebral compression fractures with narrow pedicles: a retrospective controlled study.

PURPOSE: To evaluate the effects of percutaneous vertebroplasty (PVP) with conventional transpedicle approach (CTA) or basal transverse process-pedicle approach (BTPA) on the treatment of thoracolumbar osteoporotic vertebral compression fractures (TL-OVCFs) with narrow pedicles. METHODS: A retrospective study of TL-OVCFs with narrow pedicles was performed, including 78 cases of CTA and 84 cases of BTPA. The surgical outcomes, radiographic parameters [the width and height of the pedicle (PW, PH), the inclination angle of puncture (PIA)] and clinical indicators [visual analog scale (VAS) score, Oswestry Disability Index (ODI)] of two groups were compared. RESULTS: In terms of surgical outcomes of them, there was no difference in operation time (P > 0.05), while the volume of bone cement, the incidence of bone cement leakage and rate of good bone cement distribution were significantly worse in the CTA group (4.4 ± 0.6 ml vs. 5.5 ± 0.5 ml, 37.2% vs. 20.2%, 52.6% vs. 79.8%, P < 0.05). As for radiographic parameters and clinical indicators of them, the differences were not observed in the PH, PW, preoperative VAS score and ODI (P > 0.05), whereas the PIA, VAS score and ODI at 1 day postoperatively were significantly better in the BTPA group (17.3 ± 2.1° vs. 29.6 ± 2.8°, 2.7 ± 0.7 vs. 2.1 ± 0.8, 32.8 ± 4.6 vs. 26.7 ± 4.0, P < 0.05). CONCLUSION: The study provided solid evidence that PVP with BTPA had more advantages in the treatment of TL-OVCFs with narrow pedicles, which can better relieve postoperative pain.

A Combined Pharmacometrics Analysis of Biomarker Distribution Under Treatment With Standard- or Low-Dose Rivaroxaban in Real-World Chinese Patients With Nonvalvular Atrial Fibrillation.

Background: The rivaroxaban dose regimen for patients with nonvalvular atrial fibrillation (NVAF) is complex in Asia. Given the high interindividual variability and the risk of bleeding caused by rivaroxaban in Asians, the influencing factors and the relationship between outlier biomarkers and bleeding events need exploration. Methods: The integrated pharmacokinetics (PK)/pharmacodynamics (PD) models were characterized based on rich PK/PD data from 304 healthy volunteers and sparse PD [anti-factor Xa activity (anti-Xa) and prothrombin (PT)] data from 223 patients with NVAF. The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored. The final integrated PK/PD model was used to evaluate the influence of dosage and individual covariates on PD parameters. Results: A two-compartment, linear model with sequential zero-order and first-order absorption was adopted. The dose-specific relative bioavailability (F1), diet status, creatinine clearance, and body mass index (BMI) improved the model fit. The apparent systemic clearance was 7.39 L/h, and the central and peripheral volumes were 10.9 and 50.9 L, respectively. The linear direct-effects model with shape factor plus the additive (and/or proportional) error model described the correlation between anti-Xa/PT and plasma concentration. Bodyweight, total cholesterol (TCHO), and diet status were selected as the covariates of the anti-Xa/PT model. Anti-Xa was more sensitive to the increase in rivaroxaban exposure compared with PT. An elevated bleeding tendency was seen with higher peak anti-Xa and PT. For a typical Chinese patient, the peak anti-Xa value (median (5%-95% PI)) of 20 and 15 mg were 309 ng/ml (139-597 ng/ml) and 296 ng/ml (138-604 ng/ml), both median values were within the expected range. For patients with CrCL 30-49 ml/min, the median peak anti-Xa with recommended 10 mg other than 15 mg were within the expected range. Conclusion: Fixed doses of rivaroxaban could be prescribed for patients with NVAF without adjustment for bodyweight, BMI, and TCHO. Randomized studies should be performed to evaluate the efficacy and safety of low-dose rivaroxaban in Chinese patients with NVAF.

A Model Perspective Explanation of the Long-Term Sustainability of a Fully Human BCMA-Targeting CAR (CT103A) T-Cell Immunotherapy.

Different from canonical drugs, CAR T-cells are "living drugs", which derived from patient's own blood. Studies of the pharmacokinetics of CAR T-cells could improve our understanding of their efficacy, safety, optimal dosage, and other characterizes. We previously reported a phase I study of a novel fully human BCMA-targeting CAR (CT103A) in 18 patients with relapsed/refractory multiple myeloma. CT103A exhibited extraordinary persistence with low anti-drug antibody positivity. To figure out the pharmacokinetic characterizes and investigate the potential reason of CT103A's long-term persistence, we established a population pharmacokinetic (PopPK) model of CT103A based on 18 patients cohort by applying nonlinear mixed-effects modeling and analyzed the CAR T-cell clonal evolution. The results suggested that extramedullary spreading was found to impair Cmax and was therefore added as a covariate to the modified model. The model revealed tocilizumab and corticosteroids showed no impact on the CT103A expansion rate. No dominant clone existed in patients with persistently high peripheral CT103A by CAR integration sites analysis. Finally, patients with lower contraction rate constants and higher Cmax as well as memory CT103A fraction could achieve better clinical responses. Taken together, this study developed a PopPK model of a fully human anti-BCMA CAR T-cell therapy, and summarized its model characteristics. We suggested that the long-term persistence of CT103A was attributed to the memory CAR T-cell fraction but not the clonal evolution. This study will improve people's understanding of pharmacokinetics and PopPK of CAR T-cell immunotherapy.

Mesenchymal stem cell extracellular vesicles-derived microRNA-194-5p delays the development of intervertebral disc degeneration by targeting TRAF6.

OBJECTIVE: Mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) can improve intervertebral disc degeneration (IDD). Considering that, their concrete mechanisms from microRNA-194-5p/tumor receptor-associated factor 6 (miR-194-5p/TRAF6) axis in IDD ask for disclosure in a scientific way. METHODS: Nucleus pulposus (NP) cells and MSCs were obtained. EVs were isolated from the obtained MSCs and identified. miR-194-5p expression in MSC-EVs was altered by sequence transfection. Subsequently, MSCs-EVs were co-cultured with NP cells intervened by tumor necrosis factor α (TNF-α). NP cell proliferation and apoptosis, along with their osteogenic differentiation ability were evaluated. miR-194-5p and TRAF6 expression and their interaction were determined. RESULTS: In TNF-α-intervened NP cells, miR-194-5p was down-regulated and TRAF6 was up-regulated. Restoring miR-194-5p effectively enhanced proliferation and osteogenic differentiation, and reduced apoptosis of TNF-α-intervened NP cells. miR-194-5p-enriched MSCs-EVs protected TNF-α-intervened NP cells. miR-194-5p targeted TRAF6, TRAF6 overexpression exerted negatively for the growth of TNF-α-intervened NP cells, and could reduce the protective effects of miR-194-5p on TNF-α-intervened NP cells. CONCLUSION: It is elucidated that miR-194-5p derived from MSCs-EVs protects TNF-α-intervened NP cells through restricting TRAF6, replenishing a potential target for IDD treatment.

Transthyretin Suppressed Tumor Progression in Nonsmall Cell Lung Cancer by Inactivating MAPK/ERK Pathway.

Background: Lung malignancy is a main source of disease passing all throughout the planet, whereas the transthyretin (TTR) is a specific biomarker for clinical diagnosis. However, its role in lung malignancy stays to be obscure. Materials and Methods: In the current examination, the authors made an endeavor to research impact of abnormal expression of TTR on nonsmall cell lung carcinoma (NSCLC) by overexpression or knockdown of TTR. To further explore the instruments' fundamental mechanism part of TTR in NSCLC, several signal pathways were searched and verified. To confirm the effect of TTR overexpression on tumors, in vivo experiments were conducted. Result: It was found that upregulated TTR clearly stifled cell proliferation, migration, invasion, and expanded apoptosis. Significant suppression of phosphor-extracellular signal-regulated kinase (ERK) was observed in TTR-treated NSCLC cells, implying that TTR was important for cellular progress by regulating mitogen-activated protein kinase/ERK signaling pathway. In in vivo experiment, overexpression of TTR promoted cell apoptosis and inhibited tumor growth. Conclusion: Overall, the results suggest that TTR has a potential antitumor effect in human NSCLC progression, which provides theoretical basis for the diagnosis and treatment of NSCLC. Above all, further understanding of TTR was useful for clinical care. Clinical Trial Registration Number: 2016-08.

Effect and Mechanism of Transthyretin over-Expression on Proliferation and Cell Cycle of Lung Cancer A549 Cells.

BACKGROUND: The effects of transthyretin (TTR) over-expression on the proliferation and cell cycle of non-small cell lung cancer (NSCLC) A549 cells and its possible mechanism were verified. METHODS: A total of 196 LC patients and 20 healthy controls were enrolled at Tianjin Hospital, Tianjin, China between Apr 2017 and Oct 2017. The serum TTR content was detected by ELISA. Through lentiviral transfection method, NSCLC cells were divided into non-transfected group (group A), negative control group (group B) transfected with empty vector and experimental group (group C) transfected with TTR over-expression. Cell proliferation was detected by CCK-8 method, TTR mRNA expression was detected by real-time quantitative polymerase chain reaction (RT-qPCR), and TTR protein expression was tested by Western blot (WB). Cell cycle was detected by flow cytometry, Wnt3a/ß-catenin protein expression was detected by WB, and mRNA expression was detected by RT-qPCR. RESULTS: The serum TTR content in early, middle and late LC group was remarkably lower than that in healthy group (P<0.05). Compared with late stage, TTR content in early and middle stages of LC group was higher, and the difference was statistically marked (P < 0.05). The absorbance value of group C was lower than that of groups A and B, indicating that the cell proliferation activity dramatically decreased, with statistically marked difference (P<0.05). LC A549 cells in group C were obviously blocked in G2M, with statistical significance (P<0.05). CONCLUSION: TTR over-expression can inhibit the proliferation of NSCLC A549 cells, and the expression is related to Wnt3a/ß-catenin pathway. TTR in serum of patients was helpful for diagnosing LC and has certain clinical value.

[Retracted] Methylation­induced downregulation and tumor-suppressive role of microRNA­98 in glioma through targeting Sal­like protein 4.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell Transwell assay data in the article (featured in Figs. 4D and 6D) were strikingly similar to data appearing in different form in other articles by different authors at different research institutions, which were already under consideration for publication or had already been published elsewhere at the time of the present article's submission. Owing to the fact that the contentious data in the above article had already appeared in different form in other articles prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 41: 2651-2659, 2018; DOI: 10.3892/ijmm.2018.3464].

LRP1B mutation is associated with tumor HPV status and promotes poor disease outcomes with a higher mutation count in HPV-related cervical carcinoma and head & neck squamous cell carcinoma.

Human papillomavirus (HPV) infection and gene mutations were reputed as key factors in cervical carcinoma (CC) and head and neck squamous cell carcinoma (HNSCC). However, the associations of HPV status and gene mutations remain to be determined. This study aims to identify molecular patterns of LRP1B mutation and HPV status via rewiring tumor samples of HNSCC (n=1478) and CC (n=178) from the TCGA dataset. Here, we found that LRP1B mutation was associated with HPV status in CC (P=0.040) and HNSCC (P=0.044), especially in HPV 16 integrated CC (P=0.036). Cancer survival analysis demonstrated that samples with LRP1B mutation showed poor disease outcomes in CC (P=0.013) and HNSCC (P=0.0124). In addition, the expression status of LPR1B was more favorable for prediction than TP53 or RB1 in CC and HNSCC. Mutation clustering analysis showed that samples with LRP1B mutation showed higher mutation count in CC (P=1.76e-67) and HNSCC (P<10e-10). Further analysis identified 289 co-occurrence genes in these two cancer types, which were enriched in PI3K signaling, cell division process, and chromosome segregation process, et al. The 289-co-occurrence gene signature identified a cluster of patients with a higher portion of copy number variation (CNV) lost in the genome, different tumor HPV status (P<10e-10), higher mutation count (P<10e-10), higher fraction genome altered value (P=2.078e-4), higher aneuploidy score (P=3.362e-4), and earlier started the smoking year (P=2.572e-4), which were associated with shorter overall survival (P=0.0103) in CC and HNSCC samples. Overall, LRP1B mutation was associated with tumor HPV status and was an unfavorable prognostic biomarker for CC and HNSCC.

Optimizing accuracy of freehand cannulation of the ipsilateral ventricle for intracranial pressure monitoring in patients with brain trauma.

BACKGROUND: Intracranial pressure (ICP) monitoring in traumatic brain injury (TBI) usually requires the placement of a catheter into the ipsilateral ventricle. This surgical procedure is commonly performed via a freehand method using surface anatomical landmarks as guides. The current accuracy of the catheter placement remains relatively low and even lower among TBI patients. This study was undertaken to optimize the freehand ventricular cannulation to increase the accuracy for TBI. The authors hypothesized that an optimal surgical plan of cannulation should give an operator the greatest degrees of freedom, which could be measured as the range of operation angle, range of catheter placement depth, and size of the target area. METHODS: An imaging simulation was first performed using the computed tomography (CT) images of 47 adult patients with normal brain anatomy. On the reconstructed 3D head model, four different coronal planes of ventricular cannulation were identified: a 4-cm anterior, a 2-cm anterior, a standard (central), and a 2-cm posterior plane. The degrees of freedom during the cannulation procedure were determined, including the relevant angles, lengths of cannulation, cross-sectional area, and bounding rectangle of the lateral ventricle. Next, a retrospective assessment was performed on the CT scans of another 111 patients with TBI who underwent freehand ventricular cannulation for ICP monitoring. Postoperative measurements were also performed based on CT images to calculate the accuracy and safety of catheter placement between coronal planes in practice. RESULTS: Our simulation results showed that the 2-cm anterior plane had more extensive degrees of freedom for ventricular cannulation, in terms of length of catheter trajectory (7% longer, P<0.001), cross-sectional area of the lateral ventricle (14% larger, P=0.046), and length of the lateral ventricle (17% wider, P<0.001) than that of the standard plane, while both the 4-cm anterior and 2-cm posterior planes did not offer advantages over the standard plane in these ways. The mean length range of catheter trajectory in the 2-cm anterior plane was 41 to 58 mm. Retrospective assessment of TBI patients with ICP monitor placement also confirmed our simulation data. It showed that the accuracy of ipsilateral ventricle cannulation in the 2-cm anterior plane was 70.6%, which was a significant increase from 42.9% in the standard plane (P=0.007). CONCLUSIONS: Our imaging simulation and retrospective study demonstrate that different coronal planes could provide different degrees of freedom for cannulation, the 2-cm anterior plane has the greatest degrees of freedom in terms of larger target area and greater length range of the trajectory. The optimized surgical plan in this manner could improve cannulation accuracy and benefit a significant number of TBI patients.

Promotion of Bronchopulmonary Dysplasia Progression Using Circular RNA circabcc4 via Facilitating PLA2G6 Expression by Sequestering miR-663a.

Circular RNA (circRNA) has been increasingly proven as a new type of promising therapeutic RNA molecule in a variety of human diseases. However, the role of circRNA in bronchopulmonary dysplasia (BPD) has not yet been elucidated. Here, a new circRNA circABCC4 was identified from the Agilent circRNA chip as a differentially expressed circRNA in BPD. The relationship between circABCC4 level and BPD clinicopathological characteristics was analyzed. The function of circABCC4 was evaluated by performing CCK-8 and apoptosis analysis in vitro and BPD model analysis in vivo. RNA immunoprecipitation (RIP), luciferase reporter and rescue experiments were used to elucidate the interaction between circABCC4 and miR-663a. Luciferase reporter assay and rescue experiments were used to elucidate the interaction between PLA2G6 and miR-663a. CircABCC4 and PLA2G6 levels were increased, while miR-663a levels were decreased in the BPD group, compared to the control group. MiR-663a inhibited apoptosis by repressing PLA2G6 expression, while circABCC4 enhanced the apoptosis and inhibited the proliferation of A549 cells by sponging miR-663a and increasing PLA2G6 expression. In conclusion, circABCC4 promotes the evolving of BPD by spongening miR-663a and up-regulating PLA2G6 expression, which makes circABCC4 an ideal molecular target for early diagnosis and intervention of BPD.

Prediction of transcription factors binding events based on epigenetic modifications in different human cells.

Aim: We aim to predict transcription factor (TF) binding events from knowledge of gene expression and epigenetic modifications. Materials & methods: TF-binding events based on the Encode project and The Cancer Genome Atlas data were analyzed by the random forest method. Results: We showed the high performance of TF-binding predictive models in GM12878, HeLa, HepG2 and K562 cell lines and applied them to other cell lines and tissues. The genes bound by the top TFs (MAX and MAZ) were significantly associated with cancer-related processes such as cell proliferation and DNA repair. Conclusion: We successfully constructed TF-binding predictive models in cell lines and applied them in tissues.

Application of rib surface positioning ruler combined with volumetric CT measurement technique in endoscopic minimally invasive thoracic wall fixation surgery.

Application value of rib surface positioning ruler combined with volumetric CT measurement in selection of the incision for minimally invasive internal fixation of rib fracture was investigated. A total of 80 patients who received internal fixation of rib fractures in Tianjin Hospital Affiliated to Tianjin University (Tianjin, China) from May 2018 to April 2019 were selected. Patients were treated with the rib surface positioning ruler combined with volumetric CT measurement method (n=42) or traditional positioning method (n=38). The following parameters were compared between the two groups: Preset incision accuracy, operation incision length, operation time, intraoperative bleeding volume, postoperative wound drainage volume and postoperative pain score. Compared with the traditional positioning method, rib surface positioning ruler combined with volumetric CT measurement method can improve preset incision accuracy, reduce operation time, incision length, intraoperative bleeding volume, postoperative wound drainage volume, and postoperative pain score, with statistically significant differences (P<0.05). In conclusion, the application of rib surface positioning ruler combined with volumetric CT measurement technique has obvious effect on the selection of incision for internal fixation of rib fracture, and is an effective method worth promoting.

Potential therapeutic targets of the nuclear division cycle 80 (NDC80) complexes genes in lung adenocarcinoma.

Background: Lung cancer is the most common cancer worldwide, both in terms of the incidence and mortality. NDC80 complex comprising of NDC80, NUF2, SPC24, and SPC25 is a heterotetrameric protein complex located in the outer layer of the kinetochore and plays a critical role in mitosis. This study focuses on the effects of NDC80 complex genes on clinical features and prognosis in lung adenocarcinoma (LUAD). Materials and methods: Expression of NDC80 complex in LUAD and related clinical information was extracted from the TCGA website. NDC80 complex gene functional analysis and correlation analysis was conducted by using DAVID, BiNGO, Gene MANIA, STRING and GSEA. Survival probability was predicted by nomogram. Statistical analysis was used to predict NDC80 complex gene expression on clinical features and prognosis in patients with LUAD. Results: Expression of NDC80, NUF2, SPC24 and SPC25 was significantly elevated in LUAD tumors compared with normal tissues (P < 0.05). These genes showed diagnostic values for LUAD (P < 0.001 for each; area under the curve (AUC), 0.958, 0.968, 0.951, and 0.932 respectively); combinatorial analysis of these genes was more advantageous than single analysis alone (P < 0.001; AUC > 0.900 for each). Expression of both NDC80 and SPC25 correlated with the prognosis of LUAD (P < 0.001; AUC > 0.600 for each). Higher expression of NDC80, NUF2, SPC24 and SPC25 was associated with low overall survival (OS) in univariate analysis. Higher expression of NDC80 and SPC25 was associated with low OS in multivariate analysis. High expression of NDC80 combined with high expression of SPC25 was predictive of poor OS in LUAD in joint analysis. Conclusion: NDC80 complex gene might be an early indicator of diagnosis and prognosis of LUAD. The combined detection of NDC80, NUF2, SPC24 and SPC25 may become a new research direction in LUAD diagnosis and a new target for tumor targeted gene therapy.

Alginate oligosaccharides improve germ cell development and testicular microenvironment to rescue busulfan disrupted spermatogenesis.

Rationale: Busulfan is currently an indispensable anti-cancer drug, particularly for children, but the side effects on male reproduction are so serious that critical drug management is needed to minimize any negative impact. Meanwhile, alginate oligosaccharides (AOS) are natural products with many consequent advantages, that have attracted a great deal of pharmaceutical attention. In the current investigation, we performed single-cell RNA sequencing on murine testes treated with busulfan and/or AOS to define the mitigating effects of AOS on spermatogenesis at the single cell level. Methods: Testicular cells (in vivo) were examined by single cell RNA sequencing analysis, histopathological analysis, immunofluorescence staining, and Western blotting. Testes samples (ex vivo) underwent RNA sequencing analysis. Blood and testicular metabolomes were determined by liquid chromatography-mass spectrometry (LC/MS). Results: We found that AOS increased murine sperm concentration and motility, and rescued busulfan disrupted spermatogenesis through improving (i) the proportion of germ cells, (ii) gene expression important for spermatogenesis, and (iii) transcriptional factors in vivo. Furthermore, AOS promoted the ex vivo expression of genes important for spermatogenesis. Finally, our results showed that AOS improved blood and testis metabolomes as well as the gut microbiota to support the recovery of spermatogenesis. Conclusions: AOS could be used to improve fertility in patients undergoing chemotherapy and to combat other factors that induce infertility in humans.

The signature of pharmaceutical sensitivity based on ctDNA mutation in eleven cancers.

IMPACT STATEMENT: Gene mutations are closely related to cancers and drug sensitivity and noninvasive liquid biopsy was used to detect mutations of ctDNA in plasma. In this study, we performed exon sequencing of 416 cancer-related genes for cancer primary tissue and plasma samples of 20 patients in 11 cancers and obtained the comprehensive mutation landscape. We found that liquid biopsy is reliable in place of tissue biopsy. And 31 potential unique mutation prognostic markers were screened in 7 cancer types. Moreover, the drug-mutation network (DMN) was constructed and 9 gene mutations (B-Mut-9) were confirmed that can be served as drug biomarkers in blood. Our study showed that the variation in ctDNA can be used as the biomarkers for cancer prognosis and drug efficacy prediction. This can provide a reference for clinical noninvasive testing.