SY-707, an ALK/FAK/IGF1R inhibitor, suppresses growth and metastasis of breast cancer cells.

Focal adhesion kinase (FAK), a multi-functional cytoplasmic tyrosine kinase, plays a critical role in cancer migration, proliferation and metastasis via regulating multiple signaling pathways. SY-707 is an anaplastic lymphoma kinase (ALK)/FAK/type 1 insulin-like growth factor receptor (IGF1R) multi-kinase inhibitor which is now being evaluated in phase II clinical trials for ALK positive non-small cell lung cancer (NSCLC). However, the effect of SY-707 on breast cancer is unknown. In this study, we assessed preclinical the anti-growth and anti-metastasis potency of SY-707 in breast cancer cells. ATP content, PE-Annexin V, and would healing assays were used to examine cell proliferation, cell cycle and migration. Then, SD rat and beagle dog models were used to evaluate the pharmacokinetics profile of SY-707, and mouse xenograft model was used to evaluate the anti-cancer activities of SY-707 . We found that breast cancer cells apoptosis were induced by SY-707. Moreover, SY-707 exerted inhibition on cell migration and adhesion in a dose-dependent manner. In T47D xenograft mice, SY-707 had significant anti-tumor activities alone or synergistically with Paclitaxel. Meanwhile, SY-707 also displayed significant suppression on spontaneous metastasis of tumor to the lung in 4T1 murine breast cancer xenograft model. In conclusion, SY-707 has potent anti-proliferation and anti-migration potential in breast cancer and , implying its therapeutic application for the treatment of breast cancer in future clinical trials.

The role of surgical management of BCG vaccine-induced regional suppurative lymphadenitis in children: a 7 years' experience from one medical center.

BACKGROUND: The management strategy of Bacille Calmette-Guérin (BCG) vaccine-induced regional suppurative lymphadenitis in children is still controversial and more clinical studies are needed. We therefore present a surgical case series to explore the role of surgical management for this dilemma. METHODS: From January 2013 to June 2020, data from 65 patients diagnosed with BCG vaccine-induced regional suppurative lymphadenitis were retrospectively reviewed. Clinical characteristics, ultrasonographic findings, surgical procedures, perioperative management, and outcome were analyzed. The association between postoperative seroma and symptom duration, skin involvement, and postoperative hospital stay were compared using Yates's corrected Chi-square test and Student's t-test for statistical analysis. The follow-up period ranged from three to six months. RESULTS: Of the 65 cases, the median age at presentation was 3.4 months. All patients were full-term with normal range of birth weight and received a BCG vaccination in the first 24 h of life. All patients underwent surgical excision of the abscess with the involved lymph node(s). Postoperative seroma formation was found in 20 patients and fine needle aspiration was needed. There was no significant association between postoperative seroma formation with symptom duration, skin involvement, and postoperative hospital stay. No oral anti-tubercular agents were given postoperatively. The mean length of postoperative hospital stay was 6.02 ± 1.62 days. Sixty-four cases (98.46%) received only one procedure and recovered. One patient required a second procedure due to postoperative sinus. CONCLUSIONS: The present study showed that surgical excision of the abscess with involved lymph node(s) is one of the choices for BCG vaccine-induced suppurative lymphadenitis, but special attention should be paid to controlling the surgical indications. Intraoperative meticulous manipulation and postoperative care are crucial to achieve a good outcome.

Diagnosis and surgical management strategy for pediatric small bowel obstruction: Experience from a single medical center.

Identifying Bowel strangulation and the approach and timing of surgical intervention for pediatric SBO are still uncertain. In this study, 75 consecutive pediatric patients with surgically confirmed SBO were retrospectively reviewed. The patients were divided into group 1 (n = 48) and group 2 (n = 27) according to the presence of reversible or irreversible bowel ischemia, which was analyzed based on the degree of ischemia at the time of operation. The results demonstrated that the proportion of patients with no prior abdominopelvic surgery was higher, the serum albumin level was lower, and the proportion of patients in which ascites were detected by ultrasonography was higher in group 2 than that in group 1. The serum albumin level was negatively correlated with ultrasonographic findings of the fluid sonolucent area in group 2. There were significant differences in the choice of surgical approach between group 1 and group 2. A symptom duration of >48 h was associated with an increased bowel resection rate. The mean length of hospital stay was shorter in group 1 than that in group 2. In conclusion, immediate surgical intervention should be considered in patients with a symptom duration of >48 h or the presence of free ascites between dilated small bowel loops on ultrasonography. Laparoscopic exploration is recommended as first-line treatment in patients with stable status.

Internal hernia through hepatic falciform ligament iatrogenic defect in a neonate: A case report and review of the literature.

Internal hernia through an iatrogenic defect in the hepatic falciform ligament and acquired jejunal atresia in a 8-day-old neonate was reported. The PubMed, MEDLINE, CNKI, Wanfang and Weipu databases were searched The literature about the hepatic falciform ligament iatrogenic defect causing internal hernia was analysed. Ten other cases were collected from the world literature. Herniated intestinal necrosis was found in four cases. All cases were recovered uneventfully after operation. Internal herniation through an iatrogenic defect in the hepatic falciform ligament is extremely rare. However, the case reports are increasing, especially in the era of laparoscopic surgery. Adequate closure or open the defect is essential to prevent internal hernia occurrence.

SY-1530, a highly selective BTK inhibitor, effectively treats B-cell malignancies by blocking B-cell activation.

OBJECTIVE: B-cell antigen receptor (BCR) signaling is required to maintain the physiological functions of normal B cells and plays an important pathogenic role in B-cell malignancies. Bruton tyrosine kinase (BTK), a critical mediator of BCR signaling, is an attractive target for the treatment of B-cell malignancies. This study aimed to identify a highly potent and selective BTK inhibitor. METHODS: Homogeneous time-resolved fluorescence assays were used to screen BTK inhibitors. Typhoon fluorescence imaging and Western blot analysis were used to confirm the effects of SY-1530 on the BCR signaling pathway. Additionally, the anti-tumor activities of SY-1530 were evaluated in TMD8 xenografts and spontaneous canine B-cell lymphoma. RESULTS: We found a novel irreversible and non-competitive inhibitor of BTK, SY-1530, which provided dose-dependent and time-dependent inhibition. SY-1530 selectively bound to BTK rather than inducible T-cell kinase; consequently, it did not significantly affect T-cell receptor signaling and caused limited off-target effects. SY-1530 blocked the BCR signaling pathway through down-regulation of BTK activity, thus leading to impaired phosphorylation of BTK and its downstream kinases. Moreover, SY-1530 induced apoptosis in a caspase-dependent manner and efficaciously inhibited tumor growth in mouse xenograft models of B-cell malignancy (P < 0.001). SY-1530 also induced positive clinical responses in spontaneous canine B-cell lymphoma. CONCLUSIONS: SY-1530 is an irreversible and selective BTK inhibitor that shows inhibitory effects on B-cell malignancies by blocking the BCR signaling pathway. Therefore, it may be a promising therapeutic approach for the treatment of B-cell malignancies.

Realistic anatomically detailed open-source spinal cord stimulation (RADO-SCS) model.

OBJECTIVE: Computational current flow models of spinal cord stimulation (SCS) are widely used in device development, clinical trial design, and patient programming. Proprietary models of varied sophistication have been developed. An open-source model with state-of-the-art precision would serve as a standard for SCS simulation. APPROACH: We developed a sophisticated SCS modeling platform, named Realistic Anatomically Detailed Open-Source Spinal Cord Stimulation (RADO-SCS) model. This platform consists of realistic and detailed spinal cord and ancillary tissues anatomy derived based on prior imaging and cadaveric studies. In our finite element model of the T9-T11 spine levels, we represented the following tissues: vertebrae, intervertebral disc, epidural space, epidural space vasculature, dura mater, dural sac, intraforaminal tissue, cerebrospinal fluid (CSF), whitematter, spinal cord vasculature, Lissauer's tract, gray matter, dorsal and ventral roots and rootlets, dorsal root ganglion (DRG), sympathetic chain (trunk and ganglion), thoracic aorta and its branching, peripheral vasculature, and soft tissues (thorax). As an exemplary application to illustrate the model workflow, we simulated a bipolar SCS montage and calculated the corresponding activation thresholds for individual axons populating the spinal cord. MAIN RESULTS: RADO-SCS provides state-of-the-art precision across 19 tissue compartments. The resulting model calculations of the electric fields generated in the white-matter and gray matter, and the axonal activation thresholds are broadly consistent with prior simulations. SIGNIFICANCE: The RADO-SCS can be used to simulate any SCS approach with both unprecedented resolution (precision) and transparency (reproducibility). Freely-available online, the RADO-SCS will be updated continuously with version control.

[Analysis of 574 cases of high-fall death].

OBJECTIVE: To establish a database of high-fall death cases for future forensic study and practice, based on the scene investigation, injury characteristics and other informations. METHODS: Five hundred and four cases of high-fall death from 5 provinces and cities were included in the study. Data including personal information of the deceased, scene investigation, autopsy findings, history of mental illness and the results of toxicology were collected and analyzed. RESULTS: The male accidental death rate was significantly higher than that of female. No case of suicide was found in the 0-10 age group, while the suicide rate was apparently higher in the 60 years or over age group than that of accident. Most of the accident cases occurred at workplace, with head landing first and foot or lower-extremity landing first observed from height below 10 m and between 10-25 m, respectively. CONCLUSION: The majority of cases have obvious conclusions. A substantial set of the cases, however, is still difficult to determine the mechanism of injury and the manner of death. So further study should be performed.

Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R-YAP Axis.

Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling. CT-707 arrested tumor growth in HepG2, Bel-7402, and HCC patient-derived xenografts. Mechanistically, the inhibitory activity of CT-707 on YAP signaling was due to the interruption of hypoxia-activated IGF1R. Overall, these findings not only identify CT-707 as a promising hypoxia-targeting agent against HCC, but they also unveil IGF1R as a new modulator specifically regulating hypoxia-activated YAP signaling.Significance: CT-707 may represent a novel clinical approach for patients with HCC suffering poor drug response due to intratumor hypoxia. Cancer Res; 78(14); 3995-4006. ©2018 AACR.

DoS detection in IEEE 802.11 with the presence of hidden nodes.

The paper presents a novel technique to detect Denial of Service (DoS) attacks applied by misbehaving nodes in wireless networks with the presence of hidden nodes employing the widely used IEEE 802.11 Distributed Coordination Function (DCF) protocols described in the IEEE standard [1]. Attacker nodes alter the IEEE 802.11 DCF firmware to illicitly capture the channel via elevating the probability of the average number of packets transmitted successfully using up the bandwidth share of the innocent nodes that follow the protocol standards. We obtained the theoretical network throughput by solving two-dimensional Markov Chain model as described by Bianchi [2], and Liu and Saadawi [3] to determine the channel capacity. We validated the results obtained via the theoretical computations with the results obtained by OPNET simulator [4] to define the baseline for the average attainable throughput in the channel under standard conditions where all nodes follow the standards. The main goal of the DoS attacker is to prevent the innocent nodes from accessing the channel and by capturing the channel's bandwidth. In addition, the attacker strives to appear as an innocent node that follows the standards. The protocol resides in every node to enable each node to police other nodes in its immediate wireless coverage area. All innocent nodes are able to detect and identify the DoS attacker in its wireless coverage area. We applied the protocol to two Physical Layer technologies: Direct Sequence Spread Spectrum (DSSS) and Frequency Hopping Spread Spectrum (FHSS) and the results are presented to validate the algorithm.

Drug resistance mechanisms of Mycoplasma pneumoniae to macrolide antibiotics.

Throat swabs from children with suspected Mycoplasma pneumoniae (M. pneumoniae) infection were cultured for the presence of M. pneumoniae and its species specificity using the 16S rRNA gene. Seventy-six M. pneumoniae strains isolated from 580 swabs showed that 70 were erythromycin resistant with minimum inhibitory concentrations (MIC) around 32-512 mg/L. Fifty M. pneumoniae strains (46 resistant, 4 sensitive) were tested for sensitivity to tetracycline, ciprofloxacin, and gentamicin. Tetracycline and ciprofloxacin had some effect, and gentamicin had an effect on the majority of M. pneumoniae strains. Domains II and V of the 23S rRNA gene and the ribosomal protein L4 and L22 genes, both of which are considered to be associated with macrolide resistance, were sequenced and the sequences were compared with the corresponding sequences in M129 registered with NCBI and the FH strain. The 70 resistant strains all showed a 2063 or 2064 site mutation in domain V of the 23S rRNA but no mutations in domain II. Site mutations of L4 or L22 can be observed in either resistant or sensitive strains, although it is not known whether this is associated with drug resistance.

[Application of nested PCR and sequencing technique to detect point mutations of the 23S rRNA gene of Mycoplasma pneumoniae].

OBJECTIVE: To establish a quick method to detect drug resistance of Mycoplasma pneumoniae (MP) and study the condition of drug resistance in MP infection. METHODS: MP 23S rRNA target gene in throat swab specimens from 200 patients with suspected MP infection was detected by using nested PCR and DNA sequencing. The result of 23S rRNA gene detection was confirmed by MP isolation and drug susceptibility test in vitro for reliability. RESULTS: Of the 200 clinical specimens, 64 were proved to be positive for MP through MP-IgM antibody, MP specific 16S rRNA nested PCR and MP isolation . The 23S rRNA gene was amplified and the gene sequence was compared with MP reference strain in Genbank, 26 were identical to the reference strain, 38 had a point mutation in 23S rRNA. Among them, 35 had A to G mutation at position 2063, 1 had A to C mutation at position 2063 and 2 had A to G mutation at position 2064, the percentage of drug resistance was 59.4%. The sensitivity of the gene detection method was 10(2) ccu/ml and it was confirmed to be reliable by MP isolation and drug susceptibility test. CONCLUSIONS: The gene detection method could detect MP drug resistant gene directly from clinical specimen, which has the advantages of high specificity, high sensitivity and quickness. It is of great significance for diagnosis of MP infection because MP isolation is difficult and time-consuming.