Search

Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4c (SJ995973), a uniquely potent degrader of bromodomain and extra-terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4–11 cells at low picomolar concentrations (IC(50) = 3 pM; BRD4 DC(50) = 0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs.

Whereas the PROTAC approach to target protein degradation greatly benefits from rational design, the discovery of small-molecule degraders relies mostly on phenotypic screening and retrospective target identification efforts. Here, we describe the design, synthesis, and screening of a large diverse library of thalidomide analogues against a panel of patient-derived leukemia and medulloblastoma cell lines. These efforts led to the discovery of potent and novel GSPT1/2 degraders displaying selectivity over classical IMiD neosubstrates, such as IKZF1/3, and high oral bioavailability in mice. Taken together, this study offers compound 6 (SJ6986) as a valuable chemical probe for studying the role of GSPT1/2 in vitro and in vivo, and it supports the utility of a diverse library of CRBN binders in the pursuit of targeting undruggable oncoproteins.

Purpose To investigate whether a cocktail therapy of dexamethasone, ropivacaine, dexmedetomidine, and vitamin B12 can achieve satisfactory pain relief and promote early functional recovery after PPECD. Methods Eighty single-level patients with CDH who received PPECD were retrospectively divided into two groups: the cocktail and control groups. Clinical data were recorded and evaluated by a dedicated physician who was not involved in the patient’s treatment. The primary clinical outcomes included visual analog scores (VASs) for upper limber pain and neck disability index (NDI) scores. The follow-up time points were preoperatively and postoperative 1 week, 1 month, 3 months, 6 months, and 12 months. The modified MacNab criteria was used to evaluate the surgical effect of the last follow-up. Results The follow-up data of 74 cases were complete, except 6 cases lost to follow-up. There was no significant difference between the two groups in demographics, duration of symptoms, operation stage (p > 0.05), and operation time (80.5 ± 5.5 vs. 81.5 ± 3.5 min). The VAS in the upper limbs pain was significantly higher postoperatively than preoperatively in both groups (p p p > 0.05). In the control group, two cases with foraminal stenosis were found to have unrelieved pain in the early postoperative period, but the pain was relieved at the final follow-up and did not convert to open decompression surgery. Conclusions Cocktail treatment, in which a drug sustained-release material made of gelatin sponge was impregnated with dexamethasone, ropivacaine, dexmedetomidine and vitamin B12, facilitates pain relief and early postoperative recovery after PPECD.

We sought to compare the clinical and radiologic outcomes after anterior cervical surgery between zero-profile (Zero-P) cage and plate-cage construct (PCC).One-hundred and sixteen patients with single-level cervical disk herniation who underwent anterior cervical diskectomy and fusion between May 2015 and March 2017 were enrolled. They were divided into a Zero-P group (61 cases) and a PCC group (55 cases). At 1, 6, 12, and 24 months after the operation, routine follow-up evaluation was recommended including visual analog scale score and Japanese Orthopaedic Association score. The lateral x-ray film was performed at 1 and 24 months postoperatively.All 116 patients successfully completed the operation and achieved bone fusion. While there was no significant difference in the amount of bleeding between the 2 groups, the operation time of the Zero-P group was significantly shorter than that of the PCC group with statistically difference. The visual analog scale score and Japanese Orthopaedic Association score of the 2 groups at each follow-up interval postoperatively were significantly improved compared with that before operation; the difference was statistically significant (P0.05, respectively). While all the C2-7 cervical curvature, segmental Cobb angle, and height of adjacent vertebral body were lost at the 24-month follow-up, the significant difference was observed in the Zero-P group (P0.05, respectively).Compared with the Zero-P system, the PCC system provides a comparable clinical outcome. Although it showed the disadvantages in controlling the operation time and surgical bleeding, the radiologic outcome was better at the 2-year follow-up.

To investigate the effect of gap junction intercellular communication (GJIC) combined by connexin43 (Cx43) and its signal to the biobehavior of multiple myeloma (MM) cells, and its possible mechanism.The mesenchymal stem cell (MSC) cells were isolated and cultured from patients with MM and normal donors. The expression of connexin43 (Cx43) in MSC cells from different sources was detected by RT-PCR and Western blot. The side population (SP) cells were sorted by flow cytometry (FCM). The effect of MSC cells from different sources to the cell cycle, Cx43 expression, colony formation in vitro, stem cell related genes expression, cytokines secretion and chemoresistance in MM SP cells as well as with or without Cx43 inhibitor 18α-glycyrrhetinic acid (18α-GA) was observed.There was no significantly difference between the MSC isolated from normal donor and MM patients. Western blot showed that Cx43 expression in SP cells was up-regulated when the cells were incubated with MSC, and medium containing 18α-GA could partially inhibit it, moreover, it was more significant in MSC cells of MM patients. The ability of colony formation of SP cells in vitro was higher than those of MM cells and MM-MSC could promote the colony formation in a co-culture manner. The effect of MM-MSC to SP cells was down-regulated after 18α-GA was added. RT-PCR showed that there was several important stem cell-related genes including c-myc, Oct-4 Klf-4, and Sox-2 were found in RPMI 8226 cells, but those cells were up-regulated in SP cells (P0.001). Meanwhile, MM-MSC could up-regulate the expression of c-myc, Klf-4 and Sox-2 (P0.001), but down-regulate Oct-4 gene in the SP cells. The expression of those genes decreased after 18α-GA was added, but showed no significant difference (P0.05). Cytometry bead array assays showed that MM-MSCs could secrete high level of IL-6, but the levels of IL-6, IL-10 and TGF-β increased significantly when the MM-MSCs were co-cultured with SP cells (P0.05), especially the levels of IL-6 and IL-10 were significantly higher than cultured alone. There was no significant change in the levels of bFGF and IL-17 before and after co-cultured. The levels of IL-6, IL-10 and TGF-β in supernatant decreased significantly after GJ inhibitor 18α-GA was added. PI/Annexin V assay showed that MM cells were sensitive to bortezomib (BTZ)-induced apoptosis, but the sensitivity for SP cells was weaker. The ratio of cell apoptosis was 75.2%±0.77% and 8.12%±0.86% (P0.001), respectively. MM-MSC could down-regulate the cell apoptosis induced by BTZ, while the sensitivity of MM cells to BTZ could be partially recovered after GJ inhibitor was added.MSC derived from MM patients can enhance GJIC to maintain its "hematopoiesis" by up-regulating the expression of Cx43 in MM cells, and at the same time promote cell proliferation and drug recistance by secreting multiple cytokines, which finally contributes to the relapse of MM.连接蛋白43偶合对多发性骨髓瘤细胞生物学行为的影响.观察由连接蛋白43（Cx43）组成的细胞间隙连接通讯（GJIC）及其介导的信号对多发性骨髓瘤（MM）细胞生物学行为的影响，并探讨其可能机制。.分离、培养MM患者、正常人骨髓间充质干细胞（MSC）；采用RT-PCR及蛋白印迹检测不同来源MSC中Cx43的表达，流式细胞术分选MM侧群细胞（SP），直接共培养后观察不同来源MSC对SP细胞周期、Cx43表达、体外集落形成、干细胞相关基因表达、细胞因子分泌和耐药的变化以及加入GJIC抑制剂18α甘草次酸（18α-GA）的影响。.MM患者及正常人骨髓所获的MSC形态及表型无明显区别，蛋白印迹证实，这两种MSC均表达较高水平的Cx43，与SP细胞共培养后可上调其Cx43表达，18α-GA可部分抑制该作用，对来源于MM患者的MSC作用更为显著（P0.001）；SP细胞具较强的体外集落形成能力，MM-MSCs具促进作用，加入18α-GA后SP细胞体外集落形成能力下降；RT-PCR检测证实RPMI 8266细胞存在少量c-myc、Klf-4、Sox-2和Oct-4基因表达，但SP细胞亚群中该类基因明显上调（P0.001），MM-MSC可显著上调SP细胞c-myc、Klf-4和Sox-2基因的表达（P0.001），而下调Oct-4基因表达，加入GJ阻断剂后，上调的基因均有不同程度下调，但无明显差异（P0.05）；CBA分析结果显示，MM-MSC分泌的高水平白介素（IL），与SP细胞共培养后，其上清中IL-6、IL-10及转化生长因子-β（TGF-β）表达上调（P0.05），尤其是IL-6和IL-10较单独培养时显著上调（P0.01），碱性成纤维细胞生长因子和IL-17共培养前后则无明显变化，加入18α-GA后，上清中IL-6、IL-10和TGF-β水平均明显降低（P0.05）；PI/Annexin V检测证实，MM细胞对硼替佐米诱导的凋亡敏感，但SP细胞敏感性较差，凋亡率分别为75.2%±0.77%和8.12%±0.86%（P0.001），MM-MSC可显著减少硼替佐米介导的细胞凋亡 （P0.05），加入18α-GA可部分恢复MM细胞对硼替佐米的敏感性。.MM患者来源的MSC通过上调MM细胞Cx43表达，强化GJIC维持其“干”性，同时通过分泌多种细胞因子促进细胞增殖和耐药，是最终导致MM复发的原因之一。.

The diagnosis of Parkinson’s disease (PD) is challenging at all stages due to variable symptomatology, comorbidities, and mimicking conditions. Postmortem assessment remains the gold standard for a definitive diagnosis. While it is well recognized that PD manifests pathologically in the central nervous system with aggregation of α-synuclein as Lewy bodies and neurites, similar Lewy-type synucleinopathy (LTS) is additionally found in the peripheral nervous system that may be useful as an antemortem biomarker. We have previously found that detection of LTS in submandibular gland (SMG) biopsies is sensitive and specific for advanced PD; however, the sensitivity is suboptimal especially for early-stage disease. Further, visual microscopic assessment of biopsies by a neuropathologist to identify LTS is impractical for large-scale adoption. Here, we trained and validated a convolutional neural network (CNN) for detection of LTS on 283 digital whole slide images (WSI) from 95 unique SMG biopsies. A total of 8,450 LTS and 35,066 background objects were annotated following an inter-rater reliability study with Fleiss Kappa = 0.72. We used transfer learning to train a CNN model to classify image patches (151 × 151 pixels at 20× magnification) with and without the presence of LTS objects. The trained CNN model showed the following performance on image patches: sensitivity: 0.99, specificity: 0.99, precision: 0.81, accuracy: 0.99, and F-1 score: 0.89. We further tested the trained network on 1230 naïve WSI from the same cohort of research subjects comprising 42 PD patients and 14 controls. Logistic regression models trained on features engineered from the CNN predictions on the WSI resulted in sensitivity: 0.71, specificity: 0.65, precision: 0.86, accuracy: 0.69, and F-1 score: 0.76 in predicting clinical PD status, and 0.64 accuracy in predicting PD stage, outperforming expert neuropathologist LTS density scoring in terms of sensitivity but not specificity. These findings demonstrate the practical utility of a CNN detector in screening for LTS, which can translate into a computational tool to facilitate the antemortem tissue-based diagnosis of PD in clinical settings.

Duodenal gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract. For localized or potentially resectable GISTs, surgery is the first choice. But the important and complex anatomical structure adjacent to the duodenum makes surgical management for duodenal GISTs challenging and few comprehensive surgical strategies have been described. This study aims to provide new comprehensive surgical strategies for duodenal GISTs by summarizing the surgical approaches and outcomes of duodenal GISTs in different locations in our center in the past 11 years.Information from patients who underwent surgical resection for duodenal GISTs at our facility during the past 11 years was retrospectively analyzed.Ninety-two patients have received surgical procedures in the facility. Twenty-three, 31, 3, and 35 patients underwent wedge resection, segmental resection, pancreatic head-preserving duodenectomy, and pancreaticoduodenectomy, respectively. The mean operative times were 212.6 (150-270), 260 (180-370), 323 (300-350), and 354.9 (290-490) min; the mean blood loss was 226.1 (100-400), 303.2 (100-600), 500 (400-600), and 582.9 (200-1300) ml, respectively. R0 margins were obtained in 21, 29, 3, and 32 patients, respectively.For duodenal GISTs without invasion of the ampulla of Vater or the pancreatic head, a limited resection (such as wedge resection, segmental resection, or pancreatic head-preserving duodenectomy) is feasible. For duodenal GISTs with an invasion of the ampulla of Vater or the pancreatic head, a pancreaticoduodenectomy is still necessary.

Background: Percutaneous kyphoplasty (PKP) has been reported to provide a favorable analgesic effect for pain caused by osteoporotic vertebral compression fractures (OVCFs). However, a systematic review demonstrated that pain relief was only reported for approximately 86% of kyphoplasty treatments. Objectives: To explore whether an additional facet joint block (FJB) can minimize pain and improve the clinical outcome of PKP in patients with acute OVCFs. Study Design: Prospective study. Setting: All data were from Honghui Hospital in Xi’an. Methods: According to the inclusion and exclusion criteria, 194 patients were eventually included in our study; they were randomly divided into 2 groups of 97 patients each and treated with either PKP + FJB or PKP alone. Follow-up consultations were scheduled 1 day, 3 days, 1 week, 1 month, 3 months, and 1 year postoperatively; the demographic characteristics, related surgical information, and complications observed within both groups were recorded. The clinical evaluation parameters included the intraoperative satisfaction score, the Visual Analog Scale (VAS) score, and the Oswestry Disability Index (ODI). Results: A total of 171 patients (61 men and 110 women; age range: 62–85 years) completed the full postoperative follow-up schedule, with 83 patients in the PKP + FJB group and 88 in the PKP group. No significant differences were observed in the genders, ages, preoperative bone mineral density, surgical levels, or volume of cement injected between the 2 groups (P > 0.05, respectively). The average duration of the surgeries in the PKP + FJB group was slightly longer than that in the PKP group (35.5 ± 4.8 min vs. 31.8 ± 4.3 min; P = 0.038), and in terms of the clinical outcomes, the average intraoperative satisfaction score was significantly higher in the PKP + FJB group (8.6 ± 1.1 vs. 6.3 ± 1.3; P < 0.001). Compared with the preoperative data, significant improvements in the VAS scores of back pain and ODI were observed at each follow-up interval (P < 0.05, respectively). These scores were significantly higher in the PKP + FJB group than in the PKP group; however, this was only observed within the first month after the procedure. Limitations: A single-center noncontrol study. Conclusions: The addition of an FJB (which in our study involved a unique combination of ropivacaine, prednisolone, and vitamin B12) improved the short-term clinical outcome of PKP for acute OVCFs. The local anti-inflammatory and analgesic effects on the facet joints resulted in higher intraoperative satisfaction and lower VAS and ODI scores for the first postoperative month when compared with the PKP group. Key words: Osteoporotic vertebral compression fracture, pain, posterior elements, percutaneous kyphoplasty, facet joint block, medial branch

Growing evidence shows that cancer progression links with both heterogeneity of the tumor microenvironment and dysregulated activity of immune cells. Cancer-secreted exosomes are being recognized as indispensable mediators of the exchange cargo between cancer and immune cells. The M2-phenotype tumor-associated macrophages have the function of promoting tumor progression and drug resistance. Diffuse large B-cell lymphoma(DLBCL) is a highly heterogeneous and very common malignant non-Hodgkin's lymphoma. Here, we demonstrate that different subtype DLBCL cell-derived exosomes are internalized by macrophages, which can affect macrophages polarization. The mechanism of DLBCL-derived exosomes on macrophage polarization remains unclear currently. This study showed that DLBCL-secreted exosomes could induce the transformation of macrophages to a protumor M2-like phenotype, and block the drug-induced apoptosis of DLBCL cells in an indirect co-culture system. Different DLBCL-derived exosomes could change the phenotype of macrophages through the STAT3 signaling, which upregulated the expression of oncogenic genes and classical markers of M2-like phenotype macrophages, such as IL-10, CD206, and CD163. The addition of DLBCL-derived exosomes resulted in the activation of the STAT3 signaling pathway of M0/M2 macrophages in an indirect co-culture system. GP130 was highly enriched in DLBCL-derived exosomes, which triggered the activation of STAT3 of macrophages and subsequently induced the downstream targets such as BCL2, SURVIVIN, and BAX. The parallel changes of STAT3 and GP130 in macrophages confirmed that GP130 of DLBCL-derived exosomes promoted macrophage polarization by activating STAT3 signaling. Furthermore, all of these effects could be reversed by the GP130 inhibitor SC144. The data indicated that DLBCL-derived exosomes could trigger macrophages polarization into a pro-survival M2-like phenotype, which was at least partially through the GP130/STAT3 signaling pathway. Collectively, this study showed that DLBCL-derived exosomes could promote macrophages transformation to protumor M2-like phenotype in the tumor microenvironment.

Hepatocellular carcinoma (HCC), one of the most lethal malignancies worldwide, has limited efficient therapeutic options. Here, we first demonstrated that simultaneously targeting poly (ADP-ribose) polymerase (PARP) and autophagy could evoke striking synergistic lethality in HCC cells. Specifically, we found that the PARP inhibitor Niraparib induced cytotoxicity accompanied by significant autophagy formation and autophagic flux in HCC cells. Further experiments showed that Niraparib induced suppression of the Akt/mTOR pathway and activation of the Erk1/2 cascade, two typical signaling pathways related to autophagy. In addition, the accumulation of reactive oxygen species was triggered, which was involved in Niraparib-induced autophagy. Blocking autophagy by chloroquine (CQ) in combination with Niraparib further enhanced cytotoxicity, induced apoptosis and inhibited colony formation in HCC cells. Synergistic inhibition was also observed in Huh7 xenografts in vivo. Mechanistically, we showed that autophagy inhibition abrogated Niraparib-induced cell-cycle arrest and checkpoint activation. Cotreatment with CQ and Niraparib promoted the formation of γ-H2AX foci while inhibiting the recruitment of the homologous recombination repair protein RAD51 to double-strand break sites. Thus, the present study developed a novel promising strategy for the management of HCC in the clinic and highlighted a potential approach to expand the application of PARP inhibitors.

Objective To examine effects of percutaneous endoscopic debridement and allograft via the transforaminal approach combined with percutaneous pedicle screw fixation as treatment for single-level thoracic tuberculosis. Methods This multicenter retrospective analysis included 75 patients with single-level thoracic tuberculosis who underwent percutaneous endoscopic debridement and allograft via the transforaminal approach combined with percutaneous pedicle screw fixation and were followed for >36 months between January 2012 and December 2014. Results Follow-up was 36–48 months (average 41.1 ± 2.2 months). Intraoperative blood loss was low (average 30.5 ± 7.9 mL), and bed rest time was short (average 1.5 ± 0.3 days). No recurrence was observed in all 75 patients. Except for 3 patients, almost all patients (96%) achieved grade I or II fusion in interbody bone grafting. Segmental Cobb angle was 13.5° ± 4.1° before surgery, 10.5° ± 3.7° immediately after surgery, and 11.7° ± 3.9° at 36 months of follow-up. All patients achieved complete recovery of neurologic function (American Spinal Injury Association grade E), including 15 patients with spinal cord injury (American Spinal Injury Association grade D) before surgery. The visual analog scale and 36-Item Short-Form Health Survey scores significantly improved at 1, 3, 12, and 36 months of follow-up. No complications related to internal fixation occurred within the follow-up period; complication rate was 9.0%. Conclusions Median follow-up clinical experience with percutaneous endoscopic debridement and allograft via the transforaminal approach combined with percutaneous pedicle screw fixation indicates that the technique is safe, effective, feasible, and minimally invasive.

Objective. To compare the clinical efficacy and complications which obtained foraminoplasty at the tip or base of the superior articular process (SAP) for the patients with lateral recess stenosis treated by percutaneous endoscopic lumbar discectomy (PELD). Methods. Between January 2015 and January 2016, 156 patients of lumbar disc herniation accompanying with lateral recess stenosis were treated with PELD in five tertiary hospitals and fulfilled the 2-year follow-up. Among them, 78 patients obtained a foraminoplasty at the tip of SAP (group A), and foraminoplasty at the base of SAP was performed in the other 78 cases (group B). Clinical efficacy was evaluated using the visual analog scale (VAS) score for back and leg pain, Oswestry Disability Index (ODI), and 36-item Short-Form Health Survey (SF-36) score. The intervals of follow-up were scheduled at 1 month, 3 months, 6 months, 1 year, and 2 years after surgery. Results. Mean operative duration is shorter in group B (55 versus 61 min, P = 0.047). Only one case belonged to group A could not tolerate the neural irritation and required conversion to an open procedure. During the surgery, no dura tears, cauda equina syndrome, or infections were observed. 5 patients experienced transient dysesthesia located at the exiting nerve in group A, while no cases complained dysesthesia in group B. 2 cases who suffered temporary motor weakness all belonged to group A. A total of 5 cases obtained a revision surgery after recurrence in the follow-up, in which 3 patients belonged to group A. Compared to the preoperative data, significant improvements in VAS scores of low back pain and sciatica, ODI, and SF-36 PCS and MC were observed in the follow-up, respectively (P < 0.05, respectively). However, no statistical difference was observed at all time-points after surgery between these two groups (P > 0.05, respectively). Conclusions. For the patients of LDH accompanying with lateral recess stenosis, compared with the routine foraminoplasty at the tip of SAP, our modified foraminoplastic technique does not only change place of foraminoplasty to the base of SAP but also simplified puncture process in transforaminal PELD. Although there was no significant difference in symptom relief, the modified foraminoplasty showed the advantages in decreasing the incidence of postoperative neural dysfunction and reducing operation time.

To evaluate the curative efficacy by comparing perioperative characteristics and 1.5-year observational outcomes in 1-segment lumbar spondylolisthesis between traditional minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and optimized Endoscopic TLIF techniques.The study was a single-center, randomized controlled trial comparing two different treatment approaches for 1-segment lumbar spondylolisthesis. 102 patients treated by MIS-TLIF (48 cases) or Endo-TLIF (54 cases) were included from March 2018 to April 2019. Perioperative parameters and clinical outcomes were evaluated. Degree of slip were measured, and fusion rates were determined at 18 months after surgery.The Endo-TLIF group had similar return to work time and rate. Blood loss, left bed time, analgesic ratio were significantly less in Endo-TLIF group. The Endo-TLIF group had a significantly longer operative time. Significant postoperative reduction in %slip was showed in both groups. The VAS and ODI improved significantly in both groups after surgery. Significant decreases in low-back pain in Endo-TLIF group were found at postoperative day 1 and 3 months. The fusion rate in the two groups was similar.Endo-TLIF surgery with a C-shaped working tube and a visualization system may be regarded as an efficient alternative surgery for 1-segment lumbar spondylolisthesis. It is a safe and minimally invasive way to perform this surgery and has shown satisfactory clinical outcomes.ChiCTR1800015197, 13 March 2018.Chinese Clinical Trial Registry. Registered 13 March 2018. http://www.chictr.org.cn/showproj.aspx?proj=25865.

Primary intracerebral hemorrhage (ICH) is a leading cause of long-term disability and death worldwide. Drug delivery vehicles to treat ICH are less than satisfactory because of their short circulation lives, lack of specific targeting to the hemorrhagic site, and poor control of drug release. To exploit the fact that metal ions such as Fe2+ are more abundant in peri-hematomal tissue than in healthy tissue because of red blood cell lysis, we developed a metal ion-responsive nanocarrier based on a phosphonated calix[4]arene derivative in order to deliver the neuroprotective agent dauricine (DRC) specifically to sites of primary and secondary brain injury. The potential of the dauricine-loaded nanocarriers for ICH therapy was systematically evaluated in vitro and in mouse models of autologous whole blood double infusion. The nanocarriers significantly reduced brain water content, restored blood-brain barrier integrity and attenuated neurological deficits by inhibiting the activation of glial cells, infiltration by neutrophils as well as production of pro-inflammatory factors (IL-1β, IL-6, TNF-α) and matrix-metalloprotease-9. These results suggest that our dauricine-loaded nanocarriers can improve neurological outcomes in an animal model of ICH by reducing inflammatory injury and inhibiting apoptosis and ferroptosis.

Infrahepatic inferior vena cava (IVC) clamping is considered to be an effective method to reduce central venous pressure (CVP) and intraoperative bleeding in liver resection. However, its efficacy and safety during laparoscopic hepatectomy (LH) remain unclear. We perform this retrospective study to evaluate its efficacy and safety during LH. Consecutive patients scheduled for LH from September 2014 to August 2019 were retrospectively reviewed. The intraoperative parameters and postoperative outcomes were analyzed. All patients in the infrahepatic IVC clamping group were able to tolerate partial clamping of IVC. The CVP was significantly decreased after infrahepatic IVC clamping without hemodynamic instability (8.7 ± 1.4 cmH2O vs. 2.1 ± 1.3 cmH2O, P = 0.000). Infrahepatic IVC clamping did not significantly reduce total blood loss (287.3 ± 112.5 mL vs. 301.4 ± 127.6 mL, P = 0.133) and blood loss during parenchymal transection (273.2 ± 107.9 mL vs. 296.5 ± 118.1 mL, P = 0.618) compared with the non-clamping group. In subgroup analysis, total blood loss and blood loss during parenchymal transection were significantly reduced in patients with moderate to severe cirrhosis in the clamping group (363.6 ± 71.2 mL vs. 473.4 ± 95.6 mL, P = 0.021), (358.7 ± 70.9 mL vs. 466.9 ± 94.5 mL, P = 0.016), respectively. The complications and hospital stay were comparable. In conclusion, these data suggest that infrahepatic IVC clamping may be safe and effective.

Background Hydrogen peroxide (H2O2) solution is commonly used to irrigate wounds because of its hemostatic and antiseptic properties. Previous studies suggest that H2O2 can result in toxicity to keratinocytes and fibroblasts, but complications after H2O2 application, including oxygen embolism, which is one of the most severe, have rarely been reported. Case description A 40-year-old woman was diagnosed with L4-5 lumbar spinal stenosis and subsequently underwent minimally invasive transforaminal lumbar interbody fusion treatment at another hospital. Hypotension, hypoxia, and a decrease in end-tidal carbon dioxide pressure occurred immediately after H2O2 irrigation. After the operation, she was able to be extubated but remained comatose. Postoperative computed tomography scan revealed intracranial air trapping in the right frontal lobe and multiple cerebral infarction foci. Conclusions When using a knee-prone surgical position or in cases of dural laceration, the application of undiluted H2O2 solution should be avoided, especially in a surgical wound within a closed cavity. When hypotension, hypoxia, and a decrease in end-tidal carbon dioxide pressure occur immediately after H2O2 irrigation, oxygen embolism should be strongly suspected.

Exosomes are key mediators of intercellular communication and play a role in the pathogenesis and progression of cancer. Exosomes in circulating body fluids serve as molecular markers for cancer diagnosis. This study aimed to investigate the role of exosomal microRNA (miR)-1910-3p in breast cancer and determine its clinical diagnostic value. MiR-1910-3p promoted proliferation and migration of breast cancer cells in vitro and in vivo. In vitro, exosomes enriched in miR-1910-3p transferred miR-1910-3p to mammary epithelial cells and breast cancer cells, promoting proliferation and migration, inhibiting apoptosis, and inducing autophagy. In vivo, exosomes enriched in miR-1910-3p promoted the proliferation and migration of breast cancer cells. MiR-1910-3p downregulated myotubularin-related protein 3, activated the NF-κB and wnt/β-catenin signaling pathway, and promoted breast cancer progression. Serum miR-1910-3p in exosomes was an effective diagnostic marker that improved the sensitivity of breast cancer diagnosis when used in combination with the traditional tumor marker CA153. In conclusion, breast cancer cell-derived exosomes promoted the growth, metastasis, and autophagy of breast cancer cells by transferring miR-1910-3p. MiR-1910-3p in serum exosomes may serve as a novel molecular marker for breast cancer diagnosis.

Objective. To compare the difference in clinical and radiographic outcomes between anterior transcorporeal and transdiscal percutaneous endoscopic cervical discectomy (ATc-PECD/ATd-PECD) approaches for treating patients with cervical intervertebral disc herniation (CIVDH). Method. We selected 77 patients with single-segment CIVDH and received ATc-PECD or ATd-PECD in the Second Affiliated Hospital of Chongqing Medical University between March 1, 2010, and July 1, 2015. 35 patients suffered from ATc-PECD, and there were 42 patients in the ATd-PECD group. Obtaining the data of 1, 3, 6, 12, and 24 months postoperatively, the VAS for neck and arm pain and the modified MacNab criteria were used to evaluate the clinical outcomes, comparing radiographic outcomes and complications of these two groups. Results. We found that the mean operative time was significantly longer in the ATc-PECD group (P<0.05). At the 2-year follow-up, the mean VAS score for neck and arm pain was significantly decreased in both two groups. There was no significant difference in the VAS score for arm pain and neck pain between the two groups at the 2-year follow-up (P=0.783 and P=0.785, respectively). For the ATc-PECD group, the difference in the height of IVS or vertebral body was significant between the preoperative and postoperative groups (P<0.05, respectively). For the ATd-PECD group, there was only a significant decrease in the height of the IVS (P<0.05); the decrease in the surgical vertebral body was not significant between the preoperative and postoperative groups (P>0.05). Conclusion. In the 2-year follow-up, there is no significant difference in the clinical outcomes between the 2 approaches. While the longer time was consumed in the ATc-PECD group, the lower rate of disc collapse and recurrence is notable. Additionally, when the center diameter of tunnel was limited to 6 mm, the bony defect can be healed without the occurrence of the collapse of the superior endplate, and ATc-PECD may be preferable in the endoscopic treatment of CIVDH.

Purpose: Inflammatory myofibroblastic tumors (IMT) was a rare kind of tumor defined by WHO since 2012. Little was known about this disease. There were controversies about IMT's behavior, predilection site, age distribution, and the best treatment methods. Here we provided a systematic overview on tumor demographical, clinical, biological features as well as treatment efficacy based on real cases from Surveillance, Epidemiology, and End Results (SEER) database. Methods: 92 patients diagnosed with IMT by histopathology were drawn from SEER database between 2002 and 2014. Patient demographics, clinical features and treatment information were analyzed. Results: The mean age of onset was 47.4 ± 22.4 years (0 to 83y) and the ages prone to this disease are middle-aged (from 41y to 64y), accounting for 1/3 of all patients. Three peak ages of onsets were 0–4y, 36–40y and more than 50y. 42% of the tumors were located in the soft tissues of limbs, hip, shoulder, head, face and neck. The average tumor sizes were 6.5 ± 5.3cm (1cm to 25cm). Survival in the group of tumor size smaller than 6.5cm was better compared to group of tumor size larger than 6.5cm (P < 0.05). Most of the tumors were malignant or malignant potential (89%), though local and distant metastasis rate were low (5%). Surgery was the most common treatment. However, the survival benefit was still uncertain compared to adjuvant chemotherapy or radiotherapy. Multivariate regression analysis demonstrated that young patients had better survival than old ones. Conclusions: IMT was a malignant tumor with low risk of local and distant metastasis. The peak ages were 0-4y, 36-40y and more than 50y. The prone sites were the soft tissues of the limbs, hip, shoulder, head, face and neck. Tumor sizes and ages were the factors correlated with survival time.

Summary Background Ubiquitin-specific peptidase 9, X-linked (USP9X), a member of deubiquitylating enzymes family, has recently been reported to be associated with a variety of cancer progression. While it functions as either oncogene or tumor suppressor in a context-dependent manner, the expression and role of USP9X in gastric cancer is largely unknown. Methods Sixty-eight cases of patients with gastric cancer were enrolled in this study. The expression of USP9X and MCL1 were detected by immunohistochemistry. USP9X expression was further analyzed by Western blot. Furthermore, we analyzed the correlation between USP9X and MCL1 expression, as well as USP9X expression and clinicopathologic parameters of gastric cancer. Finally, the significance of USP9X expression in gastric cancer was analyzed by both Kaplan-Meier and Cox regression analysis. Results USP9X expression significantly increased in gastric cancer tissues compared to matched normal tissues. Moreover, expression of USP9X was positive correlated with MCL1 expression ( P = 0.006) and significant associated with lymph node metastasis ( P = 0.016), distant metastasis ( P = 0.001) and tumor staging ( P = 0.013) in gastric cancer. Importantly, the increasing expression of USP9X in gastric cancer reduces overall survival rate and was an independent factor predicts poor prognosis in patients with gastric cancer. Conclusions In this study, deubiquitylating enzyme USP9X was overexpressed in gastric cancer, suggesting a potential implication as an oncogene, and was significantly associated with a poorer survival.

Recent evidence suggests a link between cathepsin L (CTSL) and vascular diseases. However, its contribution to reactive oxygen species (ROS) homeostasis in the vasculature remains unknown. p66shc is a redox enzyme implicated in mitochondrial ROS generation and translation of oxidative signals. In this study, we explored the relationship between CTSL and oxidative damage in vasculature and whether the oxidative damage is mediated by p66shc.Carotid arteries from aged mice (24 months old) showed a reduction in CTSL expression compared with young wild-type mice (4 months old). Local knockdown of CTSL in carotid arteries of young mice by adenoviral vector encoding the short hairpin RNA targeting CTSL leading to premature vascular aging, as shown by mitochondrial disruption, increased β-galactosidase-positive cells, reduced telomerase activity, and up-regulation of p66shc. Knockdown of CTSL decreased the expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes I, III, and IV, leading to increased mitochondrial ROS and hyperpolarization of the mitochondrial membrane in vitro. Furthermore, knockdown of CTSL also stimulated ROS production and senescence in vascular cells, accompanied by the up-regulation of p66shc.However, p66shc knockdown blunted the alteration in ROS production, and senescence in CTSL knockdown vascular cells. This study suggests that CTSL knockdown partially induces vascular cells damage via increased ROS production and up-regulation of p66shc.

Background Rickettsia raoultii is frequently detected in multiple tick species, whereas human infection remains scarcely studied. Methods A surveillance study was performed at 3 sentinel hospitals in China, to recruit participants with suspected tick exposure. Rickettsia raoultii infection was identified through polymerase chain reaction, followed by sequencing, and confirmed serologically. Isolation by cell culture was performed and the isolates were genome sequenced. Results Twenty-six subjects were determined to have R. raoultii infection, including 7 with asymptomatic infection, 15 with mild to moderate illness, and 4 with severe illness. Common nonspecific manifestations in the 19 patients with mild to moderate or severe illness included fever (100%), malaise (95%), myalgia (58%), lymphadenopathy (53%), and nausea (42%). Only 5% of them had rash, and 16% had eschar. Scalp eschar and neck lymphadenopathy after a tick bite syndrome was only seen in 2 patients. Of the 4 patients with severe complications, 3 developed pulmonary edema, and 1 developed clouding of consciousness and lethargy. Frequent abnormalities of laboratory testing included leukopenia, thrombocytopenia, lymphopenia, neutropenia, hypoproteinemia, and elevated levels of total bilirubin, hepatic aminotransferases, lactate dehydrogenase, and creatine kinase. All the 19 patients recovered without sequelae after receiving doxycycline treatment. Two R. raoultii strains were isolated, and a significantly less degraded genome was observed than other more virulent Rickettsia strains, indicating a low pathogenicity of the current strain. Conclusions Human infection with R. raoultii has a wide clinical spectrum that ranged from subclinical infection to severe complications. Physicians need to be aware of the high potential and clinical complexity of R. raoultii infection, to ensure appropriate testing and treatment in endemic regions.

ObjectivesTo develop a model of in-hospital mortality using medical record front page (MRFP) data and assess its validity in case-mix standardisation by comparison with a model developed using the complete medical record data.DesignA nationally representative retrospective study.SettingRepresentative hospitals in China, covering 161 hospitals in modelling cohort and 156 hospitals in validation cohort.ParticipantsRepresentative patients admitted for acute myocardial infarction. 8370 patients in modelling cohort and 9704 patients in validation cohort.Primary outcome measuresIn-hospital mortality, which was defined explicitly as death that occurred during hospitalisation, and the hospital-level risk standardised mortality rate (RSMR).ResultsA total of 14 variables were included in the model predicting in-hospital mortality based on MRFP data, with the area under receiver operating characteristic curve of 0.78 among modelling cohort and 0.79 among validation cohort. The median of absolute difference between the hospital RSMR predicted by hierarchical generalised linear models established based on MRFP data and complete medical record data, which was built as ‘reference model’, was 0.08% (10th and 90th percentiles: −1.8% and 1.6%). In the regression model comparing the RSMR between two models, the slope and intercept of the regression equation is 0.90 and 0.007 in modelling cohort, while 0.85 and 0.010 in validation cohort, which indicated that the evaluation capability from two models were very similar.ConclusionsThe models based on MRFP data showed good discrimination and calibration capability, as well as similar risk prediction effect in comparison with the model based on complete medical record data, which proved that MRFP data could be suitable for risk adjustment in hospital performance measurement.

Cancer cells can acquire resistance to a wide variety of diverse and unrelated drugs, this phenomenon is termed multidrug resistance (MDR). Multidrug resistance has been an obstacle to the success of cancer chemotherapy. The present study investigated the reversal effect of Y6, a new compound obtained by chemically modifying the structure of epigallocatechin-3-gallate (EGCG) extracted from green tea. Y6 was proven to be effective in inhibiting cell proliferation and reversing drug resistance in doxorubicin (DOX) resistant human hepatocellular carcinoma cells (BEL-7404/DOX). BEL-7404/DOX cells were treated with either doxorubicin combination regimen (doxorubicin plus Y6 or epigallocatechin-3-gallate or verapamil separately) or doxorubicin alone. The results showed that cell proliferation was inhibited and late cell apoptosis increased in the combination treatment group, especially in the group treated with doxorubicin plus Y6. Further analysis revealed that the expressions of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein decreased at both messenger RNA and protein levels by treatments with combined drugs compared to doxorubicin alone. Our results indicated that Y6, as a drug resistance reversal agent, increased the sensitivity of drug resistant cells to doxorubicin. The mechanisms of actions of Y6 in reversal effect were associated with the decreased expression of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein.

Background Ankyrin repeat and SOCS box protein 3 (ASB3) is a member of ASB family and contains ankyrin repeat sequence and SOCS box domain. Previous studies indicated that it mediates the ubiquitination and degradation of tumor necrosis factor receptor 2 and is likely involved in inflammatory responses. However, its effects on oncogenesis are unclear. This study aimed to investigate the effects of ASB3 on the growth and metastasis of colorectal cancer (CRC). Methods We used next-generation sequencing or Sanger sequencing to detect ASB3 mutations in CRC specimens or cell lines, and used real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemical or immunofluorescence assay to determine gene expression. We evaluated cell proliferation by MTT and colony formation assays, tested cell cycle distribution by flow cytometry, and assessed cell migration and invasion by transwell and wound healing assays. We also performed nude mouse experiments to evaluate tumorigenicity and hepatic metastasis potential of tumor cells. Results We found that ASB3 gene was frequently mutated (5.3%) and down-regulated (70.4%) in CRC cases. Knockdown of endogenous ASB3 expression promoted CRC cell proliferation, migration, and invasion in vitro and facilitated tumorigenicity and hepatic metastasis in vivo. Conversely, the ectopic overexpression of wild-type ASB3, but not that of ASB3 mutants that occurred in clinical CRC tissues, inhibited tumor growth and metastasis. Further analysis showed that ASB3 inhibited CRC metastasis likely by retarding epithelial-mesenchymal transition, which was characterized by the up-regulation of β-catenin and E-cadherin and the down-regulation of transcription factor 8, N-cadherin, and vimentin. Conclusion ASB3 dysfunction resulted from gene mutations or down-regulated expression frequently exists in CRC and likely plays a key role in the pathogenesis and progression of CRC.

A phytochemical investigation on the whole plant of

To explore the serological characteristics of patients with autoimmune hemolytic anemia（AIHA） and analyze its clinical efficacy and safety of incompatible red blood cell transfusion.Sixty AIHA patients admitted in our hospital from January 2014 to January 2018 were selected. The blood type serological characteristics of 60 patients were analyzed retrospectively. According to the type of autoantibody and the composition of different red blood cells, the efficacy and safety of erythrocyte infusions were evaluated respectively.The screen results of irregular antibody in 60 AIHA patients were positive, and the direct anti-human globulin test also was positive, including 8 cases of cold autoantibodies (13.33%), 49 cases of IgG warm autoantibodies (81.67%), and 3 cases of warm cold double autoantibodies (5%). The irregular anti-body identification test confirmed the existence of homoantiboby in 17 cases (28.33%). Out of 60 cases 34 received incompatible red blood cell (RBC) infusion for 108 time including ABO homotype non washing RBC (81 tirnes) and O type washing RBC (27 times). The infusion results showed that the total [JP2]effective rate was 57.41(62/108), total partial effective rate was 14.81% (16/108) and total ineffective rate was 27.78% (30/108).The infusion of ABO homotype non-washing RBC for 81 time showed that the effective rate was 58.02%[JP] (47/81) , partial effective rate was 12.35 (10/81) and ineffective rate was 29.67% (24/81); the infusion of O type washing RBC for 27 times showed that the effective rate was 55.56% (15/27), partial effective rate was 22.22% (6/27) and ineffective rate was 22.22% (6/27), there was no significant difference in effective rate between 2 kinds of infusion (P0.05). The comparison of different antibody type infusion showed that in the infusion of IgM cold autoantiboay for 12 times, the effective rate was 41.67% (5/12), partial effective rate was 33.33% (4/12) and ineffective rate was 25% (3/12); in the infusion of IgG warm antoantibody for 93 times. The effective rate was 58.06% (54/93),partial effective rate was 12.90% (12/93) and ineffective rale was 29.04% (27/93), there was also no significant difference in effective rate between 2 kinds of infusion(P0.05). However, in infusion of cold/warm double autoantibody for 3 times, the effective rate was 100% (3/3), moreover, the hemotytic reaction of infusion was not observed during the treatment .The infusion of ABO homotype non-washing RBC and O type washing RBC both possess the high safely and efficacy for treatment of patients with AIHA, but the use of ABO homotype non-washing RBC can effectively avoid the excessive use of O type washing RBC.AIHA患者血型血清学特征及红细胞不相容输注的疗效.探究自身免疫性溶血性贫血（autoimmune hemolytic anemia, AIHA）患者的血型血清学特征，分析红细胞不相容输注的疗效.选取本院2014年1月-2018年1月我院收治的60例AIHA患者，回顾性分析60例患者的血型血清学特征，根据患者自身抗体类型及接受不同红细胞成分对红细胞不相容输注的疗效及安全性进行评价.60例AIHA患者不规则抗体筛查结果均为阳性，且直接抗人球蛋白试验也均为阳性，其中单独IgM类冷自身抗体8例（13.33%），单独IgG类温自身抗体49例（81.67%），温冷双自身抗体3例（5.00%），不规则体鉴定试验证实存在同种抗体17例（28.33%）。60例AIHA患者中，34例接受了不相容红细胞输注共108次，输注次数的总有效率为57.4%（62/108），总部分有效率为14.81%（16/108），总无效率为27.78%（30/108）。81次输注ABO同型非洗涤红细胞中的有效率为58.02%（47/81），部分有效率为12.35%(10/81)，无效率为29.63%(24/81)；27次输注O型洗涤红细胞中的有效率为55.56%（15/27），部分有效率为22.22%（6/27），无效率为22.22%（6/27），2组治疗有效率相比差异无统计学意义（P＞0.05）。不同抗体类型输注疗效比较显示，输注IgM 类冷自身抗体的有效率为41.67%（5/12），部分有效率33.33%(4/12)，无效率25.00%(3/12)；输注IgG 类温自身抗体组的有效率58.06%（54/93），部分有效率12.90%(12/93)，无效率29.04%(27/93)，2组治疗有效率相比差异无统计学意义（P＞0.05）。温冷双自身抗体组的有效率为100%(3/3)。治疗过程中无患者发生溶血性输血反应.ABO同型非洗涤红细胞和O型洗涤红细胞输注应用于AIHA患者均具有较好的疗效，但ABO同型非洗涤红细胞可避免O型洗涤红细胞过度使用.

Study objectives Sleep breathing disorders (SBD) have been linked to wake-up stroke (WUS). Respiratory arousals have an important role in responding to danger during sleep, yet currently no studies have investigated respiratory arousability in WUS. In this study, we used a clinical tool to predict low respiratory arousal threshold (ArTH), and then compared respiratory arousability in patients with WUS and non-WUS. Methods We enrolled 119 patients with acute ischemic stroke and assigned them into WUS (n = 34) and non-WUS (n = 85) groups. All participants underwent polysomnography (PSG) during the acute phase of stroke. The respiratory ArTH predictive tool assigns one point for each of the following: apnea-hypopnea index (AHI) 82.5%, and fraction of hypopneas > 58.3%. An ArTH score ≥2 represents low respiratory ArTH. Results Our results reconfirmed the association between moderate-to-severe sleep apnea syndrome and WUS (OR 2.879, 95% CI 1.17–7.089, p = 0.021). Significantly fewer participants with obstructive sleep apnea (AHI ≥ 5/h) had low respiratory ArTH in the WUS group than in the non-WUS group (34.8% vs. 68.1%, respectively, p = 0.008). High respiratory ArTH was independently associated with WUS (OR 5.556, 95% CI 1.959–15.761, p = 0.001). Conclusions The correlation between SBD and WUS suggests that sleep apnea might induce acute physiological changes that trigger the onset of stroke. We show that reduced respiratory arousability is associated with WUS, and hypothesize that reduced cortical capability to generate respiratory arousal may have a role in triggering stroke during sleep.

This study aimed at examining whether ankle–brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) were independently associated with carotid Intima-media thickness (CIMT) or carotid artery plaque (CAP) in elderly people. A cross-sectional analysis was performed in 155 individuals aged over 75 years who underwent the measurements of ABI and baPWV. Low ABI was defined as ABI ≤ 1.0. High baPWV was defined as baPWV > 2000 cm/s. The CIMT and CAP were measured with a B-mode tomographic ultrasound system. Neither ABI nor baPWV was associated with CIMT in this elderly population. The group with low ABI (≤ 1.0) was significantly associated with a higher prevalence of carotid plaque (P = 0.001), while the relationship between baPWV and prevalence of carotid plaque was not found. Linear regression analysis showed that the value of ABI was significantly associated with the thickness of carotid plaque. Even in the full adjusted model, each 0.01unit ABI decreasing still increased 0.1663 mm of carotid plaque thickness (P = 0.004). Logistic Regression Analysis demonstrated that ABI lower than 1.0 had predictive value in the formation of carotid plaque with top quartile thickness (OR 2.834, 95% CI 1.131–7.099, P = 0.026). Furthermore, individuals with low ABI (≤ 1.0) were more likely to form hypoechoic carotid plaques according to ultrasonography. Low ABI but not high baPWV was associated with the formation of carotid plaque. Furthermore, ABI was significantly associated with the thickness and morphology of carotid plaque in elderly people.

Objective Besides the facet joints interlocking, the fibrous tissue or bony callus around the dislocated segments make the reduction for this kind of old injury to be more challenging and different from that of acute injuries. This study is aimed to present 4 cases of old subaxial cervical facet dislocations (SCFD) that were successfully treated with posterior unlocking under endoscopy followed by anterior decompression, reduction, and fixation. Methods Between January 2017 and December 2017, 4 patients with old SCFD who underwent posterior unlocking of facet joints under endoscopy followed by anterior decompression, reduction, and fixation were enrolled. A cervical collar was prescribed for 4 weeks postoperatively. Postoperative follow-up evaluations were conducted at 2, 6, and 12 months, including neck visual analogue scale score and neck disability index, radiography, and computed tomography. Results The operative time averaged 145 minutes (range, 130–155 minutes). No deterioration of neural function, major vessel rupture, or iatrogenic injury to esophagus occurred. Intraoperative blood loss averaged 45 mL (range, 40–50 mL). Hospital stay for all patients was only 4 days. The neck visual analogue scale score and neck disability index were improved at the final follow-up, and interbody fusion was satisfactory without any radiologic sign of instability or internal failure. Conclusions For patients with old SCFD, the unlocking of facet joints via the posterior approach under endoscopy followed by anterior decompression, reduction, and fixation is an alternative technique.

The incidence of melanoma in children is extremely rare. However, there is convincing evidence supporting a higher risk of developing melanoma in individuals who have experienced excessive sun exposure during their childhood. A possible explanation for this phenomenon is that prior to puberty, the melanocyte stem cells in the bulge region of hair follicles are much shallower in the dermis, resulting in their increased vulnerability to sun exposure. To validate this hypothesis, a Monte Carlo simulation of light transport is applied to quantify the dose of solar UV power absorbed in the stem-cell layers at different depths in both child and adult skins. The simulated results suggest that the stem cells in vellus hair follicles would absorb over 250 times higher UV photons than those in the terminal hair follicles. Due to the thinner epidermis in child skin, the stem cells in vellus hair follicles absorb about 1.9 and 3.2 times greater ultraviolet A and ultraviolet B, respectively, than those in adult skin. These findings provide a possible explanation to why children are particularly vulnerable to sun exposure.

Objective To observe the effect of curcumol on the biological behavior of multiple myeloma (MM) cells, thus studying its possible mechanisms for MM treatment. Methods Bone marrow mesenchymal stem cells (BMSCs) and multiple myeloma cell line 8226 (RPMI 8226) were taken as sub- jects, which were then divided into the RMPI 8226 group (cultured by RMPI 8226 alone) and the BMSCs + RMPI 8226 group (cultured by BMSCs and RMPI 8226). Curcumol in different concentrations (0. 1, 0.5, 1. 0 , 10.0 μg/mL) was added to cells in the two groups respectively. Cell proliferation, cell cycle, and ap' optosis induced by curcumol were examined by flow cytometry. The expressions of receptor activator of nuclear factor Kb ligand ( RANKL ) and osteoprotegerin ( OPG) were detected using reverse tran- scriptase-polymerase chain reaction (RT-PCR). Results Curcumol induced arrested cell cycle of RMPI 8226. The arrest of RMPI 8226 cell cycle was more obviously in the RMPI 8226 group than in the BMSCs + RMPI 8226 group. After curcumol treatment the cell proliferation of RPMI 8226 was significantly inhibited (P0. 01) and its apoptosis was increased (P0. 01). Co-cultured with BMSCs decreased curcumol in- duced apoptosis of RPMI 8226. Curcumol down-regulated the expression of osteogenic differentiation related gene RANKL, and up-regulated the expression of OPG. Conclusions Curcumol disturbed the cell cycle and induced apoptosis of RPMI 8226 cells. Curcumol up-regulated the expression of OPG as well as down-regulated the expression of RANKL. Co-culture with BMSCs could obviously inhibit curcumol in- duced apoptosis of MM cells, which might be associated with drug resistance of MM cells.

Ethnopharmacological relevance Green tea is the most ancient and popular beverage worldwide and its main constituent epigallocatechin-3-gallate (EGCG) has a potential role in the management of cancer through the modulation of cell signaling pathways. However, EGCG is frangible to oxidation and exhibits low lipid solubility and bioavailability, and we synthesized a derivative of EGCG in an attempt to overcome these limitations. Aim of the study The anthracycline antibiotic daunorubicin (DNR) is a potent anticancer agent. However, its severe cardiotoxic limits its clinical efficacy. Human carbonyl reductase 1 (CBR1) is one of the most effective human reductases for producing hydroxyl metabolites and thus may be involved in increasing the cardiotoxicity and decreasing the antineoplastic effect of anthracycline antibiotics. Accordingly, in this study, we investigated the co-therapeutic effect of Y6, a novel and potent adjuvant obtained by optimization of the structure of EGCG. Material and methods The cellular concentrations of DNR and its metabolite DNRol were measured by HPLC to determine the effects of EGCG and Y6 on the inhibition of DNRol formation. The cytotoxic effects of EGCG and Y6 were tested by MTT assay in order to identify non-toxic concentrations of them. To understand their antitumor and cardioprotective mechanisms, hypoxia-inducible factor-1α (HIF-1α) and CBR1 protein expression was measured via Western blotting and immunohistochemical staining while gene expression was analyzed using RT-PCR. Moreover, PI3K/AKT and MEK/ERK signaling pathways were analyzed via Western blotting. HepG2 xenograft model was used to detect the effects of EGCG and Y6 on the antitumor activity and cardiotoxicity of DNR in vivo. Finally, to obtain further insight into the interactions of Y6 and EGCG with HIF-1α and CBR1, we performed a molecular modeling. Results Y6(10 μg/ml or 55 mg/kg) decreased the expression of HIF-1α and CBR1 at both the mRNA and protein levels during combined drug therapy in vitro as well as in vivo, thereby inhibiting formation of the metabolite DNRol from DNR, with the mechanisms being related to PI3K/AKT and MEK/ERK signaling inhibition. In a human carcinoma xenograft model established with subcutaneous HepG2 cells, Y6(55 mg/kg) enhanced the antitumor effect and reduced the cardiotoxicity of DNR more effectively than EGCG(40 mg/kg). Conclusions Y6 has the ability to inhibit CBR1 expression through the coordinate inhibition of PI3K/AKT and MEK/ERK signaling, then synergistically enhances the antitumor effect and reduces the cardiotoxicity of DNR.

The interaction between bone marrow stromal cells and leukemia cells is critical for the persistence and progression of leukemia, and this interaction may account for residual disease. However, the link between leukemia cells and their environment is still poorly understood. In our study, runt‑related transcription factor 3 (RUNX3) was identified as a novel target gene affected by As2O3 and involved in mesenchymal stem cell (MSC)‑mediated protection of leukemia cells from As2O3‑induced apoptosis. We observed induction of RUNX3 expression and the translocation of RUNX3 into the nucleus after As2O3 treatment in leukemia cells. In K562 chronic myeloid leukemia cells, downregulation of endogenous RUNX3 compromised As2O3‑induced growth inhibition, cell cycle arrest, and apoptosis. In the presence of MSC, As2O3‑induced expression of RUNX3 was reduced significantly and this reduction was modulated by CXCL12/CXCR4 signaling. Furthermore, overexpression of RUNX3 restored, at least in part, the sensitivity of leukemic cells to As2O3. We conclude that RUNX3 plays an important role in As2O3‑induced cellular responses and allows cells to overcome MSC‑mediated drug resistance. Therefore, RUNX3 is a promising target for therapeutic approaches to overcome MSC‑mediated drug resistance.

This study was carried out to determine whether changes in hemorheological parameters parallel the severity of essential hypertension. A total of 198 older hypertensive patients were recruited and classified into 3 stages of hypertension according to the grading standard of hypertension. The whole blood viscosity (WBV) at various shear rates, plasma viscosity and erythrocyte rheology (including erythrocyte rigidity index, erythrocyte aggregation index and erythrocyte deformation index) were examined. Erythrocyte rheology paralleled the severity of essential hypertension and was significantly correlated to the average 24 h systolic blood pressure and diastolic blood pressure. Logistic analysis revealed that erythrocyte rigidity and the erythrocyte aggregation index were positively correlated with the severity of hypertension, while the erythrocyte deformation index was negatively correlated. No association was found between WBV, plasma viscosity and the severity of hypertension. The rheological properties of erythrocyte viscosity were correlated with the severity of hypertension in older people but the WBV and plasma viscosity were not.

In this investigation, global DNA methylation patterns and the specific methylation status of 5 genes were studied in DNA from peripheral blood (PB) and impact on progression free survival (PFS) and overall-survival (OS) in patients with de novo or relapsed acute myeloid leukemia (AML) treated with decitabine-based regimens waas assessed. DNA was isolated from PB samples at the time of -1, 1, and 7 days of chemotherapy. Global methylation was determined by ELISA, and the CpG island DNA methylation profile of 5 genes using a DNA methylation PCR system. Our data demonstrated that patients with a high level of 5-mC had a poor prognosis after demethylation therapy and those who have low levels of 5-mC in PB achieved higher CR and better SO, but there was no significant correlation found between the 5-mC levels and other clinical features before treatment except the disease status. Higher methylation status of Sox2 and Oct4 genes was associated with differential response to demethylation therapy. A relatively low methylation percentage in one or both of these two genes was also associated with longer OS after decitabine based chemotherapy. We also suggest that global DNA and Oct-4/Sox2 methylation might impact on the pathogenesis of leukemia and play an important role in the initiation and progression. Moreover, dynamic analysis of 5-mC and Oct-4/Sox2 in peripheral blood nucleated cells of leukemia patients may provide clues to important molecular diagnostic and prognostic targets.

Background/Aims: Interferon regulatory factor 1 (IRF-1) has been shown to function as a transcriptional activator or repressor of a variety of target genes. However, its upstream, non-coding RNA-related regulatory capacity remains unknown. In this study, we focus on the miRNA-associated single nucleotide polymorphisms (SNPs) in the 3′untranslated region (UTR) of IRF-1 to further investigate the functional relationship and potential diagnostic value of the SNPs and miRNAs among Chinese gastric cancer (GC) patients. Methods: We performed a case-control study with 819 GC patients and 756 cancer-free controls. Genotyping by realtime PCR assay, cell transfection, and the dual luciferase reporter assay were used in our study, and the 5-year overall survival rate and relapse-free survival rate in different groups were investigated. Results: We found that patients suffering from Helicobacter pylori (Hp) infection were the susceptible population compared to controls. SNP rs56288038 (C/G) in IRF-1 3′UTR was involved in the occurrence of GC by acting as a tumor promoter factor. SNP rs56288038 (C/G) could be up-regulated by miR-502-5p, which caused a down-regulation of IRF-1 in cell lines and decreased apoptosis induced by IFN-γ. Carrying the G genotype was related to significantly low expression of IRF-1 and Hp infection, poor differentiation, big tumor size, invasion depth, as well as the high probability of metastasis, and moreover, the C/G SNP was associated with shorter survival of GC patients with five years of follow-up study. Conclusions: our findings have shown that the SNP rs56288038 (C/G) in IRF-1 3′UTR acted as a promotion factor in GC development through enhancing the regulatory role of miR-502-5p in IRF-1 expression.

Background: Posterior percutaneous endoscopic cervical diskectomy (P-PECD) can be used posterior microdiscectomy for cervical disc herniation. But only some small sample sizes of clinical studies have evaluated the efficacy and safety of P-PECD. This study aim to evaluated the efficacy and safety of P-PECD compared with traditional open surgery. Methods: We will search the following seven electronic databases from their initiation to the May 1, 2020: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM) and Wanfang database. All randomized controlled trials, non-randomized controlled trials and retrospective case controls that compared the efficacy and safety of P-PECD and traditional open surgery in the treatment of cervical disc herniation will be included. The pooled odds ratio with 95% credible intervals (CIs) was used for the dichotomous variables. The mean difference with 95% CIs was used for the continuous variables. All analyses were conducted by Comprehensive Meta Analysis 2.0. A 2-tailed P value

Ethnopharmacological relevance Hepatitis B, an infectious disease caused by hepatitis B virus (HBV), is still a serious problem affecting global public health. Abrus cantoniensis Hance (AC), a traditional Chinese medicinal herb, has been used as a folk medicine for treating hepatitis in China from ancient times. However, its active ingredients are still unclear. Aim of study Our previous study indicated that saponins extracted from AC (ACS) were the active anti-HBV ingredients in AC. This study aimed to further investigate the anti-HBV effect of ACS in vitro and in vivo. Materials and methods HepG2.2.15 cells which consecutively produce HBV DNA and HBV antigens were used for in vitro test, and C57BL/6 mice infected by a recombinant adeno-associated virus 8 vector carrying 1.3 copies of HBV genome (rAAV8-HBV1.3) were used for in vivo test. The histopathological changes and the immune indices were evaluated in mice model. Genechip was conducted to identify genes and pathways regulated by ACS in HepG2.2.15 cells. Results In this study, we confirmed that ACS treatment prominently inhibited production of HBV DNA, Hepatitis Be Antigen (HBeAg), and Hepatitis B surface antigen (HBsAg) in HepG2.2.15 cells. ACS treatment also decreased serum HBsAg, HBeAg, and HBV DNA level in rAAV8-1.3HBV transfected mice, which is in accordance with the in vitro results. Moreover, HBV infection-induced liver inflammation was significantly relieved by ACS, which could be observed in H&E staining and immunohistochemistry of HBcAg. ACS treatment elevated IFN-γ level in mice serum and increased CD4+ T cell percentage in splenocytes. KEGG pathway analysis showed that phenylalanine metabolism pathway and tyrosine metabolism pathway were greatly regulated by ACS treatment. Conclusion ACS exerted potent inhibitory effects on HBV replication both in vivo and in vitro, which may provide basis for its potential clinical usage.

14-3-3τ plays a critical role in tumorigenesis and metastasis of breast cancer and can be used as new drug target protein. Dicaffeoylquinic acids (DCQAs), natural products, have antioxidant, antimicrobial, and anti-inflammatory activities. In this study, the anticancer effects of DCQAs on breast cancer cells MCF-7, MDA-MB-231 cell lines and mechanism in triple negative breast cancer (TNBC) were investigated. First, we screened for DCQAs that could bind to 14-3-3τ and had a significant inhibitory effect on breast cancer cells. MTT, colony formation, transwell migration, and flow cytometric assays revealed that 1,3-DCQA was the best one of 14-3-3τ binding protein from DCQAs against breast cancer cell proliferation and metastasis but safe for normal cells. Through molecular docking simulation, overexpression and knockdown assays, we confirmed that 14-3-3τ was one of 1,3-DCQA target protein. Eukaryotic transcriptome sequencing and western blot analysis demonstrated that 1,3-DCQA binds to 14-3-3τ to prevent breast cancer proliferation and metastasis via Jak/PI3K/Akt and Raf/ERK pathway, which promote IL6 and CSF3 expression raised by CREB (CREBBP, CREB5) and induced cell apoptosis via Bad/Bax/caspase 9 signaling pathway. Our results provided evidence that 1,3-DCQA can be used as a novel lead compound against breast cancer by inhibition of 14-3-3 protein.

The aim of this study was to investigate the protective effect and mechanism of selenium-enriched Spirulina platensis (S. platensis) on chronic alcohol-induced liver injury. Selenium incubation raises the nutrition quality of S. platensis by absorption enhancement of functional elements. Our results demonstrated that the effective dose of selenium-enriched S. platensis on HL7702 cells treated with alcohol was 200 μg ml−1, containing 20% selenium. Selenium-enriched S. platensis could raise the cell survival rate by decreasing the expression of p53, Caspase3, LC3, and Caspase1 and by increasing the expression of p70s6k. In vivo experiments, where mice were pretreated with selenium-enriched S. platensis, exhibited obvious inhibition of the liver function index and this pretreatment enhanced the activity of GSH-Px and SOD in alcohol induced mice. In summary, our results indicate that the protective mechanism of selenium-enriched S. platensis on chronic alcoholic liver injury is associated with the activity enhancement of antioxidant enzymes and immunity, the inhibition of DNA damage and apoptosis, accompanied with autophagy and pyroptosis.

Suppressor of variegation 3–9 homolog 2 (SUV39H2) is a member of the SUV39H subfamily of lysine methyltransferases. Its role in colorectal cancer (CRC) proliferation and metastasis has remained unexplored. Here, we determined that SUV39H2 was upregulated in CRC tissues compared with that in adjacent non-neoplastic tissues. Further statistical analysis revealed that high SUV39H2 expression was strongly associated with distant metastasis (P = 0.016) and TNM stage (P = 0.038) and predicted a shorter overall survival (OS; P = 0.018) and progression-free survival (PFS; P = 0.018) time for CRC patients. Both in vitro and in vivo assays demonstrated that ectopically expressed SUV39H2 enhanced CRC proliferation and metastasis, while SUV39H2 knockdown inhibited CRC proliferation and metastasis. A molecular screen of SUV39H2 targets found that SUV39H2 negatively regulated the expression of SLIT guidance ligand 1 (SLIT1). Moreover, rescue assays suggested that SLIT1 could antagonize the function of SUV39H2 in CRC. Mechanistic studies indicated that SUV39H2 can directly bind to the SLIT1 promoter, suppressing SLIT1 transcription by catalyzing histone H3 lysine 9 (H3K9) tri-methylation. In summary, we propose that SUV39H2 can predict CRC patient prognosis and stimulate CRC malignant phenotypes via SLIT1 promoter tri-methylation.

In the photodynamic therapy (PDT) of cancer, zinc phthalocyanine (ZnPc) as a photosensitizer possesses superior photosensitive properties. However, the therapeutic effect of ZnPc in PDT is limited due to its aggregation, low solubility and poor selectivity. In this study, charge-reversal phthalocyanine-based coordination polymer nanoparticles (PCPN) are developed for improving the curative effect of ZnPc. Tetra(4-carboxyphenoxy)-phthalocyaninatozinc(II) (TPZnPc) is coordinated with the zinc ion to form the core of PCPN, which is coated with a lipid bilayer by self-assembly (PCPNs@Lip). TPZnPc molecules in the core of PCPN are in the monomeric state and can generate cytotoxic singlet oxygen (1O2) efficiently, which solves the solubility and aggregation problems of ZnPc. Meanwhile, 1,2-dicarboxylic-cyclohexane anhydride modified lysyl-cholesterol (DLC) is functionalized on the surface of PCPN (PCPNs@Lip/DLC), endowing PCPN with a charge-reversal ability which could be triggered by a mildly acidic tumor microenvironment. PCPNs@Lip/DLC is proved to enhance tumor cellular uptake and generate more intracellular 1O2 after irradiation. As confirmed by in vitro and in vivo studies, PCPNs@Lip/DLC remarkably increases the PDT effect. All these results demonstrate that PCPNs@Lip/DLC is a promising nanoplatform for the application of ZnPc in effective PDT.

HPLC-guided separation of twigs of Aglaia odorata led to the isolation of eight lignans, including two new ones, 3'-methoxy-N-demethylrocaglamide (1) and 4'-O-demethyl-deacetylaglaxiflorin A (2). Compound 1 showed excellent cytotoxicity against three human cancer cell lines, HeLa, SGC-7901 gastric cancer, and A-549 lung cancer with the values of 0.32, 0.12, and 0.25 μM, respectively.

Previous studies have suggested that high mobility group box-1 protein (HMGB1) binds to the toll-like receptor 4 (TLR4) signaling mediates the progression of various inflammatory diseases. But the roles of HMGB1 and TLR4 in aging remain poorly unknown. In this study, we aimed to investigate the serum levels of HMGB1 and myeloid differentiation factor 88 (MyD88), which is one of TLR4’s intracellular adaptor proteins during human aging process and their relevance with cathepsin B (CTSB). This research was conducted using the blood samples provided by healthy people (n = 90, 63 men and 27 women). Subjects were subdivided into groups with respect to age: young (about 25 years old, n = 30), middle age (about 40 years old, n = 30), and aged (above 65 years old, n = 30). Altered serum levels of HMGB1, MyD88 and CTSB were measured using an enzyme-linked immunosorbent assay. The serum levels of HMGB1 and MyD88 were significantly decreased in the aged group compared with those in the young group. Linear regression analysis showed that HMGB1 and MyD88 positively correlated with CTSB among the whole healthy people. A negative correlation was determined between MyD88 and age. The serum levels of HMGB1 and MyD88 significantly decreased with age. MyD88, but not HMGB1, was negatively correlated with age.

// Xiang Fu 1,2,* , Jiali Hu 1,* , Hong-yu Han 1,* , Yi-jun Hua 1,* , Ling Zhou 1 , Wen-di Shuai 1 , Wu-ying Du 1 , Chun-mei Kuang 1 , Shuai Chen 1 , Wenlin Huang 1,3 and Ran-yi Liu 1 1 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China 2 The Eastern Hospital of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China 3 Guangdong Provincial Key Laboratory of Tumor targeted Drugs and Guangzhou Enterprise Key Laboratory of Gene Medicine, Guangzhou Doublle Bioproducts Co. Ltd., Guangzhou, China * These authors have contributed equally in this work Correspondence to: Ran-yi Liu, email: // Wenlin Huang, email: // Keywords : nasopharyngeal carcinoma, xeroderma pigmentosum complementation group-A, platinum resistance, prognostic markers, chemoradiotherapy Received : March 30, 2015 Accepted : June 04, 2015 Published : June 10, 2015 Abstract In this study, we tried to explore if xeroderma pigmentosum complementation group-A (XPA) expression is likely a prognostic prediction factor for locally advanced nasopharyngeal carcinoma (NPC) patients treated with platinum-based chemoradiotherapy, which was considered to bring chemotherapy-related severe toxicity compared with radiotherapy alone. Firstly, MTT assay revealed that downregulating XPA expression in NPC HONE1 and CNE1 cells decreased IC 50 of cisplatin and sensitized cells to cisplatin. XPA expression was detected by immunohistochemistry in cancer tissues from locally advanced NPC patients treated with platinum-based chemoradiotherapy. The relationships between XPA expression and clinicopathologic features, overall survival and progression-free survival of patients were evaluated. The results showed that XPA expression was not associated with clinicopathologic parameters, but was likely an independent prognostic factor for patient survival. High XPA level predicts a poor prognosis, and the prediction values were higher in subgroups of younger, higher EBV antibody titer, or treated with concurrent chemoradiotherapy. Combining XPA levels and T/N classifications, we successfully classified these patients into low, medium and high risk groups for platinum-based chemoradiotherapy. These findings suggest that XPA levels may be a potential predictor of prognosis in locally advanced NPC patients treated with platinum-based chemoradiotherapy, and helpful for selecting patients likely to need and benefit from this treatment in future.

The development of targeted tyrosine kinase inhibitors (TKIs) has succeeded in altering the course of chronic myeloid leukemia (CML). However, a number of patients have failed to respond or experienced disease relapse following TKI treatment. Proviral integration site for moloney murine leukemia virus-1 (PIM-1) is a serine/threonine kinase that participates in regulating apoptosis, cell cycle, signal transduction and transcriptional pathways, which are associated with tumor progression, and poor prognosis. SMI-4a is a selective PIM-1 kinase inhibitor that inhibits PIM-1 kinase activity in vivo and in vitro. The present study aimed to explore the mechanism underlying the antitumor effect of SMI-4a in K562 and imatinib-resistant K562 (K562/G) cell lines. It was demonstrated that SMI-4a inhibited the proliferation of K562 and K562/G cells using a WST-8 assay. The Annexin V-propidium iodide assay demonstrated that SMI-4a induced apoptosis of K562 and K562/G cells in a dose-, and time-dependent manner. Furthermore, Hoechst 33342 staining was used to verify the apoptosis rate. The clone formation assay revealed that SMI-4a significantly inhibited the colony formation capacity of K562 and K562/G cells. Western blot analysis demonstrated that SMI-4a decreased phosphorylated (p)-Ser9-glycogen synthase kinase (GSK) 3β/pGSK3β and inhibited the translocation of β-catenin. In addition, the downstream gene expression of apoptosis regulator Bax and poly(ADP-ribose) polymerase-1 was upregulated, and apoptosis regulator Bcl-2 and Myc proto-oncogene protein expression levels were downregulated. Immunofluorescence results demonstrated changes in the expression level of β-catenin in the plasma and nucleus. The results of the present study suggest that SMI-4a is an effective drug to use in combination with current chemotherapeutics for the treatment of imatinib-resistant CML.