An engineered bispecific human monoclonal antibody against SARS-CoV-2.

The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires effective therapies against coronavirus disease 2019 (COVID-19), and neutralizing antibodies are a promising therapy. A noncompeting pair of human neutralizing antibodies (B38 and H4) blocking SARS-CoV-2 binding to its receptor, ACE2, have been described previously. Here, we develop bsAb15, a bispecific monoclonal antibody (bsAb) based on B38 and H4. bsAb15 has greater neutralizing efficiency than these parental antibodies, results in less selective pressure and retains neutralizing ability to most SARS-CoV-2 variants of concern (with more potent neutralizing activity against the Delta variant). We also selected for escape mutants of the two parental mAbs, a mAb cocktail and bsAb15, demonstrating that bsAb15 can efficiently neutralize all single-mAb escape mutants. Furthermore, prophylactic and therapeutic application of bsAb15 reduced the viral titer in infected nonhuman primates and human ACE2 transgenic mice. Therefore, this bsAb is a feasible and effective strategy to treat and prevent severe COVID-19.

Key mechanistic features of the trade-off between antibody escape and host cell binding in the SARS-CoV-2 Omicron variant spike proteins.

Since SARS-CoV-2 Omicron variant emerged, it is constantly evolving into multiple sub-variants, including BF.7, BQ.1, BQ.1.1, XBB, XBB.1.5 and the recently emerged BA.2.86 and JN.1. Receptor binding and immune evasion are recognized as two major drivers for evolution of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein. However, the underlying mechanism of interplay between two factors remains incompletely understood. Herein, we determined the structures of human ACE2 complexed with BF.7, BQ.1, BQ.1.1, XBB and XBB.1.5 RBDs. Based on the ACE2/RBD structures of these sub-variants and a comparison with the known complex structures, we found that R346T substitution in the RBD enhanced ACE2 binding upon an interaction with the residue R493, but not Q493, via a mechanism involving long-range conformation changes. Furthermore, we found that R493Q and F486V exert a balanced impact, through which immune evasion capability was somewhat compromised to achieve an optimal receptor binding. We propose a "two-steps-forward and one-step-backward" model to describe such a compromise between receptor binding affinity and immune evasion during RBD evolution of Omicron sub-variants.

Bispecific antibodies targeting two glycoproteins on SFTSV exhibit synergistic neutralization and protection in a mouse model.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate of up to 30% caused by SFTS virus (SFTSV). However, no specific vaccine or antiviral therapy has been approved for clinical use. To develop an effective treatment, we isolated a panel of human monoclonal antibodies (mAbs). SF5 and SF83 are two neutralizing mAbs that recognize two viral glycoproteins (Gn and Gc), respectively. We found that their epitopes are closely located, and we then engineered them as several bispecific antibodies (bsAbs). Neutralization and animal experiments indicated that bsAbs display more potent protective effects than the parental mAbs, and the cryoelectron microscopy structure of a bsAb3 Fab-Gn-Gc complex elucidated the mechanism of protection. In vivo virus passage in the presence of antibodies indicated that two bsAbs resulted in less selective pressure and could efficiently bind to all single parental mAb-escape mutants. Furthermore, epitope analysis of the protective mAbs against SFTSV and RVFV indicated that they are all located on the Gn subdomain I, where may be the hot spots in the phleboviruses. Collectively, these data provide potential therapeutic agents and molecular basis for the rational design of vaccines against SFTSV infection.

Design, Synthesis, and Ultrafast Carrier Dynamics of Core-Substituted Naphthalene Diimide-Based Covalent Organic Frameworks.

A series of two-dimensional polyimide covalent organic frameworks (2D COF) based on core-substituted naphthalene diimides (cNDIs) were designed and synthesized with the characteristic of tunable bandgap without global structural changes. Cyclic voltammetry (CV) and DFT calculations indicated that COFcNDI-OEt and COFcNDI-SEt possess higher HOMO/LUMO levels and narrower bandgaps than COFNDI-H. Further investigation indicated that the COF bandgaps are not only related to the electron-donating substituents but also varied with respect to the interlayer distances. Moreover, the femtosecond transient absorption (TA) spectra manifested that the electron donor substituents are beneficial to the charge delocalization in the π-columnar unit, resulting in a longer lifetime of charge recombination, which is one of the pivotal prerequisites for high-performance solar cells and photocatalysis.

Association of sleep quality, its change and sleep duration with the risk of type 2 diabetes mellitus: Findings from the English longitudinal study of ageing.

AIMS: This study aimed to evaluate the association of sleep quality and its long-term change with the risk of type 2 diabetes mellitus (T2DM) and to assess the relationship between sleep duration and the risk of T2DM according to categories of sleep quality. MATERIALS AND METHODS: 5728 participants free of T2DM at wave 4 from the English Longitudinal Study of Ageing were included and received a follow-up with a median time of 8 years. We created a sleep quality score to evaluate sleep quality, which was based on three Jenkins Sleep Problems Scale questions (the frequency of feeling hard to fall asleep, waking up at night, and feeling tired in the morning) and one question for rating overall sleep quality. Participants were allocated into three groups according to their baseline sleep quality scores (groups of good [4-8], intermediate [8-12], and poor quality [12-16]). Sleep duration was assessed by a self-reporting sleep hours from each participant. RESULTS: 411 (7.2%) T2DM cases were documented during the follow-up. Compared with the good quality group, subjects with poor sleep quality showed a significantly higher risk of T2DM (hazard ratio (HR) 1.45, confidence interval (CI) 1.09, 1.92). In participants with good baseline sleep quality, those who experienced worsened sleep quality showed a significantly increased T2DM risk (HR 1.77, 95% CI 1.26, 2.49). Type 2 diabetes mellitus risk was not changed regardless of sleep duration in subjects with good quality. Short sleep duration (≤4h) was associated with an elevated T2DM risk in participants with intermediate sleep quality, and both short (≤4h) and prolonged sleep time (≥9h) were associated with an increased T2DM risk in the poor sleep quality group. CONCLUSIONS: Poor sleep quality is correlated with an increase in T2DM risk, and regulating sleep quality to a good range could potentially be an effective approach for preventing T2DM.

Associations between ambient temperature and adult asthma hospitalizations in Beijing, China: a time-stratified case-crossover study.

BACKGROUND: Studies on the associations between ambient temperature and asthma hospitalizations are limited, and the results are controversial. We aimed to assess the short-term effects of ambient temperature on the risk of asthma hospitalizations and quantify the hospitalization burdens of asthma attributable to non-optimal temperature in adults in Beijing, China. METHODS: We collected daily asthma hospitalizations, meteorological factors and air quality data in Beijing from 2012 to 2015. We applied a time-stratified case-crossover design and fitted a distributed lag non-linear model with a conditional quasi-Poisson regression to explore the association between ambient temperature and adult asthma hospitalizations. The effect modifications of these associations by gender and age were assessed by stratified analyses. We also computed the attributable fractions and numbers with 95% empirical confidence intervals (eCI) of asthma hospitalizations due to extreme and moderate temperatures. RESULTS: From 2012 to 2015, we identified a total of 18,500 hospitalizations for asthma among adult residents in Beijing, China. Compared with the optimal temperature (22 °C), the cumulative relative risk (CRR) over lag 0-30 days was 2.32 with a 95% confidence interval (CI) of 1.57-3.42 for extreme cold corresponding to the 2.5th percentile (- 6.5 °C) of temperature distribution and 2.04 (95% CI 1.52-2.74) for extreme heat corresponding to the 97.5th percentile (29 °C) of temperature distribution. 29.1% (95% eCI 17.5-38.0%) of adult asthma hospitalizations was attributable to non-optimum temperatures. Moderate cold temperatures yielded most of the burdens, with an attributable fraction of 20.3% (95% eCI 9.1-28.7%). The temperature-related risks of asthma hospitalizations were more prominent in females and younger people (19-64 years old). CONCLUSIONS: There was a U-shaped association between ambient temperature and the risk of adult asthma hospitalizations in Beijing, China. Females and younger patients were more vulnerable to the effects of non-optimum temperatures. Most of the burden was attributable to moderate cold. Our findings may uncover the potential impact of climate changes on asthma exacerbations.

A nomogram model to predict prognosis of patients with hepatoblastoma.

BACKGROUND: Hepatoblastomas (HBs) are malignant liver tumors that most commonly develop in pediatric patients. Microvascular invasion may be a prognosis factor for patients with HBs. This study aimed to construct a model to predict the survival outcome in HBs. METHODS: We retrospectively analyzed the clinical data of 311 patients with HBs who underwent surgical resection at our institution between June 2014 and August 2021. First, patients were divided into two groups: those who had pathologic microvascular invasion (n = 146) and those who did not (n = 165). Propensity score-matched (PSM) analysis was carried out between the two groups. The preoperative parameters and overall survival (OS) rate were compared between the two groups. Second, all 311 patients were randomly divided into the training and validation cohort in a ratio of 4:1. A nomogram was created in the training cohort to visualize the prediction of OS. Moreover, the validation cohort was used for validation. RESULTS: Multivariate analysis suggested that age, histology type, microvascular invasion, multifocality, distant metastasis, and macrovascular involvement are independent prognostic factors for HBs. The nomogram showed good predictive ability in the training and validation cohorts with a C-index of 0.878 (95% CI, 0.831-0.925) and 0.847 (95% CI, 0.757-0.937), respectively. The calibration curve indicated good agreement between the prediction and observation for one-, two-, and three-year OS probabilities. CONCLUSION: By combining preoperative imaging results and other clinical data, we established a nomogram to predict OS probability for patients with HB, which could be a potential tool to guide personalized treatment.

Triglyceride to high-density lipoprotein cholesterol ratio and cardiovascular events in the general population: A systematic review and meta-analysis of cohort studies.

AIMS: The ratio of triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) has been regarded as a novel surrogate indicator of insulin resistance and the atherogenic index of plasma. This meta-analysis aimed to evaluate the association between the TG/HDL-C ratio and the incidence of cardiovascular events in the general population. DATA SYNTHESIS: Cohort studies reporting the association between the TG/HDL-C ratio and cardiovascular events in the general population were obtained by a systematic literature search of PubMed, Embase and Web of Science databases until April 11, 2021. 13 cohort studies with a total of 207,515 participants were included in this meta-analysis. In a random-effects model, compared with those with the lowest category of the TG/HDL-C ratio, participants with the highest category were independently associated with a higher risk of cardiovascular events (pooled HR: 1.43, 95%CI: 1.26-1.62, I2 = 72.9%). For the presence of publication bias detected by the Egger's test (p = 0.011), correction for publication bias using the trim-and-fill method reduced the HR to 1.26 (95%CI: 1.11-1.44). This result was consistent with the finding of the TG/HDL-C ratio analyzed as a continuous variable (pooled HR per unit increment of the TG/HDL-C ratio: 1.08, 95%CI: 1.04-1.12, I2 = 67.0%). Subgroup analyses indicated that population gender, geographical region, duration of follow-up, adjustment for other lipid parameters, adjustment for diabetes and categorical number did not significantly vary the relationship. CONCLUSION: Elevated TG/HDL-C ratio may be independently associated with an increased risk of cardiovascular events in the general population. More well-designed studies are needed to confirm the current findings. REGISTRATION NUMBER IN PROSPERO: CRD42021244583.

Polydatin ameliorates hepatic ischemia-reperfusion injury by modulating macrophage polarization.

BACKGROUND: Polydatin, a glucoside of resveratrol, has been shown to have protective effects against various diseases. However, little is known about its effect on hepatic ischemia-reperfusion (I/R) injury. This study aimed to elucidate whether polydatin protects liver against I/R-induced injury and to explore the underlying mechanism. METHODS: After gavage feeding polydatin once daily for a week, mice underwent a partial hepatic I/R procedure. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), hematoxylin-eosin (H&E) and TdT-mediated dUTP nick-end labeling (TUNEL) staining were used to evaluate liver injury. The severity related to the inflammatory response and reactive oxygen species (ROS) production was also investigated. Furthermore, immunofluorescence and Western blotting were used to detect macrophage polarization and the NF-κB signaling pathway in macrophages. RESULTS: Compared with the I/R group, polydatin pretreatment significantly attenuated I/R-induced liver damage and apoptosis. The oxidative stress marker (dihydroethidium fluorescence, malondialdehyde, superoxide dismutase and glutathione peroxidase) and I/R related inflammatory cytokines (interleukin-1ß, interleukin-10 and tumor necrosis factor-α) were significantly suppressed after polydatin treatment. In addition, the result of immunofluorescence indicated that polydatin reduced the polarization of macrophages toward M1 macrophages both in vivo and in vitro. Western blotting showed that polydatin inhibited the pro-inflammatory function of RAW264.7 via down-regulating the NF-κB signaling pathway. CONCLUSIONS: Polydatin protects the liver from I/R injury by remodeling macrophage polarization via NF-κB signaling.

Totally laparoscopic anatomic S7 segmentectomy using in situ split along the right intersectoral and intersegmental planes.

BACKGROUND: The traditional open or laparoscopic segmentectomy of liver segment 7 (S7) requires exposing and controlling the root of the right hepatic vein(RHV)after full mobilization and lifting up of the right liver before liver transection. This approach violates the "no-touch" principle for malignant tumors, and makes laparoscopic resection technically challenging. So reports on isolated totally laparoscopic anatomic S7 segmentectomy have rarely been reported. This study describes our experience in laparoscopic anatomic S7 segmentectomy using in situ split along the right intersectoral and intersegmental planes of the liver. To our knowledge, this is the first description of this novel approach. METHODS: From September 2017 to May 2019, patients who underwent laparoscopic anatomic S7 segmentectomy for hepatocellular carcinoma at the HPB Surgery Department, Sun Yat-Sen Memorial Hospital entered into this retrospective study. This in situ split approach was designed using main vessels as the plane markers of right intersectoral and intersegmental planes, along which liver transection was carried out. There was no need to mobilize the right liver and control the root of RHV. RESULTS: There were 9 women and 15 men. The average diameter of the tumors on preoperative CT/MR was 3.4 cm (range 2-6 cm). All the procedures were successfully carried out laparoscopically. There was no perioperative death. The average operative time was 216.5 min (range 180-310 min). The average blood loss was 320 ml (range 120-620 ml). Pathological study showed all the operations to be R0 resections. CONCLUSION: Laparoscopic anatomic S7 segmentectomy using the in situ split approach resulted in R0 liver resection in all our patients with primary liver cancer. The operation was technically feasible and it provided a better view and increased maneuverability in the cramped operative space compared with the traditional open/laparoscopic approach. The approach also better complies with the "no-touch" principle for malignant tumors. Its long-term oncological outcomes require further studies.

Association between the triglyceride-glucose index and abdominal aortic calcification in adults: A cross-sectional study.

BACKGROUND AND AIMS: The triglyceride-glucose (TyG) index is a reliable marker of insulin resistance, which is a substantial risk factor for cardiovascular diseases. Abdominal aortic calcification (AAC) is significantly associated with subclinical atherosclerotic diseases. The present study investigated the relationship between the TyG index and extensive AAC in middle-aged and elderly populations in the United States (US). METHODS AND RESULTS: We performed cross-sectional analyses of data from 1419 participants from the National Health and Nutrition Examination Survey 2013-2014. AAC was detected using dual-energy X-ray absorptiometry on Hologic Discovery model A densitometer, and quantified using the Kauppila score system. Extensive AAC was defined as a Kauppila score ≥5. Multivariable logistic regression models were used to determine the association between AAC and the TyG index. The restricted cubic spline model was used for the dose-response analysis. Extensive AAC was detected in 196 (13.8%) participants. The odds of extensive AAC increased by 41% per unit increase in the TyG index (adjusted odds ratios [OR] = 1.41, 95% confidence interval [CI]: 1.04-1.91). The multivariable-adjusted OR and 95% CI of the highest TyG index tertile compared with the lowest tertile was 1.80 (95% CI: 1.11-2.94). Extensive AAC showed a more robust association with the TyG index than with triglycerides or glycemia. The subgroup analyses indicated that the association was consistent irrespective of age, sex, hypertension, diabetes, hypercholesteremia and smoking status. CONCLUSION: The TyG index was independently associated with the presence of extensive AAC in the study population. Further studies are required to confirm this relationship.

Relationship Between Pituitary Adenoma Consistency and Extent of Resection Based on Tumor/Cerebellar Peduncle T2-Weighted Imaging Intensity (TCTI) Ratio of the Point on Preoperative Magnetic Resonance Imaging (MRI) Corresponding to the Residual Point on Postoperative MRI.

BACKGROUND Controversies exist in imaging modalities for predicting adenoma consistency. In this study, we proposed a method of predicting consistency by magnetic resonance T2-sequence imaging based on adenoma to cerebellar peduncle signal (TCTI) ratio. MATERIAL AND METHODS Between January 2013 and May 2017, 191 consecutive patients with pituitary adenoma diagnosed at our institution were retrospectively studied. The consistency grade for each lesion was assigned. And the TCTI ratio based on preoperative and postoperative T2-weighted imaging was calculated. RESULTS The median TCTI ratio was 1.55, 1.28, and 1.25 for soft, fibrous, and hard adenomas, respectively. The differences were significant for all groups (p<0.001). A cutoff value of 1.38 for soft adenomas was found to be 80.2% sensitive and 88.7% specific. The median ratio of the outermost layer of residual tumor was 1.25 (SD±0.408, 95% CI 1.27-1.42). It was less than that ratio of the upper, lower quarter, and middle region of adenoma, respectively, and the inter-group differences were all statistically significant with p≤0.001. The extent of resection for the soft group was significantly greater than that of the hard group (85.3% vs. 70.6%, p=0.011). Analysis of Variance (ANOVA) revealed that the consistency grade was the influencing factor of degree of resection. p=0.003. CONCLUSIONS The TCTI ratio showed a good correlation with pituitary adenoma consistency. We also determined the optimal ratio of the residual adenoma.

Serum Ngb (Neuroglobin) Is Associated With Brain Metabolism and Functional Outcome of Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- Hypoxic-ischemic brain damage is a well-recognized physiopathologic mechanism after aneurysmal subarachnoid hemorrhage (aSAH). The Ngb (neuroglobin) is a hemoprotein predominantly expressed in the brain with a high affinity for oxygen. Relationship between serum Ngb level and brain metabolism in aSAH patients has not been investigated previously. Methods- Thirty-six consecutive severe aSAH patients (Glasgow Coma Scale score ≤8 on admission) with multimodal neuromonitoring and 36 matched healthy subjects were included. Serum Ngb level was analyzed in combination with other time-matched cerebral microdialysis parameters, brain tissue oxygen tension, and 12-month neurological outcomes. Results- Serum Ngb level was correlated positively with cerebral microdialysis parameters and brain tissue oxygen tension ( P<0.001). Poor functional outcome (modified Rankin Scale score >3) 12 months after aSAH was associated with higher Ngb level but independent of age, sex, and disease severity ( P<0.001). A similar association was found between high Ngb level and neuropsychological test results indicative of impairments in cognition, visual conceptualization, and frontal executive functions ( P<0.001). Conclusions- Ngb may be a potential biomarker for reflecting brain tissue oxygen tension, brain metabolism, and functional outcome in severe aSAH patients and merits further study in the context of aSAH.

Laparoscopic duodenum-preserving total pancreatic head resection: a novel surgical approach for benign or low-grade malignant tumors.

BACKGROUND: Duodenum-preserving total pancreatic head resection (DPPHRt) is an accepted alternative surgical procedure for benign or low-grade malignant tumors of the pancreatic head by preserving the duodenum with its intact blood supply from the pancreatic duodenal arterial arcade. This study describes our experience in laparoscopic DPPHRt (LDPPHRt). To our knowledge, this is the first description of this novel minimally invasive operation. METHODS: From August 2016 to May 2017, all consecutive patients who underwent LDPPHRt for pancreatic head lesions at the HPB Surgery Department, Sun Yat-Sen Memorial Hospital in Guangzhou, China were enrolled into this retrospective study. RESULTS: There were ten women and two men. The average age was 37.3 years (range 8-61 years). The average diameter of the pancreatic head lesions on pre-operative CT/MR was 3.7 cm (range 2-4.8 cm). All the LDPPHRt procedures were performed successfully. There was no peri-operative death. The average operative time was 272.5 min (range 210-320 min). The average blood loss was 215 ml (range 50-450 ml). Post-operative complications included pancreatic fistula grade B (two patients, or 16.7%) and biliary fistula (two patients, or 16.7%). All the complications responded well to conservative treatment. The mean post-operative hospital stay was 11.5 days (range 6-25 days). CONCLUSIONS: LDPPHRt provided a minimally invasive approach with good organ-preservation for benign or low-grade malignant tumors of the pancreatic head. The long-term oncological outcomes, and the exocrine and endocrine pancreatic functions after this operation require further studies.

The Arabidopsis KINßγ Subunit of the SnRK1 Complex Regulates Pollen Hydration on the Stigma by Mediating the Level of Reactive Oxygen Species in Pollen.

Pollen-stigma interactions are essential for pollen germination. The highly regulated process of pollen germination includes pollen adhesion, hydration, and germination on the stigma. However, the internal signaling of pollen that regulates pollen-stigma interactions is poorly understood. KINßγ is a plant-specific subunit of the SNF1-related protein kinase 1 complex which plays important roles in the regulation of plant development. Here, we showed that KINßγ was a cytoplasm- and nucleus-localized protein in the vegetative cells of pollen grains in Arabidopsis. The pollen of the Arabidopsis kinßγ mutant could not germinate on stigma, although it germinated normally in vitro. Further analysis revealed the hydration of kinßγ mutant pollen on the stigma was compromised. However, adding water to the stigma promoted the germination of the mutant pollen in vivo, suggesting that the compromised hydration of the mutant pollen led to its defective germination. In kinßγ mutant pollen, the structure of the mitochondria and peroxisomes was destroyed, and their numbers were significantly reduced compared with those in the wild type. Furthermore, we found that the kinßγ mutant exhibited reduced levels of reactive oxygen species (ROS) in pollen. The addition of H2O2 in vitro partially compensated for the reduced water absorption of the mutant pollen, and reducing ROS levels in pollen by overexpressing Arabidopsis CATALASE 3 resulted in compromised hydration of pollen on the stigma. These results indicate that Arabidopsis KINßγ is critical for the regulation of ROS levels by mediating the biogenesis of mitochondria and peroxisomes in pollen, which is required for pollen-stigma interactions during pollination.

Comparison of clinical results between novel percutaneous pedicle screw and traditional open pedicle screw fixation for thoracolumbar fractures without neurological deficit.

OBJECTIVES: To compare the efficacy and safety of novel percutaneous minimally invasive pedicle screw fixation and traditional open surgery for thoracolumbar fractures without neurological deficit. METHODS: Sixty adult patients with single thoracolumbar fracture between June 2014 and June 2016 were recruited in this study, randomly divided into open fixation group (group A) or minimally invasive percutaneous fixation group (group B). Clinical and surgical evaluation including surgery time, blood losses, radiation times, hospital stay, and complication were performed. The two groups of patients with pre-operative and last follow-up anterior height ratio of fracture vertebral, Cobb angle of fracture vertebral, and VAS score of back pain were compared. RESULTS: All patients completed valid follow-ups, with an average time period of 15.4 months (12-26 months). Group B achieved much better results in time of operation, intra-operative blood loss, and length of stay than group A (P < 0.05). Group A was significantly better than group B in the times of radiation (P < 0.05). The VAS score was significantly lower in group B than in group A at three days after the operation (P < 0.05). There were no significant differences between the two groups in the anterior height ratio of fracture vertebral, Cobb angle, and VAS score in the last follow-up (P > 0.05). No injured nerve or other severe complications occurred in both groups; one of the patients from group A had back and loin pain lasting for about one month, which resolved after analgesia and functional training. There was no significant difference between the two groups in incidence of complications. CONCLUSIONS: Novel percutaneous pedicle screws with angle reset function can achieve the same effect as traditional open pedicle screw fixation in the treatment of thoracolumbar fractures without nerve injuries. Percutaneous minimally invasive pedicle screw fixation has the characteristics of shorter operative time, less bleeding, and less pain, but it needs more radiation times.

[Immunotherapy of Gastrointestinal Stromal Tumors].

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract and respond poorly to conventional radiochemotherapy.Complete excision is the only possible way to cure GISTs.Although targeted therapy is effective for GISTs,multiple and/or secondary mutations of KIT or PDGFRA gene have lead to increased drug resistance and disease relapse.A variety of tumor infiltrating immune cells and complex immune microenvironments have been found in GISTs.Many immune cells participate in the occurrence and development of GISTs and play key roles in targeted therapy.The feasibility and effectiveness of immunotherapy for GISTs have been well demonstrated in preclinical and clinical studies.

Shikonin sensitizes A549 cells to TRAIL-induced apoptosis through the JNK, STAT3 and AKT pathways.

BACKGROUND: TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, can selectively kill cancer cells with little or no cytotoxicity toward normal human cells and is regarded as a potential relatively safe antitumor drug. However, some cancer cells are resistant to TRAIL-induced apoptosis. Thus, reagents that potentiate TRAIL-induced cytotoxicity are needed. Herein, we investigated whether shikonin, a natural compound from the root of Lithospermum erythrorhizon, can sensitize TRAIL-resistant cells to TRAIL-induced cytotoxicity. RESULTS: The viability of A549 cells, which were resistant to TRAIL, was significantly decreased after treatment with TRAIL followed by shikonin. The underlying mechanisms by which shikonin sensitizes cells to TRAIL-induced cytotoxicity were also examined. Combined treatment with shikonin and TRAIL activated the caspase and JNK pathways, inhibited the STAT3 and AKT pathways, downregulated the expression of Mcl-1, Bcl-2, Bcl-xL, c-FLIP and XIAP and upregulated the expression of Bid. CONCLUSIONS: In conclusion, the results indicated that shikonin sensitized resistant cancer cells to TRAIL-induced cytotoxicity via the modulation of the JNK, STAT3 and AKT pathways, the downregulation of antiapoptotic proteins and the upregulation of proapoptotic proteins.

Palladium-Catalyzed Domino Reaction for Stereoselective Synthesis of Multisubstituted Olefins: Construction of Blue Luminogens.

The first Pd-catalyzed multicomponent reaction of aryl iodides, alkenyl bromides, and strained alkenes has been developed, which allowed us to synthesize a variety of multisubsituted olefins in yields of 45-96% with excellent stereoselectivity. The configuration of the product was controlled by the configuration of the alkenyl bromides. Moreover, this practical methodology employing readily available substrates was found to be tolerant to a wide range of functional groups. Fifty six examples of highly stereoselective tri- or tetrasubstituted olefins have been successfully synthesized via this methodology. Most of the synthesized tetrasubstituted olefins are good aggregation-induced emission (AIE) luminogens.

Development of a High-Sensitivity Optical Accelerometer for Low-Frequency Vibration Measurement.

Low-frequency vibration is a harmful factor that affects the accuracy of micro/nano-measuring machines. Low-frequency vibration cannot be completely eliminated by passive control methods, such as the use of air-floating platforms. Therefore, low-frequency vibrations must be measured before being actively suppressed. In this study, the design of a low-cost high-sensitivity optical accelerometer is proposed. This optical accelerometer mainly comprises three components: a seismic mass, a leaf spring, and a sensing component based on a four-quadrant photodetector (QPD). When a vibration is detected, the seismic mass moves up and down due to the effect of inertia, and the leaf spring exhibits a corresponding elastic deformation, which is amplified by using an optical lever and measured by the QPD. Then, the acceleration can be calculated. The resonant frequencies and elastic coefficients of various seismic structures are simulated to attain the optimal detection of low-frequency, low-amplitude vibration. The accelerometer is calibrated using a homemade vibration calibration system, and the calibration experimental results demonstrate that the sensitivity of the optical accelerometer is 1.74 V (m·s-2)-1, the measurement range of the accelerometer is 0.003⁻7.29 m·s-2, and the operating frequencies range of 0.4⁻12 Hz. The standard deviation from ten measurements is under 7.9 × 10-4 m·s-2. The efficacy of the optical accelerometer in measuring low-frequency, low-amplitude dynamic responses is verified.