Prompt-enhanced hierarchical transformer elevating cardiopulmonary resuscitation instruction via temporal action segmentation.

The vast majority of people who suffer unexpected cardiac arrest are performed cardiopulmonary resuscitation (CPR) by passersby in a desperate attempt to restore life, but endeavors turn out to be fruitless on account of disqualification. Fortunately, many pieces of research manifest that disciplined training will help to elevate the success rate of resuscitation, which constantly desires a seamless combination of novel techniques to yield further advancement. To this end, we collect a specialized CPR video dataset in which trainees make efforts to behave resuscitation on mannequins independently in adherence to approved guidelines, promoting an auxiliary toolbox to assist supervision and rectification of intermediate potential issues via modern deep learning methodologies. Our research empirically views this problem as a temporal action segmentation (TAS) task in computer vision, which aims to segment an untrimmed video at a frame-wise level. Here, we propose a Prompt-enhanced hierarchical Transformer (PhiTrans) that integrates three indispensable modules, including a textual prompt-based Video Features Extractor (VFE), a transformer-based Action Segmentation Executor (ASE), and a regression-based Prediction Refinement Calibrator (PRC). The backbone preferentially derives from applications in three approved public datasets (GTEA, 50Salads, and Breakfast) collected for TAS tasks, which experimentally facilitates the model excavation on the CPR dataset. In general, we probe into a feasible pipeline that elevates the CPR instruction qualification via action segmentation equipped with novel deep learning techniques. Associated experiments on the CPR dataset advocate our resolution with surpassing 91.0% on Accuracy, Edit score, and F1 score.

Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

SRPX2 boosts pancreatic cancer chemoresistance by activating PI3K/AKT axis.

BACKGROUND AND AIM: This investigation was aimed at disclosing whether SRPX2 affected pancreatic cancer (PC) chemoresistance by regulating PI3K/Akt/mTOR signaling. METHODS: Totally 243 PC patients were recruited, and they were incorporated into partial remission (PR) group, stable disease (SD) group and progressive disease (PD) group in accordance with their chemotherapeutic response. PC cell lines (i.e. AsPC1, Capan2, VFPAC-1, HPAC, PANC-1, BxPC-3 and SW1990) and human pancreatic ductal epithelial cell lines (hTERT-HPNE) were also collected. RESULTS: PC patients of SD + PD group were associated with higher post-chemotherapeutic SRPX2 level than PR group, and their post-chemotherapeutic SRPX2 level was above the pretherapeutic SRPX2 level (P < 0.05). PR population showed lower SRPX2 level after chemotherapy than before chemotherapy (P < 0.05). Besides high serum SRPX2 level and SRPX2 level change before and after chemotherapy were independent predictors of poor PC prognosis. Additionally, si-SRPX2 enhanced chemosensitivity of PC cell lines, and expressions of p-PI3K, p-AKT and p-mTOR were suppressed by si-SRPX2 (P < 0.05). IGF-1 treatment could changeover the impact of si-SRPX2 on proliferation, migration, invasion and chemoresistance of PC cells (P < 0.05). CONCLUSION: The SRPX2-PI3K/AKT/mTOR axis could play a role in modifying progression and chemoresistance of PC cells, which might help to improve PC prognosis.

The expression and the role of PIWI like RNA-mediated gene silencing 3 (PIWIL3) in lung cell line.

BACKGROUND: To determine the expression and role of PIWI-like RNA-mediated gene silencing 3 (PIWIL3) in human lung cancer. METHODS: Immunohistochemistry was performed to measure the expression of PIWIL3 in 30 of pairs lung cancer and corresponding paracancer tissues. Quantitative PCR (qPCR) was conducted to analyze the expression of PIWIL3 in four breast cancer cell lines. siRNA was used to silence PIWIL3 in the lung cancer cells (A549). Methylthiazoletetrazolium (MTT) proliferation assay and colony formation assay were conducted to detect the growth of A549 cells. Fluorescence-activated cell sorting (FACS) was performed to measure the apoptosis of A549 cells. Transwell migration assay and wound scratch healing assay were used to analyze the migration and invasion ability of A549 cells. SPSS 20.0 was used to analyze the data. RESULTS: The expression of PIWIL3 protein was higher in tumor tissues than that in paracancer tissues. In addition, PIWIL3 mRNA was highly expressed in all four lung cancer cell lines. Furthermore, RPS15A knockdown significantly suppressed cell proliferation (P<0.01), induced apoptosis (P<0.01) and inhibited metastasis (P<0.01) of A549 cells. CONCLUSIONS: PIWIL3 was highly expressed in lung cancer tissues and could promote the progression of lung cancer.

Regulatory effects of lncRNA ATB targeting miR-200c on proliferation and apoptosis of colorectal cancer cells.

This investigation was intended to elucidate whether long noncoding RNA (lncRNA)-activated by transforming growth factor-ß (ATB) interacting with miR-200c could mediate colorectal cancer (CRC) progression, offering potential strategies for diagnosing and treating CRC. Here totally 315 patients with CRC were recruited, and their CRC tissues and adjacent normal tissues were gathered. Concurrently, four colon cancer cell lines (ie, SW620, Lovo, HCT116, and SW480) and the human colon mucosal epithelial cell line (NCM460) were also purchased. Moreover, si-ATB, si-NC, miR-200c mimic, miR-200c inhibitor, and miR-NC were prepared for transfection into the CRC cells, and their effects on CRC cell lines were evaluated based on the conduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, and flow cytometry assay. Eventually, the Luciferase reporter gene assay was carried out to judge if there existed a targeted relationship between ATB and miR-200c. The results of Cox regression analyses suggested that overexpressed lncRNA ATB, underexpressed miR-200c, poor tumor differentiation, lymph-vascular invasion, and perineural invasion were symbolic of shortened survival of the patients with CRC (all P < .05). Besides, transfection of pcDNA3.1-ATB and miR-200c inhibitor could boost the viability and proliferation of Lovo and SW620 cell lines (all P < .05). Meanwhile, the expressions of p53 and p21 were also reduced under treatments of pcDNA3.1-ATB and miR-200c inhibitor (P < .05). In addition, CDK2 seemed to reverse the contribution of miR-200c to intensifying viability and proliferation of Lovo and SW420 cell lines (P < .05). Furthermore, ATB might downregulate miR-200c expression by targeting it (P < .05), and CDK2 was subjected to dual regulation of both ATB and miR-200c (P < .05). In conclusion, the lncRNA ATB/miR-200c/CDK2 signaling was responsible for intensified proliferation and prohibited apoptosis of CRC cells, which might provide effective approaches for diagnosing and treating CRC.

Schisantherin A induces cell apoptosis through ROS/JNK signaling pathway in human gastric cancer cells.

Gastric cancer is one of the most lethal cancers with unmet clinical treatment and low 5-year survival rate. Schisantherin A is a major compound derived from Fructusschisandrae while its anti-tumor role remains nearly unknown. Here, we reported that schisantherin A had an anti-proliferation effect on gastric cancer cell lines MKN45 and SGC-7901. Schisantherin A induced cell cycle arrest at G2/M phase and cell apoptosis, and inhibited cell migration in gastric cancer MKN45 and SGC7901 cells. Meanwhile, upregulation of cleaved caspase-9, cleaved caspase-3 and cleaved PARP were accompanied with the loss of mitochondrial membrane potential (MMP). Moreover, schisantherin A induced ROS-dependent JNK phosphorylation with higher ROS production. The JNK inhibitor and ROS scavenger NAC rescued the cell apoptosis and cycle inhibition elicited by schisantherin A. Furthermore, the expression level of antioxidant factor Nrf2 was suppressed by schisantherin A. These findings suggest that schisantherin A possesses an anti-tumor activity via activation of ROS/JNK with Nrf2 inhibition, indicating that schisantherin A is a promising chemotherapeutic candidate for gastric cancer.

Effect of inhibiting ACAT-1 expression on the growth and metastasis of Lewis lung carcinoma.

Accumulating evidence suggests that acetyl-CoA acetryltransferase 1 (ACAT-1) may mediate tumor development and metastasis. However, the specific function served by ACAT-1 in lung cancer is not well understood. Therefore, the present study initially verified that ACAT-1 was overexpressed in Lewis lung carcinoma (LLC) tissues compared with non-LLC mice and that this overexpression promoted the proliferation, invasion and metastasis of these LLC samples. Western blotting, immunofluorescence microscopy and flow cytometry allowed the present study to determine that the ACAT-1 inhibitor avasimibe significantly reduced the expression of ACAT-1 in LLC compared with LLC cells that are not treated with avasimibe (P<0.05). A combination of Cell Counting Kit-8 and wound healing assays demonstrated that downregulating ACAT-1 expression sufficiently inhibited the proliferation of LLC cells. Avasimibe promoted LLC cell apoptosis as assessed by a Annexin V/propidium iodide double staining assay. Furthermore, avasimibe inhibited tumor growth in vivo and improved immune responses, with tissue biopsies from LLC model mice exhibiting higher levels of ACAT-1 compared with in healthy controls. Altogether, the results of the present study reveal that avasimibe may inhibit the progression of LLC by downregulating the expression of ACAT-1, which may thus be a potential novel therapeutic target for lung cancer treatment.

Apatinib enhanced anti-tumor activity of cisplatin on triple-negative breast cancer through inhibition of VEGFR-2.

BACKGROUND: Triple-negative breast cancer (TNBC) was known as a fast-growing and an aggressive tumor. Cisplatin is the effective cytotoxic drug used for the treatment of TNBC. In addition, apatinib, a VEGFR2 inhibitor, exhibits antitumor activity in patients with TNBC. However, the effects of combination of apatinib with cisplatin on TNBC remain unclear. Thus, this study aimed to investigate the effects of apatinib in combination with cisplatin on MDA-MB-231 cells. METHODS: Immunohistochemistry was used to detect the expression of VEGFR2. In addition, CCK-8, flow cytometric, transwell assays were used to measure the cell proliferation, apoptosis, migration and invasion, respectively. Moreover, western blotting was used to detect the expressions of Bax, active caspase 3, p-VEGFR2, p-Akt and p-mTOR. RESULTS: VEGFR2 was significantly upreguated in patients with TNBC. In addition, the inhibitory effects of cisplatin on the proliferation, migration and invasion of MDA-MB-231 cells were enhanced by apatinib. Moreover, apatinib increased cisplatin-induced apoptosis on MDA-MB-231 cells via increasing the level of Bax and active caspase 3 and decreasing the expression of Bcl-2. Importantly, apatinib enhanced anti-tumor effect of cisplatin on MDA-MB-231 cells via inhibiting the levels of p-VEGFR2, p-Akt and p-mTOR. CONCLUSION: Our findings indicated that apatinib enhanced the anti-tumor effects of cisplatin on MDA-MB-231 cells via inhibition of VEGFR2. Thus, the combination of apatinib with cisplatin may serve as a potential approach in the treatment of patients with TNBC.

Successful treatment of metastatic colorectal cancer with apatinib: report of two cases and literature review.

Apatinib, a novel small molecule tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor-2, was approved for metastatic gastric adenocarcinoma in China in Oct 2014. This is the first report on its use for advanced colorectal cancer as a kind of third-line therapy to date. Here we report two Chinese patients who presented with metastatic colorectal cancer who received apatinib 850 mg daily as a third-line therapy. Both the patients achieved favorable benefits in outcomes after the administration of apatinib. Patient 1 benefited 4 months progression-free survival and 11 months overall survival, while patient 2's progression-free survival was over 10 months. Both the patients presented hand-foot syndrome, and one of them suffered a slight impairment of liver function, mild elevated blood pressure, and proteinuria. But these adverse events were manageable with symptomatic treatment and dose reduction or a short-time drug withdrawal.

Apatinib in gastric carcinoma: A case report of partial response for first-line treatment in advanced disease.

Gastric cancer (GC) is the most common gastrointestinal malignant tumor, with a gradual increasing incidence throughout the world. Mostly GC is diagnosed in its late stage. To date, there is no usable standardized treatment regimen for patients with advanced GC. Apatinib mesylate, small-molecule vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor (TKI), has been approved as third-line treatment for patients with advanced gastric adenocarcinoma in China, October, 2014. Till now, there is no case report about apatinib as first-line treatment for patients with advanced GC in literature. We present an 83-year-old Chinese man with advanced gastric adenocarcinoma, who received apatinib as first-line option and obtained clinical benefit within 2 weeks. The lung metastases disappeared completely and the liver metastases shrank significantly. The patient's progression-free survival was 163 days and overall survival was 201 days. This paper reviews and discusses apatinib as a new targeted drug for patients with advanced GC by comparison with other effective molecular-targeted therapy.

Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro.

Breast cancer is the most commonly occurring cancer and second leading cause of mortality in women. Metformin is a widely prescribed anti-hyperglycemic drug, which is emerging as a potential cancer preventative and treatment agent. However, the mechanisms underlying the suppressive effects of metformin on cancer cell growth and the induction of cancer cell apoptosis are not fully elucidated. The present study aimed to identify the pathways regulated by metformin in two breast cancer cell lines, MDA-MB-231 and MDA-MB-435. Cells were treated with various concentrations of metformin and then evaluated with respect to viability, proliferation, adenosine triphosphate (ATP) and reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆ψm), and the expression of anti- and pro-apoptotic proteins. Metformin caused apoptosis in a concentration- and time-dependent manner, and decreased cell viability and ATP production. Furthermore, metformin induced the generation of ROS and decreased the ∆ψm. Moreover, metformin downregulated the expression of the anti-apoptotic proteins B-cell lymphoma 2 (BCL-2) and myeloid cell leukemia-1, and upregulated the expression of the pro-apoptotic BCL-2-associated X protein in MDA-MB-231 cells. These results demonstrate that the apoptotic and cytotoxic effects of metformin on breast cancer cells are mediated by the intrinsic mitochondria-mediated apoptosis pathway.

SRPX2 promotes cell migration and invasion via FAK dependent pathway in pancreatic cancer.

Sushi repeat-containing protein, X-linked 2, abbreviated as SRPX2, is a candidate downstream target protein for E2A-HLF and involved in disorders of language cortex and cognition. Recent studies have demonstrated that elevated SRPX2 exhibits crucial roles in gastric cancer, however, underlying clinical significance and biological function of SRPX2 in pancreatic ductal adenocarcinoma (PDAC), remains unclear. Data from Oncomine database showed that higher SRPX2 expression is more commonly observed in PDAC compared with normal pancreatic duct, similar results were also found in 12 matched PDAC tissue samples, 7 PDAC cell lines and a tissue microarray containing 81 PDAC specimens as demonstrated by real-time quantitative PCR and immunohistochemistry, respectively. Besides, higher SRPX2 expression was closely correlated with advanced TNM stage. Silencing of endogenous SRPX2 expression reduced abilities of cell migration and invasion of PDAC cells. Further studies revealed that SRPX2 expression in PDAC tissues significantly correlated with the phosphorylation levels of FAK, indicating that FAK dependent pathway may be account for the effect of SRPX2 on cell migration and invasion in PDAC. Collectively, this study reveals that frequently elevated SRPX2 contributes to cell migration and invasion in PDAC and SRPX2-related pathways might be a potential therapeutic target for PDAC.

Immobilization of penicillin G acylase on paramagnetic aldehyde-functionalized mesostructured cellular foams.

Paramagnetic aldehyde-functionalized mesostructured cellular foams (PAMCFs), synthesized by grafting 3-aminopropyltriethoxysilane modified Fe3O4 (NH2-Fe3O4) nanoparticles with larger particle size than the window pore size of MCFs on the outer surface of aldehyde-functionalized mesostructured cellular foams (AMCFs), were investigated as efficient supports for immobilization of penicillin G acylase (PGA). The results show that NH2-Fe3O4 nanoparticles were successfully grafted on the outer surface of AMCFs and PGA molecules were mainly immobilized covalently on the inner surface of PAMCFs, which was because amino groups of NH2-Fe3O4 nanoparticles or PGA molecules reacted with aldehyde groups of AMCFs or PAMCFs to form imine bonds. PGA/PAMCFs-15 showed a rather high initial activity of 9563Ug(-1) and retained 89.1% of its initial activity after recycled for 10 times. PGA/PAMCFs are easily recycled by magnetic field in order to replace tedious separation of high-speed centrifugation for mesoporous materials.