Effect of Long Non-Coding RNA LINC01268 on the Malignant Biological Behaviors of Acute Myeloid Leukemia Cells / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of long non-coding RNA LINC01268 on apoptosis of acute myeloid leukemia (AML) cells and related mechanisms.@*METHODS@#The expression levels of LINC01268 and miR-217 in peripheral blood samples from AML patients and AML cell lines HL-60 and KG-1 were detected by qRT-PCR. HL-60 cells were divided into pcDNA3.1-NC, pcDNA3.1-LINC01268, si-NC, si-LINC01268, miR-NC, miR-217 mimics, si-LINC01268 + inhibitor-NC and si-LINC01268+ miR-217 inhibitor groups. The mRNA expressions of LINC01268 and miR-217 were detected by qRT-PCR. The targeting relationship between LINC01268 and miR-217 was detected by dual-luciferase reporter assay. Cell viability was detected by CCK-8 assay. Cell cycle distribution and apoptosis were detected by flow cytometry. The expression of cell cycle and apoptosis-related proteins p21, Bcl-2, Bax, caspase-3 and PI3K/AKT signaling pathway-related proteins were detected by Western blot.@*RESULTS@#The expression of LINC01268 in peripheral blood samples of AML patients and AML cell lines HL-60 and KG-1 was increased (P < 0.05), and the expression of miR-217 was decreased (P < 0.05). Compared with si-NC group and miR-NC group, the viability of HL-60 cells was decreased in si-LINC01268 group and miR-217 mimics group (P < 0.05), the proportion of cells in G1 phase and apoptosis rate were increased (P < 0.05), the protein expression levels of p21, Bax and caspase-3 were increased (P < 0.05), while the protein expression level of Bcl-2 was decreased (P < 0.05). LINC01268 targeted and negatively regulated the expression of miR-217, and inhibiting the expression of miR-217 partially reversed the effects of LINC01268 interference on the viability, cell cycle and apoptosis of HL-60 cells. Interference with LINC01268 could inhibit the activity of PI3K/AKT signaling pathway. Inhibiting the expression of miR-217 could partially reverse the inhibition of LINC01268 interference on PI3K/AKT signaling pathway.@*CONCLUSION@#LINC01268 is highly expressed and miR-217 is lowly expressed in AML cells. LINC01268 can promote the activity of PI3K/AKT signaling pathway, increase the survival rate and inhibit the apoptosis of AML cells by targeting miR-217 expression.

Dose escalation phase 1 study of radiotherapy in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody ipilimumab in patients with metastatic melanoma.

BACKGROUND: A synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma. PATIENTS AND METHODS: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics. RESULTS: 19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5-2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2-1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS. CONCLUSION: When combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation. TRIAL REGISTRATION NUMBER: NCT01557114.

CDK4/6 inhibitors in P16/HPV16-negative squamous cell carcinoma of the head and neck.

PURPOSE: Addition of CDK4/6 inhibitors to a variety of established treatments in squamous cell carcinoma of the head and neck (SCCHN) has the potential to improve responses to other therapies and may help overcome treatment resistance. The SCCHN is a heterogeneous group of cancers of the oral cavity, the pharynx and the larynx with poor prognosis despite the aggressive multimodal therapies. In the past decade, significant advances were made in understanding of the molecular and genetic abnormalities leading to oncogenesis in SCCHN. RECENT FINDINGS: Besides EGFR targeting agents, antiangiogenic agents have been shown to produce antitumor activity in these tumors. The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway regulates cellular proliferation by controlling the G1 to S cell cycle checkpoint. In SCCHN, the Rb pathway is frequently altered through amplification of CCND1 (cyclin D1) or deletion of CDKN2A (cyclin-dependent kinase inhibitor 2A) coding for p16INK4A, and thus promoting proliferation. This article summarizes what we actually know of the place of CDK4/6 inhibitors in the therapeutic arsenal of SCCHN. CDK4/6 inhibitors could serve as a method to target these tumors, and both p16 loss and CCND1 amplification could be investigated as biomarkers.

Effects of PRECEDE-PROCEED Model on Behavior of Patients after Total Hip Arthroplasty / 中国康复理论与实践

Objective:To explore the effect of PRECEDE-PROCEED model on health behavior and quality of life of patients after total hip arthroplasty. Methods:From February to December, 2018, 103 patients who underwent primary total hip arthroplasty were divided into control group (n = 51) and intervention group (n = 52). The control group received routine perioperative guidance, while the intervention group received PRECEDE-PROCEED model in addition, in accordance to the nine links of the model, multi-dimensional intervention measures should be formulated with tendency factors, contributing factors and strengthening factors as the core. They were followed up for six months after discharge, and were assessed with Health Promoting Life style Profile II (HPLP II) and the MOS Item Short From Health Survey (SF-36) one, three and six months after discharge, respectively. Results:There was no significant difference in the scores of HPLP II and SF-36 between two groups at discharge (P > 0.05). The scores of HPLP II and SF-36 were higher than in the intervention group than in the control group one, three and six months after discharge (t > 2.307, P < 0.05). Conclusion:PRECEDE- PROCEED model could change the undesirable life behavior after operation, and improve the health behavior and quality of life of patients with total hip arthroplasty.

Clinical Effect of Telerehabilitation after Total Knee Arthroplasty: a Meta-analysis / 中国康复理论与实践

Objective:To evaluate the outcome of telerehabilitation in pain control and function recovery after total knee arthroplasty. Methods:CNKI, Wanfang Data (WF), CBM, VIP, PubMed, Web of Science, Medline, Springer Link, and Cochrane Library were searched on the effects of telerehabilitation on the patients after total knee arthroplasty, and the literatures of random control trials (RCT) study in English and Chinese in the above databases from 2000 to 2018 were collected. Literature screening, quality evaluation, data extraction and data analysis were carried out by 2 researchers. The indexes of outcome in the RCT studies included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), extension and flexion range, the Timed Up and Go Test (TUGT), Visual Analogue Scale (VAS) and Knee Injury and Osteoarthritis Outcome Score (KOOS). Results:A total of 6 RCT studies were included, with a total of 601 cases, 301 in the intervention group and 300 in the control group. There was difference in extension range (MD = 0.30, 95%CI: 0.20 to 0.40, P < 0.001), TUGT scores (MD = -5.17, 95%CI: -9.79 to -0.55, P = 0.03), VAS scores (MD = -0.43, 95%CI: -0.85 to -0.01, P = 0.04) and KOOS scores (MD = -1.10, 95%CI: -1.63 to 0.57, P < 0.0001) between two groups. There was no significant difference in WOMAC scores (MD = -0.32, 95%CI: -2.30 to 1.65, P = 0.75), flexion range (MD = 0.68, 95%CI: -2.28 to 3.63, P = 0.65), and muscle strength (MD = 13.77, 95%CI: -3.89 to 31.43, P = 0.13) (P > 0.05) between two groups. Conclusion:Telerehabilitation is effective to improve extension range, ambulation, pain and quality of life, while it is uncertainly effective in flexion range, knee function and muscle strength.

Metabolomics techniques and its application in research of important protozoan parasites / 中国人兽共患病学报

Metabolomics is a new discipline which has developed rapidly following post-genomic,transcriptomics and proteomics.It has become an important research method because of its unique advantages.It is mainly used in drug research and development,disease surveillance and other fields.In addition,with the gradual maturation of metabolomics technology and the gradual development of new analytical methods,the application of metabolomics has been more and more widely,and metabolomics technology has been gradually applied to the field of parasite research,especially for protozoan parasites.This paper summarizes metabolomics,metabolomics research methods,and the application of metabolomics in research of protozoan parasites,with the aims of further understanding of metabolomics technology,and providing reference basis for solving problems of protozoan parasites.

Self-medication practices among female students of higher educational institutions in Selangor, Malaysia: A quantitative insight.

BACKGROUND: World Health Organization has defined self-medication as the selection and use of medications (including herbal and traditional product) by individuals to treat self-recognized illnesses or symptoms. The prevalence of self-medication is reported to be higher among female students. OBJECTIVE: To investigate the awareness and self-medication practices among female students of higher education institutions in Malaysia. METHOD: A descriptive, cross-sectional study was conducted in four higher education institutes of Selangor, Malaysia. Convenience sampling approach was used to collect data from a sample 475 students. A "pretested" questionnaire was used as a study instrument. RESULTS: A total of 461 questionnaires were returned (response rate 97.05%). The prevalence of self-medication among female students in higher educational institutions was 57.2% (n = 262). The most common source of self-prescribed medicine was a pharmacy or clinics (n = 206; 45%). It was found that antipyretics were the most common medications used without doctor's consultation (n = 212; 89.1%). Analgesics and antipyretics (n = 79; 62.7%) were highly recommended by students to their family and friends. The common reason for self-medication was prior successful experience (n = 102, 81.0%). The majority of respondents (n = 280; 61.1%) reported that they believed over-the-counter medications were as effective as medications prescribed by a doctor. CONCLUSION: The prevalence of self-medication practice among female students in the sample of the four higher education institutions was moderate. More studies are required to generalize these findings across Malaysia.

The biomechanical effect of bilateral unloading knee brace with internal-external rotation on knee joint / 医用生物力学

Objective Aiming at reducing the restrictions on lower limbs imposed by traditional knee brace, a design scheme for knee brace complying with internal-external rotation is proposed. Methods By adding the internal-external hinge, the knee brace could help to release the degree of freedom (DOM) of internal-external rotation of the knee. In the experimental group, the subject was required to wear the bilateral unloading knee brace with or without internal-external hinges, respectively, while in the control group, the subject did not wear the knee brace. Then gait experiment and mechanical testing were conducted. Results In gait experiment, the bilateral unloading knee brace with internal-external hinges imposed less restriction on the knee than that from the knee brace without internal-external hinges, and it could also provide some distractive force for the knee joint. Conclusions The internal-external hinge design can help to reduce restrictions on the knee imposed from bilateral unloading knee brace.

Vemurafenib and radiosensitization.

IMPORTANCE: The BRAF inhibitor, vemurafenib, was recently approved for the treatment of patients with BRAFV600 metastatic melanoma. Wider use of this drug and longer follow-up periods of treatment are resulting in the emergence of a growing number of reports detailing new adverse effects. Cutaneous adverse effects are preeminent with UV-A-dependent phototoxicity, hyperkeratotic folliculitis, hand-foot skin reaction, hair changes, verrucous papillomas, keratoacanthomas, and squamous cell carcinomas. OBSERVATIONS: We report 2 cases of dermatitis occurring on a previously irradiated skin area in patients treated with vemurafenib for a BRAFV600-mutated metastatic melanoma. The first case occurred 10 days after a low dose of radiation was delivered that usually does not induce any radiodermatitis, suggesting radiosensitization by vemurafenib. The second case occurred 30 days after radiotherapy and was diagnosed as radiation recall dermatitis. CONCLUSIONS AND RELEVANCE: Vemurafenib should be considered a potential cutaneous radiosensitizer and an inducer of radiation recall dermatitis. However, these adverse effects are easily managed with topical corticosteroids. Dose reduction or interruption of vemurafenib is not required. Further studies and reports will enlighten us as to whether this pharmacodynamic interaction between x-rays and vemurafenib is also seen with other BRAF or MEK inhibitors on the same mitogen-activated protein kinase pathway currently under development.

Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial.

BACKGROUND: Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC). We aimed to assess the efficacy and safety of a combination of these approaches. METHODS: In our open-label phase 3 randomised trial, we enrolled patients with locally advanced, stage III and IV (non-metastatic) HNSCC and an Eastern Cooperative Oncology Group performance status of 0-2. We randomly allocated patients centrally with a computer program (with centre, T stage, N stage, and localisation as minimisation factors) in a 1:1:1 ratio to receive conventional chemoradiotherapy (70 Gy in 7 weeks plus three cycles of 4 days' concomitant carboplatin-fluorouracil), accelerated radiotherapy-chemotherapy (70 Gy in 6 weeks plus two cycles of 5 days' concomitant carboplatin-fluorouracil), or very accelerated radiotherapy alone (64·8 Gy [1·8 Gy twice daily] in 3·5 weeks). The primary endpoint, progression-free survival (PFS), was assessed in all enrolled patients. This trial is completed. The trial is registered with ClinicalTrials.gov, number NCT00828386. FINDINGS: Between Feb 29, 2000, and May 9, 2007, we randomly allocated 279 patients to receive conventional chemoradiotherapy, 280 to accelerated radiotherapy-chemotherapy, and 281 to very accelerated radiotherapy. Median follow-up was 5·2 years (IQR 4·9-6·2); rates of chemotherapy and radiotherapy compliance were good in all groups. Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy (HR 1·02, 95% CI 0·84-1·23; p=0·88) or very accelerated radiotherapy (0·83, 0·69-1·01; p=0·060); conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy (0·82, 0·67-0·99; p=0·041). 3-year PFS was 37·6% (95% CI 32·1-43·4) after conventional chemoradiotherapy, 34·1% (28·7-39·8) after accelerated radiotherapy-chemotherapy, and 32·2% (27·0-37·9) after very accelerated radiotherapy. More patients in the very accelerated radiotherapy group had RTOG grade 3-4 acute mucosal toxicity (226 [84%] of 268 patients) compared with accelerated radiotherapy-chemotherapy (205 [76%] of 271 patients) or conventional chemoradiotherapy (180 [69%] of 262; p=0·0001). 158 (60%) of 265 patients in the conventional chemoradiotherapy group, 176 (64%) of 276 patients in the accelerated radiotherapy-chemotherapy group, and 190 (70%) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment (p=0·045). INTERPRETATION: Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy cannot compensate for the absence of chemotherapy. We noted the most favourable outcomes for conventional chemoradiotherapy, suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules. FUNDING: French Ministry of Health.

Effects of verapamil preconditioning on cardiac function in vitro and intracellular free Ca2+ and L-type calcium current in rat cardiomyocytes post ischemia-reperfusion injury / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the influences of verapamil preconditioning on cardiac function in vitro and intracellular free Ca2+ and L-type calcium current (I(Ca-L)) in rat cardiomyocytes post ischemia-reperfusion (I/R) injury.</p><p><b>METHODS</b>The isolated rat hearts in control group (37 degrees C Tyrode solution perfusion for 30 min, n = 6), I/R group (no flow for 30 min followed 30 min reperfusion with 37 degrees C Tyrode solution, n = 7) and verapamil preconditioning group [37 degrees C Tyrode solution perfusion for 10 min, adding verapamil (20 micromol/L) to Tyrode solution and perfusion for another 30 min, followed then by 30 min no flow and 30 min reperfusion, n = 7] using Langendorff perfusion system. The fluorescence intensity of intracellular Ca2+ was detected with Fluo-3/AM loading by the laser scanning confocal microscope. The I(Ca-L) was recorded via whole-cell patch clamp technique in enzymatically dissociated single rat ventricular myocytes.</p><p><b>RESULTS</b>As expected, arrhythmias and cardiac dysfunction were shown post I/R injury. The fluorescence intensities of intracellular free Ca2+ in cardiomyocytes were significantly increased compared with control group (P < 0.01). By voltage clamp protocol, peak current densities of I(Ca-L) was significantly reduced and I-V curve significantly elevated. Post I/R injury compared with control group (P < 0.01) which could be reversed by Verapamil preconditioning. Verapamil preconditioning also significantly improved diastolic and systolic functions, and reduced the incidence of arrhythmias.</p><p><b>CONCLUSIONS</b>Myocardial I/R injury might significantly impair heart functions and induce arrhythmias via cellular Ca2+ overload. Verapamil preconditioning could prevent heart I/R injury and reduce arrhythmias by decreasing influx of I(Ca-L), thereby stabilizing cardiomyocytes in myocardial stunning and avoiding occurrence of Ca2+-induced Ca2+ release during I/R injury.</p>

Tablets with material gradients fabricated by three-dimensional printing.

Complex tablets with zero-order drug release characteristics were fabricated using three-dimensional printing processes. The matrix tablets exhibited material gradients in radial direction and had drug-free release-barrier layers on both bases. The content of model drug acetaminophen incorporated in the tablets through premixing reached up to 68% of the tablets' weight. Tablets with ethylcellulose gradients showed acceptable mechanical and pharmacotechnical properties, as indicated by crushing strength, friability, and content uniformity tests. The structure and the gradients of ethylcellulose in the tablets were envisaged through environmental scanning electron microscopy and fluorescence tracing technique. Erosion and dissolution studies in vitro indicated that drug was released via a two-dimensional surface erosion mechanism, and 98% of the drug could be released linearly in 12 h. Tablets with other release-retardation material gradients such as sodium lauryl sulfate, stearic acid, and Eudragit RS-100 showed similar release-retardation effects by different release-retardation mechanisms. Through the printing of release-retardation materials, 3DP processes could easily prepare tablets with high dosage and special design features for furnishing the desired drug release characteristics.

Prognostic analysis of chronic myeloid leukemia with Cox model and the Sokal, Hasford score / 中国实验血液学杂志

This study was aimed to analyze the prognostic factors of the patients with chronic myeloid leukemia (CML). Survival curve and survival rate of 204 patients with CML were estimated with Kaplan-Meier method and Logrank respectively. Univariate and multivariate analysis of prognostic factors carried out by Cox's regression model. The Sokal and Hasford score were used to discriminate the relative risk of Hu and IFN group. The results showed that among the 204 patients, the median survival time was 50 (32-65) months, and 5 year survival rate was 32.3% (95% CI, 23.7%-42.6%). The median survival times of IFN and Hu group were 56 (41-67) and 41 (19-56) months, and 5 year survival rates were 45.4% (95% CI, 37.5%-54.2%) and 26.8% (95% CI, 21.6%-33.3%) (P < 0.001) respectively. From the Cox stepwise regression model, Ph chromosome negative, high LDH, low Hct, percentage of peripheral blood basophils > or = 10%, marrow blasts + promyelocytes > or = 10% and presence of nucleated RBCs was associated with poor prognosis, and the treatment also played an important role in CML. According to the Sokal score, the high, intermediate and low risk rates of Hu group were 72.9%, 21.5% and 5.6%, the median survival time reached 34 (23-49) months, 43 (32-58) and 50 (38-62) months respectively; while censored by the Hasford score, the high, intermediate and low risk rates of IFN group were 17.6%, 25.1% and 57.3% respectively, the median survival time was 44 (33-57), 56 (45-70) and 66 (52-76) months respectively. It is concluded that Ph chromosome, concentration of LDH, percentage of Hct, peripheral blood basophils, marrow blasts, promyelocytes, presence of nucleated RBCs and treatment are the most important prognostic factors for CML. The Sokal score can not discriminate the relative risk of Hu group well, while the Hasford score can discriminate the relative risk of IFN group.