The aerial root mealybug, Pseudococcus baliteus Lit (Hemiptera: Pseudococcidae), is an important invasive and quarantine pest that poses a potential threat to fruits, vegetables, and ornamental ...plants. As a result, phytosanitary treatments are necessary to ensure the commodities of international trade are free from these pests. To determine the minimum absorbed dose required for phytosanitary irradiation (PI) application, irradiation dose-response and large-scale confirmatory tests were conducted. Eggs that were 2, 4, and 6 days old and late gravid females (containing 0-day-old eggs) of P. baliteus were X-ray irradiated with doses of 10, 20, 40, 60, 80, 100, and 120 Gray (Gy). The efficacy of preventing egg-hatching (mortality) was compared using two-way ANOVA, 95% confidence interval overlapping and lethal dose ratio test in probit analysis. The radiotolerance sequence of mealybugs egg was found to be 0 < 2 ≈ 4 < 6-day-old eggs, and their estimated LD99.9968 values with 95% confidence interval were 132.0 (118.9–149.5), 137.6 (125.2–153.7), 145.5 (134.5–159.1), and 157.4 (144.6–173.6) Gy, respectively. Subsequently, target doses of 135 and 145 Gy were used in the confirmatory gamma radiation treatments. No F1 generation neonates developed from a total of 47,316 late females irradiated at the measured dose of 107.7–182.5 Gy, resulting in the treatment efficiency of 99.9937% at the 95% confidence level. Therefore, the highest dose of 183 Gy measured in the confirmatory tests is recommended as the minimum absorbed dose in PI treatment of P. baliteus for establishing national and international standards.
Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with ...locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population.
This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18–65 years with newly diagnosed high-risk non-metastatic stage III–IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3–4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing.
Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0–44·8; 389 alive at primary data cutoff Feb 28, 2023 and 366 94% had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% 95% CI 81–90 vs 76% 70–81; stratified hazard ratio 0·59 0·38–0·92; p=0·019). Grade 3–4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 33% vs 64 30%), leukopenia (54 26% vs 48 22%), and neutropenia (50 24% vs 46 21%). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3–4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group.
Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma.
National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center.
For the Chinese translation of the abstract see Supplementary Materials section.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
The bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles ...in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Compound 171 was found to maintain BET inhibition ability without PLK1 inhibition, and there was no selectivity among BET family members. The in vitro and in vivo results both indicated that the overall anti-tumor activity of compound 171 was improved compared with the (+)-JQ-1 or OTX-015 BET inhibitors. Furthermore, we found that compound 171 could regulate the expression of cell cycle-regulating proteins including c-Myc and p21 and induce cell cycle arrest in the G
0
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1
phase. However, compound 171 only has a quite limited effect on apoptosis, in considering that apoptosis was only observed at doses greater than 50 μM. To determine the mechanisms underlying cell death, proliferation activity assay was conducted. The results showed that compound 171 induced clear anti-proliferative effects at doses that no obvious apoptosis was induced, which indicated that the cell cycle arresting effect contributed mostly to its anti-tumor activity. The result of this study revealed the anti-tumor mechanism of compound 171, and laid a foundation for the combination therapy in clinical practice, if compound 171 or its series compounds become drug candidates in the future.
Abstract Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently ...improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
This study was designed to examine the distribution of plasma soluble CD40 ligand (sCD40L), and its relationship with carotid intima-media thickness (CIMT) in healthy controls and subjects with ...white-coat hypertension (WCH) or hypertension (HT). Thirty-five patients with HT, 35 patients with WCH, and 35 healthy controls were enrolled. The normal group (CIMT < 0.9 mm), subclinical atherosclerosis group (0.9 mm ≤ CIMT < 1.2 mm) and atherosclerosis group (CIMT ≥ 1.2 mm) were grouped based on the value of CIMT. The highest level of sCD40L was observed in HT group, followed by WCH group and healthy controls. The level of sCD40L was significantly increased in atherosclerosis group compared with subclinical atherosclerosis group and healthy controls. In the WCH group, sCD40L level was significantly and positively correlated with CIMT and systolic blood pressure. Multiple logistic regression indicated that sCD40L was a risk factor for increased CIMT (odds ratio, 1.504; 95% confidence interval, 1.054-1.956, P < 0.001). The data provided evidence that sCD40L levels in subjects with WCH and HT were significantly and consistently higher than those in healthy controls. SCD40L may represent a potential non-invasive atherosclerosis marker in WCH patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The khapra beetle, Trogoderma granarium Everts, is defined as one of the most important quarantine pests globally, and fumigation with methyl bromide, an ozone-depleting substance, is a common ...phytosanitary measure currently used. The modified atmosphere (MA), irradiation, and their combination treatments of T. granarium larvae and adults were performed at room temperature (24–26 ℃) to develop an ecofriendly phytosanitary disinfestation measure and to shorten the exposure time and overcome treatment disadvantages of irradiation. Late-stage larvae are determined as the most tolerant stage resulted in large LT99.9968 values of 32.6 (29.2–37.5) and 38.0 (35.1–41.7) days treated under 1% and 2% O2 (with N2 balance) atmosphere, respectively. Ionizing radiation was used to enhance the effect of MA and the mortality was highly significantly affected by all the interaction effects, indicating that the synergistic effects present in all the combined treatments. The synergistic ratios, which is defined as the estimated lethal time for MA treatment (LD90, LD99, and LD99.9968), divided by that of combined treatment, were between 1.47 and 2.47. In the confirmatory tests, no individuals recovered from a sum of 111,366 late-stage larvae treated under 1% O2 atmosphere for 14- or 15-d after 200 Gy irradiation, which resulted in validating the probit estimations and achieving an efficacy of 99.9973% mortality at 95% confidence level. Therefore, these treatment schedules are recommended to disinfest T. granarium infecting commodities for phytosanitary purposes under the warehouse, MA packaging, or in combination with international transportation by train or sea container.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The relationship between lipid variability and stroke among patients with hypertension were inconclusive. We aimed to investigate the association of lipid variability with ischemic stroke in ...hypertensive patients.
This retrospective cohort study included 4995 individuals with hypertension between 2013 and 2015, and recorded their status of ischemic stroke until the end of 2018. The variability in total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured using the standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM) and average absolute difference between successive values (ASV). Multivariate Cox proportional hazards models with hazard ratios (HRs) and 95% confidence interval (CI) were performed. There were 110 cases of ischemic stroke during a median follow up of 4.2 years. The multivariable adjusted HRs and 95% CIs comparing the highest versus the lowest quartiles of SD of TC, LDL-C, HDL-C and TG were 4.429 (95% CI: 2.292, 8.560), 2.140 (95% CI: 1.264, 3.621), 1.368 (95% CI: 0.793, 2.359) and 1.421 (95% CI: 0.800, 2.525), respectively. High variability in TC and LDL-C were associated with a higher risk for ischemic stroke. Similarly, the results were consistent when calculating variability of TC and LDL-C using CV, ASV and VIM, and in various subgroup analyses.
Higher variability of TC and LDL-C associated with the risk of ischemic stroke among hypertensive patients. These findings suggest reducing variability of lipid parameters may decrease adverse outcomes.
•High variability in TC and LDL-C was significantly linked with a higher risk for ischemic stroke in hypertensive patients.•Variability in lipid parameters may serve as a prognostic surrogate marker for ischemic stroke in hypertensive patients.•Lipid variability may provide information for cardiovascular risk stratification in the future.•Reducing the fluctuations in lipid parameters may be another goal to prevent adverse outcomes in hypertensive patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
To evaluate the clinical efficacy and safety of the modified technique utilizing the occipital bicortical screws and plate system in occipitocervical revision surgery.
Methods
Between ...October 2010 and May 2018, 12 consecutive patients were retrospectively evaluated. All patients had posterior occipitocervical resurgery utilizing modified technique of bicortical screws and occipital plate. The measurements of extracranial occiput on midline were conducted on computed tomography (CT) scans. The thickness of the occipital bone at the location of external occipital protuberance and below 15 mm were evaluated, respectively. For the procedure, the trajectory was drilled perpendicular to the external occipital protuberance for the specified depth with a depth‐limited drilling, 2 mm away from the internal bone plate, then the trajectory was deepened at intervals of 1 mm each time until reaching the internal bone plate. Meanwhile, a probe was used to explore all the walls of the trajectory. Bicortical screws were inserted to the occipital plate and the depth of penetration was less than 2 mm from the internal bone plate. Clinical efficacy and radiographic evaluation were followed up.
Results
The thickest point was the external occipital protuberance, which was 15.49 ± 1.47 mm and decreased gradually on the midline to 13.41 ± 1.60 mm at below 15 mm. Twelve cases (mean age 41.17 years; range, 24–62 years), including five males and seven females, were followed up for 24.08 months (14–32 months). The interval time was 40.42 months (3–156 months) after the initial operation. At the final follow‐up, JOA score increased from 8.58 ± 2.53 before surgery to 12.67 ± 1.84 (P < 0.05) and VAS score improved from 6.17 ± 1.21 to 2.08 ± 1.32 (P < 0.05). Besides, clinical symptoms were relieved in all patients after revision surgery. All patients had rigid internal fixations with bone fusion and no major complications occurred.
Conclusions
Posterior occipitocervical plate‐screw system with bicortical screws had the advantages of safety, simple and promising efficacy without excessive tissue release or intraspinal manipulation, proving that it's valuable as a modified technique for occipitocervical revision surgery.
Illustration of revision surgery: (A) Firstly, the trajectory was deepened for the specific depth with a depth‐limited drilling, 2 mm away from the inner occipital table. Meanwhile, a probe was used to explore all the walls of the trajectory in case of penetration. (B) The path was drilled with a depth‐limited drilling at intervals of 1 mm each time until reaching the internal bone plate, and a probe was used subsequently. (C) Bicortical screws were inserted to the occipital plate and the depth of penetration was less than 2 mm from the internal bone plate. (D) Posterior view of instrument.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Background： Despite the improvement in the health care industry, the rates of undetected, untreated, and uncontrolled hypertension （HTN） are still very high, especially in rural areas of China. The ...aim of this study was to investigate the efficacy and efficiency of a guideline-based HTN management （novel therapy） in population of rural areas of Guangdong Province. Methods： Totally, 3113 patients with essential HTN in a rural area of Guangdong Province were enrolled and assigned to two groups, named traditional （n = 372） and novel therapeutic （n = 2741 ） groups, respectively. Patients in the traditional group were treated routinely, and patients in the novel group were treated in a novel model characterized by regular educational programs for hypertensive populations, close monitoring of blood pressure in combination with finely tuned antihypertensive medications, strict implementation of lifestyle modification and improving medical knowledge and skill of local medical staff efficiently. After 2 years of follow-up, primary endpoints including magnitude of systolic and diastolic blood pressures （SBP and DBP） decrease, treated and controlled rates, as well as secondary endpoints, were evaluated in both groups. Results： Initially, the treated rate was significantly higher in traditional group than that of novel group （71.15% vs. 64.99%, P 〈 0.05）, while the controlled rates were comparable and insignificant difference between baseline BP in both groups （31.07% vs. 26.88%, P 〉 0.05）. Four variables were significantly different, namely smoking rate, daily vegetable consumption （VC）, and serum levels of low-density lipoprotein-cholesterol and fasting blood glucose between these two groups. After 2 years of follow-up, decreases in SBP and DBP were more prominent in the novel group （P 〈 0.001）. Treated and controlled rates in both groups were both increased. Nevertheless, in comparison to the traditional group, controlled rate increased more significantly in the novel group （64.31% vs. 37.85%, P 〈 0.001）. Variables indicating lifestyle modification such as high sodium consumption, percentages of alcohol abuse, daily VC were profoundly improved in the novel group. Conclusions： The guideline-based HTN management implemented in the current study was beneficial for HTN control in rural areas of Guangdong Province.
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