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We present a large-range and high-precision autofocus method based on an annular diffractive optical element (DOE) for a laser direct writing system. By analyzing the shape of the return spot, the defocus direction and the defocus amount can be obtained at the same time. The experimental results show that the linear detection range of the proposed method can reach at least 76 µm, the sensitivity can reach 100 nm, the detection accuracy can reach 100 nm, and the noise fluctuation does not exceed 50 nm. Apparently, with the advantages of a large detection range, high detection, and good stability, the automatic focus detection method proposed in this paper can be widely applied in various wafer-scale complex microstructure preparation systems.

The Hongshiyan landslide dammed lake on the Niulan River is a large-sized one caused by the Ludian 8•03 earthquake in 2014. Based on the uniqueness of the Hongshiyan dammed lake, after the completion of the emergency rescue, the treatment concept of “Eliminating Hazard, Utilizing Resources and Turning Waste into Treasure” was innovatively proposed and this dammed lake was then rebuilt into a large-integrated water conservancy complex with the multiple functions of flood control, water supply, irrigation, and power generation. The project is the first in the world to be developed and utilized immediately after the formation of the barrier dam. This paper systematically introduces the formation of the Hongshiyan landslide dam, the emergency rescue as well as the remediation in the later period. The reservoir has been impounded in 2019, the landslide dam has already retained to a high water level and operated safely. Through the practice of the project, this paper summaries the key technologies such as emergency treatment technology and remediation plan under the lack of information conditions, the comprehensive treatment of the 750 m high slope affected by the intense earthquake and the comprehensive treatment of the 130 m grade landslide dam composed of materials with discontinuous wide gradation, which can provide reference for the emergency rescue, development and utilization of similar landslide-dammed lakes.

Aim Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours. Methods An open-label, non-randomized phase I study was carried out. Patients received intravenous 1.4 mg m−2 eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC(0,∞) and Cmax for eribulin exposure without or with co-administration of rifampicin were subjected to an analysis of variance (anova) and corresponding 90% confidence intervals (CI) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m−2 eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti-tumour activity were assessed. Results Fourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co-administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC(0,∞) = 1.10, 90% CI 0.91, 1.34 and Cmax = 0.97, 90% 0.81, 1.17). The most common treatment-related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%). Conclusions These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.

Background & Aims: This study was designed to characterize [D-F 5 Phe 6 D-Ala 11 ]Bn(6-13)OMe (BIM26226) as a gastrin-releasing peptide (GRP)-preferring bombesin receptor antagonist and to determine whether GRP physiologically regulates gastrointestinal motility. Intravenous BIM26226 (5–500 μg · kg −1 · h −1 ) inhibits GRP-induced gallbladder contraction and plasma cholecystokinin (CCK) release in a dose-dependent fashion. Methods: Gastric emptying and small bowel transit of a solid meal were quantified using scintigraphy. Meal-stimulated gallbladder contraction was measured by sonography in a 2-period crossover design. Results: Intravenous BIM26226 potently inhibited gastric lag time (114 ± 7 vs. 41 ± 6 minutes [control]) and gastric emptying rate (0.11 ± 0.02%/min vs. 0.26 ± 0.04%/min [control]), whereas concomitant infusion of BIM26226 accelerated small bowel transit time (153 ± 41 vs. 262 ± 20 minutes [control]). A continuous liquid meal perfusion into the duodenum induced complete gallbladder contraction (t 50% , 35 ± 4 minutes), which BIM26226 inhibited significantly (t 50% , 64 ± 8 minutes). BIM26226 did not alter plasma CCK response, indicating that circulating CCK did not mediate these effects. Conclusions: These data show that BIM26226 is a potent antagonist of exogenous and endogenous GRP and suggest that GRP is a major physiologic regulator of gastric emptying, small bowel transit, and gallbladder contraction. GASTROENTEROLOGY 2001;120:361-368

Although reduced biological activity of the obese gene product, leptin, has been associated with obesity, little information is available concerning leptin alterations during anorexia. Therefore, we measured circulating leptin concentrations and hypothalamic leptin binding in anorectic tumor-bearing and pair-fed control rats. Plasma concentrations of leptin decreased in tumor-bearing rats early in the course of tumor growth, and fell to nearly non-detectable levels during severe anorexia. The pair-fed control rats that ate the same amount of food as did the anorectic tumor-bearing rats exhibited a 50% decrease in plasma leptin concentration. Concentrations of free fatty acids were elevated in both tumor-bearing and pair-fed groups, while circulating levels of triglycerides were increased only in anorectic tumor-bearing rats. Leptin receptor density was doubled in the hypothalamus of tumor bearing rats, while binding affinity was decreased by 50%. These results suggest that peripheral leptin production is down-regulated, perhaps due to increased lipolysis in tumor-bearing rats. It appears that hypothalamic leptin systems up-regulate receptor numbers in response to decreased blood leptin level, however, the decrease in binding affinity may compensate for these alterations. Therefore, the influence of leptin on hypothalamic neuropeptide Y feeding systems may be minimal in anorectic tumor-bearing rats.

Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours.An open-label, non-randomized phase I study was carried out. Patients received intravenous 1.4 mg m(-2) eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC(0,∞) and C(max) for eribulin exposure without or with co-administration of rifampicin were subjected to an analysis of variance (anova) and corresponding 90% confidence intervals (CI) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m(-2) eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti-tumour activity were assessed.Fourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co-administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC(0,∞) = 1.10, 90% CI 0.91, 1.34 and C(max) = 0.97, 90% 0.81, 1.17). The most common treatment-related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%).These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.

Bombesin was originally isolated from amph- ibian skin, wherease its mammalian counterpart, gastrin- releasing peptide (GRP), was first identified in the nervous system of the gastrointestinal tract. Whether GRP is present in the human skin is not known. Bombesin-like peptides are also known to modulate growth. We therefore investigated whether human mel- anoma cell lines express functional GRP-preferring bom- besin receptors and whether they alter growth or other specific cellular functions of these tumour cells. GRP receptor mRNA was found in HBL, D-10, Me-28 and A375-6 cell lines, but only A375-6 cells express a large number of high-affinity binding sites for ( 125 I)-(Tyr 4 ) bombesin (Kd 0 . 31 6 0 . 04 nmol L π1 , 3880 6 429 binding sites per cell). Bombesin dose-dependently increased cytosolic calcium, but did not alter interleukin (IL) 1b-induced reduction of cell viability or IL-6 secretion, both A375-6-specific cell functions. Growth of A375-6 cells was not altered by bombesin or the specific GRP receptor antagonist BIM26226 as measured by ( 3 H)- thymidine incorporation or methylene blue assay, whereas insulin alone or in combination with other potential growth factors dose-dependently stimulated growth of these cells. The newly characterized GRP-preferring bombesin receptors on highly malignant human melanoma cells could initiate studies of growth effects on solid tumours or in vivo scanning using radiolabelled tracers.