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Chatter stability prediction based on linear time-periodic delay differential equations (DDEs) of the milling dynamic process is an important issue in achieving high-performance processing operations. To obtain efficient and precise regenerative chatter prediction, a novel method for milling stability analysis based on Simpson’s 3/8 rule is proposed. First, the dynamics model of milling processes, considering the regenerative effect, is modeled by an n-dimensional delay differential equation. Second, a set of algebraic equations is obtained to determine the transition matrix by converting and discretizing periodic DDE into a system of integral equations at the neighboring sampling grid points. Then, the eigenvalues of the transition matrix are utilized to determine stability based on Floquet theory. Finally, the comparisons of lobe diagrams calculated by different methods and discretization interval number for one and two degrees of freedom milling models are discussed, and the consistency of the predicted and experimental stability boundaries is analyzed. Results show that the proposed method achieves high computation accuracy with high efficiency.

Purpose: BAT1006 is a HER2 extracellular domain II-targeted monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effect aiming for Her2-positive locally advanced/metastatic solid tumors. Previous studies have shown that de-fucosylated antibody binds to FcγRIIIa with increased affinity and can thus trigger FcγRIIIa-mediated effector functions more efficiently than native antibody. BAT1006 was expressed in an FUT8-knockout CHO cell line, resulting in antibody completely devoid of fucose modification. With approximate 5-fold higher level of ADCC effect compared to Pertuzumab, BAT1006 also exhibited potent anti-tumor activity in HER2 positive Calu-3 xenograft mice model. The ongoing phase I, open-label, first-in-human study is evaluating the safety, pharmacokinetics (PK), immunogenicity and preliminary efficacy of BAT1006 to determine the Maximum-Tolerated Dose (MTD) and/or recommended phase II dose (RP2D). Methods: Patients with locally advanced/metastatic solid tumors received escalating doses of BAT1006 (3, 6, 10, 15 mg/kg), administered intravenously (IV) once every three weeks. Patients must have had documented HER2 positivity defined as 3+ by validated immunohistochemistry or amplified on in situ hybridization (ISH). Assessments include archival tumor molecular status, PK, and efficacy by Response Evaluation Criteria in Solid Tumors (RECIST). Results: Fifteen patients [with 2-9 prior lines of therapy] have been treated with BAT1006. All patients had metastatic breast cancer and had received previous HER2-targeted therapies including Trastuzumab, Pertuzumab, T-DM1 and Pyrotinib. No treatment related ≥ Grade 3 AEs have been observed. Of 9 patients at 10mg/kg and 15mg/kg, 1 in 3 patients had CR at 10mg/kg, 2 in 6 patients had PR at 15mg/kg. Conclusion: BAT1006 was well tolerated and showed promising anti-tumor activity in patients with heavily pre-treated HER2-positive cancers. Based on the safety and efficacy results, one additional dose level (20 mg/kg) will be added to the escalation phase and combination therapy with other HER2-based therapy will also be initiated. Citation Format: Xingxing Mei, Weijia Tang, Shuqiang Song, Hao Wang, Chuanqi Cao, Cuiying Feng, Bert E. Thomas, Shengfeng Li, Jin-Chen Yu. A phase I study of BAT1006, a novel anti-HER2 antibody, in patients with locally advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT189.

FRα is overexpressed in a number of cancers, including ovarian, breast, lung cancer, and endometrial carcinoma, yet limited expression in normal tissue. Efficacy of anti-FRα ADC have been demonstrated in clinical trials for high FRα expression ovarian cancer. These results validate FRα as a viable target for cancer treatment. We have developed a novel FRα ADC with strong bystander killing effect, BAT8006, which consists of a high-affinity antibody, an enzymatically cleavable linker and a topoisomerase I inhibitor as the payload, with DAR of 8. BAT8006 shows high affinity for the FRα antigen (KD < 0.5 nM) and FRα-expressing tumor cells. Upon binding to FRα on cell surface, BAT8006 internalizes effectively and traffics to the lysosome where payload is proteolytically released. BAT8006 demonstrated potent in vitro cell growth inhibitory activity to FRα-positive cells with IC50 values of ~ 1 nM. In an in vitro bystander killing assay, proliferation of FRα-negative cells was potently inhibited by addition of culture medium of BAT8006-treated FRα-positive cells, but not that of BAT8006-treated FRα-negative cells, indicating the bystander killing effect of the released payload in the culture medium. Less than 0.03% of the payload was released from BAT8006 when incubated with human or monkey plasma for 4 days in 37oC, suggesting the stability of BAT8006 in blood circulation. BAT8006 led to potent and dose-dependent tumor regression in patient-derived xenograft (PDX) model of SCLC. Furthermore, single dose of 2.5 mg/kg of BAT8006 showed complete eradication of tumor in choriocarcinoma JeG-3 xenograft mice model. In PDX of ovarian cancer, 2.5 mg/kg of BAT8006 (DAR8) demonstrated superior tumor inhibition activity than 5 mg/kg of BAT8006 with DAR4, suggesting the high DAR approach of BAT8006 would be more effective. In addition, BAT8006 showed favorable pharmacokinetic and safety profiles in cynomolgus monkeys with the highest non-severely toxic dose (HNSTD) of 30 mg/kg when dosed once every three weeks for 3 times. Together these results indicate that BAT8006 could potentially provide a therapeutic benefit to treat FRα-positive tumors including breast cancer in clinical trial. Citation Format: siqi mai, xingxing Mei, weijia Tang, Xin Zhou, Xuekang qi, Zhi Zhong, Shuoxu Li, Jianjun fan, Jirong Gan, Binghua Tan, Yao Qi, Yanling Guo, Shengfeng li, Jin-Chen Yu. BAT8006, a novel FRα ADC with strong bystander effect, for the treatment of advanced solid tumor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-12.

Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas, yet is expressed at much lower level on normal tissue. Elevated expression of TROP-2 is often associated with tumor invasion/aggression, progression, and metastasis. Efficacy of anti-TROP2 ADC have been demonstrated in clinical trials for both TNBC (triple negative breast cancer) and HR+/HER2- breast cancer. We have developed a novel Trop-2 ADC with strong bystander killing effect, BAT8008, which consists of an enzymatically cleavable linker and a topoisomerase I inhibitor as the payload, with DAR of 6. BAT8008 demonstrated potent in vitro cell growth inhibitory activity to Trop2-positive cells with IC50 values of < 1 nM. In an in vitro bystander killing assay, proliferation of Trop-2-negative cells was potently inhibited by addition/transfer of culture medium of BAT8008-treated Trop-2-positive cells, but not that of BAT8008-treated Trop-2-negative cells, indicating the bystander killing effect of the released payload in the culture medium. Less than 0.1% of the payload was released from BAT8008 when incubated with human or monkey plasma for 7 days in 37°C, suggesting the stability of BAT8008 in blood circulation. Single dose of BAT8008 at 1 and 2.5 mg/kg could inhibit 73% and 81% tumor growth in the Trop-2-positive MDA-MB-468 and MX-1 xenograft mice model, respectively. BAT8008 also demonstrated superior tumor inhibition activity than a modified ADC using Daiichi’s ADC technology or Trodelvy in a pancreatic BxPC-3 xenograft mice model. In addition, BAT8008 showed favorable pharmacokinetic and safety profiles in cynomolgus monkeys with the highest non-severely toxic dose (HNSTD) of at least 25 mg/kg when dosed once every two weeks for 3 times. Together these results indicate that BAT8008 could potentially provide a therapeutic benefit to treat TROP2-positive breast cancers in clinical trial. Citation Format: Xingxing Mei, Weijia Tang, Xin Zhou, Xuekang Qi, Siqi Mai, Zhi Zhong, Shuoxu Li, Jianjun Fan, Jirong Gan, Binghua Tan, Yao Qi, Yanling Guo, Jin-Chen Yu, Shengfeng Li. BAT8008, a novel Trop-2 ADC with strong bystander effect, for the treatment of Trop-2 positive cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-32.

Background The introductions of anti‐ human epidermal growth factor receptor‐2 (HER2) agents have significantly improved the treatment outcome of patients with HER2‐positive breast cancer. BAT8001 is a novel antibody‐drug conjugate targeting human epidermal growth factor receptor‐2 (HER2)‐expressing cells composed of a trastuzumab biosimilar linked to the drug‐linker Batansine. This dose‐escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti‐tumor activity of BAT8001 in patients with HER2‐positive locally advanced or metastatic breast cancer. Methods This trial was conducted in subjects with histologically confirmed HER2‐positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21‐day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective. Results Between March 2017 to May 2018, 29 HER2‐positive breast cancer patients were enrolled. The observed dose‐limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ‐glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%‐61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%‐94.2%) patients. Conclusions BAT8001 demonstrated favorable safety profiles, with promising anti‐tumor activity in patients with HER2‐positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2‐positive breast cancer., BAT8001 demonstrated favorable safety and tolerability profiles, with promising anti‐tumour activity in patients with HER2‐positive advanced or recurrent solid tumours. BAT8001 has the potential to provide a new therapeutic option in heavily pretreated patients with metastatic Her2‐positive breast cancer.

Impervious surfaces are key indicators for urbanization monitoring and watershed degradation assessment over space and time. However, most empirical studies only extracted impervious surface from spatial, temporal or spectral perspectives, paying less attention to integrating multiple dimensions in acquiring continuous changes in impervious surfaces. In this study, we proposed a neighborhood-based spatio-temporal filter (NSTF) to obtain the continuous change information of impervious surfaces from multi-temporal Landsat images in the Qinhuai River Basin (QRB), Jiangsu, China from 1988–2017, based on the results from semi-automatic decision tree classification. Moreover, we used the expansion intensity index (EII) and the landscape extension index (LEI) to further characterize the spatio-temporal characteristics of impervious surfaces on different spatial scales. The preliminary results showed that the overall accuracies of the final classification were about 95%, with the kappa coefficients ranging between 0.9 and 0.96. The QRB underwent rapid urbanization with the percentage of the impervious surfaces increasing from 2.72% in 1988 to 25.6% in 2017. Since 2006, the center of urbanization expansion was shaped from the urban built-up areas of Nanjing and Jiangning to non-urban built-up areas of the Jiangning, Lishui, and Jurong districts. The edge expansion occupied 73% on average among the different landscape expansion types, greatly beyond outlying (12%) and infilling (15%). The window size in the NSTF has a direct impact on the subsequent analysis. Our research could provide decision-making references for future urban planning and development in the similar basins.

In spite of the successful development of effective countermeasures against Covid-19, variants have and will continue to emerge that could compromise the efficacy of currently approved neutralizing antibodies and vaccines. Consequently, novel and more efficacious agents are urgently needed. We have developed a bispecific antibody, 2022, consisting of two antibodies, 2F8 and VHH18. 2F8 was isolated from our proprietary fully synthetic human IDEAL (Intelligently Designed and Engineered Antibody Library)-VH/VL library and VHH18 is a single domain antibody isolated from IDEAL-nanobody library. 2022 was constructed by attaching VHH18 to the C-terminal of Fc of 2F8. 2022 binds two non-overlapping epitopes simultaneously on the RBD of the SARS-CoV-2 spike protein and blocks the binding of RBD to human angiotensin-converting enzyme 2 (ACE2). 2022 potently neutralizes SARS-CoV-2 and all of the variants tested in both pseudovirus and live virus assays, including variants carrying mutations known to resist neutralizing antibodies approved under EUA and that reduce the protection efficiency of current effective vaccines. The half-maximum inhibitory concentration (IC50) of 2022 is 270 pM, 30 pM, 20 pM, and 1 pM, for wild-type, alpha, beta, and delta pseudovirus, respectively. In the live virus assay, 2022 has an IC50 of 26.4 pM, 13.3 pM, and 88.6 pM, for wild-type, beta, and delta live virus, respectively. In a mouse model of SARS-CoV-2, 2022 showed strong prophylactic and therapeutic effects. A single administration of 2022 intranasal (i.n.) or intraperitoneal (i.p.) 24 hours before virus challenge completely protected all mice from bodyweight loss, as compared with up to 20% loss of bodyweight in placebo treated mice. In addition, the lung viral titers were undetectable (FRNT assay) in all mice treated with 2022 either prophylactically or therapeutically, as compared with around 1×105pfu/g lung tissue in placebo treated mice. In summary, bispecific antibody 2022 showed potent binding and neutralizing activity across a variety of SARS-CoV-2 variants and could be an attractive weapon to combat the ongoing waves of the COVID-19 pandemic propagated mainly by variants, especially, the much more contagious delta variant.

This paper investigates the dynamic interactions of firms' financial behaviours using a five-variable structural vector autoregression (SVAR) framework. We provide empirical evidence that firms' financial behaviours are jointly determined. We demonstrate that a single-equation analysis on one financial behaviour generates biased estimates. We find that firms deviate from the desired level of each financial characteristic to absorb shocks to the other financial characteristics. Following such deviations, the characteristics revert in subsequent periods. Among these inter-related financial behaviours, equity decisions are the most independent, followed by dividend target, investment, and leverage target. Although firms prioritize financial behaviours differently, it appears that there is neither one financial behaviour that firms use only to absorb shocks nor one that never responds to the others.

Compared with a single loop, a FLL-assisted-PLL (Frequency-locked Loop, FLL; Phase-locked Loop, PLL) tracking loop which integrates both the dynamic robustness of FLL and the accuracy performance of PLL has better carrier tracking performance. However, under highly dynamic conditions, its tracking ability still cannot meet the requirements. To overcome this problem, a novel combined control loop based on FLL-assisted-PLL is proposed in this paper. The combined control loop adjusts the action effects of FLL and PLL automatically according to the current tracking state without the need for decision processing, which makes full use of the characteristics of FLL and PLL. Simulation results demonstrate that the proposed combined loop does achieve a shorter convergence time and higher tracking accuracy than the traditional FLL-assisted-PLL tracking loop under significant dynamics.

In recent years, a new emerging Interleave-Division Multiple Access (IDMA) developed from the Code-Division Multiple Access (CDMA), with its unique advantages, has been introduceded into the satellite communication systems to provide a new multi-user access solution. In IDMA satellite systems, the random distribution of the geographical locations of different user ends (UEs) within the coverage of the satellite ground spot beam will cause serious asynchronous transmission. In this case, the computational complexity of MUD will increase sharply compared to the case of synchronization. Unfortunately, although many simplified algorithms were studied, this problem is still not solved effectively. In this paper, inspired by the successful application of the Belief Propagation (BP)-based joint iterative detection and decoding algorithm in CDMA systems, we adopt this method in asynchronous IDMA satellite systems. Analysis and simulations verify that the BP-based iterative algorithm can effectively reduce the algorithm complexity and has better performance than traditional turbo iterative algorithms in the asynchronous IDMA satellite system.

Background: To compare the pharmacokinetic (PK) profile, safety, and immunogenicity between golimumab and the biosimilar BAT2506 in healthy Chinese male subjects. Research design and methods: A tot...

Deep eutectic solvent (DES) combined with ultrasound-assisted extraction (UAE) was successfully developed and fully validated to simultaneously determine Icarrin, IcarisidⅡ, Epimcdin A, Epimcdin B and Epimcdin C for the quality evaluation of Herba Epimedii. Twelve kinds of DESs were initially screened, and then the effective extraction was achieved by the tailor-made DES consisting of the mixture of l -proline and ethylene glycol with the molar ratio of 1:4 in this study. The optimal conditions were further optimized by the orthogonal experimental design (OED). 0.2 g sample powder was ultrasonic extracted by using 4.00 mL of aqueous solution containing 70 % (v/v) the above DES for 45 min, resulting to the optimum extraction efficiency. The FT-IR and NMR spectra showed the chemical structural characteristic correlation between l -proline and ethylene glycol, and could infer the formation of hydrogen bonds between the hydroxyl group of ethylene glycol and the nitrogen atom of l -proline. The hierarchical cluster analysis (HCA) was further processed for the quality evaluation of Herba Epimedii. Finally, DES could be used to distinguish different origins and different kinds of Herba Epimedii, and to evaluate the quality of Herba Epimedii. This method provided good linearity, precision and accuracy. The recoveries of the five main bioactive flavonoids in Herba Epimedii were within the range of 88.5–107.7 % (RSD less than 3.4 %). Compared to the traditional extraction method of Icarin in the Chinese Pharmacopoeia (2015 edition), the solvent consumption was decreased by 80 % and the extraction time was shortened by 25 %, leading to more efficient and more convenient of this DES-UAE method. This work indicated that DES would be a promising high effective solvent for the analytical sample preparations of plant herbs, and it might have a broad application in the quality control of traditional Chinese medicines.

In this paper, Thiele&ndash, Newton&rsquo, s blending expansion of a bivariate function is firstly suggested by means of combining Thiele&rsquo, s continued fraction in one variable with Taylor&rsquo, s polynomial expansion in another variable. Then, the Viscovatov-like algorithm is given for the computations of the coefficients of this rational expansion. Finally, a numerical experiment is presented to illustrate the practicability of the suggested algorithm. Henceforth, the Viscovatov-like algorithm has been considered as the imperative generalization to find out the coefficients of Thiele&ndash, s blending expansion of a bivariate function.

BAT1706 is a proposed biosimilar of bevacizumab (BEV). The objective of this phase I clinical trial was to establish pairwise similarity between BAT1706, US-sourced BEV (US-BEV), and EU-sourced BEV (EU-BEV) after a single intravenous (IV) infusion in healthy male subjects.This phase I clinical trial was a randomized, double-blinded, three-arm study in 128 healthy adult male subjects. Every subject received a single IV infusion of 1 mg/kg of study drug and was subsequently monitored for 14 weeks. Pharmacokinetic, safety, and immunogenicity data were collected from each patient. The primary pharmacokinetic endpoint of this clinical study was area under the concentration curve from time zero to infinity (AUCThe pharmacokinetic parameters were comparable for the three drug products evaluated. The 90% CI for the AUCIn this study, BAT1706, a proposed biosimilar of BEV, was shown to be highly similar to EU-BEV and US-BEV in terms of pharmacokinetic equivalence, safety, and immunogenicity in healthy subjects after a single IV infusion.NCT03030430.

In recent years, many studies have focused on the changes of partial or single African ecosystems and the drivers of those changes. However, focusing only on partial or single ecosystems has limited the understanding of the relationships between the vegetation and climate changes in all of the African ecosystems. In this study, the temporal trends of the satellite-derived annual mean leaf area index (GLASS-LAI) were analyzed, and the inter-annual relationships were developed between the annual mean LAI and the climate variables (precipitation and temperature) for the time period ranging from 1982 to 2013. Additionally, this study applied seasonal curves and step-wise multiple regression methods to investigate the relationships between intra-annual LAI and climate changes. It was found that the GLASS-LAI over half of Africa had shown general significant greening or browning trends during the period from 1982 to 2013. From the results of inter-annual analysis, with mean annual precipitation lower than 600 mm, the greening of the savannas and grasslands in the Sahel was found to highly correspond with the increased precipitation. In contrast, the evergreen broadleaf forests in the Gulf of Guinea and Congo Basin showed strongly positive responses to the annual temperature when the mean annual temperature was below 25 °C. In regard to the intra-annual responses, the precipitation with 1-month lags was found to be helpful for the vegetation growth, with the exception of the evergreen broadleaf. The results of this research study indicated that the different land-covers in Africa had displayed clear differences in their annual trends during the examined 32-year period and had responded differently to the inter- and intra-annual climate drivers. This difference was evident by the characteristics of the vegetation covers and the geographic distributions. Therefore, further examinations of these differences can potentially improve the understanding of the land surface-atmosphere interactions among the different African ecosystems.

Purpose The present study has proposed a novel orthodontic extraction method with a removable appliance to avoid inferior alveolar nerve (IAN) injury during impacted mandibular third molar removal. Patients and Methods In the present study, 16 patients were enrolled and divided into 2 groups per patient choice. In the orthodontic extraction group (n = 8), a removable appliance was first applied to move the root tips away from the IAN, and the tooth was subsequently removed. In the traditional extraction group (n = 8), each patient had the tooth removed immediately by the same surgeon. Results All teeth were extracted successfully. All 8 patients in the orthodontic extraction group had had their impacted mandibular third molar removed without IAN injury after surgery. In contrast, 4 patients in the traditional extraction group had experienced transient IAN injury, and the symptoms persisted for 2 to 8 weeks. None of the patients experienced permanent IAN damage. Conclusions Orthodontic extraction with a removable appliance to separate the IAN and impacted mandibular third molar could be a good alternative treatment option to avoid IAN injury in high-risk cases.

Objectives Salivary adenoid cystic carcinoma (SACC) is one of the most common malignant salivary gland tumors. Our study aims to investigate whether hypoxia-induced autophagy was up-regulated in the progression of SACC. Materials and methods We performed differentially expressed gene analysis and pathway enrichment analysis and then calculated the correlation analysis on GSE59701 and GSE28996 datasets. The expression of HIF-1ɑ and MAP1LC3B was analyzed in the paraffin-embedded specimens by immunohistochemical method and in the hypoxic SACC-LM cells by immunofluorescence. TEM microscopy was also performed to observe the formation of autophagosomes in SACC tissue and the hypoxic SACC-LM cells. Results The autophagy pathway was up-regulated in SACC datasets, and five genes including MAP1LC3B were positively correlated with HIF-1ɑ. Immunohistochemistry results showed that autophagy was activated and the expression of HIF-1ɑ and MAP1LC3B was positively correlated in SACC specimens. In hypoxic SACC-LM cells, we also identified the up-regulation of autophagy and the close correlation between HIF-1ɑ and MAP1LC3B expression. Autophagosomes were observed both in the tissue and the hypoxic SACC-LM cells by TEM microscopy. Conclusions Our study showed that autophagy is up-regulated in dataset, SACC tissue, and hypoxic cell line; hypoxia-induced autophagy in SACC might play a vital role in the development of SACC.

The product quality of selective laser melting (SLM) is closely related to the alloy powder size distribution. The small voidage of fine-sized alloy powder bed is beneficial to improve the density of SLM product. While, the fine-sized alloy powder would result in the poor powder spreading uniformity in the SLM equipment, which leads to the formation of holes in the SLM product. In this work, the 316L stainless steel powder was prepared by a vacuum atomization furnace and sieved into a coarse-sized distribution and a fine-sized distribution. Then, the coarse-sized powder and the fine-sized powder are mixed according to different ratios. The results show that, under the condition of same SLM parameters, the density and strength of the SLM sample gradually decrease, with the increasing amount of fine-sized powder. The main reason for this phenomenon is that the fine-sized powder, with the large specific surface, is easy to bond with the coarse-sized powder. It reduces the fluidity of powder, resulting in the pores and cracks during the SLM layering process. Furthermore, the addition of fine-sized powder to the coarse-sized powder results in a decrease in the elongation of SLM sample. However, with the increase of the addition amount of the fine-sized powder, the residual stress is released due to the formation of a large number of cracks and pores, so that the elongation of SLM sample is slightly increases.

Techniques used to extract shale gas, hydraulic fracturing or fracking, do have draw-backs not least the large consumption of water. We provide the first estimate of water consumption in Chinese shale gas fracking. A case study from Fuling, Chongqing, Southwest China, shows that average water consumption is 27490 m3 per well, much higher (by 29%-160%) than in the USA. Data analysis indicates a significant correlation between water consumption and lateral length of wells (p

T-DM1, an antibody drug conjugate (ADC), has been approved by FDA for patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane. DM1 is released because it is connected to the linker of T-DM1 by a thio-ether bond, which can be broken via retro-Michael addition. To improve the antibody-drug stability, we created an anti-HER2 ADC (BAT8001) which used a novel uncleavable linker to connect trastuzumab and a payload of maytansine derivative. BAT8001 exhibits similar level of potency against proliferation of HER2-overexpressed cells as T-DM1 and demonstrates strong inhibition activity on tumor growth in both cell-line and patient-derived xenograft models. Pharmacokinetics (PK) study in monkey reveals BAT8001 has similar level of exposure, half-life, and Cmax as T-DM1. BAT8001 Ph1 clinical trial in patients with HER2+ late-stage breast cancer recently was completed. The clinical study used standard “3+3” multiple-dose escalation method, evaluated BAT8001 safety, PK and explored the efficacy. Twenty-nine subjects were randomized and 27 subjects received the treatment with escalated dose 1.2mg/kg, 2.4mg/kg,3.6mg/kg, 4.8mg/kg and 6.0mg/kg. Two subjects died during the screening time without treatment due to disease progression. Nineteen (79.2%) subjects completed at least 4-cycle treatment. The PK parameter (Cmax and AUC(0-t)) values demonstrated dose-dependent linear relationship. In the safety evaluation, the incidences of AE and AE with CTCAE >=3 increased when dose escalated. The platelet count decrease and AST elevation were found to be the most common and severe AEs. Three subjects had serious adverse events (SAE) of bone destruction which were considered to be not investigated-drug related by the PI. Among those 3 subjects, 2 subjects withdrew from the study due to the SAE and 1 subject continued the treatment. The preliminary efficacy assessment after 10 months treatment found that 1 (3.7%) patient exhibited the complete response (CR), 5 (18.5%) patients exhibited the partial responses (PR), and 5(18.5%) patients exhibited the stable diseases. Based on the information above, the dose of 3.6mg/kg achieved target drug exposure and was found to be the effective and well-tolerated, which was selected to be the dose in the confirmatory clinical trial. Currently, a Phase 3, multicenter, randomized, open-label, controlled trial evaluating the efficacy and safety of BAT8001 has been initiated in patients with HER2+ metastatic breast cancer who previously received trastuzumab separately or in combination with taxanes. The trial is designed to compare BAT8001 versus lapatinib combined with capecitabine which is 2nd-line standard of care for metastatic breast cancer patients in China. This Phase 3 trial plans to recruit approximately 410 patients and by Jan 2019 more than 130 patients have received the treatment of BAT8001. The BAT8001 benefit-risk profile continues to support further development and the clinical results will be revealed by early 2020. Citation Format: Shusen Wang, Fei Xu, Ruoxi Hong, Wen Xia, Jin-Chen Yu, Weijia Tang, Jin Wei, ShuQiang Song, Zhaohe Wang, Li Zhang, Shengfeng Li. BAT8001, a potent anti-HER2 antibody drug conjugate with a novel uncleavable linker to reduce toxicity for patients with HER2-positive tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT053.

This paper describes an efficient synthesis of carbohydrate fatty acid esters based on a highly stereo- and regio-selective esterification. The suitably protected glycosyl was esterified with stearic acid to give mainly the β-anomer in good yield using p-toluenesulfonic acid as catalyst. The structures of these compounds were fully confirmed by 1H, 13C NMR, mass spectra and HRMS.

Depletion of malignant B cells using anti-CD20 antibodies is one of the most effective approaches for CD20-positive non-Hodgkin lymphoma therapy. Anti-CD20 antibodies can activate several pathways including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or programmed cell death to kill tumor cells. ADCC is mediated via Fc region of antibody binding to FcγRIIIa receptor on effector cells, such as NK cells. Previous studies have shown that non-fucosylated antibody binds to FcγRIIIa with increased affinity and can thus trigger FcγRIIIa-mediated effector functions more efficiently than native, fucosylated antibody. Obinutuzumab, an FDA-approved anti-CD20 antibody with approximate 30% fucose level of a normal antibody, has demonstrated better efficacy than fucosylated rituximab. We generated BAT4306F, which has the same sequence as obinutuzumab yet is completely devoid of fucose modification. BAT4306F induced higher level of ADCC effect compared with rituximab and obinutuzumab in vitro. BAT4306F also showed significantly superior activity on depleting B cells in whole blood compared to rituximab, and superior activity compared to obinutuzumab. In monkeys dosed once with these antibodies, BAT4306F demonstrated much stronger B-cell depletion activity than that of obinutuzumab and rituximab, whether detected in serum, spleen, or lymph node. The residual B cells detected in spleen of monkey treated with BAT4306F were 8-fold less than that of obinutuzumab, and 10-fold less than that of rituximab. Furthermore, BAT4306F demonstrated stronger tumor-inhibition activity than rituximab in a DLBCL tumor cell xenograft mouse model. Preclinical acute and long-term toxicity studies in monkey reveal that BAT4306F is well tolerated. Together these data demonstrate that BAT4306F is more potent than obinutuzumab and rituximab due to a complete defucosylation. The result warrants further clinical development of BAT4306F. Citation Format: Jin-Chen Yu, Chao Qin, Shengfeng Li. Bat4306f, an anti-CD20 antibody devoid of fucose modification, demonstrates enhanced ADCC effect and potent in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3823.

Two robust tree-ring width chronologies were developed for the western Tianmu Moun- tains and the Xianyu Mountains of southeast China. Both chronologies were significantly correlated with each other and were arithmetically averaged to build a regional chronology (RC). The RC had significant and positive correlations with winter temperature before the growing season. Based on this relationship, the average temperatures of the previous December to the current March were reconstructed using the RC chronology for the period 1852 to 2006. The temperature reconstruction was significantly correlated with the winter half-year temperature in the eastern Qinling Mountains of central China, 720 km west of the study region, suggesting a large-scale coherence of winter tem- perature variability. The reconstruction corresponds well with an East Asian winter monsoon (EAWM) index in extreme years and reflects the strong influences of the EAWM in this study region. Thus, there is great potential to use tree-ring chronologies to reconstruct past climate change in southeast China, where little dendroclimatic work has been done until now.

Influenza A virus is responsible for influenza epidemics in avian and human populations and poses a great threat to human health. Many researches have been focused on the prevention and treatment of influenza A virus infection. The nucleoprotein (NP) of the virus is an important protein due to its ability to interact with a variety of viral and cellular factors and its role in the viral RNA synthesis. In this study, we have used the influenza A virus nucleoprotein as target for anti-viral therapy through a new approach. By screening a human single-chain intracellular antibody (intrabody) cDNA library using nucleoprotein as bait in a yeast antigen-antibody two-hybrid system, we have identified several intrabodies that specifically interact with the viral nucleoprotein. Interaction between nucleoprotein and anti-nucleoprotein intrabodies was further confirmed by mammalian two-hybrid analysis. Results showed that anti-nucleoprotein intrabodies changed their cellular distribution in association with the viral nucleoprotein. Further studies indicated that anti-nucleoprotein intrabodies abolished the accumulation of not only the complementary RNA and virion RNA but also messenger RNA of influenza virus. In addition, anti-nucleoprotein intrabodies significantly inhibited influenza A virus transcription and replication through blocking the interaction of nucleoprotein with the viral polymerase proteins, polymerase basic protein 1 and polymerase basic protein 2. Thus, this study not only provides a powerful tool for the study of viral protein's functions, but also opens a new potential avenue for the prevention and treatment of influenza virus infections.

We made multi-proxy analysis of 14C, grain size, microfossils, plant seeds, and geochemical elements on samples from a profile in the central West Lake of Lop Nur. The grain size suggests relatively stable sedimentary environment around the Medieval Warm Period (MWP) with weak storm effect, which is followed by frequent strong storm events. Abundant microfossils and plant seeds in this stage indicate a warm and humid fresh to brackish lake environment. C, N, and stable elements are high in content in the sediments while Rb/Sr, Ba/Sr, and Ti/Sr are in a steady low level. In addition, plenty of red willows lived here prior to about 700 a B.P., indicating a favorable environmental condition. The results indicate that the environment in Lop Nur and its west bank turned to be favorable at about 2200 a B.P., where the Loulan Culture began to thrive. Then the climate and environment came to be in the good condition in the Tang and Song Dynasties, when the storm effect became weaker, rainfall increased and the salty lake water turned to be brackish to fresh lake water. Hence, limnic biomass increased with higher species diversity.

Based on the diatom analysis the climatic sequence between 11 000 and 6 000 aBP in Angren, southern Tibet is established, i.e. cold period (11 095-9 970 aBP)→ temperate period (9 970-9 870 aBP) → Anathermal (9 870-9 770 aBP)→ cool-dry period (9 770-8 740 aBP) → super-megathermal (8 740-8 590 aBP)→ Megathermal (8 590-5 970 aBP). And the opinion that the reaction of diatom to temperature change is more sensitive than to other ecological factors has been pointed out and certified.

Many of the antimicrobial, immunomodulatory and cell growth inhibitory activities of the interferons are mediated by interferon-inducible proteins. Earlier we characterized an interferon-inducible murine protein, p202, whose expression in transfected cells inhibits cell proliferation and which can form a complex with retinoblastoma protein (pRb). Here we report that in transfected cells expression of p202 inhibits E2F-stimulated transcription of a reporter gene and of endogenous genes. Inhibition of the transcriptional activity of E2F by p202 does not depend on fully functional pRb and is correlated with inhibition of the sequence-specific DNA binding of E2F. p202 interacts with the transcription factor E2F (E2F-1/DP-1) in vitro and in vivo. Inhibition of E2F activity by p202 may contribute to growth inhibition by the interferons.