Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase Ⅱ single-arm study

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity troponin.Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile,especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Analysis of Continuous Thunderstorm in One Week at Qingdao Airport Based on Sounding Data

Continuous thunderstorm occurring at Qingdao Airport in China from August 7 to 13,2022 was analyzed based on sounding data.The weather was divided into thunderstorm gale,thunderstorm and heavy precipitation,and some physical quantities and time variables which can effectively identify severe convective weather types were preliminarily obtained.The results show that CAPE was sensitive to different types of weather,but the uncertainty was relatively large.Convective temperature T_(CON),temperature difference between 500 and 850 hPa,and vertical wind shear can distinguish thunderstorm gale,thunderstorm and heavy precipitation weather obviously.Besides,K index,Showalter index,θ_(se) difference between 500 and 850 hPa were also important basis to distinguish thunderstorm and heavy precipitation weather.Thunderstorm gale can be distinguished by the 24-hour variations of K index,and the difference of dew point between 500 and 850 hPa.The 24-hour variations of(T-T_(d))_(500) and vertical wind shear can be used to distinguish between heavy precipitation and thunderstorm weather;the 24-hour variation of stratification stability Δθ_(se) can distinguish the three kinds of weather well.For the wind field,the existence of vertical wind shear was required for strong convective weather,and the 24-hour increment of thunderstorm gale and thunderstorm was larger than that of heavy precipitation.

抗SARS-CoV-2变异株的广谱mRNA疫苗RQ3013的临床前研究

全球SARS-CoV-2病毒的不同变异株导致已接种疫苗的人群中突破性感染的比例上升,迫切需要研发更为有效和广谱的COVID-19疫苗.本研究报告了一项mRNA疫苗RQ3013的临床前研究结果,旨在提供对SARS-CoV-2各种变异株(VOCs)的广谱保护.RQ3013疫苗包含经过假尿苷修饰的mRNA,制备成脂质纳米颗粒的形式.该mRNA编码了SARS-CoV-2的刺突(S)蛋白嵌合体,包含与免疫逃逸有关的重要突变位点.我们在多种动物模型中对RQ3013的免疫原性、保护效果和安全性进行了评估.RQ3013在小鼠、仓鼠和非人灵长类动物(NHP)中引发了显著的免疫反应.它能够诱导高滴度的抗体产生,具备对野生型、B.1.1.7、B.1.351、B.1.617.2和奥密克戎系列变异株的广泛中和能力.在小鼠和NHP中,两剂RQ3013疫苗能够有效保护上呼吸道和下呼吸道免受SARS-CoV-2及其变异株的感染.此外,在NHP中对RQ3013的安全性进行了评估,未观察到不良反应.这些结果为在临床试验中评估RQ3013提供了有力的支持,表明它可能成为对抗COVID-19及其变种的广泛保护的有希望的候选疫苗.

I-IBV life cycle is restricted in mouse hepatocytes .~xpressing human NTCP

Recent studies have revealed that human sodium taurocholate cotransporting polypeptide （SLC10A1 or NTCP） is a functional cellular receptor for hepatitis B virus （HBV）. However, whether human NTCP can support HBV infection in mouse hepatocyte cell lines has not been clarified. Because an HBV-permissible mouse model would be helpful for the study of HBV pathogenesis, it is necessary to investigate whether human NTCP supports the susceptibility of mouse hepatocyte cell lines to HBV. The results show that exogenous human NTCP expression can render non-susceptible HepG2 （human）, Huh7 （human）, Hepal-6 （mouse）, AML-12 （mouse） cell lines and primary mouse hepatocyte （PMH） cells susceptible to hepatitis D virus （HDV） which employs HBV envelope proteins. However, human NTCP could only introduce HBV susceptibility in human-derived HepG2 and Huh7 cells, but not in mouse-derived Hepal-6, AML-12 or PMH cells. These data suggest that although human NTCP is a functional receptor that mediates HBV infection in human cells, it cannot support HBV infection in mouse hepatocytes. Our study indicated that the restriction of HBV in mouse hepatocytes likely occurs after viral entry but prior to viral transcription. We have excluded the role of mouse hepatocyte nuclear factors in the restriction of the HBV life cycle and showed that knockdown or inhibition of Sting, TBK1, IRF3 or IRF7, the components of the anti-viral signaling pathways, had no effect on HBV infection in mouse hepatocytes. Therefore, murine restriction factors that limit HBV infection need to be identified before a HBV-permissible mouse line can be created.

MPC-Based Downshift Control of Automated Manual Transmissions

Automated manual transmissions,which usually adopt synchronizers to complete the gear shift process,have many advantageous features.However,the torque interruption and the challenging control objectives during the gear shift process limit its industrial application,especially for the power-on gear downshift.This paper proposes a model predic-tive control(MPC)method to control the clutch engagement process and effectively shorten the torque interruption,consequently enhancing the gear downshift quality.During the control law deduction,the proposed MPC also accounts for time-domain constraints explicitly.After the control law was deduced,it was validated through simulations under two typical power-on gear downshift working scenarios.Both of the simulation results demonstrate that the controller proposed in this paper can shorten the torque interruption time during power-on gear downshifts while minimizing vehicle jerk for overall satisfactory drivability.