An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.     

化学气相沉积法制备碳化铬薄膜的研究

以三（2,2,6,6-四甲基-3,5-庚二酮）化铬为前驱体,采用化学气相沉积（CVD）法在氧化铝（Al₂O₃）陶瓷基板上制备碳化铬（Cr₃C₂）薄膜,其中沉积温度为723 K至923 K,沉积时间为1 200 s。研究了不同沉积温度对Cr₃C₂薄膜的相组成、择优取向、宏观表面、微观结构及电学性能的影响。结果表明,在723 K至923 K下制备得到具有高度（130）择优取向的Cr₃C₂薄膜。随着沉积温度的升高,Cr₃C₂薄膜表面先由光滑变粗糙,后逐渐变光滑;薄膜晶粒呈椭球型生长;薄膜的厚度先增加后减小,从而导致电阻先减小后增大。在798 K时制备得到厚度最大且电阻最小的（130）择优取向的最佳Cr₃C₂薄膜。同时,在实验条件下Cr₃C₂薄膜表面存在少量的碳和Cr₂O₃。     

重芳烃轻质化催化剂n（Ni）/n（Ni+Mo）的优化与分析

以β分子筛为载体,在保持金属总负载量不变的情况下,采用等体积浸渍法制备了4种不同n（Ni）/n（Ni+Mo）的催化剂。分别采用X射线衍射（XRD）、比表面积测试（BET）、氨程序升温脱附（NH₃-TPD）、氢程序升温还原（H₂-TPR）、氢程序升温脱附（H₂-TPD）和热重-差热分析（TG-DTG）等方法对催化剂进行了表征。结果表明,4种催化剂的酸量和酸强度相近,在n（Ni）/n（Ni+Mo）等于基准+0.2时,Mo与载体之间的相互作用最弱,其氢气吸附量最多且积炭量最少;采用某炼厂重整C₁₀⁺ 重芳烃对4种催化剂进行评价,结果表明n（Ni）/n（Ni+Mo）等于基准+0.2催化剂具有最优的催化活性和稳定性。上述结果表明,影响重芳烃轻质化催化剂活性和稳定性的关键因素是催化剂氢气吸附量的多少,氢气吸附量越多金属表面的溢流氢效应越明显,积炭前驱体被溢流氢及时消除,从而保护了催化剂的加氢活性中心不被积炭覆盖,有助于催化剂在较高活性下保持稳定。     

预分离色谱法直接测定微量组份无限稀释活度系数

预分离色谱法可直接测定混合物中微量组份的无限稀释活度系数(γ~∞),而不必把此组份从混合物中分离出来。主要由四步组成:被测组份的预浓缩,被测组份的定性,选择预分离柱和γ~∞的测定。预浓缩样品经过预分离柱分出被测组份,然后进入测量柱测定γ~∞。此方法简捷、可靠与常规以纯溶质进样的色谱测y~∞的方法具有相同的测定精度,可广泛用于缺少纯样的场合。用此法测定了戊烯-1-炔-4、丁炔-2在若干酸醇中的γ~∞,分别求得了修正和未修正的UNlFAC参数,对kikic修正模型其值为ac=c,CooH=694.9(K)acooH,c=c=-99.08(K),ac=c,oH=812.99(K),aoH,c=c=143.36(K)     

Determination of the solubility parameter of poly(ethylene oxide) at 25°C by gas-liquid chromatography

The solubility parameter of poly(ethylene oxide) at 25°C has been determined using the method developed by DiPaola-Baranyi and Guillet, by the extrapolation of the values of the interaction parameter χ, at high temperatures, ranging from 70°–90°, 90°–110° and 110°–130°C down to 25°C. The values of the solubility parameter obtained, depending on the temperature ranges employed, are 9.8, 9.9 and 10.1, respectively.     

ON THE UNIMODALITY OF THE EXACT LIKELIHOOD FUNCTION FOR NORMAL AR(2) SERIES

Abstract. For stationary second-order autoregressive normal processes, the conjecture of uniqueness of the solution of the exact likelihood equations is examined. A sufficient condition for uniqueness is given; this condition is satisfied with very high probability if the number of observations is not extremely small. Moreover, it is shown that not more than two maxima may exist. Examples of data which actually produce a likelihood function with two local maxima are given.     

适用于扩展有限元裂缝计算的钢筋与混凝土粘结滑移关系

以定量分析钢筋与混凝土粘结滑移关系为目标,利用RCXFEHohai-P扩展有限元程序,计算采用不同粘结滑移公式时钢筋混凝土简支梁的最大裂缝宽度。结果表明,计算所得最大裂缝宽度各不相同,且都与《混凝土结构设计规范》(GB 50010—2010)所列最大裂缝宽度公式计算值存在差别。为此,基于GA-BP神经遗传网络,以规范最大裂缝宽度公式计算值为预测目标,反演得到适用于扩展有限元裂缝计算的粘结滑移公式,算例表明该公式能满足扩展有限元裂缝宽度计算要求。研究成果对提高扩展有限元裂缝分析的准确性具有一定的参考价值。     

含水量对渠道保温板保温耐久性的影响及保温板厚度设计

北方渠道大多使用保温板防止混凝土衬砌受冻胀破坏。在计算保温板厚度时为了降低成本,容易忽略保温板使用过程中受各种因素的影响导致保温效果变差的情况,使混凝土衬砌达不到设计使用年限便提前被破坏。内蒙古河套灌区试验结果表明,由于受酸雨、冻融作用、含水量等因素的影响,保温板保温效果平均每年降低0.9℃,其中受含水量变化的影响最大。经试验测得:聚苯乙烯保温板(EPS)含水量每增加1%,会导致导热系数增大5%。基于多层材料串联热阻叠加原理和热阻等效原理,对保温板厚度计算公式进行完善,并提出相应的铺设方法和施工技术要求。该设计对保温板在季节性冻土区的推广应用具有一定参考价值。     

墩头超长实用堰泄洪安全分析及模型试验验证——以缅甸DAPEIN(Ⅰ)水电站工程为例

以缅甸DAPEIN(Ⅰ)水电站工程为例,论述了将WES实用堰的闸墩墩头向上游超长延伸之后,对泄洪安全所造成的影响。针对WES实用堰流量系数、堰面动水压力容易受边界因子影响的特点,对设计断面的堰顶布置和墩头形状进行了优化。根据堰面空化数计算公式及水流特性推导出计算的关键部位,对空化数进行计算。采用几何比尺为1∶60的物理模型对溢流堰的泄流能力和堰面动水压力进行了试验测试。试验结果表明:溢流堰的模型试验泄流能力和设计泄流能力非常相近。堰面动水压力除工况2的B4测点出现了-1.2 k Pa的微小负压值外,其余堰面时均压强值均大于0。从而,在泄流能力和堰面动水压力两方面都验证了这种设计方案的合理性。该工程所遇到的结构布置问题在中低溢流坝工程中属常见问题,解决思路可为今后类似工程建设借鉴参考。     

A RANDOM PARAMETER PROCESS FOR MODELING AND FORECASTING TIME SERIES

Abstract. A generalized autoregressive (GAR) process {Z ( t ) ; t = 0 , ±1, …} is defined to satisfy the recurrence relation Z(t) = A_θ (t)Z (t -l)+ u( t ), where {A_θ(t); t = 0,±1, …} is itself a stochastic process depending on a vector parameter θ and where {u( t ); t = 0, ±1, …} is white noise with Eu ² ( t ) = a ². This paper develops theory and methodology and implementing the class of GAR processes for time series modeling and forecasting. Conditions on the 'parameter process' { A _θ ( t ); t = 0, ±1, …} are obtained for the existence of a GAR process; necessary and sufficient conditions on { A_θ ( t ) ; t = 0, ±1, …} for existence of a stationary GAR process are also obtained. Procedures are developed for computing maximum likelihood estimates of the parameters 0 and u² and for computing the minimum mean squared error forecasts for GAR processes.