Red flags for early recognition of adult patients with PTEN Hamartoma Tumour Syndrome

Patients with PTEN Hamartoma Tumour Syndrome (PHTS) are at increased risk of developing cancer. Many adult PHTS patients are not recognized as such and do not receive the cancer surveillance they need. Our aim was to define phenotypic characteristics that can easily be assessed and manifest by early adulthood, and hence could serve as red flags (i.e. alerting signals) for early recognition of adult patients at high risk of PHTS. Phenotypic characteristics including macrocephaly, multinodular goitre (MNG), and oral features were examined in 81 paediatric and 86 adult PHTS patients by one of two medical experts during yearly surveillance visits at our Dutch PHTS expert centre between 1997 and 2020. MNG was defined as signs of thyroid nodules and/or goitre. Oral features included gingival hypertrophy, high palate (adults only) and oral papillomas. Based on the characteristics’ prevalence in different age groups, combinations of phenotypic characteristics were defined and evaluated on their potential to recognize individuals with PHTS. Macrocephaly was present in 100% of paediatric and 67% of adult patients. The prevalence of MNG was ∼50% in paediatric and gradually increased to >90% in adult patients. Similar percentages were observed for any of the oral features. Scoring two out of three of these characteristics yielded a sensitivity of 100% (95%CI 94–100%) in adults. The presence of the combination macrocephaly, MNG, or multiple oral features could serve as a red flag for general practitioners, medical specialists, and dentists to consider further assessment of the diagnosis PHTS in adults. In this way, recognition of adult PHTS patients might be improved and cancer surveillance can be offered timely.     

Broadband Dielectric Relaxation Spectroscopy of Functionalized Biobased Castor Oil Copolymer Thermosets

Novel biorenewable copolymer thermosets are successfully synthesized by the ring‐opening metathesis polymerization (ROMP) of norbornenyl‐functionalized castor oil (NCO) and norbornenyl‐functionalized castor oil alcohol (NCA) with controlled amounts of 0.8 and 1.8 norbornene rings per fatty acid chain, respectively. The NCO and NCA monomers are mixed in different concentrations and simultaneously polymerized via ROMP using Grubbs catalyst. Broadband dielectric relaxation spectroscopy (BDRS) is used to investigate the molecular dynamics of the fully cured copolymer thermosets over a wide range of frequencies (5 × 10^?2 to 0.5 × 10⁷ Hz) at different constant temperatures (?70 to 125 °C). Four phenomena, namely α‐, β‐, and γ‐relaxation processes and ionic conductivity are observed for all the measured samples.

     

胰腺癌干细胞研究进展

胰腺癌干细胞（PCSC）在胰腺癌的发生、发展过程中起着重要作用,且与胰腺癌的耐药、转移机制关系密切。PCSC的表面标志物、分离、鉴定、信号通路、微环境、耐药、转移和靶向治疗等方面的研究,将为临床胰腺癌的治疗提供新的方向。     

颈内动脉中重度狭窄或闭塞患者同侧颈总动脉血流动力学的观察

目的观察颈内动脉(ICA)中、重度狭窄或闭塞患者同侧颈总动脉(CCA)血流动力学的改变,分析CCA血流动力学改变与ICA狭窄程度之间的关系。方法选择单侧ICA颅外段50%～99%狭窄或闭塞,且双侧CCA管径正常或狭窄率<50%的患者200例。按患侧ICA狭窄率将患者分为50%～69%狭窄组(50例)、70%～99%狭窄组(68例)及闭塞组(82例)。采用彩色多普勒超声测量双侧CCA的管径(ID)、收缩期峰值流速(PSV)、舒张末期流速(EDV)、平均流速(MV)及阻力指数(RI)。计算颈动脉血流量(BFV)、患侧的ICA与CCA峰值流速比值(PSVICA/PSVCCA)以及健侧与患侧CCA血流动力学各参数比值。结果①各组内患侧与健侧及各组间患侧CCA的ID比较,差异均无统计学意义。②与健侧比较,50%～69%组除患侧的PSVICA/PSVCCA增高外(1.90±0.36对0.88±0.23,P<0.001),其他参数差异均无统计学意义。③与同组健侧比较及与50%～69%组患侧比较,70%～99%组和闭塞组(闭塞组无PSVICA/PSVCCA)患侧的PSVICA/PSVCCA、RI增高(P<0.001);PSV...     

Numerical Modeling and Analysis of Ti6Al4V Alloy Chip for Biomedical Applications

The influence of cutting forces during the machining of titanium alloys has attained prime attention in selecting the optimal cutting conditions to improve the surface integrity of medical implants and biomedical devices. So far, it has not been easy to explain the chip morphology of Ti6Al4V and the thermo-mechanical interactions involved during the cutting process. This paper investigates the chip configuration of the Ti6Al4V alloy under dry milling conditions at a macro and micro scale by employing the Johnson-Cook material damage model. 2D modeling, numerical milling simulations, and post-processing were conducted using the Abaqus/Explicit commercial software. The uncut chip geometry was modeled with variable thicknesses to accomplish the macro to micro-scale cutting by adapting a trochoidal path. Numerical results, predicted for the cutting reaction forces and shearing zone temperatures, were found in close approximation to experimental ones with minor deviations. Further analyses evaluated the influence of cutting speeds and contact friction coefficients over the chip flow stress, equivalent plastic strain, and chip morphology. The methodology developed can be implemented in resolving the industrial problems in the biomedical sector for predicting the chip morphology of the Ti6Al4V alloy, fracture mechanisms of hard-to-cut materials, and the effects of different cutting parameters on workpiece integrity.     

Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition

Protein conformational diseases exhibit complex pathologies linked to numerous molecular defects. Aggregation of a disease-associated protein causes the misfolding and aggregation of other proteins, but how this interferes with diverse cellular pathways is unclear. Here, we show that aggregation of neurodegenerative disease-related proteins (polyglutamine, huntingtin, ataxin-1, and superoxide dismutase-1) inhibits clathrin-mediated endocytosis (CME) in mammalian cells by aggregate-driven sequestration of the major molecular chaperone heat shock cognate protein 70 (HSC70), which is required to drive multiple steps of CME. CME suppression was also phenocopied by HSC70 RNAi depletion and could be restored by conditionally increasing HSC70 abundance. Aggregation caused dysregulated AMPA receptor internalization and also inhibited CME in primary neurons expressing mutant huntingtin, showing direct relevance of our findings to the pathology in neurodegenerative diseases. We propose that aggregate-associated chaperone competition leads to both gain-of-function and loss-of-function phenotypes as chaperones become functionally depleted from multiple clients, leading to the decline of multiple cellular processes. The inherent properties of chaperones place them at risk, contributing to the complex pathologies of protein conformational diseases.Many neurodegenerative diseases are characterized by protein misfolding and aggregation (1–5). Although the underlying disease origins may be genetically inherited or manifest sporadically, as exemplified by Huntington disease and ALS, respectively, the pathologies of these maladies all share the common molecular occurrence of protein aggregation (6). A network of protein folding and clearance mechanisms (the proteostasis network) is proposed to maintain a healthy proteome for normal cellular function (7, 8). Central to the proteostasis network are molecular chaperones and cochaperones, a diverse group of proteins that modulate the synthesis, folding, transport, and degradation of proteins (7). The conformations of aggregation-prone proteins are subject to multiple layers of regulation by the proteostasis network; however, as evidenced by the widespread pathologies of protein conformational diseases, the aggregation propensity of proteins associated with these diseases ultimately overwhelms the proteostasis machineries, thus initiating a cascade of cellular dysfunction (9–11).It is increasingly common for diseases of protein aggregation to be described as the result of gain-of-function toxicity. This toxicity is largely attributed to the dominant appearance of diverse aggregate species and the subsequent aberrant association of various proteostasis network components and other metastable proteins with these aggregates. This position is supported by experiments using immunohistochemical, biochemical, and MS methods on diseased patient tissues, as well as on numerous cellular and animal model systems (12–16). Some of these molecular interactions, such as those between aggregates and proteasomal subunits, appear irreversible, suggesting a permanent sequestration of these proteins. The association of molecular chaperones with aggregates, on the other hand, appears transient (17, 18), indicating that chaperones may be functionally recognizing aggregates as substrates for potential disaggregation and refolding (19).Beyond refolding of toxic misfolded proteins, chaperones are also essential for the folding of endogenous metastable client proteins, as well as in the assembly and disassembly of functional protein complexes. Thus, chaperones regulate a wide range of essential cellular processes, including gene expression, vesicular trafficking, and signal transduction (20–25). This dual role of chaperones suggests that a “competition” may arise between aggregates and endogenous protein clients for finite chaperone resources in situations where aggregates have accumulated. It has been proposed that such an imbalance may trigger the onset of many neurodegenerative diseases (10, 26), and recent studies report that polyglutamine (polyQ)-based aggregates can sequester and inhibit the function of a low-abundance cochaperone, Sis1p/DNAJB1, in protein degradation (27).Here, we show that diverse disease-associated aggregates sequester the highly abundant major chaperone heat shock cognate protein 70 (HSC70) to the point of functional collapse of an essential cellular process, clathrin-mediated endocytosis (CME). Importantly, aggregate-driven CME inhibition is reversible and can be rescued by nominally increasing HSC70 levels. Aggregate-driven chaperone depletion may help explain the phenotypic complexities displayed in protein conformational diseases.     

MR-DWI与MSCT对原发性腹膜后肿瘤的诊断价值研究

目的分析磁共振扫描弥散成像（magnetic resonance diffusion-weighted imaging,MR-DWI）和多层螺旋CT（multi-slice spiral CT,MSCT）在原发性腹膜后肿瘤（primary retroperitoneal tumor,PRT）中的评估与应用价值。     

Point process modelling of the Afghan War Diary

Modern conflicts are characterized by an ever increasing use of information and sensing technology, resulting in vast amounts of high resolution data. Modelling and prediction of conflict, however, remain challenging tasks due to the heterogeneous and dynamic nature of the data typically available. Here we propose the use of dynamic spatiotemporal modelling tools for the identification of complex underlying processes in conflict, such as diffusion, relocation, heterogeneous escalation, and volatility. Using ideas from statistics, signal processing, and ecology, we provide a predictive framework able to assimilate data and give confidence estimates on the predictions. We demonstrate our methods on the WikiLeaks Afghan War Diary. Our results show that the approach allows deeper insights into conflict dynamics and allows a strikingly statistically accurate forward prediction of armed opposition group activity in 2010, based solely on data from previous years.     

舌鳞状细胞癌中肿瘤干细胞耐药性研究

目的：探讨舌鳞状细胞癌中肿瘤干细胞对化疗的耐受作用。方法：用磁珠分选技术、细胞免疫荧光染色和药物毒性试验等方法,研究经分选后得到的肿瘤干细胞和阴性细胞在化疗药物作用后其细胞增殖活性的差异。结果：细胞免疫荧光结果显示,CD133和CD44在分选出来的CD133^＋／CD44^＋细胞高表达而在CD133^-／CD44^-细胞基本不表达。CCK8实验结果显示分选出来的CD133^＋／CD44^＋细胞较CD133^-／CD44^-细胞在化疗药物作用下有更高的细胞成活率。结论：经磁珠分选出来的舌癌肿瘤干细胞（CD133^＋／CD44^＋细胞）更能耐受化疗药物的作用。