MATHEMATICAL MODELING AND BIFURCATION ANALYSIS FOR A BIOLOGICAL MECHANISM OF CANCER DRUG RESISTANCE

Drug resistance is one of the most intractable issues in targeted therapy for cancer diseases.It has also been demonstrated to be related to cancer heterogeneity,which promotes the emergence of treatment-refractory cancer cell populations.Focusing on how cancer cells develop resistance during the encounter with targeted drugs and the immune system,we propose a mathematical model for studying the dynamics of drug resistance in a conjoint heterogeneous tumor-immune setting.We analyze the local geometric properties of the equilibria of the model.Numerical simulations show that the selectively targeted removal of sensitive cancer cells may cause the initially heterogeneous population to become a more resistant population.Moreover,the decline of immune recruitment is a stronger determinant of cancer escape from immune surveillance or targeted therapy than the decay in immune predation strength.Sensitivity analysis of model parameters provides insight into the roles of the immune system combined with targeted therapy in determining treatment outcomes.

Single-cell RNA-seq reveals the immune escape and drug resistance mechanisms of mantle cell lymphoma

Objective:Mantle cell lymphoma(MCL)is a rare subtype of non-Hodgkin lymphoma(NHL)with high heterogeneity and a high recurrence rate.How heterogenous cell populations contribute to relapse remains to be elucidated.Methods:We performed single cell RNA sequencing(scRNA-seq)on approximately 4,000 bone marrow cells sampled from one patient with multidrug resistant MCL.We identified 10 subpopulations comprising 4 malignant B cell subtypes,3 T cell subtypes,2 dendritic cell subtypes and 1 natural killer(NK)cell subtype.Subsequently,we identified cell markers,including a series of genes associated with immune escape and drug resistance.In addition,we explored the roles of these genes in the mechanism of immune escape and drug resistance,and we verified the expression imbalance and clinical prognostic potential by using GEO datasets including 211 MCL samples.Results:The major immune escape mechanisms of MCL included anti-perforin activity,decreased immunogenicity and direct inhibition of apoptosis and cell killing,as mediated by type I and II B cells.The drug resistance mechanisms of different cell clusters included drug metabolism,DNA damage repair,apoptosis and survival promotion.Type III B cells closely communicate with other cells.The key genes involved in the resistance mechanisms showed dysregulated expression and may have significant clinical prognostic value.Conclusion:This study investigated potential immune escape and drug resistance mechanisms in MCL.The results may guide individualized treatment and promote the development of therapeutic drugs.

Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly(ADP-ribose)polymerase inhibitors(PARPi).Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations,which restore the open-reading frame of the affected allele.This platinum/PARPi crossresistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies.There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance;however,their actual clinical relevance remains to be established.In addition,studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells.These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure,but become outcompeted by BRCA1-deficient cells during therapy holidays.Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches,which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.

Cancer cell cycle heterogeneity as a critical determinant of therapeutic resistance

Intra-tumor heterogeneity is now arguably one of the most-studied topics in tumor biology,as it represents a major obstacle to effective cancer treatment.Since tumor cells are highly diverse at genetic,epigenetic,and phenotypic levels,intra-tumor heterogeneity can be assumed as an important contributing factor to the nullification of chemotherapeutic effects,and recurrence of the tumor.Based on the role of heterogeneous subpopulations of cancer cells with varying cell-cycle dynamics and behavior during cancer progression and treatment;herein,we aim to establish a comprehensive definition for adaptation of neoplastic cells against therapy.We discuss two parallel and yet distinct subpopulations of tumor cells that play pivotal roles in reducing the effects of chemotherapy:"resistant"and"tolerant"popula-tions.Furthermore,this review also highlights the impact of the quiescent phase of the cell cycle as a survival mechanism for cancer cells.Beyond understanding the mechanisms under-lying the quiescence,it provides an insightful perspective on cancer stem cells(CsCs)and their dual and intertwined functions based on their cell cycle state in response to treatment.More-over,CSCs,epithelial-mesenchymal transformed cells,circulating tumor cells(CTCs),and disseminated tumor cells(DTCs),which are mostly in a quiescent state of the cell cycle are proved to have multiple biological links and can be implicated in our viewpoint of cell cycle heterogeneity in tumors.Overall,increasing our knowledge of cell cycle heterogeneity is a key to identifying new therapeutic solutions,and this emerging concept may provide us with new opportunities to prevent the dreadful cancer recurrence.

Investigation of fractured rock aquifer in South China using electrical resistivity tomography and self-potential methods

Assessment of fractured rock aquifers in many parts of the world is complicated given their strong heterogeneity. Delineation of the subsurface geological formation in the weathered terrain is essential for groundwater exploration. To achieve this goal, 2D electrical resistivity tomography(ERT) and self-potential(SP) in combination with joint profile method(JPM) and boreholes have been carried out to delineate the subsurface geological units, detect the fracture/fault zones in hard rock, monitor the groundwater flow, and estimate the groundwater reserves contained within the weathered terrain at a complex heterogeneous site of Huangbu, South Guangdong of China. The integration of resistivity images with the borehole lithology along three profiles delineates three subsurface distinct layers namely topsoil cover, weathered and unweathered layers. The incorporation of ERT and SP with JPM reveal five fractures/faults, i.e., F_1, F_2, F_3, F_4 and F_5. 2D ERT models interpret the less resistive anomalies as the fractures/faults zones, and high resistive anomalies as the fresh bedrock. The inversion program based on the smoothness-constraint is used on the resistivity field data to get more realistic three layered model. SP measurements are obtained along the same electrical profiles which provide the negative anomalies clearly indicating the groundwater preferential flow pathways along the fracture/fault zones. Hydraulic parameters namely hydraulic conductivity and transmissivity were determined to estimate the groundwater resources contained within the fractures/faults. The integrated results suggest that the fractures/faults zones are most appropriate places of drilling for groundwater exploration in the investigated area. Geophysical methods coupled with the upfront borehole data provides better understanding about the conceptual model of the subsurface geological formations. The current investigation demonstrates the importance of the integrated geophysical methods as a complementary approach for groundwater assessment in the hard rock weathered areas.

Role of chromosomal instability and clonal heterogeneity in the therapy response of breast cancer cell lines

Objective:Chromosomal instability(CIN)is a hallmark of cancer characterized by cell-to-cell variability in the number or structure of chromosomes,frequently observed in cancer cell populations and is associated with poor prognosis,metastasis,and therapeutic resistance.Breast cancer(BC)is characterized by unstable karyotypes and recent reports have indicated that CIN may influence the response of BC to chemotherapy regimens.However,paradoxical associations between extreme CIN and improved outcome have been observed.Methods:This study aimed to 1)evaluate CIN levels and clonal heterogeneity(CH)in MCF7,ZR-751,MDA-MB468,BT474,and KPL4 BC cells treated with low doses of tamoxifen(TAM),docetaxel(DOC),doxorubicin(DOX),Herceptin(HT),and combined treatments(TAM/DOC,TAM/DOX,TAM/HT,HT/DOC,and HT/DOX)by using fluorescence in situ hybridization(FISH),and 2)examine the association with response to treatments by comparing FISH results with cell proliferation.Results:Intermediate CIN was linked to drug sensitivity according to three characteristics:estrogen receptorα(ERα)and HER2 status,pre-existing CIN level in cancer cells,and the CIN induced by the treatments.ERα+/HER2-cells with intermediate CIN were sensitive to treatment with taxanes(DOC)and anthracyclines(DOX),while ERα-/HER2-,ERα+/HER2+,and ERα-/HER2+cells with intermediate CIN were resistant to these treatments.Conclusions:A greater understanding of CIN and CH in BC could assist in the optimization of existing therapeutic regimens and/or in supporting new strategies to improve cancer outcomes.

Graphite Surface Modification by Heterogeneous Nucleation Process

Flaky graphite particles were coated by ZrOCl2 · 8H2O as precursors by heterogeneous nucleation process. The effects of factors such as pH values （ 2. 4 - 5. 1 ）, concentration of the precursor solution （ 0. 005 - 0. 1 mol · L^-1） , mixing method of graphite and precursor solution on the surface modification of graphite were studied. Result shows that ：1 ） the preferable technical process for heterogeneous nucleation modified graphite is to mix the graphite suspension and precursor solution with concentration 0. 025 mol ·L^-1 and then drip ammonia water to adjust the pH value to 3.6 ; 2 ） By surface modification, the ZrO2 particles are evenly coated on graphite surface and therefore improve oxidation resistance and dispersion ability of graphite.

Heterogeneity of Heterotrophic Bacteria Dominating in Brackish Lake Shira (Republic of Khakasia, Russia) Subjected to Anthropogenic Impact

In this work data on heterogeneity in halotolerance and the resistance to antibiotics of heterotrophic bacteria dominating in Lake Shira (Republic of Khakasia, Russia) were presented. It was established that halotoler-ance of the bacteria is determined by genetic and epigenetic mechanisms. Influence of anthropogenic factor (entering the ecosystem allochthonous bacteria) on the appearance of multiple antibiotic resistance appear-ance by dominating bacterial species is discussed.

文过饰非:股权质押与MD&A文本信息粉饰——基于机器学习文本分析方法的实证研究

文章基于2013—2021年我国A股上市公司数据,研究控股股东股权质押对管理层讨论与分析(MD&A)文本信息粉饰的影响,并分析机构投资者异质性对二者关系的调节作用。研究发现:控股股东在进行股权质押后,会策略性地粉饰MD&A文本信息;压力抵制型机构投资者对股权质押与MD&A文本信息粉饰之间的关系发挥负向调节作用,压力敏感型机构投资者未发挥调节作用;进一步分析发现,在融资约束程度高、企业声誉差、信息不对称程度高的企业中,控股股东粉饰MD&A文本信息的动机更强,压力抵制型机构投资者的监督作用也更强。对此,今后应加强对控股股东的监管,制定年报文本信息披露细则,优化机构投资者结构,促进我国资本市场良性发展。

异时性多复发灶耐药基因分子异质性的胃肠道间质瘤1例报告及文献复习

目的:分析1例长期伊马替尼治疗后多部位、异时性复发病灶敏感/耐药共存的少见胃肠道间质瘤(GISTs)患者的临床资料,揭示GISTs继发突变的异质性是复发耐药过程中的重要属性。方法:收集1例复发GISTs患者的临床资料,采用HE染色法进行组织学观察,免疫组织化学染色检测相关蛋白表达,一代和二代测序技术分析肿瘤基因变异情况。结果:患者,男性,66岁,因胃间质瘤行胃部分切除术。一代测序技术检测结果显示为原癌基因,受体酪氨酸激酶(KIT)基因11号外显子缺失突变(p.551-554del)。伊马替尼治疗1年左右,停药4个月后复发,患者出现脾区病灶,继续采用伊马替尼一线治疗,脾区病灶得到控制。59个月后盆腔发现新病灶,采用伊马替尼加量(600 mg·d^(-1))并舒尼替尼二线治疗,治疗2个月后CT检查结果显示患者脾区病灶大小趋于稳定,而盆腔新病灶体积持续增大。二代测序技术检测结果显示两复发灶在原有KIT基因11号外显子缺失突变的基础上,分别继发KIT基因13号外显子(p.V654A)和17号外显子(p.Y823D)突变。结论:GISTs在靶向药物选择作用的压力下,肿瘤生物学行为表现出复杂性,即时间异质性、空间异型性和分子异质性,不同复发灶可以出现不同的耐药机制。

深层页岩油气用抗非均质载荷套管开发和性能评价

针对深层页岩油和页岩气开采特点及服役条件,开发出BG125HC高强度抗非均质载荷套管,并对其力学性能进行了测试。结果表明,BG125HC高强度抗非均质载荷套管冲击功不小于名义屈服强度值的10%(Akv≥YS_(min)/10),150℃下屈服强度降低5.9%;压溃强度超出API标准要求37%;抗剪切变形能力较Q125钢级套管提高17%。BG125HC高强度抗非均质载荷套管适用于深层页岩油和页岩气资源规模开发。

卵巢高级别浆液性癌肿瘤异质性的研究进展

肿瘤异质性是近年来恶性肿瘤研究中的热点话题,为解决肿瘤转移、复发和耐药带来新的思考。肿瘤的连续动态演化和时空进展导致瘤体内部及不同瘤灶之间的细胞与基因变异呈现出高度异质性,为实现肿瘤精准诊治带来挑战。卵巢癌是死亡率最高的妇科恶性肿瘤,其中最常见的亚型为高级别浆液性癌,其异质性极高,表现为分子、细胞和解剖水平上存在时空变化,这一特点直接影响患者对手术和/或全身治疗的反应,最终影响预后。因此,本综述讨论了卵巢高级别浆液性癌中肿瘤异质性的研究进展,以期为临床治疗决策提供一些参考。

Unlocking wear resistance in an ultrastrong dual-phase highentropy alloy by interface-constrained deformation of brittle Laves phases

The pronounced brittleness of hard Laves phase intermetallics is detrimental to their tribological properties at room temperature.In this study,we utilized a heterogeneous structure to engineer an ultrastrong dual-phase(Laves+B2)AlCoFeNiNb high-entropy alloy that exhibits a low wear rate(3.82×10-6 mm3/(N·m))at room temperature.This wear resistance in the ball-on-disc sliding friction test with the counterpart of Al2O3 balls stems from the activated deformation ability in the ultrafine Laves lamellae under heterogeneous interface constraints.Furthermore,as tribological stress intensifies,the surface deformation mechanism transitions from dislocation slip on the basal and pyramidal planes to a unique combination of local shear and grain rotation within the Laves phase.Our study illuminates fresh perspectives for mitigating the embrittling effect of Laves phase intermetallics under tribological loading and for the development of wear-resistant materials.

ecDNA在小细胞肺癌致癌相关性、异质性和耐药性的机制研究进展

随着染色体外DNA(extrachromosomal DNA,ecDNA)研究的深入,研究发现ecDNA大多只存在于肿瘤细胞内,并且在肿瘤异质性和耐药中起着关键作用。ecDNA存在于多种恶性肿瘤中,但在正常细胞中极少出现。因为ecDNA具有强大的癌基因扩增和动态改变能力,故肿瘤细胞中含有ecDNA的患者临床预后更差。目前的研究已经证实小细胞肺癌(small cell lung cancer,SCLC)患者癌细胞中存在ecDNA。本文综述了ecDNA的形成机制并以此为基础讨论了ecDNA在癌细胞中扩增的过程,其促进肿瘤生长,复发和转移的机制以及ecDNA与SCLC高耐药性的关系。最后本文总结了ecDNA富集的SCLC的治疗方向,为未来进一步的研究提供一定指导。

肿瘤可塑性与药物治疗抵抗

药物治疗抵抗在临床实践中成为肿瘤治疗失败的主因。最近的研究指出,肿瘤细胞的耐药性可能源于其内部高度的细胞异质性,而这种异质性的基础则是肿瘤可塑性。肿瘤细胞可塑性可能引发一系列反应,包括对治疗的耐药性发展、免疫系统逃逸以及对周围组织和血管系统的侵袭和转移等。本文简要介绍肿瘤细胞可塑性的表现形式以及其在药物治疗抵抗的非遗传适应性机制与靶向治疗新策略。

泌尿系感染中头孢曲松异质性耐药大肠埃希菌的耐药性分析

目的探讨泌尿系感染中头孢曲松异质性耐药大肠埃希菌的耐药性分析。方法收集2022年1月至2022年12月间临床尿液培养中分离的非重复大肠埃希菌106株,采用KB法初筛,群体谱分析确证。将研究对象分头孢曲松敏感组(CRO-S)、头孢曲松异质性耐药组(CRO-HR)以及头孢曲松耐药组(CRO-R),用WHONET 5.6软件对3组菌株的常规药敏数据进行分析。结果在106株大肠埃希菌中,3组的构成分别比为分别为49.1%(52/106)、16.0%(17/106)和34.9%(37/106)。耐药性分析中,产超广谱β内酰胺酶与对头孢呋辛、头孢吡肟的耐药率是均表现为CRO-S<CRO-HR<CRO-R(P<0.05)。结论本院尿液培养分离的大肠埃希菌中存在对头孢曲松异质性耐药现象,而头孢曲松敏感、异质性耐药以及耐药三种分组间的耐药率有一定差异。应采取有针对性的防控措施,科学合理选用抗菌药物,防控异质性耐药大肠埃希菌的感染和传播。

异质梯度结构对高铁钢轨材料耐磨性的影响

随着客运铁路运输朝着高速化的方向发展,轮轨之间剧烈的磨损会严重制约列车运行的安全性,因此需要提高钢轨材料的表面耐磨性能。基于此,采用表面机械研磨处理(Surface mechanical attrition treatment,SMAT)技术对U71Mn钢轨材料表面进行改性处理,利用扫描电镜、透射电镜、X射线衍射仪和微米划痕仪等表征了其表层异质梯度结构(HGS)的组织演变、力学性能和耐磨性。结果表明:经过表面改性处理后,U71Mn钢轨材料表层形成了约130μm厚的异质梯度结构;越靠近表层,材料的变形程度越大,珠光体内的片状渗碳体发生断裂和溶解,呈短条形或颗粒状,铁素体被挤压成细长的塑性流线,并出现亚晶粒。随着距离表面深度的增加,变形程度减弱,渗碳体片层不规则弯曲起皱,部分渗碳体碎裂。SMAT技术可以大幅提高U71Mn钢轨材料的耐磨性能,其磨损率较原始材料下降了89%。越靠近表面,U71Mn钢轨材料的硬度和断裂韧性越高,相较于基体分别提高了34.6%和30.5%。SMAT后钢轨材料的晶粒出现细化,位错大量增殖,因此具有异质梯度结构的U71Mn钢轨材料力学性能及耐磨性提高的主要原因是细晶强化和位错强化。

万古霉素异质性耐药葡萄球菌的分离及其药物敏感性分析

目的 调查葡萄球菌对万古霉素异质性耐药亚群发生频率以及对常见抗生素的药物敏感性。方法 利用菌群分析法筛选万古霉素异质性耐药葡萄球菌亚群 ,Microscan Microbiology System对萄萄球菌分型和鉴定并分析对 19种常用抗生素的药物敏感性。结果 115株耐甲氧西林的葡萄球菌 ,9株对万古霉素耐药亚群的 MIC8～ 12 mg/ L,其发生频率为 10 - 4～ 10 - 7,其中 3株金葡球菌 ,6株溶血性葡萄球菌。传至 7代后万古霉素 MIC6 4 mg/ L。对 19种抗生素药敏显示 ,万古霉素敏感 2株、中介 7株 ,敏感率 2 2 .2 % ;利福平敏感7株 (MIC≤ 1mg/ L)、中介 1株 (MIC=2 mg/ L)及耐药 1株 (MIC>2 mg/ L)、敏感率 77.8% ;SMZ/ TMP敏感 6株 (MIC≤ 2 / 38mg/ L)、耐药 3株 (MIC>2 / 38mg/ L) ,敏感率 6 6 .7% ;克林霉素敏感 3株 (MIC=0 .5或≤ 0 .2 5 )、耐药 6株 (MIC>2 mg/ L) ,敏感率 33.3% ;四环素敏感 3株 (MIC≤ 2 mg/ L)、耐药 6株 (MIC>8mg/L) ,敏感率 33.3% ;左氧氟沙星敏感 1株 (MIC≤ 2 mg/ L)、耐药 8株 (MIC>4 mg/ L) ,敏感率 11.1%。其余 13种抗生素耐药。结论 下呼吸道分离的葡萄球菌存在一定频率的对万古霉素异质性耐药株 ,可能是万古霉素治疗失败的原因之一 ,利福平、SMZ/ TMP具有较好的敏感性 。

基于电阻率测井的天然气水合物饱和度估算及估算精度分析

利用电阻率测井基于阿尔奇公式能够估算孔隙空间中天然气水合物饱和度。基于神狐海域的水合物钻井(SH2站位)资料,利用密度反演的地层孔隙度与地层因子交会图,计算出估算水合物饱和度的阿尔奇常数。假定地层中水合物呈均匀分布,利用电阻率资料计算的该站位水合物饱和度平均为24%,最高达44%,水合物饱和度在垂向上具有明显的不均匀性;利用孔隙水氯离子异常估算的SH2站位水合物饱和度平均值为25%,最高值达48%,厚度为25 m。这两种方法估算的水合物饱和度基本吻合,利用电阻率资料计算的饱和度与阿尔奇常数和饱和度指数及孔隙度有关。

异质性利奈唑胺耐药金黄色葡萄球菌耐药机制研究

目的筛选异质性利奈唑胺耐药金黄色葡萄球菌(heterogeneous linezolid resistant Staphylococcus aureus,hLRSA)并对其耐药机制进行分析。方法采用菌谱分析法筛选hLRSA,琼脂稀释法和E-test法检测MIC值,PCR方法扩增介导利奈唑胺耐药葡萄球菌耐药的cfr基因,同时扩增hLRSA 23S RNA基因并测序,并登陆GenBank,与基因库中金葡菌ATCC29213 23S RNA基因比对。结果 hLRSA检出率为1.26%(2/158);琼脂稀释法和E-test法检测异质性耐药菌株MIC结果基本一致;PCR方法没有检出cfr基因,2株hLRSA 23S RNA基因扩增后测序,与金黄色葡萄球菌23S RNA基因一致性大于99%,其中1株hLRSA 23S RNA基因序列在2474位点出现"G"→"T"点突变,可能与介导hLRSA耐药性有关。结论利奈唑胺在体外对金黄色葡萄球菌具有较强抗菌活性,没有检出利奈唑胺中介或耐药葡萄球菌,hLRSA检出率为1.26%,耐药性可能与其23S RNA发生的点突变有关。