非生长因子依赖的MDS细胞系的建立及其生物学特性研究

本研究的目的是从骨髓增生异常综合征-慢性粒-单核细胞白血病(MDS-CMML)病人获取骨髓细胞,建立 非生长因子依赖的细胞株。该细胞株在不添加任何生长因子的含15％胎牛血清的RPMI 1640和DMEM混合培养 液中进行了培养,并分别从细胞株的形态、细胞表面抗原分子、细胞增殖、分化、凋亡等方面检测其生物学特性。结 果表明:在不添加任何生长因子的培养条件下该细胞株可以长期存活和生长,并能向单核及巨核细胞分化。结论: 成功建立了一株非生长因子依赖的MDS-JSN04(MDS-江苏南京04)细胞株,并阐明了其部分生物学特性。

MDS发病分子机制、预后和表观遗传学治疗进展——第12届骨髓增生异常综合征(MDS)国际研讨会采撷

1MDS基因突变 MDS是一组克隆性造血千细胞疾病，其特征是血细胞减少，髓系细胞一系或多系发育异常（dysplasia），无效造血（ineffective haematopoiesis）及演变为急性髓系白血病（AML）的风险增高。MDS主要病理生理本质是：（1）起源于造血干细胞的克隆性疾病；（2）粒系、

福氏志贺菌mdoC基因对其在洗菜水中生长及生物膜形成的影响

【目的】研究福氏志贺菌mdoC基因对细菌在不同洗菜水中生长及生物膜形成的影响。【方法】以福氏志贺菌野生型和敲除mdoC基因的opgC突变体为出发菌株,采用生长曲线法和结晶紫染色法,在低渗透压及正常渗透压的菠菜、芹菜、生菜及白菜洗菜水中,研究福氏志贺菌野生型和opgC突变体生长及生物膜的产生能力。【结果】在不同洗菜水中,福氏志贺菌opgC突变体生长速率明显较野生型慢,加盐提高渗透压之后,野生型和opgC突变体稳定生长期均提前。野生型和opgC突变体的生物膜产量在菠菜水、生菜水和白菜水中有显著区别;提高渗透压之后,福氏志贺菌野生型在菠菜水中的生物膜产量显著提高,而在生菜水和白菜水中生物膜产量显著下降,opgC突变体在菠菜水、生菜水和白菜水中生物膜产量均显著提高。【结论】低渗条件下,福氏志贺菌mdoC基因的缺失显著地延缓了细菌生长。提高渗透压后,在菠菜、生菜和白菜洗菜水中,mdoC基因的缺失促进了生物膜的形成。

Prevalence of unsuspected thyroid nodules in adults on contrast enhanced 16-and 64-MDCT of the chest

AIM: To determine the prevalence of unsuspected thyroid nodules on contrast enhanced 16and 64-modified discrete cosine transform (MDCT) of the chest, in a population of adult outpatients imaged for indications other than thyroid disease. METHODS: This retrospective study involved review of intravascular contrast-enhanced MDCT scans of the chest from 3077 consecutive adult outpatients, to identify unsuspected thyroid nodules. Exclusion criteria included history of thyroid cancer, known thyroid nodules or thyroid disease and risk factors for thyroid cancer, as evidenced by their medical records. One of 9 radiologists recorded number of nodules, location and bidirectional measurement of largest nodule, as well as amount of thyroid visualized on the chest computed tomography (CT). Presence of nodule was correlated with age, gender, race and percentage of thyroid imaged. RESULTS: A total of 2510 (2510/3077 or 81.6%) study subjects were included in the data analysis; among them,one or more nodules were identified in 629 subjects (629/2510 or 25.1%), with 242 (242/629 or 38.5%) having multiple nodules. Patients with nodule(s) were significantly older than those without (64 ± 13 years vs 58 ± 14 years, P < 0.0001), and female gender was associated with presence of nodule(s) (373/1222 or 30.5% vs 256/1288 or 19.9%, P < 0.0001). Women were also more likely having multiple nodules (167/373 or 44.8%) compared to men (75/256 or 29.3%, P < 0.0001). The majority of nodules (427/629 or 67.9%) were less than 1 cm. CONCLUSION: This retrospective review revealed a prevalence of 25.1% for unsuspected thyroid nodules on contrast-enhanced chest CT.

EEMD and bidimensional RLS to suppress physiological interference for heterogeneous distribution in fNIRS study

Near-infrared spectroscopy(NIRS)can provide the hemodynamics information based on the hemoglobin concentration representing the blood oxygen metabolism of the cerebral cortical,which can be deployed for the cerebral function study.However,NIRS-based cerebral function detection accuracy can be signi¯cantly in°uenced by the physiological activities such as cardic cycle,respiration,spontaneous low-frequency oscillation and ultra-low frequency oscillation.The distribution difference of the capillary,artery and vein leads to the heterogeneity feature of the cerebral tissues.In the case that the heterogeneity is not serious,good detection accuracy and stable performance can be achieved through the regression analysis as the reference signal can well represent the interference in the measurement signal when conducting the multi-distance measurement approach.The direct use of the reference signal to estimate the interference is not able to achieve good performance in the case that the heterogeneity is serious.In this study,the cerebral function activity signal is extracted using recursive least square(RLS)method based on the multi-distance measurement method in which the reference signal is processed by ensemble empirical mode decomposition(EEMD)algorithm.The temporal and dimensional correlation of the neighboring sampling values are applied to estimate the interference in the measurement signal.Monte Carlo simulation based on a heterogeneous model is adopted here to investigate the effectiveness of this methodology.The results show that this methodology can effectively suppress the physiological interference and improve the detection accuracy of cerebral activity signal.

Mdm proteins： critical regulators of embryogenesis and hornoeostasis

Mdm2 and Mdm4 are negative regulators of the tumour suppressor p53; hence, this relationship is the focus of many cancerrelated studies. A multitude of experiments across various developmental stages have been conducted to explore the tissuespecific roles of these proteins in the mouse. When Mdm2 or Mdm4 are deleted in the germiine or specific tissues, they display different phenotypic defects, some of which lead to embryonic lethaLity. Mdm2 loss is often more deleterious than toss of its homotogue Mdm4. ALL tissues experience activation of p53 target genes upon toss of Mdm2 or Mdm4; however, the degree to which the p53 pathway is perturbed is highly tissue-specific and does not correlate to the severity of the morphological pheno- types. Therefore, a need for further understanding of how these proteins regulate p53 activity is warranted, as therapeutic targeting of the p53 pathway is rapidly evoLving and gaining attention in the field of cancer research. In this review, we discuss the tissue-specificity of Mdm proteins in regulating p53 and expose the need for investigation at the celt-specific level.

MDR1基因多态性与儿童难治性癫痫的相关性研究

目的探讨多药耐药基因1(multidrug resistance gene 1,MDR1)单核苷酸多态性与儿童难治性癫痫的相关性.方法2014年12月至2017年3月本院小儿神经门诊就诊的200例癫痫患儿及100名体检正常儿,提取DNA、PCR扩增、琼脂糖凝胶电泳,目标位点测序对rs1922242、rs2235048、rs10808072、rs868755、rs1202184单核苷酸位点进行基因分型.结果耐药组与药物敏感组rs1922242、rs2235048、rs10808072、rs868755位点基因型分布和等位基因频率及rs1202184等位基因频率的差异均无统计学意义,而rs1202184位点基因型分布差异有统计学意义(P=0.008),两组不同单倍型频率差异无统计学意义.结论MDR1基因rs1202184位点基因型与难治性癫痫相关,且以AA基因型为主.

放射外科在MD安德森肿瘤中心的实践及进展

非小细胞肺癌（NSCLC）是我国最常见的恶性肿瘤之一.立体放射外科（SABR）,也称立体定向放疗（SBRT）,是一种无创性治疗,在现代精确的影像引导技术下给予局部肿瘤以高剂量、低分割的放射治疗,可获得超过90％的肿瘤局部控制率,已成为不可切除早期NSCLC的标准治疗,也是可手术早期NSCLC的治疗选择之一.美国德州大学MD安德森肿瘤中心（MDACC）作为全美肿瘤治疗排名第一的机构,对NSCLC的放射治疗进行了一系列颇具影响力的SABR临床试验和研究,促进了SABR在早期和晚期NSCLC中的应用.本文将MDACC对SABR的临床应用、研究结果和进展做一总结.

乳腺大体标本取材：美国MD安德森癌症中心乳腺癌标本取材介绍

随着医学的发展,精准医疗逐渐成为现代医疗的发展方向.为了给患者制定有效的个体化治疗方案,临床医师对病理诊断的精准性提出了更高的要求.规范化的取材是精准病理诊断的基础,也是精准治疗的前提[1].近几年来,随着乳腺B超引导下粗针穿刺活检已经逐渐取代手术活检,多数患者在手术切除时已经有了明确诊断.为了更精准测量肿瘤的位置,客观地评判手术范围,准确地评估肿瘤分期和治疗反应,乳腺标本的大体取材受到临床与病理的共同重视,取材方法也在逐渐改进[1-5].准确的大体检查往往依赖于病理医师、放射医师及外科医师的合作.我们旨在介绍乳腺癌手术切除标本和前哨淋巴结的大体取材方法,其主要内容来自于美国MD安德森癌症中心（MD Anderson Cancer Center,MDACC） 行之有效的多年实践.

Comparison of Optical Transport Schemes for LMDS with Optical Fiber Backbone

We investigate and compare the performance of four optical transport schemes for distributing Local Multipoint Distribution Service (LMDS) signals using an optical fiber backbone.

Design of ultrahigh-affinity and dual-specificity peptide antagonists of MDM2 and MDMX for P53 activation and tumor suppression

Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53 in vitro and in vivo,representing a viable therapeutic strategy for cancer treatment.Using phage display techniques,we previously identified a potent peptide activator of P53,termed PMI(TSFAEYWNLLSP),with binding affinities for both MDM2 and MDMX in the low nanomolar concentration range.Here we report an ultrahigh affinity,dual-specificity peptide antagonist of MDM2 and MDMX obtained through systematic mutational analysis and additivitybased molecular design.Functional assays of over 100 peptide analogs of PMI using surface plasmon resonance and fluorescence polarization techniques yielded a dodecameric peptide termed PMI-M3(LTFLEYWAQLMQ)that bound to MDM2 and MDMX with K_(d)values in the low picomolar concentration range as verified by isothermal titration calorimetry.Co-crystal structures of MDM2 and of MDMX in complex with PMI-M3 were solved at 1.65 and 3.0 A resolution,respectively.Similar to PMI,PMI-M3 occupied the P53-binding pocket of MDM2/MDMX,which was dominated energetically by intermolecular interactions involving Phe3,Tyr6,Trp7,and Leu 10.Notable differences in binding between PMI-M3 and PMI were observed at other positions such as Leu4 and Met11 with MDM2,and Leu1 and Met11 with MDMX,collectively contributing to a significantly enhanced binding affinity of PMI-M3 for both proteins.By adding lysine residues to both ends of PMI and PMI-M3 to improve their cellular uptake,we obtained modified peptides termed PMI-2K(KTSFAEYWNLLSPK)and M3-2K(KLTFLEYWAQLMQK).Compared with PMI-2K,M3-2K exhibited significantly improved antitumor activities in vitro and in vivo in a P53-dependent manner.This super-strong peptide inhibitor of the P53-MDM2/MDMX interactions may become,in its own right,a powerful lead compound for anticancer drug development,and can aid molecular design of other classes of P53 activators as well for anticancer therapy.

Sex-dependent alterations in extracellular vesicles linking chronic spinal cord injury to brain neuroinflammation and neurodegeneration

Traumatic spinal cord injury(SCI)is a devastating exogenous injury with long-lasting consequences and a leading cause of death and disability worldwide.Advances in assistive technology,rehabilitative interventions,and the ability to identify and intervene in secondary conditions have significantly increased the long-term survival rate of SCI patients,with some people even living well into their seventh or eighth decade.These survival changes have led neurotrauma researchers to examine how SCI interacts with brain aging.Public health and epidemiological data showed that patients with long-term SCI can have a lower life expectancy and quality of life,along with a higher risk of comorbidities and complications.

New glucocerebrosidase antibodies can advance research in the field of neurodegenerative disorders

In medical research,there are times when the introduction of a new tool can launch scientific discovery in new directions.While antibody development may be considered mundane,in the field of glucocerebrosidase(GCase)research,the dearth of validated antibodies for different applications has impeded progress in studies of disease pathogenesis and therapeutic development.The recent introduction of new,rigorously evaluated antibodies can now propel research into the link between glucocerebrosidase and Parkinson’s disease(PD)as well as aspects of the pathobiology of Gaucher disease(Jong et al.,2024).

Compartmentalized regulation of organelle integrity in neurodegenerative diseases:lessons from the Drosophila motor neuron

Neurons are highly polarized,morphologically asymmetric,and functionally compartmentalized cells that contain long axons extending from the cell body.For this reason,their maintenance relies on spatiotemporal regulation of organelle distribution between the somatodendritic and axonal domains.Although some organelles,such as mitochondria and smooth endoplasmic reticulum,are widely distributed throughout the neuron,others are segregated to either the somatodendritic or axonal compartment.For example,Golgi outposts and acidified lysosomes are predominantly present in the somatodendritic domain and rarely distributed along the axon,whereas newly formed autophagosomes and synaptic vesicles are mainly distributed in the distal axon(Britt et al.,2016).

TARC和MDC在日本血吸虫感染小鼠Th2应答及肝纤维化中的作用

目的探讨胸腺活化调节趋化因子（ thymus activation regulated chemokine, TARC）和巨噬细胞来源的趋化因子（ macrophage-derived chemokine, MDC）对日本血吸虫感染宿主Th2应答及肝脏纤维化的影响。方法建立日本血吸虫感染小鼠模型，取肠系膜淋巴结及肝脏，胞内细胞因子染色法和ELISA法检测Th2应答；实时荧光定量RT—PCR法检测TARC和MDC的mRNA表达；通过测定肝脏羟脯氨酸含量以反映其纤维化水平。结果宿主肝脏Th2应答趋势与肠系膜淋巴结一致，但感染7周时肝脏局部浸润T细胞中IL-13＋Th2约为5．3％，高于肠系膜淋巴结T细胞中IL-13＋Th2水平（3％）；肝脏羟脯氨酸含量在感染第5、7、10周分别为2．9μg／mg、5．1μg／mg和8．3μg／mg，随感染进程呈进行性加剧。感染第7周时宿主肠系膜淋巴结中的TARC和MDC的表达分别为对照组的0．5倍和0．4倍，而此时宿主肝脏中TARC和MDC的表达则显著增高，分别为对照组的12．8倍和8．2倍，并且在感染进入慢性期时仍维持较高水平，分别为对照组的3．8倍和4．4倍。结论血吸虫感染刺激宿主肝脏产生Th2类趋化因子TARC和MDC，促进Th2从外周淋巴器官向肝脏局部募集从而参与肝脏病理变化。

Emerging role of A-kinase anchoring protein 5 signaling in reward circuit function

There is a strong evidence supporting the hypothesis of synaptic dysfunction as a major contributor to neural circuit and network disruption underlying emotional and mood dysregulation in psychiatric disorders(Simmons et al.,2024).Diverse sets of distinct molecular signaling pathways converge on the synapse to regulate synaptogenesis,synaptic function,and synaptic plasticity in brain regions and circuits through complex interactions organized by numerous multivalent protein scaffolds,including the family of proteins known as A-kinase anchoring proteins(AKAPs).

Amyloid-beta pathology-induced nanoscale synaptic disruption:the case of the GABA_B-GIRK assembly

Alzheimer's disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks,leading to aberrant homeostatic synaptic plasticity.AD has progressively been recognized as syna ptopathy and syna ptic dysfunction has been identified as a key component of its pathogenesis (Schirinzi et al.,2020).Syna ptic dysfunction is believed to precede synapse loss,a primary biological correlate of cognitive decline in AD,inevita bly associated with neuronal death.

以甲基转移酶抑制剂为基础联合治疗中高危MDS/AML研究现状

甲基转移酶(DNMT)抑制剂通过表观遗传学调控发挥治疗作用。由于DNMT抑制剂单药治疗骨髓增生异常综合征(MDS)疗效的局限性,以DNMT抑制剂为基础的联合治疗不断被研究和试用于临床。临床试验表明,DNMTs与靶向药物如组蛋白乙酰化酶抑制剂、免疫调节剂来那度胺等的联合在治疗MDS和部分急性髓系白血病(AML)疗效优于单药治疗。而近年来与传统化疗药物的联合在中高危MDS及AML的疗效也初露端倪。但对于高危MDS及难治AML,以DNMT抑制剂为基础的联合治疗方案仍有许多问题需要进一步探索和研究。

Aryl hydrocarbon receptor signaling promotes ORMDL3- dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase

Aryl hydrocarbon receptor(AhR),a cellular chemical sensor,controls cellular homeostasis,and sphingosine-1-phosphate(S1P),a bioactive intermediate of sphingolipid metabolism,is believed to have a role in immunity and inflammation,but their potential crosstalk is currently unknown.We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism.We showed that AhR ligands,including an environmental polycyclic aromatic hydrocarbon(PAH),induced S1P generation,and inhibited S1P lyase(S1PL)activity in resting cells,antigen/IgE-activated mast cells,and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge.The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317,which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein,whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect.Furthermore,analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3–S1PL complex,which was confirmed by FRET analysis.This change increased the S1P levels,which in turn,induced mast cell degranulation via S1PR2 signaling.In addition,elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects.These results suggest a new regulatory pathway whereby the AhR–ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL,which may contribute to the expression of allergic diseases.

Loss of ID3 in pancreatic cancer cells increases DNA damage without impairingMDC1 recruitment to the nuclear foci

Dear Editor,Pancreatic cancer is one of the most aggressive human cancers and is predicted to become the second leading cause of cancer-related death by the year 2030[1,2].In the United States,approximately 60,000 newly diagnosed cases and 48,000 deaths were estimated to occur in 2021[3].Because early screening is very difficult and most patients are diagnosed with advanced disease,curing pancreatic cancer patients still faces huge challenges.Accordingly,a comprehensive understanding of the pathogenesis of pan-creatic cancer is required to promote the development of efficient treatment modalities.