Animal models of tendon calcification:Past,present,and future

Tendon calcification is a common clinical condition that frequently occurs as a complication after tendon injury and surgery,or as an expression of fibrodysplasia ossificans progressiva.This condition can be referred to by various names in clinical practice and literature,including tendon ossification,tendon mineralization,heterotopic ossification,and calcific tendonitis.The exact pathogenesis of tendon calcification remains uncertain,but current mainstream research suggests that calcification is mostly cell mediated.To further elucidate the pathogenesis of tendon calcification and to better simulate the overall process,selecting appropriate experimental animal models is important.Numerous animal models have been utilized in various clinical studies,each with its own set of advantages and limitations.In this review,we have discussed the advancements made in research on animal models of tendon calcification,with a focus on the selection of experimental animals,the sites of injury in these models,and the methods employed for modeling.

外周血检测指标联合TCF1^(+)CD8^(+)T淋巴细胞占比预测中晚期肺癌免疫治疗疗效及预后的临床队列研究

背景与目的免疫检查点抑制剂治疗目前缺乏可用于预测疗效的生物标志物,本研究旨在探讨外周血实验室检查指标联合淋巴细胞亚群分布与中晚期肺癌免疫治疗疗效及预后的相关性。方法前瞻性纳入2021年5月至2023年7月四川大学华西医院接受一线免疫治疗的中晚期肺癌患者,收集患者临床信息,同时采用流式细胞术检测患者治疗前后外周血淋巴细胞亚群。分别采用Logistic回归分析和Cox模型探究疗效和预后的影响因素。结果Logistic回归表明基线转录因子T细胞因子1(transcription factor T cell factor 1,TCF1)^(+)CD8^(+)T细胞占比及治疗1个周期后外周血白细胞计数、淋巴细胞百分比、细胞角蛋白19片段(cytokeratin 19 fragment,CYFRA21-1)水平、中性粒细胞淋巴细胞比率(neutrophil-lymphocyte ratio,NLR)是疗效的影响因素(P<0.05)。Cox回归分析显示基线TCF1^(+)CD8^(+)T细胞占比(P=0.020)、治疗1个周期后外周血白细胞计数(P<0.001)是预后的影响因素。结论基线高水平TCF1^(+)CD8^(+)T细胞占比和治疗1个周期后低水平白细胞计数和CYFRA21-1可能是患者从免疫治疗中获益的有利因素。

Long-term potentiation-based screening identifies neuronal PYGM as a synaptic plasticity regulator participating in Alzheimer's disease

Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer's disease(AD).High-frequency stimulation(HFS)-induced long-term potentiation(LTP)has been widely used to study synaptic plasticity,with impaired LTP found to be associated with AD.However,the exact molecular mechanism underlying synaptic plasticity has yet to be completely elucidated.Whether genes regulating synaptic plasticity are altered in AD and contribute to disease onset also remains unclear.Herein,we induced LTP in the hippocampal CA1 region of wildtype(WT)and AD model mice by administering HFS to the CA3 region and then studied transcriptome changes in the CA1 region.We identified 89 genes that may participate in normal synaptic plasticity by screening HFS-induced differentially expressed genes(DEGs)in mice with normal LTP,and 43 genes that may contribute to synaptic dysfunction in AD by comparing HFS-induced DEGs in mice with normal LTP and AD mice with impaired LTP.We further refined the 43 genes down to 14 by screening for genes with altered expression in pathological-stage AD mice without HFS induction.Among them,we found that the expression of Pygm,which catabolizes glycogen,was also decreased in AD patients.We further demonstrated that down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice,while its overexpression attenuated synaptic dysfunction and cognitive deficits in AD mice.Moreover,we showed that PYGM directly regulated energy generation in neurons.Our study not only indicates that PYGM-mediated energy production in neurons plays an important role in synaptic function,but also provides a novel LTP-based strategy to systematically identify genes regulating synaptic plasticity under physiological and pathological conditions.

屈光参差性弱视儿童双眼与正常眼SD-OCT参数的比较

目的:比较单眼屈光参差性弱视儿童双眼与正常眼黄斑区视网膜厚度及视盘周围视网膜神经纤维层(RNFL)厚度的差异。方法:选取2021-01/2022-10于成都市妇女儿童中心医院就诊的单眼屈光参差性弱视儿童62例124眼作为试验组,另选取同时间段就诊的正常视力儿童60例60眼(右眼)作为对照组。采用频域光学相干断层成像(SD-OCT)检测两组儿童黄斑区视网膜厚度及视盘周围RNFL厚度,并进行对比分析。结果:试验组儿童弱视眼黄斑区视网膜厚度和视盘周围RNFL厚度均厚于对照组,且多数具有显著差异性(P<0.05)。试验组儿童对侧非弱视眼黄斑区视网膜厚度和视盘周围RNFL厚度多较对照组变薄,但多数无显著差异(P>0.05)。结论:单眼屈光参差性弱视儿童弱视眼和对侧非弱视眼黄斑区视网膜厚度及视盘周围RNFL厚度与正常眼存在一定差异性,且对侧非弱视眼并不能完全等同于正常眼。

Large area^(3)He tube array detector with modular design for multi‑physics instrument at CSNS

The multi-physics instrument(MPI)is the first user cooperative instrument at the China Spallation Neutron Source(CSNS).It was designed to explore the structures of complex materials at multiple scales based on the neutron total scattering technique.This imposes the requirements for the detector,including a high detection efficiency to reduce the measurement time and a large solid angle coverage to cover a wide range of momentum transfers.To satisfy these demands,a large-area array of 3He-filled linear position-sensitive detectors(LPSDs)was constructed,each with a diameter of 1 inch and pressure of 20 atm.It uses an orbicular layout of the detector and an eight-pack module design for the arrangement of 3He LPSDs,covering a range of scattering angles from 3°to 170°with a total detector area of approximately 7 m2.The detector works in air,which is separated from the vacuum environment to facilitate installation and maintenance.The characteristics of the MPI detector were investigated through Monte Carlo(MC)simulations using Geant4 and experimental measurements.The results suggest that the detectors are highly efficient in the wavelength range of the MPI,and an efficiency over 25%is achievable for above 0.1 A neutrons.A minimal position resolution of 6.4 mm full width at half maximum(FWHM)along the tube length was achieved at a working voltage of 2200 V,and a deviation below 2 mm between the real and measured positions was attained in the beam experiment.The detector module exhibited good consistency and an excellent counting rate capacity of up to 80 kHz,which satisfied the requirements of experiments with a high event rate.Observations of its operation over the past year have shown that the detector works steadily in sample experiments,which allows the MPI to serve the user program successfully.

FAR591 promotes the pathogenesis and progression of SONFH by regulating Fos expression to mediate the apoptosis of bone microvascular endothelial cells

The specific pathogenesis of steroid-induced osteonecrosis of the femoral head(SONFH)is still not fully understood,and there is currently no effective early cure.Understanding the role and mechanism of long noncoding RNAs(lnc RNAs)in the pathogenesis of SONFH will help reveal the pathogenesis of SONFH and provide new targets for its early prevention and treatment.In this study,we first confirmed that glucocorticoid(GC)-induced apoptosis of bone microvascular endothelial cells(BMECs)is a pre-event in the pathogenesis and progression of SONFH.Then,we identified a new lnc RNA in BMECs via lnc RNA/m RNA microarray,termed Fosassociated linc RNA ENSRNOT00000088059.1(FAR591).FAR591 is highly expressed during GC-induced BMEC apoptosis and femoral head necrosis.Knockout of FAR591 effectively blocked the GC-induced apoptosis of BMECs,which then alleviated the damage of GCs to the femoral head microcirculation and inhibited the pathogenesis and progression of SONFH.In contrast,overexpression of FAR591 significantly promoted the GC-induced apoptosis of BMECs,which then aggravated the damage of GCs to the femoral head microcirculation and promoted the pathogenesis and progression of SONFH.Mechanistically,GCs activate the glucocorticoid receptor,which translocates to the nucleus and directly acts on the FAR591 gene promoter to induce FAR591 gene overexpression.Subsequently,FAR591 binds to the Fos gene promoter(–245–51)to form a stable RNA:DNA triplet structure and then recruits TATA-box binding protein associated factor 15 and RNA polymerase II to promote Fos expression through transcriptional activation.Fos activates the mitochondrial apoptotic pathway by regulating the expression of Bcl-2 interacting mediator of cell death(Bim)and P53 upregulated modulator of apoptosis(Puma)to mediate GC-induced apoptosis of BMECs,which leads to femoral head microcirculation dysfunction and femoral head necrosis.In conclusion,these results confirm the mechanistic link between lnc RNAs and the pathogenesis of SONFH,which helps reveal the pathogenesis of SONFH and provides a new target for the early prevention and treatment of SONFH.

Characterization of oral and gut microbiome and plasma metabolomics in COVID-19 patients after 1-year follow-up

Background:Due to the outbreak and rapid spread of coronavirus disease 2019(COVID-19),more than 160 million patients have become convalescents worldwide to date.Significant alterations have occurred in the gut and oral microbiome and metabonomics of patients with COVID-19.However,it is unknown whether their characteristics return to normal after the 1-year recovery.Methods:We recruited 35 confirmed patients to provide specimens at discharge and 1 year later,as well as 160healthy controls.A total of 497 samples were prospectively collected,including 219 tongue-coating,129 stool and 149 plasma samples.Tongue-coating and stool samples were subjected to 16S rRNA sequencing,and plasma samples were subjected to untargeted metabolomics testing.Results:The oral and gut microbiome and metabolomics characteristics of the 1-year convalescents were restored to a large extent but did not completely return to normal.In the recovery process,the microbial diversity gradually increased.Butyric acid-producing microbes and Bifidobacterium gradually increased,whereas lipopolysaccharideproducing microbes gradually decreased.In addition,sphingosine-1-phosphate,which is closely related to the inflammatory factor storm of COVID-19,increased significantly during the recovery process.Moreover,the predictive models established based on the microbiome and metabolites of patients at the time of discharge reached high efficacy in predicting their neutralizing antibody levels one year later.Conclusions:This study is the first to characterize the oral and gut microbiome and metabonomics in 1-year convalescents of COVID-19.The key microbiome and metabolites in the process of recovery were identified,and provided new treatment ideas for accelerating recovery.And the predictive models based on the microbiome and metabolomics afford new insights for predicting the recovery situation which benefited affected individuals and healthcare.

Management of granulomatous lobular mastitis: an international multidisciplinary consensus(2021 edition)

Granulomatous lobular mastitis(GLM) is a rare and chronic benign inflammatory disease of the breast. Difficulties exist in the management of GLM for many front-line surgeons and medical specialists who care for patients with inflammatory disorders of the breast. This consensus is summarized to establish evidence-based recommendations for the management of GLM. Literature was reviewed using PubMed from January 1, 1971 to July 31, 2020. Sixty-six international experienced multidisciplinary experts from 11 countries or regions were invited to review the evidence.Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Experts discussed and concluded 30 recommendations on historical definitions,etiology and predisposing factors, diagnosis criteria, treatment, clinical stages, relapse and recurrence of GLM. GLM was recommended as a widely accepted definition. In addition, this consensus introduced a new clinical stages and management algorithm for GLM to provide individual treatment strategies. In conclusion, diagnosis of GLM depends on a combination of history, clinical manifestations, imaging examinations, laboratory examinations and pathology.The approach to treatment of GLM should be applied according to the different clinical stage of GLM. This evidencebased consensus would be valuable to assist front-line surgeons and medical specialists in the optimal management of GLM.

单眼屈光参差性弱视黄斑区及视盘周围神经纤维层厚度的Meta分析

目的:评估应用光学相干断层成像术(OCT)评价单眼屈光参差性弱视青少年儿童双眼黄斑区及视盘周围神经纤维层厚度(RNFL)的差异,为探讨弱视的发病机制及指导弱视的诊疗提供依据。方法:检索维普、万方、PubMed、EMBASE等中英文数据库,对1995-01-01/2019-12-08采用OCT检查单眼屈光参差性弱视青少年儿童患者双眼黄斑区及RNFL的相关临床研究进行筛选、评估和数据提取,将单眼屈光参差性弱视患者双眼黄斑中心小凹、黄斑中心凹1mm直径中央区、1~3mm内环区、3~6mm外环区及RNFL厚度纳入研究,采用RevMan 5.3软件进行Meta分析。结果:采用时域OCT(TD-OCT)的研究结果显示,弱视眼黄斑中心小凹、黄斑中心凹1mm直径中央区厚度均大于对侧非弱视眼(P<0.05),弱视眼RNFL平均厚度大于对侧非弱视眼(P>0.05)。采用频域OCT(SD-OCT)的研究结果显示,弱视眼黄斑中心小凹及各分区厚度均大于对侧非弱视眼,除黄斑中心凹1mm直径中央区、3~6mm的外环区下方外,余比较均有差异(P<0.05);弱视眼RNFL平均厚度及鼻侧各分区厚度均大于对侧非弱视眼(P<0.05)。结论:单眼屈光参差性弱视患者弱视眼黄斑区及RNFL厚度高于对侧非弱视眼,且弱视主要引起黄斑中心凹1mm直径区域内厚度增厚。

MicroRNA396-mediated alteration in plant development and salinity stress response in creeping bentgrass

The conserved microRNA396(miR396)is involved in plant growth,development,and abiotic stress response in multiple plant species through regulating its targets,Growth Regulating Factor(GRF)transcription factor genes.However,the role of miR396 has not yet been characterized in perennial monocot species.In addition,the molecular mechanism of miR396-mediated abiotic stress response remains unclear.To elucidate the role of miR396 in perennial monocot species,we generated transgenic creeping bentgrass(Agrostis stolonifera)overexpressing Osa-miR396c,a rice miRNA396 gene.Transgenic plants exhibited altered development,including less shoot and root biomass,shorter internodes,smaller leaf area,fewer leaf veins,and epidermis cells per unit area than those of WT controls.In addition,transgenics showed enhanced salt tolerance associated with improved water retention,increased chlorophyll content,cell membrane integrity,and Na^(+)exclusion during high salinity exposure.Four potential targets of miR396 were identified in creeping bentgrass and up-regulated in response to salt stress.RNA-seq analysis indicates that miR396-mediated salt stress tolerance requires the coordination of stress-related functional proteins(antioxidant enzymes and Na+/H+antiporter)and regulatory proteins(transcription factors and protein kinases).This study establishes a miR396-associated molecular pathway to connect the upstream regulatory and downstream functional elements,and provides insight into the miRNA-mediated regulatory networks.

Influencing factors and mechanism of high-temperature oxidation of high-entropy alloys: A review

High-temperature oxidation is a common failure in high-temperature environments,which widely occur in aircraft engines and aerospace thrusters;as a result,the development of anti-high-temperature oxidation materials has been pursued.Ni-based alloys are a common high-temperature material;however,they are too expensive.High-entropy alloys are alternatives for the anti-oxidation property at high temperatures because of their special structure and properties.The recent achievements of high-temperature oxidation are reviewed in this paper.The high-temperature oxidation environment,temperature,phase structure,alloy elements,and preparation methods of high-entropy alloys are summarized.The reason why high-entropy alloys have anti-oxidation ability at high temperatures is illuminated.Current research,material selection,and application prospects of high-temperature oxidation are introduced.

A large area ^(3)He tube array detector with vacuum operation capacity for the SANS instrument at the CSNS

The small-angle neutron scattering(SANS)instrument,one of the first three instruments of the China Spallation Neutron Source(CSNS),is designed to probe the microscopic and mesoscopic structures of materials in the scale range 1–100 nm.A large-area ^(3)He tube array detector has been constructed and operates at the CSNS SANS instrument since August 2018.It consists of 120 linear position-sensitive detector tubes,each 1 m in length and 8 mm in diameter,and filled with ^(3)He gas at 20 bar to obtain a high detection efficiency.The ^(3)He tubes were divided into ten modules,providing an overall area of 1000 mm×1020 mm with a high count rate capability.Because each tube is installed independently,the detector can be quickly repaired in situ by replacing damaged tubes.To reduce air scattering,the SANS detector must operate in a vacuum environment(0.1 mbar).An all-metal sealing technique was adopted to avoid high-voltage breakdown by ensuring a high-voltage connection and an electronic system working in an atmospheric environment.A position resolution of 7.8±0.1 mm(full width at maximum)is measured along the length of the tubes,with a high detection efficiency of 81±2% at 2A.Operating over the past four years,the detector appears to perform well and with a high stability,which supports the SANS instrument to finish approximately 200 user scientific programs.

Survivors of COVID-19 exhibit altered amplitudes of low frequency fluctuation in the brain: a resting-state functional magnetic resonance imaging study at 1-year follow-up

Although some short-term follow-up studies have found that individuals recovering from coronavirus disease 2019(COVID-19)exhibit anxiety,depression,and altered brain microstructure,their long-term physical problems,neuropsychiatric sequelae,and changes in brain function remain unknown.This observational cohort study collected 1-year follow-up data from 22 patients who had been hospitalized with COVID-19(8 males and 11 females,aged 54.2±8.7 years).Fatigue and myalgia were persistent symptoms at the 1-year follow-up.The resting state functional magnetic resonance imaging revealed that compared with 29 healthy controls(7 males and 18 females,aged 50.5±11.6 years),COVID-19 survivors had greatly increased amplitude of low-frequency fluctuation(ALFF)values in the left precentral gyrus,middle frontal gyrus,inferior frontal gyrus of operculum,inferior frontal gyrus of triangle,insula,hippocampus,parahippocampal gyrus,fusiform gyrus,postcentral gyrus,inferior parietal angular gyrus,supramarginal gyrus,angular gyrus,thalamus,middle temporal gyrus,inferior temporal gyrus,caudate,and putamen.ALFF values in the left caudate of the COVID-19 survivors were positively correlated with their Athens Insomnia Scale scores,and those in the left precentral gyrus were positively correlated with neutrophil count during hospitalization.The long-term follow-up results suggest that the ALFF in brain regions related to mood and sleep regulation were altered in COVID-19 survivors.This can help us understand the neurobiological mechanisms of COVID-19-related neuropsychiatric sequelae.This study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University(approval No.2020 S004)on March 19,2020.

Watershed environmental management framework based on economic theory

Based on the meaning of economic theory as well as analysis of relevant characteristics of watershed environmental management,a watershed environmental management framework will be created,with building systems of theory,principles,methods,and supporting measures.Through the general structure,the watershed environmental management system design can be explored to optimize the allocation of resources and achieve coordinated development of watershed economic growth and environmental protection.

Statistical Analysis of Regularity of Pesticide Residues in Vegetables Produced in Inner Mongoli

[Objective]The paper was to study regularity of pesticide residues in vegetables produced in Inner Mongolia.[Method]Mathematical statistic analysis was carried out on 6 800 samples of veggies,fruits,leguminous vegetables,nuts and seeds produced in Inner Mongolia.[Result]The dominated vegetables in Inner Mongolia were green leafy vegetables,solanaceous vegetables and melon vegetables,and their yields accounted for 70%of the total vegetables production.Since 2003,with the rapid increase of detected vegetable numbers,the status of vegetable quality safety had entered into a new stage of sustainable steady after a rapid decline or periodic fluctuation,and the differences in safety levels were obvious,of which the range of exceeding standard rate of pesticide residues in solanaceous vegetables,melon vegetables and leguminous vegetables(about 55%of the total vegetables)was under 2%,with average values of 1.1%,1.6%and 3.1%,respectively.They belonged to stable type.The exceeding standard rate of pesticide residues in green leafy vegetables and Chinese cabbage group(about 30%of total vegetables)presented a decreasing trend year by year,wondering in the range of 7%-10%.They belonged to main risk type.The time period of exceeding standard of pesticide residues in root vegetables and cole vegetables was under predictable,and its exceeding standard rate in some years was over 5%(amplitude variation is over 15percentage points).They belonged to random risk type.The kinds of pesticides,which exceeding standard rate in vegetables were relatively intensive,presented variance in different vegetable species.70%of the pesticides belonged to intermittent over-limits and the probability was below 5%.About 20%tradition pesticides often exceeded standard and their probabilities were over 30%.The exceeding standard of organophosphorus and carbamates pesticides in vegetables presented a decreasing tend,while the risk of some new pesticides containing nitrogen element and high effective pyrethroids showed an increasing tendency.[Conclusion]The paper provided decision making services for agricultural management departments.

Improved Prefix Based Format-Preserving Encryption for Chinese Names

In the era of big data, government, business and personal digital information will be possible for data mining. Data mining requires massive data as a support. However, the direct release of the original mass data, which usually contain some sensitive information of personal or analysis, will result in leakage of user privacy. Therefore, it is becoming increasingly important to protect privacy information in data publishing. In this paper, we focus on the multi-type self-identified format-preserving encryption. First, we introduce a multi-type self-identified format-preserving encryption system and discuss the encryption of various types of data in this system. Then, for the format preserving encryption(FPE) about Chinese name, we study from the encryption model construction and basic encryption scheme. The format-preserving encryption model about Chinese name is constructed and the concept of the name library is presented. Based on this, it is used to not only limit the message space to reduce complexity, but also ensure the cipher in accordance with the Chinese naming habits. In addition, according to the encryption and decryption model, format-preserving encryption process of Chinese name is designed. In order to add new names, the algorithm of name space expansion is proposed. Based on the Prefix, this paper put forward an algorithm named Cycle-Prefix, which enhances the security and dynamics of FPE by using two adjustment factors and the circular encryption. Compared with the traditional Prefix algorithm, experiments show that Cycle-Prefix can not only complete the task of FPE for Chinese name, but also encrypt same plain text into different ciphers under the premise of similar efficiency with Prefix.

MiR396 is involved in plant response to vernalization and flower development in Agrostis stolonifera

MicroRNA396(miR396)has been demonstrated to regulate flower development by targeting growth-regulating factors(GRFs)in annual species.However,its role in perennial grasses and its potential involvement in flowering time control remain unexplored.Here we report that overexpression of miR396 in a perennial species,creeping bentgrass(Agrostis stolonifera L.),alters flower development.Most significantly,transgenic(TG)plants bypass the vernalization requirement for flowering.Gene expression analysis reveals that miR396 is induced by long-day(LD)photoperiod and vernalization.Further study identifies VRN1,VRN2,and VRN3 homologs whose expression patterns in wild-type(WT)plants are similar to those observed in wheat and barley during transition from short-day(SD)to LD,and SD to cold conditions.However,compared to WT controls,TG plants overexpressing miR396 exhibit significantly enhanced VRN1 and VRN3 expression,but repressed VRN2 expression under SD to LD conditions without vernalization,which might be associated with modified expression of methyltransferase genes.Collectively,our results unveil a potentially novel mechanism by which miR396 suppresses the vernalization requirement for flowering which might be related to the epigenetic regulation of VRN genes and provide important new insight into critical roles of a miRNA in regulating vernalization-mediated transition from vegetative to reproductive growth in monocots.

A Geometry-Based Stochastic Scattering Channel Model for V2V Communications in Dense Urban Street Environments

In this paper,we propose a stochastic channel model in three-dimensional(3D)space for multiple input multiple output(MIMO)vehicle-to-vehicle(V2V)communications in dense urban environments.The movement of the mobile transmitter and mobile receiver results in the V2V channel model behave temporal non-stationarity.Therefore,the time-varying parameters of the propagation paths and angles are derived to characterize such property.Using this channel model,we investigate the propagation characteristics of V2V channels in terms of the road section and moving time/directions/speeds of the transmitter and receiver.Numerical results show that the theoretical results of the propagation characteristics of the V2V channel model are very close to those of the simulation ones,which show that the proposed channel model is suitable for depicting the V2V communications in dense urban scenarios.

Circulating tumor DNA genomic profiling reveals the complicated olaparib-resistance mechanism in prostate cancer salvage therapy: A case report

BACKGROUND The poly(ADP-ribose)polymerase(PARP)inhibitor olaparib has displayed superior clinical effect in metastatic castration-resistant prostate cancer(mCRPC)patients with the homologous recombination repair(HRR)genes mutations.However,when a patient’s tumor tissue volume is insufficient for genomic profiling of HRR gene mutations,circulating tumor DNA(ctDNA)may be useful in helping to determine and monitor the efficacy of olaparib,as well as in abiraterone-combination treatment,and for understanding any resistance mechanism related to such mutations.CASE SUMMARY A 61-year-old man who was diagnosed with metastatic prostate adenocarcinoma was initially hormone sensitivity,showing high Gleason score(5+5=10)and absolute positive rate(14/14 biopsied specimens).Following failure of several standard therapies,the patient progressed to mCRPC.Surprisingly,the patient showed good response to olaparib-abiraterone-prednisone combination treatment(an androgen-deprivation therapy,provided as the‘final choice’in China).Serum total prostate-specific antigen(TPSA)level reduced and symptoms remitted for 4 months.However,thereafter,serum TPSA levels began slowly increasing,indicating development of olaparib resistance.Subsequent comprehensive genomic profiling of ctDNA, screening 508 cancer-related genes by next-generation sequencing,identified 10 somatic variants as well as 3 copy number alterations. Two identified reversemissense mutations in partner and localizer of BRCA2 (PALB2) may have recovered the readingframe, restoring function of the primary germline PALB2 mutation and causing resistance to thePARP inhibitor olaparib.CONCLUSIONReverse mutations in PALB2, discovered via genomic profiling of ctDNA, may represent apotential resistance mechanism against olaparib in mCRPC.

Analysis of a Large Grounding System and Subsequent Field Test Validation Using the Fall of Potential Method

This paper examines various aspects of the design process and subsequent field test measurements of a large and complex substation grounding system. The study and measurements show that soil layering and lead interference can have a significant impact on the appropriate test location that yields the exact substation ground impedance. Applying a specific percentage rule such as the 61.8% rule for uniform soils to obtain the true ground impedance may lead to unacceptable errors for large grounding systems. This poses significant problems when attempting to validate a design based on raw test data that are interpreted using approximate methods to evaluate substation ground impedance, and determine ground potential rise (GPR), touch and step voltages. Advanced measurement methodologies and modern software packages were used to obtain and effectively analyze fall of potential test data, compute fault current distribution, and evaluate touch and step voltages for this large substation. Fault current distribution between the grounding system and other metallic paths were computed to determine the portion of fault current discharged in the grounding system. The performance of the grounding system, including its GPR and touch and step voltages, has been accurately computed and measured, taking into account the impedance of the steel material used of the ground conductors and circulating currents within the substation grounding system.