NbN quantum dots anchored hollow carbon nanorods as efficient polysulfide immobilizer and lithium stabilizer for Li-S full batteries

The shuttle effect of lithium polysulfides(LiPSs)and uncontrollable lithium dendrite growth seriously hinder the practical application of lithium-sulfur(Li-S)batteries.To simultaneously address such issues,monodispersed Nb N quantum dots anchored on nitrogen-doped hollow carbon nanorods(NbN@NHCR)are elaborately developed as efficient Li PSs immobilizer and Li stabilizer for high-performance Li-S full batteries.Density functional theory(DFT)calculations and experimental characterizations demonstrate that the sulfiphilic and lithiophilic NbN@NHCR hybrid can not only efficiently immobilize the soluble Li PSs and facilitate diffusion-conversion kinetics for alleviating the shuttling effect,but also homogenize the distribution of Li+ions and regulate uniform Li deposition for suppressing Li-dendrite growth.As a result,the assembled Li-S full batteries(NbN@NHCR-S||Nb N@NHCR-Li)deliver excellent long-term cycling stability with a low decay rate of 0.031%per cycle over 1000 cycles at high rate of 2 C.Even at a high S loading of 5.8 mg cm^(-2)and a low electrolyte/sulfur ratio of 5.2μL mg^(-1),a large areal capacity of 6.2 mA h cm^(-2)can be achieved in Li-S pouch cell at 0.1 C.This study provides a new perspective via designing a dual-functional sulfiphilic and lithiophilic hybrid to address serious issues of the shuttle effect of S cathode and dendrite growth of Li anode.

Fe-N_(x) sites coupled with core-shell FeS@C nanoparticles to boost the oxygen catalysis for rechargeable Zn-air batteries

The development of efficient single-atom catalysts(SACs) for the oxygen reduction reaction(ORR)remains a formidable challenge,primarily due to the symmetric charge distribution of metal singleatom sites(M-N_(4)).To address such issue,herein,Fe-N_(x) sites coupled synergistic catalysts fabrication strategy is presented to break the uniform electronic distribution,thus enhancing the intrinsic catalytic activity.Precisely,atomically dispersed Fe-N_(x) sites supported on N/S-doped mesoporous carbon(NSC)coupled with FeS@C core-shell nanoparticles(FAS-NSC@950) is synthesized by a facile hydrothermal reaction and subsequent pyrolysis.Due to the presence of an in situ-grown conductive graphitic layer(shell),the FeS nanoparticles(core) effectively adjust the electronic structure of single-atom Fe sites and facilitate the ORR kinetics via short/long-range coupling interactions.Consequently,FAS-NSC@950displays a more positive half-wave potential(E_(1/2)) of 0.871 V with a significantly boosted ORR kinetics(Tafel slope=52.2 mV dec^(-1)),outpacing the commercial Pt/C(E_(1/2)=0.84 V and Tafel slope=54.6 mV dec^(-1)).As a bifunctional electrocatalyst,it displays a smaller bifunctional activity parameter(ΔE) of 0.673 V,surpassing the Pt/C-RuO_(2) combination(ΔE=0.724 V).Besides,the FAS-NSC@950-based zincair battery(ZAB) displays superior power density,specific capacity,and long-term cycling performance to the Pt/C-Ir/C-based ZAB.This work significantly contributes to the field by offering a promising strategy to enhance the catalytic activity of SACs for ORR,with potential implications for energy conversion and storage technologies.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

Effects of Fe solid solute on grain boundaries of bi-crystal Cu: A molecular dynamics simulation

Grain boundaries(GBs)play a crucial role on the structural stability and mechanical properties of Cu and its alloys.In this work,molecular dynamics(MD)simulations are employed to study the effects of Fe solutes on the formation energy,excess volume,dislocations and melting behaviors of GBs in CuFe alloys.It is illustrated that Fe solute affects the structural stability of Cu GBs substantially,the formation energy of GBs is reduced,but the thickness and melting point of GBs are increased,that is,the structural stability of Cu GBs is significantly improved owing to the Fe solutes.A strong scaling law exists between the formation energy,excess volume,thickness and melting point of GBs.Therefore,Fe solid solute plays an important role in the characteristics of GBs in bi-crystal Cu.

Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2(HER2)-positive early-stage breast cancer: A real-world retrospective study in Chinese patients

Objective: To assess the long-term effectiveness and safety of trastuzumab in adjuvant therapy for Chinese patients with early-stage human epidermal growth factor 2(HER2)-positive breast cancer in a real-world setting.Methods: This retrospective observational study analyzed the medical records of HER2-positive breast cancer patients between 2000 and 2012 at the Chinese Academy of Medical Sciences. Patients who received adjuvant chemotherapy alone or adjuvant chemotherapy followed by/combined with trastuzumab were included. The Kaplan-Meier method was used to estimate disease-free survival(DFS) and overall survival(OS). Hazard ratios(HR) and 95% confidence intervals(95% CI) were calculated using the Cox regression model.Results: Of the 1,348 patients analyzed, 909 received chemotherapy alone and 439 received chemotherapy plus trastuzumab. The 3-year, 5-year and 10-year DFS rates were 83.70%, 76.38% and 68.94%, respectively, in the chemotherapy-alone cohort, and 90.21%, 86.19% and 83.45% in the chemotherapy plus trastuzumab cohort. The3-year, 5-year and 10-year OS rates were 96.10%, 91.40% and 81.88% in the chemotherapy-alone cohort, and98.17%, 94.91% and 90.01% in the chemotherapy plus trastuzumab cohort. The chemotherapy plus trastuzumab group had a significantly lower risk of disease recurrence and death than the chemotherapy-alone group(DFS:HR=0.50, 95% CI, 0.37-0.68;P<0.001;OS: HR=0.53, 95% CI, 0.34-0.81;P=0.004) after adjusting for covariates.In the 439 patients treated with trastuzumab, multivariate analysis suggested that lymph node positivity, higher T stages, and hormone receptor-negative status were significantly associated with higher risks of disease recurrence,and lymph node positivity and hormone receptor-negative status were significantly associated with higher risks of death. Grade 3/4 adverse events(incidence ≥1%) were more common in patients receiving trastuzumab(54.44% vs.15.73%).Conclusions: Early-stage HER2-positive breast cancer patients treated with trastuzumab plus adjuvant chemotherapy have a significant survival benefit compared with chemotherapy-alone in real-world settings. Lymph node positivity, hormone receptor-negative status, and higher T stages may be associated with higher risks of recurrence, and effective therapy for patients with these factors is required.

Ultrasound Features Improve Diagnostic Performance of Ovarian Cancer Predictors in Distinguishing Benign and Malignant Ovarian Tumors

To determine whether ultrasound features can improve the diagnostic performance of tumor markers in distinguishing ovarian tumors,we enrolled 719 patients diagnosed as having ovarian tumors at Nanfang Hospital from September 2014 to November 2016.Age,menopausal status,histopathology,the International Federation of Gynecology and Obstetrics(FIGO)stages,tumor biomarker levels,and detailed ultrasound reports of patients were collected.The area under the curve(AUC),sensitivity,and specificity of the bellow-mentioned predictors were analyzed using the receiver operating characteristic curve.Of the 719 patients,531 had benign lesions,119 had epithelial ovarian cancers(EOC),44 had borderline ovarian tumors(BOT),and 25 had non-EOC.AUCs and the sensitivity of cancer antigen 125(CAI25),human epididymis-specific protein 4(HE4),Risk of Ovarian Malignancy Algorithm(ROMA),Risk of Malignancy Index(RMI1),HE4 model,and Rajavithi-Ovarian Cancer Predictive Score(R-OPS)in the overall population were 0.792,0.854,0.856,0.872,0.893,0.852,and 70.2%,56.9%,69.1%,60.6%,77.1%,71.3%,respectively.For distinguishing EOC from benign tumors,the AUCs and sensitivity of the above mentioned predictors were 0.888,0.946,0.947,0.949,0.967,0.966,and 84.0%,79.8%,87.4%,84.9%,90.8%,89.1%,respectively.Their specificity in predicting benign diseases was 72.9%,94.4%,87.6%,95.9%,86.3%,90.8%,respectively.Therefore,we consider biomarkers in combination with ultrasound features may improve the diagnostic performance in distinguishing malignant from benign ovarian tumors.

Hepatocellular carcinoma with tumor thrombus in bile duct:A proposal of new classification according to resectability of primary lesion

BACKGROUND Hepatocellular carcinoma(HCC)with tumor thrombus in the bile duct(BDTT)is easily misdiagnosed or mistreated due to the clinicopathological diversity of the thrombus and its relationship with primary lesions.AIM To propose a new classification for HCC with BDTT in order to guide its diagnosis and treatment.METHODS A retrospective review of the diagnosis and treatment experience regarding seven typical HCC patients with BDTT between January 2010 and December 2019 was conducted.RESULTS BDTT was preoperatively confirmed by computed tomography/magnetic resonance imaging in only four patients.Three patients with recurrent HCC and one patient with first-occurring HCC had no visible intrahepatic tumors;of these,misdiagnosis occurred in two patients,and three patients died.One patient was mistreated as having common bile duct stones,and another patient with a history of multiple recurrent HCC was misdiagnosed until obvious biliary dilation could be detected.Only one patient who received hepatectomy accompanied by BDTT extraction exhibited disease-free survival during the follow-up period.A new classification was proposed for HCC with BDTT as follows:HCC with microscopic BDTT(Type Ⅰ);resectable primary or recurrent HCC mass in the liver with BDTT(Type Ⅱ);BDTT without an obvious HCC mass in the liver(Type Ⅲ)and BDTT accompanied with unresectable intra-or extrahepatic HCC lesions(Type Ⅳ).CONCLUSION We herein propose a new classification system for HCC with BDTT to reflect its pathological characteristics and emphasize the significance of primary tumor resectability in its treatment.

Helicobacter pylori and 17β-estradiol induce human intrahepatic biliary epithelial cell abnormal proliferation and oxidative DNA damage

BACKGROUND: Biliary cancers are more common in females, and previous studies have suggested that Helicobacter pylori (H. pylori) exists in the biliary system. However, the effects of H. pylori infection and estrogen on the biological behaviors of human biliary epithelium mucosa remain unknown. The present study aimed to clarify their effects on the proliferation, apoptosis, migration and oxidative DNA damage of a human intrahepatic biliary epithelial cell (HIBEC) line in vitro. METHODS: HIBECs were co -cultured with 17 beta-estradiol (at 10(-9) mol/L, 10(-7) mol/L, and 10(-5) mol/L) and H. pylori (at MOI=0.5:1, 1:1, and 2:1) and continuously passaged until the 15th generation (approximately 45 days). Then, the following assays were performed. HIBEC proliferation was measured using the CCK-8 assay, plate clone-formation assay and by determining Ki-67 expression with immunocytochemistry; cell apoptosis and migration were investigated using Annexin-V/PI and transwell assays, respectively; and reactive oxygen species (ROS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) production were detected by flow cytometry and immunofluorescence staining combined with confocal laser scanning microscopy, respectively. The results were the basis for evaluating the level of oxidative stress and the related DNA damage in HIBECs. RESULTS: HIBECs maintained a normal morphology and vitality when treated with 17 beta-estradiol (at 10(-9) mol/L) and H. pylori (at MOI=0.5:1 and 1:1). 17 beta-estradiol at 10(-7) mol/L and 10(-5) mol/L and H. pylori at MOI=2:1, by contrast, caused cell death. Compared with controls, HIBECs treated with 17 beta-estradiol (10(-9) mol/L) and H. pylori (MOI=1:1) had a higher up-regulation of proliferation, Ki-67 expression, clone formation, migration activity and the expression of ROS and 8-OHdG and exhibited a down-regulation of apoptosis. The above effects were further increased when 17 beta-estradiol and H. pylori were combined (P<0.05). CONCLUSIONS: H. pylori and 17 beta-estradiol, separately or in combination, promoted cell proliferation and suppressed apoptosis of HIBECs in vitro. The above phenomena might be related to oxidative stress and its subsequent DNA damage with H. pylori and 17 beta-estradiol.

Phylogenetic analysis of 48 gene families revealing relationships between Hagfishes, Lampreys, and Gnathostomata

It has become clear that the extant vertebrates are divided into three major groups, that is, hagfishes, lampreys, and jawed vertebrates. Morphological and molecular studies, however, have resulted in conflicting views with regard to their interrelationships. To clarify the phylogenetic relationships between them, 48 orthologous protein-coding gene families were analyzed. Even as the analysis of 34 nuclear gene families supported the monophyly of cyclostomes, the analysis of 14 mitochondrial gene families suggested a closer relationship between lampreys and gnathostomes compared to hagfishes. Lampreys were sister group of gnathostomes. The results of this study supported the cyclostomes. Choice of outgroup, tree-making methods, and software may affect the phylogenetic prediction, which may have caused much debate over the subject. Development of new methods for tackling such problems is still necessary.

The effect of Mn-doped ZnSe passivation layer on the performance of CdS/CdSe quantum dot-sensitized solar cells

ZnSe as a surface passivation layer in quantum dot-sensitized solar cells plays an important role in preventing charge recombination and thus improves the power conversion efficiency(PCE).However, as a wide bandgap semiconductor, ZnSe cannot efficiently absorb and convert long-wavelength light.Doping transition metal ions into ZnSe semiconductors is an effective way to adjust the band gap, such as manganese ions.In this paper, it is found by the method of density functional theory calculation that the valence band of ZnSe moves upward with manganese ions doping, which leads to acceleration of charge separation, wider light absorption range, and enhancing light harvesting.Finally, by using ZnSe doped with manganese ions as the passivation layer, the TiO2/CdS/CdSe co-sensitized solar cell has a PCE of 6.12%, and the PCE of the solar cell increases by 9% compared with the undoped one(5.62%).

Direct impact characteristics of magnesite fragmentation by pulsed discharge in water

To clarify direct impact characteristics(pressure and position) of middle-grade magnesite fragmentation by pulsed discharge in water, this work uses pressure film to accomplish passive measurement through pulsed discharge experiment and obtain the pressure. The impact position is determined by image analysis of fragmentation product morphology, crack edge and discharge channel. Then, pressure load on magnesite surface is numerically analyzed based on the measured pressure obtained from the film. Results indicate that, at 10 mm discharge gap, the impact pressure increases with the discharge voltage, and the discharge voltage to disintegrate magnesite is-40 kV. The impact position is normally in the boundary among different mineral components.Simulation analysis indicates that, the pressure load applied directly on magnesite surface is approximately 142.5 MPa at-40 kV and greater than the compressive strength of magnesite, thus leading to the fragmentation.

Gastrointestinal metastasis secondary to invasive lobular carcinoma of the breast:A case report

BACKGROUND Gastrointestinal metastasis of breast cancer is rare,and clinicians may not have previously encountered this disease in clinical practice.CASE SUMMARY We report a patient with invasive lobular carcinoma of the breast who developed gastrointestinal metastasis two years after modified radical surgery.Mild elevation of carbohydrate antigen 15-3 was observed in the patient at an early stage;however,diagnosis and treatment were delayed due to non-specific clinical manifestations and no identifiable metastasis observed on imaging.CONCLUSION Clinicians should pay attention to gastrointestinal metastasis of breast cancer,especially invasive lobular carcinoma of the breast.

Tuina massage combined with traditional Chinese prescription improves quality of life and motor symptoms in a spasmodic torticollis patient:A case report

Objective:A case study was performed to discuss the efficacy of traditional Chinese medicine(TCM)treatments on spasmodic torticollis.Materials and methods:A 28-year-old male was diagnosed with spasmodic torticollis due to twist and turn of neck after being frightened,who was unable to take care of himself for over 3 months.He once took an oral non-steroidal anti-inflammatory drug,but no significant improvement was seen in his symptoms.After a few months,his symptoms got worse,with onset of spasms.Therefore,he was treated at our hospital with traditional Chinese prescription and Tuina massage therapy for 3 months and followed up for 6 months.The Toronto Western Spasmodic Torticollis Rating Scale(TWSTRS)and the Craniocervical Dystonia Questionnaire(CDQ-24)scores were recorded before and after treatment and during follow-up observations to evaluate the therapeutic efficacy.Results:Compared to the baseline,the TWSTRS and CDQ-24 scores decreased significantly,and there was no evident recurrence of his symptoms for at least 6 months of follow-up.Moreover,no apparent discomfort or side effects were observed during the treatment.Conclusion:Jingu abdominal massage combined with traditional Chinese prescription has a certain efficacy in the treatment of spasmodic torticollis,with almost no side effects,which can be easily accepted by patients.

可循环利用的生物质基环氧树脂类玻璃高分子材料的研究进展

类玻璃高分子材料(Vitrimer)是一种具有独特功能的新兴材料,基于生物质资源制备的生物质基环氧树脂Vitrimer材料不仅具有良好的力学性能和耐溶剂性,而且具有可循环利用特性(重塑再加工、化学溶解回收、自修复),有望解决传统环氧树脂热固性材料难以可持续循环利用的问题。文中综述了近年来不同生物质资源制备的生物质基环氧树脂以及不同动态化学键构筑的生物质基环氧树脂Vitrimer材料性能的研究进展,展望了生物质基环氧树脂Vitrimer材料未来可能的发展方向,对实现环氧树脂材料的循环利用和可持续发展有重要意义。

Chemical composition of walnuts from three regions in China

To reveal the characteristic chemicals of walnuts from different origins, we analyzed fatty acid composition,tocopherols, phytosterols and total phenolic content (TPC) of walnuts from three main producing regions inChina. The results showed that walnuts were rich in polyunsaturated fatty acids, and the ratio of ω-6 to ω-3 fattyacids was close to the recommendation of Chinese Nutrition Society. Moreover, walnuts contain high contents oftocopherols (331.20–414.71 mg/kg), phytosterols (97.17–110.35 mg/100 g) and phenols (38.51–48.08 mg GAE/kg). Significant chemical differences exist among walnuts from three production regions. The highest content ofpolyunsaturated fatty acids was found in walnuts from the northern China, the highest content of tocopherols inwalnuts from southwest China, and the highest contents of phytosterol and TPC in walnuts from northwest China.However, there was no significant difference in the tocopherol, phytosterol and TPC content of walnuts betweenthe Northern China and Northwest China. The above results provide important references for manufacturers andconsumers to select suitable walnut scientifically and reasonably.

Interface and M^(3+)/M^(2+)Valence Dual-Engineering on Nickel Cobalt Sulfoselenide/Black Phosphorus Heterostructure for Efficient Water Splitting Electrocatalysis

The catalyst innovation that aims at noble-metal-free substitutes is one key aspect for future sustainable hydrogen energy deployment.In this paper,a nickel cobalt sulfoselenide/black phosphorus heterostructure(NiCoSe|S/BP)was fabricated to realize the highly active and durable water electrolysis through interface and valence dual-engineering.The NiCoSe|S/BP nanostructure was constructed by in-situ growing NiCo hydroxide nanosheet arrays on few-layer BP and subsequently one-step sulfoselenization by SeS2.Besides the conductive merit of BP substrate,holes in p-type BP are capable of oxidizing the Co^(2+)to high-valence and electron-accepting Co^(3+),benefiting the oxygen evolution reaction(OER).Meanwhile,Ni^(3+)/Ni^(2+)ratio in the heterostructure is reduced to maintain the electrical neutrality,which corresponds to the increased electron-donating character for boosting hydrogen evolution reaction(HER).As for HER and OER,the heterostructured NiCoSe|S/BP electrocatalyst exhibits small overpotentials of 172 and 285 mV at 10 mA cm^(-2)(η_(10))in alkaline media,respectively.And overall water splitting has been achieved at a low cell potential of 1.67 V at η_(10) with high stability.Molecular sensing and density functional theory(DFT)calculations are further proposed for understanding the rate-determine steps and enhanced catalytic mechanism.The investigation presents a deep-seated perception for the electrocatalytic performance enhancement of BP-based heterostructure.

吡咯替尼对携带HER-2突变的HER-2阴性晚期乳腺癌患者的疗效观察

目的:评估吡咯替尼对携带HER-2突变的HER-2阴性晚期乳腺癌患者的治疗疗效和安全性。方法:回顾性分析2018年1月至2019年6月于北京市朝阳区桓兴肿瘤医院收治的13例携带HER-2突变的HER-2阴性晚期乳腺癌患者的临床资料,均使用吡咯替尼单药行抗HER-2治疗,对患者的治疗疗效和不良反应进行综合评估。结果:13例患者中3例因不良反应难以耐受出组,未行疗效评价,其余10例患者中获得完全缓解(complete response,CR)1例、部分缓解(partial response,PR)3例、疾病稳定(stable disease,SD)3例、疾病进展(progressive disease,PD)3例。客观缓解(CR+PR)率为40%(4/10),临床获益(CR+PR+SD≥6.0个月)率为60%(6/10),疾病控制(CR+PR+SD)率为70%(7/10)。无进展生存时间最长者达15.5个月,中位无进展生存期(progression-free survival,PFS)为4.9个月(95%CI:3.8~6.0)。吡咯替尼最常见的不良反应为腹泻、占84.6%(11/13),3级及以上的不良反应包括腹泻为15.4%(2/13)、恶心为7.7%(1/13)、呕吐为7.7%(1/13)。结论:携带HER-2突变的HER-2阴性晚期乳腺癌患者,可能从吡咯替尼的抗HER-2治疗中获益。

Expert Consensus on the Diagnosis and Treatment of Anticancer Drug-Induced Interstitial Lung Disease

Drug-induced interstitial lung disease(DILD)is the most common pulmonary adverse event of anticancer drugs.In recent years,the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer agents.Due to the diverse clinical manifestations and the lack of specific diagnostic criteria,DILD is difficult to diagnose and may even become fatal if not treated properly.Herein,a multidisciplinary group of experts from oncology,respiratory,imaging,pharmacology,pathology,and radiology departments in China has reached the“expert consensus on the diagnosis and treatment of anticancer DILD”after several rounds of a comprehensive investigation.This consensus aims to improve the awareness of clinicians and provide recommendations for the early screening,diagnosis,and treatment of anticancer DILD.This consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.

Combined chemo-endocrine therapy as a potential new option for HR+/HER2−advanced breast cancer:a prospective study of fulvestrant plus oral vinorelbine

Objective:Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro.This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with hormone receptor positive(HR+)/human epidermal growth factor receptor-2-negative(HER2−)recurrent or metastatic breast cancer.Methods:Patients were intramuscularly administered fulvestrant 500 mg(day 1 per cycle for 28 days)and oral vinorelbine(60 mg/m2 on days 1,8,and 15 of each cycle).The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall survival,objective response rate,disease control rate,duration of response,and safety.Results:A total of 38 patients with HR+/HER2−advanced breast cancer included in the study were followed up for a median time of 25.1 months.The overall median PFS was 9.86 months[95%confidence interval(CI)7.2-23.13],and the median PFS of the first-line and the second-line treatment population was 20.73 months(95%CI 9.82 to NR)and 4.27 months(95%CI 3.68 to NR),respectively.Most adverse events reported were of grade 1/2,and none were of grade 4/5.Conclusions:This is the first exploratory study of a fulvestrant and oral vinorelbine regimen in the treatment of HR+/HER2−recurrent and metastatic breast cancer.The combination chemo-endocrine therapy was efficacious,safe,and promising for patients with HR+/HER2−advanced breast cancer.

Expression dynamics of periodic transcripts during cancer cell cycle progression and their correlation with anticancer drug sensitivity

Background:The cell cycle is at the center of cellular activities and is orchestrated by complex regulatory mechanisms,among which transcriptional regulation is one of the most important components.Alternative splicing dramatically expands the regulatory network by producing transcript isoforms of genes to exquisitely control the cell cycle.However,the patterns of transcript isoform expression in the cell cycle are unclear.Therapies targeting cell cycle checkpoints are commonly used as anticancer therapies,but none of them have been designed or evaluated at the alternative splicing transcript level.The utility of these transcripts as markers of cell cycle-related drug sensitivity is still unknown,and studies on the expression patterns of cell cycle-targeting drug-related transcripts are also rare.Methods:To explore alternative splicing patterns during cell cycle progression,we performed sequential transcriptomic assays following cell cycle synchronization in colon cancer HCT116 and breast cancer MDA-MB-231 cell lines,using flow cytometry and reference cell cycle transcripts to confirm the cell cycle phases of samples,and we developed a new algorithm to describe the periodic patterns of transcripts fluctuating during the cell cycle.Genomics of Drug Sensitivity in Cancer(GDSC)drug sensitivity datasets and Cancer Cell Line Encyclopedia(CCLE)transcript datasets were used to assess the correlation of genes and their transcript isoforms with drug sensitivity.We identified transcripts associated with typical drugs targeting cell cycle by determining correlation coefficients.Cytotoxicity assays were used to confirm the effect of ENST00000257904 against cyclin dependent kinase 4/6(CDK4/6)inhibitors.Finally,alternative splicing transcripts associated with mitotic(M)phase arrest were analyzed using an RNA synthesis inhibition assay and transcriptome analysis.Results:We established high-resolution transcriptome datasets of synchronized cell cycle samples from colon cancer HCT116 and breast cancer MDA-MB-231 cells.The results of the cell cycle assessment showed that 43,326,41,578 and 29,244 transcripts were found to be periodically expressed in HeLa,HCT116 and MDA-MB-231 cells,respectively,among which 1280 transcripts showed this expression pattern in all three cancer cell lines.Drug sensitivity assessments showed that a large number of these transcripts displayed a higher correlation with drug sensitivity than their corresponding genes.Cell cycle-related drug screening showed that the level of the CDK4 transcript ENST00000547281 was more significantly associated with the resistance of cells to CDK4/6 inhibitors than the level of the CDK4 reference transcript ENST00000257904.The transcriptional inhibition assay following M phase arrest further confirmed the M-phase-specific expression of the splicing transcripts.Combined with the cell cycle-related drug screening,the results also showed that a set of periodic transcripts,for example,ENST00000314392(a dolichylphosphate mannosyltransferase polypeptide 2 isoform transcript),was more associated with drug sensitivity than the levels of their corresponding gene transcripts.Conclusions:In summary,we identified a panel of cell cycle-related periodic transcripts and found that the levels of transcripts of drug target genes showed different values for predicting drug sensitivity,providing novel insights into alternative splicing-related drug development and evaluation.