Chemotherapy is currently the mainstay of systemic management for triple-negative breast cancer (TNBC), but chemoresistance significantly impacts patient outcomes. Our research indicates that Doxorubicin (Dox)-resistant TNBC cells exhibit increased glycolysis and ATP generation compared to their parental cells, with this metabolic shift contributing to chemoresistance. We discovered that ALKBH3, an m¹A demethylase enzyme, is crucial in regulating the enhanced glycolysis in Dox-resistant TNBC cells. Knocking down ALKBH3 reduced ATP generation, glucose consumption, and lactate production, implicating its involvement in mediating glycolysis. Further investigation revealed that aldolase A (ALDOA), a key enzyme in glycolysis, is a downstream target of ALKBH3. ALKBH3 regulates ALDOA mRNA stability through m¹A demethylation at the 3'-untranslated region (3'UTR). This methylation negatively affects ALDOA mRNA stability by recruiting the YTHDF2/PAN2-PAN3 complex, leading to mRNA degradation. The ALKBH3/ALDOA axis promotes Dox resistance both in vitro and in vivo. Clinical analysis demonstrated that ALKBH3 and ALDOA are upregulated in breast cancer tissues, and higher expression of these proteins is associated with reduced overall survival in TNBC patients. Our study highlights the role of the ALKBH3/ALDOA axis in contributing to Dox resistance in TNBC cells through regulation of ALDOA mRNA stability and glycolysis.

Purpose To investigate the diagnostic value of postsystolic shortening in ischemia with non-obstructive coronary arteries(INOCA).Materials and Methods A total of 85 INOCA patients admitted to People's Hospital of Liaoning Province from May 2020 to December 2022 were selected and divided into two groups according to the ratio of distal diastolic average blood velocity of left anterior descending branch before and after treatment obtained by thymosidine load echocardiography(coronary flow velocity reserve,CFVR):CFVR<2.0 was in the coronary microvascular dysfunction(CMD)group(n=40),and CFVR≥2.0 was in the control group(n=45).Conventional echocardiographic parameters of all enrolled subjects were measured:left ventricular end-diastolic diameter index(LVEDDI),left ventricular end-diastolic volume index(LVEDVI),left ventricular end-systolic volume index(LVESVI),left ventricular ejection fraction(LVEF),early and late mitral valve diastolic blood flow velocity(E,A),E/A,average velocity of mitral valve annulus and interventricular septum in early diastolic(e')and E/e'on the wall and septal side were measured.The global longitudinal strain(GLS)and the post systolic index(PSI)of the left ventricle were measured by two-dimensional speckle tracking automated functional imaging.The differences of echocardiographic parameters,GLS and PSI between CMD group and control group were observed.The relationship between CFVR and PSI in CMD group was analyzed.Results There were no significant differences in LVEDDI,LVEDVI,LVESVI,LVEF,E,A,E/A,e',E/e'and GLS between control group and CMD group(t=-0.577-1.472,P>0.05).There was a statistically significant difference in PSI increase between CMD group and control group(t=-5.370,P<0.05).There was a good correlation between CFVR and PSI in CMD group(r=-0.486,P<0.05).The receiver operator characteristic curve showed that the area under the curve predicted by PSI for CMD was 0.786,the sensitivity was 68.0%,and the specificity was 77.8%.Conclusion PSI has good application value in evaluating left ventricular systolic function in INOCA patients,and can detect left ventricular systolic function injury in such patients at an early stage.

Objective:To investigate the clinicopathological characteristics of giant cell tumor of bone (GCTB) in children.Methods:A total of 35 cases of GCTB diagnosed at Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiaotong University School from 2016 to 2023 were collected, and a retrospective analysis of clinicopathological features and imaging findings was conducted.Results:Pediatric GCTB accounted for approximately 4.6% of total GCTB cases during the study period. There were 11 males and 24 females. The onset age ranged from 9 to 18 years (mean age 15 years, median age 16 years), with 8 cases (8/35, 22.9%) experiencing postoperative recurrence. Twenty-eight cases (28/35, 80%) primarily affected long bones, while 7 cases involved small or irregular bones. Imaging revealed osteolytic changes as the predominant feature, with 3 cases exhibited open physis, one of which had the tumor primarily at the diaphysis without crossing the physis. Histologically, pediatric GCTB resembled adult cases, characterized by mononuclear cells and osteoclast-like giant cells. Seven cases with denosumab treatment demonstrated degrees of giant cell disappearance, increased fibrous tissue and reactive bone proliferation in the stroma. One case was diagnosed as pediatric multicentric GCTB, and three cases as pediatric primary malignant GCTB, with malignant transformation into osteosarcoma. In all 35 cases, mutations in the H3F3A gene were identified, comprising 32 cases with H3.3 p.G34W mutations, one case with H3.3 p.G34V mutation, and 2 cases with H3.3 p.G34L mutations. Notably, the former two categories were successfully validated at the protein level through immunohistochemical staining, utilizing highly specific antibodies tailored for these mutation types: H3.3 p.G34W antibody and H3.3 p.G34V antibody. However, immunohistochemical staining was not available for the last category.Conclusions:Pediatric GCTB predominantly affects females and occurs primarily in long bones, mainly around the knee joint, the majority of tumors predominantly arise in the epiphysis and extend into the metaphysis; however, in cases where the epiphyseal plates are still unclosed, the tumors may be restricted to the metaphysis. Detection of H3F3A gene mutation is crucial for the diagnosis and differential diagnosis of pediatric GCTB.

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.
Humans ; Brain Neoplasms/pathology* ; Neoplasm Recurrence, Local/metabolism* ; Glioma/pathology* ; Neural Stem Cells/pathology* ; Oligodendrocyte Precursor Cells/pathology* ; Tumor Microenvironment

Purpose To investigate the clinicopathological and molecular genetic features of oncocytic carcinoma of the thy-roid(OCA).Methods The clinicopathological and immuno-histochemical data of 25 patients with oncocytic carcinoma of the thyroid were retrospectively reviewed.Genetic features were determined by fluorescence quantitative PCR.Results The male to female ratio of the 25 patients was 1 ∶ 1.8,and the aver-age age was 49 years.The tumor was confined to the thyroid gland.Of the 22 cases with a single nodule,5 cases were ill-de-marcated and 3 cases were multiple nodular lesions.The average size was 2.7 centimeter in diameter.Cytologically,the tumor cells were arranged in detached clusters with abundant eosino-philic and granular cytoplasm and hyperchromatic nuclei with prominent nucleoli.Histologically,the oncocytic tumor cells mainly arranged in trabecular and solid architecture.Capsular,blood and lymphoid vascular invasion could be observed in a cer-tain extent.Among 25 cases of OCA,8 cases were minimally in-vasive,14 cases were encapsulated angio-invasive and 3 cases were widely invasive.Positive immunoreaction with TTF-1,thy-roglobulin and CD56 supported the thyroid epithelial origination of the tumour.One recurrent case was found to have cervical lymph node metastasis,and another case was presented with bone metastasis,which was determined to harbor TERT promoter mu-tation(C228T)in each case.Different point mutation of RAS gene was determined in 2 cases(8%),respectively.Conclu-sion Oncocytic carcinoma of the thyroid shows typical eosino-philic and granular cytoplasm,immunohistochemical staining is helpful in differential diagnosis with other oncocytic lesions.It lacks BRAF-like mutation.Low frequency of RAS mutations could be found.Rare TERT promoter mutation has significant mutation with clinical behavior of OCA.

Objective:To explore the relationship between polycyclic aromatic hydrocarbons (PAHs) exposure and sleep quality in workers from a coking plant.Methods:From April to June 2019. Selected 632 employed workers in the coking plant of a large state-owned enterprise in Shanxi Province as the exposed group, and 477 employed workers in the water-pump plant belonged to the same enterprise as the control group. We used self-designed questionnaires to collect the basic information of subjects. We measured the concentrations of 12 PAHs in the peripheral blood of workers using gas chromatography-mass spectrometry (GC-MS) ; Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality of workers; The relationship between plasma PAHs concentration and sleep quality was analyzed using multiple linear regression model, restricted cubic spline (RCS) regression and logistic regression.Results:The concentration of 12 polycyclic aromatic hydrocarbons in the peripheral blood of the exposure group was (2.36±1.46) ng/ml, which was significantly higher than that of the control group (2.19±1.21) ng/ml. The detection rate of sleep disorder in the exposure group (18.0%) was higher than that in the control group (16.8%) , which was manifested by the significantly increased scores in subjective sleep quality, sleep latency, sleep disorders, daytime dysfunction, and PSQI. Multiple linear regression analysis showed that the PSQI score of workers in the high exposure group decreased by 0.80 (95% CI: -1.40~-0.19) points compared with the low exposure group, with a statistically significant difference ( P<0.05) . RCS analysis showed a non-linear dose-response relationship of PSQI score with PAHs cumulative exposure (plasma PAHs concentration multiplied by length of service) . The results of logistic regression showed that compared with the low level group, the risk of somnipathy in the middle level group of PAHs cumulative exposure decreased by 44%, among which the risk of sleep disorder in the drinkers decreased by 40%, while the risk of somnipathy in the high level group increased by 96% compared with the low level group. Stratified analysis of alcohol drinking habit showed non-significant difference in PSQI score with low, medium, and high levels of PAHs cumulative exposure in non-drinkers ( P>0.05) , and that the PSQI score was significantly increased in alcohol drinkers with high level of PAHs cumulative exposure compared to those with low and medium levels of PAHs cumulative exposure. Conclusion:The workers in the coking plant had high levels of PAHs in plasma and poor sleep quality, Higher level of PAHs cumulative exposure (>1396.56ng/ml) is a risk factor of poor sleep quality.

Objective:To explore the relationship between polycyclic aromatic hydrocarbons (PAHs) exposure and sleep quality in workers from a coking plant.Methods:From April to June 2019. Selected 632 employed workers in the coking plant of a large state-owned enterprise in Shanxi Province as the exposed group, and 477 employed workers in the water-pump plant belonged to the same enterprise as the control group. We used self-designed questionnaires to collect the basic information of subjects. We measured the concentrations of 12 PAHs in the peripheral blood of workers using gas chromatography-mass spectrometry (GC-MS) ; Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality of workers; The relationship between plasma PAHs concentration and sleep quality was analyzed using multiple linear regression model, restricted cubic spline (RCS) regression and logistic regression.Results:The concentration of 12 polycyclic aromatic hydrocarbons in the peripheral blood of the exposure group was (2.36±1.46) ng/ml, which was significantly higher than that of the control group (2.19±1.21) ng/ml. The detection rate of sleep disorder in the exposure group (18.0%) was higher than that in the control group (16.8%) , which was manifested by the significantly increased scores in subjective sleep quality, sleep latency, sleep disorders, daytime dysfunction, and PSQI. Multiple linear regression analysis showed that the PSQI score of workers in the high exposure group decreased by 0.80 (95% CI: -1.40~-0.19) points compared with the low exposure group, with a statistically significant difference ( P<0.05) . RCS analysis showed a non-linear dose-response relationship of PSQI score with PAHs cumulative exposure (plasma PAHs concentration multiplied by length of service) . The results of logistic regression showed that compared with the low level group, the risk of somnipathy in the middle level group of PAHs cumulative exposure decreased by 44%, among which the risk of sleep disorder in the drinkers decreased by 40%, while the risk of somnipathy in the high level group increased by 96% compared with the low level group. Stratified analysis of alcohol drinking habit showed non-significant difference in PSQI score with low, medium, and high levels of PAHs cumulative exposure in non-drinkers ( P>0.05) , and that the PSQI score was significantly increased in alcohol drinkers with high level of PAHs cumulative exposure compared to those with low and medium levels of PAHs cumulative exposure. Conclusion:The workers in the coking plant had high levels of PAHs in plasma and poor sleep quality, Higher level of PAHs cumulative exposure (>1396.56ng/ml) is a risk factor of poor sleep quality.

ObjectiveTo investigate the effect of macrophages (MCs) on the differentiation of mouse induced pluripotent stem cells (iPSCs) into hepatic progenitor cells (HPCs). MethodsA total of 24 C57BL/6N mice were used to obtain MCs by peritoneal irrigation, and the supernatant was collected to obtain the conditioned medium of MCs (MC-CDM). Activin A, bone morphogenetic protein 4, and fibroblast growth factor were used to induce the differentiation of mouse iPSCs into HPCs. The differentiation of HPCs were randomly divided into control group (normal medium) and experimental group (MC group; use of MC-CDM medium on day 5 of induction). Morphology, immunofluorescence assay, and Western blot were used to compare the morphology of HPCs and the expression of related proteins between the control group and the MC group. The t-test was used for comparison of continuous data between two groups. ResultsHPCs derived from iPSCs were established in vitro, and HPCs had the potential to differentiate into hepatocytes. Immunofluorescence assay showed that compared with the D12 control group, the D12 MC group had a significant increase in the protein expression of the HPC-specific protein CK19 (0.901±0.072 vs 0.686±0.097, t=-3.093, P＜0.05). Western blot showed that compared with the D12 control group, the D12 MC group had a significant increase in the protein expression of the HPC-related protein CK19 (1.922±0.103 vs 1.448±0.012, t =-7.881, P ＜005), as well as a significant increase in the protein expression of the autophagy-related protein LC3 (1.392±0.042 vs 1.101±0048, t =-5.978, P＜005). ConclusionMCs can promote the differentiation of mouse iPSCs into HPCs, possibly by increasing the autophagy level of HPCs.

Objective:To Investigate comprehensive predictive ability of first-trimester complete blood count combined with maternal characteristics for gestational diabetes mellitus (GDM).Methods:From May 2015 to July 2018, 1 412 pregnant women were retrospectively screened at the Fifth People′s Hospital of Shanghai, Fudan University. We recruited 258 women who developed GDM and 1 154 women who had normal glucose level during pregnancy. At the first visit, clinical data and complete blood count result were obtained. GDM prediction models were established through logistic regression analysis of GDM related risk factors and the prediction abilities of each model were compared.Results:Logistic regression analyses identified age, pre-pregnancy body mass index, previous GDM history, family history of diabetes mellitus, the neutrophil-to-lymphocyte ratio, leukocyte, neutrophil, and monocyte counts were significantly independent predictors of GDM. In the entire cohort, the predictive ability of neutrophil and monocyte counts together with maternal basal characteristics model for the development of GDM [areas under the receiver operating characteristic curve (AUC-ROC)=0.809, integrated discrimination improvement (IDI)=0.056, P=0.001] was the best among various models (basal characteristics model, AUC-ROC=0.753; Monocyte count+ basal characteristics model, AUC-ROC=0.764; neutrophil count + basal characteristics model, AUC-ROC=0.775). Similar results obtained by the same way in all pregnant women without previous GDM history. Conclusion:It could improve the prediction of GDM with model incorporated maternal characteristics and first-trimester neutrophil and monocyte counts.

Objective:To understand the concentration level of radon and its progeny in outdoor air in Beijing area and to analyze the related variation pattern and influencing factors.Methods:The continuous measurement device for radon and its progeny concentration is used for the one-year continuous measurement at three points in different directions in Beijing area.Results:The annual concentration average value was (10.9±4.9) Bq/m 3 for radon and (5.8±3.4) Bq/m 3 for its progeny (equilibrium equivalent radon concentration EEC) in outdoor air in Beijing with the annual average value of 0.52±0.19 for equilibrium factor F. Clear diurnal variations of the concentrations of radon and its progeny was observed. Conclusions:The result of one-year continuous measurement show that the concentrations of radon and its progeny in the outdoor air in Beijing area are close to the world average, lower than the typical values in China given by grab sampling measurement. The daily variation pattern of radon and its progeny concentrations is similar to those at home and abroad. The seasonal variation pattern features local climate in Beijing.