As the most aggressive breast cancer, triple-negative breast cancer (TNBC) is still incurable and very prone to metastasis. The transform growth factor β (TGF-β)-induced epithelial-mesenchymal transition (EMT) is crucially involved in the growth and metastasis of TNBC. This study reported that a natural compound isotoosendanin (ITSN) reduced TNBC metastasis by inhibiting TGF-β-induced EMT and the formation of invadopodia. ITSN can directly interact with TGF-β receptor type-1 (TGFβR1) and abrogated the kinase activity of TGFβR1, thereby blocking the TGF-β-initiated downstream signaling pathway. Moreover, the ITSN-provided inhibition on metastasis obviously disappeared in TGFβR1-overexpressed TNBC cells in vitro as well as in mice bearing TNBC cells overexpressed TGFβR1. Furthermore, Lys232 and Asp351 residues in the kinase domain of TGFβR1 were found to be crucial for the interaction of ITSN with TGFβR1. Additionally, ITSN also improved the inhibitory efficacy of programmed cell death 1 ligand 1 (PD-L1) antibody for TNBC in vivo via inhibiting the TGF-β-mediated EMT in the tumor microenvironment. Our findings not only highlight the key role of TGFβR1 in TNBC metastasis, but also provide a leading compound targeting TGFβR1 for the treatment of TNBC metastasis. Moreover, this study also points out a potential strategy for TNBC treatment by using the combined application of anti-PD-L1 with a TGFβR1 inhibitor.

BackgroundCompared with adult-onset schizophrenia， patients with adolescent-onset schizophrenia experience a high genetic susceptibility， severe negative symptoms， high recurrence rate， poor prognosis and social function recovery. And clarifying the brain functional alterations in adolescent-onset schizophrenia is of great significance for further elucidating the pathogenesis of the disease and exploring personalized and precise treatment. ObjectiveTo investigate the altered functional and effective connectivity of bilateral precuneus in first-episode patients with adolescent-onset schizophrenia based on resting-state functional magnetic resonance imaging （rs-fMRI）， thus providing reliable imaging evidence in guiding the study on mechanism involved in adolescent-onset schizophrenia. MethodsTwenty-one drugnaïve first-episode patients with adolescent-onset schizophrenia who met the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） criteria for schizophrenia were enrolled， and another 21 psychiatrially healthy controls matched on age， educational background and gender were concurrently selected. The schizophrenic subjects were evaluated using the Psychotic Symptom Rating Scales （PSYRATS） and Positive and Negative Symptom Scale （PANSS）. All participants underwent rs-fMRI scans， and the whole-brain seed-based functional and effective connectivity analyses were conducted in bilateral cuneus region. Then the correlation between functional connectivity strength and clinical symptoms of patients was discussed. ResultsIn terms of functional connectivity， the functional connectivity of bilateral precuneus and left middle temporal gyrus was increased in patient group compared with healthy control group ［P<0.01， family-wise error （FWE） correction at cluster level， P<0.05］. In terms of effective connectivity， patient group responded to negative feedback with greater activation of seed region and left middle frontal gyrus than healthy control group. Correlation analysis within patient group denoted that the decreased effective connectivity of bilateral precuneus and left middle frontal gyrus was positively correlated with the total PANSS score （r=0.450， P<0.05）. ConclusionThe resting-state functional and effective connectivity of bilateral precuneus is abnormally alerted in drugnaïve first-episode patients with adolescent-onset schizophrenia， and the decreased effective connectivity of bilateral precuneus and left middle frontal gyrus may be related to the development of clinical symptoms. ［Funded by National Key Research and Development Program of China （number， 2022YFC2009901， 2022YFC2009900）］

Objective:To describe the baseline characteristics of the subjects enrolled in the China Quantitative CT (QCT) big data program in 2018—2019.Methods:Based on baseline data from the Chinese health big data project from January 2018 to December 2019 from the eligible enrolled population, measurements of bone mineral density (BMD) and visceral adipose tissue (VAT) were performed using Mindways′ QCT Pro Model 4 system. The baseline data of age, gender, regional distribution, height, weight, abdominal circumference, blood pressure, blood routine and blood biochemical tests were analyzed. And the single factor analysis of variance (ANOVA) was used to check the age related trend of BMD and VAT in both genders.Results:After screening the inclusion exclusion criteria and outliers of the main indicators, 86 113 people were enrolled in the project. The enrollment rate was 92.47%, including 35 431 (41.1%) women and 50 682 (58.9%) men, and the ratio of men to women was 1.43. The mean age was (50.3±12.7) years in all the subjects, and it was (50.2±12.8) years and (50.4±12.5) years in men and women, respectively, and there was no statistical difference between the two genders ( P>0.05). Total of 43 833 people were enrolled in east China, it was the largest group by region (50.90%), it was followed by central China (16 434 people, 19.08%), and the number of people enrolled in Northeast China was the lowest (2 914 people, 3.38%). The rate of completing of health information indicators related to the main outcome of the study were all above 70%, and there were significant differences between men and women (all P<0.05). The mean BMD was (139.33±46.76) mg/cm 3 in women, (135.90±36.48) mg/cm 3 in men, which showed a decreasing trend with age in both gender (both P<0.001); the mean intra-abdominal fat area was (116.39±56.23) cm 2 in women, (191.67±77.07) cm 2 in men, and there was an increasing trend with age in both men and women (both P<0.001). Conclusions:There are gender differences in BMD and VAT measured by QCT with different age tendency, and there are gender differences in health information index. Regional factors should also be taken into account for regional differences in the inclusion of data.

Objective:To investigate the normal reference values of spinal bone mineral density measured by quantitative computed tomography (QCT) and the differences of bone mineral density (BMD) in different regions of in Chinese adult males.Methods:Men who underwent low-dose CT lung scan for cancer screening in regions of Northeast, North, East, South, Central and Southwest of China from January 2018 to December 2019 were selected. And the lumbar vertebrae BMD values in the male subjects were measured by the QCT system (Mindways Software, Inc.). The mean BMD values and their decline rates were calculated at an age interval of 10 years, and the prevalence of osteoporosis was calculated according to the American College of Radiology spine QCT osteoporosis diagnostic criteria.Results:A total of 50 682 males with a mean age of (50.22±12.79) years (ranged 20 to 98 years) were included in this study. The peak BMD of (173.11±28.56) mg/cm 3 in the healthy Chinese adult male population appeared in the age group of 20 to 29 years and then declined with age. Before the age of 70 years, the BMD was relatively higher in males in South China, and it was lower in Central China and Southwest China, and it was intermediate in Northeast, North and East of China, with statistically significant differences. There was no significant differences in BMD in the males in the two age groups of 70 to 79 years and 80 and older among the regions in China. The overall decline rate of spinal BMD in Chinese males under QCT was about 46.92% over the lifetime, and it declined obviouslyin the 40-49 age group. The overall prevalence of osteoporosis in Chinese male population aged 50 years and above was approximately 11.42%, with the highest prevalence in Southwest China and Central China (14.72% and 13.87%, respectively) and the lowest in North China and South China (8.53% and 7.71%, respectively). Conclusions:A reference of lumbar spine BMD values for healthy males in China based on QCT is established. BMD values were highest in South China and Lowest in Central China.

Objective:To analyze the clinical characteristics of patients with bisphosphonates related atypical femoral fractures(AFFS), thereby to facilitate early diagnosis.Methods:The clinical manifestations, biochemical indexes, imaging features and treatment follow-up of AFFS patients who were diagnosed in the Department of Osteoporosis and Bone Disease, the Sixth People′s Hospital Affiliated to Shanghai Jiaotong University from 2011 to 2019 were analyzed retrospectively, and the literature was reviewed.Results:A total of 5 cases of atypical bisphosphonate related femoral fractures were collected, all of them were female, with an average age of 68 years. All the 5 patients were treated with alendronate. Three patients were treated with 70 mg/week throughout the course, and two patients were treated with 10 mg/day at first, and changed to 70 mg/week later. The average course of treatment was 8.7 years, ranging from the shortest 5 years to the longest 17 years. Among the 5 cases, the shortest onset time was 3 years after taking medicine, and the longest was 16 years. The clinical features are as follows: all patients had prodromal pain before fracture which was characterized as dull except for case 4. Case 1 was bilateral thigh pain, the rest were unilateral thigh pain, which began to appear within 2-3 years before fracture. X-ray plain film showed thickening of the lateral bone cortex; radionuclide bone scan(ECT) showed active bone metabolism in the affected area. The abnormal manifestations of ECT were earlier than X-ray and MRI. The recognition of these features is helpful to the early diagnosis of AFFS. All 5 patients stopped bisphosphonates immediately, and continued to take calcium tablets. Active vitamin D was added to 4 cases. One case of incomplete fracture was treated conservatively with Teriparatide for one year, which was helpful to deter it from becoming complete fracture. 4 cases of complete fracture were treated with reduction and fixation, and all healed.Conclusion:Long-term use of bisphosphonates can increase the risk of AFFS. Strengthening the risk assessment during use can reduce the incidence of such fractures. Early diagnosis and reasonable treatment can improve the prognosis.

Objective:To identify causative genes for autosomal recessive woolly hair (ARWH) in a family.Methods:Clinical data were collected from two patients and other family members in a Chinese pedigree of Han nationality with ARWH. Peripheral blood samples were obtained from the two patients, their unaffected parents and 100 unrelated healthy individuals, and DNA was extracted from the blood samples. A next-generation skin-targeted sequencing panel was used to detect gene mutations in the patients, and Sanger sequencing was performed to verify the sequencing results. The function of protein encoded by the mutant gene was predicted.Results:Two missense mutations c.530T>G (p.Leu177Arg) and c.736T>A (p.Cys246Ser) were both identified in the LIPH gene of the two patients, which were inherited from their father and mother respectively. Neither of the two mutations was identified in the 100 unrelated healthy controls. Interspecies sequence alignment showed that leucine at amino acid position 177 and cysteine at amino acid position 246 of the protein encoded by the LIPH gene were highly evolutionarily conserved. As SIFT and Polyphen-2 softwares showed, the mutations c.530T>G (p.Leu177Arg) and c.736T>A (p.Cys246Ser) were both predicted to be detrimental variations.Conclusion:Two missense mutations c.530T>G (p.Leu177Arg) and c.736T>A (p.Cys246Ser) in the LIPH gene may contribute to the clinical phenotype of the two patients with ARWH in this family.

OBJECTIVES: To explore the method and significance of prenatal counseling in cardiac surgery for fetal congenital heart disease (CHD). METHODS: The prenatal counseling should be provided by experienced CHD experts. The preliminary clinical diagnosis based on relevant data was carried out, the prognosis risk for fetal CHD was graded, and the pathophysiological process and potential hazards of the disease were analyzed. The current condition of CHD in the treatment plan, the long-term quality of life, and the special requirements of parturition in place, period and mode were described. A reliable follow-up system of the fetuses was established, the diagnosis after delivery was verified, and surgical treatment was carried out timely. RESULTS: From January 2016 to December 2018, 225 parents with fetal CHD received prenatal counseling, including 60 fetuses (26.7%) with simple CHD and 165 (73.3%) with complex CHD, among which 59 cases (98.3%) and 93 cases (56.4%) decided to continue the pregnancy, respectively. During the follow-up, 118 fetuses were born, of which 66 infants received surgical treatment within 6 months after birth, 63 infants (95.5%) recovered and 3 infants (4.5%) died. The rest 52 infants continued to be followed up. CONCLUSIONS The prenatal counseling for fetal CHD can provide the parents a comprehensive medical information about CHD, which is beneficial to making appropriate pregnancy decisions, and can turn the fetuses from unreasonable birth and passive treatment to selective birth and active treatment in CHD.
Cardiac Surgical Procedures ; Counseling ; Female ; Fetus ; Heart Defects, Congenital ; surgery ; Humans ; Pregnancy ; Prenatal Diagnosis ; Quality of Life ; Ultrasonography, Prenatal

Hypercalcemic crisis (HC) is a rare but critical electrolyte disorder, which may result in death if rapid correct management is not given due to the injury of the neurologic, cardiovascular and renal systems. Severe primary hyperthyroidism (PHPT) is listed as the most common cause of hypercalcemic crisis. Prompt surgical removal of the parathyroid glands is the most effective cure for HC. Nevertheless, hypercalcemic crisis after a successful parathyroidectomy is infrequent. Now, we report a case admitted to the Department of General Surgery of the Shanghai Jiao Tong University Affiliated Sixth People’s Hospital about a successful therapy of hypercalcemic crisis postparathyroidectomy in Sep. 2019, aiming to remind clinicians of the individualized program of calcium supplement after surgery of hyperparathyroidism and emphasize the value of renal dialysis in HC.

Objective To quantitative evaluate the myocardial microcirculation dysfunction in patients with end-stage renal disease (ESRD),and to provide the imaging characteristic for early detection myocardial dysfunction and microcirculation damage in the ESRD patients after dialysis therapy.Methods Sixty-seven patients with ESRD and 1 9 healthy subj ects were enrolled in our study, and the ESRD patients were divided into two groups including patients with preserved systolic function (n=51,EF≥50%)and patients with impaired systolic function (n=16,EF＜50%).The LV regional myocardial perfusion parameters were analyzed including upslope, time to maximum signal intensity (TTM)and max signal intensity (Max SI).Those continuous variables were compared using one-way analysis of variance (A N OVA )in all three groups.Results Compared with the controls and the ESRD patients with preserved EF,the ESRD patients with impaired EF had a significantly lower SV and markedly increased LV mass (all P＜0.001).For the fist-pass perfusion analysis,first-pass perfusion Max SI of all segments were significantly reduced in the ESRD patients with preserved/impaired EF compared with the normal subjects (all P＜0.05).Compared with the ESRD patients with preserved EF and controls,the ESRD patients with impaired EF had lower upslope in the basal segment (P＜0.05).And the ESRD patients with preserved/impaired EF had shorter TTM in the apical segment than that in normal controls (P＜0.01).Conclusion The CMR first-pass perfusion can detect the myocardial deformation and dysfunction in ESRD patients,the Max SI may be more valuable to early detect myocardial microcirculation dysfunction.

Objective To investigate the differences between indocyanine green (ICG) fluorescence imaging plus methylene blue and plus Carbon Nanoparticles Suspension Injection for sentinel lymph node biopsy (SLNB)in breast cancer patients. Methods A total of 134 cases of early breast cancer patients performed SLNB from November 2013 to November 2016 were involved,of which 48 cases were performed with ICG fluorescence imaging plus methylene blue,and another 86 cases plus Carbon Nanoparticles Suspension Injection. Results There was no significant difference between ICG plus Methylene Blue group and ICG plus nano carbon group in terms of detection rate(P>0.05),detected numbers(P>0.05),sensitivity(P>0.05),accuracy(P>0.05)and false negative rate(P > 0.05). Age,and body mass index(BMI)exerted no influence on the detection rate and accuracy of SLNB in two groups(P>0.05). Conclusion ICG Fluorescence Imaging plus Methylene Blue showed similar detection rate , detected numbers , sensitivity , accuracy and false negative rate as it plus Carbon Nanoparticles Suspension Injection for SLNB in breast cancer patients ,and both of them can be performed easily and conveniently.