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The human placenta is a dynamic and heterogeneous organ critical in the establishment of the fetomaternal interface and the maintenance of gestational well-being. It is also the major source of cell-free fetal nucleic acids in the maternal circulation. Placental dysfunction contributes to significant complications, such as preeclampsia, a potentially lethal hypertensive disorder during pregnancy. Previous studies have identified significant changes in the expression profiles of preeclamptic placentas using whole-tissue analysis. Moreover, studies have shown increased levels of targeted RNA transcripts, overall and placental contributions in maternal cell-free nucleic acids during pregnancy progression and gestational complications, but it remains infeasible to noninvasively delineate placental cellular dynamics and dysfunction at the cellular level using maternal cell-free nucleic acid analysis. In this study, we addressed this issue by first dissecting the cellular heterogeneity of the human placenta and defined individual cell-type–specific gene signatures by analyzing more than 24,000 nonmarker selected cells from full-term and early preeclamptic placentas using large-scale microfluidic single-cell transcriptomic technology. Our dataset identified diverse cellular subtypes in the human placenta and enabled reconstruction of the trophoblast differentiation trajectory. Through integrative analysis with maternal plasma cell-free RNA, we resolved the longitudinal cellular dynamics of hematopoietic and placental cells in pregnancy progression. Furthermore, we were able to noninvasively uncover the cellular dysfunction of extravillous trophoblasts in early preeclamptic placentas. Our work showed the potential of integrating transcriptomic information derived from single cells into the interpretation of cell-free plasma RNA, enabling the noninvasive elucidation of cellular dynamics in complex pathological conditions.

PurposeDespite numerous studies on the utility of GATA-3 as breast cancer marker, its comparison with other breast markers, its concordance between primary and metastatic tumors and its expression in primary cancers from sites with frequent breast metastases remains unclear.MethodsTo address these questions, totally 993 invasive breast cancers (IBC), 254 paired nodal metastases, 23 distant metastases, and 208 lung carcinomas were included. GATA-3 expression was analyzed by immunohistochemistry and compared to other breast markers [gross cystic disease fluid protein 15 (GCDFP-15) and mammaglobin (MGB)].ResultsGATA-3 was expressed in 82.5% of IBC, predominantly in luminal (93.9%), and lower in non-luminal cancers [59.6% of HER2 overexpressing (HER2-OE) and 38.1% of triple negative breast cancer (TNBC) subtypes]. GATA-3 identified more IBC than GCDFP-15 (23.9%) and MGB (46.6%). However, MGB showed a comparable sensitivity for non-luminal cancers to GATA-3. Combining MGB and GATA-3 improved sensitivity for both HER2-OE (80.8%) and TNBC cases (55.4%). GATA-3 showed a high sensitivity for nodal metastases and distant metastases, with good concordance with primary tumors. GATA-3 was expressed in 1.0% of lung carcinomas, with sensitivity and specificity of 82.5 and 99.0% in differentiating IBC and lung carcinoma.ConclusionsGATA-3 expression was the highest in luminal breast carcinomas, and showed higher sensitivity than GCDFP-15 and MGB. However, in the poorly differentiated IBC, its utility was still limited. One should be aware of the possible GATA-3 expression in lung carcinomas.

PurposeSETD2 is one of the key epigenetic regulatory genes involved in histone modifications. Its alterations were potentially oncogenic and commonly found in cancers. Interestingly, SETD2 is one of the most frequent mutated genes found exclusively in phyllodes tumor of the breast (PT). However, little has been done to further characterize SETD2 alterations in PT.MethodsIn this study, we examined the alterations of SETD2 gene and protein expression in a large cohort of PTs. Their correlations with SETD2 downstream target, H3K36me3 expression, and clinicopathologic features in PT were also assessed.ResultsSETD2 mutation was found in 15.9% of our cases and was mostly predicted to be damaging mutations. Interestingly, SETD2 mutations were associated with lower H3K36me3 expression, particularly those with damaging mutations (p = .041). Neither SETD2 mutations nor H3K36me3 expression was associated with PT grading and other clinicopathological features. By contrast, the SETD2 protein expression cannot reflect its mutation status and showed a different trend of clinicopathological correlations from H3K36me3.ConclusionsOur findings may suggest a potential involvement of epigenetic regulation via SETD2 alterations and downstream H3K36me3 on PT development. SETD2 mutations may occur early in the pathogenic process of PTs and its loss per se may not be sufficient for progression to malignancy. Exclusive alterations of SETD2 in PT can be used as markers for the diagnosis of fibroepithelial lesions. The association of H3K36me3 with SETD2 mutations may also indicate the value of evaluation of H3K36me3 expression in the diagnosis of fibroepithelial lesions.

The proportion of cardiac abnormalities in patients with idiopathic scoliosis(IS) who required surgery is relatively high. However, the specific cause and underlying risk factors remain poorly elucidated. A retrospective study. To investigate the proportion of cardiac abnormalities in patients with IS and identify the related risk factors. Clinical and imaging data from 289 IS patients aged 6–18 years including 225 females and 64 males admitted to our center from January 2015 and March 2023 were analyzed. The records of echocardiography, spinal radiographs and magnetic resonance imaging were reviewed. Calculate the proportion of congenital heart disease and cardiac abnormalities related to heart valves in patients with IS, and screen the risk factors by multivariate analysis. Twelve patients (4.15%) had congenital heart disease, with atrial septal defect being the most common type (1.73%). Eighty-eight patients (30.45%) had cardiac abnormalities related to heart valves, with mild tricuspid regurgitation being the most common type (17.65%). There were no statistically significant differences in the proportion of congenital heart disease among groups based on gender( P  = 0.096), age(6 ~ 10 vs. 11–18, P  = 0.200), ethnicity(Han vs. Minority, P  = 0.969), BMI grade(Emaciation vs. Normal vs. Overweight/Obesity, P  = 0.512), altitude(< 2000 m vs. ≥ 2000 m, P  = 0.078), main curvature location(Thoracic vs. Thoracolumbar vs. Lumbar, P  = 0.326), severity of scoliosis(Deformed vs. Highly deformed, P  = 0.841), main direction( P  = 0.102), and chest aspect ratio(< 0.45 vs. ≥ 0.45, P  = 0.341). The proportion of cardiac abnormalities related to heart valves was higher in males, patients with thoracolumbar IS, and patients with left-sided scoliosis ( P  < 0.05). Multivariate analysis showed that males and thoracolumbar scoliosis were risk factors for cardiac abnormalities related to heart valves in patients with IS ( P  < 0.05). Linear regression analysis showed that altitude had a weak correlation with IS combined with congenital heart disease (R²=0.018, P  < 0.05). Among 289 patients with idiopathic scoliosis who required surgery, 4.15% had congenital heart disease, and 30.45% had cardiac abnormalities related to heart valves. Males and scoliosis in thoracolumbar were risk factors for cardiac abnormalities related to heart valves in patients with idiopathic scoliosis.

Scoliosis is often associated with syringomyelia (SM). As an important role in SM formation, the influence from abnormal cerebrospinal fluid (CSF) flow is still unclear to scoliosis. The aim of this experimental work is to explore the connection between CSF flow and scoliosis through imaging and histological analysis on the basis of a kaolin-induced scoliotic rabbit model. For imaging observation, in 40 kaolin-induced rabbits by C7 spinal cord injection, through pre- and postoperative MRI and radiography, CSF flow and scoliosis formation were detected at consecutive phases. According to the final formation of scoliosis until postoperative week 12, the kaolin-induced rabbits were divided into 2 groups. Through comparing the 2 groups, the relationship between the changes of CSF flow velocity and scoliosis formation were reviewed and analyzed. For histological observation, another 20 kaolin-induced rabbits were used for consecutive histological observations of spinal cord at postoperative 3-day, 2-week, 4-week and 6-week. After kaolin-induction, abnormal spinal coronal curve was observed from postoperative week 6 in the 37 survived rabbits. At postoperative week 12, scoliosis formation was detected in 73.0% kaolin-induced rabbits and the mean Cobb angle was 27.4°. From the comparison between scoliotic and non-scoliotic groups, the difference of the velocities of CSF flow was more obviously from postoperative week 4 to 12, especially after week 6. In the scoliotic group, the peak velocity of CSF flow was diseased gradually following scoliosis formation after induction. Moreover, the decrease of the peak velocities of CSF flow from preoperation to postoperative 12 weeks (ΔVmax), including up-flow (ΔVUmax) and down-flow (ΔVDmax), were positively correlated to the final scoliotic Cobb angle ( P  < 0.01). Through histological observation at different phases, the distinctive pathological changes of the spinal cord included early inflammatory reaction, adhesion and blockage in the subarachnoid space and the central canal, perivascular space enlargement, central canal expansion, which suggested the CSF flow being blocked by multiple ways after kaolin-induction. In conclusion, experimental scoliosis can be successfully induced by intraspinal kaolin injection. In this model, continuous hypodynamic change of CSF flow was correlated to the formation of scoliosis, which could be an important factor of scoliotic pathogenesis being explored furtherly.

PurposeTo develop a clinically feasible classification for severe spinal deformity based on X-ray features.MethodsA total of 223 consecutive severe spinal deformity cases who underwent corrective operation were enrolled from 2004 to 2015 retrospectively. Based on X-ray features, a novel classification was developed containing three components: curve types, curve angle and apex location. There were five curve types as follows: single scoliosis (SS), kyphoscoliosis (KS), angular deformity (AD), long curve (LC), and double curves (DC). Curve angle subsection on coronal and sagittal planes including A:90–109, B:110–129, C:130–149, D: > 150. Apex location means the exact level of apex located. Reliability of the classification was tested.ResultsThe kappa values for inter-observer and intra-observer reliability of the curve types, curve angle, and apex level were larger than 0.80. X-ray classification for overall patients with severe spinal deformity showed that there were 101 SS cases, 47 KS, 46 AD, 19 LC and 10 DC. For the curve angle, there were grade A 123 cases, B 43, C 18, D 15 on coronal plane and grade A 38, B 17, C 16, and D 19 on sagittal plane. Apex location showed there were 27 patients at T7 or upper levels, 31 on T8, 58 on T9, 45 on T10, 18 on T11, and 44 at T12 or lower levels.ConclusionA novel classification for severe spinal deformity was described based on X-ray morphology. A high value for inter-observer and intra-observer reliability was shown. Each subgroup has its particular influence on decision-making and prognostic prediction.

The underlying basis for cancer immune evasion is important for effective immunotherapy and prognosis in breast cancers. Human leucocyte antigens (HLA)-I comprising three classical antigens (HLA-A, -B and -C) is mandatory for anti-tumor immunity. Its loss occurred frequently in many cancers resulting in effective immune evasion. Most studies examined HLA-I as a whole. Alterations in specific locus could have different clinical ramifications. Hence, we evaluated the expression of the three HLA-I loci in a large cohort of breast cancers. Low expression of HLA-A, -B and -C were found in 71.1%, 66.3%, and 60.2% of the cases. Low and high expression in all loci was found in 48.3% and 17.9% of the cases respectively. The remaining showed high expression in one or two loci. Cases with all HLA high expression (all HLA high) was frequent in the ER-HER2- (27.4%) and ER-HER2+ (23.1%) cases and was associated with characteristic pathologic features related to these tumor (higher grade, necrosis, high tumor infiltrating lymphocyte (TIL), pT stage, low hormonal receptor, high basal marker expression) (p ≤ 0.019). Interestingly, in HER2+ cancers, only cases with all HLA high and high TIL showed significantly better survival. In node positive cancers, concordant high HLA expression in primary tumors and nodal metastases was favorable prognostically (DFS: HR = 0.741, p < 0.001; BCSS: HR = 0.699, p = 0.003). The data suggested an important clinical value of a combined analysis on the co-expression HLA-I status in both primary and metastatic tumors. This could be a potential additional key component to be incorporated into TIL evaluation for improved prognostication.

AimsIn breast cancer models, the functional roles of CD147 in proliferation, invasion and treatment resistance have been widely reported. However, there are only a few studies examining the clinicopathological correlation and prognostic relevance of CD147 in breast cancer, especially in relation to breast cancer molecular subtypes.MethodsIn this study, we analysed CD147 expression in a large cohort of breast cancers, correlating with clinicopathological features and the expression of a comprehensive panel of biomarkers in triple-negative breast cancer (TNBC) and non-TNBC subsets. Its relationship with patients’ survival was also analysed.ResultsCD147 was expressed in 11.9%(140/1174) of all cases and in 23.8% (40/168) of TNBC. The expression was associated with tumour histological subtypes (p=0.01) and most commonly seen in carcinoma with medullary features (26.0%). CD147 expression correlated with high tumour grade, presence of necrosis and basal-like breast cancer (BLBC) subtype, high Ki67 and expression of some other basal markers and stem-like markers. CD147 expression was also associated with poor overall survival in chemotherapy treated patients with TNBC.ConclusionsCD147 is a putative marker in identifying TNBC or BLBC, and may be useful as a prognosis indicator for patients with TNBC or BLBC post chemotherapy.

AimsIHC4 score, based on expression of four routine markers (oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker, Ki67), is a recently developed, cost-effective prognostic tool in breast cancer. Possibly, the score may be useful also in advanced diseases where only core needle biopsy (CNB) is available and neoadjuvant therapy. However, its studies on CNB are scant. This study examined whether IHC4 score assessment on CNB is comparable to that from whole section (WS).MethodsImmunohistochemical (IHC) analysis was performed for ER, PR, HER2 and Ki67 on 108 paired CNB and WS to evaluate IHC4 score (with follow-up range 1–230 months and 5 relapse/death). Concordance between the two was examined. Factors that affected the concordance were analysed. Additionally, IHC4 score was compared with Nottingham Prognostic Index (NPI).ResultsThere was moderate concordance between IHC4 score on CNB and WS (all cases: κ=0.699, p<0.001; ER+ cases: κ=0.595, p<0.001). Among the IHC4 components, concordance for HER2 was the poorest (κ=0.178, p<0.001 in all cases; ER+ cases: κ=0.082, p<0.097). Significant factors affecting concordance between CNB and WS included number of cores, total core length and percentage of tumour cells in cores (p≤0.030), indicating the importance of sufficient sampling. Interestingly, the concordance was also affected by patients’ age (p=0.039). There was poor agreement between IHC4 score and NPI (κ≤0.160).ConclusionOur results suggested that IHC4 score can be used on adequately sampled CNB. Its poor agreement with NPI highlights the independence of the two factors.

Phyllodes tumor (PT) of the breast is a rare but clinically important fibroepithelial tumor with potential risks of recurrence and metastasis. Recent studies identified recurrent TERT promoter mutations in PTs. However, the clinical significance of this alteration has not been fully examined. Two hundred and seven PTs from two intuitions were included. All cases were subjected to immunohistochemical analysis for TERT expression. Analysis of TERT promoter mutations was further performed by Sanger sequencing targeting the hotspot mutation region on cases from one of the involved institutions. The expression of TERT was correlated with clinicopathologic features, mutation status and recurrence. There was an association of TERT expression and its promoter mutation. Both stromal TERT expression and its promoter mutation correlated with PT grading and older patient age. Recurrence free survival (RFS) of PT patients with high stromal TERT expression was shorter if the excision margin was positive. Our findings suggested a possible pathogenic role of TERT alteration in PT malignancy. Currently there is no consensus for re-excision for PT patients with positive surgical margin, particularly for low grade cases. Stromal TERT expression could be potentially useful to guide management patients with benign PTs.