Clinical and biological heterogeneities in triple-negative breast cancer reveals a non-negligible role of HER2-low.

BACKGROUND: HER2-low could be found in some patients with triple-negative breast cancer (TNBC). However, its potential impacts on clinical features and tumor biological characteristics in TNBC remain unclear. METHODS: We enrolled 251 consecutive TNBC patients retrospectively, including 157 HER2-low (HER2low) and 94 HER2-negtive (HER2neg) patients to investigate the clinical and prognostic features. Then, we performed single-cell RNA sequencing (scRNA-seq) with another seven TNBC samples (HER2neg vs. HER2low, 4 vs. 3) prospectively to further explore the differences of tumor biological properties between the two TNBC phenotypes. The underlying molecular distinctions were also explored and then verified in the additional TNBC samples. RESULTS: Compared with HER2neg TNBC, HER2low TNBC patients exhibited malignant clinical features with larger tumor size (P = 0.04), more lymph nodes involvement (P = 0.02), higher histological grade of lesions (P < 0.001), higher Ki67 status (P < 0.01), and a worse prognosis (P < 0.001; HR [CI 95%] = 3.44 [2.10-5.62]). Cox proportional hazards analysis showed that neoadjuvant systemic therapy, lymph nodes involvement and Ki67 levels were prognostic factors in HER2low TNBC but not in HER2neg TNBC patients. ScRNA-seq revealed that HER2low TNBC which showed more metabolically active and aggressive hallmarks, while HER2neg TNBC exhibited signatures more involved in immune activities with higher expressions of immunoglobulin-related genes (IGHG1, IGHG4, IGKC, IGLC2); this was further confirmed by immunofluorescence in clinical TNBC samples. Furthermore, HER2low and HER2neg TNBC exhibited distinct tumor evolutionary characteristics. Moreover, HER2neg TNBC revealed a potentially more active immune microenvironment than HER2low TNBC, as evidenced by positively active regulation of macrophage polarization, abundant CD8+ effector T cells, enriched diversity of T-cell receptors and higher levels of immunotherapy-targeted markers, which contributed to achieve immunotherapeutic response. CONCLUSIONS: This study suggests that HER2low TNBC patients harbor more malignant clinical behavior and aggressive tumor biological properties than the HER2neg phenotype. The heterogeneity of HER2 may be a non-negligible factor in the clinical management of TNBC patients. Our data provide new insights into the development of a more refined classification and tailored therapeutic strategies for TNBC patients.

Survival prediction and analysis of drug-resistance genes in HER2-positive breast cancer.

Despite the approval of several therapeutic agents for HER2-positive breast cancer, drug resistance remains a significant challenge, hindering the patient's prognosis. Thus, our study aimed to establish a risk model to predict the prognosis of patients and identify key genes regulating drug resistance in HER2-positive breast cancer. Utilizing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), a predictive model was constructed based on 5 drug resistance-related genes, which demonstrated a notable capacity to indicate the survival rates of patients. Besides, through eccDNA and transcriptome sequencing of drug-sensitive and resistant cancer cells, 3 significant DEGs were identified: MED1, MED24, and NMD3. Among them, MED1 showed the most significant elevation in drug-resistance cells, highlighting its crucial role in mediating drug resistance. MED1 may serve as a valuable target for alleviating drug resistance in HER2-positive breast cancer.

Status of mental and social activities of young and middle-aged patients after papillary thyroid cancer surgery.

Background: Papillary thyroid cancer (PTC) is prevalent among younger populations and has a favorable survival rate. However, a significant number of patients experience psychosocial stress and a reduced quality of life (QoL) after surgical treatment. Therefore, comprehensive evaluations of the patients are essential to improve their recovery. Methods: The present study enrolled 512 young and middle-aged patients diagnosed with PTC who underwent surgery at our institution between September 2020 and August 2021. Each participant completed a series of questionnaires: Generalized Anxiety Disorder 7 (GAD-7), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), Thyroid Cancer-Specific Quality of Life Questionnaire (THYCA-QoL), and Readiness to Return-to-Work Scale (RRTW). Results: GAD-7 data showed that almost half of the study subjects were experiencing anxiety. Regarding health-related quality of life (HRQoL), participants reported the highest levels of fatigue, insomnia, voice problems, and scarring, with patients in anxious states reporting worse symptoms. Based on RRTW, more than half of the subjects had returned to work and had better HRQoL compared to the others who were evaluating a possible return to work. Age, gender, BMI, education, diet, residence, health insurance, months since surgery, monthly income, and caregiver status were significantly correlated with return to work. Additionally, having a caregiver, higher monthly income, more time since surgery, and living in a city or village were positively associated with return to work. Conclusion: Young and middle-aged patients with PTC commonly experience a range of health-related issues and disease-specific symptoms following surgery, accompanied by inferior psychological well-being, HRQoL, and work readiness. It is crucial to prioritize timely interventions targeting postoperative psychological support, HRQoL improvement, and the restoration of working ability in PTC patients.

Nomogram for predicting the risk of central lymph node metastasis in papillary thyroid microcarcinoma: a combination of sonographic findings and clinical factors.

Background: A considerable controversy over performing thyroidectomy and central lymph node dissection in patients with papillary thyroid microcarcinoma (PTMC) remained. However, accurate prediction of central lymph node metastasis (CLNM) is crucial for surgical extent and proper management. The aim of this study was to develop and validate a practical nomogram for predicting CLNM in patients with PTMC. Methods: A total of 1,029 patients with PTMC who underwent thyroidectomy and central lymph node dissection at Tangdu Hospital (the Second Affiliated Hospital of Air Force Medical University) and Xijing Hospital (the First Affiliated Hospital of Air Force Medical University) were selected. Seven hundred and nine patients were assigned to the training set and 320 patients to the validation set. Data encompassing demographic characteristics, ultrasonography results, and biochemical indicators were obtained. Stepwise backward selection and multiple logistic regression were used to screen the variables and establish the nomogram. Concordance index (C-index), receiver operating characteristic (ROC) curve analysis, and decision curve analysis (DCA) were employed to evaluate the nomogram's distinguishability, accuracy, and clinical utility. Results: Young age, multifocality, bigger tumor, presence of microcalcification, aspect ratio (height divided by width) ≥1, loss of fatty hilum, high free thyroxine (FT4), and lower anti-thyroid peroxidase antibody (TPOAb) were significantly associated with CLNM. The nomogram showed strong predictive capacity, with a C-index and accuracy of 0.784 and 0.713 in the training set and 0.779 and 0.703 in the external validation set, respectively. DCA indicated that the nomogram demonstrated strong clinical applicability. Conclusions: We established a reliable, cost-effective, reproducible, and noninvasive nomogram for predicting CLNM in patients with PTMC. This tool could be a valuable guidance for deciding on management in PTMC.

Biomechanical analysis of spinal cord injury during scoliosis correction surgery.

Introduction: Surgical correction is a common treatment for severe scoliosis. Due to the significant spinal deformation that occurs with this condition, spinal cord injuries during corrective surgery can occur, sometimes leading to paralysis. Methods: Such events are associated with biomechanical changes in the spinal cord during surgery, however, their underlying mechanisms are not well understood. Six patient-specific cases of scoliosis either with or without spinal complications were examined. Finite element analyses (FEA) were performed to assess the dynamic changes and stress distribution of spinal cords after surgical correction. The FEA method is a numerical technique that simplifies problem solving by replacing complex problem solving with simplified numerical computations. Results: In four patients with poor prognosis, there was a concentration of stress in the spinal cord. The predicted spinal cord injury areas in this study were consistent with the clinical manifestations of the patients. In two patients with good prognosis, the stress distribution in the spinal cord models was uniform, and they showed no abnormal clinical manifestations postoperatively. Discussion: This study identified a potential biomechanical mechanism of spinal cord injury caused by surgical correction of scoliosis. Numerical prediction of postoperative spinal cord stress distribution might improve surgical planning and avoid complications.

Mechanical influence of periacetabular osteotomy on late total hip arthroplasty.

Periacetabular osteotomy (PAO) is an effective technique to treat symptomatic hip dysplasia. However, following PAO, some patients still experience persistent pain or development of hip arthritis, requiring total hip arthroplasty (THA). Issues such as whether patients with PAO are necessarily at increased risk of post-THA complications and revision of the prosthesis remain debatable. The purpose of this study was to evaluate the biomechanical influence of PAO on the acetabulum after THA by finite element analysis. Eight patients with developmental dysplasia of the hip (DDH) diagnosed in the Fourth Medical Center of the PLA General Hospital were enrolled in this research. Patient-specific hip joint models were reconstructed from computed tomography scans, and the hip prosthesises, were established via computer-aided design (CAD) modeling technology. The finite element analysis was conducted to compare the surface and internal stress through the process mapping of the model due to the THA. Compared with the THA after PAO, the position of the high-stress area of the acetabular fossa of patients without PAO decreased, and the high-stress area developed toward the lower edge of the acetabulum. Although the high-stress area of the suprapubic branch did not change significantly, the peak stress was higher (t = .00237). The analysis of the section plane showed that the high-stress area of cancellous bone had a large distribution. The acetabular size and vertical distance of rotation center (VDRC) were significantly correlated with the maximum postoperative acetabular equivalent stress (p = .011, p = .001). In the Post group, both the horizontal distance of rotation center (HDRC) and A-ASA were significantly correlated with postoperative maximal acetabular equivalent stress, with a significance of 0.014 and 0.035, respectively. The risk of postoperative prosthetic revision following THA is not increased by PAO, although the risk of postoperative suprapubic branch fracture is increased.

An Analysis of Trabecular Bone Structure Based on Principal Stress Trajectory.

To understand the mechanism of Wolff's law, a finite element analysis was performed for a human proximal femur, and the principal stress trajectories of the femur were extracted using the principal stress visualization method. The mechanism of Wolff's law was evaluated theoretically based on the distribution of the principal stress trajectories. Due to the dynamics of the loads, there was no one-to-one correspondence between the stress trajectories of the fixed load and the trabeculae in the cancellous architecture of the real bone. The trabeculae in the cancellous bone were influenced by the magnitude of the principal stress trajectory. Equivalent principal stress trajectories suitable for different load changes were proposed through the change in load cycle and compared with the anatomical structure of the femur. In addition, the three-dimensional distribution of the femoral principal stress trajectory was established, and the adaptability potential of each load was discussed. The principal stress visualization method could also be applied to bionic structure design.

Clusterin is a biomarker of breast cancer prognosis and correlated with immune microenvironment.

Background: It has been established that clusterin is involved in the invasion of immune cells in the tumor microenvironment, but it remains unknown how it promotes immune invasion in breast cancer. Methods: We used Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to assess the relation between expression of clusterin and immunoinfiltration-related marker genes. TIMER database was used to evaluate the expression of clusterin, and its relation to tumor immune invasion was examined. Based on Kaplan-Meier plotter database, we investigated the association between clusterin expression and prognosis in patients with cancer, and the impact of clinicopathological factors and cancer-related outcomes. Results: Clusterin expression was markedly associated with prognosis of a variety of tumors, specifically breast cancer. Enhanced clusterin expression was markedly associated with molecular typing of breast cancer and expression of multiple markers related to specific immune cell subsets. Conclusions: These results indicate that clusterin is connected to prognosis of breast cancer patients and tumor immune cell infiltration. This demonstrates that clusterin may be a biomarker of immune cell recruitment into breast tumors and an important biomarker for immune cell infiltration; consequently being a valuable prognostic factor in breast cancer patients.

Effects of COVID-19 vaccination on cervical lymph nodes in patients with thyroid cancer.

Background: Cervical lymph node enlargement caused by coronavirus disease 2019 (COVID-19) vaccination has been reported, but little is known on whether the vaccination would influence preoperative cervical lymph node evaluation and its risk of lymph node metastasis in thyroid cancer. Methods: We retrospectively analyzed data of patients who underwent thyroid cancer surgery in Tangdu Hospital, China, from 1 March 2021 to 30 June 2021. A total of 182 patients were included in the cohort study. All patients with suspected malignant tumors underwent ultrasound (US)-guided fine needle aspiration (FNA) of thyroid lesions before surgery to confirm the diagnosis. Cervical lymph nodes were evaluated by preoperative physical examination and imaging. Wilcoxon rank-sum test and Fisher's exact test were used to evaluate the effect of vaccination on cervical lymph nodes in patients with thyroid cancer. Statistical significance was defined at P<0.05. Results: The patients were divided into two groups according to whether they had been vaccinated or not. Our results showed that there were no significant differences between the two groups in the brand of the vaccine, operation method, and the extent of surgery. Moreover, there was no significant difference in the evaluation of US characteristics of cervical lymph nodes between the two groups regardless of having the vaccination or not. Interestingly, US evaluation found that the experimental group's proportion of cervical lymph node enlargement increased significantly within 14 days after vaccination, which was statistically significant. Conclusions: This study found that vaccination against COVID-19 did not increase the number of cervical lymph node metastases, but inaccurate assessment of cervical lymph nodes in thyroid cancer patients within 14 days of vaccination (due to temporary lymph node enlargement) may lead to more extensive surgery.

Role of the Anterior Center-Edge Angle on Acetabular Stress Distribution in Borderline Development Dysplastic of Hip Determined by Finite Element Analysis.

Background: The joint with hip dysplasia is more likely to develop osteoarthritis because of the higher contact pressure, especially in the socket. The lateral center-edge angle (LCEA) is the major indicator for hip dysplasia via radiography. However, the pathological conditions of LCEA angles in the range of 18°-25° are still controversial, which challenges precise diagnosis and treatment decision-making. Objective: The purpose of this study is to investigate the influence of anterior center-edge angle (ACEA) on the mechanical stress distribution of the hip joint, via finite element analysis, to provide insights into the severity of the borderline development dysplasia. Methods: From 2017 to 2019, there were 116 patients with borderline developmental dysplasia of the hip (BDDH) enrolled in this research. Based on the inclusion criteria, nine patients were involved and categorized into three LCEA groups with the maximal ACEA differences. Patient-specific hip joint models were reconstructed from computed tomography scans, and the cartilages, including the labrum, were established via a modified numerical method. The finite element analysis was conducted to compare the stress distributions due to the different ACEA. Results: As ACEA decreased, the maximum stress of the acetabulum increased, and the high stress area developed toward the edge. Quantitative analysis showed that in the cases with lower ACEA, the area ratio of high stress increased, and the contact facies lunata area significantly affected the stress distribution. Conclusion: For patients with BDDH, both the ACEA and the area of facies lunata played essential roles in determining the severity of hip dysplasia and the mechanical mechanism preceding osteoarthritis.

Tumor microbiome diversity influences papillary thyroid cancer invasion.

Papillary thyroid carcinoma (PTC) has a high incidence, and its proper treatment remains challenging. Therefore, identifying PTC progression markers is essential. Here, using 16S RNA sequences, we analyzed the PTC intratumor microbiome and its role in tumor progression. Substantial microbial abundance was detected in PTC from all patients. The tumor bacterial diversity in patients with advanced lesions (T3/T4) was significantly higher than that in patients with relatively mild lesions (T1/T2). Importantly, we identified signatures of eight tumor bacterial taxa highly predictive of PTC invasion status. Hence, microbial host factors-independent of the genomic composition of the tumor-may determine tumor behaviors and patient outcomes. Furthermore, the correlation between specific bacterial genus and thyroid hormones or autoimmune thyroid disease-related antibodies may indicate the potential contribution of the microbiome in the relationship between autoimmune thyroid disease or irregular thyroid function and PTC progression, intervention of which might therefore be worth exploring for advancing oncology care.

EccDNA-oriented ITGB7 expression in breast cancer.

Background: Extrachromosomal circular DNA (eccDNA) is omnipresent in cancers and related to the progression of tumors and oncogene amplification. However, its function in breast cancer (BC) is unclear. Methods: After constructing the DNA library, CLeavage Effects by Circularization for In vitro Reporting of sequencing was performed for eccDNA detection using 1 BC tissue sample. Fastqc was used to evaluate the quality of the original data. Burrows-Wheeler-Alignment Tool was used to compare the original data to the reference genome. A Circle-MAP was subsequently performed to detect eccDNA, and Bedtools was used to annotate the eccDNA genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted by ClusterProfiler. The Genotype-Tissue Expression and the Cancer Genome Atlas databases were used to collect the ribonucleic acid-sequencing data of the BC and normal samples. A Gene Expression Profiling Interactive Analysis, the University of Alabama at Birmingham CANcer data analysis Portal, and Kaplan-Meier survival curves were used to analyze the Cancer Genome Atlas data. Results: A total of 200 eccDNA genes, including IGTB7, were obtained. About the biological processes (BPs), these 200 genes were mainly enriched in actin cytoskeleton reorganization and axon guidance. Concerning the molecular functions (MFs), these 200 genes were mainly enriched in sodium ion transmembrane transporter activity and metal ion transmembrane transporter activity. As for cellular components (CCs), these 200 genes were mainly enriched in the transcription regulator complex and focal adhesion. ITGB7 was significantly enriched in cell-matrix adhesion and localization within the membrane in the BPs, integrin binding in the MFs, and cell-substrate junction and focal adhesion in the CCs. The 200 eccDNA genes were mainly enriched in the PI3K-Akt signaling pathway and focal adhesion. Notably, ITGB7 was enriched in focal adhesion, ECM-receptor interaction, the PI3K-Akt signaling pathway, and human papillomavirus infection. Besides, ITGB7 was significantly upregulated in BC patients and was associated with the menopause status of the BC patients. Conclusions: ITGB7 might serve as a prognostic marker for BC patients. ITGB7 has important implications for the individualized clinical treatment of BC patients.

Development and external validation of a prognostic nomogram for patients with gastric cancer after radical gastrectomy.

BACKGROUND: Gastric cancer (GC) is one of the most malignant diseases and threatens the health of individuals across the globe. Hitherto, the identification of prognosis risk stratification on GC has mainly depended on the TNM staging, but owing to its inaccuracy and incompleteness, the prognostic value it offers remains controversial in the current clinical setting. Thus, an effective prognostic model for GC after radical gastrectomy is still needed. METHODS: Patients with pathologically confirmed GC who underwent radical gastrectomy from 2 different centers were retrospectively enrolled into a training and the validation cohort, respectively. The least absolute shrinkage and selection operator (LASSO) algorithm was applied to select variables among multiple factors, including clinical characteristics, pathological parameters, and surgery- and treatment-related indicators. The multivariate Cox regression method was used to establish the model to predict 1-, 2-, and 3-year survival. Both internal and external validations of the nomogram were then completed in terms of discrimination, calibration, and clinical utility. Finally, prognostic risk stratification of GC was conducted with X-tile software. RESULTS: A total of 1,424 patients with GC were eligible in this study, including 1,010 in the training cohort and 414 in the validation cohort. Seven indicators were selected by LASSO to develop the nomogram, including the number of positive lymph nodes, tumor size, adjacent organ invasion, vascular invasion, the level of carbohydrate antigen 125 (CA 125), depth of invasion, and human epidermal growth factor receptor 2 (HER2) status. The nomogram demonstrated a robust predictive capacity with favorable accuracy, discrimination, and clinical utility both in the internal and external validations. Moreover, we divided the population into 3 risk groups of survival according to the cutoff points generated by X-tile, and in this way, the nomogram was further improved into a risk-stratified prognosis model. CONCLUSIONS: We have developed a prognostic risk stratification nomogram for GC patients after radical gastrectomy with 7 available indicators that may guide clinical practice and help facilitate tailored decision-making, thus avoiding overtreatment or undertreatment and improving communication between clinicians and patients.

PLCE1 Polymorphisms Are Associated With Gastric Cancer Risk: The Changes in Protein Spatial Structure May Play a Potential Role.

BACKGROUND: Gastric cancer (GC) is one of the most significant health problems worldwide. Some studies have reported associations between Phospholipase C epsilon 1 (PLCE1) single-nucleotide polymorphisms (SNPs) and GC susceptibility, but its relationship with GC prognosis lacked exploration, and the specific mechanisms were not elaborated fully yet. This study aimed to further explore the possible mechanism of the association between PLCE1 polymorphisms and GC. MATERIALS AND METHODS: A case-control study, including 588 GC patients and 703 healthy controls among the Chinese Han population, was performed to investigate the association between SNPs of PLCE1 and GC risk by logistic regression in multiple genetic models. The prognostic value of PLCE1 in GC was evaluated by the Kaplan-Meier plotter. To explored the potential functions of PLCE1, various bioinformatics analyses were conducted. Furthermore, we also constructed the spatial structure of PLCE1 protein using the homology modeling method to analyze its mutations. RESULTS: Rs3765524 C > T, rs2274223 A > G and rs3781264 T > C in PLCE1 were associated with the increased risk of GC. The overall survival and progression-free survival of patients with high expression of PLCE1 were significantly lower than those with low expression [HR (95% CI) = 1.38 (1.1-1.63), P < 0.01; HR (95% CI) = 1.4 (1.07-1.84), P = 0.01]. Bioinformatic analysis revealed that PLCE1 was associated with protein phosphorylation and played a crucial role in the calcium signal pathway. Two important functional domains, catalytic binding pocket and calcium ion binding pocket, were found by homology modeling of PLCE1 protein; rs3765524 polymorphism could change the efficiency of the former, and rs2274223 polymorphism affected the activity of the latter, which may together play a potentially significant role in the tumorigenesis and prognosis of GC. CONCLUSION: Patients with high expression of PLCE1 had a poor prognosis in GC, and SNPs in PLCE1 were associated with GC risk, which might be related to the changes in spatial structure of the protein, especially the variation of the efficiency of PLCE1 in the calcium signal pathway.