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.

A High-Efficiency Capture-Based NGS Approach for Comprehensive Analysis of Mitochondrial Transcriptome.

The transcription of the mitochondrial genome is pivotal for maintenance of mitochondrial functions, and the deregulated mitochondrial transcriptome contributes to various pathological changes. Despite substantial progress having been achieved in uncovering the transcriptional complexity of the nuclear transcriptome, many unknowns and controversies remain for the mitochondrial transcriptome, partially owing to the lack of a highly efficient mitochondrial RNA (mtRNA) sequencing and analysis approach. Here, we first comprehensively evaluated the influence of essential experimental protocols, including strand-specific library construction, two RNA enrichment strategies, and optimal rRNA depletion, on accurately profiling mitochondrial transcriptome in whole-transcriptome sequencing (WTS) data. Based on these insights, we developed a highly efficient approach specifically suitable for targeted sequencing of whole mitochondrial transcriptome, termed capture-based mtRNA seq (CAP), in which strand-specific library construction and optimal rRNA depletion were applied. Compared with WTS, CAP has a great decrease of required data volume without affecting the sensitivity and accuracy of detection. In addition, CAP also characterized the unannotated mt-tRNA transcripts whose expression levels are below the detection limits of conventional WTS. As a proof-of-concept characterization of mtRNAs, the transcription initiation sites and mtRNA cleavage ratio were accurately identified in CAP data. Moreover, CAP had very reliable performance in plasma and single-cell samples, highlighting its wide application. Altogether, the present study has established a highly efficient pipeline for targeted sequencing of mtRNAs, which may pave the way toward functional annotation of mtRNAs and mtRNA-based diagnostic and therapeutic strategies in various diseases.

Growth factor receptor bound protein-7 regulates proliferation, cell cycle, and mitochondrial apoptosis of thyroid cancer cells via MAPK/ERK signaling.

It is of great significance to explore the molecular mechanism of thyroid cancer (TC) pathogenesis for its improvement and therapy. Growth factor receptor bound protein-7 (GRB7) has been regarded as an important regulatory gene in the developments of various malignant tumors. Our study aimed to illustrate the role of GRB7 in the TC pathology mechanism. Firstly, GRB7 was found to be significantly upregulated in 49 cases of TC tissues and 5 TC cell lines by using real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. Silencing GRB7 with siRNA dramatically inhibited proliferation and induced cell cycle arrest in TC cells. Besides, GRB7 silence resulted in the decrease of adenosine triphosphate content, glucose uptake, and lactose production in TC cells and attenuated the activity and expression of mitochondrial respiratory complex. We also demonstrated that GRB7 downregulation increased the levels of Bax and caspase 3, and inhibited the expression of Bcl-2, suggesting the induced mitochondrial apoptosis. More importantly, our study proved that mitogen-activated protein kinase/extracellular-regulated protein kinases (MAPK/ERK) signaling played a crucial role in the regulation of GRB7 on TC cell functions. In general, the present research verified that GRB7 was upregulated during TC development and modulated the proliferation, cell cycle, and mitochondrial apoptosis of TC cells by activating MAPK/ERK pathway. This may provide a novel target for the therapeutic strategy of TC.

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.

Low KCNQ1 expression is associated with unfavorable outcome and metabolism of gastric cancer.

BACKGROUND: Potassium voltage-gated channel subfamily Q member 1 (KCNQ1), is implicated in the onset and progression of gastric carcinoma (GC), one of the most common types of stomach malignancies. This research aims to investigate the potential prognostic implications of KCNQ1 mRNA in GC using various databases such as The Cancer Genome Atlas (TCGA), The Human Protein Atlas (HPA), LinkedOmics, TISIDB, ESTIMATE, and TIMER. METHODS: We searched the HPA database to obtain information on KCNQ1 levels in human normal tissues, organs, and cell lines as well as in pan-cancer tissues. Then, we used TIMER and UALCAN to comparatively analyze the KCNQ1 mRNA levels in different types of cancers relative to their adjacent normal counterparts. Based on TCGA and Gene Expression Omnibus, the correlation of clinical information with KCNQ1 expression was analyzed using logistic regression model. Univariable and Multivariate Cox analyses were then carried out to compare differences in survival among patients with different clinical characteristics. The multivariate methods, such as Kaplan-Meier plotter and GEPIA survival curves, were further employed to identify the correlation of KCNQ1 expression with overall survival (OS). Besides, LinkedOmics was used to identify differentially expressed genes for functional enrichment analysis. RESULTS: KCNQ1 exhibited tissue-specific imprinting and expression in human normal tissues, organs and cell lines, while it was aberrantly expressed in pan-cancer tissues. Lower KCNQ1 mRNA expression was determined in GC tissue samples versus normal counterparts. In GC cases, elevated KCNQ1 levels were strongly linked to a longer OS and strongly correlated with invasion depth (χ2=12.631, P=0.006), TNM stage (χ2=8.750, P=0.033), differentiation grade (χ2=7.426, P=0.024), and vital status (χ2=5.676, P=0.017). Furthermore, KCNQ1 was identified by univariable and multivariate Cox analyses as an independent risk factor for GC. Based on Gene Ontology analysis, digestion as well as tricarboxylic acid metabolic, carbohydrate catabolic, and small molecule catabolic processes were differentially enriched in the up-regulated KCNQ1 phenotypic pathway. While carbon metabolism, fatty acid degradation, peroxisome, and citrate cycle (TCA cycle) were identified by the Kyoto Encyclopedia of Genes and Genomes-based analysis as pathways with differential enrichment. CONCLUSION: Being a prognostic biomarker, KCNQ1 may play an inhibitory role and involve in the metabolic process of GC.

Enhancing vulnerability of Afatinib using Erastin via xCT-mediated ROS/P38MAPK signaling feedback loop in gastric cancer cells.

Ferroptosis, being classified as a form of regulated cell death, was driven by the oxidative injury induced by lipid peroxidation (LPO). Recently, ferroptosis has been confirmed to exert a critical effect in the pathogenesis and treatment of various tumors, including gastric cancer (GC). Erastin, as a frequently used ferroptosis inducer, caused ferroptosis by downregulating the xCT expression resulting in increasing reactive oxygen species (ROS) and aggravating the LPO. However, the mechanisms of Erastin in ferroptosis regulation, especially in GC, remain largely elusive. This work firstly demonstrated that Erastin inhibited cell growth and promoted apoptosis and ferroptosis in AGS and BGC823 cells. Then, based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of Erastin-related targets screened by using PharmMapper Web, the P38MAPK signaling was explored and validated in AGS and BGC-823 cells. Besides, the Fer-1 and P38 inhibitor were performed to investigate the mechanisms of ferroptosis induced by Erastin in depth. This work revealed a feedback mode among xCT, ROS and the P38MAPK pathway, which affected each other. It meant that Erastin regulated ferroptosis through the xCT-mediated ROS/P38MAPK signaling feedback loop. In addition, it was noticed that in co-operation with Erastin, the cytotoxic effects of Afatinib on cells were aggravated by further strengthening ferroptosis with activation of the P38MAPK pathway. In summary, those works provided evidence that Erastin plays an important role in increasing the cytotoxic effect on GC cells treated with Afitinib. Furthermore, the Erastin-induced ferroptosis via the xCT-mediated ROS/P38MAPK pathway feedback loop provides new strategies for GC comprehensive treatment.

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.

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.

Preoperative Nomogram for Predicting Sentinel Lymph Node Metastasis Risk in Breast Cancer: A Potential Application on Omitting Sentinel Lymph Node Biopsy.

BACKGROUND: Sentinel lymph node (SLN) biopsy is feasible for breast cancer (BC) patients with clinically negative axillary lymph nodes; however, complications develop in some patients after surgery, although SLN metastasis is rarely found. Previous predictive models contained parameters that relied on postoperative data, thus limiting their application in the preoperative setting. Therefore, it is necessary to find a new model for preoperative risk prediction for SLN metastasis to help clinicians facilitate individualized clinical decisions. MATERIALS AND METHODS: BC patients who underwent SLN biopsy in two different institutions were included in the training and validation cohorts. Demographic characteristics, preoperative tumor pathological features, and ultrasound findings were evaluated. Multivariate logistic regression was used to develop the nomogram. The discrimination, accuracy, and clinical usefulness of the nomogram were assessed using Harrell's C-statistic and ROC analysis, the calibration curve, and the decision curve analysis, respectively. RESULTS: A total of 624 patients who met the inclusion criteria were enrolled, including 444 in the training cohort and 180 in the validation cohort. Young age, high BMI, high Ki67, large tumor size, indistinct tumor margins, calcifications, and an aspect ratio ≥1 were independent predictive factors for SLN metastasis of BC. Incorporating these parameters, the nomogram achieved a robust predictive performance with a C-index and accuracy of 0.92 and 0.85, and 0.82 and 0.80 in the training and validation cohorts, respectively. The calibration curves also fit well, and the decision curve analysis revealed that the nomogram was clinically useful. CONCLUSIONS: We established a nomogram to preoperatively predict the risk of SLN metastasis in BC patients, providing a non-invasive approach in clinical practice and serving as a potential tool to identify BC patients who may omit unnecessary SLN biopsy.

Near-infrared laparoscopy with indocyanine green for axillary sentinel lymph node biopsy in early breast cancer: preliminary experience of a single unit.

BACKGROUND: A sentinel lymph node biopsy (SLNB) is a routine procedure for axillary staging in cN0 breast cancer (BC) patients. Indocyanine green (ICG) fluorescence can detect sentinel lymph nodes with higher sensitivity than carbon nanoparticle suspension (CNS). The present study investigated the availability and benefits of a near-infrared (NIR) laparoscopy-assisted SLNB using ICG and carbon nanoparticle suspension as tracers. METHODS: Forty patients with invasive BC, who had clinically negative axillary lymph nodes, participated in this observational study. ICG and CNS tracers were injected into the periareolar region simultaneously or sequentially. In the endoscopy-assisted group (n=20), the patients were given NIR laparoscopic SLNB based on ICG fluorescence and CNS staining. In the open-surgery group, the patients were given traditional SLNB using an open incision, and CNS tracers were injected into the same region as that in the endoscopy-assisted group. RESULTS: In the endoscopy-assisted group, lymphatic vessels and sentinel lymph nodes (SLNs) were successfully identified using ICG fluorescence imaging in most patients (19/20). The average number of SLNs removed was 2.85 (range, 1-4) in the endoscopy-assisted group, and 3.40 (range, 1-7) in the open-surgery group. There was no significant difference between the number of detected nodes (P=0.30). The patients who underwent endoscopy-assisted SLNBs had similar operating times, blood loss and hospital-stay lengths, but lower postoperative drainage volumes and higher satisfaction scores, as they did not have axillary incisions. CONCLUSIONS: The NIR laparoscopy-assisted ICG-guided technique is a feasible and surgeon-friendly method for SLNB with good efficacy and acceptable safety. When combined with CNS, more SLNs can be detected and dissected.

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.

Neoadjuvant targeted therapy for apocrine carcinoma of the breast: A case report.

BACKGROUND: Apocrine carcinoma of the breast is a special type of invasive ductal carcinoma of the breast that is rare in clinical practice. Neoadjuvant therapy, especially neoadjuvant targeted therapy, has rarely been reported for apocrine carcinoma of the breast. CASE SUMMARY: A 63-year-old woman presented with apocrine carcinoma of the left breast underwent core needle biopsy. The patient was diagnosed with apocrine carcinoma by immunohistochemical staining and negative hormone status (estrogen receptor and progesterone receptor) but showed overexpression of human epidermal factor receptor 2 (HER-2). Moreover, positive expression of androgen receptor (approximately 60%) and gross cystic disease fluid protein 15 was observed. The patient was treated with neoadjuvant targeted therapy consisting of the TCH regimen (docetaxel, carboplatin area under curve 6 and trastuzumab) every 21 d. The mass in the left breast was significantly reduced, and pain in the breast and left upper arm also improved. CONCLUSION: HER-2 positive apocrine carcinoma of the breast can be improved by neoadjuvant chemotherapy combined with targeted therapy.

Potential protection of indocyanine green on parathyroid gland function during near-infrared laparoscopic-assisted thyroidectomy: A case report and literature review.

BACKGROUND: In recent decades, significant advances have been made in protecting the parathyroid glands and recurrent laryngeal nerves during thyro-idectomy. However, reliable and convenient technical means are still lacking. In this study, the reliability, safety and feasibility of near-infrared (NIR) laparoscopy-assisted thyroid lobectomy with isthmectomy and prophylactic central lymph node dissection (CLND) were reported. CASE SUMMARY: A 63-year-old female patient with a free previous medical history, was admitted to our department due to multiple thyroid nodules. Ultrasonic examination suggested diffuse thyroid changes and one thyroid nodule in the right upper lobe with the largest diameter of 1.5 cm adjacent to the trachea and Breast Imaging Reporting and Data System grade 4B. Imaging examination of the neck showed no obvious enlarged lymph nodes. Fine needle aspiration biopsy suggested a papillary thyroid carcinoma. Combined with thyroid function examination, the patient was diagnosed with papillary thyroid carcinoma and Hashimoto's thyroiditis. Considering the risk of invading the capsule and the patient's extreme anxiety, a right thyroid lobectomy with isthmectomy and prophylactic CLND was planned. No significant abnormalities were found during preoperative examinations, except for an increased thyroid stimulating hormone level. The patient underwent NIR laparoscopy-assisted thyroid lobectomy with isthmectomy and prophylactic CLND. During the operation, two right parathyroid glands (PGs) adjacent to the thyroid gland capsule and the right recurrent laryngeal nerve (RLN) were examined by indocyanine green (ICG) fluorescence using a NIR fluorescence camera, and the PGs and RLN were reliably preserved. Considering the ICG-positive PG, prophylactic CLND was performed. The postoperative parathyroid hormone level was in the normal range and no significant hypocalcemia symptoms were observed. CONCLUSION: During NIR laparoscopy-assisted thyroidectomy, ICG fluorescence may aid PG identification and protection.

Genetic polymorphisms in folate-metabolizing genes associated with gastric cancer prognosis in northwest China subjects.

Influence of folate metabolism has long been studied in cancer and copies evidences have suggested that the key genes involved were correlated with GC risk and prognosis. However, their genetically association and contribution for GC prognosis are still elusive. To evaluate the effect of folate metabolism related genes polymorphisms on the prognosis of gastric cancer (GC), the genotype of seven single nucleotide polymorphisms (SNPs) of three genes were selected and genotyped in a cohort of 664 GC patients, including genes of Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), and Methionine synthase (MTR). Kaplan-Meier Curve, long-rank tests and multivariate Cox proportional hazard model were used for prognosis analysis. The results demonstrated that TT or CT/TT genotypes of SNP rs1532268 in MTRR gene coding region are significantly associated with a poorer overall survival (OS) when compared with CC genotype (HR=2.340, 95% CI: 1.240-4.414, p=0.009; or HR=1.502, 95% CI: 1.083-2.085, p=0.015, respectively). Furthermore, comparing to that of the CC genotype, the detrimental effect of rs1532268 TT genotype was also evident in the special subgroups of GC patients, especially in patients with BMI<24 and H. pylori infection. Moreover, significant association between increased relapse and TT genotype of rs1532268 was also observed in patients who are females, BMI<24 and without chemotherapy. In addition, the joint analysis demonstrated that integration of rs1532268 genotypes and BMI, H. pylori infection status, clinical stage and tumor site may significantly improve the predictive abilities for predicting OS of GC patients. In conclusion, it suggested that the MTRR rs1532268 polymorphism is significantly associated with clinical outcomes of GC patients, especially in those with lower BMI (BMI<24) or positive H. pylori infection status, which warrants further validation. And the polymorphism of MTRR rs1532268 may be a potential prognostic factor for GC patients.