A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.

Mitochondria play essential roles in cancer cell adaptation to hypoxia, but the underlying mechanisms remain elusive. Through mitochondrial proteomic profiling, we here find that the prolyl hydroxylase EglN1 (PHD2) accumulates on mitochondria under hypoxia. EglN1 substrate-binding region in the ß2ß3 loop is responsible for its mitochondrial translocation and contributes to breast tumor growth. Furthermore, we identify AMP-activated protein kinase alpha (AMPKα) as an EglN1 substrate on mitochondria. The EglN1-AMPKα interaction is essential for their mutual mitochondrial translocation. After EglN1 prolyl-hydroxylates AMPKα under normoxia, they rapidly dissociate following prolyl-hydroxylation, leading to their immediate release from mitochondria. In contrast, hypoxia results in constant EglN1-AMPKα interaction and their accumulation on mitochondria, leading to the formation of a Ca2+ /calmodulin-dependent protein kinase 2 (CaMKK2)-EglN1-AMPKα complex to activate AMPKα phosphorylation, ensuring metabolic homeostasis and breast tumor growth. Our findings identify EglN1 as an oxygen-sensitive metabolic checkpoint signaling hypoxic stress to mitochondria through its ß2ß3 loop region, suggesting a potential therapeutic target for breast cancer.

Programmable Lanthanide Metal-Organic Framework for Ultra-Efficient Nucleic Acids Extraction and Interaction Analysis.

Efficient, mild, and reversible adsorption of nucleic acids onto nanomaterials represents a promising analytical approach for medical diagnosis. However, there is a scarcity of efficient and reversible nucleic acid adsorption nanomaterials. Additionally, the lack of comprehension of the molecular mechanisms governing their interactions poses significant challenges. These issues hinder the rational design and analytical applications of the nanomaterials. Herein, we propose an ultra-efficient nucleic acid affinity nanomaterial based on programmable lanthanide metal-organic frameworks (Ln-MOFs). Through experiments and density functional theory calculations, a rational design guideline for nucleic acid affinity of Ln-MOF was proposed, and a modular and flexible preparation scheme was provided. Then, Er-TPA (terephthalic acid) MOF emerged as the optimal candidate due to its pore size-independent adsorption and desorption capabilities for nucleic acids, enabling ultra-efficient adsorption (about 150% mass ratio) within 1 min. Furthermore, we elucidate the molecular-level mechanisms underlying the Ln-MOF adsorption of single- and double-stranded DNA and G4 structures. The affinity nanomaterial based on Ln-MOF exhibits robust nucleic acid extraction capability (4-fold higher than commercial reagent kits) and enables mild and reversible CRISPR/Cas9 functional regulation. This method holds significant promise for broad application in DNA/RNA liquid biopsy and gene editing, facilitating breakthroughs in analytical chemistry, pharmacy, and medical research.

Improving the Data Quality of Untargeted Metabolomics through a Targeted Data-Dependent Acquisition Based on an Inclusion List of Differential and Preidentified Ions.

Metabolomics based on high-resolution mass spectrometry has become a powerful technique in biomedical research. The development of various analytical tools and online libraries has promoted the identification of biomarkers. However, how to make mass spectrometry collect more data information is an important but underestimated research topic. Herein, we combined full-scan and data-dependent acquisition (DDA) modes to develop a new targeted DDA based on the inclusion list of differential and preidentified ions (dpDDA). In this workflow, the MS1 datasets for statistical analysis and metabolite preidentification were first obtained using full-scan, and then, the MS/MS datasets for metabolite identification were obtained using targeted DDA of quality control samples based on the inclusion list. Compared with the current methods (DDA, data-independent acquisition, targeted DDA with time-staggered precursor ion list, and iterative exclusion DDA), dpDDA showed better stability, higher characteristic ion coverage, higher differential metabolites' MS/MS coverage, and higher quality MS/MS spectra. Moreover, the same trend was verified in the analysis of large-scale clinical samples. More surprisingly, dpDDA can distinguish patients with different severities of coronary heart disease (CHD) based on the Canadian Cardiovascular Society angina classification, which we cannot distinguish through conventional metabolomics data collection. Finally, dpDDA was employed to differentiate CHD from healthy control, and targeted metabolomics confirmed that dpDDA could identify a more complete metabolic pathway network. At the same time, four unreported potential CHD biomarkers were identified, and the area under the receiver operating characteristic curve was greater than 0.85. These results showed that dpDDA would expand the discovery of biomarkers based on metabolomics, more comprehensively explore the key metabolites and their association with diseases, and promote the development of precision medicine.

Prophylactic Central Neck Dissection Based on Preoperative Imaging and Intraoperative Surgeon's Palpation Versus Total Thyroidectomy Alone for Papillary Thyroid Cancer.

INTRODUCTION: To compare the overall morbidity and recurrence of papillary thyroid cancer (PTC) after total thyroidectomy (TT) with or without prophylactic central compartment neck dissection (CCND) in cases of both preoperative and intraoperative nonsuspicious central lymph nodes (CLNs). METHODS: A total of 570 PTC patients who harbored no preoperative and intraoperative suspicious CLNs at two institutions were enrolled. They were randomly assigned to TT alone or TT with prophylactic CCND (pCCND) after intraoperative assessment of CLNs during the surgery. Lymph nodes that were hard or large enough to be palpated were regarded as suspicious metastatic lymph nodes during the surgery. The characteristics, postoperative complications, and locoregional recurrence of the two groups were recorded and compared. RESULTS: With a median follow-up of 5 y, the rates of lymph node recurrence in the TT alone and TT with pCCND groups were similar (7.3% versus 4.6%, P = 0.247), but there were significantly higher rates of overall morbidity (6.6% versus 19.1%, P < 0.001) when pCCND was performed. CONCLUSIONS: pCCND is not recommended for patients with clinically node-negative PTC preoperatively and intraoperatively because of the high complication rate and lack of benefit of reducing recurrence.

Comparison of Rehabilitation Training at Different Timepoints to Restore Shoulder Function in Patients With Breast Cancer After Lymph Node Dissection: A Randomized Controlled Trial.

OBJECTIVE: To investigate whether advancing the initiation of rehabilitation training compared with the time recommended by the guidelines after breast cancer (BC) surgery is beneficial to the recovery of shoulder function and quality of life. DESIGN: Prospective, observational, single center, randomized controlled trial. SETTING: The study was conducted between September 2018 and December 2019, with a 12-week supervised intervention and 6-week home-exercise period concluding in May 2020. PARTICIPANTS: Two hundred BC patients received axillary lymph node dissection (N=200). INTERVENTIONS: Participants were recruited and randomly allocated into 4 groups (A, B, C, and D). Group A started range of motion (ROM) training at 7 days postoperative and progressive resistance training (PRT) at 4 weeks postoperative; group B started ROM training at 7 days postoperative and PRT at 3 weeks postoperative; group C started ROM training at 3 days postoperative and PRT at 4 weeks postoperative; and group D started ROM training at 3 days postoperative and PRT at 3 weeks postoperative. MAIN OUTCOME MEASURES: The primary outcome measure was Constant-Murley Score. Secondary outcome measures included ROM, shoulder strength, grip, European Organization Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module (EORTC QLQ-BR23), and SF-36. Incidence of adverse reactions (drainage and pain) and complications (ecchymosis, subcutaneous hematoma, lymphedema) were also assessed. RESULTS: Participants who started ROM training at 3 days postoperative obtained more benefits in mobility, shoulder function, and EORTC QLQ-BR23 score, while patients who started PRT at 3 weeks postoperative saw improvements in shoulder strength and SF-36. Incidence of adverse reactions and complications were low in all 4 groups, with no significant differences among the 4 groups. CONCLUSIONS: Advancing ROM training initiation to 3 days postoperative or PRT to 3 weeks postoperative can better restore shoulder function after BC surgery and lead to faster quality of life improvement.

Patterns of lymph node metastasis in level IIB and contralateral level VI for papillary thyroid carcinoma with pN1b and safety of low collar extended incision for neck dissection in level II.

OBJECTIVE: To explore relevant clinical factors of level IIB and contralateral level VI lymph node metastasis and evaluate the safety of low-collar extended incision (LCEI) for lymph node dissection in level II for papillary thyroid carcinoma (PTC) with pN1b. METHOD: A retrospective analysis was performed on 218 patients with PTC with pN1b who were treated surgically in the Head and Neck Surgery Center of Sichuan Cancer Hospital from September 2021 to May 2022. Data on age, sex, body mass index (BMI), tumor location, maximum tumor diameter, multifocality, Braf gene, T staging, surgical incision style, and lymph node metastasis in each cervical subregion were collected. The chi-square test was used for comparative analysis of relevant factors. All statistical analyses were completed by SPSS 24 software. RESULT: Each subgroup on sex, age, BMI, multifocality, tumor location, extrathyroidal extension, Braf gene, and lymphatic metastasis in level III, level IV, and level V had no significant difference in the positive rate of lymph node metastasis in level IIB (P > 0.05). In contrast, patients with bilateral lateral cervical lymphatic metastasis were more likely to have level IIB lymphatic metastasis than those with unilateral lateral cervical lymphatic metastasis, with a statistically significant difference (P = 0.000). In addition, lymph node metastasis in level IIA was significantly associated with lymph node metastasis in level IIB (P = 0.001). After multivariate analysis, lymph node metastasis in level IIA was independently associated with lymph node metastasis in level IIB (P = 0.010). The LCEI group had a similar lymphatic metastasis number and lymphatic metastasis rate in both level IIA and level IIB as the L-shaped incision group (P > 0.05). There were 86 patients with ipsilateral central lymphatic metastasis (78.2%). Patients with contralateral central lymphatic metastasis accounted for 56.4%. The contralateral central lymphatic metastasis rate was not correlated with age, BMI, multifocality, tumor invasion, or ipsilateral central lymphatic metastasis, and there was no significant difference (P > 0.05). The contralateral central lymphatic metastasis in males was slightly higher than that in females, and the difference was statistically significant (68.2% vs. 48.5%, P = 0.041). CONCLUSION: Lymphatic metastasis in level IIA was an independent predictor of lymphatic metastasis in level IIB. When bilateral lateral cervical lymphatic metastasis or lymph node metastasis of level IIA is found, lymph node dissection in level IIB is strongly recommended. When unilateral lateral cervical lymphatic metastasis and lymphatic metastasis in level IIA are negative, lymph node dissection in level IIB may be performed as appropriate on the premise of no damage to the accessory nerve. LCEI is safe and effective for lymph node dissection in level II. When the tumor is located in the unilateral lobe, attention should be given to contralateral central lymph node dissection because of the high lymphatic metastasis rate.

Nephrotoxicity assessment of Esculentoside A using human-induced pluripotent stem cell-derived organoids.

Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI). A major obstacle in predicting AKI is the lack of a comprehensive experimental model that mimics stable and physiologically relevant kidney functions and accurately reflects the changes a drug induces. Organoids derived from human-induced pluripotent stem cells (iPSCs) are promising models because of their reproducibility and similarity to the in vivo conditions. In this study, Esculentoside A, the triterpene saponin with the highest concentration isolated from the root of Phytolacca acinose Roxb., was used to induce kidney injury models in vivo and kidney organoids. Esculentoside A induced AKI in mice, together with pathological changes and enhanced apoptosis. Moreover, Esculentoside A damaged podocytes and proximal tubular endothelial cells in kidney organoids in a similar way as in vivo. We also found that treatment with 60 µM Esculentoside A induced the known biomarkers of kidney damage and inflammatory cytokines (such as kidney injury molecule (KIM-1), ß2-microglobulin (ß2-M), and cystatin C (CysC)) in the organoids, in which activation of Cleaved Caspase-3 was involved, possibly due to lowered mitochondrial membrane potential. In summary, this study strongly suggests using kidney organoids as a reliable platform to assess Chinese medicine-induced nephrotoxicity.

Stepwise Limited Axillary Lymph Node Dissection Based on Lymphatic Drainage from the Breast to Decrease Breast Cancer-Related Lymphedema: A Randomized Controlled Trial.

BACKGROUND: Comprehensive axillary surgery is associated with an elevated rate of morbidity. This trial aimed to demonstrate the feasibility of axillary dissection of lymph nodes from the breast (bALND) for the purpose of limiting the extent of surgery. METHODS: Patients enrolled from two tertiary referral centers from September 2018 to September 2019 were randomly allocated to two groups: bALND and standard axillary lymph node dissection (sALND). In the bALND group, the sentinel lymph node was filled with 0.1 ml methylene blue before resection. Then, bALND based on lymphatic drainage was subsequently performed. Lymph nodes at each breast lymphatic level and lymph nodes at Berg levels were sent for separate pathological examination. Arm lymphedema, locoregional recurrence, and distant metastasis were documented. RESULTS: In the bALND group, lymphatic vessels and subsequent-echelon lymph nodes from the breast were stained blue after injection of methylene blue in 404 (89.0%, 404/454) cases, and 57.8% (228/394) of the patients harbored fewer than four metastatic nodes. With a median follow-up of 18 months, the incidence of arm lymphedema was 6.6% (26/394) in the bALND group versus 13.7% (60/438) in the sALND group (p = 0.008), while regional recurrence presented no difference between the two surgical procedures (0.76% vs 0.68%, p = 0.896). CONCLUSION: For node-positive breast cancer patients, bALND based on lymphatic drainage is a less radical axillary surgery that can eliminate morbidity without impairing cancer control.

Intraoperative Radiofrequency Ablation for Contralateral Benign Nodules in Unilateral Thyroid Cancer Patients to Relieve Anxiety.

INTRODUCTION: For unilateral papillary thyroid carcinoma (PTC) with contralateral benign nodules, optimal extent of surgery remains controversial. This retrospective cohort study was performed to evaluate the life quality of patients who underwent lobectomy alone and lobectomy with radiofrequency ablation (RFA). METHODS: From October 2014 to October 2018, unilateral PTC patients with contralateral benign nodules reported by fine-needle aspiration cytology who encountered anxiety about contralateral nodule progression underwent lobectomy for PTC and intraoperative RFA for contralateral nodules. The patients who underwent thyroid lobectomy were matched for sex, age at time of surgery, number, size, and location of primary tumors and contralateral nodules to the patients who underwent lobectomy with intraoperative RFA. Three questionnaires were used to evaluate life quality in the two groups. The complications and rate of patients who were not required to receive thyroid-stimulating hormone suppression therapy were recorded. RESULTS: One hundred forty-eight patients with 194 contralateral nodules underwent RFA in the lobectomy plus RFA group, and age- and sex-matched patients underwent thyroid lobectomy alone. The mean volume reduction ratio was 67.7% at 12 mo and 95.2% at 24 mo. After a median follow-up of 4.2 y, nine patients (6.1%) in the lobectomy plus RFA group and 17 (11.5%) in the thyroid lobectomy-alone group underwent completion thyroidectomy (P = 0.100). Patients who underwent lobectomy plus RFA had a better quality of life in terms of anxiety, physiological health, social and family aspects, and psychological and sensory features that were measured cross-sectionally at 6 mo using three instruments. CONCLUSIONS: Intraoperative RFA is effective in terms of volume reduction of contralateral nodules and improved quality of life for unilateral PTC patients with anxiety about disease progression.

Recurrent Laryngeal Nerve with Loss of Signal During Monitored Thyroidectomy: Percentage Reduction in Sum of the Amplitude of Left and Right Channel.

PURPOSE: The prognostication for the injured recurrent laryngeal nerve (RLN) with incomplete loss of signal (LOS) and its function outcome have not been well unified. A warning criterion was proposed to predict RLN injury during monitored thyroidectomy. METHODS: A retrospective review of prospectively collected data from consecutive 357 patients with 560 nerves at risk was conducted. Vocal cords mobility with laryngoscope was performed preoperatively, on the second day, and once a month postoperatively until complete recovery. Different cutoff values of the percentage reduction in sum of the amplitude of left and right channel at the end of the surgery, for postoperative vocal cord paralysis (VCP) prediction were compared. RESULTS: Percentage reduction in sum of the amplitude of left and right channel at the end of operation ranged from 30.2 to 63.6% in 27 nerves with incomplete LOS (absolute amplitude value of final R2 > 100 µV with reduction > 50% of R1). Seven (1.25%) nerves experienced transient postoperative VCP, in which one nerve with postoperative VCP showed no amplitude reduction. The positive predictive value of VCP for the sum amplitude reduction exceeding 30, 40, 50, and 60% was 22.2, 40, 85.7, and 100%, respectively. Accuracy was 96.1, 98.2, 99.6, 99.4%, respectively. CONCLUSION: Percentage reduction in sum of the amplitude of left and right channel is a meaningful method to improve the accuracy of VCP prediction. When the sum amplitude reduction ≥ 50%, surgeons should consider the possibility of postoperative VCP and correct some surgical maneuvers.

A seven-autophagy-related gene signature for predicting the prognosis of differentiated thyroid carcinoma.

BACKGROUND: Numerous studies have implicated autophagy in the pathogenesis of thyroid carcinoma. This investigation aimed to establish an autophagy-related gene model and nomogram that can help predict the overall survival (OS) of patients with differentiated thyroid carcinoma (DTHCA). METHODS: Clinical characteristics and RNA-seq expression data from TCGA (The Cancer Genome Atlas) were used in the study. We also downloaded autophagy-related genes (ARGs) from the Gene Set Enrichment Analysis website and the Human Autophagy Database. First, we assigned patients into training and testing groups. R software was applied to identify differentially expressed ARGs for further construction of a protein-protein interaction (PPI) network for gene functional analyses. A risk score-based prognostic risk model was subsequently developed using univariate Cox regression and LASSO-penalized Cox regression analyses. The model's performance was verified using Kaplan-Meier (KM) survival analysis and ROC curve. Finally, a nomogram was constructed for clinical application in evaluating the patients with DTHCA. Finally, a 7-gene prognostic risk model was developed based on gene set enrichment analysis. RESULTS: Overall, we identified 54 differentially expressed ARGs in patients with DTHCA. A new gene risk model based on 7-ARGs (CDKN2A, FGF7, CTSB, HAP1, DAPK2, DNAJB1, and ITPR1) was developed in the training group and validated in the testing group. The predictive accuracy of the model was reflected by the area under the ROC curve (AUC) values. Univariate and multivariate Cox regression analysis indicated that the model could independently predict the prognosis of patients with THCA. The constrained nomogram derived from the risk score and age also showed high prediction accuracy. CONCLUSIONS: Here, we developed a 7-ARG prognostic risk model and nomogram for differentiated thyroid carcinoma patients that can guide clinical decisions and individualized therapy.

[Comparative study on short and long-term intervention impacts of six Chinese herbs with cold or heat property on lipid and energy metabolism in mice].

This study selected three typical Chinese herbs with cold property(Rhei Radix et Rhizoma, Scutellariae Radix, and Coptidis Rhizoma) and another three with heat property(Cinnamomi Cortex, Zingiberris Rhizoma, and Aconiti Lateralis Radix Praeparata) to observe their regulatory effects on metabolism in animal organism, especially on lipid and energy metabolism in mice after a short-(7 d) and long-term(35 d) intervention. The mRNA expression levels of lipid metabolism genes in epididymal adipose tissue and liver were determined by real-time PCR. The oxygen consumption, carbon dioxide production, and energy consumption were detected by metabolic system. After the short-term intervention, the Chinese herbs with heat property significantly reduced epididymal adipose tissue index and elevated the expression levels of acetyl-CoA carboxylase(ACC), lipoprotein lipase(LPL), and carnitine-palmityl transferase 1(CPT-1) in liver and epididymal adipose tissues. However, those with cold property promoted the expression of above-mentioned genes in epididymal adipose tissue. After the long-term intervention, cold and heat Chinese herbs had no significant effect on epididymal adipose tissue index of animals, while cold Chinese herbs could increase carbon dioxide production and energy consumption and reduce activity. These findings demonstrated that the short-term intervention effects of cold and heat Chinese herbs on animal metabolism were significantly stronger than the long-term intervention effects. Specifically, the short-term intervention with cold Chinese herbs enhanced the lipid metabolism in epididymal adipose tissue, while the heat Chinese herbs promoted lipid metabolism in epididymal adipose tissue and liver. The long-term intervention with cold and heat Chinese herbs resulted in no obvious change in lipid level, but long-term intervention with cold Chinese herbs accelerated energy consumption of the body. This study preliminarily observed the effects of cold and heat Chinese herbs on normal animal physiology from lipid and energy metabolism, which would provide reference for explaining the biological basis of Chinese herbs with cold or heat property based on biological response.

Development and Validation of an Intraoperative Nomogram to Predict Breast Cancer-Related Lymphedema Based on the Arm Lymphatics Distribution.

BACKGROUND: Preoperatively determining those patients who are at high risk of encountering breast cancer-related lymphedema (BCRL) is still not well understood. OBJECTIVE: This study aimed to develop a simple intraoperative nomogram for BCRL, incorporating a protective factor. METHODS: Overall, 320 breast cancer patients at Zhongnan Hospital (training set) and 221 patients at Dongfeng General Hospital (external validation cohort) treated between November 2017 and December 2018 were included. Prior to axillary lymph node dissection (ALND), 1 mL (2.5 mg) of indocyanine green was administered to the area of the internal bicipital sulcus of the upper limb. The fluorescence image was obtained and the proportion of arm lymph flow above the level of the axillary vein was calculated. Multivariate logistic regression was performed using this proportion together with clinical data. A nomogram was then constructed and assessed for its discrimination and calibration ability and clinical utility in the training and external validation sets. RESULTS: The cumulative incidence of BCRL was 18.7% (60/320), with a median follow-up of 29 months (20-34). In the multivariate logistic regression analysis, body mass index, taxane, radiotherapy, and proportion of arm lymph flow above the level of the axillary vein were identified as independent risk factors. In the training and validation cohorts, the calibration curve performed well (p = 0.721 and p = 0.315, respectively), and the area under the receiver operating characteristic curve values were 0.829 (95% confidence interval [CI] 0.773-0.885) and 0.804 (95% CI 0.732-0.877), respectively. CONCLUSION: High-risk patients could be identified intraoperatively with this nomogram, and timely intervention could be performed with preservation of the arm lymphatics.

New insights into M1/M2 macrophages: key modulators in cancer progression.

Infiltration of macrophages in and around tumor nest represents one of the most crucial hallmarks during tumor progression. The mutual interactions with tumor cells and stromal microenvironment contribute to phenotypically polarization of tumor associated macrophages. Macrophages consist of at least two subgroups, M1 and M2. M1 phenotype macrophages are tumor-resistant due to intrinsic phagocytosis and enhanced antitumor inflammatory reactions. Contrastingly, M2 are endowed with a repertoire of tumor-promoting capabilities involving immuno-suppression, angiogenesis and neovascularization, as well as stromal activation and remodeling. The functional signature of M2 incorporates location-related, mutually connected, and cascade-like reactions, thereby accelerating paces of tumor aggressiveness and metastasis. In this review, mechanisms underlying the distinct functional characterization of M1 and M2 macrophages are demonstrated to make sense of M1 and M2 as key regulators during cancer progression.

Minimize the extent and morbidity of axillary dissection for node-positive breast cancer patients: implementation of axillary lymph node dissection based on breast lymphatics level.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is associated with extensive axillary dissection. Axillary lymph node dissection (ALND) based on breast lymphatics level (BLL) was proposed to minimize the surgical extent for node-positive breast cancer patients. METHODS: A total of 156 consecutive sentinel lymph node-positive (SLN+) or clinically node-positive (cN+) patients underwent sentinel lymph node biopsy (SLNB) with indocyanine green and methylene blue (MB). The SLNs were injected with 0.1 ml MB before removal, and a standard ALND was subsequently performed. The nodes adjacent to the blue-stained axillary lymph nodes from the breast (bALNs) were sent for pathological examination separately by resecting serial tissue every 0.5 cm away from the marginal blue-stained bALNs. Then, a pilot study comparing ALND based on BLL and standard ALND was performed. RESULTS: BLL were successfully identified in 20 SLN+ (100%) and 134 cN+ (98.5%) patients. The median number of BLL was four, ranging from three to six. A horizontal line 1.0 cm away from the superior blue-stained bALN and a vertical line 1.0 cm away from the medial blue-stained bALN formed BLL II, III, and IV. All of the additional positive nodes were within 1.0 cm of the blue-stained bALNs. The minimized axillary dissection should resect upwards from the lowest BLL that contains the first confirmed negative blue-stained bALNs. In the pilot study, no patient developed axillary recurrence. CONCLUSION: The ALND surgical procedure based on BLL could minimize the surgical extent for pathological node-positive breast cancer patients and potentially reduce the BCRL rate. TRIAL REGISTRATION: ChiCTR1800014247 .

Prognosis of Surgical Treatment After Ipsilateral Breast Tumor Recurrence.

BACKGROUND: Ipsilateral breast tumor recurrence (IBTR) was determined to be a powerful independent risk factor of distant disease and increased mortality. Although mastectomy is the standard salvage treatment for IBTR after breast conserving treatment, there is evidence that repeat breast conserving surgery (rBCS) might be a feasible alternative treatment. MATERIALS AND METHODS: The data of patients who were diagnosed with IBTR between 1998 and 2013 were obtained from the Surveillance, Epidemiology, and End Results database. Breast cancer-specific survival (BCSS) and overall survival (OS) were calculated using the Kaplan-Meier method. The Cox proportional hazards model was used for multivariate analysis, and propensity score matching analysis was applied to compensate for the differences in some baseline characteristics. RESULTS: A total of 475 patients (22.9%) who underwent rBCS and 1600 (77.1%) who underwent mastectomy after IBTR were included in the study. During a median follow-up of 130 mo, no significant differences were observed in BCSS and OS between the rBCS and mastectomy groups of patients before and after propensity score matching. Multivariate analysis revealed that race, the American Joint Committee on Cancer stage of the recurrent tumor, and reirradiation were independent prognostic factors for both BCSS and OS. CONCLUSIONS: The results of our study indicate that rBCS can be a feasible alternative treatment option for patients with IBTR. Nevertheless, further studies should be conducted to identify the prognosis of patients after rBCS as well as the best candidates for a second breast conserving surgery.

Overexpression of CCNE1 confers a poorer prognosis in triple-negative breast cancer identified by bioinformatic analysis.

BACKGROUND: Triple-negative breast cancer (TNBC) is a major subtype of breast cancer. Due to the lack of effective therapeutic targets, the prognosis is poor. In order to find an effective target, despite many efforts, the molecular mechanisms of TNBC are still not well understood which remain to be a profound clinical challenge. METHODS: To identify the candidate genes in the carcinogenesis and progression of TNBC, microarray datasets GSE36693 and GSE65216 were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and functional and pathway enrichment analyses were performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases via DAVID. We constructed the protein-protein interaction network (PPI) and performed the module analysis using STRING and Cytoscape. Then, we reanalyzed the selected DEG genes, and the survival analysis was performed using cBioportal. RESULTS: A total of 140 DEGs were identified, consisting of 69 upregulated genes and 71 downregulated genes. Three hub genes were upregulated among the selected genes from PPI, and biological process analysis uncovered the fact that these genes were mainly enriched in p53 pathway and the pathways in cancer. Survival analysis showed that only CCNE1 may be involved in the carcinogenesis, invasion, or recurrence of TNBC. The expression levels of CCNE1 were significantly higher in TNBC cells than non-TNBC cells that were detected by qRT-PCR (P < 0.05). CONCLUSION: CCNE1 could confer a poorer prognosis in TNBC identified by bioinformatic analysis and plays key roles in the progression of TNBC which may contribute potential targets for the diagnosis, treatment, and prognosis assessment of TNBC.

A prognostic eight-lncRNA expression signature in predicting recurrence of ER-positive breast cancer receiving endocrine therapy.

Long noncoding RNAs (lncRNAs) have the main role in the tumorigenesis of breast cancer. In the present study, lncRNA expression profiling was collected to identify a lncRNA expression signature from the Gene Expression Omnibus database. An eight-lncRNA signature was established to predict the survival of patients with estrogen receptor (ER)-positive breast cancer receiving endocrine therapy. Patients were separated into a low-risk group and a high-risk group based on this signature. Patients in high-risk group have worse survival compared to those in low-risk group using Kaplan-Meier curve analysis with log-rank test. Receiver operating characteristic analysis suggested good diagnostic efficiency of the eight-lncRNA signature. When adjusting the clinical features, including age, grade, lymph node status, and tumor size, this signature was independently associated with the relapse-free survival. The prognostic value of the lncRNA prognostic model was then validated in validation sets. When validated in a cohort of patients treated with neoadjuvant chemotherapy and endocrine therapy, this signature demonstrated good performance as well. Besides, we have built a nomogram that integrated the conventional clinicopathological features and the eight-lncRNA-based signature. To sum up, our results indicated that the eight-lncRNA prognostic model was a reliable tool to group patients at high and low risk of disease relapse. This signature may have possible implication in prognostic evaluations of patients with ER-positive breast cancer receiving endocrine therapy.

Weighted gene correlation network analysis identifies RSAD2, HERC5, and CCL8 as prognostic candidates for breast cancer.

As the most commonly diagnosed malignant tumor in female population, the prognosis of breast cancer is affected by complex gene interaction networks. In this research weighted gene co-expression network analysis (WGCNA) would be utilized to build a gene co-expression network to identify potential biomarkers for prediction the prognosis of patients with breast cancer. We downloaded GSE25065 from Gene Expression Omnibus database as the test set. GSE25055 and GSE42568 were utilized to validate findings in the research. Seven modules were established in the GSE25065 by utilizing average link hierarchical clustering. Three hub genes, RSAD2, HERC5, and CCL8 were screened out from the significant module (R 2 = 0.44), which were considerably interrelated to worse prognosis. Within test dataset GSE25065, RSAD2, and CCL8 were correlated with tumor stage, grade, and lymph node metastases, whereas HERC5 was correlated with lymph node metastases and tumor grade. In the validation dataset GSE25055 and RSAD2 expression was correlated with tumor grade, stage, and size, whereas HERC5 was related to tumor stage and tumor grade, and CCL8 was associated with tumor size and tumor grade. Multivariable survival analysis demonstrated that RSAD2, HERC5, and CCL8 were independent risk factors. In conclusion, the WGCNA analysis conducted in this study screened out novel prognostic biomarkers of breast cancer. Meanwhile, further in vivo and in vitro studies are required to make the clear molecular mechanisms.

A prognostic eight-gene expression signature for patients with breast cancer receiving adjuvant chemotherapy.

Breast cancer is a popularly diagnosed malignant tumor. Genomic profiling studies suggest that breast cancer is a disease with heterogeneity. Chemotherapy is one of the chief means to treat breast cancer, while its responses and clinical outcomes vary largely due to the conventional clinicopathological factors and inherent chemosensitivity of breast cancer. Using the least absolute shrinkage and selection operator (LASSO) Cox regression model, our study established a multi-mRNA-based signature model and constructed a relative nomogram in predicting distant-recurrence-free survival for patients receiving surgery and following chemotherapy. We constructed a signature of eight mRNAs (IPCEF1, SYNDIG1, TIGIT, SPESP1, C2CD4A, CLCA2, RLN2, and CCL19) with the LASSO model, which was employed to separate subjects into groups with high- and low-risk scores. Obvious differences of distant-recurrence-free survival were found between these two groups. This eight-mRNA-based signature was independently associated with the prognosis and had better prognostic value than classical clinicopathologic factors according to multivariate Cox regression results. Receiver operating characteristic results demonstrated excellent performance in diagnosing 3-year distant-recurrence by the eight-mRNA signature. A nomogram that combined both the eight-mRNA-based signature and clinicopathological risk factors was constructed. Comparing with an ideal model, the nomograms worked well both in the training and validation sets. Through the results that the eight-mRNA signature effectively classified patients into low- and high-risk of distant recurrence, we concluded that this eight-mRNA-based signature played a promising predictive role in prognosis and could be clinically applied in breast cancer patients receiving adjuvant chemotherapy.