Factors associated with postoperative muscle reconnection in children's congenital muscular torticollis.

Background: In prior studies, there has been no report of clinical observation of postoperative reconnection of the sternocleidomastoid muscle (SCM) in children with congenital muscular torticollis (CMT). Therefore, the objective of this study is to investigate the factors associated with postoperative reconnection of the SCM in children with CMT, and to provide clinical evidence. Methods: A retrospective study was conducted, wherein 83 CMT children without any missing data were followed up from November 2019 to June 2021. The age at the time of surgery, sex, preoperative and postoperative follow-up duration, laterality, neck mass history, preoperative physical therapy history, and severity type were recorded. The severity classification of CMT was based on clinical features and ultrasound images of SCM. The postoperative reconnection of SCM was measured. Results: Out of 83 patients, ten had postoperative reconnection. The rate of postoperative reconnection of SCM in children with CMT who had undergone unipolar SCM release surgery was 18.994 times higher than in patients who had not undergone such surgery. This difference was statistically significant [odds ratio (OR) =18.994, 95% confidence interval (CI): 1.583 to 227.897, P=0.020]. Conclusions: The history of SCM release surgery in CMT children can predict the postoperative reconnection of SCM, which will aid in determining the optimal surgical approach for recurrent CMT patients.

Genome-wide identification of Apetala2 gene family in Hypericum perforatum L and expression profiles in response to different abiotic and hormonal treatments.

The Apetala2 (AP2) gene family of transcription factors (TFs) play important functions in plant development, hormonal response, and abiotic stress. To reveal the biological functions and the expression profiles of AP2 genes in Hypericum perforatum, genome-wide identification of HpAP2 family members was conducted. Methods: We identified 21 AP2 TFs in H. perforatum using bioinformatic methods; their physical and chemical properties, gene structures, conserved motifs, evolutionary relationships, cis-acting elements, and expression patterns were investigated. Results: We found that based on the structural characteristics and evolutionary relationships, the HpAP2 gene family can be divided into three subclasses: euANT, baselANT, and euAP2. A canonical HpAP2 TF shared a conserved protein structure, while a unique motif 6 was found in HpAP2_1, HpAP2_4, and HpAP2_5 from the euANT subgroup, indicating potential biological and regulatory functions of these genes. Furthermore, a total of 59 cis-acting elements were identified, most of which were associated with growth, development, and resistance to stress in plants. Transcriptomics data showed that 57.14% of the genes in the AP2 family were differentially expressed in four organs. For example, HpAP2_18 was specifically expressed in roots and stems, whereas HpAP2_17 and HpAP2_11 were specifically expressed in leaves and flowers, respectively. HpAP2_5, HpAP2_11, and HpAP2_18 showed tissue-specific expression patterns and responded positively to hormones and abiotic stresses. Conclusion: These results demonstrated that the HpAP2 family genes are involved in diverse developmental processes and generate responses to abiotic stress conditions in H. perforatum. This article, for the first time, reports the identification and expression profiles of the AP2 family genes in H. perforatum, laying the foundation for future functional studies with these genes.

GAPDH: A common housekeeping gene with an oncogenic role in pan-cancer.

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is one of the most prominent housekeeping proteins and is widely used as an internal control in some semi-quantitative assays. In addition to glycolysis, GAPDH is involved in several cancer-related biological processes and has been reported to be commonly dysregulated in multiple cancer types. Therefore, its role in the physiological process of cancer needs to be urgently elucidated. Pan-cancer analysis indicated that GAPDH is ubiquitously highly expressed in most cancer types, and that patients with a high GAPDH expression of in tumor tissues have a poor prognosis. The concordance of GAPDH expression in tumors with the infiltration of immune cells and immune checkpoints implies a certain association between GAPDH and the tumor microenvironment as well as tumor development. Gene Set Enrichment Analysis revealed that GAPDH may contribute to multiple important cancer-related pathways and biological processes. Multi-omics analysis and in vitro cell experiments revealed that GAPDH overexpression is regulated by DNA copy number amplification and promoter methylation modification. Importantly, a transcription factor, forkhead box M1 (FOXM1), which is capable of regulating GAPDH expression, was also identified and was confirmed to be an oncogene and ubiquitously highly expressed in multiple cancer types. Semi-quantitative chromatin immunoprecipitation, quantitative PCR, and dual-luciferase assays showed that FOXM1 mainly binds to the promoter region of GAPDH in two cancer cell lines. The present findings revealed the implication of GAPDH in tumor development, thus bringing attention to this important molecule and casting doubts on its role as an internal reference gene in cancer studies.

SIRT6 deficiency in endothelial cells exacerbates oxidative stress by enhancing HIF1α accumulation and H3K9 acetylation at the Ero1α promoter.

BACKGROUND: SIRT6, an important NAD+ -dependent protein, protects endothelial cells from inflammatory and oxidative stress injuries. However, the role of SIRT6 in cardiac microvascular endothelial cells (CMECs) under ischemia-reperfusion injury (IRI) remains unclear. METHODS: The HUVECs model of oxygen-glucose deprivation/reperfusion (OGD/R) was established to simulate the endothelial IRI in vitro. Endoplasmic reticulum oxidase 1 alpha (Ero1α) mRNA and protein levels in SIRT6-overexpressing or SIRT6-knockdown cells were measured by qPCR and Western blotting. The levels of H2 O2 and mitochondrial reactive oxygen species (ROS) were detected to evaluate the status of oxidative stress. The effects of SIRT6 deficiency and Ero1α knockdown on cellular endoplasmic reticulum stress (ERS), inflammation, apoptosis and barrier function were detected by a series of molecular biological experiments and functional experiments in vitro. Chromatin immunoprecipitation, Western blotting, qPCR, and site-specific mutation experiments were used to examine the underlying molecular mechanisms. Furthermore, endothelial cell-specific Sirt6 knockout (ecSirt6-/- ) mice were subjected to cardiac ischemia-reperfusion surgery to investigate the effects of SIRT6 in CMECs in vivo. RESULTS: The expression of Ero1α was significantly upregulated in SIRT6-knockdown endothelial cells, and high Ero1α expression correlated with the accumulation of H2 O2 and mitochondrial ROS. In addition, SIRT6 deficiency increased ERS, inflammation, apoptosis and endothelial permeability, and these effects could be significantly attenuated by Ero1α knockdown. The deacetylase catalytic activity of SIRT6 was important in regulating Ero1α expression and these biological processes. Mechanistically, SIRT6 inhibited the enrichment of HIF1α and p300 at the Ero1α promoter through deacetylating H3K9, thereby antagonizing HIF1α/p300-mediated Ero1α expression. Compared with SIRT6-wild-type (SIRT6-WT) cells, cells expressing the SIRT6-H133Y-mutant and SIRT6-R65A-mutant exhibited increased Ero1α expression. Furthermore, ecSirt6-/- mice subjected to ischemia-reperfusion surgery exhibited increased Ero1α expression and ERS in CMECs and worsened injuries to microvascular barrier function and cardiac function. CONCLUSIONS: Our results revealed an epigenetic mechanism associated with SIRT6 and Ero1α expression and highlighted the therapeutic potential of targeting the SIRT6-HIF1α/p300-Ero1α axis.

Component Costs of CAR-T Therapy in Addition to Treatment Acquisition Costs in Patients with Multiple Myeloma.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), is a B-cell maturation antigen-directed, genetically modified autologous chimeric antigen receptor T-cell (CAR-T) immunotherapy. It is indicated for treatment for adult patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The objective of this study was to estimate the per-patient US commercial healthcare costs related to cilta-cel (CARVYKTI®) CAR-T therapy (i.e., costs separate from cilta-cel therapy acquisition) for patients with RRMM. METHODS: US prescribing information for cilta-cel, publicly available data, and published literature were used with clinician input to identify the cost components and unit costs associated with administration of cilta-cel. Cost components included apheresis, bridging therapy, conditioning therapy, administration, and postinfusion monitoring for 1 year of follow-up. Adverse event (AE) management costs for all grades of cytokine release syndrome and neurologic toxicities, and additional AEs grade ≥ 3 occurring in > 5% of patients were included in the analysis. RESULTS: The estimated per-patient average costs of cilta-cel CAR-T therapy administered exclusively in an inpatient setting, excluding cilta-cel therapy acquisition costs, totaled US$160,933 over a 12 month period. Costs assuming different proportions of inpatient/outpatient administration (85%/15% and 70%/30%) were US$158,095 and US$155,257, respectively. CONCLUSION: Cost estimates from this analysis, which disaggregates CAR-T therapy costs, provide a comprehensive view of the cost components of CAR-T therapy that can help healthcare decision-makers make informed choices regarding the use of cilta-cel. Real-world costs may differ with improved AE prevention and mitigation strategies.

lncRNA ZNRD1-AS1 promotes malignant lung cell proliferation, migration, and angiogenesis via the miR-942/TNS1 axis and is positively regulated by the m6A reader YTHDC2.

RATIONALE: Lung cancer is the most prevalent form of cancer and has a high mortality rate, making it a global public health concern. The N6-methyladenosine (m6A) modification is a highly dynamic and reversible process that is involved in a variety of essential biological processes. Using in vitro, in vivo, and multi-omics bioinformatics, the present study aims to determine the function and regulatory mechanisms of the long non-coding (lnc)RNA zinc ribbon domain-containing 1-antisense 1 (ZNRD1-AS1). METHODS: The RNAs that were bound to the m6A 'reader' were identified using YTH domain-containing 2 (YTHDC2) RNA immunoprecipitation (RIP)-sequencing. Utilizing methylated RIP PCR/quantitative PCR, pull-down, and RNA stability assays, m6A modification and ZNRD1-AS1 regulation were analyzed. Using bioinformatics, the expression levels and clinical significance of ZNRD1-AS1 in lung cancer were evaluated. Using fluorescent in situ hybridization and quantitative PCR assays, the subcellular location of ZNRD1-AS1 was determined. Using cell migration, proliferation, and angiogenesis assays, the biological function of ZNRD1-AS1 in lung cancer was determined. In addition, the tumor suppressor effect of ZNRD1-AS1 in vivo was validated using a xenograft animal model. Through bioinformatics analysis and in vitro assays, the downstream microRNAs (miRs) and competing endogenous RNAs were also predicted and validated. RESULTS: This study provided evidence that m6A modification mediates YTHDC2-mediated downregulation of ZNRD1-AS1 in lung cancer and cigarette smoke-exposed cells. Low levels of ZNRD1-AS1 expression were linked to adverse clinicopathological characteristics, immune infiltration, and prognosis. ZNRD1-AS1 overexpression was shown to suppress lung cancer cell proliferation, migration, and angiogenesis in vitro and in vivo, and to reduce tumor growth in nude mice. ZNRD1-AS1 expression was shown to be controlled by treatment of cells with either the methylation inhibitor 3-Deazaadenosine or the demethylation inhibitor Meclofenamic. Furthermore, the miR-942/tensin 1 (TNS1) axis was demonstrated to be the downstream regulatory signaling pathway of ZNRD1-AS1. CONCLUSIONS: ZNRD1-AS1 serves an important function and has clinical relevance in lung cancer. In addition, the findings suggested that m6A modification could mediate the regulation of the ZNRD1-AS1/miR-942/TNS1 axis via the m6A reader YTHDC2.

Autophagy involvement in T lymphocyte signalling induced by nickel with quantitative phosphoproteomic analysis.

Nickel-induced allergic contact dermatitis (ACD) is a common skin disease. The mechanism by which nickel causes ACD is not clear. There is no treatment for it, only symptomatic therapy. However, due to the lifetime sensitization characteristics, the recurrence rate in patients is high. T lymphocytes play a key role in nickel-induced ACD. Elucidating the potential mechanism underlying nickel-induced T lymphocyte signalling might make it possible to achieve targeted treatment of nickel-induced ACD. In our study, a phosphoproteomic approach based on tandem mass tag (TMT) labelling and LCMS/MS analyses was employed. An animal model of nickel allergy was established. Splenic T lymphocytes were purified for quantitative phosphoproteomic analysis. The numbers of phosphoproteins, phosphopeptides and phosphosites identified in this study were 3072, 7977 and 10,200, respectively. Comprehensive gene ontology (GO) analysis combined with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that nickel can significantly affect the phosphorylation of the mTOR signalling pathway in T lymphocytes. Western blotting analysis was used to detect changes in the expression of autophagy-related proteins (Beclin 1, LC3II, and p62). Nickel allergy changed autophagy-related protein expression (p < 0.05). It has been demonstrated that nickel causes autophagy of T lymphocytes in the spleen. Using autophagy inhibitors to intervene, it was found that Th1 differentiation was inhibited, and the expression of Th1-related inflammatory factors was downregulated. Overall, the identification of relevant signalling pathways yielded new insights into the molecular mechanisms underlying nickel allergy and might help in the discovery and development of mechanism-based drugs.

Characteristics of macular microvasculature before and after idiopathic macular hole surgery.

AIM: To evaluate the macular microvasculature before and after surgery for idiopathic macular hole (MH) and the association of preoperative vascular parameters with postoperative recovery of visual acuity and configuration. METHODS: Twenty eyes from 20 patients with idiopathic MH were enrolled. Optical coherence tomography angiography (OCTA) images were obtained before, 2wk, 1, and 3mo after vitrectomy with internal limiting membrane peeling. Preoperative foveal avascular zone (FAZ) area and perimeter and regional vessel density (VD) in both layers were compared according to the 3-month best-corrected visual acuity (BCVA). RESULTS: The BCVA improved from 0.98±0.59 (logMAR, Snellen 20/200) preoperatively to 0.30±0.25 (Snellen 20/40) at 3mo postoperatively. The preoperative deep VD was smaller and the FAZ perimeter was larger in the 3-month BCVA<20/32 group (all P<0.05). A significant reduction was observed in FAZ parameters and all VDs 2wk postoperatively. Except for deep perifoveal VD, all VDs recovered only to their preoperative values. The postoperative FAZ parameters were lower during follow-up. Decreases in preoperative deep VDs were correlated with worse postoperative BCVA (Pearson's r=-0.667 and -0.619, respectively). A larger FAZ perimeter (Spearman's r=-0.524) and a lower deep perifoveal VD preoperatively (Pearson's r=0.486) were associated with lower healing stage. CONCLUSION: The status of the deep vasculature may be an indicator of visual acuity in patients with a closed MH. Except for the deep perifoveal region, VD recovers only to preoperative levels.

Downregulation of m6A Reader YTHDC2 Promotes the Proliferation and Migration of Malignant Lung Cells via CYLD/NF-κB Pathway.

Lung cancer is one of the most common types of carcinoma worldwide. Cigarette smoking is considered the leading cause of lung cancer. Aberrant expression of several YT521-B homology (YTH) family proteins has been reported to be closely associated with multiple cancer types. The present study aims to evaluate the function and regulatory mechanisms of the N6-methyladenosine (m6A) reader protein YTH domain containing 2 (YTHDC2) by in vitro, in vivo and bioinformatics analyses. The results revealed that YTHDC2 was reduced in lung cancer and cigarette smoke-exposed cells. Notably, bioinformatics and tissue arrays analysis demonstrated that decreased YTHDC2 was highly associated with smoking history, pathological stage, invasion depth, lymph node metastasis and poor outcomes. The in vivo and in vitro studies revealed that YTHDC2 overexpression inhibited the proliferation and migration of lung cancer cells as well as tumor growth in nude mice. Furthermore, YTHDC2 decreased expression was modulated by copy number deletion in lung cancer. Importantly, the cylindromatosis (CYLD)/NF-κB pathways were confirmed as the downstream signaling of YTHDC2, and this axis was mediated by m6A modification. The present results indicated that smoking-related downregulation of YTHDC2 was associated with enhanced proliferation and migration in lung cancer cells, and appeared to be regulated by DNA copy number variation. Importantly, YTHDC2 functions as a tumor suppressor through the CYLD/NF-κB signaling pathway, which is mediated by m6A modification.

Modulation of microglial phenotypes by dexmedetomidine through TREM2 reduces neuroinflammation in heatstroke.

No FDA approved pharmacological therapy is available to reduce neuroinflammation following heatstroke. Previous studies have indicated that dexmedetomidine (DEX) could protect against inflammation and brain injury in various inflammation-associated diseases. However, no one has tested whether DEX has neuro-protective effects in heatstroke. In this study, we focused on microglial phenotypic modulation to investigate the mechanisms underlying the anti-inflammatory effects of DEX in vivo and in vitro. We found that DEX treatment reduced the expression of CD68, iNOS, TNF-α, and IL-1ß, and increased the expression of CD206, Arg1, IL-10 and TGF-ß in microglia, ameliorating heatstroke induced neuroinflammation and brain injury in mice. TREM2, whose neuro-protective function has been validated by genetic studies in Alzheimer's disease and Nasu-Hakola disease, was significantly promoted by DEX in the microglia. TREM2 esiRNA reversed the DEX-induced activation of PI3K/Akt signalling. Overall these findings indicated that DEX may serve, as a potential therapeutic approach to ameliorate heatstroke induced neuroinflammation and brain injury via TREM2 by activating PI3K/Akt signalling.

Comparison of three lymph node staging methods for predicting outcome in breast cancer patients with mastectomy.

BACKGROUND: Axillary lymph node (ALN) staging is essential in predicting the clinical outcome of breast cancer (BC) patients. Traditionally, it follows the tumor-node-metastasis (TNM) staging, but its accuracy needs further improvement. METHODS: A total of 9,616 BC patients from the Surveillance, Epidemiology, and End Results (SEER) database and 675 patients from the First Affiliated Hospital of China Medical University underwent mastectomy together with ALN dissection were reviewed. Univariate and multivariate logistic analyses were conducted to find the most meaningful factors relevant to prognosis. RESULTS: After univariate and multivariate analyses, age, race, primary site, radiation, chemotherapy, grade, T-stage, estrogen receptor (ER), progesterone receptor (PR), total number of positive lymph nodes (pN), positive lymph node ratio (LNR) and log odds of positive LNs (LODDS) were found to be significantly associated with overall survival (OS). Using these non-LN risk factors, we further compared the efficacy of three different ALN staging methods in prognosis via nomograms. Harrell's concordance index (C-index) and Akaike Information Criterion (AIC) were used to measure nomogram performance of the ALN staging methods: pN: C-index=0.687 (95% CI: 0.678-0.696), AIC =61,398.24; LNR: C-index =0.691 (95% CI: 0.683-0.701), AIC =61,313.56; and LODDS: C-index =0.691 (95% CI: 0.682-0.700), AIC =61,315.60. We found that the nomogram incorporating LODDS had better predictive ability compared with other two methods. Furthermore, an external validation revealed a C-index of 0.753 (95% CI: 0.690-0.816) for the Asian population, which indicates the nomogram based on LODDS may have universality for both Western and Asian populations. CONCLUSIONS: Compared with pN and LNR, LODDS showed higher homeostasis in LN evaluation, and showed marked efficacy in evaluating survival differences among patients with negative LN staging. We constructed a BC prognosis model by incorporating highly relevant clinical pathological factors and a new method of LN staging, which may greatly aid in guiding postoperative treatment.

Laser therapy versus topical desensitising agents in the management of dentine hypersensitivity: A meta-analysis.

OBJECTIVES: To compare the effectiveness of lasers and topical desensitising agent treatments for dentine hypersensitivity. METHODS: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and ISI Web of Knowledge were electronically searched without restrictions. Study search, selection, data extraction and assessment of risk of bias were conducted independently by two reviewer authors. All analyses were performed using Review Manager 5.3 (Cochrane Collaboration). RESULTS: This meta-analysis included 13 eligible studies that compared topical desensitising agents and Nd:YAG or diode laser. Four, six and three studies were considered to have low, moderate and high risks of bias, respectively. The follow-up period varied from immediate to 9 months. All comparisons except the 3-month Nd:YAG laser parallel group and 6-month diode laser group showed that the clinical efficacy of lasers for dentine hypersensitivity was not significantly different with topical desensitising agents. CONCLUSION: We found low-quality evidence that was insufficient to draw any conclusions regarding the superiority of lasers or conventional topical desensitising agents in the treatment of DH. Further well-designed RCTs on this topic are needed to draw definitive conclusions.

Evaluation of the SureX HPV genotyping test for the detection of high-risk HPV in cervical cancer screening.

BACKGROUND: The SureX HPV genotyping test (SureX HPV test), which targets the human papillomavirus (HPV) E6/E7 genes was compared with the Cobas 4800 and Venus HPV tests for detecting 14 high-risk HPV (HR-HPV) types in clinical referral and follow-up patients to evaluate its value for cervical cancer screening. METHODS: Two different populations were enrolled in the study. The first population comprised 185 cases and was used for comparing the SureX HPV test (Health, China) with the Cobas 4800 test (Roche, USA). The second population comprised 290 cases and was used for comparing the SureX HPV test (Health, China) with the Venus HPV test (Zhijiang, China). Polymerase chain reaction (PCR) sequencing was performed for further confirmation of discordant results. RESULTS: In the first population, the overall agreement rate was 95.6% for 14 high-risk HPV types. Eight discordant cases were confirmed by PCR sequencing, which showed that the agreement rates were 75.0% between the SureX HPV test and PCR sequencing and 25.0% between the Cobas 4800 test and PCR sequencing (P < 0.01). In the second population, the overall agreement rate was 95.5%. Thirteen discordant cases were confirmed by PCR sequencing, which showed that the agreement rates were 76.9% between the SureX HPV test and PCR sequencing and 23.1% between the Venus HPV test and PCR sequencing (P < 0.01). With cervical intraepithelial neoplasia grade 2+ (CIN2+) as the reference standard, the sensitivity values of the SureX HPV test and the Venus HPV test were 93.5% and 92.0%, (P > 0.05), while the specificity values were 43.3% and 46.7%, respectively (P > 0.05). CONCLUSION: The SureX HPV test had good consistency with both the Cobas 4800 and Venus HPV tests for 14 HR-HPV types. In addition, it avoided some false negatives and false positives. Therefore, the SureX HPV test can be used for cervical cancer screening.

Updated Bayesian Network Meta-Analysis of Adjuvant Targeted Treatment Regimens for Early Human Epidermal Growth Factor Receptor-2 Positive Breast Cancer.

PURPOSE: Combining targeted agents with adjuvant chemotherapy prolongs survival in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, but also increases the risk of adverse effects. The updated results of 3 randomized controlled trials (RCTs) were reported in 2019. Given the lack of adequate head-to-head pairwise assessment for anti-HER2 agents, network meta-analysis facilitates obtaining more precise inference for evidence-based therapy. METHODS: RCTs comparing at least 2 anti-HER2 regimens in an adjuvant setting for HER2-positive early-stage breast cancer (EBC) were included. Hazard ratios for overall survival (OS) and disease free survival (DFS), with respective 95% confidence intervals were pooled for assessment of efficacy. A Bayesian statistical model was used, and odds ratios (ORs) for adverse events (AEs) were used to pool effect sizes. RESULTS: We demonstrated that 1-year trastuzumab plus chemotherapy had increased efficacy compared to shorter or longer treatment duration. The OR of cardiac events gradually increased from 6 months to 1 and 2-year trastuzumab arms, relative to chemotherapy only. Compared to trastuzumab plus chemotherapy, dual HER2-targeting therapies increased DFS, especially for hormone receptor negative patients. Dual anti-HER2 blockade regimens revealed an increased probability of gastrointestinal reactions. As a second agent, pertuzumab showed significantly higher DFS and OS. CONCLUSION: We conclude that 1-year adjuvant trastuzumab should remain as the standard treatment for HER2-positive EBC patients, as it has greater efficacy and a manageable proportion of AEs. Clinical efficacy can be increased for hormone receptor-negative tumors by including a second HER2-targeted agent to the treatment regimen. For hormone receptor-positive cases with basal disease, it is acceptable to reduce the risk of cardiotoxicity by shortening the duration of trastuzumab.

Metabolic Reprogramming in Triple-Negative Breast Cancer.

Metabolic reprogramming is an emerging hallmark of cancer cells, in which cancer cells exhibit distinct metabolic phenotypes to fuel their proliferation and progression. The significant advancements made in the area of metabolic reprogramming make possible new strategies for overcoming malignant cancer, including triple-negative breast cancer. Triple-negative breast cancer (TNBC) is associated with high histologic grade, aggressive phenotype, and poor prognosis. Even though triple-negative breast cancer patients benefit from standard chemotherapy, they still face high recurrence rates and are more likely to develop resistance to chemotherapeutic drugs. Therefore, there is an urgent need to explore vulnerabilities of triple-negative breast cancer and develop novel therapeutic drugs to improve clinical outcomes for triple-negative breast cancer patients. Metabolic reprogramming may provide promising therapeutic targets for the treatment of triple-negative breast cancer. In this paper, we primarily discuss how triple-negative breast cancer cells reprogram their metabolic phenotype and that of stromal cells in the microenvironment to survive under nutrient-poor conditions. Considering that metastasis and chemoresistance are the main contributors to mortality in triple-negative breast cancer patients, we also focus on the role of metabolic adaption in mediating metastasis and chemoresistance of triple-negative breast cancer tumors.

Can ACEI/ARB prevent the cardiotoxicity caused by chemotherapy in early-stage breast cancer?-a meta-analysis of randomized controlled trials.

BACKGROUND: Administration of anthracycline-based chemotherapy with or without trastuzumab is recognized as standard care for breast cancer, but it is associated with a decline in left ventricular ejection fraction (LVEF). Angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB) might decrease this cardiac dysfunction caused by the anti-cancer therapy. We sought to evaluate the prophylactic effects of the cardioprotective agents ACEI/ARB for early-stage breast cancer. METHODS: We systematically searched the electronic databases Cochrane, PubMed, and Embase for randomized controlled trials (RCTs) evaluating the effect of ACEI/ARB. This meta-analysis calculated weighted mean differences with 95% CI, for ejection fraction and pooled odds ratios (OR) with 95% CI, for cardiac events. Pooled analyses were used in a random-effect model. The primary endpoint was the change of LVEF in the ACEI/ARB group versus the control group from baseline through completion of the studies. RESULTS: our meta-analysis includes 5 studies encompassing 702 early-stage breast cancer patients. There was statistically significant diversity in the magnitude of the change of mean LVEF in patients receiving ACEI/ARB compared with control groups, with a mean difference of 4.08% (95% CI: 0.8% to 7.35%, P=0.01). However, regarding patient outcomes, ACEI/ARB did not significantly reduce the risk of cardiac events (OR 0.91, 95% CI: 0.62 to 1.34, P=0.64) or increase the incidence of hypotension events as compared with controls (OR 2.72, 95% CI: 0.69 to 10.73, P=0.15). CONCLUSIONS: Our study suggests that ACEI/ARB significantly attenuate the cardiac dysfunction caused by anthracycline-based chemotherapy and/or trastuzumab. Further studies are required to confirm the effectiveness of this cardioprotective agent.

Nomogram for predicting axillary lymph node status after neoadjuvant chemotherapy in breast cancer.

BACKGROUND: Many breast cancer patients benefit from neoadjuvant chemotherapy (NAC). However, sentinel lymph node biopsy (SLNB) after NAC remains controversial, especially for patients with axillary lymph node metastasis (ALNM) at diagnosis. We developed a nomogram for predicting axillary lymph node (ALN) status after NAC to screen for patients for whom SLNB may be beneficial. METHODS: A total of 320 cT1-4N0-1M0 breast cancer patients receiving ALN dissection (ALND) after NAC were included. Univariate and multivariate logistic regression analyses determined significant factors for predicting ALN status. Efficacy of the resulting nomogram was assessed using receiver operating characteristic (ROC) and calibration curves, while decision curve analysis (DCA) was used to evaluated net clinical benefit. Our nomogram was validated using female patients grouped according to a diagnosis of node-positive (cN1) or node-negative (cN0) by ultrasound-guided needle biopsy of suspected lymph nodes before NAC. RESULTS: Logistic regression analyses indicated that estrogen receptor (ER), Ki67, degree of tumor regression, clinical tumor T stage after NAC, and ALN Breast Imagining-Reporting and Data System (BI-RADS) category after NAC, were associated with ALN status. The resulting nomogram had an area under the curve (AUC) of 0.802 [95% confidence interval (CI), 0.7485-0.8554], and the calibration plot showed strong uniformity between predicted and actual ALN status. DCA indicated a positive net benefit of nomogram predictions in our cohort. After internal validation, the cN1 and cN0 groups had an AUC of 0.7926 (95% CI, 0.7187-0.8665) and 0.8165 (95% CI, 0.7381-0.8949), respectively. The calibration plot indicated better performance in the cN0 group. CONCLUSIONS: After NAC, some patients may benefit from SLNB. Our nomogram predicts ALN status after NAC and has great potential to assist in clinical decision-making.

The Undervalued Effects of Polychlorinated Biphenyl Exposure on Breast Cancer.

The incidence of breast cancer across the world has been on the rise in recent decades. Because identified risk factors can only explain a relatively small portion of the cases, environmental exposure to organic pollutants is suspected to play a role in breast cancer etiology. Polychlorinated biphenyls (PCBs) are among the most abundant pollutants, and the impact of their exposure on breast cancer risk has been extensively studied in recent decades. However, the results of most epidemiologic studies do not support an association between PCB exposure and breast cancer risk. We hypothesized that the effects of PCBs on breast cancer might have been undervalued for reasons such as insufficient recognition of the confounding effects of several factors and lack of attention on the innate heterogeneity of PCB mixtures or breast cancer. After reviewing the evidence in the existing literature, we concluded that early life exposure, known risk factors of breast cancer, and impact of exposure to other pollutants are the main sources of confounding effects and have potentially masked the associations between PCBs and breast cancer. Because PCBs are mixtures of congeners with varied properties, and because breast cancers of different subtypes are etiologically distinct diseases, the absence of stratified subgroup analysis on individual PCBs and patients with specific biological subtypes and insufficient attention paid to the results of these subgroup analyses may result in an underestimation of the correlations between PCBs and breast cancer. In future studies, these factors must be taken into consideration when exploring the effect of PCB exposure on breast cancer risk.

Neoadjuvant endocrine therapy: A potential strategy for ER-positive breast cancer.

A potential strategy for patients with estrogen receptor (ER)-positive breast cancer is necessary to replace neoadjuvant chemotherapy which has limited benefit. Neoadjuvant endocrine therapy (NAE) has been indicated to be a favorable alternate approach to downstage large or locally advanced breast cancer in ER-positive, human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) patients, especially postmenopausal women. Previous studies have demonstrated the efficacy of various endocrine agents in NAE. Aromatase inhibitors (AIs) have proven superiority over tamoxifen as a suitable choice to optimize treatment efficacy. Fulvestrant was recently reported as an effective agent, similar to AIs. Furthermore, the addition of targeted agents exerts synergistic antiproliferative effects with endocrine agents and rapidly improves response rates in both endocrine sensitive and resistant tumors. The neoadjuvant platform provides a unique opportunity to define the appropriate strategy and address the mechanisms of endocrine resistance. In addition, the predictive value of biomarkers and genomic assays in NAE is under investigation to evaluate individual effects and validate biomarker-based strategies. In this review, we discuss the most relevant evidence on the potential of NAE for ER+ breast cancer. The current understanding also offers new insights into the identification of the optimal settings and valuable predictive tools of NAE to guide clinical treatment decisions and achieve beneficial therapeutic effects.

Enhancing the taste of raw soy sauce using low intensity ultrasound treatment during moromi fermentation.

Sonication can significantly enhance amino acids (AAs) release to accelerate maturation during short-term and low-salt soy sauce fermentation. Here, sonication was applied at 68 kHz (60 W/L/10 min/8 circles) to determine its effects on the taste during long-term and high-salt soy sauce fermentation. The possible mechanisms were explored by analyzing differences in enzymes profile, proximate indices, molecular weight distribution of peptides, AAs composition and microstructures of sonicated moromis and their controls. Sonication greatly elevated levels of organic taste compounds ranging from 8.4% to 22.2%, but lowered levels of NaCl (6.0%), peptides ≤ 1 kDa (5.2%), histidine (20.5%) and glutamic acid (3.4%). Compared to its controls, sonicated raw soy sauces also had a more harmonious and palatable taste. Increased enzymes' activities and formation of more surface area and reaction sites in sonicated moromis might be the possible mechanisms for sonication to elevate levels of taste compounds and sensory quality of soy sauce.