Low-density lipoprotein receptor promotes crosstalk between cell stemness and tumor immune microenvironment in breast cancer: a large data-based multi-omics study.

BACKGROUND: Tumor cells with stemness in breast cancer might facilitate the immune microenvironment's suppression process and led to anti-tumor immune effects. The primary objective of this study was to identify potential targets to disrupt the communication between cancer cell stemness and the immune microenvironment. METHODS: In this study, we initially isolated tumor cells with varying degrees of stemness using a spheroid formation assay. Subsequently, we employed RNA-seq and proteomic analyses to identify genes associated with stemness through gene trend analysis. These stemness-related genes were then subjected to pan-cancer analysis to elucidate their functional roles in a broader spectrum of cancer types. RNA-seq data of 3132 patients with breast cancer with clinical data were obtained from public databases. Using the identified stemness genes, we constructed two distinct stemness subtypes, denoted as C1 and C2. We subsequently conducted a comprehensive analysis of the differences between these subtypes using pathway enrichment methodology and immune infiltration algorithms. Furthermore, we identified key immune-related stemness genes by employing lasso regression analysis and a Cox survival regression model. We conducted in vitro experiments to ascertain the regulatory impact of the key gene on cell stemness. Additionally, we utilized immune infiltration analysis and pan-cancer analysis to delineate the functions attributed to this key gene. Lastly, single-cell RNA sequencing (scRNA-seq) was employed to conduct a more comprehensive examination of the key gene's role within the microenvironment. RESULTS: In our study, we initially identified a set of 65 stemness-related genes in breast cancer cells displaying varying stemness capabilities. Subsequently, through survival analysis, we pinpointed 41 of these stemness genes that held prognostic significance. We observed that the C2 subtype exhibited a higher stemness capacity compared to the C1 subtype and displayed a more aggressive malignancy profile. Further analysis using Lasso-Cox algorithm identified LDLR as a pivotal immune-related stemness gene. It became evident that LDLR played a crucial role in shaping the immune microenvironment. In vitro experiments demonstrated that LDLR regulated the cell stemness of breast cancer. Immune infiltration analysis and pan-cancer analysis determined that LDLR inhibited the proliferation of immune cells and might promote tumor cell progression. Lastly, in our scRNA-seq analysis, we discovered that LDLR exhibited associations with stemness marker genes within breast cancer tissues. Moreover, LDLR demonstrated higher expression levels in tumor cells compared to immune cells, further emphasizing its relevance in the context of breast cancer. CONCLUSION: LDLR is an important immune stemness gene that regulates cell stemness and enhances the crosstalk between breast cancer cancer cell stemness and tumor immune microenvironment.

Clinical outcomes of radiofrequency ablation for solitary T1aN0M0 versus T1bN0M0 papillary thyroid carcinoma: a propensity-matched cohort study.

OBJECTIVE: To conduct a cohort study comparing the treatment outcomes of radiofrequency ablation (RFA) therapy for solitary T1aN0M0 (T1a) versus T1bN0M0 (T1b) papillary thyroid carcinoma (PTC). METHODS: This retrospective analysis comprised 310 patients with low-risk PTC undergoing RFA classified into T1a (n = 272) and T1b (n = 38) groups according to the tumor size. A comparative analysis between the two groups was conducted for the volume reduction ratio (VRR), volume, local tumor progression (LTP), and recurrence-free survival (RFS) before and after 1:2 propensity score matching (PSM). Cox analysis was conducted to examine the influence of several variables, including T1b, on recurrence following RFA for PTC. RESULTS: The total VRR was 99.99 ± 0.11% throughout the median follow-up duration of 26 months, and the overall incidence of LTP was 2.58% (8/310). No irrecoverable complications occurred after RFA. The variations between the T1a and T1b groups following PSM were insignificant in terms of volume (p = 0.574), VRR (p = 0.574), complete disappearance rate (p = 0.210), LTP incidence (p = 1.000), and RFS rate (p = 0.610). The correlation between T1b and LTP continued to be insignificant (p = 0.686). No distant metastasis or delayed surgery occurred. CONCLUSIONS: The presence of T1b did not influence the patients' prognoses following RFA for T1N0M0 PTC. After appropriate patient selection and adequate preoperative assessment, RFA has the potential to serve as an effective therapy for individuals with T1a and T1b PTC.

Different effects of intravenous and local anesthesia in patients undergoing ultrasound-guided radiofrequency ablation of thyroid nodules: a prospective cohort study.

PURPOSE: To compare the efficacy and safety of intravenous anesthesia (IV) with local anesthesia (LA) in patients undergoing ultrasound (US)-guided radiofrequency ablation (RFA) of thyroid nodules. METHODS: 50 patients with American Society of Anesthesiologists classification grades I-II undergoing US-guided thyroid RFA were enrolled and randomly (1:1) divided into IV (conscious sedation with Ramsay Sedation Scale [RSS] scores of 2-3 with an anesthesiologist) and LA (subcutaneous anesthesia with lidocaine without an anesthesiologist) groups. Pre-, intra- and post-procedural blood pressure (BP) (SBP0/DBP0, SBP1/DBP1, and SBP2/DBP2), intra- and post-procedural pain (NRS1 and NRS2), ablated area volume, treatment time and adverse events were analyzed and compared. RESULTS: Age, sex, weight, number, nature, volume of nodules, and SBP0/DBP0 showed no difference between both groups. 11 and 0 patients' SBP1/DBP1 were elevated in the LA and IV groups. NRS1 differed between both groups. 6 patients in the LA group had moderate or severe pain, but none in the IV group. No between-group difference in SBP2/DBP2, NRS2, ablation completion rate and ablated volume was noted. The median procedure duration differed from 1109 (176) s in IV group and 723 (227) s in LA groups. There was no increased incidence of adverse events in IV group. CONCLUSIONS: IV with RSS scores of 2-3 maintained intra-procedural BP and relieved intra-procedural pain better, without affecting the ablation efficacy and increasing complications. Despite increased treatment time, IV is a potential option for patients undergoing US-guided RFA of thyroid nodules.

Long-term follow-up results of PTMC treated by ultrasound-guided radiofrequency ablation: a retrospective study.

OBJECTIVES: To confirm the long-term efficacy and safety of radiofrequency ablation (RFA) for low-risk papillary thyroid microcarcinoma (PTMC). METHODS: We retrospectively reviewed data of 102 primary papillary thyroid carcinoma patients (82 women, 20 men; mean age: 43 [19] years) treated with radiofrequency ablation and thyroid-stimulating hormone (TSH) suppression therapy before December 2018. All patients were at high surgical risk or refused surgery. They were followed up at 1, 3, 6, 9, and 12 months and every 6-12 months thereafter using ultrasound and contrast-enhanced ultrasound. The volume and volume reduction ratio was calculated. Recurrence and lymph node or distant metastasis were evaluated. RESULTS: The mean initial tumor diameter was 0.50 (0.29) cm; the mean initial volume was 0.06 (0.09) mL. At 1, 3, 6, 9, 12, 24, 36, 48, and 60 months after RFA, complete resorption rates were 0, 0, 9.8 (10/102), 33.3 (34/102), 91.2 (93/102), 96.1 (98/102), 99 (101/102), 100, and 100%, respectively. Two patients had developed ipsilateral neck lymph node metastasis in regions IV and VI at 30- and 18-month follow-ups, respectively. After RFA, 3/102 patients (2.9%) developed hoarseness-the main side effect. No life-threatening or delayed complications occurred. The TSH value in the initial period was 0.06 (0.02) µIU/mL; the rate of reaching the TSH target was 85.7%. The TSH value at follow-up was 1.47 (0.91) µIU/mL; the compliance rate was 99.3%. CONCLUSIONS: Ultrasound-guided RFA for PTMC is highly effective and safe. RFA can serve as a minimally invasive treatment for PTMC patients who refuse surgery or active surveillance.

Efficacy and safety of radiofrequency, microwave and laser ablation for treating papillary thyroid microcarcinoma: a systematic review and meta-analysis.

Background: To evaluate the efficacy and safety of radiofrequency ablation (RFA), microwave ablation (MWA) and laser ablation (LA) for treating papillary thyroid microcarcinoma (PTMC).Materials and methods: PUBMED and EMBASE were searched for studies on the efficacy and safety of RFA, MWA and LA for treating PTMC. The standard mean difference of the tumor volume before and after therapy and the proportion of complete disappearance, local recurrence, distant metastasis and complications were assessed using both fixed or random-effects modeling. Heterogeneity among studies was determined using the Q statistic for the pooled estimates and the inconsistency index I2.Results: A total of 12 eligible studies, including a sample size of 1187 patients and 1284 PTMCs, were used. RFA, MWA and LA all showed a significant reduction in tumor volume of PTMCs (p < 0.05). Though MWA demonstrated superior efficacy over the other two therapies for volume reduction, the differences were not statistically significant. Additionally, the pooled proportion of complete disappearance after RFA was the highest (76.2%), and the pooled proportion of recurrence for RFA was the lowest (0.01%) among the three therapeutic methods, but no significant difference was detected. There was no event of distant metastasis during the follow-up in all of these studies. Few major complications were encountered; the pooled proportion of complications for RFA (1.73%), MWA (6.0%) and LA (0.92%) was low, revealing no significant differences (p > 0.05).Conclusion: RFA, MWA and LA are acceptable treatments to manage PTMCs in terms of efficacy and safety for non-surgical candidates.

Aurora-A Kinase: A Potent Oncogene and Target for Cancer Therapy.

The Aurora kinase family is comprised of three serine/threonine kinases, Aurora-A, Aurora-B, and Aurora-C. Among these, Aurora-A and Aurora-B play central roles in mitosis, whereas Aurora-C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases has been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis. Aurora kinases therefore represent promising targets for anticancer therapeutics. A number of Aurora kinase inhibitors (AKIs) have been generated; some of which are currently undergoing clinical evaluation. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora-A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora-A kinases in promoting tumorigenesis, the recent preclinical and clinical AKI data, and potential alternative routes for Aurora-A kinase inhibition.

Identification and Expression of the CorA/MRS2/ALR Type Magnesium Transporters in Tomato.

Magnesium (Mg2+) is the most abundant divalent ion in plants, participating in numerous metabolic processes in growth and development. CorA/MRS2/ALR type Mg2+ transporters are essential for maintaining Mg2+ homeostasis in plants. However, the candidate protein and its potential functions in the tomato plant have not been fully understood. In this study, we identified seven MGT genes (SlMRS2) in tomato based on sequence similarity, domain analysis, conserved motif identification, and structure prediction. Two SlMRS2 genes were analyzed in the bacterial strain MM281, and a functional complementary assay demonstrated their high-affinity transport of Mg2+. Quantitative real-time PCR analysis revealed that the expressions of these Mg2+ transporters were down-regulated in leaves under Mg2+ limitation, with a greater impact on lower and middle leaves compared to young leaves. Conversely, under Mg2+ toxicity, several genes were up-regulated in leaves with a circadian rhythm. Our findings indicate that members of the SlMRS2 family function as Mg2+ transporters and lay the groundwork for further analysis of their distinct functions in tomato.

Recurrent medullary thyroid carcinoma treated with percutaneous ultrasound-guided radiofrequency ablation: A case report.

BACKGROUND: Treatment for neck lymph node metastases after adequate initial surgery in medullary thyroid carcinoma (MTC) has been controversial. Ultrasound (US)-guided radiofrequency ablation (RFA) has been widely used in recurrent well-differentiated thyroid carcinoma. Here, we report for the first time the use of RFA in a patient with recurrent MTC. CASE SUMMARY: We report the case of a 56-year-old woman with cervical lymph node metastases of MTC. Four years previously, she had undergone a total thyroidectomy and neck lymph node dissection. A neck US revealed many enlarged nodes during the follow-up period. Moreover, the serum calcitonin jumped to 198.17 pg/mL, which strongly indicated the recurrence of MTC. Subsequently, two metastatic lymph nodes were confirmed by US-guided fine-needle aspiration-cytology and fine-needle aspiration-calcitonin, and then the patient was treated with RFA. Four months later, the neck US and a contrast-enhanced US showed obvious shrinkage in the ablation zones, and the serum calcitonin dropped to 11.80 pg/mL. CONCLUSION: This case suggests that RFA may be an effective and safe treatment for local recurrent MTC.

Tumor invasive ability of papillary thyroid carcinomas is not conferred by acquired gene mutations.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The ability to predict whether a carcinoma would exhibit invasive ability in patients with PTC is important and has clinical implications for the selection of therapeutic strategies. Although several studies have focused on the genetic characterization of invasive cancer cells, the factors critical to the origination of invasive cancer cells are still unclear. This study aimed to determine whether genomic mutations contribute to the acquisition of the tumor invasion phenotype and to investigate the genetic features of invasive cancer cells in patients with PTC. We performed customized 48-gene deep exon sequencing in samples obtained from 88 patients with PTC via fine needle aspiration; the results revealed that no genetic changes were specifically associated with the tumor aggressiveness phenotype. Our results indicate that genetic mutations do not cause indolent PTCs to become invasive.

Erratum: Primary sternum diffuse large B-cell lymphoma: A case report and a review of the literatur.

[This corrects the article DOI: 10.3892/ol.2015.3122.].

Traditional Chinese Medicine as Potential Therapy for COVID-19.

In December 2019, a novel coronavirus SARS-CoV-2, causing the disease COVID-19, spread from Wuhan throughout China and has infected people over 200 countries. Thus far, more than 3,400,000 cases and 240,000 deaths have occurred worldwide, and the coronavirus pandemic continues to grip the globe. While numbers of cases in China have been steadying, the number of infections outside China is increasing at a worrying pace. We face an urgent need to control the spread of the COVID-19 epidemic, which is currently expanding to a global pandemic. Efforts have focused on testing antiviral drugs and vaccines, but there is currently no treatment specifically approved. Traditional Chinese medicine (TCM) is grounded in empirical observations and the Chinese people use TCM to overcome these sorts of plagues many times in thousands of years of history. Currently, the Chinese National Health Commission recommended a TCM prescription of Qing-Fei-Pai-Du-Tang (QFPDT) in the latest version of the "Diagnosis and Treatment guidelines of COVID-19" which has been reported to provide reliable effects for COVID-19. While doubts about TCM still exist today, this review paper will describe the rationalities that QFPDT is likely to bring a safe and effective treatment of COVID-19.

Identification and functional analysis of the CorA/MGT/MRS2-type magnesium transporter in banana.

Magnesium (Mg) plays an irreplaceable role in plant growth and development. Mg transporters, especially CorA/MGT/MRS2 family proteins, played a vital role in regulating Mg content in plant cells. Although extensive work has been conducted in model crops, such as Arabidopsis, rice, and maize, the relevant information is scarce in tropical crops. In this study, 10 MaMRS2 genes in banana (Musa acuminata) were isolated from its genome and classified into five distinct clades. The putative physiochemical properties, chromosome location, gene structure, cis-acting elements, and duplication relationships in between these members were analyzed. Complementary experiments revealed that three MaMRS2 gene members (MaMRS2-1, MaMRS2-4, MaMRS2-7), from three distinct phylogenetic branches, were capable of restoring the function of Mg transport in Salmonella typhimurium mutants. Semi-quantitative RT-PCR showed that MaMRS2 genes were differentially expressed in banana cultivar 'Baxijiao' (Musa spp. AAA Cavendish) seedlings. The result was confirmed by real-time PCR analysis, in addition to tissue specific expression, expression differences among MaMRS2 members were also observed under Mg deficiency conditions. These results showed that Mg transporters may play a versatile role in banana growth and development, and our work will shed light on the functional analysis of Mg transporters in banana.

Longitudinal whole-genome sequencing reveals the evolution of MPAL.

PURPOSE: Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia and its progressive genomic basis over time remains unclear. We aimed to investigate the longitudinal genomic evolution of MPAL from diagnosis to relapse. METHODS: We performed whole genome sequencing (WGS) on bone marrow (BM) samples obtained at the four stages of this disease in a male patient with Philadelphia chromosome positive (Ph+) MPAL, including primary, complete cytogenetic remission (CCR), complete molecular remission (CMR), and relapse stage during the 3 year follow-up period. RESULTS: 156 single-nucleotide variants (SNVs) and indels were detected, which exhibited distinctive evolutionary behaviors. Seventeen mutations disappeared quickly upon DCTER treatment and never came back. Seven mutations, although disappeared initially, reoccurred with the withdrawal of TKI treatment. Notably, ten mutations emerged in spite of the active DCTER chemotherapy. Moreover, copy number loss played critical roles in monitoring MPAL progression, displaying 7, 0, 0, and 383 losses at the stages of primary, CCR, CMR, and relapse respectively. CONCLUSION: This longitudinal genomic investigation of the Ph+ MPAL patient established one MPAL evolution model in which the primary tumor acquired additional variations leading to tumor relapse. Moreover, the event of copy number loss remained a valuable hallmark in the progression of MPAL.

Emerging Role of Chinese Herbal Medicines in the Treatment of Pancreatic Fibrosis.

Pancreatic fibrosis is the main pathologic characteristic in chronic pancreatitis (CP), a common disease that arises from surgery. Pancreatitis is caused by various etiologies, but the mechanism of fibrosis is not completely understood. Existing clinical approaches mainly focus on mitigating the symptoms and therefore do not cure the phenomena. In recent years, there has been a heightened interest in the use of Chinese herbal medicine (CHMs) in the prevention and cure of CP as expressed by increasing numbers of clinical and experimental research. Despite early cell culture and animal models, CHMs are able to interact with plenty of molecular targets involved in the pathogenesis of pancreatic fibrosis mostly via the TGF- ß /Smads pathway; however, integrated and up-to-date communication in this domain is unavailable. This review focuses on the research progress of CHMs against pancreatic fibrosis due to CP in vitro and in vivo and summarizes the potential mechanisms. We also outlined the toxicology of some CHMs for fibrosis treatment in order to provide a fuller understanding of drug safety. This review may provide reference for further innovative drug research and the future development of treatments for CP with pancreatic fibrosis.

5-Hydroxymethylcytosine as a potential epigenetic biomarker in papillary thyroid carcinoma.

DNA methylation at the 5 position of cytosine (5-mC) is an epigenetic hallmark that is critical in various biological and pathological processes such as DNA methylation regulation, and initiation and development of cancers. 5-mC can be oxidized to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation family of DNA hydroxylases. Accumulating evidence has reported that loss of 5-hmC is associated with cancer development. However, its level in papillary thyroid carcinoma (PTC) remains unclear. The present study reports that the loss of 5-hmC is an epigenetic mark of PTCs, associated with their malignant biological behavior, providing diagnostic and predictive advantages over DNA hypomethylation (5-mC), an acknowledged epigenetic alteration in cancer. In addition, the 5-hmC staining levels were decreased in cases of micro-carcinoma with lymph node metastasis, which suggests that 5-hmC expression levels could be used as valuable biomarkers for predicting malignant potential and assist in the selection of therapeutic strategies in PTC; therefore, 5-hmC has the potential to provide a more precise direction for PTC therapy.

New insights from the widening homogeneity perspective to target intratumor heterogeneity.

Precision medicine has shed new light on the treatment of heterogeneous cancer patients. However, intratumor heterogeneity strongly constrains the clinical benefit of precision medicine. Thus, rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions, but also provide an avenue for precision medicine. Here, we explore the current approaches for targeting intratumor heterogeneity and their limitations. Furthermore, we propose a theoretical strategy with a "homogenization" feature based on iatrogenic evolutionary selection to target intratumor heterogeneity.

Transcriptomic but not genomic variability confers phenotype of breast cancer stem cells.

BACKGROUND: Breast cancer stem cells (BCSCs) are considered responsible for cancer relapse and drug resistance. Understanding the identity of BCSCs may open new avenues in breast cancer therapy. Although several discoveries have been made on BCSC characterization, the factors critical to the origination of BCSCs are largely unclear. This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs. METHODS: We detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency, and then performed target deep DNA sequencing at bulk-cell and single-cell levels. To identify the transcriptional program associated with BCSCs, bulk-cell and single-cell RNA sequencing was performed. RESULTS: By using whole-genome sequencing of bulk cells, potential BCSC phenotype-associated mutation hotspot regions were detected. Validation by target deep DNA sequencing, at both bulk-cell and single-cell levels, revealed no genetic changes specifically associated with BCSC phenotype. Moreover, single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features. Notably, this transcriptomic variability was enriched during the transcription of 74 genes, revealed as BCSC markers. Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse, thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers. CONCLUSIONS: Transcriptomic variability, not genetic mutations, distinguishes BCSCs from non-BCSCs. The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.

Estrogen receptor ß upregulated by lncRNA-H19 to promote cancer stem-like properties in papillary thyroid carcinoma.

Estrogen receptor ß (ERß) plays critical roles in thyroid cancer progression. However, its role in thyroid cancer stem cell maintenance remains elusive. Here, we report that ERß is overexpressed in papillary thyroid cancer stem cells (PTCSCs), whereas ablation of ERß decreases stemness-related factors expression, diminishes ALDH+ cell populations, and suppresses sphere formation ability and tumor growth. Screening estrogen-responsive lncRNAs in PTC spheroid cells, we find that lncRNA-H19 is highly expressed in PTCSCs and PTC tissue specimens, which is correlated with poor overall survival. Mechanistically, estradiol (E2) significantly promotes H19 transcription via ERß and elevates H19 expression. Silencing of H19 inhibits E2-induced sphere formation ability. Furthermore, H19 acting as a competitive endogenous RNA sequesters miRNA-3126-5p to reciprocally release ERß expression. ERß depletion reverses H19-induced stem-like properties upon E2 treatment. Appropriately, ERß is upregulated in PTC tissue specimens. Notably, aspirin attenuates E2-induced cancer stem-like traits through decreasing both H19 and ERß expression. Collectively, our findings reveal that ERß-H19 positive feedback loop has a compelling role in PTCSC maintenance under E2 treatment and provides a potential therapeutic targeting strategy for PTC.

Primary sternum diffuse large B-cell lymphoma: A case report and review of the literature.

Primary bone lymphoma (PBL) is a rare disease, accounting for >1% of all cases of malignant lymphoma. Diffuse large B-cell lymphoma (DLBCL) is the most common histological type of PBL. The present study reported the case of a 68-year-old male with primary bone DLBCL, originally occurred in the sternum, which is a rare form of presentation. Computed tomography (CT), magnetic resonance imaging and bone emission CT were performed, followed by immunohistochemical analysis of a biopsy specimen, and the results were used to establish the diagnosis. At the time of diagnosis, no osseous involvement was observed. The clinical, radiological and histological features of PBL can mimic other medical conditions, thereby making the diagnosis difficult, and frequently leading to delays in treatment. The present study investigated the clinical features, management and prognosis of PBL, and reviewed previous relevant cases.