Primary lung adenocarcinoma with breast metastasis harboring the EML4­ALK fusion: A case report.

Pulmonary adenocarcinoma with breast metastasis is rarely encountered in clinical practice. Therefore, precise clinical diagnosis of patients with this disease is crucial when selecting subsequent treatment modalities and for overall prognosis assessment. The present study reported on a case of lung cancer with breast metastasis harboring the EML4-ALK fusion. The patient was initially diagnosed with triple-negative breast cancer with lung metastasis, but comprehensive breast cancer treatment was ineffective. Reevaluation of the patient's condition via lung biopsy revealed primary lung adenocarcinoma. In addition, the results of genetic testing revealed the EML4-ALK fusion protein in both lung and breast tissues. After treatment with ALK inhibitors, the patient's symptoms improved rapidly. This case highlights the prolonged diagnostic journey from presentation with a breast mass to ultimately being diagnosed with lung cancer with breast metastasis, underscoring the critical need for heightened awareness among clinicians regarding the possibility of rare metastatic patterns. Timely identification of lung cancer with breast metastasis, facilitated by comprehensive genetic testing, not only refines treatment decisions but also emphasizes the importance of interdisciplinary collaboration in navigating complex clinical scenarios. Such insight contributes to the ongoing development of personalized cancer care that guides clinicians toward more effective and tailored therapeutic strategies for patients with similar diagnostic challenges.

Gingival diffuse large B-cell lymphoma: report of 2 cases.

Diffuse large B-cell lymphoma (DLBCL) in the oral gums is very rare and is prone to misdiagnosis and mistreatment. In this paper, 2 cases of oral gingival DLBCL were reported. Their clinicopathological features, diagnosis, and differential diagnosis were discussed based on the literature of 21 cases of gingival DLBCL reported at home and abroad from 2008 to 2023.

Effect of scanning speeds on mechanical properties of CoCrNi medium entropy alloy prepared by laser additive manufacturing.

Medium entropy alloy (MEA) is a hot spot in the field of material research in recent years. At present, the most widely used processing method of MEAs is "casting-rolling-heat treatment", and the preparation of CoCrNi MEA by laser additive manufacturing (LAM) is still in primary stage. In this study, CoCrNi MEAs were fabricated with different scanning speeds by laser additive manufacturing, and the influence of scanning speed on its mechanical properties was investigated. The results show that higher scanning speed can significantly improve the mechanical properties of CoCrNi MEA. Compared with the low-speed laser additive manufacturing (LSLAM) MEA, the tensile strength of high-speed laser additive manufacturing (HSLAM) MEA is increased by 5.6 % and the fracture strain is increased by 60 %, which is mainly due to the entanglement of 1/6<112> and 1/2<110> dislocations and the defect structure at the grain boundary. LAM is a promising technology that can promote the development and application of MEAs in industry.

Case Report: Myocardial dissection caused by ruptured sinus of Valsalva aneurysm in association with a bicuspid aortic valve.

In this report, we present a case of left-right sinus fusion in a Ruptured sinus of Valsalva aneurysm (RSVA) that perforated into the myocardium, giving rise to myocardial dissection. The existence of an anomalous bicuspid aortic valve (BAV) is contemplated as a potential etiological element in this context. Employing multimodal imaging modalities, encompassing transthoracic echocardiography and computed tomography (CT), facilitated the visualization of a dissecting hematoma situated within the myocardium subsequent to the RSVA. Following this, our patient underwent an Cabrol surgical intervention, received patch repair, and underwent mitral valve annuloplasty, during which a three-year period transpired without the occurrence of any deleterious cardiac events. In summary, this report establishes the cornerstone for the surgical intervention of RSVA, shedding light on the efficacious handling of RSVA-associated myocardial dissection. It posits that the presence of a BAV may serve as a predisposing factor to RSVA rupture, potentially elevating the susceptibility to myocardial dissection. The utilization of diverse multimodal imaging methodologies played an indispensable role in the detection of a hematoma within the myocardial tissue subsequent to the RSVA rupture. The uneventful three-year postoperative follow-up of the patient underscores the efficacy of the undertaken interventions.

Transcriptome profile analysis revealed the potential mechanism of LIPUS treatment for Adriamycin-induced chronic kidney disease rat.

Background: Developing effective therapeutic strategies to delay the progression of chronic kidney disease (CKD) remains a significant challenge. Low-intensity pulsed ultrasound (LIPUS) has demonstrated potential for treating CKD, but the underlying molecular mechanisms are still elusive. This study aimed to evaluate the therapeutic efficacy of LIPUS and to elucidate the involved genes and signaling pathways. Methods: The CKD model was established in rats using Adriamycin (ADR). The bilateral kidneys of CKD rats were continuously stimulated with LIPUS for a period of four weeks. The therapeutic efficacy was defined by renal function and histopathological evaluation. RNA sequencing was employed to profile the transcriptome of rat kidneys in each group. Cluster analysis was utilized to identify differentially expressed genes (DEGs), followed by enrichment analysis of their associated pathways using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Results: LIPUS treatment improved ADR-induced renal dysfunction in the CKD group. Renal fibrosis and pathological damages were also alleviated in the ADR + LIPUS group compared to the ADR group. Cluster analysis identified 844 DEGs. GO enrichment analysis revealed enrichment in inflammatory response terms, while KEGG enrichment analysis highlighted the nuclear factor kappa B (NF-κB) signaling and ferroptosis-related pathways. Conclusion: Continuous LIPUS treatment improved ADR-induced renal fibrosis and dysfunction. The therapeutic effect of LIPUS was primarily due to its ability to suppress the CKD-related inflammation, which was associated with the modulation of the NF-κB and ferroptosis signaling pathways. These findings provide a new insight into the potential molecular mechanisms of LIPUS in treating CKD. Further research is necessary to confirm these findings and to identify potential therapeutic targets within these pathways.

CRISPR-Based KCC2 Upregulation Attenuates Drug-Resistant Seizure in Mouse Models of Epilepsy.

OBJECTIVE: The precise intervention of K-Cl cotransporter isoform 2 (KCC2) as a promising target for drug-resistant epilepsy remains elusive. METHODS: Here, we used a CRISPRa system delivered by adeno-associated viruses to specifically upregulate KCC2 in the subiculum to confirm its therapeutic potential in various in vivo epilepsy models. Calcium fiber photometry was used to reveal the role of KCC2 in the restoration of impaired GABAergic inhibition. RESULTS: CRISPRa system effectively upregulated KCC2 expression both in in vitro cell culture and in vivo brain region. Delivery of CRISPRa with adeno-associated viruses resulted in upregulating the subicular KCC2 level, contributing to alleviating the severity of hippocampal seizure and facilitating the anti-seizure effect of diazepam in a hippocampal kindling model. In a kainic acid-induced epilepticus status model, KCC2 upregulation greatly increased the termination percentage of diazepam-resistant epilepticus status with the broadened therapeutic window. More importantly, KCC2 upregulation attenuated valproate-resistant spontaneous seizure in a kainic acid-induced chronic epilepsy model. Finally, calcium fiber photometry showed CRISPRa-mediated KCC2 upregulation partially restored the impaired GABAA -mediated inhibition in epilepsy. INTERPRETATION: These results showed the translational potential of adeno-associated viruses-mediated delivery of CRISPRa for treating neurological disorders by modulating abnormal gene expression that is directly associated with neuronal excitability, validating KCC2 as a promising therapeutic target for treating drug-resistant epilepsy. ANN NEUROL 2023;94:91-105.

Establishing a prognostic model of chromatin modulators and identifying potential drug candidates in renal clear cell patients.

BACKGROUND: Renal carcinoma is a common malignant tumor of the urinary system. Advanced renal carcinoma has a low 5-year survival rate and a poor prognosis. More and more studies have confirmed that chromatin regulators (CRs) can regulate the occurrence and development of cancer. This article investigates the functional and prognostic value of CRs in renal carcinoma patients. METHODS: mRNA expression and clinical information were obtained from The Cancer Genome Atlas database. Univariate Cox regression analysis and LASSO regression analysis were used to select prognostic chromatin-regulated genes and use them to construct a risk model for predicting the prognosis of renal cancer. Differences in prognosis between high-risk and low-risk groups were compared using Kaplan-Meier analysis. In addition, we analyzed the relationship between chromatin regulators and tumor immune infiltration, and explored differences in drug sensitivity between risk groups. RESULTS: We constructed a model consisting of 11 CRs to predict the prognosis of renal cancer patients. We not only successfully validated its feasibility, but also found that the 11 CR-based model was an independent prognostic factor. Functional analysis showed that CRs were mainly enriched in cancer development-related signalling pathways. We also found through the TIMER database that CR-based models were also associated with immune cell infiltration and immune checkpoints. At the same time, the genomics of drug sensitivity in cancer database was used to analyze the commonly used drugs of renal clear cell carcinoma patients. It was found that patients in the low-risk group were sensitive to medicines such as axitinib, pazopanib, sorafenib, and gemcitabine. In contrast, those in the high-risk group may be sensitive to sunitinib. CONCLUSION: The chromatin regulator-related prognostic model we constructed can be used to assess the prognostic risk of patients with clear cell renal cell carcinoma. The results of this study can bring new ideas for targeted therapy of clear cell renal carcinoma, helping doctors to take corresponding measures in advance for patients with different risks.

Sitagliptin Ameliorates Creb5/lncRNA ENSMUST00000213271-Mediated Vascular Endothelial Dysfunction in Obese Mice.

PURPOSE: Obesity is mediated by the changes in dyslipidemia, oxidative stress, and inflammation, leading to vascular endothelial dysfunction. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 inhibitors prevent the development of endothelial dysfunction. However, the underlying mechanism still remains largely unclear. Long non-coding RNAs (lncRNAs), one class of non-coding small RNAs, have been shown to exert a regulatory impact on the endothelial function in obesity. This study aimed to investigate whether the elevation of GLP-1 by a DPP-4 inhibitor sitagliptin improved vascular endothelial function by modulating lncRNAs in obese mice and to clarify the underlying molecular mechanism. METHODS: Male C57BL/6J mice were fed a high-fat diet for 4 months to induce obesity and some obese mice were treated with sitagliptin for the last 1 month. Levels of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and glucagon-like peptide-1 (GLP-1) in plasma were detected by ELISA. LncRNA expression profile was analyzed via microarray. Aortic relaxations were examined by myograph. Protein expressions and phosphorylations were determined using western blot. The differentially expressed lncRNAs were validated using qRT-PCR. RESULTS: Obese mice exhibited increased levels of TC and LDL, decreased concentrations of HDL and GLP-1 in plasma, and impaired aortic endothelium-dependent relaxations; such effects could be reversed by sitagliptin. Moreover, the altered expression profile of lncRNAs in the obese mouse aortae could be modulated by sitagliptin. Consistent with microarray analysis, qRT-PCR also revealed that lncRNA ENSMUST00000213271 was up-regulated in obese mouse aortae and aortic endothelial cells (ECs), which could be down-regulated by sitagliptin. Creb5 silencing reduced lncRNA ENSMUST00000213271 in obese mouse ECs. Knockdown of either Creb5 or lncRNA ENSMUST00000213271 restored the activation of AMPK/eNOS in obese mouse ECs. Furthermore, sitagliptin also suppressed Creb5 and lncRNA ENSMUST00000213271 and increased the phosphorylations of AMPK and eNOS in obese mice. CONCLUSION: Creb5/lncRNA ENSMUST00000213271 mediated vascular endothelial dysfunction through inhibiting AMPK/eNOS cascade in obesity. Elevation of GLP-1 by sitagliptin possibly improved endothelial function by suppressing Creb5/lncRNA ENSMUST00000213271 and subsequently restoring AMPK/eNOS activation in obese mice. This study will provide new evidence for the benefits of GLP-1 against vasculopathy in obesity.

A case of death of patient with ovarian fibroma combined with Meigs Syndrome and literature review.

Ovarian fibroma is the most common benign pure stromal tumor. It has no specific clinical manifestation, most of which are pelvic or adnexal masses. 10-15% of cases with hydrothorax or ascites, after tumor resection, hydrothorax and ascites disappear, known as Meigs Syndrome. The elevated level of CA125 in a few patients was easily misdiagnosed as ovarian malignant tumor. A case of bilateral Ovarian fibroma associated with Meigs Syndrome is reported and the literature is reviewed in order to improve the understanding of the changes and avoid misdiagnosis.

Lateral Hypothalamus Calcium/Calmodulin-Dependent Protein Kinase II α Neurons Encode Novelty-Seeking Signals to Promote Predatory Eating.

Predatory hunting is an innate appetite-driven and evolutionarily conserved behavior essential for animal survival, integrating sequential behaviors including searching, pursuit, attack, retrieval, and ultimately consumption. Nevertheless, neural circuits underlying hunting behavior with different features remain largely unexplored. Here, we deciphered a novel function of lateral hypothalamus (LH) calcium/calmodulin-dependent protein kinase II α (CaMKIIα +) neurons in hunting behavior and uncovered upstream/downstream circuit basis. LH CaMKIIα + neurons bidirectionally modulate novelty-seeking behavior, predatory attack, and eating in hunting behavior. LH CaMKIIα + neurons integrate hunting-related novelty-seeking information from the medial preoptic area (MPOA) and project to the ventral periaqueductal gray (vPAG) to promote predatory eating. Our results demonstrate that LH CaMKIIα + neurons are the key hub that integrate MPOA-conveyed novelty-seeking signals and encode predatory eating in hunting behavior, which enriched the neuronal substrate of hunting behavior.

Significant efficacy of paclitaxel plus carboplatin (TP) as a neoadjuvant regimen for metaplastic squamous cell carcinoma of the breast: a rare case report and literature review.

Background: Metaplastic squamous cell carcinoma of the breast (MSCCB) is a rare and aggressive type of cancer. So far, no standard treatment regimen has been established due to the absence of clinical data. Case Description: We report a case of a 48-year-old female admitted to our hospital as a result of a left breast mass with skin rupture. Core needle biopsy under ultrasonic guidance confirmed MSCCB. Immunohistochemistry revealed negative staining for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2/neu). After receiving 4 cycles of paclitaxel and carboplatin neoadjuvant chemotherapy, the patient was treated with modified radical mastectomy. Postoperative pathology revealed a Miller-Payne score of 4 and no metastasis in the axillary lymph nodes (0/13), indicating a good response to neoadjuvant chemotherapy. She recovered well post-surgery and was discharged to home after admission. No recurrence was identified during the 2 years post-surgery follow-up. Conclusions: MSCCB is a rare and aggressive type of cancer. However, the treatment of MSCCB has not been standardized due to its rarity. Given the observation that the majority of patients with MSCCB had ER, PR, HER2-negative neoplasms, we refer to the triple negative breast cancer (TNBC) treatment protocol. TP regimen was demonstrated to be an effective treatment for TNBC. The results of this case suggest that the TP regimen is effective in neoadjuvant chemotherapy of MSCCB.

The Effect of Health on the Elderly's Labor Supply in Rural China: Simultaneous Equation Models With Binary, Ordered, and Censored Variables.

In this study, we examined the effect of health on the elderly's labor supply in rural China based on the data of the Chinese Health and Nutrition Survey (CHNS) from 1997 to 2006. We used simultaneous equations to address the endogeneity problem of health and estimate the models with censored data of labor supply by the full information maximum likelihood estimation. We found that the failing health does not significantly decrease the elderly's labor supply in rural areas when using both the subjective (self-reported health status) and objective (hypertension diagnosed or not) health indicators. Our finding indicates the phenomenon of "ceaseless toil" for the elderly in rural China, i.e., the elderly almost work their whole life even if they are not physically capable. The results remain robust when using a two-stage limited information maximum likelihood estimation.

Soluble Epoxide Hydrolase Inhibitor t-AUCB Ameliorates Vascular Endothelial Dysfunction by Influencing the NF-κB/miR-155-5p/eNOS/NO/IκB Cycle in Hypertensive Rats.

Epoxyeicosatrienoic acids (EETs), angiogenic mediators degraded by soluble epoxide hydrolase (sEH), have been shown to exert beneficial effects on the cardiovascular system. The current study assessed the impact of increased EETs with an sEH inhibitor, t-AUCB, on two-kidney-one-clip (2K1C)-induced renovascular endothelial dysfunction, associated with hypertension, in rats. The hypertensive rats exhibited increased systolic blood pressure, reduced renal blood flow, impaired endothelium-dependent relaxation and eNOS phosphorylation in the renal arteries, elevated ROS production in the endothelium of the renal arteries, and decreased EET levels in plasma, the renal arteries, and endothelial cells; however, t-AUCB reversed all the deleterious effects. Moreover, we found that the stimulation of AMPK/UCP2 scavenged ROS and restored endothelial function in the renal arteries of hypertensive rats undergoing therapy with t-AUCB. In addition, we were the first to reveal the potential role of miR-155-5p in the occurrence and development of vascular endothelial dysfunction in hypertension. Importantly, t-AUCB recovered NO bioavailability by regulating the NF-κB/miR-155-5p/eNOS/NO/IκB cycle after the activation of AMPK/UCP2 and the subsequent inhibition of ROS in hypertensive rat renal artery endothelial cells. This study will provide evidence for this additional new mechanism, underlying the benefits of EETs and the related agents against hypertensive vasculopathy.

In missed abortion the decrease of IGF-1 down-regulates PI3K/AKT signaling pathway reducing the secretion of progesterone and ß-hCG.

OBJECTIVE: To explore whether the reduction of IGF-1 in missed abortion down-regulates PI3K/AKT signaling pathway, thereby causing trophoblast cell apoptosis and reducing the secretion of ß-hCG and progesterone. DESIGN: 12 pairs of serum and villous tissues were selected from missed abortion patients and normal early pregnant women who had terminated pregnancy by artificial abortion. The subjects in two groups had same age and gestational week. Wes Simple Western system and qRT-PCR were used to detect the expression of IGF-1, IGF-1R, PI3K/AKT signaling pathway and apoptosis-related factors in villous tissues. Radioimmunoassay and Enzyme-linked immunosorbent assay were used to detect ß-hCG, progesterone and IGF-1 in serum. RESULTS: The serum levels of ß-hCG, progesterone and IGF-1 were decreased in missed abortion group than those in normal early pregnant women. In addition, compared with normal early pregnant women, the genes and proteins levels of IGF-1 and PI3K/AKT signaling pathway and anti-apoptosis related factors were significantly decreased. CONCLUSIONS: Our results suggested that the reduction of IGF-1 in missed abortion patients could down-regulate the expression of PI3K/AKT signaling pathway, thereby increasing the apoptosis of trophoblast cells, leading to decreased secretion of ß-hCG and progesterone, which may be one of the important mechanisms of missed abortion.

Evaluating the Residual Stress and Its Effect on the Quasi-Static Stress in Polyethylene Pipes.

Residual stress is generated during the production process. It can significantly affect the mechanical performance of pressurized polymer pipes. In this paper, six polyethylene (PE) pipes, including three high-density PEs (HDPE) and three medium-density PEs (MDPE) provided by different suppliers, were tested using a one-slit-ring method to measure the residual stress distribution along the hoop direction. Finite element (FE) simulation and mechanical testing were also employed in an iteration process to obtain the mechanical parameters of the six PE pipes. For the same PE pipe code from different suppliers, the results show that the magnitude of the residual hoop stress can be very different, resulting in different mechanical behaviors. In addition, the results are proposed to explain the scenario that was reported previously, i.e., the different critical quasi-static stress (the time-independent stress) levels of the PE pipes with the same pipe code. Since the quasi-static stress is expected to dominate the long-term behavior of the PE pipes, it is of great importance to carefully consider the effect of the residual stress on the determination of the quasi-static stress.

An H2R-dependent medial septum histaminergic circuit mediates feeding behavior.

Novel targets for treating feeding-related diseases are of great importance, and histamine has long been considered an anorexigenic agent. However, understanding its functions in feeding in a circuit-specific way is still limited. Here, we report a medial septum (MS)-projecting histaminergic circuit mediating feeding behavior. This MS-projecting histaminergic circuit is functionally inhibited during food consumption, and bidirectionally modulates feeding behavior via downstream H2, but not H1, receptors on MS glutamatergic neurons. Further, we observed a pathological decrease of histamine 2 receptors (H2Rs) expression in MS glutamatergic neurons in diet-induced obesity (DIO) mice. Genetically, down-regulation of H2Rs expression in MS glutamatergic neurons accelerates body-weight gain. Importantly, chronic activation of H2Rs in MS glutamatergic neurons (with its clinical agonist amthamine) significantly slowed down the body-weight gain in DIO mice, providing a possible clinical utility to treat obesity. Together, our results demonstrate that this MS-projecting histaminergic circuit is critically involved in feeding, and H2Rs in MS glutamatergic neurons is a promising target for treating body-weight problems.

Effect of Chinese Traditional Wushu on Cancer-Related Fatigue, Sleep Quality and Upper Limb Dysfunction of Breast Cancer Survivors: A Systematic Review and Meta-Analysis.

Objective: This study is aimed at evaluating the effect of Chinese traditional Wushu (CTW) on cancer-related fatigue (CRF), sleep quality, and upper limb dysfunction. Data Sources. We searched studies containing randomized controlled trials up to July 2021 in PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang database, and China Biological Medicine on this topic. Methods: A randomized controlled trial of CTW on major outcome indicators such as CRF, sleep quality, and upper limb dysfunction of breast cancer survivors. Study screening, data extraction, and risk of bias assessment were performed independently by two reviewers. Meta-analysis was conducted with Stata 16.0 software. The quality of the evidence was assessed by the Cochrane Collaboration Risk of Bias (ROB2.0). Results: Eighteen studies met the requirements for meta-analysis (n = 1331). We found that CTW has no obvious effect on improving breast cancer survivors' CRF (SMD = -0.733; P = 0.059; I 2 = 89.3%), but it can effectively improve their sleep quality (WMD = -2.266; P = 0.022; I 2 = 99.2%) and upper limb dysfunction (SMD = 1.262; P ≤ 0.001; I 2 = 88.5%). Conclusion: Although more studies on this topic are needed to prove the effectiveness of this method, the results of our review show that CTW is significantly helpful for better sleep and upper limb dysfunction. But the effects on CRF will need to be confirmed further. Implications for Cancer Survivors. In the future intervention process, to verify the effectiveness of CTW on improving CRF for breast cancer survivors, it would be suggested to pay close attention to breast cancer survivors' response to exercise, achieve regular follow-up, strictly conduct the intervention scheme on the premise of ensuring absolute security, and reduce the loss of intervention objects.

Early hepatoid adenocarcinoma of the stomach with signet ring cell carcinoma: A case report and clinicopathological features.

Background: Hepatoid adenocarcinoma of the stomach (HAS) is a rare subtype of gastric cancer with poor prognosis, and its clinicopathological features are not well understood, so the pathology from the clinical biopsy is easily misdiagnosed, especially for special or atypical HAS. We present an extremely rare early HAS with signet ring cell carcinoma and evaluate its clinicopathological features. Case presentation: A 51-year-old female patient of Chinese Han ethnicity with upper abdominal pain for 5 years and worsened abdominal pain for 1 month was admitted to our hospital. Esophagogastroduodenoscopy showed a submucosal tumor-like elevated lesion with central depression in the greater curvature of the junction between the antrum and body. Histopathological examination from the biopsy revealed medium-low-differentiation adenocarcinoma with signet ring cell carcinoma. Radical gastrectomy was performed, and the final diagnosis was early HAS with signet ring cell carcinoma. Conclusions: HAS with signet ring cell carcinoma is a special type of HAS and extremely rare. It is first presented for this extremely rare type of HAS, which contributes to strengthen the understanding for the clinicopathological characteristics of HAS and especially promote early detection of HAS.

Oncotype DX 21-gene test has a low recurrence score in both pure and mixed mucinous breast carcinoma.

The Oncotype DX 21-gene test can be used to predict chemotherapy efficacy in patients with estrogen receptor (ER)-positive and HER2-negative breast cancer; however, the data on the 21-gene recurrence score (RS) for mucinous breast carcinoma (MBC) are limited. The present study aimed to evaluate the distribution pattern and clinical value of the 21-gene RS in patients with MBC. A total of 38 pure MBC (PMBC) and 11 mixed MBC (MMBC) cases were retrospectively analyzed, and a total of 29 ER-positive and HER2-negative MBCs underwent the Oncotype DX 21-gene test. There were no statistically significant differences between the PMBCs and MMBCs in age, tumor size and molecular subtype; however, patients with MMBC showed a significantly higher incidence rate of nodal metastases compared with that in patients with PMBC (72.7 vs. 16.2%, respectively). Following surgery, 87.8 and 59.2% of the enrolled patients received endocrine therapy and chemotherapy, respectively. With a median follow-up of 65.6 months, the 5-year disease-free survival and overall survival rates were 97.0 and 100.0%, respectively. The 21-gene test revealed that the proportions of patients with MBC categorized into low (RS <18), intermediate (RS ≥18-30) and high (RS ≥30) risk groups were 51.7, 44.8 and 3.5%, respectively, and there was no statistically significant difference between the PMBC and MMBC cases. Notably, among the genes in the 21-gene RS testing, the expression levels of cathepsin V, progesterone receptor (PR) and CD68 were significantly higher in the PMBC group compared with that in the MMBC group. In conclusion, the current study demonstrated that patients with MBC had a favorable prognosis, and both PMBC and MMBC cases had a low- and intermediate-risk RS, which suggests that a considerable proportion of patients may be able to avoid chemotherapy. In addition, the high expression level of PR, based on the 21-gene test in PMBCs, indicated that they may have a more favorable response to endocrine therapy than MMBCs.

LncRNA ENSMUST00000155383 is Involved in the Improvement of DPP-4 Inhibitor MK-626 on Vascular Endothelial Function by Modulating Cacna1c-Mediated Ca2+ Influx in Hypertensive Mice.

Objective: This study investigated the protective effects of dipeptidyl peptidase-4 inhibitor MK-626 on vascular endothelial function by regulating lncRNAs in hypertensive vasculature. Methods: Angiotensin Ⅱ (Ang Ⅱ)-loaded osmotic pumps were implanted in mice with or without MK-626 administration. GLP-1 levels in plasma were measured by ELISA. Aortic rings were suspended in myograph for tension measurement. Microarray was performed to analyze lncRNA and mRNA expression profiles. Protein expression and phosphorylation were examined by Western blot. The differentially expressed (DE)-genes were validated by qRT-PCR. The intracellular Ca2+ concentration was detected by laser confocal system. Results: MK-626 elevated plasma GLP-1 level, increased eNOS phosphorylation, improved endothelium-dependent relaxations, and reduced systolic blood pressure in Ang Ⅱ-induced hypertensive mice. Microarray revealed the dysregulations of 723 lncRNAs and 742 mRNAs were reversed by MK-626 in hypertensive mouse aortae. qRT-PCR validation showed that 13 DE-lncRNAs and eight dysregulated mRNAs in both hypertensive mouse aortae and mouse aortic endothelial cells (MAECs) were rescued by MK-626. Among them, four mRNAs (Cacna1C, Itgav, Itga8, and Npnt) were co-expressed with lncRNA ENSMUST00000155383. Cacna1C protein expression was reduced in the ECs but was elevated in smooth muscle cells from Ang Ⅱ-infused mice, which were both reversed by MK-626. Knockdown of lncRNA ENSMUST00000155383 suppressed the increased Cacna1c protein and mRNA expression, elevated Ca2+ level, and enhanced eNOS phosphorylation induced by MK-626 in the hypertensive mouse ECs. Conclusion: The dysregulations of lncRNA ENSMUST00000155383-associated genes might play crucial roles in hypertension-induced endothelial dysfunction through affecting calcium pathway. MK-626 might ameliorate endothelial dysfunction by upregulating lncRNA ENSMUST00000155383, enhancing Ca2+ concentration, and subsequently restoring eNOS activity in hypertension.