Disturbed glycolipid metabolism activates CXCL13-CXCR5 axis in senescent TSCs to promote heterotopic ossification.

Heterotopic ossification (HO) occurs as a common complication after injury, while its risk factor and mechanism remain unclear, which restricts the development of pharmacological treatment. Clinical research suggests that diabetes mellitus (DM) patients are prone to developing HO in the tendon, but solid evidence and mechanical research are still needed. Here, we combined the clinical samples and the DM mice model to identify that disordered glycolipid metabolism aggravates the senescence of tendon-derived stem cells (TSCs) and promotes osteogenic differentiation. Then, combining the RNA-seq results of the aging tendon, we detected the abnormally activated autocrine CXCL13-CXCR5 axis in TSCs cultured in a high fat, high glucose (HFHG) environment and also in the aged tendon. Genetic inhibition of CXCL13 successfully alleviated HO formation in DM mice, providing a potential therapeutic target for suppressing HO formation in DM patients after trauma or surgery.

Hnrnpk protects against osteoarthritis through targeting WWC1 mRNA and inhibiting Hippo signaling pathway.

Osteoarthritis (OA) is an age-related or post-traumatic degenerative whole joint disease characterized by the rupture of articular cartilage homeostasis, the regulatory mechanisms of which remain elusive. This study identifies the essential role of heterogeneous nuclear ribonucleoprotein K (hnRNPK) in maintaining articular cartilage homeostasis. Hnrnpk expression is markedly downregulated in human and mice OA cartilage. The deletion of Hnrnpk effectively accelerates the development of post-traumatic and age-dependent OA in mice. Mechanistically, the KH1 and KH2 domain of Hnrnpk bind and degrade the mRNA of WWC1. Hnrnpk deletion increases WWC1 expression, which in turn leads to the activation of Hippo signaling and ultimately aggravates OA. In particular, intra-articular injection of LPA and adeno-associated virus serotype 5 expressing WWC1 RNA interference ameliorates cartilage degeneration induced by Hnrnpk deletion, and intra-articular injection of adeno-associated virus serotype 5 expressing Hnrnpk protects against OA. Collectively, this study reveals the critical roles of Hnrnpk in inhibiting OA development through WWC1-dependent downregulation of Hippo signaling in chondrocytes and defines a potential target for the prevention and treatment of OA.

The role of gut microbiota and drug interactions in the development of colorectal cancer.

The human gut microbiota is a complex ecosystem regulating the host's environmental interaction. The same functional food or drug may have varying bioavailability and distinct effects on different individuals. Drugs such as antibiotics can alter the intestinal flora, thus affecting health. However, the relationship between intestinal flora and non-antibiotic drugs is bidirectional: it is not only affected by drugs; nevertheless, it can alter the drug structure through enzymes and change the bioavailability, biological activity, or toxicity of drugs to improve their efficacy and safety. This review summarizes the roles and mechanisms of antibiotics, antihypertensive drugs, nonsteroidal anti-inflammatory drugs, lipid-lowering drugs, hypoglycemic drugs, virus-associated therapies, metabolites, and dietary in modulating the colorectal cancer gut microbiota. It provides a reference for future antitumor therapy targeting intestinal microorganisms.

Periostin drives extracellular matrix degradation, stemness, and chemoresistance by activating the MAPK/ERK signaling pathway in triple-negative breast cancer cells.

BACKGROUND: Adipose tissue, which is mainly composed of adipocytes, is a crucial component of the tumor microenvironment, particularly in breast cancer. Adipocytes surround breast cancer cells and may participate in cell‒cell interactions in the breast microenvironment. However, little is currently known about how adipocytes influence the biological behavior of the surrounding breast cancer cells. Hence, this study sought to investigate the role and underlying mechanisms of periostin in triple-negative breast cancer (TNBC) cells cocultured with adipogenic conditioned medium (ACM) and palmitic acid (PA). METHODS: Human TNBC cell lines (MDA‒MB‒231 and SUM159PT) were treated with ACM and PA, then the expression of periostin, matrix metalloproteinases (MMPs) and stemness-related molecules were assessed by Western blotting and RT‒qPCR. The cellular viability was assessed using CCK‒8 assay. Plasmid transfection, RNA sequencing, and pathway inhibitor were used to explore the specific mechanisms of periostin. RESULTS: ACM and PA elevated the expression of both MMPs and stemness-related molecules in TNBCs. MMPs can promote tumor cell infiltration and migration by degrading the extracellular matrix, and stemness expression increases the development of tumor chemoresistance. Additionally, ACM and PA increased periostin expression, while inhibiting periostin disrupted the involvement of ACM and PA in promoting extracellular matrix degradation, stemness, and chemoresistance in TNBCs. Furthermore, this study found that periostin promoted TNBC progression by activating the MAPK/ERK signaling pathway and that inhibition of MAPK/ERK signaling reduced the phenotype caused by periostin upregulation in TNBCs treated with ACM or PA. Finally, the present results showed that the high expression of POSTN, which encodes periostin, was substantially related to worse survival in TNBC patients. CONCLUSIONS: The results of the study elucidated for the first time how periostin is the key protein secreted in TNBCs in response to the adipocyte-regulated tumor microenvironment, while periostin-neutralizing antibodies may serve as potential therapeutic agents in relation to TNBC progression.

FOXQ1 inhibits breast cancer ferroptosis and progression via the circ_0000643/miR-153/SLC7A11 axis.

Dysregulation of ferroptosis is involved in breast cancer progression and therapeutic responses. Inducing ferroptosis can be a potential therapeutic strategy for breast cancer treatment. Forkhead box Q1 (FOXQ1) is an oncogenic transcription factor that highly expressed and related with poor outcomes in various tumors. However, the specific effects of FOXQ1 on ferroptosis in breast cancer is unclear. In this study, we intended to explore the functions and potential mechanisms of FOXQ1 in breast cancer ferroptosis. By CCK-8, colony formation, wound healing, transwell and ferroptosis related assays, we explored the functions of FOXQ1 in breast cancer ferroptosis and progression. Through bioinformatics analysis of public database, luciferase reporter assay, RIP and ChIP assay, we investigated the potential mechanisms of FOXQ1 in breast cancer ferroptosis and progression. We found that FOXQ1 was overexpressed in breast cancer and associated with worse survival. Additionally, inhibition of FOXQ1 suppressed breast cancer ferroptosis and progression. Mechanically, we confirmed that FOXQ1 could bind to the promoter of circ_0000643 host gene to increase the levels of circ_0000643, which could sponge miR-153 and enhance the expression of SLC7A11, leading to reduced cell ferroptosis in breast cancer cells. Targeting the FOXQ1/circ_0000643/miR-153/SLC7A11 axis could be a promising strategy in breast cancer treatment.

α-Cyperone ameliorates depression in mammary gland hyperplasia and chronic unpredictable mild stress rat by regulating hormone, inflammation, and oxidative stress.

BACKGROUND: Hyperplasia of mammary gland (HMG) is caused by endocrine disorders, and patients are prone to anxiety and depression. α-Cyperone has a variety of pharmacological activities including antidepressant. The purpose of this study was to explore the effect and its possible mechanism of α-Cyperone on HMG-associated depression rats. METHODS: The depression model was constructed using chronic unpredictable mild stress (CUMS), while the HMG model was induced by estrogen, with or without α-Cyperone intervention. The effect of α-Cyperone on the depression-like phenotype of model rats was measured by sucrose preference test (SPT), forced swim test (FST), and open field test (OFT). Dendritic spines density in ventral medial prefrontal cortex (vmPFC) neurons was evaluated by Golgi staining. The second pair of nipple height, diameter, organ index, and oxidative stress-related factors were analyzed. Serum sex hormone concentration, histopathological changes, inflammatory factor expression, and p65 were evaluated by enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (HE) staining, real-time quantitative PCR and western blot, respectively. RESULTS: The sucrose preference rate, dendritic spine density decreased, and immobility time increased in CUMS rats; α-Cyperone reversed the effect of CUMS on depression-like behavior and dendritic spine density in rats. α-Cyperone reduced nipple height and diameter, uterine index, estradiol concentration, increased ovary, thymus, spleen index, progesterone, and testosterone concentration, relieved pathological damage, oxidative stress, depression-like behavior, and inflammatory reaction in HMG combine CUMS rats. In addition, α-Cyperone inhibited the phosphorylation of p65 in HMG and CUMS rats. CONCLUSIONS: α-Cyperone has an effective therapeutic effect on HMG combined with CUMS rats.

Dihydroartemisinin Attenuated Intervertebral Disc Degeneration via Inhibiting PI3K/AKT and NF-κB Signaling Pathways.

Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP). However, effective therapeutic drugs for IDD remain to be further explored. Inflammatory cytokines play a pivotal role in the onset and progression of IDD. Dihydroartemisinin (DHA) has been well reported to have powerful anti-inflammatory effects, but whether DHA could ameliorate the development of IDD remained unclear. In this study, the effects of DHA on extracellular matrix (ECM) metabolism and cellular senescence were firstly investigated in nucleus pulposus cells (NPCs) under tumor necrosis factor alpha (TNFα)-induced inflammation. Meanwhile, AKT agonist sc-79 was used to determine whether DHA exerted its actions through regulating PI3K/AKT and NF-κB signaling pathways. Next, the therapeutic effects of DHA were tested in a puncture-induced rat IDD model. Finally, we detected the activation of PI3K/AKT and NF-κB signaling pathways in clinical degenerative nucleus pulposus specimens. We demonstrated that DHA ameliorated the imbalance between anabolism and catabolism of extracellular matrix and alleviated NPCs senescence induced by TNFα in vitro. Further, we illustrated that DHA mitigated the IDD progression in a puncture-induced rat model. Mechanistically, DHA inhibited the activation of PI3K/AKT and NF-κB signaling pathways induced by TNFα, which was undermined by AKT agonist sc-79. Molecular docking predicted that DHA bound to the PI3K directly. Intriguingly, we also verified the activation of PI3K/AKT and NF-κB signaling pathways in clinical degenerative nucleus pulposus specimens, suggesting that DHA may qualify itself as a promising drug for mitigating IDD.

Combination of Melatonin and Zoledronic Acid Suppressed the Giant Cell Tumor of Bone in vitro and in vivo.

Melatonin (Mlt) confers potential antitumor effects in various types of cancer. However, to the best of our knowledge, the role of Mlt in the giant cell tumor of bone (GCTB) remains unknown. Moreover, further research is required to assess whether Mlt can enhance the therapeutic effect of zoledronic acid (Zol), a commonly used anti-GCTB drug. In this research, we investigated the effects of Mlt, Zol, and the combination of these two drugs on GCTB cells' characteristics, including cell proliferation, apoptosis, osteogenic differentiation, migration, and invasion. The cell counting kit-8 (CCK-8) assay, colony formation assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay (TUNEL), alkaline phosphatase (ALP) staining, alizarin red staining (ARS), scratch wound healing assay, and transwell experiment were performed, respectively. Our results showed that Mlt could effectively inhibit the proliferation, migration, and invasion of GCTB cells, as well as promote the apoptosis and osteogenic differentiation of tumor cells. Of note, a stronger antitumor effect was observed when Mlt was combined with Zol treatment. This therapeutic effect might be achieved by inhibiting the activation of both the Hippo and NF-κB pathways. In conclusion, our study suggests that Mlt can be a new treatment for GCTB, which could further enhance the antitumor effect of Zol.

Trends in incidence and survival in patients with melanoma, 1974-2013.

Melanoma is a rare malignancy that invades the skin and the mucosa. Research has been conducted on melanoma incidence and the survival of patients with melanoma; however, no studies in melanoma incidence and the survival spanning 40 years and based on a large population have thus far been reported. We obtained data on patients with melanoma for each decade from 1974 to 2013 from the Surveillance, Epidemiology, and End Results (SEER) database. Disparities in survival by decade, age group, gender, race, site, and socioeconomic status (SES) within the aforementioned period were analyzed by comparison of Kaplan-Meier curves. We collected data on 133,996 melanoma patients in 18 SEER registry regions for the period 1974-2013. Our study found that the melanoma incidence increased continuously for the total population as well as for most age groups. The survival of patients with melanoma (except mucosal melanoma) also increased. This study showed increases in incidence and survival in melanoma across four decades in a large sample; meanwhile, the survival rates for mucosal melanoma decreased in the latter three decades, suggesting the need to improve melanoma diagnosis, broaden melanoma awareness among health care providers, and initiate the development of more effective treatments than the existing ones.

Incidence and Risk Factors of Cardiac Abnormalities in Patients with Idiopathic Scoliosis.

OBJECTIVE: We sought to investigate the incidence of cardiac abnormalities in patients with idiopathic scoliosis and identify risk factors related to cardiac abnormalities. METHODS: A cohort of 531 patients with idiopathic scoliosis requiring surgical treatment in our hospital from March 2009 to August 2017 were recorded. Clinical data including medical records, radiograph, and echocardiogram were collected. All patients were divided into groups: control, congenital heart disease (CHD), and other cardiac abnormalities (OCAs). The incidence and related factors for cardiac abnormalities were analyzed. RESULTS: The age of the study cohort was 17.8 ± 7.3 years. The average Cobb angle was 57.7 ± 16.5 degrees. Cardiac abnormalities were found in 149 (28.06%) patients, including 22 (4.14%) with CHD and 127 (23.92%) with OCAs. Atrial septal defect was the most common CHD with an incidence of 1.13% (6 of 531). Mitral valve prolapse was detected in 62 (11.68%) patients, which was the most prevalent OCA. Patients with CHD or OCAs weighed less as compared with patients without cardiac abnormalities. Low height was associated with CHD in patients with idiopathic scoliosis. Six patients with severe cardiac abnormalities must undergo cardiac intervention before scoliosis surgery. CONCLUSIONS: The overall incidence of cardiac abnormalities was 28.81% in patients with idiopathic scoliosis. An echocardiogram may be helpful as a preoperative examination for patients with idiopathic scoliosis before scoliosis surgery.

Improved survival in ovarian cancer, with widening survival gaps of races and socioeconomic status: a period analysis, 1983-2012.

Introduction: Ovarian cancer is the first leading cause of cancer-related deaths among gynecologic malignancies, and the 7th most common female cancer worldwide. However, previous studies on changes in the long-term survival of ovarian cancer were limited. Methods: Our data were extracted from Surveillance, Epidemiology, and End Results (SEER) registries to assess the incidence and relative survival changes of patients with ovarian cancer during 1983-2012. Patients with ovarian cancer were stratified by age, race, and socioeconomic status (SES). Cox regression analysis and Spearman rank correlation analysis were performed by STATA 12 software. Results: The overall incidence of ovarian cancer per 100,000 decreased from 13.7 to 12.4 to 10.8 over three decades with peak incidence occurring in the 70+ age group at 47.6, 45.7 and 40.2 in each respective decade. Median survival improved from 34 months to 46 months to 52 months over three decades, with the 5-year relative survival rate (RSR) increasing from 39.3% to 43.4% to 45.4% (p < 0.0001). However, Whites showed higher median survival (34 months) than Blacks (27 months) in the first decade, and the survival difference significantly increased to 16 months in the third decade. Additionally, the median survival difference between the low-poverty group and high poverty group increased from 4 months to 12 months in the three decades. Discussion: This study demonstrated the decreasing incidence of ovarian cancer with an observed improvement in relative survival over three decades in a large sample. However, the survival gaps among races and SESs significantly widened over the three decades.

Trend in relative survival in squamous cervical cancer by decade from 1983 to 2012: a period analysis.

OBJECTIVE: Squamous cervical cancer (SCC), the predominant histological type, represents approximately 75-80% of all cervical cancers. Although the overall incidence of cervical cancer has declined worldwide, the data describing the changes in the incidence and long-term survival in SCC remain limited. METHODS: The data were extracted from Surveillance, Epidemiology, and End Results (SEER) registries for an evaluation of the changes in the incidence and survival associated with SCC during 1983-2012. In addition, the patients with SCC were stratified by age, race, and socioeconomic status (SES). Stata 12.0 software was used to perform the Cox regression and Spearman's rank correlation analyses. RESULTS: The overall incidence of SCC constantly declined from 7.3 to 5.6 to 4.3 per 100,000 people; the peak age of incidence was 55-69 years in the first decade, while the 40-54 age group served as another incidence peak in the last 2 decades. Median survival increased from 189 months to 231 months in the first 2 decades and was not reached in the third decade. The 10-year relative survival rates (RSRs) changed from 63.2% to 66.5% to 62.1% across the 3 decades. Additionally, the survival gaps narrowed from 13% to 8% between Whites and Blacks and from 5.4% to 3.5% between low- and medium-poverty groups in the 3 decades. CONCLUSION: This study demonstrated a declining incidence over the 3 decades with an improvement in median survival. However, the relative survival associated with SCC did not improve in the last decade. Furthermore, the survival gaps between races and various SESs significantly narrowed over the 3 decades.

Increased survival of patients aged 0-29 years with osteosarcoma: A period analysis, 1984-2013.

PURPOSE: Osteosarcoma is the most common primary malignancy of bone, and typically occurs among children and adolescence. This study aims to evaluate treatment outcomes among children, adolescents and young adults with osteosarcoma over the three decades by the changes in the long-term relative survival. METHODS: Osteosarcoma incidence and relative survival data from Surveillance, Epidemiology, and End Results (SEER) registries during 1984-2013 were analyzed. The survival differences over three decades, age, sex, race, and socioeconomic status (SES) were assessed by comparing Kaplan-Meier curves. RESULTS: The overall incidence of osteosarcoma kept relatively stable with 0.4 per 100 000 in the three decades with the peak incidence occurring in the aged 10-19 group. The 10-year relative survival rate (RSR) increased from 57.7% to 61.0% in the three decades, with the greatest increase in the aged 0-9 group from 48.2% to 65.7%. The 10-year RSR improved from 54.1% to 61.5% in males, and from 62.4% to 63.0% in females, respectively, in the three decades. Furthermore, survival dramatically improved from 30% to 60% in the high-poverty group over the three decades. CONCLUSION: This study demonstrated that the overall incidence of osteosarcoma remained stable, with an improvement in survival in the three decades. The improved survival was greater in males than in females in the three decades. Furthermore, the survival significantly increased in high-poverty group, which was attributed to increasing improved health care system and patients with low finance can also have access to receiving effective and consistent treatment without distinction.

Correlation of SASH1 expression and ultrasonographic features in breast cancer.

OBJECTIVE: SASH1 is a member of the SH3/SAM adapter molecules family and has been identified as a new tumor suppressor and critical protein in signal transduction. An ectopic expression of SASH1 is associated with decreased cell viability of breast cancer. The aim of this study was to explore the association between SASH1 expression and the ultrasonographic features in breast cancer. PATIENTS AND METHODS: A total of 186 patients diagnosed with breast cancer were included in this study. The patients received preoperative ultrasound examination, and the expression of SASH1 was determined using immunohistochemistry methods. Spearman's rank correlation analysis was used to analyze the correlation between SASH1-positive expression and the ultrasonographic features. RESULTS: The positive expression of SASH1 was observed in 63 (33.9%) patients. The positive expression rate of SASH1 was significantly decreased in patients with breast cancer (63/186, 33.9%) compared with controls (P<0.001). The positive expression rate of SASH1 was significantly decreased in patients with edge burr sign (P=0.025), lymph node metastasis (P=0.007), and a blood flow grade of III (P=0.013) compared with patients without those adverse ultrasonographic features. The expression of SASH1 was negatively correlated with edge burr sign (P=0.025), lymph node metastasis (P=0.007), and blood flow grade (P=0.003) of the patients with breast cancer. CONCLUSION: The expression of SASH1 was inversely correlated with some critical ultrasonographic features, including edge burr sign, lymph node metastasis, and blood flow grade in breast cancer, and decreased SASH1 expression appears to be associated with adverse clinical and imaging features in breast cancer.