METTL14 promotes fibroblast-like synoviocytes activation via the LASP1/SRC/AKT axis in RA.

BACKGROUND: To explore the specific roles of a crucial N6-methyladenosine (m6A) methyltransferase, methyltransferase-like 14 (METTL14), in FLSs activation of rheumatoid arthritis (RA). METHODS: RA rat model was induced by administering intraperitoneally collagen antibody alcohol. Primary fibroblast-like synoviocytes (FLSs) were isolated from joint synovium tissues from rats. shRNA transfection tools were used to downregulated METTL14 expression in vivo and vitro. The injury of joint synovium showed by HE staining. The cell apoptosis of FLSs was determined by flow cytometry. The levels of IL-6, IL-18 and CXCL10 in serum and culture supernatants were measured by ELISA kits. The expressions of LIM and SH3 domain protein 1(LASP1), p-SRC/SRC, and p-AKT/AKT in FLSs and joint synovium tissues were determined by western blots. RESULTS: The expression of METTL14 was greatly induced in the synovium tissues of RA rat compared with normal control rat. Compared with sh-NC treated FLSs, METTL14 knockdown significantly increased cell apoptosis, inhibited cell migration and invasion, and suppressed the production of IL-6, IL-18 and CXCL10 induced by TNF-a. METTL14 Silencing suppresses the expression of LASP1 and the activation of Src/AKT axis induce by TNF-a in FLSs. METTL14 improves the mRNA stability of LASP1 through m6A modification. In contrast, these were reversed by LASP1 overexpression. Moreover, METTL14 silencing clearly alleviates FLSs activation and inflammation in a RA rat model. CONCLUSION: These results suggested that METTL14 promote FLSs activation and related inflammatory response via the LASP1/SRC/AKT signaling pathway and identified METTL14 as a potential target for treating RA.

The preoperative geriatric nutritional risk index predicts long-term prognosis in elderly locally advanced rectal cancer patients: a two-center retrospective cohort study.

BACKGROUND: The objective is to explore the value of preoperative geriatric nutritional risk index (GNRI) in evaluating long-term prognosis in elderly locally advanced rectal cancer (LARC) patients who accepted neoadjuvant chemoradiotherapy (NCRT) and to compare GNRI with established nutritional markers, including prognostic nutritional index (PNI) and controlling nutritional status (CONUT) score. METHODS: Preoperative GNRI was retrospectively assessed in 172 LARC patients aged ≥ 60 years who underwent radical resection after NCRT at two centers. Optimal cutoff value of GNRI was determined by X-tile program. The association of GNRI with clinicopathological parameters and nutritional markers was analyzed. The survival ability of markers was evaluated using time-dependent receiver-operating characteristic (ROC) curve analysis. Finally, survival analysis was performed using Kaplan-Meier and Cox regression analysis. RESULTS: GNRI was highly correlated with nutritional markers. An optimal cutoff value for the GNRI was 96. In the time-dependent ROC curve, GNRI demonstrated a stable predictive ability for both disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that GNRI was the only nutritional marker that independently predicted DFS (HR 2.457, 95% CI 1.066-5.665, P = 0.035) and OS (HR 9.002, 95% CI 3.100-26.146, P < 0.001). As an additional benefit, GNRI was able to stratify survival in subgroups of ypTNM and tumor response. CONCLUSION: Preoperative GNRI is a promising predictor of long-term survival for elderly LARC patients undergoing NCRT, superior to the established nutritional markers.

Iron overload accelerated lipid metabolism disorder and liver injury in rats with non-alcoholic fatty liver disease.

Background/aims: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. Iron overload has been implicated in chronic non-communicable liver diseases, but its relationship with NAFLD remains unclear. This study aimed to investigate the underlying roles of iron overload in the development of NAFLD. Methods: Male Sprague Dawley rats were fed with a high-fat diet (HFD) and/or iron for 8, 12, and 20 weeks. Some rats fed with HFD plus iron also received intraperitoneal injection of deferoxamine (DFO) for 8 weeks. Liver steatosis, lipid metabolism and injury were evaluated. Results: A NAFLD model, including typical liver steatosis, was established by feeding rats with a HFD, while iron overload alone is not enough to induce severe NAFL. Compared with rats fed a HFD, excess iron further increased lipid accumulation, serum levels of lipids, enzymes of liver function, and expression levels of CD36 and FAS in rat liver. In addition, iron overload decreased the activities of antioxidative enzymes in liver compared with HFD rats. The levels of CPT1 and the ratios of p-ACC/ACC were also decreased by iron overload. DFO effectively reversed the abnormal lipid metabolism and liver damage induced by a high-fat, high-iron diet. Conclusion: A HFD plus iron overload might synergistically aggravate lipid metabolism disorders, liver injury, and oxidative damage, compared with a HFD alone. DFO might help to alleviate lipid metabolism dysfunction and improve the pathogenesis of NAFLD.

Molecular Characteristics of Antimicrobial Resistance and Virulence in Klebsiella pneumoniae Strains Isolated from Goose Farms in Hainan, China.

We retrospectively investigated 326 samples that were collected from goose farms in Hainan Province, China, in 2017. A total of 33 carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates were identified from 326 samples, and the 33 CRKP isolates were characterized based on whole-genome sequencing (WGS) data from the Illumina and Oxford Nanopore Technologies (ONT) platforms. All of these 33 CRKP isolates possessed blaNDM-5, and a single isolate coharbored mcr-1 and blaNDM-5, while 4 isolates carried multiple virulence and metal tolerance gene clusters. One CRKP strain (CMG-35-2) was selected for long sequence reading. A hybrid plasmid carrying the virulence, resistance, and metal resistance gene in the strain was found. It possessed 2 backbones [IncFIB(K)-IncFII(K)] within a single plasmid that were closely related to K. pneumoniae plasmids from a human-associated habitat in the United States and from a human isolate in Hong Kong. A mouse abdominal infection model indicated that that strain was of the moderate virulence phenotype. This study revealed that K. pneumoniae on goose farms is an important reservoir for blaNDM-5 and these bacteria are represented by a diversity of sequence types. The heterozygous multiple drug resistance genes carried on plasmids highlighted the genetic complexity of CRKP and the urgent need for continued active surveillance. IMPORTANCE CRKP is one of the most important pathogens, which can cause infection not only in humans but also in waterfowl. The discovery of blaNDM-5-producing K. pneumoniae in waterfowl farms in recent years suggests that waterfowl are an important reservoir for blaNDM-5-producing Enterobacteriaceae. However, there are few studies on the spread of blaNDM-5-producing bacteria in waterfowl farms. Our study showed that the IncX3 plasmid carrying blaNDM-5 in goose farms is widely present in K. pneumoniae isolates and a large number of resistance genes are accumulated in it. We found a transferable IncFIB-FII hybrid plasmid that combines virulence, resistance, and metal resistance genes, which allow transfer of these traits between bacteria in different regions. The results of this study contribute to a better understanding of the prevalence and transmission of carbapenem-resistant K. pneumoniae in goose farms.

Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis.

Acral melanoma, the most common melanoma subtype among non-White individuals, is associated with poor prognosis. However, its key molecular drivers remain obscure. Here, we perform integrative genomic and clinical profiling of acral melanomas from 104 patients treated in North America (n = 37) or China (n = 67). We find that recurrent, late-arising focal amplifications of cytoband 22q11.21 are a leading determinant of inferior survival, strongly associated with metastasis, and linked to downregulation of immunomodulatory genes associated with response to immune checkpoint blockade. Unexpectedly, LZTR1 - a known tumor suppressor in other cancers - is a key candidate oncogene in this cytoband. Silencing of LZTR1 in melanoma cell lines causes apoptotic cell death independent of major hotspot mutations or melanoma subtypes. Conversely, overexpression of LZTR1 in normal human melanocytes initiates processes associated with metastasis, including anchorage-independent growth, formation of spheroids, and an increase in MAPK and SRC activities. Our results provide insights into the etiology of acral melanoma and implicate LZTR1 as a key tumor promoter and therapeutic target.

Comparison of PK/PD Targets and Cutoff Values for Danofloxacin Against Pasteurella multocida and Haemophilus parasuis in Piglets.

Danofloxacin is a synthetic fluoroquinolone with broad-spectrum activity developed for use in veterinary medicine. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) targets, PK/PD cutoff values and the optimum doses of danofloxacin against P. multocida and H. parasuis in piglets. Single dose serum pharmacokinetics was determined in piglets after intravenous and intramuscular administration of 2.5 mg/kg. Danofloxacin was well absorbed and fully bioavailable (95.2%) after intramuscular administration of 2.5 mg/kg. The epidemiological cutoff (ECOFF) values of danofloxacin from 931 P. multocida isolates and 263 H. parasuis isolates were 0.03 and 4 mg/L, respectively. Danofloxacin MICs determined in porcine serum were markedly lower than those measured in artificial broth, with a broth/serum ratio of 4.33 for H. parasuis. Compared to P. multocida, danofloxacin exhibited significantly longer post-antibiotic effects (3.18-6.60 h) and post-antibiotic sub-MIC effects (7.02-9.94 h) against H. parasuis. The mean area under the concentration-time curve/MIC (AUC24h/MIC) targets of danofloxacin in serum associated with the static and bactericidal effects were 32 and 49.8, respectively, for P. multocida, whereas they were 14.6 and 37.8, respectively, for H. parasuis. Danofloxacin AUC24h/MIC targets for the same endpoints for P. multocida were higher than those for H. parasuis. At the current dose of 2.5 mg/kg, the PK/PD cutoff (COPD) values of danofloxacin against P. multocida and H. parasuis were calculated to be 0.125 and 0.5 mg/L, respectively, based on Monte Carlo simulations. The predicted optimum doses of danofloxacin for a probability of target attainment (PTA) of > 90% to cover the overall MIC population distributions of P. multocida and H. parasuis in this study were 2.38 and 13.36 mg/kg, respectively. These PK/PD-based results have potential relevance for the clinical dose optimization and evaluation of susceptibility breakpoints for danofloxacin in the treatment of swine respiratory tract infections involving these pathogens.

Comparison of clinical and imaging features between pulmonary tuberculosis complicated with lung cancer and simple pulmonary tuberculosis: a systematic review and meta-analysis.

This review aimed to compare the clinical features and CT imaging features between patients with pulmonary tuberculosis (PTB) and lung cancer and patients with PTB alone. That would help to analyse the differences between the two and consequently providing a theoretical basis for the clinical diagnosis and treatment for the patients. Relevant case-control studies focusing on the clinical and CT imaging characteristics between PTB with lung cancer and PTB alone were systematically searched from five electronic databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for comparison. As of 2021-07-06, a total of 1735 articles were retrieved. But only 15 articles were finally included for meta-analysis. The results showed a higher proportion of irritable cough, haemorrhagic pleural effusion and lower proportion of night sweating in PTB patients with lung cancer than in PTB patients, and the differences were statistically significant (irritable cough: OR 2.43, 95% CI 1.43-4.11; haemorrhagic pleural effusion: OR 5.73, 95% CI 1.63-20.12; night sweating: OR 0.56, 95% CI 0.36-0.87). In addition, there are many differences in the imaging characteristics of the two types of patients. In conclusion, this review summarises the similarities and differences in clinical symptoms and imaging features between patients with PTB and lung cancer and patients with PTB alone, suggesting that we should be alert to the occurrence of lung cancer in patients with obsolete PTB relapse.

3D printing guide plate for accurate hemicortical bone tumor resection in metaphysis of distal femoral: a technical note.

BACKGROUND: Surgical resection and reconstruction for low-grade bone sarcoma in the metaphysis of the distal femur remain challenging. We hypothesized that 3D printing osteotomy guide plate could assist to accurately resect the tumor lesion and save the joint function. METHODS: From January 2017 to August 2019, five patients diagnosed with low-grade bone sarcoma in the metaphysis of the distal femur were treated with hemicortical resection using 3D printing guide plate. Autologous bone graft was inactivated in a high-temperature water bath and re-implanted in situ fixed with plate and screw. Patients were followed up from 17 to 33 months. The Musculoskeletal Tumor Society Score was used to evaluate the joint function. X-ray was used to evaluate the bone union. RESULTS: One patient was paracorticular osteosarcoma, and four cases had highly differentiated chondrosarcoma. All cases were involved in the metaphysis of the distal femur. Patients were followed up from 13 to 33 months, with an average of 23.6 months. There was neither post-operation infection, internal fixation loosening, nor fracture occurrence in any of the patients. The Musculoskeletal Tumor Society Score averaged at 28.1, while the International Society of Limb Salvage imaging score examination averaged 89.8%. CONCLUSIONS: Here, we demonstrate that the 3D printing osteotomy guide plate-assisted hemicortical bone resection is a beneficial strategy to effectively resect the primary low-grade malignant bone tumors in the metaphysis of the distal femur and retained satisfied joint function.

Application of the ACOSOG Z0011 criteria to Chinese patients with breast cancer: a prospective study.

BACKGROUND: Although the ACOSOG Z0011 study showed that axillary lymph node dissection (ALND) could be avoided in a specific population of sentinel lymph node-positive patients, it is not widely accepted by Chinese surgeons. We conducted a prospective single-arm study to confirm whether or not the results of Z0011 are applicable to Chinese patients. METHODS: Patients conforming to the Z0011 criteria were prospectively enrolled at the Peking University People's Hospital Breast Center from November 2014 to June 2019. The clinicopathological features of the study group were compared with those of the Z0011 study group. Lymphedema after surgery, the incidence of local-regional recurrence, and survival were analyzed. RESULTS: One hundred forty-two patients who met the Z0011 eligibility criteria were enrolled in this study; 115 underwent sentinel lymph node biopsy (SLNB) alone. Compared with the Z0011 trial, younger patients were included (median age, 52 [26-82] years vs 54 [25-90] years; P = 0.03). For clinical T stage, tumor histology, hormone status, lymphovascular invasion, and the number of positive sentinel lymph nodes (SLNs), no statistically significant differences were observed. More patients received adjuvant chemotherapy and endocrine therapy in this study (90.85% vs 58.0% and 80.99% vs 46.6% respectively, P <0.001). A similar percentage of patients received radiotherapy, but more nodal radiotherapy procedures were carried out in our study (54.5% vs 16.9%). After a median follow-up of 29 months, only 1 patient (0.9%) had ipsilateral breast tumor recurrence, and no regional recurrence occurred. CONCLUSION: Our study showed that it is achievable to avoid ALND in patients eligible for Z0011 in China. TRIAL REGISTRATION: ClinicalTrials.gov. Registration number NCT03606616 . Retrospectively registered on 31 July 2018.

Efficient and Consistent Orthotopic Osteosarcoma Model by Cell Sheet Transplantation in the Nude Mice for Drug Testing.

Osteosarcoma is a big challenge on clinical treatment. The breakthrough associated with osteosarcoma in basic research and translational research depends on the reliable establishment of an animal model, whereby mice are frequently used. However, a traditional animal modeling technique like tumor cell suspension injection causes batch dynamics and large mice consumption. Here, we suggested a novel approach in establishing an orthotropic osteosarcoma model in nude mice rapidly by cell sheet culture and transplantation. Our findings demonstrated that the 143b osteosarcoma cell sheet orthotopically implanted into the nude mice could form a visible mass within 10 days, whereas it took over 15 days for a similar amount of cell suspension injection to form a visible tumor mass. Living animal imaging results showed that a tumor formation rate was 100% in the cell sheet implantation group, while it was 67% in the cell suspension injection group. The formed tumor masses were highly consistent in both growth rate and tumor size. Massive bone destruction and soft tissue mass formation were observed from the micro CT analysis, suggesting the presence of osteosarcoma. The histopathological analysis demonstrated that the orthotropic osteosarcoma model mimicked the tumor bone growth, bone destruction, and the lung metastasis. These findings imply that such a cell sheet technology could be an appropriate approach to rapidly establish a sustainable orthotropic osteosarcoma model for tumor research and reduce mice consumption.

miR-34a regulates lipid metabolism by targeting SIRT1 in non-alcoholic fatty liver disease with iron overload.

BACKGROUND: Micro-ribonucleic acids (miRNAs) have been implicated in the regulation of non-alcoholic fatty liver disease (NAFLD), a leading cause of chronic liver disease worldwide. The mechanisms by which miR-34a influences NAFLD through the Sirtuin 1 (SIRT1)-related pathway were investigated herein. METHODS: Male C57BL/6 mice were injected with a miR-34a lentivirus vector inhibitor or control. HepG2 cells were transfected with a miR-34a mimic, inhibitor, SIRT1 small interfering RNA (siRNA), SIRT1 plasmid, and a negative oligonucleotide control to evaluate their role in oleic acid (OA) and excess iron-induced NAFLD. The accumulation of lipids in the mice liver and HepG2 cells was analyzed by triglyceride (TG) detection and hematoxylin and eosin (HE) staining. Additionally, the indexes of oxidative stress related to lipid metabolism were evaluated by western blotting and real-time PCR (qRT-PCR). The levels of intracellular reactive oxygen species (ROS) and mitochondrial membrane potentials were measured by flow cytometry and laser confocal microscopy, respectively. Finally, the dual luciferase reporter assay was conducted to further confirm whether SIRT1 was a direct target of miR-34a. RESULTS: Overexpression of miR-34a resulted in increased triglyceride accumulation as well as in decreased mitochondrial membrane potential and SIRT1 levels. Silencing of miR-34a increased SIRT1 expression and alleviated triglyceride accumulation in the presence of OA and iron. Additionally, miR-34a directly inhibited SIRT1 by binding to the 3'-untranslated region, as determined via the luciferase reporter assay. CONCLUSIONS: Our results support the existence of a link between the liver cell mitochondria and miR-34a/SIRT1 signaling. Potential endogenous modulators of NAFLD pathogenesis may ultimately provide new tools for therapeutic intervention.

LncRNA GAS5 Regulates Osteosarcoma Cell Proliferation, Migration, and Invasion by Regulating RHOB via Sponging miR-663a.

INTRODUCTION: Emerging evidence has revealed the importance of long non-coding RNAs (lncRNAs) in carcinogenesis. The aim of this work was to investigate the roles of lncRNA growth arrest specific 5 (GAS5) in osteosarcoma (OS) progression. METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to explore GAS5, microRNA-663a (miR-663a), and ras homolog family member B (RHOB) expression levels in OS tissues and cells. Moreover, cell counting kit-8 assay, wound-healing assay, and transwell invasion assay were conducted to investigate biological roles of GAS5 in OS progression. In addition, mechanisms underlying the functions of GAS5 in OS were investigated by bioinformatic analysis, luciferase activity reporter assay, and rescue experiments. RESULTS: The GAS5 expression level was significantly decreased in OS tissues and cells compared with normal tissues and cells, and could negatively regulate miR-663a expression. Moreover, we found RHOB expression can be negatively regulated by miR-663a. Overexpression of GAS5 and RHOB suppresses, while overexpression of miR-663a stimulates, OS cell proliferation, migration, and invasion in vitro. In summary, we revealed lncRNA GAS5 was a downregulated lncRNA in OS and impaired OS malignant behaviors. In addition, this regulation relied on miR-663a and its target gene, RHOB. DISCUSSION: To sum up, we showed lncRNA GAS5 regulates OS progression via regulating the miR-663a/RHOB axis.

Characterizations of Gene Alterations in Melanoma Patients from Chinese Population.

Melanoma is a human skin malignant tumor with high invasion and poor prognosis. The limited understanding of genomic alterations in melanomas in China impedes the diagnosis and therapeutic strategy selection. We conducted comprehensive genomic profiling of melanomas from 39 primary and metastatic formalin-fixed paraffin-embedded (FFPE) samples from 27 patients in China based on an NGS panel of 223 genes. No significant difference in gene alterations was found between primary and metastasis melanomas. The status of germline mutation, CNV, and somatic mutation in our cohort was quite different from that reported in Western populations. We further delineated the mutation patterns of 4 molecular subgroups (BRAF, RAS, NF1, and Triple-WT) of melanoma in our cohort. BRAF mutations were more frequently identified in melanomas without chromic sun-induced damage (non-CSD), while RAS mutations were more likely observed in acral melanomas. NF1 and Triple-WT subgroups were unbiased between melanomas arising in non-CSD and acral skin. BRAF, RAS, and NF1 mutations were significantly associated with lymph node metastasis or presence of ulceration, implying that these cancer driver genes were independent prognostic factors. In summary, our results suggest that mutational profiles of malignant melanomas in China are significantly different from Western countries, and both gene mutation and amplification play an important role in the development and progression of melanomas.

Suppression of Progranulin Expression Leads to Formation of Intranuclear TDP-43 Inclusions In Vitro: A Cell Model of Frontotemporal Lobar Degeneration.

Mutations in the GRN gene coding for progranulin (PGRN) are responsible for many cases of familial frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein 43 (TDP-43)-positive inclusions (FTLD-TDP). GRN mutations create null alleles resulting in decreased progranulin protein or haploinsufficiency. FTLD-TDP with GRN mutations is characterized by lentiform neuronal intranuclear inclusions that are positive for TDP-43 in affected brain regions. In this study, by stably expressed short hairpin RNA, we established a neuroblastoma cell line with decreased PGRN level. This cell line reveals TDP-43-positive intranuclear inclusions. In addition, replacement with purified PGRN protein restores normal TDP-43 nuclear distribution. This cell model can be valuable for the study of the role of PGRN in the pathogenesis in FTLD-TDP.

MiR-9 promotes synovial sarcoma cell migration and invasion by directly targeting CDH1.

BACKGROUND: Invasion and metastasis of synovial sarcoma is the leading cause of death in patients. Epithelial mesenchymal transition (EMT) accelerates tumor cell invasion and metastasis. MiR-9 promotes tumor metastasis by inducing EMT. However, the role of miR-9 in synovial sarcoma is still not clear. METHODS: Overexpression or knockdown of miR-9 in human synovial sarcoma (HSS) cell lines was carried out by miR-9 mimics or miR-9 inhibitors transfection. Cell proliferation, apoptosis, migration and invasion were detected using MTS and colony formation assays, flow cytometry, wound healing and transwell assays, respectively. Luciferase reporter assay was applied to study the interaction between miR-9 and CDH1. Nude mice xenograft model was established, and immunohistochemistry staining assessed Ki-67 level. The related mRNA and protein expression levels were evaluated by qRT-PCR and Western blotting. RESULTS: The bioinformatics analyses and luciferase reporter assay showed that miR-9 can target CDH1 3'-UTR. Moreover, miR-9 could induce EMT of HSS cells via targeting CDH1. The negative regulation of miR-9 on CDH1 expression was also confirmed in a mouse xenograft model of synovial sarcoma. Furthermore, miR-9 was observed to induce HSS cell proliferation, migration and invasion and inhibit apoptosis. MAPK/ERK and Wnt/ß-catenin signal pathways were activated by the miR-9 overexpression in HSS cells, and then further enhancing tumorigenesis of HSS, which was further confirmed in the mouse model. CONCLUSION: MiR-9 induces EMT by targeting CDH1, and activates MAPK/ERK and Wnt/ß-catenin signal pathways, thus promoting HSS tumorigenesis.

Propranolol induced G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway.

Both preclinical and epidemiology studies associate ß-adrenoceptors-blockers (ß-blockers) with activity against melanoma. However, the underlying mechanism is still unclear, especially in acral melanoma. In this study, we explored the effect of propranolol, a non-selective ß-blocker, on the A375 melanoma cell line, two primary acral melanoma cell lines (P-3, P-6) and mice xenografts. Cell viability assay demonstrated that 50µM-400µM of propranolol inhibited viability in a concentration and time dependent manner with an IC50 ranging from 65.33µM to 148.60µM for 24h -72h treatment, but propranolol (less than 200µM) had no effect on HaCaT cell line. Western blots showed 100µM propranolol significantly reduced the expression of Bcl-2 while increasing the expressions of Bax, cytochrome c, cleaved capase-9 and cleaved caspase-3, and down-regulated the levels of p-AKT, p-BRAF, p-MEK1/2 and p-ERK1/2 in melanoma cells, after a 24h incubation. The in vivo data confirmed the isolation results. Mice received daily ip. administration of propranolol at the dose of 2 mg/kg for 3 weeks and the control group was treated with the same volume of saline. The mean tumor volume at day 21 in A375 xenografts was 82.33 ± 3.75mm3vs. 2044.67 ± 54.57mm3 for the propranolol-treated mice and the control group, respectively, and 31.66 ± 4.67 mm3vs. 1074.67 ± 32.17 mm3 for the P-3 xenografts. Propranolol also reduced Ki67, inhibited phosphorylation of AKT, BRAF, MEK1/2 and ERK1/2 in xenografts. These are the first data to demonstrate that propranolol might inhibit melanoma by activating the intrinsic apoptosis pathway and inactivating the MAPK and AKT pathways.

Regulatory T cells in the immunotherapy of melanoma.

Patients with melanoma are supposed to develop spontaneous immune responses against specific tumor antigens. However, several mechanisms contribute to the failure of tumor antigen-specific T cell responses, inducing immune escape. Importantly, immunosuppression mediated by regulatory T cells (Tregs) in tumor lesions is a dominant mechanism of tumor immune evasion. Based on this information, several therapies targeting Tregs such as cyclophosphamide, IL-2-based therapies, and antibodies against the surface molecular of Tregs have been developed. However, only some of these strategies showed clinical efficacy in patients with melanoma in spite of their success in shifting immune systems to antitumor responses in animal models. In the future, strategies specifically depleting local Tregs, inhibiting Treg migration to the tumor lesion, and Treg depletion in combination with other chemotherapies or immune modulation will hopefully bring benefits to melanoma patients.

Tenuigenin inhibits RANKL-induced osteoclastogenesis by down-regulating NF-κB activation and suppresses bone loss in vivo.

Tenuigenin, a major active component of polygala tenuifolia root, has been used to treat patients with insomnia, dementia, and neurosis. In this study, we aimed to investigate the effects of tenuigenin on osteoclastogenesis and clarify the possible mechanism. We showed that tenuigenin inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and bone resorption without cytotoxicity, which was further demonstrated by reduced osteoclast specific gene expression such as TRAP, c-Src, ATP6v0d2, etc. Moreover, the inhibitory effect of tenuigenin was associated with impaired NF-κB activity owing to delayed degradation/regeneration of IkBa and inhibition of p65 nuclear translocation. Consistent with the in vitro results, micro-ct scanning and analysis data showed that tenuigenin suppressed RANKL-induced bone loss in an animal model. Taken together, our data demonstrate that tenuigenin inhibit osteoclast formation and bone resorption both in vitro and in vivo, and comprise a potential therapeutic alternative for osteoclast-related disorders such as osteoporosis and cancer-induced bone destruction.

Omental transplantation improves surgical outcome of large squamous cell carcinoma: A case report.

Cutaneous squamous cell carcinoma (SCC) is an major health issue due to the significant health costs and marked disfigurement following surgical excision. The conventional reconstructive options may not be suitable for patients with large SCCs of the lower part of the leg, due to the regional tissue damage and ischemic environment. The omental transposition flap is a highly vascularized tissue that is resistant to infection and provides a recipient bed for skin grafts. This is the case report of a male patient with a large SCC in the lower part of his right leg, which was treated with extensive resection. The patient subsequently underwent reconstruction using a free omental flap, followed by transplantation of a secondary skin graft. The patient did not experience recurrence or metastasis during the 2 years of follow-up, indicating that, when dealing with postoperative skin cancer defects in an ischemic environment, omental transplantation may be a viable treatment option.