Using a Nomogram to Preoperatively Predict Distant Metastasis of Pancreatic Neuroendocrine Tumor in Elderly Patients.

Objective To establish a nomogram for predicting the distant metastasis risk of pancreatic neuroendocrine tumors (pNETs) in elderly patients. Methods We extracted data of patients with diagnosis of pNETs at age ≥65 years old between 1973 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. All eligible patients were divided randomly into a training cohort and validation cohort. Uni- and multivariate logistic regression analyses were performed on the training cohort to identify independent factors for distant metastasis. A nomogram was developed based on the independent risk factors using rms packages of R software, and was validated internally by the training cohort and externally by the validation cohort using C-index and calibration curves. Results A total of 411 elderly patients were identified, of which 260 were assigned to training cohort and 151 to validation cohort. Univariate and multivariate logistic regression analyses indicated the tumor site (body/tail of pancreas: odds ratio [OR]=2.282; 95% confidence interval [CI]: 1.174 - 4.436, P<0.05), histological grade (poorly differentiated/undifferentiated: OR=2.600, 95% CI: 1.266-5.339, P<0.05), T stage (T2: OR=8.913, 95% CI: 1.985-40.010, P<0.05; T3: OR=11.830, 95% CI: 2.530-55.350, P<0.05; T4: OR=68.650, 95% CI: 8.020-587.600, P<0.05), and N stage (N1: OR=3.480, 95% CI: 1.807-6.703, P<0.05) were identified as independent risk factors for distant metastasis of pNETs in elderly. The nomogram exhibited good predicting accuracy, with a C-index of 0.809 (95% CI: 0.757 - 0.861) in internal validation and 0.795 (95% CI: 0.723 - 0.867) in external validation, respectively. The predicted distant metastasis rates were in satisfactory agreement with the observed values by the calibration curves. Conclusion The nomogram we established showed high discriminative ability and accuracy in evaluation of distant metastasis risk in elderly pNETs patients, and could provide a reference for individualized tumor evaluation and treatment decision in elderly pNETs patients.

Does Prior Cancer Have an Influence on the Survival Outcomes of Patients with Localized Pancreatic Neuroendocrine Tumors?

Objective To investigate the impact of prior non-pancreatic cancer on the survival outcomes of patients with localized pancreatic neuroendocrine tumors (PanNETs). Methods We reviewed the Surveillance, Epidemiology, and End Results database and selected patients with localized PanNETs diagnosed between 1973 and 2015. We divided the patients into two groups according to the presence or absence of prior non-pancreatic malignancy. Before and after propensity score matching, we compared the clinicopathological characteristics and studied the overall survival and cancer-specific survival. Results A total of 357 (12.9%) of 2778 patients with localized PanNETs had prior cancer. A total of 1211 cases with only a localized PanNET and 133 cases with a localized PanNET and prior cancer had complete data and met the inclusion criteria of the current study. Patients with prior cancer were associated with advanced age (>65 years, 57.9% prior cancer vs. 31.0% no prior cancer, P<0.001), later year of diagnosis (87.2% vs. 80.2%, P=0.049), a higher proportion of poorly differentiated/undifferentiated grade tumors (4.5% vs. 1.5%, P=0.025), and a higher proportion of no primary site surgery (19.5% vs. 10.4%, P=0.003). Prostate (29.32%), breast (18.05%), other genitourinary and retroperitoneal (16.54%), and gastrointestinal (12.78%) cancers were the most common prior cancer types. Most of the prior cancers (95.49%) were localized and regional, and only 4.51% of the prior cancers were distant. Patients with interval periods between the prior cancer and PanNET of ≤36 months, 36-60 months, 60-120 months, and >120 months accounted for 33.08%, 13.53%, 24.06%, and 29.32% of all cases with prior cancers, respectively. Univariate and multivariate Cox proportional hazards analyses were performed. The presence/absence of prior cancers did not impact survival outcomes of patients with localized PanNETs before and after propensity score matching (PSM). Further subgroups analysis showed that, patients with localized PanNETs and prior distant cancer had worse cancer-specific survival than patients with prior local/regional cancer or patients without prior cancer (P<0.001). No significant differences in cancer-specific survival were observed in terms of the different sites of the prior cancers and the different interval periods of prior cancers and PanNETs (P<0.05). Conclusions Patients with localized PanNETs and a history of prior cancer had survival outcomes that were comparable to those of patients with no history of prior cancer. Patients with localized PanNETs and prior cancer could be candidates for clinical trials if they satisfy all other conditions; aggressive and potentially curative therapies should be offered to these patients.

Intestinal Perforation Secondary to Pits of Jujube Ingestion: A Single-Center Experience with 18 Cases.

BACKGROUND: Ingestion of jujube pits is a common clinical problem, which can be difficult to diagnose and life-threatening if accompanied with intestinal perforation and peritonitis. In this study, 18 cases of intestinal perforation caused by ingestion of jujube pits were reviewed and summarized to discuss the clinical characteristics, diagnosis and treatments. METHODS: From 2012 to 2018, a total of 18 patients diagnosed as intestinal perforation due to ingested pits of jujube in our center were retrospectively reviewed and the manifestations, laboratory tests, imaging examinations and treatment strategies were summarized. RESULTS: The patients comprised of 11 males and 7 females with an average age of 63.5 years. The main clinical manifestation was abdominal pain. Twelve patients (67%) presented to the emergency department with signs of localized peritonitis. CT imaging revealed positive findings in 17 (94%) patients. Conservative treatments were attempted in 3 patients, and the other 15 patients received emergency surgical exploration, where 7 patients had more than one perforation identified during surgery. Five patients were admitted in the surgical intensive care unit after surgery. The average length of stay of all 18 patients was 9.8 days (range 5-24 days). CONCLUSION: Ingestion of jujube pits is a common clinical problem and potentially leads to intestinal perforation and peritonitis. CT imaging is the first imaging modality of choice. Patients with milder symptoms might be managed with cautious conservative treatment, and patients with more than one perforation can be identified during surgery.

Lichtenstein repair of indirect inguinal hernias with acellular tissue matrix grafts in adolescent patients: a prospective, randomized, controlled trial.

PURPOSE: To evaluate the outcomes of Lichtenstein hernioplasty using acellular tissue matrix (ACTM) grafts in adolescent patients. METHODS: One hundred patients, 13-18 years old, with primary unilateral indirect inguinal hernias, were randomly assigned to receive Lichtenstein hernioplasty using ACTM or traditional high ligation of the hernia sac (control group).The outcome measures were the length of the operation, postoperative visual analogue scale (VAS) pain score, length of hospitalization, postoperative complications and recurrence rate. RESULTS: The length of hospitalization and VAS score were not different between the groups, and the minimum follow-up was 30 months. No postoperative wound infections, chronic postoperative pain or local foreign body sensation occurred in either group. Six patients (14.3 %) in the experimental group and five (11.6 %) in the control group developed scrotal hydroceles (P > 0.05); all resolved with conservative management. There were no recurrences in the experimental group, while there were three (6 %) in the control group (P > 0.05) and all occurred in patients with Gilbert type 3 hernias. CONCLUSIONS: Lichtenstein hernioplasty using ACTM grafts has comparable safety and efficacy to traditional high ligation of the indirect hernia sac in adolescent patients. ACTM can reduce the incidence of recurrence in adolescents with Gilbert type 3 hernias.

Mechanism of highly efficient oil removal from spent hydrodesulfurization catalysts by ultrasound-assisted surfactant cleaning methods.

The removal of crude oil from spent hydrodesulfurization catalysts constitutes the preliminary stage in the recovery process of valuable metals. However, the traditional roasting method for the removal exhibits massive limitations. In view of this, the present study used an ultrasound-assisted surfactant cleaning method to remove crude oil from spent hydrodesulfurization catalysts, which demonstrated effectiveness. Furthermore, the study investigated the mechanism governing the process with calculation and experiments, so as to provide a comprehensive understanding of the cleaning method's efficacy. The surfactant selection was predicated on the performance in the IFT test, with SDBS and TX-100 finally being chosen. Subsequent calculations and analysis were then conducted to elucidate their frontier molecular orbitals, electrostatic potential, and polarity. It has been found that both SDBS and TX-100 possess the smallest LUMO-HOMO energy gap (ΔE), registering at 4.91 eV and 4.80 eV, respectively, and presenting the highest interfacial reactivity. The hydrophilic structure in the surfactant regulates the wettability of the oil-water interface, and the long-chain alkanes have excellent non-polar properties that promote the dissolution of crude oil. The ultrasonic-assisted process further improves the interface properties and enhances the oil removal effect. Surprisingly, the crude oil residue was reduced to 0.25% under optimal conditions. The final phase entailed the techno-economic evaluation of the entire process, revealing that, in comparison to the roasting method, this process saves $0.38 per kilogram of spent HDS catalyst, with the advantages of operational simplicity and emission-free. Generally, this study shed new light on the realization of efficient oil removal, with the salience of green, sustainable, and economical.

Tick cysteine protease inhibitors suppress immune responses in mannan-induced psoriasis-like inflammation.

Protease inhibitors regulate various biological processes and prevent host tissue/organ damage. Specific inhibition/regulation of proteases is clinically valuable for treating several diseases. Psoriasis affects the skin in the limbs and scalp of the body, and the contribution of cysteine and serine proteases to the development of skin inflammation is well documented. Cysteine protease inhibitors from ticks have high specificity, selectivity, and affinity to their target proteases and are efficient immunomodulators. However, their potential therapeutic effect on psoriasis pathogenesis remains to be determined. Therefore, we tested four tick cystatins (Sialostatin L, Sialostatin L2, Iristatin, and Mialostatin) in the recently developed, innate immunity-dependent mannan-induced psoriasis model. We explored the effects of protease inhibitors on clinical symptoms and histological features. In addition, the number and percentage of immune cells (dendritic cells, neutrophils, macrophages, and γδT cells) by flow cytometry, immunofluorescence/immunohistochemistry and, the expression of pro-inflammatory cytokines (TNF-a, IL-6, IL-22, IL-23, and IL-17 family) by qPCR were analyzed using skin, spleen, and lymph node samples. Tick protease inhibitors have significantly decreased psoriasis symptoms and disease manifestations but had differential effects on inflammatory responses and immune cell populations, suggesting different modes of action of these inhibitors on psoriasis-like inflammation. Thus, our study demonstrates, for the first time, the usefulness of tick-derived protease inhibitors for treating skin inflammation in patients.

Cathelicidin-HG Alleviates Sepsis-Induced Platelet Dysfunction by Inhibiting GPVI-Mediated Platelet Activation.

Platelet activation contributes to sepsis development, leading to microthrombosis and increased inflammation, which results in disseminated intravascular coagulation and multiple organ dysfunction. Although Cathelicidin can alleviate sepsis, its role in sepsis regulation remains largely unexplored. In this study, we identified Cath-HG, a novel Cathelicidin from Hylarana guentheri skin, and analyzed its structure using nuclear magnetic resonance spectroscopy. The modulatory effect of Cath-HG on the symptoms of mice with sepsis induced by cecal ligation and puncture was evaluated in vivo, and the platelet count, degree of organ damage, and microthrombosis were measured. The antiplatelet aggregation activity of Cath-HG was studied in vitro, and its target was verified. Finally, we further investigated whether Cath-HG could regulate thrombosis in vivo in a FeCl3 injury-induced carotid artery model. The results showed that Cath-HG exhibited an α-helical structure in sodium dodecyl sulfate solution and effectively reduced organ inflammation and damage, improving survival in septic mice. It alleviated sepsis-induced thrombocytopenia and microthrombosis. In vitro, Cath-HG specifically inhibited collagen-induced platelet aggregation and modulated glycoprotein VI (GPVI) signaling pathways. Dot blotting, enzyme-linked immunosorbent assay, and pull-down experiments confirmed GPVI as the target of Cath-HG. Molecular docking and amino acid residue truncations/mutations identified crucial sites of Cath-HG. These findings suggest that GPVI represents a promising therapeutic target for sepsis, and Cath-HG may serve as a potential treatment for sepsis-related thrombocytopenia and thrombotic events. Additionally, identifying Cath-HG as a GPVI inhibitor provides insights for developing novel antithrombotic therapies targeting platelet activation mediated by GPVI.

Effectiveness and safety of n-butyl-2-cyanoacrylate medical adhesive for noninvasive patch fixation in laparoscopic inguinal hernia repair.

BACKGROUND: Our purpose was to compare the recurrence rate and other clinical outcomes of laparoscopic (LS) transabdominal preperitoneal (TAPP) inguinal hernia repair using n-butyl-2-cyanoacrylate (NBCA) for mesh fixation with those of no mesh fixation and mesh fixation with titanium spiral tacks (ST). METHODS: The medical records of patients who received LS TAPP inguinal hernia repair between 2009 and 2012 at our institution were reviewed. Patients were included if the received LS TAPP with either no mesh fixation, mesh fixation with NBCA only, fixation with ST only, or fixation with NBCA + ST. Outcome measures were operation time, postoperative length of stay, visual analogue scale (VAS) pain score 24 h after surgery, postoperative complications, and hernia recurrence. RESULTS: A total of 1,027 TAPP cases were included. In 552 cases, meshes were fixed with NBCA only, in 89 cases only ST were used, in 47 cases ST and NBCA were used, and in 339 cases meshes were not fixed. The groups were comparable with respect to demographic and clinical characteristics. No surgical complications occurred in any group. VAS pain scores were significantly lower in the nonfixation and NBCA only groups (1.4 ± 0.6 and 1.3 ± 0.6, respectively) than in the ST and NBCA + ST groups (2.2 ± 0.9 and 2.2 ± 0.7, respectively; P = 0.001). The mean follow-up duration was ~19 months. At the final follow-up, no wound infections or hernia recurrences had occurred in any of the groups. No occurrence of chronic pain was noted in the nonfixation and NBCA only groups, whereas two cases (2.2%) were noted in the ST group and one case (2.1%) in the NBCA + ST group (P = 0.005). CONCLUSIONS: The use of NBCA medical adhesive for noninvasive patch fixation in laparoscopic hernia repair (TAPP) is effective and safe.

The first Brevinin-1 antimicrobial peptide with LPS-neutralizing and anti-inflammatory activities in vitro and in vivo.

Antimicrobial peptide is one important component of the first protective barrier of organisms. They not only have potent antimicrobial activity which can protect the body from the invading pathogens, but also participate in the immune regulation of the body. In this study, a Brevinin-1 peptide named by Brevinin-1GHd was identified from Hoplobatrachus rugulosus, and the similarity of mature peptide sequence among Brevinin-1GHd, Brevinin-1HL and Brevinin-1GHa supported the close species relationship between H. rugulosus, Hylarana latouchii and Hylarana guertheri. Moreover, the secondary structure of Brevinin-1GHd was found to possess α-helical characteristics and high thermal stability. In addition, Brevinin-1GHd could bind to LPS with a Kd value of 6.49 ± 5.40 mM and suppress the release of TNF-α, NO, IL-6 and IL-1ß by inactivation of MAPK signaling pathway in RAW 264.7 cells induced by LPS. Furtherly, Brevinin-1GHd had a significant inhibitory effect on acute edema development in the right paw of mice injected by carrageenan. Thus, the significant LPS-neutralizing and anti-inflammatory activities of Brevinin-1GHd were demonstrated in this study, which made it become the first Brevinin-1 family peptide with anti-inflammatory activity reported so far, and the biological activity of Brevinin-1GHd made it promising to be a novel therapeutic drug for infectious inflammation.

Prognostic values of the miR-17-92 cluster and its paralogs in colon cancer.

BACKGROUND: MicroRNAs have been shown to offer great potential in both the diagnosis and prognosis of cancer. Despite the well-established role of the miR-17-92 in cancer formation and progression, the contribution of each individual miRNA remains to be characterized. Thus, we investigated whether deregulation of the miR-17-92 associated with colon cancer prognosis. METHODS: Expression levels of the miR-17-92 cluster and its paralogs were determined in 48 colon tumor and 48 paired normal tissues by real-time qRT-PCR. Associations with miRNA expression, age, sex, TNM staging, and survival prognosis were evaluated. RESULTS: MiR-17-92 cluster and its paralogs were significantly overexpressed in colon tumor. No significant associations were found between the deregulation of certain miRNAs and the clinical and pathologic characteristics observed in patients. Kaplan-Meier curves demonstrated significantly reduced overall survival in patients expressing high levels of miR-17. In multivariate Cox models, miR-17 overexpression (HR 2.67; P = 0.007) and TNM staging (HR 8.87; P = 0.002) were significantly associated with a risk of death. CONCLUSIONS: The miR-17-92 cluster and its paralogs were significantly elevated in patients with colon cancer, and heightened expression of miR-17 was associated with poor survival. Moreover, miR-17 and TNM staging were both identified as significant, but independent, prognostic biomarkers in colon cancer.

Hyperthermia synergizes with tissue factor knockdown to suppress the growth and hepatic metastasis of colorectal cancer in orthotopic tumor model.

BACKGROUND: Tissue factor (TF) is a significant risk factor for tumor growth and hepatic metastasis in patients with colorectal cancer (CRC). This study aimed to investigate whether hyperthermia has synergistic anti-tumor effects with TF knockdown in suppressing CRC progression and metastasis in vitro and in vivo. METHODS: Human colorectal cancer LOVO cells were treated by hyperthermia at 44°C for 2 hr or/and TF siRNA. Then the cells were subjected to colony formation assay. Apoptosis was analyzed by flow cytometry, confocal microscopy, and transmission electron microscopy. The cell migration and invasion abilities were analyzed by wound healing and matrigel assay. In addition, orthotopic nude mice model of CRC was established. RESULTS: Hyperthermia synergized with TF knockdown to reduce colony formation ability, induce apoptosis, and suppress the migration and invasion of LOVO cells in vitro. Moreover, hyperthermia in combination with TF depletion inhibited the growth and hepatic metastasis of CRC in orthotopic nude mice model. Mechanistically, the synergistic effects were at least partly mediated by inducing JNK mediated apoptosis and suppressing matrix metalloproteinases (MMPs) mediated invasion. CONCLUSIONS: Hyperthermia in combination with TF-targeted therapy could be a potential approach for CRC treatment.

circEPS15 Overexpression in Hepatocellular Carcinoma Modulates Tumor Invasion and Migration.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Recent evidence has shown that circular RNAs (circRNAs) play important roles in tissue development, gene transcription, signal regulation and tumorigenesis. However, whether circRNAs are involved in HCC progression and encode functional proteins remains largely unknown. In the present study, we aimed to explore the function and molecular mechanism of circRNAs in HCC. First, many circRNAs were found to be differentially expressed in HCC samples and paired adjacent normal liver tissues. The validation of dysregulated circRNAs by qRT-PCR revealed that circEPS15 expression was downregulated in HCC tissues, and the survival curves showed that low circEPS15 levels were associated with poor overall survival in HCC patients. Then, the overexpression of circEPS15 suppressed tumor cell invasion and migration by inhibiting the TJP1/CDH2/VIM signaling pathway and retarded cell cycle progression, which was confirmed by the Transwell culture system, wound healing assays, flow cytometry and western blot assays. After that, the spanning junction open reading frame in circEPS15 driven by IRES was shown to encode a novel protein, which was verified by western blotting with full-length, mutated, and truncated sequences of circEPS15 with a FLAG tag. Moreover, ceRNA analysis and qRT-PCR results suggest a possible circRNA (circEPS15)-miRNA-mRNA network in HCC. Collectively, our study reveals that endogenous circEPS15 plays a novel role in repressing HCC through the ceRNA network and encodes a functional protein.

Development and Validation of a Dynamic Prediction Model for Massive Hemorrhage in Trauma.

Objectives: Early warning prediction of massive hemorrhages can greatly reduce mortality in trauma patients. This study aimed to develop and validate dynamic prediction models for massive hemorrhage in trauma patients. Methods: Based on vital signs (e.g., heart rate, respiratory rate, pulse pressure, and peripheral oxygen saturation) time-series data and the gated recurrent unit algorithm, we characterized a group of models to flexibly and dynamically predict the occurrence of massive hemorrhages in the subsequent T hours (where T = 1, 2, and 3). Models were evaluated in terms of accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and the area under the curve (AUC). Results: Results show that of the 2205 trauma patients selected for model development, a total of 265 (12.02%) had a massive hemorrhage. The AUCs of the model in the 1-h-group, 2-h-group, and 3-h-group were 0.763 (95% CI: 0.708-0.820), 0.775 (95% CI: 0.728-0.823), and 0.756 (95% CI: 0.715-0.797), respectively. Finally, the models were used in a web calculator and information system for the hospital emergency department. Conclusions: This study developed and validated a group of dynamic prediction models based on vital sign time-series data and a deep-learning algorithm to assist medical staff in the early diagnosis and dynamic prediction of a future massive hemorrhage in trauma.

Cyclic-di-AMP Phosphodiesterase Elicits Protective Immune Responses Against Mycobacterium tuberculosis H37Ra Infection in Mice.

Many antigens from Mycobacterium tuberculosis (M. tuberculosis) have been demonstrated as strong immunogens and proved to have application potential as vaccine candidate antigens. Cyclic di-AMP (c-di-AMP) as a bacterial second messenger regulates various bacterial processes as well as the host immune responses. Rv2837c, the c-di-AMP phosphodiesterase (CnpB), was found to be relative to virulence of M. tuberculosis and interference with host innate immune response. In this study, recombinant CnpB was administered subcutaneously to mice. We found that CnpB had strong immunogenicity and induced high levels of humoral response and lung mucosal immunity after M. tuberculosis intranasally infection. CnpB immunization stimulated splenocyte proliferation and the increasing number of activated NK cells but had little effects on Th1/Th2 cellular immune responses in spleens. However, CnpB induced significant Th1/Th2 cellular immune responses with a decreased number of T and B cells in the lungs, and significantly recruits of CD4+ and CD8+ T cells after M. tuberculosis attenuated strain H37Ra infection. Besides, we first reported that CnpB could stimulate IFN-ß expression transitorily and inhibit the autophagy of macrophages in vitro. In mice intranasally infection model, CnpB immunization alleviated pathological changes and reduced M. tuberculosis H37Ra loads in the lungs. Thus, our results suggested that CnpB interferes with host innate and adaptive immune responses and confers protection against M. tuberculosis respiratory infection, which should be considered in vaccine development as well as a drug target.

Multiple Mechanistic Action of Brevinin-1FL Peptide against Oxidative Stress Effects in an Acute Inflammatory Model of Carrageenan-Induced Damage.

Amphibian skin is acknowledged to contain an antioxidant system composed of various gene-encoded antioxidant peptides, which exert significant effects on host defense. Nevertheless, recognition of such peptides is in its infancy so far. Here, we reported the antioxidant properties and underlying mechanism of a new antioxidant peptide, brevinin-1FL, identified from Fejervarya limnocharis frog skin. The cDNA sequence encoding brevinin-1FL was successfully cloned from the total cDNA of F. limnocharis and showed to contain 222 bp. The deduced mature peptide sequence of brevinin-1FL was FWERCSRWLLN. Functional analysis revealed that brevinin-1FL could concentration-dependently scavenge ABTS+, DPPH, NO, and hydroxyl radicals and alleviate iron oxidation. Besides, brevinin-1FL was found to show neuroprotective activity by reducing contents of MDA and ROS plus mitochondrial membrane potential, increasing endogenous antioxidant enzyme activity, and suppressing H2O2-induced death, apoptosis, and cycle arrest in PC12 cells which were associated with its regulation of AKT/MAPK/NF-κB signal pathways. Moreover, brevinin-1FL relieved paw edema, decreased the levels of TNF-α, IL-1ß, IL-6, MPO, and malondialdehyde (MDA), and restored catalase (CAT) and superoxide dismutase (SOD) activity plus glutathione (GSH) contents in the mouse injected by carrageenan. Together, these findings indicate that brevinin-1FL as an antioxidant has potent therapeutic potential for the diseases induced by oxidative damage. Meanwhile, this study will help us further comprehend the biological functions of amphibian skin and the mechanism by which antioxidants protect cells from oxidative stress.

Antimicrobial and Anti-inflammatory Effects of a Novel Peptide From the Skin of Frog Microhyla pulchra.

Brevinins are an important antimicrobial peptide (AMP) family identified in the skin of Ranidae frogs and generally contain a characteristic ranabox structure at their C-terminal sequence. Herein a novel AMP named brevinin-2MP has been identified from the skin of the frog Microhyla pulchra by molecular cloning. Brevinin-2MP (GVITDTLKGVAKTVAAELLRKAHCKLTNSC) with a high amphipathic α-helix in sodium dodecyl sulfate solutions can destroy bacterial cell membrane and kill microbes. Furthermore, brevinin-2MP has been found to inhibit the lipopolysaccharide (LPS)-induced expression of pro-inflammatory NO, MCP-1, IL-6, and TNF-α via binding unidentified targets on the cell membrane and consequently suppressing the activation of MAPK/NF-κB signaling cascades induced by LPS in RAW 264.7 cells. Consistently, brevinin-2MP significantly alleviates the acute inflammatory response in carrageenan-induced mice paw. In conclusion, brevinin-2MP with anti-inflammatory and antimicrobial properties will be an ideal candidate drug molecule for bacterial inflammation treatment.

The Protective Effects of Cath-MH With Anti-Propionibacterium Acnes and Anti-Inflammation Functions on Acne Vulgaris.

Acne vulgaris is a common adolescent skin condition which is mainly caused by Propionibacterium acnes overcolonization and subsequent inflammation. Our previous studies have demonstrated that Cath-MH, an antimicrobial peptide from the skin of the frog Microhyla heymonsivogt, possesses potential antimicrobial, LPS-binding, and anti-septicemic properties. However, its protective effects and potential mechanisms against acne vulgaris are still unclear. In the present study, its anti-P. acnes effects were measured by two-fold broth dilution method, agglutination assay, scanning electron microscopy and confocal laser scanning microscopy experiments. Its treatment potential for acne vulgaris was further evaluated in mice ear inoculated by P. acnes. In addition, the binding ability between Cath-MH and LTA was measured by the Circular Dichroism and antibacterial assay. Moreover, the anti-inflammatory efficiency of Cath-MH was evaluated in LTA- and LPS-induced RAW 264.7 macrophage cells. Cath-MH was found to kill P. acnes with a MIC value of about 1.56 µM by membrane disruption mechanism. It also exhibited agglutination activity against P. acnes. Cath-MH was able to bind LTA as well as LPS, inhibit LTA/LPS-stimulated TLR2/4 expression, and subsequently decreased the inflammatory response in RAW 264.7 cells. As expected, Cath-MH alleviated the formation of edema and the infiltration of inflammatory cells in acne mouse model with concurrent suppression of P. acnes growth and inflammatory cytokines expression in vivo. The potent P. acnes inhibition activity combined with powerful anti-inflammatory effect of Cath-MH indicates its potential as a novel therapeutic option for acne vulgaris.

FM-CATH, A Novel Cathelicidin From Fejervarya Multistriata, Shows Therapeutic Potential for Treatment of CLP-Induced Sepsis.

Sepsis is an exacerbated inflammatory reaction induced by severe infection. As important defensive molecules in innate immunity, several AMPs are reported to prevent septic shock. In this study, we characterized a novel cathelicidin, FM-CATH, from the frog skin of F. multistriata. FM-CATH was found to adopt an amphipathic α-helix structural in membrane-mimetic environments and possess favorable antimicrobial effects against bacteria and fungus. In addition, it triggered the agglutination of bacteria. It could also strongly bind to LPS and LTA. Additionally, FM-CATH affected the enzymatic activities of thrombin, plasmin, ß-tryptase, and tPA, leading to coagulation inhibition in vitro and in vivo. Finally, we observed that FM-CATH improved survival rate and inhibited pathological alteration, bacterial count, serum biochemistry, and pro-inflammatory cytokine expression in the cecal ligation and puncture-induced sepsis mice. Taken together, these findings suggest that FM-CATH might be served as a promising agent for the treatment of sepsis.

Brevinin-2GHk, a Peptide Derived from the Skin of Fejervarya limnocharis, Inhibits Zika Virus Infection by Disrupting Viral Integrity.

Several years have passed since the Zika virus (ZIKV) pandemic reoccurred in 2015-2016. However, there is still a lack of proved protective vaccines or effective drugs against ZIKV. The peptide brevinin-2GHk (BR2GK), pertaining to the brevinin-2 family of antimicrobial peptides, has been reported to exhibit only weak antibacterial activity, and its antiviral effects have not been investigated. Thus, we analyzed the effect of BR2GK on ZIKV infection. BR2GK showed significant inhibitory activity in the early and middle stages of ZIKV infection, with negligible cytotoxicity. Furthermore, BR2GK was suggested to bind with ZIKV E protein and disrupt the integrity of the envelope, thus directly inactivating ZIKV. In addition, BR2GK can also penetrate the cell membrane, which may contribute to inhibition of the middle stage of ZIKV infection. BR2GK blocked ZIKV E protein expression with an IC50 of 3.408 ± 0.738 µΜ. In summary, BR2GK was found to be a multi-functional candidate and a potential lead compound for further development of anti-ZIKV drugs.

Impact of a Prior Nonpancreatic Malignancy on Survival Outcomes of Patients With Stage IV Pancreatic Neuroendocrine Tumor: A Population-Based and Propensity Score Matching Study.

OBJECTIVE: The aim of the study was to investigate the impact of a previous nonpancreatic malignancy on the survival outcomes in patients with a stage IV pancreatic neuroendocrine tumor (PanNET). METHODS: The Surveillance, Epidemiology, and End Results database was reviewed, and patients diagnosed with a stage IV PanNET between 2004 and 2015 were selected. Patients were divided into 2 groups according to the presence or absence of a previous nonpancreatic malignancy. Clinicopathological characteristics and survival outcomes were compared. RESULTS: A total of 1582 patients with stage IV PanNET were identified, of whom 116 (7.3%) had a prior malignancy. Prostate (33.62%), breast (17.24%), and gastrointestinal (12.07%) malignancies were the most common. Most prior malignancies (84.48%) were localized and regional. Patients with intervals of 36 months or less, 36 to 60 months, 60 to 120 months, and more than 120 months account for 25.86%, 14.66%, 31.03%, and 28.45% of all cases, respectively. Before and after propensity score matching, there was no significant difference detected regarding survival outcomes. CONCLUSIONS: Stage IV PanNET patients with a history of a prior cancer had comparable survival outcomes with patients without such history. These patients could be candidates for clinical trials if otherwise appropriate, and aggressive and potentially curative therapies should be offered.