Particulate matter facilitates amphiregulin-dependent lung cancer proliferation through glutamine metabolism.

Although many cohort studies have reported that long-term exposure to particulate matter (PM) causes lung cancer, the molecular mechanisms underlying the PM-induced increases in lung cancer progression remain unclear. We applied the lung cancer cell line A549 (Parental; A549.Par) to PM for an extended period to establish a mimic PM-exposed lung cancer cell line, A549.PM. Our results indicate that A549.PM exhibits higher cell growth and proliferation abilities compared to A549.Par cells in vitro and in vivo. The RNA sequencing analysis found amphiregulin (AREG) plays a critical role in PM-induced cell proliferation. We observed that PM increases AREG-dependent lung cancer proliferation through glutamine metabolism. In addition, the EGFR/PI3K/AKT/mTOR signaling pathway is involved in PM-induced solute carrier family A1 member 5 (SLC1A5) expression and glutamine metabolism. Our findings offer important insights into how lung cancer proliferation develops upon exposure to PM.

Chlorogenic acid prevents ovariectomized-induced bone loss by facilitating osteoblast functions and suppressing osteoclast formation.

Osteoporosis is a usual bone disease in aging populations, principally in postmenopausal women. Anti-resorptive and anabolic drugs have been applied to prevent and cure osteoporosis and are associated to a different of adverse effects. Du-Zhong is usually applied in Traditional Chinese Medicine to strengthen bone, regulate bone metabolism, and treat osteoporosis. Chlorogenic acid is a major polyphenol in Du-Zhong. In the current study, chlorogenic acid was found to enhance osteoblast proliferation and differentiation. Chlorogenic acid also inhibits the RANKL-induced osteoclastogenesis. Notably, ovariectomy significantly decreased bone volume and mechanical properties in the ovariectomized (OVX) rats. Administration of chlorogenic acid antagonized OVX-induced bone loss. Taken together, chlorogenic acid seems to be a hopeful molecule for the development of novel anti-osteoporosis treatment.

CXCL13 promotes TNF-α synthesis in rheumatoid arthritis through activating ERK/p38 pathway and inhibiting miR-330-3p generation.

Rheumatoid arthritis (RA) is a well-known autoimmune disorder associated with joint pain, joint swelling, cartilage and bone degradation as well as deformity. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays a crucial role in multiple cellular pathogenesis processes, including RA. TNF-α is a vital proinflammatory factor in the progression of RA. However, the role of CXCL13 in TNF-α production in RA has not been fully explored. Our analysis of both database and clinical samples revealed higher levels of CXCL13 and TNF-α in RA samples compared to healthy controls. CXCL13 concentration-dependently induces TNF-α synthesis in RA synovial fibroblasts. CXCL13 enhances TNF-α expression by interacting with the CXCR5 receptor, activating the ERK/p38 pathways, and inhibiting miR-330-3p generation. Importantly, treatment with CXCL13 shRNA counteracted the upregulation of TNF-α production induced by collagen-induced arthritis. Our findings support the notion that CXCL13 is a promising target in the treatment of RA.

FGF23 facilitates IL-1ß synthesis in rheumatoid arthritis through activating PI3K, Akt, and NF-κB pathways.

Rheumatoid arthritis (RA) is a well-known autoimmune disorder related with joint pain, joint swelling, cartilage and bone degradation as well as deformity. Fibroblast growth factor 23 (FGF23) is an endocrine factor of the FGF family primarily produced by osteocytes and osteoblasts, involves an essential effect in pathogenesis of RA. IL-1ß is a vital proinflammatory factor in the development of RA. However, the role of FGF23 on IL-1ß synthesis in RA has not been fully explored. Our analysis of database revealed higher levels of FGF23 and IL-1ß in RA samples compared with healthy controls. High-throughput screening demonstrated that IL-1ß is a potential candidate factor after FGF23 treatment in RA synovial fibroblasts (RASFs). FGF23 concentration dependently promotes IL-1ß synthesis in RASFs. FGF23 enhances IL-1ß expression by activating the PI3K, Akt, and NF-κB pathways. Our findings support the notion that FGF23 is a promising target in the remedy of RA.

High-mobility group box-1 impedes skeletal muscle regeneration via downregulation of Pax-7 synthesis by increasing miR-342-5p expression.

High mobility group box-1 (HMGB1) is a driver of inflammation in various muscular diseases. In a previous study, we determined that HMGB1 induced the atrophy of skeletal muscle by impairing myogenesis. Skeletal muscle regeneration after injury is dependent on pair box 7 (Pax-7)-mediated myogenic differentiation. In the current study, we determined that the HMGB1-induced downregulation of Pax-7 expression in myoblasts inhibited the regeneration of skeletal muscle. We also determined that HMGB1 inhibits Pax-7 and muscle differentiation by increasing miR-342-5p synthesis via receptors for advanced glycation end-products (RAGE), toll-like receptor (TLR) 2, TLR4, and c-Src signaling pathways. In a mouse model involving glycerol-induced muscle injury, the therapeutic inhibition of HMGB1 was shown to rescue Pax-7 expression and muscle regeneration. The HMGB1/Pax-7 axis is a promising therapeutic target to promote muscular regeneration.

mAb therapy controls CNS-resident lyssavirus infection via a CD4 T cell-dependent mechanism.

Infections with rabies virus (RABV) and related lyssaviruses are uniformly fatal once virus accesses the central nervous system (CNS) and causes disease signs. Current immunotherapies are thus focused on the early, pre-symptomatic stage of disease, with the goal of peripheral neutralization of virus to prevent CNS infection. Here, we evaluated the therapeutic efficacy of F11, an anti-lyssavirus human monoclonal antibody (mAb), on established lyssavirus infections. We show that a single dose of F11 limits viral load in the brain and reverses disease signs following infection with a lethal dose of lyssavirus, even when administered after initiation of robust virus replication in the CNS. Importantly, we found that F11-dependent neutralization is not sufficient to protect animals from mortality, and a CD4 T cell-dependent adaptive immune response is required for successful control of infection. F11 significantly changes the spectrum of leukocyte populations in the brain, and the FcRγ-binding function of F11 contributes to therapeutic efficacy. Thus, mAb therapy can drive potent neutralization-independent T cell-mediated effects, even against an established CNS infection by a lethal neurotropic virus.

Ugonin L inhibits osteoclast formation and promotes osteoclast apoptosis by inhibiting the MAPK and NF-κB pathways.

Bone loss is a major issue for patients with osteoporosis, arthritis, periodontitis, and bone metastasis; however, anti-resorption drugs used to treat bone loss have been linked to a variety of adverse effects. Helminthostachys zeylanica (L.) Hook, belonging to the family Ophioglossaceae, is commonly used in traditional Chinese medicine to treat inflammation and liver problems. In the current study, ugonin L extracted from H. zeylanica was shown to reduce the receptor activator of nuclear factor kappa beta ligand (RANKL)-induced osteoclastogenesis in RAW264.7 cells in a concentration-dependent manner. Ugonin L treatment also inhibited the mRNA expression of osteoclast markers. Ugonin L was also shown to promote cell apoptosis in mature osteoclasts and suppress RANKL-induced ERK, p38, JNK, and NF-κB activation. Taken together, ugonin L appears to be a promising candidate for the development of novel anti-resorption therapies.

HMGB1 Promotes In Vitro and In Vivo Skeletal Muscle Atrophy through an IL-18-Dependent Mechanism.

Skeletal muscle atrophy occurs due to muscle wasting or reductions in protein associated with aging, injury, and inflammatory processes. High-mobility group box-1 (HMGB1) protein is passively released from necrotic cells and actively secreted by inflammatory cells, and is implicated in the pathogenesis of various inflammatory and immune diseases. HMGB1 is upregulated in muscle inflammation, and circulating levels of the proinflammatory cytokine interleukin-18 (IL-18) are upregulated in patients with sarcopenia, a muscle-wasting disease. We examined whether an association exists between HMGB1 and IL-18 signaling in skeletal muscle atrophy. HMGB1-induced increases of IL-18 levels enhanced the expression of muscle atrophy markers and inhibited myogenic marker expression in C2C12 and G7 myoblast cell lines. HMGB1-induced increases of IL-18 production in C2C12 cells involved the RAGE/p85/Akt/mTOR/c-Jun signaling pathway. HMGB1 short hairpin RNA (shRNA) treatment rescued the expression of muscle-specific differentiation markers in murine C2C12 myotubes and in mice with glycerol-induced muscle atrophy. HMGB1 and IL-18 signaling was suppressed in the mice after HMGB1 shRNA treatment. These findings suggest that the HMGB1/IL-18 axis is worth targeting for the treatment of skeletal muscle atrophy.

Integrated Medicine for Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of typical chemotherapeutics among cancer survivors. Despite the recent progress, the effective prevention and treatment strategies for CIPN remain limited. Better understanding of the pathogenesis of CIPN may provide new niches for developing a new ideal therapeutic strategy. This review summarizes the current understanding of CIPN and current recommendations along with completed/active clinical trials and aims to foster translational research to improve the development of effective strategies for managing CIPN.

Sero-evaluation of Immune Responses to Vibrio cholerae in a Postelimination Setting.

Cholera remains a significant public health problem worldwide. In settings of declining incidence, serosurveillance may be used to augment clinical surveillance. We utilized dried blood spot sampling and cholera-specific antibody testing to examine the serologic profiles of vaccinated and unvaccinated children in southern Vietnam, where cholera was recently eliminated.

Monitoring fine root growth to identify optimal fertilization timing in a forest plantation: A case study in Northeast Vietnam.

Fertilizer is applied widely to improve the productivity of plantations. Traditionally, fertilization is conducted in spring and/or in the early rainy season, and it is believed to support the growth of planted trees in the growing season. Little attention to date has been paid on identification of the optimal timing of fertilization and fertilizer dose. In this study, application of the fine root monitoring technique in identifying optimal fertilization timing for an Acacia plantation in Vietnam is described. The study used two fertilizer doses (100 and 200 g NPK/tree) and three fertilization timings (in spring; in the early rainy season; and based on the fine root monitoring technique to identify when the fine roots reach their growth peak). As expected fertilization timings significantly affected growth and above-ground biomass (AGB) of the plantation. Fertilization based on the fine root monitoring technique resulted in the highest growths and AGB, followed by fertilization in the early rainy season and then in spring. Applying fertilizer at 200 g NPK/tree based on the fine root monitoring technique increased diameter at breast height (DBH) by 16%, stem height by 8%, crown diameter (Dc) by 16%, and AGB by 40% as compared to early rainy season fertilization. Increases of 32% DBH, 23% stem height, 44% Dc, and 87% AGB were found in fertilization based on fine root monitoring technique compared to spring fertilization. This study concluded that forest growers should use the fine root monitoring technique to identify optimal fertilization timing for higher productivity.

Association of Human Leukocyte Antigen Haplotypes With End-Stage Renal Disease in Vietnamese Patients Prior to First Transplantation.

INTRODUCTION: The prevalence of chronic kidney failure is significantly increasing in Vietnam, causing a burden for health care. This study assessed the relationship of HLA-A, -B, and -DRB1 alleles with end-stage renal disease (ESRD). METHOD: A retrospective, cross-sectional study and a comparative study using secondary data analysis were conducted on 196 ESRD patients and 187 controls from 2009 to 2017. The patient and donor profiles were collected from medical records, including age, sex, etiology of renal failure, and HLA phenotypes. HLA-A*, -B*, and -DRB1* typing were done by polymerase chain reaction-sequence specific primers. RESULT: The most frequent HLA alleles in Vietnamese patients with ESRD were HLA-A*02, -A*11, -B*15, -B*46, -DRB1*04, -DRB1*09, and -DRB1*12. The haplotypes HLA-A*0233 (odds ratio [OR] = 0.40, 95% CI: 0.15-0.98) had a negative association for ESRD. The haplotypes HLA-B*1515 (OR = 4.14, 95% CI: 1.52-11.26) and HLA-DRB1*1212 (OR = 2.01, 95% CI: 1.06-3.81) had a positive association for ESRD. The haplotypes HLA-B*1515 (OR = 4.69, 95% CI: 1.69-13.03) and -DRB1*1212 (OR = 2.15, 95% CI: 1.10-4.21) had a positive association for ESRD related to glomerulonephritis. The HLA-B*1557 (OR = 17.34, 95% CI: 2.70-11.49) had a positive association for ESRD related to hypertension. CONCLUSION: The haplotypes of HLA class I and II had significant relationships with ESRD. The results of our study should be confirmed in further investigations.

Role of Phenol-Soluble Modulins in Staphylococcus epidermidis Biofilm Formation and Infection of Indwelling Medical Devices.

Phenol-soluble modulins (PSMs) are amphipathic, alpha-helical peptides that are secreted by staphylococci in high amounts in a quorum-sensing-controlled fashion. Studies performed predominantly in Staphylococcus aureus showed that PSMs structure biofilms, which results in reduced biofilm mass, while it has also been reported that S. aureus PSMs stabilize biofilms due to amyloid formation. We here analyzed the roles of PSMs in in vitro and in vivo biofilms of Staphylococcus epidermidis, the leading cause of indwelling device-associated biofilm infection. We produced isogenic deletion mutants for every S. epidermidis psm locus and a sequential deletion mutant in which production of all PSMs was abolished. In vitro analysis substantiated the role of all PSMs in biofilm structuring. PSM-dependent biofilm expansion was not observed, in accordance with our finding that no S. epidermidis PSM produced amyloids. In a mouse model of indwelling device-associated infection, the total psm deletion mutant had a significant defect in dissemination. Notably, the total psm mutant produced a significantly more substantial biofilm on the implanted catheter than the wild-type strain. Our study, which for the first time directly quantified the impact of PSMs on biofilm expansion on an implanted device, shows that the in vivo biofilm infection phenotype in S. epidermidis is in accordance with the PSM biofilm structuring and detachment model, which has important implications for the potential therapeutic application of quorum-sensing blockers.

Estimation of the standardized ileal digestible lysine requirement and optimal sulphur amino acids to lysine ratio for 30-50 kg pigs.

Two experiments were conducted to determine the standardized ileal digestible (SID) lysine (Lys) requirement and the ideal SID sulphur amino acids (SAA) to Lys ratio for 30-50 kg crossbred pigs. In experiment 1, a total of 72 crossbred pigs with an average initial body weight (BW) of 28.9 kg were allotted to one of six dietary treatments in a randomized complete block design. Each diet was assigned to six pens containing two pigs each. Six diets were obtained by supplementing graded levels of L-Lysine∙HCl to create six dietary levels of SID Lys (0.70%, 0.80%, 0.90%, 1.00%, 1.10% and 1.20%). Responses of weight gain (ADG) and gain:feed (G:F) to increasing the SID Lys content of the diet fitted well with the curvilinear-plateau model; whereas, for plasma urea nitrogen (PUN) two-slope linear broken-line model was well fitted. The optimal SID Lys requirement for the pigs of this period was 1.10%. Experiment 2 was a dose-response study using SID Met+Cys to Lys ratios of 50%, 55%, 60%, 65%, 70% and 64%. A total of 72 crossbred pigs with initial BW of 32.9 kg were randomly allotted to receive one of the six diets. Diets 1-5 were formulated to contain 1.0% SID Lys to be second limiting in Lys and diet 6 contained 1.11% SID Lys to be adequate in Lys. The average optimal SID SAA:Lys ratio for maximal ADG and G:F and minimal PUN was 65.2% using curvilinear-plateau and linear broken-line models.

The Incidence of Ocular Injuries in Isolated Orbital Fractures.

BACKGROUND: Prompt identification of significant ocular injuries in patients who sustain an orbital fracture is important to prevent any potential long-term visual sequelae. The true incidence of these injuries has not been determined, however. As a consequence, most surgeons choose to have all patients evaluated by an ophthalmologist. The objective of this study was to conclusively identify the incidence of significant ocular injuries in patients with isolated orbital fractures and to determine their predictors to guide more efficient patient care. METHODS: A prospective cohort study powered to detect a 15% incidence of ocular injuries was designed. All patients presenting to our center with computed tomography findings of an isolated orbital fracture were included and evaluated by plastic surgery and ophthalmology services. Patients were followed up for a minimum of 1 week to identify any delayed injuries. RESULTS: Eighty patients were enrolled from 2012 to 2014. There were 46 men and 34 women with a mean age of 42.8 years. Assault was the most common mechanism of injury. There were 8 ocular injuries (10%): ruptured globe (1), uveal prolapse (1), retrobulbar hemorrhage (2), hyphema (2), hemorrhagic glaucoma with hyphema (1), and scleral tear (1). Predictors for significant ocular injuries were grossly abnormal visual acuity and abnormal pupillary reactivity of the affected eye. CONCLUSIONS: The incidence of significant ocular injuries in isolated orbital fractures is lower than previously reported. Patients presenting with grossly abnormal visual acuity or abnormal pupillary reactivity are at high risk and should receive prompt ophthalmology service evaluation.

Safety of Outpatient Isolated Orbital Floor Fracture Repair.

Orbital fractures are common, accounting for nearly 40% of all facial fractures. Open repair is required to restore preinjury orbital volume and relieve any extra-ocular muscle entrapment. Monitoring for postoperative intraorbital hemorrhage, and its consequent potential for visual impairment, has triggered most surgeons to observe their patients in the hospital overnight postoperatively. The real risk of postoperative hemorrhage in this patient group, however, is uncertain and the need to contain healthcare costs clear. The objective of this study was thus to determine the incidence of emergent postoperative complications in patients undergoing orbital fracture repair to determine the feasibility of performing this operation on an outpatient basis. Patients who sustained isolated orbital fractures and underwent open repair at this level-1 trauma center between January 2002 and January 2012 using International Classification of Disease-9 and Current Procedural Terminology 2012 coding were identified. Demographic data and postoperative complications were identified by reviewing the electronic medical record. Furthermore, critical analysis of available published evidence was performed. Ninety-three patients who satisfied the inclusion criteria were selected. There were no patients of an intraorbital hematoma or other immediate postoperative complications that required operative intervention. Average hospital length of stay was 0.85 days. Repair of orbital fractures on an outpatient basis appears to be safe. The theoretical risk of a complicating intraorbital hematoma seems to be between 0 and 3.2%. This can be minimized through: the use of open surgical access site and perforated floor replacement materials, careful early monitoring, education of patients, and admission of those at potentially elevated risk.

International Programs in the Education of Residents: Benefits for the Resident and the Home Program.

There is a significant need for basic surgical care worldwide. In recent years, modest improvement in fulfilling this demand has been achieved through international medical mission trips from various organizations. These humanitarian endeavors and global health experiences have generated increasing interest in participating in international missions from surgical residents. However, many academic institutions currently do not have the infrastructure or desire to support surgical residents participating in medical missions. This paper aims to illustrate that careful, planned integration of medical mission trips into the residency curriculum will develop and enhance resident education and experience by fulfilling all six Accreditation Council for Graduate Medical Education (ACGME) core competencies and by benefitting the native program.

The Present Status of Global Mission Trips in Plastic Surgery Residency Programs.

OBJECTIVE: The present status of global mission trips of all of the academic Plastic Surgery programs was surveyed. We aimed to provide information and guidelines for other interested programs on creating a global health elective in compliance with American Board of Plastic Surgery (ABPS) and Accreditation Council for Graduate Medical Education Residency Review Committee (ACGME/RRC) requirements. DESIGN: A free-response survey was sent to all of the Plastic Surgery Residency program directors inquiring about their present policy on international mission trips for residents and faculty. Questions included time spent in mission, cases performed, sponsoring organizations, and whether cases are being counted in their resident Plastic Surgery Operative Logs (PSOL). RESULTS: Thirty-one programs responded, with 23 programs presently sponsoring international mission trips. Thirteen programs support residents going on nonprogram-sponsored trips where the majority of these programs partner with outside organizations. Many programs do not count cases performed on mission trips as part of ACGME index case requirement. Application templates for international rotations to comply with ABPS and ACGME/RRC requirements were created to facilitate the participation of interested programs. CONCLUSIONS: Many Plastic Surgery Residency programs are sponsoring international mission trips for their residents; however, there is a lack of uniformity and administrative support in pursuing these humanitarian efforts. The creation of a dynamic centralized database will help interested programs and residents seek out the global health experience they desire and ensure standardization of the educational experience they obtain during these trips.

Molecular determinants of staphylococcal biofilm dispersal and structuring.

Staphylococci are frequently implicated in human infections, and continue to pose a therapeutic dilemma due to their ability to form deeply seated microbial communities, known as biofilms, on the surfaces of implanted medical devices and host tissues. Biofilm development has been proposed to occur in three stages: (1) attachment, (2) proliferation/structuring, and (3) detachment/dispersal. Although research within the last several decades has implicated multiple molecules in the roles as effectors of staphylococcal biofilm proliferation/structuring and detachment/dispersal, to date, only phenol soluble modulins (PSMs) have been consistently demonstrated to serve in this role under both in vitro and in vivo settings. PSMs are regulated directly through a density-dependent manner by the accessory gene regulator (Agr) system. They disrupt the non-covalent forces holding the biofilm extracellular matrix together, which is necessary for the formation of channels, a process essential for the delivery of nutrients to deeper biofilm layers, and for dispersal/dissemination of clusters of biofilm to distal organs in acute infection. Given their relevance in both acute and chronic biofilm-associated infections, the Agr system and the psm genes hold promise as potential therapeutic targets.

Production of an attenuated phenol-soluble modulin variant unique to the MRSA clonal complex 30 increases severity of bloodstream infection.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSMα3 peptide. We found that this variant, PSMα3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSMα3. Our findings describe a molecular mechanism contributing to attenuated pro-inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms.