Fecal Pharmacokinetics and Gut Microbiome Effects of Oral Omadacycline Versus Vancomycin in Healthy Volunteers.

BACKGROUND: Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults. METHODS: This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations were assessed, and microbiome changes were compared. RESULTS: Sixteen healthy volunteers with a mean age of 26 (standard deviation [SD], 5) years were enrolled; 62.5% were male, and participants' mean body mass index was 23.5 (SD, 4.0) kg/m2. Omadacycline was well tolerated with no safety signal differences between the 2 antibiotics. A rapid initial increase in fecal concentrations of omadacycline was observed compared to vancomycin, with maximum concentrations achieved within 48 hours. A significant difference in alpha diversity was observed following therapy in both the omadacycline and vancomycin groups (P < .05). Bacterial abundance and beta diversity analysis showed differing microbiome changes in subjects who received omadacycline versus vancomycin. CONCLUSIONS: Subjects given omadacycline had high fecal concentrations with a distinct microbiome profile compared to vancomycin. CLINICAL TRIALS REGISTRATION: NCT06030219.

Investigating and analyzing the current situation and factors influencing chronic neck, shoulder, and lumbar back pain among medical personnel after the epidemic.

BACKGROUND: Chronic shoulder and neck pain is one of the most common chronic occupational disorders, with an average incidence rate of 48.5%, severely affecting patients' quality of life and ability to work. According to epidemiological research, the prevalence of chronic neck, shoulder, and low back pain in adults over the age of 45 ranges from 40 to 80%. According to reports, medical staff have a higher incidence rate than other populations, and there is a positive correlation between the grade of the medical institution and the incidence rate, making medical staff a priority group for the prevention of chronic neck, shoulder, and low back pain. By the end of 2022, China has been fully opened to epidemic prevention and control, the total number of patients in domestic hospitals has increased significantly, and resulting in medical personnel shoulting great pressure, which seriously affects the physical and mental health of medical personnel. The aim of this study was to explore the risk factors of chronic neck, shoulder and lumbar back pain in medical staff. To provide guidelines for medical staff to improve cervical and lumbar subacute pain and reduce the emergence of spinal lesions. METHODS: From January to February 2023, 602 staff members of a third-grade hospital in Zunyi City were studied by Questionnaire star. Univariate and multivariate Logistic regression were used to analyze the independent risk factors of chronic neck, shoulder and lumbar back pain in medical staff, with stepwise regression utilized to choose the optimum model. The model was selected using Akaike's information criterion (AIC) and the Hosmer-Lemeshow goodness-of-fit test. RESULTS: A total of 602 medical staff were polled, and the findings revealed that 588 cases of chronic neck, shoulder, and low back pain of varied severity had occurred in the previous 1 to 2 years, with a 97.7% incidence rate; logistic regression analysis revealed that anxiety level, frequency of bending over in the previous 1 to 2 years, whether related preventive measures were taken at work, gender, positive senior title, daily ambulation time, and whether the department they worked in organized independent influencing factors. CONCLUSION: The incidence of chronic neck, shoulder, and lumbar back pain among medical staff is high; its influencing factors are different and have not been systematically identified. Hospitals should take effective measures tailored to local conditions to improve the physical and mental health of medical staff.

Elevated expression of CXCL3 in colon cancer promotes malignant behaviors of tumor cells in an ERK-dependent manner.

BACKGROUND: CXC chemokine ligand 3 (CXCL3) is a member of CXC-type chemokine family that is identified as a major regulator in immune and inflammation responses. Recently, numerous evidence indicated that CXCL3 is broadly expressed in various human tumor types, and it is also known to play a critical role in mediating tumor development and progression. However, the expression profile of CXCL3 and the exact molecular mechanism behind the role of CXCL3 in colon adenocarcinoma (COAD) has not been fully elucidated. METHODS: The expression and clinical significance of CXCL3 mRNA and protein in the tissues from COAD patients were estimated using bioinformatics and immunohistochemistry assays. The expression and roles of exogenous administration or overexpression of CXCL3 in HT-29 and SW480 COAD cells were determined using enzyme-linked immunosorbent assay(ELISA), Cell Counting Kit-8 (CCK-8) and Transwell assays. Mechanically, CXCL3-induced malignant behaviors were elucidated using western blotting assay and extracellular signal-regulated protein kinase 1/2 (ERk1/2) inhibitor PD98059. RESULTS: The cancer genome atlas (TCGA)-COAD data analysis revealed that CXCL3 mRNA is highly expressed and has high clinical diagnostic accuracy in COAD. Increased expression of CXCL3 mRNA was associated with patient's clinical stage, race, gender, age, histological subtype, nodal mestastasis and tumor protein 53 (TP53) mutation status. Similarly, immunohistochemistry assay also exhibited that CXCL3 protein in COAD tissues was significantly up-regulated. Gene expression associated assay implied that CXC chemokine ligand 1 (CXCL1) and CXC chemokine ligand 2 (CXCL2) were markedly correlated with CXCL3 in COAD. Protein-protein interaction (PPI) analysis revealed that cyclin B1 (CCNB1), mitotic arrest deficient 2 like 1 (MAD2L1), H2A family member Z (H2AFZ) and CXCL2 may be the important protein molecules involved in CXCL3-related tumor biology. Gene set enrichment analysis (GSEA) analysis revealed that CXCL3 was mainly enriched in the cell cycle, DNA replication, NOD-like receptors, NOTCH and transforming growth factor-ß (TGF-ß) Signal pathways. In vitro, exogenous administration or overexpression of CXCL3 resulted in increased malignant behaviors of HT-29 and SW480 cells, and down-regulation of CXCL3 expression inhibited the malignant behaviors of these tumor cells. In addition, overexpression of CXCL3 affected the expression of genes related to extracellular signal regulated kinase (ERK) pathway, including ERK1/2, p-ERK, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax) and Cyclin D1. Finally, CXCL3-induced malignant behaviors in HT-29 and SW480 cells were obviously attenuated following treatment with ERK inhibitor PD98059. CONCLUSION: CXCL3 is upregulated in COAD and plays a crucial role in the control of malignant behaviors of tumor cells, which indicated its involvement in the pathogenesis of COAD.

Prevention of myopia shift and myopia onset using 0.01% atropine in premyopic children - a prospective, randomized, double-masked, and crossover trial.

This study aims to evaluate the efficacy of 0.01% atropine eye drops in preventing myopia shift and myopia onset in premyopic children. A prospective, randomized, double-masked, placebo-controlled, and crossover trial was conducted over 13 months. Sixty premyopic children aged 6-12 years with cycloplegic spherical equivalent refraction (SER) > - 0.75 D and ≤ + 0.50 D in both eyes were assigned in a 1:1 ratio to receive one drop of 0.01% atropine or placebo once nightly for 6 months (period 1), followed by a 1-month recovery period. Then, the 0.01% atropine group was crossed over to the placebo group, and the latter was crossed over to the 0.01% atropine group for another 6 months (period 2). The primary outcomes were changes in SER and axial length (AL), and the secondary outcomes were the proportion of myopia onset (SER ≤ - 0.75D) and fast myopic shift (change in SER ≤ - 0.25D) in the two periods. Generalized estimating equation (GEE) model performed a statistically significant treatment effect of 0.01% atropine compared with placebo (pSER = 0.02, pAL < 0.001), with a mean SER and AL difference of 0.20D (- 0.15 ± 0.26D vs. - 0.34 ± 0.34D) and 0.11 mm (0.17 ± 0.11 mm vs. 0.28 ± 0.14 mm) in period 1, and 0.17D (- 0.18 ± 0.24D vs. - 0.34 ± 0.31D) and 0.10 mm (0.15 ± 0.15 mm vs. 0.24 ± 0.11 mm) in period 2. The GEE model showed that the proportion of myopia onset (p = 0.004) and fast myopic shift (p = 0.009) was significantly lower in the 0.01% atropine group than that in the placebo group. The period effect was not statistically significant (all p > 0.05). A total of 0.01% atropine significantly prevented myopic shift, axial elongation, and myopia onset in premyopic schoolchildren in central Mainland China. CONCLUSION: Within the limits of only two consecutive 6-month observation period, 0.01% atropine eye drops effectively prevented myopic shift, axial elongation, and myopia onset in premyopic children. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2000034760). Registered 18 July 2020. WHAT IS KNOWN: • Minimal studies on interventions for pre-myopia, despite the International Myopia Institute stating that preventing myopia is an "even more valuable target" for science and practice than reducing progression after onset. WHAT IS NEW: • A total of 0.01% atropine eye drops may safely and effectively reduce the proportion of myopia onset and fast myopic shift in premyopic schoolchildren.

Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial.

BACKGROUND: This study was the first human validation of the gram-positive bacterial DNA polymerase IIIC target in patients with Clostridioides difficile infection. The primary objectives were to assess clinical cure rates and adverse events (AEs). Secondary objectives were to evaluate plasma/fecal pharmacokinetics, microbiologic eradication, microbiome and bile acid effects, and sustained clinical cure (SCC) with ibezapolstat. METHODS: This single-arm, open-label, phase 2a study enrolled adults with C. difficile infection at 4 US centers. Patients received ibezapolstat 450 mg orally every 12 hours for 10 days and followed for an additional 28 days to assess study objectives. RESULTS: Ten patients with a mean (standard deviation [SD]) age of 49 [15] years were enrolled. Seven AEs were reported classified as mild-moderate. Plasma levels of ibezapolstat ranged from 233 to 578 ng/mL while mean (SD) fecal levels were 416 (494) µg/g stool by treatment day 3 and >1000 µg/g stool by days 8-10. A rapid increase in alpha diversity in the fecal microbiome was noted after starting ibezapolstat therapy, which was maintained after completion of therapy. A proportional decrease in Bacteroidetes phylum was observed (mean change [SD], -10.0% [4.8%]; P = .04) with a concomitantly increased proportion of Firmicutes phylum (+14.7% [5.4%]; P = .009). Compared with baseline, total primary bile acids decreased by a mean (SD) of 40.1 (9.6) ng/mg stool during therapy (P < .001) and 40.5 (14.1) ng/mg stool after completion of therapy (P = .007). Rates of both initial clinical cure and SCC at 28 days were 100% (10 of 10 patients). CONCLUSIONS: In this phase 2a study, 10 of 10 patients achieved SCC, demonstrated favorable pharmacokinetics, minimal AEs, and beneficial microbiome and bile acids results. These results support continued clinical development.

Functional and Metagenomic Evaluation of Ibezapolstat for Early Evaluation of Anti-Recurrence Effects in Clostridioides difficile Infection.

Reduction of Clostridioides difficile infection (CDI) recurrence is an essential endpoint for CDI-directed antibiotic development that is often not evaluated until Phase III trials. The purpose of this project was to use a functional and metagenomic approach to predict the potential anti-CDI recurrence effect of ibezapolstat, a DNA polymerase IIIC inhibitor, in clinical development for CDI. As part of the Phase I ibezapolstat clinical study, stool samples were collected from 22 healthy volunteers, who were given either ibezapolstat or vancomycin. Stool samples were evaluated for microbiome changes and bile acid concentrations. Ibezapolstat 450 mg and vancomycin, but not ibezapolstat 300 mg, showed statistically significant changes in alpha diversity over time compared to that of a placebo. Beta diversity changes confirmed that microbiota were significantly different between study groups. Vancomycin had a more wide-ranging effect on the microbiome, characterized by an increased proportion of Gammaproteobacteria. Ibezapolstat demonstrated an increased proportion of Actinobacteria, including the Bifidobacteriaceae family. Using a linear regression analysis, vancomycin was associated with significant increases in primary bile acids as well as primary:secondary bile acid ratios. An overabundance of Enterobacteriaceae was most highly correlated with primary bile acid concentrations (r = 0.63; P < 0.0001). Using Phase I healthy volunteer samples, beneficial changes suggestive of a lower risk of CDI recurrence were associated with ibezapolstat compared to vancomycin. This novel omics approach may allow for better and earlier prediction of anti-CDI recurrence effects for antibiotics in the clinical development pipeline.

Dyadobacter diqingensis sp. nov., isolated from Baima snow mountain of Diqing Tibetan Autonomous Prefecture in Yunnan province, south-west China.

A Gram-negative, aerobic, nonmotile, rod-shaped and yellow-pigment-producing bacteria was isolated from Baima snow mountain of Diqing Tibetan Autonomous Prefecture in Yunnan province, south-west China and characterized using a polyphasic approach. The results of 16S rRNA gene sequence similarity analysis showed that strain YIM B04101T was closely related to the type strain of Dyadobacter koreensis DSM 19938T (97.81%) and Dyadobacter frigoris AR-3-8T (97.95%). The predominant respiratory quinone was menaquinone-7 (MK-7). The major polar lipid was phosphatidylethanolamine. The major fatty acids were summed feature 3 (C16:1ω7c/C16:1ω6c), C18:1ω9c and C16:0. The DNA G + C content was 43.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain YIM B04101T belonged to a cluster comprising species of the genus Dyadobacter. However, it differed from its closest relative, Dyadobacter koreensis KCTC 12537T and Dyadobacter frigoris AR-3-8T, in many physiological properties. Based on these phenotypic characteristics and phylogenetic distinctiveness, strain YIM B04101T is considered to be a novel species of the genus Dyadobacter, for which the name Dyadobacter diqingensis sp. nov. is proposed. The type strain is YIM B04101T (= CGMCC 1.19249T = CCTCC AB 2021270).

Comprehensive analysis of CXCR family members in lung adenocarcinoma with prognostic values.

BACKGROUND: The expression profiles and molecular mechanisms of CXC chemokine receptors (CXCRs) in Lung adenocarcinoma (LUAD) have been extensively explored. However, the comprehensive prognostic values of CXCR members in LUAD have not yet been clearly identified. METHODS: Multiple available datasets, including Oncomine datasets, the cancer genome atlas (TCGA), HPA platform, GeneMANIA platform, DAVID platform and the tumor immune estimation resource (TIMER) were used to detect the expression of CXCRs in LUAD, as well as elucidate the significance and value of novel CXCRs-associated genes and signaling pathways in LUAD. RESULTS: The mRNA and/or protein expression of CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CXCR6 displayed predominantly decreased in LUAD tissues as compared to normal tissues. On the contrary, compared with the normal tissues, the expression of CXCR7 was significantly increased in LUAD tissues. Subsequently, we constructed a network including CXCR family members and their 20 related genes, and the related GO functions assay showed that CXCRs connected with these genes participated in the process of LUAD through several signal pathways including Chemokine signaling pathway, Cytokine-cytokine receptor interaction and Neuroactive ligand-receptor interaction. TCGA and Timer platform revealed that the mRNA expression of CXCR family members was significantly related to individual cancer stages, cancer subtypes, patient's gender and the immune infiltration level. Finally, survival analysis showed that low mRNA expression levels of CXCR2 (HR = 0.661, and Log-rank P = 1.90e-02), CXCR3 (HR = 0.674, and Log-rank P = 1.00e-02), CXCR4 (HR = 0.65, and Log-rank P = 5.01e-03), CXCR5 (HR = 0.608, and Log-rank P = 4.80e-03) and CXCR6 (HR = 0.622, and Log-rank P = 1.85e-03) were significantly associated with shorter overall survival (OS), whereas high CXCR7 mRNA expression (HR = 1.604, and Log-rank P = 4.27e-03) was extremely related with shorter OS in patients. CONCLUSION: Our findings from public databases provided a unique insight into expression characteristics and prognostic values of CXCR members in LUAD, which would be benefit for the understanding of pathogenesis, diagnosis, prognosis prediction and targeted treatment in LUAD.

Deletion of YJL218W reduces salt tolerance of Saccharomyces cerevisiae.

The YJL218W open reading frame may be involved in peroxisomal biogenesis. However, whether it mediates salt tolerance is unclear. We found that after knockdown of YJL218W in Saccharomyces cerevisiae (S. cerevisiae), its salt tolerance was reduced and cell death was increased. Transcriptome sequencing and analysis further revealed that YJL218W knockdown mediated significant changes in the expression of 1432 messenger RNA (mRNAs), of which 603 were upregulated. KEGG enrichment analysis and polymerase chain reaction (PCR) assay indicated that YJL218W mediated the regulation of peroxisome-related genes. Therefore, YJL218W may regulate salt stress in S. cerevisiae by regulating peroxisome assembly.

Antioxidant Properties of Hemp Proteins: From Functional Food to Phytotherapy and Beyond.

As one of the oldest plants cultivated by humans, hemp used to be banned in the United States but returned as a legal crop in 2018. Since then, the United States has become the leading hemp producer in the world. Currently, hemp attracts increasing attention from consumers and scientists as hemp products provide a wide spectrum of potential functions. Particularly, bioactive peptides derived from hemp proteins have been proven to be strong antioxidants, which is an extremely hot research topic in recent years. However, some controversial disputes and unknown issues are still underway to be explored and verified in the aspects of technique, methodology, characteristic, mechanism, application, caution, etc. Therefore, this review focusing on the antioxidant properties of hemp proteins is necessary to discuss the multiple critical issues, including in vitro structure-modifying techniques and antioxidant assays, structure-activity relationships of antioxidant peptides, pre-clinical studies on hemp proteins and pathogenesis-related molecular mechanisms, usage and potential hazard, and novel advanced techniques involving bioinformatics methodology (QSAR, PPI, GO, KEGG), proteomic analysis, and genomics analysis, etc. Taken together, the antioxidant potential of hemp proteins may provide both functional food benefits and phytotherapy efficacy to human health.

A comprehensive review of wheat phytochemicals: From farm to fork and beyond.

The health benefits of whole wheat consumption can be partially attributed to wheat's phytochemicals, including phenolic acids, flavonoids, alkylresorcinols, carotenoids, phytosterols, tocopherols, and tocotrienols. It is of increasing interest to produce whole wheat products that are rich in bioactive phytochemicals. This review provides the fundamentals of the chemistry, extraction, and occurrence of wheat phytochemicals and includes critical discussion of several long-lasting issues: (1) the commonly used nomenclature on distribution of wheat phenolic acids, namely, soluble-free, soluble-conjugated, and insoluble-bound phenolic acids; (2) different extraction protocols for wheat phytochemicals; and (3) the chemistry and application of in vitro antioxidant assays. This review further discusses recent advances on the effects of genotypes, environments, field management, and processing techniques including ultrafine grinding, germination, fermentation, enzymatic treatments, thermal treatments, and food processing. These results need to be interpreted with care due to varied sample preparation protocols and limitations of in vitro assays. The bioaccessibility, bioavailability, metabolism, and potential health benefits of wheat phytochemicals are also reviewed. This comprehensive and critical review will benefit scientific researchers in the field of bioactive compounds of cereal grains and also those in the cereal food industry to produce high-quality functional foods.

Optimizing pharmacokinetics/pharmacodynamics of ß-lactam/ß-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria.

OBJECTIVES: Reduced in vitro ß-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of ß-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a ß-lactamase inhibitor. We evaluated different ß-lactam/ß-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria. METHODS: Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating ß-lactamase inhibitor (tazobactam or avibactam) concentrations on ß-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of ß-lactam/ß-lactamase inhibitor combinations was predicted using %T>MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning. RESULTS: A concentration-dependent reduction in ß-lactam MIC was observed (r2 ≥0.93). Regrowth could be suppressed in all six experiments using %T>MICi ≥73.6%, but only one out of six experiments below the threshold (P = 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam. CONCLUSIONS: A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected ß-lactam/ß-lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.

CXCL3 overexpression affects the malignant behavior of oral squamous cell carcinoma cells via the MAPK signaling pathway.

OBJECTIVE: CXCL3, a member of the chemokine family, plays a key role in angiogenesis, tumorigenesis, and cell invasion and migration. However, the role of CXCL3 in oral squamous cell carcinoma (OSCC) remains unclear. The purpose of this study is to explore the expression of CXCL3 in OSCC and to explore the role of CXCL3 in human OSCC HSC-4 cells and its molecular mechanism. METHODS: The expression of CXCL3 in human OSCC tissues was assessed using immunohistochemistry and The Cancer Genome Atlas (TCGA) database. In vivo and in vitro experiments investigated the effects of CXCL3 on the proliferation, migration, and invasion of OSCC cells. RESULTS: The expression of CXCL3 in tumors is higher than that in normal tissues and is closely related to stage and lymph node metastasis. In vitro experiments showed that the proliferation and migration ability of HSC-4 cells treated with exogenous recombinant human CXCL3 and HSC-4 cells overexpressing CXCL3 were enhanced. Experiments on xenografts in nude mice showed that overexpression of CXCL3 promotes tumor growth in vivo. GSEA showed that patients with high expression of CXCL3 have varying degrees of enrichment in cytokine-cytokine receptor interaction, apoptosis, Jak-STAT signaling pathway, and MAPK signaling pathway. Subsequent mechanism studies showed that the use of ERK1/2 blocker PD98059 can attenuate the proliferation and migration effects induced by CXCL3. CONCLUSION: CXCL3 is involved in the occurrence of OSCC and may become a potential therapeutic target.

Comparison of Administration of 0.02% Atropine and Orthokeratology for Myopia Control.

OBJECTIVE: To compare the efficacies of 0.02% atropine eye drops and orthokeratology to control axial length (AL) elongation in children with myopia. METHODS: In this historical control study, 247 children with myopia whose administration of 0.02% atropine (n=142) or underwent orthokeratology from an earlier study (n=105, control group) were enrolled. Data on AL and other baseline parameters were recorded at baseline and after 1 and 2 years of treatment. RESULTS: The mean changes in AL in the first and second years of treatment were 0.30±0.21 and 0.28±0.20 mm, respectively, in the 0.02% atropine group and 0.16±0.20 and 0.20±0.16 mm, respectively, in the orthokeratology group. Axial length elongations after 2 years of treatment were 0.58±0.35 and 0.36±0.30 mm (P=0.007) in the 0.02% atropine and orthokeratology groups, respectively. Multivariate regression analyses showed that the AL elongation was significantly faster in the 0.02% atropine group than in the orthokeratology group (ß=0.18, P=0.009). In multivariate regression analyses, younger age and shorter baseline AL were associated with a rapid AL elongation in the 0.02% atropine group (ßage=-0.04, P=0.01; ßAL=-0.17, P=0.03), while younger age, lower baseline spherical equivalent refractive error (SER), and shorter baseline AL were associated with a greater increase in AL in the orthokeratology group (ßage=-0.03, P=0.04; ßSER=0.06, P=0.03; ßAL=-0.11, P=0.009). Faster AL elongation was found in the 0.02% atropine group compared with the orthokeratology group at higher baseline SER (P=0.04, interaction test). CONCLUSION: Within the limits of this study design, orthokeratology seems to be a better method for controlling AL elongation compared with administration of 0.02% atropine in children with higher myopia over a treatment period of 2 years.

SIMULTANEOUS IN VITRO SIMULATION OF MULTIPLE ANTIMICROBIAL AGENTS WITH DIFFERENT ELIMINATION HALF-LIVES IN A PRE-CLINICAL INFECTION MODEL.

Combination therapy for treatment of multi-drug resistant bacterial infections is becoming common. In vitro testing of drug combinations under realistic pharmacokinetic conditions is needed before a corresponding combination is eventually put into clinical use. The current standard for design of such in vitro simulations for drugs with different half-lives is heuristic and limited to two drugs. To address that void, we develop a rigorous design method suitable for an arbitrary number of N drugs with different half-lives. The method developed offers substantial flexibility and produces novel designs even for two drugs. Explicit design equations are rigorously developed and are suitable for immediate use by experimenters. These equations were used in experimental verification using a combination of three antibiotics with distinctly different half-lives. In addition to antibiotics, the method is applicable to any anti-infective or anti-cancer drugs with distinct elimination pharmacokinetics.

CXCL3 overexpression promotes the tumorigenic potential of uterine cervical cancer cells via the MAPK/ERK pathway.

CXCL3 belongs to the CXC-type chemokine family and is known to play a multifaceted role in various human malignancies. While its clinical significance and mechanisms of action in uterine cervical cancer (UCC) remain unclear. This investigation demonstrated that the UCC cell line HeLa expressed CXCL3, and strong expression of CXCL3 was detected in UCC tissues relative to nontumor tissues. In addition, CXCL3 expression was strongly correlated with CXCL5 expression in UCC tissues. In vitro, HeLa cells overexpressing CXCL3, HeLa cells treated with exogenous CXCL3 or treated with conditioned medium from WPMY cells overexpressing CXCL3, exhibited enhanced proliferation and migration activities. In agreement with these findings, CXCL3 overexpression was also associated with the generation of HeLa cell tumor xenografts in athymic nude mice. Subsequent mechanistic studies demonstrated that CXCL3 overexpressing influenced the expression of extracellular signal-regulated kinase (ERK) signaling pathway associated genes, including ERK1/2, Bcl-2, and Bax, whereas the CXCL3-induced proliferation and migration effects were attenuated by exogenous administration of the ERK1/2 blocker PD98059. The data of the current investigation support that CXCL3 appears to hold promise as a potential tumor marker and interference target for UCC.

Characterization of Amikacin Drug Exposure and Nephrotoxicity in an Animal Model.

Despite excellent in vitro activity, aminoglycosides are used conservatively to treat multidrug-resistant bacterial infections due to their associated nephrotoxicity. Aminoglycosides are known to accumulate in the kidneys, but the quantitative relationship between drug exposures and nephrotoxicity is not well established. To bridge the knowledge gap, the objective of this study was to develop an animal model with clinically relevant conditions to mimic human disease progression. Single-dose pharmacokinetics were studied in Sprague-Dawley rats dosed either with 100 or 500 mg/kg of body weight of amikacin subcutaneously. Serial blood samples were collected, and serum amikacin concentrations were measured using liquid chromatography tandem mass spectrometry. Rats were also dosed with amikacin once daily for up to 10 days; blood samples were taken at baseline and daily to detect nephrotoxicity (defined as doubling of serum creatinine from baseline). Kidneys from both studies were harvested from selected rats, and amikacin concentrations in renal tissues were measured. A dose-dependent increase in systemic area under the curve (AUC) was observed, which ranged from approximately 1/3 (AUC of 53 mg·h/liter) to 3 times (AUC of 650 mg·h/liter) the expected exposure resulting from standard dosing in humans. Nephrotoxicity was significantly higher in rats given 500 mg/kg (100% versus 30%, P = 0.003). Kaplan-Meier analysis also showed a significant difference in nephrotoxicity onset between the two groups (P = 0.001). Finally, analysis of the renal tissues showed that the accumulation of amikacin could be associated with nephrotoxicity. These results are consistent with clinical observations, which support using this model in the future to investigate an intervention(s) that can be used clinically to alleviate nephrotoxicity.

MiR-330-3p contributes to INS-1 cell dysfunction by targeting glucokinase in gestational diabetes mellitus.

AIMS: High-expressed miR-330-3p in gestational diabetes mellitus (GDM) patients was reported. However, the role and mechanism of miR-330-3p in GDM are rarely reported. In this research, we aim to investigate the effects of miR-330-3p on GDM. METHODS: MiR-330-3p expression in the GDM patients' blood was determined by q-PCR. Blood glucose of blood samples was detected using blood glucose detection kits. Glucokinase (GCK) was confirmed to be a target gene of miR-330-3p by bioinformatics and luciferase analysis. Correlations between miR-330-3p with GCK and blood glucose were analyzed by Pearson correlation analysis. After INS-1 cells were treated with glucose and transfected with mimic, inhibitor or siGCK, GCK expression was detected by western blot, and q-PCR, enzyme-linked immunosorbent assays, cell counting kit-8 and Annexin-V/propidium iodide were conducted to examine the expression of insulin, cell viability and apoptosis. RESULTS: MiR-330-3p was high-expressed in GDM patients' blood, while GCK was low-expressed. The miR-330-3p expression level positively correlated with blood glucoseand and it was highly expressed in glucose-treated INS-1 cells (11 and 22 mmol/L), while miR-330-3p expression negatively correlated with GCK expression. GCK expression was inhibited by miR-330-3p mimic and enhanced by the miR-330-3p inhibitor. MiR-330-3p mimic inhibited INS-1 cells' insulin expression, cell viability and induced apoptosis. Yet miR-330-3p inhibitor and siGCK exhibited opposite effects which miR-330-3p mimic and GCK played on INS-1 cells. In addition, siGCK reversed the effect of miR-330-3p inhibitor on INS-1 cells. CONCLUSION: Our findings proved that miR-330-3p targeting GCK lead to the dysfunction of INS-1 cells in GDM, and could become a therapeutic target for GDM treatment.

Influence Factors on Contrast Agent Venous Intravasation During Transvaginal 4-Dimensional Hysterosalpingo-Contrast Sonography.

OBJECTIVES: To explore the risk factors on contrast agent venous intravasation during transvaginal 4-dimensional hysterosalpingo-contrast sonography (TVS 4D-HyCoSy). METHODS: The TVS 4D-HyCoSy imaging data were collected from 276 female infertile patients. The correlation between endometrial thickness, days after menstruation, intrauterine intervention history, fallopian tubal patency degree, and contrast agent venous intravasation, respectively, was analyzed. RESULTS: In our study, the incidence of contrast agent venous intravasation was 13.04%. Endometrial thickness and days after menstruation were significantly associated with venous intravasation (P < .05). However, there was no significance for intrauterine intervention history and fallopian tube patency degree. CONCLUSIONS: Contrast agent intravasation during TVS 4D-HyCoSy is not infrequent. Performing TVS 4D-HyCoSy according to endometrial thickness and menstrual period could reduce intravasation incidence to some extent.

Assessment of Fallopian Tube Fimbria Patency With 4-Dimensional Hysterosalpingo-Contrast Sonography in Infertile Women.

OBJECTIVES: The purpose of this study was to evaluate the performance of 4-dimensional (4D) hysterosalpingo-contrast sonography (HyCoSy) for assessing fallopian tube fimbria patency in infertile women. METHODS: Seventy-seven infertile female patients with obstruction at the tubal fimbria or partial obstruction with pelvic adhesions were included. All of the patients underwent 4D HyCoSy enhanced by dynamic observation after a flush of normal saline and were followed with laparoscopic chromopertubation using methylene blue within 6 months. RESULTS: The overall accordance between 4D HyCoSy and laparoscopic chromopertubation was 92.9%. The sensitivity and specificity of 4D HyCoSy with laparoscopic chromopertubation as a reference standard were 93.8% and 92.2%, respectively. CONCLUSIONS: Four-dimensional HyCoSy can be the preferred method for assessment of tubal fimbria patency and pelvic adhesions surrounding the ovaries, with its advantages of accuracy, noninvasiveness, and a good safety profile.