Global spread characteristics of CTX-M-type extended-spectrum ß-lactamases: A genomic epidemiology analysis.

BACKGROUND: Extended-spectrum ß-lactamases (ESBLs) producing bacteria have spread worldwide and become a global public health concern. Plasmid-mediated transfer of ESBLs is an important route for resistance acquisition. METHODS: We collected 1345 complete sequences of plasmids containing CTX-Ms from public database. The global transmission pattern of plasmids and evolutionary dynamics of CTX-Ms have been inferred. We applied the pan-genome clustering based on plasmid genomes and evolution analysis to demonstrate the transmission events. FINDINGS: Totally, 48 CTX-Ms genotypes and 186 incompatible types of plasmids were identified. The geographical distribution of CTX-Ms showed significant differences across countries and continents. CTX-M-14 and CTX-M-55 were found to be the dominant genotypes in Asia, while CTX-M-1 played a leading role in Europe. The plasmids can be divided into 12 lineages, some of which forming distinct geographical clusters in Asia and Europe, while others forming hybrid populations. The Inc types of plasmids are lineage-specific, with the CTX-M-1_IncI1-I (Alpha) and CTX-M-65_IncFII (pHN7A8)/R being the dominant patterns of cross-host and cross-regional transmission. The IncI-I (Alpha) plasmids with the highest number, were presumed to form communication groups in Europe-Asia and Asia-America-Oceania, showing the transmission model as global dissemination and regional microevolution. Meanwhile, the main kinetic elements of blaCTX-Ms showed genotypic preferences. ISEcpl and IS26 were most frequently involved in the transfer of CTX-M-14 and CTX-M-65, respectively. IS15 has become a crucial participant in mediating the dissemination of blaCTX-Ms. Interestingly, blaTEM and blaCTX-Ms often coexisted in the same transposable unit. Furthermore, antibiotic resistance genes associated with aminoglycosides, sulfonamides and cephalosporins showed a relatively high frequency of synergistic effects with CTX-Ms. CONCLUSIONS: We recognized the dominant blaCTX-Ms and mainstream plasmids of different continents. The results of this study provide support for a more effective response to the risks associated with the evolution of blaCTX-Ms-bearing plasmids, and lay the foundation for genotype-specific epidemiological surveillance of resistance, which are of important public health implications.

Characterization of Trivalently Crosslinked C-Terminal Telopeptide of Type I Collagen (CTX) Species in Human Plasma and Serum Using High-Resolution Mass Spectrometry.

With an aging population, the increased interest in the monitoring of skeletal diseases such as osteoporosis led to significant progress in the discovery and measurement of bone turnover biomarkers since the 2000s. Multiple markers derived from type I collagen, such as CTX, NTX, PINP, and ICTP, have been developed. Extensive efforts have been devoted to characterizing these molecules; however, their complex crosslinked structures have posed significant analytical challenges, and to date, these biomarkers remain poorly characterized. Previous attempts at characterization involved gel-based separation methods and MALDI-TOF analysis on collagen peptides directly extracted from bone. However, using bone powder, which is rich in collagen, does not represent the true structure of the peptides in the biofluids as it was cleaved. In this study, our goal was to characterize plasma and serum CTX for subsequent LC-MS/MS method development. We extracted and characterized type I collagen peptides directly from human plasma and serum using a proteomics workflow that integrates preparative LC, affinity chromatography, and HR-MS. Subsequently, we successfully identified numerous CTX species, providing valuable insights into the characterization of these crucial biomarkers.

Decoding dynamic interactions between EGFR-TKD and DAC through computational and experimental approaches: A novel breakthrough in lung melanoma treatment.

In the quest for effective lung cancer treatments, the potential of 3,6-diaminoacridine-9-carbonitrile (DAC) has emerged as a game changer. While DAC's efficacy against glioblastoma is well documented, its role in combating lung cancer has remained largely untapped. This study focuses on CTX-1, exploring its interaction with the pivotal EGFR-TKD protein, a crucial target in lung cancer therapeutics. A meticulous molecular docking analysis revealed that CTX-1 exhibits a noteworthy binding affinity of -7.9 kcal/mol, challenging Erlotinib, a conventional lung cancer medication, which displayed a binding affinity of -7.3 kcal/mol. For a deeper understanding of CTX-1's molecular mechanics, this study employed rigorous 100-ns molecular dynamics simulations, demonstrating CTX-1's remarkable stability in comparison with erlotinib. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method further corroborated these results, with CTX-1 showing a free binding energy of -105.976 ± 1.916 kJ/mol. The true prowess of CTX-1 was tested against diverse lung cancer cell lines, including A549, Hop-62 and H-1299. CTX-1 not only significantly outperformed erlotinib in anticancer activity but also exhibited a spectrum of therapeutic effects. It effectively diminished cancer cell viability, induced DNA damage, halted cell cycle progression, generated reactive oxygen species (ROS), impaired mitochondrial transmembrane potential, instigated apoptosis and successfully inhibited EGFR-TKD. This study not only underscores the potential of CTX-1 a formidable contender in lung cancer treatment but also marks a paradigm shift in oncological therapeutics, offering new horizons in the fight against this formidable disease.

Vibrio mimicus Lineage Carrying Cholera Toxin and Vibrio Pathogenicity Island, United States and China.

Vibrio mimicus bacteria have caused sporadic cases and outbreaks of cholera-like diarrhea throughout the world, but the association of lineages with such events is unexplored. Genomic analyses revealed V. mimicus lineages carrying the virulence factors cholera toxin and toxin coregulated pilus, one of which has persisted for decades in China and the United States.

Population pharmacokinetic model of ABL001/CTX-009 (anti-VEGF/DLL4) in adult cancer patients with solid tumor.

ABL001/CTX-009 is a bispecific antibody targeting delta-like ligand-4 and vascular endothelial growth factor A. In this study, we developed a population pharmacokinetic (PK) model of ABL001/CTX-009 in patients with solid tumors. A total of 712 plasma concentrations from 30 patients with relapsed or refractory solid tumors were collected from a phase 1 study (NCT03292783). A population PK model was developed using a nonlinear mixed-effect method and was evaluated by graphical and numerical methods. Using the model, the steady-state concentrations were simulated to compare weight-based and fixed-dose regimens and to find optimal dosing intervals. The PK of ABL001/CTX-009 was well described by a two-compartment model with a parallel first-order and Michaelis-Menten elimination kinetics. Body weight was selected as a significant covariate on V1. Model evaluation results suggested that the model was adequate and robust with good precision. Simulations after administrations of fixed or weight-based doses showed similar plasma concentrations. Additionally, 10 mg/kg for every other week and 15 mg/kg for every three-week administration showed comparable plasma concentrations. In conclusion, the model well described the plasma concentrations of ABL001/CTX-009 in patients with solid tumors. The simulation suggested that weight-based dose and fixed dose can provide equivalent systemic exposure.

IncC plasmid genome rearrangements influence the vertical and horizontal transmission tradeoff in Escherichia coli.

It has been shown that an evolutionary tradeoff between vertical (host growth rate) and horizontal (plasmid conjugation) transmissions contributes to global plasmid fitness. As conjugative IncC plasmids are important for the spread of multidrug resistance (MDR), in a broad range of bacterial hosts, we investigated vertical and horizontal transmissions of two multidrug-resistant IncC plasmids according to their backbones and MDR-region rearrangements, upon plasmid entry into a new host. We observed plasmid genome deletions after conjugation in three diverse natural Escherichia coli clinical strains, varying from null to high number depending on the plasmid, all occurring in the MDR region. The plasmid burden on bacterial fitness depended more on the strain background than on the structure of the MDR region, with deletions appearing to have no impact. Besides, we observed an increase in plasmid transfer rate, from ancestral host to new clinical recipient strains, when the IncC plasmid was rearranged. Finally, using a second set of conjugation experiments, we investigated the evolutionary tradeoff of the IncC plasmid during the critical period of plasmid establishment in E. coli K-12, by correlating the transfer rates of deleted or non-deleted IncC plasmids and their costs on the recipient strain. Plasmid deletions strongly improved conjugation efficiency with no negative growth effect. Our findings indicate that the flexibility of the MDR-region of the IncC plasmids can promote their dissemination, and provide diverse opportunities to capture new resistance genes. In a broader view, they suggest that the vertical-horizontal transmission tradeoff can be manipulated by the plasmid to improve its fitness.

Releasing Au Electrons to Mo Site for Weakened Mo─H Bond of Mo2C MXene Cocatalyst Toward Improved Photocatalytic H2 Production.

Mo2C MXene (Mo2CTx) is one of the most promising noble-metal-free cocatalysts for photocatalytic H2 production because of its excellent electron transport capacity and abundant Mo sites. However, Mo2CTx typically exhibits a strong Mo─Hads bond, resulting in that the produced H2 difficultly desorbs from the Mo surface for the limited activity. To effectively weaken the Mo─Hads bond, in this paper, a regulation strategy of electron donor Au releasing electrons to the d-orbitals of Mo sites in Mo2CTx is proposed. Herein, the Mo2CTx-Au/CdS photocatalysts are prepared through a two-step process, including the initial loading of Au nanoparticles on the Mo2CTx surface and the subsequent in situ growth of CdS onto the Mo2CTx-Au surface. Photocatalytic measurements indicate that the maximal H2-production rate of Mo2CTx-Au/CdS reaches up to 2799.44 µmol g-1 h-1, which is 30.99 and 3.60 times higher than that of CdS and Mo2CTx/CdS, respectively. Experimental and theoretical data corroborate that metallic Au can transfer free electrons to Mo2CTx to generate electron-enriched Moδ- sites, thus causing the increased antibonding-orbital occupancy state and the weakened Mo─Hads bond for the boosted H2-production efficiency. This research provides a promising approach for designing Mo2CTx-based cocatalysts by regulating the antibonding-orbital occupancy of Mo sites for improved photocatalytic performance.

Interfacial Polarization Locked Flexible ß-Phase Glycine/Nb2CTx Piezoelectric Nanofibers.

Biomolecular piezoelectric materials show great potential in the field of wearable and implantable biomedical devices. Here, a self-assemble approach is developed to fabricating flexible ß-glycine piezoelectric nanofibers with interfacial polarization locked aligned crystal domains induced by Nb2CTx nanosheets. Acted as an effective nucleating agent, Nb2CTx nanosheets can induce glycine to crystallize from edges toward flat surfaces on its 2D crystal plane and form a distinctive eutectic structure within the nanoconfined space. The interfacial polarization locking formed between O atom on glycine and Nb atom on Nb2CTx is essential to align the ß-glycine crystal domains with (001) crystal plane intensity extremely improved. This ß-phase glycine/Nb2CTx nanofibers (Gly-Nb2C-NFs) exhibit fabulous mechanical flexibility with Young's modulus of 10 MPa, and an enhanced piezoelectric coefficient of 5.0 pC N-1 or piezoelectric voltage coefficient of 129 × 10-3Vm N-1. The interface polarization locking greatly improves the thermostability of ß-glycine before melting (≈210°C). A piezoelectric sensor based on this Gly-Nb2C-NFs is used for micro-vibration sensing in vivo in mice and exhibits excellent sensing ability. This strategy provides an effective approach for the regular crystallization modulation for glycine crystals, opening a new avenue toward the design of piezoelectric biomolecular materials induced by 2D materials.

Oxide Derivatives of Nb2CTx MXene and Their Application as Electron Transport Layers in Perovskite Solar Cells: Unraveling the Oxidation Process and Functionalization.

In the realm of photovoltaic research, 2D transition metal carbides (MXenes) have gained significant interest due to their exceptional photoelectric capabilities. However, the instability of MXenes due to oxidation has a direct impact on their practical applications. In this work, the oxidation process of Nb2CTx MXene in aqueous systems is methodically simulated at the atomic level and nanosecond timescales, which elucidates the structural variations influenced by the synergistic effects of water and dissolved oxygen, predicting a transition from metal to semiconductor with 44% C atoms replaced by O atoms in Nb2CTx. Moreover, Nb2CTx with varying oxidation degrees is utilized as electron transport layers (ETLs) in perovskite solar cells (PSCs). Favorable energy level alignments with superior electron transfer capability are achieved by controlled oxidation. By further exploring the composites of Nb2CTx to its derivatives, the strong interaction of the nano-composites is demonstrated to be more effective for electron transport, thus the corresponding PSC achieves a better performance with long-term stability compared with the widely used ETLs like SnO2. This work unravels the oxidation dynamics of Nb2CTx and provides a promising approach to designing ETL by exploiting MXenes to their derivatives for photovoltaic technologies.

Chenodeoxycholic acid (CDCA) treatment during pregnancy in women with cerebrotendinous xanthomatosis (CTX): Lessons learned from 19 pregnancies.

PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder. Biallelic pathogenic variants in CYP27A1, encoding for sterol 27-hydroxylase, impair cholic acid (CA) and chenodeoxycholic acid (CDCA) synthesis and lead to accumulation of cholestanol and C27 bile alcohols. Treatment with CDCA decreases the accumulation of these harmful metabolites and slows disease progression. Currently, CDCA is contraindicated for use during pregnancy based on animal studies that showed that high-dose CDCA may cause fetal harm when administered to pregnant animals. Data regarding the safety of CDCA treatment in humans are lacking. METHODS: We present a case series of 19 pregnancies in 9 women with CTX who either received CDCA treatment throughout pregnancy or did not. RESULTS: In 11 pregnancies where mothers continued CDCA treatment, no complications were reported, and newborns were born at or near full term, with normal birth weight and Apgar scores. In 8 pregnancies where mothers did not receive CDCA, 2 newborns experienced elevated bilirubin soon after birth. One woman who stopped treatment during her pregnancy deteriorated neurologically while off treatment. CONCLUSION: The data we present support the benefit of continued CDCA treatment in pregnant women with CTX for both the affected women and their offspring.

Prevalence and molecular characterization of ESBL/pAmpC producing faecal Escherichia coli strains with widespread detection of CTX-M-15 isolated from healthy poultry flocks in Eastern Algeria.

The intensification of livestock farming has led to the widespread use of massive amounts of antibiotics worldwide. Poultry production, including white meat, eggs and the use of their manure as fertiliser, has been identified as one of the most crucial reservoirs for the emergence and spread of resistant bacteria, including E. coli in poultry as an important opportunistic pathogen representing the greatest biological hazard to human and wildlife health. Thus, this study aimed to analyse E. coli in the faecal carriage of healthy poultry flocks and to investigate the phenotypic and genotypic characteristics of antimicrobial resistance, including integrons genes and phylogenetic groups. A total of 431 cloacal swabs from apparently healthy poultry from four regions in Eastern Algeria from December 2021 to October 2022. 360 E. coli were isolated; from broilers (n = 151), broiler breeders (n = 91), laying hens (n = 72), and breeding hens (n = 46). Among this, 281 isolates exhibited multidrug resistance (MDR) phenotype, 17 of the 360 E. coli isolates exhibited ESBL, and one isolate exhibited both ESBL/pAmpC. A representative collection of 183 among 281 MDR E. coli was selected for further analysis by PCR to detect genes encoding resistance to different antibiotics, and sequencing was performed on all positive PCR products of blaCTX-M and blaCMY-2 genes. Phylogenetic groups were determined in 80 E. coli isolates (20 from each of the four kinds of poultry). The blaCTX-M gene was found in 16 (94.11 %) ESBL-producing E. coli isolates within 11 strains co-expressing the blaSHV gene and 8 strains co-expressing the blaTEM gene. Sequence analysis showed frequent diversity in CTX-M-group-1, with blaCTX-M-15 being the most predominant (n = 11), followed by blaCTX-M-1 (n = 5). The blaCMY-2 gene was detected only in one ESBL/pAmpC isolate. Among the 183 tested isolates, various antimicrobial resistance genes were found (number of strains) blaTEM (n = 121), blaSHV (n = 12), tetA (n = 100), tetB (n = 29), sul1(n = 67), sul2 (n = 32), qnrS (n = 45), qnrB (n = 10), qnrA (n = 1), catA1(n = 13), aac-(6')-Ib (n = 3). Furthermore, class 1 and class 2 integrons were found in 113 and 2 E. coli, respectively. The isolates were classified into multiple phylogroups, including A (35 %), B1 (27.5 %), B2 and D each (18.75 %). The detection of integrons and different classes of resistance genes in the faecal carriage of healthy poultry production indicates that commensal E. coli could potentially act as a reservoir for antimicrobial resistance, posing a significant One Health challenge encompassing the interconnected domains of human, animal health and the environment. Here, we present the first investigation to describe the diversity of blaCTX-M producing E. coli isolates with widespread detection of CTX-M-15 and CTX-M-1 in healthy breeders (Broiler and breeding hens) in Eastern Algeria.

A novel chicken-origin colistin-resistant Klebsiella pneumoniae ST5982 Co-harboring mcr-3.11 and CTX-M-27.

Klebsiella pneumoniae (K. pneumoniae) is an important zoonotic opportunistic pathogen of Enterobacteriaceae that has become one of the most common infectious diseases causing Enterobacteriaceae after Escherichia coli. In this study, we identified a colistin-resistant, multidrug-resistant ST5982 K. pneumoniae strain of broiler origin. The isolate carried 35 resistance genes of 10 antibiotics classes, detected by whole genome sequencing (WGS); 11.4 % (4/35) of the resistance genes were distributed in the chromosome, and 88.6 % (31/35) of the resistance genes were located in four different resistance plasmids. Among the four plasmids, we found for the first time that CTX-M-27 and mcr-3.11 simultaneously coexisted in K. pneumoniae, and a resistance plasmid of IncI1 carrying a combination of mcr-3.11 and qnrS1 was identified. We successfully transferred mcr-3.11, qnrS1 and CTX-M-27 genes into E. coli J53 through conjugation experiments. In the present study, the co-occurrence of CTX-M-27 and mcr-3.11 in multidrug-resistant K. pneumoniae strain ST5982 was detected for the first time; its drug resistance was evaluated, and the risk of its transmission was assessed to provide a reference for further prevention and treatment of K. pneumoniae.

Surface Termination (-O, -F or -OH) and Metal Doping on the HER Activity of Mo2CTx MXene.

Two-dimensional MXenes have recently garnered significant attention as electrocatalytic materials for hydrogen evolution reaction (HER). However, previous theoretical studies mainly focused on the effect of pure functional groups while neglecting hybrid functional groups that are commonly observed in experiments. Herein, we investigated the hybrid functionalized Mo2CTx MXene (T=-O, -F or -OH) to probe the HER properties. In binary O/F co-functionalization, the presence of F groups would attenuate the H adsorption and lead to the enhanced HER activity than the fully O-terminated Mo2CO2. However, the surface HER activity of ternary O/F/OH functionalized Mo2CTx is not satisfactory owing to the relatively weak H adsorption capacity. To further enhance the catalytic activity, modification was performed by introducing another metal element into its lattice structure. The doped metal (Fe, Co, Ni, Cu) exhibits reduced charge transfer to O compared to Mo atoms, leading to enhanced H adsorption and improved overall activity. The synergistic effect of hybrid functionalization and TM modification provides useful guidance for achieving feasible Mo2CTx candidates with high HER performance, which can be applied to the electrocatalytic applications of other MXenes.

Emergence of a clinical Salmonella enterica serovar 1,4,[5], 12: i:-isolate, ST3606, in China with susceptibility decrease to ceftazidime-avibactam carrying a novel blaCTX-M-261 variant and a blaNDM-5.

PURPOSE: The detection rate of Salmonella enterica serovar 1,4,[5], 12: i: - (S. 1,4,[5], 12: i: -) has increased as the most common serotype globally. A S. 1,4,[5], 12: i: - strain named ST3606 (sequence type 34), isolated from a fecal specimen of a child with acute diarrhea hospitalized in a tertiary hospital in China, was firstly reported to be resistant to carbapenem and ceftazidime-avibactam. The aim of this study was to characterize the whole-genome sequence of S. 1,4,[5], 12: i: - isolate, ST3606, and explore its antibiotic resistance genes and their genetic environments. METHODS: The genomic DNA of S. 1,4,[5], 12: i: - ST3606 was extracted and performed with single-molecule real-time sequencing. Resistance genes, plasmid replicon type, mobile elements, and multilocus sequence types (STs) of ST3606 were identified by ResFinder 3.2, PlasmidFinder, OriTfinder database, ISfinder database, and MLST 2.0, respectively. The conjugation experiment was utilized to evaluate the conjugation frequency of pST3606-2. Protein expression and enzyme kinetics experiments of CTX-M were performed to analyze hydrolytic activity of a novel CTX-M-261 enzyme toward several antibiotics. RESULTS: Single-molecule real-time sequencing revealed the coexistence of a 109-kb IncI1-Iα plasmid pST3606-1 and a 70.5-kb IncFII plasmid pST3606-2. The isolate carried resistance genes, including blaNDM-5, sul1, qacE, aadA2, and dfrA12 in pST3606-1, blaTEM-1B, aac(3)-lld, and blaCTX-M-261, a novel blaCTX-M-1 family member, in pST3606-2, and aac(6')-Iaa in chromosome. The blaCTX-M-261 was derived from blaCTX-M-55 by a single-nucleotide mutation 751G>A leading to amino acid substitution of Val for Met at position 251 (Val251Met), which conferred CTX-M increasing resistance to ceftazidime verified by antibiotics susceptibility testing of transconjugants carrying pST3606-2 and steady-state kinetic parameters of CTX-M-261. pST3606-1 is an IncI1-α incompatibility type that shares homology with plasmids of pC-F-164_A-OXA140, pE-T654-NDM-5, p_dm760b_NDM-5, and p_dmcr749c_NDM-5. The conjugation experiment demonstrated that pST3606-2 was successfully transferred to the Escherichia coli recipient C600 with four modules of OriTfinder. CONCLUSION: Plasmid-mediated horizontal transfer plays an important role in blaNDM-5 and blaCTX-M-261 dissemination, which increases the threat to public health due to the resistance to most ß-lactam antibiotics. This is the first report of blaCTX-M-261 and blaNDM-5 in S. 1,4,[5], 12: i: -. The work provides insights into the enzymatic function and demonstrates the ongoing evolution of CTX-M enzymes and confirms urgency to control resistance of S. 1,4,[5], 12: i: -.

Ginseng-DF ameliorates intestinal mucosal barrier injury and enhances immunity in immunosuppressed mice by regulating MAPK/NF-κB signaling pathways.

PURPOSE: Dietary fiber (DF) has a good application prospect in effectively restoring the integrity of the intestinal mucosal barrier. Ginseng-DF has good physicochemical properties and physiological activity and shows positive effects in enhancing immunity. The aim of this study was to investigate the protective effect of Ginseng-DF on intestinal mucosal barrier injury induced by cyclophosphamide (CTX) in immunosuppressed mice and its possible mechanism. METHODS: The effects of Gginseng-DF on immune function in mice were studied by delayed-type hypersensitivy, lymphocyte proliferation assay and NK cytotoxicity assay, the T lymphocyte differentiation and intestinal barrier integrity were analyzed by flow cytometry and western blot. RESULTS: Ginseng-DF (2.5% and 5%) could attenuate the inhibition of DTH response by CTX, promote the transformation and proliferation of lymphocytes, and stimulate NK effector cell activity. At the same time, Ginseng-DF could restore the proportion of CD4+/CD8+ T lymphocytes induced by CTX to different extents, improved spleen tissue damage, promoted the secretion of immunoglobulin IgG, and enhanced body immunity. More importantly, Ginseng-DF could up-regulate the contents of TNF-α, IFN-γ, IL-6 and IL-1ß in serum and intestine of immunosuppressed mice to maintain the balance between Th1/Th2 cytokines, and improve the permeability of intestinal mucosal barrier. Meanwhile, Ginseng-DF could reduce intestinal epithelial cell apoptosis and improve intestinal adaptive immunity in CTX-induced immunosuppressed mice by regulating MAPK/NF-κB signaling pathway. CONCLUSION: Ginseng-DF can be used as a safe dietary supplement to enhance body immunity and reduce intestinal mucosal injury caused by CTX.

COMPANION-002 A clinical trial of investigational drug CTX-009 plus paclitaxel vs paclitaxel in second line advanced BTC.

Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone as second-line treatment for patients with advanced biliary tract cancer. The primary end point is ORR, and crossover is allowed.Clinical Trial Registration: NCT05506943 (ClinicalTrials.gov).

Looking for new options for patients with advanced biliary tract cancer? Explore COMPANION-002, Compass Therapeutics' phase II/III study of CTX-009 + paclitaxel as a second line treatment.#CMPX #biotech #healthcare #rarecancer.

Prevalence of streptomycin and tetracycline resistance and increased transmissible third-generation cephalosporin resistance in Salmonella enterica isolates derived from food handlers in Japan from 2006 to 2021.

AIMS: The increasing prevalence of AmpC ß-lactamase (AmpC)- and extended-spectrum ß-lactamase (ESBL)- producing food pathogens is a serious public health concern. AmpC- and ESBL-producing Salmonella species pose a high risk of food contamination. This study aimed to investigate changes in the prevalence of Salmonella among food handlers in Japan from 2006 to 2021 using 100 randomly selected isolates from 2006, 2012, 2018, and 2021 with different serotypes and antimicrobial resistance patterns. METHODS AND RESULTS: The average Salmonella isolation rate was 0.070% (19 602/27 848 713). Serotyping revealed that the most common serotypes were Enteritidis in 2006, Infantis in 2012, Agoueve/Cubana in 2018, and Schwarzengrund in 2021. Antimicrobial susceptibility testing showed that Salmonella isolates exhibited the highest resistance to streptomycin (<40%), followed by tetracycline (<20%-40%). Moreover, 6% of the Salmonella isolates produced cephalosporinases with the blaCMY-2, blaCTX-M-14, and blaTEM genes. The annual incidence of cephalosporin resistance has increased. Plasmid conjugation assays revealed that cephalosporin-resistant Salmonella spp. transmitted their resistance to Escherichia coli. Additionally, plasmid genome analysis showed that the insertion sequence IS26 was encoded in the upstream and downstream regions of blaCTX-M-14 and qnrS1 in the IncHI1 plasmid, which could be transmitted to other bacteria. CONCLUSIONS: The tested Salmonella isolates showed high resistance to specific antibiotics, with differences in resistance depending on the serotype. Further increase and spread of transmissible cephalosporin-resistant strains should be noted.

Prevalence and characteristics of ESBL-producing Escherichia coli in clinically healthy pigs: implications for antibiotic resistance spread in livestock.

AIM: This study aimed to compare and characterize the resistance profile and the presence of extended-spectrum beta-lactamase (ESBL) related genes in Escherichia coli isolated from healthy finishing pigs fed with or without antibiotics in their diets. METHODS AND RESULTS: A total of 27 ceftiofur-resistant E. coli isolates were obtained from 96 healthy pigs. The antibiotic resistance profile was tested, and all 27 isolates were classified as multidrug-resistant (MDR). A high proportion of isolates were resistant to cephalosporins, ampicillin, ciprofloxacin, and tetracyclines. The ESBL production was observed in 85% of isolates by double-disc synergy test. The MDR-E. coli isolates harbored ESBL genes, such as blaTEM, blaCTX-M-1, blaCTX-M-2, and blaCTX-M-8,25. In addition, other antibiotics resistance genes (ARGs) were also detected, such as sul2, ant(3″)-I, tetA, and mcr-1. The mobilization of the blaCTX-M gene was confirmed for nine E. coli isolates by conjugation assays. The presence of blaCTX-M on mobile genetic elements in these isolates was demonstrated by Southern blot hybridization, and the resistance to cephalosporins was confirmed in the transconjugants. Our results indicate the prevalence of CTX-M-producing E. coli strains harboring mobile genetic elements in the normal microbiota of healthy pigs. CONCLUSIONS: These findings highlight the significance of ESBL genes as a global health concern in livestock and the potential spread of antimicrobial resistance to other members of the gastrointestinal tract microbiota.

Dasatinib promotes muscle differentiation and disrupts normal muscle regeneration.

Dasatinib is one of the second-generation tyrosine kinase inhibitors used to treat chronic myeloid leukemia and has a broad target spectrum, including KIT, PDGFR, and SRC family kinases. Due to its broad drug spectrum, dasatinib has been reported at the basic research level to improve athletic performance by eliminating senescent cell removal and to have an effect on muscle diseases such as Duchenne muscular dystrophy, but its effect on myoblasts has not been investigated. In this study, we evaluated the effects of dasatinib on skeletal muscle both under normal conditions and in the regenerating state. Dasatinib suppressed the proliferation and promoted the fusion of C2C12 myoblasts. During muscle regeneration, dasatinib increased the gene expressions of myogenic-related genes (Myod, Myog, and Mymx), and caused abnormally thin muscle fibers on the CTX-induced muscle injury mouse model. From these results, dasatinib changes the closely regulated gene expression pattern of myogenic regulatory factors during muscle differentiation and disrupts normal muscle regeneration. Our data suggest that when using dasatinib, its effects on skeletal muscle should be considered, particularly at regenerating stages.

Extended-spectrum ß-lactamase-producing Plesiomonas shigelloides isolated from the stool of a Japanese traveler returning from Rwanda: A case report.

A 21-year-old previously healthy Japanese woman visited an outpatient clinic because of abdominal pain, watery diarrhea, vomiting, and mild fever that had started on the previous day. She traveled to rural and urban areas of Rwanda and returned to Japan 3 days before. Stool culture yielded the Plesiomonas shigelloides strain TMCH301018, against which minimum inhibitory concentrations of cefotaxime and cefotaxime-clavulanate were 128 and ≤0.12/4 µg/mL, respectively. The strain had the blaCTX-M-27 gene and an IncA/C replicon-type plasmid. Moreover, a transformant produced by introduction of an IncA/C plasmid extracted from TMCH301018 into Escherichia coli DH5α was positive for the blaCTX-M-27 gene and fulfilled the criteria of extended-spectrum ß-lactamase (ESBL) production described by the Clinical and Laboratory Standards Institute, indicating that TMCH301018 produced ESBL of CTX-M-27 and the ESBL-encoding gene was located on an IncA/C plasmid. Pathogenicity of TMCH301018 for the patient's complaints was uncertain because a molecular assay detected other enteropathogens in the stool specimen and the symptoms improved within 2 days with administration of oral ciprofloxacin, to which TMCH301018 was not susceptible. To our knowledge, this is the first report describing the isolation of ESBL-producing P. shigelloides.