The Safety, Tolerability, and Preliminary Efficacy of a Gemcitabine-releasing Intravesical System (TAR-200) in American Urological Association-defined Intermediate-risk Non-muscle-invasive Bladder Cancer Patients: A Phase 1b Study.

Background and objective: Patients with intermediate-risk non-muscle-invasive bladder cancer (IR NMIBC) have a high risk of recurrence and need effective therapies to reduce the risk of disease recurrence or progression. This phase 1b study (NCT02720367) assessed the safety and tolerability of TAR-200, an intravesical drug delivery system, in participants with IR NMIBC. Methods: Participants with recurrent IR NMIBC were eligible. Participants received either two 7-d or two 21-d TAR-200 dosing cycles over a 4-6-wk period in a marker lesion/ablation design. TAR-200 was placed in the window between the cystoscopy showing recurrent papillary disease and the subsequent complete transurethral resection of the bladder tumour. The primary endpoint was TAR-200 safety. The secondary endpoints included TAR-200 tolerability, pharmacokinetics, and preliminary efficacy. Key findings and limitations: Twelve participants received TAR-200 treatment. No TAR-200-related serious or grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred. Nine participants had grade ≤ 2 TAR-200-related TEAEs, with urgency, dysuria, and haematuria being most common. Two participants refused a second dosing cycle due to urinary urgency and frequency. Insertion and removal of TAR-200 was successful in all cases. Plasma gemcitabine concentrations remained below the lower limit of detection. Five participants (42%) had complete response (CR): four had pathological CR and one had CR based on visual assessment. Conclusions and clinical implications: TAR-200 appears to be safe and well tolerated, with encouraging preliminary efficacy in participants with IR NMIBC. This study lays the groundwork for the multiple phase 2 and 3 global studies that are currently on-going for TAR-200. Patient summary: In this study, researchers evaluated the safety of the novel drug delivery system TAR-200 in participants with intermediate-risk non-muscle-invasive bladder cancer. They concluded that TAR-200 was safe and well tolerated with promising antitumour activity.

Evaluation of ivermectin antiviral activity against avian infectious bronchitis virus using a chicken embryo model.

Ivermectin is widely used in both animals and humans as an FDA-approved parasiticide. Ivermectin has also been reported to have antiviral activity against several viruses including coronaviruses. There are reports that indicate ivermectin may have some role in diminishing the disease caused by SARS-CoV-2, but the evidence is inconclusive. The objective of this study was to determine if ivermectin was efficacious in inhibiting avian infectious bronchitis virus (IBV, a coronavirus) replication in chicken embryos. Briefly, our approach was to use the Massachusetts vaccine strain of IBV in combination with various doses of ivermectin and then inoculate these preparations into chicken embryos to determine if IBV replication was inhibited. The embryos were examined for IBV lesions and samples of chorioallantoic fluid were collected for IBV RT-PCR analysis. Several trials were performed, and the results of our study indicate that ivermectin did not inhibit IBV replication in chicken embryos.

The safety, tolerability, and efficacy of a neoadjuvant gemcitabine intravesical drug delivery system (TAR-200) in muscle-invasive bladder cancer patients: a phase I trial.

OBJECTIVES: Neoadjuvant chemotherapy and radical cystectomy (RC) are underutilized standards of care for the treatment of muscle-invasive bladder cancer (MIBC) due to high patient burden from systemic toxicities and postoperative complications, respectively. TAR-200 is a novel intravesical drug delivery system developed to release gemcitabine into the bladder urine continuously, resulting in distribution of drug into stromal layers of the bladder. The primary aim of the TAR-200-101 study was to evaluate the safety of TAR-200 in patients with MIBC prior to RC (NCT02722538). METHODS AND MATERIALS: This phase I, open-label study was conducted across 6 US and European sites. Eligible patients were aged ≥18 years with histologically confirmed T2a-T3b N0-N1 M0 urothelial cancer and had refusal or were ineligible to receive cisplatin-based combination chemotherapy. Two arms were enrolled serially. Patients in Arm 1 had residual tumor >3 cm after transurethral resection of bladder tumor (TURBT); those in Arm 2 had undergone maximal TURBT (residual tumor <3 cm). Patients received two 7-day cycles of intravesical gemcitabine delivery via TAR-200 before undergoing RC. Primary outcome was safety; secondary outcomes were tolerability, pharmacokinetics, and preliminary efficacy. RESULTS: Of 23 patients in the intention-to-treat population (11 in Arm 1, 12 in Arm 2), 20 completed both dosing cycles of TAR-200. No patients were classified as intolerant to TAR-200. Ten patients (4 in Arm 1, 6 in Arm 2) experienced ≥1 treatment-emergent adverse events (TEAEs). The most common TAR-200-related TEAEs were pollakiuria (n = 3) and urinary incontinence (n = 2). All TEAEs prior to RC were grade ≤2; 1 patient in Arm 2 experienced a grade 3 non-treatment-related TEAE. Plasma gemcitabine levels were undetectable. In Arm 1, those with residual tumor, 4 of 10 patients exhibited pathologic downstaging; 1 experienced a complete response (CR) and 3 a partial response (PR). In Arm 2, those undergoing maximal TURBT, 6 of 10 patients exhibited downstaging; 3 experienced a CR and 3 a PR. CONCLUSION: Controlled intravesical gemcitabine release via TAR-200 was safe and well tolerated in patients with MIBC.

Decrease in Hatchability of Pheasant Eggs Associated with Enterococcus faecalis.

A game bird producer in the North Central region of the United States submitted unhatched ring-neck pheasant (Phasianus colchicus) eggs for diagnostic evaluation. The submitting complaint was a drastic drop in hatchability. This operation has its own breeder birds that are housed in outside pens. This hatch occurred in the latter third of the production cycle. Typical hatchability for this operation is around 75% (± 3%). The hatchability of this hatch was between 14%-15%. Approximately 30,000 eggs were set with an expected hatchability of about 23,000 birds. The number of birds from this hatch was less than 4500, with a net loss approaching 20,000 chicks. All unhatched eggs submitted were in late stage development. The chick embryos had pipped through the shell but died before hatching. Approximately 5000 eggs originating from an outside breeder source were also set at the same time in the same machines and experienced a normal hatch. The exterior surfaces of the eggshells of the unhatched eggs experiencing low hatchability were swabbed and submitted for bacteriologic evaluation. Additionally, embryos from some of the unhatched eggs were removed aseptically from their eggshells, and their internal organs were harvested and submitted for bacteriologic evaluation. The bacteriology results identified no pathogenic bacteria from the eggshells. However, the embryo samples revealed large quantities of Enterococcus faecalis. In discussions with the producer, the only factor identified was an unusually warm period followed by an atypically cold and wet period during the time of egg collection for those eggs experiencing low hatchability.

Contribution of the multidrug efflux transporter CmeABC to antibiotic resistance in different Campylobacter species.

CmeABC, a multidrug efflux system in Campylobacter jejuni, plays an important role in the resistance to different antimicrobials and toxic compounds. Although this efflux system has been well characterized in C. jejuni and to a less extent in C. coli, it is unknown if CmeABC homologs are functional in other Campylobacter spp. In this study, the cmeABC homologs were identified and functionally characterized in five Campylobacter species including C. jejuni, C. coli, C. lari, C. upsaliensis, and C. fetus. Our results indicated that cmeABC is present in all five Campylobacter spp. and the genomic organization of this efflux operon is similar among the Campylobacter spp. Insertional mutagenesis of cmeB increased the susceptibilities of all the five Campylobacter spp. to structurally diverse antimicrobials. Together, these results indicated that the CmeABC efflux system is conserved at both the genomic and functional levels in all five Campylobacter spp. examined in this study, further highlighting the significant role of CmeABC in Campylobacter pathobiology.

CmeR functions as a pleiotropic regulator and is required for optimal colonization of Campylobacter jejuni in vivo.

CmeR functions as a transcriptional repressor modulating the expression of the multidrug efflux pump CmeABC in Campylobacter jejuni. To determine if CmeR also regulates other genes in C. jejuni, we compared the transcriptome of the cmeR mutant with that of the wild-type strain using a DNA microarray. This comparison identified 28 genes that showed a > or = 2-fold change in expression in the cmeR mutant. Independent real-time quantitative reverse transcription-PCR experiments confirmed 27 of the 28 differentially expressed genes. The CmeR-regulated genes encode membrane transporters, proteins involved in C4-dicarboxylate transport and utilization, enzymes for biosynthesis of capsular polysaccharide, and hypothetical proteins with unknown functions. Among the genes whose expression was upregulated in the cmeR mutant, Cj0561c (encoding a putative periplasmic protein) showed the greatest increase in expression. Subsequent experiments demonstrated that this gene is strongly repressed by CmeR. The presence of the known CmeR-binding site, an inverted repeat of TGTAAT, in the promoter region of Cj0561c suggests that CmeR directly inhibits the transcription of Cj0561c. Similar to expression of cmeABC, transcription of Cj0561c is strongly induced by bile compounds, which are normally present in the intestinal tracts of animals. Inactivation of Cj0561c did not affect the susceptibility of C. jejuni to antimicrobial compounds in vitro but reduced the fitness of C. jejuni in chickens. Loss-of-function mutation of cmeR severely reduced the ability of C. jejuni to colonize chickens. Together, these findings indicate that CmeR governs the expression of multiple genes with diverse functions and is required for Campylobacter adaptation in the chicken host.

Development of a novel method of lytic phage delivery by use of a bacteriophage P22 site-specific recombination system.

Bacteriophage therapy represents a potential alternative to the use of antibiotics to control proliferation of pathogenic bacteria. As an alternative to the strategy where a limited number of doses of large numbers of lytic bacteriophages are administered, a novel method delivery system was developed so that phages are continually released into the culture. Specifically, a non-pathogenic Escherichia coli strain was constructed that was lysogenic for a lytic mutant of bacteriophage lambda. This lysogen was shown to be effective at decreasing the number of lambda-sensitive E. coli in vitro. Construction of this E. coli strain was accomplished by development of a plasmid-based system utilizing the site-specific recombination machinery of bacteriophage P22 to integrate DNA constructs into the host chromosome. This recombination system is useful for strain construction and other genetic manipulations in both E. coli and Salmonella enterica serovars.