Efficacy and safety of BVAC-C in HPV type 16- or 18-positive cervical carcinoma who failed 1st platinum-based chemotherapy: a phase I/IIa study.

Background: BVAC-C, a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV-positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16- or 18-positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy.

Patients And Methods: Patients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks.

First-in-Human Phase 1 Study of a B Cell- and Monocyte-Based Immunotherapeutic Vaccine against HER2-Positive Advanced Gastric Cancer.

Purpose: BVAC-B is an autologous B cell- and monocyte-based immunotherapeutic vaccine that contains cells transfected with a recombinant human epidermal growth factor receptor 2 (HER2) gene and loaded with the natural killer T cell ligand alpha-galactosylceramide. Here, we report the first BVAC-B study in patients with HER2-positive advanced gastric cancer.

Materials And Methods: Patients with advanced gastric cancer refractory to standard treatment with HER2+ immunohistochemistry ≥ 1 were eligible for treatment.

The Chimeric Adenovirus (Ad5/35) Expressing Engineered Spike Protein Confers Immunity against SARS-CoV-2 in Mice and Non-Human Primates.

Several COVID-19 platforms have been licensed across the world thus far, but vaccine platform research that can lead to effective antigen delivery is still ongoing. Here, we constructed AdCLD-CoV19 that could modulate humoral immunity by harboring SARS-CoV-2 antigens onto a chimeric adenovirus 5/35 platform that was effective in cellular immunity. By replacing the S1/S2 furin cleavage sequence of the SARS-CoV-2 Spike (S) protein mounted on AdCLD-CoV19 with the linker sequence, high antigen expression was confirmed in various cell lines.

Phase I Study of a B Cell-Based and Monocyte-Based Immunotherapeutic Vaccine, BVAC-C in Human Papillomavirus Type 16- or 18-Positive Recurrent Cervical Cancer.

BVAC-C is a B cell-based and monocyte-based immuno-therapeutic vaccine transfected with a recombinant human papillomavirus (HPV) 16/18 E6/E7 gene and loaded with alpha-galactosyl ceramide, which is a natural killer T cell ligand. This phase I study sought to determine the tolerability and immunogenicity of BVAC-C in platinum-resistant recurrent cervical cancer patients. Patients with HPV 16-positive or 18-positive recurrent or persistent cervical cancer who had received at least one prior platinum-based combination chemotherapy were enrolled.

IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours.

During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours.

Virtual screening and synthesis of novel antitubercular agents through interaction-based pharmacophore and molecular docking studies.

Tuberculosis continues to become a major threat and wide spreading disease though out the world. Therefore it is required to identify the new drugs for the treatment of tuberculosis with better activity profile than the prevalent compounds. In present study we have screened and modified the antitubercular compounds from commercial chemical database using the interaction-based pharmacophore and molecular docking studies.

Synthesis and in vitro evaluation of the antitubercular and antibacterial activity of novel oxazolidinones bearing octahydrocyclopenta[c]pyrrol-2-yl moieties.

A novel series of oxazolidinone-class antimicrobial agents with 5-substituted octahydrocyclopenta[c]pyrrole moieties at the C-ring of linezolid and an acetamide or 1,2,3-triazole ring as the C-5 side chain of the oxazolidinone ring were prepared. The resulting series of compounds were evaluated for in vitro antimicrobial activity against Mycobacterium tuberculosis and a panel of clinically important resistant Gram-positive and -negative bacteria. Among them, endo-alcohol 2a and exo-alcohol 2b showed potent inhibitory activity against M.

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis.

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials.

Efficacy and safety of metronidazole for pulmonary multidrug-resistant tuberculosis.

Pulmonary lesions from active tuberculosis patients are thought to contain persistent, nonreplicating bacilli that arise from hypoxic stress. Metronidazole, approved for anaerobic infections, has antituberculosis activity against anoxic bacilli in vitro and in some animal models and may target persistent, nonreplicating bacilli. In this double-blind, placebo-controlled trial, pulmonary multidrug-resistant tuberculosis subjects were randomly assigned to receive metronidazole (500 mg thrice daily) or placebo for 8 weeks in addition to an individualized background regimen.

Isoniazid could be used for antibiotic-loaded bone cement for musculoskeletal tuberculosis: an in vitro study.

Background: Antibiotic-loaded bone cement (ALBC) has been used in serious cases of musculoskeletal tuberculosis, but the type and amount of antibiotic that should be used in ALBC have not been determined.

Questions/purposes: We therefore determined the (1) elution characteristics and (2) antimycobacterial activity of isoniazid- and rifampicin-loaded bone cement.

Methods: A total of 240 elution samples of each of three discs from 40 g bone cement mixed with one of eight dosages: 1 g, 2 g, and 4 g isoniazid, 1 g, 2 g, and 4 g rifampicin, and a combination of 1 + 1 g or 2 + 2 g of isoniazid and rifampicin.

Panosialins, inhibitors of enoyl-ACP reductase from Streptomyces sp. AN1761.

In the continued search for inhibitors of enoyl-acyl carrier protein (ACP) reductase, we found that four acylbenzenediol sulfate metabolites from Streptomyces sp. AN1761 potently inhibited bacterial enoyl-ACP reductases of Staphylococcus aureus, Streptococcus pneumoniae, and Mycobacterium tuberculosis. Their structures were identified as panosialins A, B, wA, and wB by MS and NMR data.

Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents.

The natural product tryptanthrin (1a) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb). However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB. Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds.

Design and synthesis of 1H-1,2,3-triazoles derived from econazole as antitubercular agents.

Econazole has been known to be active against Mycobacterium tuberculosis. We have designed and synthesized 1H-1,2,3-triazoles derived from econazole as antitubercular agents. The majority of triazole derivatives have been prepared by microwave-assisted click chemistry.

Macrolide treatment for Mycobacterium abscessus and Mycobacterium massiliense infection and inducible resistance.

Rationale: Macrolides, such as clarithromycin (CLR) and azithromycin (AZM), are frequently the only oral antibiotics that are active against Mycobacterium abscessus and M. massiliense infections.

Objectives: To compare the activity of CLR and AZM in experimental models.

Synthesis and in vitro antibacterial activity of novel 3-azabicyclo[3.3.0]octanyl oxazolidinones.

We synthesized a series of oxazolidinone-type antibacterials in which morpholine C-ring of linezolid has been modified by substituted 3-azabicyclo[3.3.0]octanyl rings.

Conversion of Mycobacterium smegmatis to a pathogenic phenotype via passage of epithelial cells during macrophage infection.

Mycobacteria encounter many different cells during infection within their hosts. Although alveolar epithelial cells play an essential role in host defense as the first cells to be challenged upon contact with mycobacteria, they may contribute to the acquisition of mycobacterial virulence by increasing the expression of virulence or adaptation factors prior to being ingested by macrophages on the side of pathogens. From this aspect, the enhanced virulence of nonpathogenic Mycobacterium smegmatis (MSM) passed through human alveolar A549 epithelial cells (A-MSM) was compared to the direct infection of MSM (D-MSM) in THP-1 macrophages and mouse models.

Synthesis and antitubercular activity of monocyclic nitroimidazoles: insights from econazole.

We have designed and synthesized econazole-derived nitroimidazoles to investigate the antitubercular activity of the nitroimidazole compounds. The introduction of a nitro group at the 4-position of the imidazole on econazole abolished the antitubercular activity. However, alcoholic nitroimidazoles 4 and 6 compounds were active against Mycobacterium tuberculosis (Mtb).

Identification of novel antitubercular compounds through hybrid virtual screening approach.

Growing resistance of prevalent antitubercular (antiTB) agents in clinical isolates of Mycobacterium tuberculosis (MTB) provoked an urgent need to discover novel antiTB agents. Enoyl acyl carrier protein (ACP) reductase (InhA) from Mtb is a well known and thoroughly studied as antitubucular therapy target. Here we have reported the discovery of potent antiTB agents through ligand and structure based approaches using computational tools.

Polymorphisms associated with resistance and cross-resistance to aminoglycosides and capreomycin in Mycobacterium tuberculosis isolates from South Korean Patients with drug-resistant tuberculosis.

The aminoglycosides streptomycin, amikacin, and kanamycin and the cyclic polypeptide capreomycin are all widely used in second-line therapy for patients who develop multidrug-resistant tuberculosis. We have characterized a set of 106 clinical isolates of Mycobacterium tuberculosis using phenotypic drug susceptibility testing (DST) to determine the extent of resistance to each agent and cross-resistance between agents. These results were compared with polymorphisms in the DNA sequences of ribosome-associated genes previously implicated in resistance and with the clinical outcomes of subjects from whom these isolates were obtained.