Ketoconazole (Ketoconazole HRA™), an imidazole derivative, is a useful treatment option in the management of endogenous Cushing's syndrome in adults and adolescents > 12 years of age, based on evidence from more than three decades of use of the drug in clinical practice. Originally developed as an antifungal agent, ketoconazole is a potent steroidogenesis inhibitor. Approximately 60% (range, 45–88% across key studies) of patients with Cushing's syndrome who are treated with ketoconazole achieve control of hypercortisolism, with efficacy demonstrated in all aetiologies of the disease. Furthermore, reductions in cortisol levels in patients treated with ketoconazole are associated with improvements in clinical and biochemical features of Cushing's syndrome and common comorbidities. Hepatotoxicity, the main safety concern with ketoconazole, can be managed effectively with careful monitoring of hepatic enzymes, with hepatic enzyme abnormalities generally being mild to moderate, asymptomatic and reversible upon dose reduction or drug withdrawal.
The reported incidence and effects of bacteriophage infections occurring in the industrial acetone butanol (AB) fermentation processes operated in the USA, Japan, and Puerto Rico during the earlier part of the twentieth century is reviewed. The growth characteristics and solvent-producing ability of a lysogenic strain of Clostridium madisonii isolated from a phage infection in Puerto Rico was determined in molasses fermentation medium. The host strain harbours a large lysogenic phage belonging to the Siphoviridae and the growth rate of the lysogenic strain was found to be slower than the non-lysogenic parent strain and exhibited reduced solvent production. The history of phage infections that occurred in the South African AB process is documented along with the various remedial actions that were taken to restore production. A more detailed account of the last phage infection that occurred in 1980 involving a small pseudo-lysogenic phage belonging to the Podoviridae is given. This phage infected Clostridium beijerinckii P260 and a number of closely related industrial strains. Factory-scale fermentations contaminated by this phage were compared with equivalent laboratory-scale control fermentations. The effect of the phage infection in the full-scale and laboratory-scale fermentations were monitored. Results obtained in laboratory-based studies included an assessment of the effect of the multiplicity of infection and the timing of phage infection. The general effects and symptoms of phage infections in the industrial AB fermentation are reviewed including gross changes in the fermentation and changes in cell morphology. Common techniques used for the diagnosis of phage infections and approaches for controlling phage contamination in the AB fermentation are discussed. Prevention strategies included good factory hygiene, sterilisation, decontamination and disinfection, and the use of resistant strains immunised against specific phages.
Starting with the first-in-class agent ibrutinib, the development of Bruton tyrosine kinase (BTK) inhibitors has led to dramatic improvements in the management of B-cell malignancies. Subsequently, more-highly selective second-generation BTK inhibitors (including acalabrutinib, zanubrutinib, tirabrutinib and orelabrutinib) have been developed, primarily with an aim to reduce off-target toxicities. More recently, third-generation agents including the non-covalent BTK inhibitors pirtobrutinib and nemtabrutinib have entered later-stage clinical development. BTK inhibitors have shown strong activity in a range of B-cell malignancies, including chronic lymphocytic leukaemia/small lymphocytic lymphoma, mantle cell lymphoma, Waldenström's macroglobulinaemia and marginal zone lymphoma. The agents have acceptable tolerability, with adverse events generally being manageable with dosage modification. This review article summarises the evidence supporting the role of BTK inhibitors in the management of B-cell malignancies, including highlighting some differential features between agents. Bruton tyrosine kinase (BTK) is a key signalling molecule in the B-cell receptor pathway which is important for B-cell proliferation and survival. The development of drugs which inhibit BTK has led to dramatic improvements in the management of B-cell malignancies, difficult-to-treat diseases that primarily affect older populations. Following ibrutinib (the first-in-class BTK inhibitor), second-generation agents (including acalabrutinib, zanubrutinib, tirabrutinib and orelabrutinib) have been developed, primarily with an aim to improve drug tolerability. More recently, third-generation agents (including pirtobrutinib and nemtabrutinib) have entered later-stage clinical development, aiming to provide further treatment options. BTK inhibitors have shown strong activity in a range of B-cell malignancies. The agents have acceptable tolerability, with adverse events generally being manageable with dosage modification. This review article summarises the evidence supporting the role of BTK inhibitors in the management of B-cell malignancies, a rapidly developing field.
Abstract Members of the ATP-dependent SWI/SNF chromatin remodeling complexes are among the most frequently mutated genes in cancer, suggesting their dysregulation plays a critical role. The synthetic lethality between SWI/SNF catalytic subunits BRM/SMARCA2 and BRG1/SMARCA4 has instigated great interest in targeting BRM. Here we have performed a critical and in-depth investigation of novel dual inhibitors (BRM011 and BRM014) of BRM and BRG1 in order to validate their utility as chemical probes of SWI/SNF catalytic function, while obtaining insights into the therapeutic potential of SWI/SNF inhibition. In corroboration of on-target activity, we discovered compound resistant mutations through pooled screening of BRM variants in BRG1 -mut cancer cells. Strikingly, genome-wide transcriptional and chromatin profiling (ATAC-Seq) provided further evidence of pharmacological perturbation of SWI/SNF chromatin remodeling as BRM011 treatment induced specific changes in chromatin accessibility and gene expression similar to genetic depletion of BRM. Finally, these compounds have the capacity to inhibit the growth of tumor-xenografts, yielding important insights into the feasibility of developing BRM/BRG1 ATPase inhibitors for the treatment of BRG1 -mut lung cancers. Overall, our studies not only establish the feasibility of inhibiting SWI/SNF catalytic function, providing a framework for SWI/SNF therapeutic targeting, but have also yielded successful elucidation of small-molecule inhibitors that will be of importance in probing SWI/SNF function in various disease contexts.
Pyoverdines are siderophores secreted by Pseudomonas aeruginosa. Uptake of ferripyoverdine in P. aeruginosa PAO1 occurs via the FpvA receptor protein and requires the energy-transducing protein TonB1. Interaction of (ferri)pyoverdine with FpvA activates pyoverdine gene expression in a signaling process involving the cytoplasmic-membrane-spanning anti-sigma factor FpvR and the sigma factor PvdS. Here, we show that mutation of a region of FpvA that interacts with TonB1 (the TonB box) prevents this signaling process, as well as inhibiting bacterial growth in the presence of the iron-chelating compound ethylenediamine-di(o-hydroxy-phenylacetic acid). Signaling via wild-type FpvA was also eliminated in strains lacking TonB1 but was unaffected in strains lacking either (or both) of two other TonB proteins in P. aeruginosa, TonB2 and TonB3. An absence of pyoverdine-mediated signaling corresponded with proteolysis of PvdS. These data show that interactions between FpvA and TonB1 are required for (ferri)pyoverdine signal transduction, as well as for ferripyoverdine transport, consistent with a mechanistic link between the signaling and transport functions of FpvA.
'/%3e%3cuse xlink:href='%23a' transform='rotate(72 0 0)'/%3e%3cuse xlink:href='%23a' transform='rotate(-72 0 0)'/%3e%3cuse xlink:href='%23a' transform='scale(-1 1) rotate(72)'/%3e%3c/g%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h1200v600H0z'/%3e%3cpath stroke='%23FFF' stroke-width='60' d='m0 0 600 300M0 300 600 0' clip-path='url(%23b)'/%3e%3cpath stroke='%23C8102E' stroke-width='40' d='m0 0 600 300M0 300 600 0' clip-path='url(%23c)'/%3e%3cpath stroke='%23FFF' stroke-width='100' d='M300 0v300M0 150h600' clip-path='url(%23b)'/%3e%3cpath stroke='%23C8102E' stroke-width='60' d='M300 0v300M0 150h600' clip-path='url(%23b)'/%3e%3cuse xlink:href='%23d' fill='%23FFF' transform='matrix(45.4 0 0 45.4 900 120)'/%3e%3cuse xlink:href='%23d' fill='%23C8102E' transform='matrix(30 0 0 30 900 120)'/%3e%3cg transform='rotate(82 900 240)'%3e%3cuse xlink:href='%23d' fill='%23FFF' transform='rotate(-82 519.022 -457.666) scale(40.4)'/%3e%3cuse xlink:href='%23d' fill='%23C8102E' transform='rotate(-82 519.022 -457.666) scale(25)'/%3e%3c/g%3e%3cg transform='rotate(82 900 240)'%3e%3cuse xlink:href='%23d' fill='%23FFF' transform='rotate(-82 668.57 -327.666) scale(45.4)'/%3e%3cuse xlink:href='%23d' fill='%23C8102E' transform='rotate(-82 668.57 -327.666) scale(30)'/%3e%3c/g%3e%3cuse xlink:href='%23d' fill='%23FFF' transform='matrix(50.4 0 0 50.4 900 480)'/%3e%3cuse xlink:href='%23d' fill='%23C8102E' transform='matrix(35 0 0 35 900 480)'/%3e%3c/svg%3e)