Antibiotics: The Need for Innovation
Nathan Keighley in Miraculous Medicines and the Chemistry of Drug Design, 2020
Despite been discovered in 1928, it was not until 1941 that effective methods of isolating penicillin were developed by Florey and Chain. This drug revolutionised the battle against infection. However, penicillin is not effective against all types of infections. Since it was discovered that penicillin is a toxic fungal metabolite that kills bacteria and allows the fungi to compete for nutrients, it encouraged scientists to investigate microbial cultures from across the globe in search of other possible therapeutic agents. In 1944, the systematic search of soil microbes revealed the antibiotic streptomycin, which extended the range of therapy to the tubercle bacillus and a variety of gram-negative bacteria. Continued research led to the discovery of the other major classes of antibiotic: peptide antibiotics, tetra-cycline antibiotics, macrolide, and cyclic peptide; and synthetic agents including cephalosporin C, isoniazid, nalidixic acide, ciprofloxacin, and many others.
Genetics of liver cancer
J. K. Cowell in Molecular Genetics of Cancer, 2003
Cyclin D1 combines with and activates CDKs to promote cell progression from the G1 to the S phase. It is generally considered to be an oncogene and is overexpressed, as a consequence of gene amplification, in many types of human cancer. Zhang et al. (1993) studied cyclin D1 in HCCs by Southern blotting and immunohistochemistry, and demonstrated amplification and protein overexpression in a small fraction (13%) of these tumors. Furthermore, Nishida et al. (1994) found that cyclin D1 was amplified in 11% of HCCs, and that this was accompanied by mRNA overexpression. Their data also suggest that cyclin D1 amplification is associated with the advanced stages of HCC. Recently, Ito et al. (1999) reported that cyclin D1 overexpression occurred in 32% of HCCs and was significantly associated with poor disease-free survival. In their study, cyclin E overexpression was also detected in 36% of HCCs but was not significantly related to patient outcome.
Steroidal control of cell proliferation in the breast and breast cancer
Barry G. Wren in Progress in the Management of the Menopause, 2020
The increase in cyclin D1 mRNA following progestin treatment was accompanied by an increase in cyclin D1 protein abundance (Figure 4). Little effect was apparent within 3 h but by 6 h cyclin D1 levels had increased by three- to four-fold (Musgrove and colleagues, in preparation). This response preceded entry into S phase, which began after > 9 h treatment The induction of cyclin D1 protein was accompanied by a corresponding increase in the abundance of cyclin D1/Cdk4 complexes and an increase in the relative amount of pRB in the hyperphosphorylated form (Figure 5). In contrast with the marked increase in cyclin D1 abundance, cyclin E abundance and kinase activity increased by at most two-fold (Figure 4). Overall, the data indicate substantial induction of cyclin D1 but more modest effects on cyclin E, consistent with induction of cyclin D1 being a critical component of the mitogenic response to progestins.
Emerging antibiotics for community-acquired pneumonia
Published in Expert Opinion on Emerging Drugs, 2019
Adamantia Liapikou, Catia Cilloniz, Andrea Palomeque, Toni Torres
Solithromycin benefits from having multiple binding sites in the 50S ribosome, making it more potent than other macrolides. Its oral formulation appears to be clinically effective, well tolerated, and to be suitable for once daily dosing over 5 days. We anticipate that its development will be pursued to treat infections in children and pregnancy given its desirable antibacterial activities and safety profile in preclinical studies. Omadacycline (a newly approved cycline) offers a single-agent parenteral or oral alternative to traditional empirical therapy in bacterial CAP. Additionally, it is significantly more active than doxycycline or minocycline against Enterobacteriaceae and A. baumannii, and meets the FDA criterion for susceptibility of K. pneumoniae. Unfortunately, patients with severe CAP (Fine class V) or those who presented in septic shock were excluded from the RCTs of solithromycin and omadacycline, so we lack clinical data for their use in those patients.
Neuro-Ophthalmic Literature Review
Published in Neuro-Ophthalmology, 2021
David A. Bellows, Noel C.Y. Chan, John J. Chen, Hui-Chen Cheng, Peter W. MacIntosh, Jenny A. Nij Bijvank, Michael S. Vaphiades, Konrad P. Weber, Sui H. Wong
There were several significant characteristics that distinguish the two groups including sex distribution, symptoms, cerebrospinal fluid pressure, comorbidities, and outcomes. The older age group showed a lower preponderance of females (78.5% vs. 92.3%). In regards to symptoms the older group of patients had fewer headaches (50.8% vs. 80%). However, the incidence of other symptoms such as pulse-synchronous tinnitus, vision changes, transient visual obscurations, and diplopia were similar in both cohorts. The older age group had a higher rate of comorbidities (hypertension, diabetes, and thyroid disease) but there was no difference between the groups in the rates of sleep apnoea, anaemia, or polycystic ovarian syndrome. Older patients were less likely to be on cycline-type antibiotics (0% vs. 10.8%). Interestingly, an older age was not found to be associated with a worse outcome as determined by mean deviation on perimetry or need for surgical intervention.
Defining and targeting wild-type BRCA high-grade serous ovarian cancer: DNA repair and cell cycle checkpoints
Published in Expert Opinion on Investigational Drugs, 2019
S. Percy Ivy, Charles A. Kunos, Fernanda I. Arnaldez, Elise C. Kohn
Cyclins and their paired cyclin-dependent kinases (CDKs) are key regulators of cell division. Cyclin/CDK pairs are key in activation or inhibition of the CDK and generation of subsequent downstream signals (Figures 1 and 2). Cyclin-dependent kinases (CDKs) trigger the transition from G1 to S phase and from G2 to M phase by phosphorylating distinct sets of substrates. D-type cyclins and CDK4 or CDK6 regulate events in early G1 phase, cyclin E-CDK2 triggers S phase, cyclin A-CDK2 and cyclin A-CDK1 regulate the completion of S phase, and CDK1-cyclin B regulates mitosis. Sequential activation of CDKs is essential in the control of mitosis progression. Cyclins D and E have been found upregulated in HGSOC, with cyclin E the most commonly affected. Cyclin E amplification may be seen at diagnosis, and it also may be found as a part of a resistance response to treatment [69]. This family of inhibitors now has three agents approved, palbociclib, ribociclib, and abemaciclib, all in combination with an anti-estrogenic agent for the treatment of ER/PR positive HER2 negative breast cancer (Table 2). There are no data to date for the use of these agents in HGSOC. It is unclear that they will be effective in HGSOC has G1/S dysregulation by p53mut which may abrogate or attenuate the inhibitory benefit of the CDK4/6 disruption.
Related Knowledge Centers
- CDKN1B
- Cyclin
- Cyclin A
- Cyclin D
- Enzyme Inhibitor
- G1 Phase
- S Phase
- Phosphorylation
- Cyclin-Dependent Kinase 2
- Cell Cycle