Paclitaxel, a standard chemotherapeutic agent for several types of cancer, including ovarian, breast, and non-small-cell lung cancer, causes peripheral neuropathy as an adverse effect in 60–70% of ...the patients. The utility of combination therapy with paclitaxel and goshajinkigan, a traditional Japanese Kampo medicine, in managing paclitaxel-induced neuropathy during chemotherapy has been explored. Paclitaxel is predominantly metabolized in the liver by cytochrome P450 (CYP) 2C8 to produce 6α-hydroxypaclitaxel and by CYP3A4 to produce 3′-p-hydroxypaclitaxel. In this study, we evaluated the inhibitory or inducing effects of goshajinkigan extract (GJG) and its representative and bioavailable constituents, geniposidic acid, plantagoguanidinic acid, paeoniflorin, catalpol, loganin, and neoline, on the metabolism of paclitaxel via CYP2C8 and CYP3A4 using pooled human liver microsomes and cultured human cryopreserved hepatocytes to provide the drug information about the pharmacokinetic interaction of this combination therapy. GJG significantly inhibited the production of 3’-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel in vitro in a concentration-dependent manner. The half maximal inhibitory concentration (IC
50
) values of GJG were 4.5 and 7.8 mg/ml, respectively, for 3′-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel productions. Neoline inhibited the production of 3′-p-hydroxypaclitaxel at 50 μM, but not at lower concentrations. Apart from neoline, other GJG constituents (at concentrations up to 50 or 10 μM of all test substances) did not exhibit inhibitory or inducing effects. Since GJG showed the inhibitory effect on the metabolism of paclitaxel at much higher concentrations than those used clinically, it can be concluded that GJG product does not exhibit any pharmacokinetic interaction with paclitaxel in clinical practice.
Graphic abstract
•Desorption kept effluent MIB concentrations at measurable levels.•AC with low adsorptive removal capacity showed high relative MIB desorption rate.•Two-component reversible-adsorption model ...described desorption kinetics in NOM water.•Half-dosed superfine PAC showed similar adsorption-desorption kinetics to normal PAC.•A branched-pore kinetic model described the effect of AC particle size on kinetics.
Submerged-membrane hybrid systems (SMHSs) that combine membrane filtration with powdered activated carbon (PAC) take advantage of PAC's ability to adsorb and remove contaminants dissolved in water. However, the risk of contaminant desorption due to temporal changes in the influent concentration of the contaminant has not been thoroughly explored. In this study, we used a SMHS with conventionally-sized PAC or superfine PAC (SPAC) to remove 2-methylisoborneol (MIB), a representative micropollutant, from water containing natural organic matter (NOM), with the goal of elucidating adsorption–desorption phenomena in the SMHS. We found that 20–40% of the MIB that adsorbed on PAC and SPAC while the influent was contaminated with MIB (6 h, contamination period) desorbed to the liquid phase within 6 h from the time that the MIB-containing influent was replaced by MIB-free influent (no-contamination period). The percentage of desorption during the no-contamination period increased with increasing MIB breakthrough concentration during the contamination period. These findings indicate that the PAC/SPAC in the SMHS should be replaced while the breakthrough concentration is low, not only to keep a high removal rate but also to decrease the desorption risk. SPAC is fast in removal by adsorption, but it is also fast in release by desorption. SPAC (median diameter: 0.94 µm) showed almost the same adsorption-desorption kinetics as PAC (12.1 µm) of a double dose. A two-component branched-pore diffusion model combined with an IAST (ideal adsorbed solution theory)–Freundlich isotherm was used to describe and analyze the adsorption–desorption of MIB. The diffusivity of MIB molecules in the pores of the activated carbon particles decreased markedly in a short period of time. This decrease, which was attributed to fouling of the activated carbon in the SMHS by coagulant-treated water containing NOM, not only reduced the rate of MIB removal during the contamination period but also hindered the rate of MIB desorption during the no-contamination period and thus prevented the effluent MIB concentration from becoming high. On the other hand, coagulation did not change the concentration of NOM that competes with MIB for adsorption sites.
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Whole-body magnetic resonance imaging (WB-MRI) is currently used worldwide for detecting bone metastases from prostate cancer. The 5-year survival rate for prostate cancer is > 95%. However, an ...increase in survival time may increase the incidence of bone metastasis. Therefore, detecting bone metastases is of great clinical interest. Bone metastases are commonly located in the spine, pelvis, shoulder, and distal femur. Bone metastases from prostate cancer are well-known representatives of osteoblastic metastases. However, other types of bone metastases, such as mixed or inter-trabecular type, have also been detected using MRI. MRI does not involve radiation exposure and has good sensitivity and specificity for detecting bone metastases. WB-MRI has undergone gradual developments since the last century, and in 2004, Takahara et al., developed diffusion-weighted Imaging (DWI) with background body signal suppression (DWIBS). Since then, WB-MRI, including DWI, has continued to play an important role in detecting bone metastases and monitoring therapeutic effects. An imaging protocol that allows complete examination within approximately 30 min has been established. This review focuses on WB-MRI standardization and the automatic calculation of tumor total diffusion volume (tDV) and mean apparent diffusion coefficient (ADC) value. In the future, artificial intelligence (AI) will enable shorter imaging times and easier automatic segmentation.
Activities as diverse as migration, proliferation and patterning occur simultaneously and in a coordinated fashion during tissue morphogenesis. In the growing vasculature, the formation of motile, ...invasive and filopodia-carrying endothelial sprouts is balanced with the stabilization of blood-transporting vessels. Here, we show that sprouting endothelial cells in the retina have high rates of VEGF uptake, VEGF receptor endocytosis and turnover. These internalization processes are opposed by atypical protein kinase C activity in more stable and mature vessels. aPKC phosphorylates Dab2, a clathrin-associated sorting protein that, together with the transmembrane protein ephrin-B2 and the cell polarity regulator PAR-3, enables VEGF receptor endocytosis and downstream signal transduction. Accordingly, VEGF receptor internalization and the angiogenic growth of vascular beds are defective in loss-of-function mice lacking key components of this regulatory pathway. Our work uncovers how vessel growth is dynamically controlled by local VEGF receptor endocytosis and the activity of cell polarity proteins.
Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, ...lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo3,2-dpyrimidine derivatives capable of fitting into the receptors’ ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C ...lambda/iota (aPKCλ) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKCλ impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKCλ phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a potential therapeutic strategy for treatment of malignant cancers, like angiosarcoma.
Somatic mutations in human epidermal growth factor receptor 2 (HER2) are present in approximately 3% of breast cancers. Some HER2 mutations are activating, and they represent a mechanism of ...resistance to conventional anti‐HER2 therapies such as trastuzumab and lapatinib. Consistently, in patients with HER2‐amplified breast cancer, these mutations are predominantly observed in metastatic tumors obtained after exposure to anti‐HER2 systemic therapies, possibly after clonal selection. Therefore, it is rare to find coexistent HER2 mutation and amplification in the early clinical course, and thus, the clinical relevance of HER2 mutation to the sensitivity to HER2‐targeted drugs, particularly antibody‐drug conjugates (ADCs) such as ado‐trastuzumab emtansine (T‐DM1) and the recently approved fam‐trastuzumab deruxtecan (T‐DXd), remains unclear. In this article, we describe a patient with de novo metastatic breast cancer who exhibited both HER2 amplification and the L755S mutation in the untreated primary breast tumor obtained at the initial diagnosis, and the lesion responded to T‐DM1 and T‐DXd after exhibiting clinical resistance to other HER2‐targeted drugs. Our current case findings suggested that anti‐HER2 ADCs should be prioritized over conventional trastuzumab‐ or lapatinib‐based therapies for patients with HER2‐amplified and comutated tumors.
Key Points
Although HER2 mutations were implicated in resistance to anti‐HER2 monoclonal antibodies or HER2 tyrosine kinase inhibitors in preclinical studies, their clinical impact on sensitivity to anti‐HER2 drugs is unclear owing to the rarity of concomitant HER2 mutation and HER2 amplification.
A case of de novo metastatic breast cancer harboring both HER2 amplification and the L755S mutation in an untreated breast primary tumor displayed clinical resistance to standard trastuzumab‐ or lapatinib‐based therapies but good responses to ado‐trastuzumab emtansine (T‐DM1) and fam‐trastuzumab deruxtecan (T‐DXd).
Anti‐HER2 antibody‐drug conjugates such as T‐DM1 and T‐DXd may be prioritized over conventional trastuzumab‐ or lapatinib‐containing therapies for patients with HER2‐amplified and comutated tumors.
This article reports the case of a patient with de novo metastatic breast cancer who harbored both HER2 amplification and the L755S mutation in the untreated primary breast tumor obtained at the initial diagnosis, detailing her response to treatment with HER2‐targeted drugs.
The aim was to compare the effects of metal artifacts from a pacemaker on pulmonary nodule detection among computed tomography (CT) images reconstructed using filtered back projection (FBP), ...single-energy metal artifact reduction (SEMAR), and forward-projected model-based iterative reconstruction solution (FIRST).Nine simulated nodules were placed inside a chest phantom with a pacemaker. CT images reconstructed using FBP, SEMAR, and FIRST were acquired at low and standard dose, and were evaluated by 2 independent radiologists.FIRST demonstrated the most significantly improved metal artifact and nodule detection on low dose CT (P < .0032), except at 10 mA and 5-mm thickness. At standard-dose CT, SEMAR showed the most significant metal artifact reduction (P < .00001). In terms of nodule detection, no significant differences were observed between FIRST and SEMAR (P = .161).With a pacemaker present, FIRST showed the best nodule detection ability at low-dose CT and SEMAR is comparable to FIRST at standard dose CT.
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