Changes in DNA superhelicity during DNA replication are mediated primarily by the activities of DNA helicases and topoisomerases. If these activities are defective, the progression of the replication fork can be hindered or blocked, which can lead to double-strand breaks, elevated recombination in regions of repeated DNA, and genome instability. Hereditary diseases like Werner's and Bloom's Syndromes are caused by defects in DNA helicases, and these diseases are associated with genome instability and carcinogenesis in humans. Here we report a Saccharomyces cerevisiae gene, MGS1 ( M aintenance of G enome S tability 1), which encodes a protein belonging to the AAA + class of ATPases, and whose central region is similar to Escherichia coli RuvB, a Holliday junction branch migration motor protein. The Mgs1 orthologues are highly conserved in prokaryotes and eukaryotes. The Mgs1 protein possesses DNA-dependent ATPase and single-strand DNA annealing activities. An mgs1 deletion mutant has an elevated rate of mitotic recombination, which causes genome instability. The mgs1 mutation is synergistic with a mutation in top3 (encoding topoisomerase III), and the double mutant exhibits severe growth defects and markedly increased genome instability. In contrast to the mgs1 mutation, a mutation in the sgs1 gene encoding a DNA helicase homologous to the Werner and Bloom helicases suppresses both the growth defect and the increased genome instability of the top3 mutant. Therefore, evolutionarily conserved Mgs1 may play a role together with RecQ family helicases and DNA topoisomerases in maintaining proper DNA topology, which is essential for genome stability.
Critical limb ischemia (CLI) is commonly caused by atherosclerotic arterial obstruction or stenosis in the leg, as demonstrated by rest pain, skin ulcers and gangrene (Fontaine III or IV), often fails to respond to conservative treatments, and carries a high risk for limb amputation, with a particularly dismal prognosis. Although surgical revascularization techniques may be used for certain CLI patients, such techniques are not indicated for most CLI patients due to the diffuse nature of the responsible lesions, distal location of the obstruction, or coexisting systemic comorbidities. For such CLI patients with no alternative treatments, the potential utility of cell therapies has been investigated. Indeed many clinical trials are being carried out by academic sectors, and their achievements will facilitate clinical development by pharmaceutical companies.In order to understand the situation regarding competitive international R&D of revascularization seeds for CLI, we surveyed the status of clinical trials. As a result, we identified 58 clinical trials on revascularization for CLI, with the majority in the early phase (
A 61-year-old female presented with shortness of breath and was found to have moderate aortic regurgitation with annulo-aortic ectasia and an aneurysm involving the aortic arch. She underwent Bentall operation and total arch replacement with a branched prosthesis. The patient developed hypesthesia and paresis of the left forearm one day after the surgery. Computed tomography revealed complete occlusion of the left subclavian artery (LSA). An emergency operation was performed 15 hours after the initial operation. A new bypass graft to the axillary artery was placed since the LSA was occluded by the wide arterial dissection. However, her left forearm showed rapid swelling within a few hours. Under the diagnosis of acute compartment syndrome (ACS) of the forearm, emergency decompression fasciotomy was performed. She was discharged with a mild dysfunction of her forearm and hand 40 days after the operation. The rapid progression of ACS was thought to have been associated with not only the severe and prolonged ischemia but also the venous obstruction caused by the ligation of left brachiocephalic vein during the initial operation. Immediate and complete decompression, including the deep compartment of the forearm, was essential to achieve a full functional recovery from ACS.
Sarcoidosis is occasionally associated with malignant lymphoma. Cases of sarcoidosis associated with malignant lymphoma are called sarcoidosis-lymphoma syndrome. We report a 63-year-old man with sarcoidosis associated with primary central nervous system lymphoma (PCNSL). Definitive diagnosis by clinical and radiological findings was difficult. Finally, brain biopsy could produce the correct diagnosis. We could provide appropriate treatment for PCNSL and the patient has survived over 2 years. Thus, it is very important to make an early definitive diagnosis by biopsy for intracranial lesion, because it can prolong survival in patients with sarcoidosis.
We report a patient with idiopathic intracranial hypertension (IIH) with bilateral transverse sinus occlusion treated by a lumboperitoneal shunt. A 45-year-old woman presented with visual disturbance and chronic headache. Magnetic resonance (MR) venography and three-dimensional computed tomography angiography (3D-CTA) showed occlusion of both transverse sinuses. After the surgery, MR venography and 3D-CTA showed no blockages in both transverse sinuses. This phenomenon reveals that obstruction of the bilateral transverse sinus is a consequence of intracranial hypertension, not just a single cause. Since many patients have an obstruction or stenosis of the venous sinus, there are some reports of endovascular treatment. Sinus reconstruction is usually effective, but it is not effective in some cases. Reversal of sinus occlusion suggests that endovascular therapy for IIH is inadequate in some cases.
For immune checkpoint inhibitor (ICI)-pretreated patients, docetaxel and ramucirumab (DOC+RAM) combination therapy may be more effective compared to patients not receiving ICI treatment.From June 2013 to July 2018, 39 patients with advanced/recurrent non-small cell lung cancer underwent DOC+RAM therapy. We analyzed the efficacy and safety of DOC+RAM therapy based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history.Of the 39 patients treated with DOC+RAM, we identified 18 (46%) pre-ICI+ patients. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI- patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80]. Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients.Despite increased toxicity concerns, DOC+RAM therapy in pre-ICI+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS.
Background In cancer patients treated with vancomycin, therapeutic drug monitoring is currently performed by the Bayesian method that involves estimating individual pharmacokinetics from population pharmacokinetic parameters and trough concentrations rather than the Sawchuk–Zaske method using peak and trough concentrations. Although the presence of malignancy influences the pharmacokinetic parameters of vancomycin, it is unclear whether cancer patients were included in the Japanese patient populations employed to estimate population pharmacokinetic parameters for this drug. The difference of predictive accuracy between the Sawchuk–Zaske and Bayesian methods in Japanese cancer patients is not completely understood. Objective To retrospectively compare the accuracy of predicting vancomycin concentrations between the Sawchuk–Zaske method and the Bayesian method in Japanese cancer patients. Methods Using data from 48 patients with various malignancies, the predictive accuracy (bias) and precision of the two methods were assessed by calculating the mean prediction error, the mean absolute prediction error, and the root mean squared prediction error. Results Prediction of the trough and peak vancomycin concentrations by the Sawchuk–Zaske method and the peak concentration by the Bayesian method showed a bias toward low values according to the mean prediction error. However, there were no significant differences between the two methods with regard to the changes of the mean prediction error, mean absolute prediction error, and root mean squared prediction error. Conclusion The Sawchuk–Zaske method and Bayesian method showed similar accuracy for predicting vancomycin concentrations in Japanese cancer patients.
