Mild Encephalopathy with Reversible Lesion in the Splenium of the Corpus Callosum and Bilateral Frontal White Matter

A 59-year-old man visited an emergency room due to the sudden onset of severe dysarthria with a drowsy mental status. MRI demonstrated T2 prolongation and restricted diffusion involving the splenium of the corpus callosum and bilateral frontal white matter neurological signs and symptoms were mild, and the recovery was complete within a week. Follow-up MRI performed one month later revealed complete resolution of the lesions. The clinical and radiological courses were consistent with previously reported reversible isolated splenial lesions in mild encephalitis/encephalopathy except for the presence of frontal lesions. This case suggests that such reversible lesions can occur outside the splenium

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 worldwide1, 2. 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 tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

Photovoltaic Device Application of a Hydroquinone-Modified Conductive Polymer and Dual-Functional Molecular Si Surface Passivation Technology

In the last decades, the conductive polymer PEDOT:PSS has been introduced in Si-based hybrid solar cells, gaining noticeable research interest and being considered a promising candidate for next generation solar cells which can achieve both of low manufacturing cost and high power conversion efficiency. This study succeeded in improving the electrical conductivity of PEDOT:PSS to 937 S/cm through a simple process of adding hydroquinone (HQ) to the pristine PEDOT:PSS solution. The results also showed that the addition of HQ to PEDOT:PSS(HQ-PEDOT:PSS) could not only dramatically improve the conductivity but also well-sustain the work function characteristics of PEDOT:PSS by promoting the formation of more continuous conductive-PEDOT channels without removing the insulating PSS. In this report, we reveal that the application of the HQ-PEDOT:PSS to the Si/PEDOT:PSS HSC could significantly improve the short-circuit current and open-circuit voltage characteristics to increase the power conversion efficiency of the HSCs compared to the conventional approaches. Moreover, we also treated the Si surface with the organic monomer, benzoquinone (BQ) to (1) passivate the excess Si surface defect states and (2) to improve the properties of the Si/PEDOT:PSS interface. We show that BQ treatment is able to dramatically increase the minority carrier lifetime induced by effective chemical and field-effect passivation in addition to enhancing the wettability of the Si surface with the PEDOT:PSS solution. As a result, the power conversion efficiency was increased by 10.6% by introducing HQ and BQ into the fabrication process of the Si/PEDOT:PSS HSC

Clinical Significance of Pre-to-Postoperative Dynamics of Aspartate Transaminase/Alanine Transaminase Ratio in Predicting the Prognosis of Renal Cell Carcinoma after Surgical Treatment

Background. This study is aimed at examining the prognostic role of pre-to-postoperative dynamics of De Ritis ratio (aspartate aminotransaminase (AST)/alanine aminotransaminase (ALT)) in patients with nonmetastatic renal cell carcinoma (RCC) following radical nephrectomy. Methods. We retrospectively reviewed the records of 670 patients who underwent radical nephrectomy for nonmetastatic RCC between 1996 and 2012 at our institution. The cutoff points for preoperative (=1.0) and postoperative AST/ALT ratios (=1.12) were assigned based on the median values. We categorized patients into four groups according to the dynamics of AST/ALT ratios: group 1 (lower (≤1.0) ⟶ lower (≤1.12)), group 2 (lower (≤1.0) ⟶ higher (>1.12)), group 3 (higher (>1.0) ⟶ lower (≤1.12)), and group 4 (higher (>1.0) → higher (>1.12)). Results. When grouped by a preoperative AST/ALT ratio alone, the groups were not statistically different in cancer-specific survival (CSS) or overall survival (OS). In contrast, in Kaplan-Meier analysis, CSS (P=0.0296) and OS (P=0.0324) were both significantly shorter with an increased postoperative AST/ALT ratio. According to the pre-to-postoperative dynamics of the AST/ALT ratio, group 2 (lower (≤1.0) ⟶ higher (>1.12)) had a significantly lower CSS (P=0.0028) and OS (P=0.0194) than the other groups. On multivariate Cox regression analysis, the pre-to-postoperative dynamics of the AST/ALT ratio were a significant prognostic factor for CSS (hazard ratio, HR=3.45) and OS (HR=2.18). Conclusion. This study is the first to suggest that the dynamics of the pre-to-postoperative De Ritis ratio represent an independent prognostic factor for RCC patients following nephrectomy

Pharmacological perturbation of thiamine metabolism sensitizes Pseudomonas aeruginosa to multiple antibacterial agents

New therapeutic concepts are critically needed for carbapenem-resistant Pseudomonas aeruginosa, an opportunistic pathogen particularly recalcitrant to antibiotics. The screening of around 230,000 small molecules yielded a very low hit rate of 0.002% after triaging for known antibiotics. The only novel hit that stood out was the antimetabolite oxythiamine. Oxythiamine is a known transketolase inhibitor in eukaryotic cells, but its antibacterial potency has not been reported. Metabolic and transcriptomic analyses indicated that oxythiamine is intracellularly converted to oxythiamine pyrophosphate and subsequently inhibits several vitamin-B1-dependent enzymes, sensitizing the bacteria to several antibiotic and non-antibiotic drugs such as tetracyclines, 5-fluorouracil, and auranofin. The positive interaction between 5-fluorouracil and oxythiamine was confirmed in a murine ocular infection model, indicating relevance during infection. Together, this study revealed a system-level significance of thiamine metabolism perturbation that sensitizes P. aeruginosa to multiple small molecules, a property that could inform on the development of a rational drug combination.Ministry of Education (MOE)National Research Foundation (NRF)Submitted/Accepted versionThis work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIT) (NRF-2014K1A4A7A01074645, 2017M3A9G6068246, and 2019M3E5D5064653 to S.J.), by the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 2 (grant MOE2017-T2-1-063 to K.P.), and by the National Research Foundation, Singapore, under its Investigatorship Program (NRF-NRFI06-2020-0004 to K.P.)

Property-Based Optimization of Hydroxamate-Based γ‑Lactam HDAC Inhibitors to Improve Their Metabolic Stability and Pharmacokinetic Profiles

Hydroxamate-based HDAC inhibitors have promising anticancer activities but metabolic instability and poor pharmacokinetics leading to poor in vivo results. QSAR and PK studies of HDAC inhibitors showed that a γ-lactam core and a modified cap group, including halo, alkyl, and alkoxy groups with various carbon chain linkers, improved HDAC inhibition and metabolic stability. The biological properties of the γ-lactam HDAC inhibitors were evaluated; the compound designated <b>8f</b> had potent anticancer activity and high oral bioavailability