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Background and Objectives : In this study, our objective was to assess and compare the changes in visual and structural outcomes among patients with neovascular age-related macular degeneration (nAMD) who were switched from intravitreal aflibercept (IVA) to either intravitreal brolucizumab (IVBr) or intravitreal faricimab (IVF) injections in a clinical setting. Materials and Methods : This observational clinical study included 20 eyes of 20 patients switched to brolucizumab and 15 eyes of 14 patients switched to faricimab from aflibercept in eyes with nAMD. We measured the structural outcome (central macular thickness (CMT)) and the visual outcome (best-corrected visual acuity (BCVA); logMAR) as follows: just before the most recent IVA injection (B0), one month after the most recent IVA injection (B1), just before the first IVBr or IVF injection (A0), one month after (A1) and three months after (A3) the first IVBr or IVF injection. Results : BCVA showed significant improvement at A1 (0.25 ± 0.34) and at A3 (0.19 ± 0.24) compared to A0 (0.38 ± 0.35) in the IVBr group ( p = 0.0156, p = 0.0166, respectively). CMT (μm) was significantly thinner at A1 (IVBr: 240.55 ± 51.82, IVF: 234.91 ± 47.29) and at A3 (IVBr: 243.21 ± 76.15, IVF: 250.50 ± 72.61) compared to at A0 (IVBr: 303.55 ± 79.18, IVF: 270.33 ± 77.62) in the IVBr group (A1: p = 0.0093, A3: p = 0.0026) and in the IVF group (A1: p = 0.0161, A3: p = 0.0093). There was no significant difference in BCVA and CMT improvement observed between two groups at any time point ( p > 0.05 for all). Conclusions : Switching from aflibercept to either brolucizumab or faricimab has a significant anatomical effect in eyes with nAMD and both treatments appear to be effective short-term treatment options. There is a trend towards greater visual improvements and reductions in CMT with brolucizumab.

Familial episodic pain syndrome (FEPS) is an early childhood onset disorder of severe episodic limb pain caused mainly by pathogenic variants of SCN11A , SCN10A , and SCN9A , which encode three voltage-gated sodium channels (VGSCs) expressed as key determinants of nociceptor excitability in primary sensory neurons. There may still be many undiagnosed patients with FEPS. A better understanding of the associated pathogenesis, epidemiology, and clinical characteristics is needed to provide appropriate diagnosis and care. For this study, nationwide recruitment of Japanese patients was conducted using provisional clinical diagnostic criteria, followed by genetic testing for SCN11A , SCN10A , and SCN9A . In the cohort of 212 recruited patients, genetic testing revealed that 64 patients (30.2%) harbored pathogenic or likely pathogenic variants of these genes, consisting of 42 (19.8%), 14 (6.60%), and 8 (3.77%) patients with variants of SCN11A , SCN10A , and SCN9A , respectively. Meanwhile, the proportions of patients meeting the tentative clinical criteria were 89.1%, 52.0%, and 54.5% among patients with pathogenic or likely pathogenic variants of each of the three genes, suggesting the validity of these clinical criteria, especially for patients with SCN11A variants. These clinical diagnostic criteria of FEPS will accelerate the recruitment of patients with underlying pathogenic variants who are unexpectedly prevalent in Japan.

Background: The aim of this study is to examine the outcomes of an accelerated fractionated irradiation for N0 glottic carcinoma., Methods: In this retrospective analysis, 29 patients with N0 glottic carcinoma treated by radiation therapy were enrolled. Thirteen patients had T1a disease, six had T1b disease, and ten had T2 disease. A fractional dose of 2.1 Gy was administered to seven patients. The total doses were 65.1 and 67.2 Gy in four and three patients, respectively. A fractional dose of 2.25 Gy was administered to 22 patients. The total doses were 63 and 67.5 Gy in 21 patients and 1 patient with T2 disease, respectively. Additionally, 13 patients underwent the use of TS-1 (80-100 mg per day)., Results: The median follow-up period was 33 months, and the 3-year local control rate was 95.6%. No patient had a lymph node or distant recurrence. As acute adverse events, grades 2 and 3 dermatitis were observed in 18 patients and 1 patient, and grades 2 and 3 mucositis were observed in 15 patients and 1 patient. As a late adverse event, one patient required tracheotomy because of laryngeal edema occurring., Conclusions: Accelerated fractionated irradiation may be an option in the radiation therapy of N0 glottic carcinoma because of its ability to shorten the treatment time.

Although the 20S core particle (CP) of the proteasome is an important component of the 26S holoenzyme, the stand-alone 20S CP acts directly on intrinsically disordered and oxidized/damaged proteins to degrade them in a ubiquitin-independent manner. It has been postulated that some structural features of substrate proteins are recognized by the 20S CP to promote substrate uptake, but the mechanism of substrate recognition has not been fully elucidated. In this study, we screened peptides that bind to the 20S CP from a random eight-residue pool of amino acid sequences using complementary DNA display an in vitro molecular evolution technique. The identified 20S CP-binding amino acid sequence was chemically synthesized and its effects on the 20S CP were investigated. The 20S CP-binding peptide stimulated the proteolytic activity of the inactive form of 20S CP. The peptide bound directly to one of the α-subunits, opening a gate for substrate entry on the α-ring. Furthermore, the attachment of this peptide sequence to α-synuclein enhanced its degradation by the 20S CP in vitro. In addition to these results, docking simulations indicated that this peptide binds to the top surface of the α-ring. These peptides could function as a key to control the opening of the α-ring gate.

Children with Kawasaki disease are prescribed acetylsalicylic acid powder as an antipyretic analgesic and antiplatelet agent; however, some of it remains in the mouth, leading to a bitter or sour taste. To address this issue, an in-hospital mini-tablet formulation of acetylsalicylic acid was developed. In order to use the mini-tablets safely and effectively, dissolution tests alone are not sufficient. Therefore, an open-label crossover study on six healthy participants was conducted to evaluate comparative pharmacokinetic parameters. The pharmacokinetic parameters of salicylic acid were C max : 4.80 ± 0.79 mg/L (powder; P), 5.03 ± 0.97 mg/L (mini-tablet; MT), AUC 0-12 : 18.0 ± 3.03 mg-h/L (P), 18.9 ± 4.59 mg-h/L (MT), those of acetylsalicylic acid C max : 0.50 ± 0.20 mg/L (P), 0.41 ± 0.24 mg/L (MT), AUC 0-12 : 0.71 ± 0.27 mg-h/L (P), 0.61 ± 0.36 mg-h/L (MT), with no significant differences between the mini-tablet and powder formulations. Although pharmacokinetic results obtained from adults cannot be directly applied to children, the results of this study are important for predicting pharmacokinetics. Furthermore, a formulation that can improve medication adherence in children who have difficulty taking acetylsalicylic acid powder, thus contributing to pediatric drug therapy.

Peracetic acid (PAA) disinfectants are effective against a wide range of pathogenic microorganisms, including bacteria, fungi, and viruses. Several studies have shown the efficacy of PAA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, its efficacy in SARS-CoV-2 variants and the molecular mechanism of action of PAA against SARS-CoV-2 have not been investigated. SARS-CoV-2 infection depends on the recognition and binding of the cell receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD) of the spike protein. Here, we demonstrated that PAA effectively suppressed pseudotyped virus infection in the Wuhan type and variants, including Delta and Omicron. Similarly, PAA reduced the authentic viral load of SARS-CoV-2. Computational analysis suggested that the hydroxyl radicals produced by PAA cleave the disulfide bridges in the RBD. Additionally, the PAA treatment decreased the abundance of the Wuhan- and variant-type spike proteins. Enzyme-linked immunosorbent assay showed direct inhibition of RBD-ACE2 interactions by PAA. In conclusion, the PAA treatment suppressed SARS-CoV-2 infection, which was dependent on the inhibition of the interaction between the spike RBD and ACE2 by inducing spike protein destabilization. Our findings provide evidence of a potent disinfection strategy against SARS-CoV-2.

Many important biological processes such as protein folding and ligand binding are too fast to be fully resolved using conventional stopped-flow techniques. Although advances in mixer design and detection methods have provided access to the microsecond time regime, there is room for improvement in terms of temporal resolution and sensitivity. To address this need, we developed a continuous-flow mixing instrument with a dead time of 12 to 27 µs (depending on solution viscosity) and enhanced sensitivity, sufficient for monitoring tryptophan or tyrosine fluorescence changes at fluorophore concentrations as low as 1 µM. Relying on commercially available laser microfabrication services, we obtained an integrated mixer/flow-cell assembly on a quartz chip, based on a cross-channel configuration with channel dimensions and geometry designed to minimize backpressure. By gradually increasing the width of the observation channel downstream from the mixing region, we are able to monitor a reaction progress time window ranging from ~10 µs out to ~3 ms. By combining a solid-state UV laser with a Galvano-mirror scanning strategy, we achieved highly efficient and uniform fluorescence excitation along the flow channel. Examples of applications, including refolding of acid-denatured cytochrome c triggered by a pH jump and binding of a peptide ligand to a PDZ domain, demonstrate the capability of the technique to resolve fluorescence changes down to the 10 µs time regime on modest amounts of reagents.

The aim of this study was to establish a drug delivery system (DDS) for marked therapy of tumors using a thermoresponsive polymer, polyoxazoline (POZ). The effectiveness of the following was investigated: (i) the delivery of gold nanorods (GNRs) to tumor tissues, (ii) heat production of GNR upon irradiation with near-infrared (NIR) light, and (iii) high accumulation of an intravenously injected radiolabeled POZ as a drug carrier in tumors by sensing heat produced by GNRs. When the GNR solution was irradiated with NIR light (808 nm), the solution temperature was increased both in a GNR-concentration-dependent manner and in a light-dose-dependent manner. POZ, with a lower critical solution temperature of 38 °C, was aggregated depending on the heat produced by the GNR irradiated by NIR light. When it was intratumorally pre-injected into colon26-tumor-bearing mice, followed by NIR light irradiation (GNR+/Light+ group), the tumor surface temperature increased to approximately 42 °C within 5 min. Fifteen minutes after irradiation with NIR light, indium-111 ( 111 In)-labeled POZ was intravenously injected into tumor-bearing mice, and the radioactivity distribution was evaluated. The accumulation of POZ in the tumor was significantly (approximately 4-fold) higher than that in the control groups (GNR+/without NIR light irradiation (Light-), without injection of GNR (GNR-)/Light+, and GNR-/Light- groups). Furthermore, an in vivo confocal fluorescence microscopy study, using fluorescence-labeled POZ, revealed that uptake of POZ by the tumor could be attributed to the heat produced by GNR. In conclusion, we successfully established a novel DDS in which POZ could be efficiently delivered into tumors by using the heat produced by GNR irradiated with NIR light.

Colorectal cancer (CRC) screening is effective for detecting cancer in average-risk adults. For prostate cancer (PCa) patients considered for carbon ion radiotherapy (CIRT), pre-treatment CRC screening is performed empirically to avoid post-treatment colonoscopic manipulation. However, the outcomes of screening this population remain unclear. Here, we compared the outcomes of routine pre-CIRT CRC screening of 2412 PCa patients at average risk for CRC with data from two published datasets: the Japan National Cancer Registry (JNCR) and a series of 17 large-scale screening studies analyzing average-risk adults. The estimated prevalence rate was calculated using the pooled sensitivity elucidated by a previous meta-analysis. Consequently, 28 patients (1.16%) were diagnosed with CRC. CRC morbidity was significantly associated with high pre-treatment levels of prostate-specific antigen ( p = 0.023). The screening positivity rate in this study cohort exceeded the annual incidence reported in the JNCR for most age brackets. Furthermore, the estimated prevalence rate in this study cohort (1.46%) exceeded that reported in all 17 large-scale studies, making the result an outlier ( p = 0.005). These data indicate the possibility that the prevalence of CRC in PCa patients is greater than that in general average-risk adults, warranting further research in a prospective setting.

Interstitial lung disease (ILD) is a risk factor both for the development and treatment failure of lung cancer. In this retrospective study, we analyzed the outcome of carbon-ion radiotherapy (CIRT) in 124 patients with clinical stage I non-small cell lung cancer (NSCLC), of whom 26 (21%) had radiological signs of pre-existing ILD. ILD was diagnosed retrospectively by a pulmonologist based on critical review of CT-scans. Ninety-eight patients were assigned to the non-ILD group and 26 patients (21.0%) to the ILD group. There were significant differences in pre-treatment KL-6 values between the two groups. The three year overall survival and cause-specific survival rates were 83.2% and 90.7%, respectively, in the non-ILD group, and 59.7% and 59.7%, respectively, in the ILD group (between-group differences, p = 0.002 and p < 0.001). Radiation pneumonitis worse than Grade 2 was observed in three patients (3.0%) in the non-ILD group and two patients (7.6%) in the ILD group ( p = 0.29). There were no cases of acute exacerbation in the ILD group. CIRT for stage I NSCLC was as safe in the ILD group as in the non-ILD group. Coexisting ILD was a poor prognostic factor in CIRT for clinical stage I lung cancer.

R(+)-α-lipoic acid (RALA) is a naturally-occurring substance, and its protein-bound form plays significant role in the energy metabolism in the mitochondria. RALA is vulnerable to a variety of physical stimuli, including heat and UV light, which prompted us to study the stability of its complexes with cyclodextrins (CDs). In this study, we have prepared and purified a crystalline RALA-αCD complex and evaluated its properties in the solid state. The results of ¹H NMR and PXRD analyses indicated that the crystalline RALA-αCD complex is a channel type complex with a molar ratio of 2:3 (RALA:α-CD). Attenuated total reflection/Fourier transform infrared analysis of the complex showed the shift of the C=O stretching vibration of RALA due to the formation of the RALA-αCD complex. Raman spectroscopic analysis revealed the significant weakness of the S-S and C-S stretching vibrations of RALA in the RALA-αCD complex implying that the dithiolane ring of RALA is almost enclosed in glucose ring of α-CD. Extent of this effect was dependent on the direction of the excitation laser to the hexagonal morphology of the crystal. Solid-state NMR analysis allowed for the chemical shift of the C=O peak to be precisely determined. These results suggested that RALA was positioned in the α-CD cavity with its 1,2-dithiolane ring orientated perpendicular to the plane of the α-CD ring.

Constitutive activation of oncogenes by fusion to partner genes, caused by chromosome translocation and inversion, is a critical genetic event driving lung carcinogenesis. Fusions of the tyrosine kinase genes ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) occur in 1%-5% of lung adenocarcinomas (LADCs) and their products constitute therapeutic targets for kinase inhibitory drugs. Interestingly, ALK, RET, and ROS1 fusions occur preferentially in LADCs of never- and light-smokers, suggesting that the molecular mechanisms that cause these rearrangements are smoking-independent. In this study, using previously reported next generation LADC genome sequencing data of the breakpoint junction structures of chromosome rearrangements that cause oncogenic fusions in human cancer cells, we employed the structures of breakpoint junctions of ALK, RET, and ROS1 fusions in 41 LADC cases as "traces" to deduce the molecular processes of chromosome rearrangements caused by DNA double-strand breaks (DSBs) and illegitimate joining. We found that gene fusion was produced by illegitimate repair of DSBs at unspecified sites in genomic regions of a few kb through DNA synthesis-dependent or -independent end-joining pathways, according to DSB type. This information will assist in the understanding of how oncogene fusions are generated and which etiological factors trigger them.

α-Lipoic acid (ALA) has a chiral center at the C6 position, and exists as two enantiomers, R(+)-ALA (RALA) and S(-)-ALA (SALA). RALA is naturally occurring, and is a cofactor for mitochondrial enzymes, therefore playing a major role in energy metabolism. However, RALA cannot be used for pharmaceuticals or nutraceuticals because it readily polymerizes via a 1,2-dithiolane ring-opening when exposed to light or heat. So, it is highly desired to find out the method to stabilize RALA. The purpose of this study is to provide the spectroscopic information of stabilized RALA and SALA through complexation with cyclodextrins (CDs), α-CD, β-CD and γ-CD and to examine the physical characteristics of the resultant complexes in the solid state. The RALA-CD structures were elucidated based on the micro fourier transform infrared (FT-IR) and Raman analyses. The FT-IR results showed that the C=O stretching vibration of RALA appeared at 1717 cm⁻¹ and then shifted on formation of the RALA-CD complexes. The Raman spectra showed that the S-S and C-S stretching vibrations for RALA at 511 cm⁻¹ (S-S), 631 cm⁻¹ (C-S) and 675 cm⁻¹ (C-S) drastically weakened and almost disappeared upon complexation with CDs. Several peaks indicative of O-H vibrations also shifted or changed in intensity. These results indicate that RALA and CDs form host-guest complexes by interacting with one another.