A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.

Phase Ib study of durvalumab (MEDI4736) in combination with carbon-ion radiotherapy and weekly cisplatin for patients with locally advanced cervical cancer (DECISION study): study protocol for a prospective open-label single-arm study.

INTRODUCTION: Concurrent chemoradiotherapy is considered the standard treatment strategy for locally advanced cervical cancer. Most recent reports indicate that patients with bulky tumours or adenocarcinoma subtypes have poorer local control. Carbon-ion radiotherapy (CIRT) with the concurrent use of chemotherapy has shown promising results in such cases of difficult-to-treat uterine cervical cancer. Programmed death-ligand 1 (PD-L1) upregulation was observed in tumour tissue samples from patients who had undergone CIRT. Thus, a combination of CIRT and anti-PD-L1 antibody may suppress metastasis by activating antitumour immune response, in addition to exhibiting strong local effects. OBJECTIVE: We will assess the safety and tolerability (primary endpoint) of the concomitant use of durvalumab, an anti-PD-L1 antibody, with CIRT and weekly cisplatin for locally advanced cervical cancer. METHODS AND ANALYSIS: This study is a non-randomised, open-label, prospective phase 1b study. Up to 10 patients with histologically proven uterine cervical cancer at stage IIB, IIIA, IIIB, IIIC1 or IVA as per International Federation of Gynecology and Obstetrics (2018) staging will be enrolled. All patients will receive CIRT of 74.4 Gy relative biological effectiveness in 20 fractions over 5 weeks (four fractions per week). Weekly cisplatin at a dose of 40 mg/m2 will be administrated up to five times. Durvalumab at a dose of 1500 mg/body will be administrated at weeks 2 and 6. Safety and tolerability will be evaluated based on the frequency of dose-limiting toxicities until 92 days after CIRT starts. Patients will be followed-up strictly as per the scheduled protocol for 1 year after CIRT initiation. ETHICS AND DISSEMINATION: The Human Research Ethics Committees of QST Hospital (#C21-002) and Chiba University (#2021006) have approved this study protocol. The findings will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCT2031210083), registered on 12 May 2021.

Improvements of Retinal Sensitivity after Intravitreal Injection of Aflibercept in Eyes with Neovascular Age-Related Macular Degeneration with or without Polypoidal Choroidal Vasculopathy.

PURPOSE: We aim to determine the effects of intravitreal aflibercept (IVA) on the mean sensitivity (MS) of the central retina, best-corrected visual acuity (BCVA), and central foveal thickness (CFT) in eyes with neovascular age-related macular degeneration (nAMD) with or without polypoidal choroidal vasculopathy (PCV). METHODS: This was a prospective, interventional study. All eyes were treatment-naive with nAMD with or without PCV. Each eye received 3 monthly IVA injections followed by an IVA injection every 2 months for 12 months. The primary outcome was the change in the MS within the central 2°. The secondary outcomes were the changes in BCVA, CFT, greatest linear dimension (GLD), and percentage of eyes with a dry macula. RESULTS: Thirty-seven eyes of 37 patients were studied. A significant improvement of the MS (dB) was observed +4.9 ± 4.6 dB (mean ± standard deviation) at 3 M (p < 0.001), +5.5 ± 4.9 dB at 6 (p < 0.001), and +7.0 ± 3.4 dB at 12 M (p < 0.001) compared to the baseline in all eyes. The MS of the eyes with non-PCV was not significantly different from that of eyes with PCV (p = 1.00, 1.00, 1.00, and 0.76 at baseline, 3, 6, and 12 M, respectively). The MS of 11 patients whose BCVA remained unchanged was significantly improved by +6.5 ± 2.8 dB at 3 M (p < 0.001), +6.1 ± 4.3 dB at 6 M (p < 0.001), and +6.4 ± 4.8 dB at 12 M (p = 0.003) compared to the baseline. The mean BCVA was significantly improved from the baseline to 3 M (p < 0.001), 6 M (p = 0.027), and 12 M (p = 0.003) in all eyes. The BCVA was improved or maintained in 97% of the patients at 12 M. The mean CFT and GLD were significantly reduced at 12 M (p < 0.001). Twenty-two eyes (71%) had a dry macula at 12 M. CONCLUSIONS: IVA administered by a fixed dosing regimen led to significant improvements of the central MS, BCVA, and macular morphology at 1 year in eyes with nAMD with or without PCV. These results were not significantly different between eyes with non-PCV and with PCV. The improvements of the MS of the retina of the central 2° in a subgroup whose BCVA remained unchanged through the 12-month experimental period was also significant. We conclude that the MS of the central 2° might be a better marker than the BCVA in determining the effectiveness of IVA treatments and might be helpful in determining early effects on the retina before BCVA changes can be detected.

Metabolite and Phytohormone Profiling Illustrates Metabolic Reprogramming as an Escape Strategy of Deepwater Rice during Partially Submerged Stress.

Rice varieties that can survive under submergence conditions respond to flooding either by enhancing internode elongation or by quiescence of shoot elongation. Despite extensive efforts to identify key metabolites triggered by complete submergence of rice possessing SUBMERGENCE 1 (SUB1) locus, metabolic responses of internode elongation of deepwater rice governed by the SNORKEL 1 and 2 genes remain elusive. This study investigated specific metabolomic responses under partial submergence (PS) to deepwater- (C9285) and non-deepwater rice cultivars (Taichung 65 (T65)). In addition, we examined the response in a near-isogenic line (NIL-12) that has a C9285 genomic fragment on chromosome 12 introgressed into the genetic background of T65. Under short-term submergence (0-24 h), metabolite profiles of C9285, NIL-12, and T65 were compared to extract significantly changed metabolites in deepwater rice under PS conditions. Comprehensive metabolite and phytohormone profiling revealed increases in metabolite levels in the glycolysis pathway in NIL-12 plants. Under long-term submergence (0-288 h), we found decreased amino acid levels. These metabolomic changes were opposite when compared to those in flood-tolerant rice with SUB1 locus. Auxin conjugate levels related to stress response decreased in NIL-12 lines relative to T65. Our analysis helped clarify the complex metabolic reprogramming in deepwater rice as an escape strategy.

Mycobacterium pseudoshottsii isolated from 24 farmed fishes in western Japan.

Mycobacteria isolated from epizootics of farmed fishes in western Japan were examined for the first time using multigenotypic analysis. By analysis of the sequences of the internal transcribed spacer between the 16S and 23S rRNA genes (ITS) region and the partial 16S rRNA, hsp65 and rpoB genes, M. pseudoshottsii was identified as the causative agent in these infections. Prior to this study, only M. marinum has been known as the causative agent of lethal mycobacterial disease in marine fishes in Japan.

Vacuolar proton pumps and aquaporins involved in rapid internode elongation of deepwater rice.

Rapid growth of the submerged shoots of deepwater rice is essential for survival during the rainy season. We investigated changes in the expression of vacuolar H(+)-ATPase (V-ATPase), H(+)-pyrophosphatase (V-PPase), and aquaporins under submerged conditions. The amounts of vacuolar proton pumps, which support the active transport of ions into the vacuoles, were maintained on a membrane protein basis in the developing vacuoles. Among the six isogenes of V-PPase, OsVHP1;3 was markedly enhanced by submersion. The gene expression of efficient water channels, OsTIP1;1, OsTIP2;2, OsPIP1;1, OsPIP2;1, and OsPIP2;2, was markedly enhanced by submersion. The increase in aquaporin expression might support quick elongation of internodes. The mRNA levels of OsNIP2;2 and OsNIP3;1, which transport silicic and boric acids respectively, clearly decreased. The present study indicates that internodes of deepwater rice upregulate vacuolar proton pumps and water channel aquaporins and downregulate aquaporins that allow permeation of the substrates that suppress internode growth.

Rice growth adapting to deepwater.

Flooding is one of the most hazardous natural disasters, and there are several levels of flooding. Recently, research on flood-tolerant rice plants revealed that some rice varieties have evolved to overcome two different flood types, 'flash flood' and 'deepwater flood', using two different mechanisms, and their molecular mechanisms were determined. During flash flooding, the tolerant plants that are fully submerged for a few weeks stop elongating and thus avoid energy consumption that will be needed to restart growth when the water recedes. On the contrary, during deepwater flooding, with water depth up to several meters for several months, the deepwater-flood-tolerant rice plants promote elongation of internodes to keep the foliage above the water surface and thus allow respiration and photosynthesis.

Development of an evaluation scale for self-monitoring by patients with heart failure.

Many chronic heart failure patients are hospitalized repeatedly because many of them are still uncertain about the methods necessary for managing their own health. "Self-monitoring" is a useful concept for breaking through this vicious cycle. However, there are no suitable tools to measure aspects of self- monitoring. This study aimed at the development of an evaluation scale for self-monitoring by patients with chronic heart failure based on the concept of self-monitoring. Outpatient with chronic heart failure completed a self-administered scale comprises 2 domains and covers 38 items. Domain 1 deals with "awareness" and "measurement" of aspects of self-monitoring, domain 2 with "interpretation" of aspects of self-monitoring. The reliability and validity of this scale were thoroughly evaluated. Of the 167 patients asked to participate in the study, 142 gave valid responses. Factor analysis showed that the domain1 comprised six factors (21 items) and the domain2 four factors (16 items). Cronbach's α coefficient was 0.91 for domain1, 0.89 for domain2. The intra-class correlation coefficient of total score was 0.74 for domain1, 0.67 for domain2. Concurrent validity with the Heart Failure Self-care Behavior Scale was demonstrated. The scale is reasonably reliable and valid, and was proved to be useful for assessing conditions related to patient self-monitoring. Since it has become an indicator that shows to what degree patients can perceive their own health status, and nurses have been utilizing it to provide individual support to reduce the risks of exacerbated heart failure.

Crystallization and preliminary X-ray analysis of dimeric and trimeric cytochromes c from horse heart.

Cytochrome c (cyt c) is an electron-transfer protein in the respiratory chain of mitochondria. It is known to form polymers, but its polymerization mechanism is still unknown. Dimeric and trimeric cyt c from horse were successfully crystallized by the sitting-drop vapour-diffusion method using polyethylene glycol as a precipitating reagent. The crystal of dimeric cyt c belonged to space group P1, with unit-cell parameters a = 41.8, b = 56.3, c = 60.8 Å, α = 66.3, ß = 89.9, γ = 73.7°, whereas that of trimeric cyt c belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 57.2, b = 95.7, c = 130.9 Å. Initial structure models showed that the crystals of dimeric and trimeric cyt c contained two dimers and two trimers, respectively, in the asymmetric unit.

Cytochrome c polymerization by successive domain swapping at the C-terminal helix.

Cytochrome c (cyt c) is a stable protein that functions in a monomeric state as an electron donor for cytochrome c oxidase. It is also released to the cytosol when permeabilization of the mitochondrial outer membrane occurs at the early stage of apoptosis. For nearly half a century, it has been known that cyt c forms polymers, but the polymerization mechanism remains unknown. We found that cyt c forms polymers by successive domain swapping, where the C-terminal helix is displaced from its original position in the monomer and Met-heme coordination is perturbed significantly. In the crystal structures of dimeric and trimeric cyt c, the C-terminal helices are replaced by the corresponding domain of other cyt c molecules and Met80 is dissociated from the heme. The solution structures of dimeric, trimeric, and tetrameric cyt c were linear based on small-angle X-ray scattering measurements, where the trimeric linear structure shifted toward the cyclic structure by addition of PEG and (NH(4))(2)HPO(4). The absorption and CD spectra of high-order oligomers (approximately 40 mer) were similar to those of dimeric and trimeric cyt c but different from those of monomeric cyt c. For dimeric, trimeric, and tetrameric cyt c, the DeltaH of the oligomer dissociation to monomers was estimated to be about -20 kcal/mol per protomer unit, where Met-heme coordination appears to contribute largely to DeltaH. The present results suggest that cyt c polymerization occurs by successive domain swapping, which may be a common mechanism of protein polymerization.

Stunt or elongate? Two opposite strategies by which rice adapts to floods.

Expansion of habitat is important for the perpetuation of species. In particular, plants which are sedentary must evolve specialized functions to adapt itself to new environment. Deepwater rice is cultivated mainly in the lowland areas of South and Southeast Asia that are flooded during the rainy season. The internodes of deepwater rice elongates in response to increasing water level to keep its leaves above the water surface and avoid anoxia. This elongation is stimulated by ethylene-regulated genes, Snorkel1 and Snorkel2. In contrast, when a flash flood occurs at the seedling stage, submergence-tolerant rice, which carries Submergence-1A, remains stunted and survives in water for a few weeks to avoid the energy consumption associated with plant elongation, and restarts its growth using its conserved energy after the water recedes. Interestingly, both Snorkel genes and Submergence-1A encode ethylene-responsive factor-type transcription factor and are connected to gibberellin biosynthesis or signal transduction. However, deepwater and submergence-tolerant rice seem to have opposite flooding response; namely, escape by elongation or remain stunted under water until flood recedes.

Pravastatin use and cancer risk: a meta-analysis of individual patient data from long-term prospective controlled trials in Japan.

PURPOSE: To assess the influence of pravastatin therapy on cancer morbidity and mortality by a meta-analysis of individual patient data (IPD) from three independent Japanese large-scale clinical trials. METHODS: We conducted a meta-analysis of IPD collected from three large-scale prospective studies, the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, Kyushu Lipid Intervention Study (KLIS), and Hokuriku Lipid Coronary Heart Disease Study-Pravastatin Atherosclerosis Trial (Holicos-PAT), which compared cardiovascular outcomes with pravastatin therapy and non-statin therapy in Japanese patients with hypercholesterolemia over a follow-up period of >or=4 years. The incidence of cancer or cancer death in the pravastatin and non-statin therapy groups was compared by multivariate Cox proportional hazard models stratified by trial. Subgroup analyses by sex and age were also conducted using the same methods. RESULTS: In a total of 13 724 patients (mean age, 58 years; women, 48%) included in the analyses, pravastatin was not associated with an increased risk of developing cancer (hazard ratio [HR], 0.99; 95% confidence interval [95%CI], 0.81-1.19). Similarly, pravastatin therapy did not statistically affect cancer death (HR, 0.86; 95%CI, 0.61-1.21). Moreover, in subgroups analyses, no influence was observed on cancer incidence or death in relation to sex and age. CONCLUSION: Pravastatin did not increase the rate of cancer incidence or cancer death in a large population of Japanese patients followed for >70,000 patient-years.

The ethylene response factors SNORKEL1 and SNORKEL2 allow rice to adapt to deep water.

Living organisms must acquire new biological functions to adapt to changing and hostile environments. Deepwater rice has evolved and adapted to flooding by acquiring the ability to significantly elongate its internodes, which have hollow structures and function as snorkels to allow gas exchange with the atmosphere, and thus prevent drowning. Many physiological studies have shown that the phytohormones ethylene, gibberellin and abscisic acid are involved in this response, but the gene(s) responsible for this trait has not been identified. Here we show the molecular mechanism of deepwater response through the identification of the genes SNORKEL1 and SNORKEL2, which trigger deepwater response by encoding ethylene response factors involved in ethylene signalling. Under deepwater conditions, ethylene accumulates in the plant and induces expression of these two genes. The products of SNORKEL1 and SNORKEL2 then trigger remarkable internode elongation via gibberellin. We also demonstrate that the introduction of three quantitative trait loci from deepwater rice into non-deepwater rice enabled the latter to become deepwater rice. This discovery will contribute to rice breeding in lowland areas that are frequently flooded during the rainy season.

Measurement and evaluation of the acoustic noise of a 3 Tesla MR scanner.

We measured the sound level and frequencies of the acoustic noise generated by a 3 Tesla (T) MR scanner, and investigated the subjective sound level for 30 healthy volunteers with either earplugs, headphones or both. The sound level of 3T was found to be higher than that of 1.5T in all sequences. The peak sound pressure level of 3T ranged from 125.7 dB for MR angiography to 130.7 dB for single shot EPI on the linear scale. The equivalent noise level was from 110.0 dB for FLAIR to 115.8 dB for T1-IR on the A-weighted scale, which exceeded 99 dB, the level regulated by the International Electrotechnical Commission (IEC). The study of the subjective sound level showed that the effect of noise reduction was not significantly different between earplugs and headphones. However, the use of both devices could reduce the subjective sound level significantly better than either one alone (P < 0.01). Thus we propose wearing both devices for ear-protection during 3T examinations.

[Development of a brief communication ability scale for Japanese demented elderly].

We developed a brief scale to evaluate communication ability of the demented elderly. This scale assesses not only abilities related to overall communication such as verbal function, judgment and emotional function, but also non-verbal communication such as eye-contact, nodding and smiling. The scale places little burden on the demented elderly subject and takes only a few minutes to perform, even if the dementia is severe. We evaluated 106 demented elderly residents of nursing homes using this brief communication ability scale, and the following results were obtained. The validity of this scale was confirmed by the high correlation coefficient between this scale and the formal caregiver questionnaire scores concerning communication ability, and the high-correlation coefficient between this scale and intellectual functions (r = -0.904), emotional functions (r = -0.841) and motor functions (r = -0.679) of dementia syndromes rating scale (Gottfries, Bråne, Steen scale; GBS scale), Hasegawa's Dementia Scale-Revised (HDS-R) (r = 0.625) and the Mini-Mental State Examination (MMS) (r = 0.733). The reliability of this scale was confirmed by the high interrater reliability coefficient of 0.828, test-retest reliability coefficient of 0.940 and Cronbach alpha coefficient of 0.938. These results indicate that the new scale is useful in the assessment of communication ability among the demented elderly.

Assessment of utility of meiosis-associated promoters of lily for induction of germinal ds transposition in transgenic rice.

In order to suppress the somatic excision of the Ds element and increase the independent transposition events of the Ac/Ds transposon tagging system in rice, we employed promoters of two meiosis-specific genes of lily, LIM10 and LIM18. The LIM10 promoter directed GUS expression specifically in anthers, with the LIM18 promoter doing the same in the anthers and somatic tissue. Both promoters induced independent germinal transposition with the frequency of approximately 1%. The LIM10 promoter, lacking induction of somatic transposition, is considered to be useful for improving transposon-tagging efficiencies in rice.