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Objectives To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Methods We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomized into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day and IVMP 1.0 g/day. The primary outcome was all-cause mortality, and the secondary outcomes were composite all-cause mortality and kidney failure, severe relapse and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine–Gray subdistribution hazard model were used. Results In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (3%) died, 4 (2.0%) had kidney failure, 11 (5.5%) had severe relapse, and 40 (19.9%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause mortality 0.46 (95% CI: 0.07, 2.81) and 0.07 (95% CI: 0.01, 0.41), respectively; all-cause mortality/kidney failure 1.18 (95% CI: 0.26, 5.31) and 0.59 (95% CI: 0.08, 4.52), respectively; subdistribution HRs for severe relapse were 1.26 (95% CI: 0.12, 13.70) and 3.36 (95% CI: 0.49, 23.29), respectively; and for serious infection 1.88 (95% CI: 0.76, 4.65) and 0.94 (95% CI: 0.28, 3.13), respectively. Conclusion IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA. [ABSTRACT FROM AUTHOR]

Objectives: To identify the optimal dose of intravenous cyclophosphamide (IVCY) for induction therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis. Methods: We retrospectively assessed patients with antibody-associated vasculitis who received IVCY every 2–3 weeks during the remission induction phase. The associations of the IVCY dose with infection-free survival and relapse-free survival were analysed using a Cox regression model. We compared patients in three categories: very low-dose (VLD), low-dose (LD), and conventional dose (CD) (<7.5 mg/kg, 7.5–12.5 mg/kg, and >12.5 mg/kg, respectively). The non-linear association between IVCY dose and the outcomes was also evaluated. Results: Of the 80 patients (median age 72 years), 12, 42, and 26 underwent the VLD, LD, and CD regimens, respectively, of whom 4, 3, and 7 developed infection or died. The adjusted hazard ratios for infection or death were 4.3 (95% confidence interval (CI) 0.94–19.8) for VLD and 5.1 (95% CI 1.21–21.3) for CD, compared with LD. We found the hazard ratio for infection or death increased when the initial IVCY dose exceeded 9 mg/kg. Relapse-free survival did not differ clearly. Conclusion: Low-dose IVCY (7.5–12.5 mg/kg) may result in fewer infections and similar relapse rates compared with the conventional regimen (>12.5 mg/kg). [ABSTRACT FROM AUTHOR]

Objectives To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. Methods We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine–Gray model to assess the association between low IgG (the minimum IgG levels <500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups. Results Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03–3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. Conclusion Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation. [ABSTRACT FROM AUTHOR]

We introduce a seismic identification method for collapse events using moment tensors (MTs). We start by computing full (six-element) MT solutions for 43 identified collapse events from around the world, and statistically characterizing the population on the MT hypersphere. We then test a large data set of over 1000 full MTs for the western U.S. against the distribution of collapses using a MT-based identification method similarly as used for testing explosions. Known collapses and explosions are readily identified, along with other anomalous events in the Geysers and central California coast. Misidentification rates are determined for various screening angles with optimal misidentification rates between earthquakes and collapses on the order of 3 per cent. The method is demonstrated to be very effective at identifying non-earthquake sources with a 97–98 per cent accuracy. It is likely to be transportable to other regions, and can be used for event identification anywhere full MT solutions are routinely calculated. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the appropriate timing, useful findings and combination of magnetic resonance imaging (MRI) and ultrasound (US) for predicting the radiographic progression in early rheumatoid arthritis (RA). Methods: Forty-four active RA patients, who examined by both of MRI and US in the symptomatic wrist and finger joints, were recruited in Nagasaki University Hospital from 2010 to 2017 and treated by the treat-to-target therapeutic strategy for 1 year. MRI was evaluated by RA MRI scoring and US by Outcomes Measures in Rheumatology Clinical Trial, respectively. Plain radiographs were assessed by the Genant-modified Sharp score for the symptomatic side in the same manner as MRI and US. Radiographic progression was defined as an annual increase ≥0.75 at 1 year. Factors associated with radiographic progression were analysed. Also, the optimal combination of MRI and US at each timepoint was considered. Results: Logistic regression model revealed that MRI-proven bone marrow oedema at baseline and 6 months and joint counts of power-Doppler grade ≥2 articular synovitis at 3 or 6 months were significantly associated with radiographic progression at 1 year. Conclusion: This study may suggest the favourable timing and combination of MRI and US at each point to predict radiographic progression in patients with early-stage RA. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES This study aimed to compare the real-world outcomes of segmentectomy and lobectomy for lung cancer after adjusting for background factors and the extent of lymphadenectomy. METHODS This retrospective cohort study used a nationwide database in Japan. The data of patients with clinical stage 0/IA lung cancer who underwent segmentectomy or lobectomy between 2017 and 2019 were retrieved. Short-term postoperative outcomes were compared between the segmentectomy and lobectomy groups using propensity score-matched analysis. RESULTS In the total cohort of 59 663 patients, 11 975 and 47 688 patients were in the segmentectomy and lobectomy groups, respectively. After propensity score matching, 8426 matched patients from each group were retrieved. All confounders including age, sex, comorbidities, smoking history, respiratory function, tumour size, clinical stage, affected lobe and extent of lymphadenectomy were appropriately adjusted. The overall complication rate and the cardiopulmonary complication rate were lower in the segmentectomy group than in the lobectomy group (8.5% vs 11.2%, P  < 0.001 and 7.5% vs 10.3%, P  < 0.001, respectively). The incidence of prolonged air leak was also lower after segmentectomy than after lobectomy (3.6% vs 5.3%). Surgical mortality, operative time and blood loss volume were comparable between the 2 groups. CONCLUSIONS The postoperative complication rate was lower with segmentectomy than with lobectomy for early-stage lung cancer. [ABSTRACT FROM AUTHOR]

We experienced a case of humeral head impression fracture accounting for approximately 20% of the anterior articular surface. Open reduction and internal fixation of the proximal humeral fracture combined with arthroscope-assisted reduction and internal fixation of the humeral head impression fracture were performed, and good clinical and radiographic outcomes were obtained. Untreated impression fracture may be a potential risk for subluxation or osteoarthritis. However, our arthroscopic approach is minimally invasive and allows for the prevention of these risks. [ABSTRACT FROM AUTHOR]

Rapeseed contains high levels of glucosinolates (GSLs), playing pivotal roles in defense against herbivores and pests. As their presence in rapeseed reduces the value of the meal for animal feeding, intensive efforts to reduce them produced low-seed GSL cultivars. However, there is no such variety suitable for the south part of Japan. Here, we tested the effects of cold oxygen plasma (oxygen CP) on seed germination and GSL and lipid content, in 3 rapeseed cultivars. According to the cultivars, oxygen CP slightly stimulated seed germination and modified the GSL levels, and decreased GSL levels in Kizakinonatane but increased those in Nanashikibu. In contrast, it negligibly affected the lipid content and composition in the 3 cultivars. Thus, oxygen CP modulated seed GSL levels without affecting seed viability and lipid content. Future optimization of this technique may help optimize rapeseed GSL content without plant breeding. [ABSTRACT FROM AUTHOR]

Neopterin (NP), biopterin (BP) and monapterin (MP) exist in saliva. The physiological role of salivary NP as well as the pathophysiological role of increased NP in the immune-activated state has been unclear. Saliva is a characteristic specimen different from other body fluids. In this study, we analysed salivary NP and related pterin compounds, BP and MP and revealed some of its feature. High-performance liquid chromatography (HPLC) analysis of saliva and plasma obtained from 26 volunteers revealed that salivary NP existed mostly in its fully oxidized form. The results suggested that salivary NP as well as BP would mostly originate from the oral cavity, perhaps the salivary glands, and that salivary NP levels might not reflect those in the plasma. We also found that a gender difference existed in correlations between concentrations of salivary total concentrations of NP (tNP) and BP (tBP). HPLC analysis of saliva obtained from 5 volunteers revealed that the concentrations of salivary tNP as well as tBP fluctuated in an irregular fashion in various individuals. MP, a diastereomer of NP, might have come from oral cavity NP itself or its precursor. These results indicated that the nature of salivary NP might be different from that of NP in the blood or urine. [ABSTRACT FROM AUTHOR]

Exposure to hydrogen sulfide (H2S) can cause neurotoxicity and cardiopulmonary arrest. Resuscitating victims of sulfide intoxication is extremely difficult, and survivors often exhibit persistent neurological deficits. However, no specific antidote is available for sulfide intoxication. The objective of this study was to examine whether administration of a sulfonyl azide-based sulfide-specific scavenger, SS20, would rescue mice in models of H2S intoxication: ongoing exposure and post-cardiopulmonary arrest. In the ongoing exposure model , SS20 (1250 µmol/kg) or vehicle was administered to awake CD-1 mice intraperitoneally at 10 min after breathing 790 ppm of H2S followed by another 30 min of H2S inhalation. Effects of SS20 on survival were assessed. In the post-cardiopulmonary arrest model , cardiopulmonary arrest was induced by an intraperitoneal administration of sodium sulfide nonahydrate (125 mg/kg) in anesthetized mice. After 1 min of cardiopulmonary arrest, mice were resuscitated with intravenous administration of SS20 (250 µmol/kg) or vehicle. Effects of SS20 on survival, neurological outcomes, and plasma H2S levels were evaluated. Administration of SS20 during ongoing H2S inhalation improved 24-h survival (6/6 [100%] in SS20 vs 1/6 [17%] in vehicle; p  =  .0043). Post-arrest administration of SS20 improved 7-day survival (4/10 [40%] in SS20 vs 0/10 [0%] in vehicle; p  =  .0038) and neurological outcomes after resuscitation. SS20 decreased plasma H2S levels to pre-arrest baseline immediately after reperfusion and shortened the time to return of spontaneous circulation and respiration. These results suggest that SS20 is an effective antidote against lethal H2S intoxication, even when administered after cardiopulmonary arrest. [ABSTRACT FROM AUTHOR]

Breast cancer arising from fibroadenoma (FA) is rare, in which almost all reported cases are human epidermal growth factor receptor 2 (HER2)-negative. This is the first report to describe a case of HER2-positive breast cancer arising from FA that was treated with chemotherapy plus anti-HER2 therapy. In this early case, upfront surgery outcomes guided the selection of appropriate systemic therapy. A 31-year-old woman previously diagnosed with FA experienced tumor growth. Core needle biopsy and imaging studies confirmed a diagnosis of stage IIA HER2-positive invasive ductal carcinoma (IDC) with no evidence of lymph node metastasis (cT2N0M0). Breast-conserving surgery was performed. Pathological diagnosis revealed stage IA IDC with a predominant intraductal component (pT1aN0M0), arising from FA. In conclusion, we encountered an extremely rare case of HER2-positive breast cancer arising from FA in which pathological infiltration was difficult to predict based on preoperative imaging. [ABSTRACT FROM AUTHOR]

Objectives: Our previous study showed that the effectiveness of tumor necrosis factor (TNF) inhibitors was attenuated in anti-human T-cell leukemia virus type 1 (HTLV-1) antibody-positive patients with rheumatoid arthritis (RA). We aimed to evaluate the effectiveness and safety of non-TNF inhibitors in anti-HTLV-1 antibody-positive patients with RA. Methods: We reviewed patients with RA who received abatacept or tocilizumab as the first biologic agent. We used the data of patients treated with TNF inhibitors from our previous study to compare the effectiveness between the anti-HTLV-1 antibody-positive patients treated with TNF inhibitors and non-TNF inhibitors using the inverse probability of treatment weights (IPTW) method. Results: A total of 359 patients were divided into anti-HTLV-1 antibody-negative and -positive patients of 332 and 27, respectively. No statistically significant difference was observed in the change in the clinical disease activity index between the anti-HTLV-1 antibody-positive and -negative patients. The results using the IPTW method showed a significant association between the non-TNF inhibitors treatment and a better response. None of the patients developed adult T-cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis during the 24 weeks. Conclusion: Our results indicate that non-TNF inhibitors treatment is safety, and the effectiveness is not attenuated also in anti-HTLV-1 antibody-positive patients. [ABSTRACT FROM AUTHOR]

Granulomatous mastitis is a rare breast disease that is categorized as a benign tumor with chronic inflammation. Since the cause of the chronic inflammation is usually unknown, it is sometimes called idiopathic granulomatous mastitis (IGM). Although imaging modalities, such as ultrasound, magnetic resonance imaging and mammography can detect tumors, they are sometimes unable to differentiate between benign and malignant tumors. In such cases, biopsy is needed to make a correct diagnosis. We experienced three cases of IGM after breast conserving surgery in breast cancer patients in whom we needed to rule out recurrence of breast cancer. In our cases, tumorectomy was performed in two cases for pathological diagnosis, since neither biopsy nor cytology was able to reveal a conclusive pathological diagnosis. Our management of these three cases might suggest the appropriate management of granulomatous tumors after breast conserving surgery in breast cancer survivors. [ABSTRACT FROM AUTHOR]

Objective We aimed to compare life prognosis and renal relapse after induction therapy in proliferative (PLN) and pure membranous LN (MLN). Methods We retrospectively analysed the cases of 140 of 172 patients with LN who underwent a renal biopsy at our hospital or community hospitals from 1993 to 2016. We determined the complete response (CR) rate at 12 months after the patients had started induction therapy, and we evaluated the predictive factors for CR, life prognosis and renal relapse in PLN and pure MLN. We defined PLN as International Society of Neurology and the Renal Pathology Society (ISN/RPS) Class III or IV and MLN as ISN/RPS Class V. Results The renal pathology of 99 (70.7%) patients was classified as PLN, and that of the other 41 (29.3%) patients as MLN. Fifty patients (50.5%) with PLN and 22 patients (53.7%) with MLN achieved a CR at 12 months. A multivariate analysis showed that a lower index of chronicity in PLN and a higher total haemolytic complement (CH50) level in MLN were predictive factors for achieving a CR at 12 months. A Kaplan–Meier analysis showed that the life prognosis (P  = 0.93) and renal relapse (P  = 0.52) were not significantly different between PLN and MLN. Conclusions The predictive factors for a CR at 12 months post-induction therapy were index of chronicity in PLN and CH50 level in MLN. There were no significant differences in life prognosis or renal relapse between PLN and MLN in the achievement of a CR at 12 months post-induction therapy. [ABSTRACT FROM AUTHOR]

In larviculture facilities, rotifers are generally used as an initial food source, while a proper size of live feeds to connect rotifer and Artemia associated with fish larval growth is needed. The improper management of feed size and density induces mass mortality and abnormal development of fish larvae. To improve the survival and growth of target larvae, this study applied carbon and argon heavy-ion-beam irradiation in mutation breeding to select rotifer mutants with larger lorica sizes. The optimal irradiation conditions of heavy-ion beam were determined with lethality, reproductivity, mutant frequency, and morphometric characteristics. Among 56 large mutants, TYC78, TYC176, and TYA41 also showed active population growth. In conclusion, (1) heavy-ion-beam irradiation was defined as an efficient tool for mutagenesis of rotifers and (2) the aforementioned 3 lines that have larger lorica length and active population growth may be used as a countermeasure of live feed size gap during fish larviculcure. [ABSTRACT FROM AUTHOR]

Background: Chemosensitivity testing, including collagen gel droplet-embedded culture drug sensitivity test, has proven to be a useful tool in therapeutic decision-making. This retrospective analysis investigated chemosensitivity testing of peritoneal metastases collected during cytoreductive surgery (CRS), and its impact on survival in patients with colorectal cancer. Methods: All patients with peritoneal metastasis from colorectal cancer who underwent CRS with or without hyperthermic intraperitoneal chemotherapy (HIPEC) between November 2008 and October 2014 were included. The growth inhibition rate was expressed as the ratio between the image density after treatment (T) and that before treatment (control, C). Tumours with a reduction in T/C ratio of less than 20 per cent were defined as resistant and those with a reduction of 20 per cent or more as sensitive. Groups were compared for overall (OS) and disease-free (DFS) survival. Results: Of 84 eligible patients, 81 received neoadjuvant chemotherapy (NACT), including 56 patients with an oxaliplatin-based regimen. Mean(s.d.) follow-up was 23⋅4(22⋅9) months. The median overall survival of all patients was 19⋅0 (i.q.r. 5⋅7-36⋅1) months, with a progression-free survival time of 10⋅1 (4⋅5-17⋅0) months. Patients who received oxaliplatin-based NACT had significantly altered chemosensitivity to oxaliplatin; only 20 of 51 such patients showed chemosensitivity to oxaliplatin compared with 16 of 24 who did not undergo oxaliplatin-based NACT (P = 0⋅046). However, patients who showed chemoresistance to oxaliplatin had similar OS to those with chemosensitivity (18⋅8 versus 18⋅1 months; P = 0⋅835). The choice of HIPEC agents in patients who received oxaliplatin-based NACT did not significantly influence survival (oxaliplatin versus mitomycin C: median OS 20⋅6 (10⋅9-24⋅8) versus 19⋅0 (10⋅5-34⋅6) months, P = 0⋅811; DFS 6⋅6 (2⋅8-25⋅7) versus 9⋅3 (4⋅1-13⋅9) months, P = 0⋅191). Conclusion: Patients who had oxaliplatin-based NACT showed a higher rate of chemoresistance to oxaliplatin at the time of CRS and HIPEC. The impact of chemosensitivity testing on OS remains unclear and needs further investigation. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether specific parameters contribute to clinical outcomes at 1 year post-diagnosis in early rheumatoid arthritis (RA) patients under the 'treat-to-target' strategy in clinical practice. Methods: We retrospectively analyzed 125 RA patients selected according to the following criteria; the patients' symptom duration was ≤6 months, and none had experience with DMARDs. We evaluated the patients' clinical disease activity at baseline and 1 year of treatment and the musculoskeletal ultrasound (MSUS)-detected synovitis activity at baseline. We performed an analysis to identify parameters that contribute to SDAI remission and the use of biologic/targeted synthetic (b/ts) DMARDs at 1 year post-diagnosis. Results: Forty-seven patients received b/tsDMARDs therapy, and 58 patients achieved SDAI remission at 1 year post-diagnosis. Rheumatoid factor positivity, low patient's/evaluator's global assessment at baseline, and methotrexate use at 1 year post-diagnosis were associated with SDAI remission. The baseline clinical disease activity and MSUS scores were not associated with SDAI remission. Anti-cyclic citrullinated peptide antibody positivity/high titer and high swollen joint counts or the presence of severe synovial hypertrophy at baseline were associated with the use of b/tsDMARDs therapy. Conclusion: The value of the expected poor-prognosis factors may be diminished by intensive therapy within the 'windows of opportunity'. [ABSTRACT FROM AUTHOR]

Ralstonia solanacearum injects type III effectors into host cells to cause bacterial wilt in Solanaceae plants. To identify R. solanacearum effectors that suppress effector-triggered immunity (ETI) in plants, we evaluated R. solanacearum RS1000 effectors for their ability to suppress a hypersensitive response (HR) induced by the avirulence (Avr) effector RipAA in Nicotiana benthamiana. Out of the 11 effectors tested, 4 suppressed RipAA-triggered HR cell death. Among them, RipAC contains tandem repeats of the leucine-rich repeat (LRR) motif, which serves as the structural scaffold for a protein–protein interaction. We found that the LRR domain of RipAC was indispensable for the suppression of HR cell death during the recognition of RipAA and another Avr effector RipP1. By yeast two-hybrid screening, we identified N. benthamiana SGT1, an adaptor protein that forms a molecular chaperone complex with RAR1, as a host factor of the RipAC target. RipAC interacted with NbSGT1 in yeast and plant cells. Upon the formation of the molecular chaperone complex, the presence of RipAC markedly inhibits the interaction between NbSGT1 and NbRAR1. The RipAA- and RipP1-triggered HR cell deaths were not observed in NbSGT1 -silenced plants. The introduction of RipAC was complementary to the reduced growth of the R. solanacearum mutant strain in N. benthamiana. These findings indicate that R. solanacearum uses RipAC to subvert the NbSGT1-mediated formation of the molecular chaperone complex and suppress ETI responses during the recognition of Avr effectors. [ABSTRACT FROM AUTHOR]

There is growing evidence supporting the effectiveness of a comprehensive school health program. However, implementation in developing countries is a challenge. Furthermore, the available information on the association between a comprehensive school health program and students' academic attainment is limited. In Kenya, a project to verify the effects of a comprehensive school health program was carried out in Mbita sub-county, Homa Bay County from September 2012 to August 2017. This study aimed to clarify the improvement of school health during the project years and the association between school health and students' academic attainment. Primary schools in Mbita sub-county were selected as study sites. We assessed 44 schools' scores on a school health checklist developed from the Kenyan Comprehensive School Health Program, the students' mean score on the Kenya Certificate of Primary Education (KCPE), and absenteeism during the project years (2013–16). The mean school health checklist score (n  = 44 schools) was 135.6 in 2013, 169.9 in 2014, 158.2 in 2015 and 181.3 in 2016. The difference of the mean score between 2013 and 2016 was significant. In addition, correlation analysis showed a significant association between mean KCPE score in the project years and school health checklist score (Pearson's coefficient was 0.43, p  = 0.004). The results of this study suggest improvements of school health by the implementation of the Kenyan Comprehensive School Health Program and students' academic attainment. [ABSTRACT FROM AUTHOR]

Pentatricopeptide repeat (PPR) proteins are RNA-binding proteins that function in posttranscriptional regulation as gene-specific regulators of RNA metabolism in plant organelles. Plant PPR proteins are divided into four classes: P, PLS, E and DYW. The E- and DYW-class proteins are mainly implicated in RNA editing, whereas most of the P-class proteins predominantly participate in RNA cleavage, splicing and stabilization. In contrast, the functions of PLS-class proteins still remain obscure. Here, we report the function of PLS-class PpPPR_31 and PpPPR_9 in Physcomitrella patens. The knockout (KO) mutants of PpPPR_31 and PpPPR_9 exhibited slower protonema growth compared to the wild type. The PpPPR_31 KO mutants showed a considerable reduction in the splicing of nad5 intron 3 and atp9 intron 1. The PpPPR_9 KO mutants displayed severely reduced splicing of cox1 intron 3. An RNA electrophoresis mobility shift assay showed that the recombinant PpPPR_31 protein bound to the 5′ region of nad5 exon 4 and the bulged A region in domain VI of atp9 group II intron 1 while the recombinant PpPPR_9 bound to the translated region of ORF622 in cox1 intron 3. These results suggest that a certain set of PLS-class PPR proteins may influence the splicing efficiency of mitochondrial group II introns. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES We retrospectively investigated oncological outcomes after video-assisted thoracoscopic surgery (VATS) lobectomy with lobe-specific mediastinal lymph node dissection (MLND). METHODS Between April 2008 and December 2016, a total of 660 patients underwent VATS lobectomy with lobe-specific MLND for clinical T1-3N0M0 non-small-cell lung cancer, of which 54 (8.2%) patients had pathological node-positive disease (18 N1 and 36 N2). We evaluated their oncological outcomes. RESULTS The predominant histological type was adenocarcinoma (87%). Six (33%) patients in the pN1 and 11 (31%) patients in the pN2 received adjuvant chemotherapy. The median follow-up period was 51.6 months. Postoperative recurrence was observed in 5 (28%) pN1 and 22 (61%) pN2 patients. One (6%) pN1 and 12 (33%) pN2 patients experienced locoregional recurrence. None of the pN1 patient experienced local recurrence at the dissected zone, whereas 11 (31%) pN2 patients had lymph node recurrence, including four at the dissected area and three in the area omitted from dissection in the lobe-specific MLND. The 5-year overall survival rates were 88.1% in the pN1 patients and 80.0% in the pN2 patients; the 5-year recurrence-free survival rates were 63.9% in the pN1 patients and 34.8% in the pN2 patients. In pN2 patients, pathological T classification was a prognostic factor for overall survival (P  <   0.001) and recurrence-free survival (P  =   0.034), and single-station N2 disease was also prognostic factor for overall survival (P  =   0.023). CONCLUSIONS Recurrence at the omitted zone is an issue for this type of MLND. For pN1 patients, adequate MLND is an important factor for curative treatment. However, for pN2 patients, systemic treatment after recurrence may also contribute to survival. [ABSTRACT FROM AUTHOR]

Glucosinolates (GSLs) are secondary metabolites that play important roles in plant defense and are suggested to act as storage compounds. Despite their important roles, metabolic dynamics of GSLs under various growth conditions remain poorly understood. To determine how light conditions influence the levels of different GSLs and their distribution in Arabidopsis leaves, we visualized the GSLs under different light conditions using matrix-assisted laser desorption/ionization mass spectrometry imaging. We observed the unique distribution patterns of each GSL in the inner regions of leaves and marked decreases under darkness, indicating light conditions influenced GSL metabolism. GSLs are hydrolyzed by a group of ß-glucosidase (BGLU) called myrosinase. Previous transcriptome data for GSL metabolism under light and dark conditions have revealed the highly induced expression of BGLU30 , one of the putative myrosinases, which is also annotated as Dark INducible2 , under darkness. Impairment of the darkness-induced GSL decrease in the disruption mutants of BGLU30 , bglu30 , indicated that BGLU30 mediated GSL hydrolysis under darkness. Based on the GSL profiles in the wild-type and bglu30 leaves under both conditions, short-chain GSLs were potentially preferable substrates for BGLU30. Our findings provide an effective way of visualizing GSL distribution in plants and highlighted the carbon storage GSL function. [ABSTRACT FROM AUTHOR]

Objective: Recently, Human T-cell leukemia virus type-1 proviral load (HTLV-1 PVL) has been evaluated as an important predictor of adult T-cell leukemia/lymphoma (ATL) in HTLV-1 carriers. We aimed to evaluate whether HTLV-1 PVL is also important for the development of ATL among HTLV-1-positive patients with rheumatoid arthritis (RA). Methods: We established a cohort of 82 HTLV-1-positive RA patients between 2017 and 2018. Of those, 27 (32.9%) were treated with biological disease-modifying anti-rheumatic drugs (bDMARDs) with/without methotrexate. We measured HTLV-1 PVL in peripheral blood mononuclear cells (PBMCs) at study entry and compared the value by clinical status and treatment options. Results: The median PVL for all was 9.6 copies per 1000 PBMCs without sex difference (male 17.2 and female 8.6; p = .24). The median PVL was significantly higher for patient's comorbid bronchiectasis, malignancies, and opportunistic infectious diseases, compared with patients without comorbidity. There were no significant differences in PVL levels among types of bDMARDs, although the level was tended to be higher for patients treated with JAK inhibitor. Conclusions: HTLV-1 seropositive RA patients comorbid for any diseases having higher HTLV-1 PVLs will be a higher risk for developing ATL. Careful follow-up of these patients is necessary to detect ATL development. [ABSTRACT FROM AUTHOR]

Sulfur (S) is an essential element for plants, and S deficiency causes severe growth retardation. Although the catabolic process of glucosinolates (GSLs), the major S-containing metabolites specific to Brassicales including Arabidopsis , has been recognized as one of the S deficiency (−S) responses in plants, the physiological function of this metabolic process is not clear. Two β-glucosidases (BGLUs), BGLU28 and BGLU30, are assumed to be responsible for this catabolic process as their transcript levels were highly upregulated by −S. To clarify the physiological function of BGLU28 and BGLU30 and their roles in GSL catabolism, we analyzed the accumulation of GSLs and other S-containing compounds in the single and double mutant lines of BGLU28 and BGLU30 and in wild-type plants under different S conditions. GSL levels were highly increased, while the levels of sulfate, cysteine, glutathione and protein were decreased in the double mutant line of BGLU28 and BGLU30 (bglu28/30) under −S. Furthermore, transcript level of Sulfate Transporter1;2 , the main contributor of sulfate uptake from the environment, was increased in bglu28/30 mutants under −S. With these metabolic and transcriptional changes, bglu28/30 mutants displayed obvious growth retardation under −S. Overall, our results indicate that BGLU28 and BGLU30 are required for −S-induced GSL catabolism and contribute to sustained plant growth under −S by recycling sulfate to primary S metabolism. [ABSTRACT FROM AUTHOR]

Event screening is an explosion monitoring practice that aims to identify an event as an explosion ('screened in') or not ('screened out'). Confidence in event screening can be increased if multiple independent approaches are used. We describe a new approach to event screening using the seismic moment tensor and its representation on the hypersphere, specifically the 5-sphere of 6-degree unit vectors representing the normalized symmetric moment tensor. The sample of moment tensors from an explosion data set is unimodal on the 5-sphere and can be parametrized by the Langevin distribution, which is sometimes referred to as the Normal distribution on the hypersphere. Screening is then accomplished by finding the angle from the explosion population mean to any newly measured moment tensor and testing if that angle is in the tail of the Langevin distribution (conservatively quantified as greater than 99.9 per cent of the cumulative density). We apply the screen to a sample of earthquakes from the Western USA and the September 2017 explosion and subsequent collapse at the Pungyye-Ri Test Site in North Korea. All the earthquakes and the collapse screen out, but the explosion does not. [ABSTRACT FROM AUTHOR]

Objectives: To investigate predictors of inadequate response to first conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) including methotrexate (MTX) in untreated rheumatoid arthritis (RA) patients in daily clinical practice. Methods: Inadequate response to MTX or other csDMARDs was defined as being not low disease activity at 12 months in more than 3 of 4 composite measures, and discontinuation or start of biologic DMARDs. The association between baseline factors and csDMARDs-IR was assessed by univariate and multivariate logistic regression analyses. Results: Four hundred and eleven and 146 patients were started on MTX and other csDMARDs, respectively; 218 patients were responsive to MTX, with a response rate of 47.0%. Tender joint count (TJC, 6 in 28joints, odds ratio [OR]=1.67, 95% confidence interval [CI] 1.06-2.64) and CRP (1.0mg/ dL, OR = 1.72, 95%CI: 1.10-2.70) at baseline were identified as predictors on multivariate logistic regression analysis. TJC (OR = 3.60, 95%CI: 1.29-10.00) was the factor identified as a predictor of the development of other csDMARDs-IR. Conclusion: In this observational study, patients with untreated RA at risk of inadequate response to MTX included those with a higher TJC and higher CRP, while a higher TJC was the only independent predictor of an inadequate response to csDMARDs other than MTX. [ABSTRACT FROM AUTHOR]

T-add patients had the best prognosis in both the pathological and clinical TNM stage cohorts, followed by T-size and T-multiple patients, and T-multiple patients had the worst prognosis. In the present study, although T3-add provided the greatest survival benefit for T3 NSCLC patients compared to other T3 descriptors, the pathological definition of T3-add was made by surgical resection in only 51% of cases [[2]]. Keywords: Non-small-cell lung cancer; TNM staging; T3 descriptors EN Non-small-cell lung cancer TNM staging T3 descriptors 1 2 2 04/04/23 20230301 NES 230301 The American Joint Committee on Cancer tumour-node-metastasis (TNM) staging manual is revised every few years. [Extracted from the article]

One complementary or alternative control measure to chemical insecticide is interplanting of plants that affect insect behavior. While few successes are known based on interplanting of different varieties of the same crop, such intra-crop interplanting may be effective against insects that feed on a limited range of plants and have persistent preference to one cultivar. Here, we report three field trials that examined the efficacy of intra-crop interplanting of sweet potato varieties, Ipomoea batatas (L.) Lamarck (Solanales: Convolvulaceae), on an oligophagous weevil, Euscepes postfasciatus (Fairmaire) (Coleoptera: Curculionidae), planting a preferred variety, Beni-masari, together with a less preferred one, Kyushu 166. In the first experiment, Beni-masari was planted as a border around Kyushu 166 and this arrangement decreased tuber damage in the main crop (Kyushu 166), although damage reduction was not statistically significant from monoculture plantings of Kyushu 166. In the second experiment, both varieties were planted in plots spaced 3 m apart to test the attractiveness of Beni-masari to weevils from Kyushu 166. No attractive effects of Beni-masari were observed. In the third experiment, the two varieties were planted in separate plots that were contiguous to each other, and in this experiment Beni-masari preferentially attracted weevils away from Kyushu 166 within 3 m distance, and tuber damage in Kyushu 166 within that zone was reduced owing to the attractiveness of Beni-masari. We discuss the potential of the intra-crop interplanting in pest management. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study is to evaluate the efficacy and safety of bortezomib for treating systemic lupus erythematosus (SLE), in patients whose disease activity could not be controlled. Methods: Fourteen SLE patients with persistent disease activity were selected, who required prednisolone doses of >10 mg/d despite concomitant immunosuppressive therapy. Patients were randomly administered either bortezomib or a placebo, eight times. The primary and secondary end-points were a change in anti-dsDNA antibody titer at week 24 and the SLE Responder Index (SRI), respectively. Results: In the bortezomib group, four out of eight patients discontinued the trial; three others failed to complete the minimum protocol treatment due to adverse reactions. The changes in anti-dsDNA antibody titers at week 24 were 4.24% and -1.96%, for the bortezomib and placebo groups, respectively, disconfirming bortezomib's efficacy. In contrast, the corresponding SRI at week 12 was 75% and 40%. Conclusions: As bortezomib therapy for SLE is associated with many adverse reactions, treatment indications should be selected carefully, and protocols should aim to prevent these occurrences. Although the change in anti-dsDNA antibody titer did not support the efficacy of bortezomib as a treatment for SLE, high SRI in the treatment group suggests bortezomib may utilize mechanisms other than inhibition of anti-dsDNA antibody production. [ABSTRACT FROM AUTHOR]

Two-component systems (TCSs) are signal transduction mechanisms for responding to various environmental stimuli. In angiosperms, TCSs involved in phytohormone signaling have been intensively studied, whereas there are only a few reports on TCSs in basal land plants. The moss Physcomitrella patens possesses several histidine kinases (HKs) that are lacking in seed plant genomes. Here, we studied two of these unique HKs, PAS-histidine kinase 1 (PHK1) and its paralog PHK2, both of which have PAS (Per–Arnt–Sim) domains, which are known to show versatile functions such as sensing light or molecular oxygen. We found homologs of PHK1 and PHK2 only in early diverged clades such as bryophytes and lycophytes, but not in seed plants. The PAS sequences of PHK1 and PHK2 are more similar to a subset of bacterial PAS sequences than to any angiosperm PAS sequences. Gene disruption lines that lack either PHK1 or PHK2 or both formed gametophores earlier than the wild-type, and consistently, more caulonema side branches were induced in response to light in the disruption lines. Therefore, PHK1 and PHK2 delay the timing of gametophore development, probably by suppressing light-induced caulonema branching. This study provides new insights into the evolution of TCSs in plants. [ABSTRACT FROM AUTHOR]

A 71-year-old man was admitted to our hospital with muscle pain on legs, anorexia, vomiting and fever after the discontinuation of oral betamethasone. Laboratory studies revealed elevated CRP, and acute adrenal insufficiency. We diagnosed atypical familial Mediterranean fever (FMF) based on the clinical manifestations and a genetic analysis revealing multiple heterozygous mutations in exon 2 of the MEFV gene (L110P/E148Q). The administration of oral daily colchicine (0.5 mg/day) resolved the clinical and laboratory findings. This case suggests that genetic factors such as heterozygous mutations of MEFV gene and environmental factors such as steroid withdrawal are involved in the onset of FMF. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the performance of the 2012 Systemic Lupus International Collaborating Clinics criteria (SLICC-12) on classifying systemic lupus erythematosus (SLE) in an uncontrolled multi-centered study with real-life scenario of the patients in Japan. Methods: This study comprised 495 patients with SLE or non-SLE rheumatic diseases and allied conditions from 12 institutes in Japan. Chart review of each patient was performed by the 27 expert rheumatologists and diagnosis of 487 cases reached to the consensus. Value of the SLICC-12 on SLE classification was analyzed comparing with the 1997 revised American College of Rheumatology SLE classification criteria (ACR-97) employing the expert-consented diagnoses. Results: Compared to the ACR-97, the SLICC-12 had a higher sensitivity (ACR-97 vs. SLICC-12: 0.88 vs. 0.99, p<.01) and comparable specificity (0.85 vs. 0.80). The rate of misclassification (0.14 vs. 0.11) or the area under the receiver operating characteristic curves (0.863 vs. 0.894) was not statistically different. In the cases that diagnoses corresponded in high rates among experts, both criteria showed high accordance of SLE classification over 85% with the expert diagnoses. Conclusion: Although employment of SLICC-12 for the classification for SLE should be carefully considered, the SLICC-12 showed the higher sensitivity on classifying SLE in Japanese population. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The number of octogenarian lung cancer patients undergoing radical surgery has been increasing recently. However, knowledge regarding the risk factors for postoperative complications and reliable predictive factors for long-term survival is limited. This study aimed to investigate the risk factors of postoperative complications, and reliable prognostic factors, in lung cancer patients older than 80 years. METHODS: Lung cancer patients aged 80 years or older who underwent radical surgery were retrospectively studied; a multi-institutional analysis was conducted from January 1998 to December 2015. Preoperative and postoperative clinical data, including age, gender, smoking history, body mass index, respiratory function, Charlson Comorbidity Index, Glasgow Prognostic Score, surgical procedure, cancer histology, clinical and pathological stage, surgical result and survival time, were collected. RESULTS: A total of 337 patients, comprising 216 (64.1%) men and 121 (35.9%) women were enrolled. The median age was 82 (range 80– 92) years. Of the 337 patients, 205 (60.8%) had preoperative comorbidities. Postoperative complications were observed in 119 (35.3%) patients; postoperative mortalities occurred in 6 (1.8%) patients. Univariate and multivariate analyses showed that male gender (P = 0.01) and operation time (P = 0.047) were associated with postoperative complications; in contrast, pathological Stage III (P < 0.001), male gender (P = 0.01), Charlson Comorbidity Index ≥2 (P = 0.03) and Glasgow Prognostic Score = 1/2 (P = 0.04) were independent prognostic factors for overall survival. CONCLUSIONS: The risk factors for postoperative complications (male gender and operation time) and the predictive factors affecting long-term survival (male gender, Charlson Comorbidity Index, Glasgow Prognostic Score and P-stage) should be taken into account for the effective management of patients older than 80 years with lung cancer, undergoing surgery. [ABSTRACT FROM AUTHOR]

Objective. We sought to identify the microRNA (miRNA) profile and potential biomarkers in FMF and to clarify their gene targets to elucidate the pathogenesis of FMF. Methods. We performed an miRNA microarray using serum from FMF patients in attack and in remission. We then examined the expression of miRNAs in macrophages derived from THP-1 cells stimulated with toll-like receptor (TLR) ligands. Macrophages derived from THP-1 cells transfected with pre-miRNA were stimulated with lipopolysaccharides (LPSs) for the quantification of inflammatory cytokine production. To identify the target genes, we overexpressed their miRNA and performed a complementary DNA microarray. Transfection with reporter construct and the precursor miRNA was performed to confirm the suppression of target mRNA. Results. We found that miR-204-3p was greatly decreased in the serum from FMF patients in attack. The expression of miR-204-3p was suppressed by LPS stimulation in the macrophages derived from THP-1 cells and the inhibition of miR-204-3p significantly induced the production of TLR4-related cytokines. The bioinformatic analysis showed that miR-204-3p is predicted to target genes implicated in the TLR pathway through the regulation of PI3Kγ signalling. The reporter assay revealed that miR-204-3p directly suppressed the luciferase activity of 3'-UTR of PIK3CG reporter construct. The inhibition of PI3Kγ resulted in decreased amounts of IL-6 and IL-12p40 in monocytes from FMF patients. Conclusion. These data suggest that serum miR-204-3p has potential as a useful biomarker in FMF patients and that miR-204-3p serves as a suppressor of inflammatory cytokine production in FMF by targeting the PI3Kγ pathway. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: We previously demonstrated that lansoprazole provided hepatoprotection in a drug‐induced hepatitis animal model partially through the Nrf2/HO‐1 pathway. Here, we examined whether lansoprazole could also provide hepatoprotection in a rat model of non‐alcoholic steatohepatitis (NASH). Methods: Six‐week‐old rats were fed a normal chow or a choline‐deficient amino acid‐defined (CDAA) diet to establish a rat model of NASH. The groups fed a CDAA diet for 5 weeks were subcutaneously administered either a vehicle or a lansoprazole suspension for 4 weeks beginning the second week of the experiment. Key findings: Bridging fibrosis was observed in the livers of almost all the NASH model rats (six of seven), but it was not always observed in NASH model rats (one of seven) continuously administered lansoprazole. The serum aspartate aminotransferase level elevated by the CDAA diet was significantly decreased following lansoprazole administration. Lansoprazole also increased the expression of Nrf2, but not HO‐1, in the liver of NASH model rats. Lansoprazole decreased the level of activated TGF‐β protein. Furthermore, interleukin‐6 gene and protein expression were decreased. Conclusions: Lansoprazole inhibits hepatic fibrogenesis, at least during the early stages, in CDAA diet‐induced NASH model rats. The mechanisms might be associated with cytokine suppression but not the inhibition of reactive oxygen species. [ABSTRACT FROM AUTHOR]

Objective: To examine whether magnetic resonance imaging (MRI) findings at baseline predict radiographic progression in early-stage rheumatoid arthritis (RA) patients who have achieved sustained good clinical response. Methods: This is a sub-analysis from the one-year observational study of Nagasaki University Early Arthritis Cohort. Definition of 'good clinical response' was a decrement of disease activity score (DAS) 28-1.2 at three months with achievement of DAS28 remission through 6-12 months. Gd-enhanced MRI of both wrists and finger joints were examined at baseline and scored using rheumatoid arthritis magnetic resonance imaging score (RAMRIS). Annual increment of Genant-modified Sharp score (GSS)>0 was defined as 'radiographic progression'. Predictors of radiographic progression were determined by logistic regression analysis. Results: Twenty-four subjects were selected in the present study. Each median RAMRIS synovitis, bone edema, bone erosion, and GSS at baseline were 6.5, 0.5, 0, and 0, respectively. Five patients developed radiographic progression at one year. Multivariate logistic regression analysis has shown that RAMRIS bone erosion at baseline is the only independent predictor of radiographic progression at one year (p=.032). Conclusions: Our data suggest that MRI bone erosion predicts poor radiographic outcome of earlystage RA even if it has been successfully treated. [ABSTRACT FROM AUTHOR]

Objectives: To determine the prevalence of ultrasonographic abnormalities of sternoclavicular joints (SCJ) and peripheral joints (PJ) in patients with synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. Methods: Thirteen patients with SAPHO syndrome who fulfilled diagnostic criteria proposed by Kahn for SAPHO syndrome 2003 and 13 healthy individuals age- and sex-matched were enrolled. Synovitis, defined by synovial hypertrophy with power Doppler (PD) signals, of the SCJ and the PJ including wrist, MCP, PIP, and the other symptomatic joints were evaluated by ultrasound (US). Results: Synovitis with PD signals was detected in 16 (61.5%) of the 26 SCJ and 11 (84.6%) of the SAPHO syndrome patients, and none of the controls. Synovitis with PD signals in any PJ was detected in 4 (30.7%) of the SAPHO syndrome patients. Conclusions: Synovitis of the SCJ and PJ in SAPHO syndrome was detectable by US with a PD method. US can be useful for the diagnosis of SAPHO syndrome. [ABSTRACT FROM AUTHOR]

Objectives: Autonomic dysfunction is closely associated with autoimmune diseases (AID) including primary biliary cirrhosis (PBC). The objective of this study was to determine the prevalence of anti-ganglionic (nicotinic) acetylcholine receptor (gAChR) antibodies in patients with AID. Methods: We determined the presence of gAChR antibodies in serum samples from 146 patients (systemic lupus erythematosus [SLE]=32; rheumatoid arthritis [RA]=43; systemic sclerosis [SSc]=38; PBC=33) without information regarding autonomic symptoms, as well as 34 patients with other neurological diseases (OND), and 73 healthy controls (HC). We specifically analyzed sera for anti-gAChRa3 and -b4 antibodies using the luciferase immunoprecipitation system (LIPS) assay. Results: LIPS assay detected anti-gAChRa3 and -b4 antibodies in the sera from patients with SLE (12.5%, 4/32), RA (18.6%, 8/43), SSc (13.2%, 5/38), PBC (9.1%, 3/33), OND (2.9%, 1/34), and HC (0.0%, 0/73). There were no significant correlations between the levels of anti-gAChRa3 and -b4 antibodies, and the total titers of autoantibodies in AID. Conclusions: The results demonstrated a significant prevalence of anti-gAChR antibodies in patients with AID, which is independent of the production of other autoantibodies in patients with autoimmune diseases. These anti-gAChR antibodies could mediate the autonomic dysfunction involved in the autoimmune mechanisms of AID. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the association between hand dysfunction and ultrasound (US)- detected articular synovitis and tenosynovitis in patients with rheumatoid arthritis (RA). Methods: Thirty RA patients were examined. In both hands of all subjects, articular synovitis and tenosynovitis were assessed by US at 22 joints and 12 tendons. Each joint and tendon was scored by gray-scale (GS) and power Doppler (PD) on a scale from 0 to 3. The sums of the GS or PD scores were used as the articular synovitis score and the tenosynovitis score. The sum of the articular synovitis and tenosynovitis scores was used as the combined US score. Hand dysfunction was evaluated by a grip-Health Assessment Questionnaire (HAQ) and visual analog scale of morning stiffness (MS-VAS). We used Spearman's correlation coefficient to determine the relationships among the US scores, the two hand dysfunction indices, and the DAS28-ESR. Results: The articular synovitis scores were significantly correlated with grip-HAQ (GS: rs = 0.47, p = 0.009, PD: rs = 0.48, p = 0.006), but not with MS-VAS. The tenosynovitis scores were correlated with MS-VAS (GS: rs = 0.38, p = 0.039, PD: rs = 0.36, p = 0.053), but not with grip- HAQ. Both grip-HAQ (GS: rs = 0.53, p = 0.002, PD: rs = 0.55, p = 0.001) and the MS-VAS (GS: rs = 0.39, p = 0.031, PD: rs = 0.47, p = 0.008) were correlated with the combined US scores. Conclusions: The US scores combined with articular synovitis and tenosynovitis scores well reflect the severity of hand dysfunction in early-stage RA patients. [ABSTRACT FROM AUTHOR]

Aspergillus oryzae cytochrome P450 monooxygenase (CYP57B3) is capable of catalyzing hydroxylation of genistein to produce 3'-hydroxygenistein. Because hydroxylated derivatives of genistein, including 3'-hydroxygenistein, exhibit various pharmacological activities, CYP57B3 would potentially be useful as a biocatalyst in the pharmaceutical field. We therefore performed random mutagenesis of CYP57B3 to improve its catalytic activities for genistein. Random mutations were introduced by error-prone PCR into CYP57B3, resulting in construction of a library of mutants. From 2000 mutants, we isolated one with a triple mutation in CYP57B3, resulting in three amino acid substitutions (V138I, S243N and V463F). The altered protein, designated CYP57B3-mut, had a high level of activity for the production of 3'-hydroxygenistein from genistein. In bioconversion reactions, Saccharomyces cerevisiae expressing CYP57B3-mut showed 14-fold higher production of 3'-hydroxygenistein than that of wild-type CYP57B3. In vitro kinetic analysis revealed that Km values of wild-type and CYP57B3-mut were 14.6 × 10³ ± 2.7 × 10³ µM and 15.7 ± 1.0 µM, respectively. These results suggest that the affinity of CYP57B3 for genistein could be dramatically improved by the alterations of V138, S243 and V463 in CYP57B3. [ABSTRACT FROM AUTHOR]

Background. The CA031 trial suggested weekly nanoparticle albumin-bound-paclitaxel (nab-PTX) was superior in efficacy to paclitaxel (PTX) once every 3 weeks when combined with carboplatin (CBDCA) for advanced non-small cell lung cancer (NSCLC) patients; a subgroup analysis of elderly patients looked promising. In a multicenter phase II trial, we prospectively evaluated the efficacy and tolerability of modified CBDCA plus weekly nab-PTX for elderly patients with untreated advanced NSCLC. Methods. Eligible patients received CBDCA (area under the curve [AUC] 6 mg/mL/min) on day 1 and nab-PTX (75 mg/m²) on days 1, 8, and 15 every 4 weeks. The primary endpoint was an overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Results. Of 32 patients (median age of 78 years), 84% were male, 56% had stage IV NSCLC, and 56% had squamous cell carcinoma. ORR and disease control rates were 50% (95% confidence interval (CI): 33-67) and 94% (95% CI: 85-100), respectively. Median PFS and OS were 6.4 months (95% CI: 4.8-8.0) and 17.5 months (95% CI: 11.9-23.1), respectively. Grade ≥3 toxicities were neutropenia (47%), leukopenia (38%), anemia (34%), thrombocytopenia (25%), and anorexia (9%). Febrile neutropenia and treatment-related deaths were not observed. Conclusion. Modified CBDCA plus weekly nab-PTX demonstrated significant efficacy and acceptable toxicities in elderly patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]