Despite recent improvements in microscope technologies, segmenting and tracking cells in three-dimensional time-lapse images (3D + T images) to extract their dynamic positions and activities remains ...a considerable bottleneck in the field. We developed a deep learning-based software pipeline, 3DeeCellTracker, by integrating multiple existing and new techniques including deep learning for tracking. With only one volume of training data, one initial correction, and a few parameter changes, 3DeeCellTracker successfully segmented and tracked ~100 cells in both semi-immobilized and 'straightened' freely moving worm's brain, in a naturally beating zebrafish heart, and ~1000 cells in a 3D cultured tumor spheroid. While these datasets were imaged with highly divergent optical systems, our method tracked 90-100% of the cells in most cases, which is comparable or superior to previous results. These results suggest that 3DeeCellTracker could pave the way for revealing dynamic cell activities in image datasets that have been difficult to analyze.
To evaluate the safety and efficacy of simultaneous Kamra corneal inlay implantation and laser in situ keratomileusis (LASIK) for the treatment of presbyopia in emmetropic, hyperopic, or myopic ...patients.
Private center, Tokyo, Japan.
Cohort study.
Patients had bilateral LASIK with simultaneous implantation of a corneal inlay in the nondominant eye to treat presbyopia and ametropia between September 2009 and April 2010. The efficacy and safety were determined by the spherical equivalent (SE) in the eye with the inlay.
The study enrolled 360 eyes of 180 patients with a mean age of 52.4 years ± 5.1 (SD) (range 41 to 65 years). Sixty-four patients were available for the 6-month postoperative examination. The mean logMAR uncorrected near visual acuity in the eye with the inlay improved 7 lines in hyperopic eyes, 6 lines in emmetropic eyes, and 2 lines in myopic eyes. The mean logMAR uncorrected distance visual acuity improved by 3 lines, 1 line, and 10 lines, respectively.
Simultaneous intracorneal inlay implantation and LASIK to treat presbyopia with emmetropia, hyperopia, or myopia was clinically safe and effective, yielding improvement in distance and near visual acuity. Patients were satisfied with decreased dependence on reading glasses regardless of the preoperative SE range. However, postoperative symptoms, such as dry eyes, halo, glare, or night-vision disturbances, occurred occasionally.
Dr. Waring has a financial interest in and is world surgical monitor for Acufocus. No other author has a financial or proprietary interest in any material or method mentioned.
Purpose
The Recurrence Score test is validated to predict benefit of adjuvant chemotherapy. TransNEOS, a translational study of New Primary Endocrine-therapy Origination Study (NEOS), evaluated ...whether Recurrence Score results can predict clinical response to neoadjuvant letrozole.
Methods
NEOS is a phase 3 clinical trial of hormonal therapy ± adjuvant chemotherapy for postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer, after six months of neoadjuvant letrozole and breast surgery. TransNEOS patients had tumors ≥ 2 cm and archived core-biopsy samples taken before neoadjuvant letrozole and subsequently sent for Recurrence Score testing. The primary endpoint was to evaluate clinical (complete or partial) response to neoadjuvant letrozole for RS < 18 versus RS ≥ 31. Secondary endpoints included evaluation of clinical response and rate of breast-conserving surgery (BCS) by continuous Recurrence Score result,
ESR1
and
PGR
single-gene scores, and ER gene-group score.
Results
Of 295 TransNEOS patients (median age 63 years; median tumor size 25 mm; 66% grade 1), 53.2% had RS < 18, 28.5% had RS18–30, and 18.3% had RS ≥ 31. Clinical response rates were 54% (RS < 18), 42% (RS18–30), and 22% (RS ≥ 31). A higher proportion of patients with RS < 18 had clinical responses (
p
< 0.001 vs. RS ≥ 31). In multivariable analyses, continuous Recurrence Score result (
p
< 0.001),
ESR1
score (
p
= 0.049),
PGR
score (
p
< 0.001), and ER gene-group score (
p
< 0.001) were associated with clinical response. Recurrence Score group was significantly associated with rate of BCS after neoadjuvant treatment (RS < 18 vs. RS ≥ 31,
p
= 0.010).
Conclusion
The Recurrence Score test is validated to predict clinical response to neoadjuvant letrozole in postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer.
The current study was initiated when our specific-pathogen-free laboratory toms developed unexpectedly high levels of cross-reactive antibodies to human SARS-CoV-2 (SCoV2) receptor binding domain ...(RBD) upon mating with feline coronavirus (FCoV)-positive queens. Multi-sequence alignment analyses of SCoV2 Wuhan RBD and four strains each from FCoV serotypes 1 and 2 (FCoV1 and FCoV2) demonstrated an amino acid sequence identity of 11.5% and a similarity of 31.8% with FCoV1 RBD (12.2% identity and 36.5% similarity for FCoV2 RBD). The sera from toms and queens cross-reacted with SCoV2 RBD and reacted with FCoV1 RBD and FCoV2 spike-2, nucleocapsid, and membrane proteins, but not with FCoV2 RBD. Thus, the queens and toms were infected with FCoV1. Additionally, the plasma from six FCoV2-inoculated cats reacted with FCoV2 and SCoV2 RBDs, but not with FCoV1 RBD. Hence, the sera from both FCoV1-infected cats and FCoV2-infected cats developed cross-reactive antibodies to SCoV2 RBD. Furthermore, eight group-housed laboratory cats had a range of serum cross-reactivity to SCoV2 RBD even 15 months later. Such cross-reactivity was also observed in FCoV1-positive group-housed pet cats. The SCoV2 RBD at a high non-toxic dose and FCoV2 RBD at a 60-400-fold lower dose blocked the in vitro FCoV2 infection, demonstrating their close structural conformations essential as vaccine immunogens. Remarkably, such cross-reactivity was also detected by the peripheral blood mononuclear cells of FCoV1-infected cats. The broad cross-reactivity between human and feline RBDs provides essential insights into developing a pan-CoV vaccine.
Reactive astrocytes and microglia in Alzheimer's disease surround amyloid plaques and secrete proinflammatory cytokines that affect neuronal function. Relationship between cytokine signaling and ...amyloid-β peptide (Aβ) accumulation is poorly understood. Thus, we generated a novel Swedish β-amyloid precursor protein mutant (APP) transgenic mouse in which the interferon (IFN)-γ receptor type I was knocked out (APP/GRKO). IFN-γ signaling loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age. Aggregated Aβ induced IFN-γ production from co-culture of astrocytes and microglia, and IFN-γ elicited tumor necrosis factor (TNF)-α secretion in wild type (WT) but not GRKO microglia co-cultured with astrocytes. Both IFN-γ and TNF-α enhanced Aβ production from APP-expressing astrocytes and cortical neurons. TNF-α directly stimulated β-site APP-cleaving enzyme (BACE1) expression and enhanced β-processing of APP in astrocytes. The numbers of reactive astrocytes expressing BACE1 were increased in APP compared with APP/GRKO mice in both cortex and hippocampus. IFN-γ and TNF-α activation of WT microglia suppressed Aβ degradation, whereas GRKO microglia had no changes. These results support the idea that glial IFN-γ and TNF-α enhance Aβ deposition through BACE1 expression and suppression of Aβ clearance. Taken together, these observations suggest that proinflammatory cytokines are directly linked to Alzheimer's disease pathogenesis.
ABSTRACT
Natriuretic peptides, brain (B‐type) natriuretic peptide (BNP) and N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) are globally and most often used for the diagnosis of heart ...failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor–neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up‐to‐date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptide‐guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions.
This study aimed to investigate whether the administration of mononuclear cells derived from human umbilical cord blood cells (UCBCs) could ameliorate hypoxic-ischemic brain injury in a neonatal rat ...model. The left carotid arteries of 7-day-old rats were ligated, and the rats were then exposed to 8% oxygen for 60 min. Mononuclear cells derived from UCBCs using the Ficoll-Hypaque technique were injected intraperitoneally 6 h after the insult (1.0 × 10(7) cells). Twenty-four hours after the insult, the number of cells positive for the oxidative stress markers 4-hydroxy-2-nonenal and nitrotyrosine, in the dentate gyrus of the hippocampus in the UCBC-treated group, decreased by 36 and 42%, respectively, compared with those in the control group. In addition, the number of cells positive for the apoptosis markers active caspase-3 and apoptosis-inducing factor decreased by 53 and 58%, respectively. The number of activated microglia (ED1-positive cells) was 51% lower in the UCBC group compared with the control group. In a gait analysis performed 2 weeks after the insult, there were no significant differences among the sham-operated, control and UCBC groups. An active avoidance test using a shuttle box the following week also revealed no significant differences among the groups. Neither the volumes of the hippocampi, corpus callosum and cortices nor the numbers of neurons in the hippocampus were different between the UCBC and control groups. In summary, a single intraperitoneal injection of UCBC-derived mononuclear cells 6 h after an ischemic insult was associated with a transient reduction in numbers of apoptosis and oxidative stress marker-positive cells, but it did not induce long-term morphological or functional protection. Repeated administration or a combination treatment may be required to achieve sustained protection.
Abstract Background The prognosis of heart failure patients with reduced ejection fraction (HFrEF) in Japan remains poor, although there is growing evidence for increasing use of evidence-based ...pharmacotherapies in Japanese real-world HF registries. Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor shown to reduce mortality and morbidity in the recently completed largest outcome trial in patients with HFrEF (PARADIGM-HF trial). The prospectively designed phase III PARALLEL-HF (Prospective comparison of ARNI with ACE inhibitor to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients) study aims to assess the clinical efficacy and safety of LCZ696 in Japanese HFrEF patients, and show similar improvements in clinical outcomes as the PARADIGM-HF study enabling the registration of LCZ696 in Japan. Methods and design This is a multicenter, randomized, double-blind, parallel-group, active controlled study of 220 Japanese HFrEF patients. Eligibility criteria include a diagnosis of chronic HF (New York Heart Association Class II-IV) and reduced ejection fraction (left ventricular ejection fraction ≤35%) and increased plasma concentrations of natriuretic peptides N-terminal pro B-type natriuretic peptide (NT-proBNP) ≥600 pg/mL, or NT-proBNP ≥400 pg/mL for those who had a hospitalization for HF within the last 12 months at the screening visit. The study consists of three phases: (i) screening, (ii) single-blind active LCZ696 run-in, and (iii) double-blind randomized treatment. Patients tolerating LCZ696 50 mg bid during the treatment run-in are randomized (1:1) to receive LCZ696 100 mg bid or enalapril 5 mg bid for 4 weeks followed by up-titration to target doses of LCZ696 200 mg bid or enalapril 10 mg bid in a double-blind manner. The primary outcome is the composite of cardiovascular death or HF hospitalization and the study is an event-driven trial. Conclusions The design of the PARALLEL-HF study is aligned with the PARADIGM-HF study and aims to assess the efficacy and safety of LCZ696 in Japanese HFrEF patients.
Atypical femoral fractures (AFFs) are defined as atraumatic or low-trauma fractures located in the subtrochanteric or diaphyseal sites. Long-term bisphosphonates (BPs) are administered to prevent ...fragility fractures in patients with primary osteoporosis or collagen diseases who are already taking glucocorticoids (GCs). Long-term BP use is one of the most important risk factors for AFFs. Its pathogenesis is characterized by severely suppressed bone turnover (SSBT), but whether the characteristics of patients are different regarding to location of fracture site remains unknown. In this study, we compared the characteristics and bone histomorphometric findings between subtrochanteric and diaphyseal sites in patients with BP-associated AFFs. Nine women with BP-associated AFFs were recruited, including 3 with systemic lupus erythematosus, 2 with rheumatoid arthritis, 2 with primary osteoporosis, 1 with polymyalgia rheumatica, and 1 with sarcoidosis. Patients were divided into the subtrochanteric group (n = 5; average age, 52 years; BP treatment, 5.9 years) and the diaphyseal group (n = 4; average age, 77 years; BP treatment, 2.6 years). Compared with the diaphyseal group, the subtrochanteric group had significantly higher daily GC doses (average, 10.9 vs. 2.3 mg/day) and significantly lower serum 25-hydroxyvitamin-D levels (17.8 vs. 25.6 ng/mL). Bone histomorphometry of the biopsied iliac bone showed SSBT in 3 cases (subtrochanteric, n = 1; diaphyseal, n = 2). Osteoid volume and trabecular thickness were significantly lower in the subtrochanteric group than in the diaphyseal group. Bone formation was inhibited more severely in subtrochanteric than in the diaphyseal group due to the higher GC doses used.
A photoelectric conversion efficiency of over 10% has been achieved in thin-film microcrystalline silicon solar cells which consist of a 2
μm thick layer of polycrystalline silicon. It was found that ...an adequate current can be extracted even from a thin film due to the very effective light trapping effect of silicon with a low absorption coefficient. As a result, this technology may eventually lead to the development of low-cost solar cells. Also, an initial aperture efficiency as high as 13.5% has been achieved with a large area (91
cm
×
45
cm) tandem solar cell module of microcrystalline silicon and amorphous silicon (thin film Si hybrid solar cell). An even greater initial efficiency of 14.7% has been achieved in devices with a small size (area of 1
cm
2), and further increases of efficiency can be expected.
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