Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively ...preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.
This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.
A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS 6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).
Trilaciclib demonstrated an improvement in the patient’s tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib’s myelopreservation benefits.
NCT02499770.
This study examined the prevalence of major depressive disorder (MDD), and the correlations and co-morbid conditions associated with MDD, in the adult Taiwanese population, which a previous estimate ...in the 1980s had found to be at the lower end of the spectrum worldwide. Possible explanations for the reported low prevalence of MDD were evaluated.
As part of a survey of common psychiatric disorders in a nationally representative sample of individuals aged ≥ 18 years who were non-institutionalized civilians in Taiwan, a face-to-face interview using the paper version of the World Mental Health Survey of the World Health Organization (WHO) Composite International Diagnostic Interview (WMH-CIDI) was conducted between 2003 and 2005. Functional impairment and help-seeking behaviors were compared between Taiwanese subjects with MDD and their counterparts in the USA.
Among the 10 135 respondents, the lifetime prevalence of MDD was 1.20% standard error (S.E.)=0.2%. Individuals who were divorced or widowed, aged ≤ 40 years, and female were at increased risk, whereas rural residents were at lower risk for MDD. The proportion of MDD cases co-morbid with other psychiatric disorders in this study was much lower than in the US study. Only one-third of Taiwanese individuals with MDD sought help despite having twice the number of lost workdays compared with the US sample.
Despite the low prevalence of MDD in Taiwanese adults, the pattern of low help-seeking behavior and profound functional impairment indicates much room for improvement in the early detection of and intervention in major depression in this population.
Abstract
We present a large sample of 2.5–38
μ
m galaxy spectra drawn from a cross-archival comparison in the AKARI–Spitzer Extragalactic Spectral Survey, and investigate a subset of 113 star-forming ...galaxies with prominent polycyclic aromatic hydrocarbon (PAH) emission spanning a wide range of star formation properties. With AKARI’s extended 2.5–5
μ
m wavelength coverage, we self-consistently model for the first time
all
PAH emission bands using a modified version of
Pahfit
. We find
L
PAH
3.3
/
L
IR
∼ 0.1%, and the 3.3
μ
m PAH feature contributes ∼1.5%–3% to the total PAH power—somewhat less than earlier dust models have assumed. We establish a calibration between 3.3
μ
m PAH emission and star formation rate, but also find regimes where it loses reliability, including at high luminosity and low metallicity. The 3.4
μ
m aliphatic emission and a broad plateau feature centered at 3.47
μ
m are also modeled. As the PAH feature with the shortest wavelength, the one at 3.3
μ
m is susceptible to attenuation, leading to differences of a factor of ∼3 in the inferred star formation rate at high obscuration with different assumed attenuation geometries. Surprisingly,
L
PAH
3.3
/
L
Σ
PAH
shows no sign of decline at high luminosities, and the low-metallicity dwarf galaxy II Zw 40 exhibits an unusually strong 3.3
μ
m band; both results suggest either that the smallest PAHs are better able to survive under intense radiation fields than presumed, or that PAH emission is shifted to shorter wavelengths in intense and high-energy radiation environments. A photometric surrogate for 3.3
μ
m PAH luminosity using JWST/NIRCam is provided and found to be highly reliable at low redshift.
ABSTRACT
Planets migrating in their natal discs can be captured into mean-motion resonance (MMR), in which the planets’ periods are related by integer ratios. Recent observations indicate that ...planets in MMR can be either apsidally aligned or anti-aligned. How these different configurations arise is unclear. In this paper, we study the MMR capture process of migrating planets, focusing on the property of the apsidal angles of the captured planets. We show that the standard picture of MMR capture, in which the planets undergo convergent migration and experience eccentricity damping due to planet–disc interactions, always leads to apsidal anti-alignment of the captured planets. However, when the planets experience eccentricity driving from the disc, apsidally aligned configuration in MMR can be produced. In this configuration, both planets’ resonance angles circulate, but a ‘mixed’ resonance angle librates and traps the planets near the nominal resonance location. The MMR capture process in the presence of disc eccentricity driving is generally complex and irregular, and can lead to various outcomes, including apsidal alignment and anti-alignment, as well as the disruption of the resonance. We suggest that the two resonant planets in the K2-19 system, with their moderate eccentricities and aligned apsides, have experienced eccentricity driving from their natal disc in the past.
We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese ...population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 α-N-acetyl- neuraminide α-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with P-values of 4.87 × 10(-7) (rs2709736) and 6.05 × 10(-6) (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P=9.74 × 10(-6)) and in CACNB2 (Calcium channel, voltage-dependent, β-2 subunit) gene (rs11013860, P=5.15 × 10(-5)), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P=6.55 × 10(-5) and P=1.48 × 10(-5), respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.
Balling defect of the additively manufactured titanium lattice implants easily leads to muscle tissue rejection, which might cause failure of implantation. Electropolishing is widely used in surface ...polishing of complex components and has potential to deal with the balling defect. However, a clad layer could be formed on the surface of titanium alloy after electropolishing, which may affect the biocompatibility of the metal implants. To manufacture lattice structured β-type Ti-Ni-Ta-Zr (TNTZ) for bio-medical applications, it is necessary to investigate the impact of electropolishing on material biocompatibility. In this study, animal experiments were conducted to investigate the in vivo biocompatibility of the as-printed TNTZ alloy with or without electropolishing; and proteomics technology was used to elaborate the results. The following conclusions were drawn: (a) a 30% oxalic acid electropolishing treatment was effective in solving balling defects, and ~21 nm amorphous clad layer would be formed on the surface of the material after polishing; (b) the electropolished TNTZ suggested decreased cell cytotoxicity and improved blood biocompatibility as compared to as-printed TNTZ; (c) the amorphous clad layer could make a barrier to prevent Ta and Zr ions from penetrating into the muscle tissue, and could form a good tissue regeneration at the implantation site during 4 weeks, indicating that the electropolished TNTZ has the potential as implants; and (d) the cells attached to the electropolished TNTZ showed higher antioxidant capacity but less proliferation than attached to as-printed TNTZ.
Graphical Abstract
Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves ...the outcome warrants investigation.
This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received three cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30mg/m2 cisplatin weekly during radiotherapy, which was delivered as 1.8–2.2Gy per fraction with five daily fractions per week, to a total dose of 70Gy or greater to the primary tumor and 66–70Gy to the involved neck. The primary end point was disease-free survival (DFS).
In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side-effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm 5-year rate 61% versus 50%; hazard ratio=0.739, 95% confidence interval (CI)=0.565–0.965; P=0.0264, after stratified for N3b and LDH, and adjusted for T stage.
Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved.
NCT00201396.
Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the ...current standard therapy in most centers.
We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events.
From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean ±SD age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change in the mean (±SE) aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139±0.013 and -0.107±0.013 standard-deviation units per year, respectively; P=0.08). Both slopes were significantly less than zero, indicating a decrease in the aortic-root diameter relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups.
Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.).
Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment.
We ...selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample.
Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing.
Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).
Abstract We present a focused study of radially resolved varying PAH emission in the low-luminosity active galactic nucleus (AGN)-host NGC 4138 using deep Spitzer/infrared spectrograph spectral maps. ...Using new model PAH spectra, we investigate whether these variations could be associated with changes to the PAH grain size distribution due to photodestruction by the AGN. Separately, we model the effects of the varying radiation field within NGC 4138, and we use this model to predict the corresponding changes in the PAH emission spectrum. We find that PAH band ratios are strongly variable with radius in this galaxy with short-to-long wavelength band ratios peaking in the starburst ring. The changing mix of starlight appears to have a considerable effect on the trends in these band ratios, and our radiation model predicts the shapes of these trends. However, the amplitude of observed variation is ∼2.5 × larger than predicted for some ratios. A cutoff of small grains in the PAH size distribution, as has been suggested for AGN, together with changes in PAH ionization fraction could explain the behavior of the shorter bands, but this model fails to reproduce longer band behaviors. Additionally, we find that short-to-long wavelength PAH band ratios increase slightly within ∼270 pc of the center, suggesting that the AGN may directly influence PAH emission there.
PDF
