Pegfilgrastim is a sustained-duration form of filgrastim, a recombinant methionyl form of human granulocyte colony-stimulating factor (G-CSF), to which a 20 kDa polyethylene glycol molecule is ...covalently bound to the N-terminal methionine residue. Similar to filgrastim, pegfilgrastim increases the proliferation and differentiation of neutrophils from committed progenitor cells, induces maturation, and enhances the survival and function of mature neutrophils, resulting in dose-dependent increases in neutrophils. After subcutaneous administration, pegfilgrastim exhibits nonlinear pharmacokinetics and exposure to pegfilgrastim increases in more than a dose-proportional manner, suggesting that the clearance of pegfilgrastim decreases with increased dosing. Filgrastim is primarily eliminated by the kidney and neutrophils/neutrophil precursors; the latter presumably involves binding of the growth factor to the G-CSF receptor on the cell surface, internalization of the growth factor-receptor complexes via endocytosis, and subsequent degradation inside the cells. Pegylation of filgrastim renders renal clearance insignificant, which was demonstrated in bilaterally nephrectomized rats and confirmed in subjects with renal impairment. As a result, the neutrophil-mediated clearance is the predominant elimination pathway for pegfilgrastim. During chemotherapy-induced neutropenia, the clearance of pegfilgrastim is significantly reduced and the concentration of pegfilgrastim is sustained until onset of neutrophil recovery. Pegfilgrastim concentrations are sustained longer in patients with profound neutropenia. Evidence supports the use of a postnadir absolute neutrophil count (ANC) of ≥ 1 × 109/L as a surrogate marker threshold for the clearance of pegfilgrastim to subtherapeutic levels. After repeated administration of pegfilgrastim, the peak concentrations of pegfilgrastim decrease, likely due to increased neutrophil and neutrophil precursor mass. A pharmacokinetic-pharmacodynamic model was developed to describe the pharmacokinetic and ANC profiles of pegfilgrastim; the analysis supported that 100 μg/kg was an adequate weight-based dose of pegfilgrastim and predicted that 6 mg would be an optimal fixed dose of pegfilgrastim to simplify treatment. Data from a pivotal study confirmed that a once-per-chemotherapy-cycle injection of pegfilgrastim at 6 mg was as safe and effective as 11 daily injections of filgrastim at 5 μg/kg in reducing neutropenia and its complications in patients with breast cancer receiving four cycles of doxorubicin/docetaxel chemotherapy. Because of the highly efficient regulation of pegfilgrastim clearance via neutrophils and neutrophil precursors, a single fixed dose of pegfilgrastim can be given once per chemotherapy cycle in conjunction with a variety of myelosuppressive chemotherapy regimens.
The first metal iodate fluoride, Bi(IO3)F2, with a strong second harmonic generation (SHG) effect has been prepared. Bi(IO3)F2 crystallizes in the polar space group C2 and features a ...three‐dimensional BiF2+ cationic framework with IO3 groups capping the inner walls of the one‐dimensional tunnels. This BiF2+ cationic framework acts as a template for the assembly of the polar IO3 units in a favorable superposed fashion, which leads to the polar structure of the material. Bi(IO3)F2 displays a rather wide transmittance window (0.3–11 μm) and exhibits a very strong SHG response that is about 11.5 times larger than that of KH2PO4 (KDP) under 1064 nm laser radiation and the same as that of KTiOPO4 (KTP) under 2.05 μm laser radiation. Preliminary investigations indicate that Bi(IO3)F2 is a promising nonlinear optical material in the visible and mid‐IR region.
The metal iodate fluoride Bi(IO3)F2 was prepared through the introduction of fluoride anions into bismuth iodate. It features a three‐dimensional BiF2+ framework that acts as a template for the alignment of the IO3 units and displays a significant second harmonic generation effect that is about 11.5 times larger than that of KH2PO4 (KDP).
Grain size is an important component trait of grain yield, which is frequently threatened by abiotic stress. However, little is known about how grain yield and abiotic stress tolerance are regulated. ...Here, we characterize GSA1, a quantitative trait locus (QTL) regulating grain size and abiotic stress tolerance associated with metabolic flux redirection. GSA1 encodes a UDP-glucosyltransferase, which exhibits glucosyltransferase activity toward flavonoids and monolignols. GSA1 regulates grain size by modulating cell proliferation and expansion, which are regulated by flavonoid-mediated auxin levels and related gene expression. GSA1 is required for the redirection of metabolic flux from lignin biosynthesis to flavonoid biosynthesis under abiotic stress and the accumulation of flavonoid glycosides, which protect rice against abiotic stress. GSA1 overexpression results in larger grains and enhanced abiotic stress tolerance. Our findings provide insights into the regulation of grain size and abiotic stress tolerance associated with metabolic flux redirection and a potential means to improve crops.
In the early stages of the outbreak of coronavirus disease 2019 (COVID-19) in Hubei, China, the local health-care system was overwhelmed. Physicians and nurses who had no infectious disease expertise ...were recruited to provide care to patients with COVID-19. To our knowledge, no studies on their experiences of combating COVID-19 have been published. We aimed to describe the experiences of these health-care providers in the early stages of the outbreak.
We did a qualitative study using an empirical phenomenological approach. Nurses and physicians were recruited from five COVID-19-designated hospitals in Hubei province using purposive and snowball sampling. They participated in semi-structured, in-depth interviews by telephone from Feb 10 to Feb 15, 2020. Interviews were transcribed verbatim and analysed using Haase's adaptation of Colaizzi's phenomenological method.
We recruited nine nurses and four physicians. Three theme categories emerged from data analysis. The first was “being fully responsible for patients' wellbeing—‘this is my duty’”. Health-care providers volunteered and tried their best to provide care for patients. Nurses had a crucial role in providing intensive care and assisting with activities of daily living. The second category was “challenges of working on COVID-19 wards”. Health-care providers were challenged by working in a totally new context, exhaustion due to heavy workloads and protective gear, the fear of becoming infected and infecting others, feeling powerless to handle patients' conditions, and managing relationships in this stressful situation. The third category was “resilience amid challenges”. Health-care providers identified many sources of social support and used self-management strategies to cope with the situation. They also achieved transcendence from this unique experience.
The intensive work drained health-care providers physically and emotionally. Health-care providers showed their resilience and the spirit of professional dedication to overcome difficulties. Comprehensive support should be provided to safeguard the wellbeing of health-care providers. Regular and intensive training for all health-care providers is necessary to promote preparedness and efficacy in crisis management.
National Key R&D Program of China, Project of Humanities and Social Sciences of the Ministry of Education in China.
The relationship between chromatin organization and gene regulation remains unclear. While disruption of chromatin domains and domain boundaries can lead to misexpression of developmental genes, ...acute depletion of regulators of genome organization has a relatively small effect on gene expression. It is therefore uncertain whether gene expression and chromatin state drive chromatin organization or whether changes in chromatin organization facilitate cell-type-specific activation of gene expression. Here, using the dorsoventral patterning of the Drosophila melanogaster embryo as a model system, we provide evidence for the independence of chromatin organization and dorsoventral gene expression. We define tissue-specific enhancers and link them to expression patterns using single-cell RNA-seq. Surprisingly, despite tissue-specific chromatin states and gene expression, chromatin organization is largely maintained across tissues. Our results indicate that tissue-specific chromatin conformation is not necessary for tissue-specific gene expression but rather acts as a scaffold facilitating gene expression when enhancers become active.
Ovarian cancer is one of the most common gynecologic malignancy with poor prognosis. Recently, long noncoding RNAs (lncRNAs) have been identified as key regulators in cancer development. The current ...study investigated the role of lncRNA P73 antisense RNA 1T (TP73‐AS1) in ovarian cancer. Quantitative real‐time polymerase chain reaction determined the expression levels of TP‐73AS1, matrix metallopeptidases (MMPs) messenger RNA. Cell proliferative ability, cell invasion, and migration were CCK‐8 and colony formation, and transwell invasion and migration assays, respectively. The protein levels of matrix metallopeptidase 2 (MMP2) and MMP9 were measured by Western blot. TP73‐AS1 was upregulated in the ovarian cancer tissues and ovarian cancer cells, and upregulation of TP73‐AS1 was associated with poor prognosis. Knockdown of TP73‐AS1 significantly suppressed cell proliferation, invasion, and migration of SKOV3 cells, and overexpression of TP73‐AS1 promoted cell proliferation, invasion, and migration of OVCA429 cells. In addition, knockdown of TP73‐AS1 suppressed the in vivo tumor growth. Tumor metastasis RT2 profiler polymerase chain reaction array showed that MMP2 and MMP9 was significantly upregulated by TP73‐AS1 overexpression in ovarian cancer cells. TP73‐AS1 overexpression enhanced the expression of MMP2 and MMP9 in ovarian cancer cells. Knockdown of MMP2 and MMP9 attenuated the effects of TP73‐AS1 overexpression on cell invasion and migration. The clinical data showed that MMP2 and MMP9 were upregulated and positively correlated with TP73‐AS1 expression in ovarian cancer tissues. Collectively, our results demonstrated the oncogenic role of TP73‐AS1 in ovarian cancer, and targeting TP73‐AS1 may represent a novel approach in battling against ovarian cancer.
TP73‐AS1 was upregulated in the ovarian cancer tissues and ovarian cancer cells, and the long noncoding RNA TP73‐AS1 promotes ovarian cancer cell proliferation and metastasis via modulation of MMP2 and MMP9.
AIM To analyze the risk factors for pancreatic fistula after pancreaticoduodenectomy.METHODS We conducted a retrospective analysis of 539 successive cases of pancreaticoduodenectomy performed at our ...hospital from March 2012 to October 2015. Pancreatic fistula was diagnosed in strict accordance with the definition of pancreatic fistula from the International Study Group on Pancreatic Fistula. The risk factors for pancreatic fistula were analyzed by univariate analysis and multivariate logistic regression analysis.RESULTS A total of 269(49.9%) cases of pancreatic fistula occurred after pancreaticoduodenectomy,including 71(13.17%) cases of grade A pancreatic fistula,178(33.02%) cases of grade B,and 20(3.71%) cases of grade C. Univariate analysis showed no significant correlation between postoperative pancreatic fistula(POPF) and the following factors: age,hypertension,alcohol consumption,smoking,history of upper abdominal surgery,preoperative jaundice management,preoperative bilirubin,preoperative albumin,pancreatic duct drainage,intraoperative blood loss,operative time,intraoperative blood transfusion,Braun anastomosis,and pancreaticoduodenectomy(with or without pylorus preservation). Conversely,a significant correlation was observed between POPF and the following factors: gender(male vs female: 54.23% vs 42.35%,P = 0.008),diabetes(non-diabetic vs diabetic: 51.61% vs 39.19%,P = 0.047),body mass index(BMI)(≤ 25 vs > 25: 46.94% vs 57.82%,P = 0.024),blood glucose level(≤ 6.0 mmol/L vs > 6.0 mmol/L: 54.75% vs 41.14%,P = 0.002),pancreaticojejunal anastomosis technique(pancreatic duct-jejunum double-layer mucosa-to-mucosa pancreaticojejunal anastomosis vs pancreatic-jejunum single-layer mucosa-tomucosa anastomosis: 57.54% vs 35.46%,P = 0.000),diameter of the pancreatic duct(≤ 3 mm vs > 3 mm: 57.81% vs 38.36%,P = 0.000),and pancreatic texture(soft vs hard: 56.72% vs 29.93%,P = 0.000). Multivariate logistic regression analysis showed that gender(male),BMI > 25,pancreatic duct-jejunum double-layer mucosa-to-mucosa pancreaticojejunal anastomosis,pancreatic duct diameter ≤ 3 mm,and soft pancreas were risk factors for pancreatic fistula after pancreaticoduodenectomy.CONCLUSION Gender(male),BMI > 25,pancreatic duct-jejunum double-layer mucosa-to-mucosa pancreaticojejunal anastomosis,pancreatic duct diameter ≤ 3 mm,and soft pancreas were risk factors for pancreatic fistula after pancreaticoduodenectomy.
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