Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that has important roles in regulating energy balance and glucose and lipid homeostasis through a heterodimeric receptor complex ...comprising FGF receptor 1 (FGFR1) and β-klotho. Administration of FGF21 to rodents or non-human primates causes considerable pharmacological benefits on a cluster of obesity-related metabolic complications, including a reduction in fat mass and alleviation of hyperglycaemia, insulin resistance, dyslipidaemia, cardiovascular disorders and non-alcoholic steatohepatitis (NASH). However, native FGF21 is unsuitable for clinical use owing to poor pharmacokinetic and biophysical properties. A large number of long-acting FGF21 analogues and agonistic monoclonal antibodies for the FGFR1-β-klotho receptor complexes have been developed. Several FGF21 analogues and mimetics have progressed to early phases of clinical trials in patients with obesity, type 2 diabetes mellitus and NASH. In these trials, the primary end points of glycaemic control have not been met, whereas substantial improvements were observed in dyslipidaemia, hepatic fat fractions and serum markers of liver fibrosis in patients with NASH. The complexity and divergence in pharmacology and pathophysiology of FGF21, interspecies variations in FGF21 biology, the possible existence of obesity-related FGF21 resistance and endogenous FGF21 inactivation enzymes represent major obstacles to clinical implementation of FGF21-based pharmacotherapies for metabolic diseases.
The ice arches that usually develop at the northern and southern ends of Nares Strait play an important role in modulating the export of Arctic Ocean multi-year sea ice. The Arctic Ocean is evolving ...towards an ice pack that is younger, thinner, and more mobile and the fate of its multi-year ice is becoming of increasing interest. Here, we use sea ice motion retrievals from Sentinel-1 imagery to report on the recent behavior of these ice arches and the associated ice fluxes. We show that the duration of arch formation has decreased over the past 20 years, while the ice area and volume fluxes along Nares Strait have both increased. These results suggest that a transition is underway towards a state where the formation of these arches will become atypical with a concomitant increase in the export of multi-year ice accelerating the transition towards a younger and thinner Arctic ice pack.
Abstract
We searched for shocked carbon chain chemistry (SCCC) sources with C
3
S abundances surpassing those of HC
5
N toward the dark cloud L1251, using the Effelsberg telescope at the
K
band ...(18–26 GHz). L1251-1 and L1251-3 are identified as the most promising SCCC sources. The two sources harbor young stellar objects. We conducted mapping observations toward L1251-A, the western tail of L1251, at
λ
∼ 3 mm with the Purple Mountain Observatory 13.7 m and the Nobeyama Radio Observatory 45 m telescopes in lines of C
2
H, N
2
H
+
, CS, HCO
+
, SO, HC
3
N, and C
18
O as well as in CO 3–2 using the James Clerk Maxwell Telescope (JCMT). The spectral data were combined with archival data including Spitzer and Herschel continuum maps for further analysis. Filamentary substructures labeled as F1–F6 were extracted in L1251, with F1 being associated with L1251-A hosting L1251-1. The peak positions of dense gas traced by HCO
+
are misaligned relative to those of the dust clumps. Episodic outflows are common in this region. The twisted morphology of F1 and velocity distribution along L1251-A may originate from stellar feedback. SCCC in L1251-1 may have been caused by outflow activities originated from the infrared source IRS1. The signposts of ongoing SCCC and the broadened line widths of C
3
S and C
4
H in L1251-1 as well as the distribution of HC
3
N are also related to outflow activities in this region. L1251-1 (IRS1) together with the previously identified SCCC source IRS3 demonstrate that L1251-A is an excellent region to study SCCC.
This randomized, double‐blind, placebo‐controlled study evaluated whether lamivudine given during late pregnancy can reduce hepatitis B virus (HBV) perinatal transmission in highly viraemic mothers. ...Mothers were randomized to either lamivudine 100 mg or placebo from week 32 of gestation to week 4 postpartum. At birth, infants received recombinant HBV vaccine with or without HBIg and were followed until week 52. One hundred and fifty mothers, with a gestational age of 26–30 weeks and serum HBV DNA >1000 MEq/mL (bDNA assay), were treated. A total of 141 infants received immunoprophylaxis at birth. In lamivudine‐treated mothers, 56 infants received vaccine + HBIg (lamivudine + vaccine + HBIg) and 26 infants received vaccine (lamivudine + vaccine). In placebo‐treated mothers, 59 infants received vaccine + HBIg (placebo + vaccine + HBIg). At week 52, in the primary analyses where missing data was counted as failures, infants in the lamivudine + vaccine + HBIg group had a significant decrease in incidence of HBsAg seropositivity (10/56, 18%vs 23/59, 39%; P = 0.014) and in detectable HBV DNA (11/56, 20%vs 27/59, 46%; P = 0.003) compared to infants in the placebo + vaccine + HBIg group. Sensitivity analyses to evaluate the impact of missing data at week 52 resulting from a high dropout rate (13% in the lamivudine + vaccine + HBIg group and 31% in the placebo + vaccine + HBIg group) remained consistent with the primary analysis in that lower transmission rates were still observed in the infants of lamivudine‐treated mothers, but the differences were not statistically significant. No safety concerns were noted in the lamivudine‐treated mothers or their infants. Results of this study suggest that lamivudine reduced HBV transmission from highly viraemic mothers to their infants who received passive/active immunization.
Aberrant DNA hypermethylation contributes to myelomagenesis by silencing tumor-suppressor genes. Recently, a few reports have suggested that a novel class of small non-coding RNAs, called ...Piwi-interacting RNAs (piRNAs), may be involved in the epigenetic regulation of cancer. In this study, for the first time we provided evidence that the expression of piRNA-823 was upregulated in multiple myeloma (MM) patients and cell lines, and positively correlated with clinical stage. Silencing piRNA-823 in MM cells induced deregulation of cell cycle regulators and apoptosis-related proteins expression, accompanied by inhibition of tumorigenicity in vitro and in vivo. Moreover, piRNA-823 was directly relevant to de novo DNA methyltransferases, DNMT3A and 3B, in primary CD138(+) MM cells. The inhibited expression of piRNA-823 in MM cells resulted in marked reduction of DNMT3A and 3B at both mRNA and protein levels, which in turn led to decrease in global DNA methylation and reexpression of methylation-silenced tumor suppressor, p16(INK4A). In addition, piRNA-823 abrogation in MM cells induced reduction of vascular endothelial growth factor secretion, with consequent decreased proangiogenic activity. Altogether, these data support an oncogenic role of piRNA-823 in the biology of MM, providing a rational for the development of piRNA-targeted therapeutic strategies in MM.
Background
The aim of this study was to evaluate whether adjuvant chemotherapy is associated with improved survival in patients with resectable gastric neuroendocrine carcinomas (G‐NECs) or mixed ...adenoneuroendocrine carcinomas (G‐MANECs).
Methods
The study included patients with G‐NECs or G‐MANECs who underwent surgery in one of 21 centres in China between 2004 and 2016. Propensity score matching analysis was used to reduce selection bias, and overall survival (OS) in different treatment groups was estimated by the Kaplan–Meier method.
Results
In total, 804 patients with resectable G‐NECs or G‐MANECs were included, of whom 490 (60·9 per cent) received adjuvant chemotherapy. After propensity score matching, OS in the chemotherapy group was similar to that in the no‐chemotherapy group. Among patients with G‐NECs, survival in the fluorouracil (5‐FU)‐based chemotherapy group and the non‐5‐FU‐based chemotherapy group was similar to that in the no‐chemotherapy group. Similarly, etoposide plus cisplatin or irinotecan plus cisplatin was not associated with better OS in patients with G‐NECs. Among patients with G‐MANECs, OS in the non‐5‐FU‐based chemotherapy group was worse than that in the no‐chemotherapy group. Patients with G‐MANECs did not have better OS when platinum‐based chemotherapy was
used.
Conclusion
There was no survival benefit in patients who received adjuvant chemotherapy for G‐NECs or G‐MANECs.
Antecedentes
El objetivo de este estudio fue evaluar si la quimioterapia adyuvante mejoraba la supervivencia en pacientes con carcinomas gástricos resecables neuroendocrinos (gastric neuroendocrine carcinomas, G‐NECs) y carcinomas adenoneuroendocrinos mixtos (mixed adenoneuroendocrine carcinomas, G‐MANECs).
Métodos
Se incluyeron pacientes con G‐NECs y G‐MANECs tratados quirúrgicamente en 21 centros en China entre 2004 y 2016. Se utilizó un análisis de emparejamiento por puntaje de propensión para reducir el sesgo de selección y el método de Kaplan‐Meier para estimar la supervivencia global (overall survival, OS) de los pacientes en los diferentes grupos de tratamiento.
Resultados
En total, se incluyeron en el estudio 804 pacientes con G‐NECs y G‐MANECs resecables y 490 pacientes (60,9%) recibieron quimioterapia adyuvante. Después del emparejamiento por puntaje de propensión, la OS del grupo con quimioterapia fue similar a la del grupo sin quimioterapia. En los pacientes con G‐NECs, la supervivencia en los grupos con quimioterapia basada en 5‐FU (fluorouracilo) y de quimioterapia sin 5‐FU fue similar a la del grupo sin quimioterapia. Asimismo, la combinación de etopósido y cisplatino o de irinotecán y cisplatino no se asoció con una mejor OS en pacientes con G‐NECs. En pacientes con G‐MANECs, la OS del grupo con quimioterapia sin 5‐FU fue peor que la del grupo sin quimioterapia. Los pacientes con G‐MANECs no presentaron una mejor OS cuando se administró quimioterapia basada en platinos.
Conclusión
La administración de quimioterapia adyuvante en pacientes con G‐NECs y G‐MANECs no mejoró la supervivencia.
This multicentre study enrolled 804 patients with resectable gastric neuroendocrine carcinomas and gastric mixed adenoneuroendocrine carcinomas. In propensity score matching analysis, there were no associations between the use of adjuvant chemotherapy and improved overall survival. Similar results were obtained in stratified analysis according to different chemotherapy regimens.
No benefit
The increasing impact of both climatic change and human activities on global river systems necessitates an increasing need to identify and quantify the various drivers and their impacts on fluvial ...water and sediment discharge. Here we show that mean Yangtze River water discharge of the first decade after the closing of the Three Gorges Dam (TGD) (2003-2012) was 67 km(3)/yr (7%) lower than that of the previous 50 years (1950-2002), and 126 km(3)/yr less compared to the relatively wet period of pre-TGD decade (1993-2002). Most (60-70%) of the decline can be attributed to decreased precipitation, the remainder resulting from construction of reservoirs, improved water-soil conservation and increased water consumption. Mean sediment flux decreased by 71% between 1950-1968 and the post-TGD decade, about half of which occurred prior to the pre-TGD decade. Approximately 30% of the total decline and 65% of the decline since 2003 can be attributed to the TGD, 5% and 14% of these declines to precipitation change, and the remaining to other dams and soil conservation within the drainage basin. These findings highlight the degree to which changes in riverine water and sediment discharge can be related with multiple environmental and anthropogenic factors.
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