Neoadjuvant chemotherapy (NACT) is an important treatment option for patients with ovarian cancer. Although intravenous NACT can improve optimal resection rates and decrease surgical morbidity and mortality, these advantages do not translate into a survival benefit. Ovarian carcinoma is mainly confined to the peritoneal cavity, which makes it a potential target for hyperthermic intraperitoneal chemotherapy (HIPEC). Our previous study showed that HIPEC could be used in the neoadjuvant setting, which was named neoadjuvant HIPEC (NHIPEC). Since hyperthermia is an excellent chemosensitiser, we hypothesised that the combination of NHIPEC and intravenous NACT could show superior efficacy to intravenous NACT alone.
This study is a single-centre, open-label, randomised (11 allocation ratio) phase 2 trial. A total of 80 patients will be randomly assigned into an experimental group (NHIPEC+intravenous NACT) or a control group (intravenous NACT). Patients in the experimental group will receive NHIPEC following laparoscopic evaluation, and four tubes will be placed via the laparoscopic ports, which will be used to administer NHIPEC. Then, perfusion with docetaxel (60-75 mg/m
) will be performed (43°C for 60 min, Day 0) followed by cisplatin (75 mg/m
, Day 1) infusion (43°C for 60 min) 24 hours later. After NHIPEC, two cycles of intravenous NACT will be given. Patients in the control group will receive three cycles of intravenous NACT. The primary endpoint is the proportion of patients who achieve a Chemotherapy Response Score (CRS) of 3 according to the CRS system. The secondary endpoints include progression-free survival, overall survival and the rates of complete resection and NHIPEC-related adverse events.
This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital (approval number 2020-ky-050). Results will be submitted to peer-reviewed journals and presented at national and international conferences.
ChiCTR2000038173.
ChiCTR2000038173.
To document the regulatory environment of new tobacco and nicotine products (NTNPs), including electronic nicotine delivery systems (ENDS) and heated tobacco products (HTPs), in Latin America and the Caribbean (LAC).
Review of market research reports and databases, regulatory websites, Campaign for Tobacco-Free Kids, relevant published literature and the 2021 WHO Report on the Global Tobacco Epidemic.
ENDS entered the LAC market in the 2010s and are now available in most LAC countries. A majority of LAC countries (n=18) have either banned the commercialisation of ENDS (n=7) or regulated ENDS as tobacco products (n=7), medicinal products (n=1) or consumer products (n=3). The remaining LAC countries (n=15) do not regulate ENDS. HTPs were first introduced in 2017 and have been officially launched in five countries (Colombia, Guatemala, Dominican Republic, Mexico and Costa Rica). Few countries have banned HTP commercialisation (n=3) or regulated commercialisation and use (n=7), while the majority of countries have existing legislation that applies to HTPs (n=19). A few countries (n=4) have no tobacco control legislation and therefore do not regulate HTPs.
NTNPs are emerging products in the LAC region. Governments should follow WHO guidance and the decisions of the Conference of Parties to the WHO Framework Convention on Tobacco Control and ban or regulate NTNPs as tobacco products; otherwise NTNPs could create a new generation of tobacco and nicotine users.
NTNPs are emerging products in the LAC region. Governments should follow WHO guidance and the decisions of the Conference of Parties to the WHO Framework Convention on Tobacco Control and ban or regulate NTNPs as tobacco products; otherwise NTNPs could create a new generation of tobacco and nicotine users.Site-specific pseudouridylation of human ribosomal and spliceosomal RNAs is directed by H/ACA guide RNAs composed of two hairpins carrying internal pseudouridylation guide loops. The distal "antisense" sequences of the pseudouridylation loop base-pair with the target RNA to position two unpaired target nucleotides 5'-UN-3', including the 5' substrate U, under the base of the distal stem topping the guide loop. Therefore, each pseudouridylation loop is expected to direct synthesis of a single pseudouridine (Ψ) in the target sequence. However, in this study, genetic depletion and restoration and RNA mutational analyses demonstrate that at least four human H/ACA RNAs (SNORA53, SNORA57, SCARNA8, and SCARNA1) carry pseudouridylation loops supporting efficient and specific synthesis of two consecutive pseudouridines (ΨΨ or ΨNΨ) in the 28S (Ψ3747/Ψ3749), 18S (Ψ1045/Ψ1046), and U2 (Ψ43/Ψ44 and Ψ89/Ψ91) RNAs, respectively. In order to position two substrate Us for pseudouridylation, the dual guide loops form alternative base-pairing interactions with their target RNAs. This remarkable structural flexibility of dual pseudouridylation loops provides an unexpected versatility for RNA-directed pseudouridylation without compromising its efficiency and accuracy. Besides supporting synthesis of at least 6% of human ribosomal and spliceosomal Ψs, evidence indicates that dual pseudouridylation loops also participate in pseudouridylation of yeast and archaeal rRNAs.Eukaryotic cells maintain an optimal level of mRNAs through unknown mechanisms that balance RNA synthesis and degradation. We found that inactivation of the RNA exosome leads to global reduction of nascent mRNA transcripts, and that this defect is accentuated by loss of deposition of histone variant H2A.Z. We identify the mRNA for the sirtuin deacetylase Hst3 as a key target for the RNA exosome that mediates communication between RNA degradation and transcription machineries. These findings reveal how the RNA exosome and H2A.Z function together to control a deacetylase, ensuring proper levels of transcription in response to changes in RNA degradation.The regenerative potential of neural stem cells (NSCs) declines during aging, leading to cognitive dysfunctions. This decline involves up-regulation of senescence-associated genes, but inactivation of such genes failed to reverse aging of hippocampal NSCs. Because many genes are up-regulated or down-regulated during aging, manipulation of single genes would be insufficient to reverse aging. https://www.selleckchem.com/products/LBH-589.html Here we searched for a gene combination that can rejuvenate NSCs in the aged mouse brain from nuclear factors differentially expressed between embryonic and adult NSCs and their modulators. We found that a combination of inducing the zinc finger transcription factor gene Plagl2 and inhibiting Dyrk1a, a gene associated with Down syndrome (a genetic disorder known to accelerate aging), rejuvenated aged hippocampal NSCs, which already lost proliferative and neurogenic potential. Such rejuvenated NSCs proliferated and produced new neurons continuously at the level observed in juvenile hippocampi, leading to improved cognition. Epigenome, transcriptome, and live-imaging analyses indicated that this gene combination induces up-regulation of embryo-associated genes and down-regulation of age-associated genes by changing their chromatin accessibility, thereby rejuvenating aged dormant NSCs to function like juvenile active NSCs. Thus, aging of NSCs can be reversed to induce functional neurogenesis continuously, offering a way to treat age-related neurological disorders.
Cell-free DNA is involved in the pathogenesis of systemic lupus erythematosus (SLE) but the clinical value of cell-free DNA measurements in SLE is unknown. Our aim was therefore to examine the utility of mitochondrial (mt) DNA and nuclear (n) DNA quantification in SLE.
EDTA plasma was drawn from 103 consecutive patients with SLE and from 56 healthy blood donors. mtDNA and nDNA copy numbers were quantified by PCR from cell-free plasma. Clinical parameters were recorded prospectively.
Circulating mtDNA copy numbers were increased 8.8-fold in the plasma of patients with SLE (median 6.6×10
/mL) compared with controls (median 7.6×10
/mL, p<0.0001). Among all 159 individuals, a cut-off set at 1.8×10
mtDNA copies in a receiver operated curve identified patients with SLE with 87.4% sensitivity and 94.6% specificity; the area under the curve was 0.95 (p<0.0001). mtDNA levels were independent of age or gender, but correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) on multivariable analysis (p=0.004). Conversely, SLEDAI was associated with prednisone dose (p<0.001), anti-double stranded DNA-titres (p=0.003) and mtDNA levels (p=0.005), but not nDNA copy numbers. In 33 patients with SLE with available follow-up, the changes of mtDNA, but not those of nDNA concentrations, robustly correlated with the evolution of the SLEDAI (r=0.55, p=0.001).
Circulating mtDNA unlike nDNA molecules are markedly increased in SLE plasma. Regardless of disease activity, circulating mtDNA levels distinguish patients with SLE from healthy controls with high sensitivity and represent an independent marker of SLE activity.
Circulating mtDNA unlike nDNA molecules are markedly increased in SLE plasma. Regardless of disease activity, circulating mtDNA levels distinguish patients with SLE from healthy controls with high sensitivity and represent an independent marker of SLE activity.The question of why our conceptions of space and time are intertwined with memory in the hippocampal formation is at the forefront of much current theorizing about this brain system. In this article I argue that animals bridge spatial and temporal gaps through the creation of internal models that allow them to act on the basis of things that exist in a distant place and/or existed at a different time. The hippocampal formation plays a critical role in these processes by stitching together spatiotemporally disparate entities and events. It does this by 1) constructing cognitive maps that represent extended spatial contexts, incorporating and linking aspects of an environment that may never have been experienced together; 2) creating neural trajectories that link the parts of an event, whether they occur in close temporal proximity or not, enabling the construction of event representations even when elements of that event were experienced at quite different times; and 3) using these maps and trajectories to simulate possible futures. As a function of these hippocampally driven processes, our subjective sense of both space and time are interwoven constructions of the mind, much as the philosopher Immanuel Kant postulated.The thyroid maintains systemic homeostasis by regulating serum thyroid hormone concentrations. Here we report the establishment of three-dimensional (3D) organoids from adult thyroid tissue representing murine and human thyroid follicular cells (TFCs). The TFC organoids (TFCOs) harbor the complete machinery of hormone production as visualized by the presence of colloid in the lumen and by the presence of essential transporters and enzymes in the polarized epithelial cells that surround a central lumen. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1, while the thyroid hormone precursor thyroglobulin is expressed at comparable levels to tissue. Single-cell RNA sequencing and transmission electron microscopy confirm that TFCOs phenocopy primary thyroid tissue. Thyroid hormones are readily detectable in conditioned medium of human TFCOs. We show clinically relevant responses (increased proliferation and hormone secretion) of human TFCOs toward a panel of Graves' disease patient sera, demonstrating that organoids can model human autoimmune disease.