Episodic eddy-driven upwelling may supply a significant fraction of the nutrients required to sustain primary productivity of the subtropical ocean. New observations in the northwest Atlantic reveal ...that, although plankton blooms occur in both cyclones and mode-water eddies, the biological responses differ. Mode-water eddies can generate extraordinary diatom biomass and primary production at depth, relative to the time series near Bermuda. These blooms are sustained by eddy/wind interactions, which amplify the eddy-induced upwelling. In contrast, eddy/wind interactions dampen eddy-induced upwelling in cyclones. Carbon export inferred from oxygen anomalies in eddy cores is one to three times as much as annual new production for the region.
Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R).
Patients received cixutumumab, 6 mg/kg i.v. weekly, and ...temsirolimus, 25 to 37.5 mg i.v. weekly (4-week cycles), with restaging after 8 weeks. Median follow-up was 8.9 months.
Twenty patients 17 with Ewing's sarcoma (EWS), 3 with desmoplastic small-round cell tumor (DSRCT) were enrolled. Twelve patients (60%) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting. The most frequent toxicities were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%; mostly grade I-II). Seven of 20 patients (35%) achieved stable disease (SD) for more than 5 months or complete/partial (CR/PR) responses. Tumor regression of more than 20% (23%, 23%, 27%, 100%, 100%) occurred in five of 17 (29%) patients with EWS, and they remained on study for 8 to 27 months. One of six patients with EWS who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR. Four of the seven best responders developed grade III mucositis, myelosuppression, or hyperglycemia, which were controlled while maintaining drug dose.
Cixutumumab combined with temsirolimus was well-tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated EWS family tumors.
Vitamin D deficiency has been implicated in the pathogenesis of several pregnancy complications attributed to impaired or abnormal placental function, but there are few clues indicating the ...mechanistic role of vitamin D in their pathogenesis. To further understand the role of vitamin D receptor (VDR)-mediated activity in placental function, we used heterozygous Vdr ablated C57Bl6 mice to assess fetal growth, morphological parameters and global gene expression in Vdr null placentae. Twelve Vdr+/- dams were mated at 10-12 weeks of age with Vdr+/- males. At day 18.5 of the 19.5 day gestation in our colony, females were euthanised and placental and fetal samples were collected, weighed and subsequently genotyped as either Vdr+/+, Vdr+/- or Vdr-/-. Morphological assessment of placentae using immunohistochemistry was performed and RNA was extracted and subject to microarray analysis. This revealed 25 genes that were significantly differentially expressed between Vdr+/+ and Vdr-/- placentae. The greatest difference was a 6.47-fold change in expression of Cyp24a1 which was significantly lower in the Vdr-/- placentae (P<0.01). Other differentially expressed genes in Vdr-/- placentae included those involved in RNA modification (Snord123), autophagy (Atg4b), cytoskeletal modification (Shroom4), cell signalling (Plscr1, Pex5) and mammalian target of rapamycin (mTOR) signalling (Deptor and Prr5). Interrogation of the upstream sequence of differentially expressed genes identified that many contain putative vitamin D receptor elements (VDREs). Despite the gene expression differences, this did not contribute to any differences in overall placental morphology, nor was function affected as there was no difference in fetal growth as determined by fetal weight near term. Given our dams still expressed a functional VDR gene, our results suggest that cross-talk between the maternal decidua and the placenta, as well as maternal vitamin D status, may be more important in determining pregnancy outcome than conceptus expression of VDR.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
While implantation of an inflatable penile prosthesis (IPP) is commonly performed via infrapubic or penoscrotal approaches, the subcoronal (SC) approach for IPP implantation may safely and reliably ...allow for additional reconstructive procedures through a single incision.
The aim of this study is to report outcomes, including complications, of the SC approach and to determine common characteristics of patients undergoing the SC approach.
A retrospective chart review from May 11, 2012, to January 31, 2022, was performed at a single, tertiary care institution to identify patients with IPP implantation via the SC approach.
Postoperative information was reviewed and extracted from all clinic notes available following the date of IPP implantation in the electronic medical record, detailing any complications including wound complications, need for revision or removal, device malfunction, and infections.
Sixty-six patients had IPP implantation via the SC approach. Median follow-up duration was 29.4 (interquartile range 14.9-50.1) months. One (1.8%) patient had a simple wound complication. Two (3.6%) experienced postoperative infection of the prosthesis, which resulted in explantation of the device. One of these infected prostheses later experienced partial glans necrosis. Revision for mechanical failure or unsatisfactory cosmetic result was performed in 3 (7.3%) IPPs placed via a SC incision.
The SC approach for implantation of IPP is safe and feasible with low complication and revision rates. It offers urologists an alternative to the classic infrapubic and penoscrotal approaches, both of which would require a second incision for additional reconstructive procedures required to adequately address deformities associated with severe Peyronie's disease. Therefore, urologists who treat these specialized populations of men may benefit from having the SC approach in their array of techniques for IPP implantation.
The limitations of this study include its retrospective nature, risk of selection bias, lack of comparison groups, and sample size. This study reports on early experience with the SC approach performed by a single high-volume reconstructive surgeon, who treats a specialized population of patients requiring complex repair during implantation of an IPP, particularly those with Peyronie's disease.
The SC incision for IPP implantation has low rates of complications and remains our approach of choice for IPP implantation in patients with severe Peyronie's disease, including curvatures >60°, severe indentation with hinge, and grade 3 calcification, which are unlikely to respond adequately to manual modeling alone.
Background
Carcinomas of the seminal vesicle are exceedingly rare, with a limited number of cases described in the literature. Reported cases span a relatively wide morphological spectrum, and their ...genomic features remain unexplored.
Design
In this study, we interrogated five primary epithelial neoplasms of the seminal vesicle using a targeted DNA sequencing platform (OncoPanel, 447 genes).
Results
The tumours included one adenocarcinoma with intestinal phenotype presenting after external beam radiation (for prostatic adenocarcinoma), one carcinoma with Müllerian‐type clear cell phenotype, two mucinous tumours resembling low‐grade mucinous neoplasms of the appendix (LAMN) and one mucinous cystadenoma. The post‐radiation mucinous adenocarcinoma had genomic findings consistent with bi‐allelic inactivation of TP53, as well as multiple copy‐number changes with regional and chromosomal arm‐level copy‐number losses. The Müllerian‐type clear cell carcinoma exhibited a complex copy‐number profile with numerous regional and arm‐level copy‐number changes, as well as focal amplification events, including copy‐number gain of 8q and amplification of a region within 20q13. Both low‐grade mucinous tumours resembling LAMN harboured hot‐spot gain‐of‐function KRAS variants (p.G12V and p.G13D) as the only genomic alteration. No genomic alterations were detected inthe lesion diagnosed as mucinous cystadenoma.
Conclusion
Our results suggest that primary low‐grade mucinous neoplasms of the seminal vesicle may represent a distinct entity equivalent to appendiceal counterparts, driven by gain‐of‐function variants of RAS GTPases. The remaining tumours showed genomic features that closely resembled those of neoplasms with comparable phenotypes and/or biological characteristics arising in other sites, suggesting that they could be managed similarly, with special considerations related to their anatomical location.
Application of biogeochemical models to the study of marine ecosystems is pervasive, yet objective quantification of these models' performance is rare. Here, 12 lower trophic level models of varying ...complexity are objectively assessed in two distinct regions (equatorial Pacific and Arabian Sea). Each model was run within an identical one‐dimensional physical framework. A consistent variational adjoint implementation assimilating chlorophyll‐a, nitrate, export, and primary productivity was applied and the same metrics were used to assess model skill. Experiments were performed in which data were assimilated from each site individually and from both sites simultaneously. A cross‐validation experiment was also conducted whereby data were assimilated from one site and the resulting optimal parameters were used to generate a simulation for the second site. When a single pelagic regime is considered, the simplest models fit the data as well as those with multiple phytoplankton functional groups. However, those with multiple phytoplankton functional groups produced lower misfits when the models are required to simulate both regimes using identical parameter values. The cross‐validation experiments revealed that as long as only a few key biogeochemical parameters were optimized, the models with greater phytoplankton complexity were generally more portable. Furthermore, models with multiple zooplankton compartments did not necessarily outperform models with single zooplankton compartments, even when zooplankton biomass data are assimilated. Finally, even when different models produced similar least squares model‐data misfits, they often did so via very different element flow pathways, highlighting the need for more comprehensive data sets that uniquely constrain these pathways.
Iron–sulfur (Fe‐S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR‐210‐ISCU1/2 ...axis cause Fe‐S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR‐210 and repression of the miR‐210 targets ISCU1/2 down‐regulated Fe‐S levels. In mouse and human vascular and endothelial tissue affected by PH, miR‐210 was elevated accompanied by decreased ISCU1/2 and Fe‐S integrity. In mice, miR‐210 repressed ISCU1/2 and promoted PH. Mice deficient in miR‐210, via genetic/pharmacologic means or via an endothelial‐specific manner, displayed increased ISCU1/2 and were resistant to Fe‐S‐dependent pathophenotypes and PH. Similar to hypoxia or miR‐210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise‐induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR‐210‐ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe‐S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings.
Synopsis
Hypoxia‐inducible miR‐210 down‐regulates its targets ISCU1/2 to regulate pulmonary vascular and endothelial levels of Fe‐S clusters upon acquired injury or mutations. A patient with ISCU loss‐of‐function mutation presents with pulmonary vasculopathy.
In mouse and human pulmonary vascular and endothelial tissue affected by PH, hypoxic induction of miR‐210 and repression of its targets ISCU1/2, down‐regulates iron‐sulfur levels.
Using genetic and pharmacologic methods to perform gain‐of‐function and loss‐of‐function analyses of miR‐210 and ISCU1/2 in the pulmonary vasculature of mice, the miR‐210‐ISCU1/2 axis is shown to be necessary and sufficient for induction of hypoxic PH.
Cardiopulmonary exercise testing of a woman with ISCU mutations revealed exercise‐induced pulmonary vascular dysfunction.
Hypoxia‐inducible miR‐210 down‐regulates its targets ISCU1/2 to regulate pulmonary vascular and endothelial levels of Fe‐S clusters upon acquired injury or mutations. A patient with ISCU loss‐of‐function mutation presents with pulmonary vasculopathy.
The alternative mechanism proposed by Mahadevan
et al
. is an unlikely explanation for our observations because their model predicts a bloom at the periphery of the eddy, whereas the observations ...show it located at the eddy center, and because the vertical displacements caused by the nonlinear Ekman effect are too small to lead to an extraordinary biological response in this eddy.
Highlights • Studies using hypertension/elastase have induced cerebral aneurysms (CA) in mice. • Using lower dose elastase, early CA pathology was sought at arterial bifurcations. • Pathology ...included endothelial change and internal elastic lamina degeneration. • Such bifurcation changes have not been systematically/simultaneously studied before. • A spectrum of early CA pathology permits study of factors influencing CA formation.
The traditionally used “Redfield” formula for the average composition of the organic tissue of marine phytoplankton, (CH
2O)
106(NH
3)
16(H
3PO
4), is found to be in disagreement with observations ...regarding its oxygen and hydrogen content. Based on considerations of metabolite composition and various observations, a new formula is proposed, C
106H
175O
42N
16P, which should be a better approximation to mean algal elemental composition. Estimates suggest that Redfield's algal C
org/N/P ratio of 106/16/1 is consistent with
−
O
2
P
oxidation ratios between 140 and 160, rather than the traditional value of 138.
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