Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release ...syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions.
The Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy. Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania (Penn) was used to develop the Penn grading scale for CRS. The Penn grading scale depends on easily accessible clinical features; does not rely on location of care or quantitation of supportive care; assigns grades to guide CRS management; distinguishes between mild, moderate, severe, and life-threatening CRS; and applies to both early-onset and delayed-onset CRS associated with T cell therapies. Clinical data from 55 pediatric patients with r/r B cell acute lymphoblastic leukemia and 42 patients with r/r chronic lymphocytic lymphoma treated with tisagenlecleucel were used to demonstrate the current application of the Penn grading scale.
We show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms.
Ammonia excretion at the gills of fish has been studied for 80 years, but the mechanism(s) involved remain controversial. The relatively recent discovery of the ammonia-transporting function of the ...Rhesus (Rh) proteins, a family related to the Mep/Amt family of methyl ammonia and ammonia transporters in bacteria, yeast and plants, and the occurrence of these genes and glycosylated proteins in fish gills has opened a new paradigm. We provide background on the evolution and function of the Rh proteins, and review recent studies employing molecular physiology which demonstrate their important contribution to branchial ammonia efflux. Rhag occurs in red blood cells, whereas several isoforms of both Rhbg and Rhcg occur in many tissues. In the branchial epithelium, Rhcg appears to be localized in apical membranes and Rhbg in basolateral membranes. Their gene expression is upregulated during exposure to high environmental ammonia or internal ammonia infusion, and may be sensitive to synergistic stimulation by ammonia and cortisol. Rhcg in particular appears to be coupled to H(+) excretion and Na(+) uptake mechanisms. We propose a new model for ammonia excretion in freshwater fish and its variable linkage to Na(+) uptake and acid excretion. In this model, Rhag facilitates NH(3) flux out of the erythrocyte, Rhbg moves it across the basolateral membrane of the branchial ionocyte, and an apical "Na(+)/NH (+)(4) exchange complex" consisting of several membrane transporters (Rhcg, V-type H(+)-ATPase, Na(+)/H(+) exchanger NHE-2 and/or NHE-3, Na(+) channel) working together as a metabolon provides an acid trapping mechanism for apical excretion. Intracellular carbonic anhydrase (CA-2) and basolateral Na(+)/HCO (-)(3) cotransporter (NBC-1) and Na(+)/K(+)-ATPase play indirect roles. These mechanisms are normally superimposed on a substantial outward movement of NH(3) by simple diffusion, which is probably dependent on acid trapping in boundary layer water by H(+) ions created by the catalysed or non-catalysed hydration of expired metabolic CO(2). Profitable areas for future investigation of Rh proteins in fish are highlighted: their involvement in the mechanism of ammonia excretion across the gills in seawater fish, their possible importance in ammonia excretion across the skin, their potential dual role as CO(2) transporters, their responses to feeding, and their roles in early life stages prior to the full development of gills.
We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19
relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant ...tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.
Adverse effects of spaceflight on sensorimotor function have been linked to altered somatosensory and vestibular inputs in the microgravity environment. Whether these spaceflight sequelae have a ...central nervous system component is unknown. However, experimental studies have shown spaceflight-induced brain structural changes in rodents' sensorimotor brain regions. Understanding the neural correlates of spaceflight-related motor performance changes is important to ultimately develop tailored countermeasures that ensure mission success and astronauts' health.
Head down-tilt bed rest (HDBR) can serve as a microgravity analog because it mimics body unloading and headward fluid shifts of microgravity. We conducted a 70-day 6° HDBR study with 18 right-handed males to investigate how microgravity affects focal gray matter (GM) brain volume. MRI data were collected at 7 time points before, during and post-HDBR. Standing balance and functional mobility were measured pre and post-HDBR. The same metrics were obtained at 4 time points over ~90 days from 12 control subjects, serving as reference data.
HDBR resulted in widespread increases GM in posterior parietal regions and decreases in frontal areas; recovery was not yet complete by 12 days post-HDBR. Additionally, HDBR led to balance and locomotor performance declines. Increases in a cluster comprising the precuneus, precentral and postcentral gyrus GM correlated with less deterioration or even improvement in standing balance. This association did not survive Bonferroni correction and should therefore be interpreted with caution. No brain or behavior changes were observed in control subjects.
Our results parallel the sensorimotor deficits that astronauts experience post-flight. The widespread GM changes could reflect fluid redistribution. Additionally, the association between focal GM increase and balance changes suggests that HDBR also may result in neuroplastic adaptation. Future studies are warranted to determine causality and underlying mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present the results of our survey of 1612-MHz circumstellar OH maser emission from asymptotic giant branch (AGB) stars and red supergiants (RSGs) in the Large Magellanic Cloud (LMC). We have ...discovered four new circumstellar maser sources in the LMC, and increased the number of reliable wind speeds from infrared (IR) stars in the LMC from 5 to 13. Using our new wind speeds, as well as those from Galactic sources, we have derived an updated relation for dust-driven winds: ... We compare the subsolar metallicity LMC OH/IR stars with carefully selected samples of more metal-rich OH/IR stars, also at known distances, in the Galactic Centre and Galactic bulge. We derive pulsation periods for eight of the bulge stars for the first time by using near-IR photometry from the Vista Variables in the Via Lactea survey. We have modelled our LMC OH/IR stars and developed an empirical method of deriving gas-to-dust ratios and mass-loss rates by scaling the models to the results from maser profiles. We have done this also for samples in the Galactic Centre and bulge and derived a new mass-loss prescription which includes luminosity, pulsation period, and gas-to-dust ratio ... The tightest correlation is found between mass-loss rate and luminosity. We find that the gas-to-dust ratio has little effect on the mass-loss of oxygen-rich AGB stars and RSGs within the Galaxy and the LMC. This suggests that the mass-loss of oxygen-rich AGB stars and RSGs is (nearly) independent of metallicity between a half and twice solar. (ProQuest: ... denotes formulae/symbols omitted.)
Highlights ► A review of the role of Rh proteins in branchial ammonia excretion in freshwater and seawater fish. ► Impact of environmental ammonia on gill remodeling, trans epithelial potential and ...ventilation in fish. ► Authors pose questions and/or suggestions for research approaches to shed light on questions related to ammonia in fish.
Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene ...expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6-12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes using a gene-gene interaction network, and place the genetic risk loci in the context of the intrinsic subsets. To identify gene expression modules common to three independent datasets from three different clinical centers, we developed a consensus clustering procedure based on mutual information of partitions, an information theory concept, and performed a meta-analysis of these genome-wide gene expression datasets. We created a gene-gene interaction network of the conserved molecular features across the intrinsic subsets and analyzed their connections with SSc-associated genetic polymorphisms. The network is composed of distinct, but interconnected, components related to interferon activation, M2 macrophages, adaptive immunity, extracellular matrix remodeling, and cell proliferation. The network shows extensive connections between the inflammatory- and fibroproliferative-specific genes. The network also shows connections between these subset-specific genes and 30 SSc-associated polymorphic genes including STAT4, BLK, IRF7, NOTCH4, PLAUR, CSK, IRAK1, and several human leukocyte antigen (HLA) genes. Our analyses suggest that the gene expression changes underlying the SSc subsets may be long-lived, but mechanistically interconnected and related to a patients underlying genetic risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these ...patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance. Methods In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing. Findings Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4–48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6–25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma. Interpretation A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach. Funding None.
Nitrogen metabolism in fishes has been a focus of comparative physiologists for nearly a century. In this Review, we focus specifically on early life stages of fishes, which have received ...considerable attention in more recent work. Nitrogen metabolism and excretion in early life differs fundamentally from that of juvenile and adult fishes because of (1) the presence of a chorion capsule in embryos that imposes a limitation on effective ammonia excretion, (2) an amino acid-based metabolism that generates a substantial ammonia load, and (3) the lack of a functional gill, which is the primary site of nitrogen excretion in juvenile and adult fishes. Recent findings have shed considerable light on the mechanisms by which these constraints are overcome in early life. Perhaps most importantly, the discovery of Rhesus (Rh) glycoproteins as ammonia transporters and their expression in ion-transporting cells on the skin of larval fishes has transformed our understanding of ammonia excretion by fishes in general. The emergence of larval zebrafish as a model species, together with genetic knockdown techniques, has similarly advanced our understanding of ammonia and urea metabolism and excretion by larval fishes. It has also now been demonstrated that ammonia excretion is one of the primary functions of the developing gill in rainbow trout larvae, leading to new hypotheses regarding the physiological demands driving gill development in larval fishes. Here, we highlight and discuss the dramatic changes in nitrogen handling that occur over early life development in fishes.
Purpose: Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression. Myeloid-derived suppressor
cells (MDSC) represent one mechanism by which tumors induce ...T-cell suppression. Several factors pivotal to the accumulation
of MDSC are targeted by the tyrosine kinase inhibitor, sunitinib. The effect of sunitinib on MDSC-mediated immunosuppression
in RCC patients has been investigated.
Experimental Design: Patient peripheral blood levels of MDSC and regulatory T-cell (Treg) and T-cell production of IFN-γ were evaluated before
and after sunitinib treatment. Correlations between MDSC and Treg normalization as well as T-cell production of IFN-γ were
examined. The in vitro effect of sunitinib on patient MDSC was evaluated.
Results: Metastatic RCC patients had elevated levels of CD33 + HLA-DR â and CD15 + CD14 â MDSC, and these were partially overlapping populations. Treatment with sunitinib resulted in significant reduction in MDSC
measured by several criteria. Sunitinib-mediated reduction in MDSC was correlated with reversal of type 1 T-cell suppression,
an effect that could be reproduced by the depletion of MDSC in vitro . MDSC reduction in response to sunitinib correlated with a reversal of CD3 + CD4 + CD25 hi Foxp3 + Treg cell elevation. No correlation existed between a change in tumor burden and a change in MDSC, Treg, or T-cell production
of IFN-γ. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at â¥1.0 μg/mL. Sunitinib did not induce MDSC
maturation in vitro .
Conclusions: Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.
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