IL-21 is the most recently discovered common gamma-chain cytokine that promotes persistent T-cell responses in chronic infections, autoimmunity and cancer. However, the therapeutic potential of ...inhibiting the IL-21-BATF signaling axis, particularly in transplant rejection, remains unclear. We used heart transplant models to examine the effects of IL-21 blockade in prevention of chronic cardiac allograft vasculopathy (CAV) using genetic knock-out and therapeutic approaches. Both wild-type C57BL/6 and IL-21-/- strains acutely rejected Balb/c skin grafts and once immunized with this skin graft, rejected Balb/c heart allografts in an accelerated fashion. However, when transplanted with heart grafts from the class-II major histocompatibility complex mutant, B6bm12 mice; wild-type recipients developed CAV, while IL-21-/- recipients were protected, even at day 100 post-transplant. Similarly, BATF-/- recipients, lacking the transcription factor BATF responsible for IL-21 production, did not develop CAV in B6-bm12 heart allografts. Strikingly, in a transient treatment protocol, the development of CAV in wild-type recipients of B6-bm12 hearts allografts was blocked by the administration of IL-21 receptor fusion protein (R-Fc). Thus, we demonstrate that CAV is regulated at least in part by IL-21 signaling and its blockade by genetic approaches or therapy with IL-21R-Fc prevents CAV in mice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Over the next 2 decades, a dramatic shift in the demographics of society will take place, with a rapid growth in the population of older adults. One of the most common complaints with ...healthy aging is a decreased ability to successfully perceive speech, particularly in noisy environments. In such noisy environments, the presence of visual speech cues (i.e., lip movements) provide striking benefits for speech perception and comprehension, but previous research suggests that older adults gain less from such audiovisual integration than their younger peers. To determine at what processing level these behavioral differences arise in healthy-aging populations, we administered a speech-in-noise task to younger and older adults. We compared the perceptual benefits of having speech information available in both the auditory and visual modalities and examined both phoneme and whole-word recognition across varying levels of signal-to-noise ratio. For whole-word recognition, older adults relative to younger adults showed greater multisensory gains at intermediate SNRs but reduced benefit at low SNRs. By contrast, at the phoneme level both younger and older adults showed approximately equivalent increases in multisensory gain as signal-to-noise ratio decreased. Collectively, the results provide important insights into both the similarities and differences in how older and younger adults integrate auditory and visual speech cues in noisy environments and help explain some of the conflicting findings in previous studies of multisensory speech perception in healthy aging. These novel findings suggest that audiovisual processing is intact at more elementary levels of speech perception in healthy-aging populations and that deficits begin to emerge only at the more complex word-recognition level of speech signals.
Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these ...drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes.
Toxicities (> or = grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were evaluated. Toxicity incidence and VEGFR2 H472Q and V297I status were compared to clinical outcomes.
Individuals experiencing HT had longer PFS following bevacizumab therapy than those without this toxicity in trials utilizing bevacizumab in patients with prostate cancer (31.5 vs 14.9 months, n = 60, P = 0.0009), and bevacizumab and sorafenib in patients with solid tumors (11.9 vs. 3.7 months, n = 27, P = 0.052). HT was also linked to a > 5-fold OS benefit after sorafenib and bevacizumab cotherapy (5.7 versus 29.0 months, P = 0.0068). HFSR was a marker for prolonged PFS during sorafenib therapy (6.1 versus 3.7 months respectively, n = 113, P = 0.0003). HT was a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib (OR(95%CI) = 3.2(1.5-6.8), P = 0.0024). Carriers of variant alleles at VEGFR2 H472Q experienced greater risk of developing HT (OR(95%CI) = 2.3(1.2 - 4.6), n = 170, P = 0.0154) and HFSR (OR(95%CI) = 2.7(1.3 - 5.6), n = 170, P = 0.0136).
This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib.
Purpose: Polymorphisms that are associated with ABCB1 expression and function may be linked to treatment efficacy and the development
of neutropenia and neurotoxicity in patients with ...androgen-independent prostate cancer receiving docetaxel.
Experimental Design: Patients with androgen-independent prostate cancer treated with docetaxel alone ( n = 23) or docetaxel and thalidomide ( n = 50) were genotyped for the ABCB1 1236C>T, 2677 G>T/A, and 3435 C>T alleles by direct sequencing, and diplotypes were constructed using an EM algorithm. The
data were then compared with duration to onset of peripheral neuropathy, neutropenia grade, and survival after docetaxel.
Results: For patients receiving docetaxel alone, individuals carrying a diplotype consisting of the 1236C-2677G-3435C linked alleles
had improved overall survival after treatment ( P = 0.0017). Additionally, patients treated with docetaxel and thalidomide carrying a diplotype consisting of the 2677T-3435T
haplotype had a shorter median survival ( P = 0.045). After adjusting for a particular set of polymorphisms and diplotype groupings, a hazard ratio of 10.87 was found
for patients carrying the 2677GG genotype versus patients carrying other genotypes ( P = 0.0048) in the docetaxel and thalidomide cohort. Among both treatment arms together, individuals carrying the 2677GG genotype
also had a significantly longer time to neuropathy ( P = 0.035). Finally, there was a strong trend toward patients carrying the 2677TT-3435TT diplotype having higher grades of
neutropenia ( P = 0.053).
Conclusion: The data suggest that docetaxel-induced neuropathy, neutropenia grade, and overall survival could be linked to ABCB1 allelic variants with ensuing negative implications for docetaxel treatment in patients carrying ABCB1 variant genotypes.
Pharmacologic inhibition of bromodomain and extra-terminal (BET) proteins is currently being explored as a new therapeutic approach in cancer. Some studies have also implicated BET proteins as ...regulators of cell identity and differentiation through their interactions with lineage-specific factors. However, the role of BET proteins has not yet been investigated in melanocyte differentiation. Melanocyte inducing transcription factor (MITF) is the master regulator of melanocyte differentiation, essential for pigmentation and melanocyte survival. In this study, we tested the hypothesis that BET proteins regulate melanocyte differentiation through interactions with MITF.
Here we show that chemical inhibition of BET proteins prevents differentiation of unpigmented melanoblasts into pigmented melanocytes and results in de-pigmentation of differentiated melanocytes. BET inhibition also slowed cell growth, without causing cell death, increasing the number of cells in G1. Transcriptional profiling revealed that BET inhibition resulted in decreased expression of pigment-specific genes, including many MITF targets. The expression of pigment-specific genes was also down-regulated in melanoma cells, but to a lesser extent. We found that RNAi depletion of the BET family members, bromodomain-containing protein 4 (BRD4) and bromodomain-containing protein 2 (BRD2) inhibited expression of two melanin synthesis enzymes, TYR and TYRP1. Both BRD4 and BRD2 were detected on melanocyte promoters surrounding MITF-binding sites, were associated with open chromatin structure, and promoted MITF binding to these sites. Furthermore, BRD4 and BRD2 physically interacted with MITF.
These findings indicate a requirement for BET proteins in the regulation of pigmentation and melanocyte differentiation. We identified changes in pigmentation specific gene expression that occur upon BET inhibition in melanoblasts, melanocytes, and melanoma cells.
Inflammatory Bowel Disease (IBD) represents a collection of gastrointestinal disorders resulting from genetic and environmental factors. Microcystin-leucine arginine (MC-LR) is a toxin produced by ...cyanobacteria during algal blooms and demonstrates bioaccumulation in the intestinal tract following ingestion. Little is known about the impact of MC-LR ingestion in individuals with IBD. In this study, we sought to investigate MC-LR's effects in a dextran sulfate sodium (DSS)-induced colitis model. Mice were separated into four groups: (a) water only (control), (b) DSS followed by water (DSS), (c) water followed by MC-LR (MC-LR), and (d) DSS followed by MC-LR (DSS + MC-LR). DSS resulted in weight loss, splenomegaly, and severe colitis marked by transmural acute inflammation, ulceration, shortened colon length, and bloody stools. DSS + MC-LR mice experienced prolonged weight loss and bloody stools, increased ulceration of colonic mucosa, and shorter colon length as compared with DSS mice. DSS + MC-LR also resulted in greater increases in pro-inflammatory transcripts within colonic tissue (TNF-α, IL-1β, CD40, MCP-1) and the pro-fibrotic marker, PAI-1, as compared to DSS-only ingestion. These findings demonstrate that MC-LR exposure not only prolongs, but also worsens the severity of pre-existing colitis, strengthening evidence of MC-LR as an under-recognized environmental toxin in vulnerable populations, such as those with IBD.
This review provides an overview of the pharmacogenetics of membrane transporters including selected ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and OATPs (OATP1B1 and OATP1B3). Membrane ...transporters are heavily involved in drug clearance and alters drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have significant effects on the absorption, distribution, metabolism and excretion of compounds, and may alter pharmacodynamics of many agents. This review discusses the techniques used to identify substrates and inhibitors of these proteins and subsequently to assess the effect of genetic mutation on transport, both in vitro and in vivo. A comprehensive list of substrates for the major drug transporters is included. Finally, studies linking transporter genotype with clinical outcomes are discussed.
Summary
We examined what happened during a 6‐year period to 1121 end‐stage renal disease patients who registered with their willing/incompatible living donors for kidney exchanges with the Alliance ...for Paired Donation (APD). Of all patients, 65% were transplanted: 37% in kidney paired donation (APD‐KPD, APD‐other‐KPD); 10% with compatible live donors (APD‐LD); and 18% with deceased donors (APD‐DD). The remaining patients were withdrawn (sick/died/others; 15%), or were still waiting (20%). For those patients with a cPRA 0–94%, 72% received a transplant. In contrast, only 49% of very highly sensitized (VHS; cPRA 95–100%) were transplanted. Of the VHS patients, 50% were transplanted by KPD/APD‐LD while 50% benefited through prioritization of deceased donors in the modified kidney allocation system (KAS introduced in 2014). All APD transplanted groups had similar death‐censored 4‐year graft survivals as their relevant Organ Procurement and Transplantation Network (OPTN) groups. It is noteworthy that VHS graft and patient survival results were comparable to less sensitized and nonsensitized patients. All patients should be encouraged to search for compatible donors through different options. Expanding the donor pool through KPD and the new KAS of the OPTN increases the likelihood of transplantation for VHS patients.
Purpose: Romidepsin is a potent histone deacetylase inhibitor under clinical development. The objective of this study was to evaluate
the effect of demographic, clinical, and pharmacogenetic ...covariates on the pharmacokinetics of romidepsin in patients with
T-cell lymphoma.
Experimental Design: Pharmacokinetic assessment was done in 98 patients enrolled in a phase II study who received 14 or 18 mg/m 2 of romidepsin as a 4-hour infusion on day 1 during their first treatment cycle. Population modeling was done using a nonlinear
mixed effects modeling approach to explore the effects of polymorphic variations in CYP3A4, CYP3A5, SLCO1B3 , and ABCB1 , all of which encode genes thought to be involved in romidepsin disposition.
Results: A two-compartment model with linear kinetics adequately described the romidepsin disposition. Population clearance was 15.9
L/h with between-patient variability of 37%. ABCB1 2677G>T/A variant alleles tended toward a reduced clearance and lower volume of tissue distribution, but this was not supported
by a statistical significance. Genetic variations in CYP3A4/5 and SCLO1B3 had no effect on the systemic exposure.
Conclusion: The population pharmacokinetic analysis indicates moderate interindividual variability in romidepsin pharmacokinetics and
no clinically relevant covariates associated with the unexplained pharmacokinetic variability of romidepsin in this population.
Unlike many solid tumors which present as a single mass, prostate cancer is usually multifocal and more difficult to detect.1 Additionally, prostate cancer symptoms do not typically present until the ...cancer has reached an advanced stage.2 As a result, physicians have consistently relied on biomarkers as indicators of the presence and progression of cancer; an ideal biomarker would allow the physician to determine cancerous tissue from non-cancerous, and perhaps even metastatic cancer from localized.
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