A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma.
Anti-PD-1 ...naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS).
Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs.
With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.
Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium ...marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A4 hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B4. We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.
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► Conserved eicosanoids are regulated by LTA4H activity and impact inflammatory state ► Genotype-directed modulation of TNF improves outcomes in a zebrafish tuberculosis model ► Drug therapies tailored to lta4h genotype improve infection outcome in zebrafish ► In humans, LTA4H genotype associates with responsiveness to therapy for TB meningitis
A polymorphism in a locus that controls the balance between pro- and anti-inflammatory mediators is predictive of response to anti-inflammatory therapy in tuberculous meningitis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Anti-NMDA receptor (NMDAR) autoantibodies have been postulated to play a role in the pathogenesis of NMDAR hypofunction, which contributes to the etiology of psychotic symptoms.
is a pathogen ...implicated in psychiatric disorders and associated with elevation of NMDAR autoantibodies. However, it remains unclear whether parasite infection is the cause of NMDAR autoantibodies. By using mouse models, we found that NMDAR autoantibody generation had a strong temporal association with tissue cyst formation, as determined by MAG1 antibody seroreactivity (
= 0.96;
< 0.0001), which is a serologic marker for the cyst burden. The presence of MAG1 antibody response, but not
IgG response, was required for NMDAR autoantibody production. The pathogenic relevance of NMDAR autoantibodies to behavioral abnormalities (blunted response to amphetamine-triggered activity and decreased locomotor activity and exploration) and reduced expression of synaptic proteins (the GLUN2B subtype of NMDAR and PSD-95) has been demonstrated in infected mice. Our study suggests that NMDAR autoantibodies are specifically induced by persistent
infection and are most likely triggered by tissue cysts. NMDAR autoantibody seroreactivity may be a novel pathological hallmark of chronic toxoplasmosis, which raises questions about NMDAR hypofunction and neurodegeneration in the infected brain.
Schizophrenia has long been considered as a disorder with multifactorial origins. Recent discoveries have advanced our understanding of the genetic architecture of the disease. However, even with the ...increase of identified risk variants, heritability estimates suggest an important contribution of non-genetic factors. Various environmental risk factors have been proposed to play a role in the etiopathogenesis of schizophrenia. These include season of birth, maternal infections, obstetric complications, adverse events at early childhood, and drug abuse. Despite the progress in identification of genetic and environmental risk factors, we still have a limited understanding of the mechanisms whereby gene-environment interactions (G × E) operate in schizophrenia and psychoses at large. In this review we provide a critical analysis of current animal models of G × E relevant to psychotic disorders and propose that dimensional perspective will advance our understanding of the complex mechanisms of these disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Influenza severity increases with age, with hospitalization and mortality rates during seasonal influenza epidemics being higher in older men than age-matched women. As it is known that with age, ...circulating testosterone levels decline in males, we hypothesized that reduced testosterone contributes to age-associated increases in influenza severity. A murine model was used to test this hypothesis. As in men, testosterone concentrations were lower in aged (18 mo) than young (2 mo) male C57BL/6 mice. Following inoculation with influenza A virus (IAV), aged males experienced greater morbidity, clinical disease, and pulmonary inflammation than young males, and had lower neutralizing and total anti-influenza IgG antibody responses. Peak titers of virus in the lungs did not differ between aged and young males, but virus clearance was delayed in aged males. In young males, removal of the gonads increased-whereas treatment of gonadectomized males with testosterone reduced-morbidity, clinical illness, and pulmonary pathology, but viral replication was not altered by hormone manipulation in young males. Treatment of aged males with testosterone improved survival following infection but did not alter either virus replication or pulmonary pathology. These results indicate that low concentrations of testosterone, whether induced surgically in young males or naturally occurring in aged males, negatively impact the outcome of influenza.
•Chronic Toxoplasma infection blunts psychostimulant-induced hyperactivity.•Chronic Toxoplasma infection reduces levels of DAT and VMAT2 in the brain.•Deletion of parasite AAH2 gene does not alter ...dopamine-dependent abnormalities.•Deletion of parasite AAH2 gene does not affect neuroinflammation.•Parasite-produced neurobehavioral pathology may be associated with neuroinflammation.
Infection with the protozoan parasite, Toxoplasma gondii (T. gondii), has been associated with the increased risk for several psychiatric disorders. The exact mechanisms of a hypothesized contribution of T. gondii infection are poorly understood. The T. gondii genome contains two aromatic amino acid hydroxylase genes (AAH1 and AAH2) that encode proteins that can produce L-DOPA. One popular hypothesis posits that these encoded enzymes might influence dopamine (DA) production and hence DA synaptic transmission, leading to neurobehavioral abnormalities in the infected host. Prior studies have shown that deletion of these genes does not alter DA levels in the brain or exploratory activity in infected mice. However, possible effects of AAH gene deficiency on infection-induced brain and behavior alterations that are directly linked to DA synaptic transmission have not been evaluated. We found that chronic T. gondii infection of BALB/c mice leads to blunted response to amphetamine or cocaine and decreased expression of Dopamine Transporter (DAT) and Vesicular Monoamine Transporter 2 (VMAT2). Deletion of AAH2 had no effects on these changes in infected mice. Both wild type and Δaah2 strains produced comparable levels of neuroinflammation. Our findings demonstrate that AAH2 is not required for T. gondii infection-produced DA-dependent neurobehavioral abnormalities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract only
9536
Background: Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with ...immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) reduces MDSC frequency. This analysis seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in advanced melanoma patients. Methods: This single arm, single institution, phase I/II study (NCT03200847) enrolled 24 patients diagnosed with stage IV melanoma. Eligible patients were over the age of 18 and had not been previously treated anti-PD-1 therapy. Treatment consisted of 200mg Q3W pembrolizumab plus the supplemental treatment of 150 mg/m2 ATRA orally for 3 days surrounding each of the first four infusions of pembrolizumab, with patients continuing pembrolizumab for up to two years until confirmed disease progression or unacceptable toxicity. The primary endpoints were safety and reduction in circulating MDSCs. Secondary endpoints were overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) according to RECIST v1.1. Results: At data cut off (Feb, 2021) 22 patients were evaluable for tumor response. Median follow-up was 1.0 years (0.3-2 years). In general, the combination of pembrolizumab and ATRA was well tolerated. The most common treatment-related adverse events (AEs) were grade 1 or 2, including headache (22 pts, 92%), fatigue (18 pts, 75%), rash (16 pts, 66%), and nausea (8 pts, 33%), most of which corresponded with the 3-day course of ATRA treatment. Ten patients had grade 3 or higher AEs with most being common ICI-related AEs. The ORR was 60% and DCR was 83%. Six-month PFS rate was 62%. Excluding patients diagnosed with uveal melanoma (n = 2) the ORR was 72%, DCR was 86%, and the six-month PFS rate was 68%. Paired analysis showed sustained decreases in absolute numbers ( p = 0.002) and percentage ( p = 0.007) of circulating MDSCs (CD3
-
CD19
-
CD56
-
CD11b
+
CD33
+
HLA-DR
-/low
) 4-6 weeks after stopping ATRA. The study is ongoing and further data will be presented in the future. Conclusions: This study demonstrates that the combination of ATRA and pembrolizumab is well tolerated and suggests that reducing MDSCs with ATRA may enhance the efficacy of pembrolizumab. This strategy of targeting MDSCs in combination with pembrolizumab warrants further development. Research Funding: Merck. Clinical trial information: NCT03200847.
Contaminants in general do not occur as single chemicals but as mixtures at any contaminated site. Gasworks sites are the typical mixed contaminated sites. These sites are not only subjected to PAH ...contamination but also varying degrees of heavy metal contamination. Bioremediation in these sites is often hindered by the presence of heavy metals. The co-occurrence of PAHs with heavy metals has not been systematically investigated. Metals are reported to inhibit the general soil microbiological processes. The total concentration of soluble metal in the system includes both free metal ion and complexed forms. Within bioavailable fraction, the most toxic form is the free metal species, which was not addressed well so far in gas works site characterisation. This study underpins the science and importance of metal bioavailability and speciation based site characterisation in mixed contaminated sites. In this study a detailed elemental chemistry of the gas works site soils are discussed using different methods. The PAH contamination was contributed by both low and high molecular weight PAHs. The total PAHs concentration ranged from 335 to 8645
mg/kg. Among most toxic metals Pb was found in high concentration ranging from 88 to 671
mg/kg, Cd 8 to 112
mg/kg and Zn varied from 64 to 488
mg/kg. Thermodynamic chemical equilibrium model VMINTEQ (Ver 2.52) was used to calculate the free metal species in gas works site soils. The percentage free metal species showed a different trend compared to total metal concentrations, free Zn species ranged 18–86%, free Cd was 26–87% and Pb showed lowest free metal percentage (0–17%). The bioavailable metal species and its implications to bioremediation have also been discussed.
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