Review of: "The establishment of a prognostic scoring model based on the new tumor immune microenvironment classification in acute myeloid leukemia"

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Extracorporeal photopheresis for graft-versus-host disease: The role of patient, transplant, and classification criteria and hematologic values on outcome - Results from a large single-center study

BACKGROUND: Extracorporeal photopheresis (ECP) has been shown as active therapy for graft-versus-host disease (GVHD). STUDY DESIGN AND METHODS: The aim was to ascertain the role of ECP in 71 patients with steroid-refractory or -dependent acute and chronic GVHD (aGVHD and cGVHD) with special focus on hematologic variables and GVHD staging classification. A total of 34 patients were treated for aGVHD and 37 for cGVHD. RESULTS: The overall response rate (ORR) for aGVHD was 65% and the complete aGVHD-free survival was 50% (95% confidence interval [CI], 36%-70%). The ORR for cGVHD response was 81% while the complete cGVHD-free survival was 50% (95% CI, 34%-73%). The aGVHD-free survival was associated with aGVHD grading (Grade II 81%, Grade III 33%, and Grade IV 0%, p ≤ 0.00) and the absence of visceral involvement (77% vs. 33%, p = 0.03). The cGVHD-free survival was associated with the female sex (67% vs. 25%, p = 0.01) and with the limited form according to the Seattle classification (67% vs. 20%, p = 0.003). No role for hematologic values or apheresis cell count was found, except for the cGVHD ORR (p = 0.037). Transplant-related mortality and overall survival were associated with ECP response 0% versus 54% (p = 0.0001) and 77% versus 45% (p = 0.03) for aGVHD patients and 7% versus 14% (p = 0.02) and 73% versus 20% (p = 0.0003) for cGVHD patients, respectively. CONCLUSIONS: While confirming a higher probability of GVHD responses for early GVHD, our study shows no role of hematologic values or apheresis cell count on GVHD response

Rational policymaking during a pandemic

Policymaking during a pandemic can be extremely challenging. As COVID-19 is a new disease and its global impacts are unprecedented, decisions are taken in a highly uncertain, complex, and rapidly changing environment. In such a context, in which human lives and the economy are at stake, we argue that using ideas and constructs from modern decision theory, even informally, will make policymaking a more responsible and transparent process

HIV-1 Coreceptor Activity of CCR5 and Its Inhibition by Chemokines: Independence from G Protein Signaling and Importance of Coreceptor Downmodulation

AbstractHIV-1 infection requires the presence of specific chemokine receptors on CD4+ target cells to enable the fusion reactions involved in virus entry. CCR5 is a major fusion coreceptor for macrophage-tropic HIV-1 isolates. HIV-1 entry and fusion are mediated by the viral envelope glycoprotein (Env) and are inhibited by CCR5 ligands, but the mechanisms are unknown. Here, we test the role of G protein signaling and CCR5 surface downmodulation by two separate approaches: direct inactivation of CCR5 signaling by mutagenesis and inactivation of Gi-type G proteins with pertussis toxin. A CCR5 mutant lacking the last 45 amino acids of the cytoplasmic C-terminus (CCR5306) was created that was expressed on transfected cells at levels comparable to cells expressing CCR5 and displayed normal chemokine binding affinity. CCR5 ligands induced calcium flux and receptor downmodulation in cells expressing CCR5, but not in cells expressing CCR5306. Nevertheless, CCR5 or CCR5306, when coexpressed with CD4, supported comparable HIV-1 Env-mediated cell fusion. Consistent with this, treatment of CCR5-expressing cells with pertussis toxin completely blocked ligand-induced transient calcium flux, but did not affect Env-mediated cell fusion or HIV-1 infection. Also, pertussis toxin did not block chemokine inhibition of Env-mediated cell fusion or HIV-1 infection. However, chemokines inhibited Env-mediated cell fusion less efficiently for CCR5306than for CCR5. We conclude that the C-terminal domain of CCR5 is critical for G protein signaling and receptor downmodulation from the surface, but that neither function is required for CCR5 fusion coreceptor activity. The contrasting phenotypes of CCR5 and CCR5306suggest that coreceptor downmodulation and direct blockage of Env interaction sites both contribute to chemokine inhibition of HIV-1 infection

Adipogenic and energy metabolism gene networks in longissimus lumborum during rapid post-weaning growth in Angus and Angus × Simmental cattle fed high-starch or low-starch diets

<p>Abstract</p> <p>Background</p> <p>Transcriptional networks coordinate adipocyte differentiation and energy metabolism in rodents. The level of fiber and starch in diets with adequate energy content fed to young cattle has the potential to alter intramuscular adipose tissue development in skeletal muscle. Post-weaning alterations in gene expression networks driving adipogenesis, lipid filling, and intracellular energy metabolism provide a means to evaluate long-term effects of nutrition on longissimus muscle development across cattle types.</p> <p>Results</p> <p><it>Longissimus lumborum </it>(LL) from Angus (n = 6) and Angus × Simmental (A × S; n = 6) steer calves (155 ± 10 days age) fed isonitrogenous high-starch (HiS; 1.43 Mcal/kg diet dry matter; n = 6) or low-starch (LoS; 1.19 Mcal/kg diet dry matter; n = 6) diets was biopsied at 0, 56, and 112 days of feeding for transcript profiling of 31 genes associated with aspects of adipogenesis and energy metabolism. Intake of dietary energy (9.44 ± 0.57 Mcal/d) across groups during the study did not differ but feed efficiency (weight gain/feed intake) during the first 56 days was greater for steers fed HiS. Expression of <it>PPARG </it>increased ca. 2-fold by day 56 primarily due to HiS in A × S steers. Several potential <it>PPARG</it>-target genes (e.g., <it>ACACA</it>, <it>FASN</it>, <it>FABP4</it>, <it>SCD</it>) increased 2.5-to-25-fold by day 56 across all groups, with responses (e.g., <it>FASN</it>, <it>FABP4</it>) being less pronounced in A × S steers fed LoS. This latter group of steers had markedly greater blood plasma glucose (0.99 vs. 0.79 g/L) and insulin (2.95 vs. 1.17 μg/L) by day 112, all of which were suggestive of insulin resistance. Interactions were observed for <it>FABP4</it>, <it>FASN</it>, <it>GPAM</it>, <it>SCD</it>, and <it>DGAT2</it>, such that feeding A × S steers high-starch and Angus steers low-starch resulted in greater fold-changes by day 56 or 112 (<it>GPAM</it>). Marked up-regulation of <it>INSIG1 </it>(4-to-8-fold) occurred throughout the study across all groups. <it>SREBF1 </it>expression, however, was only greater on day 112 namely due to LoS in A × S steers. The lipogenic transcription factor <it>THRSP </it>was 6-to-60-fold greater by day 56 primarily due to HiS in A × S steers, constituting the greatest response among all genes.</p> <p>Conclusion</p> <p>Results involving gene markers of mature adipocytes (e.g., <it>PPARG</it>, <it>THRSP</it>, <it>SCD</it>) provided evidence of intramuscular adipose tissue differentiation during the early portion of the growing phase. The resulting gene networks underscored a central role for <it>PPARG </it>in controlling transcription of genes which are known to co-ordinately regulate adipocyte differentiation and lipid filling in non-ruminants. Unlike rodents, <it>INSIG1 </it>appears to play an important role in cattle muscle adipogenesis. We propose that a network of transcription regulators and nuclear receptors including <it>PPARG</it>-target genes,<it> INSIG1</it>, and <it>THRSP</it>, coordinate activation of adipocyte differentiation and lipid filling at an early age.</p