Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

Siglec interactions with a sialylated bacterial pathogen

Group B Streptococcus (Streptococcus agalactiae or GBS) is the leading cause of bacterial sepsis and meningitis in human newborns. The GBS capsular polysaccharide (CPS) is a major virulence factor that contains terminally linked sialic acids (Sias) that are important for escaping detection by the innate immune system. The structure, position, and linkages of the Sia-capped oligosaccharide subunits that make up the CPS of GBS are identical to some of the most common Sia-capped glycans that coat the cell surface of all human cells. The Sia recognizing immunoglobulin (Ig) superfamily lectins (Siglecs) are a family of type I transmembrane surface proteins many of which are expressed on the surfaces of human leukocytes. The human CD33/Siglec-3 Related Siglecs (hCD33rSiglecs) are a rapidly evolving subgroup of the Siglecs that are composed of (a) an extracellular V-set domain that engages Sia-capped glycans, and (b) an intracellular domain that contains inhibitory motifs that are classically involved in reducing leukocyte activation. The CD33rSiglecs are postulated, but not proven, to interact with "self" Sias present on the surface of human cells, thereby reducing leukocyte-mediated autoimmune responses. We hypothesized that sialylated microorganisms producing mimics of host cell glycans would engage CD33rSiglecs, thus causing inhibition of leukocyte activation. Here we demonstrate that the sialylated pathogen, GBS, functionally engages human CD33rSiglecs by two distinct mechanisms. The first mechanism by which GBS binds CD33rSiglecs is dependent on CPS sialylation as we had hypothesized. The second mechanism involves a novel interaction between a GBS surface protein and human Siglec-5 that is Sia- independent. This latter finding opens up the possibility that the capacity of microorganisms to target CD33rSiglecs may not be restricted to sialylated pathogens, but instead may be a more universal mechanism of immune evasion. Using a novel experimental system incorporating immobilized, synthetic sialylated glycans, we confirm that CD33rSiglec engagement of Sias in trans can cause inhibition of neutrophil activation. These findings further support the hypothesis that the natural function of CD33rSiglecs is to recognize endogenous glycans. but that certain microorganisms have evolved to target these cell surface receptors in order to subvert the immune syste

Siglec interactions with a sialylated bacterial pathogen

Group B Streptococcus (Streptococcus agalactiae or GBS) is the leading cause of bacterial sepsis and meningitis in human newborns. The GBS capsular polysaccharide (CPS) is a major virulence factor that contains terminally linked sialic acids (Sias) that are important for escaping detection by the innate immune system. The structure, position, and linkages of the Sia-capped oligosaccharide subunits that make up the CPS of GBS are identical to some of the most common Sia-capped glycans that coat the cell surface of all human cells. The Sia recognizing immunoglobulin (Ig) superfamily lectins (Siglecs) are a family of type I transmembrane surface proteins many of which are expressed on the surfaces of human leukocytes. The human CD33/Siglec-3 Related Siglecs (hCD33rSiglecs) are a rapidly evolving subgroup of the Siglecs that are composed of (a) an extracellular V-set domain that engages Sia-capped glycans, and (b) an intracellular domain that contains inhibitory motifs that are classically involved in reducing leukocyte activation. The CD33rSiglecs are postulated, but not proven, to interact with "self" Sias present on the surface of human cells, thereby reducing leukocyte-mediated autoimmune responses. We hypothesized that sialylated microorganisms producing mimics of host cell glycans would engage CD33rSiglecs, thus causing inhibition of leukocyte activation. Here we demonstrate that the sialylated pathogen, GBS, functionally engages human CD33rSiglecs by two distinct mechanisms. The first mechanism by which GBS binds CD33rSiglecs is dependent on CPS sialylation as we had hypothesized. The second mechanism involves a novel interaction between a GBS surface protein and human Siglec-5 that is Sia- independent. This latter finding opens up the possibility that the capacity of microorganisms to target CD33rSiglecs may not be restricted to sialylated pathogens, but instead may be a more universal mechanism of immune evasion. Using a novel experimental system incorporating immobilized, synthetic sialylated glycans, we confirm that CD33rSiglec engagement of Sias in trans can cause inhibition of neutrophil activation. These findings further support the hypothesis that the natural function of CD33rSiglecs is to recognize endogenous glycans. but that certain microorganisms have evolved to target these cell surface receptors in order to subvert the immune syste

Virtue ethics and social psychology

Virtue ethics has emerged as an alternative to deontological and utilitarian theory in recent moral philosophy. The basic notion of virtue ethics is to reassert the importance of virtuous character in ethical judgement in contrast to the emphasis on principles and consequences. Since questions of virtue have been largely neglected in modern moral theory, there has been a return to Aristotle’s account of virtue as character. This in turn has been questioned as the basis of virtue ethics and there has been a search for alternative accounts of moral agency. One aspect of this critical reflection on virtue ethics is an engagement with social psychology as a source of criticism of the Aristotelian conception of character and as a more plausible alternative foundation for a theory of moral character with contemporary relevance. This paper aims to introduce this area of moral theory to a psychological audience and reflect on the interpretation of social psychological theory and evidence in criticisms of virtuous character, focusing on the use of Milgram’s (1974) experiments on obedience to authority as an argument for situationism. A number of questions emerge concerning the interpretation and use of social psychological theory and evidence in debates within moral philosophy

Halofuginone for non-hospitalized adult patients with COVID-19 a multicenter, randomized placebo-controlled phase 2 trial. The HALOS trial.

BackgroundHalofuginone (PJS-539) is an oral prolyl-tRNA synthetase inhibitor that has a potent in vitro activity against SARS-CoV-2 virus. The safety and efficacy of halofuginone in Covid-19 patients has not been studied.MethodsWe conducted a phase II, randomized, double-blind, placebo-controlled, dose ranging, safety and tolerability trial of halofuginone in symptomatic (≤ 7 days), mostly vaccinated, non-hospitalized adults with mild to moderate Covid-19. Patients were randomized in a 1:1:1 ratio to receive halofuginone 0.5mg, 1mg or placebo orally once daily for 10 days. The primary outcome was the decay rate of the SARS-CoV-2 viral load logarithmic curve within 10 days after randomization.ResultsFrom September 25, 2021, to February 3, 2022, 153 patients were randomized. The mean decay rate in SARS-CoV-2 viral load log10 within 10 days was -3.75 (95% CI, -4.11; -3.19) in the placebo group, -3.83 (95% CI, -4.40; -2.27) in the halofuginone 0.5mg group and -4.13 (95% CI, -4.69; -3.57) in the halofuginone 1mg group, with no statistically significant difference in between placebo vs. halofuginone 0.5mg (mean difference -0.08; 95% CI -0.82 to 0.66, p = 0.96) and between placebo vs. halofuginone 1mg (mean difference -0.38; 95% CI, -1.11; 0.36, p = 0.41). There was no difference on bleeding episodes or serious adverse events at 28 days.ConclusionsAmong non-hospitalized adults with mild to moderate Covid-19 halofuginone treatment was safe and well tolerated but did not decrease SARS-CoV-2 viral load decay rate within 10 days

Rhinorrhea-free days up to day 10.

BackgroundHalofuginone (PJS-539) is an oral prolyl-tRNA synthetase inhibitor that has a potent in vitro activity against SARS-CoV-2 virus. The safety and efficacy of halofuginone in Covid-19 patients has not been studied.MethodsWe conducted a phase II, randomized, double-blind, placebo-controlled, dose ranging, safety and tolerability trial of halofuginone in symptomatic (≤ 7 days), mostly vaccinated, non-hospitalized adults with mild to moderate Covid-19. Patients were randomized in a 1:1:1 ratio to receive halofuginone 0.5mg, 1mg or placebo orally once daily for 10 days. The primary outcome was the decay rate of the SARS-CoV-2 viral load logarithmic curve within 10 days after randomization.ResultsFrom September 25, 2021, to February 3, 2022, 153 patients were randomized. The mean decay rate in SARS-CoV-2 viral load log10 within 10 days was -3.75 (95% CI, -4.11; -3.19) in the placebo group, -3.83 (95% CI, -4.40; -2.27) in the halofuginone 0.5mg group and -4.13 (95% CI, -4.69; -3.57) in the halofuginone 1mg group, with no statistically significant difference in between placebo vs. halofuginone 0.5mg (mean difference -0.08; 95% CI -0.82 to 0.66, p = 0.96) and between placebo vs. halofuginone 1mg (mean difference -0.38; 95% CI, -1.11; 0.36, p = 0.41). There was no difference on bleeding episodes or serious adverse events at 28 days.ConclusionsAmong non-hospitalized adults with mild to moderate Covid-19 halofuginone treatment was safe and well tolerated but did not decrease SARS-CoV-2 viral load decay rate within 10 days.</div

Cough-free days up to day 10.

BackgroundHalofuginone (PJS-539) is an oral prolyl-tRNA synthetase inhibitor that has a potent in vitro activity against SARS-CoV-2 virus. The safety and efficacy of halofuginone in Covid-19 patients has not been studied.MethodsWe conducted a phase II, randomized, double-blind, placebo-controlled, dose ranging, safety and tolerability trial of halofuginone in symptomatic (≤ 7 days), mostly vaccinated, non-hospitalized adults with mild to moderate Covid-19. Patients were randomized in a 1:1:1 ratio to receive halofuginone 0.5mg, 1mg or placebo orally once daily for 10 days. The primary outcome was the decay rate of the SARS-CoV-2 viral load logarithmic curve within 10 days after randomization.ResultsFrom September 25, 2021, to February 3, 2022, 153 patients were randomized. The mean decay rate in SARS-CoV-2 viral load log10 within 10 days was -3.75 (95% CI, -4.11; -3.19) in the placebo group, -3.83 (95% CI, -4.40; -2.27) in the halofuginone 0.5mg group and -4.13 (95% CI, -4.69; -3.57) in the halofuginone 1mg group, with no statistically significant difference in between placebo vs. halofuginone 0.5mg (mean difference -0.08; 95% CI -0.82 to 0.66, p = 0.96) and between placebo vs. halofuginone 1mg (mean difference -0.38; 95% CI, -1.11; 0.36, p = 0.41). There was no difference on bleeding episodes or serious adverse events at 28 days.ConclusionsAmong non-hospitalized adults with mild to moderate Covid-19 halofuginone treatment was safe and well tolerated but did not decrease SARS-CoV-2 viral load decay rate within 10 days.</div

Symptoms free-days up to day 10.

BackgroundHalofuginone (PJS-539) is an oral prolyl-tRNA synthetase inhibitor that has a potent in vitro activity against SARS-CoV-2 virus. The safety and efficacy of halofuginone in Covid-19 patients has not been studied.MethodsWe conducted a phase II, randomized, double-blind, placebo-controlled, dose ranging, safety and tolerability trial of halofuginone in symptomatic (≤ 7 days), mostly vaccinated, non-hospitalized adults with mild to moderate Covid-19. Patients were randomized in a 1:1:1 ratio to receive halofuginone 0.5mg, 1mg or placebo orally once daily for 10 days. The primary outcome was the decay rate of the SARS-CoV-2 viral load logarithmic curve within 10 days after randomization.ResultsFrom September 25, 2021, to February 3, 2022, 153 patients were randomized. The mean decay rate in SARS-CoV-2 viral load log10 within 10 days was -3.75 (95% CI, -4.11; -3.19) in the placebo group, -3.83 (95% CI, -4.40; -2.27) in the halofuginone 0.5mg group and -4.13 (95% CI, -4.69; -3.57) in the halofuginone 1mg group, with no statistically significant difference in between placebo vs. halofuginone 0.5mg (mean difference -0.08; 95% CI -0.82 to 0.66, p = 0.96) and between placebo vs. halofuginone 1mg (mean difference -0.38; 95% CI, -1.11; 0.36, p = 0.41). There was no difference on bleeding episodes or serious adverse events at 28 days.ConclusionsAmong non-hospitalized adults with mild to moderate Covid-19 halofuginone treatment was safe and well tolerated but did not decrease SARS-CoV-2 viral load decay rate within 10 days.</div

Mean SARS-CoV-2 viral load log 10 between groups.

BackgroundHalofuginone (PJS-539) is an oral prolyl-tRNA synthetase inhibitor that has a potent in vitro activity against SARS-CoV-2 virus. The safety and efficacy of halofuginone in Covid-19 patients has not been studied.MethodsWe conducted a phase II, randomized, double-blind, placebo-controlled, dose ranging, safety and tolerability trial of halofuginone in symptomatic (≤ 7 days), mostly vaccinated, non-hospitalized adults with mild to moderate Covid-19. Patients were randomized in a 1:1:1 ratio to receive halofuginone 0.5mg, 1mg or placebo orally once daily for 10 days. The primary outcome was the decay rate of the SARS-CoV-2 viral load logarithmic curve within 10 days after randomization.ResultsFrom September 25, 2021, to February 3, 2022, 153 patients were randomized. The mean decay rate in SARS-CoV-2 viral load log10 within 10 days was -3.75 (95% CI, -4.11; -3.19) in the placebo group, -3.83 (95% CI, -4.40; -2.27) in the halofuginone 0.5mg group and -4.13 (95% CI, -4.69; -3.57) in the halofuginone 1mg group, with no statistically significant difference in between placebo vs. halofuginone 0.5mg (mean difference -0.08; 95% CI -0.82 to 0.66, p = 0.96) and between placebo vs. halofuginone 1mg (mean difference -0.38; 95% CI, -1.11; 0.36, p = 0.41). There was no difference on bleeding episodes or serious adverse events at 28 days.ConclusionsAmong non-hospitalized adults with mild to moderate Covid-19 halofuginone treatment was safe and well tolerated but did not decrease SARS-CoV-2 viral load decay rate within 10 days.</div

Vomit-free days up to day 10.

BackgroundHalofuginone (PJS-539) is an oral prolyl-tRNA synthetase inhibitor that has a potent in vitro activity against SARS-CoV-2 virus. The safety and efficacy of halofuginone in Covid-19 patients has not been studied.MethodsWe conducted a phase II, randomized, double-blind, placebo-controlled, dose ranging, safety and tolerability trial of halofuginone in symptomatic (≤ 7 days), mostly vaccinated, non-hospitalized adults with mild to moderate Covid-19. Patients were randomized in a 1:1:1 ratio to receive halofuginone 0.5mg, 1mg or placebo orally once daily for 10 days. The primary outcome was the decay rate of the SARS-CoV-2 viral load logarithmic curve within 10 days after randomization.ResultsFrom September 25, 2021, to February 3, 2022, 153 patients were randomized. The mean decay rate in SARS-CoV-2 viral load log10 within 10 days was -3.75 (95% CI, -4.11; -3.19) in the placebo group, -3.83 (95% CI, -4.40; -2.27) in the halofuginone 0.5mg group and -4.13 (95% CI, -4.69; -3.57) in the halofuginone 1mg group, with no statistically significant difference in between placebo vs. halofuginone 0.5mg (mean difference -0.08; 95% CI -0.82 to 0.66, p = 0.96) and between placebo vs. halofuginone 1mg (mean difference -0.38; 95% CI, -1.11; 0.36, p = 0.41). There was no difference on bleeding episodes or serious adverse events at 28 days.ConclusionsAmong non-hospitalized adults with mild to moderate Covid-19 halofuginone treatment was safe and well tolerated but did not decrease SARS-CoV-2 viral load decay rate within 10 days.</div