Paradoxical effects of altruism on efforts to mitigate climate change.

It is common wisdom that altruism is a crucial element in addressing climate change and other public good issues. If individuals care about the welfare of others (including future generations) they can be expected to unilaterally adapt their behaviour to preserve the common good thus enhancing the wellbeing of all. We introduce a network game model featuring both altruism and a public good (e.g. climate) whose degradation affects all players. As expected, in an idealistic fully connected society where all players care about each other, increasing altruism results in a better protection of the public good. However, in more realistic networks where people are not all related to each other, we highlight an intrinsic trade-off between the effects of altruism on reducing inequality and the preservation of a global public good: the consumption redistribution generated by a higher altruism is partly achieved by lowering income transfers towards protection of the public good. Therefore, it increases overall consumption and is thereby detrimental to the public good. These results suggest that altruism, although good from a welfarist point of view, is not in itself sufficient to simultaneously solve public good and inequality issues.

A systematic review and meta-analysis of PD-1/PD-L1 inhibitors in specific patient subgroups with advanced gastro-oesophageal junction and gastric adenocarcinoma.

BACKGROUND: immune checkpoint inhibitors(ICIs) have shown contradictory results in patients with advanced gastro-oesophageal junction/gastric cancer(GOJ/GC). AIM: to identify specific patient subgroups that would derive survival benefit from ICIs. METHODS: a subgroup meta-analysis of randomised clinical trials(RCTs) was carried out. RESULTS: four phase-III-RCTs were identified with data on the following variables: primary location(Gastric vs GOJ); age(≤ 65 vs >65); gender(male vs female); ECOG PS(0 vs 1); ethnicity (Asian vs non-Asian), histology(intestinal vs diffuse), PD-L1 expression(≥ 1% vs < 1%). PD-L1 positivity was significantly associated with survival benefit from ICIs (HR: 0.82, p 0.047), with a significant interaction between PD-L1 expression and ICI efficacy (interaction HR: 1.41, p 0.02). Numerically, the second most relevant interaction was ICI efficacy and gender, with ICI being more effective in males. CONCLUSION: The PD-L1 positive patient subgroup derives significant survival benefit from ICI in GOJ/GC, however other predictors are eagerly needed to further refine patient selection.

Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study.

We designed a phase II, open-label study to evaluate the efficacy, tolerability, safety, and pharmacokinetics of orally doxycycline (100 mg BID) and tauroursodeoxycholic acid (TUDCA) (250 mg three times/day) administered continuously for 12 months. Primary endpoint is response rate defined as nonprogression of the neuropathy and of the cardiomyopathy. Since July 2010, we enrolled 20 patients. Seventeen patients have hereditary ATTR, two patients have senile systemic amyloidosis, and one is a domino recipient. Seven patients completed 12-month treatment, 10 completed 6-month treatment, two discontinued because of poor tolerability, and one is lost at follow-up. No serious adverse events were registered. No clinical progression of cardiac involvement was observed. The neuropathy (Neuropathy Impairment Score in the Lower Limbs [NIS-LL] and Kumamoto score) remained substantially stable over 1 year. These preliminary data indicate that the combination of Doxy-TUDCA stabilizes the disease for at least 1 year in the majority of patients with an acceptable toxicity profile.

Novel heterocyclic analogues of the new potent class of calcium entry blockers: 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines.

Several heterocyclic analogues of the potent 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines were synthesized and evaluated for their antagonistic calcium activities in comparison with the 1-sulfonylindolizine SR 33557 and the usual calcium antagonist references verapamil, cis-(+)-diltiazem, and nifedipine. The bicyclic nine-membered rings were, in general, more potent than the bicyclic 10-membered or five-membered rings. Among the bicyclic nine-membered rings, the indole nucleus appeared to be extremely favorable to support the calcium antagonistic activity. In particular, compound 36, with an IC50 value for the inhibition of [3H]nitrendipine equal to 0.072 nM, is among the most potent calcium antagonist known. This compound has been selected for clinical development.

A novel class of calcium-entry blockers: the 1[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines.

The synthesis and initial biological evaluation of a series of 1-sulfonylindolizines is described. These compounds have been shown to be representatives of a novel class of potent, slow-channel calcium antagonists. All compounds were found to be at least as active as the reference calcium antagonists verapamil and cis-(+)-diltiazem. Structure-activity relationship studies have shown that all compounds possessing an aralkyl group in the amine moiety and an isopropyl or cyclopropyl group at the 2 position of the indolizine are among the most potent calcium antagonists known outside the 1,4-dihydropyridine series. The IC50 values for the inhibition of [3H]nitrendipine binding vary between 0.19 and 4.5 nM whereas the IC50 value for nifedipine is 2.5 nM. One of the compounds in this group (9ab) has now been selected for clinical development.