Empathy for another's physical pain has been demonstrated in humans [1] and mice [2]; in both species, empathy is stronger between familiars. Stress levels in stranger dyads are higher than in cagemate dyads or isolated mice [2, 3], suggesting that stress might be responsible for the absence of empathy for the pain of strangers. We show here that blockade of glucocorticoid synthesis or receptors for adrenal stress hormones elicits the expression of emotional contagion (a form of empathy) in strangers of both species. Mice and undergraduates were tested for sensitivity to noxious stimulation alone and/or together (dyads). In familiar, but not stranger, pairs, dyadic testing was associated with increased pain behaviors or ratings compared to isolated testing. Pharmacological blockade of glucocorticoid synthesis or glucocorticoid and mineralocorticoid receptors enabled the expression of emotional contagion of pain in mouse and human stranger dyads, as did a shared gaming experience (the video game Rock Band) in human strangers. Our results demonstrate that emotional contagion is prevented, in an evolutionarily conserved manner, by the stress of a social interaction with an unfamiliar conspecific and can be evoked by blocking the endocrine stress response.

Venetoclax is a specific B cell lymphoma 2 (BCL-2) inhibitor with promising activity against acute myeloid leukemia (AML), but its clinical efficacy as a single agent or in combination with hypomethylating agents (HMAs), such as azacitidine, is hampered by intrinsic and acquired resistance. Here, we performed a genome-wide CRISPR knockout screen and found that inactivation of genes involved in mitochondrial translation restored sensitivity to venetoclax in resistant AML cells. Pharmacologic inhibition of mitochondrial protein synthesis with antibiotics that target the ribosome, including tedizolid and doxycycline, effectively overcame venetoclax resistance. Mechanistic studies showed that both tedizolid and venetoclax suppressed mitochondrial respiration, with the latter demonstrating inhibitory activity against complex I [nicotinamide adenine dinucleotide plus hydrogen (NADH) dehydrogenase] of the electron transport chain (ETC). The drugs cooperated to activate a heightened integrated stress response (ISR), which, in turn, suppressed glycolytic capacity, resulting in adenosine triphosphate (ATP) depletion and subsequent cell death. Combination treatment with tedizolid and venetoclax was superior to either agent alone in reducing leukemic burden in mice engrafted with treatment-resistant human AML. The addition of tedizolid to azacitidine and venetoclax further enhanced the killing of resistant AML cells in vitro and in vivo. Our findings demonstrate that inhibition of mitochondrial translation is an effective approach to overcoming venetoclax resistance and provide a rationale for combining tedizolid, azacitidine, and venetoclax as a triplet therapy for AML.

Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent, Azacytidine, achieves complete response with or without count recovery in approximately 70% of treatment-naïve elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that Venetoclax directly activated T cells to increase their cytotoxicity against AML in vitro and in vivo. Venetoclax enhanced T cell effector function by increasing ROS generation through inhibition of respiratory chain supercomplexes formation. In addition, Azacytidine induced a viral-mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T-cell mediated cytotoxicity. Similar findings were seen in patients treated with Venetoclax as this treatment increased ROS generation and activated T cells. Collectively, this study demonstrates a new immune mediated mechanism of action for Venetoclax and Azacytidine in the treatment of AML and highlights a potential combination of Venetoclax and adoptive cell therapy for patients with AML.

Background: Prurigo pigmentosa (PP) is a rare inflammatory dermatosis characterized by pruritic erythematous papules that coalesce to form a reticulate pattern. PP is often misdiagnosed, and patients are treated with ineffective therapies. Although the majority of reports about PP are from East Asia, patients of all backgrounds can be affected.Objectives: To perform a systematic review of reported PP cases with the purpose of summarizing the clinical presentation and treatment of PP.Methods: MEDLINE and Embase were searched for original articles describing PP. We identified 115 studies from 24 countries representing 369 patients to include in the analysis.Results: Of the 369 patients included in the analysis, the mean age was 25.6 years (range: 13-72 years) with 72.1% (266 of 369) female. Risk factors or aggravating factors were described in 52.3% (193 of 369) of patients and included dietary changes (25.5%, 94 of 369), friction (8.4%, 31 of 369), sweat (7.6%, 28 of 369), and ketonuria (5.1%, 19 of 369). Of those patients who experienced PP following dietary changes, 40.4% (38 of 94) started a ketogenic diet. Minocycline monotherapy was the most frequently prescribed treatment for PP (20.9%, 77 of 369), achieving complete resolution in 48.1% (37 of 77) of patients.Conclusions: PP is sometimes associated with ketogenic diets and can be effectively managed with oral tetracyclines.