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Abstract The immune response to acute hypoxemia may play a critical role in high‐altitude acclimatization and adaptation. However, if not properly controlled, hypoxemia‐induced inflammation may exacerbate high‐altitude pathologies, such as acute mountain sickness (AMS), or other hypoxia‐related clinical conditions. Several studies report changes in immune cell subsets at high altitude. However, the mechanisms underlying these changes, and if these alterations are beneficial or maladaptive, remains unknown. To address this, we performed multiparameter flow cytometry on peripheral blood mononuclear cells (PBMCs) collected throughout 3 days of high‐altitude acclimatization in healthy sea‐level residents (n = 20). Additionally, we conducted in vitro stimulation assays to test if high‐altitude hypoxia exposure influences responses of immune cells to subsequent inflammatory stimuli. We found several immune populations were altered at high altitude, including monocytes, T cells, and B cells. Some changes in immune cell populations are potentially correlated with AMS incidence and severity. In vitro high‐altitude PBMC cultures stimulated with lipopolysaccharide (LPS) showed no changes in pro‐inflammatory cytokine production after 1 day at high‐altitude. However, by day three pro‐inflammatory cytokine production in response to LPS decreased significantly. These results indicate that high‐altitude exposure may initiate an inflammatory response that encompasses innate immune sensitization, with adaptive immune suppression following acclimatization.

Recent findings from comparative and evolutionary physiologists reveal novel insights into the regulation of inflammation and immune function under conditions of chronic-sustained and intermittent hypoxia. Comparative approaches provide a valuable gateway for discovering essential principals of physiology and adaptive molecular strategies utilized in nature that protect against clinically relevant stressors, which can guide therapeutic developments in biomedical science.

Abstract Background Health disparities in underserved communities, such as inadequate healthcare access, impact COVID-19 disease outcomes. These disparities are evident in Hispanic populations nationwide, with disproportionately high infection and mortality rates. Furthermore, infected individuals can develop long COVID with sustained impacts on quality of life. The goal of this study was to identify immune and endothelial factors that are associated with COVID-19 outcomes in Riverside County, a high-risk and predominantly Hispanic community, and investigate the long-term impacts of COVID-19 infection. Methods 112 participants in Riverside County, California, were recruited according to the following criteria: healthy control (n = 23), outpatients with moderate infection (outpatient, n = 33), ICU patients with severe infection (hospitalized, n = 33), and individuals recovered from moderate infection (n = 23). Differences in outcomes between Hispanic and non-Hispanic individuals and presence/absence of co-morbidities were evaluated. Circulating immune and vascular biomarkers were measured by ELISA, multiplex analyte assays, and flow cytometry. Follow-up assessments for long COVID, lung health, and immune and vascular changes were conducted after recovery (n = 23) including paired analyses of the same participants. Results Compared to uninfected controls, the severe infection group had a higher proportion of Hispanic individuals (n = 23, p = 0.012) than moderate infection (n = 8, p = 0.550). Disease severity was associated with changes in innate monocytes and neutrophils, lymphopenia, disrupted cytokine production (increased IL-8 and IP-10/CXCL10 but reduced IFNλ2/3 and IFNγ), and increased endothelial injury (myoglobin, VCAM-1). In the severe infection group, a machine learning model identified LCN2/NGAL, IL-6, and monocyte activation as parameters associated with fatality while anti-coagulant therapy was associated with survival. Recovery from moderate COVID infection resulted in long-term immune changes including increased monocytes/lymphocytes and decreased neutrophils and endothelial markers. This group had a lower proportion of co-morbidities (n = 8, p = 1.0) but still reported symptoms associated with long COVID despite recovered pulmonary function. Conclusion This study indicates increased severity of COVID-19 infection in Hispanic individuals of Riverside County, California. Infection resulted in immunological and vascular changes and long COVID symptoms that were sustained for up to 11 months, however, lung volume and airflow resistance was recovered. Given the immune and behavioral impacts of long COVID, the potential for increased susceptibility to infections and decreased quality of life in high-risk populations warrants further investigation.

Background: Systemic mastocytosis is a rare hematologic malignancy that leads to the accumulation of neoplastic mast cells in the bone marrow, visceral organs, and skin. Mutations in the receptor tyrosine kinase, KIT are seen in most patients with systemic mastocytosis. The most common mutation is a gain of function mutation in KIT D816V. Avapritinib is a highly selective KIT D816V inhibitor approved for the treatment of advanced systemic mastocytosis. Recent studies have also suggested that avapritinib is active across other KIT mutations located in exon 11 and exon 17. Case Presentation: A 68 year old woman was referred for a history of lymphadenopathy and diarrhea and was ultimately found to have systemic mastocytosis with involvement in her bone marrow, gastrointestinal tract, liver, and spleen. The bone marrow biopsy reveled a novel KIT p.D816-N822delinsMIDSI mutation in exon 17. The patient was started on avapritinib leading to significant decrease in the frequency of her diarrhea and a significant reduction in her tryptase levels. Her course was complicated by arthralgias leading to a decrease in her avapritinib dose and ultimately a degranulation episode requiring hospitalization. Following dose re-escalation, patient has remained clinically stable without any further adverse events. Conclusion: We report a case of aggressive systemic mastocytosis with a novel KIT mutation on exon 17 treated with avapritinib leading to a sustained response. While avapritinib is known as a potent inhibitor against the D816V mutation, our case suggests that it may also be effective against other rare KIT mutations in systemic mastocytosis offering more potential treatment options in patients with rare mutations.

Abstract Background Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. Methods In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. Results Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P

Abstract Background Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib. Methods This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Dose escalation involved 200 mg once daily (QD) alpelisib, initially, followed by 250 and 350 mg. These were combined with 400 mg QD imatinib until maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) of alpelisib in combination with imatinib was determined. This MTD/RP2D dose was tested to evaluate the clinical activity of this combination in dose expansion. Results Fifty-six patients were enrolled, 21 and 35 in the dose escalation and expansion phases, respectively. The MTD of alpelisib given with imatinib was determined as 350 mg QD. Combination treatment showed partial response in 1 (2.9%) and stable disease in 15 (42.9%) patients. Median progression-free survival was 2 months (95% CI 1.8–4.6). Overall, 92.9% patients had adverse events (AEs) while 46.4% had grade 3/4 AEs, hyperglycemia being the most common (23.2%). Conclusions The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing. Trial registration ClinicalTrials.gov NCT01735968 (date of initial registration 28/11/2012).

Abstract Background Avapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST). Methods This retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan–Meier survival curves were compared by Cox regression. Results Fifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose (n = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan–Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002. Conclusions In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST. Trial registration The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .

The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.

Abstract Sojourners to high altitude often experience poor sleep quality due to sleep‐disordered breathing. Additionally, multiple aspects of cognitive function are impaired at high altitude. However, the impact of acclimatization on sleep‐disordered breathing and whether poor sleep is a major contributor to cognitive impairments at high altitude remains uncertain. We conducted nocturnal actigraphy and polygraphy, as well as daytime cognitive function tests, in 15 participants (33% women) at sea level and over 3 days of partial acclimatization to high altitude (3800 m). Our goal was to determine if sleep‐disordered breathing improved over time and if sleep‐disordered breathing was associated with cognitive function. The apnea–hypopnea index and oxygen desaturation index increased on night 1 (adj. p = 0.026 and adj. p = 0.026, respectively), but both improved over the subsequent 2 nights. These measures were matched by poorer self‐reported sleep quality on the Stanford Sleepiness Scale and PROMIS questionnaires following 1 night at high altitude (adj. p = 0.027 and adj. p = 0.022, respectively). The reaction time on the psychomotor vigilance task was slower at high altitude and did not improve (SL: 199 ± 27, ALT1: 224 ± 33, ALT2: 216 ± 41, ALT3: 212 ± 27 ms). The reaction times on the balloon analog risk task decreased at high altitude (SL: 474 ± 235, ALT1: 375 ± 159, ALT2: 291 ± 102, ALT3: 267 ± 90 ms), perhaps indicating increased risk‐taking behavior. Finally, multiple cognitive function measures were associated with sleep‐disordered breathing and measures of subjective sleep quality, rather than low daytime arterial oxygen saturation. These data indicate that sleep‐disordered breathing at moderately high altitude improves with partial acclimatization and that some aspects of cognitive performance in unacclimatized sojourners may be impacted by poor sleep rather than hypoxemia alone.

The key regulators of the transcriptional response to hypoxia and inflammation (hypoxia inducible factor, HIF, and nuclear factor-kappa B, NF-κB, respectively) are evolutionarily conserved and share significant crosstalk. Tissues often experience hypoxia and inflammation concurrently at the site of infection or injury due to fluid retention and immune cell recruitment that ultimately reduces the rate of oxygen delivery to tissues. Inflammation can induce activity of HIF-pathway genes, and hypoxia may modulate inflammatory signaling. While it is clear that these molecular pathways function in concert, the physiological consequences of hypoxia-induced inflammation and how hypoxia modulates inflammatory signaling and immune function are not well established. In this review, we summarize known mechanisms of HIF and NF-κB crosstalk and highlight the physiological consequences that can arise from maladaptive hypoxia-induced inflammation. Finally, we discuss what can be learned about adaptive regulation of inflammation under chronic hypoxia by examining adaptive and maladaptive inflammatory phenotypes observed in human populations at high altitude. We aim to provide insight into the time domains of hypoxia-induced inflammation and highlight the importance of hypoxia-induced inflammatory sensitization in immune function, pathologies, and environmental adaptation.

Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

Heme oxygenase (HO) enzymes catalyze heme into biliverdin, releasing carbon monoxide (CO) and iron into circulation. These byproducts of heme degradation can have potent cytoprotective effects in the face of stressors such as hypoxia and ischemia-reperfusion events. The potential for exogenous use of CO as a therapeutic agent has received increasing attention throughout the past few decades. Further, HO and CO are noted as putatively adaptive in diving mammals and certain high-altitude human populations that are frequently exposed to hypoxia and/or ischemia-reperfusion events, suggesting that HO and endogenous CO afford an evolutionary advantage for hypoxia tolerance and are critical in cell survival and injury avoidance. Our goal is to describe the importance of examining HO and CO in several systems, the physiological links, and the genetic factors that underlie variation in the HO/CO pathway. Finally, we emphasize the ways in which evolutionary perspectives may enhance our understanding of the HO/CO pathway in the context of diverse clinical settings.

Andean highlanders are challenged by chronic hypoxia and many exhibit elevated hematocrit (Hct) and blunted ventilation compared to other high-altitude populations. While many Andeans develop Chronic Mountain Sickness (CMS) and excessive erythrocytosis, Hct varies markedly within Andean men and women and may be driven by individual differences in ventilatory control and/or sleep events which exacerbate hypoxemia. To test this hypothesis, we quantified relationships between resting ventilation and ventilatory chemoreflexes, sleep desaturation, breathing disturbance, and Hct in Andean men and women. Ventilatory measures were made in 109 individuals (n = 63 men; n = 46 women), and sleep measures in 45 of these participants (n = 22 men; n = 23 women). In both men and women, high Hct was associated with low daytime SpO2 (p < 0.001 and p < 0.002, respectively) and decreased sleep SpO2 (mean, nadir, and time

In strong enough electric fields the non-linear response of electrons in crystals is expected to lead to spatial localization but so far this has only been seen in artificial structures. Schmidt et al. present evidence of this Wannier-Stark localization effect in bulk GaAs driven by intense mid-infrared pulses.