Permafrost is a defining characteristic of the Arctic environment. However, climate warming is thawing permafrost in many areas leading to failures in soil structure called thermokarst. An extensive ...survey of a 600 km2 area in and around the Toolik Lake Natural Research Area (TLNRA) revealed at least 34 thermokarst features, two thirds of which were new since ∼1980 when a high resolution aerial survey of the area was done. Most of these thermokarst features were associated with headwater streams or lakes. We have measured significantly increased sediment and nutrient loading from thermokarst features to streams in two well‐studied locations near the TLNRA. One small thermokarst gully that formed in 2003 on the Toolik River in a 0.9 km2 subcatchment delivered more sediment to the river than is normally delivered in 18 years from 132 km2 in the adjacent upper Kuparuk River basin (a long‐term monitoring reference site). Ammonium, nitrate, and phosphate concentrations downstream from a thermokarst feature on Imnavait Creek increased significantly compared to upstream reference concentrations and the increased concentrations persisted over the period of sampling (1999–2005). The downstream concentrations were similar to those we have used in a long‐term experimental manipulation of the Kuparuk River and that have significantly altered the structure and function of that river. A subsampling of other thermokarst features from the extensive regional survey showed that concentrations of ammonium, nitrate, and phosphate were always higher downstream of the thermokarst features. Our previous research has shown that even minor increases in nutrient loading stimulate primary and secondary production. However, increased sediment loading could interfere with benthic communities and change the responses to increased nutrient delivery. Although the terrestrial area impacted by thermokarsts is limited, the aquatic habitat altered by these failures can be extensive. If warming in the Arctic foothills accelerates thermokarst formation, there may be substantial and wide‐spread impacts on arctic stream ecosystems that are currently poorly understood.
In non-small-cell lung cancers with programmed death-ligand 1 (PD-L1) expression on ≥50% of tumor cells, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared with ...platinum-doublet chemotherapy. Whether higher PD-L1 levels within the expression range of 50%–100% predict for even greater benefit to pembrolizumab is currently unknown.
In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment of non-small-cell lung cancer (NSCLC) with a PD-L1 expression of ≥50% and negative for genomic alterations in the EGFR and ALK genes.
Among 187 patients included in this analysis, the ORR was 44.4% 95% confidence interval (CI) 37.1% to 51.8%, the mPFS was 6.5 months (95% CI 4.5–8.5), and the mOS was not reached. The median PD-L1 expression level among patients who experienced a response to pembrolizumab was significantly higher than among patients with stable or progressive disease (90% versus 75%, P < 0.001). Compared with patients with PD-L1 expression of 50%–89% (N = 107), patients with an expression level of 90%–100% (N = 80) had a significantly higher ORR (60.0% versus 32.7%, P < 0.001), a significantly longer mPFS 14.5 versus 4.1 months, hazard ratio (HR) 0.50 (95% CI 0.33–0.74), P < 0.01, and a significantly longer mOS not reached versus 15.9 months, HR 0.39 (95% CI 0.21–0.70), P = 0.002.
Among patients with NSCLC and PD-L1 expression of ≥50% treated with first-line pembrolizumab, clinical outcomes are significantly improved in NSCLCs with a PD-L1 expression of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.
The success of agents that reverse T-cell inhibitory signals, such as anti-PD-1/PD-L1 therapies, has reinvigorated cancer immunotherapy research. However, since only a minority of patients respond to ...single-agent therapies, methods to test the potential anti-tumor activity of rational combination therapies are still needed. Conventional murine xenograft models have been hampered by their immune-compromised status; thus, we developed a hematopoietic humanized mouse model, hu-CB-BRGS, and used it to study anti-tumor human immune responses to triple-negative breast cancer (TNBC) cell line and patient-derived colorectal cancer (CRC) xenografts (PDX).
BALB/c-Rag2
Il2rγ
SIRPα
(BRGS) pups were humanized through transplantation of cord blood (CB)-derived CD34+ cells. Mice were evaluated for human chimerism in the blood and assigned into experimental untreated or nivolumab groups based on chimerism. TNBC cell lines or tumor tissue from established CRC PDX models were implanted into both flanks of humanized mice and treatments ensued once tumors reached a volume of ~150mm
. Tumors were measured twice weekly. At end of study, immune organs and tumors were collected for immunological assessment.
Humanized PDX models were successfully established with a high frequency of tumor engraftment. Humanized mice treated with anti-PD-1 exhibited increased anti-tumor human T-cell responses coupled with decreased Treg and myeloid populations that correlated with tumor growth inhibition. Combination therapies with anti-PD-1 treatment in TNBC-bearing mice reduced tumor growth in multi-drug cohorts. Finally, as observed in human colorectal patients, anti-PD-1 therapy had a strong response to a microsatellite-high CRC PDX that correlated with a higher number of human CD8+ IFNγ+ T cells in the tumor.
Hu-CB-BRGS mice represent an in vivo model to study immune checkpoint blockade to human tumors. The human immune system in the mice is inherently suppressed, similar to a tumor microenvironment, and thus allows growth of human tumors. However, the suppression can be released by anti-PD-1 therapies and inhibit tumor growth of some tumors. The model offers ample access to lymph and tumor cells for in-depth immunological analysis. The tumor growth inhibition correlates with increased CD8 IFNγ+ tumor infiltrating T cells. These hu-CB-BRGS mice provide a relevant preclinical animal model to facilitate prioritization of hypothesis-driven combination immunotherapies.
Cytoplasmic dynein is a microtubule-based motor required for intracellular transport and cell division. Its movement involves coupling cycles of track binding and release with cycles of ...force-generating nucleotide hydrolysis. How this is accomplished given the ∼25 nanometers separating dynein's track- and nucleotide-binding sites is not understood. Here, we present a subnanometer-resolution structure of dynein's microtubule-binding domain bound to microtubules by cryo—electron microscopy that was used to generate a pseudo-atomic model of the complex with molecular dynamics. We identified large rearrangements triggered by track binding and specific interactions, confirmed by mutagenesis and single-molecule motility assays, which tune dynein's affinity for microtubules. Our results provide a molecular model for how dynein's binding to microtubules is communicated to the rest of the motor.
Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in ...depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HT(Ext)). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT(1A) receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT(2A) receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5-HT(2A) receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy.
Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. ...Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined.
To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB.
We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141.
PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade.
•In patients with NSCLC and PD-L1 ≥50%, TMB is lower in never and light smokers compared with heavy smokers.•PD-(L)1 inhibitors are active in a significant subset of never and light smokers with NSCLC and PD-L1 ≥50%.•Nonetheless, we observed numerically shorter PFS/DOR among never and light smokers compared to heavy smokers.•Distinct immunobiologic features may underlie initial response versus durability of response to PD-1 inhibitors in NSCLC.
Highlights • Supraspinal causes of delayed automatic postural responses in people with MS are unknown. • We correlated supraspinal structural connectivity to postural response latency. • ...Pedunculopontine nucleus structural connectivity was worse in people with MS. • Pedunculopontine nucleus connectivity was correlated to tibialis onset latency. • Altered supraspinal connectivity may contribute to delayed postural responses in MS.
VM202, a plasmid DNA that expresses two isoforms of hepatocyte growth factor, may elicit angiogenic effects that could benefit patients with critical limb ischemia (CLI). In a phase 2, double-blind ...trial in 52 CLI patients, we examined the safety and potential efficacy of intramuscular injections of low-dose (n=21) or high-dose (n=20) VM202 or placebo (n=11) in the affected limb (days 0, 14, 28 and 42). Adverse events and serious adverse events were similar among the groups; no malignancy or proliferative retinopathy was seen. In exploratory efficacy analyses, we found no differences in ankle or toe-brachial index, VAS, VascuQuol or amputation rate among the groups. Complete ulcer healing was significantly better in high-dose (8/13 ulcers; P<0.01) versus placebo (1/9) patients. Clinically meaningful reductions (>50%) in ulcer area occurred in high-dose (9/13 ulcers) and low-dose (19/27) groups versus placebo (1/9; P<0.05 and P<0.005, respectively). At 12 months, significant differences were seen in TcPO2 between the high-dose and placebo groups (47.5 ± 17.8 versus 36.6 ± 24.0 mm Hg, respectively; P<0.05) and in the change from baseline among the groups (P<0.05). These data suggest that VM202 is safe and may provide therapeutic bioactivity in CLI patients.
A comparative15N-tracer study of nitrogen dynamics in headwater streams from biomes throughout North America demonstrates that streams exert control over nutrient exports to rivers, lakes, and ...estuaries. The most rapid uptake and transformation of inorganic nitrogen occurred in the smallest streams. Ammonium entering these streams was removed from the water within a few tens to hundreds of meters. Nitrate was also removed from stream water but traveled a distance 5 to 10 times as long, on average, as ammonium. Despite low ammonium concentration in stream water, nitrification rates were high, indicating that small streams are potentially important sources of atmospheric nitrous oxide. During seasons of high biological activity, the reaches of headwater streams typically export downstream less than half of the input of dissolved inorganic nitrogen from their watersheds.
1. We studied whole‐ecosystem metabolism in eight streams from several biomes in North America to identify controls on the rate of stream metabolism over a large geographic range. The streams studied ...had climates ranging from tropical to cool‐temperate and from humid to arid and were all relatively uninfluenced by human disturbances.
2. Rates of gross primary production (GPP), ecosystem respiration (R) and net ecosystem production (NEP) were determined using the open‐system, two‐station diurnal oxygen change method.
3. Three general patterns in metabolism were evident among streams: (1) relatively high GPP with positive NEP (i.e. net oxygen production) in early afternoon, (2) moderate primary production with a distinct peak in GPP during daylight but negative NEP at all times and (3) little or no evidence of GPP during daylight and a relatively constant and negative NEP over the entire day.
4. Gross primary production was most strongly correlated with photosynthetically active radiation (PAR). A multiple regression model that included log PAR and stream water soluble reactive phosphorus (SRP) concentration explained 90% of the variation in log GPP.
5. Ecosystem respiration was significantly correlated with SRP concentration and size of the transient storage zone and, together, these factors explained 73% of the variation in R. The rate of R was poorly correlated with the rate of GPP.
6. Net ecosystem production was significantly correlated only with PAR, with 53% of the variation in log NEP explained by log PAR. Only Sycamore Creek, a desert stream in Arizona, had positive NEP (GPP: R > 1), supporting the idea that streams are generally net sinks rather than net sources of organic matter.
7. Our results suggest that light, phosphorus concentration and channel hydraulics are important controls on the rate of ecosystem metabolism in streams over very extensive geographic areas.
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