Tumor Dormancy and Slow-Cycling Cancer Cells.

Cancer cell heterogeneity is a universal feature of human tumors and represents a significant barrier to the efficacy and duration of anticancer therapies, especially targeted therapeutics. Among the heterogeneous cancer cell populations is a subpopulation of relatively quiescent cancer cells, which are in the G0/G1 cell-cycle phase and refractory to anti-mitotic drugs that target proliferative cells. These slow-cycling cells (SCCs) preexist in untreated tumors and frequently become enriched in treatment-failed tumors, raising the possibility that these cells may mediate therapy resistance and tumor relapse. Here we review several general concepts on tumor cell heterogeneity, quiescence, and tumor dormancy. We discuss the potential relationship between SCCs and cancer stem cells (CSCs). We also present our current understanding of how SCCs and cancer dormancy might be regulated. Increasing knowledge of SCCs and tumor dormancy should lead to identification of novel molecular regulators and therapeutic targets of tumor relapse, residual diseases, and metastasis.

Cerebral autoregulation index at high altitude assessed by thigh-cuff and transfer function analysis techniques.

NEW FINDINGS: What is the central question of this study? Whether cerebral autoregulation (CA) is impaired at high altitude and associated with acute mountain sickness remains controversial. We sought to compare two of the most common methods to assess dynamic CA in subjects who ascended to 3424 m and acclimatized. What is the main finding and its importance? We found that CA was reduced at 3424 m when assessed by the classic thigh-cuff inflation-deflation technique, but not when evaluated by transfer function analysis. These findings suggest that the cerebral vasculature of healthy individuals may become less able to buffer a large, abrupt drop in arterial blood pressure, while still maintaining the ability to regulate slow rhythmical oscillations, during periods of moderate hypoxaemia. ABSTRACT: The occurrence and implications of changes in cerebral autoregulation (CA) at high altitude are controversial and confounded by differences in methods used to assess CA. To compare two of the most common methods of dynamic CA assessment, we studied 11 young, healthy sea-level residents (six females and five males; 20.5 ± 2.3 years old) as they ascended to 3424 m and acclimatized over 13 days. A common autoregulation index (ARI) was calculated from the following: (i) transfer function analysis (TFA ARI) of resting oscillations in arterial blood pressure (ABP; finger plethysmography) and middle cerebral artery blood velocity (MCAv; transcranial Doppler); and (ii) MCAv responses following large, abrupt reductions in ABP using the classic thigh-cuff technique (Cuff ARI). Symptoms of acute mountain sickness (AMS) were monitored using the Lake Louise AMS Questionnaire. Cuff ARI scores decreased (P = 0.021) as subjects ascended from low (4.7 ± 1.5) to high altitude (3.2 ± 1.6) and did not change after 13 days of acclimatization (2.9 ± 1.3). The TFA ARI scores were not affected by ascent or acclimatization to 3424 m. Neither Cuff nor TFA ARI scores were correlated with AMS symptoms. These findings suggest that the cerebral vasculature of healthy individuals may become less able to buffer large step changes in ABP, while still maintaining the ability to regulate slow rhythmical oscillations, during periods of moderate hypoxaemia. Given the inherent differences in the autoregulatory stimulus between methods, multiple assessment techniques may be needed to clarify the implications of changes in cerebrovascular regulation at high altitude.

Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells.

BACKGROUND: CDK4/6 inhibitors (CDKi) have improved disease control in hormone-receptor-positive, HER2-negative metastatic breast cancer, but most patients develop progressive disease. METHODS: We asked whether host stromal senescence after CDK4/6 inhibition affects metastatic seeding and growth of CDKi-resistant mammary cancer cells by using the p16-INK-ATTAC mouse model of inducible senolysis. RESULTS: Palbociclib pretreatment of naïve mice increased lung seeding of CDKi-resistant syngeneic mammary cancer cells, and this effect was reversed by depletion of host senescent cells. RNA sequencing analyses of lungs from non-tumor-bearing p16-INK-ATTAC mice identified that palbociclib downregulates immune-related gene sets and gene expression related to leukocyte migration. Concomitant senolysis reversed a portion of these effects, including pathway-level enrichment of TGF-ß- and senescence-related signaling. CIBERSORTx analysis revealed that palbociclib alters intra-lung macrophage/monocyte populations. Notably, lung metastases from palbociclib-pretreated mice revealed senescent endothelial cells. Palbociclib-treated endothelial cells exhibit hallmark senescent features in vitro, upregulate genes involved with the senescence-associated secretory phenotype, leukocyte migration, and TGF-ß-mediated paracrine senescence and induce tumor cell migration and monocyte trans-endothelial invasion in co-culture. CONCLUSIONS: These studies shed light on how stromal senescence induced by palbociclib affects lung metastasis, and they describe palbociclib-induced gene expression changes in the normal lung and endothelial cell models that correlate with changes in the tumor microenvironment in the lung metastatic niche.

Normobaric Hypoxia Effects on Balance Measured by Computerized Dynamic Posturography.

Wagner, Dale R., Skyler Saunders, Brady Robertson, and John E. Davis. Normobaric hypoxia effects on balance measured by computerized dynamic posturography. High Alt Med Biol. 17:222-227, 2016.-Background/Aim: Equilibrium was measured by computerized dynamic posturography at varying levels of normobaric hypoxia before and after exercise. METHODS: Following a familiarization trial, 12 males (27.3 ± 7.1 years) completed three sessions in random order on a NeuroCom SMART Balance Master: a sham trial at the ambient altitude of 1500 m and simulated altitudes of 3000 and 5000 m created by a hypoxic generator. The NeuroCom provided composite scores for a sensory organization test of equilibrium and a motor control test to assess the appropriate motor response. Additional information on somatosensory, visual, and vestibular responses was obtained. Each session consisted of 20 minutes of rest followed by the NeuroCom test, then 10 minutes of exercise, and 10 minutes of recovery followed by a second NeuroCom test, all while connected to the hypoxic generator. Mean differences were identified with a two-way (pre/postexercise and altitude condition), repeated-measures analysis of variance. RESULTS: The composite sensory score was significantly lower (p < 0.001) during the 5000 m trial (73.4 ± 12.0) compared to the 1500 m (80.8 ± 7.0) and 3000 m (84.1 ± 5.0) altitudes. The inability to ignore inaccurate visual cues in a situation of visual conflict was the most common sensory error. Motor control was not affected by altitude or exercise. DISCUSSION: These results suggest that moderate hypoxia does not affect balance, but severe hypoxia significantly reduces equilibrium. Furthermore, it appears that the alterations in equilibrium are primarily from impairments in visual function.

Cognitive and psychomotor responses to high-altitude exposure in sea level and high-altitude residents of Ecuador.

BACKGROUND: High-altitude inhabitants have cardiovascular and respiratory adaptations that are advantageous for high-altitude living, but they may have impaired cognitive function. This study evaluated the influence of altitude of residence on cognitive and psychomotor function upon acute exposure to very high altitude. FINDINGS: Ecuadorians (31 residing at 0-1,500 m [LOW], 78 from 1,501-3,000 m [MOD], and 23 living >3,000 m [HIGH]) were tested upon their arrival to a hut at 4,860 m on Mount Chimborazo. Cognitive/psychomotor measurements included a go-no-go test (responding to a non-visual stimulus), a verbal fluency test (verbalizing a series of words specific to a particular category), and a hand movement test (rapidly repeating a series of hand positions). Mean differences between the three altitude groups on these cognitive/psychomotor tests were evaluated with one-way ANOVA. There were no significant differences (p = 0.168) between LOW, MOD, and HIGH for the verbal fluency test. However, the go-no-go test was significantly lower (p < 0.001) in the HIGH group (8.8 ± 1.40 correct responses) than the LOW (9.8 ± 0.61) or MOD (9.8 ± 0.55) groups, and both MOD (97.9 ± 31.2) and HIGH (83.5 ± 26.7) groups completed fewer correct hand movements than the LOW (136.6 ± 37.9) subjects (p < 0.001). CONCLUSIONS: Based on this field study, high-altitude residents appear to have some impaired cognitive function suggesting the possibility of maladaptation to long-term exposure to hypobaric hypoxia.

Orthostatic responses at 4860 m in low, moderate, and high altitude residents.

This study evaluated the influence of altitude of residence on orthostatic responses when exposed to high altitude. Data collection took place at the Carrel hut (4860 m) on Chimborazo in Ecuador. After being transported to the hut by vehicle, 69 people volunteered for the study. A 3-min stand test (rapid change from supine to standing) provided an orthostatic challenge while resting heart rate (RHR), systolic (SBP) and diastolic (DBP) blood pressures, and arterial oxygen saturation (SpO2) were measured. Participants were separated into four groups based on altitude of residence and ethnicity: LOW (<1500 m; n=15), MOD (1500-3000 m, n=30), and HIGH (>3000 m, n=11) Ecuadorians, and non-Ecuadorian lowlanders (NE-LOW, n=13). Supine and standing RHRs were lower (p<0.05) for HIGH compared to other groups. Furthermore, standing increased RHR in LOW, MOD, and NE-LOW by 11.9 ± 5.3, 9.5 ± 4.1, and 11.6 ± 7.4 bpm, respectively, while HIGH stayed the same (0.6 bpm increase ± 3.3). Additionally, mean arterial pressure decreased slightly but not significantly upon standing in all groups except HIGH. The difference in Spo2 among groups was not significant (p>0.05). Altitude of residence influences the cardiovascular responses to orthostatic stress with HIGH having blunted responses and greater tolerance.