Purpose
Triple-negative breast cancer (TNBC) accounts for approximately 20% of breast cancer cases. Although there have been advances in the treatment of hormone receptor-positive and human epidermal ...growth factor receptor 2-positive breast cancers, targeted therapies for TNBC remain unavailable. In this narrative review, we summarize recent discoveries related to the underlying biology of the phosphoinositide 3-kinase (
PI3K
)/protein kinase B (
AKT
)/mechanistic target of rapamycin (
mTOR
) pathway in TNBC, examine clinical progress to date, and suggest rational future approaches for investigational therapies in TNBC.
Results
As with other subtypes of breast cancer, aberrations in the
PI3K/AKT/mTOR
pathway are common in TNBC. Preclinical data support the notion that these aberrations predict TNBC inhibition by targeted agents. In a recently published phase 2 clinical trial, an AKT inhibitor (ipatasertib) improved outcomes in a subset of patients with metastatic TNBC when combined with paclitaxel in the first-line setting. In addition, new compounds with distinct specificity and potency targeting different PI3K/AKT/mTOR components and cognate molecules (e.g., mitogen-activated protein kinase) are being developed. These agents present a wide range of toxicity profiles and early efficacy signals, which must be considered prior to the advancement of new agents in later-phase clinical trials.
Conclusions
The development of drugs targeting the PI3K/AKT/mTOR pathway for the treatment of TNBC is an evolving field that should take into account the efficacies and toxicities of new agents in addition to their interactions with different cancer pathways.
Due to gastrointestinal tract adaptability, the study aimed to determine the impact of gut-training protocol over 2 weeks on gastrointestinal status, blood glucose availability, fuel kinetics, and ...running performance. Endurance runners (n = 25) performed a gut-challenge trial (GC1), consisting of 2 h running exercise at 60% V̇O
2max
whilst consuming gel-discs containing 30 g carbohydrates (2:1 glucose/fructose, 10% w/v) every 20 min and a 1 h distance test. Participants were then randomly assigned to a carbohydrate gel-disc (CHO-S), carbohydrate food (CHO-F), or placebo (PLA) gut-training group for 2 weeks of repetitive gut-challenge intervention. Participants then repeated a second gut-challenge trial (GC2). Gastrointestinal symptoms reduced in GC2 on CHO-S (60%; p = 0.008) and CHO-F (63%; p = 0.046); reductions were greater than PLA (p < 0.05). H
2
peak was lower in GC2 on CHO-S (mean (CI): 6 (4–8) ppm) compared with CHO-F (9 (6–12) ppm) and PLA (12 (2–21) ppm) (trial × time: p < 0.001). Blood glucose concentration was higher in GC2 on CHO-S (7.2 (6.3–8.1) mmol·L
−1
) compared with CHO-F (6.1 (5.7–6.5) mmol·L
−1
) and PLA (6.2 (4.9–7.5) mmol·L
−1
) (trial × time: p = 0.015). No difference in oxidation rates, plasma I-FABP, and cortisol concentrations were observed between groups and trials. Distance test improved on CHO-S (5.2%) and CHO-F (4.3%) in GC2, but not on PLA (–2.1%) (trial × time: p = 0.009). Two weeks of gut-training with CHO-S and CHO-F improved gastrointestinal symptoms and running performance compared with PLA. CHO-S also reduced malabsorption and increased blood glucose availability during endurance running compared with PLA.
Human epidermal growth factor receptor 2-positive (HER2
) breast cancer accounts for ~25% of breast cancer cases. Monoclonal antibodies (mAbs) against HER2 have led to unparalleled clinical benefit ...for a subset of patients with HER2
breast cancer. In this narrative review, we summarize advances in the understanding of immune system interactions, examine clinical developments, and suggest rationales for future investigation of immunotherapies for HER2
breast cancer. Complex interactions have been found between different branches of the immune system, HER2
breast cancer, and targeted treatments (approved and under investigation). A new wave of immunotherapies, such as novel HER2-directed mAbs, antibody drug conjugates, vaccines, and adoptive T-cell therapies, are being studied in a broad population of patients with HER2-expressing tumors. The development of immunotherapies for HER2
breast cancer represents an evolving field that should take into account interactions between different components of the immune system.
The study aimed to determine the effects of 24-h high (HFOD) and low (LFOD) fermentable oligo-, di-, monosaccharide, and polyol (FODMAP) diets before exertional heat stress on gastrointestinal ...integrity, function, and symptoms. Eighteen endurance runners consumed a HFOD and a LFOD (double-blind crossover design) before completing 2 h of running at 60% maximal oxygen uptake in 35 °C ambient temperature. Blood samples were collected before and after exercise to determine plasma cortisol and intestinal fatty acid binding protein (I-FABP) concentrations, and bacterial endotoxin and cytokine profiles. Breath hydrogen (H
2
) and gastrointestinal symptoms (GIS) were determined pre-exercise, every 15 min during, and in recovery. No differences were observed for plasma cortisol concentration between diets. Plasma I-FABP concentration was lower on HFOD compared with LFOD (p = 0.033). A trend for lower lipopolysaccharide binding protein (p = 0.088), but not plasma soluble CD14 (p = 0.478) and cytokine profile (p > 0.05), responses on HFOD was observed. A greater area under the curve breath H
2
concentration (p = 0.031) was observed throughout HFOD (mean and 95% confidence interval: HFOD 2525 (1452–3597) ppm·4 h
−1
) compared with LFOD (1505 (1031–1978) ppm·4 h
−1
). HFOD resulted in greater severity of GIS compared with LFOD (pre-exercise, p = 0.017; during, p = 0.035; and total, p = 0.014). A 24-h HFOD before exertional heat stress ameliorates disturbances to epithelial integrity but exacerbates carbohydrate malabsorption and GIS severity in comparison with a LFOD.
Novelty
Twenty-four-hour high FODMAP diet ameliorated disturbances to gastrointestinal integrity.
Twenty-four-hour high FODMAP diet results in greater carbohydrate malabsorption compared with low FODMAP diet.
Incidence of GIS during exertional heat stress were pronounced on both low and high FODMAP diets, but greater GIS severity was observed with high FODMAP diet.
Purpose
The study aimed to determine the effects of exertional-heat stress on gastrointestinal integrity, symptoms, systemic endotoxin and inflammatory responses; and assess the relationship between ...changes in body temperature and gastrointestinal perturbations.
Methods
Ten endurance runners completed 2 h running at 60%
V
˙
O
2max
in hot (HOT: 35 °C) and temperate (TEMP: 22 °C)-ambient conditions. Rectal temperature (
T
re
) and gastrointestinal symptoms were recorded every 10 min during exercise. Blood samples were collected pre- and post-exercise, and during recovery to determine plasma intestinal fatty acid binding protein (I-FABP), cortisol, bacterial endotoxin and cytokine profile. Calprotectin was determined from pre- and post-exercise faecal samples. Urinary lactulose:
l
-rhamnose ratio was used to measure intestinal permeability.
Results
Compared with TEMP, HOT significantly increased
T
re
(1.4 ± 0.5 vs 2.4 ± 0.8 °C,
p
< 0.001), cortisol (26 vs 82%,
p
< 0.001), I-FABP (127 vs 432%,
p
< 0.001), incidence (70 vs 90%) and severity (58 counts vs 720 counts,
p
= 0.008) of total gastrointestinal symptoms. Faecal calprotectin and circulating endotoxin increased post-exercise in both trials (mean increase 1.5 ± 2.5 µg/g,
p
= 0.032, and 6.9 ± 10.3 pg/ml,
p
= 0.047, respectively), while anti-endotoxin antibodies increased 28% post-exercise in TEMP and decreased 21% in HOT (
p
= 0.027). However, intestinal permeability did not differ between trials (
p
= 0.185). Inflammatory cytokines were greater on HOT compared to TEMP (
p
< 0.05). Increases in
T
re
were positively associated with I-FABP, IL-10, cortisol, nausea and urge to regurgitate (
p
< 0.05).
Conclusions
Exertional-heat stress induces a thermoregulatory strain that subsequently injures the intestinal epithelium, reduces endotoxin clearance capacity, promotes greater cytokinaemia, and development of gastrointestinal symptoms.
Off-road running continues to grow in popularity, with differing event categories existing, and terminologies are often used interchangeably and without precision. Trail running, mountain running, ...skyrunning, fell running, orienteering, obstacle course racing and cross-country running all take place predominantly in off-road terrain. Ultramarathon running refers to any running event over marathon distance conducted in any terrain and surface. Although some overlap may exist between these running events, mainly through the common denominator of off-road terrain, distinct features need to be recognised. As scientific interest in these activities grows, it becomes important to clarify these terms and develop a universal language for discussing these events. Similarly, off-road running athletes are generally not properly defined within the scientific literature, which makes intra- and inter-study comparisons difficult. The current position statement of the Ultra Sports Science Foundation highlights the different off-road running events and recommends clear reference to distance, surface, elevation change and altitude, type of event (continuous vs. staged), type of support, name and year of the event, governing body, and guidance on terminology. We further recommend to describe off-road running athletes by basic data, physiological determinants, training and competition characteristics in the scientific literature in order to facilitate and guide further research and practice.
Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC ...has fostered interest in checkpoint inhibitors such as anti-PD-1 nivolumab.
The primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety.
Single-arm, multicenter, phase 2 clinical trial with two-stage design.
Comprehensive cancer center.
Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy.
Nivolumab (240 mg) IV every 2 weeks.
Ten patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment one died of disease progression, one discontinued due to adverse events (AEs), one withdrew after beginning treatment. The median PFS was 1.8 months. The median follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had stable disease for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an AE. Most AEs were grade 1/2. The most common grade 3/4 treatment-related AEs were aspartate aminotransferase and alanine aminotransferase elevations, mucositis, and odynophagia.
Nivolumab demonstrated modest antitumor activity in patients with advanced ACC. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population.
Exertional heat stress (EHS) disturbs the integrity of the gastrointestinal tract leading to endotoxaemia and cytokinaemia, which have symptomatic and health implications. This study aimed to ...determine the effects of carbohydrate and protein intake during EHS on gastrointestinal integrity, symptoms, and systemic responses. Eleven (male, n = 6; female, n = 5) endurance runners completed 2 h of running at 60% maximal oxygen uptake in 35 °C ambient temperature on 3 occasions in randomised order, consuming water (WATER), 15 g glucose (GLUC), or energy-matched whey protein hydrolysate (WPH) before and every 20 min during EHS. Rectal temperature and gastrointestinal symptoms were recorded every 10 min during EHS. Blood was collected pre- and post-EHS, and during recovery to determine plasma concentrations of intestinal fatty-acid binding protein (I-FABP) as a marker of intestinal epithelial injury, cortisol, endotoxin, and inflammatory cytokines. Urinary lactulose/
l
-rhamnose ratio was used to measure small intestine permeability. Compared with WATER, GLUC, and WPH ameliorated EHS associated intestinal epithelial injury (I-FABP: 897 ± 478 pg·mL
−1
vs. 123 ± 197 pg·mL
−1
and 82 ± 156 pg·mL
−1
, respectively, p < 0.001) and small intestine permeability (lactulose/
l
-rhamnose ratio: 0.034 ± 0.014 vs. 0.017 ± 0.005 and 0.008 ± 0.002, respectively, p = 0.001). Endotoxaemia was observed post-EHS in all trials (10.2 pg·mL
−1
, p = 0.001). Post-EHS anti-endotoxin antibodies were higher (p < 0.01) and cortisol and interleukin-6 lower (p < 0.05) on GLUC than WATER only. Total and upper gastrointestinal symptoms were greater on WPH, compared with GLUC and WATER (p < 0.05), in response to EHS. In conclusion, carbohydrate and protein intake during EHS ameliorates intestinal injury and permeability. Carbohydrate also supports endotoxin clearance and reduces stress markers, while protein appears to increase gastrointestinal symptoms, suggesting that carbohydrate is a more appropriate option.
The aim was to test the hypothesis that one night of sleep deprivation will impair pre-loaded 30 min endurance performance and alter the cardio-respiratory, thermoregulatory and perceptual responses ...to exercise. Eleven males completed two randomised trials separated by 7 days: once after normal sleep (496 (18) min: CON) and once following 30 h without sleep (SDEP). After 30 h participants performed a 30 min pre-load at 60%
followed by a 30 min self-paced treadmill distance test. Speed, RPE, core temperature (
T
re
), mean skin temperature (
T
sk
), heart rate (HR) and respiratory parameters (
,
,
, RER pre-load only) were measured. Less distance (
P
= 0.016,
d
= 0.23) was covered in the distance test after SDEP (6037 (759) 95%CI 5527 to 6547 m) compared with CON (6224 (818) 95%CI 5674 to 6773 m). SDEP did not significantly alter
T
re
at rest or thermoregulatory responses during the pre-load including heat storage (0.8°C) and
T
sk
. With the exception of raised
at 30 min on the pre-load, cardio-respiratory parameters, RPE and speed were not different between trials during the pre-load or distance test (distance test mean HR, CON 174 (12), SDEP 170 (13) beats min
−1
: mean RPE, CON 14.8 (2.7), SDEP 14.9 (2.6)). In conclusion, one night of sleep deprivation decreased endurance performance with limited effect on pacing, cardio-respiratory or thermoregulatory function. Despite running less distance after sleep deprivation compared with control, participants’ perception of effort was similar indicating that altered perception of effort may account for decreased endurance performance after a night without sleep.
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