Purpose:
This study assessed the biological reliability of peripheral human cytokines and adipokines, and the influence of participant characteristics on total error. This has essential application ...to interventional cytokine measurement to ensure that reported results are interpreted with confidence.
Methods:
Participants (49% female, 18–85 years,
n
= 84) completed two consecutive-day testing sessions. Participants provided a venous blood sample at the same time of day across two consecutive days, under standardized participant presentation, including 24-h rested and 12-h fasted conditions. Multiplex immunoassay was used to assess inflammatory analytes from samples (predominantly plasma). Repeat measurements were conducted between-day for total precision quantification, and technical (technique) error was negated from the total to provide an estimate of biological (attributed to participant presentation) error.
Results:
Whilst there was no evidence of statistically significant biological error, a small amount of biological error was consistently present across most analytes (∼3.3%/0.07 pg/ml), which was largest for measurement of leptin (7.3%/210 pg/ml). There was also an influence of sex on reliability of leptin and adiponectin (total model explained 6–7% of error variation), where females demonstrated the greatest error.
Conclusion:
Biological error reported in this study should be applied to any future study or individual with a repeated measurement of cytokine concentrations over time that maintain best practice procedures (12-h fasted, 24-h rested). In most cases, raw error should be used, with exceptions for women for measurement of leptin and adiponectin. This approach will ensure that results are reported with certainty for improved reporting of intervention efficacy.
Exercise has been shown to improve physical and psychosocial outcomes for people across the cancer care continuum. A proposed mechanism underpinning the relationship between exercise and cancer ...outcomes is exercise-induced immunomodulation via secretion of anti-inflammatory myokines from skeletal muscle tissue. Myokines have the potential to impair cancer growth through modulation of natural killer (NK) cells and CD8+ T cells while improving the effectiveness of cancer therapies. Interleukin-15 (IL-15), one of the most abundant myokines found in skeletal muscle, has a key immunoregulatory role in supporting the proliferation and maturation of T cells and NK cells, which have a key role in the host's immune response to cancer. Furthermore, IL-15 is being explored clinically as an immunotherapy agent with doses similar to the IL-15 concentrations released by skeletal muscle during exercise. Here we review the role of IL-15 within the immune system, examine how IL-15 is produced as a myokine during exercise, and how it may improve outcomes for people with cancer, specifically as an adjuvant or neoadjuvant to immunotherapy. We summarize the available evidence showing changes in IL-15 in response to both acute exercise and training, and the results are inconsistent; higher quality research is needed to advance the understanding of how exercise-mediated increases in IL-15 potentially benefit those who are being treated for, or who have had, cancer.
Reliability of body composition measurement techniques is essential to the accurate reporting of intervention outcomes. However, the between-day precision error of commonly used techniques, as well ...as the reference multi-compartment model, in a population-representative sample are currently unknown.
To quantify technical and biological precision error of body composition techniques in comparison to the referent 4-compartment (4C) model.
Men and women (1:1 ratio; 18–85 years old; n = 90) completed 2 consecutive-day body composition testing sessions, including individual components of the referent 4C model. Testing was undertaken in accordance with best practice guidance for each technique, including standardized presentation and a consistent time of day. Repeat measurements were conducted on day 1 for technical precision, and between-day measurements were conducted for biological precision quantification.
On average, all measurements met acceptable error limits and presented typically low technical and biological error <2% fat-free mass (FFM) and < 3% fat mass (FM) precision error. For technical precision of FFM, all techniques met a priori cut points (80%; CV = 0.45–0.81%). For FM, all techniques were equivalent to the best-rating method on average (CV = 0.78–1.35%), except air displacement plethysmography (CV = 2.13%). For biological precision, only 3-compartment (3C) and 4C equations sufficiently met the a priori determined cut point for estimates for FFM (CV = 0.77–0.79%), and only DXA met the 80% cut point (CV = 1.17%) for FM.
The primary purpose of a study design is imperative when deciding on body composition assessment techniques used for longitudinal measurements. If reliable longitudinal assessments of FFM are central, a 3C or 4C model may be indicated. If FM is a primary outcome, DXA may be preferable. However, considering the low error rates presented within the current study across a broad age span of healthy adults with implementation of best-practice guidelines, any technique assessed here may be used, provided that strict protocols are adhered to.
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Purpose
Growing recognition of the gut microbiome as an influential modulator of cancer treatment efficacy and toxicity has led to the emergence of clinical interventions targeting the microbiome to ...enhance cancer and health outcomes. The highly modifiable nature of microbiota to endogenous, exogenous, and environmental inputs enables interventions to promote resilience of the gut microbiome that have rapid effects on host health, or response to cancer treatment. While diet, probiotics, and faecal microbiota transplant are primary avenues of therapy focused on restoring or protecting gut function in people undergoing cancer treatment, the role of physical activity and exercise has scarcely been examined in this population.
Methods
A narrative review was conducted to explore the nexus between cancer care and the gut microbiome in the context of physical activity and exercise as a widely available and clinically effective supportive care strategy used by cancer survivors.
Results
Exercise can facilitate a more diverse gut microbiome and functional metabolome in humans; however, most physical activity and exercise studies have been conducted in healthy or athletic populations, primarily using aerobic exercise modalities. A scarcity of exercise and microbiome studies in cancer exists.
Conclusions
Exercise remains an attractive avenue to promote microbiome health in cancer survivors. Future research should elucidate the various influences of exercise modalities, intensities, frequencies, durations, and volumes to explore dose-response relationships between exercise and the gut microbiome among cancer survivors, as well as multifaceted approaches (such as diet and probiotics), and examine the influences of exercise on the gut microbiome and associated symptom burden prior to, during, and following cancer treatment.
This study investigated the acceptable accuracy of common body composition techniques compared with the reference 4-compartment (4C-R) model, which has not been investigated in a sample with diverse ...characteristics, including age and sex. Techniques included components of the 4C-R model dual-energy X-ray absorptiometry, air displacement plethysmography, deuterium dilution (DD) and surrogate compartment models, which utilised bioelectrical impedance spectroscopy (BIS) rather than DD. Men and women (sex = 1:1, 18–85 years, n = 90) completed body composition testing under best-practice guidance. For measurement of individuals, only the reference 3-compartment (3C-R) equation met acceptable error limits (<5% error among individuals) within the a priori cut-point (80%) for fat-free mass (FFM; CV = 0.52%) and fat mass (FM; CV = 1.61%). However, all investigated techniques reached equivalency to the 4C-R model for FFM on average (CV = 0.52–4.31%), but for FM only the 3C and 4C equations that included quantification of total body water (TBW) by DD or BIS reached equivalency overall (CV = 1.61–6.68%). Sex and age minimally influenced accuracy. Only the 3C-R or 4C-R equations are supported for acceptable individual accuracy for both FFM and FM. For group estimates any investigated technique could be used with acceptable accuracy for FFM; however, for FM, inclusion of TBW measurement within a compartment model is necessary.
Novelty:
Only the referent 3C and 4C models (including deuterium dilution) provide accurate body composition results that are acceptable for measurement of individuals in the general population.
For group estimates of lean mass in the general population, compartments models that include TBW must be used for accurate measurement.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An expanded sedimentary section provides an opportunity to elucidate conditions in the nascent Chicxulub crater during the hours to millennia after the Cretaceous‐Paleogene (K‐Pg) boundary impact. ...The sediments were deposited by tsunami followed by seiche waves as energy in the crater declined, culminating in a thin hemipelagic marlstone unit that contains atmospheric fallout. Seiche deposits are predominantly composed of calcite formed by decarbonation of the target limestone during impact followed by carbonation in the water column. Temperatures recorded by clumped isotopes of these carbonates are in excess of 70°C, with heat likely derived from the central impact melt pool. Yet, despite the turbidity and heat, waters within the nascent crater basin soon became a viable habitat for a remarkably diverse cross section of the food chain. The earliest seiche layers deposited with days or weeks of the impact contain earliest Danian nannoplankton and dinocyst survivors. The hemipelagic marlstone representing the subsequent years to a few millennia contains a nearly monogeneric calcareous dinoflagellate resting cyst assemblage suggesting deteriorating environmental conditions, with one interpretation involving low light levels in the impact aftermath. At the same horizon, microbial fossils indicate a thriving bacterial community and unique phosphatic fossils including appendages of pelagic crustaceans, coprolites and bacteria‐tunneled fish bone, suggesting that this rapid recovery of the base of the food chain may have supported the survival of larger, higher trophic‐level organisms. The extraordinarily diverse fossil assemblage indicates that the crater was a unique habitat in the immediate impact aftermath, possibly as a result of heat and nutrients supplied by hydrothermal activity.
Plain Language Summary
The newly formed Chicxulub crater was rapidly filled by seawater then disturbed by tsunami and seiche waves. Sedimentary layers deposited as wave energy declined provide a unique window into the environment of the nascent crater in the months and years to millennia after the impact. Geochemical data show temperatures in hotter regions of the crater in excess of 70°C for the first few years with heat derived from the underlying melt sheet via hydrothermal circulation. Cooler regions of the crater became habitats soon after impact with a suite of fossils indicating diverse life on the seafloor and sea surface, ranging from microbes to marine arthropods, and possibly fish. We suggest that this community was sustained by nutrients and heat from the hydrothermal system. The rapid early recovery in the Chicxulub crater and ocean above demonstrates the resiliency of life under extraordinarily harsh conditions, which has important ramifications for early life on Earth and life on other planets.
Key Points
Sediments derived from decarbonation of the Chicxulub impact target were deposited by tsunami and seiche waves over months to years followed by a layer with atmospheric fallout
Temperatures in the ocean above the hotter regions of the crater were in excess of 70°C, with heat likely derived from the central impact melt pool
Cooler regions within the crater basin became habitats soon after impact with diverse life ranging from microbes to marine arthropods, and possibly fish
To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic ...nerve edema, splenomegaly, anhidrosis, and migraine headache.
Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members.
We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, p.Thr237Met), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis.
Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.
Soft tissue sarcomas (STS) are rare, heterogenous malignancies with an unmet need for novel immunotherapies. Tumor infiltrating lymphocytes (TILs) have been linked with favorable outcomes in STS ...patients, though the contribution of natural killer (NK) cells and spatial relationships of TILs with MHC-I expressing cells lacks detailed characterization.
Using archived and prospectively collected specimens, we evaluated intratumoral NK cells by immunohistochemistry (IHC), flow cytometry, and immunofluorescence (IF). We assessed spatial localization of NK and T cells by multiplex IF, analyzing the effects of MHC-I expression status on NK and T cell clustering.
Both intratumoral NKp46 and CD56
expression were associated with significantly improved overall survival (P=0.05), while higher infiltrates of CD56bright NK cells predicted a worse prognosis (P=0.05). The presence of intratumoral NK cells was inversely proportional to CD3
T cells. Spatial analyses showed NK cells preferentially clustering close to other NK cells with sparse CD3
T and CD8
T cells in range (P<0.0001). Additionally, CD3
T and CD8
T cells showed significantly greater co-localization with MHC-I
cells, compared to NK cells (P<0.0001). After neoadjuvant radiotherapy, there was greater CD8 clustering, while after neoadjuvant chemotherapy, there was overall lower TIL clustering.
Intratumoral NK cells are prognostic in STS and localize closer to MHC-I- cells than T cells. Although both NK and T cells are associated with improved survival in STS, their differential distribution in the TME based on MHC-I expression status may serve as a biomarker for improved immunotherapy treatment selection.
The cancer stem cell (CSC) hypothesis postulates that heterogeneous human cancers harbor a population of stem-like cells which are resistant to cytotoxic therapies, thus providing a reservoir of ...relapse following conventional therapies like chemotherapy and radiation (RT). CSCs have been observed in multiple human cancers, and their presence has been correlated with worse clinical outcomes. Here, we sought to evaluate the impact of drug dosing of the multi-tyrosine kinase inhibitor, sorafenib, on CSC and non-CSCs in soft tissue sarcoma (STS) models, hypothesizing differential effects of sorafenib based on dose and target cell population. In vitro, human cancer cell lines and primary STS from surgical specimens were exposed to escalating doses of sorafenib to determine cell viability and expression of CSC marker aldehyde dehydrogenase (ALDH). In vivo, ALDH
CSCs were isolated, exposed to sorafenib, and xenograft growth and survival analyses were performed. We observed that sarcoma CSCs appear to paradoxically respond to the tyrosine kinase inhibitor sorafenib at low doses with increased proliferation and stem-like function of CSCs, whereas anti-viability effects dominated at higher doses. Importantly, STS patients receiving neoadjuvant sorafenib and RT on a clinical trial (NCT00864032) showed increased CSCs post therapy, and higher ALDH scores post therapy were associated with worse metastasis-free survival. These data suggest that low-dose sorafenib may promote the CSC phenotype in STS with clinically significant effects, including increased tumor growth and higher rates of metastasis formation in sarcoma patients.
The Cretaceous/Palaeogene mass extinction eradicated 76% of species on Earth
. It was caused by the impact of an asteroid
on the Yucatán carbonate platform in the southern Gulf of Mexico 66 million ...years ago
, forming the Chicxulub impact crater
. After the mass extinction, the recovery of the global marine ecosystem-measured as primary productivity-was geographically heterogeneous
; export production in the Gulf of Mexico and North Atlantic-western Tethys was slower than in most other regions
, taking 300 thousand years (kyr) to return to levels similar to those of the Late Cretaceous period. Delayed recovery of marine productivity closer to the crater implies an impact-related environmental control, such as toxic metal poisoning
, on recovery times. If no such geographic pattern exists, the best explanation for the observed heterogeneity is a combination of ecological factors-trophic interactions
, species incumbency and competitive exclusion by opportunists
-and 'chance'
. The question of whether the post-impact recovery of marine productivity was delayed closer to the crater has a bearing on the predictability of future patterns of recovery in anthropogenically perturbed ecosystems. If there is a relationship between the distance from the impact and the recovery of marine productivity, we would expect recovery rates to be slowest in the crater itself. Here we present a record of foraminifera, calcareous nannoplankton, trace fossils and elemental abundance data from within the Chicxulub crater, dated to approximately the first 200 kyr of the Palaeocene. We show that life reappeared in the basin just years after the impact and a high-productivity ecosystem was established within 30 kyr, which indicates that proximity to the impact did not delay recovery and that there was therefore no impact-related environmental control on recovery. Ecological processes probably controlled the recovery of productivity after the Cretaceous/Palaeogene mass extinction and are therefore likely to be important for the response of the ocean ecosystem to other rapid extinction events.
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