The Effects of High-Repetition Strength Training on Performance in Competitive Endurance Athletes: A Systematic Review and Meta-Analysis.

ABSTRACT: Nugent, FJ, Flanagan, EP, Darragh, I, Daly, L, and Warrington, GD. The effects of high-repetition strength training on performance in competitive endurance athletes: A systematic review and meta-analysis. J Strength Cond Res 37(6): 1315-1326, 2023-The aim of this systematic review and meta-analysis was to evaluate the effects of high-repetition strength training (HRST) on performance in competitive endurance athletes. The methodology followed the Preferred Reporting Items for Systematic Review and Meta-Analysis protocol. A search of databases was performed until December 2020. Inclusion criteria were (a) competitive endurance athletes, (b) ≥4 weeks HRST intervention, (c) control or comparison group, (d) outcome measures of performance (either physiological or time trial performance), and (e) all experimental designs. Quality assessment was performed using the Physiotherapy Evidence Database (PEDro) scale. Of the 615 studies retrieved, 11 studies were included (216 subjects) and 9 studies provided sufficient data for the meta-analysis (137 subjects). The PEDro scale score had a mean of 5 of 10 points (range: 3-6). There was no significant difference between the HRST and control groups (g = 0.35; 95% confidence interval [CI] = -0.38 to 1.07; p = 0.35) or HRST and low-repetition strength training (LRST) groups (g = 0.24; 95% CI = -0.24 to 0.72; p = 0.33). The findings of this review and meta-analysis indicate that HRST does not result in improved performance over a 4- to 12-week period, and the results seem to be similar to LRST. The majority of studies involved recreational endurance athletes and had a mean duration of 8 weeks, which is a limitation of the findings. Future intervention studies should be > 12 weeks in duration and involve well-trained endurance athletes (maximal oxygen uptake [V̇o2max] of >65 ml·kg-1·min-2).

Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer.

The horizontal transfer of mtDNA and its role in mediating resistance to therapy and an exit from dormancy have never been investigated. Here we identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal therapy-resistant (HTR) metastatic breast cancer. We generated xenograft models of HTR metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HTR cells had acquired host-derived (murine) mtDNA promoting estrogen receptor-independent oxidative phosphorylation (OXPHOS). Functional studies identified cancer-associated fibroblast (CAF)-derived EVs (from patients and xenograft models) laden with whole genomic mtDNA as a mediator of this phenotype. Specifically, the treatment of hormone therapy (HT)-naive cells or HT-treated metabolically dormant populations with CAF-derived mtDNAhi EVs promoted an escape from metabolic quiescence and HTR disease both in vitro and in vivo. Moreover, this phenotype was associated with the acquisition of EV mtDNA, especially in cancer stem-like cells, expression of EV mtRNA, and restoration of OXPHOS. In summary, we have demonstrated that the horizontal transfer of mtDNA from EVs acts as an oncogenic signal promoting an exit from dormancy of therapy-induced cancer stem-like cells and leading to endocrine therapy resistance in OXPHOS-dependent breast cancer.

Implementing person-centred key performance indicators to strengthen leadership in community nursing: A feasibility study.

AIMS: To explore the utility and feasibility of implementing eight person-centred nursing key performance indicators in supporting community nurses to lead the development of person-centred practice. BACKGROUND: Policy advocates person-centred health care, but few quality indicators exist that explicitly focus on evaluating person-centred practice in community nursing. Current quality measurement frameworks in the community focus on incidences of poor or missed opportunities for care, with few mechanisms to measure how clients perceive the care they receive. METHODS: An evaluation approach derived from work of the Medical Research Council was used, and the study was underpinned by the Person-centred Practice Framework. Participatory methods were used, consistent with person-centred research. RESULTS: Data were thematically analysed, revealing five themes: giving voice to experience; talking the language of person-centredness; leading for cultural change; proud to be a nurse; and facilitating engagement. CONCLUSIONS: The findings suggest that implementing the eight person-centred nursing key performance indicators (KPIs) and the measurement framework is feasible and offers a means of evidencing person-centredness in community nursing. IMPLICATIONS FOR NURSING MANAGEMENT: Person-centred KPI data, used alongside existing quality indicators, will enable nurse managers to evidence a high standard of care delivery and assist in the development of person-centred practice.

Caring for people with multiple sclerosis who use cannabis for symptom control.

Research suggests that a large proportion of people living with multiple sclerosis (PwMS) are using cannabis to self-manage symptoms, or at least believe there are potential benefits in using this drug. Since community nurses are frontline caregivers, they are likely to encounter PwMS who use cannabis within the home setting. The literature base surrounding this topic is largely driven by quantitative research examining the effectiveness of cannabis as a medicine. This review found that qualitative research exploring the experiences of PwMS who use cannabis is lacking worldwide and is completely absent within UK nursing literature. PwMS using cannabis may not feel safe discussing this with health professionals, as they might fear being judged. This literature review discusses how people perceive the effectiveness of cannabis in helping symptoms associated with MS, while also considering the stigma and legal concerns people face. This review may help community nurses inform their practice and enhance person-centred relationships between them and PwMS.

The IL-6 feed-forward loop: a driver of tumorigenesis.

IL-6 signaling plays a prominent role in tumorigenesis and metastasis. In this review we discuss the recent evidence describing the tumor intrinsic and extrinsic functions of this signaling pathway. Although blockade of this pathway in pre-clinical models leads to a reduction in tumor growth and metastasis, its clinical success is less evident. Thus, identifying the features of tumors/patients that predict response to anti-IL6 therapy are needed.

STAT3 negatively regulates thyroid tumorigenesis.

Although tyrosine-phosphorylated or activated STAT3 (pY-STAT3) is a well-described mediator of tumorigenesis, its role in thyroid cancer has not been investigated. We observed that 63 of 110 (57%) human primary papillary thyroid carcinoma (PTC) cases expressed nuclear pY-STAT3 in tumor cells, preferentially in association with the tumor stroma. An inverse relationship between pY-STAT3 expression with tumor size and the presence of distant metastases was observed. Using human thyroid cancer-derived cell lines [harboring rearranged during transfection (RET)/PTC, v-RAF murine sarcoma viral oncogene homolog B (BRAF), or rat sarcoma virus oncogene (RAS) alterations], we determined that IL-6/gp130/JAK signaling is responsible for STAT3 activation. STAT3 knockdown by shRNA in representative thyroid cancer cell lines that express high levels of pY-STAT3 had no effect on in vitro growth. However, xenografted short hairpin STAT3 cells generated larger tumors than control cells. Similarly, STAT3 deficiency in a murine model of BRAFV600E-induced PTC led to thyroid tumors that were more proliferative and larger than those tumors expressing STAT3wt. Genome expression analysis revealed that STAT3 knockdown resulted in the down-regulation of multiple transcripts, including the tumor suppressor insulin-like growth factor binding protein 7. Furthermore, STAT3 knockdown led to an increase in glucose consumption, lactate production, and expression of Hypoxia-inducible factor 1 (HIF1α) target genes, suggesting that STAT3 is a negative regulator of aerobic glycolysis. Our studies show that, in the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth. These findings suggest that targeting STAT3 in these cancers could enhance tumor size and highlight the complexities of the role of STAT3 in tumorigenesis.

Cyclist route choice, traffic-related air pollution, and lung function: a scripted exposure study.

BACKGROUND: A travel mode shift to active transportation such as bicycling would help reduce traffic volume and related air pollution emissions as well as promote increased physical activity level. Cyclists, however, are at risk for exposure to vehicle-related air pollutants due to their proximity to vehicle traffic and elevated respiratory rates. To promote safe bicycle commuting, the City of Berkeley, California, has designated a network of residential streets as "Bicycle Boulevards." We hypothesized that cyclist exposure to air pollution would be lower on these Bicycle Boulevards when compared to busier roads and this elevated exposure may result in reduced lung function. METHODS: We recruited 15 healthy adults to cycle on two routes - a low-traffic Bicycle Boulevard route and a high-traffic route. Each participant cycled on the low-traffic route once and the high-traffic route once. We mounted pollutant monitors and a global positioning system (GPS) on the bicycles. The monitors were all synced to GPS time so pollutant measurements could be spatially plotted. We measured lung function using spirometry before and after each bike ride. RESULTS: We found that fine and ultrafine particulate matter, carbon monoxide, and black carbon were all elevated on the high-traffic route compared to the low-traffic route. There were no corresponding changes in the lung function of healthy non-asthmatic study subjects. We also found that wind-speed affected pollution concentrations. CONCLUSIONS: These results suggest that by selecting low-traffic Bicycle Boulevards instead of heavily trafficked roads, cyclists can reduce their exposure to vehicle-related air pollution. The lung function results indicate that elevated pollutant exposure may not have acute negative effects on healthy cyclists, but further research is necessary to determine long-term effects on a more diverse population. This study and broader field of research have the potential to encourage policy-makers and city planners to expand infrastructure to promote safe and healthy bicycle commuting.

Validity of clinical measures of smooth pursuit eye movement control in patients with idiopathic neck pain.

BACKGROUND: Electrooculography is useful in detecting smooth pursuit neck torsion (SPNT) abnormalities in patients with neck pain, however, a validated, clinically relevant measure is lacking. OBJECTIVES: To explore the validity of visual assessment of formal and clinical videotaped SPNT tests in comparison to electrooculography. DESIGN: Cross-sectional observational study. METHOD: Twenty patients with idiopathic neck pain (INP) and twenty healthy controls performed the electrooculography SPNT test: first in neutral, then 45° trunk-under-head torsion to the left then right. The formal video test involved the participant following a horizontal laser stimulus simultaneous to electrooculography. The clinical video test was then performed where the participant followed the clinician's finger in the horizontal direction. One blinded investigator interpreted and analysed the electrooculography trace and two others interpreted the videos. RESULTS: Patients with INP had a significantly (p < 0.05) greater SPNT difference than healthy controls. Visual observation of the formal test had 82.5% agreement with electrooculography and showed fair sensitivity (63.5%) and good specificity (89.6) whilst the clinical test had 65% agreement with electrooculography and showed poor sensitivity (27.3%) and good specificity (79.3%). There was an 82.5% agreement between investigators for the formal video taped measure. CONCLUSIONS: Visual analysis of assessment of SPNT is sufficient for detecting SPNT abnormalities in patients with INP. Accuracy of the clinical method could be improved by, altering how the visual stimulus is presented and including subjective reporting of symptoms to aid diagnosis resulting in implications for future research.

p-STAT3 in luminal breast cancer: Integrated RNA-protein pooled analysis and results from the BIG 2-98 phase III trial.

In the present study, in order to investigate the role of signal transducer and activator of transcription 3 (STAT3) in estrogen receptor (ER)-positive breast cancer prognosis, we evaluated the phosphorylated STAT3 (p-STAT3) status and investigated its effect on the outcome in a pooled analysis and in a large prospective adjuvant trial. By using the TCGA repository, we developed gene signatures that reflected the level of p-STAT3. Using pooled analysis of the expression data from luminal breast cancer patients, we assessed the effects of the p-STAT3 expression signature on prognosis. We further validated the p-STAT3 prognostic effect using immunohistochemistry (IHC) and immunofluorescence staining of p-STAT3 tissue microarrays from a large randomised prospective trial. Our analysis demonstrated that p-STAT3 expression was elevated in luminal A-type breast cancer (Kruskal-Wallis test, P<10e-10) and was significantly associated with a good prognosis (log-rank, P<10e-10). Notably, the p-STAT3 expression signature identified patients with a good prognosis irrespective of the luminal subtype (log-rank: luminal A, P=0.026; luminal B, P=0.006). p-STAT3 staining by IHC in the stroma or tumour was detected in 174 out of 610 ER-positive samples (28.5%) from the BIG 2-98 randomised trial. With a median follow-up of 10.1 years, p-STAT3 was associated with a reduced risk of recurrence in ER-positive/HER2-negative breast cancer (Cox univariate HR, 0.66; 95% CI, 0.44-0.98; P=0.04). On the whole, our data indicate that p-STAT3 is associated with an improved outcome in ER-positive breast cancer.

Influence of neck torsion on near point convergence in subjects with idiopathic neck pain.

BACKGROUND: People with neck pain (NP) experience sensorimotor and oculomotor deficits thought to be due to abnormal cervical afferent input. Convergence insufficiency (CI) measured by near point convergence (NPC) may be a feature in NP and neck torsion might help to differentiate a cervical cause. OBJECTIVES: This study aimed to investigate repeatability and reliability of NPC in neutral and torsion and compare between idiopathic NP and controls along with correlation to the Convergence Insufficiency Symptom Survey (CISS). DESIGN: Comparative cross sectional observational study. METHOD: A Royal Airforce (RAF) Rule measured NPC with the neck in neutral and in 45° torsion to the left and right in 42 subjects. A revised 15 item CISS was also completed. The average of 3 trials in each position and torsion difference were calculated. Within one week, NPC inter-rater and test-retest reliability was evaluated in 10 subjects. RESULTS: A significant NPC torsion difference was demonstrated in participants with NP compared to controls (P = 0.01). No significant differences were seen for NPC values in neutral (P = 0.73). High inter-rater reliability (ICC = 0.95) and repeatability (ICC = 0.84) was obtained. No correlations were present between the CISS and NPC measures (r ≤ 0.18). CONCLUSIONS: NPC is impaired in neck torsion compared to neutral in NP supporting a cervical afferent cause. NPC, measured using the RAF Rule, is a reliable and repeatable measure and can be used to assess NPC and CI in those with NP. Objective rather than self-reported measures should be used to examine CI in NP.

Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles.

The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ERlo/Notchhi feed-forward loop responsible for the generation of CD133hi CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221hi CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to de novo HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133hi cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133hi CSCs. Conversely, in models of CD133neg, HT-sensitive cancer cells, both murine and human CAFs promoted de novo HT resistance via the generation of CD133hi CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. Cancer Res; 77(8); 1927-41. ©2017 AACR.

Malignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells.

Purpose: While the tumor microenvironment has been known to play an integral role in tumor progression, the function of nonresident bone marrow-derived cells (BMDC) remains to be determined in neurologic tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas.Experimental Design: We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet-derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression. Levels of CD11b+/GR1+ BMDCs were analyzed at discrete stages of tumor progression. Using bone marrow transplantation, we determined the unique influence of BMDCs in the transition from low- to high-grade glioma. The functional role of these BMDCs was then examined using a JAK 1/2 inhibitor (AZD1480).Results: CD11b+ myeloid cells were significantly increased during tumor progression in peripheral blood and tumors of glioma patients. Increases in CD11b+/GR1+ cells were observed in murine peripheral blood, bone marrow, and tumors during low-grade to high-grade transformation. Transient blockade of CD11b+ cell expansion using a JAK 1/2 Inhibitor (AZD1480) impaired mobilization of these cells and was associated with a reduction in tumor volume, maintenance of a low-grade tumor phenotype, and prolongation in survival.Conclusions: We demonstrate that impaired recruitment of CD11b+ myeloid cells with a JAK1/2 inhibitor inhibits glioma progression in vivo and prolongs survival in a murine glioma model. Clin Cancer Res; 23(12); 3109-19. ©2016 AACR.

Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.

The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ER(lo)/OXPHOS(lo). These cells exit metabolic dormancy via an IL6-driven feed-forward ER(lo)-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133(hi)/ER(lo) cells mediating metastatic progression, which is sensitive to dual targeted therapy.

JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors.

Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells' dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC.

The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis.

We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis.

AZD1480 blocks growth and tumorigenesis of RET- activated thyroid cancer cell lines.

Persistent RET activation is a frequent event in papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC). In these cancers, RET activates the ERK/MAPK, the PI3K/AKT/mTOR and the JAK/STAT3 pathways. Here, we tested the efficacy of a JAK1/2- inhibitor, AZD1480, in the in vitro and in vivo growth of thyroid cancer cell lines expressing oncogenic RET. Thyroid cancer cell lines harboring RET/PTC1 (TPC-1), RET M918T (MZ-CRC1) and RET C634W (TT) alterations, as well as TPC-1 xenografts, were treated with JAK inhibitor, AZD1480. This inhibitor led to growth inhibition and/or apoptosis of the thyroid cancer cell lines in vitro, as well as to tumor regression of TPC-1 xenografts, where it efficiently blocked STAT3 activation in tumor and stromal cells. This inhibition was associated with decreased proliferation, decreased blood vessel density, coupled with increased necrosis. However, AZD1480 repressed the growth of STAT3- deficient TPC-1 cells in vitro and in vivo, demonstrating that its effects in this cell line were independent of STAT3 in the tumor cells. In all cell lines, the JAK inhibitor reduced phospho-Y1062 RET levels, and mTOR effector phospho-S6, while JAK1/2 downregulation by siRNA did not affect cell growth nor RET and S6 activation. In conclusion, AZD1480 effectively blocks proliferation and tumor growth of activated RET- thyroid cancer cell lines, likely through direct RET inhibition in cancer cells as well as by modulation of the microenvironment (e.g. via JAK/phospho-STAT3 inhibition in endothelial cells). Thus, AZD1480 should be considered as a therapeutic agent for the treatment of RET- activated thyroid cancers.