Changes in the consumption of isoflavones, omega-6, and omega-3 fatty acids in women with metastatic breast cancer adopting a whole-food, plant-based diet: post-hoc analysis of nutrient intake data from an 8-week randomized controlled trial.

Background: Diets rich in minimally processed plant-based foods are recommended to breast cancer patients, and some may have an interest in whole-food, plant-based (WFPB) diets that avoid animal-based foods, added fats, and refined sugars. Within WFPB diets, the intakes of isoflavones, omega-6 polyunsaturated fatty acids (n-6 PUFAs), and omega-3 polyunsaturated FAs (n-3 PUFAs), which have been discussed in reference to breast cancer outcomes, have not been well characterized. Methods: Women with stage IV breast cancer on stable therapy were randomized 2:1 into (1) a WFPB intervention (N = 21) or (2) usual care (N = 11) for 8 weeks. Three meals per day were provided. Outcomes presented here include dietary intake of isoflavones, n-3 and n-6- PUFAs, which were assessed using three-day food records at baseline and 8 weeks. Baseline and 8-week mean intake within groups were compared using the Wilcoxon signed-rank test and between control and intervention groups by a two-sample t-test. Results: The WFPB intervention participants increased their daily consumption of total isoflavones from a mean of 0.8 mg/day to 14.5 mg/day (p < 0.0001) and decreased the n-6:n-3 ratio of their diet from a mean of 9.3 to 3.7 (p < 0.0001). Within the WFPB group, linoleic acid (n-6 PUFA) consumption decreased by a mean of 3.8 g (p = 0.0095), from 12.8 g/day to 9.0 g/day; total n-3 PUFA consumption increased by a mean of 1.1 g (p = 0.0005), from 1.6 g/day to 2.7 g/day. Conclusion: Transitioning to a WFPB diet resulted in significantly increased isoflavone intake and decreased n-6:n-3 ratio in women with breast cancer.

A whole food, plant-based randomized controlled trial in metastatic breast cancer: feasibility, nutrient, and patient-reported outcomes.

PURPOSE: Quality of life (QOL) is among the most important outcomes for women with metastatic breast cancer (MBC), and it predicts survival. QOL is negatively impacted by cognitive impairment, fatigue, and weight gain. We assessed whether a whole food, plant-based (WFPB) diet-promoting weight loss is feasible and might improve QOL. METHODS: Women with MBC on stable systemic treatments were randomized 2:1 to 1) WFPB dietary intervention (n = 21) or 2) usual care (n = 11) for 8 weeks. Participants attended weekly education visits and consumed an ad libitum WFPB diet (3 prepared meals/day provided). Patient-reported outcomes and 3-day food records were assessed at baseline and 8 weeks. The effects of WFPB diet on changes in outcomes were assessed by analysis of covariance model controlling for baseline. RESULTS: 20 intervention and 10 control participants completed the trial. Intervention participants were highly adherent to the WFPB diet (94.3 % total calories on-plan). Intervention group nutrient intakes changed significantly including dietary fat (35.8 % to 20.4 % percent calories from fat, p < 0.001) and fiber content (12.7 to 30.8 g fiber/1000 kcal, p < 0.001). Perceived cognitive function (FACT-Cog total + 16.1; 95 % confidence interval [CI] = 0.8-31.7; p = 0.040) and emotional well-being (FACT-B emotional well-being subscale + 2.3; CI = 0.5-4.1; p = 0.016) improved in the WFPB versus the control group. Fatigue, measured by the BFI, improved within the WFPB group for fatigue severity (M = 4.7 ± 2.5[SD] to 3.7 ± 2.3, p = 0.047) and fatigue at its worst (5.8 ± 2.8 to 4.4 ± 2.4, p = 0.011). CONCLUSIONS: Significant dietary changes in this population are feasible and may improve QOL by improving treatment-related symptoms. Additional study is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03045289. Registered 7 February 2017.

A whole-food, plant-based randomized controlled trial in metastatic breast cancer: weight, cardiometabolic, and hormonal outcomes.

PURPOSE: Breast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy. METHODS: Women with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole-food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks. RESULTS: Within the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01), and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15-3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline. CONCLUSION: WFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight, cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes. Trial registration First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017.

Post hoc analysis of food costs associated with Dietary Approaches to Stop Hypertension diet, whole food, plant-based diet, and typical baseline diet of individuals with insulin-treated type 2 diabetes mellitus in a nonrandomized crossover trial with meals provided.

BACKGROUND: Americans consume diets that fall short of dietary recommendations, and the cost of healthier diets is often cited as a barrier to dietary change. We conducted a nonrandomized crossover trial with meals provided utilizing 2 diets: Dietary Approaches to Stop Hypertension (DASH) and whole food, plant-based (WFPB), and thus had intake data from baseline and both intervention diets. OBJECTIVES: Using actual diet records, describe food costs of baseline diets of individuals with type 2 diabetes (T2DM) as well as therapeutic DASH and WFPB diets. METHODS: Three-day food records were collected and analyzed for each 7-d diet phase: baseline, DASH, and WFPB. Nutrient content was analyzed using the Nutrient Data System for Research and cost was determined using Fillet, an application to manage menu pricing. Food costs were calculated for each diet as consumed and adjusted to a standardized 1800 kcal/d. Ingredient-only costs of food away from home (FAFH) were approximated and analyzed. Costs were analyzed using linear mixed-effect models as a function of diet. RESULTS: Fifteen subjects enrolled; 12 completed all dietary phases. The baseline, DASH, and WFPB diets, as consumed, cost $15.72/d (95% CI; $13.91, $17.53), $12.74/d ($11.23, $14.25), and $9.78/d ($7.97, $11.59), respectively. When adjusted to an 1800 kcal/d intake, the baseline, DASH, and WFPB diets cost $15.69/d ($13.87, $17.52), $14.92/d ($13.59, $16.26), and $11.96/d ($10.14, $13.78), respectively. When approximated ingredient-only costs of FAFH were analyzed, as consumed baseline [$11.01 ($9.53, $12.49)] and DASH diets [$11.81 ($10.44, $13.18)] had similar costs; WFPB diet [$8.83 ($7.35, $10.31)] cost the least. CONCLUSIONS: In this short-term study with meals provided, the food costs of plant-predominant diets offering substantial metabolic health benefits were less than or similar to baseline food costs of adults with insulin-treated T2DM. Longer-term data without meal provision are needed for more generalizable results. This trial was registered at clinicaltrials.gov as NCT04048642.

A Whole Food, Plant-Based Randomized Controlled Trial in Metastatic Breast Cancer: Feasibility, Nutrient, and Patient-Reported Outcomes.

Purpose: Quality of life (QOL) is among the most important outcomes for women with metastatic breast cancer (MBC) and it predicts survival. QOL is negatively impacted by cognitive impairment, fatigue, and weight gain. We assessed whether a whole food, plant-based (WFPB) diet promoting weight loss is feasible and might improve QOL. Methods: Women with MBC on stable systemic treatments were randomized 2:1 to 1) WFPB dietary intervention (n = 21) or 2) usual care (n = 11) for 8 weeks. Participants attended weekly education visits and consumed an ad libitum WFPB diet (3 prepared meals/day provided). Patient-reported outcomes and 3-day food records were assessed at baseline and 8 weeks. The effects of WFPB diet on changes in outcomes were assessed by analysis of covariance model controlling for baseline. Results: 20 intervention and 10 control participants completed the trial. Intervention participants were highly adherent to the WFPB diet (94.3% total calories on-plan). Intervention group nutrient intakes changed significantly including dietary fat (35.8-20.4% percent calories from fat, p < 0.001) and fiber content (22.1 to 40.8 grams fiber/1000 kcal, p < 0.001). Perceived cognitive function (FACT-Cog total + 16.1; 95% confidence interval [CI] = 0.8-31.7; p = 0.040) and emotional well-being (FACT-B emotional well-being subscale + 2.3; CI = 0.5-4.1; p = 0.016) improved in the WFPB versus the control group. Fatigue, measured by the BFI, improved within the WFPB group for fatigue severity (M = 4.7 ± 2.5[SD] to 3.7 ± 2.3, p = 0.047) and fatigue at its worst (5.8 ± 2.8 to 4.4 ± 2.4, p = 0.011). Conclusions: Significant dietary changes in this population are feasible and may improve QOL by improving treatment-related symptoms. Additional study is warranted. Trial registration: ClinicalTrials.gov identifier: NCT03045289. Registered 7 February 2017.

A Whole-Food, Plant-Based Randomized Controlled Trial in Metastatic Breast Cancer: Weight, Cardiometabolic, and Hormonal Outcome.

Purpose: Breast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy. Methods: Women with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks. Results: Within the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01) and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15 - 3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline. Conclusion: WFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight and cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes. Trial registration: First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017.

The acute effects of a DASH diet and whole food, plant-based diet on insulin requirements and related cardiometabolic markers in individuals with insulin-treated type 2 diabetes.

AIMS: There is limited research regarding insulin dosing changes following adoption of plant-based diets. We conducted a nonrandomized crossover trial utilizing two plant-based diets (Dietary Approaches to Stop Hypertension, or DASH, and Whole Food, Plant-Based, or WFPB) to assess acute changes in insulin requirements and associated markers among individuals with insulin-treated type 2 diabetes. METHODS: Participants (n = 15) enrolled in a 4-week trial with sequential, one-week phases: Baseline, DASH 1, WFPB, and DASH 2. Each diet was ad libitum and meals were provided. RESULTS: Compared to baseline, daily insulin usage was 24%, 39%, and 30% lower after DASH 1, WFPB, and DASH 2 weeks respectively (all p < 0.01). Insulin resistance (HOMA-IR) was 49% lower (p < 0.01) and the insulin sensitivity index was 38% higher (p < 0.01) at the end of the WFPB week before regressing toward baseline during DASH 2. Total, LDL, and HDL cholesterol, leptin, urinary glucose, and hsCRP decreased to a nadir at the end of the WFPB week before increasing during DASH 2. CONCLUSIONS: Adopting a DASH or WFPB diet can result in significant, rapid changes in insulin requirements, insulin sensitivity, and related markers among individuals with insulin-treated type 2 diabetes, with larger dietary changes producing larger benefits.

Medication Deprescribing Among Patients With Type 2 Diabetes: A Qualitative Case Series of Lifestyle Medicine Practitioner Protocols.

This study is a qualitative case series of lifestyle medicine practitioners' protocols for medication de-escalation in the context of reduced need for glucose-lowering medications due to lifestyle modifications. Increasing numbers of lifestyle medicine practitioners report achieving reductions in medications among patients with type 2 diabetes, and in some cases remission, but limited data exist on the clinical decision-making process used to determine when and how medications are deprescribed. Practitioners interviewed here provide accounts of their deprescribing protocols. This information can serve as pilot data for other practitioners seeking examples of how deprescribing in the context of lifestyle medicine treatment is conducted.

Lifestyle Medicine and Economics: A Proposal for Research Priorities Informed by a Case Series of Disease Reversal.

Chronic disease places an enormous economic burden on both individuals and the healthcare system, and existing fee-for-service models of healthcare prioritize symptom management, medications, and procedures over treating the root causes of disease through changing health behaviors. Value-based care is gaining traction, and there is a need for value-based care models that achieve the quadruple aim of (1) improved population health, (2) enhanced patient experience, (3) reduced healthcare costs, and (4) improved work life and decreased burnout of healthcare providers. Lifestyle medicine (LM) has the potential to achieve these four aims, including promoting health and wellness and reducing healthcare costs; however, the economic outcomes of LM approaches need to be better quantified in research. This paper demonstrates proof of concept by detailing four cases that utilized an intensive, therapeutic lifestyle intervention change (ITLC) to dramatically reverse disease and reduce healthcare costs. In addition, priorities for lifestyle medicine economic research related to the components of quadruple aim are proposed, including conducting rigorously designed research studies to adequately measure the effects of ITLC interventions, modeling the potential economic cost savings enabled by health improvements following lifestyle interventions as compared to usual disease progression and management, and examining the effects of lifestyle medicine implementation upon different payment models.

Lifestyle Medicine Reimbursement: A Proposal for Policy Priorities Informed by a Cross-Sectional Survey of Lifestyle Medicine Practitioners.

Lifestyle medicine (LM) is a rapidly emerging clinical discipline that focuses on intensive therapeutic lifestyle changes to treat chronic disease, often producing dramatic health benefits. In spite of these well-documented benefits of LM approaches to provide evidence-based care that follows current clinical guidelines, LM practitioners have found reimbursement challenging. The objectives of this paper are to present the results of a cross-sectional survey of LM practitioners regarding lifestyle medicine reimbursement and to propose policy priorities related to the ability of practitioners to implement and achieve reimbursement for these necessary services. Results from a closed, online survey in 2019 were analyzed, with a total of n = 857 included in this analysis. Results were descriptively analyzed. This manuscript articulates policy proposals informed by the survey results. The study sample was 58% female, with median age of 51. A minority of the sample (17%) reported that all their practice was LM, while 56% reported that some of their practice was LM. A total of 55% of practitioners reported not being able to receive reimbursement for LM practice. Of those survey respondents who provided an answer to the question of what would make the practice of LM easier (n = 471), the following suggestions were offered: reimbursement overall (18%), reimbursement for more time spent with patients (17%), more support from leadership (16%), policy measures to incentivize health (13%), education in LM for practitioners (11%), LM-specific billing codes and billing knowledge along with better electronic medical record (EMR) capabilities and streamlined reporting/paperwork (11%), and reimbursement for the extended care team (10%). Proposed policy changes focus on three areas of focus: (1) support for the care process using a LM approach, (2) reimbursement emphasizing outcomes of health, patient experience, and delivering person-centered care, and (3) incentivizing treatment that produces disease remission/reversal. Rectifying reimbursement barriers to lifestyle medicine practice will require a sustained effort from health systems and policy makers. The urgency of this transition towards lifestyle medicine interventions to effectively address the epidemic of chronic diseases in a way that can significantly improve outcomes is being hindered by current reimbursement policies and models.

Plant-based dietary approach to stage 3 chronic kidney disease with hyperphosphataemia.

A 69-year-old man with type 2 diabetes, hypertension and stage 3 chronic kidney disease (CKD), hyperphosphataemia and borderline hyperkalaemia presented to an office visit interested in changing his diet to improve his medical conditions. He adopted a strict whole-foods, plant-based diet, without calorie or portion restriction or mandated exercise, and rapidly reduced his insulin requirements by >50%, and subsequently saw improvements in weight, blood pressure and cholesterol. His estimated glomerular filtration rate (eGFR) increased from 45 to 74 mL/min after 4.5 months on the diet and his microalbumin/creatinine ratio decreased from 414.3 to 26.8 mg/g. His phosphorus level returned to the normal range. For individuals with CKD, especially those with obesity, hypertension, or diabetes, a strict, ad libitum whole-food, plant-based diet may confer significant benefit, although one must consider potential limitations of a creatinine-based GFR equation in the face of significant weight loss.

ERα Binding by Transcription Factors NFIB and YBX1 Enables FGFR2 Signaling to Modulate Estrogen Responsiveness in Breast Cancer.

Two opposing clusters of transcription factors (TF) have been associated with the differential risks of estrogen receptor positive or negative breast cancers, but the mechanisms underlying the opposing functions of the two clusters are undefined. In this study, we identified NFIB and YBX1 as novel interactors of the estrogen receptor (ESR1). NFIB and YBX1 are both risk TF associated with progression of ESR1-negative disease. Notably, they both interacted with the ESR1-FOXA1 complex and inhibited the transactivational potential of ESR1. Moreover, signaling through FGFR2, a known risk factor in breast cancer development, augmented these interactions and further repressed ESR1 target gene expression. We therefore show that members of two opposing clusters of risk TFs associated with ESR1-positive and -negative breast cancer can physically interact. We postulate that this interaction forms a toggle between two developmental pathways affected by FGFR2 signaling, possibly offering a junction to exploit therapeutically.Significance: Binding of the transcription factors NFIB and YBX1 to the estrogen receptor can promote an estrogen-independent phenotype that can be reverted by inhibiting FGFR2 signaling. Cancer Res; 78(2); 410-21. ©2017 AACR.

Lifestyle Medicine: A Brief Review of Its Dramatic Impact on Health and Survival.

By ignoring the root causes of disease and neglecting to prioritize lifestyle measures for prevention, the medical community is placing people at harm. Advanced nations, influenced by a Western lifestyle, are in the midst of a health crisis, resulting largely from poor lifestyle choices. Epidemiologic, ecologic, and interventional studies have repeatedly indicated that most chronic illnesses, including cardiovascular disease, cancer, and type 2 diabetes, are the result of lifestyles fueled by poor nutrition and physical inactivity.In this article, we describe the practice of lifestyle medicine and its powerful effect on these modern instigators of premature disability and death. We address the economic benefits of prevention-based lifestyle medicine and its effect on our health care system: A system on the verge of bankruptcy. We recommend vital changes to a disastrous course. Many deaths and many causes of pain, suffering, and disability could be circumvented if the medical community could effectively implement and share the power of healthy lifestyle choices. We believe that lifestyle medicine should become the primary approach to the management of chronic conditions and, more importantly, their prevention. For future generations, for our own health, and for the Hippocratic Oath we swore to uphold ("First do no harm"), the medical community must take action. It is our hope that the information presented will inspire our colleagues to pursue lifestyle medicine research and incorporate such practices into their daily care of patients. The time to make this change is now.

Identification of Post-Transcriptional Modulators of Breast Cancer Transcription Factor Activity Using MINDy.

We have recently identified transcription factors (TFs) that are key drivers of breast cancer risk. To better understand the pathways or sub-networks in which these TFs mediate their function we sought to identify upstream modulators of their activity. We applied the MINDy (Modulator Inference by Network Dynamics) algorithm to four TFs (ESR1, FOXA1, GATA3 and SPDEF) that are key drivers of estrogen receptor-positive (ER+) breast cancer risk, as well as cancer progression. Our computational analysis identified over 500 potential modulators. We assayed 189 of these and identified 55 genes with functional characteristics that were consistent with a role as TF modulators. In the future, the identified modulators may be tested as potential therapeutic targets, able to alter the activity of TFs that are critical in the development of breast cancer.

FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness.

The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.

Regulators of genetic risk of breast cancer identified by integrative network analysis.

Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.

Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation.

Although ion channels are increasingly being discovered in cancer cells in vitro and in vivo, and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their expression. Here, we focus on voltage-gated Na(+) channels (VGSCs) which are upregulated in many types of carcinomas where their activity potentiates cell behaviours integral to the metastatic cascade. Regulation of VGSCs occurs at a hierarchy of levels from transcription to post-translation. Importantly, mainstream cancer mechanisms, especially hormones and growth factors, play a significant role in the regulation. On the whole, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a negative association between genomic steroid hormone sensitivity and functional VGSC expression. Activity-dependent regulation by positive feedback has been demonstrated in strongly metastatic cells whereby the VGSC is self-sustaining, with its activity promoting further functional channel expression. Such auto-regulation is unlike normal cells in which activity-dependent regulation occurs mostly via negative feedback. Throughout, we highlight the possible clinical implications of functional VGSC expression and regulation in cancer.

Functional expression of the voltage-gated Na⁺-channel Nav1.7 is necessary for EGF-mediated invasion in human non-small cell lung cancer cells.

Various ion channels are expressed in human cancers where they are intimately involved in proliferation, angiogenesis, invasion and metastasis. Expression of functional voltage-gated Na(+) channels (Nav) is implicated in the metastatic potential of breast, prostate, lung and colon cancer cells. However, the cellular mechanisms that regulate Nav expression in cancer remain largely unknown. Growth factors are attractive candidates; they not only play crucial roles in cancer progression but are also key regulators of ion channel expression and activity in non-cancerous cells. Here, we examine the role of epidermal growth factor receptor (EGFR) signalling and Nav in non-small cell lung carcinoma (NSCLC) cell lines. We show unequivocally, that functional expression of the α subunit Nav1.7 promotes invasion in H460 NSCLC cells. Inhibition of Nav1.7 activity (using tetrodotoxin) or expression (by using small interfering RNA), reduces H460 cell invasion by up to 50%. Crucially, non-invasive wild type A549 cells lack functional Nav, whereas exogenous overexpression of the Nav1.7 α subunit is sufficient to promote TTX-sensitive invasion of these cells. EGF/EGFR signalling enhances proliferation, migration and invasion of H460 cells but we find that, specifically, EGFR-mediated upregulation of Nav1.7 is necessary for invasive behaviour in these cells. Examination of Nav1.7 expression at mRNA, protein and functional levels further reveals that EGF/EGFR signalling via the ERK1/2 pathway controls transcriptional regulation of channel expression to promote cellular invasion. Immunohistochemistry of patient biopsies confirms the clinical relevance of Nav1.7 expression in NSCLC. Thus, Nav1.7 has significant potential as a new target for therapeutic intervention and/or as a diagnostic or prognostic marker in NSCLC.

Reducing the risk of noncontact anterior cruciate ligament injuries in the female athlete.

High school and collegiate female athletes have a significantly increased risk of sustaining a noncontact anterior cruciate ligament injury compared with male athletes participating in the same sport. This review summarizes the current knowledge of the risk factors hypothesized to influence this problem, and the neuromuscular training programs designed to correct certain biomechanical problems noted in female athletes. The risk factors include a genetic predisposition for sustaining a knee ligament injury, environmental factors, anatomical indices, hormonal influences, and neuromuscular factors. The greatest amount of research in this area has studied differences between female and male athletes in movement patterns during athletic tasks; muscle strength, activation, and recruitment patterns; and knee joint stiffness under controlled, preplanned, and reactive conditions in the laboratory. Neuromuscular retraining programs have been developed in an attempt to reduce these differences. The successful programs teach athletes to control the upper body, trunk, and lower body position; lower the center of gravity by increasing hip and knee flexion during activities; and develop muscular strength and techniques to land with decreased ground reaction forces. In addition, athletes are taught to preposition the body and lower extremity prior to initial ground contact to obtain the position of greatest knee joint stability and stiffness. Two published programs have significantly reduced the incidence of noncontact anterior cruciate ligament injuries in female athletes participating in basketball, soccer, and volleyball. Other programs were ineffective, had a poor study design, or had an insufficient number of participants, which precluded a true reduction in the risk of this injury. In order to determine which risk factors for noncontact anterior cruciate ligament ruptures are significant, future investigations should include larger cohorts of athletes in multiple sports, analyze factors from all of the major risk categories, and follow athletes for at least one full athletic season. Future risk assessment studies should incorporate reactive tasks under more realistic sports conditions.