Tumour, whole-blood, plasma and tissue concentrations of metformin in lung cancer patients.

AIM: Metformin is used for the management of type 2 diabetes mellitus (T2DM) and is being tested clinically as an anticancer agent. Metformin concentrations safely achievable in human solid tissues including tumours are unknown. This study was designed to determine metformin concentration in tissue compartments as a function of dose to inform rational dosing in preclinical models and interpretation of clinical results." METHODS: Subjects with solid tumours to be treated by resection and either (A) willingness to take metformin for 7-10 days before surgery or (B) taking metformin for T2DM were eligible. Whole blood, plasma, tumour, tumour-adjacent uninvolved tissue and subcutaneous adipose tissue were obtained for liquid chromatography with tandem mass spectrometry to measure metformin concentrations. RESULTS: All subjects had primary lung tumours. Metformin dose was significantly correlated with drug concentrations in all tissues analysed. Intersubject metformin concentrations varied by over two orders of magnitude. Metformin concentrations were significantly higher in tumour tissues and lower in adipose tissues compared to other tissues. Concentrations in blood and plasma were significantly correlated with concentrations in solid tissues. CONCLUSION: Metformin accumulates in cellular compartments. Concentrations observed in plasma, blood, lung and tumour tissues in subjects treated with US Food and Drug Administration-approved doses for T2DM are lower than those typically used in tissue culture studies. However, such tissue concentrations are in line with those found within cultured cells treated with supra-pharmacological doses of metformin. Given the large intersubject variability in metformin concentrations, it is imperative to determine whether there is an association between tissue metformin concentration and anticancer activity in humans.

Enhancement of Radiation Therapy through Blockade of the Immune Checkpoint, V-domain Ig Suppressor of T Cell Activation (VISTA), in Melanoma and Adenocarcinoma Murine Models.

Radiation therapy (RT) has recently demonstrated promise at stimulating an enhanced immune response. The recent success of immunotherapies, such as checkpoint inhibitors, CART cells, and other immune modulators, affords new opportunities for combination with radiation. The aim of this study is to evaluate whether and to what extent blockade of VISTA, an immune checkpoint, can potentiate the tumor control ability of radiation therapy. Our study is novel in that it is the first comparison of two VISTA-blocking methods (antibody inhibition and genetic knockout) in combination with RT. VISTA was blocked either through genetic knockout (KO) or an inhibitory antibody and combined with RT in two syngeneic murine flank tumor models (B16 and MC38). Selected mRNA, immune cell infiltration, and tumor growth delay were used to assess the biological effects. When combined with a single 15Gy radiation dose, VISTA blockade via genetic knockout in the B16 model and via anti-VISTA antibodies in the MC38 model significantly improved survival compared to RT alone by an average of 5.5 days and 6.3 days, respectively (p < 0.05). The gene expression data suggest that the mechanism behind the enhanced tumor control is primarily a result of increased apoptosis and immune-mediated cytotoxicity. VISTA blockade significantly enhances the anti-tumor effect of a single dose of 15Gy radiation through increased expression and stimulation of cell-mediated apoptosis pathways. These results suggest that VISTA is a biologically relevant immune promoter that has the potential to enhance the efficacy of a large single radiation dose in a synergic manner.

One-Sided Multidimensional Statistical Significance Testing: A New Method of Calculating the Statistical Significance of Spectra Used to Demonstrate Magnetic Nanoparticle Sensitivity.

Estimating statistical significance of the difference between two spectra or series is a fundamental statistical problem. Multivariate significance tests exist but the limitations preclude their use in many common cases; e.g., one-sided testing, unequal variance and when few repetitions are acquired all of which are required in magnetic spectroscopy of nanoparticle Brownian motion (MSB). We introduce a test, termed the T-S test, that is powerful and exact (exact type I error). It is flexible enough to be one- or two-sided and the one-sided version can specify arbitrary regions where each spectrum should be larger. The T-S test takes the-one or two-sided p-value at each frequency and combines them using Stouffer's method. We evaluated it using simulated spectra and measured MSB spectra. For the single-sided version, mean of the spectrum, A-T, was used as a reference; the T-S test is as powerful when the variance at each frequency is uniform and outperforms when the noise power is not uniform. For the two-sided version, the Hotelling T2 two-sided multivariate test was used as a reference; the two-sided T-S test is only slightly less powerful for large numbers of repetitions and outperforms rather dramatically for small numbers of repetitions. The T-S test was used to estimate the sensitivity of our current MSB spectrometer showing 1 nanogram sensitivity. Using eight repetitions the T-S test allowed 15 pM concentrations of mouse IL-6 to be identified while the mean of the spectra only identified 76 pM.

mNP hyperthermia and hypofractionated radiation activate similar immunogenetic and cytotoxic pathways.

OBJECTIVE: The goal of this study is to better understand the immunogenetic expression and related cytotoxic responses of moderate but clinically relevant doses of hypofractionated radiation (1x15 Gy and 3x8 Gy) and magnetic nanoparticle hyperthermia (mNPH, CEM43 30). METHODS: Genetic, protein, immunopathology and tumor growth delay assessments were used to determine the immune and cytotoxic responses following radiation and mNPH alone and in combination. Although the thermal dose used, 43 C°/30 min (CEM43 30), typically results in modest independent cytotoxicity, it has shown the ability to stimulate an immune response and enhance other cancer treatments. The radiation doses studied (15 Gy and 3x8 Gy) are commonly used in preclinical research and are effective in selected stereotactic and palliative treatment settings, however they are not commonly used as first-line primary tumor treatment regimens. RESULTS: Our RNA-based genetic results suggest that while many of the cytotoxic and immune gene and protein pathways for radiation and hyperthermia are similar, radiation, at the doses used, results in a more consistent and expansive anti-cancer immune/cytotoxic expression profile. These results were supported by immunohistochemistry based cytotoxic T-cell tumor infiltration and tumor growth delay studies. When used together radiation and hyperthermia led to greater immune and cytotoxic activity than either modality alone. CONCLUSION: This study clearly shows that modest, but commonly used hypofractionated radiation and hyperthermia doses share many important immune and cytotoxic pathways and that combining the treatments, as compared to either treatment alone, results in genetic and biological anti-cancer benefits.

Downstream targets of GWAS-detected genes for breast, lung, and prostate and colon cancer converge to G1/S transition pathway.

Genome-wide association studies (GWASs) identified over 500 single nucleotide polymorphisms (SNPs) influencing cancer risk. It is logical to expect the cancer-associated genes to cluster in pathways directly involved in carcinogenesis, e.g. cell cycle. Nevertheless, analyses of the GWAS-detected cancer risk genes usually show no or weak enrichment by known cancer genes.We hypothesized that GWAS-detected cancer risk-associated genes function as upstream regulators of the genes directly involved in carcinogenesis. We have analyzed four common cancers: breast, colon, lung, and prostate. To identify downstream targets of GWAS-detected cancer risk genes we used MedScan, which is a text mining tool offered by PathwayStudio. We also used data on protein/protein interactions reported by BioGRID database. Among all identified targets we have selected common downstream targets. A gene was considered a common downstream target if it was a downstream target for at least three GWAS-detected genes for a given cancer type. Common downstream targets were identified separately for each cancer type. We found that common downstream targets for all four cancer types were enriched by cell cycle genes, more specifically, the genes involved in G1/S transition. Common downstream targets for bipolar disorder, Crohn's disease, and type 2 diabetes did not show G1/S transition enrichment.The results of this analysis suggest that many cancer risk genes function as upstream regulators of the genes directly involved in G1/S transition and exert their risk effects by reducing threshold for G1/S transition, elevating the background level of cell proliferation and cancer risk.

Transcutaneous oxygen measurement in humans using a paramagnetic skin adhesive film.

PURPOSE: Transcutaneous oxygen tension (TcpO2 ) provides information about blood perfusion in the tissue immediately below the skin. These data are valuable in assessing wound healing problems, diagnosing peripheral vascular/arterial insufficiency, and predicting disease progression or the response to therapy. Currently, TcpO2 is primarily measured using electrochemical skin sensors, which consume oxygen and are prone to calibration errors. The goal of the present study was to develop a reliable method for TcpO2 measurement in human subjects. METHODS: We have developed a novel TcpO2 oximetry method based on electron paramagnetic resonance (EPR) principles with an oxygen-sensing skin adhesive film, named the superficial perfusion oxygen tension (SPOT) chip. The SPOT chip is a 3-mm diameter, 60-µm thick circular film composed of a stable paramagnetic oxygen sensor. The chip is covered with an oxygen-barrier material on one side and secured on the skin by a medical adhesive transfer tape to ensure that only the oxygen that diffuses through the skin surface is measured. The method quantifies TcpO2 through the linewidth of the EPR spectrum. RESULTS: Repeated measurements using a cohort of 10 healthy human subjects showed that the TcpO2 measurements were robust, reliable, and reproducible. The TcpO2 values ranged from 7.8 ± 0.8 to 22.0 ± 1.0 mmHg in the volar forearm skin (N = 29) and 8.1 ± 0.3 to 23.4 ± 1.3 mmHg in the foot (N = 86). CONCLUSIONS: The results demonstrated that the SPOT chip can measure TcpO2 reliably and repeatedly under ambient conditions. The SPOT chip method could potentially be used to monitor TcpO2 in the clinic.

Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer.

Hyperactivation of the PI3K pathway has been implicated in resistance to antiestrogen therapies in estrogen receptor α (ER)-positive breast cancer, prompting the development of therapeutic strategies to inhibit this pathway. Autophagy has tumor-promoting and -suppressing roles and has been broadly implicated in resistance to anticancer therapies, including antiestrogens. Chloroquine (CQ) is an antimalarial and amebicidal drug that inhibits autophagy in mammalian cells and human tumors. Herein, we observed that CQ inhibited proliferation and autophagy in ER+ breast cancer cells. PI3K inhibition with GDC-0941 (pictilisib) induced autophagy. Inhibition of autophagy using CQ or RNA interference potentiated PI3K inhibitor-induced apoptosis. Combined inhibition of PI3K and autophagy effectively induced mitochondrial membrane depolarization, which required the BH3-only proapoptotic proteins Bim and PUMA. Treatment with GDC-0941, CQ, or the combination, significantly suppressed the growth of ER+ breast cancer xenografts in mice. In an antiestrogen-resistant xenograft model, GDC-0941 synergized with CQ to provide partial, but durable, tumor regression. These findings warrant clinical evaluation of therapeutic strategies to target ER, PI3K, and autophagy for the treatment of ER+ breast cancer.-Yang, W., Hosford, S. R., Traphagen, N. A., Shee, K., Demidenko, E., Liu, S., Miller, T. W. Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer.

Technology-assisted nursing for postpartum support: A randomized controlled trial.

AIM: To determine if an electronic nursing intervention during the first 6 months postpartum was effective in improving mood and decreasing stress. BACKGROUND: Unmet needs postpartum can have a negative impact on mood and parenting stress. Technology-assisted nursing care may provide needed support and reduce risk. DESIGN: Randomized controlled trial (RCT) with three conditions. METHODS: Enrollment began on 11 May 2017. Participants were randomized into one of three groups after completion of the baseline survey. Intervention I participants received standardized electronic messages four times/week for 6 months postpartum. Intervention II participants additionally received the option for nurse contact. Depression and parenting stress as measured using the Edinburgh Postnatal Depression Scale (EPDS) and Parenting Stress Index-Short form (PSI-SF) was obtained at 3 weeks, 3 months and 6 months postpartum and results compared with a usual care group. Patient satisfaction and nursing factors were measured. RESULTS: Significantly higher satisfaction scores were found in both intervention groups as compared with control, but there were no significant changes in EPDS or PSI-SF. CONCLUSION: The interventions were perceived as helpful and not burdensome. Better nurse-sensitive outcome measures are needed to adequately assess effectiveness. IMPACT: Postpartum women report unmet needs for support and education. The interventions were perceived as being helpful but did not significantly reduce depressive symptoms or parenting stress. Nurses can use this research to inform development of innovative approaches to support postpartum women. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02843022.

Measuring outcomes of digital technology-assisted nursing postpartum: A randomized controlled trial.

AIM: To determine if delivering electronic messages from nurses during the first 6 months postpartum is feasible, acceptable and effective in improving mood and decreasing parenting stress. BACKGROUND: Competing demands during the postpartum hospitalization make focused time for nurses to provide education and support difficult. Unmet needs following discharge may increase the incidence of postpartum depression. Untreated depression negatively affects families, especially for vulnerable women with limited access to health care. DESIGN: This is a longitudinal cohort study in three phases. Feasibility and acceptability were assessed during Phases 1 & 2. Phase 3 is a randomized controlled trial (RCT) with three conditions. METHODS: This protocol was approved by the Institutional Review Board of the maternity hospital on 12 May 2015 and reviewed annually. Women are enrolled during the maternity hospitalization, after which randomization occurs. The control group receives usual care. Intervention I participants receive a standardized electronic message four times/week for 6 months postpartum. Intervention II participants receive the messages and the option to request a call from a nurse. Electronic surveys at 3 weeks, 3 months and 6 months postpartum measure depressive symptoms using the Edinburgh Postnatal Depression Scale and parenting stress using the Parenting Stress Index-Short form. Patient satisfaction, nursing time and expertise required are also measured. DISCUSSION: Phase 1 and 2 have demonstrated the intervention is feasible and acceptable to women. Phase 3 enrolment is completed, and the last follow-up surveys were emailed to participants in February 2018. Results will help inform efforts to continue nursing care after hospital discharge.

Optimal Adaptive Designs with Inverse Ordinary Differential Equations.

Many industrial and engineering applications are built on the basis of differential equations. In some cases, parameters of these equations are not known and are estimated from measurements leading to an inverse problem. Unlike many other papers, we suggest to construct new designs in the adaptive fashion 'on the go' using the A-optimality criterion. This approach is demonstrated on determination of optimal locations of measurements and temperature sensors in several engineering applications: (1) determination of the optimal location to measure the height of a hanging wire in order to estimate the sagging parameter with minimum variance (toy example), (2) adaptive determination of optimal locations of temperature sensors in a one-dimensional inverse heat transfer problem and (3) adaptive design in the framework of a one-dimensional diffusion problem when the solution is found numerically using the finite difference approach. In all these problems, statistical criteria for parameter identification and optimal design of experiments are applied. Statistical simulations confirm that estimates derived from the adaptive optimal design converge to the true parameter values with minimum sum of variances when the number of measurements increases. We deliberately chose technically uncomplicated industrial problems to transparently introduce principal ideas of statistical adaptive design.

Single toxin dose-response models revisited.

The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of the four models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48h) toxicity tests with mortality as a function of NiCl or CuSO4 toxin.

Leveraging global gene expression patterns to predict expression of unmeasured genes.

BACKGROUND: Large collections of paraffin-embedded tissue represent a rich resource to test hypotheses based on gene expression patterns; however, measurement of genome-wide expression is cost-prohibitive on a large scale. Using the known expression correlation structure within a given disease type (in this case, high grade serous ovarian cancer; HGSC), we sought to identify reduced sets of directly measured (DM) genes which could accurately predict the expression of a maximized number of unmeasured genes. RESULTS: We developed a greedy gene set selection (GGS) algorithm which returns a DM set of user specified size based on a specific correlation threshold (|rP|) and minimum number of DM genes that must be correlated to an unmeasured gene in order to infer the value of the unmeasured gene (redundancy). We evaluated GGS in the Cancer Genome Atlas (TCGA) HGSC data across 144 combinations of DM size, redundancy (1-3), and |rP| (0.60, 0.65, 0.70). Across the parameter sweep, GGS allows on average 9 times more gene expression information to be captured compared to the DM set alone. GGS successfully augments prognostic HGSC gene sets; the addition of 20 GGS selected genes more than doubles the number of genes whose expression is predictable. Moreover, the expression prediction is highly accurate. After training regression models for the predictable gene set using 2/3 of the TCGA data, the average accuracy (ranked correlation of true and predicted values) in the 1/3 testing partition and four independent populations is above 0.65 and approaches 0.8 for conservative parameter sets. We observe similar accuracies in the TCGA HGSC RNA-sequencing data. Specifically, the prediction accuracy increases with increasing redundancy and increasing |rP|. CONCLUSIONS: GGS-selected genes, which maximize expression information about unmeasured genes, can be combined with candidate gene sets as a cost effective way to increase the amount of gene expression information obtained in large studies. This method can be applied to any organism, model system, disease, or tissue type for which whole genome gene expression data exists.

Local hyperthermia treatment of tumors induces CD8(+) T cell-mediated resistance against distal and secondary tumors.

Combinatorial use of iron oxide nanoparticles (IONPs) and an alternating magnetic field (AMF) can induce local hyperthermia in tumors in a controlled and uniform manner. Heating B16 primary tumors at 43°C for 30 min activated dendritic cells (DCs) and subsequently CD8(+) T cells in the draining lymph node (dLN) and conferred resistance against rechallenge with B16 (but not unrelated Lewis Lung carcinoma) given 7 days post hyperthermia on both the primary tumor side and the contralateral side in a CD8(+) T cell-dependent manner. Mice with heated primary tumors also resisted rechallenge given 30 days post hyperthermia. Mice with larger heated primary tumors had greater resistance to secondary tumors. No rechallenge resistance occurred when tumors were heated at 45°C. Our results demonstrate the promising potential of local hyperthermia treatment applied to identified tumors in inducing anti-tumor immune responses that reduce the risk of recurrence and metastasis. FROM THE CLINICAL EDITOR: Local heating of tumors via iron oxide NPs and an alternating magnetic field led to activation of anti-cancer CD8 T cells, which resulted in resistance against re-challenge and greater resistance to secondary tumors. Similar local heating-based strategies may become an important weapon in enhancing tumor elimination via a naturally existing but attenuated immune response.

Differential Toxicity of Arsenic in Daphnia pulex Under Phosphorus and Food Limitation.

The on-going anthropogenic degradation of freshwater habitats has drastically altered the environmental supply of both nutrients and common pollutants. Most organisms living in these altered habitats experience interactive effects of various stressors that can initiate adjustments at multiple levels impacting their fitness. Hence, studies measuring response to a single environmental parameter fail to capture the complexities of the status quo. We tested both the individual and the interactive effect of arsenic (As) exposure, food quantity, and dietary phosphorus (P)-supply on six life-history traits (Juvenile Growth Rate; Adult Growth Rate; Age and Size at Maturity, Lifespan, and Fecundity) as surrogates for organismal fitness in the keystone aquatic grazer Daphnia pulex. We also tested the effect of food quantity and P-supply on somatic As accumulation in Daphnia. Our results indicated an influence of P-supply on neonatal growth and an influence of As and food quantity on growth and maintenance later in life. Maturation was strongly influenced by all three variables, with no reproduction observed in the presence of two or more environmental stressors. We found a strong interaction between As and dietary P, with increased P-supply intensifing the toxicity effect of As. No such effects were seen between As and food quantity, indicating a differential role of quantity versus quality on As toxicity. We found a nominal effect of diet on somatic As accumulation. The results from the present study emphasize the importance of considering such interactions between co-occurring environmental stressors and the dietary status of organisms, to better predict and manage impacts and risks associated with common environmental toxicants in highly vulnerable ecosystems. Environ Toxicol Chem 2024;00:1-13. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Does ROSE matter? Evaluation of final diagnostic, PD-L1 immunohistochemistry, and molecular testing yields of CT-guided lung biopsies performed before and after the onset of the COVID-19 pandemic.

INTRODUCTION: The onset of the COVID-19 pandemic, with urgent implementation of safety protocols limiting the number of on-site personnel, essentially terminated the use of rapid on-site evaluation (ROSE) for computed tomography (CT)--guided lung biopsies at our institution. The diminished use of ROSE during the pandemic prompted us to reevaluate the potential value of ROSE for CT-guided lung biopsies. MATERIALS AND METHODS: We retrospectively identified all CT-guided lung biopsies from 2017 to 2022. Associations between the use of ROSE, adequate diagnostic and ancillary testing (programmed death-ligand 1 immunohistochemistry and next-generation sequencing) outcomes, and other factors such as the number of passes performed and lesion size, were evaluated. RESULTS: Nine hundred twelve CT-guided lung biopsies were performed from 2017 to 2022; 171 (19%) utilized ROSE. The use of ROSE had been steadily decreasing prior to the pandemic but was essentially eliminated with the onset of the pandemic. By univariable analysis, the employment of ROSE was more likely to be associated with an adequate final diagnosis (odds ratio = 2.14, 95% confidence interval: [1.24-3.70], P = 0.006) and successful molecular testing (odds ratio = 2.16, 95% confidence interval: [1.11-4.21], P = 0.024). However, those associations were not present in multivariable analyses that incorporated the number of passes performed or lesion size. There were no differences in diagnostic adequacy or ancillary testing yields when comparing the periods 2017-2019 and 2020-2022, despite declining use of ROSE. CONCLUSIONS: If ROSE is not requested for CT-guided lung biopsies, proceduralists should err on the side of performing more, rather than fewer, passes, particularly for smaller lesions.

Cutaneous alpha, beta and gamma human papillomaviruses in relation to squamous cell carcinoma of the skin: a population-based study.

Human papillomavirus (HPV) infection is common worldwide and, in immunodeficient populations, may contribute to the pathogenesis of keratinocyte cancers, particularly squamous cell carcinomas (SCC). However, their role in SCC in the general population is less clear. We conducted a comprehensive analysis to investigate the independent effects of seropositivity for cutaneous alpha, beta and gamma HPV types on risk of SCC, and a meta-analysis of the available literature. In a population-based case-control study from New Hampshire, USA (n = 1,408), histologically confirmed SCC cases and controls were tested for L1 antibodies to alpha, beta and gamma cutaneous HPV types 2-5, 7-10, 15, 17, 20, 23, 24, 27b, 36, 38, 48-50, 57, 65, 75-77, 88, 92, 95, 96, 101, 103 and 107 using multiplex serology. An increasing risk of SCC with number of beta HPVs to which an individual tested positive was observed even among those seronegative for gamma types (p for trend = 0.016) with an odds ratio of 1.95 (95% confidence interval (CI) = 1.07-3.56) for four or more beta types positive. In a meta-analysis of six case-control studies, increased SCC risks in relation to beta HPV seropositivity were found across studies (meta odds ratio = 1.45, CI = 1.27-1.66). While the prevalence of gamma HPVs assayed was somewhat higher among SCC cases than controls, the association was only weakly evident among those seronegative for beta HPVs. Overall, the association between cutaneous HPVs and skin cancers appears to be specific to SCC and to genus beta HPVs in a general US population.

Standard error of inverse prediction for dose-response relationship: approximate and exact statistical inference.

This paper develops a new metric, the standard error of inverse prediction (SEIP), for a dose-response relationship (calibration curve) when dose is estimated from response via inverse regression. SEIP can be viewed as a generalization of the coefficient of variation to regression problem when x is predicted using y-value. We employ nonstandard statistical methods to treat the inverse prediction, which has an infinite mean and variance due to the presence of a normally distributed variable in the denominator. We develop confidence intervals and hypothesis testing for SEIP on the basis of the normal approximation and using the exact statistical inference based on the noncentral t-distribution. We derive the power functions for both approaches and test them via statistical simulations. The theoretical SEIP, as the ratio of the regression standard error to the slope, is viewed as reciprocal of the signal-to-noise ratio, a popular measure of signal processing. The SEIP, as a figure of merit for inverse prediction, can be used for comparison of calibration curves with different dependent variables and slopes. We illustrate our theory with electron paramagnetic resonance tooth dosimetry for a rapid estimation of the radiation dose received in the event of nuclear terrorism.

In utero arsenic exposure and early childhood motor development in the New Hampshire Birth Cohort Study.

Introduction: High-level prenatal and childhood arsenic (As) exposure characteristic of several regions in Asia (e.g., Bangladesh), may impact motor function. However, the relationship between lower-level arsenic exposure (characteristic of other regions) and motor development is largely unstudied, despite the potential for deficient motor skills in childhood to have adverse long-term consequences. Thus, we sought to investigate the association between prenatal As exposure and motor function among 395 children in the New Hampshire Birth Cohort Study, a rural cohort from northern New England. Methods: Prenatal exposure was estimated by measuring maternal urine speciated As at 24-28 weeks of gestation using high-performance liquid chromatography (HPLC) inductively coupled plasma mass spectrometry (ICP-MS) and summing inorganic As, monomethylarsonic acid, and dimethylarsinic acid to obtain total urinary As (tAs). Motor function was assessed with the Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2) at a mean (SD) age of 5.5 (0.4) years. Results: Children who completed this exam were largely reported as white race (97%), born to married mothers (86%) with a college degree or higher (67%). The median (IQR) gestational urine tAs concentration was 4.0 (5.0) µg/L. Mean (SD) BOT-2 scores were 48.6 (8.4) for overall motor proficiency and 48.2 (9.6) for fine manual control [standard score = 50 (10)], and were 16.3 (5.1) for fine motor integration and 12.5 (4.1) for fine motor precision [standard score = 15 (5)]. We found evidence of a non-linear dose response relationship and used a change-point model to assess the association of tAs with overall motor proficiency and indices of fine motor integration, fine motor precision, and their composite, fine manual control, adjusted for age and sex. In models adjusted for potential confounders, each doubling of urine tAs decreased overall motor proficiency by -3.3 points (95% CI: -6.1, -0.4) for tAs concentrations greater than the change point of 9.5 µg/L and decreased fine motor integration by -4.3 points (95% CI: -8.0, -0.6) for tAs concentrations greater than the change point of 17.0 µg/L. Discussion: In summary, we found that levels of prenatal As exposure above an empirically-derived threshold (i.e., the change point) were associated with decrements in childhood motor development in a US population.

Alternating 17ß-Estradiol and Aromatase Inhibitor Therapies Is Efficacious in Postmenopausal Women with Advanced Endocrine-Resistant ER+ Breast Cancer.

PURPOSE: Strategies to implement estrogen therapy for advanced estrogen receptor-positive (ER+) breast cancer are underdeveloped. Preclinical data suggest that cycling treatment with 17ß-estradiol followed by estrogen deprivation can control tumor growth long-term. PATIENTS AND METHODS: Postmenopausal women with advanced ER+/HER2- breast cancer with recurrence or progression on ≥ 1 antiestrogen or aromatase inhibitor (AI)-based therapy were eligible. Patients received 17ß-estradiol (2 mg orally, three times a day) for 8 weeks followed by AI (physician's choice) for 16 weeks, alternating treatments on an 8-week/16-week schedule until disease progression. Patients then optionally received continuous single-agent treatment until a second instance of disease progression. Endpoints included 24-week clinical benefit and objective response per RECIST, and tumor genetic alterations. RESULTS: Of 19 evaluable patients, clinical benefit rate was 42.1% [95% confidence interval (CI), 23.1%-63.9%] and objective response rate (ORR) was 15.8% (95% CI, 5.7%-37.9%). One patient experienced a grade 3 adverse event related to 17ß-estradiol. Among patients who received continuous single-agent treatment until a second instance of disease progression, clinical benefit was observed in 5 of 12 (41.7%) cases. Tumor ER (ESR1) mutations were found by whole-exome profiling in 4 of 7 (57.1%) versus 2 of 9 (22.2%) patients who did versus did not experience clinical benefit from alternating 17ß-estradiol/AI therapy. The only two patients to experience objective responses to initial 17ß-estradiol had tumor ESR1 mutations. CONCLUSIONS: Alternating 17ß-estradiol/AI therapy may be a promising treatment for endocrine-refractory ER+ breast cancer, including following progression on CDK4/6 inhibitors or everolimus. Further study is warranted to determine whether the antitumor activity of 17ß-estradiol differs according to ESR1 mutation status.