Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial.

BACKGROUND: Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH-) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH- was combined with temozolomide and radiotherapy. As P-AscH- relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH- therapy in glioblastoma participants. METHODS: Participants (n = 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory. RESULTS: Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival. CONCLUSIONS: This study analyzes iron-related biomarkers in the context of P-AscH- therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.

HIGHLIGHTS: Pharmacological ascorbate shows significant promise to enhance glioblastoma clinical outcomes. Transferrin receptor and ferritin heavy chain expression represent potential molecular markers to predict pharmacological ascorbate treatment response. Quantitative Susceptibility Mapping is an MRI technique that can serve as a non-invasive marker of iron metabolism to evaluate progression-free survival. Systemic iron metabolic markers are readily available diagnostic tests that can potentially be used to prognosticate overall survival.

UK B.1.1.7 variant exhibits increased respiratory replication and shedding in nonhuman primates.

The continuing emergence of SARS-CoV-2 variants calls for regular assessment to identify differences in viral replication, shedding and associated disease. In this study, African green monkeys were infected intranasally with either a contemporary D614G or the UK B.1.1.7 variant. Both variants caused mild respiratory disease with no significant differences in clinical presentation. Significantly higher levels of viral RNA and infectious virus were found in upper and lower respiratory tract samples and tissues from B.1.1.7 infected animals. Interestingly, D614G infected animals showed significantly higher levels of viral RNA and infectious virus in rectal swabs and gastrointestinal tract tissues. Our results indicate that B.1.1.7 infection in African green monkeys is associated with increased respiratory replication and shedding but no disease enhancement similar to human B.1.1.7 cases. ONE-SENTENCE SUMMARY: UK B.1.1.7 infection of African green monkeys exhibits increased respiratory replication and shedding but no disease enhancement.

Gaussian versus Non-Gaussian Filtering of Phase-Insensitive Nonclassicality.

Measures of quantum properties are essential to understanding the fundamental differences between quantum and classical systems as well as quantifying resources for quantum technologies. Here, two broad classes of bosonic phase-space functions, which are filtered versions of the Glauber-Sudarshan P function, are compared with regard to their ability to uncover nonclassical effects of light through their negativities. Gaussian filtering of the P function yields the family of s-parametrized quasiprobabilities, while more powerful regularized nonclassicality quasiprobabilities are obtained by non-Gaussian filtering. A method is proposed to directly sample such phase-space functions for the restricted case of phase-independent quantum states from balanced homodyne measurements. This overcomes difficulties of previous approaches that manually append uniformly distributed optical phases to the measured quadrature data. We experimentally demonstrate this technique for heralded single- and two-photon states using balanced homodyne detection with varying efficiency. The s-parametrized quasiprobabilities, which can be directly sampled, are non-negative for detection efficiencies below 0.5. By contrast, we show that significant negativities of non-Gaussian filtered quasiprobabilities uncover nonclassical effects for arbitrarily low efficiencies.

The Funding, Administrative, and Policy Influences on the Evaluation of Primary Prevention Programs in Australia.

Evaluation of primary prevention and health promotion programs contributes necessary information to the evidence base for prevention programs. There is increasing demand for high-quality evaluation of program impact and effectiveness for use in public health decision making. Despite the demand for evidence and known benefits, evaluation of prevention programs can be challenging and organizations face barriers to conducting rigorous evaluation. Evaluation capacity building efforts are gaining attention in the prevention field; however, there is limited knowledge about how components of the health promotion and primary prevention system (e.g., funding, administrative arrangements, and the policy environment) may facilitate or hinder this work. We sought to identify the important influences on evaluation practice within the Australian primary prevention and health promotion system. We conducted in-depth semi-structured interviews with experienced practitioners and managers (n = 40) from government and non-government organizations, and used thematic analysis to identify the main factors that impact on prevention program evaluation. Firstly, accountability and reporting requirements impacted on evaluation, especially if expectations were poorly aligned between the funding body and prevention organization. Secondly, the funding and political context was found to directly and indirectly affect the resources available and evaluation approach. Finally, it was found that participants made use of various strategies to modify the prevention system for more favorable conditions for evaluation. We highlight the opportunities to address barriers to evaluation in the prevention system, and argue that through targeted investment, there is potential for widespread gain through improved evaluation capacity.

The scaling or ontogeny of human gait kinetics and walk-run transition: The implications of work vs. peak power minimization.

A simple model is developed to find vertical force profiles and stance durations that minimize either limb mechanical work or peak power demands during bipedal locomotion. The model predicts that work minimization is achieved with a symmetrical vertical force profile, consistent with previous models and observations of adult humans, and data for 487 participants (predominantly 11-18 years old) required to walk at a range of speeds at a Science Fair. Work minimization also predicts the discrete walk-run transition, familiar for adult humans. In contrast, modeled peak limb mechanical power demands are minimized with an early skew in vertical ground reaction force that increases with speed, and stance durations that decrease steadily with speed across the work minimizing walk-run transition speed. The peak power minimization model therefore predicts a continuous walk-run gait transition that is quantitatively consistent with measurements of younger children (1.1-4.7 years) required to locomote at a range of speeds but free to select their own gaits.

Relationship of American Indian blood quantum with osteoporosis risk: a cross-sectional study of American Indian women in Oklahoma.

Information regarding the prevalence and risk of osteoporosis among American Indian (AI) women is limited. This study showed that with increasing AI blood quantum, the prevalence of osteoporosis at the hip based on BMD T-scores decreased and this appeared to be independent of other risk factors. INTRODUCTION: This study was designed to investigate the effects of AI blood quantum (BQ) on osteoporosis prevalence and risk in a cohort of AI women in Oklahoma. METHODS: Women (n = 301), aged 50 years and older, were recruited to participate in the Oklahoma American Indian Women's Osteoporosis Study. Baseline bone density, fracture history, bone biochemical markers, and potential risk factors were assessed. Participants were stratified by AI BQ into BQ1 ≤ 25%, BQ2 = 25-49%, BQ3 = 50-74%, and BQ4 = 75-100%. The effects of BQ on the prevalence and risk of osteoporosis were evaluated. RESULTS: Based on T-scores, one in approximately eight women in the study was osteoporotic at one or more sites. The prevalence of osteoporosis decreased (p < 0.05) with increasing BQ, especially at the hip, trochanteric, and intertrochanter regions. No differences in bone-specific alkaline phosphatase and C-telopeptide were observed across BQ that could account for the differences in bone density. 25-OH vitamin D decreased with increasing BQ, but mean for each BQ1-4 was > 40 ng/mL. Fracture history did not differ across BQ, and though 52% of the population consumed less than the RDA for calcium, no effect of BQ was observed. CONCLUSIONS: In this cohort of women who identified as AI, greater Indian BQ was associated with a decrease in the prevalence of osteoporosis.

Organizational determinants of evaluation practice in Australian prevention agencies.

Program evaluation is essential to inform decision making, contribute to the evidence base for strategies, and facilitate learning in health promotion and disease prevention organizations. Theoretical frameworks of organizational learning, and studies of evaluation capacity building describe the organization as central to evaluation capacity. Australian prevention organizations recognize limitations to current evaluation effectiveness and are seeking guidance to build evaluation capacity. This qualitative study identifies organizational facilitators and barriers to evaluation practice, and explores their interactions in Australian prevention organizations. We conducted semi-structured interviews with 40 experienced practitioners from government and non-government organizations. Using thematic analysis, we identified seven key themes that influence evaluation practice: leadership, organizational culture, organizational systems and structures, partnerships, resources, workforce development and training and recruitment and skills mix. We found organizational determinants of evaluation to have multi-level interactions. Leadership and organizational culture influenced organizational systems, resource allocation and support of staff. Partnerships were important to overcome resource deficits, and systems were critical to embed evaluation within the organization. Organizational factors also influenced the opportunities for staff to develop skills and confidence. We argue that investment to improve these factors would allow organizations to address evaluation capacity at multiple levels, and ultimately facilitate effective evaluation practice.

Erythritol and Lufenuron Detrimentally Alter Age Structure of Wild Drosophila suzukii (Diptera: Drosophilidae) Populations in Blueberry and Blackberry.

We report on the efficacy of 0.5 M (61,000 ppm) erythritol (E) in Truvia Baking Blend, 10 ppm lufenuron (L), and their combination (LE) to reduce egg and larval densities of wild populations of Drosophila suzukii (Matsumura) infesting fields of rabbiteye blueberries (Vaccinium virgatum) and blackberries (Rubus sp.). Formulations included the active ingredients (lufenuron, erythritol, or both), sugar (in control and erythritol treatments), and Dawn hand-soap applied to plants with pressurized 3-gallon garden spray tanks. The three chemical treatments (E, L, and LE) had no effect on D. suzukii ovipositing in blackberry and blueberry fruit, but they did reduce larval infestation by 75%, particularly densities of first and second instars. Erythritol and lufenuron were equally efficacious compounds as a D. suzukii ovicide and larvicide, but they did not display additive or synergistic activity. Extremely high larval mortality in control fruits show an age structure heavily skewed toward egg output.

Impaired glucose tolerance attenuates bone accrual by promoting the maturation of osteoblasts: Role of Beclin1-mediated autophagy.

Patients with type 2 diabetes mellitus (T2DM) experience a 1.5-3.5 fold increase in fracture risk, but the mechanisms responsible for these alterations in bone biomechanical properties remain elusive. Macroautophagy, often referred to as autophagy, is regulated by signaling downstream of the insulin receptor. Metabolic changes associated with the progression of glucose intolerance have been shown to alter autophagy in various tissues, but limited information is available in relation to bone cells. The aim of this study was to (a) investigate whether autophagy is altered in bone tissue during impaired glucose tolerance, and (b) determine how autophagy impacts osteoblast differentiation, activity, and maturation. Four-week-old, male C57BL/6 mice were fed a control (Con) or high fat (HF) diet for 2, 8, or 16 wks. Mice on the HF diet demonstrated elevated fasting blood glucose and impaired glucose tolerance. Reduced trabecular bone in the femoral neck was evident in the mice on the HF diet by 8 wks compared to Con mice. Histological evaluation of the tibia suggested that the high fat diet promoted terminal differentiation of the osteoblast to an osteocyte. This shift of the osteoblasts towards a non-mineralizing, osteocyte phenotype appears to be coordinated by Beclin1-mediated autophagy. Consistent with these changes in the osteoblast in vivo, the induction of autophagy was able to direct MC3T3-E1 cells towards a more mature osteoblast phenotype. Although these data are somewhat observational, further investigation is warranted to determine if Beclin1-mediated autophagy is essential for the terminal differentiation of the osteoblasts and whether autophagy is having a protective or deleterious effect on bone in T2DM.

Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains.

Bak and Bax mediate apoptotic cell death by oligomerizing and forming a pore in the mitochondrial outer membrane. Both proteins anchor to the outer membrane via a C-terminal transmembrane domain, although its topology within the apoptotic pore is not known. Cysteine-scanning mutagenesis and hydrophilic labeling confirmed that in healthy mitochondria the Bak α9 segment traverses the outer membrane, with 11 central residues shielded from labeling. After pore formation those residues remained shielded, indicating that α9 does not line a pore. Bak (and Bax) activation allowed linkage of α9 to neighboring α9 segments, identifying an α9:α9 interface in Bak (and Bax) oligomers. Although the linkage pattern along α9 indicated a preferred packing surface, there was no evidence of a dimerization motif. Rather, the interface was invoked in part by Bak conformation change and in part by BH3:groove dimerization. The α9:α9 interaction may constitute a secondary interface in Bak oligomers, as it could link BH3:groove dimers to high-order oligomers. Moreover, as high-order oligomers were generated when α9:α9 linkage in the membrane was combined with α6:α6 linkage on the membrane surface, the α6-α9 region in oligomerized Bak is flexible. These findings provide the first view of Bak carboxy terminus (C terminus) membrane topology within the apoptotic pore.

Bioavailability of pollutants in bacterial communities of Rodrigo de Freitas Lagoon, Rio de Janeiro, Brazil.

Processes involving heavy metals and other contaminants continue to present unsolved environmental questions. To advance the understanding of geochemical processes that involve the bioavailability of contaminants, cores where collected in the Rodrigo de Freitas lagoon, and analyzed for bacterial activity and metal concentrations. Results would suggest an extremely reducing environment where organic substances seem to be the predominant agents responsible for this geochemical process. Analytical data showed sulphate reduction to be the main agent driving this process, since this kind of bacteria was found to be active in all of the samples analyzed. Esterase enzyme production did not signal the influence of heavy metals and hydrocarbon concentrations and heavy metals were found to be unavailable for biota. However, correlation between results for bacterial biomass and the potentially mobile percentage of the total Ni concentrations would suggest a negative impact.

Nonclassical light manipulation in a multiple-scattering medium.

We investigate the possibility of using a scattering medium as a highly multimode platform for implementing quantum walks. We demonstrate the manipulation of a single photon propagating through a strongly scattering medium using wavefront-shaping technique. Measurement of the scattering matrix allows the wavefront of the photon to be shaped to compensate the distortions induced by multiple scattering events. The photon can thus be directed coherently to a specific output mode. Using this approach, we show how entanglement of a single photon across different modes can be manipulated despite the enormous wavefront disturbance caused by the scattering medium.

Bioavailability of pollutants in bacterial communities of Rodrigo de Freitas Lagoon, Rio de Janeiro, Brazil

Processes involving heavy metals and other contaminants continue to present unsolved environmental questions. To advance the understanding of geochemical processes that involve the bioavailability of contaminants, cores where collected in the Rodrigo de Freitas lagoon, and analyzed for bacterial activity and metal concentrations. Results would suggest an extremely reducing environment where organic substances seem to be the predominant agents responsible for this geochemical process. Analytical data showed sulphate reduction to be the main agent driving this process, since this kind of bacteria was found to be active in all of the samples analyzed. Esterase enzyme production did not signal the influence of heavy metals and hydrocarbon concentrations and heavy metals were found to be unavailable for biota. However, correlation between results for bacterial biomass and the potentially mobile percentage of the total Ni concentrations would suggest a negative impact.

Plasmid CDS5 influences infectivity and virulence in a mouse model of Chlamydia trachomatis urogenital infection.

The native plasmid of both Chlamydia muridarum and Chlamydia trachomatis has been shown to control virulence and infectivity in mice and in lower primates. We recently described the development of a plasmid-based genetic transformation protocol for Chlamydia trachomatis that for the first time provides a platform for the molecular dissection of the function of the chlamydial plasmid and its individual genes or coding sequences (CDS). In the present study, we transformed a plasmid-free lymphogranuloma venereum isolate of C. trachomatis, serovar L2, with either the original shuttle vector (pGFP::SW2) or a derivative of pGFP::SW2 carrying a deletion of the plasmid CDS5 gene (pCDS5KO). Female mice were inoculated with these strains either intravaginally or transcervically. We found that transformation of the plasmid-free isolate with the intact pGFP::SW2 vector significantly enhanced infectivity and induction of host inflammatory responses compared to the plasmid-free parental isolate. Transformation with pCDS5KO resulted in infection courses and inflammatory responses not significantly different from those observed in mice infected with the plasmid-free isolate. These results indicate a critical role of plasmid CDS5 in in vivo fitness and in induction of inflammatory responses. To our knowledge, these are the first in vivo observations ascribing infectivity and virulence to a specific plasmid gene.

Factors affecting surgical results of Wassel type IV thumb duplications.

The aim of this study is to review the outcomes of Wassel type IV thumb duplications with a minimum of one year follow-up, and to identify any factors that may compromise the quality of results. Forty one patients (42 thumbs) returned for assessment of thumb alignment, metacarpophalangeal joint and interphalangeal joint stability and motion; carpometacarpal joint motion; pinch and grip strengths; and thumb size. The subjective assessment considered thumb shape and contour, scarring, nail deformity and examiner and patient/parent satisfaction. The mean age at surgery was 16 months and the mean follow-up time was 79 months. Metacarpophalangeal joint and interphalangeal joint mal-alignment was present in 56% and 38% of cases, respectively. Interphalangeal ulnar collateral ligament laxity was significant. Metacarpophalangeal joint and interphalangeal joint motion was significantly decreased. Pinch and grip strength measurements were normal. A novel and comprehensive assessment scale is introduced, which revealed results of one (2.5%) excellent, 23 (59%) good, 14 (36%) fair and one (2.5%) poor. We consider that greater attention should be directed to the avoidance of mal-alignment and instability to improve these results.

Effects of dried plum supplementation on bone metabolism in adult C57BL/6 male mice.

Dietary supplementation of dried plum (DP) prevents bone loss and restores bone mass in osteopenic animal models. This study was designed to determine the effects of DP supplementation on bone metabolic activity over time using adult (6-month-old) male C57BL/6 mice (n = 40) receiving control (CON = AIN93 M) or CON+DP 25 % (w/w) diets for 4 or 12 weeks. After 4 weeks of treatment, animals consuming the DP diet had a higher whole-body bone mineral density, vertebral trabecular bone volume (BV/TV), and femoral cortical thickness compared to the CON animals. In the distal metaphysis of the femur, BV/TV was increased in the DP-treated animals, but only after 12 weeks. Bone histomorphometric analyses revealed that DP decreased osteoblast surface (67 %) and osteoclast surface (62 %) at 4 weeks, but these surfaces normalized to the CON animals by 12 weeks. Coincident with these changes, the mineralizing surface (MS/BS) and cancellous bone formation rate (BFR/BS) were reduced at 4 weeks in the DP group compared to the CON, but by 12 weeks of DP supplementation, BFR/BS (~twofold) and MS/BS (~1.7-fold) tended to be increased (p < 0.10). The relative abundance of RNA for key regulators of osteoblast and osteoclast differentiation and indicators of osteoblast activity were reduced in the DP group at 4 weeks with no difference between groups at 12 weeks. These results indicate that supplementing the diet with DP initially suppressed cancellous bone turnover, but a biphasic response occurs over time, resulting in a positive effect on bone mass and structure.

Large-alphabet time-frequency entangled quantum key distribution by means of time-to-frequency conversion.

We introduce a novel time-frequency quantum key distribution (TFQKD) scheme based on photon pairs entangled in these two conjugate degrees of freedom. The scheme uses spectral detection and phase modulation to enable measurements in the temporal basis by means of time-to-frequency conversion. This allows large-alphabet encoding to be implemented with realistic components. A general security analysis for TFQKD with binned measurements reveals a close connection with finite-dimensional QKD protocols and enables analysis of the effects of dark counts on the secure key size.

Sharing milk but not messages: campylobacteriosis associated with consumption of raw milk from a cow-share program in Alaska, 2011.

Alaska public and environmental health authorities investigated a cluster of campylobacteriosis cases among people who had consumed raw, unpasteurized milk obtained from a cow-share program in Alaska. Although raw milk is not permitted by law to be offered commercially, consumers can enter into cow-share agreements whereby they contribute funds for the upkeep of cows and in turn receive a share of the milk for their personal use. Laboratory testing of stool specimens collected from ill persons and from cows on the farm revealed an indistinguishable strain of Campylobacter. In this outbreak, numerous confirmed and suspected cases were not among cow shareholders; therefore, these individuals had not been advised of the potential health hazards associated with consumption of raw milk nor were they informed of the outbreak developments.

A randomized trial of decision-making in asymptomatic carotid stenosis.

OBJECTIVE: We sought to evaluate whether different presentation formats, presenter characteristics, and patient characteristics affect decision-making in asymptomatic carotid stenosis. METHODS: Subjects included individuals presenting to a neurology clinic. Participants included those over age 18 without known carotid stenosis. Subjects were randomized to a 30-second video with 1 of 5 presentation formats (absolute risk, absolute event-free survival, annualized absolute risk, relative risk, and a qualitative description) delivered by 1 of 4 presenter physicians (black woman, white woman, black man, white man). Subjects then completed a one-page form regarding background demographics and their decision regarding treatment choice. RESULTS: A total of 409 subjects watched the video and completed the survey. Overall, 48.4% of subjects chose surgery. Presentation format strongly predicted choice of surgery (qualitative [64%], relative risk [63%], absolute risk [43%], absolute event-free survival [37%], and annualized absolute risk [35%], p < 0.001). There was a trend for younger age (mean age 52 vs 55, p = 0.054), male gender (53% vs 45%, p = 0.08), and advanced education (42% for high school education or less vs 52% for more than high school education, p = 0.052) to predict surgery choice. Gender and race of presenter, and race of subject, had no influence on the choice of treatment. CONCLUSIONS: Presentation format (information framing) strongly determines patient decision-making in asymptomatic carotid stenosis. Subject age, gender, and education level may also influence the decision. Clinicians should consider the influence of these variables when counseling patients.

Development of a method to produce hemoglobin in a bioreactor culture of Escherichia coli BL21(DE3) transformed with a plasmid containing Plesiomonas shigelloides heme transport genes and modified human hemoglobin genes.

We describe a method for production of recombinant human hemoglobin by Escherichia coli grown in a bioreactor. E. coli BL21(DE3) transformed with a plasmid containing hemoglobin genes and Plesiomonas shigelloides heme transport genes reached a cell dry weight of 83.64 g/liter and produced 11.92 g/liter of hemoglobin in clarified lysates.