Perspective: Food Access at Dollar Stores and its Implications for Public Health: Report of a Workshop on Identifying Research Priorities.

The rapid growth of dollar stores as retail sources of food in the United States is a phenomenon with implications for diets, nutrition, and well-being. We convened a broadly interdisciplinary group of researchers and experts from government and academia at the 2-day Food Access at Dollar Stores (FADS) workshop, held in Boston, MA in 2022. The event brought together economists, social scientists, public health researchers and advocates to discuss the concerns and research questions raised by the growth of dollar stores, and their increased role in food retail and access. In-person, moderated discussions on day two of the workshop generated a range of topics considered important for future research. A subsequent survey, using a modified Delphi approach, identified priority research areas. Nine research area categories emerged as a result of discussion at the FADS workshop and received prioritization from the experts: Local Community Impacts; Health and Nutrition Impacts; Policy and Programs; Systemic Issues - Racism, Poverty, and Food Access; Store Offerings and Locations; Shoppers and Customers; Employees and Employment; Corporate Distribution, Strategy, and Marketing; and Dollar Stores vs. Other Food Sources. The growth of dollar stores as food retailers remains an under-researched area of study for food access and nutrition that requires interdisciplinary expertise and collaboration to understand. STATEMENT OF SIGNIFICANCE: Dollar stores have grown rapidly as food retailers in the United States over the past decade. This work reports the findings of a research workshop and provides a roadmap for prioritizing research topics and tools related to understanding the public health, equity and economic impacts of this important change in how many consumers are accessing food.

The Impact of Colleague Peer Review on the Radiotherapy Treatment Planning Process in the Radical Treatment of Lung Cancer.

AIMS: Modern radiotherapy uses techniques to reliably identify tumour and reduce target volume margins. However, this can potentially lead to an increased risk of geographic miss. One source of error is the accuracy of target volume delineation (TVD). Colleague peer review (CPR) of all curative-intent lung cancer plans has been mandatory in our institution since May 2013. At least two clinical oncologists review plans, checking treatment paradigm, TVD, prescription dose tumour and critical organ tolerances. We report the impact of CPR in our institution. MATERIALS AND METHODS: Radiotherapy treatment plans of all patients receiving radical radiotherapy were presented at weekly CPR meetings after their target volumes were reviewed and signed off by the treating consultant. All cases and any resultant change to TVD (including organs at risk) or treatment intent were recorded in our prospective CPR database. The impact of CPR over a 13 month period from May 2013 to June 2014 is reported. RESULTS: One hundred and twenty-two patients (63% non-small cell lung carcinoma, 17% small cell lung carcinoma and 20% 'clinical diagnosis') were analysed. On average, 3.2 cases were discussed per meeting (range 1-8). CPR resulted in a change in treatment paradigm in 3% (one patient proceeded to induction chemotherapy, two patients had high-dose palliative radiotherapy). Twenty-one (17%) had a change in TVD and one (1%) patient had a change in dose prescription. In total, 6% of patients had plan adjustment after review of dose volume histogram. CONCLUSION: The introduction of CPR in our centre has resulted in a change in a component of the treatment plan for 27% of patients receiving curative-intent lung radiotherapy. We recommend CPR as a mandatory quality assurance step in the planning process of all radical lung plans.

Disrupted brain thyroid hormone homeostasis and altered thyroid hormone-dependent brain gene expression in autism spectrum disorders.

The present study examined human postmortem brains for changes consistent with the hypothesis of local brain TH deficiency in autism spectrum disorders (ASD). Brain levels of oxidative stress marker - 3-nitrotyrosine (3-NT), iodothyronine deiodinase type 2(D2) and type 3 (D3), 3',3,5-triiodothyronine (T3) content, mercury content and gene expression levels were analyzed and compared in the several regions of postmortem brains derived from both male and female control and ASD cases, age 4-16 years. We report that some parameters measured, such as D2 are subject to rapid postmortem inactivation, while others that were analyzed showed both brain region- and sex-dependent changes. Levels of 3-NT were overall increased, T3 was decreased in the cortical regions of ASD brains, while mercury levels measured only in the extracortical regions were not different. The expression of several thyroid hormone (TH)-dependent genes was altered in ASD. Data reported here suggest the possibility of brain region-specific disruption of TH homeostasis and gene expression in autism.

Regulation of the activation of the Fanconi anemia pathway by the p21 cyclin-dependent kinase inhibitor.

Fanconi anemia (FA) is a rare disease characterized by congenital defects, progressive bone marrow failure and heightened cancer susceptibility. The FA proteins, BRCA1 and FANCD1/BRCA2 function cooperatively in the FA-BRCA pathway to repair damaged DNA. Activation of the FA-BRCA pathway occurs via the monoubiquitination of the FANCD2 and FANCI proteins, targeting these proteins to discrete nuclear foci where they function in DNA repair. The cellular regulation of FANCD2/I monoubiquitination, however, remains poorly understood. In this study, we have examined the roles of the p53 tumor suppressor protein, as well as its downstream target, the p21(Cip1/Waf1) cyclin-dependent kinase inhibitor, in the regulation of the activation of the FA-BRCA pathway. We demonstrate that, in contrast to p53, p21 has a major role in the regulation of the activation of the FA-BRCA pathway: p21 promotes S-phase and DNA damage-inducible FANCD2/I monoubiquitination and nuclear foci formation. Several lines of evidence establish that this effect is not a consequence of a defective G1-S checkpoint or altered cell-cycle progression in the absence of p21. Instead, we demonstrate that p21 is required for the transcriptional repression of the USP1 deubiquitinating enzyme upon exposure to DNA-damaging agents. In the absence of p21, persistent USP1 expression precludes the DNA damage-inducible accumulation of monoubiquitinated FANCD2 and FANCI. Consequently, p21(-/-) cells exhibit increased levels of mitomycin C-inducible complex chromosomal aberrations and elevated γH2AX nuclear foci formation. Our results demonstrate that p21 has a critical role in the regulation of the activation of the FA-BRCA pathway and suggest a broader role for p21 in the orchestration of DNA repair processes following exposure to DNA crosslinking agents.

Physiological role and regulation of iodothyronine deiodinases: a 2011 update.

T4 is a prohormone secreted by the thyroid. T4 has a long half life in circulation and it is tightly regulated to remain constant in a variety of circumstances. However, the availability of iodothyronine selenodeiodinases allow both the initiation or the cessation of thyroid hormone action and can result in surprisingly acute changes in the intracellular concentration of the active hormone T3, in a tissue- specific and chronologically-determined fashion, in spite of the constant circulating levels of the prohormone. This fine-tuning of thyroid hormone signaling is becoming widely appreciated in the context of situations where the rapid modifications in intracellular T3 concentrations are necessary for developmental changes or tissue repair. Given the increasing availability of genetic models of deiodinase deficiency, new insights into the role of these important enzymes are being recognized. In this review, we have incorporated new information regarding the special role played by these enzymes into our current knowledge of thyroid physiology, emphasizing the clinical significance of these new insights.

Assessing the daily consistency of bladder filling using an ultrasonic Bladderscan device in men receiving radical conformal radiotherapy for prostate cancer.

OBJECTIVE: Consistency in target organ and organ at risk position from planning to treatment is an important basic principle of radiotherapy. This study evaluates the effectiveness of bladder-filling instructions in achieving a consistent and reproducible bladder volume at the time of planning CT and daily during the course of radical radiotherapy for prostate cancer. It also assessed the rate of bladder filling before and at the end of radiotherapy. METHODS: 30 men attending for radiation therapy planning for prostate cancer received written and verbal bladder-filling instructions. They had their bladder volume assessed using a bladder ultrasound scanner post-void, immediately prior to planning CT scan and then daily immediately prior to treatment while in the therapy position. The inflow was calculated using the void and full bladder volumes and the time for the bladder to fill. RESULTS: The mean bladder volume at the time of planning was 282 ml (range 89-608 ml, standard deviation (SD) = 144.5 ml). This fell during treatment, with a mean value for all treatments of 189 ml (range 11-781 ml, SD = 134 ml). During radiotherapy, 76% (828/1090), 53% (579/1090) and 36% (393/1090) of bladder volumes had >50 ml, >100 ml and >150 ml difference, respectively when compared with their volume at the time of planning. Inflow reduced from 4.6 ml min(-1), SD = 2.9 min(-1) at planning to 2.5 min(-1), SD = 1.8 min(-1) after radiotherapy. CONCLUSION: The Bladderscan device (BVI 6400 Bladderscan, Verathon Medical UK, Sandford, UK) provides an effective means of assessing bladder volume prior to radiotherapy for prostate cancer. The evaluated bladder-filling protocol does not produce consistent, reproducible bladder volumes for radiotherapy.

Primary adenoid cystic carcinoma of the bronchus in a female teenager.

Primary adenoid cystic carcinoma (ACC) of the lung is an extremely rare malignant lung neoplasm. ACC of salivary glands of the head and neck, lachrymal glands, breast, skin, vulva and trachea have been frequently reported disease patterns in the literature, but it is unique to see this rare lung tumour in a patient as young as 14 years old. No double blind placebo, multicentre treatment data are available. Surgery is considered as the cornerstone of the treatment. Prognosis is variable and adjuvant radiotherapy has been found beneficial for prolonged survival. Our report of primary lung ACC in a young girl is a complex case due to young age, a different way of presentation and staging on diagnosis. It has been a quite challenging clinical scenario for the multidisciplinary lung cancer treating team involved in the clinical care. Prognosis remains unpredictable and uncertain despite the best present day evidence-based treatment.

Plasma serotonin levels and the platelet serotonin transporter.

Serotonin (5HT) is a platelet-stored vasoconstrictor. Altered concentrations of circulating 5HT are implicated in several pathologic conditions, including hypertension. The actions of 5HT are mediated by different types of receptors and terminated by a single 5HT transporter (SERT). Therefore, SERT is a major mechanism that regulates plasma 5HT levels to prevent vasoconstriction and thereby secure a stable blood flow. In this study, the response of platelet SERT to the plasma 5HT levels was examined within two models: (i) in subjects with chronic hypertension or normotension; (ii) on platelets isolated from normotensive subjects and pretreated with 5HT at various concentrations. The platelet 5HT uptake rates were lower during hypertension due to a decrease in Vmax with a similar Km; also, the decrease in Vmax was primarily due to a decrease in the density of SERT on the platelet membrane, with no change in whole cell expression. Additionally, while the platelet 5HT content decreased 33%, the plasma 5HT content increased 33%. Furthermore, exogenous 5HT altered the 5HT uptake rates by changing the density of SERT molecules on the plasma membrane in a biphasic manner. Therefore, we hypothesize that in a hypertensive state, the elevated plasma 5HT levels induces a loss in 5HT uptake function in platelets via a decrease in the density of SERT molecules on the plasma membrane. Through the feedback effect of this proposed mechanism, plasma 5HT controls its own concentration levels by modulating the uptake properties of platelet SERT.

At diabetes-like concentration, glucose down-regulates the placental serotonin transport system in a cell-cycle-dependent manner.

Serotonin [5-hydroxytryptamine (5HT)] is a vasoconstrictor that also acts as a developmental signal early in embryogenesis. The 5HT transporter (SERT) on the membranes of the placental trophoblast cells controls 5HT levels in the maternal bloodstream to maintain stable transplacental blood flow and simultaneously provide 5HT to the embryo. The 5HT uptake rate of placental SERT is important for both the mother and the developing embryo. The impact of glucose on the placental SERT system during diabetic pregnancy is not known. The present in vitro study investigated this important issue in human placental choriocarcinoma (JAR) cells that were cultured for 24-96 h in a medium containing either 5.5 (physiologic concentration) or 25 mmol/L D-glucose (diabetic-like concentration). The 5HT uptake rates of the cultured cells were not altered at exogenous D-glucose concentrations in the range of 5.5-15 mmol/L, but were decreased significantly at a diabetic-like concentration (>or=25 mmol/L). To understand better the role of glucose on the placental 5HT system, we first characterized SERT in JAR cells at different cell-cycle phases and then determined the expression levels of SERT on the plasma membrane and in the intracellular pools of JAR cells at the late-S and G2 phases, where the uptake rates were decreased 73% under diabetic-like glucose concentrations. Finally, the importance of self-association of SERT molecules was examined. In JAR cells co-expressing Flag- and myc-tagged SERT, myc-antibody precipitated 70% of Flag-SERT, indicating that a large percentage of SERT proteins exist as oligomers in situ. Under diabetic conditions, myc-antibody no longer precipitated Flag-SERT, suggesting a disruption in the aggregation of SERT molecules. Therefore, we propose that under uncontrolled diabetic conditions, glucose down-regulates 5HT uptake rates of placental SERT by interfering with its functional expression in a cell-cycle-dependent manner.

Progesterone's effects to reduce anxiety behavior of aged mice do not require actions via intracellular progestin receptors.

RATIONALE: Aging is associated with reduced secretion of, and down-regulation of receptors for, progesterone (P); yet, P's effects when administered to younger and older animals have not been systematically investigated. Some of P's antianxiety effects may be due to its conversion to 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) and its subsequent actions as a positive modulator at GABAA receptor complexes (GBRs). OBJECTIVES: We investigated whether P administration can decrease anxiety behavior of progestin receptor (PR) knockout (PRKO) or wild-type control mice. METHODS: P (10 mg/kg) or vehicle (propylene glycol) were administered subcutaneously to intact, female or male wild-type or PRKO mice that were either 9-12 or 18-24 months of age. Behavior in tasks that assess spontaneous activity (activity monitor and roto-rod), free exploration of a novel environment (open field, elevated plus maze, and elevated zero maze), and conflict behavior (mirror chamber, dark-light transition, and punished drinking) were examined 1 h after injection. RESULTS: P significantly decreased anxiety behavior of both PRKO and wild-type mice. P did not alter motor behavior but increased central entries in the open field, time in the open quadrants of the elevated zero maze, time in the mirrored chamber, time in the light compartment of the dark-light transition, and punished drinking in young and old mice. P-administered mice had higher levels of hippocampal 3alpha,5alpha-THP and GABA-stimulated chloride flux than did vehicle-administered PRKO or wild-type mice. CONCLUSIONS: The effects of P to decrease anxiety behavior of younger and older mice do not require classic PRs and may involve actions of 3alpha,5alpha-THP at GBRs.

Cancer chemotherapy administered via hemodialysis fistulas.

End-stage renal failure (ESRF) patients can develop cancer before or after kidney disease occurs. Cancer chemotherapy often needs to be administered via the sort of central venous catheter that is normally avoided in ESRF care. Three cases are presented in which ESRF patients received chemotherapy for cancer via existing hemodialysis fistulas, and the consequences of central venous access in a fourth patient are discussed.

Primary central nervous system lymphoma with testicular relapse.

We report the case of a 54-year-old man with primary central nervous system lymphoma (PCNSL) who achieved a radiological complete response to high-dose methotrexate and 6 months later had a simultaneous local and testicular relapse.

A phase I/II study of CHARTWEL with concurrent chemotherapy in locally advanced, inoperable carcinoma of the oesophagus.

AIM: To evaluate the feasibility, efficacy and toxicity of concurrent chemotherapy and continuous, hyperfractionated, accelerated radiotherapy weekend less (CHARTWEL) in the treatment of locally advanced, inoperable oesophageal cancer. METHODS: A prospective study of 19 patients with histologically confirmed, locally advanced, inoperable carcinoma of the oesophagus. CHARTWEL was prescribed from day 1 to doses of 40.5 Gy (three patients), 42 Gy (five patients), 45 Gy (four patients), 46.5 Gy (three patients) and 49.5 Gy (four patients). Cisplatin 75 mg/m2 was administered on day 1 of radiotherapy, followed by 5-fluorouracil (5-FU) 1000 mg daily for 4 days. RESULTS: All patients completed radiotherapy, with two requiring modification of their chemotherapy dose. Acute toxicity was acceptable, with no interruptions to treatment. The median dysphagia free time was 9.6 months with 38% of patients being dysphagia free at 42 months. The median time to locoregional relapse was 13.2 months with 50% being free at 1 year and 35% at 3.5 years. There was a trend towards greater control when the higher doses (45-49.5 Gy) were compared with the lower doses (40.5-42 Gy), P = 0.07. The median survival time was 10.7 months with 1- and 2-year survival rates of 50 and 26%, respectively. Strictures developed in seven out of 18 patients (38%), but five were found on biopsy to be due to recurrent disease. There was no other long-term toxicity and no treatment-related death occurred. CONCLUSIONS: CHARTWEL with concomitant cisplatin/5-FU chemotherapy is a feasible treatment option in these patients. It is well tolerated, achieves a high rate of local control and effectively palliates the symptoms of dysphagia, all with relatively rapid resolution of treatment-related toxicity. The results warrant continued dose escalation to 51 Gy.

Overexpression of type 2 iodothyronine deiodinase in follicular carcinoma as a cause of low circulating free thyroxine levels.

Thyroid function is normally undisturbed in patients with thyroid carcinoma. We have identified three patients with large or widely metastatic follicular thyroid carcinoma who had a persistently increased ratio of serum T(3) to T(4) in the absence of autonomous production of T(3) by the tumor. To investigate the possibility of tumor-mediated T(4) to T(3) conversion, we assayed types 1 and 2 iodothyronine selenodeiodinase (D1 and D2) activity in a 965-g follicular thyroid carcinoma resected from one of these patients. The V(max) for D2 was 8-fold higher than in normal human thyroid tissue. Resection of this tumor, leaving the left thyroid lobe intact, normalized the serum T(3) to T(4) ratio. In two other patients, treatment with sufficient levothyroxine to suppress TSH was associated with a high normal T(3) and a subnormal free T(4) index. In one, concomitant administration of the D1 inhibitors, propylthiouracil and propranolol, did not decrease the elevated serum T(3) to T(4) ratio. These data illustrate that increased T(4) to T(3) conversion in follicular thyroid carcinomas, probably by D2, can cause a significant perturbation in peripheral thyroid hormone concentrations.

The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue.

Type 2 iodothyronine deiodinase (D2) is a selenoenzyme, the product of the recently cloned cAMP-dependent Dio2 gene, which increases 10- to 50-fold during cold stress only in brown adipose tissue (BAT). Here we report that despite a normal plasma 3,5,3'-triiodothyronine (T3) concentration, cold-exposed mice with targeted disruption of the Dio2 gene (Dio2(-/-)) become hypothermic due to impaired BAT thermogenesis and survive by compensatory shivering with consequent acute weight loss. This occurs despite normal basal mitochondrial uncoupling protein 1 (UCP1) concentration. In Dio2(-/-) brown adipocytes, the acute norepinephrine-, CL316,243-, or forskolin-induced increases in lipolysis, UCP1 mRNA, and O(2) consumption are all reduced due to impaired cAMP generation. These hypothyroid-like abnormalities are completely reversed by a single injection of T3 14 hours earlier. Recent studies suggest that UCP1 is primarily dependent on thyroid hormone receptor beta (TR beta) while the normal sympathetic response of brown adipocytes requires TR alpha. Intracellularly generated T3 may be required to saturate the TR alpha, which has an approximately fourfold lower T3-binding affinity than does TR beta. Thus, D2 is an essential component in the thyroid-sympathetic synergism required for thermal homeostasis in small mammals.

Testosterone reduces pentylenetetrazole-induced ictal activity of wildtype mice but not those deficient in type I 5alpha-reductase.

Testosterone's (T) anti-seizure effects may be mediated in part by actions of its 5alpha-reduced metabolites. To test this hypothesis, T was administered to knockout mice deficient in the 5alpha-reductase type I enzyme and wildtype controls and their ictal activity following pentylenetetrazole (PTZ; 85 mg/kg i.p.) was compared to mice administered vehicle. T to wildtype mice increased latencies to forelimb clonus, tonic clonic seizures, hindlimb extension, and death compared to that seen with vehicle administration. Moreover, incidence of tonic clonic seizures and hindlimb extension were reduced in wildtype mice administered T compared to vehicle-administered mice. T administration to wildtype mice reduced ictal activity compared to T to knockout mice, which were not different than vehicle-administered control mice. T to wildtype mice increased the latencies and decreased the incidence of forelimb clonus compared to T to knockout mice, which were not different from vehicle-administered mice. These data are consistent with T having anti-convulsant effects and that 5alpha-reduced metabolites may mitigate some of T's anti-seizure effects.

Selenocysteine incorporation directed from the 3'UTR: characterization of eukaryotic EFsec and mechanistic implications.

The mechanism of selenocysteine incorporation in eukaryotes has been assumed for almost a decade to be inherently different from that in prokaryotes, due to differences in the architecture of selenoprotein mRNAs in the two kingdoms. After extensive efforts in a number of laboratories spanning the same time frame, some of the essential differences between these mechanisms are finally being revealed, through identification of the factors catalyzing cotranslational selenocysteine insertion in eukaryotes. A single factor in prokaryotes recognizes both the selenoprotein mRNA, via sequences in the coding region, and the unique selenocysteyl-tRNA, via both its secondary structure and amino acid. The corresponding functions in eukaryotes are conferred by two distinct but interacting factors, one recognizing the mRNA, via structures in the 3' untranslated region, and the second recognizing the tRNA. Now, with these factors in hand, crucial questions about the mechanistic details and efficiency of this intriguing process can begin to be addressed.

Interplay between termination and translation machinery in eukaryotic selenoprotein synthesis.

Termination of translation in eukaryotes is catalyzed by eRF1, the stop codon recognition factor, and eRF3, an eRF1 and ribosome-dependent GTPase. In selenoprotein mRNAs, UGA codons, which typically specify termination, serve an alternate function as sense codons. Selenocysteine incorporation involves a unique tRNA with an anticodon complementary to UGA, a unique elongation factor specific for this tRNA, and cis-acting secondary structures in selenoprotein mRNAs, termed SECIS elements. To gain insight into the interplay between the selenocysteine insertion and termination machinery, we investigated the effects of overexpressing eRF1 and eRF3, and of altering UGA codon context, on the efficiency of selenoprotein synthesis in a transient transfection system. Overexpression of eRF1 does not increase termination at naturally occurring selenocysteine codons. Surprisingly, selenocysteine incorporation is enhanced. Overexpression of eRF3 did not affect incorporation efficiency. Coexpression of both factors reproduced the effects with eRF1 alone. Finally, we show that the nucleotide context immediately upstream and downstream of the UGA codon significantly affects termination to incorporation ratios and the response to eRF overexpression. Implications for the mechanisms of selenocysteine incorporation and termination are discussed.