In situ incubation of iron(II)-bearing minerals and Fe(0) reveals insights into metabolic flexibility of chemolithotrophic bacteria in a nitrate polluted karst aquifer.

Groundwater nitrate pollution is a major reason for deteriorating water quality and threatens human and animal health. Yet, mitigating groundwater contamination naturally is often complicated since most aquifers are limited in bioavailable carbon. Since metabolically flexible microbes might have advantages for survival, this study presents a detailed description and first results on our modification of the BacTrap© method, aiming to determine the prevailing microbial community's potential to utilize chemolithotrophic pathways. Our microbial trapping devices (MTDs) were amended with four different iron sources and incubated in seven groundwater monitoring wells for ∼3 months to promote growth of nitrate-reducing Fe(II)-oxidizing bacteria (NRFeOxB) in a nitrate-contaminated karst aquifer. Phylogenetic analysis based on 16S rRNA gene sequences implies that the identity of the iron source influenced the microbial community's composition. In addition, high throughput amplicon sequencing revealed increased relative 16S rRNA gene abundances of OTUs affiliated to genera such as Thiobacillus, Rhodobacter, Pseudomonas, Albidiferax, and Sideroxydans. MTD-derived enrichments set up with Fe(II)/nitrate/acetate to isolate potential NRFeOxB, were dominated by e.g., Acidovorax spp., Paracoccus spp. and Propionivibrio spp. MTDs are a cost-effective approach for investigating microorganisms in groundwater and our data not only solidifies the MTD's capacity to provide insights into the metabolic flexibility of the aquifer's microbial community, but also substantiates its metabolic potential for anaerobic Fe(II) oxidation.

Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study.

BACKGROUND: Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS. METHODS: The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236). FINDINGS: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; p<0·001). The boost group had higher rates of grade 2 or higher breast pain (10% [8-12%] vs 14% [12-17%], p=0·003) and induration (6% [5-8%] vs 14% [11-16%], p<0·001). INTERPRETATION: In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results. FUNDING: National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

The tragedy of the canon; or, path dependence in the history and philosophy of science.

We have previously argued that historical cases must be rendered canonical before they can plausibly serve as evidence for philosophical claims, where canonicity is established through a process of negotiation among historians and philosophers of science (Bolinska and Martin, 2020). Here, we extend this proposal by exploring how that negotiation might take place in practice. The working stock of historical examples that philosophers tend to employ has long been established informally, and, as a result, somewhat haphazardly. The composition of the historical canon of philosophy of science is therefore path dependent, and cases often become stock examples for reasons tangential to their appropriateness for the purposes at hand. We show how the lack of rigor around the canonization of case studies has muddied the waters in selected philosophical debates. This, in turn, lays the groundwork for proposing ways in which they can be improved.

Negotiating history: Contingency, canonicity, and case studies.

Objections to the use of historical case studies for philosophical ends fall into two categories. Methodological objections claim that historical accounts and their uses by philosophers are subject to various biases. We argue that these challenges are not special; they also apply to other epistemic practices. Metaphysical objections, on the other hand, claim that historical case studies are intrinsically unsuited to serve as evidence for philosophical claims, even when carefully constructed and used, and so constitute a distinct class of challenge. We show that attention to what makes for a canonical case can address these problems. A case study is canonical with respect to a particular philosophical aim when the features relevant to that aim provide a reasonably complete causal account of the results of the historical process under investigation. We show how to establish canonicity by evaluating relevant contingencies using two prominent examples from the history of science: Eddington's confirmation of Einstein's theory of general relativity using his data from the 1919 eclipse and Watson and Crick's determination of the structure of DNA.

International comparison of cosmetic outcomes of breast conserving surgery and radiation therapy for women with ductal carcinoma in situ of the breast.

PURPOSE: To assess the cosmetic impact of breast conserving surgery (BCS), whole breast irradiation (WBI) fractionation and tumour bed boost (TBB) use in a phase III trial for women with ductal carcinoma in situ (DCIS) of the breast. MATERIALS AND METHODS: Baseline and 3-year cosmesis were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Cosmetic Rating System and digital images in a randomised trial of non-low risk DCIS treated with postoperative WBI +/- TBB. Baseline cosmesis was assessed for four geographic clusters of treating centres. Cosmetic failure was a global score of fair or poor. Cosmetic deterioration was a score change from excellent or good at baseline to fair or poor at three years. Odds ratios for cosmetic deterioration by WBI dose-fractionation and TBB use were calculated for both scoring systems. RESULTS: 1608 women were enrolled from 11 countries between 2007 and 2014. 85-90% had excellent or good baseline cosmesis independent of geography or assessment method. TBB (16 Gy in 8 fractions) was associated with a >2-fold risk of cosmetic deterioration (p < 0.001). Hypofractionated WBI (42.5 Gy in 16 fractions) achieved statistically similar 3-year cosmesis compared to conventional WBI (50 Gy in 25 fractions) (p ≥ 0.18). The adverse impact of a TBB was not significantly associated with WBI fractionation (interaction p ≥ 0.30). CONCLUSIONS: Cosmetic failure from BCS was similar across international jurisdictions. A TBB of 16 Gy increased the rate of cosmetic deterioration. Hypofractionated WBI achieved similar 3-year cosmesis as conventional WBI in women treated with BCS for DCIS.

Conflict of Interest Mitigation Procedures May Have Little Influence on the Perceived Procedural Fairness of Risk-Related Research.

Two between-subject experiments explored perceived conflict of interest (COI)-operationalized as perceived procedural unfairness-in a hypothetical public-private research partnership to study the health risks of trans fats. Perceived fairness was measured as subjects' perceptions that health researchers would be willing to listen to a range of voices and minimize bias (i.e., COI) in the context of a research project. Experiment 1 (n = 1,263) randomly assigned research subjects to a partnership that included (1) a combination of an industry partner, a university partner, and a nongovernmental organization (NGO) partner; and (2) one of three processes aimed at mitigating the potential for COI to harm the quality of the research. The procedures included an arm's-length process meant to keep the university-based research team from being influenced by the other partners, an independent advisory board to oversee the project, and a commitment to making all data and analyses openly available. The results suggest that having an industry partner has substantial negative effects on perceived fairness and that the benefit of employing a single COI-mitigation process may be relatively small. Experiment 2 (n = 1,076) assessed a partnership of (1) a university and either an NGO or industry partner and (b) zero, one, two, or three of the three COI-mitigation procedures. Results suggest there is little value in combining COI-mitigation procedures. The study has implications for those who aim to foster confidence in scientific findings for which the underlying research may benefit from industry funding.

Perceived conflict of interest in health science partnerships.

University scientists conducting research on topics of potential health concern often want to partner with a range of actors, including government entities, non-governmental organizations, and private enterprises. Such partnerships can provide access to needed resources, including funding. However, those who observe the results of such partnerships may judge those results based on who is involved. This set of studies seeks to assess how people perceive two hypothetical health science research collaborations. In doing so, it also tests the utility of using procedural justice concepts to assess perceptions of research legitimacy as a theoretical way to investigate conflict of interest perceptions. Findings show that including an industry collaborator has clear negative repercussions for how people see a research partnership and that these perceptions shape people's willingness to see the research as a legitimate source of knowledge. Additional research aimed at further communicating procedures that might mitigate the impact of industry collaboration is suggested.

Prestige Asymmetry in American Physics: Aspirations, Applications, and the Purloined Letter Effect.

Argument Why do similar scientific enterprises garner unequal public approbation? High energy physics attracted considerable attention in the late-twentieth-century United States, whereas condensed matter physics - which occupied the greater proportion of US physicists - remained little known to the public, despite its relevance to ubiquitous consumer technologies. This paper supplements existing accounts of this much remarked-upon prestige asymmetry by showing that popular emphasis on the mundane technological offshoots of condensed matter physics and its focus on human-scale phenomena have rendered it more recondite than its better-known sibling field. News reports about high energy physics emphasize intellectual achievement; reporting on condensed matter physics focuses on technology. And whereas frontier-oriented rhetoric of high energy physics communicates ideals of human potential, discoveries that smack of the mundane highlight human limitations and fail to resonate with the widespread aspirational vision of science - a consequence I call "the purloined letter effect."

Gastrointestinal radiation injury: symptoms, risk factors and mechanisms.

Ionising radiation therapy is a common treatment modality for different types of cancer and its use is expected to increase with advances in screening and early detection of cancer. Radiation injury to the gastrointestinal tract is important factor working against better utility of this important therapeutic modality. Cancer survivors can suffer a wide variety of acute and chronic symptoms following radiotherapy, which significantly reduces their quality of life as well as adding an extra burden to the cost of health care. The accurate diagnosis and treatment of intestinal radiation injury often represents a clinical challenge to practicing physicians in both gastroenterology and oncology. Despite the growing recognition of the problem and some advances in understanding the cellular and molecular mechanisms of radiation injury, relatively little is known about the pathophysiology of gastrointestinal radiation injury or any possible susceptibility factors that could aggravate its severity. The aims of this review are to examine the various clinical manifestations of post-radiation gastrointestinal symptoms, to discuss possible patient and treatment factors implicated in normal gastrointestinal tissue radiosensitivity and to outline different mechanisms of intestinal tissue injury.

Gastrointestinal radiation injury: prevention and treatment.

With the recent advances in detection and treatment of cancer, there is an increasing emphasis on the efficacy and safety aspects of cancer therapy. Radiation therapy is a common treatment for a wide variety of cancers, either alone or in combination with other treatments. Ionising radiation injury to the gastrointestinal tract is a frequent side effect of radiation therapy and a considerable proportion of patients suffer acute or chronic gastrointestinal symptoms as a result. These side effects often cause morbidity and may in some cases lower the efficacy of radiotherapy treatment. Radiation injury to the gastrointestinal tract can be minimised by either of two strategies: technical strategies which aim to physically shift radiation dose away from the normal intestinal tissues, and biological strategies which aim to modulate the normal tissue response to ionising radiation or to increase its resistance to it. Although considerable improvement in the safety of radiotherapy treatment has been achieved through the use of modern optimised planning and delivery techniques, biological techniques may offer additional further promise. Different agents have been used to prevent or minimize the severity of gastrointestinal injury induced by ionising radiation exposure, including biological, chemical and pharmacological agents. In this review we aim to discuss various technical strategies to prevent gastrointestinal injury during cancer radiotherapy, examine the different therapeutic options for acute and chronic gastrointestinal radiation injury and outline some examples of research directions and considerations for prevention at a pre-clinical level.

Prognostic significance of the Epstein-Barr virus, p53, Bcl-2, and survivin in nasopharyngeal cancer.

PURPOSE: Nasopharyngeal cancer (NPC) is a malignant epithelial carcinoma which is intimately associated with EBV. The latent presence of EBV affects the function of p53, Bcl-2, and survivin. We thus investigated the relationship between EBV status, p53, Bcl-2, and survivin in biopsy specimens from patients with primary NPC. EXPERIMENTAL DESIGN: Archival formalin-fixed, paraffin-embedded NPC biopsies were evaluated in 80 patients treated with curative radiation from a single institution. The presence of EBV was determined using EBER in situ hybridization, whereas p53, Bcl-2, and survivin were assessed using immunohistochemistry. RESULTS: The majority of NPC specimens in this patient cohort were EBER-positive (64 of 78, or 82%), which in turn, was significantly associated with ethnicity (P = 0.0007), and WHO subtype 2A/2B (P = 0.04). EBER-positive tumors were also associated with p53 (P = 0.002), Bcl-2 (P = 0.04), and nuclear survivin (P = 0.03) expression. Patients with EBER-positive NPC fared better, with a 10-year overall survival of 68% versus 48% for EBER-negative patients (P = 0.03). For nuclear survivin, patients with either low or high nuclear survivin fared worse than patients with intermediate survivin expression (P = 0.05), suggesting that there is an optimal proportion of survivin-expressing cells for best function and clinical outcome. CONCLUSIONS: With an extended median follow-up time of 11.4 years, EBV status remains a strong predictor for overall survival in NPC. EBV-positive NPC has strong molecular associations with p53, Bcl-2, and survivin expression. Furthermore, we provide clinical data revealing the potentially dual nature of survivin in predicting clinical outcome.

Papillary serous carcinoma--a less radio-sensitive subtype of endometrial cancer.

OBJECTIVE: To explore factors that determine the response of endometrial cancer to radiation therapy. Such factors may influence treatment outcome and yield predictive information about individual patients and their tumors. METHODS: A retrospective study of the complete pathologic response (pCR) rates in the hysterectomy specimens of patients, who had undergone pre-operative radiotherapy for > or = Stage II biopsy-proven endometrial carcinoma, was performed. 62 patient records were reviewed with respect to patient characteristics, tumor stage, histological grade and subtype, radiation technique and dose, and presence or absence of pCR in the post-operative hysterectomy specimen. RESULTS: 24 of 62 specimens exhibited a pCR. The only significant factor with respect to pCR was presence of uterine papillary serous carcinoma (UPSC). None of the seven cases of UPSC displayed a pCR (P = 0.036 Fischer's exact test), despite not differing from the non-UPSC cases in any other tumor, treatment, or patient factors. No factors were found that separated non-UPSC cases with a pCR from those without. CONCLUSIONS: These data suggest an intrinsic radioresistance within UPSC, which may have implications for future treatment strategies. UPSC has documented genetic aberrations that may account for this, although its true radiosensitivity has yet to be quantitated directly. Future studies should focus on the molecular basis of its response to radiation. The reasons for the heterogeneous response of non-UPSC has yet to be elucidated and should also be investigated.

Carotid artery stenosis in asymptomatic patients who have received unilateral head-and-neck irradiation.

PURPOSE: To determine the prevalence of carotid artery stenosis in patients who have received ipsilateral head-and-neck radiotherapy and have no symptoms of cerebrovascular disease. METHODS AND MATERIALS: Forty patients underwent ultrasound and computed tomography angiography of their carotid arteries. The vessels on the irradiated side were compared with those on the unirradiated side in a matched-pair analysis with regard to any stenosis, stenosis > or =60% in the internal carotid artery/carotid bulb, intima medial thickness (IMT), and grade of wall abnormalities. History, physical, and fasting blood levels were taken to detect risk factors for carotid disease. RESULTS: Fourteen irradiated carotid trees bore one or more stenosis vs. five in the unirradiated ones (p = 0.03). There were six bulb/internal carotid artery stenoses > or =60% in the irradiated carotids vs. one in the unirradiated (OR 6:1, p = 0.13). IMT and grade of vessel wall abnormality were higher in the irradiated carotids, but only at doses > or =50 Gy, and only at measurement points that lay within the radiation portals. CONCLUSION: Radiation appears to cause carotid artery stenosis. There may be a dose threshold for carotid wall changes, which has relevance for radiotherapy in several tumor sites.