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To characterise and compare the response of EBT-XD and EBT3 radiochromic films at high doses (up to 4500 cGy) for a 175 MeV energy proton beam. EBT-XD and EBT3 film dosimeters were irradiated by a proton beam with 175 MeV. In order to establish dose response curves, each film piece was exposed to radiation doses 50–4500 cGy. The films were irradiated to doses of 200, 1000, 2000, and 4000 cGy and non-irradiated to determine the lateral response artifact (LRA) for varied lateral positions. The influence of film orientations (0°, 90°, and 45°) on the scanner bed was examined. Net optical density (netOD) for the films was measured at 24, 48, 72 h and 1-week post-irradiation. Digital images were created using an EPSON 11 000 XL scanner. To analyse and present our results we use: ImageJ (v. 2.0) and OriginPro 2015. The red mode netOD was lower in the EBT-XD film, with a netOD for 4500 cGy of 0.610 (EBT-XD) versus 0.893 (EBT3). The EBT-XD film presented a better lateral response than the EBT3. For films irradiated at 4000 cGy placed near the scanner edge, the differences from the central position were 17 and 16.7% (EBT3) and 10.8 and 9.1% (EBT-XD). The EBT3 film presented a satisfactory dose-response for doses <2000 cGy and would be suitable for dosimetry in standard and hypofractionated proton therapy. The EBT-XD film, however, performs better for ultra-hypofractionated proton therapy (>2000 cGy). The new EBT-XD could be a suitable dosimeter for emerging techniques, such as FLASH and Arc proton therapy. [ABSTRACT FROM AUTHOR]

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Although Renal Cell Cancer (RCC) is known to be immunogenic, clinical efficacy of various immunotherapeutic approaches remains unsatisfactory. Novel targeted therapies showing cytostatic rather than cytotoxic activity are unable to cure RCC patients. In our studies, we evaluated the therapeutic efficacy of whole-cell vaccine based on irradiated murine RENCA cells genetically modified to secrete designer cytokine—Hyper-IL6 (H6)—comprising IL-6 and soluble IL-6 receptor. An orthotopic RCC model based on a subcapsular implantation of RENCA cells into kidneys of Balb/C mice was employed. The efficacy of RENCA-H6 vaccine was compared with control vaccine (RENCA-wt) in relation to naive (non-immunized) animals. Three sets of vaccination experiments were carried out in a (i) protective, (ii) palliative and (iii) adjuvant (following nephrectomy) setting. The influence of vaccination on survival of RCC-bearing animals was analyzed. Specificity of vaccine-induced immune response was studied using model antigen—GFP. RCC-bearing animals immunized with RENCA-H6 vaccine showed prolonged survival compared with other groups. In palliative and adjuvant settings the survival RENCA-H6-immunized animals exceeded 75%. Administration of RENCA-H6 inhibited formation and recruitment of Treg cells (CD4+CD25+Foxp3+) and increased maturation of DCs. RENCA tumors in RENCA-H6- vaccinated animals contained large populations of NK cells and activated CD4+, CD8+ T cells. In addition, in mice vaccinated with RENCA-H6 cells large population of CD4+ and CD8+ memory cells (CD62Llow) were detected. In the orthotopic RCC model, RENCA-H6 vaccine showed high therapeutic potential, which resulted from modulation of numerous immunological mechanisms. [ABSTRACT FROM AUTHOR]

Recent advances in tumor immunology and molecular drug development have ushered in a new era of cancer immunotherapy. Immunotherapy has shown promising results for several types of tumors, such as advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancers, and refractory Hodgkin's lymphoma. Similarly, efforts have been made to develop immunotherapies such as adoptive T-cell transplantation, peptide vaccines, and dendritic cell vaccines, specifically for gastrointestinal tumors. However, before the advent of immune checkpoint inhibitors, immunotherapy did not work as well as expected. In this article, we review immunotherapy, focusing on cancer vaccines for gastrointestinal tumors, which generally target eliciting tumor-specific CD8 + cytotoxic T lymphocytes (CTLs). We also review various vaccine therapies and describe the relationship between vaccines and adjuvants. Finally, we discuss prospects for the combination of immunotherapy with immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Ciliopathies are a diverse group of disorders resulting from abnormalities in the development or function of multiple organs. While significant research has clarified the role of the primary cilium in transducing numerous signalling pathways, elucidating causes of neuronal and skeletal development disorders, the origins of other ciliopathy-related conditions, such as hepatic fibrocystic diseases, remain elusive. Additionally, attempts to correlate specific ciliary proteins with distinct phenotypes have been largely unsuccessful due to the variable and overlapping symptoms of ciliopathies. This study aims to elucidate the extraciliary roles of the protein B9D2 in the development of biliary dysgenesis, a condition present in Meckel-Gruber and Joubert syndromes caused by mutations in this protein. Traditionally, B9D2 is known for its role at the transition zone of the primary cilium in the transduction of signalling pathways notably Wingless and Hedgehog. Our work demonstrates that before ciliogenesis occurs, B9D2 is crucial for the maturation and maintenance of tight junctions ensuring epithelial barrier tightness and appropriate biliary lumen formation. This study provides new insights into the mechanisms underlying biliary dysgenesis in hepatic ciliopathies, suggesting that further exploration of the non-ciliary functions of proteins involved in ciliopathies could lead to a better understanding and treatment of these complex disorders. [ABSTRACT FROM AUTHOR]

Effluent reuse is a rapidly growing field of research where assessing the quality of effluent is one of the focus areas. This research examines the viability of using wastewater in agriculture by testing an integrated Upflow Anaerobic Sludge Blanket (UASB) reactor with a trickling filter (TF) system during the dry season. Compliance monitoring was conducted for 30 days from May 11 to June 9 of 2021. Samples were collected, handled, and analyzed following standard wastewater analysis procedures for biological oxygen demand (BOD), chemical oxygen demand (COD), total suspended solids (TSS), volatile suspended solids (VSS), cations, anions, heavy metals, E. coli, and helminth egg. The UASB-TF system in Kality wastewater treatment performed well in removing COD, BOD5, and TSS with average removal rates of 80.5%, 82.9%, and 80.9%, respectively, compared well with similar treatment configurations. The effluent quality satisfied the national inland discharge limit with a residual concentration of 125.1 mg/L for COD, 61.7 mg/L for BOD5 and 85.8 mg/L for TSS. On the other hand, high concentrations of chromium, nitrate-nitrogen, and helminth egg count restricted effluent reuse for agricultural purposes due to high health risks and environmental contamination. We found out that discharging industrial sewage into the domestic sewer network could inhibit microbial growth and affect the biological treatment processes. Furthermore, adopting integrated treatment systems in developing countries might face operational challenges and monitoring nitrate, helminth egg, and heavy metals would help provide timely operational feedback. An appropriate tertiary treatment unit—constructed wetlands or polishing ponds—is therefore needed to be introduced to ensure effluent reuse for agricultural purposes. [ABSTRACT FROM AUTHOR]

Tropical teleost fish Danio rerio is increasingly used as a model object for electrophysiological studies of human cardiac physiology and pathology. D. rerio is characterized by the similarity with humans in such functional parameters of the electrical activity of the heart as heart rate, action potential morphology, as well as in a set of ion currents depolarizing and repolarizing the cell membrane. D. rerio is easy to breed, easy to handle experimentally, and easy to genetically modify. This overview presents current data on the structural and functional organization of ion channels in D. rerio heart myocytes. [ABSTRACT FROM AUTHOR]

This computational investigation examines the capability of electronic portal imaging devices (EPIDs) in detecting anatomical changes during radiation therapy. A photon beam for 6 MV was simulated using compliant phase-space files via BEAMnrc (an EGSnrc user code). Initially, the dose calculation was carried out using DOSXYZnrc, an EGSnrc user code, on a water-based calibration phantom made of water. Phantoms, constructed utilizing patient computed tomography data, were subsequently used to simulate clinically relevant parotid gland (PG) shrinkage through image deformation using ImSimQA software. Two EPID geometries were implemented; a simple water slab, and a comprehensive multi-layer representation of the EPID (referred to as the 17-slab model). Using a 1%/1 mm gamma index the 17-slab geometry was sensitive to volume reductions in the PG ≥ − 26% from its original volume, while the water slab detected volume reduction of ≥ − 28.5%. In a clinical setting, replanning of head and neck patients is initiated when a reduction of 24–30% in PG volume is detected through cone-beam computed tomography. The sensitivity index, indicative of the signal to error ratio between the reference and evaluated images, showed an increase as the gland volume decreased for both models. Notably, the 17-slab model consistently more sensitive than the water slab. This computational study highlights the prospective use of EPIDs in monitoring and detecting clinically significant volume changes in the PG during radiation treatment. Advances in knowledge: While EPIDs are frequently employed for patient setup and alignment, this computational work constructed a virtual EPID to assess its detection abilities for the anatomical changes in the PG due to radiation exposure in head and neck cancer cases. [ABSTRACT FROM AUTHOR]

Previous evidence on productivity losses from neoplasms focuses mostly on the economic burden from mortality, covers single cancer diagnoses and neglects non-malignant neoplasms. This study aims to broaden this perspective by analysing losses resulting from work absence and all neoplasm diagnoses. The analysis applies the human capital method and social insurance data to estimate productivity losses attributable to neoplasm-related short-term work absence in Poland in the period 2012–2022. The productivity losses due to work absence attributable to all neoplasms in Poland were €583 million in 2012 (0.143% of gross domestic product) and they increased to €969 million in 2022 (0.164%). Around 60% of the losses were associated with cancers while the remaining part of the burden was due to non-malignant neoplasms. The neoplasms that led to the highest losses were benign neoplasms, breast cancer, colorectum cancer and prostate cancer. The cancer sites characterised by the greatest losses per absence episode were brain cancer, lung cancer and oesophageal cancer. For most of the neoplasms, we observed increasing losses in an 11-year period analysed. Investing in effective public health policies that tackle neoplasms has the potential to reduce both the health burden and economic losses resulting from these diseases. [ABSTRACT FROM AUTHOR]

Introduction: The USA continues to face a fentanyl-driven overdose epidemic. Prior research has demonstrated users of illicit opioids are concerned about fentanyl exposure and overdose, but the strategies they report using to detect fentanyl's presence lack empirical support. This study compares self-report and biologically detected fentanyl use and investigates overdose risk and risk reduction behaviors among a sample of high-risk people who use opioids. Methods: Structured enrollment interviews conducted as part of a larger clinical trial assessed self-reported fentanyl exposure as well as strategies used to determine believed fentanyl exposure and prevent overdose among 240 participants enrolled at a Chicago, IL syringe service program. Urinalysis measured actual fentanyl exposure. Results: Most participants identified as African American (66.7%) and had considerable overdose experience (76.7% lifetime and 48% in the past year). Most also tested positive for fentanyl (93.75%) despite reporting no past year use of fentanyl or fentanyl-adulterated drugs (64.17%). The most utilized approaches reported for identifying fentanyl exposure were stronger effects of the drug (60.7%), sight or taste (46.9%), and being told by someone using the same drugs (34.2%). Few participants (14%) reported using fentanyl test strips. No significant associations were identified between self-report and urinalysis measures or urinalysis results and risk reduction strategies. Conclusion: This study adds to prior fentanyl exposure risk research. The disconnect between participants' fentanyl detection methods and reported overdose experiences supports the need for more research to identify and understand factors driving access and use of overdose prevention resources and strategies. [ABSTRACT FROM AUTHOR]

The conserved multiple PDZ-domain containing protein PATJ stabilizes the Crumbs-Pals1 complex to regulate apical-basal polarity and tight junction formation in epithelial cells. However, the molecular mechanism of PATJ’s function in these processes is still unclear. In this study, we demonstrate that knockout of PATJ in epithelial cells results in tight junction defects as well as in a disturbed apical-basal polarity and impaired lumen formation in three-dimensional cyst assays. Mechanistically, we found PATJ to associate with and inhibit histone deacetylase 7 (HDAC7). Inhibition or downregulation of HDAC7 restores polarity and lumen formation. Gene expression analysis of PATJ-deficient cells revealed an impaired expression of genes involved in cell junction assembly and membrane organization, which is rescued by the downregulation of HDAC7. Notably, the function of PATJ regulating HDAC7-dependent cilia formation does not depend on its canonical interaction partner, Pals1, indicating a new role of PATJ, which is distinct from its function in the Crumbs complex. By contrast, polarity and lumen phenotypes observed in Pals1- and PATJ-deficient epithelial cells can be rescued by inhibition of HDAC7, suggesting that the main function of this polarity complex in this process is to modulate the transcriptional profile of epithelial cells by inhibiting HDAC7. [ABSTRACT FROM AUTHOR]

Photoreceptor outer segments are surrounded by a carbohydrate-rich matrix, the interphotoreceptor matrix, necessary for physiological retinal function. Few roles for molecules characterizing the interphotoreceptor matrix have been clearly defined. Recent studies have found the presence of nonsense mutations in the interphotoreceptor matrix proteoglycan 2 (IMPG2) gene in patients affected by retinal dystrophies. IMPG2 encodes for a proteoglycan synthesized by photoreceptors and secreted in the interphotoreceptor matrix. Little is known about the structure and function of this protein, we thus decided to characterize zebrafish impg2. In zebrafish there are two Impg2 proteins, Impg2a and Impg2b. We generated a phylogenetic tree based on IMPG2 protein sequence similarity among vertebrates, showing a significant similarity between humans and teleosts. The human and zebrafish proteins share conserved domains, as also shown by homology models. Expression analyses of impg2a and impg2b show a continued expression in the photoreceptor layer starting from developmental stages and continuing through adulthood. Between 1 and 6 months post-fertilization, there is a significant shift of Impg2 expression toward the outer segment region, suggesting an increase in secretion. This raises intriguing hypotheses about its possible role(s) during retinal maturation, laying the groundwork for the generation of most needed models for the study of IMPG2-related inherited retinal dystrophies. [ABSTRACT FROM AUTHOR]

Color vision is mediated by the expression of different major visual pigment proteins (opsins) on retinal photoreceptors. Vertebrates have four classes of cone opsins that are most sensitive to different wavelengths of light: short wavelength sensitive 1 (SWS1), short wavelength sensitive 2 (SWS2), medium wavelength sensitive (RH2), and long wavelength sensitive (LWS). UV wavelengths play important roles in foraging and communication. However, direct evidence provide links between sws1 and first feeding is lacking. Here, CRISPR/Cas9 technology was performed to generate mutant zebrafish lines with sws1 deletion. sws1 mutant zebrafish larvae exhibited decreased sws1, rh2-2, and lws1 expression, and increased rod gene (rho and gnat1) expression. Furthermore, the sws1-deficient larvae exhibited significantly reduced food intake, and the orexigenic genes npy and agrp signaling were upregulated at 6 days postfertilization (dpf). The transcription expression of sws1 and rh2-3 genes decreased in sws1−/− adults compared to wild type. Surprisingly, the results of feeding at the adult stage were not the same with larvae. sws1 deficiency did not affect food intake and appetite gene expression at adult stages. These results reveal a role for sws1 in normal cone development and first feeding in larval zebrafish. [ABSTRACT FROM AUTHOR]

These levels include an activity-based prescription with patient-averaged dosimetry, an activity-based prescription with patient-specific dosimetry and, a dosimetry-based prescription and post-therapy dosimetry verification. In those documents, time of medical physicists for an outpatient therapy of thyrotoxicosis with [ SP 131 sp I]I-NaI, an in-patient therapy of differentiated thyroid carcinoma with [ SP 131 sp I]I-NaI and for a complex therapy, such as therapies with [ SP 131 sp I]I-mIBG, SP 177 sp Lu or SP 90 sp Y, are reported. It was concluded that in the UK, most medical physics groups are well equipped to provide a simple form of dosimetry service, but in most cases refrain to perform dosimetry routinely by "lack of clinical evidence and practice" and that more complex dosimetry will require additional staffing. Whole-body dosimetry using a portable radiation detector in the treatment of neuroblastoma wi... In treatments of neuroblastoma with [ SP 131 sp I]I-mIBG, patients often spend several days in the treatment room for radiation-protection purposes [[29]]. [Extracted from the article]

The purpose of this position paper is to outline the ACPSEM recommendations on Medical Physicist scope of practice and staffing levels, as they relate to the use of dedicated MRI-Linacs in the treatment of patients. A core function of Medical Physicists is to safely implement changes in medical practice via the introduction of new technology and to ensure high quality radiation oncology services are provided to patients. Determining the feasibility of MRI-Linacs in any existing setting, or in establishing a new site, mandates the knowledge and services of Radiation Oncology Medical Physicists (ROMPs) as the Qualified Experts within this setting. ROMPs are key members of the multi-disciplinary team which will be required to steer the successful establishment of MRI Linac infrastructure within departments. To support efficient implementation, ROMPs must be embedded in the process from the start, including any feasibility study, initiation of the project, and development of the business case. ROMPs must be retained throughout all stages of acquisition, service development, and ongoing clinical use and expansion. The number of MRI-Linacs in Australia and New Zealand is growing. This expansion is occurring in parallel with rapid technological evolution, expanding tumour stream applications, and increasing consumer uptake. Growth and applications of MRI-Linac therapy will continue to occur beyond current known horizons, via development on the MR-Linac platform itself and through the migration of learning from this platform to conventional Linacs (known horizons for example include the use of daily, online image guided adaptive radiotherapy and MRI data informing decision making for planning and treatment before and throughout treatment courses). Clinical use, research and development will be a significant component of expanding patient access to MRI-Linac treatment and there will be an ongoing need to attract and retain ROMPs to initially establish services and in particular to drive service development and delivery for the life of the Linacs. MRI and Linac technologies mean it is necessary to perform a specialized workforce assessment for these devices, distinct from those employed for conventional Linacs and associated services. MRI-Linacs are complex, have a heightened risk profile compared to standard Linacs, and are unique in their treatment of patients. Accordingly, the workforce needs for MRI-Linacs are greater than for standard Linacs. To ensure safe and high-quality Radiation Oncology patient services are provided, it is recommended that staffing levels should be based on the 2021 ACPSEM Australian Radiation Workforce model and calculator using the MRI-Linac specific ROMP workforce modelling guidelines outlined in this paper. The ACPSEM workforce model and calculator are closely aligned with other Australian/New Zealand and international benchmarks. [ABSTRACT FROM AUTHOR]

Purpose: Risk management (RM) is a key component of patient safety in radiation oncology (RO). We investigated current approaches on RM in German RO within the framework of the Patient Safety in German Radiation Oncology (PaSaGeRO) project. Aim was not only to evaluate a status quo of RM purposes but furthermore to discover challenges for sustainable RM that should be addressed in future research and recommendations. Methods: An online survey was conducted from June to August 2021, consisting of 18 items on prospective and reactive RM, protagonists of RM, and self-assessment concerning RM. The survey was designed using LimeSurvey and invitations were sent by e‑mail. Answers were requested once per institution. Results: In all, 48 completed questionnaires from university hospitals, general and non-academic hospitals, and private practices were received and considered for evaluation. Prospective and reactive RM was commonly conducted within interprofessional teams; 88% of all institutions performed prospective risk analyses. Most institutions (71%) reported incidents or near-events using multiple reporting systems. Results were presented to the team in 71% for prospective analyses and 85% for analyses of incidents. Risk conferences take place in 46% of institutions. 42% nominated a manager/committee for RM. Knowledge concerning RM was mostly rated "satisfying" (44%). However, 65% of all institutions require more information about RM by professional societies. Conclusion: Our results revealed heterogeneous patterns of RM in RO departments, although most departments adhered to common recommendations. Identified mismatches between recommendations and implementation of RM provide baseline data for future research and support definition of teaching content. [ABSTRACT FROM AUTHOR]

Amisulbrom is an oomycete-specific fungicide that was developed by Nissan Chemical Industries Limited. The exposure of developing zebrafish embryo to amisulbrom caused disorders in the visual phototransduction system. However, the potential toxic mechanisms of amisulbrom on retinal development remains unclear. The research purpose of this study was to evaluate the adverse effects of amisulbrom on retinal development in a model organism, the zebrafish. Zebrafish embryos were treated with 0, 0.0075, 0.075, or 0.75 μM amisulbrom from 3 h post-fertilization (hpf) to 72 hpf. Compared with the control group, amisulbrom-treated zebrafish embryos displayed phenotypic microphthalmia, dysregulation of gene transcription levels (alcama, prox1a, sox2, vsx1, rho, bluops, rdops, uvops, and grops) related to the retinal cell layer differentiation, and increased retinal apoptosis. In addition, the content of glutathione and malondialdehyde increased significantly after exposure to amisulbrom. Overall, our data demonstrate the toxicity of amisulbrom to eye development, which will help to assess the potential ecotoxicological impacts posed by amisulbrom to aquatic species. [ABSTRACT FROM AUTHOR]

The eyes of aquatic organisms may be damaged by exposure to pollutants. Zebrafish is a common laboratory model to study ocular toxicity, combining both fish and vertebrate characteristics. The toxic effects on zebrafish eyes caused by pollutants include morphological changes and damage to the retina at the molecular, cellular, and tissue levels; and abnormalities in the visual phototransduction and electrical signal transmission processes. Such damage induces functional disorders of vision-related behaviors. The underlying mechanisms include thyroid hormone signaling, retinoic acid signaling, and retinal glucose metabolism. Here, we review the ocular toxicity phenotypes and related signaling pathways induced by contaminants. We present detection methods and emerging tools for studying ocular toxicity. We also propose a model to predict the potential ocular toxicity of contaminants. [ABSTRACT FROM AUTHOR]

Long-term exposure to ionizing radiation (IR) can cause dire health consequences even less than the dose limits. Previous biomonitoring studies have focused more on complete blood counts (CBCs), with non-coherent results. In this study, we aimed to investigate the association between exposure to IR and cytokine interleukin-6 (IL-6) along with hematological parameters in Tabriz megacity's radiation workers. In this hospital-based study, blood samples were taken from 33 radiation workers (exposed group) and 34 non-radiation workers (control group) in 4 hospitals. Absorbed radiation dose was measured by a personal film badge dosimeter in radiation workers. The studied biomarkers and all of the selected covariates were measured and analyzed using adjusted multiple linear regression models. The exposed doses for all radiation workers were under the dose limits (overall mean = 1.18 mSv/year). However, there was a significant association between exposure to ionizing radiation and IL-6 (49.78 vs 36.17; t = 2.4; p = 0.02) and eosinophils (0.17 vs 0.14; t = 2.02; p = 0.049). The difference between the mean of the other biomarkers in radiation workers was not statistically significant compared to the control group. This study demonstrated that long-term exposure to ionizing radiation, even under the dose limits, is related to a significantly increased level of some blood biomarkers (Il-6 and eosinophil) that, in turn, can cause subsequent health effects such as cancer. [ABSTRACT FROM AUTHOR]

Hexafluoropropylene oxide-dimer acid (HFPO-DA) is one of the emerging replacements for the "forever" carcinogenic and toxic long-chain PFAS. HFPO-DA is a polymerization aid used for manufacturing fluoropolymers, whose global distribution and undetermined toxic properties are a concern regarding human and ecological health. To assess embryotoxic potential, zebrafish embryos were exposed to HFPO-DA at concentrations of 0.5–20,000 mg/L at 24-, 48-, and 72-h post-fertilization (hpf). Heart rate increased significantly in embryos exposed to 2 mg/L and 10 mg/L HFPO-DA across all time points. Spinal deformities and edema phenotypes were evident among embryos exposed to 1000–16,000 mg/L HFPO-DA at 72 hpf. A median lethal concentration (LC50) was derived as 7651 mg/L at 72 hpf. Shallow RNA sequencing analysis of 9465 transcripts identified 38 consistently differentially expressed genes at 0.5 mg/L, 1 mg/L, 2 mg/L, and 10 mg/L HFPO-DA exposures. Notably, seven downregulated genes were associated with visual response, and seven upregulated genes were expressed in or regulated the cardiovascular system. This study identifies biological targets and molecular pathways affected during animal development by an emerging, potentially problematic, and ubiquitous industrial chemical. [ABSTRACT FROM AUTHOR]

Bi-allelic mutations in the gene coding for human trans-membrane anterior–posterior transformation protein 1 (TAPT1) result in a broad phenotypic spectrum, ranging from syndromic disease with severe skeletal and congenital abnormalities to isolated early-onset cataract. We present here the first patient with a frameshift mutation in the TAPT1 gene, resulting in both bilateral early-onset cataract and skeletal abnormalities, in addition to several dysmorphic features, in this way further expanding the phenotypic spectrum associated with TAPT1 mutations. A tapt1a/tapt1b double knock-out (KO) zebrafish model generated by CRISPR/Cas9 gene editing revealed an early larval phenotype with eye malformations, loss of vision, increased photokinetics and hyperpigmentation, without visible skeletal involvement. Ultrastructural analysis of the eyes showed a smaller condensed lens, loss of integrity of the lens capsule with formation of a secondary lens and hyperplasia of the cells in the ganglion and inner plexiform layers of the retina. Transcriptomic analysis pointed to an impaired lens development with aberrant expression of many of the crystallin and other lens-specific genes. Furthermore, the phototransduction and visual perception pathways were found to be significantly disturbed. Differences in light perception are likely the cause of the increased dark photokinetics and generalized hyperpigmentation observed in this zebrafish model. In conclusion, this study validates TAPT1 as a new gene for early-onset cataract and sheds light on its ultrastructural and molecular characteristics. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to compare the patient journey through the head and neck clinic across 13 years of service improvement. We aimed to compare pick-up rates of cancer; number of patients receiving tissue diagnoses at first visit; and number of patients who were discharged on their first visit. Methods: In the one-stop head and neck cancer clinic, the demographic data, investigations and outcomes for 277 patients who attended in 2004 were compared to those of 205 patients who attended in 2017. The number of patients receiving ultrasonography and fine needle aspiration cytology was compared. Patient outcomes were analysed: specifically, the number discharged on first visit and the number of malignancies diagnosed. Results: The pick-up rate for malignancy from 2004 to 2017 has remained stable (17.3% vs 17.1%). The number of patients receiving ultrasound has remained stable from 264 (95%) in 2004 to 191 (93%) in 2017. The number undergoing FNA has decreased from 139 (50%) to 68 (33%) (p < 0.01). The number of patient's discharged on the first visit has significantly increased from 82 (30%) in 2004 to 89 (43%) in 2017 (p < 0.01). Conclusion: The one-stop clinic provides an effective and efficient means of head and neck lump assessment. Since inception of this service, the accuracy of diagnostic investigation has improved over time. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is one of the leading causes of blindness in the world. While there is a major focus on the study of juvenile/adult DR, the effects of hyperglycemia during early retinal development are less well studied. Recent studies in embryonic zebrafish models of nutritional hyperglycemia (high-glucose exposure) have revealed that hyperglycemia leads to decreased cell numbers of mature retinal cell types, which has been related to a modest increase in apoptotic cell death and altered cell differentiation. However, how embryonic hyperglycemia impacts cell proliferation in developing retinas still remains unknown. Here, we exposed zebrafish embryos to 50 mM glucose from 10 h postfertilization (hpf) to 5 days postfertilization (dpf). First, we confirmed that hyperglycemia increases apoptotic death and decreases the rod and Müller glia population in the retina of 5-dpf zebrafish. Interestingly, the increase in cell death was mainly observed in the ciliary marginal zone (CMZ), where most of the proliferating cells are located. To analyze the impact of hyperglycemia in cell proliferation, mitotic activity was first quantified using pH3 immunolabeling, which revealed a significant decrease in mitotic cells in the retina (mainly in the CMZ) at 5 dpf. A significant decrease in cell proliferation in the outer nuclear and ganglion cell layers of the central retina in hyperglycemic animals was also detected using the proliferation marker PCNA. Overall, our results show that nutritional hyperglycemia decreases cellular proliferation in the developing retina, which could significantly contribute to the decline in the number of mature retinal cells. [ABSTRACT FROM AUTHOR]

Healthcare relies upon the accurate and safe delivery of patient care. This is only achievable when systems are developed to ensure high quality, robust outcomes, for instance quality management systems. The concept of quality management can take on a different meaning depending on the context in which it is found. To add complication, the amount of education required for quality management will vary depending on one's exposure to the implementation of quality systems. In part to address these issues, the Australasian College of Physical Scientists and Engineers in Medicine (ACPSEM) Queensland Branch held a quality management webinar for members and non-members across Australia and New Zealand. The purpose of the webinar was to educate and facilitate discussion regarding the application of quality management principles for the ACPSEM profession. In conjunction, a pre- and post-webinar survey was conducted to gain an insight into existing knowledge and attitudes within the professions governed by the ACPSEM and students undertaking related studies. This paper authored by the webinar speakers reintroduces the quality management principles that were discussed in webinar, exemplifies the importance of quality management skills within the ACPSEM professions and presents the results of the surveys, promoting the need for more educational resources on quality management tools. [ABSTRACT FROM AUTHOR]

Scoliosis is a common spinal deformity that considerably affects the physical and psychological health of patients. Studies have shown that genetic factors play an important role in scoliosis. However, its etiopathogenesis remain unclear, partially because of the genetic heterogeneity of scoliosis and the lack of appropriate model systems. Recently, the development of efficient gene editing methods and high-throughput sequencing technology has made it possible to explore the underlying pathological mechanisms of scoliosis. Owing to their susceptibility for developing scoliosis and high genetic homology with human, zebrafish are increasingly being used as a model for scoliosis in developmental biology, genetics, and clinical medicine. Here, we summarize the recent advances in scoliosis research on zebrafish and discuss the prospects of using zebrafish as a scoliosis model. [ABSTRACT FROM AUTHOR]

The increasing worldwide burden of cancer makes it imperative that every country develop a comprehensive cancer control programme. In the past, cancer control in Central and Eastern Europe was inadequate, particularly when compared to many wealthier Western European countries. We analyse interregional differences in Europe to the approach to comprehensive cancer care, with a focus on head and neck squamous cell carcinoma using the case of Poland as a representative example. Due to national plans major improvements have been achieved in the field of prevention and in radiotherapy delivery having a measurable and positive impact on treatment outcomes. In head and neck cancers a notable move towards multidisciplinary approach has been made, combining surgery, radiotherapy and chemotherapy accompanied by rehabilitation and social support. In Poland and several other Eastern and Central European countries a shortage of physicians in the field of oncology was noted. The main conclusion is that the special plans are needed in Central and Eastern Europe or those existing must be extended for another decade to fulfil the EU requirement of providing all European citizens with equal access to quality cancer care. [ABSTRACT FROM AUTHOR]

Purpose of Review: The review focuses on the shared risk factors observed between coronary heart disease and cancer, cancer therapeutics causing coronary heart disease, and potential strategies to mitigate atherosclerosis in patients with cancer. Recent Findings: The pathophysiology behind how traditional cardiovascular risk factors also contribute to cancer development and mortality is increasingly recognized. In addition, newer cancer therapies, such as immune checkpoint inhibitors, cause increased inflammation leading to increased cardiovascular events. Summary: Traditional coronary heart disease risk factors such as obesity, hypertension, diabetes, and hyperlipidemia also contribute to cancer development and worse cancer outcomes. Cancer therapeutics can also lead to atherosclerotic events in addition to the shared risk factors present at the time of cancer diagnosis. Understanding the pathophysiology, using multidisciplinary care teams, and developing machine learning algorithms for individualized patient care will help to mitigate the risk of coronary heart disease in patients with cancer. [ABSTRACT FROM AUTHOR]

The present work reports on the microdosimetry measurements performed with the two first multi-arrays of microdosimeters with the highest radiation sensitive surface covered so far. The sensors are based on new silicon-based radiation detectors with a novel 3D cylindrical architecture. Each system consists of arrays of independent microdetectors covering 2 mm × 2 mm and 0.4 mm × 12 cm radiation sensitive areas, the sensor distributions are arranged in layouts of 11 × 11 microdetectors and 3 × 3 multi-arrays, respectively. We have performed proton irradiations at several energies to compare the microdosimetry performance of the two systems, which have different spatial resolution and detection surface. The unitcell of both arrays is a 3D cylindrical diode with a 25 μ m diameter and a 20 μ m depth that results in a welldefined and isolated radiation sensitive micro-volume etched inside a silicon wafer. Measurements were carried out at the Accélérateur Linéaire et Tandem à Orsay (ALTO) facility by irradiating the two detection systems with monoenergetic proton beams from 6 to 20 MeV at clinical-equivalent fluence rates. The microdosimetry quantities were obtained with a spatial resolution of 200 μ m and 600 μ m for the 11 × 11 system and for the 3 × 3 multi-array system, respectively. Experimental results were compared with Monte Carlo simulations and an overall good agreement was found. The good performance of both microdetector arrays demonstrates that this architecture and both configurations can be used clinically as microdosimeters for measuring the lineal energy distributions and, thus, for RBE optimization of hadron therapy treatments. Likewise, the results have shown that the devices can be also employed as a multipurpose device for beam monitoring in particle accelerators. [ABSTRACT FROM AUTHOR]

Purpose: RENORT is an application (app) developed to assess the role of radiotherapy in the treatment of cancer using the oncology information systems (OIS). Methods/Patients: The RENORT app was used to analyze the data for all patients seen and/or treated at six radiation oncology departments in Spain in 2019. This app can be used to extract the demographic data, treatment sequence, disease status, and radiotherapy treatments from the ARIA and Mosaiq OIS. Results: A total of 6564 treatments were performed at these six centers in 2019. Most patients (56.9%) were males (females 43.1%). The mean patient age was 64.9 years. The most common treatment types and sites were as follows: metastases/palliative care (25.9%), followed by breast (19.0%), genitourinary (13.7%), lung (10.1%), head and neck (6.0%), rectal (6.0%), gynecological (4.9%), and other (< 4%) cancers. Distribution by disease stage was as follows: breast cancer: 75.5% early stage (stages 0, I, and II); lung: 63.1% advanced stage (III and IV); and head and neck: 72.1% advanced. Treatment intent was curative in 76.5% of cases and palliative in 23.5%. The most common techniques were intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) (41.4%), followed by three-dimensional conformal radiation therapy (3D-CRT) (39.2%); stereotactic body radiotherapy (SBRT) (8.1%); brachytherapy (5.5%); radiosurgery (2.1%); fractionated stereotactic radiotherapy to the brain (1.4%); and intraoperative radiotherapy (1.4%). Hypofractionation was used in 62.3% of curative treatments (mean number of fractions = 16.5). Conclusions: RENORT is a free app that is available for the two main oncology information systems used in most radiation oncology departments. This app has demonstrated the capacity to extract data from these systems, which in turns allows for a comprehensive analysis and better understanding of the role of radiotherapy in the treatment of cancer. [ABSTRACT FROM AUTHOR]

Metal artefacts degrade clinical image quality which decreases the confidence of using computed tomography (CT) for the delineation of key structures for treatment planning and leads to dose errors in affected areas. In this work, we investigated accuracy of doses computed by the Eclipse treatment planning system near and inside metallic elements for two different computation algorithms. An impact of CT metal artefact reduction methods on the resulting calculated doses has also been assessed. A water phantom including Gafchromic film and metal inserts was irradiated (max dose 5 Gy) using a 6 MV photon beam. Three materials were tested: titanium, alloy 600, and tungsten. The phantom CT images were obtained with the pseudo-monoenergetic reconstruction (PMR) and the iterative metal artefact reduction (iMAR). Image sets were used for dose calculation using an Eclipse treatment planning station (TPS). Monte Carlo (MC) simulations were used to predict the true dose distribution in the phantom allowing for comparison with doses measured by film and calculated by TPS. Measured and simulated percentage depth doses (PDDs) were not statistically different (p > 0.618). Regional differences were observed at edges of metallic objects (max 8% difference). However, PDDs simulated with and without film were statistically different (p < 0.002). PDDs calculated by the Acuros XB algorithm based on the dose-to-medium approach best matched the MC reference regardless of the CT reconstruction methods and inserts used (p > 0.078). PDDs obtained using other algorithms significantly differ from the MC values (p < 0.011). The Acuros XB algorithm with a dose-to-medium approach provides reliable dose calculation in all metal regions when using the Varian system. The inability of the AAA algorithm to model backscatter dose significantly limits its clinical application in the presence of metal. No significant impact on the dose calculation was found for a range of metal artefact reduction strategies. [ABSTRACT FROM AUTHOR]

Objective: This study aims to assess the outcomes of adjuvant interstitial brachytherapy (BT) to the tumor bed for oral cavity squamous cell carcinoma (SCC), and to compare the oncological outcomes and toxicity profile of low-dose-rate (LDR) and pulsed-dose-rate (PDR) BT. Design: This retrospective single-center study included all patients who underwent postoperative LDR- or PDR-BT to the tumor bed as the sole adjuvant treatment for an oral tongue or floor of the mouth SCC between January 2000 and December 2020. Results: A total of 79 patients were eligible for this study. The cohort was divided into an LDR group (n = 38) and a PDR group (n = 41). The median time interval between surgery and brachytherapy was 55 days. Median delivered total dose was 55 Gy and median hospital stay was 5 days. Five patients (8.3%) experienced grade 3–4 early toxicity, 2 in the LDR group and 3 in the PDR group. Late toxicities were present in 28 patients (44.4%) and were dominated by grade 1–2 residual pain and dysesthesia, without a statistical difference between the groups. After a median follow-up of 65.1 months, 5‑year local control (LC), disease-free survival (DFS), and overall survival (OS) for the whole cohort were 76.3% (95% CI = 63.4–85.1), 61.6% (95% CI = 49.0–72.0), and 71.4% (95% CI = 58.6–80.8), respectively. Conclusion: Adjuvant BT after excision of oral cavity SCC provides satisfactory oncological outcomes along with good tolerance. In our study, PDR-BT showed similar oncological and functional results to LDR-BT in this indication. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is a blinding eye disease affecting nearly two million people worldwide. Dogs are affected with a similar illness termed progressive retinal atrophy (PRA). Lapponian herders (LHs) are affected with several types of inherited retinal dystrophies, and variants in PRCD and BEST1 genes have been associated with generalized PRA and canine multifocal retinopathy 3 (cmr3), respectively. However, all retinal dystrophy cases in LHs are not explained by these variants, indicating additional genetic causes of disease in the breed. We collected DNA samples from 10 PRA affected LHs, with known PRCD and BEST1 variants excluded, and 34 unaffected LHs. A genome-wide association study identified a locus on CFA20 (praw = 2.4 × 10–7, pBonf = 0.035), and subsequent whole-genome sequencing of an affected LH revealed a missense variant, c.3176G>A, in the intraflagellar transport 122 (IFT122) gene. The variant was also found in Finnish Lapphunds, in which its clinical relevancy needs to be studied further. The variant interrupts a highly conserved residue, p.(R1059H), in IFT122 and likely impairs its function. Variants in IFT122 have not been associated with retinal degeneration in mammals, but the loss of ift122 in zebrafish larvae impaired opsin transport and resulted in progressive photoreceptor degeneration. Our study establishes a new spontaneous dog model to study the role of IFT122 in RP biology, while the affected breed will benefit from a genetic test for a recessive condition. [ABSTRACT FROM AUTHOR]

Amyloid precursor protein (APP) is expressed in many tissues in human, mice and in zebrafish. In zebrafish, there are two orthologues, Appa and Appb. Interestingly, some cellular processes associated with APP overlap with cilia-mediated functions. Whereas the localization of APP to primary cilia of in vitro-cultured cells has been reported, we addressed the presence of APP in motile and in non-motile sensory cilia and its potential implication for ciliogenesis using zebrafish, mouse, and human samples. We report that Appa and Appb are expressed by ciliated cells and become localized at the membrane of cilia in the olfactory epithelium, otic vesicle and in the brain ventricles of zebrafish embryos. App in ependymal cilia persisted in adult zebrafish and was also detected in mouse and human brain. Finally, we found morphologically abnormal ependymal cilia and smaller brain ventricles in appa−/−appb−/− mutant zebrafish. Our findings demonstrate an evolutionary conserved localisation of APP to cilia and suggest a role of App in ciliogenesis and cilia-related functions. [ABSTRACT FROM AUTHOR]

Structural defects in primary cilia have robust effects in diverse tissues and systems. However, how disorders of ciliary length lead to functional outcomes are unknown. We examined the functional role of a ciliary length control mechanism of FBW7-mediated destruction of NDE1, in mesenchymal stem cell (MSC) differentiation. We show that FBW7 functions as a master regulator of both negative (NDE1) and positive (TALPID3) regulators of ciliogenesis, with an overall positive net effect on primary cilia formation, MSC differentiation to osteoblasts, and bone architecture. Deletion of Fbxw7 suppresses ciliation, Hedgehog activity, and differentiation, which are partially rescued in Fbxw7/Nde1-null cells. We also show that NDE1, despite suppressing ciliogenesis, promotes MSC differentiation by increasing the activity of the Hedgehog pathway by direct binding and enhancing GLI2 activity in a cilia-independent manner. We propose that FBW7 controls a protein-protein interaction network coupling ciliary structure and function, which is essential for stem cell differentiation. Petsouki et al. dissect the importance of FBW7-mediated regulation of NDE1 and TALPID3 in mesenchymal stem cells (MSCs). They find that by modulating the abundance of negative (NDE1) and positive (TALPID3) cilia regulators, FBW7 contributes to both the assembly and signaling functions of primary cilia that are necessary for osteoblast differentiation. [ABSTRACT FROM AUTHOR]

All vertebrates share a canonical retina with light-sensitive photoreceptors in the outer retina. These photoreceptors are of two kinds: rods and cones, adapted to low and bright light conditions, respectively. They both show a peculiar morphology, with long outer segments, comprised of ordered stacks of disc-shaped membranes. These discs host numerous proteins, many of which contribute to the visual transduction cascade. This pathway converts the light stimulus into a biological signal, ultimately modulating synaptic transmission. Recently, the zebrafish (Danio rerio) has gained popularity for studying the function of vertebrate photoreceptors. In this review, we introduce this model system and its contribution to our understanding of photoreception with a focus on the cone visual transduction cascade. [ABSTRACT FROM AUTHOR]

Evolutionary developmental biology, or Evo-Devo for short, has become an established field that, broadly speaking, seeks to understand how changes in development drive major transitions and innovation in organismal evolution. It does so via integrating the principles and methods of many subdisciplines of biology. Although we have gained unprecedented knowledge from the studies on model organisms in the past decades, many fundamental and crucially essential processes remain a mystery. Considering the tremendous biodiversity of our planet, the current model organisms seem insufficient for us to understand the evolutionary and physiological processes of life and its adaptation to exterior environments. The currently increasing genomic data and the recently available gene-editing tools make it possible to extend our studies to non-model organisms. In this review, we review the recent work on the regulatory signaling of developmental and regeneration processes, environmental adaptation, and evolutionary mechanisms using both the existing model animals such as zebrafish and Drosophila, and the emerging nonstandard model organisms including amphioxus, ascidian, ciliates, single-celled phytoplankton, and marine nematode. In addition, the challenging questions and new directions in these systems are outlined as well. [ABSTRACT FROM AUTHOR]

Purpose: Total body irradiation (TBI) can be safely delivered on TomoTherapy (Accuray, Sunnyvale, CA, USA) in both pediatric and adult patients with proper imaging and planning despite the length constraint of 135 cm. To overcome this limitation, two CT (Computed Tomography) scans (CT1& CT2) are taken in patients above 135 cm in height. Adequate junction dose coverage is important in TBI. Presently, there is no clinical report with a focus on the quality of dose distribution at the CT junction in view of the guidelines on quality of coverage from the RTOG. Hence, our main objectives were to evaluate the dose distribution and quality of coverage at the junction in 16 patients who received TBI using TomoTherapy. Methods: PTV(upper) and PTV(lower) along with a junction were created on CT1 and CT2, respectively. Subsequently, the 10 cm junction in the thigh region was divided into five target volumes of 2 cm thickness with dose prescription ranging from 10 to 90% to deliver a total dose equal to 100% when fused. Results: The D50 was equal to the prescribed dose in most of the cases ranging from 99.5 to 104% for PTV(upper), 100–103% for PTV(lower), and 99.5–108% for junctional PTVs (1PTV, 2PTV, 3PTV, 4PTV, and 5PTV). The average D95 doses from PTV(upper) and PTV(lower) were 97 ± 1.4% and 96.7 ± 1.08%, respectively. The average D95 doses for 1PTV, 2PTV, 3PTV, 4PTV, and 5PTV were 96.1 ± 1.88%, 91.6 ± 1.82%, 87.3 ± 1.5%, 91.6 ± 1.4%, and 96.2 ± 1.5% respectively. QRTOG values ranged between 0.85 and 1.05 and were in concordance with RTOG guidelines. Conclusion: Since junction-based planning was required for most TBI patients, it is essential to evaluate the quality of dose coverage in the junction for better TBI plans. [ABSTRACT FROM AUTHOR]

Cancer treatment continues to be one of the most serious public health issues in the world. The overexpression of BRD4 protein has led to a series of malignant tumors, hence the development of small molecule BRD4 protease inhibitors has always been a hot spot in the field of medical research. In this study, a series of 4,5-dihydro-[1, 2, 4] triazolo [4, 3-f] pteridine derivatives were used to establish 3D/2D-QSAR models and to discuss the relationship between inhibitor structure and activity. Four ideal models were established, including the comparative molecular field analysis (CoMFA: q cv 2 = 0.574, r ncv 2 = 0.947) model, comparative molecular similarity index analysis (CoMSIA: q cv 2 = 0.622, r ncv 2 = 0.916) model, topomer CoMFA ( q cv 2 = 0.691, r ncv 2 = 0.912) model and hologram quantitative structure–activity relationship (HQSAR: q cv 2 = 0.759, r ncv 2 = 0.963) model. They show quite good external predictive power for the test set, with r ncv 2 pred values of 0.602, 0.624, 0.671 and 0.750, respectively. In addition, the contour and color code map given by the 2D/3D-QSAR model with the results of molecular docking analyzed to chalk up modification methods for improving inhibitory activity, which was verified by designing novel compounds. The analysis results are helpful to promote the modification of the inhibitor framework and to provide a reference for the construction of new and promising BRD4 inhibitor compounds. [ABSTRACT FROM AUTHOR]

Purpose: Keratoconus is a potentially blinding condition that slowly deforms the cornea in young people. Despite the increasing prevalence of keratoconus, the exact aetiology of the condition is unknown. This first systematic review examines the evidence of eye rubbing and its association with keratoconus and presents the findings of the meta-analysis. Methods: Two independent reviewers searched the electronic databases for all potential articles published from 1st of January 1900 to 31st of July 2020 on eye rubbing and keratoconus. The researchers assessed the methodological quality of the studies using the Newcastle-Ottawa scale for observational studies. The assessment for statistical heterogeneity was estimated using chi-square and I-square (I2) tests. A p value of < 0.05 was considered as statistically significant and I2 < 30% as homogenous. Begg funnel plot was used to interpret the asymmetry or small study effects. Results: Eight case-control studies were included in this systematic review. Two studies assessed eye rubbing without odds ratios and thus were excluded. The pooled odds ratios for the six remaining studies included in the meta-analysis was 6.46 (95% CI 4.12–10.1). The study results were heterogenous (I2 = 71.69 [95% CI 35.14–87.88]). All the studies scored moderate quality methodology on the Newcastle-Ottawa scale. Begg funnel plot showed asymmetry supporting heterogeneity. Conclusion: Eye rubbing showed consistent association with keratoconus. However, the current evidence is limited to only a small number of case-control studies which present as heterogeneous and of sub-optimal methodological quality. Additionally, the cause-effect temporal relationship cannot be determined. Further studies are needed to address this intricate relationship of eye rubbing and its induction, ongoing progression, and severity of keratoconus. [ABSTRACT FROM AUTHOR]

To assess adherence to standard clinical practice for the diagnosis and treatment of patients undergoing prostate cancer (PCa) radiotherapy in four European countries using clinical audits as part of the international IROCA project. Multi-institutional, retrospective cohort study of 240 randomly-selected patients treated for PCa (n = 40/centre) in the year 2015 at six European hospitals. Clinical indicators applicable to general and PCa-specific radiotherapy processes were evaluated. All data were obtained directly from medical records. The audits were performed in the year 2017. Adherence to clinical protocols and practices was satisfactory, but with substantial inter-centre variability in numerous variables, as follows: staging MRI (range 27.5–87.5% of cases); presentation to multidisciplinary tumour board (2.5–100%); time elapsed between initial visit to the radiation oncology department and treatment initiation (42–102.5 days); number of treatment interruptions ≥ 1 day (7.5–97.5%). The most common deviation from standard clinical practice was inconsistent data registration, mainly failure to report data related to diagnosis, treatment, and/or adverse events. This clinical audit detected substantial inter-centre variability in adherence to standard clinical practice, most notably inconsistent record keeping. These findings confirm the value of performing clinical audits to detect deviations from standard clinical practices and procedures. [ABSTRACT FROM AUTHOR]

The base of the cilium comprising the transition zone (TZ) and transition fibers (TF) acts as a selecting gate to regulate the intraflagellar transport (IFT)-dependent trafficking of proteins to and from cilia. Before entering the ciliary compartment, IFT complexes and transported cargoes accumulate at or near the base of the cilium. The spatial organization of IFT proteins at the cilia base is key for understanding cilia formation and function. Using stochastic optical reconstruction microscopy (STORM) and computational averaging, we show that seven TZ, nine IFT, three Bardet–Biedl syndrome (BBS), and one centrosomal protein, form 9-clustered rings at the cilium base of a ciliate Tetrahymena thermophila. In the axial dimension, analyzed TZ proteins localize to a narrow region of about 30 nm while IFT proteins dock approximately 80 nm proximal to TZ. Moreover, the IFT-A subcomplex is positioned peripheral to the IFT-B subcomplex and the investigated BBS proteins localize near the ciliary membrane. The positioning of the HA-tagged N- and C-termini of the selected proteins enabled the prediction of the spatial orientation of protein particles and likely cargo interaction sites. Based on the obtained data, we built a comprehensive 3D-model showing the arrangement of the investigated ciliary proteins. [ABSTRACT FROM AUTHOR]

Background: Despite the pivotal role of radiotherapy in oncology, the provision of radiation treatments remains inadequate in many areas of the world. The present report is an assessment conducted among Radiation Oncology centers of Veneto region with the aim to collect information concerning radiotherapy assets and technological equipment availability. Methods: Data concerning Veneto Radiation Oncology departments about radiotherapy activities, number of treatments, techniques used and radiotherapy machines available were collected. The reference time period was 2018. Reimbursement system databases and business intelligence systems were used. Extra-regional attraction and migration were evaluated. When available, data were compared to previous years. Results: Veneto in 2018 was endowed with 1 megavolt unit for about 153,000 inhabitants. The number of megavolt machines per million inhabitants resulted to be 6.72. In 51% of radiotherapy treatments, intensity-modulated techniques were performed. Six percent of treatments were administered to extra-regional patients. Conclusion: Radiotherapy assets and equipment in Veneto seem to be appropriate to standard requests in terms of availability and technology. [ABSTRACT FROM AUTHOR]

Dynein axonemal light intermediate chain 1 (dnali1) is an important part of axonemal dyneins and plays an important role in the growth and development of animals. However, there is little information about dnali1 in fish. Herein, we cloned dnali1 gene from the genome of olive flounder (Paralichthys olivaceus), a commercially important maricultured fish in China, Japan, and Korea, and analyzed its expression patterns in different gender fish. The flounder dnali1 DNA sequence contained a 771 bp open reading frame (ORF), two different sizes of 5′ untranslated region (5′UTR), and a 1499 bp 3′ untranslated region (3′UTR). Two duplicated 922 nt fragments were found in dnali1 mRNA. The first fragment contained the downstream coding region and the front portion of 3′UTR, and the second fragment was entirely located in 3′UTR. Multiple alignments indicated that the flounder Dnali1 protein contained the putative conserved coiled-coil domain. Its expression showed sexually dimorphic with predominant expression in the flounder testis, and lower expression in other tissues. The gene with the longer 5′UTR was specifically expressed in the testis. The highest expression level in the testis was detected at stages IV and V. Transient expression analysis showed that the 922 bp repeated sequence 3′UTR of dnali1 down-regulated the expression of GFP at the early stage in zebrafish. The flounder dnali1 might play an important role in the testis, especially in the period of spermatogenesis, and the 5′UTR and the repetitive sequences in 3′UTR might contain some regulatory elements for the cilia. [ABSTRACT FROM AUTHOR]

Extracellular signals play essential roles during embryonic patterning by providing positional information in a concentration-dependent manner, and many such signals, like Wnt, fibroblast growth factor (FGF), Hedgehog (Hh), and retinoic acid, act by being secreted into the extracellular space, thereby triggering receptor-mediated responses in other cells. Isthmin1 (ism1) is a secreted protein whose gene expression pattern coincides with that of early dorsal determinants, nodal ligand genes like sqt and cyc, and with fgf8 during various phases of zebrafish development. Ism1 functions in early embryonic patterning and development are poorly understood; however, it has recently been shown to interact with nodal pathway genes to control organ asymmetry in chicken. Here, we show that misexpression of ism1 deletion constructs disrupts embryonic patterning in zebrafish and exhibits genetic interactions with both Fgf and nodal signaling. Unlike Fgf and nodal pathway mutants, CRISPR/Cas9-engineered ism1 mutants did not show obvious developmental defects. Further, in vivo single molecule fluorescence correlation spectroscopy (FCCS) showed that Ism1 diffuses freely in the extra-cellular space, with a diffusion coefficient similar to that of Fgf8a; however, our measurements do not support direct molecular interactions between Ism1 and either nodal ligands or Fgf8a in the developing zebrafish embryo. Together, data from gain- and loss-of-function experiments suggest that zebrafish Ism1 plays a complex role in regulating extracellular signals during early embryonic development. [ABSTRACT FROM AUTHOR]