Delphi consensus on stereotactic ablative radiotherapy for oligometastatic and oligoprogressive renal cell carcinoma-a European Society for Radiotherapy and Oncology study endorsed by the European Association of Urology.

The purpose of this European Society for Radiotherapy and Oncology (ESTRO) project, endorsed by the European Association of Urology, is to explore expert opinion on the management of patients with oligometastatic and oligoprogressive renal cell carcinoma by means of stereotactic ablative radiotherapy (SABR) on extracranial metastases, with the aim of developing consensus recommendations for patient selection, treatment doses, and concurrent systemic therapy. A questionnaire on SABR in oligometastatic renal cell carcinoma was prepared by a core group and reviewed by a panel of ten prominent experts in the field. The Delphi consensus methodology was applied, sending three rounds of questionnaires to clinicians identified as key opinion leaders in the field. At the end of the third round, participants were able to find consensus on eight of the 37 questions. Specifically, panellists agreed to apply no restrictions regarding age (25 [100%) of 25) and primary renal cell carcinoma histology (23 [92%] of 25) for SABR candidates, on the upper threshold of three lesions to offer ablative treatment in patients with oligoprogression, and on the concomitant administration of immune checkpoint inhibitor. SABR was indicated as the treatment modality of choice for renal cell carcinoma bone oligometatasis (20 [80%] of 25) and for adrenal oligometastases 22 (88%). No consensus or major agreement was reached regarding the appropriate schedule, but the majority of the poll (54%-58%) retained the every-other-day schedule as the optimal choice for all the investigated sites. The current ESTRO Delphi consensus might provide useful direction for the application of SABR in oligometastatic renal cell carcinoma and highlight the key areas of ongoing debate, perhaps directing future research efforts to close knowledge gaps.

Timely delivery of PORT for head and neck squamous cell carcinoma in a county hospital.

Objectives: The objective of this study was to compare the rate of post-operative radiation therapy (PORT) initiation within 6 weeks for head and neck squamous cell carcinoma patients treated at a safety net, academic institutio between 2019 and 2021 versus those treated in 2022 after implementation of a new clinical pathway. Methods: A retrospective case-control study was performed at a single tertiary care, safety-net, academic institution. Patient demographics, tumor characteristics, dates of surgery, and other treatment dates were collected from the electronic medical record. The time from surgery to PORT was calculated. Patients who started radiation treatment within 42 days of surgery were regarded as having started PORT on time. The demographics, tumor characteristics, and rate of timely PORT for the two cohorts of patients were compared. Results: From 2018 to 2021, our rate of PORT initiation within 6 weeks of surgery was 12% (n = 57). In 2022, our rate of timely PORT was 88% (n = 16), p < 0.5. Patient demographics and characteristics were similar with the exception of marital status and use of free-flap reconstruction. The 2022 cohort was more likely to be single (p < 0.5), and all patients underwent free-flap reconstruction in 2022 (p < 0.05). Conclusion: Early referrals, frequent communication, and use of a secure registry were the key to the success found by our group despite the socioeconomic challenges of our underserved, safety-net hospital patient population. The changes made at our institution should serve as a template for other institutions seeking to improve the quality of care for their HNSCC patients.

Measurement of the 2νßß Decay Half-Life of

We report on the results obtained with the global CUPID-0 background model, which combines the data collected in the two measurement campaigns for a total exposure of 8.82 kg×yr of ^{82}Se. We identify with improved precision the background sources within the 3 MeV energy region, where neutrinoless double ß decay of ^{82}Se and ^{100}Mo is expected, making more solid the foundations for the background budget of the next-generation CUPID experiment. Relying on the excellent data reconstruction, we measure the two-neutrino double ß-decay half-life of ^{82}Se with unprecedented accuracy: T_{1/2}^{2ν}=[8.69±0.05(stat)_{-0.06}^{+0.09}(syst)]×10^{19} yr.

Room-Temperature Dialkylamination of Chloroheteroarenes Using a Cu(II)/PTABS Catalytic System.

The dimethylamino functionality has significant importance in industrially relevant molecules and methodologies to install these efficiently are highly desirable. We report herein a highly efficient, room-temperature dimethylamination of chloroheteroarenes performed via the in-situ generation of dimethylamine using N,N-dimethylformamide (DMF) as precursor wiith a large substrate scope that includes various heteroarenes, purines as well as commercially relevant drugs such as altretamine, ampyzine and puromycin precursor.

Final Result on the Neutrinoless Double Beta Decay of

CUPID-0, an array of Zn^{82}Se cryogenic calorimeters, was the first medium-scale demonstrator of the scintillating bolometers' technology. The first project phase (March 2017-December 2018) allowed the most stringent limit on the neutrinoless double beta decay half-life of the isotope of interest, ^{82}Se, to be set. After a six month long detector upgrade, CUPID-0 began its second and last phase (June 2019-February 2020). In this Letter, we describe the search for neutrinoless double beta decay of ^{82}Se with a total exposure (phase I+II) of 8.82 kg yr^{-1} of isotope. We set a limit on the half-life of ^{82}Se to the ground state of ^{82}Kr of T_{1/2}^{0ν}(^{82}Se)>4.6×10^{24} yr (90% credible interval), corresponding to an effective Majorana neutrino mass m_{ßß}<(263-545) meV. We also set the most stringent lower limits on the neutrinoless decays of ^{82}Se to the 0_{1}^{+}, 2_{1}^{+}, and 2_{2}^{+} excited states of ^{82}Kr, finding 1.8×10^{23} yr, 3.0×10^{23} yr, and 3.2×10^{23} yr (90% credible interval) respectively.

Background identification in cryogenic calorimeters through α - α delayed coincidences.

Localization and modeling of radioactive contaminations is a challenge that ultra-low background experiments are constantly facing. These are fundamental steps both to extract scientific results and to further reduce the background of the detectors. Here we present an innovative technique based on the analysis of α - α delayed coincidences in 232 Th and 238 U decay chains, developed to investigate the contaminations of the ZnSe crystals in the CUPID-0 experiment. This method allows to disentangle surface and bulk contaminations of the detectors relying on the different probability to tag delayed coincidences as function of the α decay position.

Gelatin methacrylate hydrogels culture model for glioblastoma cells enriches for mesenchymal-like state and models interactions with immune cells.

Glioblastoma is the most lethal primary malignant brain tumor in adults. Simplified two-dimensional (2D) cell culture and neurospheres in vitro models fail to recapitulate the complexity of the tumor microenvironment, limiting its ability to predict therapeutic response. Three-dimensional (3D) scaffold-based models have emerged as a promising alternative for addressing these concerns. One such 3D system is gelatin methacrylate (GelMA) hydrogels, and we aimed to understand the suitability of using this system to mimic treatment-resistant glioblastoma cells that reside in specific niches. We characterized the phenotype of patient-derived glioma cells cultured in GelMA hydrogels (3D-GMH) for their tumorigenic properties using invasion and chemoresponse assays. In addition, we used integrated single-cell and spatial transcriptome analysis to compare cells cultured in 3D-GMH to neoplastic cells in vivo. Finally, we assessed tumor-immune cell interactions with a macrophage infiltration assay and a cytokine array. We show that the 3D-GMH system enriches treatment-resistant mesenchymal cells that are not represented in neurosphere cultures. Cells cultured in 3D-GMH resemble a mesenchymal-like cellular phenotype found in perivascular and hypoxic regions and recruit macrophages by secreting cytokines, a hallmark of the mesenchymal phenotype. Our 3D-GMH model effectively mimics the phenotype of glioma cells that are found in the perivascular and hypoxic niches of the glioblastoma core in situ, in contrast to the neurosphere cultures that enrich cells of the infiltrative edge of the tumor. This contrast highlights the need for due diligence in selecting an appropriate model when designing a study's objectives.

EFSA's OpenFoodTox: An open source toxicological database on chemicals in food and feed and its future developments.

Since its creation in 2002, the European Food Safety Authority (EFSA) has produced risk assessments for over 5000 substances in >2000 Scientific Opinions, Statements and Conclusions through the work of its Scientific Panels, Units and Scientific Committee. OpenFoodTox is an open source toxicological database, available both for download and data visualisation which provides data for all substances evaluated by EFSA including substance characterisation, links to EFSA's outputs, applicable legislations regulations, and a summary of hazard identification and hazard characterisation data for human health, animal health and ecological assessments. The database has been structured using OECD harmonised templates for reporting chemical test summaries (OHTs) to facilitate data sharing with stakeholders with an interest in chemical risk assessment, such as sister agencies, international scientific advisory bodies, and others. This manuscript provides a description of OpenFoodTox including data model, content and tools to download and search the database. Examples of applications of OpenFoodTox in chemical risk assessment are discussed including new quantitative structure-activity relationship (QSAR) models, integration into tools (OECD QSAR Toolbox and AMBIT-2.0), assessment of environmental footprints and testing of threshold of toxicological concern (TTC) values for food related compounds. Finally, future developments for OpenFoodTox 2.0 include the integration of new properties, such as physico-chemical properties, exposure data, toxicokinetic information; and the future integration within in silico modelling platforms such as QSAR models and physiologically-based kinetic models. Such structured in vivo, in vitro and in silico hazard data provide different lines of evidence which can be assembled, weighed and integrated using harmonised Weight of Evidence approaches to support the use of New Approach Methodologies (NAMs) in chemical risk assessment and the reduction of animal testing.

Final Result of CUPID-0 Phase-I in the Search for the

CUPID-0 is the first pilot experiment of CUPID, a next-generation project for the measurement of neutrinoless double beta decay (0νDBD) with scintillating bolometers. The detector, consisting of 24 enriched and 2 natural ZnSe crystals, has been taking data at Laboratori Nazionali del Gran Sasso from June 2017 to December 2018, collecting a ^{82}Se exposure of 5.29 kg×yr. In this Letter we present the phase-I results in the search for 0νDBD. We demonstrate that the technology implemented by CUPID-0 allows us to reach the lowest background for calorimetric experiments: (3.5_{-0.9}^{+1.0})×10^{-3} counts/(keV kg yr). Monitoring 3.88×10^{25} ^{82}Se nuclei×yr we reach a 90% credible interval median sensitivity of T_{1/2}^{0ν}>5.0×10^{24} yr and set the most stringent limit on the half-life of ^{82}Se 0νDBD: T_{1/2}^{0ν}>3.5×10^{24} yr (90% credible interval), corresponding to m_{ßß}<(311-638) meV depending on the nuclear matrix element calculations.

Evaluating Treatment Patterns for Small Cell Carcinoma of the Colon Using the National Cancer Database (NCDB).

OBJECTIVE(S): The objective of this study was to characterize the clinicopathological prognostic factors and treatment patterns for small cell carcinoma (SCC) of the colon, a rare disease without standard treatment guidelines. METHODS: We analyzed clinicopathological and treatment variables for 503 cases of histologically proven SCC colon entered into the National Cancer Database (NCDB) between 2004 and 2013. Survival curves were generated using Kaplan-Meier and compared by the log-rank test. Cox proportional hazard regression was used to control for covariates and evaluate the effect of different treatment modalities on overall survival. RESULTS: Four hundred seventy-two (93.8%) patients had complete clinical staging information and were therefore included in our analysis. Of these patients, 149 (31.5%) had limited stage disease (LD) and 323 (68.4%) had extensive stage disease (ED) at presentation. Median overall survival (OS) for patients with ED was significantly lower than for those with LD (4.04 months vs. 21.82 months; p < 0.001). Multivariate Cox regression analysis showed administration of chemotherapy was associated with improved survival in patients with LD and ED (p = 0.026, p < 0.001) while surgery was not associated with improved survival in patients with LD or ED (p = 0.943, p = 0.630). Radiation therapy was associated with improved survival in patients with ED (p = 0.044). CONCLUSIONS: SCC of the colon carries a poor prognosis, especially in patients presenting with metastatic disease. Surgery and chemotherapy are administered more frequently than radiation, and chemotherapy is associated with improved survival, unlike surgery.

Evidence of Single State Dominance in the Two-Neutrino Double-ß Decay of

We report on the measurement of the two-neutrino double-ß decay of ^{82}Se performed for the first time with cryogenic calorimeters, in the framework of the CUPID-0 experiment. With an exposure of 9.95 kg yr of Zn^{82}Se, we determine the two-neutrino double-ß decay half-life of ^{82}Se with an unprecedented precision level, T_{1/2}^{2ν}=[8.60±0.03(stat) _{-0.13}^{+0.19}(syst)]×10^{19} yr. The very high signal-to-background ratio, along with the detailed reconstruction of the background sources allowed us to identify the single state dominance as the underlying mechanism of such a process, demonstrating that the higher state dominance hypothesis is disfavored at the level of 5.5σ.

Aqueous electromigration of single-walled carbon nanotubes and co-electromigration with copper ions.

The electromigration behaviour of raw and acid purified single walled carbon nanotubes (SWCNTs) in dilute aqueous systems (0.0034 mg mL-1), in the absence of surfactant, with the addition of either 0.85 M acetic acid or 0.1 M CuSO4, was evaluated using a 2-inch copper cathode and either a 2-inch copper or 0.5-inch platinum anode. The results showed that the electromigration of raw SWCNTs (with a high catalyst residue) in the presence of CuSO4 resulted in the formation of a Cu-SWCNT composite material at the cathode. In contrast, acid purified SWCNTs were observed to diffuse to a copper anode, creating fibrillated agglomerates with "rice-grain"-like morphologies. Upon acidification with acetic acid (or addition of CuSO4) the direction of electromigration reversed towards the cathode as a result of coordination of Cu2+ to the functional groups on the SWCNT overcoming the inherent negative charge of the acid purified SWCNTs. The result was the co-deposition of SWCNTs and Cu metal on the cathode. Addition of 0.005 M EDTA sequesters some of the Cu2+ and resulted in the separation of metal decorated SWCNTs to the cathode and un-decorated SWCNTs to the anode. The resulting SWCNT and Cu/SWCNT deposits were characterized by Raman spectroscopy, XPS, SEM, EDS, and TEM.

First Result on the Neutrinoless Double-ß Decay of

We report the result of the search for neutrinoless double beta decay of ^{82}Se obtained with CUPID-0, the first large array of scintillating Zn^{82}Se cryogenic calorimeters implementing particle identification. We observe no signal in a 1.83 kg yr ^{82}Se exposure, and we set the most stringent lower limit on the 0νßß ^{82}Se half-life T_{1/2}^{0ν}>2.4×10^{24} yr (90% credible interval), which corresponds to an effective Majorana neutrino mass m_{ßß}<(376-770) meV depending on the nuclear matrix element calculations. The heat-light readout provides a powerful tool for the rejection of α particles and allows us to suppress the background in the region of interest down to (3.6_{-1.4}^{+1.9})×10^{-3} counts/(keV kg yr), an unprecedented level for this technique.

Antifungal activity of essential oils against azole-resistant and azole-susceptible vaginal Candida glabrata strains.

Candida glabrata is an opportunistic pathogen, associated with endocarditis, meningitis, and disseminated disease, and also with complicated vaginitis. Essential oils derived from aromatic plants are known in traditional medicine as antimicrobial agents and have antifungal properties. The aim of this work was to evaluate whether 12 tested essential oils (tea tree, laurel, anise, basil, bergamot, lavender, mint, oregano, grapefruit, rosemary, winter savory, and ginger) could have a transverse effect on C. glabrata sensitive strains but above all on strains resistant to the three main azole antifungals used (clotrimazole, fluconazole, itraconazole). For this reason, different strains of C. glabrata, vaginal isolated, were characterized (disk diffusion assay, minimal inhibitory concentration) with respect to their response to such antifungals. Electron microscopy analyses were performed to examine cellular damages in depth. Subsequently, we wanted to evaluate the effect of the oils on human cells to estimate their potential cytotoxicity. Oregano and winter savory were the two most effective essential oils, inducing growth inhibition, cell damage of C. glabrata strains (both sensitive and resistant to azole antifungal drugs), and medium-high level of toxicity against human keratinocytes. The results of this work support the research for new alternatives or complementary therapies against vaginal candidiasis.

Gold nanoparticle-based rapid detection and isolation of cells using ligand-receptor chemistry.

Identification and isolation of low-frequency cells of interest from a heterogeneous cell mixture is an important aspect of many diagnostic applications (including enumeration of circulating tumor cells) and is integral to various assays in (cancer) biology. Current techniques typically require expensive instrumentation and are not amenable to high throughput. Here, we demonstrate a simple and effective platform for cell detection and isolation using gold nanoparticles (Au NPs) conjugated with hyaluronic acid (HA) i.e. Au-PEG-HA NPs. The proposed platform exploits ligand-receptor chemistry to detect/isolate cells with high specificity and efficiency. When the Au-PEG-HA NPs come in contact with cells that express CD44 (the receptor for HA), a clear colorimetric change occurs (along with an accompanying SPR peak shift from 521 nm to 559 nm) in the solution due to NPs-cell interaction. This clearly discernible, colorimetric change can be leveraged by point-of-care devices employed in diagnostic applications. Finally, we show that we can successfully isolate viable cells from a heterogeneous cell population (including from human blood samples) with high specificity, which can be used in further downstream applications. The developed NPs-based platform can be a convenient and cost-efficient alternative for diagnostic applications and for cell isolation or sorting in research laboratories.

Search of the neutrino-less double beta decay of 82 Se into the excited states of 82 Kr with CUPID-0.

The CUPID-0 experiment searches for double beta decay using cryogenic calorimeters with double (heat and light) read-out. The detector, consisting of 24 ZnSe crystals 95 % enriched in 82 Se and two natural ZnSe crystals, started data-taking in 2017 at Laboratori Nazionali del Gran Sasso. We present the search for the neutrino-less double beta decay of 82 Se into the 0 1 + , 2 1 + and 2 2 + excited states of 82 Kr with an exposure of 5.74 kg · yr (2.24 × 10 25  emitters · yr). We found no evidence of the decays and set the most stringent limits on the widths of these processes: Γ ( 82 Se → 82 Kr 0 1 + )8.55 × 10 - 24  yr - 1 , Γ ( 82 Se → 82 Kr 2 1 + ) < 6.25 × 10 - 24  yr - 1 , Γ ( 82 Se → 82 Kr 2 2 + )8.25 × 10 - 24  yr - 1 (90 % credible interval).

CUPID-0: the first array of enriched scintillating bolometers for 0 ν ß ß decay investigations.

The CUPID-0 detector hosted at the Laboratori Nazionali del Gran Sasso, Italy, is the first large array of enriched scintillating cryogenic detectors for the investigation of 82 Se neutrinoless double-beta decay ( 0 ν ß ß ). CUPID-0 aims at measuring a background index in the region of interest (RoI) for 0 ν ß ß at the level of 10 - 3  counts/(keV kg years), the lowest value ever measured using cryogenic detectors. CUPID-0 operates an array of Zn 82 Se scintillating bolometers coupled with bolometric light detectors, with a state of the art technology for background suppression and thorough protocols and procedures for the detector preparation and construction. In this paper, the different phases of the detector design and construction will be presented, from the material selection (for the absorber production) to the new and innovative detector structure. The successful construction of the detector lead to promising preliminary detector performance which is discussed here.

Analysis of cryogenic calorimeters with light and heat read-out for double beta decay searches.

The suppression of spurious events in the region of interest for neutrinoless double beta decay will play a major role in next generation experiments. The background of detectors based on the technology of cryogenic calorimeters is expected to be dominated by α particles, that could be disentangled from double beta decay signals by exploiting the difference in the emission of the scintillation light. CUPID-0, an array of enriched Zn 82 Se scintillating calorimeters, is the first large mass demonstrator of this technology. The detector started data-taking in 2017 at the Laboratori Nazionali del Gran Sasso with the aim of proving that dual read-out of light and heat allows for an efficient suppression of the α background. In this paper we describe the software tools we developed for the analysis of scintillating calorimeters and we demonstrate that this technology allows to reach an unprecedented background for cryogenic calorimeters.

Predicting acute contact toxicity of pesticides in honeybees (Apis mellifera) through a k-nearest neighbor model.

Ecological risk assessment of plant protection products (PPPs) requires an understanding of both the toxicity and the extent of exposure to assess risks for a range of taxa of ecological importance including target and non-target species. Non-target species such as honey bees (Apis mellifera), solitary bees and bumble bees are of utmost importance because of their vital ecological services as pollinators of wild plants and crops. To improve risk assessment of PPPs in bee species, computational models predicting the acute and chronic toxicity of a range of PPPs and contaminants can play a major role in providing structural and physico-chemical properties for the prioritisation of compounds of concern and future risk assessments. Over the last three decades, scientific advisory bodies and the research community have developed toxicological databases and quantitative structure-activity relationship (QSAR) models that are proving invaluable to predict toxicity using historical data and reduce animal testing. This paper describes the development and validation of a k-Nearest Neighbor (k-NN) model using in-house software for the prediction of acute contact toxicity of pesticides on honey bees. Acute contact toxicity data were collected from different sources for 256 pesticides, which were divided into training and test sets. The k-NN models were validated with good prediction, with an accuracy of 70% for all compounds and of 65% for highly toxic compounds, suggesting that they might reliably predict the toxicity of structurally diverse pesticides and could be used to screen and prioritise new pesticides.