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Abstract Rivers are pivotal in the global carbon cycle, transporting terrestrial carbon to the ocean while emitting significant amount of CO2 to the atmosphere. However, the partitioning of fluvial inorganic carbon (IC) between downstream transport and atmospheric evasion remains uncertain due to intricate hydrodynamic and biogeochemical processes. Inspired by Budyko's hydrological work, this study introduces a dimensionless framework to identify critical factors in fluvial IC partitioning: the IC fraction in equilibrium with the atmosphere and the ratio of advection to evasion timescales. River catchment analyses and modeling reveal that the equilibrium ratio determines the fraction of IC stably transported downstream. The hydrodynamic‐driven timescale ratio determines the fate of out‐of‐equilibrium IC, with low‐order streams favoring atmospheric evasion and higher‐order streams promoting downstream transport. This framework provides a simple yet robust approach to predicting river carbon dynamics, with implications for land‐to‐ocean transport, fluvial emissions, and climate mitigation strategies such as enhanced weathering.

Abstract Background The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM. Methods After analyzing The Cancer Genome Atlas MM patients’ database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAFV600E MM cell lines on their response to BRAF/MEKi. We performed proteomic screening to identify proteins modulated by changes in RICTOR expression, and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Results Low RICTOR levels in BRAF-mutated MM correlate with a worse clinical outcome. Gene Set Enrichment Analysis of low-RICTOR tumors display gene signatures suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy production. RICTOR-deficient BRAFV600E cells are intrinsically tolerant to BRAF/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. Moreover, in drug-naïve cells we observed a decline in RICTOR expression shortly after BRAFi exposure. In RICTOR-depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, and their pharmacological inhibition restores sensitivity to BRAFi. Conclusions Our work unveils an unforeseen tumor-suppressing role for mTORC2 in the early adaptation phase of BRAFV600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low RICTOR tumors. Importantly, our findings indicate that the evaluation of intra-tumor RICTOR levels has a prognostic value in metastatic melanoma and may help to guide therapeutic strategies in a personalized manner.

Purpose: The purpose of this paper is to use the case of York University in Canada to analyze the connection between University Social Responsibility and voluntary disclosure. The authors examine whether the university's voluntary air emissions disclosure is performative by exploring whether York University's espoused commitment to its community stakeholders truly guides its incentive to disclose carbon emissions in the absence of a legal mandate. Design/methodology/approach: This qualitative exploratory study uses a post-humanistic approach to build on publicly available data on key measures and metrics of air quality and carbon emissions to facilitate our understanding of representational and interventionist uses of measurement models by social actors and their basis for making voluntary disclosures. Findings: York University linked the logic of capital markets with sustainability disclosures as an incentive for managing the cost of long-term debt. This paper contributes to measurement practice of sustainability disclosure by reinforcing the practice-theoretic conception of measurement that questions the independent nature of objects measured from the measurement methods and reporting tools. Practical implications: The findings of this study are important to higher education administrators, regulators and policymakers, as they offer a strategic guide for the assessment of reports on an organization's commitment to sustainability and in determining the efficacy of voluntary reporting to community stakeholders in general although they are intended for specific groups. Originality/value: Using York University as an illustrative case, the authors argue that air emissions per se are not a reality that shapes decisions at the organizations; instead, the intra-action of air emissions measurement, communications and operational investments define the reality where sustainability is advanced. Specifically, the authors find that the performative effects of emissions disclosure may be associated with socially desirable outcomes in terms of social responsibility and concrete financial rewards.

Summary: The definition of cell metabolic profile is essential to ensure skeletal muscle fiber heterogeneity and to achieve a proper equilibrium between the self-renewal and commitment of satellite stem cells. Heme sustains several biological functions, including processes profoundly implicated with cell metabolism. The skeletal muscle is a significant heme-producing body compartment, but the consequences of impaired heme homeostasis on this tissue have been poorly investigated. Here, we generate a skeletal-muscle-specific feline leukemia virus subgroup C receptor 1a (FLVCR1a) knockout mouse model and show that, by sustaining heme synthesis, FLVCR1a contributes to determine the energy phenotype in skeletal muscle cells and to modulate satellite cell differentiation and muscle regeneration.

The loss of nicotinamide adenine dinucleotide is reported to be associated with muscle mitochondrial dysfunction in murine cancer models. Here the authors show that niacin supplementation improves mitochondrial metabolism and reduces muscle wasting in mouse models of cachexia.

En la presente investigación, se desarrolla y explica paso a paso cómo identificar el ahorro de costos en una empresa que usa lean accounting, y cómo esos ahorros se integran para evaluar un proyecto de inversión. Actualmente, no hay mucha información sobre el uso de herramientas de lean accounting en pequeñas y medianas empresas de economías regionales de América Latina; por ello, este estudio busca seguir expandiendo el conocimiento sobre el tema. Se usó la herramienta value stream mapping, que permite identificar el ahorro de costos. Esta es la primera etapa para calcular los flujos de fondos recurrentes para luego aplicar las herramientas tradicionales de evaluación de proyectos. Este estudio, basado en un caso real, vincula aspectos del método de producción y mejoras aplicando lean manufacturing e indicadores financieros del proyecto. El desarrollo del proyecto de inversión permitió que la empresa que fue objeto de estudio mejore los tiempos de entrega, la seguridad de la operación, la estabilidad productiva, la automatización del proceso y el aumento de la capacidad de procesamiento de la planta a nivel global. También hizo visibles focos de ineficiencia del proceso actual que impactaban en el manipuleo de piezas, los costos de operación, los retrabajos y la mano de obra directa.

Abstract Many natural landscapes maintain steep planar hillslopes bounded at a typical angle, beyond which shallow landslides or slope failures remove the excess sediment volume by mass wasting. Here we show that the celebrated eikonal equation, derived from a landscape evolution model in conditions of negligible soil diffusion and fluvial erosion, accurately portrays the organization of these topographies. Referred to as “eikonal landscapes,” such solutions feature constant‐slope hillslopes originating from downstream boundary conditions and culminating in sharp upstream ridges. We demonstrate that the eikonal landscapes reproduce well a variety of natural landforms, including small islands, a volcano, and an extended mountain ridge. The boundary condition for the eikonal representation is specified through the natural landscape's slope‐area relation. Going beyond merely representing landscape statistical features, the present results provide a first‐of‐kind direct match of mathematical and natural landscapes.

Abstract Aridity exerts fundamental controls on terrestrial hydrology with impacts on ecosystems and society. Here we show that the global distribution of dryness index is dominated by the exponential variability of precipitation. The resulting distribution of the dryness index only has one parameter describing the balance between global mean atmospheric water demand and supply. Its shape, with a minus two power‐law tail, is well supported by observations and appears to be robust to future changes in aridity, making it a possible benchmark for Earth System Models.

Maritime Spatial Planning (MSP) promotes the sustainable human activities development and uses in the marine space, playing a role in their effective management. The enhancement of connectivity is crucial for the conservation of biodiversity and landscape planning. Ecological Corridors (ECs) are an important type of connectivity for biodiversity conservation in fragmented habitats. The EU Biodiversity Strategy 2030 includes ECs into the network of protected areas and allows for the creation of additional protected areas. MSP studies considering ECs remain still lacking, especially for the design of networks between Marine Protected Areas (MPAs) and Other Effective area-based Conservation Measures (OECMs). In this paper, knowledge, and tools for investigating marine ECs were reviewed, with a systematic bibliometric analysis to summarize the current scientific research. Previous studies integrating ecological connectivity into planning for marine conservation have focused on models of larval dispersal, adult movements, and dispersal of single species by using benthic habitat proxies. Few studies were found on ECs in marine environments: in the coral Caribbean reef systems in the Gulf of Mexico; within benthic habitats along the Pacific coast of Canada; between MPAs in British Columbia (Canada); and by analyzing migratory species in the Yangtze estuary (China). Commonly used approaches to project and map ECs in marine environments are least-cost and circuit theories allowing to incorporate movement with cost or resistance to movement, depending on species and preferred habitats. The systematic bibliometric analysis returned 25 studies, most of which were from North America (40%) and European countries (36%) and the largest share of papers (68%) from 2018 to 2022. This review pinpointed the need of integrating different disciplines to investigate connectivity and the need by policymakers and practitioners to recognize the importance of ecological connectivity, even there are significant challenges for integrating connectivity into policies, planning, and conservation.

Abstract Background Few studies have assessed predictors of outcome in dogs with thyroid tumors undergoing thyroidectomy. Objective To estimate the survival and identify prognostic factors in dogs with thyroid tumors treated by thyroidectomy. Animals A total of 144 client‐owned dogs with thyroid neoplasia that underwent thyroidectomy. Methods Retrospective study. Data for analysis included hospital attended and year of surgery, signalment, thyroxine concentration, thyroid tumor features (lobe involvement, size, invasiveness, histopathological type), thrombosis, metastasis, additional surgery and therapy, administration of adjuvant chemotherapy. The association of predictors with survival (time from surgery to death) were assessed by calculating cause‐specific hazard ratios (HRcs) and 95% confidence intervals (CI). Causes of death were classified as thyroid‐related or because of other cause. Results Overall median survival time was 802 days (CI95% = 723‐1015 days); 89 dogs (77.4%) survived >500 days. Metastases were identified at admission in 12 (8.3%) dogs and were associated with higher thyroid cancer‐related fatality (HR = 5.83, CI95% = 1.56‐21.78; P = .009). Thrombosis occurred in 40 dogs and was associated with increased risk of death because of other cause (HR = 2.73, CI95% = 1.18‐6.35; P = .019). Nonfollicular carcinoma (HR = 4.17, CI95% = 1.27‐13.69; P = .018) and administration of chemotherapy (HR = 3.45, CI95% = 1.35‐8.82; P = .01) were associated with higher risk of thyroid cancer‐related death. Conclusions and Clinical Importance Dogs with thyroid tumors undergoing thyroidectomy have a long life expectancy. Despite the rare presence of nonfollicular carcinoma and metastases, thyroidectomy should still be considered in some of these dogs.

H2 has the potential to become the green, low-carbon fuel of the future. However, hydrogen emissions impact atmospheric methane (CH4). Bertagni et al. investigate the fate of atmospheric CH4 in scenarios of H2 economy.

A rapid and effective transition to low-carbon energy production is essential to limit climate change impacts. While the scientific community has mostly focused on research and development and techno-economic aspects, quantifying the role of public acceptability and policy in shaping emission trajectories has been much more elusive. This study investigates the coupled dynamics of nonlinear socio-political acceptance and anthropogenic CO _2 emissions, with implications for climate policies and clean energy investments. Our findings show that a top-down policy approach alone may not be sufficient for effective emission cuts, highlighting the need for a multi-level strategy that combines top-down and bottom-up approaches. Additionally, opinion polarization can trigger detrimental CO _2 emission oscillations when governments decide to take heavy-handed policy interventions in highly polarized socio-political systems. Delayed perception of climate change damage or abrupt reactions to extreme weather events may also significantly affect emission reduction efforts, although in the opposite direction. Integrating these socio-political dynamics into climate models can enhance our understanding of the complex interplay between human and natural systems, enabling the development of more effective and resilient mitigation strategies.

Enhanced weathering (EW) is a promising strategy for carbon sequestration, but several open questions remain regarding the actual rates of dissolution in conditions of natural hydroclimatic variability in comparison to laboratory experiments. In this context, models play a pivotal role, as they allow exploring and predicting EW dynamics under different environmental conditions. Here a comprehensive hydro-biogeochemical model has been applied to four cropland case studies (i.e., Sicily and the Padan plain in Italy and California and Iowa in the USA) characterized by different rainfall seasonality, vegetation (i.e., wheat for Sicily and California and corn for the Padan plain and Iowa), and soil type to explore their influence on dissolution rates. The results reveal that rainfall seasonality and irrigation when applied are crucial in determining EW and carbon sequestration dynamics, given their effect on hydrological fluxes, soil pH and weathering rate. The carbon sequestration rate was found to be strongly affected also by the background weathering flux, which is one of the main factors controlling soil pH before the olivine amendment. Regarding the US case studies, Iowa sequesters the greatest amount of CO2 if compared to California (4.20 and 2.21 kg ha−1 yr−1, respectively), and the same happens for Sicily with respect to the Padan plain (0.62 and 0.39 kg ha−1 yr−1, respectively). These low carbon sequestration values suggest that an in-depth analysis at the global scale is required to assess EW efficacy for carbon sequestration.

Purpose – The technical feasibility of using Benford's law to assist internal auditors in reviewing the integrity of high-volume data sets is analysed. This study explores whether Benford's distribution applies to the set of numbers represented by the quantity of records (size) that comprise the different tables that make up a state-owned enterprise's (SOE) enterprise resource planning (ERP) relational database. The use of Benford's law streamlines the search for possible abnormalities within the ERP system's data set, increasing the ability of the internal audit functions (IAFs) to detect anomalies within the database. In the SOEs of emerging economies, where groups compete for power and resources, internal auditors are better off employing analytical tests to discharge their duties without getting involved in power struggles. Design/methodology/approach – Records of eight databases of an SOE in Argentina are used to analyse the number of records of each table in periods of three to 12 years. The case develops step-by-step Benford's law application to test each ERP module records using Chi-squared (χ²) and mean absolute deviation (MAD) goodness-of-fit tests. Findings – Benford's law is an adequate tool for performing integrity tests of high-volume databases. A minimum of 350 tables within each database are required for the MAD test to be effective; this threshold is higher than the 67 reported by earlier researches. Robust results are obtained for the complete ERP system and for large modules; modules with less than 350 tables show low conformity with Benford's law. Research limitations/implications – This study is not about detecting fraud; it aims to help internal auditors red flag databases that will need further attention, making the most out of available limited resources in SOEs. The contribution is a simple, cheap and useful quantitative tool that can be employed by internal auditors in emerging economies to perform the first scan of the data contained in relational databases. Practical implications – This paper provides a tool to test whether large amounts of data behave as expected, and if not, they can be pinpointed for future investigation. It offers tests and explanations on the tool's application so that internal auditors of SOEs in emerging economies can use it, particularly those that face divergent expectations from antagonist powerful interest groups. Originality/value – This study demonstrates that even in the context of limited information technology tools available for internal auditors, there are simple and inexpensive tests to review the integrity of high-volume databases. It also extends the literature on high-volume database integrity tests and our knowledge of the IAF in Civil law countries, particularly emerging economies in Latin America.

Miscalculating the volumes of water withdrawn for irrigation, the largest consumer of freshwater in the world, jeopardizes sustainable water management. Hydrological models quantify water withdrawals, but their estimates are unduly precise. Model imperfections need to be appreciated to avoid policy misjudgements.

The Asian yellow-legged hornet (Vespa velutina) has been invading Italy since 2013, and it was subjected to management programs to counter its spread and raise awareness about its impacts. We administered a questionnaire to a sample of 358 beekeepers in Italy, asking them about their sources of information on V. velutina and their perception of its potential impacts and severity, compared to other threats to beekeeping. We also explored Internet searching volumes on Google and Wikipedia about V. velutina, to identify seasonal and long-term trends in public awareness. Workshops, journals or bulletins, the Internet and word-of-mouth with colleagues were the primary sources of information about V. velutina. Internet searches peaked during the activity period of the species and increased over time, with thousands of visits to Wikipedia each month. Beekeepers believed V. velutina to affect beekeeping by predating on honey bees (Apis mellifera), paralyzing foraging, reducing honey availability and depleting the winter cluster. Moreover, V. velutina has been deemed a severe threat to beekeeping, similar to other threats like pesticides and the varroa mite (Varroa destructor). Our findings indicate that beekeepers seem to be aware of the potential impacts of V. velutina in Italy, both within and outside of its invaded area, considering it a major threat to beekeeping. Moreover, citizens seem to have become progressively curious about the species. Information campaigns on the Internet and specialized magazines might be helpful to communicate about the impacts of the species, and the need to develop diffused surveillance networks.

Rivers are pivotal in the global carbon cycle, transporting terrestrial carbon to the ocean while emitting significant amount of CO2 ${\mathrm{C}\mathrm{O}}_{2}$ to the atmosphere. However, the partitioning of fluvial inorganic carbon (IC) between downstream transport and atmospheric evasion remains uncertain due to intricate hydrodynamic and biogeochemical processes. Inspired by Budyko's hydrological work, this study introduces a dimensionless framework to identify critical factors in fluvial IC partitioning: the IC fraction in equilibrium with the atmosphere and the ratio of advection to evasion timescales. River catchment analyses and modeling reveal that the equilibrium ratio determines the fraction of IC stably transported downstream. The hydrodynamic‐driven timescale ratio determines the fate of out‐of‐equilibrium IC, with low‐order streams favoring atmospheric evasion and higher‐order streams promoting downstream transport. This framework provides a simple yet robust approach to predicting river carbon dynamics, with implications for land‐to‐ocean transport, fluvial emissions, and climate mitigation strategies such as enhanced weathering. Plain Language Summary: Rivers contain large amounts of dissolved inorganic carbon originating from the decomposition of organic matter and soil water fluxes. This carbon is partly transported downstream across the river network to the ocean and partly emitted as CO2 ${\mathrm{C}\mathrm{O}}_{2}$ to the atmosphere. Quantifying the partitioning between these fluxes is crucial for accurate carbon budgets from the local to the global scale, but the complex interplay of biogeophysical processes makes it challenging. Inspired by Budyko's seminal work in hydrology, we present a framework that determines the main chemical and physical processes governing the fluvial inorganic carbon partitioning. We identify two dimensionless numbers (or indexes) that can be defined with only a few parameters and provide quantitative and robust predictions on fluvial carbon fate. These numbers are linked to water turbulence and chemistry, and their values change across the river network. Key Points: Rivers partition inorganic carbon between downstream transport and CO2 ${\mathrm{C}\mathrm{O}}_{2}$ emissions to the atmosphereIncorporating key hydrodynamic and biogeochemical processes, we identify the dimensionless numbers that govern the inorganic carbon partitioningWater hydrodynamics plays a critical role in the fate of the carbon that is out of equilibrium with the atmosphere [ABSTRACT FROM AUTHOR]

Summary: Plant response to water stress involves multiple timescales. In the short term, stomatal adjustments optimize some fitness function commonly related to carbon uptake, while in the long term, traits including xylem resilience are adjusted. These optimizations are usually considered independently, the former involving stomatal aperture and the latter carbon allocation. However, short‐ and long‐term adjustments are interdependent, as 'optimal' in the short term depends on traits set in the longer term.An economics framework is used to optimize long‐term traits that impact short‐term stomatal behavior. Two traits analyzed here are the resilience of xylem and the resilience of nonstomatal limitations (NSLs) to photosynthesis at low‐water potentials.Results show that optimality requires xylem resilience to increase with climatic aridity. Results also suggest that the point at which xylem reach 50% conductance and the point at which NSLs reach 50% capacity are constrained to approximately a 2 : 1 linear ratio; however, this awaits further experimental verification.The model demonstrates how trait coordination arises mathematically, and it can be extended to many other traits that cross timescales. With further verification, these results could be used in plant modelling when information on plant traits is limited. [ABSTRACT FROM AUTHOR]

Cutaneous candidiasis is usually related to immunosuppressive diseases and/or therapies as predisposing factors. In humans, chronic mucocutaneous candidiasis (CMC) is observed with thymoma and thymectomy. In this case report we describe the clinical and pathological findings, laboratory analysis, treatment, and follow-up of a thymectomized dog with cutaneous and mucocutaneous generalized candidiasis.

Primary angle closure glaucoma is a leading cause of irreversible blindness, particularly in Asia. Its pathophysiology is based in the closure of the anterior chamber angle (ACA). In addition to gonioscopy (current reference standard), in the past decade, anterior segment optical coherence tomography (AS-OCT) has been incorporated in routine ophthalmic practice to help assess the configuration of the ACA. Especially in nonspecialist ophthalmology practice, gonioscopy may be less frequently performed and AS-OCT may not be available, leading to the need of other anterior segment evaluation methods. Evaluating the anterior chamber depth (ACD) has long been recognized as screening tool for primary angle-closure glaucoma. It can be measured with several devices, such as Scheimpflug photography and the scanning peripheral ACD analyzer. It can also be estimated with the oblique flashlight test and van Herick technique (limbal ACD assessment). More recently, goniophotographic systems have been developed to produce images of the ACA similar to those seen with manual gonioscopy. NGS-1 automated gonioscope (NIDEK Co, Gamagori, Japan) and the RetCam (Natus Medical Incorporated, Pleasanton, CA) are commercially available. However, NGS-1 is the only one with a specialized software for ACA imaging. Several prototype devices are currently being developed, such as the GonioPEN and axicon lens assisted gonioscopy. This article aims to review different modalities of ACA assessment, beyond AS-OCT, and compare their relative advantages and disadvantages.

By rigorously accounting for dimensional homogeneity in physical laws, the Π theorem and the related self-similarity hypotheses allow us to achieve a dimensionless reformulation of scientific hypotheses in a lower-dimensional context. This paper presents applications of these concepts to the partitioning of water and soil on terrestrial landscapes. For such processes, their complexity and lack of first principle formulation make dimensional analysis an excellent tool to formulate theories that are amenable to empirical testing and analytical developments. The resulting scaling laws help reveal the dominant environmental controls for these partitionings. In particular, we discuss how the dryness index and the storage index affect the long-term rainfall partitioning, the key nonlinear control of the dryness index in global datasets of weathering rates, and the existence of new macroscopic relations among average variables in landscape evolution statistics. The scaling laws for the partitioning of sediments, the elevation profile, and the spectral scaling of self-similar topographies also unveil tantalizing analogies with turbulent flows.

Abstract While it is well known that water availability controls vegetation growth and soil microbial activity, how aridity affects ecosystem carbon patterns is not completely understood. Toward a more quantitative assessment of terrestrial carbon stocks, here we apply dimensional analysis and scaling to the global joint distribution of terrestrial carbon stock, obtained from international survey data and harmonized global maps. The results show a remarkable self‐similar behavior of the global carbon stock with dryness index, whereby the key statistics (e.g., mean, quantiles, and standard deviation) of carbon stock tend to scale with the hydroclimatic regime (i.e., aridity) via a universal exponent. Such a scaling reflects the strong coupling between the hydrological cycle and biogeochemical process and enables robust predictions of carbon stocks as a function of aridity only. When normalized by its averages in the corresponding hydroclimatic regime, the carbon stock distributions collapse onto a single double Pareto lognormal distribution, often used in economics to describe income. The presence of this distribution in completely different physical contexts, such as biogeochemistry and economics, hints at generating mechanisms that transcend the details of the specific stock being considered.

High-grade mucinous colorectal cancer (HGM CRC) is particularly aggressive, prone to metastasis and treatment resistance, frequently accompanied by “signet ring” cancer cells. A sizeable fraction of HGM CRCs (20-40%) arises in the context of the Lynch Syndrome, an autosomal hereditary syndrome that predisposes to microsatellite instable (MSI) CRC. Development of patient-derived preclinical models for this challenging subtype of colorectal cancer represents an unmet need in oncology. We describe here successful propagation of preclinical models from a case of early-onset, MSI-positive metastatic colorectal cancer in a male Lynch syndrome patient, refractory to standard care (FOLFOX6, FOLFIRI-Panitumumab) and, surprisingly, also to immunotherapy. Surgical material from a debulking operation was implanted in NOD/SCID mice, successfully yielding one patient-derived xenograft (PDX). PDX explants were subsequently used to generate 2D and 3D cell cultures. Histologically, all models resembled the tumor of origin, displaying a high-grade mucinous phenotype with signet ring cells. For preclinical exploration of alternative treatments, in light of recent findings, we considered inhibition of the proteasome by bortezomib and of the related NEDD8 pathway by pevonedistat. Indeed, sensitivity to bortezomib was observed in mucinous adenocarcinoma of the lung, and we previously found that HGM CRC is preferentially sensitive to pevonedistat in models with low or absent expression of cadherin 17 (CDH17), a differentiation marker. We therefore performed IHC on the tumor and models, and observed no CDH17 expression, suggesting sensitivity to pevonedistat. Both bortezomib and pevonedistat showed strong activity on 2D cells at 72 hours and on 3D organoids at 7 days, thus providing valid options for in vivo testing. Accordingly, three PDX cohorts were treated for four weeks, respectively with vehicle, bortezomib and pevonedistat. Both drugs significantly reduced tumor growth, as compared to the vehicle group. Interestingly, while bortezomib was more effective in vitro, pevonedistat was more effective in vivo. Drug efficacy was further substantiated by a reduction of cellularity and of Ki67-positive cells in the treated tumors. These results highlight proteasome and NEDD8 inhibition as potentially effective therapeutic approaches against Lynch syndrome-associated HGM CRC, also when the disease is refractory to all available treatment options.

Systemic AA-amyloidosis is a protein-misfolding disease characterized by fibril deposition of serum amyloid-A protein (SAA) in several organs in humans and many animal species. Fibril deposits originate from abnormally high serum levels of SAA during chronic inflammation. A high prevalence of AA-amyloidosis has been reported in captive cheetahs and a horizontal transmission has been proposed. In domestic cats, AA-amyloidosis has been mainly described in predisposed breeds but only rarely reported in domestic short-hair cats. Aims of the study were to determine AA-amyloidosis prevalence in dead shelter cats. Liver, kidney, spleen and bile were collected at death in cats from 3 shelters. AA-amyloidosis was scored. Shedding of amyloid fibrils was investigated with western blot in bile and scored. Descriptive statistics were calculated. In the three shelters investigated, prevalence of AA-amyloidosis was 57.1% (16/28 cats), 73.0% (19/26) and 52.0% (13/25), respectively. In 72.9% of cats (35 in total) three organs were affected concurrently. Histopathology and immunofluorescence of post-mortem extracted deposits identified SAA as the major protein source. The duration of stay in the shelters was positively associated with a histological score of AA-amyloidosis (B = 0.026, CI95% = 0.007-0.046; p = 0.010). AA-amyloidosis was very frequent in shelter cats. Presence of SAA fragments in bile secretions raises the possibility of fecal-oral transmission of the disease. In conclusion, AA-amyloidosis was very frequent in shelter cats and those staying longer had more deposits. The cat may represent a natural model of AA-amyloidosis.