Lung Volume and Ventilation Distribution After Bariatric Surgery-High-Flow Nasal Cannula Versus CPAP.

BACKGROUND: Patients with obesity are at increased risk of postoperative pulmonary complications. CPAP has been used successfully to prevent and treat acute respiratory failure, but in many clinical scenarios, high-flow nasal cannula (HFNC) therapy is emerging as a possible alternative. We aimed to compare HFNC and CPAP in a sequential study measuring their effects on gas exchange, lung volumes, and gas distribution within the lungs measured through electrical impedance tomography (EIT). METHODS: We enrolled 15 subjects undergoing laparoscopic bariatric surgery. Postoperatively they underwent the following oxygen therapy protocol (10 min/step): baseline air-entrainment mask, HFNC at increasing (40, 60, 80, and 100 L/min) and decreasing flows (80, 60, and 40 L/min), washout air-entrainment mask and CPAP (10 cm H2O). Primary outcome was the change in end-expiratory lung impedance (ΔEELI) measured by EIT data processing. Secondary outcomes were changes of global inhomogeneity (GI) index and tidal impedance variation (TIV) measured by EIT, arterial oxygenation, carbon dioxide content, pH, respiratory frequency, and subject's comfort. RESULTS: Thirteen subjects completed the study. Compared to baseline, ΔEELI was higher during 10 cm H2O CPAP (P = .001) and HFNC 100 L/min (P = .02), as well as during decreasing flows HFNC 80, 60, and 40 L/min (P = .008, .004, and .02, respectively). GI index was lower during HFNC 100 compared to HFNC 60increasing (P = .044), HFNC 60decreasing (P = .02) HFNC 40decreasing (P = .01), and during 10 cm H2O CPAP compared to washout period (P = .01) and HFNC 40decreasing (P = .03). TIV was higher during 10 cm H2O CPAP compared to baseline (P = .008). Compared to baseline, breathing frequency was lower at HFNC 60increasing, HFNC 100, and HFNC 80decreasing (P = .01, .02, and .03, respectively). No differences were detected regarding arterial oxygenation, carbon dioxide content, pH, and subject's comfort. CONCLUSIONS: HFNC at a flow of 100 L/min induced postoperative pulmonary recruitment in bariatric subjects, with no significant differences compared to 10 cm H2O CPAP in terms of lung recruitment and ventilation distribution.

Typhoon- and pollution-driven enhancement of reactive bromine in the mid-latitude marine boundary layer.

Tropospheric reactive bromine is important for atmospheric chemistry, regional air pollution, and global climate. Previous studies have reported measurements of atmospheric reactive bromine species in different environments, and proposed their main sources, e.g. sea-salt aerosol (SSA), oceanic biogenic activity, polar snow/ice, and volcanoes. Typhoons and other strong cyclonic activities (e.g. hurricanes) induce abrupt changes in different earth system processes, causing widespread destructive effects. However, the role of typhoons in regulating reactive bromine abundance and sources remains unexplored. Here, we report field observations of bromine oxide (BrO), a critical indicator of reactive bromine, on the Huaniao Island (HNI) in the East China Sea in July 2018. We observed high levels of BrO below 500 m with a daytime average of 9.7 ± 4.2 pptv and a peak value of ∼26 pptv under the influence of a typhoon. Our field measurements, supported by model simulations, suggest that the typhoon-induced drastic increase in wind speed amplifies the emission of SSA, significantly enhancing the activation of reactive bromine from SSA debromination. We also detected enhanced BrO mixing ratios under high NOx conditions (ppbv level) suggesting a potential pollution-induced mechanism of bromine release from SSA. Such elevated levels of atmospheric bromine noticeably increase ozone destruction by as much as ∼40% across the East China Sea. Considering the high frequency of cyclonic activity in the northern hemisphere, reactive bromine chemistry is expected to play a more important role than previously thought in affecting coastal air quality and atmospheric oxidation capacity. We suggest that models need to consider the hitherto overlooked typhoon- and pollution-mediated increase in reactive bromine levels when assessing the synergic effects of cyclonic activities on the earth system.

Anthropogenic short-lived halogens increase human exposure to mercury contamination due to enhanced mercury oxidation over continents.

Mercury (Hg) is a contaminant of global concern, and an accurate understanding of its atmospheric fate is needed to assess its risks to humans and ecosystem health. Atmospheric oxidation of Hg is key to the deposition of this toxic metal to the Earth's surface. Short-lived halogens (SLHs) can provide halogen radicals to directly oxidize Hg and perturb the budget of other Hg oxidants (e.g., OH and O3). In addition to known ocean emissions of halogens, recent observational evidence has revealed abundant anthropogenic emissions of SLHs over continental areas. However, the impacts of anthropogenic SLHs emissions on the atmospheric fate of Hg and human exposure to Hg contamination remain unknown. Here, we show that the inclusion of anthropogenic SLHs substantially increased local Hg oxidation and, consequently, deposition in/near Hg continental source regions by up to 20%, thereby decreasing Hg export from source regions to clean environments. Our modeling results indicated that the inclusion of anthropogenic SLHs can lead to higher Hg exposure in/near Hg source regions than estimated in previous assessments, e.g., with increases of 8.7% and 7.5% in China and India, respectively, consequently leading to higher Hg-related human health risks. These results highlight the urgent need for policymakers to reduce local Hg and SLHs emissions. We conclude that the substantial impacts of anthropogenic SLHs emissions should be included in model assessments of the Hg budget and associated health risks at local and global scales.

Flow starvation during square-flow assisted ventilation detected by supervised deep learning techniques.

BACKGROUND: Flow starvation is a type of patient-ventilator asynchrony that occurs when gas delivery does not fully meet the patients' ventilatory demand due to an insufficient airflow and/or a high inspiratory effort, and it is usually identified by visual inspection of airway pressure waveform. Clinical diagnosis is cumbersome and prone to underdiagnosis, being an opportunity for artificial intelligence. Our objective is to develop a supervised artificial intelligence algorithm for identifying airway pressure deformation during square-flow assisted ventilation and patient-triggered breaths. METHODS: Multicenter, observational study. Adult critically ill patients under mechanical ventilation > 24 h on square-flow assisted ventilation were included. As the reference, 5 intensive care experts classified airway pressure deformation severity. Convolutional neural network and recurrent neural network models were trained and evaluated using accuracy, precision, recall and F1 score. In a subgroup of patients with esophageal pressure measurement (ΔPes), we analyzed the association between the intensity of the inspiratory effort and the airway pressure deformation. RESULTS: 6428 breaths from 28 patients were analyzed, 42% were classified as having normal-mild, 23% moderate, and 34% severe airway pressure deformation. The accuracy of recurrent neural network algorithm and convolutional neural network were 87.9% [87.6-88.3], and 86.8% [86.6-87.4], respectively. Double triggering appeared in 8.8% of breaths, always in the presence of severe airway pressure deformation. The subgroup analysis demonstrated that 74.4% of breaths classified as severe airway pressure deformation had a ΔPes > 10 cmH2O and 37.2% a ΔPes > 15 cmH2O. CONCLUSIONS: Recurrent neural network model appears excellent to identify airway pressure deformation due to flow starvation. It could be used as a real-time, 24-h bedside monitoring tool to minimize unrecognized periods of inappropriate patient-ventilator interaction.

Improving the Sustainability of Catalytic Glycolysis of Complex PET Waste through Bio-Solvolysis.

This work addresses a novel bio-solvolysis process for the treatment of complex poly(ethylene terephthalate) (PET) waste using a biobased monoethylene glycol (BioMEG) as a depolymerization agent in order to achieve a more sustainable chemical recycling process. Five difficult-to-recycle PET waste streams, including multilayer trays, coloured bottles and postconsumer textiles, were selected for the study. After characterization and conditioning of the samples, an evaluation of the proposed bio-solvolysis process was carried out by monitoring the reaction over time to determine the degree of PET conversion (91.3-97.1%) and bis(2-hydroxyethyl) terephthalate (BHET) monomer yield (71.5-76.3%). A monomer purification process, using activated carbon (AC), was also developed to remove the colour and to reduce the metal content of the solid. By applying this purification strategy, the whiteness (L*) of the BHET greatly increased from around 60 to over 95 (L* = 100 for pure white) and the Zn content was significantly reduced from around 200 to 2 mg/kg. The chemical structure of the purified monomers was analyzed via infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC), and the composition of the samples was measured by proton nuclear magnetic resonance (1H-NMR), proving a high purity of the monomers with a BHET content up to 99.5% in mol.

Statistical analysis plan for the multicenter, open, randomized controlled clinical trial to assess the efficacy and safety of intravenous tirofiban vs aspirin in acute ischemic stroke due to tandem lesion, undergoing recanalization therapy by endovascular treatment (ATILA trial).

RATIONALE: In-stent reocclusion after endovascular therapy has a negative impact on outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Optimal antiplatelet therapy approach in these patients to avoid in-stent reocclusion is yet to be elucidated. AIMS: To assess efficacy and safety of intravenous tirofiban versus intravenous aspirin in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. SAMPLE SIZE ESTIMATES: Two hundred forty patients will be enrolled, 120 in every treatment arm. METHODS AND DESIGN: A multicenter, prospective, randomized, controlled (aspirin group), assessor-blinded clinical trial will be conducted. Patients fulfilling the inclusion criteria will be randomized at MT onset to the experimental or control group (1:1). Intravenous aspirin will be administered at a 500-mg single dose and tirofiban at a 500-mcg bolus followed by a 200-mcg/h infusion during the first 24 h. All patients will be followed for up to 3 months. STUDY OUTCOMES: Primary efficacy outcome will be the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. Primary safety outcome will be the rate of symptomatic intracranial hemorrhage. DISCUSSION: This will be the first clinical trial to assess the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. TRIAL REGISTRATION: The trial is registered as NCT05225961. February, 7th, 2022.

Viability of Glycolysis for the Chemical Recycling of Highly Coloured and Multi-Layered Actual PET Wastes.

The chemical recycling of poly(ethylene terephthalate) -PET- fractions, derived from actual household packaging waste streams, using solvolysis, was investigated. This recycling strategy was applied after a previous on-line automatic identification, by near-infrared spectroscopy -NIR-, and a subsequent selective sorting of the different PET materials that were present in the packaging wastes. Using this technology, it was possible to classify fractions exclusively including PET, virtually avoiding the presence of both other plastics and materials, such as paper, cardboard and wood, that are present in the packaging wastes, as they were efficiently recognised and differentiated. The simple PET fractions, including clear and monolayered materials, were adequate to be recycled by mechanical means meanwhile the complex PET fractions, containing highly coloured and multi-layered materials, were suitable candidates to be recycled by chemical routes. The depolymerisation capacity of the catalytic glycolysis, when applied to those complex PET wastes, was studied by evaluating the effect of the process parameters on the resulting formation and recovery of the monomer bis(2-hydroxyethyl) terephthalate -BHET- and the achieved quality of this reaction product. Comparable and reasonable results, in terms of monomer yield and its characteristics, were obtained independently of the type of complex PET waste that was chemically recycled.

A Preliminary Study on the Use of Highly Aromatic Pyrolysis Oils Coming from Plastic Waste as Alternative Liquid Fuels.

In this work, the low-temperature pyrolysis of a real plastic mixture sample collected at a WEEE-authorised recycling facility has been investigated. The sample was pyrolysed in a batch reactor in different temperature and residence time conditions and auto-generated pressure by following a factorial design, with the objective of maximising the liquid (oil) fraction. Furthermore, the main polymers constituting the real sample were also pyrolysed in order to understand their role in the generation of oil. The pyrolysis oils were characterised and compared with commercial fuel oil number 6. The results showed that in comparison to commercial fuel oil, pyrolysis oils coming from WEEE plastic waste had similar heating values, were lighter and less viscous and presented similar toxicity profiles in fumes of combustion.

Telomeric DNA breaks in human induced pluripotent stem cells trigger ATR-mediated arrest and telomerase-independent telomere damage repair.

Although mechanisms of telomere protection are well-defined in differentiated cells, it is poorly understood how stem cells sense and respond to telomere dysfunction. In particular, the broader impact of telomeric double-strand breaks (DSBs) in these cells is poorly characterized. Here, we report on DNA damage signaling, cell cycle, and transcriptome-level changes in human induced pluripotent stem cells (iPSCs) in response to telomere-internal DSBs. We engineered human iPSCs with an inducible TRF1-FokI fusion protein to acutely induce DSBs at telomeres. Using this model, we demonstrate that TRF1-FokI DSBs activate an ATR-dependent DDR, which leads to p53-independent cell cycle arrest in G2. Using CRISPR-Cas9 to cripple the catalytic domain of telomerase, we show that telomerase is largely dispensable for survival and lengthening of TRF1-FokI-cleaved telomeres, which instead are effectively repaired by robust homologous recombination (HR). In contrast to HR-based telomere maintenance in mouse embryonic stem cells, we find neither evidence that HR causes extension of telomeres beyond their initial lengths, nor an apparent role for ZSCAN4 in this process. Rather, HR-based repair of telomeric breaks is sufficient to maintain iPSC telomeres at a normal length which is compatible with sustained survival of the cells over several days of TRF1-FokI induction. Our findings suggest a previously unappreciated role for HR in telomere maintenance in telomerase-positive iPSCs and reveal distinct iPSC-specific responses to targeted telomeric damage.

Photocatalytic chlorine atom production on mineral dust-sea spray aerosols over the North Atlantic.

Active chlorine in the atmosphere is poorly constrained and so is its role in the oxidation of the potent greenhouse gas methane, causing uncertainty in global methane budgets. We propose a photocatalytic mechanism for chlorine atom production that occurs when Sahara dust mixes with sea spray aerosol. The mechanism is validated by implementation in a global atmospheric model and thereby explaining the episodic, seasonal, and location-dependent 13C depletion in CO in air samples from Barbados [J.E. Mak, G. Kra, T. Sandomenico, P. Bergamaschi, J. Geophys. Res. Atmos. 108 (2003)], which remained unexplained for decades. The production of Cl can also explain the anomaly in the CO:ethane ratio found at Cape Verde [K. A. Read et al., J. Geophys. Res. Atmos. 114 (2009)], in addition to explaining the observation of elevated HOCl [M. J. Lawler et al., Atmos. Chem. Phys. 11, 7617-7628 (2011)]. Our model finds that 3.8 Tg(Cl) y-1 is produced over the North Atlantic, making it the dominant source of chlorine in the region; globally, chlorine production increases by 41%. The shift in the methane sink budget due to the increased role of Cl means that isotope-constrained top-down models fail to allocate 12 Tg y-1 (2% of total methane emissions) to 13C-depleted biological sources such as agriculture and wetlands. Since 2014, an increase in North African dust emissions has increased the 13C isotope of atmospheric CH4, thereby partially masking a much greater decline in this isotope, which has implications for the interpretation of the drivers behind the recent increase of methane in the atmosphere.

Global environmental implications of atmospheric methane removal through chlorine-mediated chemistry-climate interactions.

Atmospheric methane is both a potent greenhouse gas and photochemically active, with approximately equal anthropogenic and natural sources. The addition of chlorine to the atmosphere has been proposed to mitigate global warming through methane reduction by increasing its chemical loss. However, the potential environmental impacts of such climate mitigation remain unexplored. Here, sensitivity studies are conducted to evaluate the possible effects of increasing reactive chlorine emissions on the methane budget, atmospheric composition and radiative forcing. Because of non-linear chemistry, in order to achieve a reduction in methane burden (instead of an increase), the chlorine atom burden needs to be a minimum of three times the estimated present-day burden. If the methane removal target is set to 20%, 45%, or 70% less global methane by 2050 compared to the levels in the Representative Concentration Pathway 8.5 scenario (RCP8.5), our modeling results suggest that additional chlorine fluxes of 630, 1250, and 1880 Tg Cl/year, respectively, are needed. The results show that increasing chlorine emissions also induces significant changes in other important climate forcers. Remarkably, the tropospheric ozone decrease is large enough that the magnitude of radiative forcing decrease is similar to that of methane. Adding 630, 1250, and 1880 Tg Cl/year to the RCP8.5 scenario, chosen to have the most consistent current-day trends of methane, will decrease the surface temperature by 0.2, 0.4, and 0.6 °C by 2050, respectively. The quantity and method in which the chlorine is added, its interactions with climate pathways, and the potential environmental impacts on air quality and ocean acidity, must be carefully considered before any action is taken.

Patient-Induced Pluripotent Stem Cell-Derived Hepatostellate Organoids Establish a Basis for Liver Pathologies in Telomeropathies.

BACKGROUND & AIMS: Dyskeratosis congenita (DC) is a telomere biology disorder caused primarily by mutations in the DKC1 gene. Patients with DC and related telomeropathies resulting from premature telomere dysfunction experience multiorgan failure. In the liver, DC patients present with nodular hyperplasia, steatosis, inflammation, and cirrhosis. However, the mechanism responsible for telomere dysfunction-induced liver disease remains unclear. METHODS: We used isogenic human induced pluripotent stem cells (iPSCs) harboring a causal DC mutation in DKC1 or a CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9)-corrected control allele to model DC liver pathologies. We differentiated these iPSCs into hepatocytes (HEPs) or hepatic stellate cells (HSCs) followed by generation of genotype-admixed hepatostellate organoids. Single-cell transcriptomics were applied to hepatostellate organoids to understand cell type-specific genotype-phenotype relationships. RESULTS: Directed differentiation of iPSCs into HEPs and stellate cells and subsequent hepatostellate organoid formation revealed a dominant phenotype in the parenchyma, with DC HEPs becoming hyperplastic and also eliciting a pathogenic hyperplastic, proinflammatory response in stellate cells independent of stellate cell genotype. Pathogenic phenotypes in DKC1-mutant HEPs and hepatostellate organoids could be rescued via suppression of serine/threonine kinase AKT (protein kinase B) activity, a central regulator of MYC-driven hyperplasia downstream of DKC1 mutation. CONCLUSIONS: Isogenic iPSC-derived admixed hepatostellate organoids offer insight into the liver pathologies in telomeropathies and provide a framework for evaluating emerging therapies.

Natural short-lived halogens exert an indirect cooling effect on climate.

Observational evidence shows the ubiquitous presence of ocean-emitted short-lived halogens in the global atmosphere1-3. Natural emissions of these chemical compounds have been anthropogenically amplified since pre-industrial times4-6, while, in addition, anthropogenic short-lived halocarbons are currently being emitted to the atmosphere7,8. Despite their widespread distribution in the atmosphere, the combined impact of these species on Earth's radiative balance remains unknown. Here we show that short-lived halogens exert a substantial indirect cooling effect at present (-0.13 ± 0.03 watts per square metre) that arises from halogen-mediated radiative perturbations of ozone (-0.24 ± 0.02 watts per square metre), compensated by those from methane (+0.09 ± 0.01 watts per square metre), aerosols (+0.03 ± 0.01 watts per square metre) and stratospheric water vapour (+0.011 ± 0.001 watts per square metre). Importantly, this substantial cooling effect has increased since 1750 by -0.05 ± 0.03 watts per square metre (61 per cent), driven by the anthropogenic amplification of natural halogen emissions, and is projected to change further (18-31 per cent by 2100) depending on climate warming projections and socioeconomic development. We conclude that the indirect radiative effect due to short-lived halogens should now be incorporated into climate models to provide a more realistic natural baseline of Earth's climate system.

Serially improved GTOs for molecular applications (SIGMA): Basis sets from H to Ne.

A new approach for generating Gaussian basis sets is reported and tested for atoms from H to Ne. The basis sets thus calculated, named SIGMA basis sets, range from DZ to QZ sizes and have the same composition per shell as Dunning basis sets but with different treatment of the contractions. The standard SIGMA basis sets and their augmented versions have proven to be very suitable for providing good results in atomic and molecular calculations. The performance of the new basis sets is analyzed in terms of total, correlation, and atomization energies, equilibrium distances, and vibrational frequencies in several molecules, and the results are compared at several computational levels with those obtained with the corresponding Dunning and other basis sets.

Objective and subjective cognition in survivors of COVID-19 one year after ICU discharge: the role of demographic, clinical, and emotional factors.

BACKGROUND: Intensive Care Unit (ICU) COVID-19 survivors may present long-term cognitive and emotional difficulties after hospital discharge. This study aims to characterize the neuropsychological dysfunction of COVID-19 survivors 12 months after ICU discharge, and to study whether the use of a measure of perceived cognitive deficit allows the detection of objective cognitive impairment. We also explore the relationship between demographic, clinical and emotional factors, and both objective and subjective cognitive deficits. METHODS: Critically ill COVID-19 survivors from two medical ICUs underwent cognitive and emotional assessment one year after discharge. The perception of cognitive deficit and emotional state was screened through self-rated questionnaires (Perceived Deficits Questionnaire, Hospital Anxiety and Depression Scale and Davidson Trauma Scale), and a comprehensive neuropsychological evaluation was carried out. Demographic and clinical data from ICU admission were collected retrospectively. RESULTS: Out of eighty participants included in the final analysis, 31.3% were women, 61.3% received mechanical ventilation and the median age of patients was 60.73 years. Objective cognitive impairment was observed in 30% of COVID-19 survivors. The worst performance was detected in executive functions, processing speed and recognition memory. Almost one in three patients manifested cognitive complaints, and 22.5%, 26.3% and 27.5% reported anxiety, depression and post-traumatic stress disorder (PTSD) symptoms, respectively. No significant differences were found in the perception of cognitive deficit between patients with and without objective cognitive impairment. Gender and PTSD symptomatology were significantly associated with perceived cognitive deficit, and cognitive reserve with objective cognitive impairment. CONCLUSIONS: One-third of COVID-19 survivors suffered objective cognitive impairment with a frontal-subcortical dysfunction 12 months after ICU discharge. Emotional disturbances and perceived cognitive deficits were common. Female gender and PTSD symptoms emerged as predictive factors for perceiving worse cognitive performance. Cognitive reserve emerged as a protective factor for objective cognitive functioning. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422444; June 9, 2021.

Janus kinase inhibitor ruxolitinib in combination with nilotinib and prednisone in patients with myelofibrosis (RuNiC study): A phase Ib, multicenter study.

This phase Ib, non-randomized, open-label study evaluates the safety and tolerability of ruxolitinib in combination with nilotinib and prednisone in patients with naïve or ruxolitinib-resistant myelofibrosis (MF). A total of 15 patients with primary or secondary MF received the study treatment; 13 patients had received prior ruxolitinib treatment (86.7%). Eight patients completed seven cycles (53.3%) and six patients completed twelve cycles of treatment (40%). All the patients experienced at least one adverse event (AE) during the study (the most common AEs were hyperglycemia, asthenia, and thrombocytopenia), and 14 patients registered at least one treatment-related AE (the most common treatment-related AEs were hyperglycemia (22.2%; three grade 3 cases). Five treatment-related serious AEs (SAEs) were reported in two patients (13.3%). No deaths were registered throughout the study. No dose-limiting toxicity was observed. Four out of fifteen (27%) patients experienced a 100% spleen size reduction at Cycle 7, and two additional patients achieved a >50% spleen size reduction, representing an overall response rate of 40% at Cycle 7. In conclusion, the tolerability of this combination was acceptable, and hyperglycemia was the most frequent treatment-related AE. Ruxolitinib in combination with nilotinib and prednisone showed relevant clinical activity in patients with MF. This trial was registered with EudraCT Number 2016-005214-21.

Metabolic shift underlies tumor progression and immune evasion in S-nitrosoglutathione reductase-deficient cancer.

S-nitrosoglutathione reductase (GSNOR) is a denitrosylase enzyme that has been suggested to play a tumor suppressor role, although the mechanisms responsible are still largely unclear. In this study, we show that GSNOR deficiency in tumors is associated with poor prognostic histopathological features and poor survival in patients with colorectal cancer (CRC). GSNOR-low tumors were characterized by an immunosuppressive microenvironment with exclusion of cytotoxic CD8+ T cells. Notably, GSNOR-low tumors exhibited an immune evasive proteomic signature along with an altered energy metabolism characterized by impaired oxidative phosphorylation (OXPHOS) and energetic dependence on glycolytic activity. CRISPR-Cas9-mediated generation of GSNOR gene knockout (KO) CRC cells confirmed in vitro and in vivo that GSNOR-deficiency conferred higher tumorigenic and tumor-initiating capacities. Moreover, GSNOR-KO cells possessed enhanced immune evasive properties and resistance to immunotherapy, as revealed following xenografting them into humanized mouse models. Importantly, GSNOR-KO cells were characterized by a metabolic shift from OXPHOS to glycolysis to produce energy, as indicated by increased lactate secretion, higher sensitivity to 2-deoxyglucose (2DG), and a fragmented mitochondrial network. Real-time metabolic analysis revealed that GSNOR-KO cells operated close to their maximal glycolytic rate, as a compensation for lower OXPHOS levels, explaining their higher sensitivity to 2DG. Remarkably, this higher susceptibility to glycolysis inhibition with 2DG was validated in patient-derived xenografts and organoids from clinical GSNOR-low tumors. In conclusion, our data support the idea that metabolic reprogramming induced by GSNOR deficiency is an important mechanism for tumor progression and immune evasion in CRC and that the metabolic vulnerabilities associated with the deficiency of this denitrosylase can be exploited therapeutically. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.