Metabolic Insufficiency Research Articles

Modulation of brain energy metabolism in hepatic encephalopathy: impact of glucose metabolic dysfunction.

Cerebral function is linked to a high level of metabolic activity and relies on glucose as its primary energy source. Glucose aids in the maintenance of physiological brain activities; as a result, a disruption in metabolism has a significant impact on brain function, launching a chain of events that leads to neuronal death. This metabolic insufficiency has been observed in a variety of brain diseases and neuroexcitotoxicity disorders, including hepatic encephalopathy. It is a significant neurological complication that develops in people with liver disease, ranging from asymptomatic abnormalities to coma. Hyperammonemia is the main neurotoxic villain in the development of hepatic encephalopathy and induces a wide range of complications in the brain. The neurotoxic effects of ammonia on brain function are thought to be mediated by impaired glucose metabolism. Accordingly, in this review, we provide an understanding of deranged brain energy metabolism, emphasizing the role of glucose metabolic dysfunction in the pathogenesis of hepatic encephalopathy. We also highlighted the differential metabolic profiles of brain cells and the status of metabolic cooperation between them. The major metabolic pathways that have been explored are glycolysis, glycogen metabolism, lactate metabolism, the pentose phosphate pathway, and the Krebs cycle. Furthermore, the lack of efficacy in current hepatic encephalopathy treatment methods highlights the need to investigate potential therapeutic targets for hepatic encephalopathy, with regulating deficient bioenergetics being a viable alternative in this case. This review also demonstrates the importance of the development of glucose metabolism-focused disease diagnostics and treatments, which are now being pursued for many ailments.

The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function

Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives Tcell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ Tcells. METRNL was secreted by CD8+ Tcells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ Tcells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

Reprogramming T-cell metabolism to enhance adoptive cell therapies.

Adoptive cell therapy (ACT) is an immunotherapeutic approach that involves isolating T cells from a patient, culturing them ex vivo, then reinfusing the cells back into the patient. Although this strategy has shown remarkable efficacy in hematological malignancies, the solid-tumour microenvironment (TME) has presented serious challenges for therapy efficacy. Particularly, the TME has immunosuppressive signalling and presents a metabolically challenging environment that leads to T-cell suppression. T-cell metabolism is an expanding field of research with a focus on understanding its inherent link to T-cell function. Here, we review the current model of T-cell metabolism from naïve cells through effector and memory life stages, as well as updates to the model from recent literature. These models of metabolism have provided us with the tools and understanding to explore T-cell metabolic and mitochondrial insufficiency in the TME. We discuss manipulations that can be made to these mitochondrial and metabolic pathways to enhance the persistence of infused T cells, overcome the metabolically challenging TME and improve the efficacy of therapy in ACT models. Further understanding and investigation of the impact of metabolic pathways on T-cell performance could contribute to improving therapy efficacy for patients.

Characterization of brain metabolism, volume, and vasculature of the 5xFAD mouse model of Alzheimer’s Disease across lifespan.

AbstractBackgroundThe MODEL‐AD Consortium seeks to develop the next generation of Alzheimer’s Disease models based on human data. A popular model of familial AD is the 5xFAD mouse, characterized by early amyloid‐β deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic features over its lifespan.MethodMale and female 5xFAD and WT littermates underwent in vivo 18F‐FDG‐PET imaging at 4, 6, and 12 months of age to evaluate regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” that labels all cerebral vessels with a fluorescent dye. “Vessel painted” brains were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter.ResultsOur analyses revealed that vessel length, vessel and junction densities increased from 4 to 12 months on the cortical surface in both 5xFAD and WT mice. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but their diameters were significantly increased only in 5xFAD mice. MCA average vessel length was decreased in 5xFAD mice compared to WT. Analysis of 18F‐FDG cortical uptake found significant interactions between WT and 5xFAD mice spanning 4‐12 months of age in retrosplenial, somatosensory and visual cortices. Broadly, 5xFAD males had increased 18F‐FDG uptake at 12 months of age compared to WT mice. In most cortical regions, female 5xFAD mice had reduced FDG uptake compared to WT across the lifespan. In males these metabolic increases coincided with decreased vessel characteristics.ConclusionThe 5xFAD mouse exhibits AD‐like cognitive deficits with age that are associated with increasing amyloid‐β deposition. No significant differences were found in cortical vascular features although males and females exhibited opposite effects in 18F‐FDG uptake. The MCA supplies blood to large portions of the motor cortex and increased vessel lengths and decreased collaterals along with higher metabolic rates in 5xFAD mice may be related to increasing behavioral deficits via metabolic insufficiency or other mechanisms.

Characterization of brain metabolism, volume, and vasculature of the 5xFAD mouse model of Alzheimer’s Disease across lifespan

AbstractBackgroundThe MODEL‐AD Consortium seeks to develop the next generation of Alzheimer’s Disease models based on human data. A popular model of familial AD is the 5xFAD mouse, characterized by early amyloid‐ß deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic features over its lifespan.MethodMale and female 5xFAD and WT littermates underwent in vivo 18F‐FDG‐PET imaging at 4, 6, and 12 months of age to evaluate regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” that labels all cerebral vessels with a fluorescent dye. “Vessel painted” brains were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter.ResultOur analyses revealed that vessel length, vessel and junction densities increased from 4 to 12 months on the cortical surface in both 5xFAD and WT mice. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but their diameters were significantly increased only in 5xFAD mice. MCA average vessel length was decreased in 5xFAD mice compared to WT. Analysis of 18F‐FDG cortical uptake found significant interactions between WT and 5xFAD mice spanning 4‐12 months of age in retrosplenial, somatosensory and visual cortices. Broadly, 5xFAD males had increased 18F‐FDG uptake at 12 months of age compared to WT mice. In most cortical regions, female 5xFAD mice had reduced FDG uptake compared to WT across the lifespan. In males these metabolic increases coincided with decreased vessel characteristics.ConclusionThe 5xFAD mouse exhibits AD‐like cognitive deficits with age that are associated with increasing amyloid‐ß deposition. No significant differences were found in cortical vascular features although males and females exhibited opposite effects in 18F‐FDG uptake. The MCA supplies blood to large portions of the motor cortex and increased vessel lengths and decreased collaterals along with higher metabolic rates in 5xFAD mice may be related to increasing behavioral deficits via metabolic insufficiency or other mechanisms.

The Immune Editing Process Reshapes the AML1-ETO Fusion Protein-Induced Pre-Leukemia Microenvironment

Objective: Currently, the process of common chromosome translocation, such as AML1-ETO, recruiting chromatin-modifying enzymes that drive the malignant phenotype is an object of intense investigation. However, there exists an indeterminate understanding of how this chromosome translocation reshapes the immune microenvironment, and whether immune editing occurs during the pre-leukemia stage to facilitate their own progression. In this study, we evaluate how the AML1-ETO chromosome translocation reshapes the immune microenvironment by employing the Aml1 Eto/+; Mx1-Cre mouse model to identify potential pivotal immunotherapy targets. Methods: Four weeks after PIPC induction (5mg/kg), bone marrow-derived T cells without the AML1-ETO (AE) fusion gene and Lin - c-Kit + Sca-1 + (LSK) cells were sorted from both Aml1 Eto/+; Mx1-Cre mice (experimental group) and Aml1 Eto/+; w/o Mx1-Cre mice (control group), respectively, and subsequently mixed at 8:2 ratio for single-cell RNA-Seq(scRNA) and single-cell TCR-seq. The results are further validated by real-time PCR and flow cytometry. Results: In our preliminary cell-sorting-based dissection research, we found that despite antigen presentation existing in clonally expanded AE precursor cells and the differentiated T cells like effector T cells expanded, the established AE-expressed precursor cells are not eradicated by the host immune system as expected. To describe the mechanism underlying it, the first step is to find whether the potentially tumor-reactive T cells (pTRTs) existed. We examined the single-cell data based on the following four dimensions: the tumor-enrichment index, the proliferation index, the clonal expansion index, and the TCR signaling pathway activation index. Two clusters of Cd8 + exhausted T cells and four clusters of Cd4 +Runx3 + cytotoxic T cells were identified as pTRTs. While Cd8 + pTRTs demonstrated high expression levels of genes like Gzmk, Ifng, and Prf1, they also exhibited high expression levels of exhaustion markers such as Pdcd1, Tox, and Ctla4. More importantly, compared with virus-specific T cells recognized by machine learning trained from validated TCR databases, the Cd8 + pTRTs showed the feature of metabolic insufficiency via the Compass analysis. Cell-cell interaction analysis by CellphoneDB and NicheNet and following flow cytometry confirmation revealed that the highly expressed PVR and NECTIN2 on AE + precursor cells interacted with pTRTs via inhibitory receptor TIGIT, while they interacted with bystander T cells through stimulatory receptor CD226. At the same time, Tregs played a vital role in the maintenance of the immune equilibrium state as the Treg cells increased in the AE microenvironment but not homogeneously. There were four different Treg clusters identified, including Cd4_Treg_Ccr7+, Cd4_Treg_Tnfrsf9-, Cd4_Treg_ Cdc25b+ with high apoptosis and proliferation score, and Cd4_Treg_Tnfrsf9+ with high suppression\exhaustion/activation/migration score which was recognized as effector Treg. It was observed that only the effector Treg exhibited an increase in proportion. Monocle analysis showed that Cd4_Treg_Ccr7+ was at the beginning of common origin while the Cd4_Treg_Cdc25b+ and Cd4_Treg_Tnfrsf9+ were at the endpoint of two distinct differentiation pathways and the AE microenvironment shifted to the latter one. The flow cytometry results clearly showed a notable rise in KI67 -TNFRSF9 + effector Tregs, along with a significant decline in KI67 +TNFRSF9 - proliferative Tregs. Conclusions: Our findings demonstrate that, during the pre-leukemia stage, the immune editing process has already occurred, leading to substantial alterations in the immune microenvironment. It was identified that PVR/NECTIN2-TIGIT interaction and TNFRSF9 +Treg as targetable mechanisms to restore the function of pTRTs and break the immune equilibrium dilemma.

The dysfunctional immune response in renal cell carcinoma correlates with changes in the metabolic landscape of ccRCC during disease progression

Renal cell carcinoma is an immunogenic tumour with a prominent dysfunctional immune cell infiltrate, unable to control tumour growth. Although tyrosine kinase inhibitors and immunotherapy have improved the outlook for some patients, many individuals are non-responders or relapse despite treatment. The hostile metabolic environment in RCC affects the ability of T-cells to maintain their own metabolic programme constraining T-cell immunity in RCC. We investigated the phenotype, function and metabolic capability of RCC TILs correlating this with clinicopathological features of the tumour and metabolic environment at the different disease stages. Flow cytometric analysis of freshly isolated TILs showed the emergence of exhausted T-cells in advanced disease based on their PD-1high and CD39 expression and reduced production of inflammatory cytokines upon in vitro stimulation. Exhausted T-cells from advanced stage disease also displayed an overall phenotype of metabolic insufficiency, characterized by mitochondrial alterations and defects in glucose uptake. Nanostring nCounter cancer metabolism assay on RNA obtained from 30 ccRCC cases revealed significant over-expression of metabolic genes even at early stage disease (pT1-2), while at pT3-4 and the locally advanced thrombi stages, there was an overall decrease in differentially expressed metabolic genes. Notably, the gene PPARGC1A was the most significantly down-regulated gene from pT1-2 to pT3-4 RCC which correlated with loss of mitochondrial function in tumour-infiltrating T-cells evident at this tumour stage. Down-regulation of PPARGC1A into stage pT3-4 may be the ‘tipping-point’ in RCC disease progression, modulating immune activity in ccRCC and potentially reducing the efficacy of immunotherapies in RCC and poorer patient outcomes.

Clinical cases of toxic hepatitis: aspects of differential diagnosis with viral hepatitis

In modern conditions of environmental problems, practicing doctors increasingly have to provide assistance to patients with hepatitis, the cause of which is not only known viral agents, but also chemical poisons. General information about toxic, primarily drug‑induced, and viral hepatitis is given. The main hepatotoxic drugs are listed. Their classification, mechanism of action, clinical symptoms, biochemical and morphological changes in various toxic liver lesions are highlighted. Information on drugs with high hepatic extraction, for which there is a high risk of overdose, is highlighted. For patients from risk groups, it is advisable to at least halve the dose of such drugs in accordance with the decrease in hepatic blood flow. Drugs with low hepatic extraction have a minimal risk of overdose, although metabolic insufficiency with long‑term administration of such drugs may cause their accumulation. Finally, drugs that are excreted by the kidneys are practically devoid of the risk of hepatotoxicity. Other professional and household toxic substances that have a direct hepatotoxic effect are discussed (carbon tetrachloride, dichlorodiphenyltrichloromethylmethane, yellow phosphorus, amanito‑ and phallotoxins of the pale toadstool, various pesticides, etc.).
 Clinical cases of own clinical observations of various toxic hepatitises are included. The general characteristics of viral hepatitis are given, primarily with an emphasis on their differential diagnosis with hepatotoxic lesions. The main signs of viral and toxic hepatitis are grouped in the table. For a successful differential diagnosis of toxic and viral hepatitis, it is necessary to apply a modern complex of anamnestic, clinical, biochemical, virological, instrumental and morphological examination methods as fully as possible.

Oxygen Debt as Predictor of Mortality and Multiple Organ Dysfunction Syndrome in Severe COVID-19 Patients: A Retrospective Study.

Background: Oxygen debt (DEOx) represents the disparity between resting and shock oxygen consumption (VO2) and is associated with metabolic insufficiency, acidosis, severity, and mortality. This study aimed to assess the reliability of DEOx as an indirect quantitative measure for predicting multiple organ dysfunction syndrome (MODS) and 28-day mortality in patients admitted to the intensive care unit (ICU) with respiratory syndrome severe acute coronavirus type 2 (SARS-CoV-2) infection, in comparison to the Acute Physiology and Chronic Health Evaluation II (APACHE II), sepsis-related organ failure assessment (SOFA), and 4C scores. Methods: A retrospective cohort study was conducted, including ICU patients with SARS-CoV-2 infection between 2020 and 2021. Clinical data were extracted from the EPIMED Monitor Database®. APACHE II, SOFA, and 4C scores were calculated upon ICU admission, and their accuracy in predicting 28-day mortality and MODS was compared to DEOx. Multivariate logistic regression analysis was performed to analyze the outcome variables. Results: 708 patients were included, with a mortality rate of 44.4%. DEOx value was 11.16 ml O2/kg. The mean age was 58.7 years. Multivariate analysis showed that DEOx was independently associated with mortality, intubation, and renal injury. Each point increase in creatinine was associated with a higher risk of MODS. To determine the precision of the scores, area under the receiver operating characteristic curves (AUROC) analysis was performed with weak discrimination and similar behavior for the primary outcomes. The most accurate scale for mortality and MODS was 4C with an AUC of 0.683 and APACHE II with an AUC of 0.814, while that of the AUROC of DEOx was 0.612 and 0.646, respectively. Conclusions: DEOx showed similar predictive value to established scoring systems in critically ill patients with SARS-CoV-2 infection. The correlation of DEOx with these scores may facilitate early intervention in critically ill patients.

Clinical Case of a Combination of Endocrine, Metabolic, and Mental Pathologies: Hypopituitarism Associated with Organic Personality Disorder

Background: Psychiatric disorders are difficult to assess, diagnose, and treat in most cases. The present case describes an extremely rare psychological disorder in combination with metabolic and endocrine insufficiency. Case Presentation: The condition of a 7-year-old child with inherited psychopathology from his father was found to be aggravated by his mother's alcoholism. The child was delivered in emergency from a primigravida/primipara mother due to preeclampsia and premature membrane rupture. The examinations involved clinical signs and symptoms and instrumental and laboratory findings. All laboratory results were compared with the normal range of the local laboratory. The results of the examination showed pronounced impairment in learning and controlling behavior, and communication, as well as moderate impairment in orientation. Results: The future consequences and complications are poorly understood. Management guidelines for such complicated cases are underdeveloped. Conclusion: The child was managed by diet correction, potassium iodide and hormone replacement therapy, calcium supplement, nootropics with 2 courses per year, examination by a urologist and pediatric endocrinologist 2 times a year, and hospitalization after 6 months of treatment.

Does the Etiology, Phenomenology and Motor Subtype of Delirium Differ When It Occurs in Patients With An Underlying Dementia?: A Multi-Site, International Study.

To compare the etiology, phenomenology and motor subtype of delirium in patients with and without an underlying dementia. A combined dataset (n = 992) was collated from two databases of older adults (>65 years) from liaison psychiatry and palliative care populations in Ireland and India. Phenomenology and severity of delirium were analysed using the Delirium Symptom Rating Scale Revised (DRS-R98) and contributory etiologies for the delirium groups were ascertained using the Delirium Etiology Checklist (DEC). Delirium motor subtype was documented using the abbreviated version of the Delirium Motor Subtype Scale (DMSS4). Delirium superimposed on dementia (DSD) showed greater impairment in short term memory, long term memory and visuospatial ability than the delirium group but showed significantly less perceptual disturbance, temporal onset and fluctuation. Systemic infection, cerebrovascular and other Central nervous system etiology were associated with DSD while metabolic disturbance, organ insufficiency and intracranial neoplasm were associated with the delirium only group. The etiology and phenomenology of delirium differs when it occurs in the patient with an underlying dementia. We discuss the implications in terms of identification and management of this complex condition.

How do parasitic worms prevent diabetes? An exploration of their influence on macrophage and β-cell crosstalk.

Diabetes is the fastest growing chronic disease globally, with prevalence increasing at a faster rate than heart disease and cancer. While the disease presents clinically as chronic hyperglycaemia, two distinct subtypes have been recognised. Type 1 diabetes (T1D) is characterised as an autoimmune disease in which the insulin-producing pancreatic β-cells are destroyed, and type 2 diabetes (T2D) arises due to metabolic insufficiency, in which inadequate amounts of insulin are produced, and/or the actions of insulin are diminished. It is now apparent that pro-inflammatory responses cause a loss of functional β-cell mass, and this is the common underlying mechanism of both T1D and T2D. Macrophages are the central immune cells in the pathogenesis of both diseases and play a major role in the initiation and perpetuation of the proinflammatory responses that compromise β-cell function. Furthermore, it is the crosstalk between macrophages and β-cells that orchestrates the inflammatory response and ensuing β-cell dysfunction/destruction. Conversely, this crosstalk can induce immune tolerance and preservation of β-cell mass and function. Thus, specifically targeting the intercellular communication between macrophages and β-cells offers a unique strategy to prevent/halt the islet inflammatory events underpinning T1D and T2D. Due to their potent ability to regulate mammalian immune responses, parasitic worms (helminths), and their excretory/secretory products, have been examined for their potential as therapeutic agents for both T1D and T2D. This research has yielded positive results in disease prevention, both clinically and in animal models. However, the focus of research has been on the modulation of immune cells and their effectors. This approach has ignored the direct effects of helminths and their products on β-cells, and the modulation of signal exchange between macrophages and β-cells. This review explores how the alterations to macrophages induced by helminths, and their products, influence the crosstalk with β-cells to promote their function and survival. In addition, the evidence that parasite-derived products interact directly with endocrine cells to influence their communication with macrophages to prevent β-cell death and enhance function is discussed. This new paradigm of two-way metabolic conversations between endocrine cells and macrophages opens new avenues for the treatment of immune-mediated metabolic disease.

Factors contributing to the new coronavirus infection, increased risk of complications and death from it in the armed forces of the Russian Federation

Based on the assessment of factors that contribute to a new coronavirus infection, the risk of complications, mortality, and lethality from it in the Armed Forces of the Russian Federation were analyzed. A detailed timeline of the development of the coronavirus pandemic in the Russian Federation has been demonstrated, showing indicators of peak and overall morbidity and mortality and prevailing strains of a new coronavirus infection, depending on the waves of the pandemic. The study evaluated the features of the course of a new coronavirus infection in the Eurasian region using data from the international register Analysis of the dynamics of comorbid diseases in patients infected with severe acute respiratory syndrome-2 coronavirus. Modern ideas about the main pathogenetic mechanisms of involvement of the circulatory system, which underlie the development of a severe course, mortality, and lethal outcomes, are outlined. The study also presented the concept of metabolic and hemodynamic insufficiency, which justifies the inability of the desynchronized circulatory system and systems of vascular homeostasis and hemostasis to restore the previous level of functioning after a new coronavirus infection. The possibilities of carrying out differentiated anti-epidemiological measures, including the use of information technologies, aimed at reducing the spread of a new coronavirus infection, were evaluated. The mortality and mortality from a new coronavirus infection in the Armed Forces of the Russian Federation, including the effect of a new coronavirus infection on an increase in the incidence of non-communicable diseases in military personnel of different age groups, were presented. The study also considered issues of the need to introduce a rehabilitation strategy to correct conditions that occur after a new coronavirus infection, reduce the risk of subsequent mortality and lethality, and reduce it in the long term.

Alzheimer’s Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity

Alzheimer's disease (AD) is a progressive and degenerative disease producing the most common type of dementia worldwide. The main pathogenetic hypothesis in recent decades has been the well-known amyloidogenic hypothesis based on the involvement of two proteins in AD pathogenesis: amyloid β (Aβ) and tau. Amyloid deposition reported in all AD patients is nowadays considered an independent risk factor for cognitive decline. Vascular damage and blood-brain barrier (BBB) failure in AD is considered a pivotal mechanism for brain injury, with increased deposition of both immunoglobulins and fibrin. Furthermore, BBB dysfunction could be an early sign of cognitive decline and the early stages of clinical AD. Vascular damage generates hypoperfusion and relative hypoxia in areas with high energy demand. Long-term hypoxia and the accumulation within the brain parenchyma of neurotoxic molecules could be seeds of a self-sustaining pathological progression. Cellular dysfunction comprises all the elements of the neurovascular unit (NVU) and neuronal loss, which could be the result of energy failure and mitochondrial impairment. Brain glucose metabolism is compromised, showing a specific region distribution. This energy deficit worsens throughout aging. Mild cognitive impairment has been reported to be associated with a glucose deficit in the entorhinal cortex and in the parietal lobes. The current aim is to understand the complex interactions between amyloid β (Aβ) and tau and elements of the BBB and NVU in the brain. This new approach aimed at the study of metabolic mechanisms and energy insufficiency due to mitochondrial impairment would allow us to define therapies aimed at predicting and slowing down the progression of AD.

Comment on: Pancreatectomy With Islet-Autotransplantation As Alternative for Pancreatoduodenectomy in Patients With a High-Risk for Postoperative Pancreatic Fistula: The Jury Is Still Out.

We would like to congratulate Balzano et al1 on their randomized controlled bicenter PAN-IT trial wherein total pancreatectomy (TP) with islet-autotransplantation (IAT) was studied as an alternative for patients undergoing pancreatoduodenectomy (PD) with a high-risk for developing postoperative pancreatic fistula (POPF). However, we have some concerns regarding the authors’ final conclusions that TP-IAT may become the standard treatment in candidates for PD with a high risk for POPF. Our concerns center on (1) the primary endpoint of the PAN-IT trial, (2) the lack of assessment of patient-reported outcomes, and (3) the quality of diabetes control. First, it is questionable if postoperative morbidity is the optimal endpoint in a trial that aims to elucidate the role of TP(-IAT) as alternative to PD with a high risk for POPF. How much morbidity should be prevented to justify a lifelong apancreatic state? Indeed, TP-IAT improved the primary endpoint (ie, 90-day overall complication rate) by avoiding POPF, but the 90-day mortality did not differ statistically significant despite a clinically relevant difference (9.7% after PD vs 3.3% after TP-IAT), which is line with recent retrospective single-center series.2,3 However, the mortality after TP(-IAT) in the daily clinical practice may be substantially higher. A recent prospective European international multicenter study including 277 patients who underwent TP found a 90-day mortality rate of 7.6%, which increased to even 11.9% in centers performing less than 60 PDs per year.4 Moreover, the recent Dutch PORSCH trial demonstrated that postoperative mortality can be reduced after PD regardless of hospital volume due to the implementation of an algorithm for early detection and treatment of POPF.5 As a consequence, the vast majority of the clinically relevant POPF can be managed either conservatively or with minimally invasive interventions.5 Second, patient-reported outcomes including quality of life over time are highly relevant endpoints when determining the role of TP(-IAT) in our opinion. Surprisingly, quality of life was not evaluated over time, while the prospective nature of the PAN-IT trial offered a unique opportunity to investigate this properly. This should be included in future prospective studies. Although the interest in TP for this indication has been renewed in recent years by the improved morbidity and mortality after TP in high-volume centers4,6 and more adequate management of the associated metabolic insufficiencies, the related adverse events remain substantial.7 Quality of life on the middle- and long-term after TP is reduced in comparison to the general population.8,9 IAT after TP only (mostly temporarily) controls the endocrine insufficiency partially, whereas exocrine insufficiency remains a challenge. This is especially relevant for the currently studied indication of TP(-IAT) since patients with a high risk for POPF after PD often have long-term survival because of benign/ premalignant pancreatic diseases. Third, the quality of diabetes control and insulin independence obtained by TP-IAT. Already after 1 month, glycemic control as measured by hemoglobin A1c was worse in the TP-IAT group and at the end of follow-up (median follow-up of 388 days), only 6.7% of patients after TP-IAT were independent of insulin versus 80.6% of patients after high-risk PD. The authors argue that the absence of serious hypoglycemic events is explained by the remaining graft function. However, long-term results are missing, while these are highly important considering the likelihood that the graft function will further decrease over time. An alternative for or additive to IAT might be the bihormonal artificial pancreas, for which we recently demonstrating promising results.10 In summary, the PAN-IT is a high quality randomized trial that provides quite relevant insights, but in our opinion does not confirm that TP-IAT may become the standard treatment in patients with a high risk for POPF after PD. We question whether a 30% absolute risk reduction of short-term postoperative morbidity justifies a 73% absolute risk increase of lifelong insulin dependence and, most likely, decreased quality of life. Furthermore, early POPF recognition and step-wise minimally invasive management have an important role in the improvement of both morbidity and mortality after PD. Only future large, randomized studies with mortality and quality of life as primary outcome can answer this question.

How Can Insulin Resistance Cause Alzheimer's Disease?

Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive decline. Despite worldwide efforts to find a cure, no proper treatment has been developed yet, and the only effective countermeasure is to prevent the disease progression by early diagnosis. The reason why new drug candidates fail to show therapeutic effects in clinical studies may be due to misunderstanding the cause of AD. Regarding the cause of AD, the most widely known is the amyloid cascade hypothesis, in which the deposition of amyloid beta and hyperphosphorylated tau is the cause. However, many new hypotheses were suggested. Among them, based on preclinical and clinical evidence supporting a connection between AD and diabetes, insulin resistance has been pointed out as an important factor in the development of AD. Therefore, by reviewing the pathophysiological background of brain metabolic insufficiency and insulin insufficiency leading to AD pathology, we will discuss how can insulin resistance cause AD.

Metabolic and Cerebrovascular Perturbations in the 5xFAD Mouse Model of Alzheimer’s Disease

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium seeks to develop the next generation of AD models based on human data. A popular model of familial AD is the 5xFAD mouse. It is characterized by early amyloid‐β deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic aspects over its lifespan.MethodMales and females 5xFAD and WT littermates underwent in vivo 18F‐FDG‐PET imaging at 4, 6, and 12 months to evaluate regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” that labels all cerebral vessels with a fluorescent dye. Brains were analyzed for vascular characteristics such as vessel and junction density, vessel length, network complexity, number and diameter of collaterals.ResultOur analyses revealed that vessel length, vessel and junction densities increased from 4 to 12 months on the cortical surface in both 5xFAD and WT mice. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but interestingly their diameters were significantly increased only in 5xFAD mice. MCA average vessel length was significantly decreased at 8 and 12 months in 5xFAD mice compared to WT; primarily driven by males. Analysis of 18F‐FDG cortical uptake found significant interactions between WT and 5xFAD mice spanning 4‐12 months of age in retrosplenial somatosensory and visual cortices. Broadly, 5xFAD males had increased 18F‐FDG uptake at 12 months of age compared to WT mice. In most cortical regions, female 5xFAD mice had reduced FDG uptake compared to WT across the lifespan. In males these metabolic increases coincided with decreased vessel characteristics.ConclusionThe 5xFAD mouse exhibits AD‐like cognitive deficits with age that are associated with increasing amyloid‐β deposition. No significant differences were found in cortical vascular features although males and females exhibited opposite effects in 18F‐FDG uptake. The MCA supplies blood to large portions of the motor cortex and increased vessel lengths and decreased collaterals along with higher metabolic rates in 5xFAD mice may be related to increasing behavioral deficits via metabolic insufficiency or other mechanisms.

Exhausted Circulation: The Limits to Cement Transportation and Urban Metabolism in the West Bank

This article looks at cement as a vital material in the process of urbanization. It specifically addresses urban metabolism, examining the intricacies of the cement circulation network in the occupied Palestinian territories (oPt) during the post-Oslo period. Because of Israel’s near-total control of land and natural resources in the oPt, there is still no fully integrated Palestinian cement plant there, making the Palestinian construction sector highly dependent on imports from Israel’s Nesher cement factory. This article argues that controlling the circulation of cement constitutes sovereignty over the processes of urbanization. In the current context, the cement circulation system that is effectively controlled by Israel is characterized by exhaustion, resulting in Palestinian urban geography’s perennial metabolic insufficiency.

Local Homogeneity of PET Images Visualizes Peri-Irradiation CD8 T Cell Exhaustion

<h3>Purpose/Objective(s)</h3> The functional states of CD8⁺ T cells are associated with response to immune checkpoint inhibitors (ICI) and might become a potential biomarker indicating the timing of ICI. CD8⁺ T cells undergoing exhaustion (Tex) exhibit progressive loss of effector functions as well as metabolic insufficiency, such as suppressed glycolysis and restricted glucose uptake. We assumed that metabolic characteristics of Tex might be reflected by PET radiomic features, which could be used to noninvasively visualize the peri-irradiation dynamics of Tex and predict the optimal timing of ICI integration. Here, we aim to investigate the dynamics of Tex after ablative irradiation and develop an ¹⁸F-FDG PET/CT radiomic approach to assess tumor infiltrating Tex basing on non-small cell lung cancer (NSCLC) xenograft experiments. <h3>Materials/Methods</h3> C57BL/6 mice were inoculated with 1M Lewis Lung Carcinoma (LLC) cells subcutaneously on the right flank. On day 10 post-tumor inoculation, 20Gy was delivered to the tumors in a single fraction. For the control (D0) and those irradiated (D3, D7, D14 and D21 post-irradiation), mice received micro PET-CT scans and were sacrificed immediately after scanning, with tumors and spleens collected. The abundance of tumor-infiltrating immune cell subsets were estimated by deconvoluting the tumor microarray data with CIBERSORTx. ICI-responsive early Tex (CD8⁺PD-1^intTcf-1⁺) and ICI-nonresponsive terminal Tex (CD8⁺PD-1^hiTIM-3⁺TOX⁺) were identified by flow cytometry. Tumors on PET/CT images were manually contoured, and radiomic features were extracted by a compact proton therapy machine. Robust features which passed Test-retest analysis will undergo further selection. Least absolute shrinkage and selection operator (LASSO) logistic regression was used to select radiomic features significantly correlated with the infiltration of early or terminal Tex. <h3>Results</h3> After ablative irradiation, the tumor CD8⁺ T cell infiltration increased from D3 through the peak on D14, and then declined sharply to a below-baseline level on D21. However, dysfunctional terminal Tex significantly predominated CD8⁺ T cells from D7 to D14 (69.44%∼ 76.35%), indicating a potential window for ICI treatment between D3-D7 post-irradiation. 40 (out of 57) CT and 9 (out of 61) PET radiomic features of good robustness were brought into LASSO regression. Gray Level Co-occurrence Matrix (GLCM)-inverse variance and Gray Level Run Length Matrix (GLRLM)-long run emphasis on PET images were found to be inversely correlated with the abundance of terminal Tex, showing more heterogeneous local distribution of FDG uptake correlated with higher T exhaustion. <h3>Conclusion</h3> The dynamics of Tex help identify the proper timing to combine ICI with irradiation. Local homogeneity of PET images may provide a noninvasive approach to visualize peri-irradiation T cell exhaustion, and exhibit the potential to estimate ICI timing among more radiation dose-fractionation schedules in future study.

Fully murine CD105-targeted CAR-T cells provide an immunocompetent model for CAR-T cell biology

ABSTRACT The modeling of chimeric antigen receptor (CAR) T cell therapies has been mostly focused on immunodeficient models. However, there are many advantages in studying CAR-T cell biology in an immunocompetent setting. We generated a fully murine CAR targeting CD105 (endoglin), a component of the TGFβ receptor expressed on the surface of certain solid tumors and acute leukemias. CD105-targeted CAR-T cells can be grown from various murine backgrounds, tracked in vivo by congenic marks, and be activated by CD105 in isolation or expressed by tumor cells. CD105-targeted CAR-T cells were toxic at higher doses but proved safe in lower doses and modestly effective in treating wild-type B16 melanoma-bearing mice. CAR-T cells infiltrating the tumor expressed high levels of exhaustion markers and exhibited metabolic insufficiencies. We also generated a human CD105 CAR, which was efficacious in treating human melanoma and acute myeloid leukemia in vivo. Our work details a new murine model of CAR-T cell therapy that can be used from immunologists to further our understanding of CAR-T cell biology. We also set the foundation for further exploration of CD105 as a possible human CAR-T cell target.