Search

Abstract Quantitative systems toxicology (QST) models are increasingly being applied for predicting and understanding toxicity liabilities in pharmaceutical research and development. A European Federation of Pharmaceutical Industries and Associations (EFPIA)‐wide survey was completed by 15 companies. The results provide insights into the current use of QST models across the industry. 73% of responding companies with more than 10,000 employees utilize QST models. The most applied QST models are for liver, cardiac electrophysiology, and bone marrow/hematology. Responders indicated particular interest in QST models for the central nervous system (CNS), kidney, lung, and skin. QST models are used to support decisions in both preclinical and clinical stages of pharmaceutical development. The survey suggests high demand for QST models and resource limitations were indicated as a common obstacle to broader use and impact. Increased investment in QST resources and training may accelerate application and impact. Case studies of QST model use in decision‐making within EFPIA companies are also discussed. This article aims to (i) share industry experience and learnings from applying QST models to inform decision‐making in drug discovery and development programs, and (ii) share approaches taken during QST model development and validation and compare these with recommendations for modeling best practices and frameworks proposed in the literature. Discussion of QST‐specific applications in relation to these modeling frameworks is relevant in the context of the recently proposed International Council for Harmonization (ICH) M15 guideline on general principles for Model‐Informed Drug Development (MIDD).

Abstract Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ-expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4-deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity.

Abstract Scientific agencies spend substantial sums producing and improving forecasts of seasonal climate, but they do so without much information about these forecasts’ value in practice. Here we show that financial market participants value the production of seasonal forecasts: options traders price the uncertainty generated by upcoming United States National Oceanic and Atmospheric Administration Winter and El Niño Outlooks. Each outlook affects firms throughout the economy, with total market capitalization of $6 and $13 trillion, respectively. A 1% improvement in the skill of the El Niño Outlook reduces firms’ exposure to a one standard deviation shock by $18 billion and induces traders to spend an additional $2 million hedging the outlook’s news. Firms must not be able to undertake ex-ante adaptation that would eliminate their exposure to the forecasted portion of seasonal climate without imposing substantial costs of its own.

Summary: Sympathetic innervation of brown adipose tissue (BAT) controls mammalian adaptative thermogenesis. However, the cellular and molecular underpinnings contributing to BAT innervation remain poorly defined. Here, we show that smooth muscle cells (SMCs) support BAT growth, lipid utilization, and thermogenic plasticity. Moreover, we find that BAT SMCs express and control the bioavailability of Cxcl12. SMC deletion of Cxcl12 fosters brown adipocyte lipid accumulation, reduces energy expenditure, and increases susceptibility to diet-induced metabolic dysfunction. Mechanistically, we find that Cxcl12 stimulates CD301+ macrophage recruitment and supports sympathetic neuronal maintenance. Administering recombinant Cxcl12 to obese mice or leptin-deficient (Ob/Ob) mice is sufficient to boost macrophage presence and drive sympathetic innervation to restore BAT morphology and thermogenic responses. Altogether, our data reveal an SMC chemokine-dependent pathway linking immunological infiltration and sympathetic innervation as a rheostat for BAT maintenance and thermogenesis.

Abstract Quantum Chromodynamics, the theory of quarks and gluons, whose interactions can be described by a local SU(3) gauge symmetry with charges called “color quantum numbers”, is reviewed; the goal of this review is to provide advanced Ph.D. students a comprehensive handbook, helpful for their research. When QCD was “discovered” 50 years ago, the idea that quarks could exist, but not be observed, left most physicists unconvinced. Then, with the discovery of charmonium in 1974 and the explanation of its excited states using the Cornell potential, consisting of the sum of a Coulomb-like attraction and a long range linear confining potential, the theory was suddenly widely accepted. This paradigm shift is now referred to as the November revolution. It had been anticipated by the observation of scaling in deep inelastic scattering, and was followed by the discovery of gluons in three-jet events. The parameters of QCD include the running coupling constant, $$\alpha _s(Q^2)$$ α s ( Q 2 ) , that varies with the energy scale $$Q^2$$ Q 2 characterising the interaction, and six quark masses. QCD cannot be solved analytically, at least not yet, and the large value of $$\alpha _s$$ α s at low momentum transfers limits perturbative calculations to the high-energy region where $$Q^2\gg \varLambda _{{\textrm{QCD}}} ^2\simeq $$ Q 2 ≫ Λ QCD 2 ≃ (250 MeV) $$^2$$ 2 . Lattice QCD (LQCD), numerical calculations on a discretized space-time lattice, is discussed in detail, the dynamics of the QCD vacuum is visualized, and the expected spectra of mesons and baryons are displayed. Progress in lattice calculations of the structure of nucleons and of quantities related to the phase diagram of dense and hot (or cold) hadronic matter are reviewed. Methods and examples of how to calculate hadronic corrections to weak matrix elements on a lattice are outlined. The wide variety of analytical approximations currently in use, and the accuracy of these approximations, are reviewed. These methods range from the Bethe–Salpeter, Dyson–Schwinger coupled relativistic equations, which are formulated in both Minkowski or Euclidean spaces, to expansions of multi-quark states in a set of basis functions using light-front coordinates, to the AdS/QCD method that imbeds 4-dimensional QCD in a 5-dimensional deSitter space, allowing confinement and spontaneous chiral symmetry breaking to be described in a novel way. Models that assume the number of colors is very large, i.e. make use of the large $$N_c$$ N c -limit, give unique insights. Many other techniques that are tailored to specific problems, such as perturbative expansions for high energy scattering or approximate calculations using the operator product expansion are discussed. The very powerful effective field theory techniques that are successful for low energy nuclear systems (chiral effective theory), or for non-relativistic systems involving heavy quarks, or the treatment of gluon exchanges between energetic, collinear partons encountered in jets, are discussed. The spectroscopy of mesons and baryons has played an important historical role in the development of QCD. The famous X,Y,Z states – and the discovery of pentaquarks – have revolutionized hadron spectroscopy; their status and interpretation are reviewed as well as recent progress in the identification of glueballs and hybrids in light-meson spectroscopy. These exotic states add to the spectrum of expected $$q{{\bar{q}}}$$ q q ¯ mesons and qqq baryons. The progress in understanding excitations of light and heavy baryons is discussed. The nucleon as the lightest baryon is discussed extensively, its form factors, its partonic structure and the status of the attempt to determine a three-dimensional picture of the parton distribution. An experimental program to study the phase diagram of QCD at high temperature and density started with fixed target experiments in various laboratories in the second half of the 1980s, and then, in this century, with colliders. QCD thermodynamics at high temperature became accessible to LQCD, and numerical results on chiral and deconfinement transitions and properties of the deconfined and chirally restored form of strongly interacting matter, called the Quark–Gluon Plasma (QGP), have become very precise by now. These results can now be confronted with experimental data that are sensitive to the nature of the phase transition. There is clear evidence that the QGP phase is created. This phase of QCD matter can already be characterized by some properties that indicate, within a temperature range of a few times the pseudocritical temperature, the medium behaves like a near ideal liquid. Experimental observables are presented that demonstrate deconfinement. High and ultrahigh density QCD matter at moderate and low temperatures shows interesting features and new phases that are of astrophysical relevance. They are reviewed here and some of the astrophysical implications are discussed. Perturbative QCD and methods to describe the different aspects of scattering processes are discussed. The primary parton–parton scattering in a collision is calculated in perturbative QCD with increasing complexity. The radiation of soft gluons can spoil the perturbative convergence, this can be cured by resummation techniques, which are also described here. Realistic descriptions of QCD scattering events need to model the cascade of quark and gluon splittings until hadron formation sets in, which is done by parton showers. The full event simulation can be performed with Monte Carlo event generators, which simulate the full chain from the hard interaction to the hadronic final states, including the modelling of non-perturbative components. The contribution of the LEP experiments (and of earlier collider experiments) to the study of jets is reviewed. Correlations between jets and the shape of jets had allowed the collaborations to determine the “color factors” – invariants of the SU(3) color group governing the strength of quark–gluon and gluon–gluon interactions. The calculated jet production rates (using perturbative QCD) are shown to agree precisely with data, for jet energies spanning more than five orders of magnitude. The production of jets recoiling against a vector boson, $$W^\pm $$ W ± or Z, is shown to be well understood. The discovery of the Higgs boson was certainly an important milestone in the development of high-energy physics. The couplings of the Higgs boson to massive vector bosons and fermions that have been measured so far support its interpretation as mass-generating boson as predicted by the Standard Model. The study of the Higgs boson recoiling against hadronic jets (without or with heavy flavors) or against vector bosons is also highlighted. Apart from the description of hard interactions taking place at high energies, the understanding of “soft QCD” is also very important. In this respect, Pomeron – and Odderon – exchange, soft and hard diffraction are discussed. Weak decays of quarks and leptons, the quark mixing matrix and the anomalous magnetic moment of the muon are processes which are governed by weak interactions. However, corrections by strong interactions are important, and these are reviewed. As the measured values are incompatible with (most of) the predictions, the question arises: are these discrepancies first hints for New Physics beyond the Standard Model? This volume concludes with a description of future facilities or important upgrades of existing facilities which improve their luminosity by orders of magnitude. The best is yet to come!

Abstract Allogeneic Vγ9Vδ2 (Vδ2) T cells have emerged as attractive candidates for developing cancer therapy due to their established safety in allogeneic contexts and inherent tumor-fighting capabilities. Nonetheless, the limited clinical success of Vδ2 T cell-based treatments may be attributed to donor variability, short-lived persistence, and tumor immune evasion. To address these constraints, we engineer Vδ2 T cells with enhanced attributes. By employing CD16 as a donor selection biomarker, we harness Vδ2 T cells characterized by heightened cytotoxicity and potent antibody-dependent cell-mediated cytotoxicity (ADCC) functionality. RNA sequencing analysis supports the augmented effector potential of Vδ2 T cells derived from CD16 high (CD16Hi) donors. Substantial enhancements are further achieved through CAR and IL-15 engineering methodologies. Preclinical investigations in two ovarian cancer models substantiate the effectiveness and safety of engineered CD16Hi Vδ2 T cells. These cells target tumors through multiple mechanisms, exhibit sustained in vivo persistence, and do not elicit graft-versus-host disease. These findings underscore the promise of engineered CD16Hi Vδ2 T cells as a viable therapeutic option for cancer treatment.

Summary: White adipose tissue (WAT) development and adult homeostasis rely on distinct adipocyte progenitor cells (APCs). While adult APCs are defined early during embryogenesis and generate adipocytes after WAT organogenesis, the mechanisms underlying adult adipose lineage determination and preservation remain undefined. Here, we uncover a critical role for platelet-derived growth factor receptor beta (Pdgfrβ) in identifying the adult APC lineage. Without Pdgfrβ, APCs lose their adipogenic competency to incite fibrotic tissue replacement and inflammation. Through lineage tracing analysis, we reveal that the adult APC lineage is lost and develops into macrophages when Pdgfrβ is deleted embryonically. Moreover, to maintain the APC lineage, Pdgfrβ activation stimulates p38/MAPK phosphorylation to promote APC proliferation and maintains the APC state by phosphorylating peroxisome proliferator activated receptor gamma (Pparγ) at serine 112. Together, our findings identify a role for Pdgfrβ acting as a rheostat for adult adipose lineage confinement to prevent unintended lineage switches.

Thermogenic beige fat can reduce fat mass and improve metabolic health, yet the ability to form beige fat rapidly declines with age. Here, the authors show that targeting the age-related ramping of Pdgfrβ signalling restores the ageing adipose tissue niche to ignite beige fat development.

Background & Aims: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with dreadful clinical outcome. Tyrosine kinase inhibitors and immune checkpoint inhibitors are the only United States Food and Drug Administration-approved therapeutic options for patients with advanced HCC with limited therapeutic success. Ferroptosis is a form of immunogenic and regulated cell death caused by chain reaction of iron-dependent lipid peroxidation. Coenzyme Q10 (CoQ10)/ferroptosis suppressor protein 1 (FSP1) axis was recently identified as a novel protective mechanism against ferroptosis. We would like to explore whether FSP1 could be a potential therapeutic target for HCC. Methods: FSP1 expression in human HCC and paired non-tumorous tissue samples were determined by reverse transcription-quantitative polymerase chain reaction, followed by clinicopathologic correlation and survival studies. Regulatory mechanism for FSP1 was determined using chromatin immunoprecipitation. The hydrodynamic tail vein injection model was used for HCC induction to evaluate the efficacy of FSP1 inhibitor (iFSP1) in vivo. Single-cell RNA sequencing revealed the immunomodulatory effects of iFSP1 treatment. Results: We showed that HCC cells greatly rely on the CoQ10/FSP1 system to overcome ferroptosis. We found that FSP1 was significantly overexpressed in human HCC and is regulated by kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 pathway. FSP1 inhibitor iFSP1 effectively reduced HCC burden and profoundly increased immune infiltrates including dendritic cells, macrophages, and T cells. We also demonstrated that iFSP1 worked synergistically with immunotherapies to suppress HCC progression. Conclusions: We identified FSP1 as a novel, vulnerable therapeutic target in HCC. The inhibition of FSP1 potently induced ferroptosis, which promoted innate and adaptive anti-tumor immune responses and effectively suppressed HCC tumor growth. FSP1 inhibition therefore represents a new therapeutic strategy for HCC.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Summary: Ovarian cancer (OC) is highly lethal due to late detection and frequent recurrence. Initial treatments, comprising surgery and chemotherapy, lead to disease remission but are invariably associated with subsequent relapse. The identification of novel therapies and an improved understanding of the molecular and cellular characteristics of OC are urgently needed. Here, we conducted a comprehensive analysis of primary tumor cells and their microenvironment from 16 chemonaive and 10 recurrent OC patient samples. Profiling OC tumor biomarkers allowed for the identification of potential molecular targets for developing immunotherapies, while profiling the microenvironment yielded insights into its cellular composition and property changes between chemonaive and recurrent samples. Notably, we identified CD1d as a biomarker of the OC microenvironment and demonstrated its targeting by invariant natural killer T (iNKT) cells. Overall, our study presents a comprehensive immuno-profiling of OC tumor and microenvironment during disease progression, guiding the development of immunotherapies for OC treatment, especially for recurrent disease.

Background: Diabetes is a common comorbidity in patients with early-stage non-small cell lung cancer (NSCLC), a growing population due to increased LC screening. However, it is unknown if diabetes is associated with less aggressive NSCLC treatment and worse NSCLC outcomes. This study aimed to investigate treatment patterns and outcomes of older patients with Stage I NSCLC and diabetes. Methods: Using national cancer registry data linked to Medicare, we identified patients ≥65 years old with Stage I NSCLC. Patients were categorized as having no diabetes, diabetes without severe complications (DM-c), or diabetes with ≥1 severe complication (DM + c). We used multinomial logistic regression to assess the association of diabetes and NSCLC treatment. The association of diabetes category with NSCLC and non-NSCLC survival was analyzed with Fine-Grey competing-risks regression. Results: In 25,358 patients (75% no diabetes, 12% DM-c and 13% had DM + c), adjusted analyses showed that DM-c and DM + c were associated with increased odds of receiving limited resection rather than lobectomy (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.07–1.37 and OR 1.42, 95% CI 1.26–1.59, respectively). Competing risk regression showed diabetes was associated with increased risk of non-NSCLC death (DM-c hazard ratio [HR] 1.16, 95% CI: 1.08–1.25, DM + c HR 1.49, 95% CI: 1.40–1.59), but not NSCLC-specific death. Conclusion: This study uncovers critical information on how diabetes is associated with less aggressive early-stage NSCLC care in older patients. This study also confirms that diabetes increases death from non-lung cancer causes and managing comorbidities is crucial to improving outcomes in older early-stage NSCLC survivors.

Inflammation contributes to many chronic conditions. It is often associated with circulating pro-inflammatory cytokines and immune cells. GLP-1 levels correlate with disease severity. They are often elevated and can serve as markers of inflammation. Previous studies have shown that oxytocin, hCG, ghrelin, alpha-MSH and ACTH have receptor-mediated anti-inflammatory properties that can rescue cells from damage and death. These peptides have been studied well in the past century. In contrast, GLP-1 and its anti-inflammatory properties have been recognized only recently. GLP-1 has been proven to be a useful adjuvant therapy in type-2 diabetes mellitus, metabolic syndrome, and hyperglycemia. It also lowers HbA1C and protects cells of the cardiovascular and nervous systems by reducing inflammation and apoptosis. In this review we have explored the link between GLP-1, inflammation, and sepsis.

Abstract The use of systems‐based pharmacological modeling approaches to characterize mode‐of‐action and concentration‐effect relationships for drugs on specific hemodynamic variables has been demonstrated. Here, we (i) expand a previously developed hemodynamic system model through integration of cardiac output (CO) with contractility (CTR) using pressure‐volume loop theory, and (ii) evaluate the contribution of CO data for identification of system‐specific parameters, using atenolol as proof‐of‐concept drug. Previously collected experimental data was used to develop the systems model, and included measurements for heart rate (HR), CO, mean arterial pressure (MAP), and CTR after administration of atenolol (0.3–30 mg/kg) from three in vivo telemetry studies in conscious Beagle dogs. The developed cardiovascular (CVS)‐contractility systems model adequately described the effect of atenolol on HR, CO, dP/dtmax, and MAP dynamics and allowed identification of both system‐ and drug‐specific parameters with good precision. Model parameters were structurally identifiable, and the true mode of action can be identified properly. Omission of CO data did not lead to a significant change in parameter estimates compared to a model that included CO data. The newly developed CVS‐contractility systems model characterizes short‐term drug effects on CTR, CO, and other hemodynamic variables in an integrated and quantitative manner. When the baseline value of total peripheral resistance is predefined, CO data was not required to identify drug‐ and system‐specific parameters. Confirmation of the consistency of system‐specific parameters via inclusion of data for additional drugs and species is warranted. Ultimately, the developed model has the potential to be of relevance to support translational CVS safety studies.

Abstract Background New COVID-19 treatments are desperately needed as case numbers continue to rise and emergent strains threaten vaccine efficacy. Cell therapy has revolutionized cancer treatment and holds much promise in combatting infectious disease, including COVID-19. Invariant natural killer T (iNKT) cells are a rare subset of T cells with potent antiviral and immunoregulatory functions and an excellent safety profile. Current iNKT cell strategies are hindered by the extremely low presence of iNKT cells, and we have developed a platform to overcome this critical limitation. Methods We produced allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells through TCR engineering of human cord blood CD34+ hematopoietic stem cells (HSCs) and differentiation of these HSCs into iNKT cells in an Ex Vivo HSC-Derived iNKT Cell Culture. We then established in vitro SARS-CoV-2 infection assays to assess AlloHSC-iNKT cell antiviral and anti-hyperinflammation functions. Lastly, using in vitro and in vivo preclinical models, we evaluated AlloHSC-iNKT cell safety and immunogenicity for off-the-shelf application. Results We reliably generated AlloHSC-iNKT cells at high-yield and of high-purity; these resulting cells closely resembled endogenous human iNKT cells in phenotypes and functionalities. In cell culture, AlloHSC-iNKT cells directly killed SARS-CoV-2 infected cells and also selectively eliminated SARS-CoV-2 infection-stimulated inflammatory monocytes. In an in vitro mixed lymphocyte reaction (MLR) assay and an NSG mouse xenograft model, AlloHSC-iNKT cells were resistant to T cell-mediated alloreaction and did not cause GvHD. Conclusions Here, we report a method to robustly produce therapeutic levels of AlloHSC-iNKT cells. Preclinical studies showed that these AlloHSC-iNKT cells closely resembled endogenous human iNKT cells, could reduce SARS-CoV-2 virus infection load and mitigate virus infection-induced hyperinflammation, and meanwhile were free of GvHD-risk and resistant to T cell-mediated allorejection. These results support the development of AlloHSC-iNKT cells as a promising off-the-shelf cell product for treating COVID-19; such a cell product has the potential to target the new emerging SARS-CoV-2 variants as well as the future new emerging viruses.

Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of hypoxic hepatocellular carcinoma cells and this is dependent on HIF-1, which in turns activates the transcription of a membrane ruffling protein, EH domain-containing protein 2.

Background: The optimal antithrombotic therapy after transcatheter aortic valve replacement (TAVR) is controversial. We performed a systematic review and meta-analysis of randomized controlled trials comparing high-intensity vs. low-intensity antithrombotic therapy after TAVR in the absence of an established indication for anticoagulation. Methods: The primary efficacy and safety endpoints were a composite of death or thromboembolic events and Valve Academic Research Consortium 2–defined significant bleeding, respectively. All analyses were by intention to treat. Risk ratios (RRs) were calculated using the inverse variance random-effects model. Results: Four studies comprising 3358 patients (mean age 81 years, mean Society of Thoracic Surgery score 3.3%) were identified. Two studies compared anticoagulation vs. antiplatelet therapy after TAVR; the other 2 trials compared dual-antiplatelet therapy vs. mono-antiplatelet therapy after TAVR. The incidence of death or thromboembolic events (RR 0.66 [95% confidence interval (CI) 0.55-0.80], p < 0.0001, I2 = 0%), death (RR 0.68 [95% CI 0.51-0.92], I2 = 11%, p = 0.01), and Valve Academic Research Consortium 2–defined major bleeding (RR 0.69 [95% CI 0.48 - 1.00], p = 0.003, I2 = 44%) was significantly lower in patients on low-intensity antithrombotic therapy than in those on high-intensity antithrombotic therapy. Conclusions: In an elderly patient population undergoing TAVR, routine initiation of a high-intensity antithrombotic therapy in the absence of a clinical indication for anticoagulation was associated with increased risk of death or thromboembolic complications, increased risk of death, and increased risk of significant bleeding. Routine initiation of an anticoagulation therapy or dual-antiplatelet therapy after TAVR in the absence of an established indication for anticoagulation may not be advisable.

The ability to generate thermogenic fat could be a targeted therapy to thwart obesity and improve metabolic health. Brown and beige adipocytes are two types of thermogenic fat cells that regulate energy balance. Both adipocytes share common morphological, biochemical, and thermogenic properties. Yet, recent evidence suggests unique features exist between brown and beige adipocytes, such as their cellular origin and thermogenic regulatory processes. Beige adipocytes also appear highly plastic, responding to environmental stimuli and interconverting between beige and white adipocyte states. Additionally, beige adipocytes appear to be metabolically heterogenic and have substrate specificity. Nevertheless, obese and aged individuals cannot develop beige adipocytes in response to thermogenic fat-inducers, creating a key clinical hurdle to their therapeutic promise. Thus, elucidating the underlying developmental, molecular, and functional mechanisms that govern thermogenic fat cells will improve our understanding of systemic energy regulation and strive for new targeted therapies to generate thermogenic fat. This review will examine the recent advances in thermogenic fat biogenesis, molecular regulation, and the potential mechanisms for their failure.

People with a Fontan circulation are at risk of neurodevelopmental delay and disability, and cognitive dysfunction, that has significant implications for academic and occupational attainment, psychosocial functioning, and overall quality of life. Interventions for improving these outcomes are lacking. This review article discusses current intervention practices and explores the evidence supporting exercise as a potential intervention for improving cognitive functioning in people living with a Fontan circulation. Proposed pathophysiological mechanisms underpinning these associations are discussed in the context of Fontan physiology and avenues for future research are recommended.

This paper will propose that explanations are valuable to those impacted by a model's decisions (model patients) to the extent that they provide evidence that a past adverse decision was unfair. Under this proposal, we should favor models and explainability methods which generate counterfactuals of two types. The first type of counterfactual is positive evidence of fairness: a set of states under the control of the patient which (if changed) would have led to a beneficial decision. The second type of counterfactual is negative evidence of fairness: a set of irrelevant group or behavioral attributes which (if changed) would not have led to a beneficial decision. Each of these counterfactual statements is related to fairness, under the Liberal Egalitarian idea that treating one person differently than another is justified only on the basis of features which were plausibly under each person's control. Other aspects of an explanation, such as feature importance and actionable recourse, are not essential under this view, and need not be a goal of explainable AI.

Liver cancers consist primarily of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors have emerged as promising therapeutic agents against liver cancers. Programmed cell death protein 1 (PD‐1) is an immunoinhibitory receptor present on T cells that interacts with its ligand programmed death‐ligand 1 (PD‐L1) found on cancer cells. Blocking PD‐1/PD‐L1 binding improves T‐cell survival, proliferation and cytotoxicity, which enhances their antitumor activity. Better understanding of the molecular mechanisms governing PD‐1/PD‐L1 response is essential to the development of predictive markers and therapeutic combinations that could improve the efficiency of anti‐PD‐1/PD‐L1 treatment. Chemokine‐like factor (CKLF)–like MARVEL transmembrane domain–containing 6 (CMTM6) has been recently identified as a major regulator of PD‐L1. Another member in the CMTM family, CKLF‐like MARVEL transmembrane domain–containing 4 (CMTM4), has been shown to compensate for the effects of CMTM6 when CMTM6 is lost. Interestingly, we found that CMTM4 is the major regulator of PD‐L1 in the context of liver cancer. Up‐regulated CMTM4 in patients with HCC and ICC is associated with poor patient survival, potentially due to its function in stabilizing PD‐L1 expression, hence facilitating escape from T cell–mediated cytotoxicity. We confirmed the role of CMTM4 as a positive regulator of PD‐L1 in multiple HCC and ICC cell lines and demonstrated that CMTM4 stabilizes PD‐L1 through posttranslational mechanisms. In vivo, suppression of Cmtm4 inhibited HCC growth and increased CD8+ T‐cell infiltration in immunocompetent mice. Furthermore, we found that depletion of CMTM4 sensitized HCC tumor to anti‐PD‐L1 treatment compared with control. This suggests that CMTM4 expression level could be a predictive marker for patient response to anti‐PD‐L1 treatment, and CMTM4 depletion can potentially be used to enhance the clinical benefits of anti‐PD‐L1 immunotherapy in patients with liver cancer.

Abstract Background Idiopathic myointimal hyperplasia of the mesenteric vein (IMHMV) is a rare, often undiagnosed pathology affecting the colon. Patients typically present with severe abdominal pain and inflammation caused by smooth muscle proliferation of the veins, leading to arterialization, stenosis, and potential occlusion. The etiology remains unclear, but it has been hypothesized that an arteriovenous connection may be associated with the pathology. This is the first reported case indicating such an association. This case additionally highlights the potential utility of endovascular treatment, as endovascular embolization is generally a less invasive alternative to surgical resection in the treatment of such vascular disorders. Case Presentation This report describes a 24-year-old female patient with findings of colitis and an abnormal arteriovenous connection of the inferior mesenteric arterial and venous systems. Partial embolization of this arteriovenous connection temporarily improved the patient’s condition, but her symptoms ultimately returned due to the presence of multiple smaller feeder vessels not amenable to embolization, necessitating colonic resection for definitive treatment. Although prior reports have hypothesized that arterial pressurization of the veins may precipitate myointimal hyperplasia, to the authors’ knowledge, this is the first report of IMHMV with an associated abnormal arteriovenous connection. Conclusions This case illustrates the possibility of an association between an arteriovenous connection and IMHMV. This rare diagnosis should be considered in patients with a similar presentation of abdominal pain after common etiologies like IBD have been excluded.

Abstract Hepatocellular carcinoma (HCC) is the second most lethal cancer worldwide. Glutamine is an essential, extracellular nutrient which supports HCC growth. Dietary glutamine deficiency may be a potential therapeutic approach for HCC. HCC cells overcome metabolic challenges by rewiring their metabolic pathways for rapid adaptations. The efficiency of dietary glutamine deficiency as HCC treatment is examined and the adaptation machinery under glutamine depletion in HCC cells is unraveled. Using genome‐wide CRISPR/Cas9 knockout library screening, this study identifies that pyruvate dehydrogenase α (PDHA), pyruvate dehydrogenase β (PDHB), and pyruvate carboxylase (PC) in pyruvate metabolism are crucial to the adaptation of glutamine depletion in HCC cells. Knockout of either PDHA, PDHB or PC induced metabolic reprogramming of the tricarboxylic acid (TCA) cycle, disrupts mitochondrial function, leading to the suppression of HCC cell proliferation under glutamine depletion. Surprisingly, dietary glutamine restriction improves therapeutic responses of HCC to PDH or PC inhibitor in mouse HCC models. Stable isotope carbon tracing confirms that PDH or PC inhibitors further disrupt the metabolic rewiring of the TCA cycle induced by dietary glutamine depletion in HCC. In summary, the results demonstrate that pyruvate metabolism acts as novel targetable metabolic vulnerabilities for HCC treatment in combination with a glutamine‐deficient diet.