Iron is irreplaceably required for animal and human cells as it provides the activity center for a wide variety of essential enzymes needed for energy production, nucleic acid synthesis, carbon metabolism and cellular defense. However, iron is toxic when present in excess and its uptake and storage must, therefore, be tightly regulated to avoid damage. A growing body of evidence indicates that iron dysregulation leading to excess quantities of free reactive iron is responsible for a wide range of otherwise discrete diseases. Iron excess can promote proliferative diseases such as infections and cancer by supplying iron to pathogens or cancer cells. Toxicity from reactive iron plays roles in the pathogenesis of various metabolic, neurological and inflammatory diseases. Interestingly, a common underlying aspect of these conditions is availability of excess reactive iron. This underpinning aspect provides a potential new therapeutic avenue. Existing hematologically used iron chelators to take up excess iron have shown serious limitations for use but new purpose-designed chelators in development show promise for suppressing microbial pathogen and cancer cell growth, and also for relieving iron-induced toxicity in neurological and other diseases. Hepcidin and hepcidin agonists are also showing promise for relieving iron dysregulation. Harnessing iron-driven reactive oxygen species (ROS) generation with ferroptosis has shown promise for selective destruction of cancer cells. We review biological iron requirements, iron regulation and the nature of iron dysregulation in various diseases. Current results pertaining to potential new therapies are also reviewed. Around 2% of human genes encode for iron proteins, with more than half of these having catalytic function, with oxidoreductase class enzymes being the largest fraction [When oxygen first appeared in the Earth’s atmosphere, iron with its Fe2−) is produced constitutively by the electron transport chain in cells by slippage of an electron to O2 with concomitant reduction of Fe3 to Fe2. The human body produces around 5 g O2−/day [Seemingly paradoxical, iron is also toxic to cells because of its production of oxidizing radicals with their formation driven by redox cycling of iron. Superoxide , 28% stored within ferritin in hepatocytes and 4% in bone marrow cells . The bodHepcidin, a 25-amino acid peptide hormone produced primarily by liver hepatocytes, is the master regulator of iron homeostasis and it negatively regulates iron uptake by inactivating plasma membrane-bound ferroportin on enterocyte and macrophage cell membranes as needed for transfer of intracellular iron to extracellular compartments . This prIron dysregulation diseases often result from increased amounts of circulating labile reactive plasma iron. This can be evidenced by elevated plasma transferrin-bound iron (TBI) with transferrin saturation above its normal 30%, sometimes reaching 100% saturation . With hiExcess plasma iron in the form of TBI and NTBI LPI influences two main categories of diseases. Elevated plasma iron, especially in the form of transferrin iron, supports cell-proliferative diseases including infection and cancer. Increased plasma iron present as non-transferrin-bound LPI is part of the pathology of other diseases where excess reactive iron triggers iron-related pathologies. The various diseases we review are summarized in Borrelia burgdorferi, the agent of Lyme disease, have absolute and irreplaceable requirements for iron for their growth and replication in our bodies [B. burgdorferi can utilize manganese in place of iron [All pathogenic microorganisms, with the exception of r bodies . B. burg of iron . The ver of iron . Lactofe of iron . Further of iron . Success of iron .Iron has now been found to support infection by almost all pathogenic microbes and Interfering with bacterial iron acquisition provides a new therapeutic avenue to fight infection, as discussed later in this review.Sepsis is a life-threatening condition killing around 11 million people worldwide annually . It resuDuring sepsis, iron metabolism is altered with increased iron uptake into cells and this has been associated with increased iron-driven oxidative injury and cell death . High seSepsis therapy presents a large unmet medical need with no currently approved therapeutics available for clinical use. However, the underlying iron dysregulation provides a new therapeutic avenue for serious infection/sepsis, as discussed later in this review.Multicellular parasitic organisms also require iron to invade and mount infection in vertebrate hosts . LeishmaViruses have no direct requirements for iron, but it is now evident that viral replication in host cells is affected by host iron in the case of both DNA viruses, such as hepatitis B (HBV) and human cytomegalovirus (HCMV), and RNA viruses, such as hepatitis C (HCV) and human immunodeficiency virus (HIV) . It remaThe role of iron and its dysregulation in cancer is multi-faceted, as reviewed by Torti et al. (2018) . StevensCancer also induces a chronic anemia, as seen in other chronic diseases, and this appears to be a host attempt to restrict cancer growth . SomewhaFerroptosis is an additional form of regulated cell death (RCD), but unlike other forms such as apoptosis and necrosis, it is caused by an iron-dependent accumulation of lipid peroxides which kill cells, although it shares other common features with the other modes of RCD . ROS proPotential inhibitors of ferroptosis have been investigated including ROS-trapping antioxidants, such as α-tocopherol and ferrostatin-1, and these have shown potential for reducing ferroptotic damage .Excess labile iron driving ferroptosis has also been demonstrated through its suppression by addition of the iron chelator deferoxamine . HoweverThe excess supply of labile reactive iron observed as a feature of iron dysregulation appears to underpin tissue toxicity with a number of diseases and ferroptosis appears to be at least part of the pathology of these diseases, as further discussed below.While inflammation typically accompanies infection and cancer, other diseases appear to be primarily inflammatory in nature and iron dysregulation and its associated ROS activity are involved in the inflammatory response.Iron dysregulation of the eye has been linked to various eye diseases affecting the cornea and retina, including corneal epithelial disease, corneal endothelial cell dysfunction, retinal pigment epithelial (RPE)-associated eye diseases, glaucoma, diabetic retinopathy (DR), retinal ischemia/reperfusion injury (RIRI), retinoblastoma, retinitis pigmentosa (RP) and age-related cataracts, and common to these, ferroptosis pathology has been implicated . FerroptPulmonary iron content is also tightly regulated, as excess iron can catalyze ROS formation, and this has been linked to the pathogenesis of chronic inflammatory lung diseases such as idiopathic pulmonary fibrosis . Iron acIncreased kidney proximal tubule (PT) cell cytosolic non-transferrin Tf-bound, i.e., labile iron has been shown to induce the generation of ROS in PT cells and this could contribute to the progression of proteinuric chronic kidney diseases . Recent Nephritic kidney damage with urinary transferrin excretion is also part of the pathology associated with autoimmune diseases including lupus erythematosus  and rheuHigh dietary iron and dysregulated iron metabolism are risk factors for type 2 diabetes mellitus (T2DM), affecting most of its features of decreased insulin secretion, insulin resistance and increased hepatic gluconeogenesis . DysreguFerroptosis driven by iron dysregulation has now been implicated in several cardiovascular disease conditions including cardiomyopathy, atherosclerotic disease and myocardial ischemia/perfusion injury ,85. InhiThe role of iron regulation in immune-related diseases was recently reviewed by Cronin et al. (2019) . SubstanMany neurological conditions have been shown to coincide with altered bodily distribution of various transition series biometals, especially in the case of iron . Iron dyFor example, Parkinson’s disease (PD) is characterized by progressive motor impairment attributed to progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. In addition to an accumulation of iron, there is also an increased production of reactive oxygen/nitrogen species (ROS/RNS) and inflammatory markers seen in this pathology . In addiWhile body iron overload can follow repeated blood transfusions, as seen in patients with Thalassemia, i.e., because the body lacks an excretory pathway for excess iron, congenital disorders of iron overload such as hemochromatosis represent iron overload disorders caused by dysregulated iron homeostasis. In hemochromatosis, disruption of the hepcidin pathway due to mutations in genes encoding auxiliary factors in iron signaling to hepcidin result in insufficient hepcidin responses to iron intake or to high body iron stores. This causes loss of hepcidin-mediated feedback inhibition in dietary iron absorption and consequently unregulated uptake of dietary iron, elevated transferrin iron saturation and appearance of labile reactive non-transferrin-bound iron .Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, beginning with the presence of >5% excessive lipid accumulation in the liver, and typically developing into non-alcoholic steatohepatitis, fibrosis, cirrhosis and often hepatocellular carcinoma. Excess free reactive iron and its associated ROS-mediated tissue damage have been positively associated with severity of NAFLD .The anemia of inflammation (AI), often referred to as the anemia of chronic disease (ACD), is a secondary anemia that often develops slowly as a result of chronic inflammation during chronic infection , cancer and with at least some of the other inflammatory diseases we have reviewed, such as diabetes and autoimmune diseases ,94,95. OHigher heme iron intake and increased body iron stores were significantly associated with a greater risk of type 2 diabetes, as shown in a meta-analysis of 11 prospective studies . InteresIn principle, restriction of iron uptake would also lower amounts of deleterious liable reactive iron. However, withholding (or supplying) iron has remained controversial in medicine over the years due to the delicate balance required for iron homeostasis and the consequences of triggering anemia. While supply of dietary iron would be safer, administration of parenteral iron to treat anemia, especially the anemia of chronic disease, has serious implications. Given the roles of dysregulated iron in infection and other diseases, this requires careful consideration and likely should be avoided if possible.Iron chelators that bind and can sequester excess available labile reactive iron have shown potential for the therapy of several diseases associated with iron dysregulation. However, medical chelators to date have been developed to treat hematological conditions associated with high excess body iron stores  but were not developed as iron dysregulation therapeutics. We have provided a number of important potential attributes for ideal iron dysregulation chelator therapeutics, as summarized in A number of clinical trials or natural products with iron-chelating properties, such as curcumin and polyphenolics, have shown promise for lowering excess iron  but noneHepcidin mimetics, stimulators of its production and ferroportin inhibitors have seen early clinical stage testing as to their safety and potential efficacy . The ferWe identified a number of gaps in our current understanding of iron dysregulation in the pathology of diseases. A better understanding of the role of Fe dysregulation mechanisms for various diseases, especially related to cause or effect, is needed. There is a particular need for further understanding of anemia of chronic disease. Possible targeted ferroptosis induction in cancer can be considered once its mechanisms are elucidated.A number of conclusions can be drawn at this stage. Therapeutics affecting iron dysregulation and lowering excess levels of labile reactive ion should be readily applicable to treating infection, including sepsis, and should also apply to cancer and other non-proliferative diseases from iron dysregulation. Improved chelators have immediate appeal as the broadest and preferred therapeutic approach.Hepcidin mimetics and agonists have demonstrated potential and longer-term potential.


A consortium of global cleft professionals, predominantly from low- andmiddle-income countries, identified adaptations to cleft care protocolsduring and after COVID-19 as a priority learning area of need.A multidisciplinary international working group met on a videoconferencingplatform in a multi-staged process to make consensus recommendations foradaptations to cleft protocols within resource-constrained settings.Feedback was sought from a roundtable discussion forum and globalorganizations involved in comprehensive cleft care.Foundational principles were agreed to enable recommendations to be globallyrelevant and two areas of focus within the specified topic were identified.First the safety aspects of cleft surgery protocols were scrutinized andCOVID-19 adaptations, specifically in the pre- and perioperative periods,were highlighted. Second, surgical procedures and cleft care services wereprioritized according to their relationship to functional outcomes andtime-sensitivity. The surgical procedures assigned the highest priority wereemergent interventions for breathing and nutritional requirements andprimary palatoplasty. The cleft care services assigned the highest prioritywere new-born assessments, pediatric support for children with syndromes,management of acute dental or auditory infections and speech pathologyintervention.A collaborative, interdisciplinary and international working group deliveredconsensus recommendations to assist with the provision of cleft care in low-and middle-income countries. At a time of global cleft care delays due toCOVID-19, a united approach amongst global cleft care providers will beadvantageous to advocate for children born with cleft lip and palate inresource-constrained settings. Cleft lip and/or palate (CL/P) is the most common craniofacial congenital anomaly,occurring in approximately 1/700 live births worldwide . If untrth 2020 the World Health Organization (WHO) declared COVID-19to be a global pandemic. This had a major impact on healthcare systems and serviceswere accordingly reprioritized, with emergency and trauma services continuing butmany elective procedures being delayed or postponed : Responding to COVID.”Following the conference, an online CoCP COVID-19 Survey was designed, aiming toidentify challenges that cleft professionals face in light of the pandemic,particularly in LMICs, and to identify learning priorities . The survey was translated into six differentlanguages to facilitate broad representation and disseminated internationally onlinein February 2021 to global cleft professionals through a network alliance of 10global NGOs. The survey received 175 responses, 74% of which were from cleftprofessionals located in one of 40 LMICs. One priority area identified for furtherlearning from the survey was “adapting COVID-19 cleft care protocols in light ofevidence-based research.”The Circle of Cleft Professionals (CoCP) is a coalition of internationalnongovernmental organizations (NGOs), which aims to support healthcare workersaround the globe to provide comprehensive cleft care . OnSeptA clinical protocol  is a tool to guideevidence-based healthcare . A protoThe need to adapt the cleft protocol during and following COVID-19 has beenidentified by global partners and is important in the quest towards reestablishinginternational comprehensive cleft care services. The CoCP platform was used to bringtogether cleft professionals from diverse locations to consider adaptations toelements of the cleft care protocol by pooling experience and reviewing availableevidence. The overall aim was to formulate practical consensus recommendations tohelp providers in LMICs to deliver comprehensive cleft care protocols during andafter COVID-19.Augmenting telehealth in cleft careAssessing patient outcomes during COVID-19Adapting COVID-19 cleft care protocols in light of evidence-basedresearchPromoting parental engagement during COVID-19The application to participate in a working group was disseminated widelythrough the CoCP membership and beyond. Applicants were placed in working groupsbased on research interests, fluency in English or Spanish, and in an attempt toensure diversity of professional context, discipline, geography and NGOaffiliation. Working group members were orientated into the process andencouraged to consider their allocated topic area before meeting collectively onthree separate occasions over a six-week period in 2021. The process culminatedwith a presentation of recommendations at a round table within an internationalvirtual conference, that had free registration and was widely advertised,entitled “Solutions for Comprehensive Cleft Care (S4CCC): Covid and Beyond” onJune 2nd, 2021  as described inPreoperative safety protocols exist to assess whether the patient is safe toproceed with a procedure and often incorporate a consultation and basic tests.Post-COVID-19, preoperative assessments need to be expanded to judge the risk ofthe virus causing harm to patients, families and providers. The extent ofpreoperative modifications (such as frequency of COVID-19 testing and the needfor isolation strategies) can be adapted in response to regional COVID-19prevalence, which has been classified as low (<0.5%), medium (0.5−2%) andhigh (>2%). Whilst Perioperative safety protocols exist to maintain patient well-being whilst underthe care of health professionals. Healthcare systems are well accustomed toprotocols relating to safety during this period and should have training andequipment in place to deal with adverse events ..The WHPostoperative safety protocols exist to ensure that the surgical care episode wassuccessful and that the patient does not develop complications that requireintervention. The decision to follow-up patients in person or remotely is madeon the merits and practicalities of both options and has many influencingfactors, of which COVID-19 is just one. Irrespective of COVID-19, it remainsimportant that operative outcomes are accurately assessed and recorded andindeed the advances in telemedicine during the COVID-19 pandemic may ultimatelymake this easier. Arguably, there may not be any specific safety adaptationsrequired in this postoperative phase of the protocol during or followingCOVID-19 but maintaining levels of follow-up surveillance when resources arerestricted may be a challenge.There is a need for prioritization within the cleft protocol despite each elementof comprehensive cleft care having equal importance, because some elements aretime-sensitive and linked to functional outcomes, therefore their delay wouldlead to irreversible harm . PrioritSurgical emergencies for patients born with CL/P, such as airway ornutritional compromise, require potentially life-saving surgicalinterventions and are therefore an obvious priority. The airway can becompromised in Pierre Robin Sequence, primarily due to glossoptosis andemergent surgical procedures to secure the airway, although rare, may berequired . The utiPrimary palatoplasty was considered a high priority due to the body ofliterature identified to demonstrate its relationship with both speech andmaxillary growth outcomes (see Supplemental Primary cleft lip repair was categorized as a medium priority as earlier liprepairs have been shown to benefit mother-infant interactions and bonding. SecondaOrthognathic surgery, secondary rhinoplasty, revisional lip procedures androutine dental procedures were categorized as a lower priority, not toundermine their importance, but because they are not as acutelytime-sensitive.New-born babies with CL/P need to be assessed regarding breathing, feedingand hearing and this is a priority, both for the health of the baby and toprovide support for parents during this critical neonatal period. Somechildren with CL/P, especially those with syndromes, will require ongoinginput from medical professionals with pediatric experience. Acute dentalinfections or otitis media were prioritized because efficient treatmentreduces the likelihood of permanent damage to dentition and hearing .Speech pathology intervention was categorized in the highest priority toreflect the importance of speech outcomes and evidence to suggest thatspeech interventions reduce speech errors commonly observed in children withcleft . InnovatRoutine MDT assessments in dentistry, audiology, orthodontics, speech,psychology and surgery, as available within the local cleft team, werecategorized as a medium priority because of the ability of these services tobe delivered over a greater timescale without compromising outcomes.Presurgical orthopedics was also categorized as a medium priority becausedespite its aim to improve tissue position and ultimately functionaloutcomes, it is not utilized universally, partly due to availability andpartly due to the controversies surrounding efficacy .The structured process used in this study provided a positive collaborativeexperience, which should be encouraged in future global cleft care endeavors.The condensed six-week time period, with a preestablished “finish-line,” and aplatform for the working group to present its recommendations, helped toincrease intensity and provide urgency to the process. It became apparent thatthe variety of experience in the management of both CL/P and COVID-19 provided arich environment for discussion and mutual learning. Scheduling meetings on avideoconferencing platform at the same time and day of the week helped toprovide consistency and improve attendance, especially given the working groupmembers’ multiple time zones and working commitments. It was helpful to specifyfocused aims from the outset of the process and to set tangible action points atthe end of each group meeting. Encouraging continued discussion and the sharingof resources on virtual platforms between meetings helped to increaseproductivity. Consensus was achieved via identifying global areas of commonalityand recognizing areas of diversity and controversy.The working group was tasked to make recommendations regarding the adaptation ofcleft care protocols during and after COVID-19 to help facilitate the provisionof global comprehensive cleft care in LMICs. Foundational principles were set torespect the complex multidisciplinary nature of cleft care inresource-constrained settings and the specifics of local protocols, as it hasbeen demonstrated that familiarity with a protocol is of primary importance forthe achievement of good outcomes . Within The WHO has documented the far-reaching impact of the COVID-19 pandemic in termsof the widespread disruption to essential health services, but elective servicesare being reestablished . Global Surgical safety is recognized to be of utmost importance when delivering cleftcare . The COVIn a crowded healthcare system following delays to many areas of plannedservices, prioritization of care will be vital. In the United Kingdom, all surgical procedures were prioritized into fourcategories of urgency by the Federation of Surgical Specialty Associations inJuly 2020 to expediate the recovery of surgical services during COVID-19 . PrimaryThe prioritization of surgical procedures in this study purposefully did notincorporate threshold timings but instead categorized procedures into high,medium and lower priorities to reflect the degree of time-sensitivity withrespect to functional outcomes. There was a purposeful emphasis to prioritizeMDT cleft care services equally alongside surgical procedures as these completethe comprehensive approach. A common theme with both strands was aprioritization of speech outcomes, in recognition of the crucial role thatspeech plays globally in the life and social functioning of children born withCL/P.The main strength of this piece of work was the collaborative nature of theinternational working group, which was inclusive of multiple disciplines andaffiliation with multiple global cleft care organizations. The working group wasa favorable size in terms of productivity, but it was not inclusive of allspecialties, organizations or regions and deliberations all took place inEnglish.The consensus recommendations were based on common principles, but this is not anexhaustive document and therefore not a comprehensive guide to delivering cleftcare protocols in LMICs during and after COVID-19. It is hoped this work willhelp to support efforts of cleft care providers in resource-constrained settingsto present a united and coordinated case for the provision of comprehensivecleft care to policy makers and ultimately improve safety and outcomes forpatients. Ideally, there should be a focus on local protocols and guidance,therefore the relevance of these recommendations in specific environments may belimited .It is hoped that collaborative efforts such as this will galvanize the globalcleft community to perform multicentre international trials to reach a consensuson cleft care protocols and outcomes. Local outcome data collection must beencouraged to drive context-specific guidance. Finally, the efficacy ofinnovations highlighted by this pandemic should be explored so that they canultimately help to improve the provision of global cleft care.Comprehensive cleft care is an essential health service and every child born withCL/P deserves the opportunity to receive treatment through safe and effective cleftcare protocols. The COVID-19 pandemic has had a detrimental impact on the deliveryof comprehensive cleft care, which was already stretched in many areas of the world.As a global community, it is helpful for the providers of cleft care in LMICs to beable to recognize protocol adaptations during and after COVID-19 that may be neededto deliver care safely and elements that should be prioritized to maximizetime-sensitive outcomes. A unified approach amongst global cleft care providers mayhelp to lobby policy makers effectively at this crucial time of scarce resourceallocation.Click here for additional data file.Supplemental material, sj-docx-1-cpc-10.1177_10556656211069827 for AdaptingElements of Cleft Care Protocols in Low- and Middle-income Countries During andAfter COVID-19: A Process-driven Review With Recommendations by Matthew Fell,Michael Goldwasser, B.S. Jayanth, Rui Manuel Rodrigues Pereira, ChristianTshisuz Nawej, Rachel Winer, Neeti Daftari, Hugh Brewster, Karen Goldschmied,Collaborators: Fernando Almas, Mekonen Eshete, George W. Galiwango, Larry H.Hollier Jr., Akhter Hussain, Lun-Jou Lo, Paul Salins, Debbie Sell, AmanuelTafase and Ronald M. Zuker in The Cleft Palate Craniofacial Journal


Organ crosstalk and organs intracellular communications are the foundation for maintaining whole-body metabolic homeostasis. This constant dialogue at the organ and cellular levels is key to adapting to environmental fluctuations, assessing energy supplies, and, to a larger extent, organisms surviving. Theoretically, any molecule that cells can sense could be leveraged as a communication tool creating illimited possibilities to fine-tune the message and thereby the specificity of cellular repose. Indeed, signaling molecules including growth hormones, chemokines, peptides, and metabolites are used as means to remotely inform the whole-body state and dictate crucial decisions such as growth, survival, or programmed death.A growing body of evidence indicates that chronic overnutrition promoting disruption of these interactions leads to pathological conditions such as obesity, type 2 diabetes, liver diseases, cardiovascular diseases, and cancer. Importantly, those interactions can be hijacked by cancer cells to support their expansion or survival.The purpose of this Research Topic is to highlight new advances in this area and to help understand how metabolic status and metabolic diseases influence inter-organ crosstalk and communication.Wu et al. summarize the current knowledge on the role of gut microbiota in regulating whole-body metabolic homeostasis through a close cross-talk with adipose tissues. The authors, systematically discuss recent evidence demonstrating the central role of gut microbiota in influencing adipose tissue physiology and the development of metabolic disease and obesity. Interestingly, this relationship is a two-way communication system where adipocytes can act via adipokines to modulate the gut microbiota. These findings are particularly relevant as they can provide potential intervention strategies for obesity treatment.Obesity is a highly prevalent chronic disease characterized by excessive fat accumulation. It is the body’s response to environmental stimuli and genetic predisposition. In recent years, the gut microbiota has gained significant attention as a major environmental factor for energy homeostasis maintenance and host immunity. In this Research Topic, Somm and Jornayvaz summarize the emerging roles of interleukin-18 (IL-18), an interesting pleiotropic cytokine, that has been recently shown to control energy homeostasis. Indeed, IL-18 role in host defense against infections and regulation of the innate and adaptative immune response are well known. However, the development of animal model transgenic mouse models for IL-18 revealed an expected involvement in metabolism and obesity development. The authors discuss a body of work uncovering the physiological role of IL-18 in regulating metabolic tissue in mouse models and interesting clinical observations suggesting its potential role in human metabolic diseases including obesity, diabetes, and non-alcoholic fatty liver. Finally, the authors present their perspective of burning questions that need answering to fully understand the metabolic role of IL-18.Chronic low-grade inflammation is another hallmark of obesity and metabolic diseases. In this Research Topic, Carbinatti et al. tackle this aspect by reviewing new insights into the inter-organ crosstalk mediated by glucose sensor transcription factor ChREBP (Carbohydrate Responsive Element Binding Protein). This unique transcription factor originally recognized for its central role in controlling of glycolysis and lipogenesis has recently emerged as a key regulator of secreted factors in multiple organs. The authors summarize novel finding implicating ChREBP in the control of hepatokine and metabolite production to ensure an adequate metabolic adaptation and discuss how alteration in its expression drives pathological conditions.While secreted factors are important players in inter-organ communications the transcriptional regulation of their production and secretion by intracellular factors is crucial to maintain metabolic homeostasis. Ennis et al. highlight the crosstalk between the breast tumor and its environment most notably the establishment of close intercellular communication between tumor cells and adjacent adipocytes. The authors outline the current state of knowledge highlighting how the microenvironment created by type 2 diabetes predisposes to a more aggressive tumor. Those characteristics are particularly important since they are not considered in the treatment plans for breast cancer patients with type 2 diabetes. In this same topic, Aird et al. demonstrate an important communication axis between cancer cells and adipocytes. Interestingly, the authors show that hypoxia in both breast and ovarian cancer cells alters adipocyte metabolism (metabolites and lipolysis) to support cancer cell metabolism.Over the past decade, extensive clinical and experimental evidence linking obesity to the progression of multiple cancer subtypes had emerged. Indeed, the microenvironment during obesity seems to be suitable for cancer cells to thrive and develop. In an extensive review, In summary, the present Research Topic brought together perspectives from different angles, which we believe will help to emphasize the importance of inter-organ crosstalk in maintaining metabolic homeostasis. Although important, those communications axes represent a significant vulnerability that is closely linked to metabolic dysfunction and could be used by cancer cells to fuel their survival and aggressiveness. Importantly, a better understanding of intra and inter-organ cross-talk and cellular communication in physiology and disease will be key for innovative treatments against multiorgan diseases such as obesity and type 2 diabetes.P-DD wrote the Editorial and NR edited it. All authors contributed to the article and approved the submitted version.


The Immuno-Oncology Translational Network (IOTN) was established in 2018 as part of the Cancer Moonshot. In 2022, President Joe Biden set new goals to reduce the cancer death rate by half within 25 years and improve the lives of people with cancer and cancer survivors. The IOTN is focused on accelerating translation of cancer immunology research, from bench to bedside, and improving immunotherapy outcomes across a wide array of cancers in the adult population. The unique structure and team science approach of the IOTN is designed to accelerate discovery and evaluation of novel immune-based therapeutic and prevention strategies. In this article, we describe IOTN progress to date, including new initiatives and the development of a robust set of resources to advance cancer immunology research. We summarize new insights by IOTN researchers, some of which are ripe for translation for several types of cancers. Looking to the future, we identify barriers to the translation of immuno-oncology concepts into clinical trials and key areas for action and improvements that are suitable for high-yield investments. Based on these experiences, we recommend novel National Institutes of Health funding mechanisms and development of new resources to address these barriers. In his final State of the Union address in January 2016, former President Barack Obama tasked then–Vice President Joe Biden to head a new national effort called Cancer Moonshot to “end cancer as we know it.” Cancer Moonshot has a specific aim of accelerating cancer research to make more therapies available to more patients and improve cancer prevention and early detection. Following this recommendation, in 2018 the National Cancer Institute (NCI) established the Immuno-Oncology Translational Network (IOTN) to serve as the premier collaborative network and resource focused on immunotherapy and immunoprevention. In 2022, President Biden set new goals of “achieving a decade’s worth of progress in 5 years” and “to reduce the cancer death rate by half within 25 years” . The IOTThe IOTN is focused on accelerating the translation of cancer immunology research from bench to bedside and improving immunotherapy outcomes across a wide array of cancers in adult populations ,6. The oThe IOTN consists of a steering committee ; its working groups, including the Clinical Trials Task Force (CTTF); and 2 cross-network data-sharing resources (the Data Management and Resource Sharing Center [DMRC] and the Cellular Immunotherapy Data Resource [CIDR]). IOTN working groups focus on 5 previously identified cross-disciplinary scientific gap areas: 1) immune mechanism and recognition, 2) immuno-radiation therapy, 3) immunoprevention, 4) translational cellular therapy, and 5) bioinformatics and computational biology. Membership is cross-fertilized with allied Moonshot networks, including the Pediatric Immunotherapy Discovery and Development Network (PI-DDN), Cancer Immune Monitoring and Analysis Centers–Cancer Immunologic Data Commons (CIMAC-CIDC), and the Pre-Medical Cancer Immunotherapy Network for Canine Trials (PRECINCT) networks.The IOTN has taken a collaborative and integrative approach to accomplishing Cancer Moonshot’s goal of “achieving a decade’s worth of progress in 5 years.” Speakers from other NIH and NCI initiatives are routinely invited to present at IOTN steering committee and working group meetings to enhance awareness of preclinical and clinical translational resources and to foster research collaboration. The fall 2021 IOTN semiannual steering committee meeting included a joint immuno-oncology day, with participation from the Pancreatic Cancer Microenvironment Network, PI-DDN, PRECINCT, and the CIMAC-CIDC networks. Joint participation in working group meeting discussions and steering committee meetings helps the NCI stay abreast of the network’s progress, identify necessary resources, and develop future initiatives. The 2 resource centers—DMRC and CIDR—also provide both intranetwork and cross-network collaboration opportunities.https://www.iotnmoonshot.org/en/resources/all-resources/). The Data Sharing Catalog lists datasets deposited into NIH-designated repositories and associated with IOTN awards, currently including 55 datasets obtained from more than 3500 human and murine studies. The DMRC, in conjunction with the IOTN Immune Mechanism and the IOTN Translational Cellular Therapy working groups, created the Model Sharing Catalog, which inventories relevant immunocompetent preclinical models published by the IOTN. As of February 2023, the IOTN has contributed 11 preclinical models ranging from genetically engineered mouse models to xenografts and organoid models representing 9 cancer types. Additional resources include the Software Sharing Catalog and the Clinical Trials Catalog, combined IOTN/Drug Resistance and Sensitivity Network Data Sharing Catalog and Model Sharing Catalog databases created in collaboration with the Drug Resistance and Sensitivity Network. Finally, all IOTN publications are required to be immediately open access, thus supporting the network’s goal of disseminating research results in prompt and findable, accessible, interoperable, reusable ways , of which 212 articles  were in journals with a 5-year impact factor greater than 10 and 74 articles  were published in top-tier journals with a 5-year impact factor greater than 30. IOTN research output includes exciting preclinical discoveries and potential therapies that could be moved into early-stage clinical trials. A few examples are highlighted here.IOTN investigators are working to improve the limited efficacy of chimeric antigen receptor (CAR)-T cells in solid tumors. CAR-T cells entering solid tumors frequently enter an “exhausted” state triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors. Chen et al.  and Seo + T-cell responses in the ovarian tumor microenvironment, supporting development of CXCR6/CXCL16-targeted therapeutic approaches to enhance antitumor tissue-resident memory retention within the tumor microenvironment. To gauge efficacy of tumor microenvironment–directed therapies, Devkota et al.  external beam RT augmented responses to immune checkpoint inhibitors compared with a combination of immune checkpoint inhibitors with either targeted radionuclide therapy or external beam RT alone.Several exciting examples of potential combination therapy approaches have been developed by IOTN investigators. In the study by Pieper et al. , local aSingle agents developed by IOTN investigators  could poAmong the Blue-Ribbon Panel recommendations was one specifically to set up a Clinical Trial Immunotherapy Network with the objective of constructing a nationwide infrastructure to facilitate immunotherapy trials. Despite major breakthroughs in understanding mechanisms of antitumor immunity and treatment resistance, translation to the clinic has lagged, in many cases because of unique challenges that apply specifically to immunotherapy. For example, gold-standard approaches used to measure the effectiveness and safety of traditional chemotherapy and antitumor drugs often do not apply to immuno-oncology agents. In addition, there is no clear dose-response relationship for such agents. Similarly, traditional clinical endpoints, such as overall survival and overall response rates, do not robustly apply to immuno-oncology agents because response kinetics may be delayed or confounded by differences in tumor response patterns. Off-target effects, which can often be beneficial in specific contexts, and the complexity of assessing immune-related adverse events make it challenging to perform standard toxicity evaluations.To assist researchers in their design and clinical evaluation of immuno-oncologic agents, the IOTN committed to developing a resource to collect and make available robust patient data  and details of therapeutic agent manufacturing to help identify markers of immune suppression and observed clinical outcomes to facilitate retrospective research ,30. The During an “IOTN Future Directions” brainstorming session during the 2019 Cancer Moonshot Collaborative Meeting, IOTN investigators expressed a keen demand for new approaches and resources for clinical translation, given the particularly complex and time-consuming process of translating immunotherapies, and suggested establishment of networks connecting disparate elements to be in-sync for successful translation. At the following IOTN steering committee meeting in December 2019, a vibrant discussion ensued regarding establishment of an IOTN CTTF to fulfil the unmet need of rapid translation of preclinical discoveries into phase 1 trials. The kickoff meeting was held on January 15, 2020, and the CTTF was established under the leadership of Kunle Odunsi, MD, PhD, as chair and Andrew Sikora, MD, PhD, as co-chair. The CTTF’s mission statement was “to engage IOTN investigators with academic, clinical, and industry partners; and to identify barriers to, and opportunities for, efficient translation of fundamental immunotherapy research into clinical testing.” Andrew Sikora, MD, PhD, and Ananth Annapragada, PhD, generated an initial Immuno-Oncology Road Map, cataloging both available resources and necessary steps for clinical translation of immuno-oncology concepts. The CTTF also carried out a survey of IOTN investigators to pinpoint stages of the journey, from preclinical development to clinical translation, where guidance was most needed. The survey results, summarized in https://aaadv.org/), a not-for-profit educational initiative of the FDA, academia, advocates, and industry that provides education and resources to help researchers accelerate development and delivery of cancer treatments to patients, to host a satellite workshop at the AAADV annual meeting. Speakers included key representatives of the FDA, NIH, venture capital, and pharma venture arms as well as academics who had successfully translated immuno-oncology platforms to clinical trials. The following key recommendations to bridge gaps in clinical development of immuno-oncology platforms emerged:Based on identified priority areas, the CTTF collaborated with Accelerating Anticancer Agent Development and Validation . Investments of this magnitude will invariably require the participation of a large pharmaceutical company because these funding levels are outside the range of most other sources. Pharma participation in such product development is therefore practically inevitable. At the same time, seeking to balance risk with cost, pharma companies are willing to consider investing or partnering at all stages of development when the data are compelling. Unlike grant programs, however, which evaluate projects based on a single written document, pharma investments involve multiple rounds of evaluations and require considerable give and take between the pharma entity and the originating organization. Creating forums for increased interactions between academia and pharma is therefore a critical need. The need for such interaction takes on a particularly critical urgency in the setting of the IOTN, where an accelerated pace of discovery has led to many candidate therapeutic approaches becoming available. It is more important than ever that interactions with pharma are also accelerated to prevent this step from becoming the bottleneck. The next phase of the IOTN must therefore include forums for these discussions. Beyond matchmaking and facilitating interactions, the next phase of IOTN must include grant programs that require a pharma partner that contributes intellectually, thus ensuring that translational research has pharma development in mind from the onset and paves the way to eligibility for the orders-of-magnitude greater investment required of pharma companies to support product development.Intellectual property support: The need for higher-quality support of intellectual property development efforts emerges as a consistent theme. Although all universities and most stand-alone cancer centers have dedicated technology-transfer offices and are adept at filing invention disclosures and rapidly filing patent applications, skill in developing an intellectual property portfolio around a central invention theme and creating a defensible portfolio that provides freedom to operate are much rarer commodities, with few successful instances evident. Yet, secure intellectual property is a necessary component of IOTN discoveries that may be successfully translated to the clinic. Provision of comprehensive intellectual property portfolio development resources is therefore a necessity for the success of IOTN discoveries.Networking opportunities: It is also evident that multiple professions must work together to effect successful translation of discoveries to products. Basic scientists, engineers, clinicians, lawyers, management professionals, and pharmaceutical development specialists all need to come together to find the right combination for a given development effort. A daunting task under any circumstances, this challenge is further exacerbated by the need to accelerate progress to meet the goals of the Moonshot program. The IOTN needs to provide increased opportunities for direct networking, bringing together all necessary skill sets for successful development to take place.Specific recommendations by the CTTF include novel funding mechanisms, new workshops, creation of an IOTN Foundation, and creation of a navigator resource to direct researchers to numerous available resources to enhance translational research. The CTTF recommends the creation of multiple requests for applications, including those that continue basic and translational research but, more importantly, requests for applications that drive toward a clinical trial endpoint. The CTTF also recommends structural elements in programs that support continuing refinement of the immunotherapy clinical trial landscape.First, the CTTF recommends creation of requests for applications with a phased or staged funding mechanism consisting of 3 phases: the first phase establishing proof of concept in animal models, the second phase supporting planning and preparation for a clinical trial, and the third phase supporting the trial itself. Such mechanisms would be nondilutive and therefore highly attractive to parallel venture and/or pharma investment. A template that could be followed is the R61/33 mechanism currently used in some of the NIH Rapid Acceleration of Diagnostics programs to rapidly develop diagnostics for COVID-19. Such mechanisms would include a mandatory regulatory agency interaction component , with the intention of accelerating development activities.Second, the CTTF recommends funding mechanisms that support independent development of biomarkers and surrogate markers separately from a therapeutic approach. This mechanism is critical because proposals to develop surrogate markers that are not paired with a novel therapy generally score poorly at study sections because of a perceived lack of significance, even when those biomarkers have strong potential to guide the use of existing and future therapies.Third, the CTTF suggests a funding mechanism that requires a “development partner,” such as a venture capitalist or a pharmaceutical company. The value of such a mechanism includes built-in vetting of “project maturity” by the development partner and substantial incentives for investment by the development partner because the federal funds would not be dilutive.Fourth, the CTTF recommends a funding mechanism dedicated to good manufacturing practice and good laboratory practice testing. The NCI Experimental Therapeutics program performs these activities at NCI facilities on behalf of outside investigators, following a competitive review process. Capacity is limited, however, and not immuno-oncology specific; therefore, additional mechanisms are needed. Small Business Innovation Research Phase II is a possibility, but applicants must compete with the full spectrum of projects that are proposed to that mechanism, and study sections tend to sideline rote manufacturing applications. Yet, this important step is often an insurmountable roadblock to development. Providing an R01-Good Manufacturing Practice Manufacturing Required–type mechanism would be a huge benefit.Finally, when there is a specific focus on immuno-oncology clinical trials, the CTTF suggests an R01-type mechanism specifically for immuno-oncology, with a clinical trial required. This requirement is particularly important in the setting of unique dose-escalation strategies that apply to immuno-oncology, where, unlike conventional maximum tolerable dose approaches used for chemotherapeutics, a minimum efficacious dose approach is preferable. Novel trial designs would therefore relax traditional assumptions of monotonic relationships between adverse event severity and efficacy, recognize that immunotherapy-related adverse events could be chronic phenomena, and be designed with combination therapies incorporating independent temporal scales in mind. Such trials would also preferably use the “Network” component of IOTN to accelerate phase 1 to 2 trials.https://vailworkshop.org/) but focused on phase 1 trials for immuno-oncology, particularly educating the community on approaches relevant to immuno-oncology development. The CTTF proposes workshops on intellectual property, technology transfer, and technology licensing as they apply to immuno-oncology. This need is driven by the wide range of experience with intellectual property and technology transfer of immuno-oncology researchers as well as the nuances of drug development in the immuno-oncology space.The CTTF recommends organizing workshops such as the Vail clinical trials skill development workshop (The CTTF also recommends creating a new resource, an IOTN Foundation, which would be modeled after similar foundations, such as the GOG Foundation  and NSABAs another new resource, the CTTF recommends formation of a navigator resource as a 1-stop shop that lists all available resources and pathways through the NIH, industry, and other resources available for immuno-oncology translation. Such a road map would be a huge benefit to all researchers, providing easy access to all relevant resources in 1 easy-to-navigate location. In conclusion, the first 5 years of the IOTN program have been highly productive in generating new insights into mechanisms of cancer as well as barriers to translation. We defined key areas to overcome these barriers and proposed new funding mechanisms and other resources to increase translation and reduce cancer deaths.djad151_Supplementary_DataClick here for additional data file.


Deregulation of tumor cell metabolism is widely recognized as a “hallmark of cancer.” Many of the selective pressures encountered by tumor cells, such as exposure to anticancer therapies, navigation of the metastatic cascade, and communication with the tumor microenvironment, can elicit further rewiring of tumor cell metabolism. Furthermore, phenotypic plasticity has been recently appreciated as an emerging “hallmark of cancer.” Mitochondria are dynamic organelles and central hubs of metabolism whose roles in cancers have been a major focus of numerous studies. Importantly, therapeutic approaches targeting mitochondria are being developed. Interestingly, both plastic  and permanent  metabolic adaptations have been observed following exposure to anticancer therapeutics. Understanding the plastic or permanent nature of these mechanisms is of crucial importance for devising the initiation, duration, and sequential nature of metabolism-targeting therapies. In this review, we compare permanent and plastic mitochondrial mechanisms driving therapy resistance. We also discuss experimental models of therapy-induced metabolic adaptation, therapeutic implications for targeting permanent and plastic metabolic states, and clinical implications of metabolic adaptations. While the plasticity of metabolic adaptations can make effective therapeutic treatment challenging, understanding the mechanisms behind these plastic phenotypes may lead to promising clinical interventions that will ultimately lead to better overall care for cancer patients. This isRecently, there is growing interest in metabolic-driven mechanisms of cancer resistance as well as the development of anti-cancer drugs that target the mitochondria. Indeed, metabolic plasticity has been found to be a common adaptation in many tumor types, promoting tumor progression and metastasis . While m2), produced in the tricarboxylic acid (TCA) cycle. The electrons from NADH and FADH2 then drive the electron transport chain (ETC) by passing through its complexes and ultimately generating ATP. During electron transport, leaky electrons can escape the ETC and interact with oxygen, generating reactive oxygen species (ROS). ROS act as secondary messengers and play a crucial role in regulating metabolic responses and homeostasis within and outside the mitochondria. Several energetic molecules can feed into the TCA cycle, including long chain fatty acids (LCFAs), glutamine, pyruvate, and nucleotides. LCFAs are generated in the cytoplasm during fatty acid synthesis (FAS) or are taken up from the extracellular space. LCFAs are then imported into the mitochondria through carnitine palmitoyl transferase 1 (CPT1) where they are broken down via fatty acid β-oxidation (FAO). The breakdown of the LCFAs produces acetyl-CoA, which can directly feed into the TCA cycle. Acetyl-CoA can also be generated from pyruvate that has been oxidized from glucose and imported into the mitochondria. Besides acetyl-CoA, cytoplasmic glutamine can provide an alternative source of carbons that feeds into the TCA cycle when it gets converted to α-ketoglutarate (AKG) . Glycolysis generates pyruvate and adenosine triphosphate (ATP) from glucose. This ancient process is highly conserved across species and allows for the rapid generation of two net ATP by converting pyruvate to lactate. Oxphos occurs in the mitochondria and produces large amounts of ATP by leveraging electron carriers, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADHte (AKG) . The TCAte (AKG) .Tumors are complex ecosystems consisting of cancer cells, immune cells, endothelial cells, fibroblasts, and many others. These non-tumor stromal cells play a significant role in tumor resistance and survival . In partMitochondrial metabolism has been a target of interest in recent years for cancer treatment. Altered mitochondrial metabolism in cancer was first described by Otto Warburg with his finding that tumors relied on glycolysis rather than oxphos for their energetic needs . It has An ongoing challenge in cancer therapy is treating drug resistance in surviving cells. Reliance on mitochondrial metabolism in tumors cells presents a potential vulnerability that could be targeted via oxphos inhibitors to eliminate the residual surviving cells. Below, we first review instances of non-plastic oxphos rewiring in which therapeutics induce changes that do not appear to revert. Then, we cover therapy-induced changes in the TCA cycle and mitochondrial redox state that are correlated with resistance and/or residual cell survival. Lastly, we discuss how residual tumor cells can utilize different energy sources such as lipids, glucose, and glutamine to fuel oxphos, as well as oxphos inhibitors and inhibitors that target the production, import, or catabolism of these fuels. A summary of studies discussed in this review that demonstrate therapy induced metabolic rewiring and drug resistance can be found in Many studies have demonstrated an enhanced reliance on mitochondrial oxphos following the stress of therapeutic exposure in various cancer types. In one study, irinotecan resistant non-small cell lung cancer (NSCLC) cells had increased oxphos compared to treatment-naïve NSCLC cells . When thResistance to conventional chemotherapies remains a major clinical challenge. Several cancers exhibit increased oxphos in chemoresistant cells, and in some cases, this presents a therapeutic vulnerability. Docetaxel resistant prostate cells exhibit a reliance on oxphos through the utilization of glucose, glutamine, and lactate . By inhi2, produced mainly in the TCA cycle. Recent studies are shedding light on the roles that alteration in the TCA cycle enzymes can play in oxphos dependence and in turn, therapy resistance in cancers.Although Otto Warburg found that cancer cells may rely on glycolysis rather than oxphos for their energetic needs, studies in more recent years have found that certain cancers may preferentially utilize oxphos rather than glycolysis. Oxphos is the primary process through which cells generate ATP, one that requires the usage of electron carriers such as NADH and FADHSome studies show an increased contribution towards TCA cycle metabolites correlated with drug-resistance. Metabolomic profiling of gastric cancer cells made resistant to the anti-HER2 monoclonal antibody trastuzumab revealed that resistant cell lines maintained heightened levels of citrate synthase (CS) and ATP citrate lyase (ACLY), and had a significant increase in the metabolites citrate, fumarate, and phosphoenolpyruvic acid, compared to their sensitive counterparts . Given tIn another study, an estrogen receptor positive breast cancer cell line made resistant to doxorubicin favored anaplerotic  pyruvate metabolism. Doxorubicin resistant cells showed significantly increased RNA expression of anaplerotic genes pyruvate carboxylase, malic enzyme 1 (ME1), and malic enzyme 2 (ME2), corroborated by the enrichment of TCA cycle intermediates citrate, malate, and fumarate . Other sSome studies also indicate that there does not necessarily need to be a shift away from glycolysis for there to be increased TCA cycle activity and oxphos . In a st2. These high-energy electron carriers (reducing agents) provide the electrons to fuel the ETC embedded in the inner mitochondrial membrane. NADH donates an electron at Complex I, generating NAD+, while FADH2 donates two electrons at Complex II, generating FAD. Electrons are then passed through the ETC complexes, providing the energy required to move hydrogen atoms across the inner mitochondrial membrane into the intermembrane space, generating an electrochemical proton gradient. Electrons are ultimately donated to molecular oxygen by Complex IV to form water. Lastly, ATP synthase (Complex V) generates ATP from ADP by passing protons from the intermembrane space (Reduction-oxidation (redox) chemical reactions involve the transfer of an electron between a reducing agent (electron donor) and an oxidizing agent (electron acceptor) . The movne space . Therefone space . Herein in vitro while the combination of gossypol, irinotecan, and phenformin (Complex I inhibitor) synergistically reduced tumor size in therapy naive cells in vivo . ROS are generated when electrons “escape” their intended oxidizing agent and bind oxygen molecules to form radicals. Therefore, increased ETC activity naturally leads to increased ROS production. In addition to oxphos, major sources of ROS include NADPH oxidases and to a lesser extent peroxidases, cyclooxygenases, cytochrome p450, and xanthine oxidase . At high in vivo . Therefo in vivo . Additio in vivo . Head an in vivo . Instead radical . Further radical . This ma radical . Sirtuin radical . SIRT1 iogenesis . Human cogenesis . These fOutside the mitochondria, redox reactions are used heavily in glucose, glutamine, and lipid metabolism. Glucose and glutamine generate NADPH while glutamine also generates glutathione (GSH), which is made through a series of redox reactions . GSH is Lipid redox reactions also produce ROS and can induce a unique type of cell death called ferroptosis . Iron acSometimes, decreased ROS levels may be adaptive within drug resistant cells, even if their oxphos levels are high. Gastric cancer cell lines were subjected to chronic metabolic stress through prolonged culturing in nutrient deprived media to generate stem-like cancer cells . CSCs arIn summary, when drug resistant cells upregulate oxphos, electrons produced from redox reactions within the ETC result in increased ROS which can have toxic effects if not mediated. Cancer cells have a variety of mechanisms to buffer ROS and identifying these mechanisms may present targetable vulnerabilities in drug resistant tumors.Fatty acids are high-energy molecules whose production is fueled by the TCA cycle intermediate acetyl-CoA and whose break-down can fuel TCA cycling and oxphos . AlteredFatty acid synthase (FASN) is the rate-limiting enzyme for lipogenesis of LCFAs in the cytosol. Several studies have demonstrated a role for FASN in the resistance of HER2 over-expressing breast cancers to standard of care agents including cytotoxic chemotherapies and anti-HER2 therapies . BlockinTargeting FAO has proved promising as well. Resistance to cisplatin is a crucial determinant of overall survival in high grade serous ovarian cancer. Several studies have demonstrated the importance of FAO in residual ovarian cancer cells that are refractory to cisplatin. In one study, continuous treatment of ovarian cancer cell lines with cisplatin led to higher fatty acid uptake and subsequent FAO in the resistant cells . Cisplatin vivo, suggesting that acetylated-STAT3 promotes FAO-mediated chemoresistance. A similar finding was documented in another study in which CTP1B and STAT3 were higher in post chemotherapy TNBC patient tumors compared to pre-chemotherapy biopsies  leading to increased glucose and lactate consumption . Xenograhibition . In anothibition . ENO1 knhibition . Targetihibition , PKM2 tahibition  and in dhibition , and LDHhibition . In a sthibition . Melphalhibition . Moreovehibition . Interesoduction . In a dioduction . Glycoly+ colorectal cells surviving treatment with irinotecan, a topoisomerase-1 inhibitor, had increased oxphos , an upstream regulator of the focal adhesion kinase (FAK) signaling pathway. With decreased RORC, this pathway was more active, resulting in increased glucose import, glycolysis, and ultimately resistance  will be necessary to take advantage of plastic therapeutic windows in the surviving residual disease.Resistance to therapy remains one of the greatest challenges in cancer. Cancer cells can attain resistance through multiple mechanisms, either through selective pressures that allow outgrowth of fit cells, Increased oxphos in cells surviving therapy has been documented in a variety of cancers. Therefore, understanding the energetic sources fueling oxphos is essential for developing targeted therapies. Herein we reviewed evidence that drug resistant cancers rely on fatty acids, glucose, and/or glutamine to feed the TCA cycle and oxphos, and by using drugs to selectively target these pathways, there has been success killing tumor cells in many preclinical studies. Additionally, targeting TCA cycle enzymes or proteins involved in ROS buffering have also proven promising to mitigate drug induced oxphos reliance. While we focused on pathways promoting oxphos adaptations, it is important to consider that other metabolic pathways, such as nucleotide metabolism and the PPP, could be contributing to cancer resistance and metabolic reprogramming .An important feature of metabolic rewiring is that it is highly context dependent, often with specificity to tumor and therapy type. These studies demonstrate the critical importance of studying metabolic rewiring so that we can devise therapeutic schemes to overcome the specific type of rewiring that occurs. To address this, more systematic head-to-head studies must be done. For example, comparing various treatments within the same tumor type or expanding studies to include multiple tumor types may provide clarity on what predisposes tumors to mitochondrial metabolic rewiring. It will also be beneficial to move towards a standardization of metabolic profiling and metabolic function assays to aid in our ability to compare data across studies.in vitro and in vivo cell line and PDX work. While there is human data which suggests oxphos may be a driving force behind tumor progression, these studies have not investigated this in the context of drug resistance (In general, there has been a lack of oxphos targeting drugs that have successfully received FDA approval. Metformin is a popular drug used to target oxphos throughout these studies, and while it is FDA approved for management of diabetes, it is known for having many off-target effects. Toxicities with more selective drugs, such as IACS-010759, have also prevented FDA approval. Therefore, research involving oxphos adaptations in cancer may benefit from repurposing already approved drugs which historically are used for other diseases, such as stains for control of cholesterol. A major limitation in this field currently is a lack of animal and human experimental studies that validate sistance . Furthersistance . Patientsistance . Additiosistance . TherefoMany studies in this review test the efficacy of oxphos targeting drugs either in combination with the standard-of-care drug or in cells already resistant to the therapy of interest. There have been few studies that test oxphos targeting drugs in a true residual setting wherein treatment naive cells are treated first with standard-of-care and then followed up with an oxphos inhibitor once the metabolic reprogramming has occurred. Future studies may benefit from experiments designed in this manner given that it has clinical utility in addressing alternative treatment options for cancers that do not regress with standard-of-care treatment. Further, experiments that utilize this model may have the ability to assess the plasticity of drug induced oxphos adaptations. Most of the studies in this review do not assess the temporal nature, if any, of oxphos rewiring. Extending studies to allow for tumor relapse may reveal the plastic nature of oxphos reliance, suggesting that the timing of oxphos inhibitors may be of critical consideration. Ultimately, understanding the temporal mechanisms of mitochondrial driven adaptations to cancer therapy will lead to better overall care for cancer patients.


Editorial: Machine learning in clinical decision-making By Filiberto AC, Leeds IL, and Loftus TJ. (2023) Front. Digit. Health. 3:784495. doi: 10.3389/fdgth.2021.784495A Commentary on Machine Learning in Clinical Decision-Making published in Frontiers in Digital Health, we—the editors of the Research Topic—were pleased to expand the Topic by adding manuscripts that highlight dynamic prediction of mortality among critically ill patients, machine learning models for individualized antimicrobial use duration, electronic health record (EHR) tokenization approaches to patient acuity predictions, and a review of specific artificial intelligence (AI) applications, limitations, and requisites in the United States. These are important Research Topic additions because they embody the principles that clinicians make complex decisions under time constraints and uncertainty using hypothetical-deductive reasoning and individual judgement, which vary from clinician to clinician. Time constraints are imposed by acute diseases and high clinical workloads in which uncertainty results from insufficient knowledge, data, and evidence regarding possible diagnoses and treatments. Clinical decision-support systems often require time-consuming manual data acquisition and entry, which limit their ready adoption by physicians working in high acuity environments with critically ill patients. This General Commentary summarizes key points from the work by Patel, Giordiano, Bolton, Shickel, and their colleagues.Given the success of the Research Topic Patients in an intensive care unit (ICU) require close monitoring with a plethora of data points collected in an EHR that are updated frequently. Models predicting mortality have traditionally been used for research purposes rather than individual patient risk assessment at the bedside, and do not consider dynamic clinical status of individual patients. These risk scores are often calculated to produce a score at a single timepoint, overlooking subtle yet important updates in patients' physiology. Despite the rapidly expanding use of EHR data for model training purposes in research environments, current monitoring strategies in clinical use remain limited in their ability to accurately represent changes in patient status.In volume two of this Research Topic, Patel and colleagues introduce a novel study designed to assess the performance of a dynamic method of updating mortality risk every three hours using a criticality index mortality (CI-M) neural network methodology . The datBacterial antimicrobial resistance is a global threat and is associated with increased risk of mortality not only for index patients who develop resistant infections, but also for other patients who suffer collateral harm from spread of resistant organisms, often through healthcare worker vectors. Clinical decision support systems have the potential to increase antimicrobial stewardship, thus mitigating antimicrobial resistance. Bolton et al. use a machine learning and synthetic control-based approach to estimate patients’ length of stay (LOS) and mortality outcomes for any given day if they were to stop vs. continue antibiotic treatment . CompariShickel et al. describe their use of a transformer-based patient acuity prediction framework in the critical care setting with a data embedding scheme that captures both concept and corresponding measurement values of many disjoint clinical descriptors . The autIn a comprehensive review of peer-reviewed literature describing access to AI for clinical decision making, Giordano et al. highlight the use of machine learning models for risk stratification, early warning of acute decompensation, potential bias in machine learning algorithms, and the paradigm shift in medical training towards emerging biomedical informatics applications . With thMachine Learning in Clinical Decision-Making and Machine Learning in Clinical Decision-Making—Volume II Research Topics published in Frontiers in Digital Health.We hope that you have enjoyed and learned from these important additions to the


Mental flexibility (MF) has long been defined as cognitive flexibility. Specifically, it has been mainly studied within the executive functions domain. However, there has recently been increased attention towards its affective and physiological aspects. As a result, MF has been described as an ecological and cross-subject skill consisting of responding variably and flexibly to environmental cognitive-affective demands. Cross-sectional studies have mainly focused on samples composed of healthy individual and of patients with chronic conditions such as Mild Cognitive Impairment and Parkinson’s, emphasizing their behavioral rigidity. Our study is the first to consider a sample of healthy older subjects and to outline physiological and psychological markers typical of mental flexibility, to identify functional biomarkers associated with successful aging. Our results reveal that biomarkers (respiratory and heart rate variability assessments) distinguished between individuals high vs. low in mental flexibility more reliably than traditional neuropsychological tests. This unveiled the multifaceted nature of mental flexibility composed of both cognitive and affective aspects, which emerged only if non-linear multi-variate analytic approaches, such as Supervised Machine Learning, were used. Dichotomized Cognitive Flexibility Inventory (CFI) self-report was used as predicted variable, divided in Low flexibility and High flexibility  and RMS respiration rate shed light on how physiological parameters could interact and discriminate between High and Low Flexibility: the variability of those with lower levels of flexibility is connected to the presence of polarization at the upper and lower extremes, as the decision tree and scatterplot show . On the In conclusion, our findings suggest that physiological measures demonstrate superior discriminative capabilities between high and low flexibility compared to neuropsychological tests, highlighting the importance of considering comprehensive bio-physiological markers to understand better the complexities of flexibility in the context of cognitive and affective processes.One possible explanation for the superior discriminative capabilities of physiological measures is their ability to capture real-time responses to emotional and cognitive stimuli. Physiological indices, such as heart rate variability and electromyographic activation, directly reflect the autonomic nervous system’s dynamic changes in response to emotional experiences and cognitive demands. In contrast, traditional neuropsychological tests primarily assess cognitive abilities in controlled settings, which may only partially capture the complex and adaptive nature of flexibility in real-life scenarios.Moreover, physiological measures offer a more holistic representation of an individual’s emotional and cognitive reactivity, as they integrate both cognitive and affective aspects of flexibility. For instance, heart rate variability can reflect the interplay between cognitive appraisal and emotional regulation during adaptive responses to challenges. This comprehensive approach allows physiological measures to capture the interwoven complexities of flexibility, providing a more accurate and nuanced depiction of an individual’s flexibility profile.Furthermore, physiological measures offer the advantage of being less susceptible to conscious control or cognitive biases that can influence self-report measures used in traditional neuropsychological assessments. As a result, physiological indices may provide a more objective and reliable assessment of an individual’s cognitive-affective responses, enhancing their capacity to distinguish between high and low flexibility.Despite the enhanced discriminative capabilities of physiological measures, it remains crucial to consider and integrate both physiological and neuropsychological assessments in the comprehensive evaluation of flexibility, as they collectively provide a more comprehensive and multidimensional understanding of the cognitive-affective aspects underlying this complex construct.We hypothesize that considering the numerous behavioral and physiological markers in a complex non-linear model has allowed relationships that otherwise would not have occurred.Mental flexibility, with its cognitive-affective and physiological biomarkers, is a complex and multifaceted construct. Studying its components in healthy aging enables a better understanding of how they work and interact, as a signal of successful aging .Our findings highlight how just two physiological parameters, cardiac variability (Max HR) and RMS Respiration Rate, can discriminate between high and low flexibility. In general, physiological measurements are more discriminating and predictive than the neuropsychological test batteries usually used. Affective flexibility, on the other hand, measured continuously through physiological measures taken during stimulus display, is a sound methodology of analysis that captures the full range of changes in behavioral-physiological typical of flexibility.This study shows that nonlinear multivariate models can disclose the complicated relationship between cognitive and emotional flexibility and physiological data. Future studies could use Virtual Reality (VR) or 360° videos to test cognitive and affective flexibility jointly . Both coFinally, both would enable us to investigate flexibility in its two components continuously integrate rather than splitting them into mechanisms or sub-mechanisms.The study investigated biopsychological markers of cognitive-affective flexibility in healthy aging using a sample of 35 participants aged 62–82 years, with a gender imbalance, as approximately 77% were female. However, this gender unbalance reflects the national demographic trend of healthy ageing population, showing a higher number of females than males . One potential limitation could be gender distribution, which may impact the generalizability of the findings. A more balanced sample should be considered in further studies. Another limitation was the absence of a control group, such as socially inactive individuals or those with neurological conditions, to compare flexibility biomarkers between different populations. Therefore, future studies could consider this group comparison. However, our study minimizes this lack, with more than 100 variables per subject, including neuropsychological tests and physiological measures, ensuring high representativeness of intrasubject and between-subject variability. Although the cross-sectional design provided a snapshot of flexibility at a specific time, a longitudinal approach could be beneficial for understanding its developmental trajectory. Therefore, a further step could take into consideration longitudinal analysis on the same healthy elderly group, to trace flexibility changes  over the time.Additionally, the study adopted COVID-related images as emotional stimuli, which are very specific to the period in which the study was conducted; thus, this study could be replicated with images reporting a broader range of emotional contents. Despite these limitations, the study offered key and novel insights into cognitive-affective flexibility in healthy aging and suggested directions for future investigations.


Naturalistic decision making (NDM) is concerned with the study of how people make decisions and behave in complex, dynamic, and uncertain environments, in which decisions have significant consequences. NDM research is concerned with metacognitive expertise more broadly , and applies methods such as cognitive task analysis to understand the unique aspects of decision-making under uncertainty. These processes are then use to design technologies and learning experiences for supporting individual and team performance in complex cognitive work systems. The epistemic development of NDM-related areas continues to grow and advance our understanding of complex decision-making in action.The growing evidence base of epistemic NDM inquiry warrants that the impact of this field's innovative and rigorous task-based methods are documented for use and adoption by a larger audience of academics and practitioners. Traditionally NDM research has focussed upon high-reliability contexts and participants working in areas such as the military on land, air and sea, health and emergency services, challenging sporting decisions, intelligence, weather forecasting, fire fighting, trading, etc. often working with deep uncertainty and with complex problems completed by individuals and teams working within organizational constraints.why and how experts see and handle decision challenges differently we can support and demystify associated myths and accelerate context, domain specific epistemic cognition  knowledge and research being conducted by cognitive psychologists and social scientists with a broad reach for practitioners. This work offers valuable methods and insights for all organizations who aim to elicit, document, and share expert knowledge of professionals at work.May et al. who provide an insightful systematic synthesis and holistic narrative analysis which identifies the challenges to critical incident decision making. Results suggested that research was moderately heterogeneous, research primarily focused toward intermediate meso-level characteristics, capturing factors such as “interoperability” and “organization policy and procedure” as critical challenges to decision-making. Six key narratives were identified and discussed. Six narratives that were thought to comprise decision-making for critical incident response emerged from the analysis: (1) political reform and modernization of emergency management doctrine; (2) difficulties of operating under austerity; (3) uncertainty and accountability; (4) inter-intra government and organizational ethics; (5) failures in collaborative information networks; and (6) limited research-focused horizon scanning. Both the quality appraisal and narrative findings suggested that research should seek opportunities to experimentally assess, evaluate and validate decision-making. Whilst this has previously appeared ethically and practically problematic, May et al. suggest that advances in technology, research and analysis have allowed high-fidelity simulation experimentation to recreate critical incidents.The Research Topic opens with Reeves and Ashenden)—recommending an NDM framework to further understanding the challenges of this professional group; (ii) high performance coaches  who reveal that increasing adaptive skill is paramount to performance. Their findings suggest opportunities for utilizing Cognitive Task Analysis to investigate the cognitive challenges of sport coaching and enhance coach development practice. (iii) The adaptive performance of a drone, highlighting that decision-making can be an emergent capacity that arises from the interactions of both human and non-human agents in a socio-technical system . Kordoni et al. investigate how human-robotic interactions can inform decision-making in emergency responders during mass-casualty events. Specifically, the authors explore whether it is possible to expedite the evacuation of casualties during an emergency by utilizing “identity-adaptive” drones in the process. The findings demonstrated how implementing a “identity adaptive robot”  can aid in the evacuation efforts. This novel methodology provides promising evidence that future autonomous systems might be used to both alleviate the immediate evacuation of victims during major emergencies, whilst improving the situational awareness and reducing the cognitive load of responders.Three original research contributions provide rich cognitive insights into: (i) security operations analysts  principles, models, and tools are well-suited to tackling the challenge that artificial intelligence (AI) developers foresee may mitigate harms that might result from their creations, noting that this is exceptionally difficult given the prevalence of emergent behaviors that occur when integrating AI into complex sociotechnical systems.Klein et al. propose a plausibility transition model for sensemaking which has implications for the measurement and training of decision makers.The final contribution to our Research Topic is by one of the leaders in the field of NDM, Naturalistic Decision Making Association for their contributions, and we also wish to encourage those authors who didn't make it to publication this time, to be encouraged to continue to revise their manuscripts and engage with this pragmatic and diverse community of cognitive scholars and practitioners.These articles illustrate how, after three decades, researchers continue to utilize the NDM framework, models and methods to explore complex cognition in uncertainty across a diverse range of professions and organizations. We would like to thank the authors, reviewers and JG: Conceptualization, Writing—original draft, Writing—review & editing. NS: Writing—review & editing. NP: Writing—original draft, Writing—review & editing. OB: Writing—original draft, Writing—review & editing.


Climate change will continue to accentuate the negative impact of heat stress (HS) on ruminant livestock production, compromising animal welfare and meat quality.Mitigation strategies, including providing shade on farms, modifications of animal housing , and nutritional interventions, are important short-term measures to reduce the negative effects of HS.Climate-smart breeding for thermotolerance and matching of adapted ruminant breeds to appropriate production systems should be considered for more sustainable livestock production systems.The Intergovernmental Panel on Climate Change (IPCC) projects a 1.5 °C to 2 °C increase in global warming in the 21st century, meaning that heat stress (HS) will continue to affect the sustainability of livestock farms worldwide negatively , includiOver millennia, ruminant livestock have developed behaviors to cope with high temperatures, through natural or artificial selection. For example, ruminants tend to rest during the hottest parts of the day and become more active during cooler times. Dairy cattle graze less during the hottest period of the day, seeking shade and spending more time at the watering points to conserve energy and reduce heat production .Ruminant livestock are raised within diverse cultural and environmental production systems globally and contribute to food security. They have well-developed thermoregulatory mechanisms but adaptation to increased environmental temperature compromises animal performance production . Like otHS also has indirect effects on ruminant production through a reduction in the quantity and quality of fodder while increasing the spread of new vector-borne diseases . GeneralClimate-adapted animals have evolved physiological and behavioral mechanisms that allow the maintenance of body temperature within a narrow range, even when exposed to high temperatures. Climate-adapted phenotypes may be procured through either natural or artificial selection. Physiological mechanisms and behavioral changes conferring heat tolerance reduce the negative impact of HS on meat quality leading to reduced muscle fatigue which may improve meat tenderness. Additionally, changes in metabolism minimize the breakdown of fats, which can improve the flavor and aroma of the meat. However, severe, or prolonged HS can impact even climate-adapted animals. Under such conditions, the animal’s coping mechanisms may become overwhelmed, negatively impacting meat quality.In general, reduction in meat production has been demonstrated in both long-term and short-term HS studies  Table 1Table 1. Carcass quality is affected by HS, as reflected in the quantity of subcutaneous and intramuscular fat (IMF). Limited research  did not a*) and reduce lightness (L*) and color stability due to the higher ultimate pH and oxidation state, which causes meat to appear darker than normal  had better color stability  becomes apparent but in other studies, the influence on WHC and texture was observed only after 1 mo of exposure to hot conditions as indicated in As indicated above, effects of HS are mitigated in climate-adapted animals. Our unpublished data show that wool-shedding breeds of sheep displayed higher meat color stability compared with wool breeds under cyclic HS conditions . CompareLongissimus thoracis (LT) muscle from animals subjected to a month of summer conditions  was higher than that of meat from animals subjected to winter conditions . At least 2 wk of HS in ruminants is required before any impact on WHC and shear force of their meat occurs . If glycogen concentrations are above the threshold for postmortem glycolysis utilization, exposure to acute HS before slaughter may lead to a more rapid decline in muscle pH resulting in PSE meat . GeneralHS is also known to cause OS. In healthy biological systems, animals maintain a balance between reactive oxygen species (ROS) and antioxidants at the cellular level . HoweverAcinetobacter and Altermonas putrefaciens  into the bloodstream  are inhibited at normal pH (5.6) of meat but can grow on meat with a high ultimate pH, including efaciens . On the efaciens . An increfaciens . For exaodstream . Such inClimate change induced HS, and its challenge to livestock production requires adaptation and mitigation strategies. There are some adaptive practices that have been developed in breeding and pasture management programs including selection for more heat-resistant genotypes , silvopaA key component of adaptation is the innate genetic ability of an organism to survive under stressful conditions . Climatehttps://omia.org/OMIA001372/9913) initially identified in Senepol cattle and other South America breeds, which has been introgressed to Holsteins to improve their thermotolerance  genes. The application of OMICS technologies offers considerable scope for identification of more reliable biomarkers for HS resilience which could be incorporated in marker-assisted selection (MAS) to redefine the existing breeding goals for thermotolerance.Genetic Interventions—In the longer term, selection for heat tolerance is an effective long-term strategy, as is introgression of specific (Ruminant livestock are important contributors to global food production and an important income source for many farmers in developing countries. HS remains a major threat to ruminant livestock production, reducing feed intake, LWG, limiting meat and milk production, damaging the intestinal wall, compromising nutrient digestion and absorption, and affecting meat quality. Unfortunately, these harmful consequences of HS in terms of animal health and production are likely to be an ongoing issue across the globe, and a multidisciplinary approach integrating animal breeding, nutrition, and housing is required to counteract the impact of climate change on livestock. Amelioration strategies such as provision of shade, sprinklers, fans, energy-efficient cooling systems, water provision, feeding changes, and nutritional interventions can be utilized in the short term. However, it is important to note that some of these strategies may not be applicable to extensive systems and most of these require the use of electricity and water, which might not be a sustainable option in certain regions. In extensive systems, crossbreeding high-producing exotic breeds with local climate-adapted breeds, planting more trees in paddocks and laneways, and encouraging early morning and late afternoon grazing could be more useful.In the short term, modification of the animal’s environment and nutritional interventions can be considered mitigation strategies to sustain livestock production in a changing climate. In the long term, genetic selection for thermotolerance and climate adaptation must be prioritized in future ruminant livestock breeding programs to improve animal comfort and performance in a changing climate. The integration of new technologies and capacity building in less-developed countries offers many opportunities for further development of strategies to reduce the negative impact of climate change on livestock.Conflict of interest statement. None declared.