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The American Geriatrics Society (AGS) Beers Criteria is an explicit list of potentially inappropriate medications (PIMs) best avoided in adults ≥65 years of age. Cognitively impaired and frail surgical patients often experience poor outcomes after surgery, but the impacts of PIMs on these patients are unclear. Our objective was to assess whether perioperative PIM administration was associated with poor outcomes in geriatric surgical patients. We then evaluated the association between PIM administration and postoperative outcomes in subgroups of patients who were frail or cognitively impaired.We performed a retrospective cohort study of patients ≥65 years of age who underwent elective inpatient surgery at a large academic medical center from February 2018 to January 2020. Edmonton Frail Scale and Mini-Cog screening tools were administered to all patients at their preoperative clinic visit. A Mini-Cog score of 0 to 2 was considered cognitive impairment, and frailty was defined by an Edmonton Frail Scale score of ≥8. Patients were divided into 2 groups depending on whether they received at least 1 PIM (PIM+), based on the 2019 AGS Beers Criteria, in the perioperative period or none (PIM-). We assessed the association of preoperative frailty, cognitive impairment, and perioperative PIM administration with the length of hospital stay and discharge disposition using multiple regression analyses adjusted for age, sex, ASA physical status, and intensive care unit (ICU) admission.Of the 1627 included patients (mean age, 73.7 years), 69.3% (n = 1128) received at least 1 PIM. A total of 12.7% of patients were frail, and 11.1% of patients were cognitively impaired; 64% of the frail patients and 58% of the cognitively impaired patients received at least 1 PIM. Perioperative PIM administration was associated with longer hospital stay after surgery (PIM-, 3.56 ± 5.2 vs PIM+, 4.93 ± 5.66 days; P.001; 95% confidence interval [CI], 0.360-0.546). Frail patients who received PIMs had an average length of stay (LOS) that was nearly 2 days longer than frail patients who did not receive PIMs (PIM-, 4.48 ± 5.04 vs PIM+, 6.33 ± 5.89 days; P = .02). Multiple regression analysis revealed no significant association between PIM administration and proportion of patients discharged to a care facility (PIM+, 26.3% vs PIM-, 28.7%; P = .87; 95% CI, -0.046 to 0.054).Perioperative PIM administration was common in older surgical patients, including cognitively impaired and frail patients. PIM administration was associated with an increased hospital LOS, particularly in frail patients. There was no association found between PIM administration and discharge disposition.

We demonstrate the utility of risk stratification for postoperative delirium in geriatric patients and show that postoperative delirium can be prevented in high-risk patients when potentially inappropriate medications (PIMs) (medications that are best avoided in older adults) are avoided. In this case, a 65-year-old woman underwent two debridement procedures with similar presurgical risk for postoperative delirium. There was no risk stratification or preoperative cognitive assessment in the first procedure, she received PIMs and developed postoperative delirium. In the second procedure, PIMs were intentionally avoided and postoperative delirium did not occur. This case supports recent recommendations from the European Society of Anaesthesiology, the American Society of Anesthesiologists and the American Geriatrics Society that providers assess a patient’s cognitive function and delirium risk profile preoperatively to appropriately guide perioperative management.

Lipocalin 2 (LCN2) is a pleiotropic molecule that is induced in the central nervous system (CNS) in several acute and chronic pathologies. The acute induction of LCN2 evolved as a beneficial process, aimed at combating bacterial infection through the sequestration of iron from pathogens, while the role of LCN2 during chronic, non-infectious disease remains unclear, and recent studies suggest that LCN2 is neurotoxic. However, whether LCN2 is sufficient to induce behavioral and cognitive alterations remains unclear. In this paper, we sought to address the role of cerebral LCN2 on cognition in both acute and chronic settings. We demonstrate that LCN2 is robustly induced in the CNS during both acute and chronic inflammatory conditions, including LPS-based sepsis and cancer cachexia. In vivo, LPS challenge results in a global induction of LCN2 in the central nervous system, while cancer cachexia results in a distribution specific to the vasculature. Similar to these in vivo observations, in vitro modeling demonstrated that both glia and cerebral endothelium produce and secrete LCN2 when challenged with LPS, while only cerebral endothelium secrete LCN2 when challenged with cancer-conditioned medium. Chronic, but not short-term, cerebral LCN2 exposure resulted in reduced hippocampal neuron staining intensity, an increase in newborn neurons, microglial activation, and increased CNS immune cell infiltration, while gene set analyses suggested these effects were mediated through melanocortin-4 receptor independent mechanisms. RNA sequencing analyses of primary hippocampal neurons revealed a distinct transcriptome associated with prolonged LCN2 exposure, and ontology analysis was suggestive of altered neurite growth and abnormal spatial learning. Indeed, LCN2-treated hippocampal neurons display blunted neurite processes, and mice exposed to prolonged cerebral LCN2 levels experienced a reduction in spatial reference memory as indicated by Y-maze assessment. These findings implicate LCN2 as a pathologic mediator of cognitive decline in the setting of chronic disease.

Microglia in the mediobasal hypothalamus (MBH) respond to inflammatory stimuli and metabolic perturbations to mediate body composition. This concept is well studied in the context of high fat diet induced obesity (HFDO), yet has not been investigated in the context of cachexia, a devastating metabolic syndrome characterized by anorexia, fatigue, and muscle catabolism. We show that microglia accumulate specifically in the MBH early in pancreatic ductal adenocarcinoma (PDAC)‐associated cachexia and assume an activated morphology. Furthermore, we observe astrogliosis in the MBH and hippocampus concurrent with cachexia initiation. We next show that circulating immune cells resembling macrophages infiltrate the MBH. PDAC‐derived factors induced microglia to express a transcriptional profile in vitro that was distinct from that induced by lipopolysaccharide (LPS). Microglia depletion through CSF1‐R antagonism resulted in accelerated cachexia onset and increased anorexia, fatigue, and muscle catabolism during PDAC. This corresponded with increased hypothalamic–pituitary–adrenal (HPA) axis activation. CSF1‐R antagonism had little effect on inflammatory response in the circulation, liver, or tumor. These findings demonstrate that microglia are protective against PDAC cachexia and provide mechanistic insight into this function., • Microgliosis occurs in the mediobasal hypothalamus early in pancreatic cancer.• Microglia respond to pancreatic cancer‐derived factors and produce arginase‐1.• Microglia depletion worsens cachexia during pancreatic cancer.

Toll-like receptors 7 and 8 (TLR7 and TLR8) are endosomal pattern recognition receptors that detect a variety of single-stranded RNA species. While TLR7/8 agonists have robust therapeutic potential, clinical utility of these agents is limited by sickness responses associated with treatment induction. To understand the kinetics and mechanism of these responses, we characterized the acute and chronic effects of TLR7 stimulation. Single-cell RNA-sequencing studies, RNAscope, and radiolabeled in situ hybridization demonstrate that central nervous system gene expression of TLR7 is exclusive to microglia. In vitro studies demonstrate that microglia are highly sensitive to TLR7 stimulation, and respond in a dose-dependent manner to the imidazoquinoline R848. In vivo, both intraperitoneal (IP) and intracerebroventricular (ICV) R848 induce acute sickness responses including hypophagia, weight loss, and decreased voluntary locomotor activity, associated with increased CNS pro-inflammatory gene expression and changes to glial morphology. However, chronic daily IP R848 resulted in rapid tachyphylaxis of behavioral and molecular manifestations of illness. In microglial in vitro assays, pro-inflammatory transcriptional responses rapidly diminished in the context of repeated R848. In addition to TLR7 desensitization, we found that microglia become partially refractory to lipopolysaccharide (LPS) following R848 pretreatment, associated with induction of negative regulators A20 and Irak3. Similarly, mice pre-treated with R848 demonstrate reduced sickness responses, hypothalamic inflammation, and hepatic inflammation in response to LPS. These data combined demonstrate that TLR7 stimulation induces acute behavioral and molecular evidence of sickness responses. Following prolonged dosing, R848 induces a refractory state to both TLR7 and TLR4 activation, consistent with induced immune tolerance.

A priority in cancer research is to innovate therapies that are not only effective against tumor progression but also address comorbidities such as cachexia that limit quality and quantity of life. We demonstrate that TLR7/8 agonist R848 induces anti-tumor responses and attenuates cachexia in murine models of pancreatic ductal adenocarcinoma (PDAC). In vivo, tumors from two of three cell lines were R848-sensitive, resulting in smaller tumor mass, increased immune complexity, increased CD8+ T-cell infiltration and activity, and decreased Treg frequency. R848-treated mice demonstrated improvements in behavioral and molecular cachexia manifestations, resulting in a near-doubling of survival duration. Knockout mouse studies revealed that stromal, not neoplastic, TLR7 is requisite for R848-mediated responses. In patient samples, we found Tlr7 is ubiquitously expressed in stroma across all stages of pancreatic neoplasia, but epithelial Tlr7 expression is relatively uncommon. These studies indicate immune-enhancing approaches including R848 may be useful in PDAC and cancer-associated cachexia., In the treatment of pancreatic ductal adenocarcinoma (PDAC), comorbidities such as cachexia limit quality of life and survival. Here, the authors show TLR7/8 agonist R848 remodels host and tumour immune responses, promoting survival and attenuating cachexia in murine models of PDAC.

Background Up to 80% of pancreatic cancer patients suffer from cachexia, a devastating condition that exacerbates underlying disease, reduces quality of life, and increases treatment complications and mortality. Tumour‐induced inflammation is linked to this multifactorial wasting syndrome, but mechanisms and effective treatments remain elusive. Myeloid differentiation factor (MyD88), a key component of the innate immune system, plays a pivotal role in directing the inflammatory response to various insults. In this study, we tested whether MyD88 signalling is essential in the development of pancreatic cancer cachexia using a robust mouse tumour model. Methods Sex, age, and body weight‐matched wide type (WT) and MyD88 knockout (MyD88 KO) mice were orthotopically or intraperitoneally implanted with a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D/+ P53R172H/+ Pdx‐Cre (KPC) mouse. We observed the effects of MyD88 signalling during pancreatic ductal adenocarcinoma progression and the cachexia development through behavioural, histological, molecular, and survival aspects. Results Blocking MyD88 signalling greatly ameliorated pancreatic ductal adenocarcinoma‐associated anorexia and fatigue, attenuated lean mass loss, reduced muscle catabolism and atrophy, diminished systemic and central nervous system inflammation, and ultimately improved survival. Our data demonstrate that MyD88 signalling plays a critical role in mediating pancreatic cancer‐induced inflammation that triggers cachexia development and therefore represents a promising therapeutic target. Conclusions MyD88‐dependent inflammation is crucial in the pathophysiology of pancreatic cancer progression and contributes to high mortality. Our findings implicate the importance of innate immune signalling pathways in pancreatic cancer cachexia and a novel therapeutic target.

Weight loss and anorexia are common symptoms in cancer patients that occur prior to initiation of cancer therapy. Inflammation in the brain is a driver of these symptoms, yet cellular sources of neuroinflammation during malignancy are unknown. In a mouse model of pancreatic ductal adenocarcinoma (PDAC), we observed early and robust myeloid cell infiltration into the brain. Infiltrating immune cells were predominately neutrophils, which accumulated at a unique central nervous system entry portal called the velum interpositum, where they expressed CCR2. Pharmacologic CCR2 blockade and genetic deletion of Ccr2 both resulted in significantly decreased brain-infiltrating myeloid cells as well as attenuated cachexia during PDAC. Lastly, intracerebroventricular blockade of the purinergic receptor P2RX7 during PDAC abolished immune cell recruitment to the brain and attenuated anorexia. Our data demonstrate a novel function for the CCR2/CCL2 axis in recruiting neutrophils to the brain, which drives anorexia and muscle catabolism., eLife digest Weight loss, decreased appetite and fatigue are symptoms of a wasting disorder known as cachexia, which is common in several serious diseases such as AIDS, chronic lung disease and heart failure. Up to 80 percent of people with advanced cancer also develop cachexia, and there are no effective treatments. It is not known how cachexia develops, but symptoms like appetite loss and fatigue are controlled by the brain. One theory is that the brain may be responding to a malfunctioning immune response that causes inflammation. While the brain was thought to be protected from this, new research has shown that it is possible for cells from the immune system to reach the brain in some conditions. To find out if this also happens in cancer, Burfeind et al. studied mice that had been implanted with pancreatic cancer cells and were showing signs of cachexia. Samples from the mice’s brains showed that immune cells known as neutrophils were present and active. A protein known as CCR2 was found in higher levels in the brains of these mice. This protein is involved in the movement of neutrophil cells through the body. To see what effect this protein had, Burfeind et al. gave the mice a drug that blocks CCR2. This prevented the neutrophils from entering the brain and reduced the symptoms of cachexia in the mice. To further confirm the role of CCR2, the mice were genetically modified so that they could not produce the protein. This reduced the number of neutrophils seen in the brain but not in the rest of the body. This suggests that a drug targeting CCR2 could help to reduce the symptoms of cachexia, without disrupting the normal immune response away from the brain. This approach would still need to be tested in clinical trials before it is possible to know how effective it might be in humans.

Background Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC-associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx-Cre+/+ (KPC) mouse. Methods Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development. Results All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil-dominant leukocytosis and anaemia, and decreased serum testosterone. Conclusions Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.

Introduction The glymphatic system is a brain-wide perivascular network that facilitates clearance of proteins, including amyloid β, from the brain interstitium through the perivascular exchange of cerebrospinal fluid and interstitial fluid. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, and impairment of glymphatic function in the aging brain is associated with altered AQP4 expression and localization. In human cortical tissue, alterations in AQP4 expression and localization are associated with Alzheimer's disease (AD) status and pathology. Although this suggests a potential role for AQP4 in the development or progression of AD, the relationship between of naturally occurring variants in the human AQP4 gene and cognitive function has not yet been evaluated. Methods Using data from several longitudinal aging cohorts, we investigated the association between five AQP4 single-nucleotide polymorphisms (SNPs) and the rate of cognitive decline in participants with a diagnosis of AD. Results None of the five SNPs were associated with different rates of AD diagnosis, age of dementia onset in trial subjects. No association between AQP4 SNPs with histological measures of AD pathology, including Braak stage or neuritic plaque density was observed. However, AQP4 SNPs were associated with altered rates of cognitive decline after AD diagnosis, with two SNPS (rs9951307 and rs3875089) associated with slower cognitive decline and two (rs3763040 and rs3763043) associated with more rapid cognitive decline after AD diagnosis. Discussion These results provide the first evidence that variations in the AQP4 gene, whose gene product AQP4 is vital for glymphatic pathway function, may modulate the progression of cognitive decline in AD.

A priority in cancer research is to innovate therapies that are not only effective against tumor progression but also address comorbidities such as cachexia that limit quality and quantity of life. We demonstrate that TLR7/8 agonist R848 induces anti-tumor responses and attenuates cachexia in murine models of pancreatic ductal adenocarcinoma (PDAC). In vivo, tumors from two of three cell lines were R848-sensitive, resulting in smaller tumor mass, increased immune complexity, increased CD8

Weight loss, fatigue, and cognitive dysfunction are common symptoms in cancer patients that occur prior to initiation of cancer therapy. Inflammation in the brain is a driver of these symptoms, yet cellular sources of neuroinflammation during malignancy are unknown. In a mouse model of pancreatic ductal adenocarcinoma (PDAC), we observed early and robust myeloid cell infiltration into the brain. Infiltrating immune cells were predominately neutrophils, which accumulated at a unique central nervous system entry portal called the velum interpositum, where they expressed CCR2. CCR2 knockout mice had significantly decreased brain-infiltrating neutrophils as well as attenuated anorexia and muscle catabolism during PDAC, without any changes in neutrophils in other organs. Lastly, intracerebroventricular blockade of the purinergic receptor P2RX7 during PDAC abolished neutrophil recruitment to the brain and attenuated anorexia. Our data demonstrate a novel function for the CCR2/CCL2 axis in recruiting neutrophils to the brain, which drives anorexia and muscle catabolism.

Increased epilepsy prevalence is reported in onchocerciasis (OC) endemic areas and is associated with the occurrence of distinct syndromes such as nodding disease and Nakalanga syndrome. o date, a causal relationship between OC and epilepsy is still a matter of controversy. We conducted a case-control study of participants with epilepsy and age-and gender-matched presumably healthy controls to elucidate the relationships between OC and epilepsy and explore the role of inflammation and growth factors in an OC endemic area in the Democratic Republic of Congo (DRC). Eighty-two participants with epilepsy (mean age±SD: 23.2±8.7 years) and 27 controls (mean age±SD:22.3±12.0 years) underwent snip skin biopsies to infection status. Serum concentrations of cytokines, were measured using a Luminex Multiplex Assay determine Onchocerca volvulus chemokines, and growth factors kit. Children < 19 years of age underwent neurocognitive assessments using the Kaufman Assessment Battery for Children, 2(nd) edition (KABC-II). Overall, epilepsy was associated with OC (OR=4.51, z=3.11, p=0.0019), and children with OC were more likely to be severely stunted (OR=11.67, z=2.62, p=0.0087). The relationship between epilepsy and OC was no longer significant (z=1.27, p=0.20) when stunting was included as a correcting covariate. Epilepsy was associated with poor KABC-II test scores, high serum levels of IL-17, and low levels of IL-1RA, IL-8, and EGF. KABC-II testing scores correlated with serum levels of IL-10, MCP-1 and HGF. Familial history of epilepsy occurred frequently. Future studies should consider cytokines and/or growth factors when assessing susceptibility to epilepsy in OC endemic areas. Additional investigations, preferentially in low-prevalence OC areas, may provide further insights into the concept, risk, and burden of river epilepsy.

Hypothalamic inflammation is a key component of acute sickness behavior and cachexia, yet mechanisms of inflammatory signaling in the central nervous system remain unclear. Previous work from our lab and others showed that while MyD88 is an important inflammatory signaling pathway for sickness behavior, MyD88 knockout (MyD88KO) mice still experience sickness behavior after inflammatory stimuli challenge. We found that after systemic lipopolysaccharide (LPS) challenge, MyD88KO mice showed elevated expression of several cytokine and chemokine genes in the hypothalamus. We therefore assessed the role of an additional inflammatory signaling pathway, TRIF, in acute inflammation (LPS challenge) and in a chronic inflammatory state (cancer cachexia). TRIFKO mice resisted anorexia and weight loss after peripheral (intraperitoneal, IP) or central (intracerebroventricular, ICV) LPS challenge and in a model of pancreatic cancer cachexia. Compared to WT mice, TRIFKO mice showed attenuated upregulation of Il6, Ccl2, Ccl5, Cxcl1, Cxcl2, and Cxcl10 in the hypothalamus after IP LPS treatment, as well as attenuated microglial activation and neutrophil infiltration into the brain after ICV LPS treatment. Lastly, we found that TRIF was required for Ccl2 upregulation in the hypothalamus and induction of the catabolic genes, Mafbx, Murf1, and Foxo1 in gastrocnemius during pancreatic cancer. In summary, our results show that TRIF is an important inflammatory signaling mediator of sickness behavior and cachexia and presents a novel therapeutic target for these conditions.

Background Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC‐associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx‐Cre+/+ (KPC) mouse. Methods Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development. Results All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil‐dominant leukocytosis and anaemia, and decreased serum testosterone. Conclusions Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.

BACKGROUMD: Alteration in scapular medial border displacement often observed as scapular winging, can affect the force couples of the rotator cuff muscles and thereby shoulder function. The relationship between scapular medial border displacement and shoulder internal and external rotator muscle function in the baseball player-throwing arm has not been studied. OBJECTIVE: The purpose of the study was to determine if any relationship exists between the amounts of scapular medial border displacement measured at rest and during the sitting hand press up test position and shoulder internal and external rotator muscular strength in Division III baseball players throwing arm. METHODS: A total of 51 Division III baseball players volunteered for the study. Scapular medial border displacement was measured with a standardized posterior scapular displacement measurement tool in two positions, the resting and the sitting hand press-up position. Isokinetic strength of concentric internal rotation (IR) and external rotation (ER) peak torque and time to peak torque for each subject were measured using 3 maximal testing repetitions at 60 ◦ /s. RESULTS: The results of the study showed a linear relationship between the amount of scapular medial border displacement and concentric IR strength and also in time to peak torque. However, no linear relationships were observed between scapular medial border displacement and other isokinetic strength variables. CONCLUSIONS: Scapular medial border displacement produced during a loaded state influences shoulder internal rotatory strength. This may bear on rehabilitation and strengthening exercises in terms of focusing on proper scapular position and subsequent muscular balance to optimize shoulder function.

Signs and symptoms of multiple sclerosis are usually attributed to demyelinating lesions in the spinal cord or cerebral cortex. The hypothalamus is a region that is often overlooked yet controls many important homeostatic functions, including those that are perturbed in multiple sclerosis. In this review we discuss how hypothalamic dysfunction may contribute to signs and symptoms in people with multiple sclerosis. While dysfunction of the hypothalamic-pituitary-adrenal axis is common in multiple sclerosis, the effects and mechanisms of this dysfunction are not well understood. We discuss three hypothalamic mechanisms of fatigue in multiple sclerosis: (1) general hypothalamic-pituitary-adrenal axis hyperactivity, (2) disordered orexin neurotransmission, (3) abnormal cortisol secretion. We then review potential mechanisms of weight dysregulation caused by hypothalamic dysfunction. Lastly, we propose future studies and therapeutics to better understand and treat hypothalamic dysfunction in multiple sclerosis. Hypothalamic dysfunction appears to be common in multiple sclerosis, yet current studies are underpowered and contradictory. Future studies should contain larger sample sizes and standardize hormone and neuropeptide measurements.

Sickness behaviors and metabolic responses to invading pathogens are common to nearly all types of infection. These responses evolved to provide short-term benefit to the host to ward off infection, but impact on quality of life and when prolonged lead to neurodegeneration, depression and cachexia. Among the major infectious agents, viruses most frequently enter the brain, resulting in profound neuroinflammation. We sought to define the unique features of the inflammatory response in the brain to these infections. We demonstrate that the molecular pathway defining the central response to dsRNA is distinct from that found in the periphery. The behavioral and physical response to the dsRNA mimetic poly I:C is dependent on signaling via MyD88 when it is delivered centrally, whereas this response is mediated via the TRIF pathway when delivered peripherally. We also define the likely cellular candidates for this MyD88-dependent step. These findings suggest that symptom management is possible without ameliorating protective antiviral immune responses.

PURPOSE: With recent advances in immunotherapy, many novel cancer treatments are rapidly entering the clinical arena. However, immunotherapies may differ from traditional chemotherapies in their effects on cachexia and treatment-associated sickness. Cachexia is a common comorbidity of cancer that limits therapeutic options, decreases quality of life, and increases mortality risk. Many chemotherapy agents induce or worsen cachexia by independently causing anorexia, weight loss, muscle wasting, and fatigue. Acute systemic inflammation, an effect of many immunotherapies, results in sickness responses that are typically self-limited in healthy individuals. Whether immunotherapy-associated sickness is self-limited or chronic in the context of cancer, and how cachexia is impacted by immunotherapy, remains unknown. METHODS: We recently found that the TLR7/8 agonist R848 reduces tumor size in mice implanted with epithelial cells from a syngeneic KRASG12D/+ P53R172H/+ Pdx-Cre (KPC) pancreatic tumor. To assess cachexia outcomes and R848-induced sickness, mice were orthotopically implanted with KPC cells or saline, and 2 days later were randomized to daily IP R848 (10µg) or vehicle until sacrifice (n=5-7/group/experiment, 3 experiments). Mice were tracked for weight, food intake, body composition, and locomotor activity (LMA), with end-stage analysis of tissue mass and gene expression. RESULTS: Initially, KPC-bearing mice treated with R848 developed significant weight gain and ascites, but had a similar degree of anorexia and decreased LMA as vehicle-treated KPC-bearing mice. However, ongoing R848 resulted in subsequent tumor regression, decreased ascites, increased appetite, and increased LMA. At necropsy, KPC-bearing mice treated with R848 had a 50-70% reduction in tumor mass, histologically characterized by lymphocytic infiltrate and germinal centers. Furthermore, R848-treated KPC-bearing mice had improved total lean mass and heart mass; decreased expression of genes related to skeletal and cardiac muscle catabolism (Mafbx, Murf1, Foxo1, Bnip3, Gabarapl, Ctsl) and hepatic acute phase reactants (Orm1, Apcs); a trend toward decreased CNS inflammatory gene expression (Selp, Il1r1); and unchanged brown adipose tissue thermogenic gene expression (Ucp1). In sham-operated mice, R848 resulted in self-limited anorexia and weight loss, without muscle wasting or decreased LMA. Current work is underway to elucidate tumor intrinsic and tumor extrinsic mechanisms of R848 in this model. SUMMARY: These studies show that R848 does not independently cause sustained sickness, and in a murine model of pancreatic cancer, can induce antitumor responses and improve cachexia outcomes. This represents a key difference from many cytotoxic chemotherapies and suggests immunotherapy approaches may be useful in the treatment of cachexia-associated malignancies. Citation Format: Katherine A. Michaelis, Mason A. Norgard, Xinxia Zhu, Peter R. Levasseur, Katherine R. Pelz, Kevin G. Burfeind, Terry K. Morgan, Daniel L. Marks. The TLR7/8 agonist R848 induces antitumor responses and attenuates cachexia in a murine model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3779.

When challenged with a variety of inflammatory threats, multiple systems across the body undergo physiological responses to promote defense and survival. The constellation of fever, anorexia, and fatigue is known as the acute illness response, and represents an adaptive behavioral and physiological reaction to stimuli such as infection. On the other end of the spectrum, cachexia is a deadly and clinically challenging syndrome involving anorexia, fatigue, and muscle wasting. Both of these processes are governed by inflammatory mediators including cytokines, chemokines, and immune cells. Though the effects of cachexia can be partially explained by direct effects of disease processes on wasting tissues, a growing body of evidence shows the central nervous system (CNS) also plays an essential mechanistic role in cachexia. In the context of inflammatory stress, the hypothalamus integrates signals from peripheral systems, which it translates into neuroendocrine perturbations, altered neuronal signaling, and global metabolic derangements. Therefore, we will discuss how hypothalamic inflammation is an essential driver of both the acute illness response and cachexia, and why this organ is uniquely equipped to generate and maintain chronic inflammation. First, we will focus on the role of the hypothalamus in acute responses to dietary and infectious stimuli. Next, we will discuss the role of cytokines in driving homeostatic disequilibrium, resulting in muscle wasting, anorexia, and weight loss. Finally, we will address mechanisms and mediators of chronic hypothalamic inflammation, including endothelial cells, chemokines, and peripheral leukocytes.