Chronic Cachexia Research Articles

Tricarboxylic acid (TCA) cycle, sphingolipid, and phosphatidylcholine metabolism are dysregulated in T. gondii infection-induced cachexia

Cachexia is a life-threatening disease characterized by chronic, inflammatory muscle wasting and systemic metabolic impairment. Despite its high prevalence, there are no efficacious therapies for cachexia. Mice chronically infected with the protozoan parasite Toxoplasma gondii represent a novel animal model recapitulating the chronic kinetics of cachexia. To understand how perturbations to metabolic tissue homeostasis influence circulating metabolite availability we used mass spectrometry analysis. Despite the significant reduction in circulating triacylglycerides, non-esterified fatty acids, and glycerol, sphingolipid long-chain bases and a subset of phosphatidylcholines (PCs) were significantly increased in the sera of mice with T. gondii infection-induced cachexia. In addition, the TCA cycle intermediates α-ketoglutarate, 2-hydroxyglutarate, succinate, fumarate, and malate were highly depleted in cachectic mouse sera. Sphingolipids and their de novo synthesis precursors PCs are the major components of the mitochondrial membrane and regulate mitochondrial function consistent with a causal relationship in the energy imbalance driving T. gondii-induced chronic cachexia.

T. gondii infection induces IL-1R dependent chronic cachexia and perivascular fibrosis in the liver and skeletal muscle

Cachexia is a progressive muscle wasting disease that contributes to death in a wide range of chronic diseases. Currently, the cachexia field lacks animal models that recapitulate the long-term kinetics of clinical disease, which would provide insight into the pathophysiology of chronic cachexia and a tool to test therapeutics for disease reversal. Toxoplasma gondii (T. gondii) is a protozoan parasite that uses conserved mechanisms to infect rodents and human hosts. Infection is lifelong and has been associated with chronic weight loss and muscle atrophy in mice. We have recently shown that T. gondii-induced muscle atrophy meets the clinical definition of cachexia. Here, the longevity of the T. gondii-induced chronic cachexia model revealed that cachectic mice develop perivascular fibrosis in major metabolic organs, including the adipose tissue, skeletal muscle, and liver by 9 weeks post-infection. Development of cachexia, as well as liver and skeletal muscle fibrosis, is dependent on intact signaling through the type I IL-1R receptor. IL-1α is sufficient to activate cultured fibroblasts and primary hepatic stellate cells (myofibroblast precursors in the liver) in vitro, and IL-1α is elevated in the sera and liver of cachectic, suggesting a mechanism by which chronic IL-1R signaling could be leading to cachexia-associated fibrosis.

Hypercalcemia- Leukocytosis Syndrome: A Rare Ominous Indicator in Lung Cancer

Introduction:Paraneoplastic syndromes are signs and symptoms that occur in association with malignancy at sites distant from the primary tumor or metastases. They occur in approximately 10% of patients with lung cancer (1).Case:A 59-year-old male with a history of tobacco abuse, COPD, and Stage IV Lung Adenosquamous cancer with brain metastases status post chemotherapy presented with weakness and lethargy. Patient was normotensive and on room air. Clinical exam was significant for confusion with noted chronic cachexia. Labs most prominent were a WBC count of 46.8 (16.3 1mo prior, 44.6 3wks prior) , Cr of 1.9, Ca of 11.9 , and Lactic acid of 3.7. Imaging was consistent with an increase in his RUL cavitary lesion with pleural based lesions and 11 metastatic deposits throughout the brain. He was admitted and started on aggressive intravenous fluids. Furthermore, infectious workup was initiated and empiric antibiotics administered for possible pneumonia. By day 3 of admission his creatinine, calcium, and lactic acid normalized but his wbc continued to trend up to 98.6 despite negative infectious workup. His severe metastatic disease burden along with his failure to thrive carried a poor prognosis. Subsequently, a family meeting was held and he was transitioned to comfort measures. Patient passed away shortly thereafter.Discussion:The case clearly demonstrates poor prognostic indicators with hypercalcemia and severe leukocytosis in the setting of end stage lung adenosquamous carcinoma. Classically, paraneoplastic hypercalcemia is associated with PTHrP production in Squamous Cell carcinoma. Overall incidence of hypercalcemia in lung cancer ranges from to 8%-12% with median survival time (MST) of 3.8 months (1,2).Paraneoplastic Leukocytosis meanwhile is most often associated with adenocarcinoma (42%) and squamous cell carcinoma (36%) with incidence ranging between 16 and 30% and MST of 1.9 months (1,2). Nonetheless, the combination of these two known as Hypercalcemia-Leukocytosis syndrome has been identified an independent clinical entity with an even shorter median survival time in comparison with leukocytosis or hypercalcemia alone of 1.5 months (2). The incidence of this was studied to be 0.5% over a 10 year interval (2). Given this rare occurrence, it is prudent for clinicians to recognize this clinical syndrome and the very poor prognosis it bears .https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127595/G.R. Mundy, K.J. Ibbotson, S.M. D'Souza, E.L.Simpson, J.W. Jacobs, T.J. MartinThe hypercalcemia of cancer. Clinical implications and pathogenic mechanismsN Engl J Med, 310 (1984), pp. 1718-1727.https://www.sciencedirect.com/science/article/pii/S0169500203004549?via%3Dihub Hypercalcemia-leukocytosis syndrome associated with lung cancer DisclosuresNo relevant conflicts of interest to declare.

Toxoplasma gondii infection triggers chronic cachexia and sustained commensal dysbiosis in mice.

Toxoplasma gondii is a protozoan parasite with a predation-mediated transmission cycle between rodents and felines. Intermediate hosts acquire Toxoplasma by eating parasite cysts which invade the small intestine, disseminate systemically and finally establish host life-long chronic infection in brain and muscles. Here we show that Toxoplasma infection can trigger a severe form of sustained cachexia: a disease of progressive lean weight loss that is a causal predictor of mortality in cancer, chronic disease and many infections. Toxoplasma cachexia is characterized by acute anorexia, systemic inflammation and loss of 20% body mass. Although mice recover from symptoms of peak sickness, they fail to regain muscle mass or visceral adipose depots. We asked whether the damage to the intestinal microenvironment observed at acute time points was sustained in chronic infection and could thereby play a role in sustaining cachexia. We found that parasites replicate in the same region of the distal jejunum/proximal ileum throughout acute infection, inducing the development of secondary lymphoid structures and severe, regional inflammation. Small intestine pathology was resolved by 5 weeks post-infection. However, changes in the commensal populations, notably an outgrowth of Clostridia spp., were sustained in chronic infection. Importantly, uninfected animals co-housed with infected mice display similar changes in commensal microflora but never display symptoms of cachexia, indicating that altered commensals are not sufficient to explain the cachexia phenotype alone. These studies indicate that Toxoplasma infection is a novel and robust model to study the immune-metabolic interactions that contribute to chronic cachexia development, pathology and potential reversal.

The evolutionary atavistic endotoxin and neoplastic growth

A hypothesis on the potential role of atavistic endotoxin in carcinogenesis is proposed. The presence of an antigen identical to the endotoxin of gram-negative bacteria in tumour cells is confirmed by IgM class natural specific antibodies to endotoxin (IgMNAE) in rats by immunizing them with rat tumour tissue extracts. Rat normal tissue extracts do not increase the endogenous level of natural immunity to endotoxin, indicating the absence of a foreign antigen such as endotoxin in normal cells which are naturally devoid also of other parasitic features such as invasiveness and metastases, whereas tumour cells, during a prolonged latent period of carcinogenesis, acquire resistance to harmful factors, lose most of their genetic, antigenic, morphological and biochemical properties and become parasitic so as to survive in unfavourable conditions. With the regression of the mentioned properties of cells to the atavistic parasitic state, the synthesis of dormant endotoxin is activated together with an enhanced expression of evolutionary resistance-related genes and oncogenes. Atavistic endotoxin, produced and secreted by proliferating tumour cells, should cause chronic cachexia and septic states in cancer patients, similarly as in cases of endotoxemic septic shock where the endotoxin of gram-negative bacteria is the main pathogenic factor. Thus, the implications of the hypothesis indicate the diagnostic as well as prognostic and preventive significance of evolutionary atavistic endotoxin and also of endotoxin from gram-negative bacteria in human cancers. Natural specific antibodies to endotoxin can be helpful in creating new immunotherapeutic methods.

Altered energy balance and cytokine gene expression in a murine model of chronic infection with Toxoplasma gondii.

The temporal pattern of changes in energy balance and cytokine mRNA expression in spleen and brain were examined in a mouse model of infection with Toxoplasma gondii. During days 1-7 postinfection, food intake was unaltered, but energy expenditure was significantly increased, and this was associated with elevated tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-5, and interferon (IFN)-gamma. The hypermetabolic state persisted during subsequent anorexia, whose onset coincided with elevated IL-2, and at the end of the acute phase of cachexia, the dual anorexic and hypermetabolic states were associated with the cytokines examined: TNF-alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, and IFN-gamma. In the chronic phase of the infection, the mice showed either partial weight recovery (gainers) or no weight regain (nongainers). The infected gainers, though still hypophagic, were no longer hypermetabolic, and their cytokine mRNA was no longer elevated, except for TNF-alpha and IL-10. In contrast, the infected nongainers continued to show both anoroxia and hypermetabolism, which were associated with elevations in all cytokines examined and particularly those of the TH2 profile (IL-4 and IL-5) and IL-6. Taken together, these studies reveal a distinct pattern of cytokine mRNA expression underlying 1) hypermetabolism vs. anorexia, 2) acute vs. chronic cachexia, and 3) stable weight loss vs. partial weight recovery.

Metabolic effects of cachectin/tumor necrosis factor are modified by site of production. Cachectin/tumor necrosis factor-secreting tumor in skeletal muscle induces chronic cachexia, while implantation in brain induces predominantly acute anorexia.

We have developed a murine model of wasting by injecting intracerebrally cells which continuously secrete h-cachectin/TNF (CHO-TNF) to: (a) determine the effects of cachectin/TNF produced continuously in the central nervous system (CNS), and (b) compare the metabolic effects of cachectin/TNF-secreting tumor in the brain to the cachexia caused by CHO-TNF tumor in peripheral tissue (IM). Intracerebral CHO-TNF tumors produced increased serum h-cachectin/TNF levels with lethal hypophagia and weight loss (mean survival time of 11 d); these changes were not observed in association with nonsecretory control brain tumors. The metabolic consequences of intracerebral cachectin/TNF production were indistinguishable from acute, lethal starvation: whole-body lipid content was decreased significantly but protein was conserved. Although intramuscular cachectin/TNF-secreting tumors caused similar increases of serum h-cachectin/TNF levels, profound anorexia did not develop; wasting developed after a longer period of tumor burden (50 d) with classical signs of cachexia (i.e., anemia and depletion of both protein and lipid). These studies provide a reproducible animal model of site-specific cytokine production and suggest that, regardless of serum levels, cachectin/TNF produced locally in brain influences both the rate of development of wasting and its net metabolic effects.

Some unusual features of mycobacteriosis in the cichlid fish Oreochromis mossambicus

Adult, aquarium-reared Oreochromis mossambicus (Tilapia mossambica), which were naturally infected with Mycobacterium marinum, displayed non-healing skin ulcers and other clinical signs considered to be typical of piscine mycobacteriosis. However, in addition, they frequently had melanotic foci in the skin and spleen, due to the presence of pigment cells surrounding the cutaneous and splenic inflammation. Such melanotic foci have never been reported in response to mycobacteriosis. All fish also have variable numbers of melanomacrophages which appeared to replace pancreatic acini. The relationship of the pancreatic melanomacrophages to the pathogenesis of mycobacteriosis is uncertain, but such lesions may have contributed to the chronic cachexia associated with this case.

Cachectin: a hormone that triggers acute shock and chronic cachexia.

Septic shock and invasive infection are diseases caused by humoral mediators of both exogenous and endogenous origin. The search for and identification of these factors has led to the discovery and molecular cloning of cachectin. This pyrogenic cytokine is identical to tumor necrosis factor (TNF) and, when released into the circulation, causes profound shock and multiple organ injury. Cachectin antibodies protect against the lethal effects of mice given endotoxin and baboons given E. coli, a result suggesting that this mediator is both necessary and sufficient to provoke septic shock. Cachectin is produced in humans after endotoxin infusion; the infusion of small doses of TNF is associated with fever, rigors, headache, and hypotension. Septicemic patients also produce cachectin, and during meningococcal infection, patients with the highest serum levels of cachectin die. Chronic cachectin production causes a potentially lethal syndrome of cachexia, anemia, and protein and lipid wasting. Future investigation is being directed toward the development of cachectin antibodies for use in treating the humorally mediated systemic complications of infectious disease.

PLASMA CELL TUMORS OF THE NASAL AND NASOPHARYNGEAL MUCOSA

Most of the textbooks on pathology make little if any mention of plasma cell tumors except those occurring in the bone marrow, the plasma cell myelomas. Ewing, 1 however, in his work on neoplastic diseases, discussed extramedullary plasma cell tumors, and stated that in a rather numerous group of tumors of the mucous membranes and lymph nodes the growth is composed exclusively of plasma cells. He said: Considering their comparative frequency and rather peculiar clinical course, they have received inadequate attention. The growths occur chiefly in the nasopharynx, alveolar borders, tongue, lips, and cervical lymph nodes, but they have been observed in many other regions. The course is relatively slow, but they may recur after extirpation and become associated with a chronic cachexia. They are commonly classed as lymphosarcoma, but being, as a rule, benign processes with very indistinct neoplastic properties, it is highly important that they should be separated

PATHOLOGY OF THE HYPOPHYSIS

In 1914, Simmonds1described a pathologic condition which he designated hypophysial cachexia. The patient was a woman, the anterior lobe of whose hypophysis was transformed into a mass of cell-poor and elastin-poor connective tissue with small capillary spaces containing a few cords or small groups of round cells. He believed that the lesion was the result of a septic necrosis of the hypophysis due to a severe puerperal sepsis occurring eleven years before death. In 1916, Fraenkel2reported an essentially similar case. Simmonds3later added four cases, and, in 1923, Jakob4described two more. These eight cases showed a definite clinical picture characterized by chronic cachexia with marked atrophy of the internal organs, as in senility; wrinkling of the skin of the face; loss of the teeth; stoppage of menstruation (all of these patients were women), and loss of axillary and pubic hair. The one constant