Polycystic kidney disease (PKD) is characterized by slowly expanding renal cysts that damage the kidney, typically resulting in renal failure by the fifth decade. The most common cause of death in these patients, however, is cardiovascular disease. Expanding cysts in PKD induce chronic kidney injury that is accompanied by immune cell infiltration, including macrophages, which we and others have shown can promote disease progression in PKD mouse models. Here, we show that monocyte chemoattractant protein-1 [MCP-1/chemokine (C-C motif) ligand 2 (CCL2)] is responsible for the majority of monocyte chemoattractant activity produced by renal PKD cells from both mice and humans. To test whether the absence of MCP-1 lowers renal macrophage concentration and slows disease progression, we generated genetic knockout (KO) of MCP-1 in a mouse model of PKD [congenital polycystic kidney ( cpk) mice]. Cpk mice are born with rapidly expanding renal cysts, accompanied by a decline in kidney function and death by postnatal day 21. Here, we report that KO of MCP-1 in these mice increased survival, with some mice living past 3 mo. Surprisingly, however, there was no significant difference in renal macrophage concentration, nor was there improvement in cystic disease or kidney function. Examination of mice revealed cardiac hypertrophy in cpk mice, and measurement of cardiac electrical activity via ECG revealed repolarization abnormalities. MCP-1 KO did not affect the number of cardiac macrophages, nor did it alleviate the cardiac aberrancies. However, MCP-1 KO did prevent the development of pulmonary edema, which occurred in cpk mice, and promoted decreased resting heart rate and increased heart rate variability in both cpk and noncystic mice. These data suggest that in this mouse model of PKD, MCP-1 altered cardiac/pulmonary function and promoted death outside of its role as a macrophage chemoattractant.
Neuroinflammation has been implicated in neurodegenerative diseases and acute brain injuries such as stroke. Monocyte chemotactic protein-1-induced protein-1 (Mcpip1) is a multifunction protein known to have pro-apoptotic or anti-apoptotic actions depending on the nature of experimental settings. However, its role in brain damage after asphyxia in the developing brain has not been studied. We, therefore, explored the role of Mcpip1 in brain injury after hypoxic-ischemia in neonatal mice. At postnatal day 7, Mcpip1-deficient and wild type mice underwent a carotid artery ligation and exposure to hypoxia (8% oxygen). After hypoxic-ischemic insult, we determined the time-course of apoptotic cell death and the expression levels of genes encoding proinflammatory factors. The impact of Mcpip1 on long-term brain damage was assessed 1 week post-hypoxic-ischemia by cresyl violet staining. We found caspase-3 activity was significantly increased in the ipsilateral brain tissues within 12–24 h after hypoxic-ischemia. There was a marked increase in the levels of mRNA transcripts encoding Mcpip1, TNFα, and CCL2 in the ipsilateral brain tissues 6–48 h after hypoxic-ischemia. We found hypoxic-ischemia-induced caspase-3 activity and the levels of the proinflammatory genes were attenuated in Mcpip1-knockout mice compared to wild type mice. Histological assessment revealed that hypoxic-ischemia-induced brain tissue loss was significantly attenuated in the hippocampus of Mcpip1-knockout mice than that of wild type mice (9.0 ± 5.6% vs. 33.9 ± 11.0%, P < 0.05). Our data suggest that Mcpip1 contributes to acute and delayed brain damage, in part, via regulation of neuroinflammation after hypoxic-ischemic insult in the developing mouse brain.
Oral mucositis is a painful inflammatory response that can lead to infection, cachexia, and therapy termination. This immune-related adverse event (IRAE) has been well documented within the newly developing field of immunotherapy. This case series presents three patients, aged 73 to 81 years, who were undergoing treatment with programmed death-1 (PD-1) immunotherapy for cancer; each patient developed grade III mucositis, one after the fourth cycle and two after the seventh. All three patients had no prior history of oral pathology, yet each patient reported ulcerated and inflamed oral mucosa that was swollen and painful. These lesions involved various locations within the oral cavity and caused irritation to the point of dysphagia and odynophagia. Conservative treatments such as oral anesthetic and mouthwashes with antimicrobial properties had minimal effects. Each patient thereafter was started on systemic glucocorticoids in addition to the local treatments. The initiation of a systemic treatment resulted in a resolution of the oral lesions allowing each patient the option to return to their prior immunotherapy.Mucositis is uncommon and has no standardized treatment. This case series emphasizes the debilitative result of immunotherapy-induced mucositis and illustrates the need for systemic glucocorticoids. While conservative treatments such as oral mouthwashes can be effective in treating the symptoms of mucositis, the initiation of high-dose steroids with a prolonged taper has been shown to treat the condition at its source. Early recognition of mucositis with prompt initiation of steroids has proven to be the effective mainstay treatment to relieve mucositis while limiting pauses in cancer treatment.
Acute promyelocytic leukemia (APL) is a subgroup of acute myeloid leukemia (AML), and while not a common form of cancer, it does make up a modest portion of acute leukemia. The genetic hallmark of APL is the t(15;17)(q24.1;q21.2) promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA) protein. We present the case of a patient who had undergone prior therapy for stage IIIC squamous cell carcinoma of the anorectal region with 5-fluorouracil, mitomycin C, and radiation and developed therapy-related acute promyelocytic leukemia about 18 months later. We also review the clinical features and management of APL while also highlighting that therapy-related APL, although uncommon, can develop from chemoradiation. The specific diagnosis of therapy-related APL is its own distinct diagnosis, but its treatment remains the same as primary APL.
With tattoo prevalence on the rise in all age groups, it is important to acknowledge that it is a potential cause of lymphadenopathy while simultaneously being aware of its mimicking presence in high-risk populations such as those with current or prior cancer diagnoses. The period of time between identification and diagnosis provides a great amount of stress and anxiety for patients and their families. We present a case of a patient who had multiple recurrences of an unknown primary and underwent multiple workups with no subsequent diagnosis. One particular workup yielded the diagnosis of tattoo-related lymphadenitis; while this particular occurrence was a benign finding, the extensive workup took a toll on the patient and his family as the fear of cancer progression with an allusive diagnosis continued to be a major factor in their lives.
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