The induction of interferon-stimulated genes by signal transducer and activator of transcription (STAT) proteins, is a critical host defence to fight virus infections. Here, a highly expressed poxvirus protein 018 is shown to inhibit IFN-induced signalling by binding the SH2 domain of STAT1 to prevent STAT1 association with an activated IFN receptor. Despite the presence of additional inhibitors of IFN-induced signalling, a poxvirus lacking 018 was attenuated in mice. The 2.0-angstrom crystal structure of the 018:STAT1 complex reveals a mechanism for a high-affinity, pTyr-independent mode of binding to an SH2 domain. Furthermore, the STAT1 binding motif of 018 shows sequence similarity to the STAT1-binding proteins from Nipah virus, which like 018, block the association of STAT1 with an IFN receptor. Taken together, these results provide detailed mechanistic insight into a potent mode of STAT1 antagonism, found to exist in genetically diverse virus families.
Coprophagia or the ingestion of faeces has been associated with medical conditions (seizure disorders, cerebral atrophy and tumours) and psychiatric disorders (mental retardation, alcoholism, depression, obsessive compulsive disorder, schizophrenia, fetishes, delirium and dementia). The case of a woman in her 30s presenting with coprophagia and psychotic symptoms following hypoxic brain injury is reported. The case is discussed and literature is reviewed. We investigate cariprazine, a relatively new atypical antipsychotic for treating coprophagia, associated with psychotic symptoms. Psychiatric evaluation revealed cognitive dysfunction and psychotic symptoms. Physical examination and laboratory evaluation were unremarkable. She was treated with haloperidol resulting in resolution of coprophagia. Attempts at switching to alternative antipsychotics, due to side effects, resulted in recurrence of coprophagia. Subsequent relapses required higher doses of haloperidol for remission of coprophagia and psychotic symptoms. She finally responded to cariprazine. While firm conclusions are not possible from the experience of a single case, we suggest cariprazine may also be a treatment option for coprophagia, particularly in patients with psychotic symptoms.
Background/Aims The increasing use of immune checkpoint inhibitors (ICIs) underlies the importance of close monitoring and recognition of associated adverse events. We report a rare case of nivolumab-related peripheral vasculitis with digital gangrene and auto-amputation in a patient treated for mesothelioma. Methods A 69-year-old male with T4M0N0 pulmonary sarcoid mesothelioma was commenced on second-line Nivolumab therapy. 11 days later, he presented with worsening dyspnoea and dry cough. CTPA demonstrated new bilateral lower zone and peripheral predominant ground glass patchy consolidation consistent with acute pneumonitis. He sustained a significant clinical benefit from IV methylprednisolone and cessation of Nivolumab. 20 days after the pneumonitis episode, the patient re-presented with extremely tender, blue-black discoloration of the 2nd, 3rd and 4th fingers bilaterally, accompanied by localised sensory loss. Petechiae were also seen distributed across the digital pulp and nailbeds. Although bilateral, the left side was notably worse, with clear evidence of digital ischaemia and dry gangrene. Urine dipstix was bland. Immunology revealed normal C3/C4, ANCA and dsDNA serology, but mildly raised ANA (1.5). An echocardiogram excluded infective emboli. High dose IV methylprednisolone and iloprost infusion was commenced to treat ICI-associated peripheral vasculitis. Concurrently, dalteparin was required for a non-occlusive right subclavian venous thrombus. Nevertheless, his digital ischaemia progressed proximally to the left middle distal phalanx. MDT decision was made to avoid Cyclophosphamide given the infection risk. Sildenafil was introduced alongside a reduction regime of oral prednisolone. Unfortunately, the patient was subsequently hospitalised for acute PCP infection requiring high flow oxygen and intravenous antimicrobials. Following this stormy course, a slow but consistent and substantial clinical improvement was noted with respect to his digital ischaemia with minimal tissue loss. 7 months on, the patient’s digits remain free from ischaemia, infection and pain with good functional ability on Sildenafil treatment. Results Reports of PD-1 blockade-associated vasculitides mention ANCA-vasculitis, IgA vasculitis, leukocytoclastic vasculitis, eGPA and granulomatous vasculitis; however, drug-induced digit necrosis and auto-amputation is not widely reported. In this rare presentation of digital gangrene, immediate discontinuation of nivolumab treatment with initiation of high dose steroids and sildenafil, allowed eventual recovery of digits with limited auto-amputation and minimal sequelae. Management of nivolumab-associated vasculitis and pneumonitis required a multidisciplinary approach involving oncology, rheumatology, plastics and respiratory medicine. In the context of nivolumab discontinuation, the patient remains only on symptomatic treatment and follow up with no active cancer therapy meaning that prognosis is poor, in keeping with other reports of vasculitic reactions to nivolumab in cancer patients. Conclusion ICIs have revolutionised the management and outcomes across a range of malignancies. However, their mechanism can inadvertently induce undesired toxicity, the awareness of which is paramount. Disclosure M. Au: None. A. Faher: None. E. Htut: None.
Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
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