The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer.

The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8+ T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.

Anti-MDA5 Associated Clinically Amyopathic Dermatomyositis With Rapidly Progressive Interstitial Lung Disease.

Anti-melanoma differentiation-associated protein 5 (anti-MDA5) associated clinically amyopathic dermatomyositis (CADM) is a rare entity that is frequently associated with rapidly progressive interstitial lung disease. The disease is characterized by its association with a distinct myositis specific antibody, the lack of muscle involvement seen with other inflammatory myopathies, and a strong correlation with the development of rapidly progressive interstitial lung disease. Diagnosis is based on clinical findings and the presence of autoantibodies. Management generally involves combination immunosuppression therapy. However, the disease course is often aggressive and lends a poor prognosis. We report a case of a healthy 55-year-old male who presented with dyspnea, dry cough, and joint pain for 1 month. The patient was diagnosed with anti-MDA5 associated CADM with interstitial lung disease after a complete rheumatological workup found elevated titers of MDA5 antibodies and computed tomography of the chest without contrast revealed radiographic evidence of interstitial lung involvement. Disease course was complicated by the development of Pneumocystis pneumonia as a result of profound immunosuppression from combination immunosuppressant therapy. Our patient eventually succumbed to his illness approximately 10 weeks following initial symptom onset. This case highlights the aggressive nature of the disease and the challenges in management. Further research is warranted to establish more effective therapeutic options.

Spontaneous Subcutaneous Emphysema and Pneumomediastinum in COVID-19 Patients: An Indicator of Poor Prognosis?

BACKGROUND Novel Coronavirus 2019 (COVID-19) has been in the spotlight since the first cases were reported in December 2019. COVID-19 has been found to cause severe acute respiratory distress syndrome and, more uncommonly, subcutaneous emphysema and pneumomediastinum. We present a case series of 3 patients with COVID-19 infection managed in the Intensive Care Unit and found to have subcutaneous emphysema and pneumomediastinum on chest imaging. CASE REPORT We present a case series of 3 men, ages 36, 47, and 78 years, diagnosed with COVID-19 via RT-PCR, found to have severe acute respiratory distress syndrome, and managed in the Intensive Care Unit. Two patients described in this case series were mechanically ventilated on low positive end-expiratory pressures and developed subcutaneous emphysema and pneumomediastinum on chest imaging, and 1 patient developed subcutaneous emphysema prior to intubation. Each of these patients had a more eventful hospital course and worse outcomes than most COVID-19 infected patients. CONCLUSIONS Subcutaneous emphysema and pneumomediastinum in COVID-19 patients have been rarely reported and is poorly understood. In our institution, we have found the diagnosis of subcutaneous emphysema and pneumomediastinum in COVID-19 patients is associated with unfavorable outcomes and worse prognosis.