Anti-neoplastic sulfonamides alter the metabolic homeostasis and disrupt the suppressor activity of regulatory T cells.

Regulatory T cells (Tregs) are essential to maintain self-tolerance and immune homeostasis but, as components of the tumor microenvironment (TME), are also a major barrier to effective cancer immunosurveillance and immunotherapy. FH535 and its derivative Y3 are two N-aryl-benzene-sulfonamides (NABs) that inhibit HCC cell proliferation and tumor progression. However, the impact of NABs on the immune cells in the TME is not yet known. Analyses of explanted livers from patients with hepatocellular carcinoma (HCC) showed that high levels of tumor-infiltrating Tregs were associated with poor tumor differentiation. These results lead us to investigate the immunomodulatory effects of NABs in regulatory and effector T cells. Exposure of primary human Tregs to NABs induced a rapid but temporary increase of cell expansion, a gradual disruption of suppressor activity, and concomitant bioenergetics and autophagic flux dysregulations. In contrast to Tregs, no gross effects were observed in effector T cells. Addition of Rapamycin prevented the functional decay of Tregs and restored their metabolic profile, suggesting that NAB effects require the integrity of the mTOR pathway. This study revealed the immunomodulatory properties of NABs with a preferential impact on Treg activity and provided novel insights into the anti-tumor potential of sulfonamides.

Severe acute kidney injury caused by decompression sickness syndrome.

Decompression sickness (DCS) occurs when divers are exposed to reduced barometric pressure during their ascent from depth. We report a case of DCS causing severe acute kidney injury (AKI) after an uneventful dive in which all decompression stops were made as instructed by a dive computer. A 26-year-old man presented with abdominal and bilateral flank pain ~ 24 hours after scuba diving to a depth of 23 m. Vitals and physical exam were unremarkable. Lab results revealed elevated serum creatinine at 2.3 mg/dL from a normal baseline and elevated blood urea nitrogen at 23 mg/dL. The patient was non-oliguric. Other biochemical parameters were unremarkable. Dipstick urinalysis showed presence of blood and 100 mg/dL proteinuria. Urine microscopy revealed hyaline casts and red blood cells ~ 16 - 30/HPF but no acanthocytes. Urine protein-to-creatinine ratio was 340 mg/g. Renal ultrasound showed normal sized kidneys with increased cortical echogenicity, and computed tomography of the abdomen/pelvis showed bilateral striated nephrogram with delayed excretion, both radiographic signs of acute tubular necrosis. The patient received isotonic IV fluids and 5 sessions of hyperbaric oxygen therapy. Symptomatic improvement was observed by day 3 of hospitalization with full recovery of kidney function after discharge. Due to a wide range of associated symptomology, a thorough and prompt evaluation is warranted in suspected cases of DCS, particularly if presentation is more than 24 hours following ascent.