Therapeutic cooperation between auranofin,a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8^+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.     

Long-term surgical results for congenital aural atresia

Thirty-nine primary surgical cases for correction of congenital aural atresia were reviewed for complications and long-term hearing results. Hearing averages of 25 dB for mild atresia, 40 dB for moderate atresia, and 46 dB for severe atresia were obtained. Serviceable hearing was achieved in 64% of the cases. The two most frequent complications were stenosis and recurrent infections of the cavity and canal skin, with an incidence of 33% and 31%, respectively. Use of split-thickness instead of full-thickness skin graft was associated with fewer complications. The goal of this review is also to share the experience of the senior author in the management of this complex problem.     

Opportunistic intracranial infection in AIDS detection by technetium-99m DTPA brain scintigraphy

Radionuclide brain scintigraphy and computed tomography (CT) demonstrated cerebral lesions in two patients with acquired immunodeficiency disease syndrome (AIDS) complicated by opportunistic infection of the brain. In the detection of these cerebral lesions, [99mTc]DTPA radionuclide scintigraphy was as reliable as CT. Since malignant lymphoma involving the brain has been seen with increasing frequency in patients with AIDS, the positive brain scan alone is nonspecific and should be correlated appropriately with the clinical setting.     

Mild gentamicin nephrotoxicity reduces the progression of chronic adriamycin nephrosis

SUMMARY: The effect of mild acute tubular injury on the progression of tubulointerstitial fibrosis was studied in pair-fed uninephrectomized male Wistar rats with established adriamycin nephrosis ( n = 34). Rats were stratified into three groups according to endogenous creatinine clearance (CrCl), proteinuria (Upr) and body weight (BW): (i) group 1 (Fe, n = 12) received a single intraperitoneal injection of ferric nitrilotriacetate (5 mg Fe/kg BW); (ii) group 2 (G, n = 10) three daily subcutaneous injections of gentamicin (60 mg/kg BW) and; (iii) group 3 (C, n = 12) saline injections. Serial CrCl (day 2, day 5, weeks 2, 4, 6 and 8) and renal histology (week 8) were examined following administration of nephrotoxin. CrCl was reduced on d2 (Fe: 0.78 ± 0.23 mL/min; mean ± SD) and day 5 (G: 0.91 ± 0.36 mL/min) as compared with C (1.22 ± 0.12 mL/min; P <0.05). There was no change in the serum creatinine and functional recovery occurred by d5 (Fe) and week 2 (G). Upr decreased transiently in G at week 2 (G: 482 ± 208 mg/day vs C: 716 ± 233; P = 0.05) despite similar food intake, baseline Upr and CrCl. At week 8, CrCl in Fe (0.84 ± 0.40 mL/min) was similar to C (0.84 ± 0.58 mL/min), whereas in G it remained stable (1.27 ± 0.39 mL/min; P <0.05). By morphometric analysis, mean relative interstitial volume (RIV) and glomerulosclerosis (GS) in Fe (RIV: 28.5 ± 13.4%; GS: 10.3 ± 12.3%) was no different to C (RIV: 24.5 ± 12.5%; GS: 20.9 ± 20.0%), whereas both parameters were reduced in G (RIV: 14.1 ± 8.1%; GS: 4.0 ± 4.8%; P <0.05). Mild gentamicin nephrotoxicity therefore reduced the progression of adriamycin nephrosis. the mechanism of this finding is unclear, but it may relate to altered glomerular and tubular cell handling of protein.