Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC).

TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50-60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway. Here, we investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in TP53 mutant cell lines and xenograft models. Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models. Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. Our studies demonstrated that everolimus inhibits the growth of TP53 mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling.

Opicapone for the Treatment of Parkinson's Disease "Off" Episodes: Pharmacology and Clinical Considerations.

Parkinson's disease (PD) is a common neurodegenerative disorder. It is also the fastest-growing neurodegenerative disorder and has more than doubled between 1990 and 2016. Parkinson's disease causes significant morbidity and disability from motor dysfunction, sleep disturbances, and cognitive and psychiatric symptoms. This paper reviews recent evidence in the treatment of PD "off" episodes with the novel drug opicapone, including its efficacy, safety, and clinical indications. Opicapone is a novel, peripherally acting catechol-O-methyl transferase (COMT) inhibitor used as adjunctive therapy to carbidopa/levodopa for treatment and prevention of "off" episodes. It has been approved for use as an adjunct to levodopa since 2016 in Europe and has recently (April 2020) gained FDA approval for use in the USA. By inhibiting COMT, opicapone slows levodopa metabolism and increases its availability. Several clinical studies demonstrated significant improvement in treatment efficacy and reduction in the duration of "off" episodes The main side effect demonstrated was dyskinesia, mostly with the 100 mg dose, which is higher than the approved, effective dose of 50 mg.

Primary Renal Carcinoid: Two Rare Cases at a Single Center.

Renal carcinoid tumors are exceedingly rare. These neuroendocrine masses are most frequently found in the gastrointestinal and respiratory tracts. A renal carcinoid tumor has only been documented in around 100 cases. In this article, we report two additional cases in female patients ages 53 and 63. Both tumors were found incidentally on computed tomography scans. Both women underwent radical nephrectomies. Neither has shown evidence of metastasis nor relapse to date; however, the 63-year-old woman was lost to follow-up. In conclusion, upon discovery of the asymptomatic renal mass, renal carcinoid should be a consideration in the differentiation, and if suspected, may be treated with radical nephrectomy as was done in our hospital.

A direct comparison of mouse and human intestinal development using epithelial gene expression patterns.

BACKGROUND: Preterm infants are susceptible to unique pathology due to their immaturity. Mouse models are commonly used to study immature intestinal disease, including necrotizing enterocolitis (NEC). Current NEC models are performed at a variety of ages, but data directly comparing intestinal developmental stage equivalency between mice and humans are lacking. METHODS: Small intestines were harvested from C57BL/6 mice at 3-4 days intervals from birth to P28 (n = 8 at each age). Preterm human small intestine samples representing 17-23 weeks of completed gestation were obtained from the University of Pittsburgh Health Sciences Tissue Bank, and at term gestation during reanastamoses after resection for NEC (n = 4-7 at each age). Quantification of intestinal epithelial cell types and messenger RNA for marker genes were evaluated on both species. RESULTS: Overall, murine and human developmental trends over time are markedly similar. Murine intestine prior to P10 is most similar to human fetal intestine prior to viability. Murine intestine at P14 is most similar to human intestine at 22-23 weeks completed gestation, and P28 murine intestine is most similar to human term intestine. CONCLUSION: Use of C57BL/6J mice to model the human immature intestine is reasonable, but the age of mouse chosen is a critical factor in model development.

Intraoperative High-Frequency Jet Ventilation Is Equivalent to Conventional Ventilation During Patent Ductus Arteriosus Ligation.

BACKGROUND: Patent ductus arteriosus (PDA) treatment is typically pharmacologic, but if unsuccessful, surgical ligation is commonly performed. High-frequency jet ventilation (HFJV) is used at the University of Iowa Stead Family Children's Hospital for extremely low birth weight infants. Historically, neonates requiring PDA ligation were temporarily transferred to conventional ventilation (CV) prior to surgery. OBJECTIVE: The objective of this study was to determine whether conversion was necessary. METHODS: This retrospective cohort analysis examined outcomes following PDA ligation from 2014 to 2016 at the University of Iowa's Stead Family Children's Hospital. Infants who were transferred to CV prior to surgery and returned to HFJV postprocedure are referred to as the CV cohort. The HFJV cohort infants remained on HFJV throughout. RESULTS: We found no significant increases in morbidity or mortality with the use of intraoperative HFJV and potentially show some benefit through greater reduction in serum CO2. CONCLUSIONS: Mode of ventilation during PDA ligation does not affect surgical morbidity or mortality or short-term clinical outcomes. Conversion to CV from HFJV is not necessary.