Upper airway stimulation as an alternative to maxillomandibular advancement for obstructive sleep apnoea in a patient with dentofacial deformity: case report with literature review.

Obstructive sleep apnoea (OSA) is characterized by repeated upper airway collapse leading to oxygen desaturation resulting in cardiovascular and neurocognitive sequelae. Upper airway surgeries such as palatopharyngoplasty, tongue base surgery, and maxillomandibular advancement can improve patient tolerance of continuous positive airway pressure, quality of life, and the severity of OSA. Upper airway stimulation (UAS) of the hypoglossal nerve is a contemporary US Food and Drug Administration-approved treatment modality for OSA with a fundamentally different mechanism. We report the case of a 65-year-old male with a high body mass index, hypertension, diabetes, dentofacial deformity, and severe OSA. He presented with a respiratory distress index (RDI) of 89.1 events per hour, apnoea-hypopnoea index (AHI) of 82.7 events per hour, and minimum oxygen saturation of 75%. He chose to undergo UAS. Initially, complete concentric collapse of the velum was found during drug-induced sedation endoscopy, which was converted by palatopharyngoplasty to meet inclusion criteria for UAS. The patient achieved surgical cure with postoperative RDI and AHI of 2 events per hour with minimum oxygen saturation of 83%, and resolution of daytime somnolence. UAS is an effective surgical option to broaden the surgeon's ability to treat OSA, especially if facial skeletal surgery is contraindicated or declined by the patient with dentofacial deformity.

API5 confers cancer stem cell-like properties through the FGF2-NANOG axis.

Immune selection drives the evolution of tumor cells toward an immune-resistant and cancer stem cell (CSC)-like phenotype. We reported that apoptosis inhibitor-5 (API5) acts as an immune escape factor, which has a significant role in controlling immune resistance to antigen-specific T cells, but its functional association with CSC-like properties remains largely unknown. In this study, we demonstrated for the first time that API5 confers CSC-like properties, including NANOG expression, the frequency of CD44-positive cells and sphere-forming capacity. Critically, these CSC-like properties mediated by API5 are dependent on FGFR1 signaling, which is triggered by E2F1-dependent FGF2 expression. Furthermore, we uncovered the FGF2-NANOG molecular axis as a downstream component of API5 signaling that is conserved in cervical cancer patients. Finally, we found that the blockade of FGFR signaling is an effective strategy to control API5high human cancer. Thus, our findings reveal a crucial role of API5 in linking immune resistance and CSC-like properties, and provide the rationale for its therapeutic application for the treatment of API5+ refractory tumors.

The siRNA cocktail targeting interleukin 10 receptor and transforming growth factor-ß receptor on dendritic cells potentiates tumour antigen-specific CD8(+) T cell immunity.

Dendritic cells (DCs) are promising therapeutic agents in the field of cancer immunotherapy due to their intrinsic immune-priming capacity. The potency of DCs, however, is readily attenuated immediately after their administration in patients as tumours and various immune cells, including DCs, produce various immunosuppressive factors such as interleukin (IL)-10 and transforming growth factor (TGF)-ß that hamper the function of DCs. In this study, we used small interfering RNA (siRNA) to silence the expression of endogenous molecules in DCs, which can sense immunosuppressive factors. Among the siRNAs targeting various immunosuppressive molecules, we observed that DCs transfected with siRNA targeting IL-10 receptor alpha (siIL-10RA) initiated the strongest antigen-specific CD8(+) T cell immune responses. The potency of siIL-10RA was enhanced further by combining it with siRNA targeting TGF-ß receptor (siTGF-ßR), which was the next best option during the screening of this study, or the previously selected immunoadjuvant siRNA targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or Bcl-2-like protein 11 (BIM). In the midst of sorting out the siRNA cocktails, the cocktail of siIL-10RA and siTGF-ßR generated the strongest antigen-specific CD8(+) T cell immunity. Concordantly, the knock-down of both IL-10RA and TGF-ßR in DCs induced the strongest anti-tumour effects in the TC-1 P0 tumour model, a cervical cancer model expressing the human papillomavirus (HPV)-16 E7 antigen, and even in the immune-resistant TC-1 (P3) tumour model that secretes more IL-10 and TGF-ß than the parental tumour cells (TC-1 P0). These results provide the groundwork for future clinical development of the siRNA cocktail-mediated strategy by co-targeting immunosuppressive molecules to enhance the potency of DC-based vaccines.

Machine learning methods applied to pharmacokinetic modelling of remifentanil in healthy volunteers: a multi-method comparison.

This study compared the blood concentrations of remifentanil obtained in a previous clinical investigation with the predicted remifentanil concentrations produced by different pharmacokinetic models: a non-linear mixed effects model created by the software NONMEM; an artificial neural network (ANN) model; a support vector machine (SVM) model; and multi-method ensembles. The ensemble created from the mean of the ANN and the non-linear mixed effects model predictions achieved the smallest error and the highest correlation coefficient. The SVM model produced the highest error and the lowest correlation coefficient. Paired t-tests indicated that there was insufficient evidence that the predicted values of the ANN, SVM and two multi-method ensembles differed from the actual measured values at alpha = 0.05. The ensemble method combining the ANN and non-linear mixed effects model predictions outperformed either method alone. These results indicated a potential advantage of ensembles in improving the accuracy and reducing the variance of pharmacokinetic models.

Tissue-specific expression of the subunits of chick 20S proteasomes.

The subunit patterns of the proteasomes, that were purified from muscle, liver and brain, were found to be significantly different from one another. Furthermore, the proteasomes from adult and embryonic tissues of the same types also differed from each other in their subunit patterns. In addition, the specific activities of the purified proteasomes for peptide-cleavage, but not for casein-hydrolysis, appeared to be varied among the enzymes isolated from the different tissues. Thus, expression of a large number of proteasome subunits appears to be tissue-specific and under developmental control, although its relation with the multicatalytic activities of the proteasomes remains unclear.

Developmental regulation of proteolytic activities and subunit pattern of 20 S proteasome in chick embryonic muscle.

The proteolytic activities of the 20 S proteasome were found to change in their levels during the development of chick embryonic muscle. The peptide-cleaving activities against N-succinyl-Leu-Leu-Val-Tyr-7-amido-4-methylcoumarin and N-benzyloxycarbonyl-Ala-Arg-Arg-4-methoxy-beta-naphthylamide gradually decreased with the time of development. On the other hand, the casein-degrading activity in the presence of poly-L-lysine markedly increased from embryonic day 11 and reached a maximal level by day 17. These changes appeared to be tissue-specific because little or no change in any of the proteolytic activities was observed with developing embryonic brain, while dramatic alterations occurred in the extents of the peptide hydrolyses in liver. Furthermore, a number, but not all, of the proteasome subunits in embryonic muscle were changed in their amounts during the development. These results suggest that the alterations in the proteasome activities and subunit pattern are developmentally regulated and may be correlated.

Effects of leucine on in vitro protein synthesis and degradation in rat skeletal muscles.

Weanling rats were used to examine the role of leucine in in vitro protein turnover in skeletal muscles. In three experiments, rats were subjected to 24 or 72 hours of food deprivation or 5 days of consuming a protein-free diet or injection of streptozotocin. The soleus and extensor digitorum longus muscles were removed and utilized for measures of protein synthesis or degradation by using the isolated, incubated muscle technique of Li et al. These experiments demonstrate that supplementation of the incubation media with 0.5 mM leucine stimulates protein synthesis in these catabolic muscles and that during total starvation the stimulation decreases as the severity of the condition increases. Leucine supplementation failed to affect protein degradation in these skeletal muscles. This study demonstrates that the branched-chain amino acid leucine has the potential to stimulate protein synthesis in skeletal muscles, at least under specific catabolic conditions, but does not affect protein degradation in skeletal muscles under the conditions studied.