Impact of opioid therapy on sleep and respiratory patterns in adults with advanced cancer receiving palliative care

Context. In advanced cancer, abnormal sleep patterns may contribute to poor quality of life, but the impact of opioidrelated sleep disorders has not been explored in detail in these patients

Identification of a selective inhibitor of murine intestinal alkaline phosphatase (ML260) by concurrent ultra-high throughput screening against human and mouse isozymes

Alkaline phosphatase (AP) isozymes are present in a wide range of species from bacteria to man and are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates in vitro. In humans, four AP isozymes have been identified-one tissue-nonspecific (TNAP) and three tissue-specific-named according to the tissue of their predominant expression: intestinal (IAP), placental (PLAP) and germ cell (GCAP) APs. Modulation of activity of the different AP isozymes may have therapeutic implications in distinct diseases and cellular processes. For instance, changes in the level of IAP activity can affect gut mucosa tolerance to microbial invasion due to the ability of IAP to detoxify bacterial endotoxins, alter the absorption of fatty acids and affect ectopurinergic regulation of duodenal bicarbonate secretion. To identify isozyme selective modulators of the human and mouse IAPs, we developed a series of murine duodenal IAP (Akp3-encoded dIAP isozyme), human IAP (hIAP), PLAP, and TNAP assays. High throughput screening and subsequent SAR efforts generated a potent inhibitor of dIAP, ML260, with specificity for the Akp3-, compared to the Akp5- and Akp6-encoded mouse isozymes

Critical deposition height for sustainable restoration via laser additive manufacturing

Laser material deposition based restoration of high-value components can be a revolutionary technology in remanufacturing. The deposition process induces residual stresses due to thermomechanical behavior and metallurgical transformations. The presence of tensile residual stresses in the deposited layer will compromise the fatigue life of the restored component. We have developed a novel fully coupled metallurgical, thermal and mechanical (metallo-thermomechanical) model to predict residual stresses and identified a critical deposition height, which ensures compressive residual stresses in the deposited layer. Any lower deposition height will result in tensile residual stresses and higher deposition height will result in excessive dilution (substrate melting). We have validated the model using neutron and micro-focus X-ray diffraction measurements. This study highlights that the critical deposition height corresponds to the minimum cooling rate during solidification. It addresses one of the major outstanding problems of additive manufacturing and paves a way for "scienceenabled-technology" solutions for sustainable restoration/remanufacturing

Discovery of Sulfonamidebenzamides as Selective Apoptotic CHOP Pathway Activators of the Unfolded Protein Response

Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded proteins within the endoplasmic reticulum (ER). An adaptive pathway facilitates the clearance of the undesired proteins; however, if overwhelmed, cells trigger apoptosis by upregulating transcription factors such as C/EBP-homologous protein (CHOP). A high throughput screen was performed directed at identifying compounds that selectively upregulate the apoptotic CHOP pathway while avoiding adaptive signaling cascades, resulting in a sulfonamidebenzamide chemotype that was optimized. These efforts produced a potent and selective CHOP inducer (AC₅₀ = 0.8 μM; XBP1 > 80 μM), which was efficacious in both mouse embryonic fibroblast cells and a human oral squamous cell cancer cell line, and demonstrated antiproliferative effects for multiple cancer cell lines in the NCI-60 panel