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Obesity and type 2 diabetes (T2D) remain major global healthcare challenges and developing therapeutics necessitate using nonhuman primate models. Here, we present transcriptomic and proteomic analyses of all the major organs of cynomolgus monkeys with spontaneous obesity or T2D in comparison to healthy controls. Molecular changes occur predominantly in the adipose tissues of individuals with obesity, while extensive expression perturbations among T2D individuals are observed in many tissues, such as the liver, kidney, brain, and heart. Immune response-related pathways are upregulated in obesity and T2D, whereas metabolism and mitochondrial pathways are downregulated. Incorporating human single-cell RNA sequencing findings corroborates the role of macrophages and monocytes in obesity. Moreover, we highlight some potential therapeutic targets including SLC2A1 and PCSK1 in obesity as well as SLC30A8 and SLC2A2 in T2D. Our findings provide insights into tissue-specific molecular foundations of obesity and T2D and reveal the mechanistic links between these two metabolic disorders.

Gastric cancer is the second most common cause of cancer-associated death in Asia. The incidence and mortality rates of gastric cancer have markedly increased in the past few decades. Therefore, the identification of novel gastric cancer biomarkers are needed to determine prognosis. The role of serpin peptidase inhibitor clade A member 1 (SERPINA1) has been studied in several types of cancer; however, little is known about its mechanism in gastric cancer. The present study aimed to evaluate SERPINA1 as a potential prognostic biomarker in gastric cancer and to identify the possible mechanisms underlying its action. The expression levels of SERPINA1 in several gastric cancer datasets were assessed, and it was identified that high expression of SERPINA1 was associated to poor clinical outcomes. Furthermore, using histochemical analysis, western blotting, apoptotic analysis, gap closure and invasion assays in cell lines, it was reported that silencing of SERPINA1 inhibited the formation of cellular pseudopodia and did not affect apoptosis, but promoted cell cycle S-phase entry. In addition, overexpression of SERPINA1 increased the migration and invasion of gastric cancer cells, whereas knockdown of SERPINA1 decreased these functions. Moreover, SERPINA1 overexpression increased the protein levels of SMAD4, which is a key regulator of the transforming growth factor (TGF)-β signaling pathway. Taken together, the present data demonstrated that SERPINA1 promotes gastric cancer progression through TGF-β signaling, and suggested that SERPINA1 may be a novel prognostic biomarker from tumor tissue biopsy in gastric cancer.

Autophagy is a type of cellular catabolic degradation process that occurs in response to nutrient starvation or metabolic stress, and is a valuable resource for highly proliferating cancer cells. Autophagy also facilitates the resistance of cancer cells to antitumor therapies. However, the involvement of autophagy in regulating CXCL10 expression in gastric cancer (GC) cells and T lymphocyte migration remains unclear. In this study, we aimed to investigate the effect of autophagy inhibition on CXCL10 expression and T lymphocyte infiltration in GC and elucidate the underlying mechanism. Analysis of public databases revealed a positive correlation between CXCL10 expression and both prognosis of patients with GC and the expression profile of T lymphocyte markers in the GCs. Chemotaxis and spheroid infiltration assays revealed that CXCL10 induced T lymphocyte migration and infiltration into GC spheroids, an in vitro three-dimensional cell culture model. In addition, in vitro autophagy inhibition in GC cells increased CXCL10 expression under both normal and hypoxic culture conditions. Further investigation on the underlying mechanism showed that in vitro autophagy inhibition suppressed the JNK signaling pathway and further enhanced CXCL10 expression in GC cells. Collectively, our results provide novel insights for understanding the role of autophagy in regulation of intra-tumor immunity.

In present study, the potential drug delivery of nanoformulations was validated via the comparison of cellular uptake of nanoparticles in various cell lines and in vivo pulmonary cellular uptake in intratracheally (IT) dosed rat model. Nanoparticles were prepared by a bench scale wet milling device and incubated with a series of cell lines, including Caco-2, RAW, MDCK and MDCK transfected MDR1 cells. IT dosed rats were examined for the pulmonary cellular uptake of nanoparticles. The processes of nanoparticle preparation did not alter the crystalline state of the material. The uptake of nanoparticles was observed most extensively in RAW cells and the least in Caco-2 cells. Efflux transporter P-gp did not prevent cell from nanoparticles uptake. The cellular uptake of nanoparticles was also confirmed in bronchoalveolar lavage (BAL) fluid cells and in bronchiolar epithelial cells, type II alveolar epithelial cells in the intratracheally administrated rats. The nanoparticles uptake in MDCK, RAW cells and in vivo lung epithelial cells indicated the potential applications of nanoformulation for poorly soluble compounds. The observed limited direct uptake of nanoparticles in Caco-2 cells suggests that the improvement in oral bioavailability by particle size reduction is via increased dissolution rate rather than direct uptake.

To date the most common forms of biologics in development have been mAb, recombinant proteins, and vaccines. However, numerous new modalities are now being developed. One of these new modalities is bispecific antibodies, which are able to recognize two distinct targets at the same time and might bridge two targets together, which presents an opportunity for therapeutic gains (such as bringing cancer cells within closer proximity to cytotoxic T lymphocytes).When one considers species selection, if both complementarity-determining regions (CDRs) do not have cross reactivity to the same species, one needs to understand how to appropriately assess the safety if the full pharmacological effect cannot be generated in one species. Therefore, these new biologic modalities offer great promise for the treatment of diseases but also challenges in developing the nonclinical toxicology testing paradigm to ensure the safety of the patients in the clinical trials. Keywords: antibody drug conjugates (ADCs); DNA vaccines; mAb; nonclinical safety testing programs; pharmacokinetics; stem cells; gene therapy