Precise healing of oral and maxillofacial wounds: tissue engineering strategies and their associated mechanisms.

Precise healing of wounds in the oral and maxillofacial regions is usually achieved by targeting the entire healing process. The rich blood circulation in the oral and maxillofacial regions promotes the rapid healing of wounds through the action of various growth factors. Correspondingly, their tissue engineering can aid in preventing wound infections, accelerate angiogenesis, and enhance the proliferation and migration of tissue cells during wound healing. Recent years, have witnessed an increase in the number of researchers focusing on tissue engineering, particularly for precise wound healing. In this context, hydrogels, which possess a soft viscoelastic nature and demonstrate exceptional biocompatibility and biodegradability, have emerged as the current research hotspot. Additionally, nanofibers, films, and foam sponges have been explored as some of the most viable materials for wound healing, with noted advantages and drawbacks. Accordingly, future research is highly likely to explore the application of these materials harboring enhanced mechanical properties, reduced susceptibility to external mechanical disturbances, and commendable water absorption and non-expansion attributes, for superior wound healing.

Microflow chemistry and its electrification for sustainable chemical manufacturing.

Sustainability is vital in solving global societal problems. Still, it requires a holistic view by considering renewable energy and carbon sources, recycling waste streams, environmentally friendly resource extraction and handling, and green manufacturing. Flow chemistry at the microscale can enable continuous sustainable manufacturing by opening up new operating windows, precise residence time control, enhanced mixing and transport, improved yield and productivity, and inherent safety. Furthermore, integrating microfluidic systems with alternative energy sources, such as microwaves and plasmas, offers tremendous promise for electrifying and intensifying modular and distributed chemical processing. This review provides an overview of microflow chemistry, electrification, their integration toward sustainable manufacturing, and their application to biomass upgrade (a select number of other processes are also touched upon). Finally, we identify critical areas for future research, such as matching technology to the scale of the application, techno-economic analysis, and life cycle assessment.

A multi-hit therapeutic nanoplatform for hepatocellular carcinoma: Dual stimuli-responsive drug release, dual-modal imaging, and in situ oxygen supply to enhance synergistic therapy.

Nanomedicine has been widely studied for the diagnosis and treatment of hepatocellular carcinoma (HCC). How to synthesize a nanoplatform possessing a high synergistic therapeutic efficacy remains a challenge in this emerging research field. In this study, a convenient all-in-one therapeutic nanoplatform (FTY720@AM/T7-TL) is designed for HCC. This advanced nanoplatform consists of multiple functional elements, including gold-manganese dioxide nanoparticles (AM), tetraphenylethylene (T), fingolimod (FTY720), hybrid-liposome (L), and T7 peptides (T7). The nanoplatform is negatively charged at physiological pH and can transit to a positively charged state once moving to acidic pH environments. The specially designed pH-responsive charge-reversal nanocarrier prolongs the half-life of nanodrugs in blood and improves cellular uptake efficiency. The platform achieves a sustained and controllable drug release through dual stimulus-response, with pH as the endogenous stimulus and near-infrared as the exogenous stimulus. Furthermore, the nanoplatform realizes in situ O2 generation by catalyzing tumor over-expressed H2O2, which alleviates tumor microenvironment hypoxia and improves photodynamic therapy. Both in vitro and in vivo studies show the prepared nanoplatform has good photothermal conversion, cellular uptake efficiency, fluorescence/magnetic resonance imaging capabilities, and synergistic anti-tumor effects. These results suggest that the prepared all-in-one nanoplatform has great potential for dual-modal imaging-guided synergistic therapy of HCC.

Safety Evaluation and Anti-Inflammatory Efficacy of Lacticaseibacillus paracasei PS23.

Lacticaseibacillus paracasei strain PS23 (PS23) exhibits some probiotic properties. In this study, a genomic analysis of PS23 revealed no genes related to virulence or antibiotic resistance. Moreover, ornithine decarboxylase activity was not detected in vitro. In addition, PS23 was sensitive to the tested antibiotics. Genotoxicity tests for PS23 including the Ames test and chromosomal aberrations in vitro using Chinese hamster ovary cells and micronuclei in immature erythrocytes of ICR mice were all negative. Moreover, following a 28-day study involving repeated oral dose toxicity tests (40, 400, and 4000 mg/kg equal 1.28 × 1010, 1.28 × 1011, and 1.28 × 1012 CFU/kg body weight, respectively) using an ICR mouse model, no adverse effects were observed from any doses. In addition, supplementation with live or heat-killed PS23 ameliorates DSS-induced colonic inflammation in mice. Our findings suggest that PS23 is safe and has anti-inflammatory effects and may therefore have therapeutic implications.

NEXTorch: A Design and Bayesian Optimization Toolkit for Chemical Sciences and Engineering.

Automation and optimization of chemical systems require well-informed decisions on what experiments to run to reduce time, materials, and/or computations. Data-driven active learning algorithms have emerged as valuable tools to solve such tasks. Bayesian optimization, a sequential global optimization approach, is a popular active-learning framework. Past studies have demonstrated its efficiency in solving chemistry and engineering problems. We introduce NEXTorch, a library in Python/PyTorch, to facilitate laboratory or computational design using Bayesian optimization. NEXTorch offers fast predictive modeling, flexible optimization loops, visualization capabilities, easy interfacing with legacy software, and multiple types of parameters and data type conversions. It provides GPU acceleration, parallelization, and state-of-the-art Bayesian optimization algorithms and supports both automated and human-in-the-loop optimization. The comprehensive online documentation introduces Bayesian optimization theory and several examples from catalyst synthesis, reaction condition optimization, parameter estimation, and reactor geometry optimization. NEXTorch is open-source and available on GitHub.

A conductive dual-network hydrogel composed of oxidized dextran and hyaluronic-hydrazide as BDNF delivery systems for potential spinal cord injury repair.

Spinal cord injury (SCI) often causes neuronal death and axonal degeneration. In this study, we report a new strategy for preparing injectable and conductive polysaccharides-based hydrogels that could sustainably deliver brain-derived neurotrophic factor (BDNF) for SCI repair. We used poly(lactic-co-glycolic acid) (PLGA) as a carrier to encapsulate BDNF. The resulting microspheres were then modified with tannic acid (TA). The polysaccharides-based hydrogel composed of oxidized dextran (Dex) and hyaluronic acid-hydrazide (HA) was mixed with TA-modified microspheres to form the ultimate BDNF@TA-PLGA/Dex-HA hydrogel. Our results showed that the hydrogel had properties similar to natural spinal cords. Specifically, the hydrogel had soft mechanical properties and high electrical conductivity. The cross-sectional morphology of the hydrogel exhibited a continuous and porous structure. The swelling and degradation behaviors of the Dex-HA hydrogel in vitro indicated the incorporation of TA into hydrogel matrix could improve the stability of the hydrogel matrix as well as extend the release time of BDNF from the matrix. Furthermore, results from immunostaining and real-time PCR demonstrated that BDNF@TA-PLGA/Dex-HA hydrogel could promote the differentiation of neural stem cells (NSCs) into neurons and inhibit astrocyte differentiation in vitro. These results show the great potential of this hydrogel as a biomimetic material in SCI regeneration.

Toxicity Studies of Lactobacillus plantarum PS128TM Isolated from Spontaneously Fermented Mustard Greens.

: Probiotics are extensively available to consumers; however, the use of probiotics may not always be safe, and there are few reports on their side effects, including those of Lactobacillus. Lactobacillus plantarum strain PS128TM isolated from spontaneously fermented mustard greens in Taiwan was recently reported to exhibit probiotic properties. In this study, we aimed to assess the safety of strain PS128TM for use in humans via examining genotoxic and oral toxic effects using in vitro and in vivo testing. Five strains of Salmonella typhimurium were evaluated by the Ames test; no signs of increased reverse mutation were observed following exposure to PS128TM. Additional testing of Chinese hamster ovary (CHO) cells exposed to PS128TM revealed that the incidence of chromosomal aberrations in CHO cells had not increased. PS128TM treatment also did not affect the proportion of immature to total erythrocytes or the number of micronuclei in the immature erythrocytes of ICR mice. Moreover, following a 28 day study involving repeated oral dose toxicity tests (2400, 400, and 40 mg/kg body weight) utilizing an ICR mouse model, no observable adverse level (NOAEL) was found at any of the doses. PS128TM was sensitive to antibiotics; however, genes related to the production of biogenic amines were absent. While further research is required, these toxicological assessments suggest that PS128TM could be safe for human consumption.

Influence of obesity on in-hospital and postoperative outcomes of hepatic resection for malignancy: a 10-year retrospective analysis from the US National Inpatient Sample.

OBJECTIVES: The influence of obesity on the outcomes of curative liver resection for malignancies remains controversial. We aimed to compare the in-hospital outcomes of liver resection for malignancy between obese and non-obese patients. DESIGN: This was a population-based, retrospective, observational study using data from the Nationwide Inpatient Sample (NIS), the largest all-payer US inpatient care database. SETTING: Hospitalisations of adults ≥18 years old with diagnoses of primary hepatobiliary malignancy or secondary malignant neoplasms of liver in the USA were identified from the NIS database between 2005 and 2014. PARTICIPANTS: Data of 18 398 patients ≥18 years old and underwent liver resection without pancreatic resection in the NIS were extracted. All included subjects had primary hepatobiliary malignancy or secondary malignant neoplasms of the liver. Patients were divided into obese and non-obese groups. These groups were compared with respect to postoperative complications, length of hospital stay and hospital cost according to surgical extent and approach. INTERVENTIONS: Patients were undergoing lobectomy of liver or partial hepatectomy. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoints of this study were postoperative complications, length of hospital stay and hospital cost. RESULTS: After adjustment, obese patients were significantly more likely to experience postoperative complications than were non-obese patients (adjusted OR 1.25, 95% CI 1.10 to 1.42), regardless of whether lobectomy or partial hepatectomy was performed. Furthermore, obesity was significantly associated with increased risk of postoperative complications in patients who underwent open liver resection, but not laparoscopic resection. No significant difference was observed in length of hospital stay or total hospital costs between obese and non-obese patients. CONCLUSIONS: After adjustment for preoperative comorbidities and other potential confounders, obesity is significantly associated with greater risk of complications in patients undergoing open liver resection for malignancy, but not laparoscopic resection.

BCL2L10/BECN1 modulates hepatoma cells autophagy by regulating PI3K/AKT signaling pathway.

The aim of this study was to investigate BCL2L10 and BECN1 expression and their effect on autophagy in hepatocellular carcinoma (HCC). We found that BCL2L10 expression was low in hepatoma tissues and cells. Overexpression of BCL2L10 decreased the activity of hepatoma cells. To analyze autophagic flux, we monitored the formation of autophagic vesicles by fluorescence protein method. Autophagy-related protein LC3B-II was accumulated and P62 was decreased, which indicated that autophagy was induced by BECN1, while BCL2L10 could suppress this trend. Immunofluorescence assay showed that BCL2L10 and Beclin 1 were co-located in hepatoma cells. Immunoprecipitation showed that BCL2L10 could inhibit the autophagy of hepatoma cells by combining with Beclin 1. ELISA and co-immunoprecipitation suggested that the combination between BCL2L10 and Beclin 1 reduced the bond between Beclin 1 and PI3KC3. Based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, the PI3K/AKT signaling pathway was significantly upregulated in HCC. In conclusions, BCL2L10 had a low expression in HCC tissues and cells, which could release BECN1 to induce autophagy of hepatoma cells by downregulating PI3K/AKT signaling pathway.

Cadherin-17 and SATB2 are sensitive and specific immunomarkers for medullary carcinoma of the large intestine.

CONTEXT: Distinction of medullary carcinoma of the large intestine from other cytokeratin (CK) 7⁻/CK20⁻ carcinomas can be challenging when working on a tumor of unknown primary because the majority of medullary carcinomas are negative for CK7, CK20, and CDX2. OBJECTIVE: To investigate the expression of cadherin-17 and SATB-2 and other markers in medullary carcinomas of the large intestine and cadherin-17 and SATB2 in a large number of carcinomas and normal tissues from various organs to further test their diagnostic specificity. DESIGN: This study evaluated cadherin-17 and SATB2 expression in 18 medullary carcinoma cases and 1941 tumors and 358 normal tissues from various organs. Other immunomarkers, including MLH1, PMS2, MSH2, MSH6, CDX2, CK7, CK20, TFF3, MUC4, calretinin, p504S, villin, and synaptophysin, were also tested on the 18 medullary carcinoma cases. RESULTS: The results demonstrated (1) loss of MLH1 and PMS2 in more than 80% of medullary carcinomas; (2) expression of cadherin-17 and SATB2 in 89% of medullary carcinomas; (3) focal expression of TFF3, MUC4, calretinin, CDX2, CK20, and synaptophysin in 72%, 72%, 67%, 67%, 28%, and 17% of 18 medullary carcinoma cases, respectively; and (4) expression of SATB2 and cadherin-17 in 97% and 98% of the colorectal adenocarcinomas, respectively, whereas their expression was seen in 3.6% and 3.3% of nongastrointestinal tumors, respectively. CONCLUSION: We concluded that SATB2 and cadherin-17 were highly sensitive and specific markers for colorectal carcinomas and propose including MLH1, cadherin-17, and SATB2 in a routine immunostaining panel when working on a tumor of unknown primary, especially in an elderly patient with a CK7⁻/CK20⁻ carcinoma.

Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor.

Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC(50) values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent.

Development, cytokine profile and function of human interleukin 17-producing helper T cells.

T(H)-17 cells are a distinct lineage of proinflammatory T helper cells that are essential for autoimmune disease. In mice, commitment to the T(H)-17 lineage is dependent on transforming growth factor-beta and interleukin 6 (IL-6). Here we demonstrate that IL-23 and IL-1beta induced the development of human T(H)-17 cells expressing IL-17A, IL-17F, IL-22, IL-26, interferon-gamma, the chemokine CCL20 and transcription factor RORgammat. In situ, T(H)-17 cells were identified by expression of the IL-23 receptor and the memory T cell marker CD45RO. Psoriatic skin lesions contained IL-23-producing dendritic cells and were enriched in the cytokines produced by human T(H)-17 cells that promote the production of antimicrobial peptides in human keratinocytes. Our data collectively indicate that human and mouse T(H)-17 cells require distinct factors during differentiation and that human T(H)-17 cells may regulate innate immunity in epithelial cells.

IL-23 promotes tumour incidence and growth.

Chronic inflammation has long been associated with increased incidence of malignancy and similarities in the regulatory mechanisms have been suggested for more than a century. Infiltration of innate immune cells, elevated activities of matrix metalloproteases and increased angiogenesis and vasculature density are a few examples of the similarities between chronic and tumour-associated inflammation. Conversely, the elimination of early malignant lesions by immune surveillance, which relies on the cytotoxic activity of tumour-infiltrating T cells or intra-epithelial lymphocytes, is thought to be rate-limiting for the risk to develop cancer. Here we show a molecular connection between the rise in tumour-associated inflammation and a lack of tumour immune surveillance. Expression of the heterodimeric cytokine interleukin (IL)-23, but not of its close relative IL-12, is increased in human tumours. Expression of these cytokines antagonistically regulates local inflammatory responses in the tumour microenvironment and infiltration of intra-epithelial lymphocytes. Whereas IL-12 promotes infiltration of cytotoxic T cells, IL-23 promotes inflammatory responses such as upregulation of the matrix metalloprotease MMP9, and increases angiogenesis but reduces CD8 T-cell infiltration. Genetic deletion or antibody-mediated elimination of IL-23 leads to increased infiltration of cytotoxic T cells into the transformed tissue, rendering a protective effect against chemically induced carcinogenesis. Finally, transplanted tumours are growth-restricted in hosts depleted for IL-23 or in IL-23-receptor-deficient mice. Although many strategies for immune therapy of cancer attempt to stimulate an immune response against solid tumours, infiltration of effector cells into the tumour tissue often appears to be a critical hurdle. We show that IL-23 is an important molecular link between tumour-promoting pro-inflammatory processes and the failure of the adaptive immune surveillance to infiltrate tumours.