Cancer outcomes differ depending on where treatment is received. We assessed differences in outcomes in long-term breast cancer survivors at a specialty care hospital by location of their initial treatment.

The L-arabinose utilization pathway was established in Saccharomyces cerevisiae, by expressing the codon-optimized araA, araB, and araD genes of Lactobacillus plantarum. After overexpressing the TAL1, TKL1, RPE1, RKI1, and GAL2 genes and adaptive evolution, the L-arabinose utilization of the recombinant strain became efficient. The resulting strain displayed a maximum specific growth rate of 0.075 h(-1), a maximum specific L-arabinose consumption rate of 0.61 g h(-1) g(-1) dry cell weight, and a promising ethanol yield of 0.43 g g(-1) from L-arabinose fermentation.

Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor-targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, RB94 showed marked cytotoxicity against tumor but not normal cells. SGT-94 was administered intravenously in a first-in-man study in metastatic genitourinary cancer. Minimal side effects were observed; dose-limiting toxicity (DLT) has not been reached in 11 evaluable patients. There was evidence of clinical activity at the 2.4 mg dose with one complete remission (CR) and one partial remission (PR). The patient in CR was retreated upon progression and had a second PR. Furthermore, there was tumor-specific targeting of the SGT-94 complex. One patient had wedge resections of two lung metastases which demonstrated RB94 expression at the DNA level by polymerase chain reaction (PCR) and at the protein level by Western blotting, with no RB94 present in normal contiguous lung. In conclusion, systemically delivered SGT-94 showed evidence of selective tumor targeting and was well tolerated with evidence of clinical activity. Additional studies are warranted to explore the activity of this drug as a single agent and in combination therapy.

It has been suggested that plant phytochromes are autophosphorylating serine/threonine kinases. However, the biochemical properties and functional roles of putative phytochrome kinase activity in plant light signalling are largely unknown. Here, we describe the biochemical and functional characterization of Avena sativa phytochrome A (AsphyA) as a potential protein kinase. We provide evidence that phytochrome-interacting factors (PIFs) are phosphorylated by phytochromes in vitro. Domain mapping of AsphyA shows that the photosensory core region consisting of PAS-GAF-PHY domains in the N-terminal is required for the observed kinase activity. Moreover, we demonstrate that transgenic plants expressing mutant versions of AsphyA, which display reduced activity in in vitro kinase assays, show hyposensitive responses to far-red light. Further analysis reveals that far-red light-induced phosphorylation and degradation of PIF3 are significantly reduced in these transgenic plants. Collectively, these results suggest a positive relationship between phytochrome kinase activity and photoresponses in plants.

Multi-, extensively-, and pan-drug resistant bacteria are a threat to our health today, because their wide resistance spectra make their infections difficult to cure. In this work, we isolated an extensively drug resistant (XDR) Klebsiella pneumoniae 2-1 strain from the stool sample of a patient diagnosed of colorectal cancer. K. pneumoniae 2-1 was found to be resistant to all the antibiotics tested except for cefepime, tigecycline, and ceftazidime-avibactam. By sequencing the complete genome of K. pneumoniae 2-1, we found it contains a chromosome of 5.23 Mb and two circular plasmids with the size of 246 and 90 kb. The larger plasmid, pKP21HI1 was found to be a new conjugation-defective plasmid belonging to incompatibility group HI1B and a new sequence type. Further comparative genomics analysis and antimicrobial resistance gene analysis showed that although a great deal of changes took place on the chromosome of K. pneumoniae 2-1 in comparison with the reference genome, the extensively drug resistance phenotype of K. pneumoniae 2-1 is primarily due to the two multidrug resistant plasmids it contains. This work explains the genetic and mechanistic basis of the extensive drug resistance of K. pneumoniae 2-1, and found that plasmids play key roles in the strong antibiotic resistance of bacteria.

Malonyl-coenzyme A (malonyl-CoA) is a critical precursor for the biosynthesis of a variety of biochemicals. It is synthesized by the catalysis of acetyl-CoA carboxylase (Acc1p), which was demonstrated to be deactivated by the phosphorylation of Snf1 protein kinase in yeast. In this study, we designed a synthetic malonyl-CoA biosensor and used it to screen phosphorylation site mutations of Acc1p in Saccharomyces cerevisiae. Thirteen phosphorylation sites were mutated, and a combination of three site mutations in Acc1p, S686A, S659A, and S1157A, was found to increase malonyl-CoA availability. ACC1S686AS659AS1157A expression also improved the production of 3-hydroxypropionic acid, a malonyl-CoA-derived chemical, compared to both wild type and the previously reported ACC1S659AS1157A mutation. This mutation will also be beneficial for other malonyl-CoA-derived products.

The recombinant Saccharomyces cerevisiae strains that acquired the ability to utilize xylose through metabolic and evolutionary engineering exhibit good performance when xylose is the sole carbon source in the medium (designated the X stage in the present work). However, the xylose consumption rate of strains is generally low after glucose depletion during glucose-xylose co-fermentation, despite the presence of xylose in the medium (designated the GX stage in the present work). Glucose fermentation appears to reduce the capacity of these strains to "recognize" xylose during the GX stage, a phenomenon termed the post-glucose effect on xylose metabolism.

Little is known regarding differences in the gut microbiomes of rheumatoid arthritis (RA) patients and healthy cohorts in China. This study aimed to identify differences in the fecal microbiomes of 66 Chinese patients with RA and 60 healthy Chinese controls. The V3-V4 variable regions of bacterial 16S rRNA genes were sequenced with the Illumina system to define the bacterial composition. The alpha-diversity index of the microbiome of the RA patients was significantly lower than that of the control group. The bacterial genera Bacteroides (p = 0.02202) and Escherichia-Shigella (p = 0.03137) were more abundant in RA patients. In contrast, Lactobacillus (p = 0.000014), Alloprevotella (p = 0.0000008615), Enterobacter (p = 0.000005759), and Odoribacter (p = 0.0000166) were less abundant in the RA group than in the control group. Spearman correlation analysis of blood physiological measures of RA showed that bacterial genera such as Dorea and Ruminococcus were positively correlated with RF-IgA and anti-CCP antibodies. Furthermore, Alloprevotella and Parabacteroides were positively correlated with the erythrocyte sedimentation rate, and Prevotella-2 and Alloprevotella were positively correlated with C-reactive protein, both biomarkers of inflammation. These findings suggest that the gut microbiota may contribute to RA development via interactions with the host immune system.

The purpose of this study was to compare the anatomical and visual outcomes of inverted internal limiting membrane (ILM) flap technique and internal limiting membrane peeling in large macular holes (MH).

Radium-223 dichloride (Ra-223) is a targeted alpha therapy that induces localized cytotoxicity in bone metastases. We evaluated the efficacy and safety of Ra-223 plus hormonal therapy in hormone receptor-positive (HR+), bone-dominant metastatic breast cancer.

Peripheral nerve injuries are generally associated with incomplete restoration of motor function. The slow rate of nerve regeneration after injury may account for this. Although many benefits of resveratrol have been shown in the nervous system, it is not clear whether resveratrol could promote fast nerve regeneration and motor repair after peripheral nerve injury. This study showed that the motor deficits caused by sciatic nerve crush injury were alleviated by daily systematic resveratrol treatment within 10 days. Resveratrol increased the number of axons in the distal part of the injured nerve, indicating enhanced nerve regeneration. In the affected ventral spinal cord, resveratrol enhanced the expression of several vascular endothelial growth factor family proteins (VEGFs) and increased the phosphorylation of p300 through Akt signaling, indicating activation of p300 acetyltransferase. Inactivation of p300 acetyltransferase reversed the resveratrol-induced expression of VEGFs and motor repair in rats that had undergone sciatic nerve crush injury. The above results indicated that daily systematic resveratrol treatment promoted nerve regeneration and led to rapid motor repair. Resveratrol activated p300 acetyltransferase-mediated VEGF signaling in the affected ventral spinal cord, which may have thus contributed to the acceleration of nerve regeneration and motor repair.

Objective: Cancer-associated fibroblasts (CAFs) were associated with tumor progression in the tumor microenvironment (TME). However, their immunosuppressive roles in protecting cancer cells from the attack by cytotoxic T lymphocytes (CTLs) are not fully clear. In this study, we investigated whether and how CAFs regulate tumor-infiltrating lymphocytes as well as their role in tumor immunosuppression. Methods: Eighty-three cases of ovarian cancer and 10 controls were analyzed for CAFs and CD8+ tumor-infiltrating lymphocytes by gene array and immunohistochemistry. We evaluated presenilin 1 (PS1) expression in CAFs, CTL penetration, tumor burden, dendritic cell function, and migration of tumor-infiltrating lymphocytes and their function in vivo and in vitro after silencing PS1. In addition, the pathway via which PS1 affects the TME was also evaluated. Results: PS1 was highly expressed in CAFs, and its silencing significantly promoted CD8+ CTL proliferation and penetration in multiple ovarian models (p < 0.05), resulting in tumor regression and growth inhibition. Interleukin (IL)-1β was identified as a major immune inhibitor in the TME, and it was significantly decreased after PS1 silencing (p < 0.05), which was regulated by the WNT/β-catenin pathway. It was also showed that high expression of IL-1β in CAFs inhibits CTL penetration significantly (p < 0.05). Conclusion: Highly expressed PS1 in CAFs plays a crucial role in regulating tumor-infiltrating lymphocyte populations in the TME via the WNT/β-catenin pathway. Targeting PS1 may retrieve functional CTLs in the TME and improve the efficacy of current immunotherapies.

Colorectal cancer (CRC) is one of the most mortal cancers in the world. Multiple factors and bio-processes are associated with in tumorigenesis and metastasis of CRC, including cellular senescence and immune evasion. This study aims to identify prognostic and immune-meditating effects of INHBA in CRC. Microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database to screen the differentially expressed genes (DEGs) in senescent cells and CRC tissues from the Cancer Genome Atlas (TCGA). Key factor was settled from the alternative DEGs set. Enrichment analyses and functional networks prediction were determined from online databases. Correlation analyses were performed to reveal the association among key factor, immune infiltration, T cell biomarkers and immune checkpoints. Moreover, expressions of key factors and immune checkpoints of tissue and blood samples from CRC patients as well as human CRC cell lines were measured. Results showed that Inhibin beta A (INHBA) was sorted out as a senescence-related factor and a prognostic predictor in CRC. What's more, INHBA was found highly co-expressed with T-cell biomarkers and immune checkpoints. In conclusion, INHBA was considered as a senescence-related regulator and a prognostic predictor in CRC, which also mediating immune evasion.

Tumor-stroma ratio (TSR) is a promising new prognostic predictor for patients with rectal cancer (RC). Although several studies focused on this pathologic feature, results from those studies were still inconsistent.

The adaptation mechanism of a wild type (WT) and resistant type (Re) strain of the aerobic denitrifier Enterobacter cloacae strain HNR to short-term ZnO nanoparticle (NP) stresses was investigated. The results showed that Re maintained higher nitrite reductase (NIR) and nitrate reductase (NR) activities and showed lower increment of reactive oxygen species (ROS) than WT, under ZnO NP stresses. The affinity constant (KA) of WT to Zn2+ was 5.06 times that of Re, indicating that Re was more repulsive to Zn2+ released by ZnO NPs. Transcriptomic analysis revealed that the up-regulation of the nitrogen metabolism of Re helped maintain NIR and NR activities, that the enhancement of purine metabolism lowered the intracellular ROS increment, and that the up-regulation of cationic antimicrobial peptide resistance contributed to the lower KA of Re to Zn2+. These findings provided new insights into the adaptation mechanism of aerobic denitrifying bacteria to ZnO NPs.

Hepatocellular carcinoma (HCC) is a common human malignancy with high mortality and dismal prognosis. A growing number of novel targets underlying HCC pathophysiology have been detected using microarray high throughput screening platforms. This study carried out bioinformatics analysis to explore underlying biomarkers in HCC and assessed the potential action of the miR-193b-3p/CDK1 signaling pathway in HCC progression. A total of 241 common differentially expressed genes (DEGs) were screened from GSE33294, GSE104310, and GSE144269. Functional analysis results implicated that DEGs are significantly associated with "cell cycle," "cell division," and "proliferation." The protein-protein interaction network analysis extracted ten hub genes from common DEGs. Ten hub genes were significantly overexpression in HCC tissues. Kaplan-Meier survival analysis revealed that 10 hub genes were linked with a poorer prognosis in HCC patients. Functional assays showed that CDK1 knockdown repressed HCC cell proliferation and migration. Luciferase reporter assay showed that miR-193b-3p could target CDK1 3' untranslated region, and miR-193b-3p negatively modulated CDK1. Enforced CDK1 expression attenuated miR-193b-3p-modulated suppressive actions on HCC cell proliferation and migration. To summarize, we performed a comprehensive bioinformatics analysis and identified 10 hub genes linked to the prognosis in HCC patients. Functional analysis revealed that CDK1, negatively regulated by miR-193b-3p, may act as an oncogene to promote HCC cell proliferation and migration and may predict poor prognosis of HCC patients. However, the role of CDK1/miR-193b-3p may still require further investigation.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease worldwide, with no effective therapies available. Discovering lead compounds from herb medicine might be a valuable strategy for the treatment of NASH. Here, we discovered Alisol B, a natural compound isolated from Alisma orientalis (Sam.), that attenuated hepatic steatosis, inflammation, and fibrosis in high-fat diet plus carbon tetrachloride (DIO+CCl4)-induced and choline-deficient and amino acid-defined (CDA)-diet-induced NASH mice. RNA-seq showed Alisol B significantly suppressed CD36 expression and regulated retinol metabolism in NASH mice. In mouse primary hepatocytes, Alisol B decreased palmitate-induced lipid accumulation and lipotoxicity, which were dependent on CD36 suppression. Further study revealed that Alisol B enhanced the gene expression of RARα with no direct RARα agonistic activity. The upregulation of RARα by Alisol B reduced HNF4α and PPARγ expression and further decreased CD36 expression. This effect was fully abrogated after RARα knockdown, suggesting Alisol B suppressed CD36 via regulating RARα-HNF4α-PPARγ cascade. Moreover, the hepatic gene expression of RARα was obviously decreased in murine NASH models, whereas Alisol B significantly increased RARα expression and decreased CD36 expression, along with the downregulation of HNF4α and PPARγ. Therefore, this study showed the unrecognized therapeutic effects of Alisol B against NASH with a novel mechanism by regulating RARα-PPARγ-CD36 cascade and highlighted Alisol B as a promising lead compound for the treatment of NASH.

A comorbidity of chronic pain is sleep disturbance. Here, we identify a dual-functional ensemble that regulates both pain-like behaviour induced by chronic constrictive injury or complete Freund's adjuvant, and sleep wakefulness, in the nucleus accumbens (NAc) in mice. Specifically, a select population of NAc neurons exhibits increased activity either upon nociceptive stimulation or during wakefulness. Experimental activation of the ensemble neurons exacerbates pain-like (nociceptive) responses and reduces NREM sleep, while inactivation of these neurons produces the opposite effects. Furthermore, NAc ensemble primarily consists of D1 neurons and projects divergently to the ventral tegmental area (VTA) and preoptic area (POA). Silencing an ensemble innervating VTA neurons selectively increases nociceptive responses without affecting sleep, whereas inhibiting ensemble-innervating POA neurons decreases NREM sleep without affecting nociception. These results suggest a common NAc ensemble that encodes chronic pain and controls sleep, and achieves the modality specificity through its divergent downstream circuit targets.

Anemoside B4 has a good curative effect on cows with CM; however, its impact on their metabolic profiles is unclear. Based on similar somatic cell counts and clinical symptoms, nine healthy dairy cows and nine cows with CM were selected, respectively. Blood samples were collected from cows with mastitis on the day of diagnosis. Cows with mastitis were injected with anemoside B4 (0.05 mL/kg, once daily) for three consecutive days, and healthy cows were injected with the same volume of normal saline. Subsequently, blood samples were collected. The plasma metabolic profiles were analyzed using untargeted mass spectrometry, and the concentrations of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in serum were evaluated via ELISA. The cows with CM showed increased concentrations of IL-1β, IL-6, and TNF-α (p < 0.05). After treatment with anemoside B4, the concentrations of IL-1β, IL-6, and TNF-α were significantly decreased (p < 0.01). Untargeted metabolomics analysis showed that choline, glycocholic acid, PC (18:0/18:1), 20-HETE, PGF3α, and oleic acid were upregulated in cows with CM. After treatment with anemoside B4, the concentrations of PC (16:0/16:0), PC (18:0/18:1), linoleic acid, eicosapentaenoic acid, phosphorylcholine, and glycerophosphocholine were downregulated, while the LysoPC (14:0), LysoPC (18:0), LysoPC (18:1), and cis-9-palmitoleic acid were upregulated. This study indicated that anemoside B4 alleviated the inflammatory response in cows with CM mainly by regulating lipid metabolism.

The formula of food for special medical purpose has a direct impact on physicochemical stability, especially in hot climes and high temperature transport storage environments. An accelerated test (50 °C for 7 weeks) was used to analyze the mechanism of the physicochemical instability of formula A with lactose and maltodextrin, and formula B with maltodextrin. Deep dents and wrinkles were observed on the surface of the formula B, and more fat globules covered the surface of formula A particles after storage for a long time. Significantly higher amounts of furosine and Nε-carboxymethl-l-lysine (CML) were formed and the loss of available lysine was greater in formula A than in formula B. No significant difference was observed in lipid oxidation indicators between the two formulas. The results of this research demonstrated lactose was more active than maltodextrin and led to physicochemical instability.