Th9/IL-9 may participate in the pathogenesis of multiple myeloma.

INTRODUCTION: This research is aimed to evaluate the correlation between Th9-associated cytokine levels in MM patients, clinical features, and therapy. METHODS: Peripheral blood samples were taken in 52 MM patients and 20 healthy volunteers matched by sex and age. The patients with MM were separated into two groups: the untreated group (27) and the remission group (25). An enzyme-linked immunosorbent assay (ELISA) was used to measure the IL-9 plasma levels. The levels of Th9-associated cytokines' mRNA expression (IL-9, PU.1, and IRF4) were measured in RT-qPCR. We also analyzed the correlations between the IL-9 plasma levels and the clinical parameters of newly diagnosed MM patients. RESULTS: The IL-9 plasma levels and the Th9-associated cytokines (IL-9, PU.1, and IRF4) mRNA levels in newly diagnosed MM patients were significantly elevated than those in healthy volunteers and significantly decreased after achieving remission. Moreover, PU.1 and IRF4 had a positive correlation with the IL-9 mRNA expression. Then, we found that the upregulation of IL-9 plasma levels correlates with the severity of anemia and decreased albumin Levels. CONCLUSION: The results demonstrate that Th9/IL-9 may be involved in the pathogenesis of MM and is correlated with worse patient conditions such as lower hemoglobin and serum albumin. More work is necessary to confirm whether they might serve as a useful therapeutic target and prognostic marker for MM.

Noninvasive Monitoring of Immunotherapy in Lung Cancer by Lymphocyte Activation Gene 3 PET Imaging of Tumor-Infiltrating Lymphocytes.

Although immunotherapy has revolutionized the entire cancer treatment landscape, small fractions of patients respond to immunotherapy. Early identification of responders may improve patient management during immunotherapy. In this study, we evaluated a PET approach for monitoring immunotherapy in lung cancer by imaging the upregulation of lymphocyte activation gene 3 (LAG-3)-expressing (LAG-3+) tumor-infiltrating lymphocytes (TILs). Methods: We synthesized a LAG-3-targeted molecular imaging probe, [68Ga]Ga-NOTA-C25 and performed a series of in vitro and in vivo assays to test its specificity. Next, [68Ga]Ga-NOTA-C25 PET was used to monitor immunotherapy in murine lung cancer-bearing mice and in humanized mouse models for assessing clinical translational potential, with confirmation by immunostaining and flow cytometry analysis. Results: [68Ga]Ga-NOTA-C25 PET could noninvasively detect intertumoral differences in LAG-3+ TIL levels in different tumor models. Importantly, in Lewis lung carcinoma tumor models treated with an agonist of a stimulator of interferon genes, [68Ga]Ga-NOTA-C25 PET also detected an immunophenotyping transition of the tumor from "cold" to "hot" before changes in tumor size. Meanwhile, animals carrying "hot" tumor showed more significant tumor inhibition and longer survival than those carrying "cold" tumor. [68Ga]Ga-NOTA-C25 PET also showed markedly higher tumor uptake in immune system-humanized mice carrying human non-small cell lung cancer than immunodeficient models. Conclusion: [68Ga]Ga-NOTA-C25 PET could be used to noninvasively monitor the early response to immunotherapy by imaging LAG-3+ TILs in lung cancer. [68Ga]Ga-NOTA-C25 PET also exhibited excellent translational potential, with great significance for the precise management of lung cancer patients receiving immunotherapy.

Effects of treatment with stem cell-derived extracellular vesicles in preclinical rodent models of intrauterine adhesion: A meta-analysis.

Background: Intrauterine adhesion (IUA) results from serious complications of intrauterine surgery or infection and mostly remains incurable. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have emerged as a potential new approach for the treatment of IUA; however, their impact is not fully understood. Here, we performed a meta-analysis summarizing the effects of sEVs on IUA in preclinical rodent models. Methods: This meta-analysis included searches of PubMed, EMBASE, Cochrane, and the Web of Science databases from January 1, 1997, to April 1, 2022, to identify studies reporting the therapeutic effect of sEVs on rodent preclinical animal models of IUA. We compared improvements in endometrial thickness, endometrial gland number, fibrosis area, embryo number, vascular endothelial growth factor (VEGF), transforming growth factor ß1 (TGFß1), and leukemia inhibitory factor (LIF) levels after treatment. Results: Our search included 100 citations, of which 7 met the inclusion criteria, representing 231 animals. Compared with that in the control group, the fibrosis area in the sEV-treated group was significantly reduced (standardized mean difference (SMD) = -6.87，95 % confidence interval (CI) = -9.67 to -4.07). The number of glands increased after the intervention (95 % CI, 3.72-7.68; P = 0.000). Endometrial thickness was significantly improved in the sEV-treated group (SMD = 2.57, 95 % CI, 1.62-3.52). Conclusions: This meta-analysis is highlighting that sEV treatment can improve the area of endometrial fibrosis, as well as VEGF, and LIF level, in a mouse IUA model. This knowledge of these findings will provide new insights into future preclinical research.

Identification and Quantification of S-Sulfenylation Proteome of Mycobacterium tuberculosis under Oxidative Stress.

The ability to maintain redox homeostasis is critical for Mycobacterium tuberculosis (Mtb) to survive the redox stress of the host. There are many antioxidant systems in Mtb to ensure its normal replication and survival in the host, and cysteine thiols are one of them. S-sulfenylation is one of the reversible modifications of cysteine thiols to resist oxidative stress. In the study, we investigated the total cysteine thiols modification and S-sulfenylation modification of Mtb proteome under the oxidative stress provided by hydrogen peroxide. To determine and quantify the S-sulfenylation modified proteins, high specific IodoTMT6plex reagents and high resolution mass spectrometry were used to label and quantify the peptides and proteins modified. There are significant differences for the total cysteine modification levels of 279 proteins and S-sulfenylation modification levels of 297 proteins under hydrogen peroxide stress. Functional enrichment analysis indicated that these cysteine-modified proteins were involved in the oxidation-reduction process, fatty acid biosynthetic process, stress response, protein repair, cell wall, etc. In conclusion, our study provides a view of cysteine modifications of the Mtb proteome under oxidative stress, revealing a series of proteins that may play a role in maintaining redox homeostasis. IMPORTANCE With the continuous spread of drug-resistant tuberculosis, there is an urgent need for new antituberculosis drugs with new mechanisms. The ability of Mtb to resist oxidative stress is extremely important for maintaining redox homeostasis and survival in the host. The reversible modifications of cysteine residues have a dual role of protection from irreversible damage to protein functions and regulation, which plays an important role in the redox homeostasis system. Thus, to discover cysteine modification changes in the proteome level under oxidative stress is quintessential to elucidate its antioxidant mechanism. Our results provided a list of proteins involved in the antioxidant process that potentially could be considered targets for drug discovery and vaccine development. Furthermore, it is the first study to determine and quantify the S-sulfenylation-modified proteins in Mtb, which provided better insight into the Mtb response to the host oxidative defense and enable a deeper understanding of Mtb survival strategies.

Isolation, Structure Elucidation, and First Total Synthesis of Quinomycins K and L, Two New Octadepsipeptides from the Maowei Sea Mangrove-Derived Streptomyces sp. B475.

Mangrove actinomycetia have been proven to be one of the promising sources for discovering novel bioactive natural products. Quinomycins K (1) and L (2), two rare quinomycin-type octadepsipeptides without intra-peptide disulfide or thioacetal bridges, were investigated from the Maowei Sea mangrove-derived Streptomyces sp. B475. Their chemical structures, including the absolute configurations of their amino acids, were elucidated by a combination of NMR and tandem MS analysis, electronic circular dichroism (ECD) calculation, advanced Marfey's method, and further unequivocally confirmed by the first total synthesis. The two compounds displayed no potent antibacterial activity against 37 bacterial pathogens and had no significant cytotoxic activity against H460 lung cancer cells.

Adjuvant icotinib versus observation in patients with completely resected EGFR-mutated stage IB NSCLC (GASTO1003, CORIN): a randomised, open-label, phase 2 trial.

Background: This phase 2 trial aimed to compare adjuvant icotinib with observation in patients with epidermal growth factor receptor (EGFR) mutation-positive resected stage IB non-small cell lung cancer (NSCLC). Methods: We performed a randomised, open-label, phase 2 trial from May 1, 2015 to December 29, 2020 at Sun Yat-sen University Cancer Center in China. Patients with completely resected, EGFR-mutant, stage IB (the 7th edition of TNM staging) NSCLC without adjuvant chemotherapy were randomised (1:1) to receive adjuvant therapy with icotinib (125 mg, three times daily) for 12 months or to undergo observation until disease progression or intolerable toxicity occurred. The primary endpoint was 3-year disease-free survival (DFS). CORIN (GASTO1003) was registered with Clinicaltrials.gov, with the number NCT02264210. Findings: A total of 128 patients were randomised, with 63 patients in the icotinib group and 65 patients in the observation group. The median duration of follow-up was 39.9 months. The three-year DFS was significantly higher in the icotinib group (96.1%, 95% confidence interval [CI], 91.3-99.9) than in the observation group (84.0%, 95% CI, 75.1-92.9; P = 0.041). The DFS was significantly longer in the icotinib group than in the observation group, with a hazard ratio (HR) of 0.23 (95% CI, 0.07-0.81; P = 0.013). The OS data were immature, with three deaths in the observation arm. In the icotinib group, adverse events (AEs) of any grade were reported in 49 patients (77.8%), and grade 3 or greater AEs occurred in four patients (6.3%). No treatment-related deaths occurred. Interpretation: Our findings suggested that adjuvant icotinib improved the 3-year DFS in patients with completely resected EGFR-mutated stage IB NSCLC with a manageable safety profile. Funding: This study was sponsored by Betta Pharmaceutical Co., Ltd.

Environmental endocrine disruptor Bisphenol A induces metabolic derailment and obesity via upregulating IL-17A in adipocytes.

BACKGROUND: Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor, has been extensively demonstrated to be associated with metabolic disorders, including obesity and type 2 diabetes mellitus. However, the underlying mechanism underpinning the environmental etiology of chronic metabolic disorders has not been sufficiently elucidated. OBJECTIVES: This study is designed to explore the toxicological pathogenesis of chronic inflammation in BPA exposure during obesity. METHODS: We investigated the role of IL-17A in the association of BPA exposure and obesity from human cross-sectional study to animal models, including genetically modified IL-17A-/- mice. RESULTS: Here, our work started from case-control observation that BPA exposure was significantly associated with risk of obesity (odds ratio = 4.72, 95%CI: 3.18 - 11.18, P < 0.01), metabolic disorder and levels of interleukin-17A (IL-17A) in human adipose (estimated changes ß = 0.46, 95%CI: 0.15 - 1.01, P < 0.01) with bariatric surgery. Animal model fed with high-fat diet (HFD) confirmed that BPA exposure aggravated body weight gain and insulin resistance, concurrent with much heightened inflammatory responses in the adipose tissue including increase in IL-17A and macrophage polarization towards M1 stage. Genetically modified IL-17A ablated mice (IL-17A-/-) showed reversed adipose tissue inflammation response, improved macrophage polarization homeostasis, along with insulin sensitivity in both HFD group alone or much more significantly the HFD + BPA group. Moreover, mediation analysis in human epidemiological investigation demonstrated that plasma IL-17A attributed up to 30.01% mediating role in the associations between BPA exposure and obesity risk. DISCUSSION: This research paradigm from human to animal provides strong evidence for the elucidation of IL-17A moderating inflammation and insulin resistance in obesity. Such findings reiterate the obesogenic role of environmental endocrine disruptor BPA in metabolic disorders and unveils the potential toxicological mechanisms underpinning such effect.

Roles of cysteine in the structure and metabolic function of Mycobacterium tuberculosis CYP142A1.

CYP142A1 is a cytochrome P450 (CYP) enzyme expressed in Mycobacterium tuberculosis (Mtb), which supports the growth of Mtb H37Rv relying on cholesterol, in the absence of CYP125A1. Since cysteine residues usually play a fundamental role in maintaining the structure and function of CYP enzymes, in this study, we aimed to determine the potential biochemical functions of six cysteine residues except for the heme-binding cysteine in the amino acid sequence of recombinant Mtb CYP142A1 by replacing each one using site-directed mutagenesis. Recombinant CYP142A1 mutants were heterologously expressed, purified, and analyzed using ESI-MS, far-UV CD spectroscopy, UV-vis spectrophotometric titration, and metabolic function assays. Substitution of the cysteine residues caused various effects on the structure and function of CYP142A1. Separate substitution of the six cysteine residues resulted in numerous changes in the secondary structure, expression level, substrate-binding ability, inhibitor-binding ability, thermal stability and oxidation efficiency of the enzyme. These results contribute to our understanding of the biochemical roles of cysteine residues in the structure and function of Mtb CYP enzymes, especially their effects on the structure and function of CYP142A1.

Mintaimycins, a Group of Novel Peptide Metabolites from Micromonospora sp. C-3509.

A group of peptide metabolites (1-4), designated as mintaimycins, were isolated from Micromonospora sp. C-3509. The planar structures of mintaimycins were determined by combination of mass spectrometry, 1D and 2D NMR spectroscopy, and the stereochemistry of mintaimycins were partially resolved by Marfey's or Mosher's method. Mintaimycins featured a central ß-methylphenylalanine or phenylalanine linked at its amino group with 5-methyl-2-hexenoic acid, and at its carboxyl group with 5-hydroxy-norleucine or leucine that combined a derivative of hexanoic acid or 4-methylpentanoic acid. Mintaimycin A1 (1), the principal component, was found to exhibit the biological activity of inducing pre-adipocyte differentiation of 3T3-L1 fibroblast cells at 10.0 µmol/L.

An accessible insight into genetic findings for transplantation recipients with suspected genetic kidney disease.

Determining the etiology of end-stage renal disease (ESRD) constitutes a great challenge in the context of renal transplantation. Evidence is lacking on the genetic findings for adult renal transplant recipients through exome sequencing (ES). Adult patients on kidney transplant waitlist were recruited from 2017 to 2019. Trio-ES was conducted for the families who had multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early onset or extrarenal features. Pathogenic variants were confirmed in 62 from 115 families post sequencing for 421 individuals including 195 health family members as potential living donors. Seventeen distinct genetic disorders were identified confirming the priori diagnosis in 33 (28.7%) families, modified or reclassified the clinical diagnosis in 27 (23.5%) families, and established a diagnosis in two families with ESRD of unknown etiology. In 14.8% of the families, we detected promising variants of uncertain significance in candidate genes associated with renal development or renal disease. Furthermore, we reported the secondary findings of oncogenes in 4.4% of the patients and known single-nucleotide polymorphisms associated with pharmacokinetics in our cohort to predict the drug levels of tacrolimus and mycophenolate. The diagnostic utility of the genetic findings has provided new clinical insight in most families that help with preplanned renal transplantation.

MicroRNA-520c-3p suppresses vascular endothelium dysfunction by targeting RELA and regulating the AKT and NF-κB signaling pathways.

Endothelial injury, which can cause endothelial inflammation and dysfunction, is an important mechanism for the development of atherosclerotic plaque. This study aims to investigate the functional role of miR-520c-3p in vascular endothelium during inflammatory diseases such as atherosclerosis. Quantitative real-time PCR was used to detect miR-520c-3p expression in in human umbilical vein endothelial cells (HUVECs) after treatment with platelet-derived growth factor (PDGF). Furthermore, the effects of miR-520c-3p overexpression and silencing on cell proliferation, adhesion, and apoptosis were assessed. Bioinformatics analysis and Biotin-labeled miRNA pull-down assay were used to confirm the targets of miR-520-3p. Then, the effects of miR-520c-3p on AKT and NF-κB signaling pathways were detected by western blot. Herein, we observed that the expression level of miR-520c-3p was downregulated in HUVECs under PDGF stimulation. Overexpression of miR-520c-3p not only decreased cell adhesion but also promoted proliferation and inhibited apoptosis to protect the viability of endothelial cells. It was confirmed that RELA is the target of miR-520c-3p. MiR-520c-3p inhibited the protein phosphorylation of AKT and RELA, and si-RELA reversed the promotion of AKT and RELA protein phosphorylation by anti-miR-520c-3p. In summary, our study suggested that miRNA-520c-3p targeting RELA through AKT and NF-κB signaling pathways regulated the proliferation, apoptosis, and adhesion of vascular endothelial cells. We conclude that miR-520c-3p may play an important role in the suppression of endothelial injury, which could serve as a biomarker and therapeutic target for atherosclerosis.

Treacher Collins syndrome: Clinical report and retrospective analysis of Chinese patients.

BACKGROUND: Treacher Collins syndrome-1 (TCS1; OMIM# 154500) is a rare autosomal dominant disease that is defined by congenital craniofacial dysplasia. Here, we report four sporadic and one familial case of TCS1 in Chinese patients with clinical features presenting as hypoplasia of the zygomatic complex and mandible, downslanting palpebral fissures, coloboma of the lower eyelids, and conductive hearing loss. MATERIALS AND METHODS: Audiological, radiological, and physical examinations were performed. Targeted next-generation sequencing (NGS) was performed to examine the genetics of this disease in five probands, and Sanger sequencing was used to confirm the identified variants. A literature review discusses the pathogenesis, treatment, and prevention of TCS1. RESULTS: We identified a novel insertion of c.939_940insA (p.Gly314Argfs*35; NM_001135243.1), a novel deletion of c.1766delC (p.Pro589Leufs*7), two previously reported insertions of c.1999_2000insC (p.Arg667Profs*31) and c.4218_4219insG (p.Ser1407Valfs*23), and one previously reported deletion of c.4369_4373delAAGAA (p.Lys1457Glufs*12) in the TCOF1 gene. All five cases exhibited a degree of interfamilial and intrafamilial phenotypic variability. A review of the literature revealed no clear evidence of a genotype-phenotype correlation in TCS1. CONCLUSION: Our results expand the variant spectrum of TCOF1 and highlight that NGS is essential for the diagnosis of TCS and that genetic counseling is beneficial for guiding prevention.

Quantitative proteomics approach to investigate the antibacterial response of Helicobacter pylori to daphnetin, a traditional Chinese medicine monomer.

Helicobacter pylori is a Gram-negative bacterium related to the development of peptic ulcers and stomach cancer. An increasing number of infected individuals are found to harbor antibiotic-resistant H. pylori, which results in treatment failure. Daphnetin, a traditional Chinese medicine, has a broad spectrum of antibacterial activity without the development of bacterial resistance. However, the antibacterial mechanisms of daphnetin have not been elucidated entirely. To better understand the mechanisms of daphnetin's effect on H. pylori, a label-free quantitative proteomics approach based on an EASY-nLC 1200 system coupled with an Orbitrap Fusion Lumos mass spectrometer was established to investigate the key protein differences between daphnetin- and non-daphnetin-treated H. pylori. Using the criteria of greater than 1.5-fold changes and adjusted p value <0.05, proteins related to metabolism, membrane structure, nucleic acid and protein synthesis, ion binding, H. pylori colonization and infection, stress reaction, flagellar assembly and so on were found to be changed under daphnetin pressure. And the changes of selected proteins in expression level were confirmed by targeted proteomics. These new data provide us a more comprehensive horizon of the proteome changes in H. pylori that occur in response to daphnetin.

MicroRNA-520c-3p targeting of RelA/p65 suppresses atherosclerotic plaque formation.

Atherosclerosis is a chronic inflammatory disease, and it's the leading cause of death worldwide. Dysregulation of microRNAs (miRNAs) has been found to be associated with atherosclerosis. miR-520c-3p has been implicated in several types of cancer. However, little is known about the role of miR-520c-3p in atherosclerosis. In this study, we found that miR-520c-3p agomir decreased atherosclerotic plaque size, collagen content, the quantity of PCNA-positive cell and RelA/p65 expression of vascular smooth muscle cells (VSMCs) in the aortic valve of apoE-/- mice in vivo. The possible mechanisms of the protective effects of miR-520c-3p on atherosclerotic mice were then investigated in VSMCs. in vitro experiments showed that miR-520c-3p expressions were significantly reduced in human aortic vascular smooth muscle cell (HASMCs) treated with platelet-derived growth factor (PDGF-BB). miR-520c-3p mimics repress PDGF-BB-mediated the proliferation, migration and decrease in the percentage of cells in G2/M phase, which was associated with downregulation of RelA/p65. Mechanistically, miRNA pull-down, luciferase reporter and mRNA stability assays confirmed miR-520c-3p mimics was able to directly target 3'-UTR of RelA/p65 mRNA and decreased half-life of RelA/p65 mRNA in HASMCs. Overexpression of RelA/p65 reversed the inhibition of cell proliferation induced by miR-520c-3p mimics in HASMCs. In conclusion, our findings suggest that miR-520c-3p inhibits PDGF-BB-mediated the proliferation and migration of HASMCs by targeting RelA/p65, which may provide potential therapeutic strategies in atherosclerosis treatment.

Naringin induces endoplasmic reticulum stress-mediated apoptosis, inhibits ß-catenin pathway and arrests cell cycle in cervical cancer cells.

Naringin is a promising anticancer bioflavonoid phytochemical, mainly extracted from citrus fruits. This study evaluates the antiproliferative effect and the cell death mechanism induced by naringin on cervical cancer (CC) cells. Our results demonstrated that naringin exerts significant inhibition in cell viability and exhibits IC50 value 745, 764, 793 µM against C33A, SiHa, and HeLa cells respectively. Annexin V FITC and immunoblotting analysis reveal significant apoptosis induction in cells exposed to higher doses naringin. Mechanistically, naringin induces endoplasmic reticulum (ER) stress-associated cell killing in CC cells. Naringin increases the protein expression of ER stress sensors, phosphorylates eIF2α by and activates apoptosis-associated protein CHOP and other associated proapoptotic proteins (PARP1 and caspase-3). Intriguingly, pre-treatment with of ER stress inhibitor (salubrinal), reverses the apoptotic effect exerted by naringin. Additionally, the naringin abrogates the ß-catenin pathway by decreasing the protein expression as well as phosphorylation of ß-catenin (Ser576) and GSK-3ß (Ser9) and simultaneously triggers cell cycle arrest at a G0/G1 phase by increasing the expression of cell cycle checkpoint proteins p21/cip and p27/kip. Naringin induces ER stress-mediated apoptosis and simultaneously abrogates Wnt/ß-catenin signaling which eventually triggers the arrest of the cell cycle at a G0/G1 phase in CC cells.

An Intraoperative Multibranch Abnormal Muscle Response Monitoring Method During Microvascular Decompression for Hemifacial Spasm.

BACKGROUND: Intraoperative abnormal muscle response (AMR) is widely used as an indicator during microvascular decompression surgery for hemifacial spasm. Usually only 1 muscle is recorded, and not all patients show a response, leaving the surgery somewhat blinded. We propose an improved method to record from multiple muscles innervated by multiple branches of the facial nerve to increase the positive AMR detection rate. METHODS: Retrospective analysis was performed of 1604 patients with hemifacial spasm undergoing microvascular decompression at a single center. All patients were monitored for AMR by stimulating the zygomatic branch of the facial nerve. Only mentalis was recorded in 158 cases (single-branch AMR). Orbicularis oris, frontalis, and mentalis were simultaneously monitored in 148 cases (3-branch AMR), and platysma was further added in the remaining 1298 cases (4-branch AMR). Positive AMR detection rates were compared across the groups. RESULTS: Total positive AMR detection rates significantly increased as more muscles were included in monitoring and were 74.1% for single-branch AMR, 86.5% for 3-branch AMR, and 98.4% for 4-branch AMR. Detection rates from single muscles were not significantly different across the groups. For all available cases, rates were 73.5% from mentalis, 47.2% from frontalis, 64.1% from orbicularis oris, and 40.8% from platysma. CONCLUSIONS: This new multibranch AMR monitoring method can effectively increase the positive detection rate to as high as 98.4%. It is expected to better assist surgery.

A Rare Case of Duodenal Adenocarcinoma Presenting as a Subepithelial Lesion in a Patient Undergoing Investigation for Iron Deficiency Anaemia.

INTRODUCTION: Adenocarcinomas account for approximately 40% of small bowel cancers. They are typically mucosal lesions with distinctive features on endoscopy. We describe a rare case of duodenal adenocarcinoma presenting as a subepithelial lesion which posed a diagnostic challenge. CASE: An 85-year-old male patient presented for investigation of iron deficiency anaemia. Initial upper endoscopy found a subepithelial duodenal lesion with central depression but otherwise normal appearing mucosa. Superficial biopsies of the duodenal lesion were unremarkable. Subsequent antegrade single balloon enteroscopy revealed active bleeding from the lesion which was refractory to endoscopic treatment. A complete local excision of the lesion via laparotomy was necessary to achieve haemostasis. Histopathology from the lesion showed a moderately differentiated duodenal adenocarcinoma with invasion into the submucosa but no evidence of lymphovascular spread. CONCLUSION: Duodenal adenocarcinomas are rare gastrointestinal tumours associated with a poor prognosis. This case report outlines a rare presentation of duodenal adenocarcinoma and highlights the importance of judicious assessment of lesions found on endoscopy. Advances in endoscopic diagnostic modalities could facilitate early diagnosis and improve therapeutic outcomes.

Cytotoxic and Antibacterial Cervinomycins B1-4 from a Streptomyces Species.

AntiSMASH analysis of genome DNA of Streptomyces CPCC 204980, a soil isolate with potent antibacterial activity, revealed a gene cluster for polycyclic xanthones. A subsequent chemical study confirmed that the microorganism produced polycyclic xanthone cervinomycin A2 (1) and the new congeners cervinomycins B1-4 (2-5). The structures of 1-5 were determined by comprehensive analyses of MS and NMR data, which indicated that 2-5 featured a common dihydro-D ring in the polycyclic xanthone core moiety of their molecules. 2-5 are toxic to human cancer cells and active against Gram-positive bacteria.

Isarubrolones Containing a Pyridooxazinium Unit from Streptomyces as Autophagy Activators.

Isarubrolones are bioactive polycyclic tropoloalkaloids from Streptomyces. Three new isarubrolones (2-4), together with the known isarubrolone C (1) and isatropolones A (5) and C (6, 3( R)-hydroxyisatropolone A), were identified from Streptomyces sp. CPCC 204095. The structures of these compounds were determined using a combination of mass spectrometry, 1D and 2D NMR spectroscopy, and ECD. Compounds 3 and 4 feature a pyridooxazinium unit, which is rarely seen in natural products. Compound 6 could conjugate with amino acids or amines to expand the structural diversity of isarubrolones with a pentacyclic or hexacyclic core. Importantly, 1 and 3-6 were found to induce complete autophagy.

Synergistic Effect of Colistin Combined with PFK-158 against Colistin-Resistant Enterobacteriaceae.

As increasing numbers of colistin-resistant bacteria emerge, new therapies are urgently needed to treat infections caused by these pathogens. The discovery of new combination therapies is one important way to solve such problems. Here, we report that the antitumor drug PFK-158 and its analogs PFK-015 and 3PO can exert synergistic effects with colistin against colistin-resistant Enterobacteriaceae, including mcr-1-positive or high-level-colistin-resistant (HLCR) isolates, as shown by a checkerboard assay. The results of a time-kill assay revealed that colistin combined with PFK-158 continuously eliminated colistin-resistant Escherichia coli 13-43, Klebsiella pneumoniae H04, and Enterobacter cloacae D01 in 24 h. Images from scanning electron microscopy (SEM) at 5 h postinoculation confirmed the killing effect of the combination. Finally, in vivo treatment showed that PFK-158 had a better synergistic effect than its analogs. Compared to the corresponding rates after colistin monotherapy, the survival rates of systemically infected mice were significantly increased 30% or 60% when the mice received an intravenous injection of colistin in combination with 15 mg/kg of body weight PFK-158. These results have important implications for repurposing PFK-158 to combat colistin resistance.