Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors.

Immunometabolic reprogramming due to adenosine produced by CD73 (encoded by the 5'-ectonucleotidase gene NT5E) is a recognized immunosuppressive mechanism contributing to immune evasion in solid tumors. Adenosine is not only known to contribute to tumor progression, but it has specific roles in driving dysfunction of immune cells, including natural killer (NK) cells. Here, we engineered human NK cells to directly target the CD73-adenosine axis by blocking the enzymatic activity of CD73. In doing so, the engineered NK cells not only impaired adenosinergic metabolism driven by the hypoxic uptake of ATP by cancer cells in a model of non-small-cell lung cancer, but also mediated killing of tumor cells due to the specific recognition of overexpressed CD73. This resulted in a 'single agent' immunotherapy that combines antibody specificity, blockade of purinergic signaling, and killing of targets mediated by NK cells. We also showed that CD73-targeted NK cells are potent in vivo and result in tumor arrest, while promoting NK cell infiltration into CD73+ tumors and enhancing intratumoral activation.

Investigation of Brucellosis Caused by Raw Goat Milk - Fujian Province, China, April-June, 2019.

What is already known about this topic? Brucellosis is one of the most important zoonotic diseases in China. Goat milk and dairy products are essential pathways for foodborne transmission of brucellosis. Pasteurization can completely kill Brucellaspp. in milk, and milk-borne transmission is mainly related to unhealthy dietary hygiene habits and insufficient epidemic control among animals. What is added by this report? This epidemic is the first outbreak of brucellosis in Zhangping City, Fujian Province. A total of 6 confirmed cases were found, and the onset time was from April to June 2019. The investigation suggested that the transmission chain of the epidemic included a private butcher, an infected goat from the north, a dairy farmer, close contact spread, unsterilized goat milk, and consumers drinking raw goat milk. What are the implications for public health practices? For the non-endemic area of brucellosis, preventing the import of infected animals and enhancing the practitioner's and the public's awareness of disease prevention has important public health significance. It is necessary to strengthen the transregional quarantine of livestock, the food safety inspection and management, and the practitioners' and public's awareness of food safety.

Terahertz Birefringent Biomimetic Aerogels Based on Cellulose Nanofibers and Conductive Nanomaterials.

Biomimetic, lamellar, and highly porous transition-metal carbide (MXene) embedded cellulose nanofiber (CNF) aerogels are assembled by a facile bidirectional freeze-drying approach. The biopolymer aerogels have large-scale, parallel-oriented micrometer-sized pores and show excellent mechanical strength and flexibility, tunable electrical properties, and low densities (2.7-20 mg/cm3). The CNF, MXene, and lamellar pores are efficiently utilized to endow the aerogels with exceptionally high birefringence in the terahertz (THz) regime. Birefringence values as high as 0.09-0.27 at 0.4 THz are achieved, which is comparable to most commercial THz birefringent materials such as liquid crystals, which suffer from fast disintegration, high cost, and complicated preparation processes. Empirical modeling for different MXene contents and an experimental comparison with silver nanowire or carbon nanotube embedded CNF aerogels suggest that the intrinsic conductivity and content of embedded nanomaterials, the aerogel porosity, and the lamellar cell walls can affect the optical properties such as the THz birefringence and absorption. The determination of optical anisotropy in the biopolymer aerogels lays a foundation for further exploration of ultralight, freestanding, and low-cost biomimetic porous architecture-based THz devices.

Synthesis of the Tricyclic Picrotoxane Motif by an Oxidative Cascade Cyclization.

An oxidative cascade cyclization of ß-keto esters has been developed for the construction of the tricyclic picrotoxane motif in a single step, and DFT calculations suggested a possible cationic cyclization mechanism. This cascade cyclization can be operated on a 20 g scale to obtain a 77% total yield of the tricyclic products, which in turn can be converted to versatile intermediates for further elaboration to picrotoxanes and their structurally related compounds.

In(OTf)3-Catalyzed Cascade Cyclization for Construction of Oxatricyclic Compounds.

A highly diastereoselective cascade cyclization reaction has been developed for establishing a series of oxatricyclic compounds using Chan's diene and simple keto alkynal substrates with only 1 mol % of In(OTf)3 as the catalyst in 82-92% yields. The potential utility of this synthetic strategy has been demonstrated in model studies for the construction the core structures of 1α,8α:4α,5α-diepoxy-4,5-dihydroosmitopsin and cortistatin A.

The Chinese herbal formula Free and Easy Wanderer ameliorates oxidative stress through KEAP1-NRF2/HO-1 pathway.

Posttraumatic stress disorder (PTSD) gains a lot of attention due to high prevalence and strong psychological upset, but the etiology remains undefined and effective treatment is quite limited. Growing studies demonstrated the involvement of oxidative stress in various psychiatry diseases, suggesting anti-oxidation therapy might be a strategy for PTSD treatment. Free and Easy Wanderer (FAEW) is a poly-herbal drug clinically used in China for hundreds of years in the treatment of psychiatric disorder. We hypothesized that FAEW exerts clinical effects through the activity against oxidative stress with fluoxetine as antidepressant control drug. Our results revealed that FAEW significantly reduced both endogenous and H2O2-induced exogenous ROS levels in the human glioblastoma T98G and neuroblastoma SH-SY5Y cell lines. Transcriptome-wide microarray analysis indicated NRF2/HO-1 as the common target of FAEW and fluoxetine. Western blotting assay proved that the two drugs promoted NRF2 release from KEAP1 in the cytoplasm and translocation to the nuclei in a KEAP1-dependent manner, the expression of the protein HO-1 increased accordingly, suggesting the participation of KEAP1-NRF2/HO-1 pathway. The chemical constituents of FAEW (i.e. paeoniflorin, baicalin) bound to KEAP1 in silico, which hence might be the effective substances of FAEW. In conclusion, FAEW counteracted H2O2-induced oxidative stress through KEAP1-NRF2/HO-1 pathway.

Identification of NF-κB as Determinant of Posttraumatic Stress Disorder and Its Inhibition by the Chinese Herbal Remedy Free and Easy Wanderer.

Posttraumatic stress disorder (PTSD) is a mental disorder developing after exposure to traumatic events. Although psychotherapy reveals some therapeutic effectiveness, clinically sustainable cure is still uncertain. Some Chinese herbal formulae are reported to work well clinically against mental diseases in Asian countries, but the safety and their mode of action are still unclear. In this study, we investigated the mechanisms of Chinese remedy free and easy wanderer (FAEW) on PTSD. We used a reverse pharmacology approach combining clinical data to search for mechanisms of PTSD with subsequent in vitro verification and bioinformatics techniques as follows: (1) by analyzing microarray-based transcriptome-wide mRNA expression profiling of PTSD patients; (2) by investigating the effect of FAEW and the antidepressant control drug fluoxetine on the transcription factor NF-κB using reporter cell assays and western blotting; (3) by performing molecular docking and literature data mining based on phytochemical constituents of FAEW. The results suggest an involvement of inflammatory processes mediated through NF-κB in the progression of PTSD. FAEW was non-cytotoxic in vitro and inhibited NF-κB activity and p65 protein expression. FAEW's anti-inflammatory compounds, i.e., paeoniflorin, isoliquiritin, isoliquiritin apioside and ononin were evaluated for binding to IκK and p65-RelA in a molecular docking approach. Paeoniflorin, albiflorin, baicalin, isoliquiritin and liquiritin have been reported to relieve depression in vivo or in clinical trials, which might be the active ingredients for FAEW against PTSD.

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance.

We systematically characterised multifactorial multidrug resistance (MDR) in CEM/ADR5000 cells, a doxorubicin-resistant sub-line derived from drug-sensitive, parental CCRF-CEM cells developed in vitro. RNA sequencing and network analyses (Ingenuity Pathway Analysis) were performed. Chromosomal aberrations were identified by array-comparative genomic hybridisation (aCGH) and multicolour fluorescence in situ hybridisation (mFISH). Fifteen ATP-binding cassette transporters and numerous new genes were overexpressed in CEM/ADR5000 cells. The basic karyotype in CCRF-CEM cells consisted of 47, XX, der(5)t(5;14) (q35.33;q32.3), del(9) (p14.1), +20. CEM/ADR5000 cells acquired additional aberrations, including X-chromosome loss, 4q and 14q deletion, chromosome 7 inversion, balanced and unbalanced two and three way translocations: t(3;10), der(3)t(3;13), der(5)t(18;5;14), t(10;16), der(18)t(7;18), der(18)t(21;18;5), der(21;21;18;5) and der(22)t(9;22). CCRF-CEM consisted of two and CEM/ADR5000 of five major sub-clones, indicating genetic tumor heterogeneity. Loss of 3q27.1 in CEM/ADR5000 caused down-regulation of ABCC5 and ABCF3 expression, Xq28 loss down-regulated ABCD1 expression. ABCB1, the most well-known MDR gene, was 448-fold up-regulated due to 7q21.12 amplification. In addition to well-known drug resistance genes, numerous novel genes and genomic aberrations were identified. Transcriptomics and genetics in CEM/AD5000 cells unravelled a range of MDR mechanisms, which is much more complex than estimated thus far. This may have important implications for future treatment strategies.

A Five-year Survey of Cancer Prevalence in Sudan.

BACKGROUND: While cancer epidemiology is well-investigated in developed countries, the cancer burden in Africa is less well documented. We provide cancer statistics of 33,201 patients from all Sudan diagnosed at the Radiation and Isotope Centre in Khartoum (RICK). This hospital covers approximately 80% of patients with cancer in Sudan and is, therefore, considered representative for the situation in this country. MATERIALS AND METHODS: Data from 2009-2013 were collected at RICK. Cancer diagnoses were made by standard pathological and radiological methods. Epidemiological data were categorized by age, gender, resident state, marital status etc. and subjected to statistical analyses by SPSS 21v. RESULTS: The cancer prevalence rate per year was 5,000-7,000 among adults and 300-400 among children, with increasing tendency for adults. Male:female ratios were 1:1.18 for adults and 1.46:1 for children. The five most frequent tumour types were breast cancer, leukaemia, prostatic carcinoma, lymphoma and colorectal carcinoma in adults and leukaemia, lymphoma, eye tumours, sarcoma and brain tumours in children. Remarkably, the median age of cancer diagnosis was 10-20 years higher in men than in women, mainly due to earlier onset of gender-related tumours in females (cancer of breast, cervix, or ovary) than in men (prostatic carcinoma). Chronic myeloid leukaemia was the most frequent haematopoietic malignancy in adults and acute lymphoblastic leukaemia in children. Comparing cancer cases with population numbers of Sudanese states, Northern Sudan, River Nile and Khartoum revealed up to 8-fold higher cancer incidence rates than Al Gedarif, Southern Dafur and Blue Nile. The other states had intermediate incidence rates. Interestingly, oesophageal carcinoma occurred proportionally more frequently in Kassala (rank 3) than in the entire Sudan (rank 7) or other states. CONCLUSION: This is the largest survey on cancer burden in Sudan. It may serve as basis for governmental programmes for assessing risk factors, improving cancer prevention (e.g. by educational and vaccination programmes) and cancer therapy in the future.

Targeting epidermal growth factor receptors and downstream signaling pathways in cancer by phytochemicals.

Epidermal growth factor receptors (EGFR, HER2, HER3) activate signal transduction pathways involved in cancer proliferation, apoptosis, differentiation, metastasis, and angiogenesis. Their overexpression and activation are associated with unfavorable prognosis of cancer patients. Therefore, they are attractive targets for cancer therapy. Due to the development of drug resistance, therapeutic monoclonal antibodies and synthetic small molecule tyrosine kinase inhibitors directed against EGFR family members may fail with fatal consequences for cancer patients. Medicinal plants raised considerable interest during the past years as valuable resources to develop novel treatment therapies targeting epidermal growth factor receptors and their downstream signal transduction pathways. The present review gives an overview of isolated phytochemicals that inhibit these signaling routes. Inhibitors have been described that down-regulate the mRNA or protein expression of EGFR, HER2, or HER3 or inhibit the phosphorylation of these receptors and/or their downstream signaling kinases. Remarkably, a wealth of in vivo experiments complemented in vitro data, indicating that natural products are also active in living animals bringing this research concept closer to clinical applicability. The combination of receptor-inhibiting natural product with standard anticancer drugs frequently caused increased or even synergistic tumor inhibition in vitro and in vivo. It deserves further evaluation, if and how epidermal growth factor receptor-targeting natural products can be integrated into clinical oncology as well as to define their role for more tumor-specific and individualized tumor therapies.

Systemic study on the biogenic pathways of yezo'otogirins: total synthesis and antitumor activities of (±)-yezo'otogirin C and its structural analogues.

A systematic study of the biomimetic pathways to yezo'otogirin C under aerobic and anaerobic conditions has been investigated, and both are found to be feasible pathways to the natural product depending on the physiological conditions. Because of the lower activation energy, the aerobic process would be more favorable when the in vivo oxygen level is high. In the course of this study, a highly efficient synthetic route to (±)-yezo'otogirin C has been established in four steps (31% overall yield) from a readily available compound without using any protecting groups. The natural product and its structural analogues exhibited antitumor activities against several human cancer cell lines and appeared to arrest cell cycles in different phases.

Posttraumatic stress disorder among earthquake survivors of the Wenchuan area (Sichuan, China).

BACKGROUND: On May 12, 2008, an earthquake with a power of 8.0 M on the Richter scale occurred in the Wenchuan County of Sichuan Province in southwest China, which was unprecedented in magnitude and aftermath. Approximately 70,000 people were killed and nearly 20,000 went missing. The earthquake caused a wide number of mental and physical health outcomes among survivors, and posttraumatic stress disorder (PTSD) was one of the most commonly studied. METHODS: We conducted a systematic overview to assess research achievements about PTSD in the past 6 years after the Wenchuan earthquake, including symptoms and risk factors about PTSD among Wenchuan earthquake survivors, as well as research developments in genetics, molecular biology, and treatment of PTSD. RESULTS: The large body of research conducted after the Wenchuan earthquake suggests that the burden of PTSD among persons with high exposure was substantial. Adolescents and adults were among the most studied populations with high prevalence rates. Phytotherapy with Chinese herbs as well as acupuncture were rarely studied as of yet, although published data indicated promising therapy effects. Genome-wide microarray technologies are widely used in experimental mice and rat models to study PTSD mechanisms as well as in patients suffering from PTSD and other psychosomatic disorders to search for novel biomarkers and to monitor the effectiveness of treatment interventions. CONCLUSIONS: Using genomic and transcriptomic technologies, our future research will focus on the efficacy and safety of Chinese medicine to find potential interventions and effective treatments of PTSD.

Bioreducible cross-linked polymers based on G1 peptide dendrimer as potential gene delivery vectors.

A series of cationic polymers based on low generation (G1) peptide dendrimer were synthesized with disulfide-containing linkages. The DNA binding abilities of the target polymers were studied by gel electrophoresis and fluorescence quenching assay. The bioreducible property of the disulfide-containing polymers P2 and P3 was also investigated in the presence of dithiothreitol (DTT). Results from dynamic light scattering (DLS) and transmission electron microscopy (TEM) assays reveal that these materials may condense DNA into nanoparticles with proper sizes and zeta-potentials. In vitro cell experiments show that compared to branched 25 KDa PEI, P2 and P3 may exhibit much higher gene transfection efficiency and lower cytotoxicity in both HEK293 and U-2OS cells. Additionally, polymer prepared from Michael addition gives better gene transfection ability, while polymer prepared from ring-opening reaction has better serum tolerance. Results indicate that these polymers might be promising non-viral gene vectors for their easy preparation, very low cytotoxicity, and good transfection efficiency.

[Comparative study on characteristics of congestive heart failure patients with preserved versus abnormal left ventricular systolic function and evaluation effects of therapy].

OBJECTIVE: To compare clinical characteristics and effects of therapy for hospitalized patients with congestive heart failure (CHF) and different left ventricular ejection fraction (LVEF) during hospitalization. METHODS: The medical records of 1 074 unselected consecutive patients with CHF who were admitted to Queen Mary Hospital from January, 2001 to January, 2002 were retrospectively reviewed. Three hundred and ninety-nine patients were categorized as having either normal left ventricular systolic function or systolic dysfunction based on the results of echocardiography. Clinical features with a slightly modified version of the Framingham criteria, laboratory results and drug therapies at discharge were compared. RESULTS: Among patients, the majority were women, 95.5% were > or =65 years and 50.6% > or =80 years of age. Classification of the severity of heart failure showed that 70.2% were New York Heart Association (NYHA) III and IV. Only 399 patients had borderline LVEF at the time of hospitalization, of these patients 191 (47.9%) had preserved systolic function (LVEF > or =0.50), and 208 (52.1%) with LVEF<0.50. Patients with LVEF > or =0.50, who tended to be elderly and more often female, exhibited a lower incidence of coronary artery disease and diabetes than patients with LVEF<0.50 (all P<0.05). Patients with preserved systolic function had a significantly higher prevalence of auricular fibrillation (P<0.05), accounting for up to 84 patients (44.0%) with it, and number of hospitalization for CHF increased. Among patients with systolic dysfunction, 22.6% were discharged on a therapeutic regimen of digoxin, 63.0% on an angiotensin-converting enzyme inhibitor (ACEI), and 12.0% on a beta-blocker, 13.9% on a calcium channel blocker. These accounted for 62.3%, 35.1%, 9.4% and 18.3% in patients with preserved systolic function, respectively. There was a higher incidence of use of digoxin (P<0.05). CONCLUSION: In hospitalized patients with heart failure, the clinical signs and symptoms of chronic heart failure are similar to those of patients with CHF, LVEF is a powerful prognostic predictor to distinguish CHF patients with normal systolic function from those with systolic dysfunction. Criteria for use of ACEI and beta-blocker are still not clear cut. It is important to differentiate CHF patients with LVEF<0.50 from that with LVEF> or =0.50 in order to achieve a better therapeutic result in the treatment of CHF.