Discovery of cinnamylaldehyde-derived mono-carbonyl curcumin analogs as anti-gastric cancer agents via suppression of STAT3 and AKT pathway.

The structural modification of curcumin has always been a hotspot in drug development. In this paper, a class of cinnamylaldehyde-derived mono-carbonyl curcumin analogs (MCAs) with 7-carbon-links were designed and synthesized and their anticancer properties were evaluated. Through screening anti-gastric cancer activity of these compounds, H1 exhibited the strongest cytotoxic activity by inhibiting cell viability and colony formation, inducing cell cycle G2/M phase arrest in vitro (SGC-7901 and AGS gastric cancer cells). Moreover, the SGC-7901 subcutaneous tumor-bearing mice studies revealed that H1 significantly inhibited the tumor growth of gastric cancer. We explored the possible potential targets of H1 through network pharmacology. Mechanistically, our results demonstrated that H1 showed potential anti-gastric cancer activity through suppression of the STAT3 and AKT signaling pathway in vitro and in vivo, which was validated by molecular docking. Overall, our results indicate the potential of H1 as a potent chemotherapeutic drug against gastric cancer.

An Immunoassay for Human Chorionic Gonadotropin in Cerebrospinal Fluid: Validation of a Modified-Approved Method for Accreditation by the College of American Pathologists.

Background Human chorionic gonadotropin (hCG) detection in cerebrospinal fluid (CSF) can provide additional value in the diagnosis of germinoma. However, matrix effects can influence the results when alternative sample types are used. Therefore, modified-cleared/approved methods, which are standard methods used outside their intended scope, are of interest. The aim of the present study was to establish a model to validate modified-approved methods in agreement with the College of American Pathologists (CAP) accreditation requirements. Methods Concentrations of hCG in CSF were determined by means of electrochemiluminescence immunoassay using a Roche Cobas e 602 immunoassay analyzer. Based on the intended use, the following performance characteristics were evaluated: precision, the limit of quantitation (LoQ), and the analytical measurement range (AMR). The reference interval (RI) was also established. For the clinical application study, CSF and serum hCG were measured in 10 patients diagnosed with germinoma. Results The intra- and inter-assay precisions at two levels (10, 250 IU/L) were 0.64 and 0.57% and 4.26 and 3.54%, respectively. The LoQ for hCG was determined to be 0.25 IU/L. The AMR was set from 0.2 to 1,200 IU/L. The RI for hCG in CSF was below 0.40 IU/L. The CSF hCG levels of 10 patients were all above 0.4 IU/L before therapy. Conclusion Modified-approved methods were validated and showed that the quality specifications of the medical laboratory have a positive value in the clinical context. The illustration of quantification of hCG in CSF resulted in compliance with the CAP accreditation requirements.

Short-term outcomes of robotic versus open pancreaticoduodenectomy in elderly patients: A multicenter retrospective cohort study.

BACKGROUND: With the advances in surgical techniques and perioperative management, the surgical indications for pancreaticoduodenectomy have been extended to elderly patients. Whether robotic pancreaticoduodenectomy (RPD) is superior to open pancreaticoduodenectomy (OPD) in older patients remains uncertain. Thus, this study aimed to compare perioperative outcomes between RPD and OPD in elderly patients. METHODS: The demographics and perioperative outcomes of a consecutive series of elderly patients (aged ≥75 years) who underwent RPD or OPD at seven pancreatic centers in China between July 2011 and July 2020 were retrospectively analyzed. RESULTS: Of the 302 patients included in this study, 169 underwent RPD and 133 underwent OPD. The RPD group had a shorter operative time (OT) (264.3 vs. 278.2 min, P = 0.01) and less estimated blood loss (EBL) (100 (50 150) vs. 200 (150 300) mL, P < 0.001) than the OPD group. RPDs in 3 (1.8%) patients were converted to OPD. The postoperative length of stay (LOS) after RPD was significantly shorter than that after OPD (13.0 vs. 17.0 days, P < 0.001). No significant differences were found in the rates of clinically relevant postoperative pancreatic fistula, bile leakage, delayed gastric emptying, postoperative pancreatectomy hemorrhage, major morbidity, reoperation, 90-day readmission, or 90-day mortality between the two groups (P > 0.05). The multivariate logistic regression analysis revealed that type 2 diabetes, chronic obstructive pulmonary disease, postoperative hemorrhage, and cardiac events were independent risk factors for postoperative 90-day mortality. CONCLUSIONS: This study demonstrated that RPD was comparable to OPD in terms of safety and feasibility in elderly patients with shorter OT, lower EBL, and shorter postoperative LOS. Surgical approach was not an independent risk factor for 90-day mortality.

Pan-cancer analysis reveals homologous recombination deficiency score as a predictive marker for immunotherapy responders.

The immune context of the tumor microenvironment (TME) is critical for effective immunotherapy. Nonetheless, DNA-based biomarkers for the immune-sensitive TME and the identification of immune checkpoint inhibitor (ICI) responders are under-explored. This study aims to comprehensively landscape the homologous recombination deficiency (HRD) score, an emerging hallmark for tumor genome instability that triggers immune responsiveness across major cancer types, and to unveil their link to the TME and immunotherapeutic response. The HRD-associated genomic scars were characterized in 9088 tumor samples across 32 cancer types from TCGA. We evaluated the HRD score's performance in classifying ICI responders using an independent breast cancer cohort (GSE87049) and 11 in vivo murine mammary tumor models treated with anti-PD1/CTLA4 regimen (GSE124821). This study revealed a broad association between HRD-high genotype and neoantigenesis in the major cancer types including bladder cancer, breast cancer, head and neck squamous carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, and sarcoma. Tumors with high HRD score bears increased leukocyte infiltration and lymphocyte fraction and demonstrated immune-sensitive microenvironment. The tumor immune dysfunction and exclusion (TIDE) model further confirmed HRD score-high genotype as a potential predictor for ICI immunotherapy responders in breast cancer. In conclusion, tumors with high HRD score exhibit an immune-sensitive TME. The HRD-high genotype is a promising marker for identifying ICI therapy responders among breast cancer patients.

Establishment of reference intervals of monomeric prolactin to identify macroprolactinemia in Chinese patients with increased total prolactin.

BACKGROUND: Macroprolactin is responsible for pseudohyperprolactinemia and is a common pitfall of the prolactin immunoassay. We aimed to determine the frequency of macroprolactinemia in Chinese hyperprolactinemic patients using monomeric prolactin discriminated by precipitation with polyethylene glycol (PEG). METHODS: Post-PEG monomeric prolactin gender-specific reference intervals were established for the Elecsys immunoassay method (Roche Diagnostics) using sera from healthy female (n = 120) and male (n = 120) donors. The reference intervals were validated using 20 macroprolactinemic (as assessed by gel filtration chromatography (GFC)) sera samples, and presence of monomeric prolactin was discriminated by GFC. Patients with high total prolactin were then screened by PEG precipitation to analyze macroprolactin. The demographic and biochemical details of patients with true hyperprolactinemia and macroprolactinemia were compared. RESULTS: Reference intervals for monomeric prolactin in females and males were 3.4-18.5 and 2.7-13.1 ng/mL, respectively. Among 1140 hyperprolactinemic patients, macroprolactinemia was identified in 261 (22.9 %) patients while the other 879 (77.1 %) patients were diagnosed with true hyperprolactinemia. Menstrual disturbances were the most common clinical feature in both groups. Galactorrhea, amenorrhea, and visual disturbances occurred more frequently in true hyperprolactinemic patients (P < 0.05). CONCLUSIONS: The prevalence of macroprolactin in Chinese patients with hyperprolactinemia was described for the first time. Monomeric prolactin concentration, along with a reference interval screening with PEG precipitation, provides a diagnostic approach for hyperprolactinemia with improved accuracy.

Evolution of Intestinal Gases and Fecal Short-Chain Fatty Acids Produced in vitro by Preterm Infant Gut Microbiota During the First 4 Weeks of Life.

Background: The production of intestinal gases and fecal short-chain fatty acids (SCFAs) by infant gut microbiota may have a significant impact on their health, but information about the composition and volume of intestinal gases and SCFA profiles in preterm infants is scarce. Objective: This study examined the change of the composition and volume of intestinal gases and SCFA profiles produced by preterm infant gut microbiota in vitro during the first 4 weeks of life. Methods: Fecal samples were obtained at five time points (within 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks) from 19 preterm infants hospitalized in the neonatal intensive care unit (NICU) of Shanghai Children's Hospital, Shanghai Jiao Tong University between May and July 2020. These samples were initially inoculated into four different media containing lactose (LAT), fructooligosaccharide (FOS), 2'-fucosyllactose (FL-2), and galactooligosaccharide (GOS) and thereafter fermented for 24 h under conditions mimicking those of the large intestine at 37.8°C under anaerobic conditions. The volume of total intestinal gases and the concentrations of individual carbon dioxide (CO2), hydrogen (H2), methane (CH4), and hydrogen sulfide (H2S) were measured by a gas analyzer. The concentrations of total SCFAs, individual acetic acid, propanoic acid, butyric acid, isobutyric acid, pentanoic acid, and valeric acid were measured by gas chromatography (GC). Results: The total volume of intestinal gases (ranging from 0.01 to 1.64 ml in medium with LAT; 0-1.42 ml with GOS; 0-0.91 ml with FOS; and 0-0.44 ml with FL-2) and the concentrations of CO2, H2, H2S, and all six fecal SCFAs increased with age (p-trends < 0.05). Among them, CO2 was usually the predominant intestinal gas, and acetic acid was usually the predominant SCFA. When stratified by birth weight (<1,500 and ≥1,500 g), gender, and delivery mode, the concentration of CO2 was more pronounced among infants whose weight was ≥1,500 g than among those whose weight was <1,500 g (p-trends < 0.05). Conclusions: Our findings suggested that the intestinal gases and SCFAs produced by preterm infant gut microbiota in vitro increased with age during the first 4 weeks of life.

Increasing yield potential through manipulating of an ARE1 ortholog related to nitrogen use efficiency in wheat by CRISPR/Cas9.

Wheat (Triticum aestivum L.) is a staple food crop consumed by more than 30% of world population. Nitrogen (N) fertilizer has been applied broadly in agriculture practice to improve wheat yield to meet the growing demands for food production. However, undue N fertilizer application and the low N use efficiency (NUE) of modern wheat varieties are aggravating environmental pollution and ecological deterioration. Under nitrogen-limiting conditions, the rice (Oryza sativa) abnormal cytokinin response1 repressor1 (are1) mutant exhibits increased NUE, delayed senescence and consequently, increased grain yield. However, the function of ARE1 ortholog in wheat remains unknown. Here, we isolated and characterized three TaARE1 homoeologs from the elite Chinese winter wheat cultivar ZhengMai 7698. We then used CRISPR/Cas9-mediated targeted mutagenesis to generate a series of transgene-free mutant lines either with partial or triple-null taare1 alleles. All transgene-free mutant lines showed enhanced tolerance to N starvation, and showed delayed senescence and increased grain yield in field conditions. In particular, the AABBdd and aabbDD mutant lines exhibited delayed senescence and significantly increased grain yield without growth defects compared to the wild-type control. Together, our results underscore the potential to manipulate ARE1 orthologs through gene editing for breeding of high-yield wheat as well as other cereal crops with improved NUE.

A novel Twist1/hsa-miR138-5p/caspase-3 pathway regulates cell proliferation and apoptosis of human multiple myeloma.

The nuclear transcription factor twist-related protein 1 (Twist1) is associated with tumor malignant transformation and metastasis in various types of carcinomas. We found that Twist1 was highly expressed in clinical multiple myeloma (MM) cells, and explored its roles in proliferation and apoptosis in human MM cell lines U266 and RPMI-8226. In these cells, Twist1 transcriptionally regulated the miRNA hsa-miR138-5p, which targeted caspase-3 to control apoptosis. Silencing of Twist1 significantly suppressed cell proliferation and increased apoptosis, which was reversed by overexpression of hsa-miR138-5p or simultaneous silencing of caspase-3. This reversion was further substantiated by attenuated apoptotic signaling, including downregulated expression of the cleaved forms of caspase-3 and peroxisome proliferator-activated receptor 1 (PPAR1). We demonstrate here for the first time that the novel Twist1/hsa-miR138-5p/caspase-3 pathway contributes significantly to the proliferation and survival of human MM cells. Our study provides new insight for novel MM treatments by developing Twist1-targeted therapeutics.

The effect of total lignans from Fructus Arctii on Streptozotocin-induced diabetic retinopathy in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Arctii is the dried ripe fruit of Arctium lappa L. (family Asteraceae). It is a well-known Chinese Materia Medica that was included in the Chinese pharmacopoeia because of its traditional therapeutic actions, such as heat removal, detoxification, and elimination of swelling. Since ancient times Fructus Arctii has been used extensively in a number of classical drug formulas to treat type 2 diabetes mellitus. Modern pharmacological studies have shown that certain components of Fructus Arctii have multiple physiological activities on type 2 diabetes and its complications. AIM OF THE STUDY: We have reported the inhibitory effect of total lignans from Fructus Arctii (TLFA) on aldose reductase, the key enzyme in the polyol pathway, which is considered to be closely related to the onset of diabetic retinopathy (DR). The present study aimed to observe the preventive and therapeutic effects of TLFA on DR in Streptozotocin (STZ)-induced DR rats. MATERIALS AND METHODS: TLFA was prepared from Fructus Arctii and its content was determined using UV spectrophotometry. The DR model was induced by STZ in Wistar rats. For DR prevention, the animals were gavaged once daily for 9 weeks with TLFA (1.38, 0.69, and 0.35 g/kg/day) as soon as they were confirmed as diabetes models. Pathological changes to retinal tissues and the expression of vascular endothelial growth factor (VEGF) and protein kinase C (PKC) in the retina were detected after TLFA treatment. The effects of TLFA on blood glucose levels and body weight were also observed. For DR treatment, the animals were gavaged once daily for 12 weeks with TLFA (1.38 and 0.69 g/kg/day) at 3 months after they were confirmed as diabetes models. The therapeutic effect was studied using quantitative detection of blood-retina barrier (BRB) breakdown via an Evans Blue leakage assay. RESULTS: For DR prevention, after 9 weeks of TLFA administration, histopathological examination of retinal tissue showed that TLFA improved the lesions in the retina. Changes to retinal microstructures such as capillaries, ganglion cells, bipolar cells, and the membrane disk examined by electron microscopy further confirmed that TLFA has a preventive effect on retinopathy. Terminal deoxynucleotidyl Transferase-mediated dUTP nick end labeling (TUNEL) detection showed that TLFA could inhibit retinal cell apoptosis in the diabetic rats, and fasting blood glucose (FBG) levels of rats in the TLFA-treated groups decreased during the experiment. For DR treatment, after 3 months of administration, the amount of dye leakage in the TLFA-administered groups was reduced by more than 50% compared with that in the model group, which indicated that TLFA has a therapeutic effect on middle and late DR. Messenger RNA (mRNA) expression of VEGF and PKCß2 in the retina detected by real-time fluorescent quantitative reverse transcription-polymerase chain reaction (FQ-RT-PCR) showed that TLFA could inhibit the expression of them, which was consistent with the results of immunohistochemistry (IHC). CONCLUSION: TLFA has a preventive and therapeutic effect on DR. Its mechanism of action on DR is related to inhibiting PKC activation and blocking VEGF elevation.

RETRACTED: miR-141 alleviates LPS-induced inflammation injury in WI-38 fibroblasts by up-regulation of NOX2.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors, as they state that the data are not reproducible. The author states that the original data of the experiments do not possess reproductivity in their recent study, and that the obtained Figures 2-4 vary under different experiments.

Progress in Experimental and Clinical Research of the Diabetic Retinopathy Treatment Using Traditional Chinese Medicine.

Diabetic retinopathy (DR), one of the most common microvascular complications of diabetic mellitus, is currently the main cause of adult-acquired blindness. The pathogenesis of DR is complex and the current clinical application of various treatment methods cannot completely prevent the development of this disease. Many reports have been published regarding the treatment of DR with Traditional Chinese Medicine (TCM), which has received increasing attention from medical practitioners worldwide. Studies published between 1994 and April 2017 were collected from the CNKI, VIP, Medline and Web of Science databases, as well as from Chinese traditional books and Chinese Pharmacopoeia, subsequently obtaining more than 550 studies. Thereafter, the status quo of DR treatment using TCM had been summarized according to four aspects - compound formula therapy, Chinese herbal medicine extracts and monomer therapy, integrated traditional Chinese and Western medicine therapy, and Chinese medicine external treatment. According to the literature reviewed herein, TCM has had definite effects on the prevention and treatment of DR, especially when used in combination with modern medical methods. However, the lack of a unified standard on the syndrome differentiation of DR and the lack of support of evidence-based medicine theory in clinical practice have been consistent concerns in previous research studies and needs to be addressed in subsequent studies.

Arbuscular mycorrhiza fungi facilitate rapid adaptation of Elsholtzia splendens to copper.

Closely associated microbes have been shown to drive local adaptation of plants. However, few studies provide direct evidence, disclosing the role of arbuscular mycorrhiza fungi (AMF) in their rapid adaptation of plants toward heavy metal tolerance. Elsholtzia splendens is a Cu-tolerant plant that was used as a model plant to study seed morphological traits as well as traits related to seed germination and seedling growth. This was achieved after acclimation for two generations with 1000mg/kg CuSO4 in either absence or presence of AMF. In the absence of AMF, acclimation to Cu for two generations significantly decreased surface area, perimeter length, and perimeter width of E. splendens seeds, as well as seedling survival rate and fresh weight of the radicle of seedlings. However, in the presence of AMF, both the germination rate and the germination index of E. splendens seeds as well as the fresh weights of hypocotyl and radicle significantly increased. These results revealed that after Cu acclimation treatment, seeds and seedlings that had been inoculated with AMF outperformed those without AMF inoculation under Cu addition, indicating that AMF can facilitate rapid adaptation of E. splendens to Cu stress. In addition, two generations of Cu acclimation under AMF absence significantly increased radicle length, while amplitude increased under AMF presence, indicating that the direct adaptive plasticity response of radicle length to Cu stress helps with the Cu stress adaptation of E. splendens.

[Effects of pellet characteristics on L-lactic acid fermentation by Rhizopus oryzae].

OBJECTIVE: Effects of pellet morphology, diameter, density, and interior structure on L-lactic acid fermentation by Rhizopus oryzae were characterized for different inoculum sizes and concentrations of peptone and CaCO3. METHODS: Different initial spore concentrations were inoculated in the preculture medium with different peptone and CaCO3 concentrations, and cultivated at 30 degrees C for 36 h. Representative pellets were chosen for interior structure analysis and L-lactic acid production. RESULTS: Inoculum size was the most important factor determining pellet formation and diameter. Peptone concentration had the greatest effect on pellet density. L-lactic acid production depended heavily on pellet density but not on pellet diameter. Low-density pellets formed easily under conditions of low peptone concentration and often had a relatively hollow structure. This structure greatly decreased production. The production of L-lactic acid increased until the density reached a certain level (50 - 60 kg/m3) , which the compact part distributed homogeneously in the thick outer layer of the pellet, and loose in the central layer. Homogeneously structured, denser pellets limited mass transfer. CaCO, concentration only had a slight influence on pellet diameter and density. CONCLUSION: This work provides the insight into pellet structure and its relationship with productivity.

Chemically controlled amplified ratiometric fluorescence in surface-immobilized end-capped oligo(p-phenylene ethynylene)s.

Efficient photoexcitation energy transfer in extended pi-electron conjugated molecules is a key factor in applications of such systems as a gain media in signal-amplifying fluorescent chemodetectors. Here we report an unprecedented ratiometric fluorescence amplification phenomenon in the surface-immobilized monolayers of oligo(p-phenylene ethynylene)s end-capped with a lower energy gap receptor group. The process of covalent immobilization on the surface results in monolayer films with improved molecular organization, which display highly efficient excitation energy transfer to the lower energy receptor groups. Chemical transformation of a subtle fraction of the receptor groups on the surface leads to a very significant fluorescent ratiometric response. While fundamental understanding of this unusual "turn-on" amplification phenomenon requires further studies, it can be used to develop thin-film ratiometric fluorescent chemosensors with improved optical gain.

An organic white light-emitting fluorophore.

The synthesis of new benzo[a]- and [b]xanthene dye frameworks is described. A unique benzo[a]xanthene, seminaphtho[a]fluorone (SNAFR-1), is studied in a variety of media. The optimization of solution parameters and excitation wavelengths allows SNAFR-1 to display red, green, and blue emission bands of approximately equal intensities and also to produce white light. Ratiometric red (anion) and green (neutral) emissions are observed upon varying solution pH. A pH-independent violet-blue emission band is due to the addition of nucleophiles to the benzylic carbon of SNAFR-1.