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Recent data suggest that most genotoxic agents in cancer therapy can lead to shock of genome and increase in cell size, which leads whole genome duplication or multiplication, formation of polyploid giant cancer cells, activation of an early embryonic program, and dedifferentiation of somatic cells. This process is achieved via the giant cell life cycle, a recently proposed mechanism for malignant transformation of somatic cells. Increase in both cell size and ploidy allows cells to completely or partially restructures the genome and develop into a blastocyst-like structure, similar to that observed in blastomere-stage embryogenesis. Although blastocyst-like structures with reprogrammed genome can generate resistant or metastatic daughter cells or benign cells of different lineages, they also acquired ability to undergo embryonic diapause, a reversible state of suspended embryonic development in which cells enter dormancy for survival in response to environmental stress. Therapeutic agents can activate this evolutionarily conserved developmental program, and when cells awaken from embryonic diapause, this leads to recurrence or metastasis. Understanding of the key mechanisms that regulate the different stages of the giant cell life cycle offers new opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

The "life code" theory postulates that egg cells, which are giant, are the first cells in reproduction and that damaged or aged giant somatic cells are the first cells in tumorigenesis. However, the hereditary basis for giant cells remains undefined. Here I propose that stress-induced genomic reorganization proposed by Nobel Laureate Barbara McClintock may represent the underlying heredity for giant cells, referred to as McClintock's heredity. Increase in cell size may serve as a response to environmental stress via switching proliferative mitosis to intranuclear replication for reproduction. Intranuclear replication activates McClintock's heredity to reset the genome following fertilization for reproduction or restructures the somatic genome for neoplastic transformation via formation of polyploid giant cancer cells (PGCCs). The genome-based McClintock heredity functions together with gene-based Mendel's heredity to regulate the genomic stability at two different stages of life cycle or tumorigenesis. Thus, giant cells link McClintock's heredity to both early embryogenesis and tumor origin. Cycling change in cell size together with ploidy number switch may represent the most fundamental mechanism on how both germ and soma for coping with environmental stresses for the survival across the tree of life which evolved over millions of years on Earth. [ABSTRACT FROM AUTHOR]

Tumors arise from the transformation of normal stem cells or mature somatic cells. Intriguingly, two types of tumors have been observed by pathologists for centuries: well-differentiated tumors and undifferentiated tumors. Well-differentiated tumors are architecturally similar to the tissues from which they originate, whereas undifferentiated tumors exhibit high nuclear atypia and do not resemble their tissue of origin. The relationship between these two tumor types and the human life cycle has not been clear. Here I propose a unifying theory that explains the processes of transformation of both tumor types with our life cycle. Human life starts with fertilization of an egg by a sperm to form a zygote. The zygote undergoes successive rounds of cleavage division to form blastomeres within the zona pellucida, with progressive decreases in cell size, and the cleaved blastomeres then compact to form a 32-cell or a "64n" morula [n = 1 full set of chromosomes]. Thus early embryogenesis can be interpreted as a progressive increase in ploidy, and if the zona pellucida is considered a cell membrane and cleavage is interpreted as endomitosis, then the 32-cell morula can be considered a multinucleated giant cell (or 64n syncytium). The decrease in cell size is accompanied by an increase in the nuclear-to-cytoplasmic (N/C) ratio, which then selectively activates a combined set of embryonic transcription factors that dedifferentiate the parental genome to a zygotic genome. This process is associated with a morphologic transition from a morula to a blastocyst and formation of an inner cell mass that gives rise to a new embryonic life. If the subsequent differentiation proceeds to complete maturation, then a normal life results. However, if differentiation is blocked at any point along the continuum of primordial germ cell to embryonic maturation to fetal organ maturation, a well-differentiated tumor will develop. Depending on the level of developmental hierarchy at which the stem cell differentiation is blocked, the resulting tumor can range from highly malignant to benign. Undifferentiated tumors are derived from mature somatic cells through dedifferentiation via a recently described reprogramming mechanism named the giant cell life cycle or the giant cell cycle. This mechanism can initiate "somatic embryogenesis" via an increase in ploidy ranging from 4n to 64n or more, similar to that in normal embryogenesis. This dedifferentiation mechanism is initiated through an endocycle and is followed by endomitosis, which leads to the formation of mononucleated or multinucleated polyploid giant cancer cells (PGCCs), that is, cancer stem-like cells that mimic the blastomere-stage embryo. The giant cell life cycle leads to progressive increases in the N/C ratio and awakens the suppressed embryonic reprogram, resulting in mature somatic transformation into undifferentiated tumors. Thus, the increase in ploidy explains not only normal embryogenesis for well-differentiated tumors but also "somatic embryogenesis" for undifferentiated tumors. I refer to this ploidy increase as the 'life code". The concept of the "life code" may provide a simple theoretical framework to guide our immense efforts to understand cancer and fight this disease. [ABSTRACT FROM AUTHOR]

We generalize the Riesz conjugate functions theorem for planar harmonic K -quasiregular mappings (when 1 < p ≤ 2) and harmonic K -quasiconformal mappings (when 2 < p < ∞) in the unit disk. Moreover, if K = 1 , then our constant coincides with the classical analytic case. For the n dimensional case (n > 2), we also obtain the Riesz conjugate functions theorem for invariant harmonic K -quasiregular mappings when 1 < p ≤ 2. [ABSTRACT FROM AUTHOR]

Abstract We extend the definition of Bowen topological entropy of subsets to continuous action of amenable groups on a compact metrizable space. We investigate how Bowen topological entropy behaves for restricted actions of finite-index subgroups and verify the validity of the subgroup formula. We also show that the Bowen topological entropy of subsets for amenable group actions can be determined via the local entropies of measures. As applications, we compute the Bowen topological entropy of a subset for Bernoulli shift over amenable groups. [ABSTRACT FROM AUTHOR]

Abstract Life starts with a zygote, which is formed by the fusion of a haploid sperm and egg. The formation of a blastomere by cleavage division (nuclear division without an increase in cell size) is the first step in embryogenesis, after the formation of the zygote. Blastomeres are responsible for reprogramming the parental genome as a new embryonic genome for generation of the pluripotent stem cells which then differentiate by Waddington's epigenetic landscape to create a new life. Multiple authors over the past 150 years have proposed that tumors arises from development gone awry at a point within Waddington's landscape. Recent discoveries showing that differentiated somatic cells can be reprogrammed into induced pluripotent stem cells, and that somatic cell nuclear transfer can be used to successfully clone animals, have fundamentally reshaped our understanding of tumor development and origin. Differentiated somatic cells are plastic and can be induced to dedifferentiate into pluripotent stem cells. Here, I review the evidence that suggests somatic cells may have a previously overlooked endogenous embryonic program that can be activated to dedifferentiate somatic cells into stem cells of various potencies for tumor initiation. Polyploid giant cancer cells (PGCCs) have long been observed in cancer and were thought originally to be nondividing. Contrary to this belief, recent findings show that stress-induced PGCCs divide by endoreplication, which may recapitulate the pattern of cleavage-like division in blastomeres and lead to dedifferentiation of somatic cells by a programmed process known as "the giant cell cycle", which comprise four distinct but overlapping phases: initiation, self-renewal, termination and stability. Depending on the intensity and type of stress, different levels of dedifferentiation result in the formation of tumors of different grades of malignancy. Based on these results, I propose a unified dualistic model to demonstrate the origin of human tumors. The tenet of this model includes four points, as follows. 1. Tumors originate from a stem cell at a specific developmental hierarchy, which can be achieved by dualistic origin: dedifferentiation of the zygote formed by two haploid gametes (sexual reproduction) via the blastomere during normal development, or transformation from damaged or aged mature somatic cells via a blastomere-like embryonic program (asexual reproduction). 2. Initiation of the tumor begins with a stem cell that has uncoupled the differentiation from the proliferation program which results in stem cell maturation arrest. 3. The developmental hierarchy at which stem cells arrest determines the degree of malignancy: the more primitive the level at which stem cells arrest, the greater the likelihood of the tumor being malignant. 4. Environmental factors and intrinsic genetic or epigenetic alterations represent the risk factors or stressors that facilitate stem cell arrest and somatic cell dedifferentiation. However, they, per se, are not the driving force of tumorigenesis. Thus, the birth of a tumor can be viewed as a triad that originates from a stem cell via dedifferentiation through a blastomere or blastomere-like program, which then differentiates along Waddington's landscape, and arrests at a developmental hierarchy. Blocking the PGCC-mediated dedifferentiation process and inducing their differentiation may represent a novel alternative approach to eliminate the tumor occurrence and therapeutic resistance. [ABSTRACT FROM AUTHOR]

Let μ = μ { R n , B n } = δ R 1 − 1 B 1 ⁎ δ (R 2 R 1) − 1 B 2 ⁎ ⋯ be a Borel probability measure with a compact support, where R n ∈ M 2 (Z) , B n ⊂ Z 2 and (R n , B n , L n) forms a Hadamard triple for all n ≥ 1. In this paper, we consider the existence of exponential orthogonal basis in L 2 (μ). We extend the concept of equi-positive family in [1] to higher dimensions, and provide a new idea to characterize the spectrality of such measures. In details, we study the spectrality and non-spectrality of Moran-Sierpinski type measures specifically under some necessary assumptions. The partial findings of several previous studies are extended by this study, such as Cantor-Moran measures (An-Fu-Lai [1] , An-He-He [3]), Moran-Sierpinski type measures (Wang-Dong [47]) and Moran-Cantor-Dust type measures (Chen-Liu-Su-Wang [9]). [ABSTRACT FROM AUTHOR]

Pesticides could induce long-term impacts on aquatic ecosystem via transgenerational toxicity. However, for many chiral pesticides, the potential enantioselectivity of transgenerational toxicity has yet to be fully understood. In this study, we used zebrafish as models to evaluate the maternal transfer risk of tebuconazole (TEB), which is a chiral triazole fungicide currently used worldwide and has been frequently detected in surface waters. After 28-day food exposure (20 and 400 ng/g) to the two enantiomers of TEB (S - and R -TEB) in adult female zebrafish (F0), increased malformation rate and decreased swimming speed were found in F1 larvae, with R -TEB showing higher impacts than S -enantiomer. Additionally, enantioselective effects on the secretion of thyroid hormones (THs) and expression of TH-related key genes along the hypothalamic-pituitary-thyroid (HPT) axis were found in both F0 and F1 after maternal exposure. Both the two enantiomers significantly disrupted the triiodothyronine (T3) and thyroxine (T4) contents in F0 with different degrees, whereas in F1, significant effects were only found in R -TEB groups with decreasing of both T3 and T4 contents. Most of the HPT axis related genes in F0 were upregulated by TEB and more sensitive to R -TEB than to S -TEB. In contrast, most of the genes in F1 were downregulated by both R - and S -TEB, especially the genes that are primarily responsible for thyroid development and growth (Nkx2–1), TH synthesis (NIS and TSHꞵ) and metabolism (Deio1). Findings from this study highlight the key role of enantioselectivity in the ecological risk assessment of chiral pesticides through maternal transfer. • Maternal TEB exposure resulted in enantioselective toxicity in both F0 and F1. • R -TEB showed stronger thyroid disruptive effects than S -TEB in F0. • Changes of TH levels in parents modulated the THs in offspring. • R -TEB caused stronger developmental and behavior toxicity than S -TEB in F1. • The expression of TH-related key genes showed different patterns between F1 and F0. [ABSTRACT FROM AUTHOR]

Human telomerase reverse transcriptase (hTERT), the catalytic subunit of human telomerase, is responsible for the synthesis and maintenance of the telomeric repeats at the distal ends of human chromosomes. Telomerase expression is repressed in normal human cells and is activated in immortal cells and during tumorigenesis, but the mechanism by which telomerase expression is regulated is not fully understood. Previous studies have shown that c-Myc stimulates hTERT transcription through the binding sites located on the hTERT promoter. In this study, we sought to determine whether BRCA1 inhibits hTERT transcription through its direct interaction with c-Myc. In ovarian cancer cells, c-Myc increased hTERT expression by threefold and BRCA1 completely abrogated this activity. A mutation in the c-Myc-binding site (E-box) of the hTERT promoter resulted in the loss of activation by c-Myc and in the loss of inhibition by BRCA1. Deletion of the c-Myc-binding domain in BRCA1 resulted in the loss of BRCA1’s ability to inhibit transcription of the hTERT promoter. In addition, BRCA1 associates with c-Myc and inhibits the binding activity of c-Myc to the hTERT promoter. Our data indicate that BRCA1 is involved in regulating cellular immortalization through the modulation of c-Myc on the hTERT promoter. [Copyright &y& Elsevier]

Typical thermal processes are common sources of polychlorinated, polybrominated and mixed polybrominated/chlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs, PBDD/Fs, and PBCDD/Fs); however, very few reports have investigated their coemission. To clarify the emission characteristics of these DD/Fs, two municipal waste incinerators (MWIs), three hazardous waste incinerators (HWIs), one cement kiln coprocessing municipal waste incinerator (CMWI), one secondary copper smelter (SCu), and one iron and steel sintering smelter (ISS) in China were investigated. In total, 17 congeners of PCDD/Fs, 14 congeners of PBDD/Fs, and 12 congeners of PBCDDs in stack flue gases from these thermal processes were analyzed using a high-resolution gas chromatograph/high-resolution mass spectrometer (HRGC/HRMS) in this study. PCDD/Fs, PBDD/Fs and PBCDD/Fs were detectable in all samples, with total concentrations of 911-5.15 × 103 pg/Nm3 (80.2–414 pg TEQ/Nm3). The concentrations of each DD/F were similar within the same type of facility and varied among different types of facilities. The contributions of PBDD/Fs and PBCDD/Fs to the total concentrations exceeded that of PCDD/Fs in some cases, such as in HWIs and SCu. In general, the ∑Cl 4-7 CDFs and ∑Cl 7-8 CDDs, 1,2,3,4,6,7,8-HpBDF, and 1-B-2,3,7,8-TeCDD and 2-B-1,3,7,8-TeCDD were the dominant congeners in the PCDD/F, PBDD/F, and PBCDD/F mass concentrations, respectively. Several other congeners present at low mass concentrations, such as 1,2,3,4,7,8-HxBDF, have potential as major contributors to the TEQs due to their high toxic equivalency factors. These results reveal the necessity of synergistically inhibiting the occurrences of PCDD/Fs, PBDD/Fs, and PBCDD/Fs from these sources and provide valuable information for use in the source identification of these pollutants in the environment. Image 1 • Co-emissions of PCDD/Fs, PBDD/Fs and PBCDD/Fs from thermal processes were studied. • Feedstock composition and APCDs have effects on the distributions of PCDD/Fs, PBDD/Fs and PBCDD/Fs. • The TEQ contributions of PBDD/Fs and PBCDD/Fs exceeded those of PCDD/Fs in some cases. • Different formation mechanisms for PCDD/Fs, PBDD/Fs and PBCDD/Fs were indicated. [ABSTRACT FROM AUTHOR]

In the past few years, polyhalogenated carbazoles (PHCZs) have been of increasing concern because their structure is similar to that of legacy POPs. In the present study, an analytical method, including intensive cleanup and fractionation procedures in combination with instrumental parameters, was developed to determine ultratrace polyhalogenated carbazoles (PHCZs) in soil and sediment. The eluting sorbents, volume and packing of the column were optimized. Our results showed that 5 g of florisil and 4 g of silica gel under 150 mL of hexane/DCM = 3:1 presented good performance in terms of recovery and repeatability. GC-HRMS, GC-MS/MS (EI-MRM) and GC-MS (EI-SIM) were applied to compare the performance of PHCZ analysis. For sensitivity, EI-MRM presents method detection limits comparable to those of GC-HRMS and much lower than those of EI-SIM. Regarding selectivity, GC-HRMS performed better than the other two techniques since GC-HRMS can reduce interference from perfluorokerosene (PFK) and DDX (DDT, DDE, and DDD) due to its high resolution. GC-HRMS was then further optimized by shortening the run time and modifying the SIM ion. The final method was successfully applied to determine PHCZs in soil and sediment, and the target compounds had almost 100% detection frequency in the samples. The ubiquitous presence of PHCZ in soil and sediment calls for a further investigation of its source, distribution and degradation in the environment. • Ultratrace analysis of polyhalogenated carbazoles was performed by GC-HRMS. • p,p' -DDT and PFK greatly interfere with the detection of 3,6-CCZ (m/z = 236.9926) by GC-MS/MS in SIM and MRM mode. • DDX compounds as impurities interfere with some halogenated carbazoles. • 3,6-CCZ was the predominant congener in soil and sediment. [ABSTRACT FROM AUTHOR]

ω-transaminase has attracted growing attention for chiral amine synthesis, although it commonly suffers from severe by-product inhibition. ω-transaminase CrmG is critical for the biosynthesis of Caerulomycin A, a natural product that possesses broad bioactivity, including immunosuppressive and anti-cancer. Compared to L-Arg, amino donor L-Glu, L-Gln or L-Ala is more preferred by CrmG. In this study, we determined the crystal structure of CrmG in complex with amino donor L-Arg, unveiling the detailed binding mode. Specifically, L-Arg exhibits an extensive contact with aromatic residues F207 and W223 on the roof of CrmG active site via cation-π network. This interaction may render the deamination by-product of L-Arg to be an inhibitor against PMP-bound CrmG by stabilizing its flexible roof, thus reducing the reactivity of L-Arg as an amino donor for CrmG. These data provide further evidence to support our previous proposal that CrmG can overcome inhibition from those by-products that are not able to stabilize the flexible roof of active site in PMP-bound CrmG. Thus, our result can not only facilitate the biosynthesis of CRM A but also be beneficial for the rational design of ω-transaminase to bypass by-product inhibition. • Crystal structure of CrmG in complex with amino donor L-Arg is reported. • L-Arg interacts with the roof of CrmG active site via unique cation-π network. • The interaction with the roof impairs reactive efficiency of L-Arg as CrmG amino donor. [ABSTRACT FROM AUTHOR]

The estrogen-related receptor (ERR) family members are reported to bind DNA elements as either monomer or dimer. However, to date, only one solution NMR structure of ERRβ in complex with a half-site DNA element has been reported. To better understand the DNA regulation mechanism, we determined the crystal structure of ERRγ-DBD bound to a natural DR1 element in Pla2g12b promoter to 2.2 Å resolution. Combined with biochemical assays, we show that ERRγ acts as a dimer and the C-terminal extension region undergoes conformational rearrangement when binding to the downstream DR1 element. In addition, the T-box region on the dimerization interface exhibits unique main-chain conformation. Thus, our structure presents a novel dimer interface for NR binding on DR1 DNA and provides a molecular basis for understanding the homodimer organization of ERR on DR1 elements. • We determined the first dimeric structure of ERRγ-DBD in complex with a DR1 element. • The CTE tail of ERRγ-DBD undergoes conformational rearrangement when binding to the downstream DR1 element. • The T-box conformation of ERRγ-DBD is unique on the dimer interface when binding to DR1. [ABSTRACT FROM AUTHOR]

IDO1 (indoleamine 2, 3-dioxygenase 1), a well characterized immunosuppressive enzyme, has attracted growing attention as a potential target for cancer immunotherapy. Hydroxylamidine compounds INCB024360 and INCB14943 (INCB024360 analogue) are highly effective IDO1 inhibitors. INCB024360 is undergoing clinical trials for treatment of various types of human cancer. Here, we determined the co-crystal structure of IDO1 and INCB14943, and elucidate the detailed binding mode. INCB14943 binds to heme iron in IDO1 protein through the oxime nitrogen. Further analysis also reveals that a halogen bonding interaction between the chlorine atom (3-Cl) of INCB14943 and the sulphur atom of C129 significantly improves the inhibition activity against IDO1. Comparing with the other reported inhibitors, the oxime nitrogen and halogen bond interaction are identified as the unique features of INCB14943 among the IDO1 inhibitors. Thus, our study provides novel insights into the interaction between a small molecule inhibitor INCB14943 and IDO1 protein. The structural information will facilitate future IDO1 inhibitor design. [ABSTRACT FROM AUTHOR]

This study aims to investigate the effects of glycerol monolaurate (GML) on growth performance, non-specific immunity, antioxidant capacity and intestinal microflora in Chinese mitten crabs. The crabs were randomly arranged to three experimental diets groups containing 0 (control group), 1000 mg/kg GML (GML1000 group), and 2000 mg/kg GML (GML2000 group), respectively. After 8 weeks of breeding, results showed a better growth performance in GML2000 group, with a higher PWG, SGR and lower FCR (P < 0.05). Meanwhile, in GML2000 group the activities of phenoloxidase, alkaline phosphatase, acid phosphatase and lysozyme in hemolymph were increased (P < 0.05), also the activities of hemolymph and hepatopancreas superoxide dismutase (SOD) and glutathione peroxidase (GPx) were increased in hepatopancreas (P < 0.05). While malondialdehyde (MDA) concentrations were lower significantly (P < 0.05) both in GML1000 and GML2000 groups. Furthermore, the mRNA expression of TLR1 , TLR2 , which related to the Toll pathway were increased (P < 0.05). Supplementation of 2000 mg/kg GML up-regulated the expression of ALF and LZM (P < 0.05), and down-regulated the expression of caspase-3 (P < 0.05). The abundance of Firmicutes increased in GML2000 group (P < 0.05), and Shewanella was significantly increased (P < 0.05) in both GML1000 and GML2000 groups. In conclusion, dietary supplemented with GML enhanced the growth performance and antioxidant capacity, enhanced hemolymph immune enzymes activities and antimicrobial peptides expression through regulating the proPO system and Toll pathway, and improved gut microflora in Chinese mitten crabs. • The first study of improving effects of glyceryl monolaurate (GML) in crabs. • GML improved growth and hemolymph immune enzymes activities in crabs. • GML increased antioxidant capacity of Chinese mitten crabs. • GML enhanced immunity by regulating proPO system and Toll pathway in crabs. • GML ameliorated the gut microflora in Chinese mitten crabs. [ABSTRACT FROM AUTHOR]

As one of the oldest infectious diseases in the world, tuberculosis (TB) is the second most deadly infectious disease after COVID-19. Tuberculosis is caused by Mycobacterium tuberculosis (Mtb), which can attack various organs of the human body. Up to now, drug-resistant TB continues to be a public health threat. Pyrazinamide (PZA) is regarded as a sterilizing drug in the treatment of TB due to its distinct ability to target Mtb persisters. Previously we demonstrated that a D67N mutation in Mycobacterium tuberculosis polynucleotide phosphorylase (Mtb PNPase, Rv2783c) confers resistance to PZA and Rv2783c is a potential target for PZA, but the mechanism leading to PZA resistance remains unclear. To gain further insight into the MtbPNPase, we determined the cryo-EM structures of apo Rv2783c, its mutant form and its complex with RNA. Our studies revealed the Rv2783c structure at atomic resolution and identified its enzymatic functional groups essential for its phosphorylase activities. We also investigated the molecular mechanisms underlying the resistance to PZA conferred by the mutation. Our research findings provide structural and functional insights enabling the development of new anti-tuberculosis drugs. [Display omitted] • Cryo-EM structure of full length Mt PNPase in apo form. • Cryo-EM structure of Mt PNPase in complex with RNA substrate. • Potential molecular mechanisms responsible for the mutant-conferred resistance to POA. • Model for the mechanism of RNA substrate degradation by Mt PNPase. [ABSTRACT FROM AUTHOR]

Abstract: BRCA1 plays an important role in maintaining genomic stability through its involvement in DNA repair. Although it is known that BRCA1 and RAD51 form distinct DNA repair subnuclear complexes, or foci, following environmental insults to the DNA, the role of BRCA1 in this process remains to be characterized. The purpose of the study was therefore to determine the role of BRCA1 in the formation of RAD51 foci following treatment with cisplatin and ionizing radiation. We found that although a functional BRCA1 is required for the subnuclear assembly of BRCA1 foci following treatment with either ionizing radiation or cisplatin, a functional BRCA1 is required for RAD51 foci to form following treatment with cisplatin but not with ionizing radiation. Similar results were obtained in SKOV-3 cells when the level of BRCA1 expression was knocked down by stable expression of a retrovirus-mediated small-interfering RNA against BRCA1. We also found that the carboxyl-terminal of BRCA1 contains uncharacterized phosphorylation sites that are responsive to cisplatin. The functional BRCA1 is also required for breast and ovarian cancer cells to mount resistance to cisplatin. These results suggest that the carboxyl-terminal of BRCA1 is required for the cisplatin-induced recruitment of RAD51 to the DNA-damage site, which may contribute to cisplatin resistance. [Copyright &y& Elsevier]

Genetic and environmental factors can independently or coordinatively drive ocular axis growth. Mutations in FRIZZLED5 (FZD5) have been associated with microphthalmia, coloboma, and, more recently, high myopia. The molecular mechanism of how Fzd5 participates in ocular growth remains unknown. In this study, we compiled a list of human genes associated with ocular growth abnormalities based on public databases and a literature search. We identified a set of ocular growth-related genes from the list that was altered in the Fzd5 mutant mice by RNAseq analysis at different time points. The Fzd5 regulation of this set of genes appeared to be impacted by age and light damage. Further bioinformatical analysis indicated that these genes are extracellular matrix (ECM)-related; and meanwhile an altered Wnt signaling was detected. Altogether, the data suggest that Fzd5 may regulate ocular growth through regulating ECM remodeling, hinting at a genetic-environmental interaction in gene regulation of ocular axis control. • A list of human genes associated with ocular growth abnormalities was compiled based on public databases. • A set of ocular growth-related genes was found altered in the Fzd5 mutant retina at different ages. • The Fzd5 regulation of ocular-growth genes appeared to be impacted by age and light damage and their interaction. • Fzd5 may regulate ocular growth by ECM remodeling within the retina, likely involving Müller glia. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2) is an essential phosphoinositide required for endosome homeostasis and sorting for lysosomal degradation; however, the underlying mechanisms, especially in mammals, remain elusive or unexplored. Here we determined a structure of PI(3,5)P 2 bound to Sorting Nexin 11 (SNX11) with an opened PPII-C loop. We also obtained an SNX11 structure with its PPII-C in "closed" form that serves as a potential PI3P-binding model. In addition, our results reveal that SNX11 can interact with the V1D subunit of vacuolar H+-ATPase (V-ATPase), which provides a link between PI(3,5)P 2 and human V-ATPase and further evidence for their roles in the endosome homeostasis regulation. Lastly, a new apo-form structure of SNX11, combined with molecular dynamics (MD) studies, indicates that the α5 helix can unfold from the PX domain of SNX11 when targeting the membrane or interacting with its partner. Taken together, these findings identify a novel PI(3,5)P 2 effector, which will shed light on the PIs recognizing mechanism and the understanding of the downstream sorting events triggered by different PI binding. Unlabelled Image • PI(3,5)P2 is essential for endo-lysosomal trafficking. • The structure of PI(3,5)P2 with SNX11 reveals specific recognition mechanism. • SNX11 links PI(3,5)P2 to human V-ATPase. • A membrane binding model for SNX11 is proposed. [ABSTRACT FROM AUTHOR]

• A new method is proposed for batch preparation microfiber Bragg grating (MFBG) sensors using alkaline solution with safety and the high efficiency. • The smooth-surfaced MFBG sensors were produced with a roughness of less than 100 nm, which is nearly 30 times lower compared to the widely-used HF etching method. • The method can achieve diameter customization of MFBG sensor by controlling time with an error of only ± 1.2918 μm. • The effects of diameter reduction of FBG sensors on their optical property, sensing performance, and mechanical property were systematically investigated. Microfiber Bragg grating sensors hold great promise given their compactness and large evanescent field effect. The fabrication method of the sensors plays a pivotal role in determining the performance. In this study, a novel approach for batch manufacturing microfiber Bragg grating sensors was proposed using a NaOH solution under hydrothermal conditions. Compared to other methods, it is simpler, safer, and more efficient. Through precisely controlling the reaction time, 50 microfiber Bragg grating sensors were produced with smooth surfaces, exhibiting a surface roughness of about 87 nm, and achieved tailored fiber diameters with an error of only ± 1.2918 μm. In addition, the sensors with different diameters produced by the method to systematically investigate the effects of diameter reduction on various aspects, including spectral characteristics, temperature, strain, refractive index sensing, and bending performance, accompanied by theoretical explanations. [ABSTRACT FROM AUTHOR]

Aflatoxin-oxidase (AFO), a newly discovered oxidase isolated from Armillariella tabescens , was reported to perform aflatoxin B1 (AFB1) detoxification through breaking the bisfuran ring of AFB1. However, based on sequence alignment, we found that AFO shares high sequence identities with dipeptidyl peptidase III (DPP III) family members. To understand the functions of AFO, we determined its crystal structures in the absence and presence of zinc, copper ion, and employed HPLC to test if AFO could cleave the substrates of DPP III. Our structures reveal that AFO contains the classic DPP III activity center and the HPLC results further confirm that AFO possesses the dipeptidyl peptidase activity. Therefore, AFO should belong to DPP III family. Interestingly, unlike reported classic DPP III structure that has a large domain movement upon substrate binding, the AFO structures all adopt the closed conformation, independent of substrate binding. This conformation characteristic of AFO may be related to its enzyme activities. Taken together, our results demonstrate that AFO is a dual activity enzyme with both aflatoxin-oxidase and dipeptidyl peptidase activities and its unique conformation feature expands our understanding on the mode of reaction for this enzyme family. [ABSTRACT FROM AUTHOR]

Lipases play an important role in physiological metabolism and diseases, and also have multiple industrial applications. Rational modification of lipase specificity may increase the commercial utility of this group of enzymes, but is hindered by insufficient mechanistic understanding. Here, we report the 2.0 Å resolution crystal structure of a mono- and di-acylglycerols lipase from Malassezia globosa ( Mg MDL2). Interestingly, residues Phe278 and Glu282 were found to involve in substrate recognition because mutation on each residue led to convert Mg MDL2 to a triacylglycerol (TAG) lipase. The Phe278Ala and Glu282Ala mutants also acquired ability to synthesize TAGs by esterification of glycerol and fatty acids. By in silicon analysis, steric hindrance of these residues seemed to be key factors for the altered substrate specificity. Our work may shed light on understanding the unique substrate selectivity mechanism of mono- and di-acylglycerols lipases, and provide a new insight for engineering biocatalysts with desired catalytic behaviors for biotechnological application. [ABSTRACT FROM AUTHOR]

[Display omitted] • Crystal structures of RGS homology (RH) domains of SNX13 and SNX25 were reported. • Extended α4 and α5 helices mediate homodimerization of SNX13 RH domain. • Unique residue C362 on α6 helix triggers homodimerization of SNX25 RH domain. • RH domains of SNX-RH represent a novel non-canonical RH domain. As a subgroup of sorting nexins (SNXs) that contain regulator of G protein signaling homology (RH) domain, SNX-RH proteins, including SNX13, SNX14 and SNX25, were proposed to play bifunctional roles in protein sorting and GPCR signaling regulation. However, mechanistic details of SNX-RH proteins functioning via RH domain remain to be illustrated. Here, we delineate crystal structures of the RH domains of SNX13 and SNX25, revealing a homodimer of SNX13 RH domain mediated by unique extended α4 and α5 helices, and a thiol modulated homodimer of SNX25-RH triggered by a unique cysteine on α6 helix. Further studies showed that RH domains of SNX-RH do not possess binding capacity toward Gα subunits, owing to the lack of critical residues for interaction. Thus, this study identifies a group of novel non-canonical RH domains that can act as a dimerization module in sorting nexins, which provides structural basis for mechanism studies on SNX-RH protein functions. [ABSTRACT FROM AUTHOR]

In the last decade, the ubiquitin proteasome system (UPS), in general, and E3 ubiquitin ligases, in particular, have emerged as valid drug targets for the development of novel anti-cancer therapeutics. Cullin RING Ligases (CRLs), which can be classified into eight groups (CRL1-8) and comprise approximately 200 members, represent the largest family of E3 ubiquitin ligases which facilitate the ubiquitination-derived proteasomal degradation of a myriad of functionally and structurally diverse substrates. S phase kinase-associated protein 1 (Skp1)-Cullin1-F-Box protein (SCF) complexes are the best characterized among CRLs, which play crucial roles in numerous cellular processes and physiological dysfunctions, such as in cancer biology. Currently, there is growing interest in developing SCF-targeting anti-cancer therapies for clinical application. Indeed, the research in this field has seen some progress in the form of cullin neddylation- and Skp2-inhibitors. However, it still remains an underdeveloped area and needs to design new strategies for developing improved form of therapy. In this review, we venture a novel strategy that rational pharmacological targeting of Skp1, a central regulator of SCF complexes, may provide a novel avenue for SCF-oriented anti-cancer therapy, expected: (i) to simultaneously address the critical roles that multiple SCF oncogenic complexes play in cancer biology, (ii) to selectively target cancer cells with minimal normal cell toxicity, and (iii) to offer multiple chemical series, via therapeutic interventions at the Skp1 binding interfaces in SCF complex, thereby maximizing chances of success for drug discovery. In addition, we also discuss the challenges that might be posed regarding rational pharmacological interventions against Skp1. [ABSTRACT FROM AUTHOR]

Objectives: Response rates to immune checkpoint inhibitors (ICI) in recurrent ovarian cancer have been disappointingly low. While emerging data suggest increased activity in patients with ovarian clear cell carcinomas (OCCC), only a minority of patients benefit even among this group. The objective of the current study was to investigate correlates of long-term survival in patients with OCCC treated with ICI. Methods: A review of medical records identified 28 patients with ovarian/peritoneal clear cell carcinoma who had been treated with CTLA4 and PD1/L1 ICI immunotherapy as part of two prospective RCTs. All patients except one received tremelimumab and durvalumab, either sequentially or in combination, and one additional patient received ipilimumab and nivolumab. Clinical-pathologic and tumor somatic mutation information (obtained from clinical next-generation sequencing) were correlated with overall survival (OS) using Kaplan-Meier and log-rank methodologies. Results: The evaluable patients were heavily pre-treated, with 1-9 prior lines of therapy (median: 2). The most common mutations were ARID1A (72%), PIK3CA (57%), and PPP2R1A (25%). The overall survival was significantly longer in patients whose tumors harbored a PPP2R1A hotspot mutation (n =7) compared to those without such mutation (n =21; median OS not reached vs 6.4 months, respectively, p=0.018; HR: 0.13 [95% CI: 0.02-0.95]; Figure 1). PPP2R1A mutations were also associated with more severe (≥grade 3) immune-related adverse events (57.1% vs 9.5% for non-carriers p=0.021). PPP2R1A mutations retained their prognostic significance within the subgroup of patients with ARID1A mutations (p=0.018). However, among patients without PPP2R1A mutations, there was no association between ARID1A mutations and OS (p=0.253). Increased survival resulted from prolonged stable disease and delayed responses, often following initial progression by RECIST v1.1. [Display omitted] Conclusions: These preliminary data suggest that PPP2R1A (rather than ARID1A) mutations may serve as a biomarker for long-term survival after ICI in OCCC, and ongoing research is aimed at determining a causal relationship. Given the benefit was delayed and often followed initial progression, harboring PPP2R1A mutations on ICI treatment beyond progression in patients with OCCC may be a consideration after appropriate counseling. [ABSTRACT FROM AUTHOR]

Despite similar histologic appearance amongst high-grade serous ovarian cancers (HGSOC), anecdotally there are differences in gross appearance. However, no systematic framework to classify morphologic differences exists. Therefore, we aimed to determine whether high-grade serous ovarian cancers (HGSOC) can be reliably divided into distinct gross morphologic subtypes and to assess clinical outcomes and molecular features of these subtypes. A retrospective review was performed of video-recordings from patients who underwent laparoscopic assessment of disease burden prior to primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT). Video recordings were reviewed by at least 2 physicians. A total of 4 sites (diaphragm, omentum, peritoneum, and pelvis) were assessed and classified as type I (deep, infiltrative disease with distortion of surrounding tissue) or type II (superficial, exophytic disease bordered by normal tissue). Tumor tissues from 16 of these chemotherapy-naïve patients were analyzed by multi-platform omics (RNA sequencing, proteomics). Clinical outcomes were assessed utilizing a prospectively collected database and compared by morphology using t-test or Fisher's exact test. Of the 99 evaluable patients, 60 exhibited uniform morphology at all involved metastatic sites (65% type I and 35% type II), and 81 exhibited a predominating morphology (58% type I and 42% type II). A total of 164 images were reviewed by a third physician with 83.5% inter-rater concordance (κ=0.6446). Patients with uniform type 1 (n=34)tumor morphology were more likely to exhibit an excellent response to NACT (defined as radiologic or CA-125 complete response) than those with type II (n=16) tumor morphology (47% vs 18%, p=0.13). Patients with type II predominant tumor morphology had a significantly higher estimated blood loss at the time of interval debulking surgery (p=0.008) as well as longer operative time (p=0.03) compared with type I tumor morphology. Patients with complete type II morphology were more likely to have a modified Fagotti score of <8 (p=0.026), and thus were more likely to be triaged to PDS. On histopathologic review of 7 type I cases and 4 type II cases, no obvious histo-pathological pattern dominated either type. We identified distinct molecular differences between the 2 types, including increased TGF-β expression in type I and increased MYC expression in type II. Type I tumors seem to have abundant stroma and are immunologically active, whereas type II tumors seem to be dominated by cancer cells, have little stroma, and are immunologically cold. There are at least two distinct gross morphological patterns of HGSOC with unique molecular differences and responses to chemotherapy. These findings could have major clinical implications for tailored therapeutic strategies. [Display omitted] [ABSTRACT FROM AUTHOR]

The dengue virus NS2B-NS3 protease (NS2B-NS3p), an important antiviral target for drug development, has been reported to adopt an open or closed conformation in crystal structures with different NS2B C-terminus (NS2Bc) positioning. In solution, nevertheless, NS2B-NS3p forms a mixture of open, closed and maybe other intermediate conformations, which is difficult to characterize using conventional biophysical and biochemical techniques. In this study, we developed a new strategy to analyze these conformational changes using 19 F NMR spectroscopy. Low pH or bovine pancreatic trypsin inhibitor (BPTI) binding promote the conformation change from open to closed, showing the importance of charge forces in the interaction between NS2Bc and NS3p. The mutation H51A impairs the charge interaction and the pH dependence of the conformational changes. It stabilizes the open conformation, while the addition of BPTI still converts NS2B-NS3p from open to closed conformation. [ABSTRACT FROM AUTHOR]

(Liquid + liquid) equilibrium (LLE) data were measured experimentally at T = (298.15 or 303.15) K and atmospheric pressure for the (benzene + cyclohexane + dimethyl sulfone (DMSO)) system. The Othmer–Tobias equation was applied to verify the reliability of the data. Based on the data, the selectivity of DMSO was estimated and compared with that of ionic liquids. The highest selectivity coefficient of DMSO can reach beyond 14, which means it is able to compete with some ionic liquids and it would be a good extractant to separate benzene from cyclohexane. At the same time, the NRTL model was used to correlate the data and the results show that the model agrees on the experimental data very well. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fused tricyclic indoline-imidazolidinone analogs were discovered to be active to DENV. • Indoline carbohydrazine has derived more active compounds than indoline carboamide. • Post-treatment is effective time of addition and 15 targets the post-entry stages. • RdRp of DENV NS5 is the drug target for these series of compounds. • Hydrogen bonds and hydrophobic interactions contribute fitted low energy conformation. Dengue virus, belonging to a genus Flavivirus , caused public health problem in recent years. One controversial vaccine of DENV was approved and there is no antiviral for the clinic treatment of DENV, therefore, efficient antivirals to DENV are of great medical significance. In this study, we conducted the design, synthesis, cell-based and target-based activity evaluation of 28 compounds based on indoline structural skeleton against DENV infection. Among them, 13 active compounds against DENV infection were discovered and their structure–activity relationship (SAR) was summarized. In this study, indoline carbohydrazine has derived more active compounds than indoline carboamide. It is discovered that TBS group exhibits a good pharmacophore to enhance anti-DENV activity. Further exploration indicated that post-treatment acts as effective time of addition and compound 15 targeting the post-entry stages of DENV2 viral life cycle. SPR imaging results support there are strong interaction of 13 and 15 with RdRp and compounds 13 and 15 reduce RdRp enzymatic activity, revealing that RdRp of DENV NS5 is the drug target for these series of compounds. Molecular docking deciphered the relationship of the structural feature with the putative binding mode by 13 and 15 with RdRp domain of DENV2 NS5 by hydrogen bonds and hydrophobic interactions to establish the fitted low energy conformation. Future studies will focus on designing more potent inhibitors for the treatment and prevention of dengue virus replication and infection, and understanding the more profound underlying structural features of inhibitors and drug action of the mechanism. [ABSTRACT FROM AUTHOR]

Abstract: Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates MAPK signaling pathways and regulates cellular responses such as proliferation, migration and apoptosis. Here we report high levels of total and phospho-MLK3 in ovarian cancer cell lines in comparison to immortalized nontumorigenic ovarian epithelial cell lines. Using small interfering RNA (siRNA)-mediated gene silencing, we determined that MLK3 is required for the invasion of SKOV3 and HEY1B ovarian cancer cells. Furthermore, mlk3 silencing substantially reduced matrix metalloproteinase (MMP)-1, -2, -9 and -12 gene expression and MMP-2 and -9 activities in SKOV3 and HEY1B ovarian cancer cells. MMP-1, -2, -9 and-12 expression, and MLK3-induced activation of MMP-2 and MMP-9 requires both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activities. In addition, inhibition of activator protein-1 (AP-1) reduced MMP-1, MMP-9 and MMP-12 gene expression. Collectively, these findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells. [Copyright &y& Elsevier]

Abstract: Most lipases contain a lid domain to shield the hydrophobic binding site from the water environment. The lid, mostly in helical form, can undergo a conformational change to expose the active cleft during the interfacial activation. Here we report the crystal structures of Malassezia globosa LIP1 (SMG1) at 1.45 and 2.60Å resolution in two crystal forms. The structures present SMG1 in its closed form, with a novel lid in loop conformation. SMG1 is one of the few members in the fungal lipase family that has been found to be strictly specific for mono- and diacylglycerol. To date, the mechanism for this substrate specificity remains largely unknown. To investigate the substrate binding properties, we built a model of SMG1 in open conformation. Based on this model, we found that the two bulky hydrophobic residues adjacent to the catalytic site and the N-terminal hinge region of the lid both may act as steric hindrances for triacylglycerols binding. These unique structural features of SMG1 will provide a better understanding on the substrate specificity of mono- and diacylglycerol lipases and a platform for further functional study of this enzyme. [Copyright &y& Elsevier]

Abstract: Secreted phospholipase A2s form a large family of proteins involved in diverse biological and pathophysiological processes. Group IIE secreted phospholipase A2 (sPLA2-IIE) is one of the latest discovered members of this family. Previous studies revealed that the expression profile of sPLA2-IIE was restricted to a few tissue types including brain, heart, lung and placenta compared to the broad expression profile of other isoforms. Accumulating evidence suggests that sPLA2-IIE might play a pivotal role in the progression of inflammatory processes. However, functional study of sPLA2-IIE was hindered by the low yield of soluble expressed protein. In this study, we have expressed human and mouse sPLA2-IIE in Escherichia coli in the form of inclusion bodies. The inclusion bodies were dissolved, purified and refolded in a step-wise dialysis approach and further purified. We obtained soluble and active proteins for human and mouse sPLA2-IIE with a final yield of 1.1 and 1.2mg/500mL bacterial culture, respectively. The refolded sPLA2-IIEs exhibited similar calcium and pH dependence of their enzymatic activity with those expressed in COS cells. This protein expression and purification protocol will facilitate the further structural and functional studies of human and mouse sPLA2-IIEs. [Copyright &y& Elsevier]

Summary: The nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ; NR1C3) plays a central role in adipogenesis and is the molecular target of the thiazolidinedione class of antidiabetic drugs. To overcome the well-known shortcomings of thiazolidinediones, we have identified INT131 (formerly T131 and AMG131) as a potent selective ligand for PPARγ that is structurally and pharmacologically distinct from glitazone agonists. In vitro biochemical and cell-based functional assays showed that INT131 mediates a distinct pattern of coregulator recruitment to PPARγ. In adipocytes, INT131 showed minimal stimulation of adipocyte differentiation and partially activated PPARγ target genes involved in adipogenesis and, at the same time, showed more agonistic activity on another set of target genes that may influence insulin sensitivity directly. These unique properties of INT131 may provide a mechanistic basis for its distinct pharmacological profile. In vivo, increases in glucose tolerance were observed in Zucker (fa/fa) rats following a 14-day oral treatment with INT131. Although the maximal efficacies of INT131 and rosiglitazone were similar with respect to improvements in glucose tolerance, INT131 had less effect on heart and lung weights, weight gain, hemodilution, and plasma volume. Thus, INT131 appears to selectively modulate PPARγ responses in an in vivo preclinical model, showing antidiabetic efficacy while exhibiting an improved hemodynamic and cardiovascular adverse effect profile compared to the full agonist rosiglitazone. X-ray crystallography revealed that INT131 interacts with PPARγ through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket without direct hydrogen-bonding interactions to key residues in helix 12 that are characteristic of full agonists. Mutagenesis studies on Tyr473 in helix 12 demonstrated this residue as essential for rosiglitazone-induced receptor activation, but nonessential for INT131 function in vitro, providing one possible molecular determinant for INT131''s distinct pharmacology. INT131 is currently being evaluated in a clinical setting as a therapeutic agent for the treatment of type 2 diabetes. [Copyright &y& Elsevier]

Abstract: Background: A case of primary neuroblastoma arising from the broad ligament with excellent response to neoadjuvant bleomycin, etoposide, and cisplatin (BEP) is reported. Case: A 48-year-old woman, G0, who presented with acute renal failure, an enlarged pelvic mass, and abdominal pain was diagnosed with adult neuroblastoma arising from the broad ligament of the uterus. She received three cycles of neoadjuvant therapy consisting of bleomycin, etoposide, and cisplatin (BEP) given every 3 weeks and had an excellent initial response. She then underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and appendectomy, with pathologic analysis revealing small residual disease on the broad ligament of the uterus and omentum. The patient died of recurrent disease 20 months after her initial diagnosis. Conclusions: The clinical management of cancer in the broad ligament of the uterus must be tailored to the pathologic diagnosis. Although our patient had an excellent initial response to BEP, further study is needed to identify a treatment that can reduce recurrences and improve clinical outcomes. [Copyright &y& Elsevier]

Abstract: New ordered mesoporous carbons containing nickel oxide nanoparticles have been successfully synthesized by carbonization of sucrose in the presence of nickel acetate inside SBA-15 mesoporous silica template. The obtained samples were characterized by X-ray diffraction (XRD), nitrogen adsorption–desorption, and transmission electron microscopy (TEM). The NiO nanoparticles were embedded inside the mesoporous carbon framework due to the simultaneous pyrolysis of nickel acetate during carbonization. The electrochemical testing of the as-made nanocomposites showed a large specific capacitance of 230Fg−1 using 2M KOH as the electrolyte at room temperature. This is attributed to the nanometer-sized NiO formed inside mesoporous carbons and the high surface area of the mesopores in which the NiO nanoparticles are formed. Furthermore, the synthetic process is proposed as a simple and general method for the preparation of new functionalized mesoporous carbon materials, for various applications in catalysis, sensor or advanced electrode material. [Copyright &y& Elsevier]

Abstract: A novel gene designated as fragile site-associated (FSA) gene was recently identified by positional cloning from the CHO 1q31 fragile site which plays an important role in regulating amplification of multidrug resistance (mdr1) gene in multidrug-resistant cells. FSA produces a message of ∼16kb which encodes an open-reading frame of 5005 amino acids. FSA shares sequence similarity with that in Caenorhabditis elegans lpd-3, a lipid storage gene. Using immunohistochemical staining and RNA in situ hybridization we report here that expression of FSA is associated with developmental programs of spermatogenesis and mammary gland in mice. Real-time RT-PCR results also support the upregulation of FSA expression in mammary gland development. Expression of FSA in many tissues including colon, skin, ovary, prostate, and bladder is mainly in the postmitotic, well-differentiated compartments. Moreover, levels of FSA expression are downregulated in tumors of these tissue origins. These results suggest that FSA also plays important roles in regulating mammalian epithelial growth and differentiation and tumor development. [Copyright &y& Elsevier]

Abstract: Background.: When ovarian carcinoma is diagnosed in stage I, up to 90% of patients can be cured with surgery and currently available chemotherapy. At present, less than 25% of cases are diagnosed at this stage. To increase the fraction of ovarian cancers detected at an early stage, screening strategies have been devised that utilize a rising serum CA125 level to trigger the performance of transvaginal sonography. One limitation of CA125 as an initial step in such a screening strategy is that up to 20% of ovarian cancers lack expression of the antigen. Serum tumor markers that can be detected in ovarian cancers that lack CA125 expression might improve the sensitivity for early detection. Methods.: From 296 ovarian cancers, 65 (22%) were found to have weak or absent CA125 expression on immunoperoxidase staining. Tissue expression of CA125 was compared to serum CA125 levels. Using immunoperoxidase staining of tissue arrays, we have assessed expression of 10 potential serum tumor markers in the 65 epithelial ovarian cancers with little or no CA125 expression and in ovarian cystadenomas, tumors of low malignant potential, normal ovaries, and 16 other normal tissues. Results.: Low or absent expression of CA125 in surgical specimens of epithelial ovarian cancer was associated with low levels of serum CA125 in pre-operative serum specimens. In ovarian cancers that lacked CA125, all specimens (100%) expressed human kallikrein 10 (HK10), human kallikrein 6 (HK6), osteopontin (OPN), and claudin 3. A smaller fraction of CA125-deficient ovarian cancers expressed DF3 (95%), vascular endothelial growth factor (VEGF) (81%), MUC1 (62%), mesothelin (MES) (34%), HE4 (32%), and CA19-9 (29%). When reactivity with normal tissues was considered, however, MES and HE4 showed the greatest specificity. Differential expression was also found for HK10, OPN, DF3, and MUC1. Conclusions.: At the level of tissue expression, each of 10 potential serum markers could be detected in 29–100% of ovarian cancers that had low or absent expression of CA125. Several markers exhibited more intense expression in cancers than in normal organs. Further investigation is needed to demonstrate complementary expression of markers in serum. [Copyright &y& Elsevier]

Abstract: Background : Well-differentiated papillary mesothelioma (WDPM) of the peritoneum is a rare subtype of peritoneal epithelioid mesothelioma which typically has low malignant potential. It most commonly occurs in young women lacking a history of asbestos exposure. Only 38 female patients with peritoneal WPDM have been reported in the literature, and no uniform treatment recommendation has been established. Case report : A 74-year-old asymptomatic woman without significant past medical history underwent workup and subsequent surgery for an adnexal mass with a normal serum CA-125 level. Exploratory laparotomy identified an ovarian serous cystadenoma and an incidental multifocal peritoneal neoplasm with extensive calcifications. Histology and cytology confirmed WDPM with extensive, intimately associated mesothelial cystic inclusions and zonal calcifications with osseous metaplasia. Our patient did not receive adjuvant therapy and was without clinical or radiologic evidence of disease 12 months after diagnosis. Conclusion : WDPM of the peritoneum in women is frequently asymptomatic and associated with an indolent course. Patient outcomes are usually favorable after tumor-debulking surgery without adjuvant therapy. [Copyright &y& Elsevier]

Abstract: Objective: Receptors for estrogen (ER), progesterone (PR), or androgen (AR) are predictive and prognostic markers of malignancy of multiple endocrine organs, including endometrial and breast cancer. However, the role of ERs, PRs, or ARs in the carcinogenesis of ovarian cancer, another sex hormone-dependent malignancy, is still controversial despite numerous studies that have attempted to determine their role. The disagreement in the findings may result from the fact that the numbers of tumor samples in studies have been small and that different immunohistochemical methods have been used that can introduce variation in the scoring of the histology. We therefore examined the pattern of expression of ERs, PRs, and ARs in a large number of samples of primary ovarian carcinoma by using a tissue microarray technique. Methods: We constructed a tissue microarray with 322 samples of primary ovarian carcinoma obtained at surgery performed at The University of Texas M. D. Anderson Cancer Center between 1990 and 2000. Immunohistochemistry studies were performed by using the immunoperoxidase technique against primary antibodies (ER, PR, and AR). Results: ERs, PRs, and ARs were differently expressed in different histotypes of ovarian cancer: ERs were expressed in 77.3% of all cases but more highly expressed in serous and endometrioid types; PRs were expressed in 26.2% of all cases but most highly expressed in the endometrioid type < 64.2%; and ARs were expressed in 43.7% of all cases but were most highly expressed in serous (47.5%) carcinomas. Of particular importance, the expression of PRs, but not ERs or ARs, was associated with better survival (P < 0.0001) in univariate and multivariate analyses. Conclusions: The PR is an independent marker, with its overexpression associated with a favorable prognosis in women with ovarian cancer. [Copyright &y& Elsevier]

: BackgroundLangerhans cell histiocytosis (LCH) of the female genital tract is rare. Only, seven cases of primary vulvar LCH have been previously reported in the medical literature. We describe an additional case of LCH in which the disease was confined to the vulva.: CaseA 33-year-old gravida 0, para 0 Ethiopian woman presented with a nodular lesion on her left vulva. The lesion was biopsied, and the results were consistent with LCH. A metastatic workup did not reveal any evidence of disease beyond the vulva. The patient was initially treated with radiotherapy to the vulva. She was diagnosed with recurrent disease in the vulva 21 months after the completion of radiotherapy. At that time, she underwent a wide local excision. Five months later, we found a lesion on her right labium majus that was consistent with a recurrence. The patient''s vulva was treated with a higher dose of radiotherapy than it had been the first time. Six months later the patient again experienced a local recurrence. She underwent a wide radical vulvar excision of diffuse bilateral lesions and was free of disease for approximately 3 months, after which she experienced another recurrence and underwent treatment with thalidomide. Within 2 months of starting thalidomide therapy, the patient experienced resolution of her symptoms and of her vulvar lesions.: ConclusionPrimary LCH of the vulva is very rare. Its etiology and pathophysiology, as well as the most effective modes of therapy, remain elusive. We propose that thalidomide is a useful alternative for patients with this disease. [Copyright &y& Elsevier]

Background. Female adnexal tumors of probable wolffian origin are a distinctive epithelial neoplasm arising from the remnants of the mesonephric duct. Although generally considered a tumor of low malignant potential, these tumors can recur. Two cases are reported here.Cases. () A 38-year-old G6P6 Latin American woman presented with lower abdominal pain and a pelvic mass. She had a history of a total abdominal hysterectomy and bilateral salpingo-oophorectomy with a paratubal nodule found incidentally 3 years prior. The pathologic findings were consistent with a female adnexal tumor of probable wolffian origin. Imaging studies revealed significant metastatic disease throughout her abdomen and pelvis. The recurrence was confirmed at laparotomy and tumor debulking was performed. Four months later the patient suffered a second recurrence and is currently undergoing treatment with systemic therapy. () A 71-year-old Caucasian woman who had undergone exploratory laparotomy and tumor reductive surgery for a female adnexal tumor of probable wolffian duct origin was seen for routine evaluation 1 year after her surgery. Her computed tomography scan revealed possible evidence of recurrence.Conclusion. Most female adnexal tumors of wolffian origin behave in a benign fashion. However, there is a potential risk of recurrence. Surgical excision by total abdominal hysterectomy and bilateral salpingo-oophorectomy at the time of diagnosis may be the best recommended mode of therapy. The role of adjuvant radiation therapy or chemotherapy remains questionable. [Copyright &y& Elsevier]

The nitrite that normally exists in fermented foods is a threat to public health. Nitrite degradation by lactic acid bacteria (LAB) has the advantages of safety and low cost. This study investigated the effect of Lactobacillus plantarum DMDL 9010 (LP9010) on growth phenotype under nitrite stress from the perspective of whole genome sequencing. The results showed that LP9010 has certain tolerance to nitrite. However, high nitrite concentration (5–12.5 mmol/L) inhibited the growth and acid production. Nitrite could not only affect the morphology of LP9010 cells with longer phenotype, shrink and dent on the surface (even crack), but also decreased cell surface hydrophobicity. Correspondingly, 19 genes encoding stress proteins have been found in the genome. In addition, genes related to osmotic regulation proteins and peptidoglycans synthesis were found in the genome of LP9010, which may affect the cell wall structure under nitrite stress. Low pH lactic acid could degrade nitrite, whereas nitrite was hardly degraded when pH > 4. In addition, we found the putative nitrite reductase gene in LP9010, the nitrite ion bound to the Cd1 NiR (pgl) active site by forming two hydrogen bonds with the residues PRO87 and PRO88. This study could provide theoretical reference to reduce nitrite in food products. • Complete genome of L. plantarum DMDL 9010 (LP9010) was firstly sequenced. • This is the first report of nitrite degradation activity of LP9010 by genome sequence and corresponding phenotypes. • LP9010 has the potential to be used as probiotics to degrade nitrites. [ABSTRACT FROM AUTHOR]

Hepatocyte nuclear factor 4 alpha (HNF4α) regulates the expression of essential genes involved in very-low-density lipoprotein (VLDL) homeostasis and gluconeogenesis. 18β-glycyrrhetinic acid (GA) is an active ingredient of Glycyrrhiza uralensis an herbal medicine used for treating liver aliments. In this study, we established that GA functions as a partial antagonist of HNF4α through HNF4α-driven reporter luciferase assay and co-immunoprecipitation experiments with co-activator PGC1α. By virtual docking and site-directed mutagenesis analysis, we confirmed that serine 190 and arginine 235 of HNF4α are both essential for GA to exert its antagonistic action on HNF4α. Importantly, GA suppressed the expression of HNF4α target genes such as apolipoprotein B (ApoB), microsomal triglyceride transfer protein (MTP) and phospholipase A 2 G12B (PLA2G12B) modulating hepatic VLDL secretion in mice fed on a high fat diet. In addition, GA also suppressed gluconeogenesis and ameliorated glucose intolerance via down-regulating the expression of HNF4α target genes glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase (Pepck). Furthermore, GA significantly lowered blood glucose and improved insulin resistance in db/db mice. In all, we established that GA acts as a partial HNF4α antagonist modulating lipid and carbohydrate metabolism. [ABSTRACT FROM AUTHOR]