Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity

The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed independently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endothelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.

Development of immature ovarian teratoma after mature teratoma in a girl with familial ovarian teratoma:A case report

BACKGROUND Immature ovarian teratoma is a rare and aggressive neoplasm that affects young women.This report is the first to describe the development of immature teratoma after ovarian cystectomy for mature teratoma of the ovary in an adolescent female with a family history of ovarian teratoma.CASE SUMMARY A 16-year-old girl who had undergone bilateral ovarian cystectomy for mature teratomas 3 years ago showed bilateral adnexal tumors during her regular ultrasonography follow-up every 6 months.She received laparoscopic bilateral ovarian cystectomy,and final histopathology showed grade-1 immature teratoma of the left ovary and mature teratoma of the right ovary.Laparoscopic left salpingo-oophorectomy and staging procedures were performed again.Her mother,maternal aunt,and maternal grandmother had also received surgeries for mature ovarian teratomas.CONCLUSION It is important to have guidance on management of patient and family members with familial ovarian teratomas.

Adult neurogenesis in the primate hippocampus

Adult hippocampal neurogenesis(AHN) is crucial for learning,memory,and emotion.Deficits of AHN may lead to reduced cognitive abilities and neurodegenerative disorders,such as Alzheimer’s disease.Extensive studies on rodent AHN have clarified the developmental and maturation processes of adult neural stem/progenitor cells.However,to what extent these findings apply to primates remains controversial.Recent advances in next-generation sequencing technologies have enabled in-depth investigation of the transcriptome of AHN-related populations at single-cell resolution.Here,we summarize studies of AHN in primates.Results suggest that neurogenesis is largely shared across species,but substantial differences also exist.Marker gene expression patterns in primates differ from those of rodents.Compared with rodents,the primate hippocampus has a higher proportion of immature dentate granule cells and a longer maturation period of newly generated granule cells.Future research on species divergence may deepen our understanding of the mechanisms underlying adult neurogenesis in primates.

Inhibition of VEGF-A expression in hypoxia-exposed fetal retinal microvascular endothelial cells by exosomes derived from human umbilical cord mesenchymal stem cells

Objective:This study aimed to investigate the potential of human umbilical cord mesenchymal stem cell(hucMSC)-derived exosomes(hucMSC-Exos)in inhibiting hypoxia-induced cell hyper proliferation and overexpression of vascular endothelial growth factor A(VEGF-A)in immature human fetal retinal microvascular endothelial cells(hfRMECs).Methods:Exosomes were isolated from hucMSCs using cryogenic ultracentrifugation and characterized through various techniques,including transmission electron microscopy,nanoparticle tracking analysis,bicinchoninic acid assays,and western blotting.The hfRMECs were identified using von Willebrand factor(vWF)co-staining and divided into four groups:a control group cultured under normoxic condition,a hypoxic model group,a hypoxic group treated with low-concentration hucMSC-Exos(75μg/mL)and a hypoxic group treated with high-concentration hucMSC-Exos(100μg/mL).Cell viability and proliferation were assessed using Cell Counting Kit-8(CCK-8)assay and EdU(5-ethynyl-2′-deoxyuridine)assay respectively.Expression levels of VEGF-A were evaluated using RT-PCR,western blotting and immunofluorescence.Results:Hypoxia significantly increased hfRMECs’viability and proliferation by upregulating VEGF-A levels.The administration of hucMSC-Exos effectively reversed this response,with the high-concentration group exhibiting greater efficacy compared to the lowconcentration group.Conclusion:In conclusion,hucMSC-Exos can dose-dependently inhibit hypoxia-induced hyperproliferation and VEGF-A overexpression in immature fetal retinal microvascular endothelial cells.

Different endodontic treatments induced root development of two nonvital immature teeth in the same patient:A case report

BACKGROUND Pulp revascularization is a novel way to treat immature teeth with periapical disease,and the technique has become increasingly well established in recent years.By puncturing the periapical tissue,bleeding is induced,and a blood clot is formed in the root canal.The blood clot acts as a natural bioscaffold onto which mesenchymal stem cells from periapical tissue can be seeded and restore pulp vascularity,thus promoting root development as well as apical closure.Although the effect of pulp revascularization is ideal,there are certain requirements for the apical condition of the teeth.The apical barrier technique and apexification are still indispensable for teeth that cannot achieve ideal blood clot formation.In addition,a meta-analysis of several clinical studies concluded that pulp revascu-larization has no significant advantages over other treatments.CASE SUMMARY A 10-year-old girl complained of pain in the right upper and lower posterior teeth for 2 d.Clinical and radiological examinations revealed that both the right maxillary and mandibular second premolars were immature with periapical radiolucency.The right maxillary second premolar was treated by pulp revascu-larization,while the right mandibular second premolar was treated by conven-tional apical barrier surgery after revascularization failed.The purpose of this report is to compare the different root maturation processes induced by the pulp revascularization and apical barrier techniques in the same patient in homonymous teeth from different jaws.Twelve months of follow-up showed that the apical foramen of both teeth presented a clear tendency to close;however,the tooth treated with pulp revascularization showed a significant increase in root length as well as root canal wall thickness.CONCLUSION For the treatment of nonvital immature teeth,pulp revascularization showed a superior therapeutic effect in comparison with the apical barrier technique.

Determination of the ovine ovarian reserve during the prenatal and neonatal periods

Objective:To determine the ovine ovarian histomorphology and follicular staging at various age periods in Awassi breed.Methods:Ovaries were collected from prenatal fetuses[gestational age(95±5)days],neonatal(day 0),and prepubertal ewe lambs(two and four months of age);each age group included six animals.Ovaries(n=12,each group)were dissected and processed for hematoxylin and eosin staining.Stained sections(n=24,each group)were imaged and utilized for histomorphology assessment,follicle measurement,and classification.Results:Prenatal ovaries were mainly enriched with primordial follicles accompanied by a lower proportion of primary follicles.In addition to primordial and primary follicles,neonatal ovaries demonstrated a proportion of centrally located multilayered and antral follicles.In comparison with neonatal ovaries,the proportion of multilayered and antral follicles was significantly higher in the ovaries of two-month-old lambs;conversely,the proportion of peripherally situated primordial follicles dramatically declined compared to that of earlier age of lamb.Although there was no statistical variation in the sizes of primordial follicles across groups,the mean diameter of the primary follicle in the prenatal ovaries was substantially smaller than in postnatal ovaries.Compared to the neonatal ovaries,the size of the multilayered and antral follicles in the prepubertal ovaries was substantially larger.Conclusions:The earliest follicular developmental stages were established prenatally whereas the advanced growth stages started in the neonatal period and greatly increased in the prepubertal period.

Fractures around the shoulder in the skeletally immature:A scoping review

Fractures around the shoulder girdle in children are mainly caused by sports accidents.The clavicle and the proximal humerus are most commonly involved.Both the clavicle and the proximal humerus have a remarkable potential for remodeling,which is why most of these fractures in children can be treated conservatively.However,the key is to understand when a child benefits from surgical management.Clear indications for surgery of these fractures are lacking.This review focuses on the available evidence on the management of clavicle and proximal humerus fractures in children.The only strict indications for surgery for diaphyseal clavicle fractures in children are open fractures,tenting of the skin with necrosis,associated neurovascular injury,or a floating shoulder.There is no evidence to argue for surgery of displaced clavicle fractures to prevent malunion since most malunions are asymptomatic.In the rare case of a symptomatic malunion of the clavicle in children,corrective osteosynthesis is a viable treatment option.For proximal humerus fractures in children,treatment is dictated by the patient's age(and thus remodeling potential)and the amount of fracture displacement.Under ten years of age,even severely displaced fractures can be treated conservatively.From the age of 13 and onwards,surgery has better outcomes for severely displaced(Neer types III and IV)fractures.Between 10 and 13 years of age,the indications for surgical treatment are less clear,with varying cut-off values of angulation(30-60 degrees)or displacement(1/3–2/3 shaft width)in the current literature.

A Review of Main Factors Involved in the Maturation of Oil Palm (Elaeis guineensis Jacq.) Fruit Bunches

The oil palm (Elaeis guineensis Jacq.) is a diploid perennial plant of the Arecaceae family. It is the most important plant cultivated for oil production. To ensure this production, certain optimal conditions are required: temperature, sunshine, rainfall, etc. The oil palm ensures its survival through the fruits borne on bunches located at the axis of the 17th to 20th leaves from the central stem. From pollination to the maturity of a bunch it takes about 4.5 to 6 months. Several events occur during this period: seed enlargement, weight increase, colour change, etc., but also important physiological changes: synthesis of some pigments (anthocyanin), increase in oil content correlated with the decrease in water content, etc. All of these constitute factors that can provide a better understanding of the biology of the seed. The aim of this work was to review some of the important parameters involved in the development and maturation of oil palm fruit bunches. These factors are classified into physiological, biochemical as well as environmental. The physiological parameters are color, appearance of embryo, seed weight and fruit detachment from bunches;Biochemical parameters include water content, oil content, carbohydrate, protein, mineral contents and lipase activity while temperature is the main environmental factor that affects fruit maturation. Thorough research has not yet been done at the different stages of maturation and ripening, thus a deep look into this may open up new avenues for research on early germinated oil palm seed production prior to seed dormancy.

A Unique Aegilops tauschii Genotype Needless to Immature Embryo Culture in Cross with Wheat

Common or bread wheat ( Triticum aestivum L., AABBDD, 2n=42) originated ca. 8 000 years ago from hybridization of tetraploid wheat ( Triticum turgidum L., AABB, 2n=28) and diploid Aegilops tauschii Coss. (DD, 2n=14). An essential prerequisite for this evolutionary step is that the natural hybrids between tetraploid wheat and diploid Aegilops tauschii can produce relatively many filled seeds which germinated well. In this study, without special techniques, e.g. immature embryo culture, out of 22 Ae. tauschii accessions, the genotype AS60 produced relatively many filled seeds which germinated well. The seed germination percentages in the crosses of Ae. tauschii ×tetraploid wheat, tetraploid wheat× Ae. tauschii and Ae. tauschii ×common wheat were, respectively, 50.0%, 57.1% and 45.5%. It seems that Ae. tauschii accession AS60 has a unique genotype which facilitate hybrid seed development and viability, and which meets with the prerequisite for wheat evolutionary. Furthermore, the significance of this finding for common wheat improvement and evolution was discussed.

Unisexual Pistillate Flower Regeneration in Immature Embryo Culture of Wheat

In this experiment, floral development from tissue culture of bread wheat (Triticum aestivum L.) was investigated. Immature embryos of 45 wheat cultivars were cultured, and 11.1% of the genotypes regenerated floral organs from the calli near the bases of the green buds or plantlets regenerated. The floral buds were morphologically incomplete with the appearances of unisexual pistillate flowers which were naked, clustered with normal ovaries and exuberant feather-like stigmas, but without stamens, paleas, lemmas and glumes. The histological examination showed that the pistils originated from the meristematic cells near the green buds or plantlets, and the clustered pistils were formed by secondary pistillate regeneration. The development of the feather-like structures was earlier than that of the ovules. Biovule developed from an ovary besides normal uniovule. Statistical analysis by X 2 test for independency demonstrated highly significant difference of flower regeneration among the tested genotypes. Wheat cultivar YA-1 revealed higher percentage (44.4%) than other genotypes, and the response could well be repeated in different years. It was indicated that the floral regeneration of immature embryo explants of YA-1 is relatively stable. The frequency of floral regeneration was mainly regulated by the components in the subculture media, compared with the response of the dedifferentiation media, despite the obviously different components involving basal medium type, inorganic Fe2+ concentration and plant growth regulators. The results suggested the combination of 6-benzylaminopurine, alpha-naphthalene acetic-acid and doubled inorganic Fe2+ might be more beneficial to inducing the floral development than that of 2,4-D and normal inorganic Fe2+ concentration in subculture medium. However, both immature inflorescence and mature embryo, as cultured explants of YA-1, did not regenerate any flower organs. It is believed that the immature embryo culture of YA-1 can be used to establish ideal experimental system for the study of floral developmental mechanism in wheat.

Establishment of 6VS Telocentric Lines of Haynaldia villosa Resistant to Powdery Mildew Induced by Immature Embryo Culture

The line of T240-6 was selected from 32 SC 2 lines of immature embryo culture of T240 (common wheat (Triticum aestivum L.)× Wheat-Haynaldia villosa (L.) Schur. 6D/6V substitution line) through powdery mildew characterization, glutamate oxaloacetate transaminase (GOT) enzyme and gliadin (Gli) analyses and in situ hybridization. All of the individual plants resistant to powdery mildew lacked the locus of GOT at 6VL arm (GOT-V 2) and had gliadin locus at 6VS arm (Gli-V 2) of Haynaldia villosa. All the plants resistant to powdery mildew had one or two telocentric chromosomes that did not pair with wheat chromosomes but paired between themselves. T240-6 was identified as a telocentric line through in situ hybridization.

Establishment of Plant Regeneration System from Immature Embryos of Maize(Zea mays L.) Inbred Lines

[Objective] The aim was to explore the conditions of high frequency induction of embryonic callus and plant regeneration of maize. [Method] Immature embryos of maize inbred lines were used as explants to study the effect of different 2,4-D concentrations on the induction of callus,the effect of different 6-BA concentrations on the differentiation of test-tube plantlet,as well as the effect of different IBA concentrations on the rooting of test-tube plantlet. [Result] 2,4-D showed obvious effect on the induction of inducement rate of maize,and the optimum induction medium was：N6 ＋ 2 mg/L of 2,4-D ＋ 500 mg/L of CH ＋ 500 mg/L of Pro ＋10 mg/L of AgNO3; the optimum differentiation medium was：N6 ＋ 0.5 mg/L of BA ＋ 500 mg/L of Pro; the optimum for the rooting of test-tube plantlet was 1/2 MS ＋ 0.5 mg/L of IBA. [Conclusion] The study had provided basis for the genetic transformation of maize.

Optimization of plant regeneration system in vitro culture in wheat

Studies were carried out to establish an efficient regeneration system of three bread wheat cultivars. Results showed induction medium containing 2,4-dichlorophenoxyacetic acid (2,4-D) had a higher plantlet regeneration frequency than Piclorm, with an average frequency of 54% in all treatments. Optimal condition for different genotypic rice was as following: induction medium (MSS 3AA/2) with 0.5 mg L-1 2,4-D, regeneration medium (R) with 0.01 mg L-1 2,4-D and 3 mg L-1 KT. The average regeneration frequency reached 83.3% under the condition. Correlation analysis showed that root differentiation, in different level, correlated with green spot regeneration, and with the number of regenerated plants per callus. No correlation was found between green spots regenerated and the numbers of plants regenerated per callus.

Descriptions of the Immature Stages of Three Species of the Tribe Ozophorini (Heteroptera:Lygaeidae:Rhyparochrominae) from China

Immature stages of 3 species of the tribe Ozophorini from China are described for the first time, they are Bryanellocoris orientalis Hidaka (3rd^5th instars), Primierus longispinus Zheng (4th^5th instars) and Vertomannus brevicollum Zheng (4th^5th instars). Abrief study on fine structure of pale spots on head, pronotum and abdomen of 5th instar nymph of Bryanellocoris orientalis Hidaka was also given.

Morphology of Kuwania bipora Borchsenius (Hemiptera:Coccoidea:Margarodidae)

In this paper the morphology of adult female of Kuwania bipora Borchsenius, 1960 is redescribed. The morphologies of adult male and all immature stages of both sexes are firstly described and illustrated. A key to all stages of K. bipora is provided.

Descriptions of Male and Immature Stages of Cryptococcus ulmi Tang et Hao (Homoptera: Coccoidea: Eriococcidae) with Brief Notes on Its Biology

In this paper, the crawler, second instar female and male, prepupa, pupa and adult male of Cryptococcus ulmi are described and illustrated for the first time; adult female is redescribed; a key to all stages is given and the biology is briefly repor ted.

Research on the Educational Issues of the Emerging Tourism Industry in Developing Countries

This research explores emerging concepts of tourism education,training,and entrepreneurship development.Nowadays,the discourses on this theme have been growing in both developed and developing countries,especially to reduce unemployment rates through the education of young people.For this purpose,this study uses secondary data sources to analyze individual rationality and the creativity of educated young people for entrepreneurship development in the business sector.The analytical framework begins from the investigation of the tourism industry and the processes for empowering those people since tourism industry is considered as one of the agents of economic changes in developing countries,such as Nepal.However,skilled and trained manpower are required to operate well.The main theme of this study is that the aforesaid manpower can be developed with entrepreneurship skills by providing education and training in this business.This study entirely agrees that once the tourism industry is well run by removing the hurdles seen in this sector,there would be an increase in employment opportunities and a raise in the country’s revenue in addition to solving many other social problems.

Contentious Petroleum Geochemical Issues in China’s Sedimentary Basins

Petroleum geochemistry contributes to exploration successes by providing key constraints for geological models and critical input to exploration scenarios. One of the most important tasks in a typical exploration program is to identify the most effective source intervals or kitchens in a basin, through oil-source correlation. The results of correlation are valid only if the geochemical parameters used address adequately the genetic characteristics of the source rocks as well as the mass transport and mixing processes of hydrocarbon fluids occurring in the carrier beds and reservoirs. This manuscript discusses four of the major contentious petroleum geochemical issues in China’s sedimentary basins. It is suggested that marine incursions played a significant role in the formation of prolific petroleum source rocks in the gigantic, dominantly freshwater, Songliao Basin. Several models are proposed to account for the occurrence of immature oils in the Cathaysian rift system including the Bohai Bay Basin, thus immature source rocks are considered a mere minor contributor to the known economic immature oil resources. Both geological and geochemical evidence are reviewed to refute a dominantly coaly source for the petroleum discovered in the Turpan Basin. Results of case studies are presented to demonstrate the importance of recognizing petroleum fluid mixing to solve the oil-source correlation issues in the structurally complex Tarim Basin. In addressing the fundamental assumptions and potential flaws of the molecular geochemical parameters commonly used for oil-source correlation, the need of a mass fraction approach is proposed to deal with such contentious issues as marine versus lacustrine, coal versus lacustrine, and mature versus immature oils.

Plasma 17-hydroxyprogesterone/cortisol ratio is not a predictor of systemic hypotension in extremely premature infants

Background/aims: To determine whether the 17-hydroxyprogesterone (17-OHP)/cortisol ratio as a marker of immature11-beta hydroxylase activity can predict severe systemic hypotension in preterm neonates. Methods: Serum cortisol and 17-OHP concentrations were measured in capillary blood deposited on blotter paper on day 3 post-natal age (Day 3) in infants less than 32 weeks postmenstrual age (PMA). The predictive value of 17-OHP/cortisol ratio for a first episode of systemic hypotension occurring after Day 3 (FESH) was evaluated. Results: Of 105 infants included, 14 patients (13%) presented a FESH. Neither the 17-OHP/cortisol ratio, nor the 17-OHP or cortisol concentrations were associated with the occurrence of a FESH when adjusted for potential confounding factors. 17-OHP and cortisol were inversely associated to PMA (r = ﹣0.36 and ﹣0.40, respectively). Cortisol, but not 17-OHP, was associated with the type of hospitalization unit, the respiratory support and the presence of a patent ductus arteriosus. The 17-OHP/cortisol ratio was associated with the type of hospitalization unit only. Conclusions: The 17-OHP/ cortisol ratio at Day 3 did not predict the occurrence of a first episode of systemic hypotension after Day3 inpreterm neonates.

The Junggar Immature Continental Crust Province and Its Mineralization

According to the study on the peripheral orogenic belts of the Junggar basin and combined with the interpretation of geophysical data, this paper points out that there is an Early Paleozoic basement of immature continental crust in the Junggar area, which is mainly composed of Neoproterozoic-Ordovician oceanic crust and weakly metamorphosed covering sedimentary rocks. The Late Paleozoic tectonism and mineralization were developed on the basement of the Early Paleozoic immature continental crust. The Junggar metallogenic province is dominated by Cr, Cu, Ni and Au mineralization. Those large and medium-scale deposits are mainly distributed along the deep faults and particularly near the ophiolitic melange zones, and formed in the Late Paleozoic with the peak of mineralization occurring in the Carboniferous-Permian post-collisional stage. The intrusions related to Cu, Ni and Au mineralization generally have low Is, and positive εNd(t) values. The δ34S values of the ore deposits are mostly near zero, and the lead isotopes are mostly of normal lead. All these indicate that the ore-forming material comes either directly from the mantle-derived magma (for chromite and Cu-Ni deposits) or from recirculation of the basement material of the Early Paleozoic immature crust (for most Cu and Au deposits).