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Background: Glioblastoma multiforme (GBM) is an incurable tumor, with a median survival rate of only 14–15 months. Along with heterogeneity and unregulated growth, a central matter in dealing with GBMs is cell invasiveness. Thus, improving prognosis requires finding new agents to inhibit key multiple pathways, even simultaneously. A subset of GBM stem-like cells (GSCs) may account for tumorigenicity, representing, through their pathways, the proper cellular target in the therapeutics of glioblastomas. GSCs cells are routinely enriched and expanded due to continuous exposure to specific growth factors, which might alter some of their intrinsic characteristic and hide therapeutically relevant traits. Methods: By removing exogenous growth factors stimulation, here we isolated and characterized a subset of GSCs with a "mitogen-independent" phenotype (I-GSCs) from patient's tumor specimens. Differential side-by-side comparative functional and molecular analyses were performed either in vitro or in vivo on these cells versus their classical growth factor (GF)-dependent counterpart (D-GSCs) as well as their tissue of origin. This was performed to pinpoint the inherent GSCs' critical regulators, with particular emphasis on those involved in spreading and tumorigenic potential. Transcriptomic fingerprints were pointed out by ANOVA with Benjamini-Hochberg False Discovery Rate (FDR) and association of copy number alterations or somatic mutations was determined by comparing each subgroup with a two-tailed Fisher's exact test. The combined effects of interacting in vitro and in vivo with two emerging GSCs' key regulators, such as Wnt5a and EphA2, were then predicted under in vivo experimental settings that are conducive to clinical applications. In vivo comparisons were carried out in mouse-human xenografts GBM model by a hierarchical linear model for repeated measurements and Dunnett's multiple comparison test with the distribution of survival compared by Kaplan–Meier method. Results: Here, we assessed that a subset of GSCs from high-grade gliomas is self-sufficient in the activation of regulatory growth signaling. Furthermore, while constitutively present within the same GBM tissue, these GF-independent GSCs cells were endowed with a distinctive functional and molecular repertoire, defined by highly aggressive Wnt5aHigh/EphA2Low profile, as opposed to Wnt5aLow/EphA2High expression in sibling D-GSCs. Regardless of their GBM subtype of origin, I-GSCs, are endowed with a raised in vivo tumorigenic potential than matched D-GSCs, which were fast-growing ex-vivo but less lethal and invasive in vivo. Also, the malignant I-GSCs' transcriptomic fingerprint faithfully mirrored the original tumor, bringing into evidence key regulators of invasiveness, angiogenesis and immuno-modulators, which became candidates for glioma diagnostic/prognostic markers and therapeutic targets. Particularly, simultaneously counteracting the activity of the tissue invasive mediator Wnt5a and EphA2 tyrosine kinase receptor addictively hindered GSCs' tumorigenic and invasive ability, thus increasing survival. Conclusion: We show how the preservation of a mitogen-independent phenotype in GSCs plays a central role in determining the exacerbated tumorigenic and high mobility features distinctive of GBM. The exploitation of the I-GSCs' peculiar features shown here offers new ways to identify novel, GSCs-specific effectors, whose modulation can be used in order to identify novel, potential molecular therapeutic targets. Furthermore, we show how the combined use of PepA, the anti-Wnt5a drug, and of ephrinA1-Fc to can hinder GSCs' lethality in a clinically relevant xenogeneic in vivo model thus being conducive to perspective, novel combinatorial clinical application. [ABSTRACT FROM AUTHOR]

Background: Respectful maternal and newborn care (RMNC) is an important component of high-quality care but progress is impeded by critical measurement gaps for women and newborns. The Every Newborn Birth Indicators Research Tracking in Hospitals (EN-BIRTH) study was an observational study with mixed methods assessing measurement validity for coverage and quality of maternal and newborn indicators. This paper reports results regarding the measurement of respectful care for women and newborns.Methods: At one EN-BIRTH study site in Pokhara, Nepal, we included additional questions during exit-survey interviews with women about their experiences (July 2017-July 2018). The questionnaire was based on seven mistreatment typologies: Physical; Sexual; or Verbal abuse; Stigma/discrimination; Failure to meet professional standards of care; Poor rapport between women and providers; and Health care denied due to inability to pay. We calculated associations between these typologies and potential determinants of health - ethnicity, age, sex, mode of birth - as possible predictors for reporting poor care.Results: Among 4296 women interviewed, none reported physical, sexual, or verbal abuse. 15.7% of women were dissatisfied with privacy, and 13.0% of women reported their birth experience did not meet their religious and cultural needs. In descriptive analysis, adjusted odds ratios and multivariate analysis showed primiparous women were less likely to report respectful care (β = 0.23, p-value < 0.0001). Women from Madeshi (a disadvantaged ethnic group) were more likely to report poor care (β = - 0.34; p-value 0.037) than women identifying as Chettri/Brahmin. Women who had caesarean section were less likely to report poor care during childbirth (β = - 0.42; p-value < 0.0001) than women with a vaginal birth. However, babies born by caesarean had a 98% decrease in the odds (aOR = 0.02, 95% CI, 0.01-0.05) of receiving skin-to-skin contact than those with vaginal births.Conclusions: Measurement of respectful care at exit interview after hospital birth is challenging, and women generally reported 100% respectful care for themselves and their baby. Specific questions, with stratification by mode of birth, women's age and ethnicity, are important to identify those mistreated during care and to prioritise action. More research is needed to develop evidence-based measures to track experience of care, including zero separation for the mother-newborn pair, and to improve monitoring. [ABSTRACT FROM AUTHOR]

Background: Acute flaccid paralysis (AFP) surveillance has been adopted globally as a key strategy for monitoring the progress of the polio eradication initiative. Hereby, to evaluate the completeness of the ascertainment of AFP cases in Italy, a hospital-discharges based search was carried out.Methods: AFP cases occurring between 2007 and 2016 among children under 15 years of age were searched in the Italian Hospital Discharge Records (HDR) database using specific ICD-9-CM diagnostic codes. AFP cases identified between 2015 and 2016 were then compared with those notified to the National Surveillance System (NSS).Results: Over a 10-year period, 4163 hospital discharges with diagnosis of AFP were reported in Italy. Among these, 956 (23.0%) were acute infective polyneuritis, 1803 (43.3%) myopathy, and 1408 (33.8%) encephalitis, myelitis and encephalomyelitis. During the study period, a decreasing trend was observed for all diagnoses and overall the annual incidence rate (IR) declined from 5.5 to 4.5 per 100,000 children. Comparing NSS with HDR data in 2015-2016, we found a remarkable underreporting, being AFP cases from NSS only 14% of those recorded in HDR. In particular, the acute infective polyneuritis cases reported to NSS accounted for 42.6% of those detected in HDR, while only 0.9% of myopathy cases and 13.1% of encephalitis/myelitis/encephalomyelitis cases have been notified to NSS. The highest AFP IRs per 100,000 children calculated on HDR data were identified in Liguria (17.4), Sicily (5.7), and Veneto (5.1) Regions; regarding the AFP notified to the NSS, 11 out of 21 Regions failed to reach the number of expected cases (based on 1/100,000 rate), and the highest discrepancies were observed in the Northern Regions. Overall, the national AFP rate was equal to 0.6, therefore did not reach the target value.Conclusions: AFP surveillance data are the final measure of a country's progress towards polio eradication. The historical data obtained by the HDR have been useful to assess the completeness of the notification data and to identify the Regions with a low AFP ascertainment rate in order to improve the national surveillance system. [ABSTRACT FROM AUTHOR]

Background: Many congenitally cytomegalovirus-infected (cCMV) neonates are at risk for severe consequences, even if they are asymptomatic at birth. The assessment of the viral load in neonatal blood could help in identifying the babies at risk of sequelae. Methods: In the present study, we elaborated the results obtained on blood samples collected in the first two weeks of life from 22 symptomatic and 48 asymptomatic newborns with cCMV diagnosed through urine testing. We evaluated the performances of two quantitative methods (pp65 antigenemia test and plasma Real-time PCR) and the semi-quantitative results of dried blood sample (DBS) test in the aim of identifying a valid method for measuring viral load. Results: Plasma qPCR and DBS tests were positive in 100% of cases, antigenemia in 81%. Only the latter test gave quantitatively different results in symptomatic versus asymptomatic children. qPCR values of 10³ copies/ml were found in 52% of newborn. "Strong" DBS test positivity cases had higher median values of both pp65 positive PBL and DNA copies/ml than cases with a "weak" positivity. Conclusions: As expected antigenemia test was less sensitive than molecular tests and DBS test performed better on samples with higher rates of pp65 positive PBL and higher numbers of DNA copies/ml. The prognostic significance of the results of these tests will be evaluated on completion of the ongoing collection of follow-up data of these children. [ABSTRACT FROM AUTHOR]

Background: Congenital CMV (cCMV) infection is a serious public health issue due to both its worldwide prevalence and the severe and permanent impairments it causes. However, awareness of this infection is low in the general population and among pregnant women, and it also seems to be generally disregarded by healthcare providers. The identification of factors behind this inadequate level of knowledge could provide a basis for future preventive measures. This study aimed at evaluating awareness of CMV and cCMV infection and its correlation with socio-demographic variables in a general population. Methods: The survey was carried out by computer-assisted web interviewing (CAWI). A questionnaire was sent via e-mail to the 70,975 individuals who comprised the whole population (students, administrative staff, teaching staff) of Milan University, Italy in 2015. Results: Out of the 10,190 respondents, 5,351 (52.5 %) had already heard of CMV but only 3,216 (31.8 %) knew that this virus could be implicated in congenital infection. Urine and breastfeeding were the least recognized transmission routes for CMV infection; less than half of respondents accurately identified the right symptoms and sequelae caused by cCMV infection. The correct hygienic measures against cCMV infection were identified in percentages ranging from 55.6 to 75 % depending on the measures proposed but about one in three of interviewees deemed those measures unnecessary in the event of a pregnant woman already being CMV seropositive. From the mean knowledge scores the most complete quality of awareness of CMV turned out to be linked to childbearing-age (25-40 year) and with not having children, even if results for non-parents showed less of them having heard of cCMV than parents. Conclusion: Our results indicate a limited and confused awareness of cCMV infection in a large, fairly young and well-educated Italian population. [ABSTRACT FROM AUTHOR]

Background: Inflammation has been implicated in many disorders, including cancer and available therapies elicit adverse effects. Plants of the family Rubiaceae have shown potency against inflammation. The anti-inflammatory and anti-oxidant potential of Feretia apodanthera was investigated in this study to evaluate its effectiveness. Methods: The phytochemical, antioxidant and anti-inflammatory potential of root bark (n-Hexane, diethyl ether, ethanol and aqueous) extracts of Feretia apodanthera was investigated in this study. The extracts were subjected to various chemical tests for phytochemical constituents; their antioxidant activity was determined using in-vitro DPPH radical scavenging activity assay and their anti-inflammatory activity was determined using carrageenan induced paw oedema model. FTIR and GCMS analysis was done to determine the compounds present. Results: Phytochemical screening of extracts revealed the presence of unsaturated steroids, triterpenes, cardiac glycosides, tannins, saponin and alkaloids. Vitamin C had a median inhibitory concentration (IC50) of 0. 038 mg/ml which was lower than IC50 of all the extracts. Of all the extracts, ethanol extract had the lowest IC50 (0.044 mg/ml) which is comparable to vitamin C. Anti-inflammatory studies showed that the inflammation inhibition potential of 400 mg/kg body weight of all the extracts was significantly lower (p <0. 05) than the standard ketoprofen (50 mg/kg) at the first three hours but significantly higher (p <0.05) at the fourth hour. At the fifth hour, the inflammation inhibition potential of diethyl ether, ethanol and aqueous extracts were significantly higher (p <0.05) than that of the standard. FTIR analysis showed the presence of ketones, amines, alkenes and carboxylic groups. GCMS analysis revealed compounds that are potential antiinflammatory agents. Conclusion: This study revealed that extracts of Feretia apodanthera possess anti-inflammatory effects against right hind paw oedema of albino rats and can act as an effective antioxidant. [ABSTRACT FROM AUTHOR]

Background: The androgen receptor (AR) is a major driver of prostate cancer, and increased AR levels and co-activators of the receptor promote the development of prostate cancer. INhibitor of Growth (ING) proteins target lysine acetyltransferase or lysine deacetylase complexes to the histone H3K4Me3 mark of active transcription, to affect chromatin structure and gene expression. ING3 is a stoichiometric member of the TIP60 lysine acetyltransferase complex implicated in prostate cancer development.Methods: Biopsies of 265 patients with prostate cancer were stained for ING3, pan-cytokeratin, and DNA. LNCaP and C4-2 androgen-responsive cells were used for in vitro assays including immunoprecipitation, western blotting, Luciferase reporter assay and quantitative polymerase chain reaction. Cell viability and migration assays were performed in prostate cancer cell lines using scrambled siRNA or siRNA targeting ING3.Results: We find that ING3 levels and AR activity positively correlate in prostate cancer. ING3 potentiates androgen effects, increasing expression of androgen-regulated genes and androgen response element-driven reporters to promote growth and anchorage-independent growth. Conversely, ING3 knockdown inhibits prostate cancer cell growth and invasion. ING3 activates the AR by serving as a scaffold to increase interaction between TIP60 and the AR in the cytoplasm, enhancing receptor acetylation and translocation to the nucleus. Activation is independent of ING3's ability to target the TIP60 complex to H3K4Me3, identifying a previously unknown chromatin-independent cytoplasmic activity for ING3. In agreement with in vitro observations, analysis of The Cancer Genome Atlas (TCGA) data (n = 498) and a prostate cancer tissue microarray (n = 256) show that ING3 levels are higher in aggressive prostate cancers, with high levels of ING3 predicting shorter patient survival in a low AR subgroup. Including ING3 levels with currently used indicators such as the Gleason score provides more accurate prognosis in primary prostate cancer.Conclusions: In contrast to the majority of previous reports suggesting tumor suppressive functions in other cancers, our observations identify a clear oncogenic role for ING3, which acts as a co-activator of AR in prostate cancer. Data from TCGA and our previous and current tissue microarrays suggest that ING3 levels correlate with AR levels and that in patients with low levels of the receptor, ING3 level could serve as a useful prognostic biomarker. [ABSTRACT FROM AUTHOR]

The management of patients with colonic diverticular perforation is still evolving. Initial lavage with or without simple suture and drainage was suggested in the late 19th century, replaced progressively by the three-stage Mayo Clinic or the two-stage Mickulicz procedures. Fears of inadequate source control prompted the implementation of the resection of the affected segment of colon with formation of a colostomy (Hartman procedure) in the 1970's. Ensuing development of the treatment strategies was driven by the recognition of the high morbidity and mortality and low reversal rates associated with the Hartman procedure. This led to the wider use of resection and primary anastomosis during the 1990's. The technique of lavage and drainage regained popularity during the 1990's. This procedure can also be performed laparoscopically with the advantage of faster recovery and shorter hospital stay. This strategy allows resectional surgery to be postponed or avoided altogether in many patients; and higher rates of primary resection and anastomosis can be achieved avoiding the need for a stoma. The three recent randomized controlled trials comparing laparoscopic peritoneal lavage alone to resectional surgery reported inconsistent outcomes. The aim of this review is to review the historical evolution and future reflections of surgical treatment modalities for diffuse purulent and feculent peritonitis. In this review we classified the various surgical strategies according to Krukowski et al. and Vermeulen et al. and reviewed the literature related to surgical treatment separately for each period. [ABSTRACT FROM AUTHOR]

Background: VanYn, encoded by the dbv7 gene (also known as vanYn) of the biosynthetic cluster devoted to A40926 production, is a novel protein involved in the mechanism of self-resistance in Nonomuraea sp. ATCC 39727. This filamentous actinomycete is an uncommon microorganism, difficult-to-handle but biotechnologically valuable since it produces the glycopeptide antibiotic A40926, which is the precursor of the second-generation dalbavancin in phase III of clinical development. In order to investigate VanYn role in glycopeptide resistance in the producer actinomycete an appropriate host-vector expression system is required. Results: The cloning strategy of vanYn gene (G-C ratio 73.3%) in the expression vector pIJ86 yielded a recombinant protein with a tag encoding for a histidine hexamer added at the C-terminus (C-His6-vanYn) or at the N-terminus (N-His6-vanYn). These plasmids were used to transform three Streptomyces spp., which are genetically-treatable high G-C content Gram-positive bacteria taxonomically related to the homologous producer Nonomuraea sp. Highest yield of protein expression and purification (12 mg of protein per liter of culture at 3 L bioreactor-scale) was achieved in Streptomyces venezuelae ATCC 10595, that is a fast growing streptomyces susceptible to glycopeptides. vanYn is a transmembrane protein which was easily detached and recovered from the cell wall fraction. Purified C-His6-vanYn showed D,D-carboxypeptidase and D,D-dipeptidase activities on synthetic analogs of bacterial peptidoglycan (PG) precursors. C-His6-vanYn over-expression conferred glycopeptide resistance to S. venezuelae. On the contrary, the addition of His6-tag at the N-terminus of the protein abolished its biological activity either in vitro or in vivo assays. Conclusions: Heterologous expression of vanYn from Nonomuraea sp. ATCC 39727 in S. venezuelae was successfully achieved and conferred the host an increased level of glycopeptide resistance. Cellular localization of recombinant VanYn together with its enzymatic activity as a D,D-peptidase/D,D-carboxypeptidase agree with its role in removing the last D-Ala from the pentapeptide PG precursors and reprogramming cell wall biosynthesis, as previously reported in glycopeptide resistant pathogens. [ABSTRACT FROM AUTHOR]

Background A number of valuable candidates as tuberculosis vaccine have been reported, some of which have already entered clinical trials. The new vaccines, especially subunit vaccines, need multiple administrations in order to maintain adequate life-long immune memory: this demands for high production levels and degree of purity. Results In this study, TB10.4, Ag85B and a TB10.4-Ag85B chimeric protein (here-after referred as full) - immunodominant antigens of Mycobacterium tuberculosis - were expressed in Escherichia coli and purified to homogeneity. The rational design of expression constructs and optimization of fermentation and purification conditions allowed a marked increase in solubility and yield of the recombinant antigens. Indeed, scaling up of the process guaranteed mass production of all these three antigens (2.5-25 mg of pure protein/L cultivation broth). Quality of produced soluble proteins was evaluated both by mass spectrometry to assess the purity of final preparations, and by circular dichroism spectroscopy to ascertain the protein conformation. Immunological tests of the different protein products demonstrated that when TB10.4 was fused to Ag85B, the chimeric protein was more immunoreactive than either of the immunogenic protein alone. Conclusions We reached the goal of purifying large quantities of soluble antigens effective in generating immunological response against M. tuberculosis by a robust, controlled, scalable and economically feasible production process. [ABSTRACT FROM AUTHOR]

Background Wounded leaves of Arabidopsis thaliana produce reactive oxygen species (ROS) within minutes after wounding and become resistant to the pathogenic fungus Botrytis cinerea at a local level. This fast response of the plants to the wound is called wound-induced resistance (WIR). However the molecular mechanisms of this response and the signal cascade between the wound and ROS production are still largely unknown. Calcium is a conserved signal and it is involved in many abiotic stress responses in plants, furthermore, calcium pathways act very fast. Results The results of this study show that leaves treated with calcium channels inhibitors (verapamil) or calcium chelators (oxalate and EGTA) are impaired in ROS production. Moreover, leaves treated with verapamil, EGTA or oxalate were more susceptible to B. cinerea after wounding. The intracellular measurements of calcium changes indicated quick but transient calcium dynamics taking place few seconds after wounding in cells neighbouring the wound site. This change in the cytosolic calcium was followed in the same region by a more stable ROS burst. Conclusions These data further extend our knowledge on the connection between wounding, calcium influx and ROS production. Moreover they provide for the first time the evidence that, following wounding, calcium changes precede a burst in ROS in the same location. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma multiforme (GBM) is one of the most aggressive forms of cancer with a high rate of recurrence. We propose a novel oncolytic vaccinia virus (VACV)-based therapy using expression of the bone morphogenetic protein (BMP)-4 for treating GBM and preventing recurrence. Methods: We have utilized clinically relevant, orthotopic xenograft models of GBM based on tumor-biopsy derived, primary cancer stem cell (CSC) lines. One of the cell lines, after being transduced with a cDNA encoding firefly luciferase, could be used for real time tumor imaging. A VACV that expresses BMP-4 was constructed and utilized for infecting several primary glioma cultures besides conventional serum-grown glioma cell lines. This virus was also delivered intracranially upon implantation of the GBM CSCs in mice to determine effects on tumor growth. Results: We found that the VACV that overexpresses BMP-4 demonstrated heightened replication and cytotoxic activity in GBM CSC cultures with a broad spectrum of activity across several different patient-biopsy cultures. Intracranial inoculation of mice with this virus resulted in a tumor size equal to or below that at the time of injection. This resulted in survival of 100% of the treated mice up to 84 days post inoculation, significantly superior to that of a VACV lacking BMP-4 expression. When mice with a higher tumor burden were injected with the VACV lacking BMP-4, 80% of the mice showed tumor recurrence. In contrast, no recurrence was seen when mice were injected with the VACV expressing BMP-4, possibly due to induction of differentiation in the CSC population and subsequently serving as a better host for VACV infection and oncolysis. This lack of recurrence resulted in superior survival in the BMP-4 VACV treated group. Conclusions: Based on these findings we propose a novel VACV therapy for treating GBM, which would allow tumor specific production of drugs in the future in combination with BMPs which would simultaneously control tumor maintenance and facilitate CSC differentiation, respectively, thereby causing sustained tumor regression without recurrence. [ABSTRACT FROM AUTHOR]

Background: Testing for viral DNA in neonatal blood dried on paper (DBS) has proved a valid means of diagnosing congenital CMV infection with both clinical and epidemiological relevance. To assess the quality of the detection of CMV-DNA on DBS in laboratories performing this test a proficiency panel consisting of nine samples with two blood spots on each filter paper was produced and distributed. Six samples were derived from whole blood, negative for CMV DNA and antibody, and spiked with cell-grown CMV Towne in various concentrations (7.3 x 10² - 9.6 x 105 copies/ml), one was a CMV positive clinical specimen (3.9 x 106 copies/ml), and two samples were CMV-negative whole blood. Results: The 27 responding laboratories from 14 countries submitted 33 datasets obtained by means of conventional PCR (n = 5) or real-time PCR (n = 28) technologies. A correct positive result was reported in at least 91% of datasets in samples with a viral load of 8.8 x 104 copies/ml or higher. However only 59% and 12% identified the 9.4 x 10³ and 7.3 x 10² copies/ml samples, respectively, correctly as positive. False positive results were reported by 9% of laboratories and in 11% of datasets. Conclusion: These results indicate a clear need for improvement of methods as sensitivity and false-positivity still appear to be a major problem in a considerable number of laboratories. [ABSTRACT FROM AUTHOR]

A comparative food ethnobotanical study was carried out in twenty-one local communities in Italy, fourteen of which were located in Northern Italy, one in Central Italy, one in Sardinia, and four in Southern Italy. 549 informants were asked to name and describe food uses of wild botanicals they currently gather and consume. Data showed that gathering, processing and consuming wild food plants are still important activities in all the selected areas. A few botanicals were quoted and cited in multiple areas, demonstrating that there are ethnobotanical contact points among the various Italian regions (Asparagus acutifolius, Reichardia picroides, Cichorium intybus, Foeniculum vulgare, Sambucus nigra, Silene vulgaris, Taraxacum officinale, Urtica dioica, Sonchus and Valerianella spp.). One taxon (Borago officinalis) in particular was found to be among the most quoted taxa in both the Southern and the Northern Italian sites. However, when we took into account data regarding the fifteen most quoted taxa in each site and compared and statistically analysed these, we observed that there were a few differences in the gathering and consumption of wild food plants between Northern and Southern Italy. In the North, Rosaceae species prevailed, whereas in the South, taxa belonging to the Asteraceae, Brassicaceae, and Liliaceae s.l. families were most frequently cited. We proposed the hypothesis that these differences may be due to the likelihood that in Southern Italy the erosion of TK on wild vegetables is taking place more slowly, and also to the likelihood that Southern Italians' have a higher appreciation of wild vegetables that have a strong and bitter taste. A correspondence analysis confirmed that the differences in the frequencies of quotation of wild plants within the Northern and the Southern Italian sites could be ascribed only partially to ethnic/cultural issues. An additional factor could be recent socio-economic shifts, which may be having a continued effort on people's knowledge of wild food plants and the way they use them. Finally, after having compared the collected data with the most important international and national food ethnobotanical databases that focus on wild edible plants, we pointed out a few uncommon plant food uses (e.g. Celtis aetnensis fruits, Cicerbita alpine shoots, Helichrysum italicum leaves, Lonicera caprifolium fruits, Symphytum officinale leaves), which are new, or have thus far been recorded only rarely. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer is poorly characterized at genetic and non-genetic levels. The current study evaluates in a large cohort of patients the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC).Methods: We performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 histologically normal pancreatic tissue samples. Cox regression models were used to study the effect on survival of molecular subtypes and 16 clinicopathological prognostic factors. In order to better understand the biology of PDAC we used iRegulon to identify transcription factors (TFs) as master regulators of PDAC and its subtypes.Results: We confirmed the PDAssign gene signature as classifier of PDAC in molecular subtypes with prognostic relevance. We found molecular subtypes, but not clinicopathological factors, as independent predictors of survival. Regulatory network analysis predicted that HNF1A/B are among thousand TFs the top enriched master regulators of the genes expressed in the normal pancreatic tissue compared to the PDAC regulatory network. On immunohistochemistry staining of PDAC samples, we observed low expression of HNF1B in well differentiated towards no expression in poorly differentiated PDAC samples. We predicted IRF/STAT, AP-1, and ETS-family members as key transcription factors in gene signatures downstream of mutated KRAS.Conclusions: PDAC can be classified in molecular subtypes that independently predict survival. HNF1A/B seem to be good candidates as master regulators of pancreatic differentiation, which at the protein level loses its expression in malignant ductal cells of the pancreas, suggesting its putative role as tumor suppressor in pancreatic cancer.Trial Registration: The study was registered at ClinicalTrials.gov under the number NCT01116791 (May 3, 2010). [ABSTRACT FROM AUTHOR]

Background: The contribution of HIV-exposure to childhood mortality in a setting with widespread antiretroviral treatment (ART) availability has not been determined.Methods: From January 2012 to March 2013, mothers were enrolled within 48 h of delivery at 5 government postpartum wards in Botswana. Participants were followed by phone 1-3 monthly for 24 months. Risk factors for 24-month survival were assessed by Cox proportional hazards modeling.Results: Three thousand mothers (1499 HIV-infected) and their 3033 children (1515 HIV-exposed) were enrolled. During pregnancy 58 % received three-drug ART, 23 % received zidovudine alone, 11 % received no antiretrovirals (8 % unknown); 2.1 % of children were HIV-infected by 24 months. Vital status at 24 months was known for 3018 (99.5 %) children; 106 (3.5 %) died including 12 (38 %) HIV-infected, 70 (4.7 %) HIV-exposed uninfected, and 24 (1.6 %) HIV-unexposed. Risk factors for mortality were child HIV-infection (aHR 22.6, 95 % CI 10.7, 47.5 %), child HIV-exposure (aHR 2.7, 95 % CI 1.7, 4.5) and maternal death (aHR 8.9, 95 % CI 2.1, 37.1). Replacement feeding predicted mortality when modeled separately from HIV-exposure (aHR 2.3, 95 % CI 1.5, 3.6), but colinearity with HIV-exposure status precluded investigation of its independent effect. Applied at the population level (26 % maternal HIV prevalence), an estimated 52 % of child mortality occurs among HIV-exposed or HIV-infected children.Conclusions: In a programmatic setting with high maternal HIV prevalence and widespread maternal and child ART availability, HIV-exposed and HIV-infected children still account for most deaths at 24 months. Lack of breastfeeding was a likely contributor to excess mortality among HIV-exposed children. [ABSTRACT FROM AUTHOR]

An abstract of the article "What does it take to be healthy? Investigating immune-deficiency in non-immunodeficient scenarios," by Elisa Binda and colleagues is presented.

Pentoxifylline (PTX), a methylxanthine derivative widely used as a hemorheological agent in the treatment of peripheral vascular disease, was studied to unveil the mechanisms responsible for its inhibitory action on B16-F10 experimental metastasis. In vitro pretreatment of B16-F10 cells with noncytotoxic concentrations of PTX significantly inhibited their adhesion to reconstituted basement membrane Matrigel[sup ®] and type IV collagen as well as the relative activity of secreted 92 kD metalloproteinase. However, PTX pretreatment of B16-F10 cells did not affect their in vitro invasiveness. Heterotypic organ adhesion assays carried out with B16-F10 cells and suspended organ tissues demonstrated that pretreatment with noncytotoxic concentrations of PTX of both, tumor cells or lung tissue, brought about a dose-dependent inhibition of melanoma cell adhesion to lung. Immunohistochemical studies using antibodies against CD31 adhesion molecule (PECAM-1) revealed that B16-F10 cells adhere to lung endothelial cells. Our results suggest that PTX may exert its inhibitory effect on tumor lodgment, and as a consequence of that on experimental metastases, through an inhibitory action on cell adhesion molecules. [ABSTRACT FROM AUTHOR]

Background: In a previous study we have shown that wounding of Arabidopsis thaliana leaves induces a strong and transient immunity to Botrytis cinerea, the causal agent of grey mould. Reactive oxygen species (ROS) are formed within minutes after wounding and are required for wound-induced resistance to B. cinerea. Results: In this study, we have further explored ROS and resistance to B. cinerea in leaves of A. thaliana exposed to a soft form of mechanical stimulation without overt tissue damage. After gentle mechanical sweeping of leaf surfaces, a strong resistance to B. cinerea was observed. This was preceded by a rapid change in calcium concentration and a release of ROS, accompanied by changes in cuticle permeability, induction of the expression of genes typically associated with mechanical stress and release of biologically active diffusates from the surface. This reaction to soft mechanical stress (SMS) was fully independent of jasmonate (JA signaling). In addition, leaves exposed soft mechanical stress released a biologically active product capable of inducing resistance to B. cinerea in wild type control leaves. Conclusion: Arabidopsis can detect and convert gentle forms of mechanical stimulation into a strong activation of defense against the virulent fungus B. cinerea. [ABSTRACT FROM AUTHOR]

Background: Standard values for birth weight by gestational age are not available for sub-Saharan Africa, but are needed to evaluate incidence and risk factors for intrauterine growth retardation in settings where HIV, antiretrovirals, and other in utero exposures may impact birth outcomes. Methods: Birth weight data were collected from six hospitals in Botswana. Infants born to HIV-negative women between 26-44 weeks gestation were analyzed to construct birth weight for gestational age charts. These data were compared with published norms for black infants in the United States. Results: During a 29 month period from 2007-2010, birth records were reviewed in real-time from 6 hospitals and clinics in Botswana. Of these, 11,753 live infants born to HIV-negative women were included in the analysis. The median gestational age at birth was 39 weeks (1st quartile 38, 3rd quartile 40 weeks), and the median birth weight was 3100 grams (1st quartile 2800, 3rd quartile 3400 grams). We constructed estimated percentile curves for birth weight by gestational age which demonstrate increasing slope during the third trimester and leveling off beyond 40 weeks. Compared with black infants in the United States, Botswana-born infants had lower median birth weight for gestational age from weeks 37 through 42 (p < .02). Conclusions: We present birth weight for gestational age norms for Botswana, which are lower at term than norms for black infants in the United States. These findings suggest the importance of regional birth weight norms to identify and define risk factors for higher risk births. These data serve as a reference for Botswana, may apply to southern Africa, and may help to identify infants at risk for perinatal complications and inform comparisons among infants exposed to HIV and antiretrovirals in utero.

Background: Chemotherapy is often ineffective as a first-line treatment for head and neck squamous cell carcinoma (HNSCC), and a more precise and effective therapeutic option is urgently needed. Methods: High-throughput screening of a histone demethylase inhibitor library was performed to identify potential drugs for treating HNSCC. The Cancer Genome Atlas (TCGA) and single-cell sequencing were used to evaluate the potential diagnostic value and expression distribution of candidate drug targets. Colony formation, transwell assays, and flow cytometry analyses were used to assess the antitumor function of the potential drugs. The CCK-8 assay was used to compare the antitumor activity of the candidate drug and the traditional chemotherapy drug. Bioinformatic analysis based on TCGA database was used for unveiling the upstream signaling. Results: Pulrodemstat, a selective KDM1A inhibitor that is ongoing clinical trial, stood out as the most effective candidate anti-HNSCC drug based on the high-throughput screening. IC50 analysis revealed that Pulrodemstat might possess stronger anti-tumor activity than 5-Fu. Additionally, Pulrodemstat dramatically suppressed HNSCC cell proliferation and migration without inducing toxicity in normal cells. TCGA analysis revealed that KDM1A is positively associated with tumor proliferation, DNA repair, and DNA replication in HNSCC. Consistent with these results, Pulrodemstat substantially induced apoptosis in the HNSCC cells. Furthermore, TCGA analysis revealed that KDM1A was aberrantly overexpressed in HNSCC, positively correlated with malignancy, and negatively associated with the clinical outcomes of HNSCC patients. Notably, single-cell analysis indicated that KDM1A was mainly distributed in the malignant cells of HNSCC samples, highlighting that Pulrodemstat may be a more precise therapeutic option for HNSCC. In addition, methylation occupancies in the KDM1A promoter were substantially low in HNCC tumors, and low methylation occupancies in the KDM1A promoter predicted poor clinical outcomes in HNSCC. These data are consistent with the KDM1A expression in HNSCC. Moreover, TET3, a DNA demethylase, was strongly and positively correlated with KDM1A expression. Conclusions: Pulrodemstat is an effective therapeutic drug for HNSCC. Thus, the TET3/KDM1A axis may account for the malignant phenotype of HNSCC. [ABSTRACT FROM AUTHOR]

Background: The potential roles of viral infections in neurodevelopmental disorders (NDDs) have been suggested based on previous studies. Given the high prevalence of human herpesviruses (HHVs), the associations between HHVs infection and the risk of NDDs warrant explored. Methods: Our study employs a two-sample Mendelian randomization (MR) analysis and systematic review with meta-analysis to investigate whether genetically predicted HHVs infection are linked to three main childhood NDDs—autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and Tourette syndrome (TS). We utilized genetic variants associated with HHV infections in genome-wide association study (GWAS) summary datasets of European populations to establish instrumental variables and statistics for three NDDs obtained from Psychiatric Genomics Consortium. MR analysis was performed using inverse-variance weighted, MR Egger, weighted median, simple median, weighted mode, and MR-PRESSO. In addition, publications associating HHVs infection with three NDDs were systematically searched using PubMed, Web of Science, and three Chinese databases for meta-analyses. Results: The MR results found no evidence to support a link between genetically predicted HHVs infection and the risk of NDDs based on existing datasets. Twenty-seven observational studies on children with HHVs infection and NDDs were considered eligible. Meta-analysis showed that cytomegalovirus and HHV-6 infection were related with ASD, while Epstein-Barr virus and cytomegalovirus infection were associated with TD in Chinese population. Conclusions: These results contribute to a comprehensive understanding of the possibilities underlying HHV infections in affecting childhood NDDs. Further research is necessary to include larger and more robust statistics of HHV infections and NDDs. Trial registration: This systematic review was registered at PROSPERO as CRD42024554169. Retrospectively registered 26 July 2024. [ABSTRACT FROM AUTHOR]

Endoscopic ultrasonography (EUS) is pivotal for diagnosing and sampling pancreatic tumor tissues. This study aimed to assess how the histological type and size of tumors influence the adequacy of macroscopic tissue cores acquired using EUS-guided fine needle biopsy (FNB). We conducted a retrospective study involving 180 patients with pathologically confirmed pancreatic malignancies at our hospital, a medical center, between July 2020 and June 2023. Personal and clinical data, EUS findings, and pathological results were extracted from the patient records. The macroscopic tissue core acquisition rate was 86.1%. Patients with tumors larger than 3 cm had a higher sufficiency rate (93.3%) compared to those with tumors 3 cm or smaller (78.9%, p = 0.005). It was more difficult to obtain sufficient tissue cores from neuroendocrine tumors than from adenocarcinomas (67.7% vs. 89.9%, p = 0.001). Interestingly, obtaining a sufficient tissue core only affected the diagnostic rate of adenocarcinoma (93.3% vs. 60%, p < 0.001) but did not significantly influence the diagnostic rate of neuroendocrine tumors. This study highlights that small tumors (< 3 cm) and neuroendocrine tumors pose a challenge in obtaining sufficient tissue cores. However, obtaining sufficient tissue cores significantly influences the pathological diagnosis of FNB in adenocarcinoma but not in neuroendocrine tumors. [ABSTRACT FROM AUTHOR]

HBO1, also known as KAT7 or MYST2, is a crucial histone acetyltransferase with diverse cellular functions. It typically forms complexes with protein subunits or cofactors such as MEAF6, ING4, or ING5, and JADE1/2/3 or BRPF1/2/3, where the BRPF or JADE proteins serve as the scaffold targeting histone H3 or H4, respectively. The histone acetylation mediated by HBO1 plays significant roles in DNA replication and gene expression regulation. Additionally, HBO1 catalyzes the modification of proteins through acylation with propionyl, butyryl, crotonyl, benzoyl, and acetoacetyl groups. HBO1 undergoes ubiquitination and degradation by two types of ubiquitin complexes and can also act as an E3 ubiquitin ligase for the estrogen receptor α (ERα). Moreover, HBO1 participates in the expansion of medullary thymic epithelial cells (mTECs) and regulates the expression of peripheral tissue genes (PTGs) mediated by autoimmune regulator (AIRE), thus inducing immune tolerance. Furthermore, HBO1 influences the renewal of hematopoietic stem cells and the development of neural stem cells significantly. Importantly, the overexpression of HBO1 in various cancers suggests its carcinogenic role and potential as a therapeutic target. This review summarizes recent advancements in understanding HBO1's involvement in acylation modification, DNA replication, ubiquitination, immunity, and stem cell renewal. [ABSTRACT FROM AUTHOR]

The WNT6 ligand is a well-known activator of the WNT signaling pathway, considered a vital player in several important physiologic processes during embryonic development and maintaining homeostasis throughout life, regulating the proliferation and differentiation of multiple stem/progenitor cell types. More recently, as it is the case for many key molecular regulators of embryonic development, dysregulation of WNT6 has been implicated in cancer development and progression in multiple studies. In this review, we overview the most significant recent findings regarding WNT6 in the context of human malignancies, exploring its influence on multiple dimensions of tumor pathophysiology and highlighting the putative underlying WNT6-associated molecular mechanisms. We also discuss the potential clinical implications of WNT6 as a prognostic and therapeutic biomarker. This critical review highlights the emerging relevance of WNT6 in multiple human cancers, and its potential as a clinically-useful biomarker, addressing key unanswered questions that could lead to new opportunities in patient diagnosis, stratification, and the development of rationally-designed precision therapies. [ABSTRACT FROM AUTHOR]