Pancreatic cancer mortality is expected to rise in the next decades. This aggressive malignancy has a dismal prognosis due to late diagnosis and resistance to treatment. Increasing evidence indicates ...that host-microbiome interactions play an integral role in pancreatic cancer development, suggesting that harnessing the microbiome might offer promising opportunities for diagnostic and therapeutic interventions. Herein, we review the associations between pancreatic cancer and the intratumoral, gut and oral microbiomes. We also explore the mechanisms with which microbes influence cancer development and the response to treatment. We further discuss the potentials and limitations of using the microbiome as a target for therapeutic interventions, in order to improve pancreatic cancer patient outcomes.
Outer membrane vesicles (OMVs) are small vesicles constitutively shed by all Gram-negative bacterium, which have been proposed to play a role in
Helicobacter pylori
persistence and pathogenesis. The ...methods currently available for the isolation of
H. pylori
OMVs are diverse and time-consuming, raising the need for a protocol standardization, which was the main aim of this study. Here, we showed that the chemically defined F12 medium, supplemented with cholesterol, nutritionally supports bacterial growth and maintains
H. pylori
viability for at least 72 h. Additionally, we developed an abridged protocol for isolation of OMVs from these bacterial cultures, which comprises a low-speed centrifugation, supernatant filtration through a 0.45 μm pore, and two ultracentrifugations for OMVs’ recovery and washing. Using this approach, a good yield of highly pure
bona fide
OMVs was recovered from cultures of different
H. pylori
strains and in different periods of bacterial growth, as assessed by nanoparticle tracking analysis, transmission electron microscopy (TEM), and proteomic analyses, confirming the reliability of the protocol. Analysis of the proteome of OMVs isolated from
H. pylori
F12-cholesterol cultures at different time points of bacterial growth revealed differentially expressed proteins, including the vacuolating cytotoxin VacA. In conclusion, this work proposes a time- and cost-efficient protocol for the isolation of
H. pylori
OMVs from a chemically defined culture medium that is suitable for implementation in research and in the biopharmaceutical field.
The time course for the development of clinically significant hereditary diffuse gastric cancer (HDGC) is unpredictable. Little is known about the progression from preclinical, indolent lesions to ...widely invasive, aggressive phenotypes. Gastroendoscopy often fails to detect early lesions, and risk-reducing/prophylactic total gastrectomy (PTG) is the only curative approach. We present an HDGC family with early-onset disease in which clinical and histologic findings provided insight into the understanding of different HDGC phenotypes.
The proband was diagnosed at age 18 years with widely invasive, metastatic DGC. CDH1 genetic testing identified a pathogenic, germline CDH1 variant (c.1901C>T, p.Ala634Val). Thirty family members were tested, and 15 CDH1 carriers were identified.
Six family members had PTG, with negative preoperative workup. The proband’s 14-year-old sister is the youngest patient, reported to date, to have PTG after negative preoperative biopsy sampling. Intramucosal HDGC foci were detected in all PTG specimens (1-33). In contrast to the “indolent” phenotype of these foci, the aggressive DGC from the proband showed pleomorphic cells, absent E-cadherin expression, increased proliferation (Ki-67 index), and activation of oncogenic events (p53, pSrc and pStat3 overexpression). All family members had Helicobacter pylori gastritis. Cag-A–positive strains were detected in all specimens, except in the proband’s sister.
HDGC is a heterogeneous disease regarding clinical behavior, endoscopic findings, histopathologic features, and immunophenotypic/molecular profile. The presence of bizarre, pleomorphic cells in endoscopic biopsy specimens is suggestive of advanced disease and should prompt clinical intervention. The involvement of a full multidisciplinary team is essential for the management of these patients.
Display omitted
The discovery that
Helicobacter pylori is associated with gastric cancer has led to numerous studies that investigate the mechanisms by which
H.
pylori induces carcinogenesis. Gastric cancer shows ...genetic instability both in nuclear and mitochondrial DNA, besides impairment of important DNA repair pathways. As such, this review highlights the consequences of
H.
pylori infection on the integrity of DNA in the host cells. By down-regulating major DNA repair pathways,
H.
pylori infection has the potential to generate mutations. In addition,
H.
pylori infection can induce direct changes on the DNA of the host, such as oxidative damage, methylation, chromosomal instability, microsatellite instability, and mutations. Interestingly,
H.
pylori infection generates genetic instability in nuclear and mitochondrial DNA.
Based on the reviewed literature we conclude that
H.
pylori infection promotes gastric carcinogenesis by at least three different mechanisms: (1) a combination of increased endogenous DNA damage and decreased repair activities, (2) induction of mutations in the mitochondrial DNA, and (3) generation of a transient mutator phenotype that induces mutations in the nuclear genome.
Gastric cancer pathogenesis Berger, Hilmar; Marques, Miguel S.; Zietlow, Rike ...
Helicobacter (Cambridge, Mass.),
September 2016, Letnik:
21, Številka:
S1
Journal Article
Recenzirano
Gastric cancer (GC) results from a multistep process that is influenced by Helicobacter pylori infection, genetic susceptibility of the host, as well as of other environmental factors. GC results ...from the accumulation of numerous genetic and epigenetic alterations in oncogenes and tumor suppressor genes, leading to dysregulation of multiple signaling pathways, which disrupt the cell cycle and the balance between cell proliferation and cell death. For this special issue, we have selected to review last year's advances related to three main topics: the cell of origin that initiates malignant growth in GC, the mechanisms of direct genotoxicity induced by H. pylori infection, and the role of aberrantly expressed long noncoding RNAs in GC transformation. The understanding of the molecular basis of GC development is of utmost importance for the identification of novel targets for GC prevention and treatment.
Pathogenesis of Gastric Cancer Figueiredo, Ceu; Costa, Susana; Karameris, Andreas ...
Helicobacter (Cambridge, Mass.),
09/2015, Letnik:
20, Številka:
S1
Journal Article
Recenzirano
Odprti dostop
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer‐related death worldwide. GC is a heterogeneous disease and the endpoint of a long multistep process ...largely influenced by Helicobacter pylori infection, genetic susceptibility, and environmental factors. In a subset of GC cases, infection with the Epstein–Barr virus (EBV) may also be involved. The development of GC is the consequence of the accumulation of multiple epi/genetic changes during the patient's lifetime that will result in oncogenic activation and/or tumor suppressor pathways’ inactivation.
This review will focus on the most recent updates on the characterization of the molecular phenotypes of sporadic and hereditary GC. This article will also update the most recent findings on the relationship between H. pylori infection and stem cells at the origin of GC.
The understanding of the molecular genetics underlying gastric carcinogenesis is of paramount importance to identify novel potential targets for the development of screening and prognostic markers that can be clinically valuable for the management of GC patients and for the design of clinical trials.
Antisense oligonucleotides (ASOs) composed of nucleic acid mimics (NAMs) monomers are considered as potential novel therapeutic drugs against bacterial infections. However, bacterial envelopes are ...generally impermeable to naked oligonucleotides. Herein, liposomes loaded with NAMs-modified oligonucleotides (LipoNAMs) were evaluated to deliver ASOs in Escherichia coli. Specifically, we tested several surface modifications that included methoxyPEG conjugated to different lipid anchors or modification of the PEG distal ends with maleimide groups and antibodies. MethoxyPEG coated LipoNAMs showed low delivery efficiency for most bacteria, but maleimide-functionalized PEG LipoNAMs were able to deliver ASOs to nearly half of the bacterial population. Conjugation of antibodies to maleimide-functionalized PEG LipoNAMs increased 1.3-fold the delivery efficiency, enhancing the selectivity towards E. coli and biocompatibility. This work demonstrated for the first time that the coupling of antibodies to PEGylated liposomes can significantly improve the delivery of ASOs in E. coli, which might bring alternative routes for the treatment of bacterial infections in the future.
Display omitted
•Delivery of oligonucleotides in E. coli depends on liposomes surface characteristics.•MethoxyPEG coated liposomes are not effective to deliver oligonucleotides in E. coli.•MaleimidePEG coated liposomes enhanced the oligonucleotides delivery in bacteria.•Anti-E. coli antibodies conjugated to PEG strands enhanced the delivery efficiency.•Conjugation of antibodies improves the liposomes‘biocompatibility.
Abstract The rising antimicrobial resistance contributes to 25000 annual deaths in Europe. This threat to the public health can only be tackled if novel antimicrobials are developed, combined with a ...more precise use of the currently available antibiotics through the implementation of fast, specific, diagnostic methods. Nucleic acid mimics (NAMs) that are able to hybridize intracellular bacterial RNA have the potential to become such a new class of antimicrobials and additionally could serve as specific detection probes. However, an essential requirement is that these NAMs should be delivered into the bacterial cytoplasm, which is a particular challenge given the fact that they are charged macromolecules. We consider these delivery challenges in relation to the gastric pathogen Helicobacter pylori , the most frequent chronic infection worldwide. In particular, we evaluate if cationic fusogenic liposomes are suitable carriers to deliver NAMs across the gastric mucus barrier and the bacterial envelope. Our study shows that DOTAP-DOPE liposomes post-PEGylated with DSPE-PEG (DSPE Lpx) can indeed successfully deliver NAMs into Helicobacter pylori , while offering protection to the NAMs from binding and inactivation in gastric mucus isolated from pigs. DSPE Lpx thus offer exciting new possibilities for in vivo diagnosis and treatment of Helicobacter pylori infections.
This study aims to assess the psychometric properties of the European Portuguese version of the Pediatric Quality of Life Inventory™ Family Impact Module in parents of children/adolescents with ...chronic health conditions.
The European Portuguese version of the Pediatric Quality of Life Inventory™ Family Impact Module was administered to 237 parents of children/adolescents with chronic disease and/or chronic disorder. Participants were recruited from the day hospital and/or outpatient services of four hospitals in Northern Portugal, the majority being mothers (87.3%) aged between 31 and 50 years (86.9%). The questionnaire was administered online through the REDCap platform. The hierarchical factor model of the Pediatric Quality of Life Inventory™ Family Impact Module proposed by Varni and colleagues was tested.
Confirmatory Factor Analysis indicated good model fit, with the following indices (χ
/gL = 2.19; comparative fit index CFI = 0.90; root mean square error of approximation RMSEA = 0.07 immune cell IC 90% = 0.06-0.07). Internal consistency values were high (parent quality of life subtotal, α = .96; family functioning subtotal, α = .92; total score, α = .96).
The European Portuguese version of the PedsQL™ FIM is a reliable and valid measurement tool for nurses to assess the impact of the child/adolescent chronic conditions on family's quality of life and to develop interventions to improve their well-being.
The intestinal microbiome is associated with colorectal cancer. Although the mucosal microbiota better represents an individual’s local microbiome, studies on the colorectal cancer microbiota mainly ...reflect knowledge obtained from fecal samples. This systematic review aimed to summarize the current evidence on the relationship between the mucosal-associated bacterial microbiota and colorectal cancer. Searches were conducted in PubMed and Web of Science databases for publications comparing the mucosal microbiome of colorectal cancer patients with that of healthy controls, or with that of non-cancerous mucosal tissues. The primary outcomes were differences in microbial diversity and taxonomy. The Newcastle-Ottawa Scale was used to assess the quality of the included studies. Of the 5080 studies identified, 39 were eligible and included in the systematic review. No consistent results were identified for the α- and β-diversity, due to high heterogeneity in reporting and to differences in metrics and statistical approaches, limiting study comparability. Qualitative synthesis of microbial taxonomy identified 12 taxa with strong positive and 18 taxa with strong negative associations with colorectal cancer. Fusobacterium, Campylobacter, Parvimonas, Peptostreptococcus, Streptococcus, and Granulicatella were defined as enriched in colorectal cancer. Despite the methodological limitations of the studies, consistent evidence on bacterial taxa associated with colorectal cancer was identified. Prospective studies in large and well-characterized patient populations will be crucial to validate these findings.
PDF
