Genomic and vaccine preclinical studies reveal a novel mouse-adapted Helicobacter pylori model for the hpEastAsia genotype in Southeast Asia

\ua9 2024 Crown Copyright.Introduction. Helicobacter pylori infection is a major global health concern, linked to the development of various gastrointestinal diseases, including gastric cancer. To study the pathogenesis of H. pylori and develop effective intervention strategies, appropriate animal pathogen models that closely mimic human infection are essential. Gap statement. This study focuses on the understudied hpEastAsia genotype in Southeast Asia, a region marked by a high H. pylori infection rate. No mouse-adapted model strains has been reported previously. Moreover, it recognizes the urgent requirement for vaccines in developing countries, where overuse of antimicrobials is fuelling the emergence of resistance. Aim. This study aims to establish a novel mouse-adapted H. pylori model specific to the hpEastAsia genotype prevalent in Southeast Asia, focusing on comparative genomic and histopathological analysis of pathogens coupled with vaccine preclinical studies. Methodology. We collected and sequenced the whole genome of clinical strains of H. pylori from infected patients in Vietnam and performed comparative genomic analyses of H. pylori strains in Southeast Asia. In parallel, we conducted preclinical studies to assess the pathogenicity of the mouse-adapted H. pylori strain and the protective effect of a new spore-vectored vaccine candidate on male Mlac:ICR mice and the host immune response in a female C57BL/6 mouse model. Results. Genome sequencing and comparison revealed unique and common genetic signatures, antimicrobial resistance genes and virulence factors in strains HP22 and HP34; and supported clarithromycin-resistant HP34 as a representation of the hpEastAsia genotype in Vietnam and Southeast Asia. HP34-infected mice exhibited gastric inflammation, epithelial erosion and dysplastic changes that closely resembled the pathology observed in human H. pylori infection. Furthermore, comprehensive immunological characterization demonstrated a robust host immune response, including both mucosal and systemic immune responses. Oral vaccination with candidate vaccine formulations elicited a significant reduction in bacterial colonization in the model. Conclusion. Our findings demonstrate the successful development of a novel mouse-adapted H. pylori model for the hpEastAsia genotype in Vietnam and Southeast Asia. Our research highlights the distinctive genotype and pathogenicity of clinical H. pylori strains in the region, laying the foundation for targeted interventions to address this global health burden

Ventricular noncompaction in a female patient with nephropathic cystinosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>We report an unusual and interesting case of a 24-year-old woman with nephropathic cystinosis in association with concomitant isolated noncompaction of the left ventricle. Left ventricular noncompaction usually presents with reduced exercise tolerance as a consequence of ventricular dysfunction, the result of embolus or with palpitations and syncope due to arrhythmia. There is no specific treatment directed at isolated noncompaction. Treatment is focused on the cause of presentation, with medication aimed at improving ventricular dysfunction, as well as treating and preventing thrombosis and arrhythmia.</p> <p>Case presentation</p> <p>Our patient presented with an episode of decompensated heart failure. Trans-thoracic echocardiography demonstrated excessive trabeculation with inter-trabecular recesses in the left ventricle typical of noncompaction of the left ventricle. The patient's admission was complicated by a cardiac arrest precipitated by ventricular tachycardia for which she subsequently underwent implantation of an automatic implantable cardioverter defibrillator.</p> <p>Conclusion</p> <p>This is, as far as we know, the first case report of the co-existence of nephropathic cystinosis and isolated noncompaction of the left ventricle. It highlights the importance of being vigilant to the diagnosis of left ventricular noncompaction.</p

Treatment incidence of and medical utilization for hospitalized subjects with pathologic fractures in Taiwan-Survey of the 2008 National Health Insurance data

<p>Abstract</p> <p>Background</p> <p>Almost all studies of pathologic fractures have been conducted based on patients with tumours and hospital-based data; however, in the present study, a nationwide epidemiological survey of pathologic fractures in Taiwan was performed and the medical utilization was calculated.</p> <p>Methods</p> <p>All claimants of Taiwan's National Health Insurance (NHI) Program in 2008 were included in the target population of this descriptive cross-sectional study. The registration and inpatient expenditure claims data by admission of all hospitalized subjects of the target population were examined and the concomitant International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes were evaluated and classified into seven major categories of fracture.</p> <p>Results</p> <p>A total of 5,244 incident cases of pathologic fracture were identified from the 2008 hospitalized patient claims data. The incidence of pathologic fracture of the humerus, distal radius/ulna, vertebrae, femoral neck, other part of the femur, and tibia/fibula was 0.67, 0.08, 10.58, 1.11, 0.56, and 0.11 per 100,000 people, respectively, and patients with those fractures were hospitalized for 43.9 ± 42.9, 31.1 ± 32.9, 29. 4 ± 34.4, 43.3 ± 41.2, 42.4 ± 38.1, and 42.0 ± 32.8 days, respectively, incurring an average medical cost of US$11,049 ± 12,730, US$9,181 ± 12,115, US$6,250 ± 8,021, US$9,619 ± 8,906, US$10,646 ± 11,024, and US$9,403 ± 9,882, respectively. The percentage of patients undergoing bone surgery for pathologic fracture of the humerus, radius/ulna, vertebrae, femoral neck, other part of the femur, and tibia/fibula was 31.2%, 44.4%, 11.3%, 46.5%, 48.4%, and 52.5% respectively.</p> <p>Conclusions</p> <p>Comparing Taiwan to other countries, this study observed for Taiwan higher medical utilization and less-aggressive surgical intervention for patients hospitalized with pathologic fractures.</p

Gastrin-Releasing Peptide Signaling Plays a Limited and Subtle Role in Amygdala Physiology and Aversive Memory

Links between synaptic plasticity in the lateral amygdala (LA) and Pavlovian fear learning are well established. Neuropeptides including gastrin-releasing peptide (GRP) can modulate LA function. GRP increases inhibition in the LA and mice lacking the GRP receptor (GRPR KO) show more pronounced and persistent fear after single-trial associative learning. Here, we confirmed these initial findings and examined whether they extrapolate to more aspects of amygdala physiology and to other forms of aversive associative learning. GRP application in brain slices from wildtype but not GRPR KO mice increased spontaneous inhibitory activity in LA pyramidal neurons. In amygdala slices from GRPR KO mice, GRP did not increase inhibitory activity. In comparison to wildtype, short- but not long-term plasticity was increased in the cortico-lateral amygdala (LA) pathway of GRPR KO amygdala slices, whereas no changes were detected in the thalamo-LA pathway. In addition, GRPR KO mice showed enhanced fear evoked by single-trial conditioning and reduced spontaneous firing of neurons in the central nucleus of the amygdala (CeA). Altogether, these results are consistent with a potentially important modulatory role of GRP/GRPR signaling in the amygdala. However, administration of GRP or the GRPR antagonist (D-Phe6, Leu-NHEt13, des-Met14)-Bombesin (6–14) did not affect amygdala LTP in brain slices, nor did they affect the expression of conditioned fear following intra-amygdala administration. GRPR KO mice also failed to show differences in fear expression and extinction after multiple-trial fear conditioning, and there were no differences in conditioned taste aversion or gustatory neophobia. Collectively, our data indicate that GRP/GRPR signaling modulates amygdala physiology in a paradigm-specific fashion that likely is insufficient to generate therapeutic effects across amygdala-dependent disorders

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Search for CP violation in D+→ϕπ+ and D+s→K0Sπ+ decays

A search for CP violation in D + → ϕπ + decays is performed using data collected in 2011 by the LHCb experiment corresponding to an integrated luminosity of 1.0 fb−1 at a centre of mass energy of 7 TeV. The CP -violating asymmetry is measured to be (−0.04 ± 0.14 ± 0.14)% for candidates with K − K + mass within 20 MeV/c 2 of the ϕ meson mass. A search for a CP -violating asymmetry that varies across the ϕ mass region of the D + → K − K + π + Dalitz plot is also performed, and no evidence for CP violation is found. In addition, the CP asymmetry in the D+s→K0Sπ+ decay is measured to be (0.61 ± 0.83 ± 0.14)%

MiR-339-5p inhibits breast cancer cell migration and invasion in vitro and may be a potential biomarker for breast cancer prognosis

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) play an important role in the regulation of cell growth, differentiation, apoptosis, and carcinogenesis. Detection of their expression may lead to identifying novel markers for breast cancer.</p> <p>Methods</p> <p>We profiled miRNA expression in three breast cancer cell lines (MCF-7, MDA-MB-231, and MDA-MB-468) and then focused on one miRNA, miR-339-5p, for its role in regulation of tumor cell growth, migration, and invasion and target gene expression. We then analyzed miR-339-5p expression in benign and cancerous breast tissue specimens.</p> <p>Results</p> <p>A number of miRNAs were differentially expressed in these cancer cell lines. Real-time PCR indicated that miR-339-5p expression was downregulated in the aggressive cell lines MDA-MB-468 and MDA-MB-231 and in breast cancer tissues compared with benign tissues. Transfection of miR-339-5p oligonucleotides reduced cancer cell growth only slightly but significantly decreased tumor cell migration and invasion capacity compared with controls. Real-time PCR analysis showed that BCL-6, a potential target gene of miR-339-5p, was downregulated in MDA-MB-231 cells by miR-339-5p transfection. Furthermore, the reduced miR-339-5p expression was associated with an increase in metastasis to lymph nodes and with high clinical stages. Kaplan-Meier analyses found that the patients with miR-339-5p expression had better overall and relapse-free survivals compared with those without miR-339-5p expression. Cox proportional hazards analyses showed that miR-339-5p expression was an independent prognostic factor for breast cancer patients.</p> <p>Conclusions</p> <p>MiR-339-5p may play an important role in breast cancer progression, suggesting that miR-339-5p should be further evaluated as a biomarker for predicting the survival of breast cancer patients.</p