Intravesical Ty21a treatment of non-muscle invasive bladder cancer induces immune responses that correlate with safety and may be associated to therapy potential.

BACKGROUND: Standard of care treatment of non-muscle invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette Guérin (BCG) is associated with side effects, disease recurrence/progression and supply shortages. We recently showed in a phase I trial (NCT03421236) that intravesical instillation in patients with NMIBC with the maximal tolerated dose of Ty21a/Vivotif, the oral vaccine against typhoid fever, might have a better safety profile. In the present report, we assessed the immunogenicity of intravesical Ty21a in patients of the clinical trial that had received the maximal tolerated dose and compared it with data obtained in patients that had received standard BCG. METHODS: Urinary cytokines and immune cells of patients with NMIBC treated with intravesical instillations of Ty21a (n=13, groups A and F in NCT03421236) or with standard BCG in a concomitant observational study (n=12, UROV1) were determined by Luminex and flow cytometry, respectively. Serum anti-lipopolysaccharide Typhi antibodies and circulating Ty21a-specific T-cell responses were also determined in the Ty21a patients. Multiple comparisons of different paired variables were performed with a mixed-effect analysis, followed by Sidak post-test. Single comparisons were performed with a paired or an unpaired Student's t-test. RESULTS: As compared with BCG, Ty21a induced lower levels of inflammatory urinary cytokines, which correlated to the milder adverse events (AEs) observed in Ty21a patients. However, both Ty21a and BCG induced a Th1 tumor environment. Peripheral Ty21a-specific T-cell responses and/or antibodies were observed in most Ty21a patients, pointing the bladder as an efficient local immune inductive site. Besides, Ty21a-mediated stimulation of unconventional Vδ2 T cells was also observed, which turned out more efficient than BCG. Finally, few Ty21a instillations were sufficient for increasing urinary infiltration of dendritic cells and T cells, which were previously associated with therapeutic efficacy in the orthotopic mouse model of NMIBC. CONCLUSIONS: Ty21a immunotherapy of patient with NMIBC is promising with fewer inflammatory cytokines and mild AE, but induction of immune responses with possible antitumor potentials. Future phase II clinical trials are necessary to explore possible efficacy of intravesical Ty21a.

Centriolar subdistal appendages promote double-strand break repair through homologous recombination.

The centrosome is a cytoplasmic organelle with roles in microtubule organization that has also been proposed to act as a hub for cellular signaling. Some centrosomal components are required for full activation of the DNA damage response. However, whether the centrosome regulates specific DNA repair pathways is not known. Here, we show that centrosome presence is required to fully activate recombination, specifically to completely license its initial step, the so-called DNA end resection. Furthermore, we identify a centriolar structure, the subdistal appendages, and a specific factor, CEP170, as the critical centrosomal component involved in the regulation of recombination and resection. Cells lacking centrosomes or depleted for CEP170 are, consequently, hypersensitive to DNA damaging agents. Moreover, low levels of CEP170 in multiple cancer types correlate with an increase of the mutation burden associated with specific mutational signatures and a better prognosis, suggesting that changes in CEP170 can act as a mutation driver but could also be targeted to improve current oncological treatments.

HTA and Reimbursement Status of Metastatic Hormone­Sensitive Prostate Cancer, Non-Metastatic Castration-Resistant Prostate Cancer, and Metastatic Castration-Resistant Prostate Cancer Treatments in Europe: A Patient Access Landscape Review.

Background: Prostate cancer is the second most common cancer in men, with up to one-third of men being diagnosed in their lifetime. Recently, novel therapies have received regulatory approval with significant improvement in overall survival for metastatic castration-resistant prostate cancer, metastatic hormone-sensitive prostate cancer, and nonmetastatic castration-resistant prostate cancer. To improve decision-making regarding the value of anticancer therapies and support standardized assessment for use by health technology assessment (HTA) agencies, the European Society for Medical Oncology (ESMO) has developed a Magnitude of Clinical Benefit Scale (MCBS). Objective: This review aimed to map HTA status, reimbursement restrictions, and patient access for 3 advanced prostate cancer indications across 23 European countries during 2011-2021. Methods: HTA, country reimbursement lists, and ESMO-MCBS scorecards were reviewed for evidence and data across 26 European countries. Results: The analysis demonstrated that only in Greece, Germany, and Sweden was there full access across all included prostate cancer treatments. Treatments available for metastatic castration-resistant prostate cancer were widely reimbursed, with both abiraterone and enzalutamide accessible in all countries. In 3 countries (Hungary, the Netherlands, and Switzerland), there was a statistically significant difference (P<.05) between status of reimbursement and ESMO-MCBS "substantial benefit" (score of 4 or 5) vs "no substantial benefit" (score <4). Conclusion: Overall, the impact of the ESMO-MCBS on reimbursement decisions in Europe is unclear, with significant variation across the countries included in this review.

Health outcomes and budget impact projection of anti-PD-(L)1s in cancer care in Portugal.

Introduction: PD-[L]1 inhibitors revolutionized cancer treatment but challenge the affordability of health systems. This policy-focused model aimed to estimate the health and budget impact of anti-PD-(L)1s in Portugal and inform current discussions. Materials and methods: The Health Impact Projection (HIP) model estimates clinical (life years, progression-free survival [PFS] years, and quality-adjusted life years [QALY] gained and adverse events [AEs] incurred) and economic (direct and indirect costs) outcomes in a world where cancer patients are initiating treatment with standard-of-care (SOC) versus SOC plus anti-PD-(L)1s over a 3-year time horizon. Indications included adjuvant and metastatic melanoma, non-small cell lung cancer (first and second line), metastatic triple-negative breast cancer, head and neck cancer, urothelial carcinoma, and renal cell carcinoma. Model inputs were based on publicly available literature data and expert opinion. Results: The model estimated that, over 3 years, 7,773 patients would be treated with anti-PD-(L)1s, realizing a gain of 4,787 life years, 6,901 PFS years, and 4,214 QALYs and avoiding 399 AEs. The introduction of anti-PD-(L)1s had a projected average annual impact of ≈ €108 million and a share of 20% of total cancer medicines expenditure and 0.6% of total healthcare expenditure in 2021. Although higher disease management costs are expected for patients living longer with anti-PD-(L)1s and drug acquisition costs are considerable, that is partially offset by a reduction in end-of-life costs (€611,092/year) and costs associated with patient productivity lost to cancer (€9,128,142/year). Discussion: This model highlights the significant survival and QoL benefit of anti-PD-(L)1s for cancer patients in Portugal, with a relatively low increased cost in total healthcare expenditure.

Stent as bridge to surgery decreases postoperative complications without worsening oncological outcomes: retrospective unicentric cohort study and stent placement protocol.

BACKGROUND: Even if the use of stent as bridge to surgery (BTS) for obstructive colon cancer was described long ago, there is still much controversy on their use. Patient recovery before surgery and colonic desobstruction are just some of the reasons to defend this management that can be found in several available articles. METHODS: This is a single-center, retrospective cohort study, including patients with obstructive colon cancer treated between 2010 and 2020. The primary aim of this study is to compare medium-term oncological outcomes (overall survival, disease-free survival) between stent as BTS and ES groups. The secondary aims are to compare perioperative results (in terms of approach, morbidity and mortality, and rate of anastomosis/stomas) between both groups and, within the BTS group, analyze whether there are any factors that may influence oncological outcomes. RESULTS: A total of 251 patients were included. Patients belonging to the BTS cohort presented a higher rate of laparoscopic approach, required less intensive care management, less reintervention, and less permanent stoma rate, when comparing with patients who underwent urgent surgery (US). There were not significant differences in terms of disease-free survival and overall survival between the two groups. Lymphovascular invasion negatively affected oncological results but was not related with stent placement. CONCLUSION: The stent as a bridge to surgery is a good alternative to urgent surgery, which leads to a decrease in postoperative morbidity and mortality without significantly worsening oncological outcomes.

BUPROPION MISUSE BY NASAL INSUFFLATION WITH A FATAL OUTCOME: CASE REPORT AND REVIEW.

Bupropion is the only FDA - approved synthetic cathinone, with increasing popularity in clinical practice due to its wide range of action, and lack of sexual side effects. However, its stimulant effect similar to amphetamines has growing the concern regarding its recreational use.

Patterns of Medication Management and Associated Medical and Clinical Features among Home-Dwelling Older Adults: A Cross-Sectional Study in Central Portugal.

Ageing is frequently associated with multimorbidity and polypharmacy. The present study aimed to identify the current medication management patterns and the profiles of home-dwelling older adults and to find any association with their conditions, including frailty and cognitive impairment. Within the scope of this cross-sectional study, 112 older adults living in the community were assessed via face-to-face structured interviews. Frailty, cognitive status, medication management and clinical and sociodemographic variables were evaluated. Descriptive and inferential statistics were calculated. The mean participant age was 76.6 ± 7.1 years, 53.6% of participants were women, and 40.2% of participants lived alone. More than half were classified as having frailty (58.9%), almost one-fifth (19.6%) presented with a moderate cognitive impairment had more than one disease, and 60.7% were polymedicated. No associations were found between polymedication and medication self-management, the use of over-the-counter medications, living alone, having a poor understanding of pharmacological therapy and/or pathology, or having more than one prescriber. Self-management was associated with age, the number of medications, frailty and cognitive status. Binary logistic regressions showed that cognitive impairment had statistically significant differences with medication management, having a poor understanding of pharmacological therapy and/or pathology, having one prescriber and the use of medications not prescribed by physicians. Interventions to prevent medication-related problems in home-dwelling older adults are recommended.

Primary Hyperparathyroidism in a Post-total Thyroidectomy Patient: An Unexpected Diagnosis.

Hypercalcemia is commonly encountered in the clinical setting. Although primary hyperparathyroidism resulting from a single parathyroid adenoma is the most common cause, in patients who undergo total thyroidectomy, especially when there is no history of radiation exposure nor parathyroid autotransplantation, it becomes an even more unexpected diagnosis. Because the majority of patients are asymptomatic, the diagnosis often is made incidentally. However, with long-standing disease, as parathyroid hormone and blood calcium levels rise, symptoms become more noticeable, and its clinical manifestations can affect nearly every organ system in the body. We present the case of a 79-year-old woman with a history of surgical hypothyroidism secondary to total thyroidectomy, hypertension and chronic kidney disease, who was admitted to the Emergency Department after an episode of syncope. She mentioned abdominal pain and vomiting in the previous week and paresthesia of both hands and feet over the last months. The initial testing identified a first-degree auriculoventricular block, a worsened renal function and severe hypercalcemia caused by primary hyperparathyroidism. The mainstay of treatment was aggressive fluid therapy, intravenous bisphosphonate and calcimimetic. Definitive treatment was achieved by the surgical removal of a mass located in the left thyroidectomy bed, compatible with a parathyroid adenoma. No further therapy was needed, as calcium levels gradually returned to normal.

An Intervention Program to Reduce Medication-Related Problems Among Polymedicated Home-Dwelling Older Adults (OptiMed): Protocol for a Pre-Post, Multisite, Pilot, and Feasibility Study.

BACKGROUND: Effective medication management is one of the essential preconditions for enabling polymedicated home-dwelling older adults with multiple chronic conditions to remain at home and preserve their quality of life and autonomy. Lack of effective medication management predisposes older adults to medication-related problems (MRPs) and adverse health outcomes, which can lead to the degradation of a patient's acute clinical condition, physical and cognitive decline, exacerbation of chronic medical conditions, and avoidable health care costs. Nonetheless, it has been shown that MRPs can be prevented or reduced by using well-coordinated, patient-centered, interprofessional primary care interventions. OBJECTIVE: This study aimed to explore the feasibility and acceptability of an evidence-based, multicomponent, interprofessional intervention program supported by informal caregivers to decrease MRPs among polymedicated home-dwelling older adults with multiple chronic conditions. METHODS: This quasi-experimental, pre-post, multisite pilot, and feasibility study will use an open-label design, with participants knowing the study's objectives and relevant information, and it will take place in primary health care settings in Portugal and Switzerland. The research population will comprise 30 polymedicated, home-dwelling adults, aged ≥65 years at risk of MRPs and receiving community-based health care, along with their informal caregivers and health care professionals. RESULTS: Before a projected full-scale study, this pilot and feasibility study will focus on recruiting and ensuring the active collaboration of its participants and on the feasibility of expanding this evidence-based, multicomponent, interprofessional intervention program throughout both study regions. This study will also be essential to projected follow-up research programs on informal caregivers' multiple roles, enhancing their coordination tasks and their own needs. Results are expected at the end of 2024. CONCLUSIONS: Designing, establishing, and exploring the feasibility and acceptability of an intervention program to reduce the risks of MRPs among home-dwelling older adults is an underinvestigated issue. Doing so in collaboration with all the different actors involved in that population's medication management and recording the first effects of the intervention will make this pilot and feasibility study's findings very valuable as home care becomes an ever more common solution. TRIAL REGISTRATION: Swiss National Clinical Trials Portal 000004654; https://tinyurl.com/mr3yz8t4.

Type 2 innate lymphoid cells are not involved in mouse bladder tumor development.

Therapies for bladder cancer patients are limited by side effects and failures, highlighting the need for novel targets to improve disease management. Given the emerging evidence highlighting the key role of innate lymphoid cell subsets, especially type 2 innate lymphoid cells (ILC2s), in shaping the tumor microenvironment and immune responses, we investigated the contribution of ILC2s in bladder tumor development. Using the orthotopic murine MB49 bladder tumor model, we found a strong enrichment of ILC2s in the bladder under steady-state conditions, comparable to that in the lung. However, as tumors grew, we observed an increase in ILC1s but no changes in ILC2s. Targeting ILC2s by blocking IL-4/IL-13 signaling pathways, IL-5, or IL-33 receptor, or using IL-33-deficient or ILC2-deficient mice, did not affect mice survival following bladder tumor implantation. Overall, these results suggest that ILC2s do not contribute significantly to bladder tumor development, yet further investigations are required to confirm these results in bladder cancer patients.

Intravesical Ty21a Treatment of Non-muscle-invasive Bladder Cancer Shows a Good Safety Profile.

Standard-of-care immunotherapy for non-muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmettte-Guérin (BCG) is associated with adverse events (AEs), disease recurrence/progression, and supply shortages. Preclinical data have shown that intravesical instillation of Ty21a/Vivotif, the oral vaccine against typhoid fever, may be an effective and safer alternative to BCG. We assessed the safety of intravesical Ty21a in NMIBC. For ethical reasons, patients with low- or intermediate-risk NMIBC not requiring BCG immunotherapy were enrolled. To determine the maximum tolerated dose, escalating doses of Ty21a/Vivotif were intravesically instilled in three patients once a week for 4 wk in phase 1a. In phase 1b, ten patients received the selected dose (1 × 108 CFU) once a week for 6 wk, as for standard BCG therapy. At this dose, all patients completed their treatment. Most patients experienced minor systemic AEs, while half reported mild local bladder AEs. AEs only occurred after one or two instillations for 40% of the patients. Ty21a bacteria were only recovered in three out of 72 urinary samples at 1 wk after instillation. Intravesical Ty21a might be well tolerated with no cumulative side effects, no fever >39 °C, and lower risk of bacterial persistence than with BCG. Ty21a treatment thus warrants clinical trials to explore its safety and antitumor efficacy in high-risk NMIBC. This trial is registered on ClinicalTrials.gov as NCT03421236. Patient summary: We examined the safety of a new intra-bladder immunotherapy for non-muscle-invasive bladder cancer as an alternative to the standard BCG treatment. Our data show that the Ty21a vaccine might be well tolerated. Further studies are needed to determine the safety and antitumor efficacy of this treatment.

Cost-Effective Fiber Optic Solutions for Biosensing.

In the last years, optical fiber sensors have proven to be a reliable and versatile biosensing tool. Optical fiber biosensors (OFBs) are analytical devices that use optical fibers as transducers, with the advantages of being easily coated and biofunctionalized, allowing the monitorization of all functionalization and detection in real-time, as well as being small in size and geometrically flexible, thus allowing device miniaturization and portability for point-of-care (POC) testing. Knowing the potential of such biosensing tools, this paper reviews the reported OFBs which are, at the moment, the most cost-effective. Different fiber configurations are highlighted, namely, end-face reflected, unclad, D- and U-shaped, tips, ball resonators, tapered, light-diffusing, and specialty fibers. Packaging techniques to enhance OFBs' application in the medical field, namely for implementing in subcutaneous, percutaneous, and endoscopic operations as well as in wearable structures, are presented and discussed. Interrogation approaches of OFBs using smartphones' hardware are a great way to obtain cost-effective sensing approaches. In this review paper, different architectures of such interrogation methods and their respective applications are presented. Finally, the application of OFBs in monitoring three crucial fields of human life and wellbeing are reported: detection of cancer biomarkers, detection of cardiovascular biomarkers, and environmental monitoring.

Targeting Endothelial Connexin37 Reduces Angiogenesis and Decreases Tumor Growth.

Connexin37 (Cx37) and Cx40 form intercellular channels between endothelial cells (EC), which contribute to the regulation of the functions of vessels. We previously documented the participation of both Cx in developmental angiogenesis and have further shown that loss of Cx40 decreases the growth of different tumors. Here, we report that loss of Cx37 reduces (1) the in vitro proliferation of primary human EC; (2) the vascularization of subcutaneously implanted matrigel plugs in Cx37-/- mice or in WT using matrigel plugs supplemented with a peptide targeting Cx37 channels; (3) tumor angiogenesis; and (4) the growth of TC-1 and B16 tumors, resulting in a longer mice survival. We further document that Cx37 and Cx40 function in a collaborative manner to promote tumor growth, inasmuch as the injection of a peptide targeting Cx40 into Cx37-/- mice decreased the growth of TC-1 tumors to a larger extent than after loss of Cx37. This loss did not alter vessel perfusion, mural cells coverage and tumor hypoxia compared to tumors grown in WT mice. The data show that Cx37 is relevant for the control of EC proliferation and growth in different tumor models, suggesting that it may be a target, alone or in combination with Cx40, in the development of anti-tumoral treatments.

Tumor-Microenvironment Characterization of the MB49 Non-Muscle-Invasive Bladder-Cancer Orthotopic Model towards New Therapeutic Strategies.

Bacillus Calmette-Guérin (BCG) instillations for the treatment of non-muscle-invasive bladder cancer patients can result in significant side effects and treatment failure. Immune checkpoint blockade and/or decreasing tumor-infiltrating myeloid suppressor cells may be alternative or complementary treatments. Here, we have characterized immune cell infiltration and chemoattractant molecules in mouse orthotopic MB49 bladder tumors. Our data show a 100-fold increase in CD45+ immune cells from day 5 to day 9 tumors including T cells and mainly myeloid cells. Both monocytic myeloid-derived suppressor-cells (M-MDSC) and polymorphonuclear (PMN)-MDSC were strongly increased in day 9 tumors, with PMN-MDSC representing ca. 70% of the myeloid cells in day 12 tumors, while tumor associated macrophages (TAM) were only modestly increased. The kinetic of PD-L1 tumor expression correlated with published data from patients with PD-L1 expressing bladder tumors and with efficacy of anti-PD-1 treatment, further validating the orthotopic MB49 bladder-tumor model as suitable for designing novel therapeutic strategies. Comparison of chemoattractants expression during MB49 bladder tumors grow highlighted CCL8 and CCL12 (CCR2-ligands), CCL9 and CCL6 (CCR-1-ligands), CXCL2 and CXCL5 (CXCR2-ligands), CXCL12 (CXCR4-ligand) and antagonist of C5/C5a as potential targets to decrease myeloid suppressive cells. Data obtained with a single CCR2 inhibitor however showed that the complex chemokine crosstalk would require targeting multiple chemokines for anti-tumor efficacy.

Percepção de portadores de diabetes sobre educação em saúde e adoção de hábitos saudáveis / Perception of people with diabetes on health education and adoption of healthy habits

Este estudo teve como objetivo conhecer a percepção de portadores de Diabetes Mellitus Tipo 2 sobre a influência da educação em saúde para a adoção de hábitos saudáveis e o controle da doença. Trata-se de um estudo qualitativo fundamentado na Teoria da Representação Social. Os depoimentos de 23 entrevistados foram analisados por meio da técnica do Discurso do Sujeito Coletivo. Emergiram das respostas quatro Ideias Centrais a respeito das orientações de profissionais quanto aos hábitos saudáveis que podem contribuir para controle da doença, e seis que versaram acerca do modo como as ações educativas podem ser mais efetivas com vistas a estimular a adoção de um estilo de vida mais saudável. Com base nas representações dos participantes, este estudo trouxe a reflexão de que a educação em saúde, como recurso para incentivar a mudança de hábitos, só se torna efetiva quando fundamentada na realidade de cada indivíduo, envolvendo diálogo, escuta qualificada e capacitação para o autocuidado.

This study aimed to know the perception of Type 2 Diabetes Mellitus patients on the influence of health education for the adoption of healthy habits and disease control. The method used was a qualitative study based on Theory of Social Representation. The testimonies of 23 interviewees were analyzed using the Collective Subject Discourse technique. Four Central Ideas emerged from the testimonies on the guidelines of professionals regarding healthy habits that can contribute to disease control, and six that dealt with how educational actions can be more effective in stimulating the adoption of a healthier lifestyle. Based on the representations of the participants, this study brought the reflection that health education, as a resource to encourage the change of habits, only becomes effective when based on the reality of each individual, involving dialogue, qualified listening and training for the self-care.

Vaccination with a nanoparticle E7 vaccine can prevent tumor recurrence following surgery in a human papillomavirus head and neck cancer model.

High-risk human papillomavirus (HPV) encoding E6/E7-HPV oncogenes are responsible for a subgroup of head and neck squamous-cell carcinoma (HNSCC) and thus therapeutic E7-vaccines may be used to control HPV+HNSCC tumors. Herein we investigated the effects of an optimized nanoparticle-conjugated E7 long-peptide vaccine adjuvanted with CpG (NP-E7LP) in an orthotopic immunocompetent mouse model of HPV+HNSCC which is based on injection of HPV16 E6/E7-expressing mEERL95-cells into the submental space. In absence of surgery, vaccination performed before or after tumor-cell injection decreased tumor growth or prolonged mice survival only marginally, despite the high numbers of vaccine-induced circulating E7-specific IFN-γ-secreting CD8+ T-cells. This contrasts with the high-efficacy of NP-E7LP-vaccination reported in the genital and subcutaneous HPV16-E6/E7-expressing TC-1 models. Our data show that in a direct comparison, NP-E7LP-vaccination fully controlled TC-1, but not mEERL95, tumors subcutaneously growing in the flanks. Immune-cell infiltration was 10-fold higher in TC-1-tumors, than in mEERL95-tumors, suggesting that vaccine-induced CD8+ T-cells can only poorly infiltrate mEERL95-tumors. Indeed, immunofluorescence staining of orthotopic mEERL95-tumors showed that CD3+ T-cells are preferentially located peritumorally. However, when NP-E7LP-vaccination was performed after mEERL95-cell injection, but before resection of primary tumors, no postsurgical recurrence was observed and 100% of the mice survived until the experimental endpoint (day 70) in the NP-E7LP-vaccinated group. In contrast, we observed a 60% recurrence rate and only 35% survival in PBS-vaccinated mice. This suggests that removal of the primary tumor modified the tumor microenvironment, allowing a therapeutic effect of the vaccine-induced anti-tumor response. E7-vaccination combined with surgery may thus benefit patients with HPV+HNSCC.

The Role of Patent Foramen Ovale Closure in the Secondary Prevention of Cryptogenic Stroke: a Meta-Analysis Report

Abstract Background: Patent foramen ovale (PFO) closure has been compared to medical therapy for secondary prevention of recurrent cryptogenic stroke. Objectives: To produce an updated meta-analysis including only data from the primary analyses of clinical trials and to evaluate the role of PFO closure in the secondary prevention of recurrent stroke. Methods: Search in Medline (PubMed) and in ISI Web of Knowledge. Parameters under analysis and meta-analyses were: stroke, transient ischemic attack (TIA) and atrial fibrillation (AF). Comprehensive Meta-analysis Software V.2.0 (Biostat) was used. Random-effects analyses were carried out. A level of significance of 5% was used. Results: In this study six, randomized trials enrolling 3,750 patients were included. Unlike other published meta-analyses on the same topic, in this case, only clinical trial data, and not follow-up data, were used. PFO closure, as compared with medical therapy alone, demonstrated superiority in reducing the rate of recurrent stroke (risk ratio with PFO closure vs. medical therapy, 0.37; 95% confidence interval [CI], 0.17 to 0.78; p = 0.01). PFO closure did not offer a significant benefit in prevention of TIA (risk ratio with PFO closure vs. medical therapy, 0.96; 95% CI, 0.64 to 1.44; p = 0.85). Among patients assigned to closure group, an increased risk of atrial fibrillation was seen (risk ratio with PFO closure vs. medical therapy, 4.64; 95% CI, 2.38 to 9.01; p < 0.01). Conclusions: In patients with cryptogenic stroke who had a patent foramen ovale, a protective effect of closure was seen concerning the risk of recurrent stroke, but not regarding the prevention of TIA.

Bivalent therapeutic vaccine against HPV16/18 genotypes consisting of a fusion protein between the extra domain A from human fibronectin and HPV16/18 E7 viral antigens.

BACKGROUND: In vivo targeting of human papillomavirus (HPV) derived antigens to dendritic cells might constitute an efficient immunotherapeutic strategy against cervical cancer. In previous works, we have shown that the extra domain A from murine fibronectin (mEDA) can be used to target antigens to toll-like receptor 4 (TLR4) expressing dendritic cells and induce strong antigen-specific immune responses. In the present study, we have produced a bivalent therapeutic vaccine candidate consisting of the human EDA (hEDA) fused to E7 proteins from HPV16 and HPV18 (hEDA-HPVE7-16/18) and evaluate its potential as a therapeutic vaccine against cervical cancer. MATERIALS AND METHODS: Recombinant fusion proteins containing HPV E7 proteins from HPV16 and HPV18 virus subtypes fused to hEDA were produced and tested in vitro on their capacity to bind TLR4 and induce the production of tumor necrosis factor-α or interleukin (IL)-12 by human monocytes and dendritic cells. The immunogenicity and potential therapeutic activity of the vaccine in combination with cisplatin or with the TLR3 agonist molecules polyinosinic-polycytidylic acid (Poly IC) or Poly ICLC was evaluated in mice bearing subcutaneous or genital orthotopic HPV16 TC-1 tumors. RESULTS: hEDA-HPVE7-16/18 prototype vaccine binds human TLR4 and stimulate TLR4-dependent signaling pathways and IL-12 production by human monocyte-derived dendritic cell. Vaccination with hEDA-HPVE7-16/18 induced strong HPVE7-specific Cytotoxic T lymphocyte (CTL) responses and eliminated established tumors in the TC-1-based tumor model. The antitumor efficacy was significantly improved by combining the fusion protein with cisplatin or with the TLR-3 ligand Poly IC and especially with the stabilized analog Poly ICLC. Moreover, hEDA-HPVE7-16/18+Poly ICLC induced full tumor regression in 100% of mice bearing orthotopic genital HPV tumors. CONCLUSION: Our results suggest that this therapeutic vaccine formulation may be an effective treatment for cervical tumors that do not respond to current therapies.

Giardia lamblia Decreases NF-κB p65RelA Protein Levels and Modulates LPS-Induced Pro-Inflammatory Response in Macrophages.

The protozoan Giardia lamblia is the most common cause of parasitic gastrointestinal infection worldwide. The parasite developed sophisticated, yet not completely disclosed, mechanisms to escape immune system and growth in the intestine. To further understand the interaction of G. lamblia with host immune cells, we investigated the ability of parasites to modulate the canonical activation of mouse macrophages (Raw 264.7 cell line) and human monocyte-derived macrophages triggered by the TLR4 agonist, lipopolysaccharide (LPS). We observed that G. lamblia impairs LPS-evoked pro-inflammatory status in these macrophage-like cells through inhibition of cyclooxygenase-2 and inducible nitric oxide synthase expression and subsequent NO production. This effect was in part due to the activity of three G. lamblia proteases, a 135 kDa metalloprotease and two cysteine proteases with 75 and 63 kDa, that cleave the p65RelA subunit of the nuclear factor-kappa B (NF-κB). Moreover, Tnf and Ccl4 transcription was increased in the presence of the parasite. Overall, our data indicates that G. lamblia modulates macrophages inflammatory response through impairment of the NF-κB, thus silencing a crucial signaling pathway of the host innate immune response.

Carboplatin/paclitaxel, E7-vaccination and intravaginal CpG as tri-therapy towards efficient regression of genital HPV16 tumors.

High-risk human papillomavirus (HPV) are responsible for genital and oral cancers associated with the expression of the E6/E7 HPV oncogenes. Therapeutic vaccines targeting those oncogenes can only partially control tumor progression, highlighting the necessity to investigate different treatment strategies. Using the genital orthotopic HPV16 TC-1 model, herein we sequentially investigated in progressively more stringent settings the effects of systemic administration of carboplatin/paclitaxel (C + P) chemotherapy combined with HPV16-E7 synthetic long peptide (E7LP) vaccination, followed by intravaginal immunostimulation with the synthetic toll-like-receptor-9 agonist CpG. Our data show that systemic delivery of C + P prior to E7LP vaccination significantly increased mice survival. This survival benefit was associated with both reduced genital tumor growth at the time of vaccination, and a decreased infiltration of Ly6G myeloid cells and tumor-associated macrophages. Adding intravaginal CpG, which results in increased E7-specific CD8 T cells locally, to E7LP vaccination and the chemotherapy formed a tri-therapy, which significantly increased mice survival as compared to any of the dual treatments. When the tri-therapy was further refined by using a recently optimized nanoparticle-conjugated E7LP vaccine, even larger end-stage genital-TC-1 tumors responded, with 90% of mice showing a survival benefit as compared to 30% of mice with the tri-therapy involving the traditional E7LP 'liquid' vaccine. C + P is commonly used to treat cervical cancer patients and its combination with E7/E6 vaccination is currently being tested in a phase I/II trial (NCT02128126). Our data suggests that new vaccine formulations combined with local immunostimulation and standard-of-care chemotherapy have promise to further benefit patients with HPV-associated cancer.