Libro de Resumen

-Abstract: ABCB5 identifies cancer stem cells (CSC) in multiple human malignancies and regulates clinical disease progression, metastasis, recurrence, and therapeutic resistance of expressing tumors, including melanoma, colorectal cancer, and glioblastoma. ABCB5 confers classical cancer multidrug resistance through drug efflux transport, but additional functions in tumor initiation and progression have emerged that include anti-apoptotic gene regulation, IL1β-dependent inflammasome activation, cell cycle control of quiescent resistant CSCs, and ABCB5-associated tumor-intrinsic PD-1 expression. Targeting ABCB5-expressing CSCs through functional ABCB5 blockade or immunotherapeutic ABCB5-targeted antibody drug conjugate (ADC) ablation represent promising novel strategies to reverse therapeutic resistance to current molecular and immune-targeted therapies in ABCB5-expressing cancers.

-Keywords: ABCB5, immunotherapy, antibody-drug-conjugate, cancer stem cell, melanoma

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-Modalidad: Conferencia

-Abstract: B lymphocytes (B cells) uniquely produce antibody protein that plays a critical role in immunological defense. In recent years it has been shown that B cells infiltrate cancerous tissue and that B cell antibody influences tumor growth. It is generally assumed that B cell antibody is distributed solely as a soluble macromolecular species; however, many cell types, including B cells, release small, phospholipid membrane delimited vesicular bodies, termed extracellular vesicles (EV). We questioned whether B cell EV might contain and distribute antibody. To address this, we examined B cell lines (WEHI-231, CH12), primary B cells, and peritoneal and plasma fluids. We isolated B cell EV by differential ultracentrifugation and sucrose gradient fractionation, and examined B cell EV by PAGE/immunoblot, ELISA assay, immunofluorescence cytometry, nanoparticle tracking, and confocal microscopy. We found that B cells from all sources produce IgM antibody-containing EV of two sizes/densities (11 kG and 110 kG) and that such antibody-containing EV are present in murine bodily fluids. Further, EV IgM antibody is monomeric and does not relate to or depend on the presence of secreted pentameric IgM antibody. B cell EV antibody is present on the EV exterior and is also contained within the EV interior where it constitutes cargo. Exterior B EV antibody is functional—it can bind antigen, and it can mediate intra-vesicular signaling. We further found that B cell EV can penetrate a target consisting of a cancer cell line (HeLa) and can deposit antibody there. These results strongly suggest that B cell EV constitute a new, distinct antibody distribution system that operates independent of soluble immunoglobulin, with the capability of crossing cell membranes and accessing target cell interiors that may enlarge the range and consequences of antibody-mediated effects.

-Keywords: B lymphocytes, extracellular vesicles, antibody

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-Modalidad: Conferencia

-Abstract: Cancer, the second leading cause of death in the world, represents a major health challenge and burden to our society. According to World Health Organization’s cancer agency, the International Agency for Research on Cancer, 20 million new cancer cases and nearly 9.7 million cancer deaths occurred in 2022. Approximately, 1 in 5 people develop cancer in their lifetime and about 1 in 9 men and 1 in 12 women die from the disease. Based on the estimation of the American Cancer Society, more than 2 million new cancer cases and 611,720 cancer deaths are projected to occur in the United States in 2024. The emerging evidence based on preclinical and clinical studies clearly demonstrate that constituents of natural products, including bioactive phytochemicals, have enormous potential for cancer prevention and treatment. During the last few decades, an overwhelming number of phytocompounds, from dietary and non-dietary sources, have been investigated using cell culture assays, animal tumor models, and human subjects to understand their efficacy and mechanisms of action for anticancer effects. Nevertheless, various limitations and challenges, including high cost, time constraint, limited source plant species, concern with intellectual property, poor solubility, stability and bioavailability, inefficient targeting, and undesirable adverse effects, limit discovery and development of phytochemical-based anticancer drugs. This presentation aims to capture recent advances in our knowledge on various techniques (e.g., phytochemical purification, accelerated dereplication, hyphenated techniques, and molecular networking), biological assays (e.g., cell culture and animal models), and improved phytochemical bioavailability and delivery systems (e.g., micelles, microemulsions, nanoparticles, liposomes, exosomes, and antibody-drug conjugates) to understand the full potential of plant secondary metabolites in cancer prevention and therapy. Current challenges/limitations and future directions of research will also be discussed.

-Keywords: phytocompounds, delivery systems, cancer prevention, cancer therapy

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-Abstract: Cervical cancer is a highly prevalent Human Papillomavirus (HPV)-associated cancer that affects women around the world and its treatment is stage-specific, being concurrent chemotherapy and pelvic irradiation the most effective treatment for locally advanced stage patients. However, recurrent and persistent disease is a phenomenon fostering search for new molecular target therapies that might improve overall patient clinical outcome. Likewise, High Grade Squamous Intraepithelial Lesions (HSILs) and genital condylomas are also highly prevalent lesions but they are associated to low-risk HPV types and rarely induce malignant transformation. On the other hand, CIGB-300 which is a clinical-grade anti-Protein Kinase CK2 peptide binds and reduces the CK2 mediated phosphorylation on the HPV-16 E7 oncoprotein as well as its binding to the tumor suppressor pRB. However, the targeting of E7 phosphorylation by CIGB-300 seemed to be dispensable for the induction of cell death in HPV-18 cervical cancer-derived C4-1 cells suggesting that many other cellular CK2 substrates can be affected by the peptide in such cellular background. Importantly, pulldown assay indicated that CIGB-300 not only targets the high-risk HPV E7 oncoprotein but also those from low-risk HPV-6 and HPV-11. Importantly, the antitumor activity of CIGB-300 has been documented when administered either as single agent or combined with cisplatin on HPV-16 positive tumors in mice. Integration of these data lead to the clinical testing of CIGB-300 by direct injections in these easy-to-access lesions. Phase 1 clinical trials in women with locally advanced cervical cancer and HSILs established the MTD and DLT with and without antihistamine pre-medication and verified high drug tumor accumulation with intratumor injections. Furthermore, downregulation of B23/nucleophosmin in cervical tumors following the administration of CIGB-300 can be considered as a potential biomarker of response in future clinical trials. Complete response rate in locally advanced cervical cancer treated with CIGB-300 and Chemoradiotherapy concomitantly was higher than that attained with single-agent CIGB-300 in the neoadjuvant setting. Therefore, such combination therapy should be further explored in efficacy studies. In HSIL patients, CIGB-300 intralesional injections were also safe and well tolerable and signs of clinical effect indicated 90 % of colposcopy regression, 50 % of HPV DNA clearance, and 19 % of full histological regression. Finally, in a Phase 2 clinical setting in women with recurrent anogenital condilomas, CIGB-300 induced a higher rate of complete response versus placebo and the clinical benefit was significant in patients with baseline lesion area ≥ 100 mm. Collectively, intralesional administration of CIGB-300 could be a rational approach to treat locally advanced cervical cancer and other genital lesions and merit further clinical research in Phase 3 setting.

-Keywords: Human Papillomavirus, HPV, CIGB-300, cervical cancer, Human Squamous Intraepithelial Lesions, Condyloma

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-Modalidad: Conferencia

-Abstract: CIMAvax-EGF is an EGF-depleting immunotherapy designed to generate specific humoral response against the EGF. CIMAvax-EGF formulation is comprised of human recombinant EGF chemically conjugated to recombinant P64K and Montanide ISA51VG, as adjuvant. CIMAvax-EGF has been extensively evaluated in the clinical setting. Treatment of more than 5000 patients in Cuba and other countries have proven its safety and immunogenicity. In addition, 2 randomized studies were completed. The Phase III study in 405 subjects, showed that patients who completed the induction vaccination, had a significant advantage in overall survival. The 5-year survival rate was 16.62% for vaccinated patients vs. 6.2% for controls. Overall survival was larger for individuals with adenocarcinoma or squamous cell carcinomas with serum EGF concentration above 870 pg/ml, confirming sensitivity of the tumors to the EGF deprivation. Recently, a phase IV trial to characterize the safety and effectiveness of CIMAvax-EGF in advanced NSCLC patients treated in 119 community polyclinics and 24 hospitals was completed. The trial demonstrated that CIMAvax-EGF was safe and effective in patients who were vaccinated in the maintenance scenario. A larger effect was seen in subjects with poor prognosis like those with squamous tumors and high EGF levels. Cimavax-EGF has also been combined with the anti-PD1 antibody nivolumab, as second line therapy, in a phase I clinical trial done in NSCLC cancer subjects with progressive disease. The combination was safe. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response. CIMAvax-EGF is currently being investigated in combination with pembrolizumab or nivolumab in a multi-arm phase II in advanced lung or head and neck cancer patients. Preliminary data, from cohort A of the trial, showed that patients with KRAS wildtype NSCLC had the longest survival.

-Keywords: CIMAvax-EGF, NSCLC, patients, cancer, immunotherapy

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-Modalidad: Conferencia

-Abstract:
Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signalling is incompletely elucidated. Here, we show that the activity of interleukin (IL)-2, a critical cytokine in T cell immunity, is profoundly affected by low pH (~6.5), limiting IL-2 signalling in a IL-2R-dependent manner. Generation of lactic acid by tumours limits STAT5 activation, effector differentiation and anti-tumour immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution by yeast display enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2R with higher affinity, triggers more potent STAT5 activation and drives CD8+ T cell effector function at acidic pH than at pH 7.2 typical of normal tissues. Consequently, Switch-2 is mainly uptake by CD8+ T cells localized in acidic tissues such as tumour and lymph-node, at the contrary of IL-2 that was found at a greater extent in CD8+ T cells in blood and lungs. High-dose Switch-2 therapy induces anti-tumour immunity in different tumour models (B16, MC38, and 4T1) with reduced on-target toxicity in normal tissues, whereas high-dose IL-2 therapy resulted in toxicity alone. Phenotypical and single-cell analysis on CD8+ tumour infiltrating lymphocytes (TILs) shows that Switch-2 increases cell proliferation, expansion of antigen specific cells, and cytokine expression as compared to IL-2. Therapeutic manipulation of the pH-selective activity of cytokines is a powerful approach to exploit the therapeutic efficacy of cytokines in pathological environments with reduced systemic side effects.

-Keywords: IL2 mutein, pH-selective activity, yeast display directed evolution, side effects

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-Abstract: A major hurdle in cancer immunotherapy with cytokines such as IL-2 is lack of selectivity, which
results in sub-optimal clinical benefit along with significant toxicities and tolerability challenges.
Selective targeting of IL-2 to tumor-specific T cells over the vast majority of non-tumor-related
TCR repertoire provides an opportunity to create a therapeutic index, hence maximizing
potential benefit while limiting safety risks. To that end, we have engineered and clinically
validated a novel class of T cell engagers, termed Immuno-STATs, that harness the TCR
specificity of tumor-specific T cells, which allows us to deliver immune activation signals, such
as IL-2, to the right T cells while avoiding the systemic activation of the broader immune
system. We have dosed >100 patients with our lead clinical candidates, CUE-101 and CUE-102,
that demonstrate single agent anti-tumor efficacy in late-stage metastatic cancer patients and
significant increase in responses in combination with anti-PD-1 mAb in frontline metastatic
cancer patients. Both clinical candidates demonstrate favorable tolerability with no evidence of
serious IL-2-related toxicities that were noted in prior studies with IL-2 immunotherapy. These
data provide compelling clinical validation and de-risking for the Immuno-STAT platform, which
can be expanded to target many different cancers.

-Keywords: Immuno-STATs, IL-2, precision immunotherapy

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-Modalidad: Conferencia

-Abstract: High dose IL-2 is registered for the treatment of melanoma and renal cell carcinoma, however this therapy has limited efficacy and severe toxicity. In this presentation we described the development at the center of molecular immunology, of Havana Cuba of IL2 variants, which attempt to overcome such limitations.

We designed and obtained an IL-2 mutein which differs from wildtype IL-2 by four-point mutations that abrogates its interaction with the -subunit of the IL-2R (referred as no- mutein). The no- mutein behaves as a weak antagonist of wtIL2, with a quite preferential activity over effector NK and T cells and not Regulatory T cells in vitro. Furthermore, the no- mutein induces a different signaling cascade over CD8 T cells, which leads to less activation inducing cell death (AICD) and less terminal differentiation into exhausted phenotypes in vitro.

In animal models, the no- mutein as monotherapy shows higher antitumoral and antimetastatic effect than wt-IL-2 in several transplantable tumor models, and when combined with anti-PDL1 Abs this antitumoral effect is enhanced. Quite relevantly, the mutein exhibits a good safety profile in mice and rats, with clearly lower signs of lung and liver toxicity than wtIL-2.

Recently, the no- mutein have completed the phase I / first in human clinical trial. 13 patients with advanced solid tumor and without therapeutic alternative were included in two Cuban hospitals. Dose was safely scaled up to 2400 IU/kg, with no signs of limiting toxicities. Expansions of total counts of Lymphocyte in patients PBMC, was evident, with some doses inducing up to a three-fold increase. Among the lymphocytes NK and CD8 T cells expand and enrich the most, with little or no sign of expansion of detrimental Regulatory T cells. Two patients achieved long stabilization of disease and a third one despite initial disease progression achieved unexpected partial response upon follow-up chemotherapy. Interestingly, patients with signs of potential clinical benefit correspond to the patients at the dose range, which the larger expansion of effector lymphocytes. A phase II trial expanding three tumors cohorts shall start in 2024.

-Keywords: IL-2, mutein, effector cells, antitumor therapy

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-Modalidad: Conferencia

-Abstract: Context: Application of hybrid technologies in cancer imaging around the world have shown significant growth over the past 10 years, and while most common PET tracers are becoming increasingly available to the population, leading research centers are drifting towards personalized patient care and are actively working with new radiopharmaceuticals (RPs), broadening the horizon of cancer imaging. Currently, there is growing interest in the diagnostic capabilities of PET/CT with 68Ga-FAPI for a variety of conditions. The accumulation of this RP in the tumor tissue is associated with the FAP protein expression in fibroblasts.
PET tracers based on boron-phenylalanine (18F-FBPA) for planning boron-neutron capture therapy, as well as fluorinated norepinephrine analogues (18F-mFBG) in diagnostics of neuroblastoma and other NET-expressing tumors show promising results. Application results of 68Ga-FAPI in gastric cancer in comparison with 18F-FDG, our first experience of 18F-FBPA usage for a variety of conditions and the first results 18F-mFBG usage in comparison with 123I-MIBG will be presented.
Objectives:
To compare the diagnostic performance of 18F-FDG and 68Ga-FAPI PET/CT in gastric cancer.
To provide the head-to-head comparison of 18F-mFBG and 123I-MIBG in neuroblastomas.
To present results of 18F-FBPA PET/CT for boron-neutron capture therapy planning and for imaging of multiple myeloma.
Materials and methods:
62 patients with a confirmed gastric cancer were enrolled in a prospective study, each of them underwent PET/CT with 18F-FDG and 68Ga-FAPI (52/62 – before treatment, 10 – after surgery or chemotherapy).
Patients with a confirmed neuroblastoma, each of whom underwent PET/CT with 18F-mFBG and SPECT/CT with 123I-MIBG followed by head-to-head comparison.
Preliminary results of 18F-FBPA PET/CT for boron-neutron capture therapy planning and for imaging of multiple myeloma.
Main results:
68Ga-FAPI detected the primary tumor in all 52 patients, 18F-FDG – in 35 patients. Detection rates for metastatic lymph nodes, peritoneal canceromatosis, bone and liver metastases were higher for 68Ga-FAPI compared to 18F-FDG (69 vs. 48 lesions, respectively). A direct correlation between the uptake level of 68Ga-FAPI (SUVmax) and tumor grade (G1-3) was revealed.

-Keywords: PET tracers, nuclear medicine, cancer imaging

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-Modalidad: Conferencia

-Abstract: Multiple myeloma (MM) is a malignancy of bone marrow resident plasma cells that remains incurable for almost all patients. We recently reported PIM2, an oncogenic serine/threonine kinase, to be overexpressed in patient CD138+ MM cells. PIM2 has a significant role in key signaling pathways (IL-6, CD28 activation) that support MM survival and confer chemotherapy resistance in MM cells. Since the increased efficacy of our novel PIM2-selective non-ATP competitive inhibitor (JP11646) was associated with specific downregulation of PIM2 mRNA and protein in vitro and in vivo, we hypothesize that PIM2 has a kinase independent (KI) function that supports MM survival.

We employed molecular and pharmacological inhibition of PIM2 using siRNA and new specific small molecules inhibitors as well as stable molecularly modified MM.1S and U266 myeloma cell lines to express either PIM2 wild type (WT) or K61 kinase dead (KD).

Both WT and KD PIM2 increased viability compared to empty vector control when transfected COS7 were treated with the proteosome inhibitor bortezomib, a first line chemotherapeutic in MM. Similar pro-survival effects of WT and KD PIM2 were also observed in MM.1S cells following serum starvation. MM.1S cells’ viability was significantly and similarly improved by WT or KD PIM2 constructs versus empty vector under JP11646 (20nM; 24h), that abrogates kinase activity and almost completely suppresses endogenous PIM2 mRNA and protein expression, supporting the PIM2 KI function. Furthermore, KI function was supported by treatment with novel small molecule compounds: C-834 which has a potent PIM2 kinase inhibitory effect but does not affect its protein level nor inhibit viability, in contrast with C-103 showing no kinase inhibition that induces PIM2 protein degradation and it’s a potent inhibitor of MM.1S cells viability.

PIM2-c-Myc binding in proliferating MM cells, identified by co-immunoprecipitation was significantly increased by IL-6 treatment. This binding was confirmed through proximity ligation assay and appeared to be KI since LGB321 (PIM kinase only inhibitor) amplified the binding as compared with JP11646 (20 nM) treatment, which significantly inhibited it.

ChIP assay showed that c-Myc occupancy enrichment at CDK4 promoter is significantly decreased when PIM2 levels are reduced at gene or protein level following either siRNA or JP11646 treatment. Interestingly, AZD1208, a PIM kinase only inhibitor did not affect c-Myc CDK4 promoter occupancy, suggesting this binding depends on a PIM2 KI function.

These data support PIM2’s critical KI pro-survival function in MM, novel finding that supports new therapeutic targets for curative treatment approaches.

-Keywords: multiple myeloma, PIM2, c-Myc, PIM2 inhibitors

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-Modalidad: Conferencia

-Abstract: The lecture focuses on the use of Poly(2-oxazoline) (POx) based polymeric micelles (PMs), which have the unique ability to carry a high load of water-insoluble drugs. This capability enhances the solubility, stability, efficacy, and safety of these drugs. The shape of the micelle influences the drug’s performance. For instance, spherical micelles accumulate rapidly in tumors and demonstrate more potent anti-tumor effects compared to worm-like micelles. The latter accumulate at a slower rate and release the drug into the bloodstream. Micelles loaded with two drugs exhibit superior anti-tumor activity compared to micelles carrying a single drug or a combination of drugs, as well as a combination of free drugs. This strategy, termed “drug design by co-formulation”, holds promise for cancer immunotherapy. The presentation will discuss the relationship between drug loading, the critical micelle concentration, the partitioning of micelles and serum proteins, pharmacokinetic and toxicokinetic profiles, and efficacy. These innovative approaches hasten the application of novel PMs for therapeutic uses in cancer and other diseases. The research was funded by NIH grants CA198999 and CA264488. The conflict-of-interest statement indicates an affiliation with DelAQUA Pharmaceuticals.

-Keywords: polymeric micelles, poly(2-oxazoline), cancer, paclitaxel, TLR7/8, CSF1R

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-Modalidad: Conferencia

-Abstract: EGFR-targeted therapies have improved clinical outcomes in colorectal cancer (CRC), but success is often limited by acquired and intrinsic therapeutic resistance. One potential mechanism of resistance consists of EMT-like CRC transitions with attenuated EGFR signaling but enhanced alternative RTK activation. However, the orchestration of this coordinated tumor escape is incompletely understood. We have identified ABCB5 as a regulator of alternative RTK signal transduction, conferring resistance to cetuximab and showed that concurrent ABCB5 blockade suppressed p-AKT/p-mTOR/p-S6 signaling profoundly and attenuated tumor size. Our results suggest the unique therapeutic potential of ABCB5 blockade for the treatment of EGFR inhibitor-resistant CRC through a reversal of redundant tumor-specific escape mechanisms conferred by alternatively activated RTKs.

-Keywords: ABCB5, EGFR resistance, colorectal cancer, AXL, MET

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-Modalidad: Conferencia

-Abstract: Multiple Myeloma is an example of many neoplasms that demonstrate significant differences in the incidences, the ages of onset, and the frequency of genetic alterations between patients from African or European ancestries. This presentation will discuss the hypothesis that both genetic polymorphisms as well as spontaneous mutations in the Tp53 tumor suppressor gene may contribute to these differences. The inherited component of the Tp53 gene that can regulate the levels of both p53 m-RNAs and the rate of degradation of the p53 protein, by its binding of the MDM-2 ubiquitin ligase to the p53 protein, contain polymorphisms in the proline rich domain (introns 2 and 3 and codon 72) which differ in nucleotide sequences between African and European ancestry. These sequences have changed over several hundred thousand years under natural selection based upon the latitude of a population that has evolved during the migrations of humans from Africa to northern Europe. Further these sequences form a portion of the Tp53 gene that us under linkage disequilibrium retaining the combination of these genetic changes together. The differences in the intracellular consentration of the p53 protein may then select for different spontanious mutation rates of the Tp53 gene depending upon the tissue type of the cancer, so that in Multiple Myelomas spontaneous Tp53 mutations are preferentially detected in patients of European ancestry. Such an hypothesis that a polymorphic difference in a gene can influence its own spontaneous mutation rate is a unique concept that may arise from the unique ability of the p53 protein to ensure the fidelity of the genome by either DNA repair or by initiating cell death in response to DNA damage, and genetic changes.
Multiple Myelomas, and indeed many cancers, may arise from predispositions encoded for by polymorphisms in the genome of the individual. These polymorphisms might raise the probability of developing a cancer which arises from additional spontaneous mutations acquired over a lifetime. Evidence for these observations will be discussed in the presentation.

-Keywords: Phenotypic differences between African and European Ancestry Cancers.
Tp53 polymorphisms regulate P53 protein levels
P53 protein levels influences p53 spontaneous mutation rates

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-Modalidad: Conferencia

-Abstract: HEBERSaVax is a novel immunotherapy treatment for cancer previously known as CIGB-247, designed to produce an immune response specific for VEGF, with the development of specific antibodies that block the interaction of VEGF and its receptors, and reduce the bioavailability of this growth factor, thus inhibiting the pro-angiogenic and immune suppressive effects of this molecule. Also, this active immunotherapy elicits cytotoxic T cells that directly eliminate tumor cells that produce VEGF (through the recognition of VEGF peptides associated with MHC class I on the surface of these cells). Two sequential phase 1a and 1b clinical trials (RPCEC00000102 and RPCEC00000155) were conducted with HEBERSaVax, and demonstrated an excellent safety profile and some indications of clinical effects in cancer patients. The more recently concluded phase II clinical trials in ovarian (RPCEC00000246) and hepatocellular carcinoma (), confirm the immunological hypothesis offering further data supporting the potential clinical benefits achievable with HEBERSaVax based immunotherapy. Additionally, VEGF levels data from the mentioned clinical trials were examined. When all data were analyzed according to the patient tumor type, the results indicated that HEBERSaVax therapy was able to reduce or stabilize VEGF levels in a large variety of tumors and were related to an increase in survival.

-Keywords: HEBERSaVax, VEGF, Cancer, Angiogenesis

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-Modalidad: Conferencia

-Abstract: Context
In recent years, the global demographic has shifted towards an older population, presenting new challenges in healthcare and disease management. Elderly chronic diseases, such as cardiovascular disease and diabetes, have become more prevalent, necessitating a deeper understanding of the factors contributing to healthy ageing and longevity. This shift has highlighted the need for comprehensive research that leverages large-scale data to unravel the complexities of ageing and chronic conditions in the elderly.
Objectives
The primary goal of this study is to identify and analyze the factors that contribute to the extension of lifespan and the prevention or management of chronic diseases in the elderly. By focusing on a broad spectrum of biomarkers and employing advanced data analytics, this research aims to uncover the biological and environmental determinants of healthy ageing. Additionally, the study seeks to provide insights into the development of therapeutic interventions and guidelines for promoting longevity and mitigating the risk of age-related diseases.
Materials and Methods
Utilizing a large-scale dataset comprising health examination records, disease report, lifestyle information, and medical histories, this study employs a multifaceted approach to analyze the interplay between various biomarkers and longevity factors. Advanced statistical models and machine learning techniques are applied to dissect the complex relationships between genetic predispositions, environmental exposures, lifestyle choices, and the onset and progression of chronic diseases in the elderly.
Main Results
Preliminary analysis reveals a significant association between certain blood and serum biomarkers and the propensity for longer, healthier lives. Lifestyle factors, including diet, physical activity, and stress management, also emerge as critical components influencing the ageing process and chronic disease manifestation. Moreover, environmental factors, such as exposure to pollutants, are linked to variations in health outcomes among the elderly population.
Conclusions
This study underscores the multifactorial nature of ageing and chronic disease in the elderly. It highlights the importance of a holistic approach in understanding and enhancing lifespan extension and provides a scientific basis for targeted preventive measures and therapeutic strategies. The findings advocate for personalized healthcare interventions that accommodate the genetic, lifestyle, and environmental uniqueness of the ageing individual, paving the way for more effective management of chronic diseases and the promotion of a healthier, longer life.

-Keywords: Healthy Ageing, Chronic Disease Prevention, Longevity Factors, Large-scale Data Analysis, Machine Learning

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-Modalidad: Conferencia

-Abstract: Context: Older adults demonstrate an increased vulnerability to viral and bacterial infections and exhibit insufficient primary vaccine responses. This reduced efficacy is likely attributable to immunosenescence, a phenomenon that describes functional changes in the immune system associated with natural aging, often linked with a mild, persistent inflammatory condition referred to as inflamm-aging. This chronic inflammation is recognized as a significant risk factor for age-related diseases and has been demonstrated to diminish the effectiveness of immune responses to vaccination and medical interventions.
Objectives: Recognizing the significance of phytochemical compounds as immune-modulators could prove pivotal in devising approaches to bolster immune function in aging populations and enhance vaccine responses among older individuals.
Materials and methods: In the validation phase of our research, we assessed a group of 52 subjects. These participants were divided into two categories: young and older. Peripheral blood mononuclear cells from our study group were collected both pre- and post-immunization with a quadrivalent influenza vaccine. Subsequently, we conducted an analysis of T cell immunophenotyping to detect any potential alterations in the immunophenotype induced by influenza vaccination on T cell responses, providing insight into their potential as regulators of immune responses and vaccine effectiveness. Furthermore, we explored the ex-vivo anti-inflammatory and antioxidant effects of oleuropein, a secoiridoid compound extracted from extra virgin olive oil, both independently and in combination with BIRB 796, a potent inhibitor of p38MAPK, on T cell responses to the influenza virus following vaccination. Following this, we stimulated the cells with specific pools of influenza virus peptides, both with and without the presence of oleuropein and BIRB 796.
Main findings and conclusion: We meticulously assessed T cells producing pro-inflammatory and anti-inflammatory cytokines to ascertain the impact of these substances, as well as their effects on reactive oxygen and reactive nitrogen species production, yielding intriguing insights into the potential modulatory role of oleuropein and BIR 796 on the examined aspects.

-Keywords: Immuno-modulators, inflamm-ageing, influenza vaccine, older adults, oleuropein.

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-Modalidad: Conferencia

-Abstract: Not available

-Keywords: microbiome, antibodies, Parkinson’s

-Authors:

-Modalidad: Conferencia

-Abstract: Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia (high blood sugar), insulin resistance, and chronic inflammation. Recent studies suggest imbalances in the gut microbiome, the community of bacteria residing in the intestines, contribute to T2DM development. Certain probiotic formulations, containing live beneficial bacteria, are hypothesized to remodel the microbiome and improve glucose control and insulin sensitivity in diabetic individuals. Objective: This study aimed to evaluate the effect of a precision symbiotic formulation, BiotiQuest™ Sugar Shift, on the gut microbiome of individuals with T2DM after 12 weeks of treatment. Methods: We conducted a clinical trial with participants diagnosed with T2DM. They were randomly assigned to either the treatment group receiving BiotiQuest™ Sugar Shift or the control group receiving a placebo. We assessed clinical parameters including fasting and postprandial glucose, HbA1c, lipid profile, insulin, and creatinine. Additionally, we measured serum lipopolysaccharide (LPS) levels, a marker of gut inflammation, and analyzed the microbiome composition using 16S rRNA gene sequencing. Results: While HbA1c levels did not show significant changes in the treated group, we observed a significant decrease in serum LPS levels (p=0.019), suggesting a potential anti-inflammatory effect. Moreover, the treated group experienced significant increases in alpha diversity within their gut microbiome (p=0.0089) compared to baseline and compared to the control group after 12 weeks (p=0.011). Further analysis revealed specific taxonomic and functional changes in the microbiome. Notably, bacterial species and biomarker genes linked to short-chain fatty acid production, which have anti-inflammatory properties, were enriched in the treated group after 12 weeks. Conclusions: Our findings suggest that BiotiQuest™ Sugar Shift may induce favorable changes in the gut microbiome of individuals with T2DM, potentially leading to reduced inflammation. These alterations were associated with an increase in short-chain fatty acid-producing bacteria and a decrease in LPS levels. While HbA1c levels remained unchanged, further research is warranted to investigate the long-term impacts of this formulation on glycemic control and other clinical outcomes in T2DM management.

-Keywords: Diabetes, Probiotics, inflammation, insulin resistance, , lipopolysaccharides (LPS), Microbiome

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-Modalidad: Conferencia

-Abstract: The microbial community that lives in and on us can perturb our metabolism and immunity, and thus significantly influence development of a variety of diseases and clinical outcomes. Understanding the structure and functions of these human microbiomes is the key in discovering novel biomarkers, product development, disease dynamics, evidence of utility, effects of drugs on the microbiome and vice-versa. Taxonomic classification of microbiome sequence data is, therefore, a critical component of this process. However, existing reference databases of known microbial sequences are far from comprehensive as not all microbial species are yet sampled, taxonomy and metadata of known sequences are not updated fast enough, and often contain low-quality and inaccurately labeled sequences. Furthermore, existing classification programs often assign sequences to known reference groups even if they belong to novel taxonomic groups which are absent from the reference taxonomy. Together, these can have a detrimental impact on the accuracy of taxonomic classifications, biodiversity estimates and reliability of our microbiome research. The introduction of genomics is profoundly changing current bacterial taxonomy by providing accurate methods for precise classification of taxa, inferring the phylogeny of higher taxonomic ranks as well as those at the subspecies level with high accuracy, discovering new microbial species, and even new strains of known species with novel characteristics. Precision taxonomy offers a new frontier in microbiome research while defining diseases by their underlying molecular causes to enable discovery and development of therapeutic candidates and companion diagnostics for microbiome-related diseases. The presentation will discuss the role of precision taxonomy in uncovering the data unseen by traditional microbiome analysis and demonstrates effective approaches to utilize Precision Taxonomy Discovery Platform to obtain highly confident and actionable results in microbiome analysis, which will eventually help shorten the time for discovery and development of microbiota-based therapeutics and companion diagnostics for microbiome-related diseases.

-Keywords: Microbiome, Biomarker, Precision Taxonomy

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-Modalidad: Conferencia

-Abstract: For decades, cancer research primarily focused on genetic alterations, environmental exposures, and their interplay in tumorigenesis and treatment response. However, recent advancements highlight the critical role of the microbiota, a complex consortium of trillions of microorganisms residing within the human body, in modulating these processes. This presentation delves into the multifaceted influence of the microbiome on cancer development, progression, and therapeutic efficacy, emphasizing its emergence as a crucial player in the fight against this devastating disease. In tumorigenesis, the microbiome's impact is multifaceted. Gut bacteria produce metabolites damaging DNA and promoting inflammation, fostering an environment conducive to cancer initiation. Specific bacterial strains compromise immune surveillance, enabling cancer cells to evade detection. The oral and skin microbiomes similarly influence localized cancer development.The microbiome's influence extends to treatment, modulating chemotherapy and immunotherapy efficacy. Certain bacteria enhance drug delivery and immune response, while others act as barriers. Fecal microbiota transplantation (FMT) emerges as a novel therapeutic approach, reshaping the gut environment to boost cancer treatment response. Understanding this intricate interplay demands a paradigm shift. Deciphering the microbiome's language opens avenues for cancer research, including prevention by identifying microbes associated with cancer risk and developing interventions to cultivate a health-promoting microbiome. Leveraging microbial signatures as non-invasive biomarkers offers prospects for early cancer diagnosis. Personalized therapy is pivotal, tailoring strategies based on individual microbiome profiles to optimize efficacy and minimize side effects. The future of cancer research lies in embracing the microbiome's complexity. By unraveling its secrets, we unlock personalized, effective strategies for this devastating disease.

-Keywords: Microbiome, Tumorigenesis, Personalized Therapy, Cancer Treatment, Biomarkers

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-Modalidad: Conferencia

-Abstract: The human body is home to a vast and diverse array of microorganisms, collectively known as the human microbiota.
Homo sapience should be seen as a holobiont, staying in co-dependent relationship with microbes. The human microbiota plays a crucial role in health support and influencing physiological processes and could be maintenance by probiotics.
Probiotics as a live cell confer health benefit to the host. Probiotic products in the form of foods or supplements known for a long time and intuitively were used mostly for digestive issues.
Probiotics could be seen as biological tools for microbiota restoration. They are fighting pathogenic bacteria; prevent bacterial overgrowth; produce bioactive compounds, interact with the host’s immune system, activate anti-infection defense and metabolism.
Rapidly growing popularity of probiotics resulted in significant technological and applicational challenges. The probiotic industry faces a substantial lack of quality scientific and clinical data to support the functionality of probiotic’s therapeutic action.
The latest bio-medical research presents a new generation of probiotic products, that include dead cells, other derivatives, named “postbiotics” and ‘metabiotic”.

“Postbiotics” refer to the byproducts of microbial metabolism and include short-chine fatty acids, organic acids, peptides, and other metabolites that influence immune responses, promote gut barrier function, and modulate inflammation.

Another powerful mechanisms of probiotic’s derivatives discovered for Lactobacillus cell structural fragments.

Multiple data showed that cell wall fragments and other cellular structural molecules are promising materials with wide therapeutical potency.

These materials are presented by cell wall peptidoglycan (PGs), muramyl peptides (MPs), teichoic and lipoteichoic acids (LPAs), and nucleotides motifs. They could be isolated from probiotic lysates, act as MAMPs and directly activate receptors such as TLRs and NODs.
Most of the studies named these types of active molecules “metabiotics”.

Metabiotic in comparison to postbiotics have a known chemical structure and their application optimize organism-specific epigenetic, physiological functions, regulatory, metabolic and/or behavioral reactions, immune system, and genetic apparatus functionality.
Metabiotic substances demonstrate immunomodulatory effects, influence gut health, have prebiotic action, have anti-inflammatory and antioxidant activities, induce wide antimicrobial abilities with strong anti-viral activity.
Stellar Biotics scientific and industrial experience gave to us sufficient scope to suggest our definition of METABIOTICS as a subgroup of derivatives from probiotic cells represented by structural components of cell walls and DNA motives without metabolites inclusion.
This presentation aims to provide a comprehensive overview of wide therapeutic efficacy for probiotic lysate Del-Immune V (Stellar Biotics, LLC, USA) and metabiotic Liasten (www.liasten.com, Ukraine).

-Keywords: microbiota, probiotics, cell fragments, postbiotics, metabiotics, biotherapeutics

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-Modalidad: Conferencia

-Abstract: Pancreatic ductal adenocarcinoma (PDAC) represents a significant challenge in oncology, with a poor 5-year survival rate and an anticipated rise in its prominence as a leading cause of cancer-related deaths. This study delves into the intricate molecular landscape of PDAC, focusing on the largely unexplored realm of long noncoding RNAs (lncRNAs). Using high-throughput single-cell RNA sequencing (scRNA-seq) on 441,758 cells, our analysis unveils cell-type-specific and conserved expression patterns of lncRNAs in PDAC. Notably, we construct an updated cell atlas of the PDAC microenvironment, shedding light on the nuanced roles of lncRNAs in gene regulatory networks during cancer progression. Our exploration extends to the dynamic expression of lncRNAs in heterogeneous ductal cells, unraveling their pivotal roles in diverse biological pathways. This research serves as a foundational resource, offering insights into the regulatory mechanisms of lncRNAs amidst intratumor heterogeneity in PDAC. By elucidating the intricate transcriptional dynamics of the tumor microenvironment, our findings hold promise for guiding future investigations and therapeutic strategies in PDAC.

-Keywords: PDAC, lncRNA, metastasis, network, scRNA-seq

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-Abstract: The endothelial-to-hematopoietic transition (EHT) process during definitive hematopoiesis in vertebrate is highly conserved. Stage-specific expression of transposable elements (TEs) has been detected during zebrafish EHT and may promote hematopoietic stem cell formation by activating inflammatory signaling. However, little is known about how TEs contribute to the EHT process in human and mouse. We reconstructed the single-cell EHT trajectories of human and mouse, and resolved the dynamic expression patterns of TEs during EHT. Most TEs presented a transient co-upregulation pattern along the conserved EHT trajectories. Enhanced TE activation was tightly associated with the temporal relaxation of epigenetic silencing systems. TE products can be sensed by multiple pattern recognition receptors, triggering inflammatory signaling to facilitate the emergence of hematopoietic stem cells. Furthermore, we observed that hypoxia-related signals were enriched in cells with higher TE expression. Additionally, we constructed the hematopoietic cis-regulatory network of accessible TEs and identified potential enhancers derived by TEs, which may boost the expression of specific EHT marker genes. Our study provides a systematic vision on how TEs are dynamically controlled to promote the hematopoietic fate decision through transcriptional and cis-regulatory networks, and pre-train the immunity of nascent hematopoietic stem cells.

-Keywords: Endothelial-to-hematopoietic transition, Transposable element, Hematopoietic stem cell, Inflammatory signaling, Cis-regulatory element, Hypoxia

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-Modalidad: Conferencia

-Abstract: Many pathogenic bacteria use type IV secretion systems (T4SSs) to deliver effectors (T4SEs) into the cytoplasm of eukaryotic cells, causing diseases. The identification of effectors is a crucial step in understanding the mechanisms of bacterial pathogenicity, but this remains a major challenge. In this study, we used the full-length embedding features generated by six pre-trained protein language models to train classifiers predicting T4SEs and compared their performance. We integrated three modules into a model called T4SEpp. The first module searched for full-length homologs of known T4SEs, signal sequences, and effector domains; the second module fine-tuned a machine learning model using data for a signal sequence feature; and the third module used the three best-performing pre-trained protein language models. T4SEpp outperformed other state-of-the-art (SOTA) software tools, achieving ~0.98 accuracy at a high specificity of ~0.99, based on the assessment of an independent validation dataset. T4SEpp predicted 13 T4SEs from Helicobacter pylori, including the well-known CagA and 12 other potential ones, among which eleven could potentially interact with human proteins. This suggests that these potential T4SEs may be associated with the pathogenicity of H. pylori. Overall, T4SEpp provides a better solution to assist in the identification of bacterial T4SEs and facilitates studies of bacterial pathogenicity. T4SEpp is freely accessible at https://bis.zju.edu.cn/T4SEpp.

-Keywords: T4SEpp; T4SE Prediction; T4SS; Deep Learning; Protein Language Model; Helicobacter pylori T4SEs

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-Modalidad: Conferencia