Despite the efforts, pancreatic ductal adenocarcinoma (PDAC) is still highly lethal. Therapeutic challenges reside in late diagnosis and establishment of peculiar tumor microenvironment (TME) ...supporting tumor outgrowth. This stromal landscape is highly heterogeneous between patients and even in the same patient. The organization of functional sub-TME with different cellular compositions provides evolutive advantages and sustains therapeutic resistance. Tumor progressively establishes a TME that can suit its own needs, including proliferation, stemness and invasion. Cancer-associated fibroblasts and immune cells, the main non-neoplastic cellular TME components, follow soluble factors-mediated neoplastic instructions and synergize to promote chemoresistance and immune surveillance destruction. Unveiling heterotypic stromal-neoplastic interactions is thus pivotal to breaking this synergism and promoting the reprogramming of the TME toward an anti-tumor milieu, improving thus the efficacy of conventional and immune-based therapies. We underscore recent advances in the characterization of immune and fibroblast stromal components supporting or dampening pancreatic cancer progression, as well as novel multi-omic technologies improving the current knowledge of PDAC biology. Finally, we put into context how the clinic will translate the acquired knowledge to design new-generation clinical trials with the final aim of improving the outcome of PDAC patients.
BackgroundComplex tumor and immune microenvironment render pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint inhibitors (ICIs). Therefore, a strategy to convert the immune ...hostile into an immunopermissive tumor is required. Recent studies showed that intratumoral injection of Toll-like receptor 9 agonist IMO-2125 primes the adaptive immune response. Phase I and II trials with intratumoral IMO-2125 demonstrated its safety and antitumoral activity.MethodsWe generated an array of preclinical models by orthotopically engrafting PDAC-derived cell lines in syngeneic mice and categorized them as high, low and no immunogenic potential, based on the ability of tumor to evoke T lymphocyte or NK cell response. To test the antitumor efficacy of IMO-2125 on locally treated and distant sites, we engrafted cancer cells on both flanks of syngeneic mice and treated them with intratumoral IMO-2125 or vehicle, alone or in combination with anti-PD1 ICI. Tumor tissues and systemic immunity were analyzed by transcriptomic, cytofluorimetric and immunohistochemistry analysis.ResultsWe demonstrated that intratumoral IMO-2125 as single agent triggers immune system response to kill local and distant tumors in a selected high immunogenic subtype affecting tumor growth and mice survival. Remarkably, intratumoral IMO-2125 in combination with systemic anti-PD1 causes a potent antitumor effect on primary injected and distant sites also in pancreatic cancer models with low immunogenic potential, preceded by a transition toward an immunopermissive microenvironment, with increase in tumor-infiltrating dendritic and T cells in tumor and lymph nodes.ConclusionWe demonstrated a potent antitumor activity of IMO-2125 and anti-PD1 combination in immunotherapy-resistant PDAC models through the modulation of immune microenvironment, providing the rationale to translate this strategy into a clinical setting.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell ...components and heterogeneity, has led to the approval of few therapies with limited efficacy. The study of the early stages of carcinogenesis provides the opportunity for the identification of actionable pathways that underpin therapeutic resistance.
We analyzed 43 Intraductal papillary mucinous neoplasms (IPMN) (12 Low-grade and 31 High-grade) by Spatial Transcriptomics. Mouse and human pancreatic cancer organoids and T cells interaction platforms were established to test the role of mucins expression on T cells activity. Syngeneic mouse model of PDAC was used to explore the impact of mucins downregulation on standard therapy efficacy.
Spatial transcriptomics showed that mucin O-glycosylation pathway is increased in the progression from low-grade to high-grade IPMN. We identified GCNT3, a master regulator of mucins expression, as an actionable target of this pathway by talniflumate. We showed that talniflumate impaired mucins expression increasing T cell activation and recognition using both mouse and human organoid interaction platforms. In vivo experiments showed that talniflumate was able to increase the efficacy of the chemotherapy by boosting immune infiltration.
Finally, we demonstrated that combination of talniflumate, an anti-inflammatory drug, with chemotherapy effectively improves anti-tumor effect in PDAC.
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The biological species concept is founded in the presence of barriers that restrict gene flow, but species delimitation remain a vivid topic in orchids. In sexually deceptive Ophrys, the role of ...postmating barriers has traditionally been thought to be weak and, despite relevant morphological and ethological differences, only low levels of phylogenetic and genetic differentiation have been recorded. In contrast, not many studies have been focused on the relevance of different barriers in closely related species on islands. Using a morphological approach and experimental crosses to evaluate postmating barriers, we here analyse the distinctness of two sardinian endemic sister‐species, Ophrys annae and O. chestermanii, both currently referred to the O. bornmuelleri group. We found that the two endemics differ sustantially in 16 functional morphological traits. We further obtained asymmetric results from manual crosses suggesting that postmating barriers may reinforce the premating barriers. Our results suggest that in closely related species of Ophrys, gene flow is limited also by postmating barriers which contribute significantly to keeping the species reproductively isolated.
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The present study analyzes the results of a biomonitoring campaign, carried out by means of Hypnum cupressiforme Hedw. moss bags around an oil refinery, located in the southwestern part of Sardinia ...island (Italy). This work focuses mainly on the effects of rainfall and distance from the source of contamination on the content of 14 trace elements measured over 16 years. In addition, to point out any increasing or decreasing trends, as well as any peak in presence of airborne pollutants in the area, annual elements’ concentration values are plotted and discussed. Coefficients of variation were also calculated on accumulation values in order to evaluate stability of measurements across the years and to evaluate if similar exposure conditions, i.e., humidity and distance from contamination source, resulted in more uniform accumulation values. In conclusion, (i) the vicinity of the source of contamination as well as rainfall influenced element content in the biomonitor in the case study differently, depending on the considered element and on the exposure condition, (ii) H. cupressiforme moss bags provided relatively stable measurements during the 16-year time frame (observed variations in elements content can be attributed to environmental inputs in the area), (iii) similar conditions of exposure determined less variable accumulation values.
In this contribution, new data concerning bryophytes, fungi and lichens of the Italian flora are presented. It includes new records, confirmations or exclusions for the bryophyte genera
Acaulon
,
...Campylopus
,
Entosthodon
,
Homomallium
,
Pseudohygrohypnum
, and
Thuidium
, the fungal genera
Entoloma
,
Cortinarius
,
Mycenella
,
Oxyporus
, and
Psathyrella
and the lichen genera
Anaptychia
,
Athallia
,
Baeomyces
,
Bagliettoa
,
Calicium
,
Nephroma
,
Pectenia
,
Phaeophyscia
,
Polyblastia
,
Protoparmeliopsis
,
Pyrenula
,
Ramalina
, and
Sanguineodiscus
.
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Type 2 diabetes (T2D) is a progressive metabolic disorder of glucose metabolism. One of the therapeutic approaches for the treatment of T2D is reducing postprandial hyperglycaemia through inhibition ...of the digestive enzymes α-glucosidase and α-amylase. In this context, aimed at identifying natural products endowed with anti-T2D potential, we focused on
(L.) Greuter, a species belonging to Asteraceae family. Enzymatic inhibition, antioxidant activity, phenolic composition and cellular assays were performed. This study revealed that the
hydroalcoholic extract exerts a potent inhibitory activity against α-glucosidase. This activity is supported by an antioxidant effect, preventing ROS formation in a stressed cellular system. HPLC-PDA-MS/MS analysis, revealed a complex polyphenolic fraction. Among the tested pure compounds, 1,5-dicaffeoylquinic acid, apigenin and rutin displayed good α-glucosidase inhibitory activity. Our study suggested new potential of
encouraging us to further testing the possible therapeutic potential of this extract.
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In this contribution, new data concerning bryophytes, fungi, and lichens of the Italian flora are presented. It includes new records and confirmations for the bryophyte genera
Aneura
,
Aulacomnium
,
...Dumortiera
,
Fossombronia
,
Hennediella
,
Hygrohypnella
,
Pohlia
,
Porella
,
Riccardia
,
Tortella
, and
Tortula
, the fungal genera
Cortinarius
,
Mycena
,
Naucoria
,
Trichoglossum
, and
Tubaria
and the lichen genera
Agonimia
,
Blastenia
,
Chaenotheca
,
Cladonia
,
Endocarpon
,
Gyalecta
,
Lecanographa
,
Parmeliella
,
Porpidia
,
Stenhammarella
, and
Thelidium
.
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In this contribution, the conservation status assessment of four vascular plants according to IUCN categories and criteria are presented. It includes the assessment of
Ophrys normanii
J.J.Wood at ...global level, and the regional assessment of
Genista anglica
L.,
Helianthemum lippii
(L.) Dum.Cours., and
Scrophularia lucida
L. (Italy).
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Volatile Organic Compounds (VOCs) are produced by plants to address a variety of physiological and ecological tasks (among others, stress resistance, and pollinator attraction). Genetics is a key ...factor in determining plants’ VOCs content and emission, nevertheless, environment strongly influences VOCs profiles in plants. Orchids are a widespread group of plants that colonize diverse environments and rely on complex and refined pollination mechanisms to reproduce. Orchids VOCs are rarely studied and discussed in relation to growing conditions. In the present study, we compare the volatile profiles of inflorescences of Himantoglossum robertianum (Loisel.) P. Delforge sampled in six ecologically diverse populations on Sardinia Island (Italy). The essential oils obtained by steam distillation were characterized by GC-FID and GC-MS analysis. A total of 79 compounds were detected, belonging to the chemical classes of saturated hydrocarbons, esters, alcohols, ketones, unsaturated hydrocarbons, sesquiterpenes, oxygenated terpenes, terpenes, acids, and aldehydes. Multivariate statistics separated H. robertianum populations based on their chemical profiles. Differences were positively linked to the distance separating populations and reflected climatological features of the sampling sites. Interestingly, our results differed from those available in the literature, pointing out the high variability of VOCs profiles in this food-deceptive orchid.
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