Biological Impact Research Articles

Biological background of colorectal polyps and carcinomas with heterotopic ossification: A national study and literature review

The biological mechanisms and potential clinical impact of heterotopic ossification (HO) in colorectal neoplasms are not fully understood. This study investigates the clinicopathological characteristics of colorectal neoplasms associated with HO and examines the potential role of the bone morphogenetic protein (BMP) pathway in development of HO. An artificial intelligence (AI) based classification of colorectal cancers (CRC) exhibiting HO and their association with consensus molecular subtypes (CMS) is performed.The study included 77 cases via the Dutch nationwide Pathology databank. Immunohistochemistry for BMP2, SMAD4, and Osterix was performed. An AI algorithm assessed the tumour-stroma ratio to approximate the CMS. A literature search yielded 96 case reports, which were analysed and compared with our cases for clinicopathological parameters.HO was more frequently observed in our cohort in traditional serrated adenomas (25%), tubulovillous adenomas (25%) and juvenile polyps (25%), while in the literature it was most often seen in juvenile polyps (38.2%) and inflammatory polyps (29.4%). In both cohorts, carcinomas were mostly conventional (>60%) followed by mucinous and serrated adenocarcinomas. Higher expression of BMP2, SMAD4, and Osterix was observed in tumour and/or stromal cells directly surrounding bone, indicating activation of the BMP pathway. The tumour-stroma analysis appointed >50% of the cases to the mesenchymal subtype (CMS4) (59%).HO has a predilection for serrated and juvenile/inflammatory polyps, mucinous and serrated adenocarcinomas. BMP signalling is activated and seems to play a role in formation of HO in colorectal neoplasms. In line with TGFβ/BMP pathway activation associated with CMS4 CRC, HO seems associated with CMS4.

Understanding the Interaction between Nanomaterials Originated from High-Temperature Processed Starch/Myristic Acid and Human Monocyte Cells.

High-temperature cooking approaches trigger many metabolically undesirable molecule formations, which pose health risks. As a result, nanomaterial formation has been observed while cooking and reported recently. At high temperatures, starch and myristic acid interact and lead to the creation of nanomaterials (cMS-NMs). We used a non-polar solvent chloroform to separate the nanomaterials using a liquid-liquid extraction technique. The physico-chemical characterization was carried out using dynamic light scattering (DLS), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FTIR). To determine the biological impact of these nanomaterials using different in vitro assays, including a cell viability assay, microscopic staining, and gene expression analysis, we adopted the THP-1 cell line as an in vitro monocyte model in our study. The TEM images revealed that fabricated cMS nanomaterials are smaller than 100 nm in diameter. There were significant concerns found in the cytotoxicity assay and gene expression analysis. At concentrations of 100-250 µg/mL, the cMS-NMs caused up to 95% cell death. We found both necrosis and apoptosis in cMS-NMs treated THP-1 cells. In cMS-NMs-treated THP-1 cells, we found decreased expression levels in IL1B and NFKB1A genes and significant upregulation in MIF genes, suggesting a negative immune response. These findings strongly suggest that cMS-NMs originated from high-temperature food processing can cause adverse effects on biological systems. Therefore, charred materials in processed foods should be avoided in order to minimize the risk of health complications.

Subthreshold micropulse diode laser treatment in diabetic macular edema: biological impact, therapeutic effects, and safety.

To introduce the treatment of diabetic macular edema (DME) with subthreshold micropulse diode laser (SMPL), to summarize the biological impact, therapeutic effects, and safety of this treatment, and to discuss the response to DME when SMPL is combined with anti-vascular endothelial growth factor (anti-VEGF) or steroid. The literature search was performed on the PubMed database, with a selection of English-language articles published from 2000 to 2023 with the following combinations of search terms: diabetes macular (o) edema, micropulse laser or subthreshold micropulse laser, anti-vascular endothelial growth factor, and steroid. SMPL is a popular, invisible retinal laser phototherapy that is inexpensive, safe, and effective in the treatment of DME. It can selectively target the retinal pigment epithelium, reduce the expression of pro-inflammatory factors, promote the absorption of macular edema, and exert a similar and lasting clinical effect to traditional lasers. No significant difference was found in the therapeutic effects of SMPL between different wavelengths. However, HbA1c level and pretreatment central macular thickness (CMT) may affect the therapeutic outcomes of SMPL. SMPL has a slow onset and produces lasting clinical effects similar to conventional photocoagulation. It has been reported that SMPL combined with the intravitreal anti-VEGF injection can significantly reduce the number of injections without influencing the therapeutic effect, which is essential for clinical applications and research. Although 577nm SMPL is widely used clinically, there are no standardized protocols for SMPL. Additionally, some important problems regarding the treatment of SMPL require further discussion and exploration.

Biological basis of extensive pleiotropy between blood traits and cancer risk.

The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk.

Impact of biologics on revision sinus surgery numbers in CRSwNP patients in a tertiary care center in Belgium.

Impact of biologics on revision sinus surgery numbers in CRSwNP patients in a tertiary care center in Belgium.

Molecular epidemiology of canine parvovirus type 2 in Sicily, southern Italy: A geographical island, an epidemiological continuum

Since it emerged as a major dog pathogen, canine parvovirus type 2 (CPV-2) has featured a remarkable genetic and phenotypic heterogeneity, whose biological, epidemiological, and clinical impact is still debated. The continuous monitoring of this pathogen is thus of pivotal importance. In the present study, the molecular epidemiology of CPV-2 in Sicily, southern Italy, has been updated by analysing 215 nearly complete sequences of the capsid protein VP2, obtained from rectal swabs/faeces or tissue samples collected between 2019 and 2022 from 346 dogs with suspected infectious gastrointestinal disease. The presence of the original CPV-2 type (4%) and CPV-2a (9%), CPV-2b (18%), or CPV-2c (69%) variants was documented. Over the years, we observed a decrease in the frequency of CPV-2a/-2b and a rapid increase of CPV-2c frequency, with a progressive replacement of the European lineage of CPV-2c by the Asian lineage.The observed scenario, besides confirming epidemiological relevance of CPV-2, highlights the occurrence of antigenic variant shifts over time, with a trend toward the replacement of CPV-2a, CPV-2b, and the European lineage of CPV-2c by the emerging Asian CPV-2c lineage. The comparison with other Italian and international sequences suggests the occurrence of viral exchange with other Italian regions and different countries, although the directionality of such viral flows could not be often established with confidence. In several instances, potential CPV-2 introductions led to epidemiological dead ends. However, major, long-lasting clades were also identified, supporting successful infection establishment, local spreading, and evolution. These results, besides demonstrating the need for implementing more effective control measures to prevent viral introductions and minimize circulation, stress the relevance of routine monitoring activities as the only tool to effectively understand CPV-2 epidemiology and evolution, and develop adequate countermeasures.

Theoretical multiscale study on the properties, aqueous solution behavior and biological impact of zinc oxide nanoparticles

The aim of this theoretical study is to describe the relationship between the structure and the physicochemical properties of zinc oxide nanoparticles (ZnO NPs) and Mn doped ZnO NPs to assess their toxicological impact. In order to do so, a multiscale modelling approach is applied. Different nanoparticles, as well as the mechanism(s) of nanoparticle aggregation and growing, are characterized in terms of size and shape considering electronic, surface, structural and topological properties via quantum mechanics simulations. To evaluate the toxicology impact of ZnO NPs in human health safety and their possible environmental impact, classical molecular dynamics simulations were carried out to study the interaction between the nanomaterials and biological target systems: a set of selected human proteins and model plasma membranes. Likewise, the simulation of nanoparticles dispersion in aqueous media along with water adsorption on their surfaces was conducted.The mayor findings may be summarized as: (i) the ZnO NPs from 12 to 96 (ZnO) units are characterized and their interaction energies, HOMO-LUMO gaps, superficial areas and volumes are reported; (ii) the (ZnO)12 NP and Zn11MnO12 NP are further characterized via their topological properties, vibrational spectra, PDOS and non-covalent interactions; (iii) the doping with Mn atoms is favourable. The interaction energies, HOMO-LUMO orbitals and gaps, PDOS, atomic charges, superficial areas and volumes are reported for NPs doped with up to 5 Mn atoms; (iv) high water affinity for ZnO NPs is reported with both quantum and classical calculations, v) (ZnO)12 NPs do not penetrate the cell membrane and (vi) the affinity energy of both ZnO and Mn doped NPs for human proteins is moderate.The reported results provide in-depth whole-chain studies of zinc oxide nanoparticles, which have been successfully applied for different technologies.

Fresh Parent's Own Milk for Preterm Infants: Barriers and Future Opportunities.

While direct at-the-breast feeding is biologically optimal, Neonatal Intensive Care Unit (NICU) admission due to infant immaturity or illness often necessitates the expression and storage of parent's milk. The provision of freshly expressed (never stored) parent's own milk to preterm infants is not widely prioritized, and this article provides an exploration of NICU practices and their implications for feeding premature or ill infants with parent's own milk. In this article, we discuss the potential biological benefits of fresh parent's own milk, highlighting its dynamic components and the changes incurred during storage. Research suggests that fresh milk may offer health advantages over stored milk. The authors advocate for further research, emphasizing the need for standardized definitions. Research is needed on the biological impact of fresh milk, both short- and long-term, as well as defining and understanding healthcare economics when using fresh milk.

P550 Short and long-term outcomes after acute severe ulcerative colitis in adults: A 12 year Canadian experience in the post biologic era

Abstract Background Patients with acute severe ulcerative colitis (ASUC) are at increased risk of colectomy following an episode of acute severe exacerbation. Medical rescue therapy in steroid non-responders has reduced the need for emergency colectomy. However, impact of biologics on longer-term colectomy risk is unclear. Methods A retrospective cohort study of adult patients aged ≥18 years hospitalized with acute exacerbation of UC requiring hospitalization and managed with intravenous corticosteroids between 2010 and 2022 at two regional hospitals in London, Ontario, Canada. Steroid non-response was defined as requirement of medical rescue therapy or colectomy. Results A total of 264 adults hospitalized with ASUC were included in the analysis (male: 51.1% [n=136], mean age at admission: 40.8±17.8 years). The majority had extensive colitis (71.3% [n=169]) at the time of diagnosis. 46.3% (n=118/255) presented within one year of disease onset and 23% (n=61) had ASUC as their first presentation with UC. 25.7% (n=66/257) of patients had prior purine analogues and 23.3% (60/257) had previous biologics prior to ASUC presentation. After admission, 55.7% (n=147) responded to intravenous corticosteroids. Of the steroid non-responders, 37.5% (n=99) patients were managed with infliximab rescue therapy and only one patient received tofacitinib rescue therapy. Median CRP, stool frequency and Lindgren index score were statistically significant between steroid responders and non-responders (Table 1). A higher proportion of steroid non-responders had prior exposure to biologics or tofacitinib compared to steroid responders (31.9% vs 16.3%, p<0.01). On multivariate analysis for various factors predicting steroid non-response, assessment by Oxford criteria on day 3 was the only factor that was statistically significant (odds ratio 4.70 (95% CI 1.06-20.8), p = 0.04). Oxford criteria on day 3 had a sensitivity, specificity of 58.6% and70.8%, respectively for predicting steroid non-response. 8% (n=21) required colectomy during index admission. An additional 13% (n = 32) underwent colectomy within 12 months of discharge, for which there was no difference between steroid responders and non-responders (12.2% vs 14.7%). The short term (3 months following discharge) and long-term (3-12 months following discharge) colectomy rates following discharge were 8% (20/245) and 5.4% (12/223) respectively. Hospitalization with UC exacerbation rate following discharge was 17% (38/223). Conclusion 8% of patients admitted for ASUC require colectomy during the same admission and additional 13% required colectomy within 12 months of discharge. Despite a high initial response to corticosteroids, long term colectomy rates and re-hospitalization rates remain high.

Proteome-Wide Analysis of Lysine 2-Hydroxyisobutyrylation in Aspergillus fumigatus

Aspergillus fumigatus is the significant causative agent in cases of invasive aspergillosis, leading to a high mortality rate in immunocompromised patients. A comprehensive understanding of its growth patterns and metabolic processes within the host is a critical prerequisite for the development of effective antifungal strategies. Lysine 2-hydroxyisobutyrylation (Khib) is a highly conserved protein posttranslational modifications (PTM) found in various organisms. In this study, we investigate the biological impact of Khib in A. fumigatus. Using a combination of antibody enrichment with the conventional LC–MS/MS method, the pattern of Khib-modification in proteins and their respective sites were analyzed in a wild type strain of A. fumigatus. Our findings revealed 3494 Khib-modified proteins with a total of 18,091 modified sites in this strain. Functional enrichment analysis indicated that these Khib-modified proteins participate in a diverse range of cellular functions, spanning various subcellular locations such as ribosome biosynthesis, protein synthesis and nucleocytoplasmic transport. Notably, when compared with other reported eukaryotes, A. fumigatus exhibited consistently higher numbers of Khib-modified proteins, suggesting the potential significance of this modification in this organism. An interesting observation is the prevalence of Khib modifications in most enzymes involved in the ergosterol synthesis pathway. The insights gathered from this study provide new avenue for studying PTM-associated mechanisms in fungal growth and offer potential implication for antifungal drug development.

Farmers´ sense of the biological impact of extreme heat and seasonality on Swedish high-yielding dairy cows – A mixed methods approach

Supporting dairy farmers in becoming resilient towards extreme weather requires a broad understanding of the experiences and perceived risks associated with these events from those who undergo them. We used a mixed methods approach to explore national trends of biological consequences on dairy cow udder health and fertility, combined with in-depth farmer conversations around extreme weather events, focusing on heat. The aim is to provide a comprehensive picture of how dairy farmer perceptions, priorities and decision-making are related to the season and extreme weather to identify preventive pathways that can reduce biological costs of heat stress on Swedish dairy cattle during summer. Data collected monthly at cow and farm level between 2016–2019 as part of the Swedish milk and disease recording system confirm seasonal trends and show increased somatic cell counts (SCC) and negatively impacted fertility during summers. In addition, transcriptions of 18 interviews with dairy farmers across the country and seasonal variations of SCC and fertility were thematically analysed. The results suggest that farmers have a broad definition of extreme weather and are aware of the negative impacts. Yet handling of extreme weather events can mainly be classified as reactive. Nevertheless, there are long-term effects on the farm economy, health and herd dynamics. Swedish dairy farmers are currently showing resilience, albeit a fragile one. The capability to ensure sufficient feed production in extreme weather is critical for farm self-perceived resilience. However, acknowledging the long-term biological costs related to fertility, currently not perceived by farmers, has the potential to support proactive planning and improve farm resilience and profitability.

The role of neighborhood deprivation in the cervicovaginal microbiota

BackgroundLactobacillus-deficient cervicovaginal microbiota is associated with spontaneous preterm birth and is more common among Black individuals. Persistent racial segregation in the United States has led to differential neighborhood exposures by race that can affect pregnancy outcomes. The extent to which neighborhood exposures may explain racial differences in the cervicovaginal microbiota is unknown. ObjectiveWe sought to determine if neighborhood deprivation, defined as material community deprivation, is associated with a Lactobacillus-deficient cervicovaginal microbiota in a prospective cohort of pregnant individuals. Our hypothesis is that racial differences in neighborhood deprivation may explain the higher prevalence of Lactobacillus-deficient cervicovaginal microbiota in Black birthing people. Design/MethodsWe analyzed data from Motherhood & Microbiome, a prospective pregnancy cohort enrolled from prenatal clinics in a single hospital system 2013-2016 in which a Lactobacillus-deficient cervicovaginal microbiota was previously shown to be associated with spontaneous preterm birth. We geocoded addresses to obtain census tract neighborhood deprivation data from the Brokamp Nationwide Community Deprivation Index that uses weighted proportions of poverty, income, public assistance, lack of health insurance, and vacant housing. Generalized linear mixed models quantified associations of deprivation with the cervicovaginal microbiota accounting for geographical clustering by census tract and potential confounders. Due to different distributions of neighborhood deprivation and the cervicovaginal microbiota, we performed race-stratified models. Mediation analyses quantified the extent to which deprivation may contribute to racial differences in the cervicovaginal microbiota. ResultsHigher neighborhood deprivation was associated with a Lactobacillus-deficient cervicovaginal microbiota. Per standard deviation increment of deprivation, participants had 28% higher adjusted odds (aOR 1.28, 95% CI: 1.04-1.58) of a Lactobacillus-deficient microbiota. Black participants had higher odds of a Lactobacillus-deficient microbiota than White participants (aOR 4.00, 95% CI: 2.05, 8.26), and mediation analysis revealed that deprivation accounted for 22% (P=0.046) of that disparity. ConclusionNeighborhood deprivation was associated a Lactobacillus-deficient cervicovaginal microbiota and may partially explain Black-White disparities in the cervicovaginal microbiota. Mechanistic studies to explore how environmental exposures modify the cervicovaginal microbiota are warranted to identify novel opportunities for future interventional strategies to prevent preterm birth. As these findings demonstrate a potential biologic impact from neighborhood conditions, policies that drive urban planning should be explored to improve pregnancy outcomes.

Mental disorders of non-psychotic level during the pandemic of coronavirus infection

The coronavirus infection (COVID-19) is a pressing problem of the 21st century, since in a short period of time the epidemic of this infection rapidly developed into the pandemic with ensuing medical and socio-economic consequences. The impact of the pandemic on the mental health of the population is explained both by the direct biological impact of the virus on the human body and by associated psychosocial factors. The purpose of our work is to study the clinical picture and dynamics of non-psychotic mental disorders caused by the COVID-19 pandemic. Materials. An analysis of 991 archival medical records of the patients who were treated in the Psychotherapy Department, Altai Regional Clinical Psychiatric Hospital named after Yury Karlovich Erdman, for 2021–2022 was carried out. Of these, 246 patients (24.8 %) had a history of COVID-19 or associated the occurrence of mental disorders with this infection. In addition, a clinical study and follow-up of 45 patients was carried out in the same department. Results. COVID-19 is a significant factor in the development of non-psychotic mental disorders. Initial use of mental health care accounts for 42 %. The mean age of the patients was 47 years. It has been found that women are more susceptible to such disorders than men. After suffering from COVID-19 infection, the level of anxiety doubled, and a significant increase in depressed mood (from 57.1 to 85.7 %), sleep disturbances (from 67.8 to 82.1 %), phobias (from 71.4 up to 78.6 %), as well as asthenic symptoms, was noted. At the end of the treatment, a reduction in mental disorders was noted. Conclusion. The study convincingly showed the high prevalence of non-psychotic mental disorders associated with COVID-19. People of working age with pre-existing neurotic disorders are more vulnerable to the effects of the pandemic than others. In the clinical picture, three main psychopathological syndromes were identified: anxious-depressive, asthenic-depressive, and anxious-phobic. Complex treatment (psychopharmacotherapy, psychotherapy) in the psychotherapy department of a 24‑hour psychiatric hospital showed high effectiveness.

Abstract C095: KRAS mutation subtypes are associated with clinical and phenotypic differences in pancreatic ductal adenocarcinoma

Abstract Background: KRAS is a significant driver gene for pancreatic ductal adenocarcinoma (PDAC) and is present in up to 90% of PDAC cases. KRAS mutant (mt) PDAC tends to have worse prognosis compared to KRAS wild-type (wt) PDAC. However, the clinical and biological impact of the KRAS mutation subtypes (e.g. G12D, G12R, G12V, G12C and Q61) remains unclear. We sought to explore the clinical and molecular characteristics of the KRAS mt subtypes. Methods: We performed a retrospective review of patients with KRAS mt PDAC who underwent next generation sequencing at our institution from December 1, 2018 to December 1, 2021. We collected patient demographics, disease characteristics, clinical outcomes, DNA and RNA sequencing results via chart review. Bulk RNA-seq was performed via Tempus and The Cancer Genome Atlas. Count data were processed and separated by KRAS mutation subtype using a custom python script. Differential gene expression was performed using the DifSeq2 R package. Results: A total of 158 KRAS mt patients (at diagnosis, average age 63.8 years, 57% male, 88 (56%) Stage IV) were included. 10% of patients had KRAS Q61 mutation, 14% G12R, 30% G12V and 46% G12D; only 1.1% had the potentially actionable G12C mutation. G12R had a longer overall survival (OS) compared to the others (median 24.8 vs 17.5 months (m), p=0.05). Among patients with de novo metastatic disease, G12V had the lowest OS (median 9.8 vs 12.4 m, p=0.02). Between the KRAS mt subtypes, there were no statistically significant differences in tumor mutation burden, location of PDAC or subsequent metastasis, lines of treatment (average 2.3), age at diagnosis, gender, or stage at diagnosis. One hundred thirty-seven (87%) patients had at least one pathogenic somatic variant, 14 of which had statistically significant differences between KRAS mt subtypes. 82 (52%) patients had at least one RNA expression variant and bulk RNA-seq showed that each KRAS G12 mutation subtype had unique gene expression patterns, including several oncogenes and tumor suppressor genes. Conclusions: Our data suggest that KRAS mt subtypes may confer different clinically significant phenotypes of PDAC. We found G12R to be associated with improved prognosis compared to other KRAS mt subtypes and that among patients with de novo metastatic disease, G12V had the worst prognostic implication. As there were no statistically significant differences in patient demographics between the KRAS mt subtypes, we hypothesize survival differences are driven by biological phenotype. This is supported by our RNA-seq findings, which demonstrated unique gene expression patterns for each KRAS mt subtype. Citation Format: Alexander Xiao, Jack Korleski, Ryan Carr. KRAS mutation subtypes are associated with clinical and phenotypic differences in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C095.

Characterization and Cellular Toxicity Studies of Commercial Manganese Oxide Nanoparticles.

Manganese oxide nanoparticles (MnOx NPs) are finding applications in several environmentally important areas such as farming and energy storage. MnOx NPs span a range of metal oxidation states that open up a wide range of applications in catalysis as well. As a result, it is important to understand how such materials can impact human health through incidental exposure. In this study, we examined a range of commercially available Mn2O3 NPs and compared our characterization data to those supplied by manufacturers. Discrepancies were noted and then measured values were used to assess the biological impact of these materials on three mammalian cell lines-A549, HepG2 and J774A.1 cells. Cell toxicity assays showed that all Mn2O3 particles exhibited cytotoxic effects that may be correlated, at least in part, to the production of reactive oxygen species. All eight nanoforms also activated caspase 3 but not caspase 1, although the magnitude of these changes varied greatly between materials.

Abstract B041: Keratin 17 excludes CD8-positive T cells and recruits CD163-positive macrophages in pancreatic ductal adenocarcinoma

Abstract Background. Keratin 17 (K17) is a negative prognostic and predictive biomarker, overexpressed in the biologically most aggressive forms of pancreatic ductal adenocarcinoma (PDAC). In other anatomic sites and disease processes, K17 expression impacts the inflammatory microenvironment, correlating with changes in the expression of inflammatory cytokines and the infiltration of CD8+ T cells. Thus, we hypothesized that K17 expression also impacts the immune response in PDAC. Methods. We aimed to determine the relationship between intratumoral and peritumoral immune cell infiltrates versus K17 expression in tumor cells, using brightfield multiplexed immunohistochemistry (mIHC) and our suite of deep learning tools to quantitatively evaluate the expression of four biomarkers of T-cells and macrophages. The study included a multi-institutional cohort of 235 PDAC cases from Stony Brook University Hospital (n=54), Thomas Jefferson University (n=67), Cedars Sinai Medical Center (n=7) and Know Your Tumor PanCAN-Perthera (n=107). Peritumoral immune cells were scored in zones defined as stromal tissue within ≤25 µm of the closest tumor cell. Intratumor immune cells were defined as those that physically touched or overlapped with tumor cells. Immune cell counts in peritumoral and intratumoral K17-negatvie areas of the tumor were normalized to immune cell counts in K17-positive areas. Results. The density of CD8+ T cells in K17-negative peritumoral zones was greater than in K17-positive peritumoral zones in 82.6% of PDACs. Similarly, the density of intratumoral CD8+ T cells in K17-negative areas was greater than in K17-positive areas in 93.2% of cases. Less striking inverse correlations for immune cell density relative to K17 expression were found for CD4+ peritumor lymphocytes and both intratumoral and peritumor CD16+ macrophages. By contrast, CD163+ (tumor-promoting) macrophages were more numerous in K17+ peritumoral and intratumoral zones. All differences were statistically significant and independent of tumor grade, stage, histologic subtype, and neoadjuvant treatment history (p< 0.0001). Conclusions. Correlations between K17 and inflammatory cells suggests K17 expression negatively influences the number and infiltration of T-cells and contributes to the marked immunosuppressive effect of PDAC. These findings suggest that the biologic impact of K17 goes beyond its role as a negative prognostic biomarker that impacts tumor growth, metastasis, and chemoresistance, to suppress the immune response to PDAC. Understanding how K17 influences immune cell function may inform future immunotherapeutic opportunities for PDAC treatment. Citation Format: Lyanne Oblein, Sruthi Babu, Mariana Torrente-Goncalves, Lucia Roa, Michael Horowitz, Mahmudul Hasan, Danielle Fassler, Jaymie Oentoro, Emanuel Petricoin, Lynn M. Matrisian, Natalia Marchenko, Edik Blais, Felicia Allard, Ali Alkalin, Wei Jiang, Brent Larson, Andrew Hendifar, Chao Chen, Shahira Abousamra, Dimitris Samaras, Tahsin Kurc, Joel Saltz, Luisa Escobar-Hoyos, Kenneth Shroyer. Keratin 17 excludes CD8-positive T cells and recruits CD163-positive macrophages in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B041.

Abstract B003: Advancing biomarker discovery using a novel window of opportunity (WOO) trial for pancreatic ductal adenocarcinoma: Trial updates

Abstract Background: There are a growing number of targeted agents that have the potential to greatly improve the clinical outcomes of patients with PDAC beyond current standard of care chemotherapy. However, there is a lack in our understanding of which patients and intrinsic PDAC tumor types will best respond to a given targeted agent(s). In order to optimizing their clinical utility, it is crucial that we a deep understanding of the biological impact that these targeted agents (alone or combination) have within the human system. As such, we designed and implemented the WOO trial to provide a highly adaptable discovery platform for the preliminary assessment of biological activity of one or more targeted agents in patients with PDAC. Utilizing paired, pre- and on-treatment biopsies, along with a robust multiomics pipeline, the WOO trial enables independent assessment of the biological impact of targeted agent(s) on key signaling pathways that can be used to explore novel therapeutic strategies. Methods: WOO is a multi-arm early phase I trial platform designed to assess the pharmacodynamic (PD) effects of one or more study agent(s) alone or in combination in patients with PDAC. A Master Protocol is used to describe overarching design and logistics, and sub-protocols separately describe each study arm comprising the different investigational agent(s). Each participants undergoes a baseline tumor biopsy, then receives their assigned study agent(s) for a specified timeframe (not exceeding 30 days), before undergoing a repeated tumor biopsy, after which they continue to receive therapy per standard of care or clinical trials. Spatially-resolved, single cell multiplex assays are used to compare the effects of the study agent(s) on tumor cell state and heterogeneity between the paired samples. The primary study objective is to independently assess the PD feasibility of detecting a measurable change in tumor biology at post-treatment from baseline for participants within a study arm. The WOO trial uses a 2-stage Bayesian efficacy monitoring approach with a futility-stopping rule for each study arm. In stage 1 of each study arm, if 6 or more of the first 10 participants have a detectable change in tumor biology measurements (i.e., pre vs. post-treatment), then the study arm may continue to enroll an additional 10 participants. To date, 4 study arms are being evaluated: 1) poly (ADP-ribose) polymerase inhibitor (PARPi), olaparib (300 mg PO BID for 10 days), 2) MEK inhibitor (MEKi), cobimetinib (60 mg PO QD for 10 days), 3) ERK inhibitor, LY3214996 (400 mg PO QD for 10 days), and 4) PLK1 inhibitor, onvansertib (12 mg/m2 PO QD for 10 days). To date, a total of 34 participants have been enrolled and treated: n = 14 cobimetinib, n= 15 olaparib, n=2 onvansertib. Future arms to be added. Trial ID: NCT04005690. Citation Format: Charles D. Lopez, Adel Kardosh, Emerson Chen, Guillame Pegna, Alexander Guimaraes, Bryan Foster, Brian Brinkerhoff, Shaun M. Goodyear, Erin Taber, Brindha Rajagopalan, Johnson Vo, Kiara Siex, Brett Johnson, Danielle Galipeau, Dove Keith, Brett Sheppard, Brody Jonathan, Rosalie Sears, Gordon Mills. Advancing biomarker discovery using a novel window of opportunity (WOO) trial for pancreatic ductal adenocarcinoma: Trial updates [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B003.

Aptamer-functionalized-nanoflower loading allicin ameliorates obesity through regulating adipose tissue energy expenditure

The aptamer-functionalized nanoflower-allicin delivery system (NFA) constructed with the adipo-8 aptamer can load allicin and target adipose tissue. This delivery strategy is considered to have a more significant effect on promoting the beiging of adipocytes. However, there has been limited research on the biological impact of NFA on brown adipose tissue (BAT). The study focuses on the regulatory effect of NFA on energy metabolism in brown adipose tissue. Compared to free allicin, NFA demonstrated a superior effect in upregulating genes associated with the activation of BAT, thermogenesis, and batokines, which can promote the beiging of WAT. This suggests that NFA accelerates fatty acid catabolism by increasing the thermogenic activity of adipose tissue throughout the body. The results of the biosafety assessment indicated that NFA demonstrates good biocompatibility and minimal side effects. In summary, our data suggest that NFA shows promise in treating obesity and provides a theoretical basis for its use in obesity treatment.

Moroccan Lavandula dentata L. essential oil: γ-irradiation effect on the chemical composition and antibacterial activity

This study delved into the impact of gamma irradiation on the chemical composition and antibacterial activity of Moroccan Lavandula dentata L., essential oil, which was obtained through the hydrodistillation method from the dried aerial parts of the plant. The principal components identified in the oil were 1,8-cineole, camphor, and borneol. Our investigation centered on examining the consequences of subjecting the essential oil to gamma radiation at doses of 5 kGy and 10 kGy, with a particular focus on alterations in its chemical composition and antibacterial properties. Our primary objectives encompassed the assessment of how gamma irradiation influences the chemical composition of the essential oil and the evaluation of its antibacterial potential against Escherichia coli ATCC and Staphylococcus aureus ATCC. The essential oil underwent in-depth analysis through gas chromatography-mass spectrometry. The results of two distinct gamma irradiation doses were comprehensively analyzed, and the antibacterial activity was rigorously tested against carefully selected bacterial strains. Subsequent to gamma irradiation, the essential oil exhibited an increased concentration of oxygenated monoterpenes and demonstrated heightened inhibitory effects against E. coli ATCC, a Gram-negative bacterium. The study's outcomes underscore the positive influence of gamma irradiation on the chemical composition and antibacterial activity of Moroccan Lavandula dentata L., essential oil. This innovative technology not only augments the variety of chemical constituents within essential oils but also enhances their overall quality while concurrently mitigating the risk of contamination, whether physical, chemical, or microbiological in nature. Consequently, it elevates the potential and biological impact of plant-based products. These findings advocate for further research aimed at identifying the optimal irradiation dosages and their effects on various plant-based products, underscoring the considerable potential of gamma irradiation technology in producing premium, biologically active plant-based goods.

The Designed Pore-Forming Antimicrobial Peptide C14R Combines Excellent Activity against the Major Opportunistic Human Pathogen Pseudomonas aeruginosa with Low Cytotoxicity.

The diminishing portfolio of mankind's available antibiotics urges science to develop novel potent drugs. Here, we present a peptide fitting the typical blueprint of amphipathic and membrane-active antimicrobial peptides, denominated C14R. This 2 kDa peptide consists of 16 amino acid residues, with seven being either hydrophobic, aromatic, or non-polar, and nine being polar or positively charged, strictly separated on opposite sides of the predicted α-helix. The affinity of the peptide C14R to P. aeruginosa membranes and its intrinsic tendency to productively insert into membranes of such composition were analyzed by dynamic simulations. Its biological impact on the viability of two different P. aeruginosa reference strains was demonstrated by determining the minimal inhibitory concentrations (MICs), which were found to be in the range of 10-15 µg/mL. C14R's pore-forming capability was verified in a permeabilization assay based on the peptide-triggered uptake of fluorescent dyes into the bacterial cells. Finally, the peptide was used in radial diffusion assays, which are commonly used for susceptibility testing of antimicrobial peptides in clinical microbiology. In comparison to reference strains, six clinical P. aeruginosa isolates were clearly affected, thereby paving the way for further in-depth analyses of C14R as a promising new AMP drug in the future.