Modulation Of Growth Research Articles

Self-Oscillated Growth Formation of Standing Ultrathin Nanosheets out of Uniform Ge/Si Superlattice Nanowires

Self-oscillation is an intriguing and omnipresent phenomenon that governs a broad range of growth dynamics and formation of nanoscale periodic and delicate heterostructures. A self-oscillating growth phenomenon of catalyst droplets, consuming surface-coating a-Si/a-Ge bilayer, is exploited to accomplish a high-frequency alternating growth of ultrathin crystalline Si and Ge (c-Si/c-Ge) nano-slates, with Ge-rich layer thickness of 14–19 nm, embedded within a superlattice nanowire structure, with pre-known position and uniform channel diameter. A subsequent selective etching of the Ge-rich segments leaves a chain of ultrafine standing c-Si nanosheets down to ∼ 6 nm thick, without the use of any expensive high-resolution lithography and growth modulation control. A ternary-phase-competition model has been established to explain the underlying formation mechanism of this nanoscale self-oscillating growth dynamics. It is also suggested that these ultrathin nanosheets could help to produce ultrathin fin-channels for advanced electronics, or provide size-specified trapping sites to capture and position hetero nanoparticle for high-precision labelling or light emission.

Expression Profile, Regulatory Network, and Putative Role of microRNAs in the Developmental Process of Asian Honey Bee Larval Guts.

MiRNAs, as a kind of key regulators in gene expression, play vital roles in numerous life activities from cellular proliferation and differentiation to development and immunity. However, little is known about the regulatory manner of miRNAs in the development of Asian honey bee (Apis cerana) guts. Here, on basis of our previously gained high-quality transcriptome data, transcriptome-wide identification of miRNAs in the larval guts of Apis cerana cerana was conducted, followed by investigation of the miRNAs' differential expression profile during the gut development. In addition to the regulatory network, the potential function of differentially expressed miRNAs (DEmiRNAs) was further analyzed. In total, 330, 351, and 321 miRNAs were identified in the 4-, 5-, and 6-day-old larval guts, respectively; among these, 257 miRNAs were shared, while 38, 51, and 36 ones were specifically expressed. Sequences of six miRNAs were confirmed by stem-loop RT-PCR and Sanger sequencing. Additionally, in the "Ac4 vs. Ac5" comparison group, there were seven up-regulated and eight down-regulated miRNAs; these DEmiRNAs could target 5041 mRNAs, involving a series of GO terms and KEGG pathways associated with growth and development, such as cellular process, cell part, Wnt, and Hippo. Comparatively, four up-regulated and six down-regulated miRNAs detected in the "Ac5 vs. Ac6" comparison group and the targets were associated with diverse development-related terms and pathways, including cell, organelle, Notch and Wnt. Intriguingly, it was noticed that miR-6001-y presented a continuous up-regulation trend across the developmental process of larval guts, implying that miR-6001-y may be a potential essential modulator in the development process of larval guts. Further investigation indicated that 43 targets in the "Ac4 vs. Ac5" comparison group and 31 targets in the "Ac5 vs. Ac6" comparison group were engaged in several crucial development-associated signaling pathways such as Wnt, Hippo, and Notch. Ultimately, the expression trends of five randomly selected DEmiRNAs were verified using RT-qPCR. These results demonstrated that dynamic expression and structural alteration of miRNAs were accompanied by the development of A. c. cerana larval guts, and DEmiRNAs were likely to participate in the modulation of growth as well as development of larval guts by affecting several critical pathways via regulation of the expression of target genes. Our data offer a basis for elucidating the developmental mechanism underlying Asian honey bee larval guts.

Long-term measurement and modelling of net herbage accumulation in grazed pastures do not align with predictions under climate change

A long-term phosphorus (P) fertiliser and sheep grazing experiment at the AgResearch Research Station at Ballantrae (1975-2022) provides a unique resource to examine long-term changes in net herbage accumulation (NHA) and animal production under conditions where soil P fertility have been non-limiting for more than 35 years. This paper examined historical NHA, soil phosphorus (P) and nitrogen (N) fertility from the high fertiliser (HF) farmlet, and pasture growth trends using the climate driven pasture growth module AgPasture within the Agricultural Production Systems Simulator (APSIM). On the medium slope of the HF farmlet, NHA in 2020-21 was only 87% of that measured on the same farmlet between 1982-88, even though P was non-limiting. The measured decline in NHA aligned with a reduction of on-site nominal sheep stocking rates since the late 1990’s. Prior to this paper, climate driven modelling has often predicted a likely positive outcome in NHA for this environment into the future. Understanding the apparent discrepancy between predictions into the future with what is happening on the ground today is discussed in the paper.

Outcome of adrenocortical carcinoma patients included in early phase clinical trials: Results from the French network ENDOCAN-COMETE

BackgroundAt metastatic stage, treatment of adrenocortical carcinoma (ACC) relies in first line on mitotane therapy, combination of mitotane with locoregional therapies or cisplatin-based chemotherapy according to initial presentation. In second line, ESMO-EURACAN recommendations favour enrolment of patients in clinical trials investigating experimental therapies. However, the benefit of this approach remains unknown. MethodsThe aim of our retrospective study was to analyse the inclusion and outcomes of all patients of the French cohort ENDOCAN-COMETE included in early clinical trials between 2009 and 2019. ResultsOf the 141 patients for whom a local or national multidisciplinary tumour board recommended, as first choice, to look for clinical trial, 27 patients (19%) were enroled in 30 early clinical trials. Median progression-free survival (PFS) was 3.02 months (95% confidence interval [95% CI]; 2.3–4.6) and median overall survival (OS) was 10.2 months (95% CI; 7.13–16.3) while the best response, evaluable in 28 of 30 trial participants according to RECIST 1.1 criteria, was partial response for 3 patients (11%) stable disease for 14 patients (50%) and progressive disease for 11 patients (39%), resulting in a disease control rate of 61%. Median growth modulation index (GMI) in our cohort was 1.32, with a significantly prolonged PFS in 52% of the patients compared to the previous line. The Royal Marsden Hospital (RMH) prognostic score was not associated with OS in this cohort. ConclusionOur study suggests that patients with metastatic ACC benefit from inclusion in early clinical trials in second line. As recommended, if a clinical trial is available, it should be the first choice for suitable patients.

Biomechanical modeling and assessment of lumbar vertebral body tethering configurations.

Vertebral body tethering (VBT) is a fusionless spinal growth modulation technique, which shows promise for pediatric idiopathic scoliosis (IS) curve correction. This technique, mainly used for thoracic curves, is increasingly being used to treat lumbar curves in order to preserve spine flexibility. It remains necessary to adequately define the cord tension to be applied during the operation and the instrumented levels to biomechanically predict correction over time for the lumbar spine. Twelve pediatric patients with lumbar IS, treated with lumbar-only or lumbar and thoracic VBT, were selected for this study. Three independent variables were tested alternately using a patient-specific finite element model (FEM), which includes an algorithm modeling vertebra growth and spinecurvechanges due to growth modulation for 24months post-operatively according to the Hueter-Volkmann principle. Parameters included cable tensioning (150N/250N), upper instrumented level (actual UIV, UIV-1) and lower instrumented level (actual LIV, LIV + 1). Each FEM was personalized using 3D radiographic reconstruction and flexibility supine radiographs. An increase in cord tension (from 150 to 250N) had significant effects on main thoracic and thoraco-lumbar/lumbar Cobb angles, as well as on lumbar lordosis, after surgery (supplementary average correction of 3° and 8°, and increase of 1.4°, respectively) and after 24months (4°, 10° and 1.1°) (p < 0.05). Adding a level to the actual UIV or LIV did not improve correction. This parametric study showed that cord tension is the most important biomechanical parameter on the simulated immediate and 2-year increase in lumbar curve correction. Our preliminary model suggests that it is not advantageous to add additional instrumented levels. This computational study uses a retrospective validation cohort (level of evidence 3).

Results of a Phase II Trial Testing the Resensitization With Trabectedin in Platinum-resistant Ovarian Cancer.

In patients with advanced platinum-resistant ovarian cancer we prospectively evaluated whether trabectedin could resensitize the tumor cells to platinum rechallenge. Upon progression to platinum-based chemotherapy, trabectedin was administered as a 3-hour infusion every three weeks and subsequently crossed over to carboplatin/carboplatin-based combinations. The primary endpoints comprised objective response rate (ORR) and time to progression after trabectedin (TTP Trab). Secondary endpoints included ORR following platinum post-trabectedin, the growth modulation index (GMI) assessed as the ratio of successive TTP to platinum, given after (TTP2) and before (TTP1) trabectedin, quality of life (QoL), and ancillary translational studies. Ten patients with platinum-resistant ovarian cancer from a single institution were treated with trabectedin, one of whom achieved a partial response (PR) reaching the ORR of 10% and six had stable disease (SD) for a disease control rate (DCR) of 70%. After the treatment with platinum post-trabectedin, one patient achieved a PR and two had SD, attaining a rate of resensitization to platinum of 37.5%. The median TTP with trabectedin treatment was 15.0 weeks, while eight patients who received platinum post-trabectedin had the median TTP2 of 19.9 weeks. One patient reached the threshold of GMI >1 (12.5%) as indicator of clinical benefit. QoL of patients was not deteriorated with trabectedin. Predictive biomarkers of response to trabectedin and/or re-exposure to platinum could not be identified. Although trabectedin did not achieve a wide resensitization to platinum in this heavily pretreated platinum-resistant population, a significant number of patients attained disease control.

Intravenous antibiotics in preterm infants have a negative effect upon microbiome development throughout preterm life

BackgroundIntestinal dysbiosis is implicated in the origins of necrotising enterocolitis and late-onset sepsis in preterm babies. However, the effect of modulators of bacterial growth (e.g. antibiotics) upon the developing microbiome is not well-characterised.In this prospectively-recruited, retrospectively-classified, case–control study, high-throughput 16S rRNA gene sequencing was combined with contemporaneous clinical data collection, to assess the within-subject relationship between antibiotic administration and microbiome development, in comparison to preterm infants with minimal antibiotic exposure.ResultsDuring courses of antibiotics, diversity progression fell in comparison to that seen outside periods of antibiotic use (-0.71units/week vs. + 0.63units/week, p < 0.01); Enterobacteriaceae relative abundance progression conversely rose (+ 10.6%/week vs. -8.9%/week, p < 0.01). After antibiotic cessation, diversity progression remained suppressed (+ 0.2units/week, p = 0.02).ConclusionsAntibiotic use has an acute and longer-lasting impact on the developing preterm intestinal microbiome. This has clinical implications with regard to the contribution of antibiotic use to evolving dysbiosis, and affects the interpretation of existing microbiome studies where this effect modulator is rarely accounted for.

Reviewing the Prospective Pharmacological Potential of Isothiocyanates in Fight against Female-Specific Cancers

Gynecological cancers are the most commonly diagnosed malignancies in females worldwide. Despite the advancement of diagnostic tools as well as the availability of various therapeutic interventions, the incidence and mortality of female-specific cancers is still a life-threatening issue, prevailing as one of the major health problems worldwide. Lately, alternative medicines have garnered immense attention as a therapeutic intervention against various types of cancers, seemingly because of their safety profiles and enhanced effectiveness. Isothiocyanates (ITCs), specifically sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate, have shown an intriguing potential to actively contribute to cancer cell growth inhibition, apoptosis induction, epigenetic alterations, and modulation of autophagy and cancer stem cells in female-specific cancers. Additionally, it has been shown that ITCs plausibly enhance the chemo-sensitization of many chemotherapeutic drugs. To this end, evidence has shown enhanced efficacy in combinatorial regimens with conventional chemotherapeutic drugs and/or other phytochemicals. Reckoning with these, herein, we discuss the advances in the knowledge regarding the aspects highlighting the molecular intricacies of ITCs in female-specific cancers. In addition, we have also argued regarding the potential of ITCs either as solitary treatment or in a combinatorial therapeutic regimen for the prevention and/or treatment of female-specific cancers. Hopefully, this review will open new horizons for consideration of ITCs in therapeutic interventions that would undoubtedly improve the prognosis of the female-specific cancer clientele. Considering all these, it is reasonable to state that a better understanding of these molecular intricacies will plausibly provide a facile opportunity for treating these female-specific cancers.

Impact of soybean-associated plant growth-promoting bacteria on plant growth modulation under alkaline soil conditions

Conventional strategies to manage iron (Fe) deficiency still present drawbacks, and more eco-sustainable solutions are needed. Knowledge on soybean-specific diversity and functional traits of their plant growth-promoting bacteria (PGPB) potentiates their applicability as bioinoculants to foster soybean performance under calcareous soil conditions. This work aimed to assess the efficacy of PGPB, retrieved from soybean tissues/rhizosphere, in enhancing plant growth and development as well as crop yield under alkaline soil conditions.Seventy-six bacterial strains were isolated from shoots (18%), roots (53%), and rhizosphere (29%) of soybean. Twenty-nine genera were identified, with Bacillus and Microbacterium being the most predominant. Based on distinct plant growth-promoting traits, the endophyte Bacillus licheniformis P2.3 and the rhizobacteria Bacillus aerius S2.14 were selected as bioinoculants.In vivo tests showed that soybean photosynthetic parameters, chlorophyll content, total fresh weight, and Fe concentrations were not significantly affected by bioinoculation. However, inoculation with B. licheniformis P2.3 increased pod number (33%) and the expression of Fe-related genes (FRO2, IRT1, F6′H1, bHLH38, and FER4), and decreased FC-R activity (45%). Moreover, bioinoculation significantly affected Mn, Zn, and Ca accumulation in plant tissues.Soybean harbors several bacterial strains in their tissues and in the rhizosphere with capacities related to Fe nutrition and plant growth promotion. The strain B. licheniformis P2.3 showed the best potential to be incorporated in bioinoculant formulations for enhancing soybean performance under alkaline soil conditions.

1032 Characterization of the human scalp hair follicle microbiome reveals differential spatial distribution, abundance and viability of intrafollicular microbiota and modulation of hair growth and metabolism by staphylococcus epidermidis

1032 Characterization of the human scalp hair follicle microbiome reveals differential spatial distribution, abundance and viability of intrafollicular microbiota and modulation of hair growth and metabolism by staphylococcus epidermidis

Exploring the roles of fungal-derived secondary metabolites in plant-fungal interactions

Fungi can produce secondary metabolites (SMs), which play important roles in their stress responses. These compounds could also regulate their diverse relationships with plants, often resulting in significant inhibition or promotion effects on plant growth. Despite a long history of research of plant-fungal interactions, many questions remain regarding fungal SM clusters, their expressions and influences to host plants. Here, we review findings on SMs, SM gene clusters and their regulatory mechanisms in plant-associated fungi, along with current techniques to identify them. We also observed the transcriptional modulation of specific genes within the SM clusters of root endophytic fungus Colletotrichum tofieldiae, and discovered that several genes are suppressed in culture conditions without the host plant, yet become activated upon interaction with the host plant, implying the existence of host-mediated regulatory mechanisms. Furthermore, this article also focuses on fungal-derived phytohormone-mimicking SMs and their roles during plant-fungus interactions. Altogether, the aim of this article is to shed light on the largely unexplored potential of fungal SMs as mediators of plant growth modulation.

TWO-YEAR FOLLOW-UP STUDY FOR PATIENTS UNDERGOING VERTEBRAL BODY TETHERING FOR IDIOPATHIC SCOLIOSIS

Anterior vertebral body tethering (AVBT) is a growth modulating procedure used to manage idiopathic scoliosis by applying a flexible tether to the convex surface of the spine in skeletally immature patients. The purpose of this study is to determine the preliminary clinical outcomes for an adolescent patient cohort.18 patients with scoliosis were selected using a narrow selection criteria to undergo AVBT. Of this cohort, 11 had reached a minimum follow up of 2 years, 4 had reached 18 months, and 3 had reached 6 months. These patients all demonstrated a primary thoracic deformity that was too severe for bracing, were skeletally immature, and were analysed in this preliminary study of coronal plane deformity correction.Using open-source image analysis software (ImageJ, NIH) PA radiographs taken pre-operatively and at regular follow-up visits post-operatively were used to measure the coronal plane deformity of the major and compensatory curves.Pre-operatively, the mean age was 12.0 years (S.D. 10.7 – 13.3), mean Sanders score 2.6 (S.D. 1.8-3.4), all Risser 0 and pre-menarchal, with mean main thoracic Cobb angle of 52° (S.D. 44.2-59.8°). Post-operatively the mean angle decreased to 26.4° (S.D. 18.4-32°) at 1 week, 30.4° (S.D. 21.3-39.6°) at 2 months, 25.7° (S.D. 18.7-32.8°) at 6 months, 27.9° (S.D. 16.2-39.6°) at 12 months, and 36.8° (S.D. 22.6– 51.0°) at 18 months and 38.2° (S.D. 27.6-48.7°) at 2 years. The change in curve at 2 years post-operative was statistically significant (P=0.004).There were 4 tether breakages identified that did not require return to theatre as yet, one patient underwent a posterior spinal instrumented fusion due to curve progression.AVBT is a promising new growth modulation technique for skeletally immature patients with progressive idiopathic scoliosis. This study has demonstrated a reduction in scoliosis severity.

Chloroplastic Sec14-like proteins modulate growth and phosphate deficiency responses in Arabidopsis and rice.

Phosphorus is an essential nutrient acquired from soil as phosphate (Pi), and its deficiency severely reduces plant growth and crop yield. Here, we show that single nucleotide polymorphisms (SNPs) at the PHOSPHATIDYLINOSITOL TRANSFER PROTEIN7 (AtPITP7) locus, which encodes a chloroplastic Sec14-like protein, are associated with genetic diversity regarding Pi uptake activity in Arabidopsis (Arabidopsis thaliana). Inactivation of AtPITP7 and its rice (Oryza sativa) homolog (OsPITP6) through T-DNA insertion and CRISPR/Cas9-mediated gene editing, respectively, decreased Pi uptake and plant growth, regardless of Pi availability. By contrast, overexpression of AtPITP7 and OsPITP6 enhanced Pi uptake and plant growth, especially under limited Pi supply. Importantly, overexpression of OsPITP6 increased tiller number and grain yield in rice. Targeted metabolome analysis of glycerolipids in leaves and chloroplasts revealed that inactivation of OsPITP6 alters phospholipid contents, independent of Pi availability, diminishing the reduction in phospholipid content and increase in glycolipid content induced by Pi deficiency; meanwhile, overexpression of OsPITP6 enhanced Pi deficiency induced metabolic alterations. Together with transcriptome analysis of ospitp6 rice plants and phenotypic analysis of grafted Arabidopsis chimeras, these results suggest that chloroplastic Sec14-like proteins play an essential role in growth modulations in response to changes in Pi availability, although their function is critical for plant growth under any Pi condition. The superior traits of OsPITP6-overexpressing rice plants also highlight the potential of OsPITP6 and its homologs in other crops as additional tools for improving Pi uptake and plant growth in low Pi environments.

Abstract 66: Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment

Abstract Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (Gal1) is a known modulator of tumor growth and progression in multiple cancer types including head and neck cancer (HNC). However, its contribution to the regulation of metastasis is poorly understood. Through this study we report a previously unknown role for Gal1 in modulating the STING pathway to regulate metastasis. The cGAS-STING pathway has paradoxical roles in cancer depending on the kinetics and strength of its induction, with chronic STING activation being linked to immune suppression and tumor progression while acute activation being associated with immune activation. However, little is known about the pathways that promote chronic STING activation. Using HNC and lung cancer models, we show that Gal-1 enhances STING protein stability, leading to sustained NF-κΒ activation and heightened chemokine-driven recruitment of myeloid derived suppressor cells (MDSCs). We show that Gal1-STING connection fosters the establishment of pre-metastatic niche through polymorphonuclear MDSCs (PMN-MDSCs), which modify the local lung microenvironment to support metastatic spread. Notably, RNA sequencing of MDSCs isolated from pre-metastatic lungs indicate the role of PMN-MDSCs in remodeling collagen and the extracellular matrix in the pre-metastatic compartment. Our findings reveal an unexpected role of STING activation in metastatic progression of HNC and lung cancer models and establish Gal1 as an endogenous positive regulator of STING. Citation Format: Dhanya K. Nambiar, Vignesh Vignesh Viswanathan, Hongbin Cao, Weiruo Zhang, Li Guan, Manish Chamoli, Brittany Holmes, Christina Kong, Rachel Hildebrand, Amanda Koong, Rie Eyben, Amato Giaccia, Lingyin Li, Edgar Engleman, Quynh Thu Le. Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 66.

Abstract 1611: Statins inhibit the collaborative metastasis mediated by VHL heterogeneity in clear cell renal cell carcinoma (ccRCC) via a non-cholesterol pathway

Abstract BACKGROUND: Despite the advancement of targeted therapies and immunotherapies, the outcome of clear cell renal cell carcinoma (ccRCC) remains poor at the metastatic stage, with a median survival of mere 7 months. This devastating outcome is partially due to an inadequate understanding of the metastatic mechanism of ccRCC. Previously, we found that two distinct cell populations co-exist in the malignancy: one with the functional von-Hippel Lindau (VHL) gene (VHL(+)) and the other without (VHL(-)). This heterogeneity in VHL plays an essential role, where the VHL(-) cells serve as the metastatic driver and promote VHL(+) cells to disseminate to distant organs such as the lungs. In this study, we sought to find small molecules that can selectively inhibit the VHL(-) cells' growth and survival. We hypothesize that these molecules will effectively inhibit ccRCC metastases by targeting the metastatic driver population. METHODS: CRISPR knockout was conducted to generate VHL(-) cells from a murine RCC cell line, RENCA. Both VHL(-) and (+) cells were then fluorescently labeled and went through high-throughput screening (HTS) with 2,530 FDA-approved drugs. We followed a ratiometric black-box approach to identify selective modulators of cell growth and survival of VHL(-) cells without affecting VHL(+) counterparts. CRISPR knockin was conducted on human ccRCC cells, as well, generating VHL(+) and (-) pairs of 786O, RCC4, and a patient-derived primary cell line. RESULTS: HTS yielded 9 hits that selectively inhibited the survival of the metastatic drivers VHL(-) cells. 4 out of 9 hits belonged to the same drug family called statins. Statins bind to HMG-CoA reductase (HMGCR) and help lower cholesterol, thus are widely prescribed to high-risk patients for cardiovascular diseases. Interestingly, not all statins showed the VHL(-) suppressing effect, resulting in IC50 varying from 0.6uM to &amp;gt;50mM. Atorvastatin and rosuvastatin, the two most potent and prescribed statins for cholesterol-lowering with the highest HMGCR affinity, did not show as much efficacy as other statins. This observation also held true in human ccRCC cell lines, suggesting an involvement of a non-cholesterol/HMGCR pathway in statins’ inhibitory effect on VHL(-) cells. Animal studies were conducted using fluvastatin, which had the lowest IC50 in our model. Intraperitoneal injection of 15mg/kg fluvastatin Q.O.D for 2 weeks successfully suppressed the growth of primary tumors, especially by eliminating VHL(-) cells, and most importantly, prevented lung metastases in the treatment group, whereas all of the control group developed metastases. CONCLUSIONS: Translational potential of this project is enormous. By investigating the mechanism of action further, we could potentially reposition the FDA-approved, cheap, and widely available small molecules as a novel anti-metastatic therapeutic in ccRCC. Citation Format: Moe Ishihara, Junhui Hu, Celine Cano-Ruiz, Maia Jackson, Aimee Wu, Stuart Conway, Robert D. Damoiseaux, Lily Wu. Statins inhibit the collaborative metastasis mediated by VHL heterogeneity in clear cell renal cell carcinoma (ccRCC) via a non-cholesterol pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1611.

Abstract 1337: Aged pancreatic fibroblasts enhance pancreatic cancer growth and progression

Abstract Advancing age is a major independent risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). However, the ways in which aging alters cells that eventually comprise the PDAC tumor microenvironment (TME) are incompletely understood. Fibroblasts comprise a large part of PDAC tumors, can alter the behavior of cancer cells, and impact treatment responses. Our studies investigate how normal pancreatic fibroblasts acquire tumor-promoting properties during aging and alter the tumorigenic properties of PDAC both in vitro and in vivo. To determine if PDAC tumor growth is altered by an aged microenvironment, we performed orthotopic injection of KPC and Panc02 PDAC cells into the pancreata of aged (&amp;gt;64-week-old) and young (6-8-week-old) C57Bl/6J mice. Tumors in aged mice are significantly larger compared to those in young mice, and there is increased incidence of liver metastases in the aged mouse cohort. We next queried whether aged pancreatic fibroblasts may contribute to this increase in tumor growth. We generated a panel of aged (donors &amp;gt;55 years old) and young (donors &amp;lt;35 years old) normal human pancreatic fibroblasts to determine the effects of healthy aging fibroblasts on PDAC cell behavior. Conditioned media from or co-culture with aged human pancreatic fibroblasts increases the proliferation, migration, and invasion of PDAC cells compared to young fibroblasts. Aged fibroblast conditioned media activated AKT signaling and enhances features of EMT and stemness. Proteomic analysis of conditioned media reveals a significantly altered secretome in aged fibroblasts, with a number of known tumor-promoting proteins released at higher levels from aged compared to young fibroblasts. We examined the contribution of GDF-15, secreted by aged fibroblasts at relatively high levels, as a paracrine modulator of PDAC growth and progression. Addition of recombinant GDF-15 to young fibroblast conditioned media increases proliferation and invasion of PDAC cells to levels similar to aged fibroblast conditioned media. Treatment of young mice with recombinant GDF-15 increases tumor growth and AKT phosphorylation in vivo. Additionally, inhibition of AKT reduces tumor size in aged but not young mice, suggesting that the aged microenvironment at least in part exerts its pro-tumor effects through AKT. In conclusion, we show that aged, non-cancer-associated pancreatic fibroblasts have the potential to promote growth, migration, and invasiveness in multiple models of pancreatic ductal adenocarcinoma. Further studies examining fibroblast-secreted factors and other changes in the aged TME are ongoing. Citation Format: Daniel J. Zabransky, Yash Chhabra, Mitchell Fane, Emma Kartalia, James Leatherman, Jacquelyn Zimmerman, Elizabeth Jaffee, Ashani Weeraratna. Aged pancreatic fibroblasts enhance pancreatic cancer growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1337.

Abstract 1710: Pharmacologic targeting or silencing of TRIP13 reduces progression of pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a 5-year overall survival rate of &amp;lt; 9%. Thus, there is a need to identify key driver signaling molecules that regulate PDAC progression and to target them for therapeutic intervention. Thyroid receptor-interacting protein 13 (TRIP13), an enzyme of the AAA-ATPase family, participates in spindle assembly checkpoints, double-strand DNA repair, and development of drug resistance. Recently, a small-molecule inhibitor of TRIP13, DCZ0415, was evaluated in experimental models of multiple myeloma and colorectal cancer. However, the expression, oncogenic role, and targeting of TRIP13 in PDAC are unknown. Thus, we examined the expression and role of TRIP13 in PDAC and investigated if targeting it with DCZ0415 had an inhibitory effect on phenotypic features, tumor growth, metastasis, and immune modulation. Methods: Publicly available cancer OMICS datasets (TCGA and CPTAC) for TRIP13 expression were analyzed by using the UALCAN portal, and results were validated with human PDAC samples. To demonstrate the oncogenic role of TRIP13 in PDAC progression, we used silencing with shRNA or pharmacologic targeting by DCZ0415 and performed MTT, colony formation, wound healing, Transwell, and western blot assays in PDAC cell lines, and assessed tumor growth and metastasis in immunocompromised NSG mice. Immunostaining and western blotting were performed to ascertain the immuno-modulatory mechanism of DCZ0415 in an immunocompetent KPC murine model of PDAC. Results: In human PDACs, TRIP13 is overexpressed at the mRNA and protein levels, relative to adjacent normal pancreatic tissues. Silencing of TRIP13 with shRNA or DCZ0415 treatment of PDAC cells reduced their proliferation, migration, and invasion; induced G2/M cell cycle arrest; and, by modulating Bcl-2 family proteins, increased apoptosis. Furthermore, DCZ0415 treatment or silencing of TRIP13 increased E-cadherin and decreased N-cadherin and vimentin, suggesting its involvement in the epithelial-mesenchymal transition process. Genetic manipulation or pharmacologic targeting of TRIP13 also resulted in reduced expression of FGFR4 and pSTAT3, leading to lower levels of β-catenin, cyclin D1, LEF1, and TCF1, indicating inactivation of the Wnt/β-catenin pathway. In a syngeneic PDCA model, DCZ0415 induced an immune response by increasing granzyme B and perforin and by decreasing PD1. DCZ0415 treatment also facilitated immune cell infiltration, as evident from elevated staining of CD3 and CD4 cells. Conclusions: In sum, silencing of TRIP13 or treatment with DCZ0415 reduces PDAC progression by downregulating the FGFR4/STAT3/β-catenin pathway. DCZ0415 treatment also enhances anti-tumor immunity. These findings suggest that DCZ0415 can be developed as a therapeutic/immunostimulatory agent to improve treatment of PDAC patients expressing elevated levels of TRIP13. Citation Format: Farrukh Afaq, Sumit Agarwal, Prachi Bajpai, Hyung-Gyoon Kim, Sameer Al Diffalha, Shajan P. Sugandha, Moh'd Khushman, Sooryanarayana Varambally, Upender Manne. Pharmacologic targeting or silencing of TRIP13 reduces progression of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1710.

Studies on Endurance of Azospirillum formosense Strains to Osmotic Stress and Modulation of Early Stage Pearl Millet Growth

Studies on Endurance of Azospirillum formosense Strains to Osmotic Stress and Modulation of Early Stage Pearl Millet Growth

Effects of the short-term fasting and refeeding on growth-related genes in Japanese eel (Anguilla japonica) larvae.

The Japanese eel (Anguilla japonica) spends a long period as the leptocephalus larval form under current rearing conditions. The duration of the larval stage until metamorphosis is influenced by body size and growth; however, little knowledge exists of the regulatory mechanism of growth in eel larvae. The present study focused on growth hormone (GH), insulin-like growth factors (IGFs), and IGF binding protein (IGFBP) as the central regulators of growth in teleost fishes and transforming growth factor-beta 3 (TGF-β3) as a possible key modulator of muscle growth and body component synthesis. Japanese eel IGFBP-1a and TGF-β3, comprising 264 and 411 amino acids, respectively, were cloned. Short-term (5-day) fasting and refeeding experiments were performed to understand changes in growth-related genes affected by nutritional status. The relative expression of gh increased with fasting and subsequently decreased with refeeding to the basal levels of the fed control. Relative igf-1 and igf-2 expression levels were high in the fasted group. Relative igf-1 was reduced after 2-day refeeding, whereas igf-2 decreased to the basal level after 1-day refeeding, suggesting that IGF-1 and IGF-2 might be regulated independently and contribute to postnatal growth in eel larvae. Relative igfbp-1a expression was sharply increased by fasting, whereas tgf-β3 showed high and low values in the fed and fasted groups, respectively. Relative igfbp-1a and tgf-β3 levels were negatively and positively correlated with body size, respectively. These results suggest that igfbp-1a and tgf-β3 are potential indices of growth for exploring optimal rearing conditions to shorten the larval stage in Japanese eels.

The role of the SNF1 signaling pathway in the growth of Saccharomyces cerevisiae in different carbon and nitrogen sources.

Cancer is a leading cause of death worldwide, reporting nearly 10 million deaths in 2020. One of the hallmarks of cancer cells is their capability to evade growth suppressors and sustain proliferative signaling resulting in uncontrolled growth. The AMPK pathway, a catabolic via to economize ATP, has been associated with cancer. AMPK activation is related to cancer progression in advanced stages, while its activation by metformin or phenformin is associated with cancer chemoprevention. Thus, the role of the AMPK pathway in cancer growth modulation is not clear. Saccharomyces cerevisiae might be a useful model to elucidate AMPK participation in growth regulation since it shares a highly conserved AMPK pathway. Therefore, this work is aimed at evaluating the role of the AMPK pathway on S. cerevisiae growth under different nutritional conditions. Herein, we provide evidence that the SNF1 gene is necessary to maintain S. cerevisiae growth with glucose as a sole carbon source at every concentration tested. Resveratrol supplementation inhibited the exponential growth of snf1∆ strain at low glucose levels and decreased it at high glucose levels. SNF1 gene deletion impaired exponential growth in a carbohydrate concentration-dependent manner independently of nitrogen source or concentration. Interestingly, deletion of genes encoding for upstream kinases (SAK1, ELM1, and TOS3) also had a glucose dose-dependent effect upon exponential growth. Furthermore, gene deletion of regulatory subunits of the AMPK complex impacted exponential growth in a glucose-dependent manner. Altogether, these results suggest that the SNF1 pathway affects the exponential growth of S. cerevisiae in a glucose-dependent manner.