Significant Growth Delay Research Articles

Post-Discharge Growth Among Extremely Preterm Infants With or Without Bronchopulmonary Dysplasia.

This study aimed to evaluate whether bronchopulmonary dysplasia (BPD) and home respiratory care (HRC) after discharge, including home oxygen therapy (HOT) or home mechanical ventilation (HMV), were associated with the growth of extremely preterm infants. This secondary study uses data from a study on the infant and early childhood development survey of low-birth-weight infants in the Health, Labor, and Welfare Science Research. We enrolled 788 singleton extremely preterm infants appropriate for gestational age (GA). BPD was defined as the requirement of supplemental oxygen or respiratory support at 36 weeks corrected GA. We compared trends of anthropometric measurements from age 0 to 5 years among infants with non-BPD, BPD without HRC, and BPD with HRC. We obtained 4113 weight and length measurements. At age 0-5 years, the BPD with the HRC group weighed less and was shorter than the other two groups. Lower GA and BPD status were significantly associated with growth failure of weight at 3 and 5 years after adjustment for potential risk factors. Lower GA was significantly associated with growth failure of length at 3 and 5 years. Conversely, although BPD status was significantly associated with growth failure of length at 3 years, it was not at 5 years. Among extremely preterm infants, BPD with HRC was associated with a significant growth delay at 0-5 years compared with non-BPD and BPD without HRC. However, the effect of different severities of BPD on growth failure of length was attenuated with age.

Resistance to Cry14A family Bacillus thuringiensis crystal proteins in Caenornabditis elegans operates via the nhr-31 transcription factor and vacuolar-type ATPase pathway.

Bacillus thuringiensis (Bt) has been successfully used commercially for more than 60 years for biocontrol of insect pests. Since 1996, transgenic plants expressing Bt crystal (Cry) proteins have been used commercially to provide protection against insects that predate on corn and cotton. More recently, Bt Cry proteins that target nematodes have been discovered. One of these, Cry14Ab, has been expressed in transgenic soybean plants and found to provide significant protection against the soybean cyst nematode, Heterodera glycines. However, to date there has been no description of high-level resistance to any Cry14A family protein in nematodes. Here, we describe forward genetic screens to identify such mutants using the nematode Caenorhabditis elegans. Although non-conditional screens failed to identify highly resistant C. elegans, a conditional (temperature-sensitive) genetic screen identified one mutant, bre-6(ye123) (for Bt protein resistant), highly resistant to both Cry14Aa and Cry14Ab. The mutant comes at a high fitness cost, showing significant delays in growth and development and reduced fecundity. bre-6(ye123) hermaphrodites are only weakly resistant to copper intoxication, indicating that the mutant is not highly resistant to all insults. Backcrossing-whole genome sequencing was used to identify the gene mutated in ye123 as the nuclear hormone receptor nhr-31. RNAi, DNA rescue, and CRISPR analyses confirm that resistance to Cry14Aa intoxication in bre-6(ye123) is due to mutation of nhr-31 and was renamed nhr-31(ye123). As predicted for a mutation in this gene, nhr-31(ye123) animals showed significantly reduced expression of most of the subunits of the C. elegans vacuolar ATPase (vATPase). Mutants in the vATPase subunits unc-32 and vha-7 also show resistance to Cry14Aa and/or Cry14Ab. These data demonstrate that nhr-31 and the vATPase play a significant role in the intoxication of C. elegans by Cry14A family proteins, that reduction in vATPase levels result in high resistance to Cry14A family proteins, and that such resistance comes at a high fitness cost. Based on the relative difficulty of finding resistant mutants and the fitness cost associated with the vATPase pathway, our data suggest that transgenic Cry14Ab plants may hold up well to resistance by nematode parasites.

Nurture growth: Ketogenic diet therapy and growth velocity in infants under 12 months with epilepsy − A systematic review and infant data study

Ketogenic diet therapy (KDT) is well established for the treatment of early epileptic encephalopathies and specific aetiologies; however, the impact on growth in infancy remains controversial. Our aim was to examine the influence of early KDT on growth velocity and height percentiles completing two tasks. First, we systematically reviewed the literature on growth in infants younger than 12 months. Second, we analysed data from our prospective database, including infants <12 months (n = 63) treated with KDT. The literature review (n = 7) remains descriptive and includes growth percentiles and z-scores as growth velocity was not described. Studies up to 2010 used fasting, calorie restrictions, and ratios >3:1. In individual cases, significant growth delays were found; other authors did not find any changes in growth parameters. Study endpoints in our own cohort included z-scores of growth velocity, standard deviation (SD) of height, weight, BMI, deviation from individual height percentile, and daily macronutrient intake. The median z-score of growth velocity was 1.03 (first year of life). After three months, median daily intake of protein and energy was 1.68 g/kg and 85 kcal/kg. Until the age of one year, neither growth velocity nor individual growth percentiles decreased. Infants showed distinct growth improvements at three months, likely due to continuous nutritional monitoring and reduction in seizures. In the second year of life, z-scores of growth velocity decreased in patients still receiving KDT (from 1.03 at 12 months to −1.5 at 24 months). Furthermore, younger age at epilepsy onset and at KDT start correlated with slower growth velocities in the first year of life.With appropriate nutritional intake and monitoring, KDT does not reduce growth in the first year of life. Future directions might be to study the impact of KDT on growth velocity and growth hormones throughout childhood.

Exopolysaccharides of lactic acid bacteria as protective agents against bacterial and viral plant pathogens

In this study, 25 exopolysaccharides produced by lactic acid bacteria (LAB) were screened for their effect on plant pathogens. The molecular masses of EPS were found to be 3,8-5,0 × 104 Da. The GC–MS analysis revealed that EPSs were majorly composed of glucose (85.85–97.98 %). The FT-IR spectra of EPSs were in agreement with the typical absorption peaks of polysaccharides. EPSs showed a hydroxyl radical scavenging ability. The scavenging rate of EPS ranged from 20 to 50 % at a concentration of 5.0 mg/mL. Significant growth delay of phytopathogenic bacteria was observed after 3–6 h of cultivation. Optical density values of indicator cultures growing in the medium with EPS (1 mg/mL) were lower compared to the control by 24–100 % for Pseudomonas fluorescens, 9–46 % for P. syringae, 47–79 % for Pectobacterium carotovorum, 14–90 % for Clavibacter michiganensis, 9–100 % for Xantomonas campestris, and 45–100 % for X. vesicatorium. EPS retained their inhibitory effect on the growth of X. campestris, X. vesicatorium and C. michiganensis strains after 24–48 h of cultivation, but stimulating effect on the growth of some strains also was observed. LAB EPS showed antibiofilm activity against P. carotovorum, P. syringae, and P. fluorescent, decreasing their biofilm formation by 16–50 %, 14–39 %, and 29–59 %, respectively. Also, stimulation of biofilm formation by X. campestris (by 8–29 %), X. vesicatorium (by 3–32 %) and C. michiganensis (by 31–41 %) strains was observed. EPSs showed antiviral activity against tobacco mosaic virus (TMV). At a concentration of 100 μg/mL, they decreased the infective ability of TMV by 61–92 %. This is the first study demonstrating that LAB EPS exhibited in vitro antibacterial and antibiofilm activity against phytopathogenic bacteria and anti-viral activity against TMV. Thus, LAB EPSs could have great potential for plant protection strategies.

The arginine transporter Can1 negatively regulates biofilm formation in yeasts.

The arginine transporter Can1 is a multifunctional protein of the conventional yeast Saccharomyces cerevisiae. Apart from facilitating arginine uptake, Can1 plays a pivotal role in regulating proline metabolism and maintaining cellular redox balance. Here, we report a novel function of Can1 in the control of yeast biofilm formation. First, the S. cerevisiae CAN1 gene knockout strain displayed a significant growth delay compared to the wild-type strain. Our genetic screening revealed that the slow growth of the CAN1 knockout strain is rescued by a functional deficiency of the FLO8 gene, which encodes the master transcription factor associated with biofilm formation, indicating that Can1 is involved in biofilm formation. Intriguingly, the CAN1 knockout strain promoted the Flo11-dependent aggregation, leading to higher biofilm formation. Furthermore, the CAN1 knockout strain of the pathogenic yeast Candida glabrata exhibited slower growth and higher biofilm formation, similar to S. cerevisiae. More importantly, the C. glabrata CAN1 gene knockout strain showed severe toxicity to macrophage-like cells and nematodes. The present results could help to elucidate both the molecular mechanism underlying yeast biofilm formation and the role it plays. Future investigations may offer insights that contribute to development of antibiofilm agents.

Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics

BackgroundDespite recent advances in immunotherapy, a substantial population of late-stage melanoma patients still fail to achieve sustained clinical benefit. Lack of translational preclinical models continues to be a major challenge...

Lonidamine Induced Selective Acidification and De-Energization of Prostate Cancer Xenografts: Enhanced Tumor Response to Radiation Therapy.

Prostate cancer is a multi-focal disease that can be treated using surgery, radiation, androgen deprivation, and chemotherapy, depending on its presentation. Standard dose-escalated radiation therapy (RT) in the range of 70-80 Gray (GY) is a standard treatment option for prostate cancer. It could be used at different phases of the disease (e.g., as the only primary treatment when the cancer is confined to the prostate gland, combined with other therapies, or as an adjuvant treatment after surgery). Unfortunately, RT for prostate cancer is associated with gastro-intestinal and genitourinary toxicity. We have previously reported that the metabolic modulator lonidamine (LND) produces cancer sensitization through tumor acidification and de-energization in diverse neoplasms. We hypothesized that LND could allow lower RT doses by producing the same effect in prostate cancer, thus reducing the detrimental side effects associated with RT. Using the Seahorse XFe96 and YSI 2300 Stat Plus analyzers, we corroborated the expected LND-induced intracellular acidification and de-energization of isolated human prostate cancer cells using the PC3 cell line. These results were substantiated by non-invasive 31P magnetic resonance spectroscopy (MRS), studying PC3 prostate cancer xenografts treated with LND (100 mg/kg, i.p.). In addition, we found that LND significantly increased tumor lactate levels in the xenografts using 1H MRS non-invasively. Subsequently, LND was combined with radiation therapy in a growth delay experiment, where we found that 150 µM LND followed by 4 GY RT produced a significant growth delay in PC3 prostate cancer xenografts, compared to either control, LND, or RT alone. We conclude that the metabolic modulator LND radio-sensitizes experimental prostate cancer models, allowing the use of lower radiation doses and diminishing the potential side effects of RT. These results suggest the possible clinical translation of LND as a radio-sensitizer in patients with prostate cancer.

Abstract 6034: PSMA targeted alpha radiopharmaceutical [211At]PSAt-3 inhibits tumor growth in a preclinical model of prostate cancer

Abstract Introduction: Prostate cancer continues to be a highly prevalent cancer diagnosis among men and a leading cause of cancer related deaths worldwide. With the introduction[177Lu]Lu-PSMA-617, targeted radionuclide therapy has proven successful in increasing survival time for patients with metastasized castration resistant prostate cancer. However, despite encouraging results, such patients tend to develop progressive disease, and thus, enhanced efficacy is warranted. To this end, the use of radiopharmaceuticals harnessing alpha-emitters is a promising venue due to the potent energy deposition and short range of alpha particles in tissue. Here, we employ the PSMA targeting vector, [211At]PSAt-3, for targeted alpha radionuclide therapy in a preclinical prostate cancer model. Methods: [211At]PSAt-3, a structural derivative of PSMA-617, in which the L-2-naphtylalanine was replaced by L-3-[211At]astato-phenylalanine, was obtained by electrophilic [211At]astatodesilylation. Evaluation of [211At]PSAt-3 was conducted in male inbred nude mice of Balb/c background xenografted subcutaneously with human prostate cancer cells (LNCaP). Prior biodistribution studies were carried out with approximately 100 kBq intravenous injections, and subsequent biodistribution 2, 6 and 24h post injection (P.I.). For establishment of therapeutic effect, a single intravenous dose of [211At]PSAt-3 was administered. To asses hematological toxicity, blood cell composition was assessed weekly. Results: Favorable tumor uptake of 15.2±6 %ID/g was observed 2h after injection of [211At]PSAt-3 in LNCaP xenografted nude mice, with subsequent 9±5.1% ID/g and 6.4±2.4% ID/g 6 and 24h P.I., respectively. [211At]PSAt-3 cleared mainly by the kidneys, in which uptake was 72, 38 and 6% ID/g at 2, 6 and 24h P.I., respectively. Thyroid/throat uptake remained low at ~0.1% ID for all timepoints investigated, indicating a low degree of de-astatination. Initial efficacy studies using a single intravenous dose of 0.5 MBq (~20 MBq/kg) demonstrated significant growth delay and tumor volume reduction compared with control mice (saline). Blood platelet count was reduced after administration of [211At]PSAt-3 and subsequently recovered. No signs of severe toxicity, and no significant weight loss between control and treated mice was observed, suggesting that the treatment is well tolerated. Conclusion: 0.5 MBq [211At]PSAt-3 was well tolerated in mice and demonstrated tumor volume reduction and significant delay of tumor growth. These findings suggest [211At]PSAt-3 as a promising candidate for clinical translation. Citation Format: Lars Hvass, Marius Müller, Anne Clausen, Matthias Herth, Andreas Kjaer. PSMA targeted alpha radiopharmaceutical [211At]PSAt-3 inhibits tumor growth in a preclinical model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6034.

Effect of anti-epileptic drugs usage on thyroid profile in Egyptian epileptic children

BackgroundThe long-term use of anti-seizure medications (ASMs) adversely affects thyroid, lipid profile and other metabolic functions. Subclinical hypothyroidism and alterations in thyroid hormone serum levels are reported with older ASMs in adults with limited and conflicting data of the influence of ASMs especially newer one on thyroid function in children. This study aimed to investigate the effects of conventional and newer ASMs whether mono or polytherapy on thyroid profile in children with epilepsy and its impact on lipid profile and metabolic functions.ResultsThis study included 155 children with epilepsy (76 on monotherapy and 79 on polytherapy) with mean age of 9.677 ± 3.981 years (54.84% euthyroid, 31.61% hypothyroid, 9.68% subclinical hyperthyroid and 3.87% subclinical hypothyroid) and 78 healthy controls. Children with epilepsy whether on monotherapy or on polytherapy had a statistically significant thyroid profile abnormalities (hypothyroidism, sub-clinical hypothyroidism or sub-clinical hyperthyroidism), dyslipidemia, delayed growth and increase in DBP compared to control group. There was a statistically significant positive correlation between hypothyroidism and dyslipidemia as well as between hypothyroidism and delayed growth and increase in DBP. There was no statistically significant difference between polytherapy and monotherapy regarding thyroid and lipid parameters but children with epilepsy on polytherapy were associated with more statistically significant delay in growth and increase in DBP compared to monotherapy group. Carbamazepine had a statistically significant association with hypothyroidism, increase in DBP and higher total and LDL-cholesterol. Valproic acid had a statistically significant association with sub-clinical hypothyroidism with a positive dose correlation. Levetiracetam (LEV) was associated with a statistically significant lower HDL-cholesterol. All echocardiography data showed no abnormality.ConclusionASMs whether older or newer generations can affect thyroid and lipid profile differently through different mechanisms that are dose and duration dependent regardless of the seizure type and age of the patient. ASMs mainly conventional ones are associated with hypothyroidism, sub-clinical hypothyroidism, sub-clinical hyperthyroidism, dyslipidemia and consequently delayed growth and diastolic blood pressure abnormalities.

Effect of ammonia addition on nanostructure of soot in laminar coflow diffusion flames of ethylene diluted with nitrogen

The effect of ammonia addition on the nanostructure of soot particles was studied experimentally for ethylene diffusion flames. To compensate the thermal effect and nitrogen-containing species production when ammonia was added, the total mole fraction of ammonia and nitrogen was fixed in the fuel stream. Soot particle size, fringe length, and fringe tortuosity were measured through transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HRTEM). A complementary X-ray photoelectron spectroscopy (XPS) analysis provided information about the chemical bonding of soot. A significant delay in soot growth was observed and the particle size increased with the addition of ammonia. While there was no obvious correlation between the fractal dimension of soot and ammonia mole fraction (XNH3) or sampling location. With the addition of ammonia, the mean fringe length increased reasonably linearly with XNH3 and the fringe tortuosity increased up to XNH3 ≈ 0.17 and then decreased with XNH3, which suggested that ammonia addition led to higher graphitization and lower oxidative activity. The soot from ammonia diluted flame exhibited lower reactivity, implying the delay of soot surface growth. With the addition of ammonia, the value of sp2/sp3 (indication of the graphitization degree of soot particles) did not change much for XNH3 from 0 to 0.17 then increased significantly, which indicated the degree of graphitization of soot particles significantly increased with ammonia addition. The intensity of the N1s peak (indication of the N-containing species in soot) increased with the addition of ammonia. This study confirmed that the addition of NH3 promotes the graphitization of soot.

Impact of PpSpi1, a glycosylphosphatidylinositol-anchored cell wall glycoprotein, on cell wall defects of N-glycosylation-engineered Pichia pastoris.

Engineering of biological pathways in various microorganisms is a promising direction for biotechnology. Since the existing microbial cells have evolved over a long period of time, any artificial engineering may cause some unexpected and harmful effects on them. Systematically studying and evaluating these engineered strains are very important and necessary. In order to produce therapeutic proteins with human-like N-glycan structures, much progress has been achieved toward the humanization of N-glycosylation pathways in yeasts. The properties of a P. pastoris strain with humanized N-glycosylation machinery were carefully evaluated in this study. Our work has identified a key glycoprotein (PpSpi1) responsible for the poor growth and morphological defects of this glycoengineered strain. Overexpression of PpSpi1 could significantly rescue the growth defect of the glycoengineered P. pastoris and facilitate its future industrial applications.

Sustainable extraction of polyphenols from vine shoots using deep eutectic solvents: Influence of the solvent, Vitis sp., and extraction technique

Vine shoots are the main by-products of grapevine pruning with no added value. In the present study, deep eutectic solvents (DESs) were used as alternatives to traditional chemical solvents, for the extraction of phytochemicals from grapevine shoots. Three levulinic acid-based DESs were tested for the first time, and their performance was compared to methanol (a standard chemical solvent) regarding the extraction of phenolic compounds from thirteen Vitis sp. shoots. Two extraction methods have been applied: ultrasound-assisted extraction and solid-liquid extraction. A total of eleven polyphenols which belongs to four families (proanthocyanins, stilbenes, hydroxycinnamic acids, and flavonols) have been identified and quantified in the extracts.The statistical analysis shows that the levulinic acid-based DES systems are novel and important alternatives to chemical solvents due to favourable eco-friendly properties and remarkable extraction performance of polyphenols. On the other hand, the ultrasound-assisted extraction technique has significantly increased the extraction rate in comparison to the solid-liquid extraction method with p-values lower than 0.05 for most compounds. The genetic factor has been shown to play an important role in the content of extracted polyphenols, being V. riparia pubescente the one that presented the highest concentrations of extracted polyphenols. Finally, the polyphenol-enriched extracts have proven important properties such as antioxidant activity and significant delay in bacteria growth against both gram-positive and gram-negative bacteria. It is important to note that, to the best of our knowledge, this is the first time that deep eutectic solvents have been used for the extraction of bioactive compounds from vine shoot residues.

Abstract 1012: Detecting and intervening on rare pre-existing resistant subclones to BRAF/MEK inhibitors in metastatic melanoma

Abstract The combination of BRAF and MEK inhibitors (BRAFi/MEKi) in metastatic melanoma patients with BRAF activating mutations have resulted in dramatic responses in most patients, but unfortunately most patients progress after one year and limited subsequent treatment options are available. Although resistance mutations to BRAFi/MEKi mainly occur in the MAPK and PI3K pathways, after progression on BRAFi/MEKi drugs, targeting these mutations have been clinically unsuccessful. One possible cause of relapse is that a resistant subpopulation to BRAFi/MEKi exists prior to treatment, raising the possibility that earlier counter-resistance treatment could be administered and potentially be more successful. However, the prevalence and clinical significance of pre-existing resistance is currently unknown in melanoma. To address this, we used quantitative blocker displacement amplification (qBDA) to quantify the VAF (down to 0.01% resolution) of resistant subclones along the MAPK/PI3K pathways from FFPE biopsies on 149 metastatic melanoma patients. Due to possible intra-tumoral heterogeneity, multiple samples were taken when available per patient. Of 29 patients currently processed, 5/29 (17%) had detectable NRAS Q61L or Q61R, 5/29 (17%) had KRAS G12 or G13 mutations, and 3/29 (10.3%) had PIK3CA H1047R/Y. As expected, BRAF activating mutations were detectable in 29/29 patients, while VAF of the resistant subclones were found to be as low as 0.16%. We expect some of the putative resistance mutations to be artifacts, and all will be validated by ddPCR. To model the behavior of low-VAF resistance mutations, we conducted in vitro spike-in experiments using paired and labeled parental and BRAF/MEK inhibitor-resistant melanoma lines. Our results show that even down to 0.1%, the resistant lines can rapidly emerge as the dominant population while under drug treatment. We also tested the timing of applying a counter-resistance therapy: early vs late. Earlier intervention led to a significant delay in growth of the resistant population, as expected. However, we are currently preparing an experiment that will determine whether an earlier intervention might not simply delay resistance, but also alter its strength, at different % VAFs. We therefore anticipate mechanistic analyses of how %VAF and drug timing can optimize counter-resistance therapies. Overall, our interim data suggest a significant percentage of metastatic BRAF-mutated melanoma patients may harbor pre-existing resistant subclones, and that early treatment with counter-resistance therapy can potentially delay resistance to targeted therapy. Citation Format: Michael Nakazawa, Lauren Cheng, Mishal Ahmed, Rossana Lazcano, Khalida Wani, Omid Veiseh, Lawrence Kwong. Detecting and intervening on rare pre-existing resistant subclones to BRAF/MEK inhibitors in metastatic melanoma [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 1012.

Abstract 4128: AJ17 potentiates agonist CD40 antibody efficacy and attenuates agonist CD40 induced PD-L1 expression and associated toxicity in murine tumor models

Abstract Agonist CD40 antibody (αCD40) has shown excellent anti-tumor efficacy in both pre and early clinical studies. However, in clinics, αCD40 has failed to prove its potential as αCD40 is associated with dose-limiting toxicity due to cytokine release syndrome (CRS), grade 3 to 4 hematological and liver toxicities. In addition, αCD40 induces immune checkpoint proteins (PD-L1, CTLA-4) which makes the tumor microenvironment (TME) immunosuppressive. In this context, this study investigates the therapeutic efficacy of a novel combination of αCD40 and AJ17, a small molecule inhibitor of receptor tyrosine kinase. Combination treatment showed a significant delay in the tumor growth and improved overall survival in mice bearing B16-F10 melanoma and 4T1 orthotopic tumor by increasing the population of CD8+ T cells and lowering the expression of PD-L1, Foxp3+, and arginase in both tumor and spleen. Most interestingly, AJ17 lowered the in vivo toxicity associated with αCD40 monotherapy by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and IL-6 in serum. In conclusion, this combination can be further explored in clinics to improve the in vivo anti-tumor efficacy of αCD40 while lowering the associated toxicity. Citation Format: Vidit Gaur, Anjali Barnwal, Bushra Ateeq, Jayanta Bhattacharyya. AJ17 potentiates agonist CD40 antibody efficacy and attenuates agonist CD40 induced PD-L1 expression and associated toxicity in murine tumor models. [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 4128.

Оцінка ризику розвитку соматотропної недостатності залежно від розподілу частот алелей і генотипів поліморфного локусу rs1544410 BsmI гена рецептора вітаміну D

Growth hormone deficiency (GHD) is a disease caused by a significant disturbance in the growth hormone (GH) /growth factor system, it occures as a result of various hereditary or acquired causes and is characterized, first of all, by a significant delay in the child's growth and physical development. GHD can be isolated or combined with deficiency of other adenohypophysis hormones. The presence of a relationship between the GH /growth factor system and vitamin D (vit D) determines the involvement of genetic changes in the vit D receptor (VDR) in the pathogenesis of GHD. Purpose - to assess the risk of developing GHD based on the investigation of the distribution of allele frequencies and genotypes of the polymorphic locus rs1544410 BsmI of the VDR gene. Materials and methods. The determination of VDR BsmI gene (rs1544410) polymorphism was performed using the polymerase chain reaction method, followed by analysis of the length of restriction fragments upon their detection by agarose gel electrophoresis in 22 prepubertal children with GHD. The serum 25-hydroxycalciferol (25(OH)D) level was determined by immunochemiluminescent method on microparticles (Abbott, USA). Results. G/A allele was most often found in children with isolated GHD and multiple pituitary insufficiency (MPH) (43.8% and 83.3%, respectively). In the presence of G/A and G/G genotypes, the risk of GHD is reliably high: OR=3.60 (95% CI 1.40-9.23); OR=10.69 (95% CI 2.34-48.85) respectively; with the A/A genotype variant the risk of GHD is reliably low OR=0.11 (95% CI 0.04-0.33). Carrying the G allele of the polymorphic locus rs1544410 Bsm I of the VDR gene is associated with the risk of developing GHD OR=5.58 (95% CI 4.51-6.90; p&lt;0.001). A significantly difference in the peak GH release was established in patients carrying the G/G and A/A, G/G and G/A alleles. 83.33% of children with MPH and 68.49% with isolated GHD had hypovitaminosis D. Vit D deficiency was recorded in carriers of all three types of alleles. Conclusions. In the presence of G/A and G/G genotypes, the risk of GHD increases, in the presence of the A/A genotype, it decreases. The G allele carrier of the polymorphic locus rs1544410 Bsm I of the VDR gene is associated with the risk of developing GHD OR=5.58 (95% CI 4.51-6.90; p&lt;0.001), despite the ideal distribution of genotypes. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Sifrim-Hitz-Weiss/CHD4-related syndrome: A new case report.

Sifrim-Hitz-Weiss/CHD4-related syndrome: A new case report.

Abstract 6353: Metabolic changes in the spleen and pancreas induced by PDAC xenografts with or without glutamine transporter downregulation

Abstract Introduction: Our ongoing studies are focused on characterizing metabolic changes induced in the organs of mice with cachexia-inducing Pa04C human pancreatic cancer xenografts. Because pancreatic cancer cells are glutamine dependent [1], we downregulated the glutamine transporter SLC1A5 in Pa04C cells to determine if metabolic changes induced in the spleen and pancreas by Pa04C tumors were normalized when SLC1A5 was downregulated in these tumors. Metabolic patterns were characterized using high-resolution quantitative 1H magnetic resonance spectroscopy (MRS) of spleen and pancreas tissue obtained from normal mice and mice with Pa04C tumors and mice with Pa04C tumors with SLC1A5 downregulated. Method: Patient derived cachexia-inducing Pa04C pancreatic cancer cells were lentivirally transduced to express shRNA to stably downregulate SLC1A5. Mice were euthanized once tumors were ~500 mm3, the spleen and pancreas were excised and snap frozen. Snap frozen spleen (normal n= 5, Pa04C n= 11, Pa04C_SLC1A5 n= 10) and pancreas (normal n= 4, Pa04C n= 16, Pa04C_SLC1A5 n= 10) tissue samples were pulverized for dual phase extraction. The aqueous phase was used for 1H MRS analysis. Topspin 3.5 software was used for data processing and analyses. Results and Discussion: Significant downregulation of SLC1A5 mRNA and protein was confirmed in Pa04C_SLC1A5 cells and tumors. SLC1A5 downregulation resulted in significant growth delay and attenuation of weight loss. A comparison of normal mice vs empty vector/wild type tumor (EV/WT) bearing mice identified significant changes in succinate, aspartate and fumarate in the spleen, lactate, acetate, pyruvate, methionine, asparagine, creatine, choline phosphocholine, uracil, histidine and phenylalanine in the pancreas, with leucine, isoleucine, valine, alanine, glutamate, glutamine, glutathione, glycerophosphocholine, glycine, glucose and tyrosine commonly altered in the spleen and pancreas. A comparison of normal vs Pa04C_ SLC1A5 tumor bearing mice identified similar metabolic changes in the spleen and pancreas but these were reduced. Fumarate did not change in the spleen, and of the metabolic changes common to spleen and pancreas, glutamine did not change when tumor SLC1A5 was downregulated. Metabolite changes induced only in the pancreas were also similar to normal vs EV/WT with the exception of a change in glutamine with SLC1A5 downregulation and no change in lactate. Our data highlight the profound metabolic changes in spleen and pancreas metabolism that occur with growth of a cachexia-inducing pancreatic cancer xenograft, and the impact on these metabolic patterns as a result of downregulating the glutamine transporter in these cancer cells. The metabolic patterns identified in the spleen and pancreas may provide novel targets to reduce the morbidity from cachexia. Reference: 1. Son J et al, Nature. 2013;496(7443):101-5. Citation Format: Raj Kumar Sharma, Santosh Kumar Bharti, Balaji Krishnamachary, Yelena Mironchik, Paul Winnard Jr., Marie-France Penet, Zaver M. Bhujwalla. Metabolic changes in the spleen and pancreas induced by PDAC xenografts with or without glutamine transporter downregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6353.

Abstract 1794: The combination of Talazoparib with anti-her2 drugs shows efficacy in drug resistant Her2+ and low Her2 PDX models

Abstract Background: Her2+ breast cancer accounts for 15% of breast cancer cases and is primarily treated with a combination of Her2-targeted agents and chemotherapy. While use of targeted agents has substantially improved survival of these patients, clinical drug resistance is prevalent. DNA repair defects are a feature of cancer that has been exploited by targeted agents such as inhibitors of poly-ADP ribose polymerase (PARP). PARP inhibitors have been shown to be effective in patients with germline mutations in other DNA repair factors such as BRCA1/2. There is limited data for the use of PARP inhibitors in HER2+ breast cancers, and in tumors without BRCA1/2 mutations. Using a collection of HER2+ and HER2-low expressing breast cancer patient-derived xenografts (PDXs) that have differential responses to the Her2-targeted agents Trastuzumab, Pertuzumab, and T-DM1, we tested the combination of these agents with Talazoparib (Talzenna™), a clinically approved Parp inhibitor. Methods: Orthotopically engrafted PDX mouse models resistant to either Trastuzumab or T-DM1 were randomized into treatment arms including Trastuzumab or T-DM1 in combination with Talazoparib, and the single agents alone. Mice are monitored for body weight and change in tumour volume every 2-3 days, then sacrificed at endpoint for survival analysis. We have also generated PDX-derived cells (PDCs) from one model with which to validate in vivo results and perform mechanistic studies. All models are being characterized for copy number changes, somatic mutations, and protein expression by immunohistochemistry. Results: The combination of Talazoparib and either Trastuzumab or T-DM1 was effective in 3 PDX models, including a Trastuzumab-resistant HER2+ PDX, a T-DM1-resistant HER2+ PDX and a T-DM1-resistant HER2-low expressing PDX. The combinations resulted in significant delays in tumour growth (p&amp;lt;0.05), including a transient tumour regression with the combination T-DM1+Talazoparib in 1 PDX. Median overall survival time was improved with the combination of Trastuzumab +Talazoparib (p&amp;lt;0.05), while the combinations of T-DM1+Talazoparib increased survival time although not significantly. Notably all models have maintained Her2 expression through treatment. Conclusion: Our results suggest that combining HER-targeted agents with Talazoparib may benefit patients with advanced HER2-therapy resistant HER2+ and low HER2+ breast cancers. Exploratory biomarker analysis and mechanistic studies using PDCs are currently underway in our laboratory. Citation Format: Kathryn Bozek, Marguerite Buchanan, Cathy Lan, Josiane Lafleur, Cedric Darini, Urszula Krzemien, Adriana Aguilar-Mahecha, Mark Basik. The combination of Talazoparib with anti-her2 drugs shows efficacy in drug resistant Her2+ and low Her2 PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1794.

Frost Delay of a Water-Absorbing Surface with Engineered Wettability via Nonfreezing Water.

Frost is common when a solid surface is subjected to a humid and cold environment. It can cause various inconveniences, complications, or fatal accidents. Water-repellent surfaces have demonstrated an antifreezing capability by enabling the water droplets to roll or bounce off before they freeze. However, these surfaces are often limited by their inability to shed the small water condensates, which can eventually grow and freeze. Recently, surfaces that can rapidly absorb and hydrogen bond with these water condensates have demonstrated significant delay in frost formation and growth. This is attributed to a lower freezing temperature of the absorbed water which makes it stay in a nonfreezing state. Herein, we report a surface with preferential wettability of water over oil (i.e., superhydrophilic and oleophobic wettability) that can significantly delay frost formation. The surface is fabricated by copolymerizing poly(ethylene glycol) diacrylate (PEGDA) and perfluorinated acrylate (1H,1H,2H,2H-heptadecafluorodecyl acrylate, HDF-acrylate) applied to a silane-grafted glass substrate (HDF-PEGDA). An HDF-PEGDA surface can quickly absorb condensed water which enables it to delay frost formation and growth for up to 20 min at a surface temperature of -35 °C. Also, the surface demonstrates that its frost-resistant capability remains almost unaffected even after being submerged in an oil bath due to its in-air oil repellency. Differential scanning calorimetry (DSC) measurements reveal that the significant quantity of absorbed water in an HDF-PEGDA surface remains in a nonfreezing state with a Tm value as low as -33 °C. A mathematical model that can predict the time at which the surface begins to be covered with frost is developed. Finally, an HDF-PEGDA is layered with a PEGDA copolymerized with sodium acrylate (Na-acrylate) that enables the continuous release of the absorbed water by posing forward osmotic pressure and regeneration of an HDF-PEGDA surface.

Antifungal properties of hybrid films containing the essential oil of Schinus molle: Protective effect against postharvest rot of tomato

The control of postharvest diseases in tomatoes using hybrid films represents an efficient and inexpensive alternative to avoid economic losses. This work reports on the design, characterization, and in situ application of hybrid films containing chitosan combined with the leaf essential oil of Schinus molle (SmEO) as antifungal agents. These materials were tested in situ on Lycopersicon esculentum cv. uva showing symptoms of soft rot caused by Fusarium oxysporum . According to our analytical conditions, SmEO contained β-phellandrene (15.7%), α-phellandrene (12.1%), elemol (9.1%), apiole (6.4%) and camphene (6.2%) as the most abundant volatiles. Four distinct hybrid films were prepared from 1% chitosan combined with different amounts of SmEO (0.05, 0.1, 0.3 and 0.7% w/v ) to generate four hybrid films named FSm1, FSm2, FSm3 and FSm4. The spectroscopic properties (FT-IR), texture and thickness (SEM), and optical properties (transmittance) of these films revealed that FSm3 and FSm4 had the best physicochemical and in situ antifungal properties to avoid conidial germination and mycelial proliferation of F. oxysporum . The fruits treated with films and essential oil showed a statistically significant delay (>50%) in mycelial growth compared with the control groups (p < 0.05) and a substantial decrease in conidial viability over 6 days (<2%). According to our results, FSm3 and FSm4 significantly avoided the in situ growth of F. oxysporum in tomatoes. Interestingly, all of the films significantly improved fruit firmness in comparison with untreated tomatoes (p < 0.05). The properties of the films reported in this work may improve the shelf life of Lycopersicon esculentum cv. uva. • Films based on chitosan and the essential oil from Schinus molle improved tomato quality. • The physicochemical properties of films suggested their potential use a new fruit barrier. • In situ testes revealed that films delayed the mycelial proliferation of F. oxysporum. • Same tests revealed that films avoided the germination of fungal conidia.