Releasing Hormone Research Articles

Network Pharmacology and Validation of the Combinative Therapy of Ligusticum striatum DC. and Borneolum against Cerebral Ischemia

Background: Ligusticum striatum DC. (LDC) is often prescribed for Cerebral Ischemia (CI) and is commonly combined with Borneolum (BO) to enhance therapeutic outcomes. However, its specific active ingredients and underlying mechanisms remain unclear. Objective: This study aimed to identify the active ingredients and mechanisms of LDC and BO combination therapy against CI using network pharmacology, molecular docking, and in vivo experiments. Methods: Potential active ingredients and targets were sourced from relevant databases, and a drug-component-target-disease network was constructed to pinpoint key ingredients. Subsequently, a protein-protein interaction analysis was conducted to confirm the key targets. Following enrichment analyses of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), molecular docking was employed to evaluate binding energies. Finally, the therapeutic effects and mechanisms of the combination against CI were validated through in vivo experiments using male ICR mice Results: Venn analysis identified a total of 41 components and 292 potential targets. The drugcomponent-target-disease network revealed that the key components in LDC were palmitic acid, tetramethylpyrazine, and (Z)-ligustilide, while those in BO were (+)-borneol, β-elemene, and (-)- borneol. The PPI analysis highlighted seven crucial targets. Docking results confirmed a stable affinity between these components and their targets. KEGG enrichment analysis indicated that the mechanism involved the PI3K/AKT signaling pathway. Subsequently, in vivo experiments confirmed that the combination ameliorated abnormal hippocampus morphology and reduced the release of inflammatory factors through the activation of the PI3K/AKT signaling pathway Conclusion: The combination of LDC and BO markedly improved CI and inhibited inflammation response via activating the PI3K/AKT pathway

A Pharmacological Overview of Degarelix and Relugolix in Advanced Prostate Cancer

Prostate cancer (PCa) ranks the second most diagnosed cancers among men globally and the sixth leading cause of cancer-related deaths. Advanced prostate cancer can be defined as the recurrence after definitive therapies (radical prostatectomy or external beam radiotherapy) and de novo metastasis (metastasis without prior treatment). Advanced PCa can be categorized as metastatic hormone sensitive prostate cancer (mHSPC), non-metastatic castration resistant prostate cancer (nmCRPC), and metastatic castration resistant prostate cancer (mCRPC). Management of advanced PCa often involves castration to reduce testosterone levels, which can be achieved by gonadotropin releasing hormone antagonists such as degarelix and relugolix. Degarelix is injectable while relugolix is an orally administered form of GnRH antagonist. This review aims to explore the latest pharmacological aspects of these drugs to inform treatment decisions for advanced PCa.

Effect of Alpha Hydroxy Acids as Dentin Conditioning Agents on Growth Factor Release: An In Vitro Study

Effect of Alpha Hydroxy Acids as Dentin Conditioning Agents on Growth Factor Release: An In Vitro Study

Advances in Diagnostic Modalities for Helicobacter pylori Infection

Helicobacter pylori (H. pylori) infection is a widespread global health issue with a varying prevalence influenced by geography, socioeconomic status, and demographics. In the U.S., the prevalence is lower, though certain groups, such as older adults and immigrants from high-prevalence regions, show higher rates. The decrease in infection rates in developed countries is due to improved sanitation, antibiotics, and healthcare, whereas developing countries continue to experience high rates due to poor living conditions. H. pylori infection can be asymptomatic or cause symptoms like dyspepsia, abdominal pain, bloating, nausea, and loss of appetite. Pathophysiologically, H. pylori contribute to conditions such as gastritis, peptic ulcers, and gastric cancer through mechanisms including urease production and the release of virulence factors, leading to chronic inflammation and an increased cancer risk. Diagnostic methods for H. pylori have progressed significantly. Non-invasive techniques, such as serological assays, stool antigen tests, and urea breath tests, are practical and sensitive. Invasive methods, including endoscopic biopsy and molecular diagnostics, are more definitive but resource intensive. Recent advancements in diagnostic technology, including matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), biosensor technology, and next-generation sequencing (NGS), promise improved speed, accuracy, and accessibility. These innovations are expected to enhance the detection and management of H. pylori, potentially reducing the global disease burden. This review aims to discuss these diagnostic modalities with a focus on further advances under investigation.

Kisspeptin in functional hypothalamic amenorrhea: Pathophysiology and therapeutic potential.

Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea, resulting in anovulation and infertility, and is a low estrogen state that increases the risk of cardiovascular disease and impairs bone health. FHA is characterized by acquired suppression of physiological pulsatile gonadotropin-releasing hormone (GnRH) release by the hypothalamus in the absence of an identifiable structural cause, resulting in a functional hypogonadotropic hypogonadism. FHA results from either decreased energy intake and/or excessive exercise, leading to low energy availability and weight loss-often in combination with psychological stress on top of a background of genetic susceptibility. The hypothalamic neuropeptide kisspeptin is a key component of the GnRH pulse generator, tightly regulating pulsatile GnRH secretion and the downstream reproductive axis. Here, we review the physiological regulation of pulsatile GnRH secretion by hypothalamic kisspeptin neurons and how their activity is modulated by signals of energy status to affect reproductive function. We explore endocrine factors contributing to the suppression of GnRH pulsatility in the pathophysiology of FHA and how hypothalamic kisspeptin neurons likely represent a final common pathway through which these factors affect GnRH pulse generation. Finally, we discuss the therapeutic potential of kisspeptin as a novel treatment for women with FHA.

N1-Methylpseudouridine and pseudouridine modifications modulate mRNA decoding during translation

The ribosome utilizes hydrogen bonding between mRNA codons and aminoacyl-tRNAs to ensure rapid and accurate protein production. Chemical modification of mRNA nucleobases can adjust the strength and pattern of this hydrogen bonding to alter protein synthesis. We investigate how the N1-methylpseudouridine (m1Ψ) modification, commonly incorporated into therapeutic and vaccine mRNA sequences, influences the speed and fidelity of translation. We find that m1Ψ does not substantially change the rate constants for amino acid addition by cognate tRNAs or termination by release factors. However, we also find that m1Ψ can subtly modulate the fidelity of amino acid incorporation in a codon-position and tRNA dependent manner in vitro and in human cells. Our computational modeling shows that altered energetics of mRNA:tRNA interactions largely account for the context dependence of the low levels of miscoding we observe on Ψ and m1Ψ containing codons. The outcome of translation on modified mRNA bases is thus governed by the sequence context in which they occur.

Macroporous PEG-Alginate Hybrid Double-Network Cryogels with Tunable Degradation Rates Prepared via Radical-Free Cross-Linking for Cartilage Tissue Engineering.

Trauma or repeated damage to joints can result in focal cartilage defects, significantly elevating the risk of osteoarthritis. Damaged cartilage has an inherently limited self-healing capacity and remains an urgent unmet clinical need. Consequently, there is growing interest in biodegradable hydrogels as potential scaffolds for the repair or reconstruction of cartilage defects. Here, we developed a biodegradable and macroporous hybrid double-network (DN) cryogel by combining two independently cross-linked networks of multiarm polyethylene glycol (PEG) acrylate and alginate.Hybrid DN cryogels are formed using highly biocompatible click reactions for the PEG network and ionic bonding for the alginate network. By judicious selection of various structurally similar cross-linkers to form the PEG network, we can generate hybrid DN cryogels with customizable degradation kinetics. The resulting PEG-alginate hybrid DN cryogels have an interconnected macroporous structure, high mechanical strength, and rapid swelling kinetics. The interconnected macropores in the cryogels support efficient mesenchymal stem cell infiltration at a high density. Finally, we demonstrate that PEG-alginate hybrid DN cryogels allow sustained release of chondrogenic growth factors and support chondrogenic differentiation of mouse mesenchymal stem cells. This study provides a novel method to generate macroporous hybrid DN cryogels with customizable degradation rates and a potential scaffold for cartilage tissue engineering.

Effect of repeated low doses of gonadotropin-releasing hormone on the secretion of luteinizing hormone and follicle-stimulating hormone, and ovarian function in dairy cows suffering from anovulation type I

The aim of the study was to evaluate the effect of repeated low doses of gonadotropin-releasing hormone (GnRH) agonist buserelin once a day for 5 days on follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release, and ovarian function in dairy cows with anovulation type I. The study was conducted on 10 anovulatory Polish Holstein-Friesian cows. Cows in Group 1 (n = 5) received 4 µg of buserelin intramuscularly. once a day for 5 days. Control cows from Group 2 (n = 5) received saline. Concentrations of progesterone, FSH, and LH in the blood were analysed using radioimmunoassay (RIA). Ovarian structures were monitored weekly after the end of treatment by ultrasound for 4 weeks. Injections of buserelin increased FSH and LH concentrations. Release of FSH and LH was largely variable, but there was significant (P < 0.001) interaction between time and treatment during all treatment days. The number of follicles in the treatment group was significantly greater (P = 0.029) than in the control group on day 5, the diameter of follicles on day 12 was also larger (P < 0.01) in treated than in control cows. Ovulation occurred in 4 of the 5 treated cows, but only in 1 of the control cows in the 40 days after treatment. In conclusion, repeated low doses of GnRH analogue buserelin once a day for 5 days may increase the concentration of FSH and LH in dairy cows with anovulation type I.

Pregnancy induction with pulsatile gonadotropin releasing hormone pump (GNRH) therapy in a patient with a KISS1 receptor mutation associated normosmic congenital hypogonadotropic hypogonadism and a very low anti-mullerian hormone: a case study

Pregnancy induction with pulsatile gonadotropin releasing hormone pump (GNRH) therapy in a patient with a KISS1 receptor mutation associated normosmic congenital hypogonadotropic hypogonadism and a very low anti-mullerian hormone: a case study

PSLBII-23 Effects of alternative production systems on growth and circulating blood profiles in Berkshire grower pigs

Abstract In this study, we compared the growth performance and circulating blood profiles of Berkshire grower pigs maintained in two different alternative swine production systems, the dry-lot production system, and the hoop structure production system. This study was conducted during a 75-d period spanning from May to July at the North Carolina Agricultural and Technical State University Swine Facility in Greensboro, N.C. Protein expression profiles associated with growth (FGF-19, PDGF-BB, IGF-1), feed intake (CCK), stress (cortisol) and the ability to handle oxidative stress (T-AOC) were analyzed in blood plasma obtained from 24 Berkshire nursery/grower pigs. Berkshire pigs (n = 12) were managed in a 12.19 m x 18.28 m hoop structure with the end walls removed for ventilation and a straw deep bedding system. Twelve additional Berkshire nursery/grower pigs were managed in a 0.08-ha dry-lot. These animals were provided with a canopy for shade and a wallowing area for evaporative cooling. All animals were provided with ad libitum ration and water. Individual body weights (BW) and blood samples were collected at 25-d intervals throughout the 75-d trial, culminating in three different time points. Plasma was isolated from the blood samples and used for ELISA and colorimetric assays. The BioTek 800 TS absorbance reader and Gen5 Microplate Reader and Imager software (Agilent Technologies, Inc., Santa Clara, CA) were used to obtain and calculate the optical densities of the plasma samples, respectively. The data were analyzed using the two-way ANOVA feature of JMP 17.2.0 software (SAS Institute, Inc., Cary, NC) with production system and growth period considered fixed variables, while either growth rate or protein concentration were considered as the response variable. There were four significant treatment effects observed (P &amp;lt; 0.05). Significantly greater concentrations of IGF-1, CCK, and T-AOC were detected in the plasma collected from Berkshire pigs managed in the dry-lot. Whereas those managed in the hoop structure production system had heavier BW. The results show that exposing pigs to higher temperatures can reduce feed intake and growth rates. However, this same stress elicits the release of hormones that promote growth, while enhancing the total antioxidant capacity in these animals. The results support the adoption of the hoop structure production system over the dry-lot production system when managing swine in regions that experience higher temperatures.

Myeloid-derived suppressor cells alleviate adverse ventricular remodeling after acute myocardial infarction.

The fundamental pathophysiological mechanism in the progression of chronic heart failure following acute myocardial infarction (AMI) is ventricular remodeling, in which innate and adaptive immunity both play critical roles. Myeloid-derived suppressor cells (MDSCs) have been demonstrated to functionina range of pathologicalconditions,such as infections, inflammation, autoimmune diseases, and tumors. However, it is unclear how MDSCs contribute to cardiac remodeling following AMI. This study aimed to identify the function and underlying mechanism of MDSCs in controlling cardiac remodelingfollowingAMI. Following AMI in mice, MDSCsfrequencies changed dynamically, considerably increased on day 7 in blood, spleens, lymph nodes and hearts, and decreased afterwards. Consistently, mice with AMI displayed enhanced cardiac function on day 14 post-AMI, reduced infract size and higher survival rates on day 28 post-AMI following theadoptive transfer of MDSCs. Furthermore, MDSCs inhibited the inflammatory response by decreasing pro-inflammatory cytokine (TNF-α, IL-17, Cxcl-1, and Cxcl-2) expression, up-regulating anti-inflammatory cytokine (TGF-β1, IL-10, IL-4, and IL-13) expression, reducing CD3+ T cell infiltration in the infarcted heart and enhancing M2 macrophage polarization. Mechanistically, MDSCs improved the release of anti-inflammatory factors (TGF-β1 and IL-10) and decreased the injury of LPS-induced cardiomyocytes in vitro in a manner dependent on cell-cell contact. Importantly,blockade of IL-10 partially abolished the cardioprotectiverole of MDSCs. This study found that MDSCs contributed to the restoration of cardiac function and alleviation of adverse cardiac remodeling after AMI possibly by inhibiting inflammation.

Mechanism of selenium-enriched Bacillus subtilis alleviating perfluorohexanoic acid toxicity in Carassius auratus through the microbiota–gut–brain axis

The extensive production and use of perfluorohexanoic acid (PFHxA) have established it as an emerging environmental pollutant on a global scale. Selenium has been shown to exert substantial antagonistic effects on harmful substances. Concurrently, probiotics may confer advantageous effects on the host's brain function by orchestrating modulation within the microbiota–gut–brain axis. However, despite the promising properties of selenium-enriched Bacillus subtilis, uncertainties persist regarding its impact on PFHxA and underlying mechanisms. This study evaluated the potential alleviating effects of selenium-enriched B. subtilis on brain damage in Carassius auratus exposed to PFHxA from the perspective of the microbiota–gut–brain axis. Supplementation with selenium-enriched B. subtilis significantly mitigated brain damage and memory loss in C. auratus. Nissl staining of the brain revealed that selenium-enriched B. subtilis mitigated neuronal damage induced by PFHxA. TUNEL staining of the intestine showed that selenium-enriched B. subtilis mitigated PFHxA-induced apoptosis, thus mitigating intestinal injury. Moreover, our study uncovered additional layers of complexity in the microbiota–gut–brain axis, as enhancements were noted in the gut microbiota. Concurrently, alterations in the expression of neurotransmitters and biomarkers associated with emotions, such as 5-hydroxytryptamine, Dopamine, Corticotropin Releasing Factor, Substance p, and ghrelin, highlighted the profound impact of selenium-enriched B. subtilis on the intricate interplay between gut health and emotional well-being. Expanding our focus to the molecular level, we found that supplementation with selenium-enriched B. subtilis further inhibited cellular apoptosis through the brain-derived neurotrophic factor (BDNF) / Tyrosine Kinase receptor B (TrKB) / Protein Kinase B (AKT) / Glycogen synthase kinase3β (GSK-3β) pathway. In conclusion, supplementation with selenium-enriched B. subtilis is a promising strategy to mitigate PFHxA-induced brain damage in C. auratus, offering a multifaceted approach through the microbiota–gut–brain axis. In addition, our study introduces the potential of selenium-enriched B. subtilis as a valuable source of micronutrients for fish, opening new avenues for developmental considerations in aquaculture practices.

Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.

The persistence of HIV-1 in long-lived latent reservoirs during suppressive antiretroviral therapy (ART) remains one of the principal barriers to a functional cure. Blocks to transcriptional elongation play a central role in maintaining the latent state, and several latency reversal strategies focus on the release of positive transcription elongation factor b (P-TEFb) from sequestration by negative regulatory complexes, such as the 7SK complex and BRD4. Another major cellular reservoir of P-TEFb is in Super Elongation Complexes (SECs), which play broad regulatory roles in host gene expression. Still, it is unknown if the release of P-TEFb from SECs is a viable latency reversal strategy. Here, we demonstrate that the SEC is not required for HIV-1 replication in primary CD4+ T cells and that a small molecular inhibitor of the P-TEFb/SEC interaction (termed KL-2) increases viral transcription. KL-2 acts synergistically with other latency reversing agents (LRAs) to reactivate viral transcription in several cell line models of latency in a manner that is, at least in part, dependent on the viral Tat protein. Finally, we demonstrate that KL-2 enhances viral reactivation in peripheral blood mononuclear cells (PBMCs) from people living with HIV (PLWH) on suppressive ART, most notably in combination with inhibitor of apoptosis protein antagonists (IAPi). Taken together, these results suggest that the release of P-TEFb from cellular SECs may be a novel route for HIV-1 latency reactivation.

Comparison of ultra-long gonadotropin releasing hormone agonist versus standard downregulation in women with adenomyosis undergoing frozen-thawed embryo transfer: a randomized clinical trial

BackgroundAdenomyosis can lead to infertility and failure of in vitro fertilization. Limited evidence suggests that the use of long-term treatment with gonadotropin-releasing hormone (GnRH) agonists followed by frozen-thawed embryo transfer (FET) may be the preferred approach for women with adenomyosis.ObjectiveThe aim of this randomized controlled trial is to compare the efficacy of an ultra-long GnRH agonist with standard downregulation in women with adenomyosis undergoing FET.Materials and methodsThis randomized controlled trial enrolled 72 women with adenomyosis diagnosed by sonographic criteria who underwent FET cycles at the Avicenna Infertility Center. These women were randomly assigned to two equal groups: one received GnRH agonist treatment for three months before the FET cycle and the other served as the standard downregulation group. Results were reported as chemical and clinical pregnancy rates.ResultsThe two groups were similar in age, body mass index, anti-Müllerian hormone levels, number of previous pregnancies and miscarriages, presence of uterine myomas, and endometriosis. However, the total dose of estradiol used until embryo transfer was significantly higher in the ultra-long GnRH agonist group than in the standard group (96.14 mg vs. 80.52 mg, p-value = 0.004). Nevertheless, chemical and clinical pregnancy rates did not differ significantly between the two groups.ConclusionsUltra-long GnRH agonist downregulation did not improve the chemical and clinical pregnancy rate in the FET cycle in women with adenomyosis compared with standard GnRH agonist downregulation in the other words, ultra-long GnRH agonist downregulation is not superior to standard protocol. In women with adenomyosis (without history of endometriosis), downregulation of standard GnRH agonists prior to frozen-thawed embryo transfer may be the preferred embryo transfer protocol to gain higher clinical/chemical pregnancy rate.Trial registrationClinical trial registry: IRCT20160717028967N9, available at: https://irct.behdasht.gov.ir/trial/36103.

Bioluminescence Resonance Energy Transfer (BRET)-Mediated Protein Release from Self-Illuminating Photoresponsive Biomaterials.

Phototriggered release of various cargos, including soluble protein factors and small molecules, has the potential to correct aberrant biological events by offering spatiotemporal control over local therapeutic levels. However, the poor penetration depth of light historically limits implementation to subdermal regions, necessitating alternative methods of light delivery to achieve the full potential of photodynamic therapeutic release. Here, we introduce a strategy exploiting bioluminescence resonance energy transfer (BRET)-an energy transfer process between light-emitting Nanoluciferase (NLuc) and a photosensitive acceptor molecule-to drive biomolecule release from hydrogel biomaterials. Through a facile, one-pot, and high-yielding synthesis (60-70%), we synthesized a heterobifunctional ruthenium cross-linker bearing an aldehyde and an azide (CHO-Ru-N3), a compound that we demonstrate undergoes predictable exchange of the azide-bearing ligand under blue-green light irradiation (>550 nm). Following site-specific conjugation to NLuc via sortase-tag enhanced protein ligation (STEPL), the modified protein was covalently attached to a poly(ethylene glycol) (PEG)-based hydrogel via strain-promoted azide-alkyne cycloaddition (SPAAC). Leveraging the high photosensitivity of Ru compounds, we demonstrate rapid and equivalent release of epidermal growth factor (EGF) via either direct illumination or via BRET-based bioluminolysis. As NLuc-originated luminescence can be controlled equivalently throughout the body, we anticipate that this unique protein release strategy will find use for locally triggered drug delivery following systemic administration of a small molecule.

Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer

Abstract Tumor stroma plays a critical role in fostering tumor progression and metastasis. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma. Identifying the key molecular determinants for the pro-tumor properties of CAFs could enable the development of more effective treatment strategies. Herein, through analyses of single-cell sequencing data, we identified a population of CAFs expressing high levels of sulfatase 1 (SULF1), which was associated with poor prognosis in colorectal cancer (CRC) patients. CRC models using mice with conditional SULF1 knockout in fibroblasts revealed the tumor-supportive function of SULF1+ CAFs. Mechanistically, SULF1+ CAFs enhanced the release of vascular endothelial growth factor A (VEGFA) from heparan sulfate proteoglycan (HSPG). The increased bioavailability of VEGFA initiated the deposition of extracellular matrix (ECM) and enhanced angiogenesis. In addition, intestinal microbiota-produced butyrate suppressed SULF1 expression in CAFs through its HDAC inhibitory activity. The insufficient butyrate production in CRC patients increased the abundance of SULF1+ CAFs, thereby promoting tumor progression. Importantly, tumor growth inhibition by HDAC inhibition was dependent on SULF1 expression in CAFs, and CRC patients with more SULF1+ CAFs were more responsive to treatment with the HDAC inhibitor chidamide. Collectively, these findings unveil the critical role of SULF1+ CAFs in CRC and provide a strategy to stratify CRC patients for HDAC inhibitor treatment.

Investigation of effect peripheral kisspeptin treatment on hypothalamo-pituitary-gonadal axis and hypothalamo-pituitary-adrenal axis in male rats.

Kisspeptin is an endogenous peptide hormone that is the most potent stimulator of the hypothalamo-pituitary-gonadal (HPG) axis. The HPG axis can be suppressed by the activation of the hypothalamo-pituitary-adrenal (HPA) axis. The physiological role of kisspeptin in the interaction of the HPG axis and the HPA axis is not fully understood yet. The purpose of the current study was to investigate the possible effects of peripheral injection (intraperitoneally) of kisspeptin on HPG axis and HPA axis activity as well. Adult male Wistar rats were randomly divided into seven groups as sham (control), kisspeptin(10nmol), p234 (10nmol), kisspeptin + p234, kisspeptin + antalarmin (10mg/kg), kisspeptin + astressin2b (100μg/kg), and kisspeptin + atosiban (0.250mg/kg) (n = 10 each group). At the end of the experiment, the hypothalamus, pituitary gland, and serum samples of the rats were collected. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin and kisspeptin + astressin2b groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin, kisspeptin + antalarmin, kisspeptin + astressin2b, and kisspeptin + atosiban groups that compared to the control group. There was no a significant difference in corticotropic releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone and corticosterone concentrations among all groups. Moreover, no significant difference was found in the concentration of pituitary oxytocin. Our results suggest that peripheral kisspeptin injection induces an activation in the HPG axis, but not in the HPA axis in male rats.

CHANGES IN CYTOKINE PROFILE AS A CRITERION FOR SEVERITY PREDICTION OF SKIN TOXICITY IN CANCER PATIENTS RECEIVING EGFRi.

BACKGROUND: Globally, colorectal cancer is the third most diagnosed cancer [1] with an increased incidence of 1.93 million cases in 2020 according to WHO. Approximately one quarter of the initial manifestations of colorectal cancer are metastatic, and 40-50% of individuals with early-stage disease eventually develop metastatic colorectal cancer (mCRC) [2]. Targeted drugs, which include epidermal growth factor receptor inhibitors (EGFRi), are a frequent choice in the therapy of mCRC. Clinical observations and in vivo studies have established a significant association between the administration of EGFRi drugs and skin inflammation, particularly acute in the first 3 months. However, the role of proinflammatory cytokines in the formation of severe skin lesions has not been definitively studied. Here we present clinical evidence of the involvement of a few cytokines in the formation of the pathologic cascade of reactions during EGFR blockade on keratinocyte membranes. AIMS: Evaluation of changes in cytokine profile parameters based on the MILLIPLEX Analyte MAP panel to identify predictors of the severity of unwanted skin toxicity associated with epidermal growth factor receptor inhibition. MATERIALS AND METHODS: Using the HCYTMAG-60K-PX41MILLIPLEX® Human Cytokine/Chemokine Magnetic Bead Panel Premixed 41 Plex (EMD Millipore Corporation, USA) in combination with the MAGPIX instrument (Luminex Corporation, USA), 81 sera from patients with varying severity of cutaneous toxicity (CT) following EGFRi administration for mCRPC and lung cancer were analysed. Subgroup analyses were performed according to the severity of CT as determined by the NCI CTCAE scale of the US National Cancer Institute [3] Statistical processing of data was performed using the R 4.3.1 programming language and the packages tidyverse, rstatix. A value of P0.05 was considered significant to determine differences. N-values for the experimental group were determined using power analysis based on our preliminary data. RESULTS: Blood serum samples from 81 patients aged 18-80 years who were taking EGFRi for oncologic disease and had adverse dermatologic reactions of severity 2 or more were analyzed. The data were analyzed using SPSS software and R 4.3.1 programming language and tidyverse, rstatix packages. Detected changes with p0.05 were analyzed considering subgroup analysis on the basis of selected CT severity degrees based on the criteria developed by the US National Cancer Institute NCI-CTC v.4. CONCLUSIONS: Blocking of EGF receptor inhibits the expression and release of vascular endothelial growth factor (VEGF), which is the main inducer of vascular proliferation, the consequence of which is inflammation of vascular endothelium of skin capillaries. Significant increase of IFN- γ and decrease of IF- α 2 level was found in patients with manifestations of skin toxicity of 2 and more severity degree. Also, a significant criterion of severity of the skin process was an increase in the level of TNF-α. At such dissociation there is induction of STING protein (interferon gene stimulator) and increase of TNF- b production that, in its turn, leads to increase of concentration of proinflammatory cytokines G-CSF, GM-CSF, IFNα2, IFNγ, IL-15, IL-17A, IL-1β, IL-3, IL-6, IL-8, IP-10, TNFα, TGF-α, IL-9. This contributes not only to the maintenance of tissue inflammation, but also to the formation of a vicious circle leading to an increase in the severity of class-mediated inflammatory response against the background of further EGFRi administration. Determination of predictors of severity of adverse dermatologic reactions is extremely important for predicting the development of severity and further personalized tactics for correction of adverse events.

Antiangiogenic tyrosine kinase inhibitors have differential efficacy in clear cell renal cell carcinoma in bone.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney neoplasm; bone metastasis (BM) develops in 35-40% of metastatic patients and results in substantial morbidity and mortality, as well as medical costs. A key feature of ccRCC is the loss of function of the von Hippel-Lindau (VHL) protein, which enhances angiogenesis via vascular endothelial growth factor release. Consequently, anti-angiogenic tyrosine kinase inhibitors (TKIs) emerged as a treatment for ccRCC. However, limited data about their efficacy in BM is available, and no systematic comparisons have been performed. We developed mouse models of bone and lung ccRCC tumors and compared their anti-cancer efficacy, impact on mouse survival, and mechanisms of action, including effects on tumor cells and both immune and non-immune (blood vessels, osteoclasts) bone stromal components. This approach elucidates the efficacy of TKIs in ccRCC bone tumors to support rational interrogation and development of therapies.

Might retrigger with human chorionic gonadotropin be a solution for empty follicle syndrome after gonadotropin releasing hormone agonist trigger?

This study aimed to determine whether the use of human chorionic gonadotropin (hCG) as a trigger could offer a potential solution for addressing empty follicle syndrome following the administration of a trigger for gonadotropin-releasing hormone agonist. A retrospective cohort analysis was conducted using data extracted from the hospital database pertaining to 415 patients who underwent in vitro fertilization (IVF) with an antagonist protocol triggered by a gonadotropin-releasing hormone (GnRH) agonist between December 2019 and January 2023 at the Acıbadem Maslak Hospital Assisted Reproductive Technologies Unit. All cases that failed to obtain oocytes and required rescue were analyzed. This study analyzed 415 women who underwent IVF using GnRH agonist-triggered antagonist protocols. Among them, 6 (1.4%) had empty folicle syndrome (EFS). Patients with EFS had lower luteinizing hormone levels and fewer oocytes, embryos, and blastocysts, resulting in lower oocyte utilization rate. However, pregnancy rates were similar, with no biochemical or ectopic pregnancies observed in the EFS group. Use of an hCG retrigger in hyperresponders with no oocytes after GnRHa trigger may prevent cycle cancelation. Although the rates of egg utilization may decrease, oocyte maturity remains comparable. Frozen embryo transfer following hCG retrigger administration yields similar positive pregnancy test results and live birth rates.