Growth Control Research Articles

Management of typical and atypical metastatic lung carcinoids: present and future perspectives.

Lung carcinoids are rare tumors representing 1-2% of all invasive lung malignancies. They include typical and atypical carcinoids, whose distinction is made based on the mitotic index and presence or absence of necrosis. The 10-year overall survival for stage IV typical carcinoid is 47% and 18% for atypical carcinoid, reflecting the indolent growth of these tumors. There are limited approved treatment options for them and most of the evidence comes from retrospective analyses, single-arm trials, subgroup analysis of phase II/III trials for metastatic neuroendocrine tumors and extrapolation of data from phase III trials for gastroenteropancreatic neuroendocrine tumors. Management of metastatic lung carcinoids requires a multidisciplinary standardized approach in specialized centers. Treatment should have a dual objective, control of tumor growth and control of symptoms related to hypersecretion syndromes, aiming to improve quality of life and survival. In the continuum of treatment disease, locoregional treatment options need to be considered in parallel with systemic treatments. In this paper, we review the present treatment options and their rational and we give an insight into future alternatives.

An evaluation of the growth, development, reproductive characteristics and pest control potential of three Trichogramma species on Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae).

Tuta absoluta is an invasive alien species that has caused major losses in the Chinese tomato industry. Investigating the growth, development, reproduction and pest control effects of three native species of Trichogramma species on the eggs of T. absoluta could provide an ecological tool for preventing and controlling T. absoluta in China. In this study, we constructed age-stage two-sex life tables for three common species of Trichogramma and determined their relative abilities to control T. absoluta in greenhouse insect cages, thus allowing us to identify the species with the most effective ability to prey on T. absoluta eggs. Analysis showed that the net reproductive rate (R0), gross reproduction rate (GRR) and intrinsic rate of increase (r) of Trichogramma ostriniae were the highest of the three species at 22.85, 32.58 and 1.31, respectively. In the presence of 10 eggs and under ideal conditions, T. ostriniae, Trichogramma chilonis, and Trichogramma dendrolimi produced 9451.04, 5199.56, and 1902.95 offspring, respectively. Following the release of T. ostriniae, tomato leaves incurred a damage index of 1 after the first week, while the number of T. absoluta reduced to 24.60 individuals by week 10 (8.75% of the control treatment). Of the three species of Trichogramma tested in this study, T. ostriniae exhibited the best growth, development, reproductive capacity and predatory ability against T. absoluta, and has broad application prospects. © 2024 Society of Chemical Industry.

DPPA4 increases aggressiveness of pituitary neuroendocrine tumors by enhancing cell stemness.

Pituitary neuroendocrine tumors, PitNETs, are often aggressive and precipitate in distant metastases that are refractory to current therapies. However, the molecular mechanism in PitNETs' aggressiveness is not well understood. Developmental pluripotency-associated 4 (DPPA4) is known as a stem cell regulatory gene and overexpressed in certain cancers, but its function in the context of PitNETs' aggressiveness is not known. We employed both rat and human models of PitNETs. In the rat pituitary tumor model (RPT), we used prenatal-alcohol-exposed (PAE) female Fischer rats which developed aggressive PitNETs following estrogen treatment, while in the human pituitary tumor (HPT) model, we used aggressively proliferative cells from pituitary tumors of patients undergone surgery. Various molecular, cellular, and epigenetic techniques were used to determine the role of DPPA4 in PitNETs' aggressiveness. We show that DPPA4 is overexpressed in association with increased cell stemness factors in aggressive PitNETs of PAE rats and of human patients. Gene-editing experiments demonstrate that DPPA4 increases the expression of cell stemness and tumor aggressiveness genes and promotes proliferation, colonization, migration, and tumorigenic potential of PitNET cells. ChIP assays and receptor antagonism studies reveal that DPPA4 binds to canonical WINTs promoters and increases directly or indirectly the Wnt/β-catenin control of cell stemness, tumor growth, and aggressiveness of PitNETs. Epigenetic studies show involvement of histone methyltransferase in alcohol activation of DPPA4. These findings support a role of DPPA4 in tumor stemness and aggressiveness and provide a preclinical rationale for modulating this stemness regulator for the treatment of PitNETs.

CRISPR perfect adaptation for robust control of cellular immune and apoptotic responses.

A central challenge in the quest for precise gene regulation within mammalian cells is the development of regulatory networks that can achieve perfect adaptation-where outputs consistently return to a set baseline post-stimulus. Here, we present such a system that leverages the CRISPR activation (CRISPRa) and anti-CRISPR proteins as two antithetic elements to establish perfect adaptation in mammalian cells and dynamically regulate gene expression. We demonstrate that this system can maintain stable expression levels of target genes in the face of external perturbations, thus providing a robust platform for biological applications. The versatility of our system is further showcased through its integration with endogenous regulatory mechanisms in T cells, such as the NF-κB-mediated immune response, and its ability to program apoptosis responses for precise spatial and temporal control of cellular growth and death. This study not only advances our understanding of gene regulation in mammalian cells but also opens new avenues for therapeutic intervention, particularly in diseases characterized by dysregulated gene expression.

Dihydroartemisinin restores the immunogenicity and enhances the anticancer immunosurveillance of cisplatin by activating the PERK/eIF2α pathway

BackgroundImmunosurveillance is pivotal in the effectiveness of anticancer therapies and tumor control. The ineffectiveness of cisplatin in activating the immunosurveillance is attributed to its lack of adjuvanticity resulting from its inability to stimulate endoplasmic reticulum stress. Dihydroartemisinin demonstrates the anti-tumor effects through various mechanisms, including the activation of the endoplasmic reticulum stress. This study aimed to develop a novel strategy to enhance the immunogenicity of dying tumor cells by combining cisplatin with dihydroartemisinin, thereby triggering effective anti-tumor immunosurveillance and improving the efficacy of cisplatin in clinical practice.MethodsLewis lung carcinoma (LLC) and CT26 colon cancer cell lines and subcutaneous tumor models were used in this study. The importance of immunosurveillance was validated in both immunocompetent and immunodeficient mouse models. The ability of dihydroartemisinin and cisplatin therapy to induce immunogenic cell death and tumor growth control in vivo was validated by prophylactic tumor vaccination and therapeutic tumor models. The underlying mechanism was elucidated through the pharmaceutical or genetic intervention of the PERK/eIF2α pathway in vitro and in vivo.ResultsDihydroartemisinin enhanced the generation of reactive oxygen species in cisplatin-treated LLC and CT26 cancer cells. The combination treatment of dihydroartemisinin with cisplatin promoted cell death and ensured an optimal release of damage-associated molecular patterns from dying cancer cells, promoting the phagocytosis of dendritic cells. In the tumor vaccination model, we confirmed that dihydroartemisinin plus cisplatin treatment induced immunogenic cell death. Utilizing immunocompetent and immunodeficient mouse models, we further demonstrated that the combination treatment suppressed the tumor growth of CT26 colon cancer and LLC lung cancer, leading to an improved prognosis through the restoration of cytotoxic T lymphocyte responses and reinstatement of anti-cancer immunosurveillance in vivo. Mechanistically, dihydroartemisinin restored the immunogenicity of cisplatin by activating the adjuvanticity of damage-associated molecular patterns, such as calreticulin exposure, through the PERK/eIF2α pathway. Additionally, the inhibition of eIF2α phosphorylation attenuated the anti-tumor efficiency of C + D in vivo.ConclusionsWe highlighted that dihydroartemisinin acts as an immunogenic cell death rescuer for cisplatin, activating anticancer immunosurveillance in a PERK/eIF2α-dependent manner and offering a strategy to enhance the anti-tumor efficacy of cisplatin in clinical practice.

An overview of benefits and risks of chronic melanocortin-1 receptor activation.

The melanocortin-1 receptor (MC1R) is a G protein-coupled receptor that plays a pivotal role in human skin pigmentation, melanin synthesis, redox homeostasis and inflammation. Loss-of-function MC1R variants suppress G protein-coupled receptor coupling or cell surface expression leading to a decrease in adenyl cyclase activation and intracellular levels of cyclic adenosine monophosphate. Chronic activation of MC1R can occur in certain medical conditions such as Addison's disease and physiologic states such as pregnancy melasma. MC1R activation is more commonly caused by environmental exposure to ultraviolet (UV) radiation. Approved pharmacologic melanocortin agonists that activate MC1R signalling in a targeted manner or as a bystander effect have recently become available for erythropoietic protoporphyria, sexual desire disorders, monogenic obesity and syndromic obesity. Further, small peptide analogues of α-melanocortin-stimulating hormone, human MC1R selective agonists, are photoprotective, decreasing the adverse impact of UV radiation (a primary risk factor for skin cancer) and are being investigated as potential chemoprevention strategies. MC1R activation through induction of UV-protective skin pigmentation increased DNA repair, and control of aberrant cell growth may reduce the risk of melanoma but importantly does not prevent melanoma particularly in individuals with risk factors and regular skin examination remains critical in high-risk individuals.

Three optical intervention methods for low myopia control in children: a one-year follow-up study

ObjectiveThis study aimed to compare the one-year efficacy of myopia prevention and control using three optical intervention methods - single vision lens (SVL), high aspherical lenticule (HAL), and orthokeratology (OK) lens - in children with low myopia.MethodsA cohort of 150 children aged 7–13 years with low myopia was recruited and divided into three groups: SVL (n = 50), HAL (n = 50), and OK lens group (n = 50), based on their preference for glasses. Follow-up assessments were carried out over one year, focusing on data from the right eye for statistical analysis. Baseline characteristics such as gender, age, axial length (AL), spherical equivalent refractive error (SER), flat keratometry (K1), steep keratometry (K2), anterior chamber depth (ACD), white-to-white corneal diameter (WTW), and non-contact tonometry (NCT) measurements were gathered and compared among the three groups before any intervention. Changes in AL growth after 1 year of intervention were assessed across the three groups. Subsequently, the AL growth control rates between the HAL and OK lens groups were compared, with the SVL group serving as the reference standard.ResultsThe study found no statistically significant variances in baseline characteristics (gender, age, SER, AL, K1, K2, WTW, and NCT) among the SVL, HAL, and OK lens groups (all p > 0.05). Following a one-year intervention, AL growth rates were as follows: HAL group (0.163 ± 0.113 mm) < OK lens group (0.280 ± 0.170 mm) < SVL group (0.516 ± 0.190 mm), with statistically significant disparities (p < 0.05). The HAL group demonstrated a higher 1-year AL growth control rate (68.41%) compared to the OK lens group (45.74%) for children aged 7–13 with low myopia, with a statistically significant differences (p < 0.001). And there was significant difference in the SER change between SVL group and HAL group (p < 0.001).ConclusionCompared to SVL, HAL and OK lens are more effective in controlling axial growth in mild myopia. Specifically, HAL maybe shows superior outcomes in both preventive and corrective measures, also it needs to be supported by more studies from randomized controlled experiments.

Diet at birth is critical for healthy growth, independent of effects on the gut microbiota

BackgroundColostrum is the first milk for a newborn. Its high content in microbiota shaping compounds and its intake at the time of gut microbiota seeding suggests colostrum may be critical in the establishment of a healthy microbiota. There is also accumulating evidence on the importance of the gut microbiota for healthy growth. Here, we aimed to investigate the contribution of colostrum, and colostrum-induced microbiota to growth promotion. Addressing this question is highly significant because (1) globally, less than half of the newborns are fully colostrum fed (2) the evidence for the importance of the microbiota for the prevention of undernutrition has only been demonstrated in juvenile or adult pre-clinical models while stunting already starts before weaning.ResultsTo address the importance of diet at birth in growth failure, we developed a unique mouse model in which neonates are breastfed by mothers at an advanced stage of lactation who no longer provide colostrum. Feeding newborn mice with mature milk instead of colostrum resulted in significant growth retardation associated with the biological features of chronic undernutrition, such as low leptin levels, dyslipidemia, systemic inflammation, and growth hormone resistance. We next investigated the role of colostrum in microbiota shaping. At the end of the lactation period, we found a major difference in gut microbiota alpha diversity, beta diversity, and taxa distribution in control and colostrum-deprived mice. To determine the causal relationship between changes in microbiota and growth trajectories, we repeated our experiment in germ-free mice. The beneficial effect of colostrum on growth remained in the absence of microbiota.ConclusionOur data suggest that colostrum may play an important role in the prevention of growth failure. They highlight that the interplay between neonatal gut microbiome assembly and diet may not be as crucial for growth control in the developing newborn as described in young adults. This opens a paradigm shift that will foster research for colostrum’s bioactives that may exert a similar effect to microbiota-derived ligands in promoting growth and lead to new avenues of translational research for newborn-tailored prevention of stunting.98mWSFedBqCALfgBr5hPfAVideo

Bioproducts derived from Bacillus stercoris isolate B.PNR1 and Streptomyces sp. isolate S.PNR29 for enhanced plant growth and disease control in tomato

ABSTRACT This study aims to develop a wettable formulation bioproduct from antagonistic bacteria, Bacillus stercoris isolate B.PNR1, and Streptomyces sp. isolate S.PNR29, targeting Fusarium oxysporum f.sp. lycopersici (Fol), the cause of Fusarium wilt disease in tomatoes, while also promoting plant growth. The survivability of bacterial cells in the product was assessed over a 180-day period at 4°C and 28°C. The bioproducts demonstrated significant control of Fusarium wilt disease, with B. stercoris isolate B.PNR1 bioproducts exhibiting superior disease control percentages compared to Streptomyces sp. isolate S.PNR29 bioproducts and commercial alternatives. Additionally, the bioproducts positively influenced tomato seed germination and seedling growth, with Streptomyces sp. isolate S.PNR29 bioproducts showing better growth performance in terms of plant length, weight measurements, and seed germination. In conclusion, B. stercoris isolate B.PNR1 and Streptomyces sp. isolate S.PNR29 bioproducts emerge as promising biocontrol agents, showcasing sustained efficacy against Fol and significant positive impacts on plant growth, thereby highlighting their potential for sustainable agriculture practices.

Antibiotic Efficacy against Methicillin-Susceptible Staphylococcus aureus Biofilms on Synthetic and Biological Vascular Grafts

Biofilm formation is one of the greatest challenges encountered in vascular graft infections. Our aim is to compare the efficacy of 5 antibiotics against methicillin-susceptible Staphylococcus aureus (MSSA) biofilms on the surface of 4 vascular grafts. Invitro study of 2 clinical MSSA strains (MSSA2 and MSSA6) and 4 vascular grafts (Dacron, Dacron-silver-triclosan (DST), Omniflow-II, and bovine pericardium). After a 24-hr incubation period, the graft samples were divided into 6 groups: growth control (no treatment), ciprofloxacin 4.5mg/L, cloxacillin 100mg/L, dalbavancin 300mg/L, daptomycin 140mg/L, and linezolid 20mg/L. Quantitative cultures were obtained and results expressed as log10colony-forming units per milliliter (CFU/mL). Analysis of variance was performed to compare biofilm formation between the different groups. The mean±standard deviation MSSA2 count on the growth control Dacron graft was 10.05±0.31CFU/mL. Antibiotic treatment achieved a mean reduction of 45%; ciprofloxacin was the most effective antibiotic (64%). Baseline MSSA2 counts were very low on the DST (0.50±1.03CFU/mL) and Omniflow-II (0.33±0.78CFU/mL) grafts. On the bovine pericardium patch, the count was 9.87±0.50CFU/mL, but this was reduced by a mean of 45% after antibiotic treatment (61% for ciprofloxacin). The mean MSSA6 count on the growth control Dacron graft was 9.63±0.53CFU/mL. Antibiotics achieved a mean reduction of 48%, with ciprofloxacin performing best (67% reduction). The baseline MSSA6 count on the DST graft was 8.54±0.73CFU/mL. Antibiotics reduced biofilm formation by 72%; cloxacillin was the most effective treatment (86%). The MSSA6 count on the untreated Omniflow-II graft was 1.17±1.52CFU/mL. For the bovine pericardium patch, it was 8.98±0.67CFU/mL. The mean reduction after antibiotic treatment was 46%, with cloxacillin achieving the greatest reduction (68%). In this invitro study, ciprofloxacin and cloxacillin performed best at reducing biofilms formed by clinical MSSA strains on the surface of biological and synthetic vascular grafts.

Subtotal resection of vestibular schwannoma with subsequent Gamma Knife irradiation - tumor growth control, facial and cochlear nerve outcome - preliminary results.

&lt;b&gt;Introduction:&lt;/b&gt; The choice of treatment of vestibular schwannoma (VS) depends on several factors, including the tumor size, the patient's age and overall health, and the presence and severity of symptoms.&lt;b&gt;Aim:&lt;/b&gt; The aim of the study was to assess the effectiveness of intentional subtotal resection (STR) of tumor followed by Gamma Knife surgery (GKS) in patients with larger VS (Koos 3 and 4).&lt;b&gt;Materials and methods:&lt;/b&gt; The retrospective analysis was performed on 18 patients. Data of VS volumes measured in MRI, the facial nerve function assessed in the House-Brackmann scoring system (HB), and the results of audiological examination expressed on the Gardner-Robertson scale (GR) were collected preoperatively, postoperatively, and post-GKS.&lt;b&gt;Results:&lt;/b&gt; Preoperatively, the main symptom was hearing loss observed in 13 out of 18 patients. The facial nerve function was assessed as HB 1 in 16, whereas HB 2 in 2 patients. The mean volume of the tumor in the initial MRI amounted to 16.81 cm&lt;sup&gt;3&lt;/sup&gt; . Postoperatively, the facial nerve was assessed as HB 1 or 2 in 16, whereas HB 3 in 2 patients. Serviceable hearing was presented by only 4 persons. The Mean diameter of the tumor after subtotal surgery amounted to 3.16 cm&lt;sup&gt;3&lt;/sup&gt; , 1.83 cm&lt;sup&gt;3&lt;/sup&gt; after GKS, and 1.58 cm&lt;sup&gt;3&lt;/sup&gt; at the last follow-up. The facial nerve function and hearing level remained the same as before GKS in all patients.&lt;b&gt;Conclusions:&lt;/b&gt; STR followed by GKS can be a safe and effective method of treatment of large VS concerning the functional outcome of the facial nerve and the tumor volume growth control.

The SASP factor IL-6 sustains cell-autonomous senescent cells via a cGAS-STING-NFκB intracrine senescent noncanonical pathway.

Senescent cells produce a Senescence-Associated Secretory Phenotype (SASP) that involves factors with diverse and sometimes contradictory activities. One key SASP factor, interleukin-6 (IL-6), has the potential to amplify cellular senescence in the SASP-producing cells in an autocrine action, while simultaneously inducing proliferation in the neighboring cells. The underlying mechanisms for the contrasting actions remain unclear. We found that the senescence action does not involve IL-6 secretion nor the interaction with the receptor expressed in the membrane but is amplified through an intracrine mechanism. IL-6 sustains intracrine senescence interacting with the intracellular IL-6 receptor located in anterograde traffic specialized structures, with cytosolic DNA, cGAS-STING, and NFκB activation. This pathway triggered by intracellular IL-6 significantly contributes to cell-autonomous induction of senescence and impacts in tumor growth control. Inactivation of IL-6 in somatotrophic senescent cells transforms them into strongly tumorigenic in NOD/SCID mice, while re-expression of IL-6 restores senescence control of tumor growth. The intracrine senescent IL-6 pathway is further evidenced in three human cellular models of therapy-induced senescence. The compartmentalization of the intracellular signaling, in contrast to the paracrine tumorigenic action, provides a pathway for IL-6 to sustain cell-autonomous senescent cells, driving the SASP, and opens new avenues for clinical consideration to senescence-based therapies.

Membrane potential as master regulator of cellular mechano-transduction.

Membrane potential is a property of all living cells 1 . Nevertheless, its physiological role in non-excitable cells is poorly understood. Resting membrane potential is typically considered fixed and under tight homeostatic control 2 . Contrary to this paradigm, we find that membrane potential is a dynamic property that directly reflects mechanical forces acting on the cell and that cells use membrane potential to assess their biomechanical state. We show that several important mechano-sensitive signal transduction pathways, like MAPK and Hippo 3-9 , are directly controlled by membrane potential and this signaling is mediated by upstream membrane-bound receptors, including FAT1. We further show that mechano-transduction via membrane potential plays a critical role in the homeostasis of epithelial tissues, setting cellular biomass density and cell number density by controlling proliferation and cell elimination. In epithelial scratch wound assays, as well as Xenopus tadpole tail regeneration, we observe a wave of depolarization caused by a drop in cellular biomass density due to mechanical stretch and we show that this depolarization wave is critical for wound closure. Together, these data are explained by a first-principles biophysical model, which demonstrates that membrane potential is physically coupled to mechanical pressure and cellular biomass density. Membrane potential thereby provides a quasi-instantaneous, global readout of the biophysical state of the cell and in turn regulates cell growth, resulting in homeostatic feedback control of biomass density and cell number density in tissues. This interplay may be an ancient mechanism for growth control in multi-cellular organisms and its misregulation may play an important role in tumorigenesis.

CD38+ Alveolar macrophages mediate early control of M. tuberculosis proliferation in the lung.

Tuberculosis, caused by M.tuberculosis (Mtb), remains an enduring global health challenge, especially given the limited efficacy of current therapeutic interventions. Much of existing research has focused on immune failure as a driver of tuberculosis. However, the crucial role of host macrophage biology in controlling the disease remains underappreciated. While we have gained deeper insights into how alveolar macrophages (AMs) interact with Mtb, the precise AM subsets that mediate protection and potentially prevent tuberculosis progression have yet to be identified. In this study, we employed multi-modal scRNA-seq analyses to evaluate the functional roles of diverse macrophage subpopulations across different infection timepoints, allowing us to delineate the dynamic landscape of controller and permissive AM populations during the course of infection. Our analyses at specific time-intervals post-Mtb challenge revealed macrophage populations transitioning between distinct anti- and pro-inflammatory states. Notably, early in Mtb infection, CD38- AMs showed a muted response. As infection progressed, we observed a phenotypic shift in AMs, with CD38+ monocyte-derived AMs (moAMs) and a subset of tissue-resident AMs (TR-AMs) emerging as significant controllers of bacterial growth. Furthermore, scATAC-seq analysis of naïve lungs demonstrated that CD38+ TR-AMs possessed a distinct chromatin signature prior to infection, indicative of epigenetic priming and predisposition to a pro-inflammatory response. BCG intranasal immunization increased the numbers of CD38+ macrophages, substantially enhancing their capability to restrict Mtb growth. Collectively, our findings emphasize the pivotal, dynamic roles of different macrophage subsets in TB infection and reveal rational pathways for the development of improved vaccines and immunotherapeutic strategies.

Planned Subtotal Resection following Stereotactic Radiosurgery of Koos 3 and 4 Vestibular Schwannomas.

Background/Objectives: Surgical resection of medium to large vestibular schwannomas (VSs, Koos grade 3 and 4) is a widely used approach, although stereotactic radiosurgery (SRS) is increasingly proposed as initial treatment. The quality of life-centered approach is challenged in cases where tumor growth control cannot be achieved with SRS, thus necessitating salvage surgery. We present a series of eight consecutive patients who required surgery due to continued tumor growth after SRS. Methods: Of the 146 patients with VS grades 3 and 4 initially treated with SRS, only eight patients (mean age, 54 ± 7.2 years; range, 42-63 years) required subsequent surgery. Their mean tumor volume was 9.9 ± 3.2 cm3. The mean time from SRS to first tumor progression and planned subtotal resection was 23 ± 5.9 months and 45 ± 17.5 months, respectively. SRS was not performed after the surgery in favor of a "wait and rescan" approach. Tumor residue was monitored on follow-up magnetic resonance imaging. In all patients, tumor growth control after planned subtotal resection was maintained at 63 ± 19.8 months. Results: None of the 146 patients had serious complications after SRS. In the eight patients who required surgery, tumor growth between 22% and 212% (mean, 4 cm3) was reported within 26 to 84 months after SRS. Before salvage surgery, they scored 1 point on the House-Brackmann scale. Subtotal excision was performed, and VIIth nerve function was preserved in all patients. At 63 ± 19.8 months, 3 patients had a House-Brackmann score of 1, four patients had a score of 2, and one patient had a score of 3. Conclusions: Surgical excision of medium to large VS after SRS can be relatively safe, provided that a quality of life-centered approach of subtotal resection is used.

Astrocytes facilitate gabazine-evoked electrophysiological hyperactivity and distinct biochemical responses in mature neuronal cultures.

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the adult brain that binds to GABA receptors and hyperpolarizes the postsynaptic neuron. Gabazine acts as a competitive antagonist to type A GABA receptors (GABAAR), thereby causing diminished neuronal hyperpolarization and GABAAR-mediated inhibition. However, the biochemical effects and the potential regulatory role of astrocytes in this process remain poorly understood. To address this, we investigated the neuronal responses of gabazine in rat cortical cultures containing varying ratios of neurons and astrocytes. Electrophysiological characterization was performed utilizing microelectrode arrays (MEAs) with topologically controlled microcircuit cultures that enabled control of neuronal network growth. Biochemical analysis of the cultures was performed using traditional dissociated cultures on coverslips. Our study indicates that, upon gabazine stimulation, astrocyte-rich neuronal cultures exhibit elevated electrophysiological activity and tyrosine phosphorylation of tropomyosin receptor kinase B (TrkB; receptor for brain-derived neurotrophic factor), along with distinct cytokine secretion profiles. Notably, neurons lacking proper astrocytic support were found to experience synapse loss and decreased mitogen-activated protein kinase (MAPK) phosphorylation. Furthermore, astrocytes contributed to neuronal viability, morphology, vascular endothelial growth factor (VEGF) secretion, and overall neuronal network functionality, highlighting the multifunctional role of astrocytes.

Therapeutic liposomal combination to enhance chemotherapy response and immune activation of tumor microenvironment

Multiple oxaliplatin-resistance mechanisms have been proposed such as increase of anti-inflammatory M2 macrophages and lack of cytotoxic T-cells. Thereby oxaliplatin chemotherapy promotes an immunosuppressive tumor microenvironment and inhibits anti-tumor efficacy. It has been shown that toll-like receptor (TLR) agonists are capable of triggering broad inflammatory responses, which may potentially reduce oxaliplatin-resistance and improve the efficacy of chemotherapy. In this study, we established colorectal tumor-bearing zebrafish and mice, and investigated the effects of TLR agonists and oxaliplatin in macrophage function and anti-tumor T cell immunity as well as tumor growth control in vivo. To increase the potential of this strategy as well minimize side effects, neutral liposomes carrying oxaliplatin and cationic liposomes co-loaded with TLR agonists Poly I:C and R848 were employed for maximum immune activation. Both of two liposomal systems exhibited good physicochemical properties and excellent biological activities in vitro. The combination strategy delivered by liposomes showed more pronounced tumor regression and correlated with decreased M2 macrophage numbers in both zebrafish and mice. Increasing numbers of dendritic cells, DC maturation and T cell infiltration mediated via immunogenic cell death were observed in treated mice. Our study offers valuable insights into the potential of liposomal combination therapy to improve cancer treatment by reprogramming the tumor microenvironment and enhancing immune responses.

11C–methionine PET/CT in meningiomas

Currently, positron emission tomography (PET) is the standard imaging modality in neuro-oncology for gliomas and metastatic lesions. The experience of PET application in meningiomas, the most frequent primary CNS neoplasms, is much less, and the interpretation of the study results has a number of differences. The aim of the study was to evaluate the possibility and peculiarities of PET application in meningiomas based on our own clinical experience and literature review. The study included 70 patients with 77 meningiomas who underwent PET/CT with 11C-methionine. The mean age at the time of examination was 57.4 years (19–86 years). The main evaluation parameter, the tumor-to-brain ratio (TBR) of 11C-methionine (11C–MET) averaged 3.13 (1.00–10.66). Meningiomas were characterized by high 11C–MET TBR, with 89.6% of cases having TBR greater than 1.5. In histologically verified WHO grade 1, 2, and 3 meningiomas, the median TBR was 4.06 [3.04, 4.57], 2.32 [2.12, 3.69], and 4.29 [2.60, 5.10] and did not differ significantly between groups. Meanwhile, in histologically unresectable slow-growing or non-growing incidental meningiomas, TBR of 11C–MET was significantly lower than in WHO grade 1 and 3 meningiomas. There was no significant difference in the accumulation index between irradiated meningiomas with tumor growth control (3.81 [2.97, 3.98]) and recurrence (3.62 [2.60, 4.30]). When irradiated and non-irradiated meningiomas of WHO grade 1, 2 and 3, as well as the combined group of grade 1–3 tumors were compared, no significant differences in 11C–MET TBR were found. The use of PET/CT in meningiomas has a number of important features. Meningiomas are characterized by high TBR of 11C–MET. According to our data PET/CT with 11C–MET does not allow differentiating between meningiomas of different degrees of malignancy – 1, 2 or 3 according to WHO. With effective radiotherapy, meningiomas show partial reduction of TBR or remain stable. Even with prolonged growth control after radiation treatment, meningiomas may still have high TBR of 11C–MET. When comparing growing and stable meningiomas, irradiated and non-irradiated tumors, no significant differences in TBR of 11C–MET are found.

Effect of girdling on phloem and xylem formation in a range of gymnosperms and angiosperms

Summary Girdling is often used as an experimental method to study source/sink controls of cambial growth. However, the phloem responses to girdling have not been well investigated. The aim of this research was to characterize the anatomical changes in the phloem and xylem of different species following trunk girdling. Different species of gymnosperm (Abies sibirica, Pinus sylvestris) and angiosperm (Alnus incana, Populus tremula) woody plants were selected. We girdled trunks during active growth and sampled tissues at two levels (1 cm and 35 cm) above the girdle at the end of the growing season. General responses to girdling were recorded for the studied species, such as increased phloem increments, parenchymatization of conducting tissues, reduction in the size of conducting elements, and an increase in the size of axial parenchyma cells in the phloem and xylem. We observed the suppression of xylogenesis in 3 out of 4 species. Differences in the structure of conducting tissues were found, which are due to species differences in the initial tissue structure. In gymnosperms, noticeable differences in the number of resin ducts in the xylem were observed between control and girdled trees. In angiosperms, we found the formation of cells with thickened cell walls in girdled trees (i.e., the formation of phloem and xylem fibers with thickened cell walls in aspen and sclereids in the phloem of alder). Based on the literature data, the observed responses may be due to both the wounding effect and the influence of the high sugar content above the girdle.

Phenylalanine-Free Infant Formula in Patients with Phenylketonuria: A Retrospective Study.

The long-term efficacy and use of phenylalanine-free infant amino acid formula (PFIF) is understudied. This retrospective, longitudinal study evaluated PFIF (PKU Start: Vitaflo International) in children with phenylketonuria, collecting data on metabolic control, growth, dietary intake, and symptoms and the child's experience with PFIF. Twenty-five children (12 males, 48%) with a median age of 3.6 years (2.0-6.2 years) were included. During 24 months follow-up, children maintained normal growth and satisfactory metabolic control. The protein intake from protein substitutes increased from 2.7 at 6 months to 2.8 g/kg/day at 24 months, while natural protein decreased from 0.6 to 0.4 g/kg/day. By 24 months, most children (n = 16, 64%) had stopped PFIF, while nine (36%) continued with a median intake of 450 mL/day (Q1:300 mL, Q3: 560 mL). Children who continued PFIF after 24 months of age had higher energy and fat intakes with higher weight/BMI z-scores compared with those who stopped earlier (p < 0.05). Constipation was reported in 44% of infants but improved with age. Initial difficulty with PFIF acceptance was reported in 20% of infants but also improved with time. Prolonged use of PFIF in pre-school children may contribute to poor feeding patterns and overweight; thus, replacing the majority of the protein equivalent provided by PFIF with a weaning protein substitute by 12 months and discontinuing PFIF before 2 years is recommended.