Contribution of collagen degradation and proteoglycan depletion to cartilage degeneration in primary and secondary osteoarthritis: an in silico study.

OBJECTIVES: Current experimental approaches cannot elucidate the effect of maladaptive changes on the main cartilage constituents during the degeneration process in osteoarthritis (OA). In silico approaches, however, allow creating 'virtual knock-out' cases to elucidate these effects in a constituent-specific manner. We used such an approach to study the main mechanisms of cartilage degeneration in different mechanical loadings associated with the following OA etiologies: (1) physiological loading of degenerated cartilage, (2) injurious loading of healthy intact cartilage and (3) physiological loading of cartilage with a focal defect. METHODS: We used the recently developed Cartilage Adaptive REorientation Degeneration (CARED) framework to simulate cartilage degeneration associated with primary and secondary OA (OA cases (1)-(3)). CARED incorporates numerical description of tissue-level cartilage degeneration mechanisms in OA, namely, collagen degradation, collagen reorientation, fixed charged density loss and tissue hydration increase following mechanical loading. We created 'virtual knock-out' scenarios by deactivating these degenerative processes one at a time in each of the three OA cases. RESULTS: In the injurious loading of intact and physiological loading of degenerated cartilage, collagen degradation drives degenerative changes through fixed charge density loss and tissue hydration rise. In contrast, the two later mechanisms were more prominent in the focal defect cartilage model. CONCLUSION: The virtual knock-out models reveal that injurious loading to intact cartilage and physiological loading to degenerated cartilage induce initial degenerative changes in the collagen network, whereas, in the presence of a focal cartilage defect, mechanical loading initially causes proteoglycans (PG) depletion, before changes in the collagen fibril network occur.

Production of afucosylated antibodies in CHO cells by coexpression of an anti-FUT8 intrabody.

Some effector functions prompted by immunoglobulin G (IgG) antibodies, such as antibody-dependent cell-mediated cytotoxicity (ADCC), strongly depend on the N-glycans linked to asparagine 297 of the Fc region of the protein. A single α-(1,6)-fucosyltransferase (FUT8) is responsible for catalyzing the addition of an α-1,6-linked fucose residue to the first GlcNAc residue of the N-linked glycans. Antibodies missing this core fucose show a significantly enhanced ADCC and increased antitumor activity, which could help reduce therapeutic dose requirement, potentially translating into reduced safety concerns and manufacturing costs. Several approaches have been developed to modify glycans and improve the biological functions of antibodies. Here, we demonstrate that expression of a membrane-associated anti-FUT8 intrabody engineered to reside in the endoplasmic reticulum and Golgi apparatus can efficiently reduce FUT8 activity and therefore the core-fucosylation of the Fc N-glycan of an antibody. IgG1-producing CHO cells expressing the intrabody secrete antibodies with reduced core fucosylation as demonstrated by lectin blot analysis and UPLC-HILIC glycan analysis. Cells engineered to inhibit directly and specifically alpha-(1,6)-fucosyltransferase activity allows for the production of g/L levels of IgGs with strongly enhanced ADCC effector function, for which the level of fucosylation can be selected. The quick and efficient method described here should have broad practical applicability for the development of next-generation therapeutic antibodies with enhanced effector functions.

Development of a recombinant murine tumour model using hepatoma cells expressing hepatitis C virus nonstructural antigens.

Hepatitis C virus (HCV) chronically infects 2%-3% of the world's population, causing liver disease and cancer with prolonged infection. The narrow host range of the virus, being restricted largely to human hepatocytes, has made the development of relevant models to evaluate the efficacy of vaccines a challenge. We have developed a novel approach to accomplish this by generating a murine hepatoma cell line stably expressing nonstructural HCV antigens which can be used in vitro or in vivo to test HCV vaccine efficacies. These HCV-recombinant hepatoma cells formed large solid-mass tumours when implanted into syngeneic mice, allowing us to test candidate HCV vaccines to demonstrate the development of an HCV-specific immune response that limited tumour growth. Using this model, we tested the therapeutic potential of recombinant anti-HCV-specific vaccines based on two fundamentally different attenuated pathogen vaccine systems-attenuated Salmonella and recombinant adenoviral vector based vaccine. While attenuated Salmonella that secreted HCV antigens limited growth of the HCV-recombinant tumours when used in a therapeutic vaccination trial, replication-competent but noninfectious adenovirus expressing nonstructural HCV antigens showed overall greater survival and reduced weight loss compared to non-replicating nondisseminating adenovirus. Our results demonstrate a model with anti-tumour responses to HCV nonstructural (NS) protein antigens and suggest that recombinant vaccine vectors should be explored as a therapeutic strategy for controlling HCV and HCV-associated cancers.

Effects of annealing atmosphere and rGO concentration on the optical properties and enhanced photocatalytic performance of SnSe/rGO nanocomposites.

The photocatalytic properties of SnSe nanostructures (NSs) and SnSe/graphene nanocomposites with different graphene concentrations (5, 10, and 15 wt%/v) were investigated. The products were synthesized by a simple and cost-effective co-precipitation method. The samples obtained demonstrated that graphene concentration at an optimum amount was an important factor in enhancing the photocatalytic performance of the products. The graphene source was graphene oxide (GO) sheets and several characterization results indicated, which were used to remove Methylene blue (MB) dye, that the GO sheets were changed into reduced graphene oxide (rGO) sheets during the synthesis process. The optical properties of the products were studied using a room temperature photoluminescence (PL) spectrometer and it was observed that the near-band-edge (NBE) position of the samples was at the end of the red region between 729 and 756 nm of the electromagnetic spectrum, which was confirmed by a UV-vis spectrometer. The PL spectra of the samples also demonstrated three emissions from the violet, green, and orange regions of the visible spectrum, which were from different defects. The samples were annealed in a hydrogen and air atmosphere at 300 °C and it was found that defect concentrations were increased by annealing for the SnSe/rGO nanocomposites. The photocatalyst studies of the post-annealed samples revealed that the photocatalytic performance of the products was enhanced by annealing in hydrogen, while it was reduced by annealing in air. In addition to MB, the photocatalytic performance of the products for the degradation of phenol as a colorless pollutant was examined. It was observed that rGO in this process also had a significant role in the enhancement of photocatalytic performance. In fact, the electron spin resonance (ESR) test showed the role of rGO in photocatalytic activity very well.

Transanal dearterialization with targeted mucopexy is effective for advanced haemorrhoids.

AIM: Transanal haemorrhoidal dearterialization (THD) has become well established for the treatment of haemorrhoids. In this study we describe a technical modification of this technique, targeted mucopexy (THD TM), and report the results for advanced haemorrhoids. METHOD: The study included a prospective evaluation of patients with Grade IV (fourth-degree) haemorrhoids operated on with the THD TM technique. This consisted of an initial dearterialization when the haemorrhoidal arteries were transfixed and a second phase of mucopexy, using a different needle from that usually used in the original technique. RESULTS: From January 2007 to December 2011, 31 consecutive patients with Grade IV haemorrhoids were operated on using the THD TM technique. Postoperative pain was reported by 22 (70%) patients on day 1 and 19 (61%) on day 7, while nine (30%) did not experience any pain at all. Severe pain was reported by only nine (16%) patients. At a mean follow-up of 32 months, two (6.4%) patients required a further intervention for on-going symptoms. CONCLUSION: Transanal haemorrhoidal dearterialization TM is effective for advanced haemorrhoids.

Development, optimization, and scale-up of suspension Vero cell culture process for high titer production of oncolytic herpes simplex virus-1.

Oncolytic viruses (OVs) have emerged as a novel cancer treatment modality, and four OVs have been approved for cancer immunotherapy. However, high-yield and cost-effective production processes remain to be developed for most OVs. Here suspension-adapted Vero cell culture processes were developed for high titer production of an OV model, herpes simplex virus type 1 (HSV-1). Our study showed the HSV-1 productivity was significantly affected by multiplicity of infection, cell density, and nutritional supplies. Cell culture conditions were first optimized in shake flask experiments and then scaled up to 3 L bioreactors for virus production under batch and perfusion modes. A titer of 2.7 × 108 TCID50 mL-1 was obtained in 3 L batch culture infected at a cell density of 1.4 × 106 cells mL-1 , and was further improved to 1.1 × 109 TCID50 mL-1 in perfusion culture infected at 4.6 × 106 cells mL-1 . These titers are similar to or better than the previously reported best titer of 8.6 × 107 TCID50 mL-1 and 8.1 × 108 TCID50 mL-1 respectively obtained in labor-intensive adherent Vero batch and perfusion cultures. HSV-1 production in batch culture was successfully scaled up to 60 L pilot-scale bioreactor to demonstrate the scalability. The work reported here is the first study demonstrating high titer production of HSV-1 in suspension Vero cell culture under different bioreactor operating modes.

Descemet's membrane endothelial keratoplasty rejection after SARS-COV2 infection or vaccination: 2-year retrospective study.

PURPOSE: To assess the incidence of Descemet's membrane endothelial keratoplasty (DMEK) rejection potentially associated with coronavirus disease 2019 (COVID-19) infection or vaccination, and its association with known rejection risk factors during the first two years of the pandemic. METHODS: This retrospective study included patients with DMEK rejection between January 2020 and December 2021. Diagnostic criteria were based on symptoms, visual acuity, and other clinical assessments. Risk factors for graft rejection were considered, and a telephone survey was conducted to identify possible preceding COVID-19 infection or vaccination. RESULTS: Of 58 patients, 44 were included. Six patients (14%) reported COVID-19 infection, with one immediate endothelial graft rejection (EGR) post-infection. After vaccine availability, 13 of 36 patients had EGR at an average of 2.7 months post-vaccination. Five (38%) had immediate EGR following vaccination, four of which had concomitant risk factors for rejection. CONCLUSION: Although the risk of endothelial graft rejection (EGR) associated with COVID-19 infection or vaccination appears to be extremely low, there may be a causative relationship, especially in patients with pre-existing risk factors for EGR. A temporary increase in anti-rejection treatment following COVID-19 infection or vaccination is recommended, especially in patients with pre-existing risk factors, along with closer monitoring during the subsequent 4 to 8 weeks.

Protease-deleted adenovirus as an alternative for replication-competent adenovirus vector.

For cancer therapy and vaccination an amplified expression of the therapeutic gene is desired. Previously, we have developed a single-cycle adenovirus vector (SC-AdV) by deleting the adenovirus protease (PS) gene. In order to keep the E1 region intact within the PS-deleted adenoviruses, we examined the insertion of two transgenes under the control of a constitutive or inducible promoters. These were inserted between E4 and the right inverted terminal repeat in a wide variety of backbones with various combinations of PS, E3 and E4 deletion. Our data showed that PS-deleted adenoviruses, expressed transgenes as strongly as replication-competent AdVs in HEK293A and a variant of HeLa cells. In a head-to-head comparison in four human cell lines, we demonstrated that SC-AdV, was comparable for transgene expression efficacy with its replication-competent counterpart. However, the SC-AdV expresses its transgene 10 to 16,000 times higher than its replication-defective counterpart.

Surgical approaches to autologous limbal stem cell transplantation (LSCT) following severe corneal chemical burns.

Chemical injury of the conjunctiva and cornea are true ocular emergencies and require immediate intervention. They can produce severe, extensive ocular damage, including limbal stem cell deficiency (LSCD), and lead to irreversible visual loss. LSCD can be treated surgically through autologous limbal stem cell transplantation (LSCT). Autologous LSCT can be performed through cultivated limbal epithelial transplantation (CLET) or by direct grafting of limbal epithelial cells through conjunctival-limbal autografting (CLAU) or simple limbal epithelial transplantation (SLET). In this review we provide an overview of each surgical approach. CLET allows for a implantation of a large graft in the recipient eye while preserving donor cells. Its success rate is higher with an increased number of transplanted stem cells; failures tend to occur within the first year. CLAU is performed by directly transplanting autologous limbal stem cells from the patient's healthy eye, reducing the risk of immune rejection. This constitutes a risk for the donor eye, as the removal of stem cells from the fellow eye may lead to LSCD in the donor eye. SLET consists of direct implantation of donor stem cells on an amniotic membrane, thus avoiding the need for ex-vivo expansion. Combinations of CLAU and SLET within a single procedure have also been successfully utilized. Autologous LCST is an effective technique for surgical management of unilateral LCSD. Depending on the patient history and status of the fellow eye, either CLET, CLAU or SLET (including the combination of mini-CLAU and SLET) can be used to restore long-term function and prevent visual impairment.

Case image and multimodal imaging of a fully-formed functional chorioretinal anastomosis using OCT angiography.

OCT-angiography description of a fully functional large-diameter chorioretinal anastomosis, or chorioretinal shunt in a 38-year-old female patient with a past history of congenital toxoplasmosis and resulting macular atrophy and scarring.

Non stripping descemet membrane endothelial keratoplasty in difficult cases: A case series.

Endothelial keratoplasty (EK) has been increasingly used instead of penetrating keratoplasty (PK) in the management of post PK graft rejection. Both DSAEK and DMEK involve the surgical removal of the diseased host endothelial cell layer and Descemet's membrane (DM) (descemetorhexis) before transplantation, a technically challenging step, especially in post-PK eyes. Understandably, interest arose when non-stripping DMEK (nDMEK) was described in 2013, and recent studies suggested encouraging results without increased early postoperative failures or complications requiring rebubbling. The purpose of our series was to further study the feasibility and safety of nDMEK and to compare the results with traditional DMEK. This is a single center case series of 3 eyes which underwent nDMEK performed by experienced surgeons (C.P, A.M). Two eyes had nDMEK as a secondary procedure following a failed/rejected PK, while the third case underwent nDMEK on a virgin eye. Undiseased donor DM and a regular host endothelium were required to be eligible for nDMEK. The average change in CCT at last follow-up was -21.2% (±13.3). All required intracameral air injection (rebubbling) within the first few days, with a mean of 2.33 rebubblings per eye, the first one occurring at 6.33±2.52 days after surgery. Non-stripping DMEK surgery appears to be a feasible option, and results are satisfactory at mid to long term. However, in our series, the immediate postoperative period was marked by an increased rebubbling rate. While foreseeable particularly in high-risk cases, surgeons considering this technique should expect a higher risk of early rejection.

In-vivo tongue stiffness measured by aspiration: Resting vs general anesthesia.

Tongue cancer treatment often results in impaired speech, swallowing, or mastication. Simulating the effect of treatments can help the patient and the treating physician to understand the effects and impact of the intervention. To simulate deformations of the tongue, identifying accurate mechanical properties of tissue is essential. However, not many succeeded in characterizing in-vivo tongue stiffness. Those who did, measured the tongue At Rest (AR), in which muscle tone subsides even if muscles are not willingly activated. We expected to find an absolute rest state in participants 'under General Anesthesia' (GA). We elaborated on previous work by measuring the mechanical behavior of the in-vivo tongue under aspiration using an improved volume-based method. Using this technique, 5 to 7 measurements were performed on 10 participants both AR and under GA. The obtained Pressure-Shape curves were first analyzed using the initial slope and its variations. Hereafter, an inverse Finite Element Analysis (FEA) was applied to identify the mechanical parameters using the Yeoh, Gent, and Ogden hyperelastic models. The measurements AR provided a mean Young's Modulus of 1638 Pa (min 1035 - max 2019) using the Yeoh constitutive model, which is in line with previous ex-vivo measurements. However, while hoping to find a rest state under GA, the tongue unexpectedly appeared to be approximately 2 to 2.5 times stiffer under GA than AR. Explanations for this were sought by examining drugs administered during GA, blood flow, perfusion, and upper airway reflexes, but neither of these explanations could be confirmed.

Farnesoid X receptor - a molecular predictor of weight loss after vertical sleeve gastrectomy?

OBJECTIVE: To determine the expression of the bile acid receptor, farnesoid X (FXR), in human gastric mucosa and investigate correlations between expression and body-mass index (BMI) and in patients with obesity, with changes in weight and BMI following vertical sleeve gastrectomy (VSG). METHODS: Human gastric mucosa was obtained from normal/overweight individuals (macroscopically-normal tissue following surgery for malignancy) or from patients with obesity (VSG). The expression of FXR and its isoforms (FXRα, FXRß) were examined by quantitative PCR and compared with the G protein-coupled bile acid receptor, GPBA. In patients with obesity, changes in BMI and weight loss were determined following VSG. RESULTS: FXRα was the predominant isoform in normal/overweight individuals. FXR expression was higher in patients with obesity but GPBA receptor expression was unchanged. For those with obesity (n = 19), no correlation was found between FXR expression and change in Body-Mass Index (BMI)/month or weight loss/month, taken 3 ± 1 months after surgery, or in BMI or weight at surgery. CONCLUSIONS: Obesity is associated with increased FXR expression in the gastric mucosa. The findings are preliminary but suggest that this increase in FXR expression is a consequence of obesity, rather than its cause.

Development of suspension adapted Vero cell culture process technology for production of viral vaccines.

Vero cells are considered as the most widely accepted continuous cell line by the regulatory authorities (such as WHO) for the manufacture of viral vaccines for human use. The growth of Vero cells is anchorage-dependent. Scale-up and manufacturing in adherent cultures are labor intensive and complicated. Adaptation of Vero cells to grow in suspension will simplify subcultivation and process scale-up significantly, and therefore reduce the production cost. Here we report on a successful adaptation of adherent Vero cells to grow in suspension in a serum-free and animal component-free medium (IHM03) developed in-house. The suspension adapted Vero cell cultures in IHM03 grew to similar or better maximum cell density as what was observed for the adherent Vero cells grown in commercial serum-free media and with a cell doubling time of 40-44 h. Much higher cell density (8 × 106 cells/mL) was achieved in a batch culture when three volume of the culture medium was replaced during the batch culture process. Both adherent and suspension Vero cells from various stages were tested for their authenticity using short tandem repeat analysis. Testing result indicates that all Vero cell samples had 100% concordance with the Vero DNA control sample, indicating the suspension cells maintained their genetic stability. Furthermore, suspension Vero cells at a passage number of 163 were assayed for tumorigenicity, and were not found to be tumorigenic. The viral productivity of suspension Vero cells was evaluated by using vesicular stomatitis virus (VSV) as a model. The suspension cell culture showed a better productivity of VSV than the adherent Vero cell culture. In addition, the suspension culture could be infected at higher cell densities, thus improving the volumetric virus productivity. More than one log of increase in the VSV productivity was achieved in a 3L bioreactor perfusion culture infected at a cell density of 6.8 × 106 cells/mL.

Evaluation of recombinant adenovirus vectors and adjuvanted protein as a heterologous prime-boost strategy using HER2 as a model antigen.

Induction of strong antigen-specific cell-mediated and humoral responses are critical to developing a successful therapeutic vaccine. Herein, using HER2 as a model antigen, we aim to evaluate a therapeutic vaccine protocol that elicits anti-tumor antibody and cytotoxic T cells to HER2/neu antigen. Replication-competent (ΔPS AdV) and non-replicating recombinant adenoviral vectors (AdV) expressing a rat HER2/neu (ErbB2) oncogene, were generated and compared for four different doses and over four time points for their ability to induce antigen-specific T and B cell responses in mice. Although ΔPS AdV:Her2 vector was shown to induce more durable antigen-specific CD8+ T cell responses, overall, the AdV:Her2 vector induced broader T and B cell responses. Hence the AdV:Her2 vector was used to evaluate a heterologous prime-boost vaccination regimen using rat HER2 protein encapsulated in archaeosomes composed of a semi-synthetic glycolipid (sulfated S-lactosylarchaeol, SLA; and lactosylarchaeol, LA) (SLA/LA:HER2enc) or admixed with archaeosomes composed of SLA alone (SLA:HER2adm). We first tested AdV:Her2 using a prime-boost approach with SLA/LA:HER2enc, and thereafter evaluated a sub-optimal AdV:Her2 dose in a heterologous prime-boost approach with SLA:HER2adm. A single administration of AdV:Her2 alone induced strong cell-mediated immune responses, whereas SLA/LA:HER2enc alone induced strong antigen-specific IgG titers. In mice primed with a suboptimal dose of AdV:Her2, strong CD8+ T-cell responses were observed after a single dose which were not further augmented by protein boost. AdV:Her2 induced CD4+ specific T-cell responses were augmented by SLA:HER2adm. Homologous vaccination using SLA:HER2adm induced strong antigen-specific antibody responses. However, the overall magnitude of the responses was similar with three doses of SLA:HER2adm or Ad:HER2 prime followed by two doses of SLA:HER2adm. We demonstrate that AdV:Her2 is capable of inducing strong antigen-specific CD8+ T cell responses, even at a low dose, and that these responses can be broadened to include antigen-specific antibody responses by boosting with SLA adjuvanted proteins without compromising CD8 T cell responses elicited by AdV priming.

Overview of current surgical management of fibroids: 'Organ-preserving modalities'.

Uterine fibroids are the most common solid tumours occurring in female pelvis and frequently encountered by gynaecologists. Generally about 50% remain asymptomatic and can be monitored through regular follow-up visits but symptomatic fibroids require surgical intervention at some stage. They occur in 25 - 50% of women over the age of 30 years, increasing with age and being more common in certain ethnic populations, especially the Afro-Caribbean. They have a major impact on women's health and were the most common indication for hysterectomy in England in 1993 - 1994.They have significant cost implications, the 72,362 hysterectomies performed in 1993 - 1994 costing the NHS an estimated pound70 million. Although hysterectomy is the most certain cure for women with symptomatic fibroids who do not wish to preserve fertility, an increasing number of women are choosing and looking for the options of organ-conserving surgery. The surgery can be carried out abdominally, laparoscopically and vaginally although all routes are associated with an appreciable rate of morbidity. The discussion of organ-preserving surgery includes mainly myomectomy, transcervical resection of fibroid, uterine artery embolisation (UAE) and MRI-guided laser ablation. Hysterectomy is associated with a high rate of satisfaction and is likely to relieve menstrual problems in almost all women. Much work has been undertaken on this subject so far, with a view to safe and effective surgical approaches.

Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties.

The insulin-like growth factor (IGF) axis has been implicated in the progression of malignant disease and identified as a clinically important therapeutic target. Several IGF-1 receptor (IGF-1R) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signalling. We previously reported on the production of a soluble fusion protein consisting of the extracellular domain of human IGF-1R fused to the Fc portion of human IgG1 (first generation IGF-TRAP) that bound human IGF-1 and IGF-2 with a 3 log higher affinity than insulin. We showed that the IGF-TRAP had potent anti-cancer activity in several pre-clinical models of aggressive carcinomas. Here we report on the re-engineering of the IGF-TRAP with the aim of improving physicochemical properties and suitability for clinical applications. We show that cysteine-serine substitutions in the Fc hinge region of IGF-TRAP eliminated high-molecular-weight oligomerized species, while a further addition of a flexible linker, not only improved the pharmacokinetic profile, but also enhanced the therapeutic profile of the IGF-TRAP, as evaluated in an experimental colon carcinoma metastasis model. Dose-response profiles of the modified IGF-TRAPs correlated with their bio-availability profiles, as measured by the IGF kinase-receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. This study provides a compelling example of structure-based re-engineering of Fc-fusion-based biologics for better manufacturability that also significantly improved pharmacological parameters. It identifies the re-engineered IGF-TRAP as a potent anti-cancer therapeutic.

Cerebral organoids reveal early cortical maldevelopment in schizophrenia-computational anatomy and genomics, role of FGFR1.

Studies of induced pluripotent stem cells (iPSCs) from schizophrenia patients and control individuals revealed that the disorder is programmed at the preneuronal stage, involves a common dysregulated mRNA transcriptome, and identified Integrative Nuclear FGFR1 Signaling a common dysregulated mechanism. We used human embryonic stem cell (hESC) and iPSC-derived cerebral organoids from four controls and three schizophrenia patients to model the first trimester of in utero brain development. The schizophrenia organoids revealed an abnormal scattering of proliferating Ki67+ neural progenitor cells (NPCs) from the ventricular zone (VZ), throughout the intermediate (IZ) and cortical (CZ) zones. TBR1 pioneer neurons and reelin, which guides cortico-petal migration, were restricted from the schizophrenia cortex. The maturing neurons were abundantly developed in the subcortical regions, but were depleted from the schizophrenia cortex. The decreased intracortical connectivity was denoted by changes in the orientation and morphology of calretinin interneurons. In schizophrenia organoids, nuclear (n)FGFR1 was abundantly expressed by developing subcortical cells, but was depleted from the neuronal committed cells (NCCs) of the CZ. Transfection of dominant negative and constitutively active nFGFR1 caused widespread disruption of the neuro-ontogenic gene networks in hESC-derived NPCs and NCCs. The fgfr1 gene was the most prominent FGFR gene expressed in NPCs and NCCs, and blocking with PD173074 reproduced both the loss of nFGFR1 and cortical neuronal maturation in hESC cerebral organoids. We report for the first time, progression of the cortical malformation in schizophrenia and link it to altered FGFR1 signaling. Targeting INFS may offer a preventive treatment of schizophrenia.