Genomic and Metabolomic Analyses of Nocardiopsis maritima YSL2 as the Mycorrhizosphere Bacterium of Suaeda maritima (L.) Dumort.

Nine bacteria were isolated from the episphere of Suaeda maritima (L.) Dumort. Among them, the bacterial strain YSL2 displayed the highest antimicrobial activity on agar plates and exhibited significant novelty compared with other bacteria based on 16S rRNA analysis. Consequently, Nocardiopsis maritima YSL2T was subjected to phenotypic characterization and whole-genome sequencing. Phylogenetic analysis revealed its close association with Nocardiopsis aegyptia SNG49T. Furthermore, genomic analysis of strain YSL2T revealed the presence of various gene clusters, indicating its potential for producing antimicrobial secondary metabolites. Upon cultivation on a large scale, maritiamides A and B (1 and 2) were isolated and characterized as cyclic hexapeptides based on nuclear magnetic resonance, ultraviolet, infrared, and mass spectrometric data. The absolute configurations of the amino acid residues in the maritiamides were determined through chiral derivatization, utilizing FDAA and GITC. Maritiamides 1 and 2 exhibited promising antibacterial activities against Staphylococcus epidermidis and weakly inhibited the growth of Escherichia coli and Pseudomonas fluorescens.

Impact of the COVID-19 pandemic on mortality and loss to follow-up among patients with dementia receiving anti-dementia medications.

The coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted vulnerable groups, such as patients with dementia. We examined changes in mortality and loss to follow-up in patients with dementia using data from the Korean National Health Insurance Service research database. Patients with dementia who visited a medical institution with a recorded dementia-related diagnostic code, including Alzheimer's disease, and who received anti-dementia medication between February 2018 and January 2020 were included in this study. We divided patients with dementia receiving anti-dementia medications into two cohorts: those newly diagnosed with dementia between February 2018 and January 2019 (n = 62,631) and those diagnosed between February 2019 and January 2020 (n = 54,494). Then, we conducted a one-year follow-up of their records, tracking the cohort diagnosed between February 2018 and January 2019 from February 2019 to January 2020, as well as the cohort diagnosed between February 2019 and January 2020 from February 2020 to January 2021. There was a significant increase in follow-up loss among patients newly diagnosed with dementia during the COVID-19 outbreak, from 42.04% in 2019 to 45.89% in 2020. Female sex, younger age, fewer comorbidities, diagnosis of dementia at the Department of Neurology or Psychiatry, and higher income were associated with decreased follow-up loss and mortality. This study highlights the importance of paying extra attention to patients with dementia receiving anti-dementia medications, particularly during pandemics, given their increased risk of loss to follow-up.

Long-term impact of late pulmonary hypertension requiring medication in extremely preterm infants with severe bronchopulmonary dysplasia.

This study investigated whether late pulmonary hypertension (LPH) independently increases the risk of long-term mortality or neurodevelopmental delay (NDD) in extremely preterm infants (EPIs) with severe bronchopulmonary dysplasia (BPD). Using prospectively collected data from the Korean Neonatal Network, we included EPIs with severe BPD born at 22-27 weeks' gestation between 2013 and 2021. EPIs having severe BPD with LPH (LPH, n = 124) were matched 1:3 with those without pulmonary hypertension (PH) as controls (CON, n = 372), via propensity score matching. LPH was defined as PH with the initiation of medication after 36 weeks' corrected age (CA). Long-term mortality after 36 weeks' CA or NDD at 18-24 months' CA was analyzed. NDD was assessed using composite scores based on various neurodevelopmental assessment modalities. LPH had significantly higher long-term mortality or NDD (45.2% vs. 23.1%, P < 0.001), mortality (24.2% vs. 4.84%, P < 0.001), and NDD (68.4% vs. 37.8%, P = 0.001), respectively than CON, even after adjusting for different demographic factors. Multivariable regression demonstrated that LPH independently increased the risk of mortality or NDD (adjusted odds ratio, 1.95; 95% confidence intervals, 1.17-3.25). When LPH occurs in EPIs with severe BPD, special monitoring and meticulous care for long-term survival and neurodevelopment are continuously needed.

Canine multiple primary tumours: Mammary tubular carcinoma, uterine leiomyosarcoma, and facial sebaceous epithelioma.

Multiple primary malignant tumours (MPMTs) are multiple neoplasms with independent pathogenetic origins, placing great importance on the tumorigenesis and clinical treatment. However, due to the rare occurrence and diagnostic confusion, MPMTs have rarely been investigated in veterinary medicine. In this report, a 10-year-old intact female Maltese dog had MPMTs, consisting of two malignant tumours and one benign tumour each derived from a topographically different site: tubular carcinoma in the mammary glands, leiomyosarcoma in the uterus and sebaceous epithelioma in the cheek. The unique combination of MPMTs would be the first case in veterinary research to give insight into the diagnosis, disease characteristics, and surgical treatment.

HLA-DRB1 is associated with cefaclor-induced immediate hypersensitivity.

Background: Drug-induced hypersensitivity such as anaphylaxis is an important cause of drug-related morbidity and mortality. Cefaclor is a leading cause of drug induced type I hypersensitivity in Korea, but little is yet known about genetic biomarkers to predict this hypersensitivity reaction. We aimed to evaluate the possible involvement of genes in cefaclor induced type I hypersensitivity. Methods: Whole exome sequencing (WES) and HLA genotyping were performed in 43 patients with cefaclor induced type I hypersensitivity. In addition, homology modeling was performed to identify the binding forms of cefaclor to HLA site. Results: Anaphylaxis was the most common phenotype of cefaclor hypersensitivity (90.69%). WES results show that rs62242177 and rs62242178 located in LIMD1 region were genome-wide significant at the 5 × 10-8 significance level. Cefaclor induced type I hypersensitivity was significantly associated with HLA-DRB1∗04:03 (OR 4.61 [95% CI 1.51-14.09], P < 0.002) and HLA-DRB1∗14:54 (OR 3.86 [95% CI 1.09-13.67], P < 0.002). Conclusion: LIMD1, HLA-DRB1∗04:03 and HLA-DRB1∗14:54 may affect susceptibility to cefaclor induced type I hypersensitivity. Further confirmative studies with a larger patient population should be performed to ascertain the role of HLA-DRB1 and LIMD1 in the development of cefaclor induced hypersensitivity.

Enhanced Recovery After Surgery for Craniotomies: A Systematic Review and Meta-analysis.

The efficacy of the enhanced recovery after surgery (ERAS) protocols in neurosurgery has not yet been established. We performed a systematic review and meta-analysis of randomized controlled trials to compare the effects of ERAS protocols and conventional perioperative care on postoperative outcomes in patients undergoing craniotomy. The primary outcome was postoperative length of hospital stay. Secondary outcomes included postoperative pain visual analog pain scores, incidence of postoperative nausea and vomiting (PONV), postoperative complications, all-cause reoperation, readmission after discharge, and mortality. A literature search up to August 10, 2023, was conducted using PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus databases. Five studies, including 871 patients, were identified for inclusion in this review. Compared with conventional perioperative care, ERAS protocols reduced the length of postoperative hospital stay (difference of medians, -1.52 days; 95% CI: -2.55 to -0.49); there was high heterogeneity across studies (I2, 74%). ERAS protocols were also associated with a lower risk of PONV (relative risk, 0.79; 95% CI: 0.69-0.90; I2, 99%) and postoperative pain with a visual analog scale score ≥4 at postoperative day 1 (relative risk, 0.37; 95% CI: 0.28-0.49; I2, 14%). Other outcomes, including postoperative complications, did not differ between ERAS and conventional care groups. ERAS protocols may be superior to conventional perioperative care in craniotomy patients in terms of lower length of hospital stay, lower incidence of PONV, and improved postoperative pain scores. Further randomized trials are required to identify the impact of ERAS protocols on the quality of recovery after craniotomy.

Clinical feature, GALC variant spectrum, and genotype-phenotype correlation in Korean Krabbe disease patients: Multicenter experience over 13 years.

Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by deficiency of the galactocerebrosidase (GALC) due to variants in the GALC gene. Here, we provide the first and the largest comprehensive analysis of clinical and genetic characteristics, and genotype-phenotype correlations of KD in Korean in comparison with other ethnic groups. From June 2010 to June 2023, 10 patients were diagnosed with KD through sequencing of GALC. Clinical features, and results of GALC sequencing, biochemical test, neuroimaging, and neurophysiologic test were obtained from medical records. An additional nine previously reported Korean KD patients were included for review. In Korean KD patients, the median age of onset was 2 years (3 months-34 years) and the most common phenotype was adult-onset (33%, 6/18) KD, followed by infantile KD (28%, 5/18). The most frequent variants were c.683_694delinsCTC (23%) and c.1901T>C (23%), while the 30-kb deletion was absent. Having two heterozygous pathogenic missense variants was associated with later-onset phenotype. Clinical features were similar to those of other ethnic groups. In Korean KD patients, the most common phenotype was the adult-onset type and the GALC variant spectrum was different from that of the Caucasian population. This study would further our understanding of KD.

Timing and impact of percutaneous endoscopic gastrostomy insertion in patients with amyotrophic lateral sclerosis: a comprehensive analysis.

Dysphagia is common in amyotrophic lateral sclerosis (ALS) patients, often requiring percutaneous endoscopic gastrostomy (PEG) for enteral nutrition. We retrospectively analyzed data from 188 Korean patients with ALS who underwent PEG tube insertion at five-time points: symptom onset (t1), diagnosis (t2), recommended time for gastrostomy (t3), PEG insertion (t4), and one-year post-insertion (t5). The recommended time point for gastrostomy (T-rec for gastrostomy) was defined as the earlier time point between a weight loss of more than 10% and advanced dysphagia indicated by the ALSFRS-R swallowing subscore of 2 or less. The T-rec for gastrostomy was reached at 22 months after symptom onset, followed by PEG insertion at 30 months, resulting in an 8-month delay. During the delay, the ALSFRS-R declined most rapidly at 1.7 points/month, compared to 0.8 points/month from symptom onset to diagnosis, 0.7 points/month from diagnosis to T-rec for gastrostomy, and 0.6 points/month after the PEG insertion. It is crucial to discuss PEG insertion before significant weight loss or severe dysphagia occurs and minimize the delay between the recommended time for gastrostomy and the actual PEG insertion. A stratified and individualized multidisciplinary team approach with careful symptom monitoring and proactive management plans, including early PEG insertion, should be prioritized to improve patient outcomes.

Concurrent primary splenic lymphoma and mammary gland tumour with polycystic ovaries in a dog.

Here, we report a rare case of concurrent primary splenic lymphoma and mammary gland tumour (MGT) with polycystic ovaries in a 10-year-old, intact female Jindo dog. The dog was presented with multiple masses in the fourth left mammary gland, the largest of which measured 6 cm in diameter, along with enlargement of the left inguinal lymph node on physical examination. Ultrasonography, radiography, and computed tomography scans revealed polycystic ovaries and a mass in the tail of the spleen, after total splenectomy and mastectomy with ovariohysterectomy, histopathological examination identified splenic diffuse large B cell lymphoma and malignant myoepithelioma of the mammary gland was found. To our knowledge, this is the first report of the concurrent occurrence of splenic lymphoma, MGT, and polycystic ovaries in a dog.

Machine learning-based analysis for prediction of surgical necrotizing enterocolitis in very low birth weight infants using perinatal factors: a nationwide cohort study.

Early prediction of surgical necrotizing enterocolitis (sNEC) in preterm infants is important. However, owing to the complexity of the disease, identifying infants with NEC at a high risk for surgical intervention is difficult. We developed a machine learning (ML) algorithm to predict sNEC using perinatal factors obtained from the national cohort registry of very low birth weight (VLBW) infants. Data were collected from the medical records of 16,385 VLBW infants registered in the Korean Neonatal Network (KNN). Infants who underwent surgical intervention were identified with sNEC, and infants who received medical treatment, with medical NEC (mNEC). We used 38 variables, including maternal, prenatal, and postnatal factors that were obtained within 1 week of birth, for training. A total of 1085 patients had NEC (654 with sNEC and 431 with mNEC). VLBW infants showed a higher incidence of sNEC at a lower gestational age (GA) (p < 0.001). Our proposed ensemble model showed an area under the receiver operating characteristic curve of 0.721 for sNEC prediction.    Conclusion: Proposed ensemble model may help predict which infants with NEC are likely to develop sNEC. Through early prediction and prompt intervention, prognosis of sNEC may be improved. What is Known: • Machine learning (ML)-based techniques have been employed in NEC research for prediction, diagnosis, and prognosis, with promising outcomes. • While most studies have utilized abdominal radiographs and clinical manifestations of NEC as data sources, and have demonstrated their usefulness, they may prove weak in terms of early prediction. What is New: • We analyzed the perinatal factors of VLBW infants acquired within 7 days of birth and used ML-based analysis to identify which infants with NEC are vulnerable to clinical deterioration and at high risk for surgical intervention using nationwide cohort data.

Recent Developments in (K, Na)NbO3-Based Lead-Free Piezoceramics.

(K0.5Na0.5)NbO3 (KNN)-based ceramics have been extensively investigated as replacements for Pb(Zr, Ti)O3-based ceramics. KNN-based ceramics exhibit an orthorhombic structure at room temperature and a rhombohedral-orthorhombic (R-O) phase transition temperature (TR-O), orthorhombic-tetragonal (O-T) phase transition temperature (TO-T), and Curie temperature of -110, 190, and 420 °C, respectively. Forming KNN-based ceramics with a multistructure that can assist in domain rotation is one technique for enhancing their piezoelectric properties. This review investigates and introduces KNN-based ceramics with various multistructures. A reactive-templated grain growth method that aligns the grains of piezoceramics in a specific orientation is another approach for improving the piezoelectric properties of KNN-modified ceramics. The piezoelectric properties of the [001]-textured KNN-based ceramics are improved because their microstructures are similar to those of the [001]-oriented single crystals. The improvement in the piezoelectric properties after [001] texturing is largely influenced by the crystal structure of the textured ceramics. In this review, [001]-textured KNN-based ceramics with different crystal structures are investigated and systematically summarized.

Improved organic and pesticide-free rice (Oryza sativa L.) authentication based on multiple stable isotope ratio analysis and rice milling state.

This study looked at the application of multiple bulk stable isotope ratio analysis to accurately authenticate organic rice and counteract organic fraud within the expanding global organic market. Variations of δ13C, δ15N, δ18O, and δ34S in organic, pesticide-free, and conventional rice were assessed across different milling states (brown, milled, and bran). Individual stable isotope ratio alone such as δ15N demonstrated limited capacity to correctly differentiate organic, pesticide-free, and conventional rice. A support vector machine model-incorporating δ13C, δ15N, δ18O, and δ34S in milled rice-yielded overall predictability (95%) in distinguishing organic, pesticide-free, and conventional rice, where δ18O emerged as the pivotal variable based on the feature weights in the SVM model. These findings suggest the potential of multi-isotope and advanced statistical approaches in combating organic fraud and ensuring authenticity in the food supply chain.

Veillonella faecalis sp. nov., a propionic acid-producing bacterium isolated from the faeces of an infant.

A strictly anaerobic, Gram-stain-negative, catalase-negative, cocci-shaped, and propionate-producing bacterial strain, named Ds1651T was isolated from the fecal sample collected from a South Korean infant. Through a comparison of 16S rRNA gene sequences, it was revealed that Ds1651T had the highest phylogenetic affinity with Veillonella nakazawae KCTC 25297 T (99.86%), followed by Veillonella infantium KCTC 25370 T (99.80%), and Veillonella dispar KCTC 25309 T (99.73%) in the family Veillonellaceae. Average nucleotide identity values between Ds1651T and three reference species were 95.48% for Veillonella nakazawae KCTC 25297 T, 94.46% for Veillonella infantium KCTC 25370 T, and 92.81% for Veillonella dispar KCTC 25309 T. The G + C content of Ds1651T was 38.58 mol%. Major fermentation end-products were acetic and propionic acids in Trypticase peptone glucose yeast extract broth with 1% (v/v) sodium lactate. The predominant cellular fatty acids that account for more than 10% were summed in Feature 8 (C17:1 ω8c and/or C17:2) and C13:0. Based on the findings from phylogenetic, genomic, phenotypic, and chemotaxonomic studies, we propose that the type strain Ds1651T (= KCTC 25477 T = GDMCC 1.3707 T) represents a novel bacterial species within the genus Veillonella, with the proposed name Veillonella faecalis sp. nov.

Comparing pronunciation challenges in South Korean preschoolers with unilateral single-sided deafness due to cochlear nerve deficiency to a norm-referenced standard.

This study aimed to compare the development of pronunciation in South Korean preschoolers with unilateral cochlear nerve deficiency (CND) to that of age-matched preschoolers with normal hearing, a topic that has not been explored previously. In a retrospective analysis, 25 preschoolers with unilateral CND who had undergone a speech evaluation battery, including a pronunciation and vocabulary test, were enrolled. Utilizing the Urimal Test of Articulation and Phonation and customized language ability tests, pronunciation and vocabulary were assessed. The subjects' speech evaluation scores were converted into age-adjusted z-scores using normal controls' data. While vocabulary performance was within normal limits, their average pronunciation z-score was -2.90, significantly lower than both the zero reference point and their vocabulary z-scores. None of the subjects scored above average in pronunciation. Thirteen patients were recommended for articulation therapy, seven were considered as potential candidates for this therapy, and the remaining five were within normal limits. There was no observed correlation between the development of pronunciation and vocabulary. Notably, some subjects' pronunciation scores did not improve, even after serial follow-up during their preschool years. Despite typical vocabulary development, preschoolers with unilateral CND exhibit significant delays in pronunciation. These findings emphasize the necessity for vigilant monitoring of their language development.

Separation of Lipoproteins for Quantitative Analysis of 14C-Labeled Lipid-Soluble Compounds by Accelerator Mass Spectrometry.

To date, 14C tracer studies using accelerator mass spectrometry (AMS) have not yet resolved lipid-soluble analytes into individual lipoprotein density subclasses. The objective of this work was to develop a reliable method for lipoprotein separation and quantitative recovery for biokinetic modeling purposes. The novel method developed provides the means for use of small volumes (10-200 µL) of frozen plasma as a starting material for continuous isopycnic lipoprotein separation within a carbon- and pH-stable analyte matrix, which, following post-separation fraction clean up, created samples suitable for highly accurate 14C/12C isotope ratio determinations by AMS. Manual aspiration achieved 99.2 ± 0.41% recovery of [5-14CH3]-(2R, 4'R, 8'R)-α-tocopherol contained within 25 µL plasma recovered in triacylglycerol rich lipoproteins (TRL = Chylomicrons + VLDL), LDL, HDL, and infranatant (INF) from each of 10 different sampling times for one male and one female subject, n = 20 total samples. Small sample volumes of previously frozen plasma and high analyte recoveries make this an attractive method for AMS studies using newer, smaller footprint AMS equipment to develop genuine tracer analyses of lipophilic nutrients or compounds in all human age ranges.

Clinical Activity of TGF-ß Inhibitor Vactosertib in Combination with Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study.

PURPOSE: The study was to determine the activity and safety of the TGF-ß inhibitor vactosertib in combination with imatinib in patients with desmoid tumors. PATIENTS AND METHODS: In this investigator-initiated, open-label, multicenter, phase Ib/II trial, patients with desmoid tumors not amenable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase Ib, the vactosertib dose was set at 100 mg (level -1) and 200 mg (level 1) to determine the recommended phase II dose (RP2D). Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. RESULTS: No dose-limiting toxicities were observed during phase Ib; therefore RP2D was defined at doses of 400 mg imatinib daily in combination with 200 mg vactosertib. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. Most toxicities were mild to moderate myalgia (n = 10, 37%), anemia (n = 10, 37%), and nausea (n = 9, 33.3%). Common grade 3 to 4 toxicities included neutropenia (n = 6, 22.2%) and anemia (n = 5, 18.5%). CONCLUSIONS: The vactosertib and imatinib combination was well tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-ß inhibitor, in this rare and difficult-to-treat desmoid tumor.

Progranulin haploinsufficiency mediates cytoplasmic TDP-43 aggregation with lysosomal abnormalities in human microglia.

BACKGROUND: Progranulin (PGRN) haploinsufficiency due to progranulin gene (GRN) variants can cause frontotemporal dementia (FTD) with aberrant TAR DNA-binding protein 43 (TDP-43) accumulation. Despite microglial burden with TDP-43-related pathophysiology, direct microglial TDP-43 pathology has not been clarified yet, only emphasized in neuronal pathology. Thus, the objective of this study was to investigate TDP-43 pathology in microglia of patients with PGRN haploinsufficiency. METHODS: To design a human microglial cell model with PGRN haploinsufficiency, monocyte-derived microglia (iMGs) were generated from FTD-GRN patients carrying pathogenic or likely pathogenic variants (p.M1? and p.W147*) and three healthy controls. RESULTS: iMGs from FTD-GRN patients with PGRN deficiency exhibited severe neuroinflammation phenotype and failure to maintain their homeostatic molecular signatures, along with impaired phagocytosis. In FTD-GRN patients-derived iMGs, significant cytoplasmic TDP-43 aggregation and accumulation of lipid droplets with profound lysosomal abnormalities were observed. These pathomechanisms were mediated by complement C1q activation and upregulation of pro-inflammatory cytokines. CONCLUSIONS: Our study provides considerable cellular and molecular evidence that loss-of-function variants of GRN in human microglia can cause microglial dysfunction with abnormal TDP-43 aggregation induced by inflammatory milieu as well as the impaired lysosome. Elucidating the role of microglial TDP-43 pathology in intensifying neuroinflammation in individuals with FTD due to PGRN deficiency and examining consequential effects on microglial dysfunction might yield novel insights into the mechanisms underlying FTD and neurodegenerative disorders.

Impact of nanopollution on plant growth, photosynthesis, toxicity, and metabolism in the agricultural sector: An updated review.

Nanotechnology provides distinct benefits to numerous industrial and commercial fields, and has developed into a discipline of intense interest to researchers. Nanoparticles (NPs) have risen to prominence in modern agriculture due to their use in agrochemicals, nanofertilizers, and nanoremediation. However, their potential negative impacts on soil and water ecosystems, as well as plant growth and physiology, have caused concern for researchers and policymakers. Concerns have been expressed regarding the ecological consequences and toxicity effects associated with nanoparticles as a result of their increased production and usage. Moreover, the accumulation of nanoparticles in the environment poses a risk, not only because of the possibility of plant damage but also because nanoparticles may infiltrate the food chain. In this review, we have documented the beneficial and detrimental effects of NPs on seed germination, shoot and root growth, plant biomass, and nutrient assimilation. Nanoparticles exert toxic effects by inducing ROS generation and stimulating cytotoxic and genotoxic effects, thereby leading to cell death in several plant species. We have provided possible mechanisms by which nanoparticles induce toxicity in plants. In addition to the toxic effects of NPs, we highlighted the importance of nanomaterials in the agricultural sector. Thus, understanding the structure, size, and concentration of nanoparticles that will improve plant growth or induce plant cell death is essential. This updated review reveals the multifaceted connection between nanoparticles, soil and water pollution, and plant biology in the context of agriculture.

Optimal Therapeutic Strategy of Bone Marrow-Originated Autologous Mesenchymal Stromal/Stem Cells for ALS.

Amyotrophic lateral sclerosis (ALS) is characterized by selective and progressive neurodegenerative changes in motor neural networks. Given the system complexity, including anatomically distributed sites of degeneration from the motor cortex to the spinal cord and chronic pro-inflammatory conditions, a cell-based therapeutic strategy could be an alternative approach to treating ALS. Lessons from previous mesenchymal stromal/stem cell (MSC) trials in ALS realized the importance of 3 aspects in current and future MSC therapy, including the preparation of MSCs, administration routes and methods, and recipient-related factors. This review briefly describes the current status and future prerequisites for an optimal strategy using bone-marrow-originated MSCs to treat ALS. We suggest mandatory factors in the optimized therapeutic strategy focused on advanced therapy medicinal products produced according to Good Manufacturing Practice, an optimal administration method, the selection of proper patients, and the importance of biomarkers.