Identification of novel candidate genes associated with non-syndromic tooth agenesis in Mongolian families.

OBJECTIVES: This study aimed to identify genetic variants associated with non-syndromic tooth agenesis (TA) in nine families from Mongolia using whole-exome sequencing (WES) and bioinformatics analysis. MATERIAL AND METHODS: The study enrolled 41 participants, including three inherited and six non-inherited families. WES analysis was performed on 14 saliva samples from individuals with non-syndromic TA. The potential candidate genes were identified through variant filtering and segregation analysis. The filtered variants were then analyzed in silico mutation impact analysis. RESULTS: WES analysis identified 21 variants associated with TA, and 5 of these variants met all filtering criteria. These variants were located in the exome region of MAST4, ITGA6, PITX2, CACNA1S, and CDON genes. The variant in PITX2 was found in eight participants from inherited and non-inherited families, while the MAST4 variant was identified in 6 participants from inherited families. CONCLUSIONS: The study identified various genetic variant candidates associated with TA in different family groups, with PITX2 being the most commonly identified. Our findings suggest that MAST4 may also be a novel candidate gene for TA due to its association with the Wnt signaling pathway. Additionally, we found that five candidate genes related to focal adhesion and calcium channel complex were significant and essential in tooth development. CLINICAL RELEVANCE: Identifying new pathogenic genes associated with TA can improve our understanding of the molecular mechanisms underlying the disease, leading to better diagnosis, prevention, and treatment. Early detection of TA based on biomarkers can improve dental management and facilitate orthodontic and prosthetic treatment.

Identification of potential key variants in mandibular premolar hypodontia through whole-exome sequencing.

Determining genotype-phenotype correlations in patients with hypodontia is important for understanding disease pathogenesis, although only a few studies have elucidated it. We aimed to identify genetic variants linked to non-syndromic bilateral mandibular second premolar hypodontia in a Korean population for the first time by specifying the phenotype of hypodontia. Twenty unrelated individuals with non-syndromic bilateral mandibular second premolar hypodontia were enrolled for whole-exome sequencing. Using a tooth agenesis gene set panel consisting of 112 genes based on literature, potential candidate variants were screened through variant filtering and prioritization. We identified 13 candidate variants in 12 genes, including a stop-gain variant (c.4750C>T) in LAMA3. Through the functional enrichment analysis of the prioritized genes, several terms related to tooth development were enriched in a protein-protein interaction network of candidate genes for mandibular premolar hypodontia. The hypodontia group also had approximately 2-fold as many mutated variants in all four genes related to these key terms, which are CDH1, ITGB4, LAMA3, LAMB3, as those in the 100 healthy control group individuals. The relationship between enriched terms and pathways and mandibular premolar hypodontia was also investigated. In addition, we identified some known oligodontia variants in patients with hypodontia, strengthening the possibility of synergistic effects in other genes. This genetic investigation may be a worthwhile preliminary attempt to reveal the pathogenesis of tooth agenesis and sets a background for future studies.

Development of bioinformatics and multi-omics analyses in organoids.

Pre-clinical models are critical in gaining mechanistic and biological insights into disease progression. Recently, patient-derived organoid models have been developed to facilitate our understanding of disease development and to improve the discovery of therapeutic options by faithfully recapitulating in vivo tissues or organs. As technological developments of organoid models are rapidly growing, computational methods are gaining attention in organoid researchers to improve the ability to systematically analyze experimental results. In this review, we summarize the recent advances in organoid models to recapitulate human diseases and computational advancements to analyze experimental results from organoids. [BMB Reports 2023; 56(1): 43-48].

Enzyme activity engineering based on sequence co-evolution analysis.

The utility of engineering enzyme activity is expanding with the development of biotechnology. Conventional methods have limited applicability as they require high-throughput screening or three-dimensional structures to direct target residues of activity control. An alternative method uses sequence evolution of natural selection. A repertoire of mutations was selected for fine-tuning enzyme activities to adapt to varying environments during the evolution. Here, we devised a strategy called sequence co-evolutionary analysis to control the efficiency of enzyme reactions (SCANEER), which scans the evolution of protein sequences and direct mutation strategy to improve enzyme activity. We hypothesized that amino acid pairs for various enzyme activity were encoded in the evolutionary history of protein sequences, whereas loss-of-function mutations were avoided since those are depleted during the evolution. SCANEER successfully predicted the enzyme activities of beta-lactamase and aminoglycoside 3'-phosphotransferase. SCANEER was further experimentally validated to control the activities of three different enzymes of great interest in chemical production: cis-aconitate decarboxylase, α-ketoglutaric semialdehyde dehydrogenase, and inositol oxygenase. Activity-enhancing mutations that improve substrate-binding affinity or turnover rate were found at sites distal from known active sites or ligand-binding pockets. We provide SCANEER to control desired enzyme activity through a user-friendly webserver.

Histogram analysis of apparent diffusion coefficient at 3.0t: Correlation with prognostic factors and subtypes of invasive ductal carcinoma.

PURPOSE: To evaluate apparent diffusion coefficient (ADC) histogram parameters that show correlations with prognostic factors and subtypes of breast cancer. MATERIALS AND METHODS: At 3.0T, various ADC histogram parameters were calculated including the entire tumor volume in 173 invasive ductal carcinomas: the minimum, 10th percentile, mean, median, 90th percentile, and maximum. ADC parameters were correlated with prognostic factors and subtype. RESULTS: The mean ADCmedian value was significantly higher in the group with lymph node metastasis, HER2 positivity, and a Ki-67 value <14% than in the group with negativity for lymph node metastasis, HER2 negativity, and a Ki-67 value ≥14% (0.907, 0.978, and 0.941 vs. 0.735, 0.778, and 0.761 × 10(-3) mm(2) /s, respectively) (P < 0.01). There was no significant correlation between ADCmedian and tumor size, histologic grade, estrogen receptor expression, and progesterone receptor expression (P = 0.272, 0.113, 0.261, and 0.181, respectively). For most ADC parameters except for ADCmin , the mean of variable ADC parameters of HER2-positive, luminal A, luminal B-HER2(+), triple-negative, and luminal B-HER2(-) diseases were arranged in descending order (1.175, 0.936, 0.863, 0.811, and 0.665 × 10(-3) mm(2) /s in ADCmedian , respectively) with statistical significant difference (P < 0.001). In multivariate analysis, histologic grade, the Ki-67 index, and HER2 expression were statistically significant explanatory prognostic factors for ADCmedian and the Ki-67 index had the most robust effects on ADC parameters (standardized coefficient = -0.317). CONCLUSION: Various ADC parameters were correlated with prognostic factors and subtype, except for ADCmin . HER2 positivity showed high ADC values and high Ki-67 index revealed low ADC values.

Successful removal of an intravesical electrical wire cable.

A few previous reports have described cases wherein electrical wire cables were inserted into the male urethra and bladder. Electrical wire cables are available at home and are easy to insert. However, after they coil in the patient's bladder, they are difficult to remove. In February 2013, a 30-year-old man presented to the emergency room of SMG-SNU Boramae Medical Center with a urethral foreign body. He had inserted an electrical wire cable into his urethra for the purpose of masturbation, despite having a regular sex partner and no underlying disease. A kidney-ureter-bladder radiography showed a tangled wire in his bladder and urethra. On the next day, we tried to remove the wire cystoscopically, but this proved to be impossible because of complex coiling and the slippery surface of the wire. A Pfannenstiel incision was made to remove the foreign body. No postoperative complications were noted.

The incidence of Fever after subinguinal microsurgical varicocelectomy.

PURPOSE: In the present study, we aimed to identify the incidence of fever in patients after subinguinal microsurgical varicocelectomy and to evaluate the clinical factors associated with the occurrence of the fever. MATERIALS AND METHODS: We retrospectively reviewed the cases of patients who underwent subinguinal microsurgical varicocelectomy (group A) under spinal anesthesia. In addition, we reviewed the cases of patients who underwent microsurgical vasovasostomy under spinal anesthesia as a control group (group B). The incidence of fever in each group was compared. We investigated the clinical factors influencing the occurrence of fever in the patients of group A. RESULTS: The incidence of fever in group A was significantly higher than that in group B (32.5% [53/163] vs. 0.4% [1/284]; p<0.001). Clinical factors such as age, varicocele grade, weight, height, operation time, number of ligated veins, usage of immediate postoperative analgesics, presence of postoperative hematoma, and duration of hospital stay were not significantly associated with the occurrence of fever. CONCLUSIONS: We found that one-third of the patients developed transient fever after subinguinal microsurgical varicocelectomy, and therefore, this information should be provided during preoperative counseling.

Reasons for delayed orchiopexies in a korean tertiary care hospital.

PURPOSE: Since the 1990s, it has been well known that orchiopexies should be performed by no later than 2 years of age. Nevertheless, studies from other countries report a substantial number of delayed orchiopexies. On the basis of an analysis of a tertiary care hospital database, we aimed to investigate the incidence of delayed orchiopexies performed in patients after 5 years of age and to understand the causes of such delays and the possible consequences. MATERIALS AND METHODS: We retrospectively analyzed the surgical database of Seoul National University Hospital between 2004 and 2012 and detected patients who underwent orchiopexy later than 5 years of age. Reasons for delayed orchiopexies were studied and the possible consequences of delayed orchiopexies were assessed with respect to surgical difficulty and testicular volume. RESULTS: We found 160 cases of delayed orchiopexies, which accounted for about 15% of all orchiopexies performed. Two major reasons for delay were related to the parents of the child: parental delay and parental request for the treatment of persistent retractile testis. Acquired cryptorchidism was found in 21 cases (13.1%), mainly associated with hypospadias. Surgical difficulty, especially owing to a short testicular cord, was encountered in 48 cases (30.2%), and a comparison with age-matched normative values showed substantially smaller testicular volume. CONCLUSIONS: Despite well-established guidelines for the optimal age of surgery, 15% of orchiopexies were not performed at a proper time. Improved propagation of an optimal age limit is necessary to reduce the rate of delayed orchiopexies considering increases in surgical difficulty and potential testicular growth retardation.

Choosing which practitioner sees the next patient in the preanesthesia evaluation clinic based on the relative speeds of the practitioner.

BACKGROUND: When a practitioner in a preanesthesia evaluation clinic is not evaluating a patient because no patient is waiting to be seen, the practitioner often has other responsibilities such as reviewing charts of patients. When practitioners differ in how quickly they complete evaluations, multiple scenarios can be created wherein the slowest practitioner would only evaluate patients when the number of patients waiting exceeds a threshold (e.g., at least 2 patients are waiting). METHODS: Review of operations research studies identified conditions for which such management of the queue can be beneficial (e.g., mean evaluation time of the fastest practitioner is less than half that of the slowest practitioner). These conditions were compared with the actual completion rates of certified registered nurse practitioners at a hospital's clinic. The 99.9% confidence intervals (CI) were calculated for ratios of mean evaluation times. RESULTS: The fastest practitioner was typically 1.23 times faster than the second fastest practitioner (CI 1.22-1.23) and 1.61 times faster than the slowest of three practitioners (1.59-1.61). These are significantly less than the 3 times and 2 times faster, respectively, that would be sufficiently large to warrant managing queue discipline. Practitioners with longer mean evaluation times had larger percentage utilizations of working time (Kendall τb = 0.56, P = 0.0001), inconsistent with preferential assignment of patients to the fastest practitioner(s) available. CONCLUSIONS: Practitioners' speeds in evaluating patients do not differ sufficiently for information systems to be used routinely to choose who evaluates the next patient (i.e., state-dependent assignment policy). Clinics aiming to reduce patient waiting should focus on reducing the overall mean evaluation time (e.g., by chart review ahead), appropriately scheduling patients, and having the right numbers of nursing assistants and practitioners.