Association Between Antibiotic Exposure and Thyroid Cancer: A Nationwide Cohort Study in South Korea.

Background: Although recent studies have introduced antibiotics as a potential risk factor for thyroid cancer, further studies are necessary. We examined the association between long-term antibiotic usage and thyroid cancer risk. Methods: This nationwide cohort study investigated 9,804,481 individuals aged 20 years or older who participated in health screening (2005-2006) with follow-up ending on December 31, 2019, using the Korean National Health Insurance Service database. Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for thyroid cancer risk according to the cumulative days of antibiotic prescription and the number of antibiotic classes, respectively. A 1:1 propensity score (PS) matching was also performed for analysis. Results: Compared with nonusers of antibiotics, participants prescribed ≥365 days of antibiotics showed an increased risk of thyroid cancer (aHR, 1.71; CI, 1.66-1.78) after adjusting for covariates including age, smoking status, comorbidities including thyroid-related diseases, and the number of head and neck computed tomography scans. Participants prescribed ≥365 days of antibiotics also had a significantly increased risk of thyroid cancer (aHR, 1.37; CI, 1.34-1.40) compared with participants prescribed 1-14 days of antibiotics. Association remained significant in the 1:1 PS-matched cohort. Moreover, compared with nonusers of antibiotics, the 5 or more antibiotic class user group had a higher thyroid cancer risk (aHR, 1.71; CI, 1.65-1.78). Conclusions: Long-term antibiotic prescriptions and an increasing number of antibiotic classes may be associated with a higher risk of thyroid cancer in a duration-dependent manner. The effects of long-term antibiotic exposure on thyroid cancer should be further investigated.

CanISO: a database of genomic and transcriptomic variations in domestic dog (Canis lupus familiaris).

BACKGROUND: The domestic dog, Canis lupus familiaris, is a companion animal for humans as well as an animal model in cancer research due to similar spontaneous occurrence of cancers as humans. Despite the social and biological importance of dogs, the catalogue of genomic variations and transcripts for dogs is relatively incomplete. RESULTS: We developed CanISO, a new database to hold a large collection of transcriptome profiles and genomic variations for domestic dogs. CanISO provides 87,692 novel transcript isoforms and 60,992 known isoforms from whole transcriptome sequencing of canine tumors (N = 157) and their matched normal tissues (N = 64). CanISO also provides genomic variation information for 210,444 unique germline single nucleotide polymorphisms (SNPs) from the whole exome sequencing of 183 dogs, with a query system that searches gene- and transcript-level information as well as covered SNPs. Transcriptome profiles can be compared with corresponding human transcript isoforms at a tissue level, or between sample groups to identify tumor-specific gene expression and alternative splicing patterns. CONCLUSIONS: CanISO is expected to increase understanding of the dog genome and transcriptome, as well as its functional associations with humans, such as shared/distinct mechanisms of cancer. CanISO is publicly available at https://www.kobic.re.kr/caniso/ .

Machine Learning Attacks-Resistant Security by Mixed-Assembled Layers-Inserted Graphene Physically Unclonable Function.

Mixed layers of octadecyltrichlorosilane (ODTS) and 1H,1H,2H,2H-perfluorooctyltriethoxysilane (FOTS) on an active layer of graphene are used to induce a disordered doping state and form a robust defense system against machine-learning attacks (ML attacks). The resulting security key is formed from a 12 × 12 array of currents produced at a low voltage of 100 mV. The uniformity and inter-Hamming distance (HD) of the security key are 50.0 ± 12.3% and 45.5 ± 16.7%, respectively, indicating higher security performance than other graphene-based security keys. Raman spectroscopy confirmed the uniqueness of the 10,000 points, with the degree of shift of the G peak distinguishing the number of carriers. The resulting defense system has a 10.33% ML attack accuracy, while a FOTS-inserted graphene device is easily predictable with a 44.81% ML attack accuracy.

Ameliorative effects of Kyung-Ok-Ko and its mixture with Pueraria lobata Ohwi on postmenopausal osteoporosis by promoting phytoestrogenic activity in rats.

Introduction: Kyung-Ok-Ko (KOK) is a popular traditional medicine used as a natural alternative to hormone replacement therapy for treating postmenopausal symptoms in Asia. Pueraria lobata Ohwi (P. lobata) is rich in isoflavones and has been traditionally used in combination with other herbs to produce synergistic and pharmaceutical effects via a multi-target approach for disease treatment. We aimed to investigate the phytoestrogenic effects of KOK extract against postmenopausal symptoms in ovariectomized (OVX) rats and confirm its efficacy by mixing KOK and P. lobata extracts. Methods: OVX rats were daily oral administrated with KOK and KOK + P. lobata mixture extracts (300-400 mg/kg) and their body weight and tail temperature were monitored for 12 weeks. The biochemical parameters, estradiol levels, and bone turnover markers were measured in the serum samples. Moreover, the estrogen receptor, ER-α and ER-ß expression in the uterus and the uterus morphology were evaluated. AMPK, ATG1/ULK1, and mTOR protein expression in the liver were assessed. Results: The 12-week treatment with KOK and KOK + P. lobata mixture extracts did not cause liver damage or hormonal changes in the OVX rats. The treatments reduced the high lipid accumulation-related body weight gain and the tail temperature increase that was induced by ovariectomy. Further, it exhibited protective effects against hyperlipidemia and osteoporosis. No significant difference was observed in uterine weight compared to the OVX-treated group, while endometrial thickness reduction inhibition was observed due to ovariectomy. Bone mineral density (BMD) and serum osteocalcin levels, which decreased in OVX rats, increased with both treatments. Western blotting analysis showed that ER-α and ER-ß were not expressed in the treated rats, whereas these proteins were expressed in Sham-operated rats. No significant differences in the phosphorylation of AMPK were observed; however, the ATG1/ULK1 and mTOR protein phosphorylation levels were upregulated and downregulated in the treated rats compared to those of OVX rats, respectively. Conclusion: This is the first in vivo study observing the efficacy and synergistic effects of the mixture of KOK and P. lobata. Our results suggest the potential of KOK and KOK + P. lobata mixture as an alternative therapy for alleviating menopausal symptoms.

Tumor-derived interleukin-1α and leukemia inhibitory factor promote extramedullary hematopoiesis.

Extramedullary hematopoiesis (EMH) expands hematopoietic capacity outside of the bone marrow in response to inflammatory conditions, including infections and cancer. Because of its inducible nature, EMH offers a unique opportunity to study the interaction between hematopoietic stem and progenitor cells (HSPCs) and their niche. In cancer patients, the spleen frequently serves as an EMH organ and provides myeloid cells that may worsen pathology. Here, we examined the relationship between HSPCs and their splenic niche in EMH in a mouse breast cancer model. We identify tumor produced IL-1α and leukemia inhibitory factor (LIF) acting on splenic HSPCs and splenic niche cells, respectively. IL-1α induced TNFα expression in splenic HSPCs, which then activated splenic niche activity, while LIF induced proliferation of splenic niche cells. IL-1α and LIF display cooperative effects in activating EMH and are both up-regulated in some human cancers. Together, these data expand avenues for developing niche-directed therapies and further exploring EMH accompanying inflammatory pathologies like cancer.

Association of antibiotic use with risk of lung cancer: A nationwide cohort study.

BACKGROUND: Although recent studies indicated that antibiotics may be a risk factor for lung cancer, further understanding is needed. We investigated the association of long-term antibiotic exposure with lung cancer risk. METHODS: This population-based retrospective cohort study investigated 6,214,926 participants aged ≥ 40 years who underwent health screening examinations (2005-2006) from the Korean National Health Insurance Service database. The date of the final follow-up was December 31, 2019. Exposures were the cumulative days of antibiotics prescription and the number of antibiotics classes. The adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for lung cancer risk according to antibiotic use were assessed using multivariable Cox proportional hazards regression. RESULTS: Compared with the antibiotic non-user group, participants with ≥ 365 days of antibiotics prescribed had a significantly increased risk of lung cancer (aHR, 1.21; 95% CI, 1.16-1.26). Participants with ≥ 365 days of antibiotics prescribed also had a significantly increased risk of lung cancer (aHR, 1.21; 95% CI, 1.17-1.24) than 1-14 days of the antibiotic user group. The results were also consistent in competing risk analyses and adjusted Cox regression models that fitted restricted cubic spline. Compared with the antibiotic non-user group, ≥ 5 antibiotic classes prescribed group had a higher lung cancer risk (aHR, 1.15; 95% CI, 1.10-1.21). CONCLUSION: The long-term cumulative days of antibiotic use and the increasing number of antibiotics classes were associated with an increased risk of lung cancer in a clear duration-dependent manner after adjusting for various risk factors.

Selective cytotoxicity of a novel mitochondrial complex I inhibitor, YK-135, against EMT-subtype gastric cancer cell lines due to impaired glycolytic capacity.

Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancers have the worst prognosis due to their higher recurrence rate, higher probability of developing metastases and higher chemoresistance compared to those of other molecular subtypes. Pharmacologically actionable somatic mutations are rarely found in EMT-subtype gastric cancers, limiting the utility of targeted therapies. Here, we conducted a high-throughput chemical screen using 37 gastric cancer cell lines and 48,467 synthetic smallmolecule compounds. We identified YK-135, a small-molecule compound that showed higher cytotoxicity toward EMT-subtype gastric cancer cell lines than toward non-EMT-subtype gastric cancer cell lines. YK-135 exerts its cytotoxic effects by inhibiting mitochondrial complex I activity and inducing AMP-activated protein kinase (AMPK)-mediated apoptosis. We found that the lower glycolytic capacity of the EMT-subtype gastric cancer cells confers synthetic lethality to the inhibition of mitochondrial complex I, possibly by failing to maintain energy homeostasis. Other well-known mitochondrial complex I inhibitors (e.g., rotenone and phenformin) mimic the efficacy of YK-135, supporting our results. These findings highlight mitochondrial complex I inhibitors as promising therapeutic agents for EMT-subtype gastric cancers and YK-135 as a novel chemical scaffold for further drug development. [BMB Reports 2022; 55(12): 645-650].

Dermoid Cyst of Nasal Tip with a Sinus Tract Extending to the Intracranium: A Case Report.

Nasal dermoid cysts are rare congenital anomalies that affect one in 20,000 to one in 40,000 individuals. Herein, we report a case of an initially misdiagnosed nasal dermoid cyst with intracranial extension. Among nasal dermoids, the lesion of the nasal tip is considered uncommon. Therefore, this should always be considered as a differential diagnosis of midline nasal masses, and a proper diagnostic approach should be taken.

A Basic Domain-Derived Tripeptide Inhibits MITF Activity by Reducing its Binding to the Promoter of Target Genes.

The keratinocytes in UV-irradiated skin produce and secrete α-melanocyte-stimulating hormone. α-Melanocyte-stimulating hormone upregulates the expression of MITF in melanocytes through the cAMP‒protein kinase A‒CREB signaling pathway. Thereafter, MITF induces the expression of melanogenic genes, including the tyrosinase gene TYR and TYRP-1 and TYRP-2 genes, which leads to the synthesis and accumulation of melanin. In this study, we examined whether MITF basic region-derived tripeptides can bind to the DNA-binding domain of MITF and inhibit MITF-induced melanogenesis through the inhibition of MITF‒DNA binding. MITF-KGR, a representative MITF-derived tripeptide, suppressed the transcriptional activity of MITF by disrupting its binding to the promoter region of the target genes, which resulted in the inhibition of skin epidermis thickness and melanin synthesis in vivo and in vitro. Our results indicate that MITF-KGR exerts an inhibitory effect on melanogenesis by targeting MITF.

Diagnosis and management of toxic shock syndrome after breast reconstructive procedures with silicone implants.

Breast implant insertion is one of the most commonly used methods for breast reconstruction after total mastectomy. However, infection is a common postoperative complication of implant insertion. In most cases, these infections can be managed with antibiotics and supportive therapy. However, severe septic conditions, such as toxic shock syndrome (TSS), can sometimes occur. TSS is an extremely rare but life-threatening complication, for which early diagnosis and proper management play a crucial role in determining patients' outcome. Although only 16 cases of TSS after breast implant insertion have been reported in the literature, most of those cases involved a serious clinical course. The reason for the seriousness of the clinical course of TSS in these cases is that the initial impression and presentation of these patients are nonspecific, and patients can easily be misdiagnosed as having a simple upper respiratory infection, causing the underlying condition to be neglected. Herein, we present two patients who were diagnosed with TSS after receiving breast reconstruction surgery via a silicone implant after total mastectomy. Both patients were misdiagnosed at the initial examination since they showed no local infectious signs on the postoperative wound.

3DIV update for 2021: a comprehensive resource of 3D genome and 3D cancer genome.

Three-dimensional (3D) genome organization is tightly coupled with gene regulation in various biological processes and diseases. In cancer, various types of large-scale genomic rearrangements can disrupt the 3D genome, leading to oncogenic gene expression. However, unraveling the pathogenicity of the 3D cancer genome remains a challenge since closer examinations have been greatly limited due to the lack of appropriate tools specialized for disorganized higher-order chromatin structure. Here, we updated a 3D-genome Interaction Viewer and database named 3DIV by uniformly processing ∼230 billion raw Hi-C reads to expand our contents to the 3D cancer genome. The updates of 3DIV are listed as follows: (i) the collection of 401 samples including 220 cancer cell line/tumor Hi-C data, 153 normal cell line/tissue Hi-C data, and 28 promoter capture Hi-C data, (ii) the live interactive manipulation of the 3D cancer genome to simulate the impact of structural variations and (iii) the reconstruction of Hi-C contact maps by user-defined chromosome order to investigate the 3D genome of the complex genomic rearrangement. In summary, the updated 3DIV will be the most comprehensive resource to explore the gene regulatory effects of both the normal and cancer 3D genome. '3DIV' is freely available at http://3div.kr.

iCSDB: an integrated database of CRISPR screens.

High-throughput screening based on CRISPR-Cas9 libraries has become an attractive and powerful technique to identify target genes for functional studies. However, accessibility of public data is limited due to the lack of user-friendly utilities and up-to-date resources covering experiments from third parties. Here, we describe iCSDB, an integrated database of CRISPR screening experiments using human cell lines. We compiled two major sources of CRISPR-Cas9 screening: the DepMap portal and BioGRID ORCS. DepMap portal itself is an integrated database that includes three large-scale projects of CRISPR screening. We additionally aggregated CRISPR screens from BioGRID ORCS that is a collection of screening results from PubMed articles. Currently, iCSDB contains 1375 genome-wide screens across 976 human cell lines, covering 28 tissues and 70 cancer types. Importantly, the batch effects from different CRISPR libraries were removed and the screening scores were converted into a single metric to estimate the knockout efficiency. Clinical and molecular information were also integrated to help users to select cell lines of interest readily. Furthermore, we have implemented various interactive tools and viewers to facilitate users to choose, examine and compare the screen results both at the gene and guide RNA levels. iCSDB is available at https://www.kobic.re.kr/icsdb/.

Corrigendum: Brain Metastases From Lung Adenocarcinoma May Preferentially Involve the Distal Middle Cerebral Artery Territory and Cerebellum.

[This corrects the article DOI: 10.3389/fonc.2020.01664.].

Brain Metastases From Lung Adenocarcinoma May Preferentially Involve the Distal Middle Cerebral Artery Territory and Cerebellum.

Although whole-brain radiation therapy (WBRT) is the mainstay of treatment for brain metastases (BMs), the concept of saving eloquent cortical lesions has been promoted. If BMs from lung cancer are spatially biased to certain regions, this approach can be justified more. We evaluated whether BMs from lung cancer show a preference for certain brain regions and if their distribution pattern differs according to the histologic subtype of the primary lung cancer. In this retrospective study, 562 BMs in 80 patients were analyzed (107 BMs from small cell carcinoma, 432 from adenocarcinoma, and 23 from squamous cell carcinoma). Kernel density estimation was performed to investigate whether BM spatial patterns differed among lung cancer subtypes. Further, we explored more detailed subregions where BMs from adenocarcinomas occur frequently using one-way analysis of variance. Finally, we divided our cohort into those with fewer (≤10) and more (>10) BMs and evaluated whether this biased pattern was maintained across limited and extensive stages. For small cell carcinoma, BMs were biased to the cerebellum, but this did not reach statistical significance. For adenocarcinoma, BMs were found more frequently near the distal middle cerebral artery (MCA) territory and cerebellum than in other arterial territories (p < 0.01). The precentral and postcentral gyri were the most significant subregions within the distal anterior cerebral artery (ACA) and MCA territories (p < 0.01). Crus I and Lobule VI were significant regions within the cerebellum (p < 0.01). Regardless of the number of BMs, the affinity to the distal MCA territory and cerebellum was maintained. The present data confirm that BMs from lung adenocarcinoma may preferentially involve the distal MCA territory and cerebellum.

Association between Use of Nutritional Labeling and the Metabolic Syndrome and Its Components.

In this study, we looked into the association between the diagnosis of metabolic syndrome (MetS) and nutritional label awareness. This study used data from the Korea National Health and Nutritional Examination Survey (KNHANES) for the years 2007 to 2015. The study population consisted of a total of 41,667 Koreans of which 11,401 (27.4%) were diagnosed with metabolic syndrome and 30,266 (72.6%) were not. Groups not using nutritional labeling had a 24% increase in odds risk (OR: 1.24, 95% CI 1.14-1.35) of MetS compared to groups using nutritional labeling. Use of nutritional labeling was associated with all components of MetS. Central obesity showed the highest increase in odds risk (OR: 1.23, 95% CI 1.13-1.35) and high blood pressure showed the lowest increase in odds risk (OR: 1.11, 95% CI 1.02-1.20). Subgroup analysis revealed that statistically significant factors were smoking status, drinking status and stress status. Groups that smoke, groups that do not drink and groups with high stress were more vulnerable to MetS when not using nutritional labeling. People not using food labels tends to develop metabolic syndromes more than people using foods labels. In the subgroup analysis, drinking status, smoking status and stress status were significant factors.

GEMiCCL: mining genotype and expression data of cancer cell lines with elaborate visualization.

Database URL: GEMiCCL is available at https://www.kobic.kr/GEMICCL/.

An underwater superoleophobic nanofibrous cellulosic membrane for oil/water separation with high separation flux and high chemical stability.

Oil spills and an increasing demand for the treatment of industrial oily wastewater are driving the need for continuous large-scale oil/water separation processes. Herein, we report a nanofibrous cellulosic membrane (NFC membrane) for the continuous high-flux separation of large amounts of oil/water mixtures. The NFC membrane was fabricated using wet electrospinning, a facile yet effective method for stacking nanofibrous membranes with uniform porous structures on a substrate. Owing to its cellulosic nature, the membrane showed excellent underwater superoleophobicity along with robust chemical stability and was able to separate oil/water mixtures at efficiencies exceeding 99%. Repetitive oil/water separations could be performed using a single membrane, during which the oil content in the filtrate remained extremely low (<29 ppm). The nanofibrous membrane exhibited a fine porous structure that was interconnected throughout the membrane, resulting in a high oil intrusion pressure (>30 kPa) that allowed not only gravity-driven but also pressure-driven separation of oil/water mixtures. The separation flux reached 120 000 L m-2 h-1 during pressure-driven separations, which is a very promising feature for actual applications such as the large-scale treatment of industrial oily wastewater.

Effect of Lowering Laser Energy on the Surface Roughness of Human Corneal Lenticules in SMILE.

PURPOSE: To determine the effect of lowering femtosecond laser energy on the surface quality of the intrastromal interface during small incision lenticule extraction (SMILE). METHODS: Forty age- and diopter-matched female patients (40 eyes) with moderate myopia received SMILE with different energy levels (100 to 150 nJ) and fixed spot separation (4.5 µm). Five human corneal lenticules from each energy group were evaluated by atomic force microscopy and scanning electron microscopy (SEM). Both anterior and posterior surface characteristics of the lenticules were assessed. RESULTS: All measurements of surface roughness were approximately three times higher and in the anterior and posterior surface of the lenticules with the energy level of 150 nJ than with 100 nJ (P < .001). Furthermore, atomic force microscopy analysis found that energy differences of 15 nJ or more made a significant difference in surface roughness at energy levels of 115 nJ or higher. Interestingly, there was no significant difference in all roughness values of both surfaces among the 100, 105, and 110 nJ groups. In addition, all values of surface roughness were significantly positively correlated with laser energy for both anterior and posterior surfaces of the lenticule (P < .001). Consistent with atomic force microscopy results, SEM also showed that the SMILE lenticules in the higher laser energy group had more irregular surfaces. CONCLUSIONS: Lowering laser energy levels can improve surface quality of the lenticule of SMILE. To achieve better visual outcomes with faster recovery after the procedure, it is recommended to reduce the laser energy to less than 115 nJ at a spot separation of 4.5 µm. [J Refract Surg. 2017;33(9):617-624.].

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of ß1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway.

The human CD99 protein is a 32-kDa glycosylated transmembrane protein that regulates various cellular responses, including cell adhesion and leukocyte extravasation. We previously reported that CD99 activation suppresses ß1 integrin activity through dephosphorylation of focal adhesion kinase (FAK) at Y397. We explored a molecular mechanism underlying the suppression of ß1 integrin activity by CD99 agonists and its relevance to tumor growth in vivo CD99-Fc fusion proteins or a series of CD99-derived peptides suppressed ß1 integrin activity by specifically interacting with three conserved motifs of the CD99 extracellular domain. CD99CRIII3, a representative CD99-derived 3-mer peptide, facilitated protein kinase A-SHP2 interaction and subsequent activation of the HRAS/RAF1/MEK/ERK signaling pathway. Subsequently, CD99CRIII3 induced FAK phosphorylation at S910, which led to the recruitment of PTPN12 and PIN1 to FAK, followed by FAK dephosphorylation at Y397. Taken together, these results indicate that CD99-derived agonist ligands inhibit fibronectin-mediated ß1 integrin activation through the SHP2/ERK/PTPN12/FAK signaling pathway.