BRAF inhibitors (e.g., vemurafenib) are widely used to treat metastatic melanoma with the BRAF V600E mutation. The initial response is often dramatic, but treatment resistance leads to disease progression in the majority of cases. Although secondary mutations in the mitogen-activated protein kinase signaling pathway are known to be responsible for this phenomenon, the molecular mechanisms governing acquired resistance are not known in more than half of patients. Here we report a genome- and transcriptome-wide study investigating the molecular mechanisms of acquired resistance to BRAF inhibitors. A microfluidic chip with a concentration gradient of vemurafenib was utilized to rapidly obtain therapy-resistant clones from two melanoma cell lines with the BRAF V600E mutation (A375 and SK-MEL-28). Exome and transcriptome data were produced from 13 resistant clones and analyzed to identify secondary mutations and gene expression changes. Various mechanisms, including phenotype switching and metabolic reprogramming, have been determined to contribute to resistance development differently for each clone. The roles of microphthalmia-associated transcription factor, the master transcription factor in melanocyte differentiation/dedifferentiation, were highlighted in terms of phenotype switching. Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.

BRAF inhibitors (e.g., vemurafenib) are widely used to treat metastatic melanoma with the BRAF V600E mutation. The initial response is often dramatic, but treatment resistance leads to disease progression in the majority of cases. Although secondary mutations in the mitogen-activated protein kinase signaling pathway are known to be responsible for this phenomenon, the molecular mechanisms governing acquired resistance are not known in more than half of patients. Here we report a genome- and transcriptome-wide study investigating the molecular mechanisms of acquired resistance to BRAF inhibitors. A microfluidic chip with a concentration gradient of vemurafenib was utilized to rapidly obtain therapy-resistant clones from two melanoma cell lines with the BRAF V600E mutation (A375 and SK-MEL-28). Exome and transcriptome data were produced from 13 resistant clones and analyzed to identify secondary mutations and gene expression changes. Various mechanisms, including phenotype switching and metabolic reprogramming, have been determined to contribute to resistance development differently for each clone. The roles of microphthalmia-associated transcription factor, the master transcription factor in melanocyte differentiation/dedifferentiation, were highlighted in terms of phenotype switching. Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.

Actinomycosis is a chronic granulomatous disease caused by the species of Actinomyces. Although it has become a rare disease in the present antibiotics era, it still needs long term antibiotic treatment and often mis- or delayed- diagnosed due to no typical sign and symptoms. Most often, it occurs in the cervicofacial region. Middle ear is not a common site for Actinomycosis, and the inner ear involvement is extremely rare. Here, we report a case of middle ear Actinomycosis involving facial nerve and lateral semicircular canal.
Actinomyces ; Actinomycosis* ; Anti-Bacterial Agents ; Ear, Inner ; Ear, Middle* ; Facial Nerve* ; Granulomatous Disease, Chronic ; Rare Diseases ; Semicircular Canals* ; Temporal Bone

Background: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease mediated by T helper type 2 (Th2) cells in acute phase. Group 2 innate lymphoid cells (ILCs) play a role in the initiation of the Th2 response. Although mold exposure is associated with the development of AD, studies on the underlying mechanisms are lacking. This study investigated whether group 2 ILCs are involved in inflammation in AD-like skin induced by Aspergillus fumigatus (Af). Methods: We investigated changes of group 2 ILCs population in Af-induced AD-like skin lesions. To induce AD-like skin lesions, Af extracts were applied to the dorsal skin of BALB/c and Rag1−/− mice five times per week, with repeat exposures at 2-week intervals. Results: The clinical parameters were higher in the Af-treated group than in the control group. Histologic findings revealed epiderrmal and dermal thickening as well as eosinophil and mast cell infiltration into the skin of Af-treated mice. Populations of group 2 ILCs in the skin were also significantly higher in the Af-treated group. In addition, interleukin-33 mRNA expression was significantly higher in the skin lesions of the Af-treated mice. In the Rag1−/− mice lacking mature lymphocytes, AD-like skin lesions were still induced by Af and ILCs depletion using an anti-CD90.2 mAb lowered the Af-induced inflammatory response. Conclusions Group 2 ILCs may play a role in a murine model of Af-induced AD-like skin lesions.

Background: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease mediated by T helper type 2 (Th2) cells in acute phase. Group 2 innate lymphoid cells (ILCs) play a role in the initiation of the Th2 response. Although mold exposure is associated with the development of AD, studies on the underlying mechanisms are lacking. This study investigated whether group 2 ILCs are involved in inflammation in AD-like skin induced by Aspergillus fumigatus (Af). Methods: We investigated changes of group 2 ILCs population in Af-induced AD-like skin lesions. To induce AD-like skin lesions, Af extracts were applied to the dorsal skin of BALB/c and Rag1−/− mice five times per week, with repeat exposures at 2-week intervals. Results: The clinical parameters were higher in the Af-treated group than in the control group. Histologic findings revealed epiderrmal and dermal thickening as well as eosinophil and mast cell infiltration into the skin of Af-treated mice. Populations of group 2 ILCs in the skin were also significantly higher in the Af-treated group. In addition, interleukin-33 mRNA expression was significantly higher in the skin lesions of the Af-treated mice. In the Rag1−/− mice lacking mature lymphocytes, AD-like skin lesions were still induced by Af and ILCs depletion using an anti-CD90.2 mAb lowered the Af-induced inflammatory response. Conclusions Group 2 ILCs may play a role in a murine model of Af-induced AD-like skin lesions.

BACKGROUND AND OBJECTIVES: Abnormal thyroid function influences the cardiovascular system. In particular, brief thyroid functional change due to levothyroxine (LT4) suppression therapy and withdrawal in papillary thyroid cancer (PTC) patients can affect cardiovascular system and other biochemical markers. However, the effect of brief thyroid functional change on arterial stiffness has not been evaluated. Therefore, we evaluated the changes in arterial stiffness according to short-term thyroid hormone levels in patients who underwent total thyroidectomy and radioactive iodine (RAI) therapy for PTC. MATERIALS AND METHODS: Patients with PTC (n=17; 15 females, mean age 52 years) who underwent total thyroidectomy and RAI therapy were enrolled in this study. The arterial stiffness was evaluated using the corrected augmentation index for heart rate (AI@75) and brachial-ankle pulse wave velocity (BaPWV). Serum thyroid hormone levels and arterial stiffness parameters were checked three times consecutively: the day before thyroidectomy (Visit 1; baseline euthyroid state), after LT4 withdrawal (Visit 2; pre-RAI hypothyroid state) and 4 weeks after RAI (Visit 3; post-RAI thyrotoxic state). Biochemical markers, which can influence the arterial stiffness, were also measured. RESULTS: The heart rate, AI@75 and serum thyroid hormone levels changed significantly at each visit. BaPWV was not significantly changed. Changes in AI@75 correlated with systolic blood pressure (SBP), serum thyroid hormone levels, total cholesterol and high density lipoprotein cholesterol in univariate analysis. In multivariate analysis, SBP was the independent factor for AI@75 changes. CONCLUSION: These results suggest that brief thyroid functional changes can influence AI@75. And SBP was important factor for AI@75 change.
Biomarkers ; Blood Pressure ; Cardiovascular System ; Cholesterol ; Cholesterol, HDL ; Female ; Heart Rate ; Humans ; Iodine* ; Multivariate Analysis ; Pulse Wave Analysis ; Thyroid Function Tests ; Thyroid Gland* ; Thyroid Neoplasms ; Thyroidectomy ; Thyroxine ; Vascular Stiffness*

Previous animal studies have not conclusively determined the association between exposure to humidifier disinfectants (HDs) containing 5-chloro-2-methyl-4-isothiazolin-3-one (CMIT) and/or 2-methyl-4-isothiazolin-3-one (MIT) and development of HD-associated lung injuries. Nonetheless, patients exposed to HDs containing only CMIT and/or MIT showed clinically similar lung injuries to those exposed to HDs containing polyhexamethylene guanidine (PHMG) or oligo (2-[2-ethoxy]ethoxyethyl) guanidinium chloride (PGH). Here, we report twin sisters with lung injuries associated with exposure to CMIT/MIT-containing HDs. At 6 months of age, a younger twin sister presented with the 3-day history of cough, sputum, and respiratory difficulty. Chest radiography revealed multiple patchy consolidation and ground-glass opacities with pneumothorax and pneumomediastinum. Thoracostomy was performed due to pneumothorax at admission and she was discharged at 11 days of hospitalization. At 5 years of age, multiple tiny nodules and faint centrilobular ground-glass opacities were observed with the small pneumatocele. The elder sister visited a tertiary hospital due to dyspnea at 12 months of age. Chest radiography showed consolidation, pneumomediastinum, and pulmonary interstitial emphysema. There was no response to the administration of immunosuppressant drugs and antifibrotic agents. At 5 years of age, chest CT revealed ground-glass opacity and multiple tiny centrilobular ground-glass opacities nodules in both lungs with exercise intolerance.
Animals ; Cough ; Disinfectants ; Dyspnea ; Emphysema ; Guanidine ; Hospitalization ; Humans ; Humidifiers ; Lung Injury* ; Lung* ; Mediastinal Emphysema ; Pneumothorax ; Radiography ; Siblings ; Sputum ; Tertiary Care Centers ; Thoracostomy ; Thorax ; Tomography, X-Ray Computed ; Twins

BACKGROUND AND OBJECTIVES: Although canal wall up mastoidectomy (CWUM) has been performed frequently as a treatment for chronic otitis media (COM), the necessity of CWUM for non-cholesteatomatous COM (NCCOM) is still controversial. Since elderly people often have systemic problems, there is a high likelihood of side effects after general anesthesia, so it is important to judge the necessity of mastoidectomy. The purpose of this study was to investigate the effect of CWUM for the treatment of NCCOM in patients over 65 years of age. SUBJECTS AND METHOD: Forty-two cases of CWUM with tympanoplasty type I performed as a treatment for NCCOM from 2007 through 2016 were reviewed retrospectively. Pure tone audiometry was performed preoperatively and postoperatively, and preoperative temporal bone CT was used to evaluate the mastoid status. The valsalva maneuver (VM) was used to evaluate the eustachian tube function. RESULTS: The total number of patients was 42 and the success rate of eardrum repair was 92.8%. Comparison of hearing results taken preoperatively and postoperatively showed significant hearing improvement in both air conduction and air-bone gap. When hearing results were compared according to the mastoid status and the response of VM, there were no significant differences. CONCLUSION: Mastoidectomy combined with tympanoplasty type I showed a high success rate of ear drum repair and good hearing improvement, with no critical side effects. Therefore, mastoidectomy does not need to be limited by one's old age. Adequate mastoidectomy after proper consideration of the mastoid status will be helpful in the treatment of the disease.
Aged ; Anesthesia, General ; Audiometry ; Ear ; Eustachian Tube ; Hearing* ; Humans ; Mastoid ; Methods ; Otitis Media* ; Otitis* ; Retrospective Studies ; Temporal Bone ; Tympanic Membrane ; Tympanoplasty* ; Valsalva Maneuver

Coronavirus disease 2019 (COVID-19) is usually less severe in children and adolescents than in adults. However, it can cause severe respiratory illness in a small proportion of children with risk factors. Here, we report a rare case of a 10-year-old boy with postinfectious bronchiolitis obliterans that developed after pneumonia caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This patient was previously healthy apart from a high body mass index (BMI, 30.13; 99.6th percentile for the age bracket), history of preterm birth (35 weeks), and low birth weight (1,850 g). He had persistent exertional dyspnea after recovering from SARS-CoV-2-related pneumonia. Spirometry revealed obstructive lung disease with the following results: predicted forced vital capacity (FVC% pred ), 71%; forced expiratory volume in 1 second (FEV 1 % pred ), 63%; FEV 1 /FVC, 0.81; and forced expiratory flow 25-75 % pred , 55%. Chest computed tomography showed multifocal areas of parenchymal hyperlucency and mosaic attenuation in both lungs. This case suggests that careful observation of children with obesity and low birth weight is necessary after recovery from SARS-CoV-2-related pneumonia.

Primary hyperparathyroidism occurs as a result of isolated parathyroid adenoma in 80% to 85% of all cases. A 99mtechnetium (99mTc) sestamibi scan or neck ultrasonography is used to localize the neoplasm prior to surgical intervention. A 53-year-old female was referred for the exclusion of metabolic bone disease. She presented with low back pain that had persisted for the past 6 months and elevated serum alkaline phosphatase (1,253 IU/L). Four years previously, she had been diagnosed at a local hospital with a 2.3-cm thyroid nodule, which was determined to be pathologically benign. Radiofrequency ablation was performed at the same hospital because the nodule was still growing during the follow-up period 2 years before the visit to our hospital, and the procedure was unsuccessful in reducing the size of the nodule. The results of the laboratory tests in our hospital were as follows: serum calcium, 14.6 mg/dL; phosphorus, 3.5 mg/dL; and intact parathyroid hormone (iPTH), 1,911 pg/mL. Neck ultrasonography and 99mTc sestamibi scan detected a 5-cm parathyroid neoplasm in the left lower lobe of the patient's thyroid; left parathyroidectomy was performed. This case indicated that thyroid ultrasonographers and pathologists need to be experienced enough to differentiate a parathyroid neoplasm from a thyroid nodule; 99mTc sestamibi scan, serum calcium, and iPTH levels can help to establish the diagnosis of parathyroid neoplasm.
Alkaline Phosphatase ; Bone Diseases, Metabolic ; Calcium ; Female ; Follow-Up Studies ; Humans ; Hyperparathyroidism, Primary ; Low Back Pain ; Middle Aged ; Neck ; Parathyroid Hormone ; Parathyroid Neoplasms ; Parathyroidectomy ; Phosphorus ; Technetium Tc 99m Sestamibi ; Thyroid Gland ; Thyroid Nodule