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.

Purpose: Patients with Mycoplasma pneumoniae pneumonia (MPP) can develop atelectasis, and some cases of atelectasis may persist for over 4 weeks. However, the risk factors for the development and persistence of atelectasis ( > 4 weeks) in children with MPP and their clinical characteristics remain understudied. We aimed to investigate the clinical characteristics and associated factors of MPP with atelectasis in children. Methods: We retrospectively analyzed the medical records of 477 children with MPP treated at Pusan National University Yangsan Hospital from November 2014 to March 2020. Demographics, clinical information, laboratory data, and radiological findings were collected from all patients. The patients were divided into 2 groups according to the presence of atelectasis with MPP. The group with atelectasis was further divided into 2 groups according to whether atelectasis was improved. Results: Among 477 children with MPP, 105 developed atelectasis, and 34 showed persistent atelectasis. Children with atelectasis had longer lengths of hospitalization than children without atelectasis. High lactate dehydrogenase (LDH) levels and whole lobar consolidation were independently associated factors for presenting with atelectasis, and long macrolide therapy duration before admission ( > 3 days) was related to persistent atelectasis ( > 4 weeks). Conclusion High LDH levels and whole lobar consolidation were independent associated factors for presenting with atelectasis, and a long macrolide therapy duration before admission was associated with persistent atelectasis. Careful observation and management of children with these associated factors for atelectasis will improve the prognosis of children with MPP.

Objectives: . Sound field (SF) audiometry tests are usually conducted in audiometric booths measuring greater than 2×2 m in size. However, most private ENT clinics carry about 1×1-m-sized audiometric booths, making SF audiometry testing difficult to perform. The aims of this study were to develop an SF audiometry system for use in smaller audiometric booths and compare its performance with traditional system. Methods: . The newly developed SF audiometry system can yield an SF signal at a distance of about 30 cm from the subject’s ears. Its height can be adjusted according to the subject’s head height. We compared SF hearing results between the new SF system and the traditional SF audiometry system in 20 adults with normal hearing (40 ears) and 24 adults with impaired hearing levels (38 ears) who wore hearing aids. Comparative parameters included warble tone audiometry threshold, a speech reception threshold (SRT), and a speech discrimination score (SDS). For statistical analysis, paired t-test was used. The equivalence of both SF systems was tested using two one-sided test (TOST) with a margin of 5 dB (normal hearing participants) and 10 dB (hearing aids wearing participants). Results: . Among participants with normal hearing, warble tone hearing thresholds of 0.5, 1, 2, and 4 kHz, average values of these four frequencies, and SRT were similar between the two systems (all P>0.05). Participants with hearing aids showed similar warble tone threshold and SRT (P>0.05) in both systems except for threshold of 4 kHz (P=0.033). SDS was significantly higher in the newly developed system (P<0.05). TOST results showed equivalent SF audiometry results using either system. Conclusion . Audiometric results of the newly developed SF audiometry system were equivalent to those of a traditional system. Therefore, the small SF audiometry system can be used at small audiometric booths present in most private ENT clinics.

The pathophysiological implications of aldosterone and adrenomedullin in the cardiac ventricular hypertrophy were examined. Male Sprague-Dawley rats were treated with deoxycorticosterone acetate (DOCA)-salt and monocrotaline (MCT) to selectively elicit left and right ventricular (LV, RV) hypertrophy, respectively. The mRNA expression of aldosterone synthase and adrenomedullin in LV and RV was determined by reverse transcription-polymerase chain reaction. The expression of aldosterone synthase and adrenomedullin was increased in LV, while not altered significantly in RV of DOCA-salt-treated rats. On the contrary, the expression was not significantly altered in LV, but increased in RV of MCT-treated rats. The enhanced expression of aldosterone synthase may be causally related with the development of ventricular hypertrophy, and the increased expression of adrenomedullin may act as a counter-regulatory mechanism.
Adrenomedullin* ; Aldosterone Synthase* ; Aldosterone* ; Animals ; Desoxycorticosterone ; Humans ; Hypertrophy ; Hypertrophy, Right Ventricular* ; Male ; Monocrotaline ; Rats* ; Rats, Sprague-Dawley ; RNA, Messenger

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*

We describe herein a case of life-threatening hypoglycemia due to spurious elevation of glucose concentration during the administration of ascorbic acid in a type 2 diabetic patient. A 31-year-old female was admitted for proliferative diabetic retinopathy treatment and prescribed high dose ascorbic acid. During hospitalization, she suddenly lost her consciousness and her glucose concentration was 291 mg/dL, measured using self-monitoring blood glucose (SMBG) device, while venous blood glucose concentration was 12 mg/dL. After intravenous injection of 50% glucose solution, the patient became alert. We reasoned that glucose measurement by SMBG device was interfered by ascorbic acid. Physicians should be aware of this interference; high dose ascorbic acid may cause spurious elevation of glucose concentration when measuring with SMBG devices.
Adult ; Ascorbic Acid/administration & dosage/adverse effects/contraindications/*therapeutic use ; Blood Glucose ; Blood Glucose Self-Monitoring/instrumentation/standards ; Diabetes Mellitus, Type 2/blood/drug therapy ; Female ; Humans ; Hypoglycemia/*diagnosis ; Renal Dialysis

A 54-year-old female patient was referred due to a mass in the left salivary gland. A neck CT was performed and surgery was agreed due to a suspected Warthin tumor. The patient was also diagnosed with Sjogren's syndrome and Hashimoto's thyroiditis and treated. Warthin tumor and extranodal marginal zone B-cell lymphoma were also diagnosed after parotidectomy. The coexistence of the two autoimmune diseases, Hashimoto's thyroiditis and Sjogren's syndrome, has been reported, as has the coexistence of Warthin tumor and malignant tumor within a single salivary gland. However, these four diseases have not previously been reported in an individual patient. The authors treated a patient who was first diagnosed with Sjogren's syndrome and Hashimoto's thyroiditis, and subsequently also with Warthin tumor and extranodal marginal zone B-cell lymphoma after superficial parotidectomy. Therefore, this case is reported together with a related literature review.
Adenolymphoma* ; Autoimmune Diseases ; Female ; Humans ; Lymphoma, B-Cell, Marginal Zone* ; Middle Aged ; Neck ; Parotid Gland* ; Salivary Glands ; Sjogren's Syndrome* ; Thyroid Gland* ; Thyroiditis*

Methimazole (MMI)-induced acute pancreatitis is very rare but severe adverse reaction. A 51-yr-old male developed a high fever, chills, and abdominal pain, two weeks after commencement on MMI for the treatment of Graves' disease. There was no evidence of agranulocytosis, and fever subsided soon after stopping MMI treatment. However, 5 hr after taking an additional dose of MMI, abdominal pain and fever developed again. His symptoms, biochemical, and imaging studies were compatible with acute pancreatitis. After withdrawal of MMI, he showed clinical improvement. This is the first case of MMI-induced acute pancreatitis in Korea. Clinicians should be aware of the rare but possible MMI-induced pancreatitis in patients complaining of fever and abdominal pain.
Abdominal Pain/*chemically induced/diagnosis ; Acute Disease ; Diagnosis, Differential ; Fever of Unknown Origin/*chemically induced/diagnosis ; Graves Disease/*drug therapy ; Humans ; Male ; Methimazole/*adverse effects/*therapeutic use ; Middle Aged ; Pancreatitis/*chemically induced/diagnosis ; Treatment Outcome

Methimazole (MMI)-induced acute pancreatitis is very rare but severe adverse reaction. A 51-yr-old male developed a high fever, chills, and abdominal pain, two weeks after commencement on MMI for the treatment of Graves' disease. There was no evidence of agranulocytosis, and fever subsided soon after stopping MMI treatment. However, 5 hr after taking an additional dose of MMI, abdominal pain and fever developed again. His symptoms, biochemical, and imaging studies were compatible with acute pancreatitis. After withdrawal of MMI, he showed clinical improvement. This is the first case of MMI-induced acute pancreatitis in Korea. Clinicians should be aware of the rare but possible MMI-induced pancreatitis in patients complaining of fever and abdominal pain.
Abdominal Pain/*chemically induced/diagnosis ; Acute Disease ; Diagnosis, Differential ; Fever of Unknown Origin/*chemically induced/diagnosis ; Graves Disease/*drug therapy ; Humans ; Male ; Methimazole/*adverse effects/*therapeutic use ; Middle Aged ; Pancreatitis/*chemically induced/diagnosis ; Treatment Outcome