Changes in Multiple microRNA Levels with Antidepressant Treatment Are Associated with Remission and Interact with Key Pathways: A Comprehensive microRNA Analysis.

Individual treatment outcomes to antidepressants varies widely, yet the determinants to this difference remain elusive. MicroRNA (miRNA) gene expression regulation in major depressive disorder (MDD) has attracted interest as a biomarker. This 4-week randomized controlled trial examined changes in the plasma miRNAs that correlated with the treatment outcomes of mirtazapine (MIR) and selective serotonin reuptake inhibitor (SSRI) monotherapy. Pre- and post- treatment, we comprehensively analyzed the miRNA levels in MDD patients, and identified the gene pathways linked to these miRNAs in 46 patients. Overall, 141 miRNA levels significantly demonstrated correlations with treatment remission after 4 weeks of MIR, with miR-1237-5p showing the most robust and significant correlation after Bonferroni correction. These 141 miRNAs displayed a negative correlation with remission, indicating a decreasing trend. These miRNAs were associated with 15 pathways, including TGF-ß and MAPK. Through database searches, the genes targeted by these miRNAs with the identified pathways were compared, and it was found that MAPK1, IGF1, IGF1R, and BRAF matched. Alterations in specific miRNAs levels before and after MIR treatment correlated with remission. The miRNAs mentioned in this study have not been previously reported. No other studies have investigated treatment with MIR. The identified miRNAs also correlated with depression-related genes and pathways.

Relationship between circulating mitochondrial DNA and microRNA in patients with major depression.

BACKGROUND: MicroRNAs (miRNAs) and circulating cell-free mitochondrial DNA (ccf-mtDNA) have attracted interest as biological markers of affective disorders. In response to stress, it is known that miRNAs in mitochondria diffuse out of the cytoplasm alongside mtDNA; however, this process has not yet been identified. We hypothesized that miRNAs derived from specific cell nuclei cause mitochondrial damage and mtDNA fragmentation under MDD-associated stress conditions. METHODS: A comprehensive analysis of the plasma miRNA levels and quantification of the plasma ccf-mtDNA copy number were performed in 69 patients with depression to determine correlations and identify genes and pathways interacting with miRNAs. The patients were randomly assigned to receive either selective serotonin reuptake inhibitors (SSRI) or mirtazapine. Their therapeutic efficacy over four weeks was evaluated in relation to miRNAs correlated with ccf-mtDNA copy number. RESULTS: The expression levels of the five miRNAs showed a significant positive correlation with the ccf-mtDNA copy number after correcting for multiple testing. These miRNAs are involved in gene expression related to thyroid hormone synthesis, the Hippo signaling pathway, vasopressin-regulated water reabsorption, and lysine degradation. Of these five miRNAs, miR-6068 and miR-4708-3p were significantly associated with the SSRI and mirtazapine treatment outcomes, respectively. LIMITATIONS: This study did not show comparison with a healthy group. CONCLUSIONS: The expression levels of specific miRNAs were associated with ccf-mtDNA copy number in untreated depressed patients; moreover, these miRNAs were linked to antidepressant treatment outcomes. These findings are expected to lead to the elucidation of new pathological mechanism of depression.

Full-thickness chest wall resection for malignant chest wall tumors and postoperative problems.

Background: Chest wall malignant tumor (including primary and metastatic lesions) is rare, representing less than 5% of all thoracic malignancies. Local control of chest wall malignancies requires wide resection with tumor-free margins. These requirements increase the risk of thoracic cavity failure and subsequent pulmonary failure. The restoration strategy for chest wall defects comprises chest wall reconstruction and soft-tissue coverage. Various reconstruction methods have been used, but both evidence and guidelines for chest wall reconstruction remain lacking. The purposes of this study were to collate our institutional experience, evaluate the outcomes of full-thickness chest wall resection and reconstruction for patients with chest wall malignant tumor, and identify problems in current practice for chest wall reconstruction with a focus on local control, complications, pulmonary function and scoliosis. Methods: Participants comprised 30 patients with full-thickness chest wall malignant tumor who underwent chest wall resection and reconstruction between 1997 and 2021 in Mie University Hospital. All patients underwent chest wall resection of primary, recurrent or metastatic malignant tumors. A retrospective review was conducted for 32 operations. Results: Recurrence was observed after 5 operations. Total 5-year recurrence-free survival (RFS) rate was 79.3%. Diameter ≥5 cm was significantly associated with poor RFS. The postoperative complication rate was 18.8%. Flail chest was observed with resection of ≥3 ribs in anterior and lateral resections or with sternum resection without polyethylene methylmethacrylate reconstruction. Postoperative EFV1.0% did not show any significant decrease. Postoperative %VC decreased significantly with resection of ≥4 ribs or an area of >70 cm2. Postoperative scoliosis was observed in 8 of 28 patients. Posterior resection was associated with a high prevalence of scoliosis (88.9%). Conclusion: With chest wall reconstruction, risks of pulmonary impairment, flail chest and scoliosis were significantly increased. New strategies including indications for rigid reconstruction are needed to improve the outcomes of chest wall reconstruction.

Two different methods of bronchial dissection and coverage in robotic bilobectomy for advanced lung cancer.

INTRODUCTION: Due to its many technical advantages, the scope of robot-assisted thoracic surgery (RATS) is expanding to include extended pulmonary resection. Among such procedures, right bilobectomy is one with a high risk of inducing development of a bronchial stump fistula. MATERIALS AND SURGICAL TECHNIQUE: The pericardial fat pad case involved a 71-year-old man with a 31-mm adenocarcinoma in the right lung that had progressed to the intermediate bronchus. During lower bilobectomy, to confirm the tumor margin, an L-shaped stapler was used with stapling only at the oral side, and the bronchus was cut using a scalpel blade grasped with robot forceps. After confirming a negative stump, the pericardial fat was collected at the pedicle and sewn onto the stump. The intercostal muscle (ICM) flap case involved a 61-year-old man with a 16-mm nodule shadow in the lower lobe of his lung and swollen #11i and 7 lymph nodes. Intraoperatively, the #7 lymph node was diagnosed as non-small-cell lung cancer by frozen sections, and lower bilobectomy was performed. The bronchus was divided using a stapler with a green cartridge, and the ICM flap was harvested by changing the direction of the camera to a look-up view and positioning the camera at the 5th intercostal site. His numeric rating score (NRS) at 30 and 90 days post-surgery was 2 and 0, respectively. DISCUSSION: Our RATS technique was useful for harvesting the ICM flap. More cases should be accumulated to extend the surgical indication for RATS.

Research on Werner Syndrome: Trends from Past to Present and Future Prospects.

A rare and autosomal recessive premature aging disorder, Werner syndrome (WS) is characterized by the early onset of aging-associated diseases, including shortening stature, alopecia, bilateral cataracts, skin ulcers, diabetes, osteoporosis, arteriosclerosis, and chromosomal instability, as well as cancer predisposition. WRN, the gene responsible for WS, encodes DNA helicase with a 3' to 5' exonuclease activity, and numerous studies have revealed that WRN helicase is involved in the maintenance of chromosome stability through actions in DNA, e.g., DNA replication, repair, recombination, and epigenetic regulation via interaction with DNA repair factors, telomere-binding proteins, histone modification enzymes, and other DNA metabolic factors. However, although these efforts have elucidated the cellular functions of the helicase in cell lines, they have not been linked to the treatment of the disease. Life expectancy has improved for WS patients over the past three decades, and it is hoped that a fundamental treatment for the disease will be developed. Disease-specific induced pluripotent stem (iPS) cells have been established, and these are expected to be used in drug discovery and regenerative medicine for WS patients. In this article, we review trends in research to date and present some perspectives on WS research with regard to the application of pluripotent stem cells. Furthermore, the elucidation of disease mechanisms and drug discovery utilizing the vast amount of scientific data accumulated to date will be discussed.

Tenascin C in radiation-induced lung damage: Pathological expression and serum level elevation.

Radiation-induced lung damage (RILD) is a critical problem in lung cancer radiotherapy, and it is difficult to predict its severity. Although no biomarkers for RILD have been established, tenascin C (TNC) is an extracellular matrix glycoprotein involved in the remodeling of damaged tissues and has been implicated in inflammation and fibrosis. We report the unique case of a 36-year-old man with adenocarcinoma of the lung, Union for International Cancer Control stage IIIB, who was treated with radiotherapy before lung surgery. The surgical specimen showed histopathological expression of TNC in the region where radiation pneumonitis was observed radiographically. Serum TNC levels were elevated after radiotherapy. In this case, TNC is suggested to be implicated in RILD and may be a potential candidate as a biomarker for the onset and severity of the condition.

Multiple Pre-Treatment miRNAs Levels in Untreated Major Depressive Disorder Patients Predict Early Response to Antidepressants and Interact with Key Pathways.

Major depressive disorder (MDD) is a life-impairing disorder, and early successful treatment is important for a favorable prognosis. However, early response to antidepressants differs widely among individuals, and is difficult to predict pre-treatment. As miRNAs have been reported to play important roles in depression, identification of miRNAs associated with antidepressant treatment responses and their interacting genes and pathways will be beneficial in understanding the predictors and molecular mechanisms of depression treatment. This randomized control trial examined miRNAs correlated with the early therapeutic effect of selective serotonin reuptake inhibitors (SSRIs; paroxetine or sertraline) and mirtazapine monotherapy. Before medication, we comprehensively analyzed the miRNA expression of 92 depressed participants and identified genes and pathways interacting with miRNAs. A total of 228 miRNAs were significantly correlated with depressive symptoms improvements after 2 weeks of SSRIs treatment, with miR-483.5p showing the most robust correlation. These miRNAs are involved in 21 pathways, including TGF-ß, glutamatergic synapse, long-term depression, and the mitogen-activated protein kinase (MAPK) signaling pathways. Using these miRNAs enabled us to predict SSRI response at week 2 with a 57% difference. This study shows that pre-treatment levels of miRNAs could be used to predict early responses to antidepressant administration, a knowledge of genes, and an identification of genes and pathways associated with the antidepressant response.

Spontaneous pneumothorax in a 17-year-old male patient with multiple exostoses: A case report and review of the literature.

BACKGROUND: Multiple exostoses generally develop in the first decade of life. They most frequently arise from the distal femur, proximal tibia, fibula, and proximal humerus. Costal exostoses are rare, contributing to 1%-2% of all exostoses in hereditary multiple exostoses (HME). They are usually asymptomatic, but a few cases have resulted in severe thoracic injuries. Pneumothorax caused by costal exostoses is rare, with only 13 previously reported cases. We report a new case of pneumothorax caused by costal exostoses. CASE SUMMARY: A 17-year-old male with HME underwent surgery for removal of exostoses around his right knee. Four months following the operation, he felt chest pain when he was playing the trumpet; however, he did not stop playing for a week. He was referred to our hospital with a chief complaint of chest pain. The computed tomography (CT) scan revealed right pneumothorax and multiple exostoses in his right ribs. The CT scan also revealed visceral pleura thickness and damaged lung tissues facing the exostosis of the seventh rib. We diagnosed that exostosis of the seventh rib induced pneumothorax. Costal exostosis resection was performed by video-assisted thoracoscopic surgery (VATS) 2 wk after the onset. The patient's postoperative course was uneventful, and there was no recurrence of pneumothorax for 2 years. CONCLUSION: Costal exostoses causing thoracic injuries should be resected regardless of age. VATS must be considered in cases with apparently benign and relatively small exostoses or HME.

Endobronchial brachytherapy as definitive treatment for endobronchial metastasis after surgery of non-small cell lung cancer.

BACKGROUND: Endobronchial metastasis is a very rare type of recurrence after lung cancer surgery. Surgical intervention may be difficult to perform due to the postoperative reduction in the activities of daily living (ADL) and the invasiveness associated with redo surgery. In such cases, endobronchial brachytherapy (EBBT) plays an important role not only as a palliative treatment, but also as a definitive treatment with curative intent. CASE PRESENTATION: Three men (64, 69, and 74 years old) underwent combination therapy of external beam radiation therapy (EBRT) and EBBT for endobronchial metastasis after lobectomy of stage I-II non-small cell lung cancer (NSCLC): 2 cases of squamous cell carcinoma and 1 of adenocarcinoma. We used a special source-centralizing applicator for EBBT to avoid eccentric distribution of the radiation dose. Follow-up was considered to start from the end of brachytherapy. None of our patients experienced severe adverse events, and none needed extensive outpatient treatment. Local control was achieved in all cases by a bronchoscopic evaluation. All patients were alive after 31, 38, and 92 months of follow-up, respectively. In the adenocarcinoma patient, two metastases to the lung were discovered 3 years after EBBT, and the patient underwent partial wedge resection. CONCLUSIONS: EBBT may be a promising treatment with curative intent for endobronchial metastasis after surgery of NSCLC.

Substrate stiffness modulates endothelial cell function via the YAP-Dll4-Notch1 pathway.

Endothelial cells adapt their functions as a consequence of sensing extracellular substrate stiffness; these alterations allow them to maintain their vascular structure and function. Substrate stiffness-mediated yes-associated protein 1 (YAP) activation plays an important role in mechano-transduction and pro-angiogenic phenotype of endothelial cells, and Delta-like ligand 4 (Dll4)-Notch1 signaling is closely related to angiogenesis; however, the impact of substrate stiffness-mediated interrelation of these pathways on endothelial cell functions remains elusive. We confirmed that endothelial cells on softer substrates not only elongate cellular aspects but also attenuate YAP activation compared to cells on stiffer substrates. Endothelial cells on softer substrates also upregulate the vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 mRNA expression that is enhanced by VEGF stimulation. We determined that endothelial cells on softer substrates increased Dll4 expression, but not Notch1 expression, via YAP signaling. Moreover, endothelial cells on soft substrates induced not only VEGFRs upregulation but also suppression of pro-inflammatory interleukin-6 and plasminogen activator inhibitor-1 mRNA expression and the facilitation of anti-coagulant thrombomodulin and pro-coagulant tissue factor mRNA expression. Our results suggest that endothelial cells activate the YAP-Dll4-Notch signaling pathway in response to substrate stiffness and dictate cellular function.

The human ribosomal DNA array is composed of highly homogenized tandem clusters.

The structure of the human ribosomal DNA (rDNA) cluster has traditionally been hard to analyze owing to its highly repetitive nature. However, the recent development of long-read sequencing technology, such as Oxford Nanopore sequencing, has enabled us to study the large-scale structure of the genome. Using this technology, we found that human cells have a quite regular rDNA structure. Although each human rDNA copy has some variations in its noncoding region, contiguous copies of rDNA are similar, suggesting that homogenization through gene conversion frequently occurs between copies. Analysis of rDNA methylation by Nanopore sequencing further showed that all the noncoding regions are heavily methylated, whereas about half of the coding regions are clearly unmethylated. The ratio of unmethylated copies, which are speculated to be transcriptionally active, was lower in individuals with a higher rDNA copy number, suggesting that there is a mechanism that keeps the active copy number stable. In addition, the rDNA in progeroid syndrome patient cells with reduced DNA repair activity had more unstable copies compared with control normal cells, although the rate was much lower than previously reported using a fiber-FISH method. Collectively, our results clarify the view of rDNA stability and transcription regulation in human cells, indicating the presence of mechanisms for both homogenizations to ensure sequence quality and maintenance of active copies for cellular functions.

Generation of disease-specific and CRISPR/Cas9-mediated gene-corrected iPS cells from a patient with adult progeria Werner syndrome.

Adult progeria Werner syndrome (WS), a rare autosomal recessive disorder, is characterized by accelerated aging symptoms after puberty. The causative gene, WRN, is a member of the RecQ DNA helicase family and is predominantly involved in DNA replication, repair, and telomere maintenance. Here, we report the generation of iPS cells from a patient with WS and correction of the WRN gene by the CRISPR/Cas9-mediated method. These iPSC lines would be a valuable resource for deciphering the pathogenesis of WS.

A founder variant in the South Asian population leads to a high prevalence of FANCL Fanconi anemia cases in India.

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, predisposition to cancer, and congenital abnormalities. FA is caused by pathogenic variants in any of 22 genes involved in the DNA repair pathway responsible for removing interstrand crosslinks. FANCL, an E3 ubiquitin ligase, is an integral component of the pathway, but patients affected by disease-causing FANCL variants are rare, with only nine cases reported worldwide. We report here a FANCL founder variant, anticipated to be synonymous, c.1092G>A;p.K364=, but demonstrated to induce aberrant splicing, c.1021_1092del;p.W341_K364del, that accounts for the onset of FA in 13 cases from South Asia, 12 from India and one from Pakistan. We comprehensively illustrate the pathogenic nature of the variant, provide evidence for a founder effect, and propose including this variant in genetic screening of suspected FA patients in India and Pakistan, as well as those with ancestry from these regions of South Asia.

Therapeutic strategy for acute pleural empyema: comparison between retrospective study and prospective study.

OBJECTIVES: The purpose of this study is to investigate the efficiency of therapeutic strategy for acute pleural empyema. METHODS: We retrospectively reviewed 121 acute empyema patients and evaluated the therapeutic strategy for acute pleural empyema. Then, we prospectively reviewed 114 acute pleural empyema patients based on the strategy. RESULTS: The duration from onset to hospitalization in our hospital is statistically shorter, and the mortality and the rate of stage 3 empyema patients are lower in the prospective study group (PSG) than in the retrospective study group (RSG). Retrospective study and prospective study found that surgical group (SG) had more favorable outcomes than non-surgical group (NSG). Although antibiotic treatment duration, hospital stay, and entire mortality were comparable in NSG of both study groups, mortality of patients with PS grade 4 was significantly lower in PSG. SG in PSG had more favorable outcomes than that in RSG, such as antibiotic treatment duration, hospital stay, complication, and mortality. CONCLUSIONS: The good outcomes may be mainly caused by shorter duration from onset to hospitalization and shorter duration from hospitalization to operation. Operative management is an effective procedure for selected patients, and it is important to refer for thoracic surgical consultation earlier.

Molecular mechanisms underlying prostaglandin E2-exacerbated inflammation and immune diseases.

Prostaglandins (PGs) are the major lipid mediators in animals and which are biosynthesized from arachidonic acid by the cyclooxygenases (COX-1 or COX-2) as the rate-limiting enzymes. Prostaglandin E2 (PGE2), which is the most abundantly detected PG in various tissues, exerts versatile physiological and pathological actions via four receptor subtypes (EP1-4). Non-steroidal anti-inflammatory drugs, such as aspirin and indomethacin, exert potent anti-inflammatory actions by the inhibition of COX activity and the resulting suppression of PG production. Therefore, PGE2 has been shown to exacerbate several inflammatory responses and immune diseases. Recently, studies using mice deficient in each PG receptor subtype have clarified the detailed mechanisms underlying PGE2-associated inflammation and autoimmune diseases involving each EP receptor. Here, we review the recent advances in our understanding of the roles of PGE2 receptors in the progression of acute and chronic inflammation and autoimmune diseases. PGE2 induces acute inflammation through mast cell activation via the EP3 receptor. PGE2 also induces chronic inflammation and various autoimmune diseases through T helper 1 (Th1)-cell differentiation, Th17-cell proliferation and IL-22 production from Th22 cells via the EP2 and EP4 receptors. The possibility of EP receptor-targeted drug development for the treatment of immune diseases is also discussed.

Thoracoscopic mediastinal tumor resection by subxiphoid approach-dual port thymectomy plus one (DPT+1).

Thoracoscopic subxiphoid approaches, such as the single-port thymectomy (SPT) and dual-port thymectomy (DPT) approaches have been demonstrated to have several advantages compared with the traditional median sternotomy approach or the bilateral or hemilateral video-assisted thoracoscopic (VATS) approach. However, SPT and DPT are technically demanding for novice surgeons since they require precise concomitant manipulation of surgical instruments and the thoracoscope within the same port, without interference. To overcome these limitations, we have developed a new method, termed DPT plus one (DPT+1), to facilitate separation of the surgical access ports and camera port by adding another intercostal port to the DPT approach. Our method is easy and safe not only for simple mediastinal resection but also for extended thymectomy.

Introduction of thoracoscopic surgery for congenital pulmonary airway malformation in infants: review of 13 consecutive surgical cases.

BACKGROUND: Although complete video-assisted thoracic surgery (C-VATS) has been demonstrated to have several advantages compared with conventional thoracotomy, there are few reports on the clinical feasibility of C-VATS for CPAM in infants. METHODS: We retrospectively evaluated 13 consecutive patients (neonates 4; infants 9) surgically treated for congenital pulmonary airway malformation (CPAM) from 1 January 2008 to 31 March 2017. RESULTS: In the group of neonates, all 4 cases were prenatally diagnosed and they underwent semi-emergent surgery after birth due to respiratory failure. In the group of 9 infants, 5 cases were prenatally diagnosed and 4 cases were diagnosed at age >2.5 years due to symptoms associated with pulmonary cystic infection. Pulmonary resection consisted of the following: 8 lobectomies, 1 segmentectomy, 2 wedge resection, 1 fractionated lung resection and 1 lobectomy with segmentectomy. Overall, there were 9 thoracotomy and 4 thoracoscopic surgeries. Mean operation time was 162 min (range, 67-290 min) and blood loss was 21 mL (range, 0-74 mL) on average. There were no complications such as thoracic deformity or respiratory failure, however in 2 of those who underwent segmentectomy the cystic remnant remained. No statistically significant differences were observed between the thoracotomy Group and C-VATS group in terms of age and height at intervention, operation time, blood loss, postoperative day of drain removal, and length of hospital stay after surgery. However, only the average body weight was heavier in C-VATS group (P=0.03). CONCLUSIONS: Since early surgical resection of asymptomatic CPAM is often recommended for the prevention of infections and the development of lung malignancy, we recommend performing surgery after the age of 1 year if the patient's condition is stable. Furthermore, C-VATS lobectomy may be feasible if they are older than 18 months or weigh more than 10 kg.

Primary racemose hemangioma with bronchial-pulmonary arterial fistula.

Primary racemose hemangioma with bronchial-pulmonary arterial fistula is a very rare abnormality. We herein report an asymptomatic case of primary racemose hemangioma with no significant size change in 5 years.

TERT enhances the survival rate of human fibroblasts under endoplasmic reticulum, Golgi apparatus, and lysosomal stresses.

OBJECTIVE: The exposure of organelles, such as the endoplasmic reticulum (ER), Golgi apparatus (GA), and lysosomes, to stress activates death mechanisms. Recently, telomerase reverse transcriptase (TERT) has been shown to be involved in cell survival. However, the relationship between TERT and the stress responses is still unclear. Here, we aimed to clarify the possible mechanisms of action through which TERT promotes cell survival by studying its effect on the stresses faced by multiple organelles in human fibroblasts. RESULTS: We found that TERT enhanced the survival rate of cells under ER stress, regardless of ER stress inducers such as tunicamycin (protein glycosylation inhibitor), thapsigargin (Ca2+-ATPase inhibitor), brefeldin A (protein transport inhibitor), or dithiothreitol (disulfide bond formation inhibitor). We also found that TERT enhanced the survival rate of cells under GA and lysosomal stresses. CONCLUSION: Collectively, these results suggest that TERT suppresses cell stress and promotes cell survival via different mechanisms. These findings may offer new insights into the implications of TERT in the treatment of stress-induced conditions such as aging, obesity, and neurodegenerative diseases.

Prolonged intravenous indocyanine green visualization by temporary pulmonary vein clamping: real-time intraoperative fluorescence image guide for thoracoscopic anatomical segmentectomy.

The real-time endoscopic colour and fluorescence-merged imaging system, using intravenous injection of indocyanine green (ICG), allows a clear surgical view, which facilitates identification of the pulmonary inter-segmental plane in thoracoscopic surgery. However, the staining time is too short to mark and cut the intersegmental plane, because the mean washout time of ICG is only a few minutes in the clinical setting. To overcome this limitation, we have developed a new technique for prolongation of ICG staining time. The technique consists of 2 simple steps. First, we cut the targeted segmental artery, vein and bronchus. Second, ICG is injected intravenously, followed by temporary clamping of the pulmonary vein of entire lobe, including the segments. Our technique may not only offer prolonged washout time for marking the surface of the lung but also facilitate identification of precise intersegmental plane to be cut.