Older age is not a negative factor for video-assisted thoracoscopic lobectomy for pathological stage I non-small cell lung cancer: a single-center, retrospective, propensity score-matching study.

PURPOSE: Video-assisted thoracoscopic surgery (VATS) has changed the surgical approach to non-small cell lung cancer (NSCLC) dramatically. The current study compares the outcomes of older and younger patients who underwent VATS lobectomy for NSCLC. METHODS: In total, 424 eligible patients with pathological stage I NSCLC underwent VATS lobectomy between 2007 and 2017. Patients were classified into two groups (< 75 and ≥ 75 years old), after which propensity score-matching was performed. RESULTS: After matching, 143 patients were identified. No significant difference in postoperative complication rates was observed; however, the ≥ 75-year-old group had a longer postoperative hospital stay (p = 0.001). The 5-year overall survival, relapse-free survival, and lung cancer-specific survival rates of the < 75- and ≥ 75-year-old groups were 87.1% vs. 85.6% (p = 0.537), 82.1% vs. 79.0% (p = 0.531), and 93.5% vs. 92.7% (p = 0.832), respectively. CONCLUSION: Despite the longer postoperative recovery following VATS lobectomy, the short- and long-term outcomes of older patients did not differ from those of younger patients. Thus, for early-stage NSCLC, older age alone was not a negative factor for lobectomy performed via minimally invasive surgery. Naturally, the systemic condition of this population must be evaluated carefully before surgery.

[Experience of Complete Video-assisted Thoracoscopic Pneumonectomy].

Thoracotomy has been preferred to video-assisted thoracoscopic surgery( VATS) for performing pulmonary pneumonectomy, and there have been no reports of complete video-assisted thoracoscopic surgery (cVATS) for such a case. We present three cases of cVATS pneumonectomy. The operation method was based on four ports, and ports were added in difficult cases. In these cases, the blood loss and length of surgery were similar to results of VATS reported previously. We experienced bleeding complications in one case but were able to manage appropriately. There were no serious postoperative complications in our cases. In addition, it was considered acceptable in terms of safety because there were no deaths within 30 days after operation in all cases. The cVATS pneumonectomy for lung cancer is one of the useful treatment option because of safety and many benefits although the long-term results are unknown at present.

Lactate Transporter Monocarboxylate Transporter 4 Induces Bone Pain in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically, as it can invade facial bones and cause bone pain that is undertreated and poorly understood. Here we studied HNSCC bone pain (HNSCC-BP) in an intratibial mouse xenograft model that uses a human HNSCC cell line (SAS cells). These mice develop HNSCC-BP associated with an upregulation of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in the dorsal root ganglia (DRGs) of sensory nerve cell bodies. Our experiments demonstrated that the inhibition of monocarboxylate transporter 4 (MCT4) by short hairpin (shRNA) transduction suppressed the HNSCC-BP, the lactate level in bone marrow, and the pERK1/2 expression in DRG. The sensory nerves also expressed increased levels of the acid-sensing receptor TRPV1. DRG neurons co-cultured with SAS cells showed increased neurite outgrowth, and were inhibited by MCT4 silencing with shRNA. Collectively, our results show that HNSCC induced an acidic bone microenvironment that evokes HNSCC-BP via MCT4 expression.

Type II cGMP-dependent protein kinase negatively regulates fibroblast growth factor signaling by phosphorylating Raf-1 at serine 43 in rat chondrosarcoma cells.

Although type II cGMP-dependent protein kinase (PKGII) is a major downstream effector of cGMP in chondrocytes and attenuates the FGF receptor 3/ERK signaling pathway, its direct target proteins have not been fully explored. In the present study, we attempted to identify PKGII-targeted proteins, which are associated with the inhibition of FGF-induced MAPK activation. Although FGF2 stimulation induced the phosphorylation of ERK1/2, MEK1/2, and Raf-1 at Ser-338 in rat chondrosarcoma cells, pretreatment with a cell-permeable cGMP analog strongly inhibited their phosphorylation. On the other hand, Ser-43 of Raf-1 was phosphorylated by cGMP in a dose-dependent manner. Therefore, we examined the direct phosphorylation of Raf-1 by PKGII. Wild-type PKGII phosphorylated Raf-1 at Ser-43 in a cGMP-dependent manner, but a PKGII D412A/R415A mutant, which has a low affinity for cGMP, did not. Finally, we found that a phospho-mimic mutant, Raf-1 S43D, suppressed FGF2-induced MAPK pathway. These results suggest that PKGII counters FGF-induced MEK/ERK activation through the phosphorylation of Raf-1 at Ser-43 in chondrocytes.

Neutralization of leukotriene C4 and D4 activity by monoclonal and single-chain antibodies.

BACKGROUND: Cysteinyl leukotrienes (LTs) are key mediators in inflammation. To explore the structure of the antigen-recognition site of a monoclonal antibody against LTC4 (mAbLTC), we previously isolated full-length cDNAs for heavy and light chains of the antibody and prepared a single-chain antibody comprising variable regions of these two chains (scFvLTC). METHODS: We examined whether mAbLTC and scFvLTC neutralized the biological activities of LTC4 and LTD4 by competing their binding to their receptors. RESULTS: mAbLTC and scFvLTC inhibited their binding of LTC4 or LTD4 to CysLT1 receptor (CysLT1R) and CysLT2 receptor (CysLT2R) overexpressed in Chinese hamster ovary cells. The induction by LTD4 of monocyte chemoattractant protein-1 and interleukin-8 mRNAs in human monocytic leukemia THP-1 cells expressing CysLT1R was dose-dependently suppressed not only by mAbLTC but also by scFvLTC. LTC4- and LTD4-induced aggregation of mouse platelets expressing CysLT2R was dose-dependently suppressed by either mAbLTC or scFvLTC. Administration of mAbLTC reduced pulmonary eosinophil infiltration and goblet cell hyperplasia observed in a murine model of asthma. Furthermore, mAbLTC bound to CysLT2R antagonists but not to CysLT1R antagonists. CONCLUSIONS: These results indicate that mAbLTC and scFvLTC neutralize the biological activities of LTs by competing their binding to CysLT1R and CysLT2R. Furthermore, the binding of cysteinyl LT receptor antagonists to mAbLTC suggests the structural resemblance of the LT-recognition site of the antibody to that of these receptors. GENERAL SIGNIFICANCE: mAbLTC can be used in the treatment of inflammatory diseases such as asthma.

Biallelic alterations of the large tumor suppressor 1 (LATS1) gene in infiltrative, but not superficial, basal cell carcinomas in a Japanese patient with nevoid basal cell carcinoma syndrome.

The present study was conducted to address the molecular pathogenesis underlying the progression of basal cell carcinoma (BCC) in a nevoid basal cell carcinoma syndrome (NBCCS) patient. We analyzed infiltrative BCCs that invaded the subcutaneous tissue of the scalp and penetrated the skull in a 61-year-old Japanese female. Whole-exome sequencing validated by Sanger sequencing was applied to assess the subcutaneously infiltrative BCCs. Differences in genetic alterations between the superficial and infiltrative BCCs were also examined. Of particular note, the infiltrative BCCs showed a nonsense mutation, c.943C>T, resulting in p.Q315X in the large tumor suppressor 1 (LATS1) gene, as well as the loss of the wild-type allele of LATS1 (6q25.1), thus indicating that the LATS1 gene was biallelically disrupted. In contrast, no alterations in the LATS1 gene were observed in the superficial BCCs. Additionally, a loss of heterozygosity analysis revealed that the distal region of chromosome 6q where LATS1 locates was deleted in a heterozygous manner. The present results imply that the biallelic disruption of LATS1 is a progressive factor of the infiltrative BCCs observed in this NBCCS patient and suggest that the Hippo pathway is a potential therapeutic target in cases of infiltrative BCC.

A novel mutation of the axonemal dynein heavy chain gene 5 (DNAH5) in a Japanese neonate with asplenia syndrome.

Asplenia syndrome (Ivemark syndrome) is a complex disorder composed of asplenia, malpositioning of the visceral organs and congenital heart defects. To elucidate the underlying molecular mechanism of asplenia syndrome, we herein analyzed the fatal case of a male neonate who exhibited three lobes of the left lung, asplenia and complex heart anomalies and died 6 hours after delivery. A whole-exome sequence (WES) analysis followed by Sanger sequence identified a heterozygous single nucleotide change (c.7829A>G) in exon 47 of the axonemal dynein heavy chain gene 5 (DNAH5), which results in the missense mutation of p.Glu2610Gly. This mutation was found only in the neonate, but not in his parents, implying de novo mutation of DNAH5 that codes dynein heavy chain, a component of outer dynein arm. The WES analysis also identified a heterozygous single nucleotide substitution (c.3697C>T) in the axonemal dynein heavy chain gene 7 (DNAH7), resulting in p.Arg1233Cys, and a rare SNP (c.2029G>A, p.Gly677Ser) of the axonemal dynein intermediate chain gene 1 (DNAI1) in the patient and his mother, but not in his father. The mutation of p.Glu2610Gly in DNAH5 is novel and we here present a first Japanese case of asplenia syndrome who exhibited a DNAH5 mutation.

[Strategies for lung cancer with ischemic heart disease].

For lung cancer surgery which merged ischemic heart disease to need coronary artery treatments, the strategy is demanded on the timing of each treatment. Our department conforms to American College of Chest Physicians( ACCP) guideline and treatment strategies are decided as follows. 1) If right heart load has already occurred, we choose limited surgery for lung cancer. 2) Two-stage surgery is performed with principle. Coronary artery treatment is given priority to against left main trunk disease and unstable angina. 3) Simultaneous surgery is chosen for lung cancer more than stage II or lung cancer pressing neighboring organ and vessel not to be able to wait coronary artery treatments. Since 2007, we performed 4 simultaneous surgeries and experienced 3 pneumonia cases, 1 patient died in 5 months. We must decide a strategy in consideration of progress of the lung cancer and cardiac urgency.

Biallelic disruption of the PTCH1 gene in multiple basal cell carcinomas in Japanese patients with nevoid basal cell carcinoma syndrome.

The aim of the present study is to address whether the molecular pathogenesis is identical among multiple basal cell carcinomas (BCCs) present in the same nevoid basal cell carcinoma syndrome (NBCCS) patient. Patient 1 is a 61-year-old (yo) Japanese female whose clinical characteristics and findings of a genetic analysis of PTCH1 have been previously described. Patient 2 is patient 1's 64-yo sister who also suffered from NBCCS with a single base deletion at nucleotide 2613 in exon 16 (c.2613delC) in one PTCH1 allele. Thirteen and 3 independent specimens of BCC were applied for a molecular analysis of loss of heterozygosity (LOH) in PTCH1 in patients 1 and 2, respectively. Of particular note is that all BCC specimens examined showed a loss of the wild-type allele of exon 16 in PTCH1, thus indicating that LOH results in the biallelic disruption of PTCH1 in multiple BCCs that develop in an age- and location-independent manner in the same patient. These results indicate that the germline single base deletion of PTCH1 (c.2613 delC) is a first hit and the LOH of the wild-type allele is a second hit, implying that all 16 BCCs detected in these NBCCS sisters fit the standard two-hit model.

Complete thoracoscopic lobectomy versus hybrid video-assisted thoracoscopic lobectomy for non-small cell lung cancer.

OBJECTIVE: Video-assisted thoracoscopic surgery (VATS) is the standard approach to lobectomy for early-stage non-small cell lung cancer (NSCLC). However, there are many different types. One of its approaches is complete thoracoscopic surgery (CTS), which may be less invasive because of low chest wall stress. This study compared the treatment outcomes of CTS and hybrid VATS lobectomy for NSCLC. METHODS: In total, 442 eligible patients with clinical N0 NSCLC underwent lobectomy between 2007 and 2016. Patients were classified into a group of patients who underwent CTS and a group of those who underwent hybrid VATS. Propensity score matching was performed between the two groups. RESULTS: There were 175 patients after matching. The median follow-up period in the CTS and hybrid VATS groups was 60 and 63 months, respectively. The CTS group showed less blood loss (CTS, 50 mL vs. 100 mL, p = 0.005), fewer complications (CTS, 25.7% vs. 36.6%, p = 0.037), and shorter postoperative hospital stays (CTS, 8 days vs. 12 days, p < 0.001). There was no significant difference in the postoperative 30-day mortality rates. Between the patients who underwent CTS and hybrid VATS groups, the 5-year overall survival rates were 85.4% and 86.0% (p = 0.701), the relapse-free survival rates were 76.5% and 74.9% (p = 0.435), and the lung cancer-specific survival rates were 91.5% and 91.7% (p = 0.90), respectively. CONCLUSIONS: CTS is less invasive and has superior short-term outcomes as an approach to lobectomy for early-stage NSCLC.

Convergence zones of coastal waters as hotspots for floating microplastic accumulation.

This study examines microplastic (MP, 1-5 mm) densities in convergence zones in a coastal sea, the Seto Inland Sea, comparing them to those of non-convergence zones and other areas. Notably, Seto convergence zones exhibit MP densities 40 to 300 times higher than non-convergence zones, with an extraordinary density of 3.7 ± 6.3 pieces m-3, similar to densities found in Tokyo Bay as known a MP hotspot. The predominant polymer found was expanded polystyrene, varying seasonally and peaking in summer. Juvenile fish associated with driftweed in these convergence zones face a risk of long-term MP exposure, potentially up to four months. This large number of MPs found in coastal convergence zones is similar to accumulation zones formed in the gyres of open oceans, with strong implications for detrimental effects on coastal marine life. However, these MPs are autochthonous, and may be manageable through local marine plastic waste management.

Amino acid deprivation in cancer cells with compensatory autophagy induction increases sensitivity to autophagy inhibitors.

Inhibition of autophagy is an important strategy in cancer therapy. However, prolonged inhibition of certain autophagies in established cancer cells may increase therapeutic resistance, though the underlying mechanisms of its induction and enhancement remain unclear. This study sought to elucidate the mechanisms of therapeutic resistance through repeated autophagy inhibition and amino acid deprivation (AD) in an in vitro model of in vivo chronic nutrient deprivation associated with cancer cell treatment. In the human cervical cancer cell line HeLa and human breast cancer cell line MCF-7, initial extracellular AD induced the immediate expression of endosomal microautophagy (eMI). However, repeated inhibition of eMI with U18666A and extracellular AD induced macroautophagy (MA) to compensate for reduced eMI, simultaneously decreasing cytotoxicity. Here, hyperphosphorylated JNK was transformed into a hypophosphorylated state, suggesting conversion of the cell death signal to a survival signal. In a nutrient medium, cell death could not be induced by MA inhibition. However, since LAT1 inhibitors induce intracellular AD, combining them with MA and eMI inhibitors successfully promoted cell death in resistant cells. Our study identified a novel therapeuic approach for promoting cell death and addressing therapeutic resistance in cancers under autophagy-inhibitor treatment.

Treatment outcomes of lobectomy with and without mediastinal lymph node dissection in older patients with clinical N0 non-small cell lung cancer.

BACKGROUND: To reduce surgical stress, we omit mediastinal lymph node dissection (MLND) in patients with non-small cell lung cancer aged ≥80 years without N1 metastasis, as confirmed via surgery. This study examined the effect of MLND omission on prognosis. METHODS: Altogether, 212 eligible patients with clinical N0 non-small cell lung cancer underwent video-assisted thoracoscopic lobectomy between 2007 and 2017. Patients were classified into two groups as follows: patients aged 75-79 years who underwent MLND group, and patients aged ≥80 years in whom MLND was omitted (non-MLND group). Propensity score matching was performed between the two groups. RESULTS: There were 86 patients after matching. The non-MLND group showed shorter operative time (237.5 min vs. 207.5 min, p = 0.018). No differences in postoperative complications were noted between the two groups. Between the MLND group and non-MLND group, the 5-year overall survival rates were 84.0% and 84.7% (p = 0.989), relapse-free survival rates were 69.8% and 74.7% (p = 0.855), and cancer-specific survival rates were 91.4% and 91.6% (p = 0.700), respectively. These results did not differ significantly. CONCLUSION: This study demonstrated that MLND does not affect the prognosis of patients with non-small cell lung cancer aged ≥80 years. Lobectomy without MLND is one of the surgical treatment options in older patients with clinical N0 non-small cell lung cancer. Naturally, the clinical stage of patients must be carefully evaluated before surgery.

Cytological characteristics of histological types of lung cancer by cytomorphometric and flow cytometric analyses using liquid-based cytology materials.

BACKGROUND: Distinguishing the histological types of lung cancer is essential for determining treatment strategies in clinical practice. In this study, cytomorphological characteristics and proliferative activities were compared among histological types of lung cancer by cytomorphometric and flow cytometric analyses using liquid-based cytology (LBC) samples. METHODS: Scraped LBC samples from 73 surgically resected specimens were collected between August 2018 and November 2019. Papanicolaou-stained and paired Ki-67-stained slides were used for cytomorphometric analyses. Another sample for each case was analyzed using a flow cytometric system (LC-1000). The cell proliferation index (CPIx) was calculated to evaluate proliferative activity. RESULTS: In total, 73 cases, including cases of adenocarcinoma (n = 53), squamous cell carcinoma (n = 14), small cell carcinoma (n = 1), large cell neuroendocrine carcinoma (NEC; n = 3), and pleomorphic carcinoma (n = 2) were evaluated. Small cell carcinoma and large cell NEC were categorized into a single group, NEC. The adenocarcinoma group tended to have a larger nuclear area and longer perimeter than other histological types. The NEC group had a considerably higher Ki-67 labeling index and significantly higher CPIx than other histological types (p = .030). A significant positive correlation was observed between the Ki-67 labeling index and CPIx for all cases (r = 0.362, p = .002). CONCLUSION: The Ki-67 labeling index and flow cytometric analyses focus on proliferative activity for the distinction of histological types of lung cancer, thereby guiding clinical decision-making.

Protective roles of cytoplasmic p21Cip1 /Waf1 in senolysis and ferroptosis of lung cancer cells.

OBJECTIVE: Therapy-induced senescent cancer cells increase the expression of the cyclin-dependent kinase inhibitors p16Ink4a and p21Cip1/Waf1 . Given that p21 regulates not only the cell cycle but also cell death, we investigated the roles of p21 in cell death using a p16-negative A549 human lung adenocarcinoma cell line. METHODS: Senescence was induced by doxorubicin (DXR) or pemetrexed (PEM). The protein expression of p21 was examined by immunoblot. Cell death, reactive oxygen species (ROS) and lipid peroxidation were determined by flow cytometry. ABT-263 and ABT-737 were used as senolytic drugs. In vivo growth of A549 cells with different levels of p21 and their sensitivity to PEM were examined in xenograft models. RESULTS: DXR-induced senescent A549 cells increased the expression of cytoplasmic p21, and the sensitivity to ABT-263 was augmented in p21-knockout A549 (A549-KOp21) cells. A similar senolytic effect was observed when PEM was combined with ABT-737. PEM alone induced a higher level of non-apoptotic cell death, ferroptosis, in A549-KOp21 cells than in A549 cells. Although there was no difference in the level of lipid peroxidation, ROS levels were higher in PEM-treated A549-KOp21 cells than in PEM-treated A549 cells. A loss of p21 increased the sensitivity of A549 cells to PEM both in vitro and in vivo. A clinical database analysis showed that CDKN1Ahigh lung adenocarcinoma patients had a poorer prognosis compared to CDKN1Alow patients. CONCLUSION: Cytoplasmic p21, which was increased in therapy-induced senescent lung cancer cells, plays protective roles in senolysis and ferroptosis.

The Transoral Endoscope-Assisted Approach for Removal of a Dental Implant Displaced into the Maxillary Sinus: A Case Report and Review of the Literature.

Purpose: A dental implant displaced into the maxillary sinus can be removed transorally or transnasally. There is no report investigating any potential positional limitations by the transoral endoscope-assisted approach. The implant's location within the maxillary sinus was reviewed to clarify indications for this approach. Case report: A 36-year-old man was referred to us for removal of a dental implant displaced into the right maxillary sinus. The implant changed position preoperatively, but the transoral endoscope-assisted approach proved successful. Methods: A literature search through October 2020 was performed in PubMed for cases of implant removal from the maxillary sinus via transoral endoscope-assisted and transnasal endoscopic approaches. Results: Sixty-two prior cases were identified, 20 cases by the transoral endoscope-assisted approach and 43 cases by one or two transnasal endoscopic approaches, including one duplicate case. There were no cases in which the implant was not identified by the transoral endoscope-assisted approach, but two cases in which the implant had moved to an unfavorable location and was not identified by only the initial transnasal endoscopic approach. Conclusion: Clinicians can preferentially choose the transoral endoscope-assisted approach, considering the possibility of unfavorable repositioning of the displaced implant within the maxillary sinus.

Optimal Preservations of Cytological Materials Using Liquid-Based Cytology Fixatives for Next-Generation Sequencing Analysis.

INTRODUCTION: Molecular targeted therapies have been established for various diseases, including cancers, and there is an increasing need for molecular testing on cytology specimens. The aim of this study was to determine the optimal preservation methods of liquid-based cytology (LBC) materials for molecular testing. METHODS: Cytological samples from 35 surgical resected non-small cell lung carcinoma specimens were obtained between June 2016 and June 2021. The samples were fixed in CytoRich™ red Preservative and stored at 4°C. One week later, three tubes were prepared from each specimen sample and divided into the following groups: the SurePath™ group (continued storage at 4°C), Frozen (Fr) group (stored at -80°C after centrifugation), and LBC-Cell Block (LBC-CB) group (generation of paraffin-embedded CB and storage at 4°C). Samples from 5 patients were used for the time course analysis, and we performed evaluations on these samples at 1, 3, 6, 12, 24, and 36 months. The concentrations and purities of extracted DNA and RNA were measured. The double-stranded DNA (dsDNA) and RNA concentrations were also measured by a fluorometer. The DNA and RNA integrities were quantified by the DNA and RNA integrity number. RESULTS: Evaluation of samples was performed at baseline and the six timepoints. In the LBC-CB group, DNA and dsDNA concentrations were higher rather than those in the other groups. The RNA concentration of the LBC-CB group was relatively high compared with those of the other groups at the 36-month timepoint. The Fr group maintained higher DNA quality compared with the other groups over 3 years. The LBC-CB group maintained a higher RNA quality than the other groups until 24 months. CONCLUSION: LBC-CB preparation is an effective method to maintain DNA/RNA quality and quantity in long-duration preservation for eventual molecular testing. Therefore, LBC-CB may have applications on preanalytical stage for molecular genomic testing such as next-generation sequencing.

Cytomorphometric and flow cytometric analyses using liquid-based cytology materials in subtypes of lung adenocarcinoma.

BACKGROUND: The histological classifications of invasive lung adenocarcinoma subtypes are considered to predict patient prognosis after surgical treatment. The objectives of this study were to evaluate cytomorphological characteristics and proliferative activities among the histological predominant patterns by performing cytomorphometric and flow cytometric analyses using liquid-based cytology materials. METHODS: Cytological samples fixed by liquid-based cytology preservatives from 53 surgically-resected lung adenocarcinoma specimens were obtained between August 2018 and November 2019. The Papanicolaou-stained and paired Ki-67-stained slides were analyzed for calculating nuclear morphology (nuclear area, nuclear perimeter and nuclear circularity) and Ki-67 labeling index using software. The cell proliferation index (CPIx) was calculated and cellular information including cell cycle stage of tumor cells was obtained by flow cytometry. RESULTS: The 53 cases included papillary (n = 29), acinar (n = 8), lepidic (n = 5), and solid (n = 4) subtypes, and invasive mucinous adenocarcinoma (n = 7) were also included. In the lepidic pattern, nuclear area (79.6 ± 28.8 µm2 ) and perimeter (34.1 ± 6.1 µm) were relatively larger and longer than those of the other predominant patterns. The Ki-67 labeling index of the solid pattern (27.9 ± 12.5%) was highest compared with those of other predominant patterns. There were statistically significant differences in the lepidic versus solid patterns and the papillary versus solid patterns (p = .013 and p = .039, respectively). The calculated mean CPIx of the lepidic and the acinar patterns were approximately two-fold higher than those of the other predominant patterns. CONCLUSION: By revealing the differences of cytomorphological characteristics, these methodologies might be used for diagnosing cytopathological materials using digital cytopathology.

MuRF1 deficiency prevents age-related fat weight gain, possibly through accumulation of PDK4 in skeletal muscle mitochondria in older mice.

Recent studies show that muscle mass and metabolic function are interlinked. Muscle RING finger 1 (MuRF1) is a critical muscle-specific ubiquitin ligase associated with muscle atrophy. Yet, the molecular target of MuRF1 in atrophy and aging remains unclear. We examined the role of MuRF1 in aging, using MuRF1-deficient (MuRF1-/- ) mice in vivo, and MuRF1-overexpressing cell in vitro. MuRF1 deficiency partially prevents age-induced skeletal muscle loss in mice. Interestingly, body weight and fat mass of more than 7-month-old MuRF1-/- mice were lower than in MuRF1+/+ mice. Serum and muscle metabolic parameters and results of indirect calorimetry suggest significantly higher energy expenditure and enhanced lipid metabolism in 3-month-old MuRF1-/- mice than in MuRF1+/+ mice, resulting in suppressed adipose tissue gain during aging. Pyruvate dehydrogenase kinase 4 (PDK4) is crucial for a switch from glucose to lipid metabolism, and the interaction between MuRF1 and PDK4 was examined. PDK4 protein levels were elevated in mitochondria from the skeletal muscle in MuRF1-/- mice. In vitro, MuRF1 interacted with PDK4 but did not induce degradation through ubiquitination. Instead, SUMO posttranscriptional modification (SUMOylation) of PDK4 was detected in MuRF1-overexpressing cells, in contrast to cells without the RING domain of MuRF1. MuRF1 deficiency enhances lipid metabolism possibly by upregulating PDK4 localization into mitochondrial through prevention of SUMOylation. Inhibition of MuRF1-mediated PDK4 SUMOylation is a potential therapeutic target for age-related dysfunction of lipid metabolism and muscle atrophy.

A Rare Case of Acute Fibrinous and Organizing Pneumonia Associated with Systemic Lupus Erythematosus and Autoimmune-associated Hemophagocytic Syndrome: The Involvement of CD163-positive Macrophages.

Acute fibrinous and organizing pneumonia (AFOP) is rare in patients with systemic lupus erythematosus (SLE). We herein report a case of AFOP with SLE and hemophagocytic syndrome. Early-phase high-resolution computed tomography showed a fine granular lung pattern. A pathological examination revealed AFOP. An immunohistological examination revealed numerous CD163+ and fewer CD68+ macrophages present in the lung tissue and in alveolar spaces as well, including fibrin balls, the interstitium, and bronchial walls. Pneumonia and thrombocytopenia worsened during high-dose steroid therapy, plasma exchange, and intravenous immunoglobulin administration. The addition of intravenous cyclophosphamide successfully ameliorated the symptoms and radiographic lesions. Therefore, this therapy may be useful for treating severe AFOP.