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Abstract There have been several reports of drug‐induced lung injury caused by molecular‐targeted agents. Additionally, medical history of interstitial lung disease and chest irradiation are established risk factors for the development and progression of drug‐induced lung injury. Moreover, the presence of fibrosis on chest computed tomography before treatment is a predictive factor for the appearance of pneumonia induced by anticancer drugs. Accordingly, patients with a history of interstitial lung disease or pneumonitis were excluded from clinical trials of dabrafenib and trametinib combination therapy for patients with previously treated BRAF V600E‐mutant metastatic non‐small‐cell lung cancer. This article presents a case of successful dabrafenib and trametinib combination therapy in a patient with BRAF V600E‐mutant non‐small‐cell lung cancer who had a history of radiation pneumonitis and developed recurrence after conventional chemoradiotherapy.

Abstract A 28‐year‐old man with ankylosing spondylitis (AS) who was treated with a tumour necrosis factor‐alpha (TNF‐α) inhibitor, adalimumab, presented with newly detected multiple bilateral pulmonary nodules on chest computed tomography (CT). We suspected bacterial infection, including those caused by acid‐fast bacilli, or adalimumab‐related condition, such as sarcoidosis. After adalimumab cessation, no resolution of the pulmonary shadows was observed. Moreover, pulmonary cavitation appeared on chest CT at 7 weeks, prompting surgical lung biopsy. Acid‐fast bacteria culture of the lung tissue showed negative results. Pathological examination suggested that confluent granulomas associated with sarcoidosis might have obstructed the blood vessels, causing necrosis and lung cavitation. Consequently, prednisolone was initiated, and these shadows were reduced. After administering anti‐interleukin (IL)‐17A antibody for treatment of AS and prednisolone withdrawal, these shadows were not exacerbated. TNF‐α inhibitor‐induced sarcoidosis could cause cavitary lesions due to vascular invasion of granulomas.

Background: Among international cardiologists it is unclear whether equipoise exists regarding the benefit of diagnosing and managing obstructive sleep apnea (OSA) to improve atrial fibrillation (AF) outcomes and whether clinical practice and equipoise are linked. Methods: Between January 2019 and June 2020 we distributed a web-based 12-question survey regarding OSA and AF management to practicing cardiologists in 16 countries. Results: The United States, Japan, Sweden, and Turkey accounted for two-thirds of responses. 863 cardiologists responded; half were general cardiologists, a quarter electrophysiologists. Responses regarding treating OSA with CPAP to improve AF endpoints were mixed. 33% of respondents referred AF patients for OSA screening. OSA was diagnosed in 48% of referred patients and continuous positive airway pressure (CPAP) was prescribed for 59% of them. Nearly 70% of respondents believed randomized controlled trials (RCTs) of OSA treatment in AF patients were necessary and indicated willingness to contribute to such trials. Conclusions: There was no clinical equipoise among surveyed cardiologists; a majority expressed certainty that combined OSA and AF treatment is superior to AF treatment alone for improving AF outcomes. However, a minority of surveyed cardiologists referred AF patients for OSA testing, and while half of screened AF patients had OSA, CPAP was prescribed in little more than half of them, reflecting the view that better clinical trial evidence is needed to support this practice. Our results underscore the need for larger, multi-national prospective studies of OSA treatment and AF outcomes to inform more uniform society guideline recommendations.

Abstract Nintedanib is a multi‐target receptor tyrosine kinase inhibitor that reduces the decline in forced vital capacity (FVC) and prevents acute exacerbations in idiopathic pulmonary fibrosis (IPF), which is a risk factor for lung cancer. However, it remains unclear whether nintedanib is an effective treatment for lung cancer in patients with IPF. Here, we describe an 82‐year‐old man with non‐small cell lung carcinoma complicated by IPF who was treated with nintedanib. High‐resolution computed tomography (HRCT) showed a subpleural basal‐predominant reticular shadow and traction bronchiectasis with a honeycomb pattern. His FVC decreased over time, and his 6‐min walk test showed oxygen desaturation. Furthermore, an enlarged nodular lesion was detected after 6 months of referral. Biopsy confirmed non‐small cell carcinoma. Because of the risk of acute exacerbation of IPF by chemotherapy, supportive care was selected. Nintedanib was started as treatment for the IPF. Nine months later, HRCT revealed partial remission without exacerbation of IPF. This case indicates the possibility of nintedanib monotherapy in suppressing lung cancer complicated by IPF. Patients with lung cancer complicated by IPF in whom treatment is effective remain unknown. Additional research is needed to identify effective therapy for lung cancer with IPF.

Abstract Background Paravertebral compartment syndrome occurring without trauma is quite rare. We report a case of compartment syndrome that occurred after spinal exercises. Case presentation A 23-year-old Japanese rower developed severe back pain and was unable to move 1 day after performing exercises for the spinal muscles. Initial evaluation at a nearby hospital revealed hematuria and elevated creatine phosphokinase levels. He was transferred to our hospital, where magnetic resonance imaging revealed no hematoma but confirmed edema in the paravertebral muscles. The compartment pressure measurements were elevated bilaterally. Despite his pain being severe, his creatine phosphokinase levels were expected to peak and decline; his urine output was normal; and surgery was undesirable. Therefore, we opted for conservative management. The next day, the patient’s compartment pressure diminished, and his pain levels decreased to 2/10. After 5 days, he was able to walk without medication. Conclusions We present a rare case of compartment syndrome of the paravertebral muscles with good resolution following conservative management. We hope our case findings will help avoid unnecessary surgery in cases of paravertebral compartment syndrome.

Abstract We report an approach to fabricate high conductivity graphite sheets based on a heat-and-current treatment of filtrated, exfoliated graphite flakes. This treatment combines heating (~ 900 °C) and in-plane electrical current flow (550 A·cm−2) to improve electrical conductivity through the reduction of crystalline defects. This process was shown to require only a 1-min treatment time, which resulted in a 2.1-fold increase in electrical conductivity (from 1088 ± 72 to 2275 ± 50 S·cm−1). Structural characterization by Raman spectroscopy and X-ray diffraction indicated that the improvement electrical conductivity originated from a 30-fold improvement in the crystallinity (Raman G/D ratio increase from 2.8 to 85.3) with no other observable structural transformations. Significantly, this treatment was found to act uniformly across a macroscopic (10 mm) sheet surface indicating it is on the development of applications, such as electrodes for energy generation and storage and electromagnetic shielding, as well as on the potential for the development of large-scale treatment technologies.

Human adrenomedullin (AM), a hypotensive peptide, also has anti-colitis activity. We prepared a polyethylene glycol (PEG) ylated form of AM through the conjugation of PEG-AM (1–15) and AM (15–52). Highly pure monomeric 20 kDa PEG-AM (20kPEG-AM) stimulated cyclic adenosine monophosphate production in HEK-293 cells stably expressing the type 1 AM receptor in a dose-dependent manner. The half-life of 20kPEG-AM was 7.4 h following subcutaneous administration in mice. We assessed the anti-colitis effect of subcutaneous 20kPEG-AM administration in the dextran sodium sulfate murine colitis model. Single and double subcutaneous injection of 20kPEG-AM significantly reduced total inflammation scores. These results suggest that 20kPEG-AM is a promising therapeutic candidate for the treatment of human inflammatory bowel diseases.

Abstract Dupilumab, a human monoclonal antibody against interleukin‐4 (IL‐4) and IL‐13, has been approved for treating severe asthma and eosinophilic chronic rhinosinusitis (ECRS). Patients with ECRS are often candidates for endoscopic sinus surgery (ESS). However, a considerable number of patients have recurrent ECRS. ECRS is an important factor influencing asthma control. Here, we present two cases of severe asthma and recurrent ECRS after ESS. Although they had been treated with inhaled corticosteroids and a long‐acting β2‐agonist, they experienced frequent asthma exacerbations. Laboratory examinations revealed increased serum eosinophils and immunoglobulin E (IgE). Furthermore, the Asthma Control Test (ACT) score and forced expiratory volume in 1 sec (FEV1) were indicative of airway obstruction. After treatment with dupilumab, asthma, rhinosinusitis symptoms, and pulmonary function improved remarkably. Dupilumab therapy improved quality of life in these patients with severe asthma and ECRS.

(1) Background: Human adrenomedullin (hAM) is a hypotensive peptide hormone that exerts powerful anti-inflammatory effects. AM also had therapeutic effects in various animal experimental models of disease. However, treatment required continuous administration as the half-life of native AM is short in blood. To resolve this, we developed four human IgG1 and IgG4 Fc-fusion proteins containing full-length hAM or hAM residues 6-52. (2) Methods: We used mammalian cells to produce recombinant Fc-AM derivatives and tested the pharmacokinetics and biological activity of Fc-AM. (3) Results: We developed four Fc-fusion AMs (Fc-AM), which are long-acting AM derivatives in mammalian cells. Fc-AM had a prolonged half-life in blood and retained its ability to bind to the AM1 receptor. Fc-AM (6-52) induced higher cAMP levels for the receptor than Fc-AM. After the administration of IgG1-AM (6-52) or IgG4-AM (6-52) to rats, tissue transfer to the kidney and small intestine was observed. In addition, treatment with IgG4-AM (6-52) inhibited blood pressure increase in spontaneously hypertensive rats. (4) Conclusions: Fc-AM produced from mammalian cells can be easily prepared and might be an effective novel therapeutic agent.

We describe a case of Trousseau's syndrome in a patient with lung carcinoma. A 69-year-old man presented with pleural effusion. Further evaluation revealed EGFR mutation-positive non-small cell carcinoma in the upper lobe with extensive lymph node, bone, and brain metastases. Administration of osimertinib, an EGFR tyrosine kinase inhibitor, resulted in partial tumor response, but caused osimertinib-induced pneumonitis 10 weeks later. Prednisolone restrained lung injury progression and was gradually tapered. However, he presented with impaired consciousness and right hemiplegia. Magnetic resonance imaging revealed a left middle cerebral artery M1 segment occlusion. D-dimer level was elevated to 19.5 μg/mL. In the absence of atherosclerotic or cardiogenic thrombi, these findings led to the diagnosis of Trousseau syndrome. Endovascular therapy, but not tissue plasminogen activator, improved his condition with no recurrences. These treatment strategies are crucial to restore function in patients with potentially disabling cerebral infarction due to Trousseau syndrome.

Background: Pancreatic cancer is obstinate and resistant to gemcitabine, a standard chemotherapeutic agent for the disease. We previously showed a therapeutic effect of glycogen synthase kinase-3β (GSK3β) inhibition against gastrointestinal cancer and glioblastoma. Here, we investigated the effect of GSK3β inhibition on pancreatic cancer cell sensitivity to gemcitabine and the underlying molecular mechanism.Methods: Expression, phosphorylation, and activity of GSK3β in pancreatic cancer cells (PANC-1) were examined by Western immunoblotting and in vitro kinase assay. The combined effect of gemcitabine and a GSK3β inhibitor (AR-A014418) against PANC-1 cells was examined by isobologram and PANC-1 xenografts in mice. Changes in gene expression in PANC-1 cells following GSK3β inhibition were studied by cDNA microarray and reverse transcription (RT)-PCR.Results: PANC-1 cells showed increased GSK3β expression, phosphorylation at tyrosine 216 (active form), and activity compared with non-neoplastic HEK293 cells. Administration of AR-A014418 at pharmacological doses attenuated proliferation of PANC-1 cells and xenografts, and significantly sensitized them to gemcitabine. Isobologram analysis determined that the combined effect was synergistic. DNA microarray analysis detected GSK3β inhibition-associated changes in gene expression in gemcitabine-treated PANC-1 cells. Among these changes, RT-PCR and Western blotting showed that expression of tumor protein 53-induced nuclear protein 1, a gene regulating cell death and DNA repair, was increased by gemcitabine treatment and substantially decreased by GSK3β inhibition.Conclusions: The results indicate that GSK3β inhibition sensitizes pancreatic cancer cells to gemcitabine with altered expression of genes involved in DNA repair. This study provides insight into the molecular mechanism of gemcitabine resistance and thus a new strategy for pancreatic cancer chemotherapy. [ABSTRACT FROM AUTHOR]

The p8 gene is barely expressed in the normal pancreas, but is overexpressed in acute pancreatitis. To elucidate the dynamic expression of p8 mRNA and its significance in the course of chronic pancreatitis, we investigated the p8 expression in spontaneous chronic pancreatitis in the WBN/Kob rat as well as in humans and arginine-treated rat pancreatic acinar AR4-2J cells. p8 mRNA was significantly increased at 12 weeks when chronic pancreatitis first appeared in the WBN/Kob rats. p8 was immunolocalized in the acinar cell nuclei. Acinar cell apoptosis was significantly increased at 12 and 20 weeks in the WBN/Kob rats. In AR4-2J cells, p8 mRNA was significantly induced at 4 hr after arginine addition. Apoptosis of AR4-2J cells was not increased during the strong expression of p8 mRNA. These results suggest that p8 is induced in the acinar cells during chronic pancreatitis as the self-defence mechanism against proapoptotic insults. [ABSTRACT FROM AUTHOR]

The Fas/Fas ligand (FasL) system is suggested to be correlated to the onset of inflammation and apoptosis in various diseases. However, whether Fas and FasL are expressed in chronic pancreatitis is unknown. The aim of this study was to examine the expression of the Fas/FasL system and to analyze its correlation with apoptosis in a spontaneous chronic pancreatitis model (the WBN/Kob rat). Four-week-old male WBN/Kob rats were fed a special pellet diet (MB-3). Different groups of rats were killed every four weeks, and pancreata were histopathologically examined. Fas and FasL mRNAs in the pancreas were detected with a reverse transcription-polymerase chain reaction method. The cellular localization of Fas and FasL mRNA and protein was determined with in situ hybridization (ISH) and immunohistochemistry (IHC). Apoptosis was detected with a terminal deoxynucleotidyltransferase-mediated method. Fas and FasL mRNA were expressed when the pancreas was still pathologically normal, and showed a biphasic peak at 12 and 20 weeks. ISH and IHC confirmed that Fas and FasL are expressed in the cytoplasm of acinar cells, ductal cells, and lymphocytes. An apoptotic index in acinar cells correlated to the expression of Fas and FasL mRNAs. These results suggest that the expression of the Fas/FasL system is involved in acinar cell apoptosis and the onset and progression of chronic pancreatitis in the WBN/Kob rat. [ABSTRACT FROM AUTHOR]

Transforming growth factor-beta1 (TGF-beta1) is suggested to be a mediator of fibrosis in chronic pancreatitis, but the serial change of TGF-beta1 expression in the onset and progression of chronic pancreatitis is still unclear. We investigated the TGF-beta1 expression in the spontaneous chronic pancreatitis model. Four-week-old male WBN/Kob rats were fed with special pellet diet (MB-3) for 20 weeks. TGF-beta1 mRNA in the pancreas was detected by reverse transcription-polymerase chain reaction assay from four weeks, and its expression peaked at 12 weeks when the pancreatic fibrosis first appeared. The localizations of TGF-beta1 mRNA and protein were confirmed in the cytoplasm of pancreatic acinar and ductal cells by in situ hybridization and immunohistochemistry, respectively. Although fibronectin expression peaked at 12 weeks and correlated with that of TGF-beta1, its elevated expression tended to be prolonged. Pancreatic fibrosis peaked at 16 weeks after the peak of TGF-beta1 expression. These results suggest that TGF-beta1 expression may be a trigger of the fibrotic process of chronic pancreatitis in the WBN/Kob rat. [ABSTRACT FROM AUTHOR]

BACKGROUND:Mouth breathing could induce not only dry throat and eventually upper respiratory tract infection, but also snoring and obstructive sleep apnea, while nasal breathing is protective against those problems. Thus, one may want to explore an approach to modify habitual mouth breathing as preferable to nasal breathing. The aim of this study was to investigate the physiological effects of our newly developed mask on facilitation of nasal breathing. METHODS:Thirty seven healthy male volunteers were enrolled in a double blind, randomized, placebo-controlled crossover trial. Participants wore a newly developed heated humidification mask or non-heated-humidification mask (placebo) for 10-min each. Subjective feelings including dry nose, dry throat, nasal obstruction, ease to breathe, relaxation, calmness, and good feeling were asked before and after wearing each mask. In addition, the effects of masks on nasal resistance, breathing pattern, and heart rate variability were assessed. RESULTS:Compared with the placebo mask, the heated humidification mask improved all components of subjective feelings except for ease to breathe; moreover, decreased nasal resistance and respiratory frequency accompanied a simultaneous increase in a surrogate maker for tidal volume. However, use of the heated humidification mask did not affect heart rate variability. CONCLUSION:Adding heated humidification to the nasopharynx could modulate breathing patterns with improvement of subjective experience and objective nasal resistance.

The serum levels of pancreatitis-associated protein (PAP) were measured in 196 patients with digestive diseases and 15 healthy subjects by an enzyme-linked immunosorbent assay. The serum PAP levels were significantly elevated in the patients with gastric, colorectal, biliary tract, hepatocellular, or pancreatic cancers compared with the healthy subjects. After curative resection of the tumor, serum PAP levels were significantly decreased. The serum PAP levels were not related to clinicopathological factors except for the tumor size of pancreatic cancer. There were some cases of PAP-positive and carcinoembryonic antigen (CEA) or carbohydrate antigen (CA) 19-9 -negative gastric and colorectal cancers. The serum PAP levels were also significantly elevated in the patients with acute pancreatitis compared with those in not only the healthy subjects but also the patients with chronic pancreatitis. The peak PAP levels were significantly correlated with the severity of acute pancreatitis and reflected the clinical healing of the disease. The peak of serum PAP was significantly delayed compared with those of other pancreatic enzymes. These results suggest that the increase of serum PAP levels in patients with gastrointestinal cancers reflects an ectopic expression of PAP in cancer cells and that increased serum levels of PAP in acute pancreatitis are correlated with the disease severity and are prolonged than those of other pancreatic markers. [ABSTRACT FROM AUTHOR]

We report a case of Cruveihier-Baumgarten syndrome associated with portal vein thrombosis that developed, slowly during a 2-year period after endoscopic variceal sclerotherapy. The thrombosis led to the disappearance of the venous hum and the dilated abdominal wall veins characteristic of this syndrome. A 73-year-old woman was hospitalized for treatment of esophageal varices in April 1988. Her spleen was markedly enlarged, and the histologic findings of her liver were not consistent with hepatic cirrhosis, but with idiopathic portal hypertension. A venous hum was audible in the upper abdomen. Superior mesenteric angiography revealed a porto-systemic shunt vessel under the abdominal wall, originating from the umbilical vein. She was injected four times with a sclerosant, and this brought about disappearance of the esophageal varices. Two years after the first admission, the venous hum was no longer audible, but there was a recurrence of the esophageal varices. More than 2 years later (4 years after the first admission), ultasonographic study, computed tomography, and angiography showed a large thrombus, which completely obstructed the portal vein at the origin of the umbilical vein, and the development of collateral vessels, seen as a "cavernous transformation." [ABSTRACT FROM AUTHOR]

An enzyme-linked immunosorbent assay, based on two monoclonal antibodies (Hreg1-1 and Hreg101-1) specific for pancreatic stone protein (PSP)/reg-protein, was developed to determine the concentration of this protein in serum from individuals with various diseases. The serum concentration of PSP/reg-protein was significantly higher in patients with various pancreatic diseases than in normal controls, and was also significantly higher in patients with acute pancreatitis or chronic relapsing pancreatitis than in patients with chronic pancreatitis. Furthermore, the serum PSP/reg-protein concentration was also significantly increased in liver cirrhosis, choledocholithiasis, and various cancers of the digestive system, and was extremely high in all patients tested with chronic renal failure. A significant correlation was apparent between the serum concentration of PSP/reg-protein and elastase-I in 68 patients with chronic pancreatitis or pancreatic cancer. Whereas only 7 of these patients showed a normal serum PSP/reg-protein concentration and a significantly increased elastase-I concentration, 15 of these patients showed a significantly increased serum PSP/reg-protein concentration and a normal serum elastase-I concentration. These results indicate that the serum PSP/reg-protein concentration may reflect pancreatic damage, especially in acute pancreatitis, and may be a sensitive a marker for such damage as elastase-1, although false positivity was apparent in renal failure and in some patients with hepatic dysfunction or digestive system malignancies. [ABSTRACT FROM AUTHOR]

The clinical significance of the measurement of c-erbB-2 oncogene product was evaluated. The subjects consisted of 404 patients, including 248 with cancer of the digestive organs and 128 with benign digestive diseases. Serum c-erbB-2 protein levels were measured by sandwich immunoenzyme assay. The positive rates of c-erbB-2 protein, at a cut-off value of 17.0 U/ml, were, for cancers: hepatocellular carcinoma 61.6%, biliary tract cancer 54.8%, pancreatic cancer 25.0%, esophageal cancer 33.3%, gastric cancer 16.9%, and colorectal cancer 5.0%. For benign digestive diseases, the rates were: liver cirrhosis 63.3%, chronic hepatitis 43.2%, acute hepatitis 42.9%, other liver diseases 42.8%, cholelithiasis 30.0%, and chronic pancreatitis 0%. Serum c-erbB-2 protein levels were significantly correlated with the markers of hepatic functional reserve, the indocyanine green retention rate and the hepaplastin test. These findings suggest that serum c-erbB-2 protein levels are greatly influenced by liver dysfunction and that their clinical usefulness as a serum tumor marker is questionable. [ABSTRACT FROM AUTHOR]

One aspect of carbon nanotube (CNT) synthesis that remains an obstacle to realize industrial mass production is the growth efficiency. Many approaches have been reported to improve the efficiency, either by lengthening the catalyst lifetime or by increasing the growth rate. We investigated the applicability of dwell time and carbon flux control to optimize yield, growth rate, and catalyst lifetime of water-assisted chemical vapor deposition of single-walled carbon nanotube (SWCNT) forests using acetylene as a carbon feedstock. Our results show that although acetylene is a precursor to CNT synthesis and possesses a high reactivity, the SWCNT forest growth efficiency is highly sensitive to dwell time and carbon flux similar to ethylene. Through a systematic study spanning a wide range of dwell time and carbon flux levels, the relationship of the height, growth rate, and catalyst lifetime is found. Further, for the optimum conditions for 10 min growth, SWCNT forests with ~2500 μm height, ~350 μm/min initial growth rates and extended lifetimes could be achieved by increasing the dwell time to ~5 s, demonstrating the generality of dwell time control to highly reactive gases.

Sleep apnea syndrome (SAS) is a very common disease involving intermittent hypoxia (IH), recurrent symptoms of deoxygenation during sleep, strong daytime sleepiness, and significant loss of quality of life. A number of epidemiological researches have shown that SAS is an important risk factor for insulin resistance and type 2 diabetes mellitus (DM), which is associated with SAS regardless of age, gender, or body habitus. IH, hallmark of SAS, plays an important role in the pathogenesis of SAS and experimental studies with animal and cellular models indicate that IH leads to attenuation of glucose-induced insulin secretion from pancreatic β cells and to enhancement of insulin resistance in peripheral tissues and cells, such as liver (hepatocytes), adipose tissue (adipocytes), and skeletal muscles (myocytes). In this review, we focus on IH-induced dysfunction in glucose metabolism and its underlying molecular mechanisms in several cells and tissues related to glucose homeostasis.

Understanding the fundamental mechanisms and limiting processes of the growth of single-walled carbon nanotube (SWCNT) would serve as a guide to achieve further control on structural parameters of SWCNT. In this paper, we have studied the growth kinetics of a series of SWCNT forests continuously spanning a wide range of diameters (1.9–3.2 nm), and have revealed an additional fundamental growth limiting process where the mass of the individual SWCNT is determined by the individual catalyst volume. Calculation of the conversion rate of carbon atoms into CNTs per Fe atom is 2 × 102 atoms per second. This rate limiting process provides an important understanding where the larger diameter SWCNT would grow faster, and thus be more suited for mass production.

Electron density of single wall carbon nanotubes (SWCNT) is effectively modified by hexaiodobenzene (HIB) molecules using liquid-phase adsorption. UV-Vis-NIR absorption spectra of the HIB-adsorbed SWCNT, especially in the NIR region, showed a disappearance of S11 transitions between the V1 valance band and the C1 conduction band of van Hove singularities which can be attributed to the effective charge transfer between HIB and the SWCNT. The adsorption of HIB also caused significant peak-shifts (lower frequency shift around 170 cm−1 and higher shift around 186 cm‑1) and an intensity change (around 100–150 cm−1 and 270–290 cm−1) in the radial breathing mode of Raman spectra. The charge transfer from SWCNT to HIB was further confirmed by the change in the C1s peak of X-ray photoelectron spectrum, revealing the oxidation of carbon in SWCNT upon HIB adsorption.