PD-1 blockade therapy augments the antitumor effects of lymphodepletion and adoptive T cell transfer.

Lymphodepleting cytotoxic regimens enhance the antitumor effects of adoptively transferred effector and naïve T cells. Although the mechanisms of antitumor immunity augmentation by lymphodepletion have been intensively investigated, the effects of lymphodepletion followed by T cell transfer on immune checkpoints in the tumor microenvironment remain unclear. The current study demonstrated that the expression of immune checkpoint molecules on transferred donor CD4+ and CD8+ T cells was significantly decreased in lymphodepleted tumor-bearing mice. In contrast, lymphodepletion did not reduce immune checkpoint molecule levels on recipient CD4+ and CD8+ T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Further analysis revealed that transfer of both donor CD4+ and CD8+ T cells was responsible for the antitumor effects of a combination therapy consisting of lymphodepletion, T cell transfer and anti-PD-1 treatment. Our findings indicate that a possible mechanism underlying the antitumor effects of lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. PD-1 blockade may reinvigorate exhausted recipient T cells and augment the antitumor effects of lymphodepletion and adoptive T cell transfer.

Efficacy of non-invasive and invasive respiratory management strategies in adult patients with acute hypoxaemic respiratory failure: a systematic review and network meta-analysis.

BACKGROUND: Although non-invasive respiratory management strategies have been implemented to avoid intubation, patients with de novo acute hypoxaemic respiratory failure (AHRF) are high risk of treatment failure. In the previous meta-analyses, the effect of non-invasive ventilation was not evaluated according to ventilation modes in those patients. Furthermore, no meta-analyses comparing non-invasive respiratory management strategies with invasive mechanical ventilation (IMV) have been reported. We performed a network meta-analysis to compare the efficacy of non-invasive ventilation according to ventilation modes with high-flow nasal oxygen (HFNO), standard oxygen therapy (SOT), and IMV in adult patients with AHRF. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Ichushi databases were searched. Studies including adults with AHRF and randomized controlled trials (RCTs) comparing two different respiratory management strategies (continuous positive airway pressure (CPAP), pressure support ventilation (PSV), HFNO, SOT, or IMV) were reviewed. RESULTS: We included 25 RCTs (3,302 participants: 27 comparisons). Using SOT as the reference, CPAP (risk ratio [RR] 0.55; 95% confidence interval [CI] 0.31-0.95; very low certainty) was associated significantly with a lower risk of mortality. Compared with SOT, PSV (RR 0.81; 95% CI 0.62-1.06; low certainty) and HFNO (RR 0.90; 95% CI 0.65-1.25; very low certainty) were not associated with a significantly lower risk of mortality. Compared with IMV, no non-invasive respiratory management was associated with a significantly lower risk of mortality, although all certainties of evidence were very low. The probability of being best in reducing short-term mortality among all possible interventions was higher for CPAP, followed by PSV and HFNO; IMV and SOT were tied for the worst (surface under the cumulative ranking curve value: 93.2, 65.0, 44.1, 23.9, and 23.9, respectively). CONCLUSIONS: When performing non-invasive ventilation among patients with de novo AHRF, it is important to avoid excessive tidal volume and lung injury. Although pressure support is needed for some of these patients, it should be applied with caution because this may lead to excessive tidal volume and lung injury. Trial registration protocols.io (Protocol integer ID 49375, April 23, 2021). https://doi.org/10.17504/protocols.io.buf7ntrn .

Long noncoding RNA NORAD regulates transforming growth factor-ß signaling and epithelial-to-mesenchymal transition-like phenotype.

Long noncoding RNAs are involved in a variety of cellular functions. In particular, an increasing number of studies have revealed the functions of long noncoding RNA in various cancers; however, their precise roles and mechanisms of action remain to be elucidated. NORAD, a cytoplasmic long noncoding RNA, is upregulated by irradiation and functions as a potential oncogenic factor by binding and inhibiting Pumilio proteins (PUM1/PUM2). Here, we show that NORAD upregulates transforming growth factor-ß (TGF-ß) signaling and regulates TGF-ß-induced epithelial-to-mesenchymal transition (EMT)-like phenotype, which is a critical step in the progression of lung adenocarcinoma, A549 cells. However, PUM1 does not appear to be involved in this process. We thus focused on importin ß1 as a binding partner of NORAD and found that knockdown of NORAD partially inhibits the physical interaction of importin ß1 with Smad3, inhibiting the nuclear accumulation of Smad complexes in response to TGF-ß. Our findings may provide a new mechanism underlying the function of NORAD in cancer cells.

1-Fluoro-2,4-dinitrobenzene and its derivatives act as secretagogues on rodent mast cells.

Accumulating evidence suggests that activated mast cells are involved in contact hypersensitivity, although the precise mechanisms of their activation are still not completely understood. We investigated the potential of common experimental allergens to induce mast cell activation using murine bone marrow-derived cultured mast cells and rat peritoneal mast cells. Among these allergens, 1-chloro-2,4-dinitrobenzene and 1-fluoro-2,4-dinirobenzene (DNFB) were found to induce degranulation of rat peritoneal mast cells. DNFB-induced degranulation is accompanied by cytosolic Ca2+ mobilization and is significantly inhibited by pertussis toxin, U73122 (a phospholipase C inhibitor), and BAPTA (a Ca2+ chelator), raising the possibility that DNFB acts on the G protein-coupled receptors and activates Gi , which induces activation of phospholipase C, as well as known mast cell secretagogues, such as compound 48/80. DNFB could induce mast cell degranulation in the absence of serum proteins and IgE. Structure-activity relationship analyses revealed an inverse correlation between the degree of degranulation and the electron density of the C1 carbon of the DNFB derivatives. These findings raise a possibility that DNFB functions as a potent contact allergen through induction of cutaneous mast cell degranulation.

A-DROP system for prognostication of NHCAP inpatients.

Nursing and healthcare-associated pneumonia (NHCAP) is a category of healthcare-associated pneumonia that was modified for the healthcare system of Japan. The NHCAP guidelines stated the difficulty in assessing the severity classifications, for instance, A-DROP. We compared the usefulness of different severity classifications (A-DROP, CURB-65, PSI, and I-ROAD) in predicting the prognosis of nursing and healthcare-associated pneumonia. We conducted a retrospective analysis on 303 adult patients hospitalized for nursing healthcare-associated pneumonia and community-acquired pneumonia, which were diagnosed at the Department of Respiratory Medicine of Niigata General City Hospital between January 2012 and December 2014. We evaluated 159 patients with community-acquired pneumonia and 144 with nursing and healthcare-associated pneumonia. In the nursing and healthcare-associated pneumonia group, 30-days mortality and in-hospital mortality rates were 6.5% and 8.7%, respectively, in severe cases and 16.1% and 25.0%, respectively, in the most severe cases, based on A-DROP. With I-ROAD, these rates were 11.1% and 11.1%, respectively, in group B and 14.9% and 20.7%, respectively, in group C. With PSI, the rates were 2.3% and 6.8%, respectively, in class IV and 14.3% and 19.8%, respectively, in class V. Despite some variability due to the small sample size, both the 30-days and in-hospital mortality rates increased as the severity increased. In this study, both the 30-days mortality and in-hospital mortality rates in the nursing and healthcare-associated pneumonia group tended to increase in severity with the A-DROP. We found that A-DROP was useful in predicting the prognosis of nursing and healthcare-associated pneumonia.

The relationship between adherence to continuous positive airway pressure and nasal resistance measured by rhinomanometry in patients with obstructive sleep apnea syndrome.

Nasal breathing disorders are associated with obstructive sleep apnea (OSA) syndrome and influence the availability of continuous positive airway pressure (CPAP) therapy. However, information is scarce about the impact of nasal resistance assessed by rhinomanometry on CPAP therapy. This study aimed to examine the relationship between CPAP adherence and nasal resistance evaluated by rhinomanometry, and to identify clinical findings that can affect adherence to CPAP therapy for patients with OSA. This study included 260 patients (199 men, 61 women; age 58 [interquartile ranges (IQR) 50-66] years) with a new diagnosis of OSA who underwent rhinomanometry (before, and 1 and 3 months after CPAP introduction) between January 2011 and December 2018. CPAP use was recorded, and the good and poor CPAP adherence groups at the time of patient registration were compared. Furthermore, those with improved and unimproved pre-CPAP high rhinomanometry values were also compared. Their apnea-hypopnea index (AHI) by polysomnography at diagnosis was 45.6 (IQR 33.7-61.6)/hour, but the residual respiratory event (estimated AHI) at enrollment was 2.5 (IQR 1.4-3.9)/hour and the usage time was 318 (IQR 226-397) minutes, indicating that CPAP was effective and adherence was good. CPAP adherence was negatively correlated with nasal resistance (r = -0.188, p = 0.002). The participants were divided into good (n = 153) and poor (n = 107) CPAP adherence groups. In the poor adherence group, rhinomanometry values before CPAP introduction were worse (inspiration, p = 0.003; expiration, p = 0.006). There was no significant difference in patient background when comparing those with improved (n = 16) and unimproved (n = 12) pre-CPAP high rhinomanometry values. However, CPAP usage time was significantly longer in the improved group 1 month (p = 0.002) and 3 months (p = 0.026) after CPAP introduction. The results suggest that nasal resistance evaluated by rhinomanometry is a useful predictor of CPAP adherence, and that improved rhinomanometry values may contribute to extending the duration of CPAP use.

Variation of respiratory and pulse events in multiple system atrophy.

INTRODUCTION: A study is eagerly awaited that will reveal the unknown mechanisms of multiple system atrophy (MSA), in which the risk of sudden death is the greatest during sleep. The blunted pulse response to nocturnal respiratory events suggests an abnormal cardiac response to a sleep-related breathing disorder. Patients with MSA have a lower pulse event index (PEI), despite a greater hypoxic burden and a similar frequency of respiratory events. However, the evidence is speculative and not directly proven, and many limitations require further study. METHODS: We conducted a retrospective analysis of 26 patients with MSA who had undergone overnight oximetry between April 2016 and December 2022. RESULTS: The median 4% oxyhemoglobin desaturation index (ODI) was 11.6/h, the 6-bpm PEI was 8.9/h, and the PEI/ODI ratio was as low as 0.91. There were three patients with suspected sudden death; all had low PEI/ODI ratios. The PEI/ODI ratio was followed over time in seven patients, all of whom had a decrease in the ratio. However, the PEI was higher than the ODI in 12/26 (46%) of the patients. CONCLUSION: A low PEI/ODI ratio, reflecting a blunted pulse response to nocturnal respiratory events in patients with MSA, may indicate a worse prognosis. This finding and the significance of the longitudinal decrease in the PEI/ODI ratio will require a prospective study.

Continuous positive airway pressure treatment reduces renal tubular damage in patients with obstructive sleep apnea: A retrospective single-center cohort study.

BACKGROUND: Chronic intermittent hypoxia (IH) plays a significant role in the pathogenesis of obstructive sleep apnea (OSA) comorbidities. The prevalence of chronic kidney disease is higher in patients with OSA than the general population, and renal function decline is well correlated with renal tubular injury. However, little is known about the impact of OSA-induced chronic IH on the renal tubules. METHODS: We conducted a retrospective survey of clinical records performing multiple regression analysis and cluster analysis with particular attention to the 3% oxygen desaturation index (ODI) and urinary N-acetyl-ß-d-glucosaminidase (NAG). RESULTS: In patients with suspicion of OSA, urinary NAG creatinine ratio (UNCR) was elevated as their 3% ODI increased (n = 197, p < 0.001), and the elevated UNCR decreased following CPAP treatment in patients with OSA (n = 46, p = 0.014). Multiple regression analysis showed that 3% ODI was associated with UNCR. Cluster analysis identified three clusters of patients with OSA, including two younger age clusters, one of which was characterized by high BMI, high 3% ODI, and high prevalence of major comorbidities. In a comparative analysis of younger age cases (age ≤ 55, n = 82), the UNCR level was higher in patients with severe 3% ODI (3% ODI > 40 events/h, n = 24) (p = 0.014). CONCLUSIONS: Our results indicate that even at younger ages, OSA patients with severe chronic IH and major comorbidities are susceptible to renal tubular damage. Early treatment with CPAP may attenuate renal tubular injury and progression toward end-stage renal disease.

Respiratory support strategy in adults with acute hypoxemic respiratory failure: a systematic review and network meta-analysis.

INTRODUCTION: Network meta-analyses (NMAs) of respiratory management strategies for acute hypoxemic respiratory failure (AHRF) have been reported, but no previous study has compared noninvasive ventilation (NIV), high-flow nasal oxygen (HFNO), standard oxygenation therapy (SOT), and invasive mechanical ventilation (IMV) for de novo AHRF. Therefore, we conducted an NMA to assess the effectiveness of these four respiratory strategies in patients with de novo AHRF. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Ichushi databases were searched. Studies including adults aged ≥18 years with AHRF and RCTs that compared two different oxygenation techniques (SOT, NIV, HFNO, or IMV) were selected. A frequentist-based approach with multivariate random-effects meta-analysis was used. The outcomes were mortality and intubation rates. RESULTS: Among the 14,263 records initially identified, 25 studies (3302 patients) were included. In the analysis of mortality, compared to SOT, NIV (risk ratio [RR], 0.76; 95% confidence interval [CI], 0.61-0.95) reduced mortality; however, IMV (RR, 1.01; 95% CI, 0.57-1.78) and HFNO (RR, 0.89; 95% CI, 0.66-1.20) did not. For assessments of the intubation incidence, compared to SOT, NIV use (RR, 0.63; 95% CI, 0.51-0.79) was associated with a reduction in intubation, but HFNO (RR, 0.82; 95% CI, 0.61-1.11) was not significant. CONCLUSIONS: Our NMA demonstrated that only NIV showed clinical benefits compared with SOT as an initial respiratory strategy for de novo AHRF. Further investigation, especially comparison with HFNO, is warranted. TRIAL REGISTRATION: PROSPERO (registration number: CRD42020213948 , 11/11/2020).

Prognostic significance of procalcitonin in small cell lung cancer.

BACKGROUND: Procalcitonin (PCT) is a serological marker whose utility has been established in infectious disease areas. Although serum calcitonin is a prognostic predictor in patients with medullary thyroid carcinoma, the clinical usefulness of PCT remains unclear in lung cancer patients. METHODS: As a discovery cohort, we retrospectively analyzed consecutive patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) who received first-line chemotherapy at our institution, and PCT blood levels were measured. As the validation cohort, PCT blood levels were prospectively evaluated in SCLC patients before first-line chemotherapy. The correlation between a PCT increase and prognosis was examined in the discovery and validation cohorts. RESULTS: Twenty-three SCLC patients and 26 NSCLC patients were enrolled as the discovery cohort, and 30 SCLC patients were enrolled as the validation cohort. The PCT level in SCLC patients was significantly higher than that in NSCLC patients. The PCT level was not associated with WBC count and weakly associated with the CRP level. In both the discovery and validation cohorts, the median survival time was significantly shorter in SCLC patients with PCT-high than in SCLC patients with PCT-normal (discovery; 11.7 vs. 89.7 months, P<0.005, validation; 9.6 vs. 22.6 months, P<0.005). CONCLUSIONS: It may be difficult to differentiate bacterial infections in SCLC patients by PCT, as PCT is elevated even in SCLC patients without infectious diseases. This is the first study to prospectively verify that pretreatment PCT levels have a significant negative correlation with prognosis in SCLC patients.

A case of bronchiolitis obliterans after living-donor renal transplantation.

We herein report the case of a 20 year-old-man who developed bronchiolitis obliterans after living-donor renal transplantation. The patient presented with dyspnea on exertion and wheezing two years after renal transplantation, and spirometry showed an obstructive pattern. Surgical lung biopsy revealed subepithelial fibrosis that constricted and obstructed the intrabronchiolar space. Based on these findings, the patient was diagnosed with bronchiolitis obliterans. He was prescribed bronchodilators and azithromycin, and he achieved stable respiratory function for two years. The differential diagnosis of respiratory symptoms after renal transplantation includes opportunistic infection and drug-induced lung injury; however, bronchiolitis obliterans should also be considered.

Optogenetic activation of DRN 5-HT neurons induced active wakefulness, not quiet wakefulness.

There has been a long-standing controversy regarding the physiological role of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) in sleep/wake architecture. Some studies have reported that 5-HT acts as a sleep-promoting agent, but several studies have suggested that DRN 5-HT neurons function predominantly to promote wakefulness and inhibit rapid eye movement (REM) sleep. Furthermore, recent studies have reported that there is a clear neurobiological difference between a waking state that includes alertness and active exploration (i.e., active wakefulness) and a waking state that is devoid of locomotion (i.e., quiet wakefulness). These states have also been shown to differ clinically in terms of memory consolidation. However, the effects of 5-HT neurons on the regulation of these two different waking states have not been fully elucidated. In the present study, we attempted to examine the physiological role of DRN 5-HT neurons in various sleep/wake states using optogenetic methods that allowed manipulation of cell-type specific neuronal activation with high temporal and anatomical precision. We crossed TPH2-tTA and TetO-ChR2(C128S) mice to obtain mice with channelrhodopsin-2 (ChR2) [C128S]-expressing central 5-HT neurons, and we activated DRN-5HT neurons or medullary 5-HT neurons. Optogenetic activation of DRN 5-HT neurons caused rapid transition from non-REM sleep to active wakefulness, not quiet wakefulness, whereas activation of medullary 5-HT neurons did not appear to affect sleep/wake states or locomotor activity. Our results may shed light on the physiological role of DRN 5-HT neurons in sleep/wake architecture and encourage further investigations of the cortical functional connectivity involved in sleep/wake state regulation.

Chronic Hypercapnic Respiratory Failure in an Adult Patient with Silver-Russell Syndrome.

A 31-year-old woman who was clinically diagnosed with Silver-Russell syndrome (SRS) in childhood was admitted with complaints of dyspnea. She had hypercapnic respiratory failure accompanied by nocturnal hypoventilation. Computed tomography revealed systemic muscle atrophy and superior mesenteric artery syndrome; however, the bilateral lung fields were normal. She was treated with nocturnal noninvasive positive pressure ventilation and showed improvement of respiratory failure. In this case, loss of methylation on chromosome 11p15 and maternal uniparental disomy of chromosome 7, which are the common causes of SRS, were not detected. This is a rare case of adult SRS manifesting as chronic hypercapnic respiratory failure.

Combination therapy of cisplatin with cilastatin enables an increased dose of cisplatin, enhancing its antitumor effect by suppression of nephrotoxicity.

Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.

The Prognostic Significance of the Continuous Administration of Anti-PD-1 Antibody via Continuation or Rechallenge After the Occurrence of Immune-Related Adverse Events.

OBJECTIVES: Although immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs. METHODS: We retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors. RESULTS: Of 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4-NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4-NE); p = 0.031]. CONCLUSION: The current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

Subsequent systemic therapy for non-small cell lung cancer patients with immune checkpoint inhibitor-related interstitial lung disease.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) are effective for advanced non-small cell lung cancer (NSCLC), ICIs may cause interstitial lung disease (ILD), which results in treatment discontinuation and is sometimes fatal. Despite the high incidence of ICI-related ILD, there are few cancer treatment options for patients. This study aimed to evaluate the safety and efficacy of subsequent systemic cancer therapy in NSCLC patients with ICI-related ILD. METHODS: We retrospectively assessed NSCLC patients who received programmed cell death-1 (PD-1) inhibitors as first- to third-line therapy at participating institutions of the Niigata Lung Cancer Treatment Group from January 2016 to October 2017. RESULTS: This analysis included 231 patients, 32 (14%) of whom developed ICI-related ILD. Of these patients, 16 (7%) received subsequent systemic cancer treatments. The median overall survival (OS) tended to be longer in the systemic cancer therapy group than in the no systemic cancer therapy group [22.2 months (95% CI: 1-NE) vs. 4.5 months (95% CI: 1-NE); P=0.067]. ICI-related ILD recurred in half of the patients who received systemic cancer therapy, and the median OS tended to be shorter in patients with recurrent ICI-related ILD [22.0 months (95% CI: 1-NE) vs. 7.0 months (95% CI: 1-NE); P=0.3154]. CONCLUSIONS: According to the current study, systemic cancer treatment is effective in patients with ICI-related ILD; however, its safety is uncertain because of the high risk of ICI-related ILD recurrence and poor survival outcome following ILD recurrence.

[Interstitial pneumonia associated with stiff-person syndrome].

A 68-year-old man who was given a diagnosis of interstitial pneumonia. Chest computerized tomography (CT) revealed subpleural honeycomb formations and traction bronchiectasis. Three months after the diagnosis of interstitial pneumonia, he noticed neurological symptoms, such as facial spasms, dysphagia, muscle rigidity and muscle cramp, and repeatedly received clonazepam. He was diagnosed with stiff-person syndrome on electromyography when he was hospitalized due to aspiration pneumonia. He has needed continuous rehabilitation due to the progression of neurological symptoms despite the partial efficacy of anti-epilepsy agents. We report a case of interstitial pneumonia with stiff-person syndrome.

Should pulmonologists be gatekeepers or supporters for preoperative patients?

Postoperative pulmonary complications (PPCs) are considered as a leading cause of poor surgical outcomes, and occur frequently even in non-cardiothoracic surgery. Several multifactorial risk indices show potential effectiveness in identification of patients at high risk of developing PPCs. In preoperative consultation from surgeons, pulmonologists often act as gatekeepers for indication of surgery. With regard to preventive strategy for PPCs, recent reports have suggested the usefulness of preoperative interventions, such as smoking cessation, inhalation therapy, medications, pulmonary rehabilitation, and sleep study followed by continuous positive airway pressure therapy. Now, pulmonologists have an important role as supporters for preoperative patient care.

Comparative analysis of TTF-1 binding DNA regions in small-cell lung cancer and non-small-cell lung cancer.

Thyroid transcription factor-1 (TTF-1, encoded by the NKX2-1 gene) is highly expressed in small-cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), but how its functional roles differ between SCLC and LADC remains to be elucidated. Here, we compared the genome-wide distributions of TTF-1 binding regions and the transcriptional programs regulated by TTF-1 between NCI-H209 (H209), a human SCLC cell line, and NCI-H441 (H441), a human LADC cell line, using chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq). TTF-1 binding regions in H209 and H441 cells differed by 75.0% and E-box motifs were highly enriched exclusively in the TTF-1 binding regions of H209 cells. Transcriptome profiling revealed that TTF-1 is involved in neuroendocrine differentiation in H209 cells. We report that TTF-1 and achaete-scute homolog 1 (ASCL1, also known as ASH1, an E-box binding basic helix-loop-helix transcription factor, and a lineage-survival oncogene of SCLC) are coexpressed and bound to adjacent sites on target genes expressed in SCLC, and cooperatively regulate transcription. Furthermore, TTF-1 regulated expression of the Bcl-2 gene family and showed antiapoptotic function in SCLC. Our findings suggest that TTF-1 promotes SCLC growth and contributes to neuroendocrine and antiapoptotic gene expression by partly coordinating with ASCL1.

Breathing Irregularity Is Independently Associated With the Severity of Obstructive Sleep Apnea in Patients With Multiple System Atrophy.

STUDY OBJECTIVES: Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the combination of cerebellar ataxia, parkinsonism, and autonomic disturbance. Patients with MSA frequently have sleep-disordered breathing. In some patients with MSA, central sleep apnea manifests during the disease's natural course or as a treatment effect. Breathing instability may be involved in the development of obstructive sleep apnea (OSA); therefore, we investigated whether breathing instability affects the severity of OSA in patients with MSA. METHODS: Patients with MSA and a control group of individuals who were matched for age, body mass index (BMI), and supine apnea-hypopnea index (AHI) were recruited. Breathing instability was evaluated by using polysomnography to determine the irregular pattern with approximate entropy (ApEn) of chest respiratory movements during wakefulness before sleep onset. The ApEn values were compared between the groups. The severity of OSA was evaluated with background parameters and ApEn values by regression analysis. RESULTS: Twenty patients with MSA (9 men; mean age, 61 years; BMI, 24.1 kg/m2; supine AHI, 37.9 events/h) were compared to the control group. The ApEn values were higher in the patients with MSA than those in the control group (1.28 versus 1.11; P < .05). Multiple regression analysis showed that supine AHI was associated with ApEn values but not with BMI in patients with MSA and associated with BMI but not with ApEn values in the individuals in the control group. CONCLUSIONS: Patients with MSA had more breathing irregularity. In patients with MSA, breathing instability may be a more influential factor for OSA than BMI. COMMENTARY: A commentary on this article appears in this issue on page 1641.