Disease control in patients with non-small cell lung cancer using pemetrexed: Investigating the best treatment strategy.

BACKGROUND: Pemetrexed (PEM) is the primary chemotherapy for non-small cell lung cancer (NSCLC), showing potential for long-term disease stability in certain cases. However, studies examining disease control with PEM therapy are lacking. This study aimed to pinpoint clinical traits in patients with NSCLC responding well to PEM therapy, predict factors influencing disease control, and suggest optimal treatment approaches. METHODS: A retrospective analysis of patients with NSCLC treated with PEM was performed to compare patients who achieved disease control after treatment with those who did not. RESULTS: Of 73 patients, 56 (76.7%) achieved disease control with PEM therapy. In the disease control group, a significantly higher proportion of patients exhibited good performance status (PS) and received PEM doses without reduction after the second cycle. Multivariate analysis identified bevacizumab (Bev) noncompliance, PEM dose reduction, and thyroid transcription factor-1 (TTF-1) negativity as significant independent risk factors for disease progression during PEM therapy. Additionally, overall survival was significantly longer in the disease control group (p < 0.001). CONCLUSIONS: Our findings indicated that maintaining the dose of PEM after the second treatment cycle in patients with NSCLC, along with concurrent use of Bev and the presence of TTF-1 positivity, could enhance disease control rates and extend survival.

Prognostic value of the serum creatinine/cystatin C ratio in patients with chronic obstructive pulmonary disease.

BACKGROUND: Sarcopenia, characterized by skeletal muscle atrophy and physical inactivity, is a manifestation of chronic obstructive pulmonary disease (COPD) and is associated with a poor prognosis. The serum creatinine (Cr)/cystatin C (CysC) ratio has been proposed as a marker of sarcopenia, given its correlation with total skeletal muscle mass, and as a prognostic indicator in COPD. This study aimed to evaluate the usefulness of the serum Cr/CysC ratio as a prognostic determinant in these patients. METHODS: A total of 124 outpatients with COPD were enrolled in this study. Their serum Cr and CysC levels were measured. Survival time analyses were conducted to compare mortality rates between the low and high serum Cr/CysC ratio groups. Multivariate analysis was performed to investigate the association between various factors. RESULTS: Using a serum Cr/CysC cut-off value of 0.885, the mortality rate (per 1000 person-years) for overall mortality was significantly higher in the low serum Cr/CysC ratio group (69.2 versus 28.6; hazard ratio, 2.47; 95% confidence interval, 1.06-5.79; p < 0.05). Similarly, the mortality rate due to respiratory disease was also higher (37.8 versus 8.2; hazard ratio, 4.68; 95% confidence interval, 1.05-20.9; p < 0.05). Multivariate Cox proportional hazards analysis revealed that serum Cr/CysC was an independent risk factor for respiratory disease mortality, regardless of age and airflow limitations. CONCLUSIONS: The serum Cr/CysC ratio could be a valuable clinical parameter for identifying sarcopenia and severe airflow obstruction. The study findings highlight the utility of this ratio as a prognostic predictor in patients with COPD.

Multicenter, Retrospective Study to Evaluate Necitumumab Plus Cisplatin and Gemcitabine After Immune Checkpoint Inhibitors in Advanced Squamous Cell Lung Cancer in Japan: The NINJA Study.

Introduction: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown. Methods: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS). Results: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths. Conclusions: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.

Investigation of response of patients with non-small cell lung cancer to docetaxel (plus ramucirumab) therapy in second-line treatment.

BACKGROUND: Several options for second-line therapy are available for patients with advanced non-small cell lung cancer (NSCLC); however, the optimal therapy remains unclear. Docetaxel (DTX) monotherapy and DTX plus ramucirumab (RAM) are the recommended second-line treatment options. However, the efficacy of these treatments remains unsatisfactory. The aim of this study was to identify the clinical characteristics of patients with NSCLC who respond to DTX or DTX + RAM and factors that predict response. METHODS: Patients with NSCLC treated with DTX or DTX + RAM after second-line therapy were retrospectively analyzed. Patients were compared with those who responded or did not respond to the post-treatment efficacy assessment. RESULTS: Of 53 patients, 12 (22.6%) had lung cancer that responded to DTX or DTX + RAM therapy (response group). Multivariate analysis identified the absence of immune checkpoint inhibitors (ICIs) in the immediate prior therapy and a reduced dose of DTX after the second cycle as significant independent risk factors predicting nonresponse to DTX and DTX + RAM therapy in patients with NSCLC. The overall survival was significantly longer in the response group compared to the nonresponse group (p = 0.016). CONCLUSIONS: Our results suggest that DTX and DTX + RAM therapies immediately after treatment with ICI-containing regimens as well as continuation of DTX without dose reduction after the second cycle may increase the response rate and prolong survival in patients with NSCLC.

Investigation of response factors for monotherapy with immune checkpoint inhibitors in non-small cell lung cancer patients with PD-L1 expression <50.

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is currently approved for the treatment of advanced non-small cell lung cancer (NSCLC) patients with programmed death ligand-1 (PD-L1) expression ≥50%. However, the efficacy of ICI monotherapy in patients with PD-L1 expression <50% has not yet been fully elucidated. The aim of this study was to identify the clinical characteristics of NSCLC patients with PD-L1 expression <50% who respond to single-agent ICIs and factors that predict response. METHODS: Patients with advanced or recurrent NSCLC with a PD-L1 tumor proportion score (TPS) of 50% or less who received new monotherapy with an ICI between July 2012 and December 2022 were retrospectively analyzed. Patients with response were compared with those without response in the post-treatment response assessment. RESULTS: Among the 37 patients, six (16.2%) NSCLC patients in the response group responded to ICI monotherapy and had a significantly lower body mass index (BMI) (p = 0.003). Significantly more patients in the response group developed immune-related adverse events (irAEs) than in the nonresponse group (p < 0.001). Multivariate analysis identified high BMI as a significant independent risk factor predicting nonresponse to ICI monotherapy in NSCLC patients with PD-L1 < 50%. CONCLUSIONS: Among NSCLC patients with PD-L1 < 50%, those with a higher BMI were more likely to be nonresponders to ICI monotherapy. In addition, the group that responded to ICI monotherapy may have been at higher risk of developing irAEs, suggesting that careful follow-up is warranted.

Influencing factors of efficacy and long-term use of amrubicin in patients with small cell lung cancer.

BACKGROUND: Amrubicin (AMR) has become the standard of care for post-relapse small cell lung cancer (SCLC). It has also been reported to achieve long-term disease control in patients with good treatment response. However, the optimal patient population for whom AMR is effective and the factors associated with long-term disease control are yet to be identified. The aim of the study was to identify the clinical characteristics and factors associated with long-term disease control in patients with recurrent SCLC who would benefit from AMR therapy. METHODS: The clinical records of 33 patients diagnosed with recurrent SCLC and treated with AMR were retrospectively reviewed. Clinical information was compared between patients who achieved disease control (effective group) and who developed disease progression (noneffective group) on the first efficacy assessment after AMR and between patients who continued AMR for more than seven cycles (maintenance group) and those who terminated treatment after 1-6 cycles (discontinuation group). RESULTS: The noneffective group included significantly more patients with AMR dose reductions after the second cycle (p = 0.006). AMR dose reduction was an independent risk factor for disease progression. The maintenance group had significantly lower pretreatment lactate dehydrogenase (LDH) levels than the discontinuation group (p = 0.046). A high LDH level was an independent risk factor for short AMR discontinuation. Overall survival was significantly longer in the effective group than in the noneffective group (p < 0.001). CONCLUSIONS: In AMR therapy for patients with relapsed SCLC, continuation of AMR without dose reduction after the second cycle may contribute to disease control and prolonged survival.

Differential response in patients with large cell neuroendocrine carcinoma of the lung to initial therapy: A case series.

BACKGROUND: Large cell neuroendocrine tumors of the lung (LCNEC) are rare. Chemotherapy with the small cell lung carcinoma (SCLC) regimen is the most appropriate treatment for LCNEC. However, there is evidence that the non-small cell lung cancer regimen is also effective in some reported cases. Due to the differences in response to LCNEC treatment, a standard of care for LCNEC has not been established. CASES: The clinical records of nine patients with LCNEC who were treated with anticancer drugs based on an SCLC regimen from March 2016 to March 2022 were retrospectively reviewed. The patients who responded to treatment after one cycle of systemic chemotherapy were compared to those who did not respond. All patients in the responder group had a performance status (PS) of 0 or 1. However, 5 of the 6 patients in the non-responder group had a PS of 2 or 3, indicating that many patients were in poor general condition. Although patients with multiple metastases to more than one organ prior to treatment were not identified in the responder group, five of these patients were in the non-responder group. In the non-responder group, all patients discontinued treatment due to deterioration of general condition during first-line treatment. Thus, none of them were able to start the second-line treatment. CONCLUSION: The results of this study may suggest that early diagnosis and initiation of treatment before multiple organ metastasis development and PS decline may have clinical implications that could lead to improved treatment response in patients with LCNEC.

Early recurrence factors in patients with stage III non-small cell lung cancer treated with concurrent chemoradiotherapy.

BACKGROUND: The clinical characteristics and risk factors for cancer recurrence have not been well evaluated regarding early recurrence in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) who receive concurrent chemoradiotherapy (CRT). The aim of this study was to determine the clinical characteristics and risk factors of patients with stage III unresectable LA-NSCLC treated with CRT who developed early recurrence. METHODS: We retrospectively reviewed the clinical records of 46 patients diagnosed with stage III unresectable LA-NSCLC treated with CRT at our center between July 2012 and July 2021. A tumor proportion score (TPS) < 50% was defined as "low expression" and a TPS > 50% was defined as "high expression." RESULTS: A total of 17 (37.0%) patients had a confirmed recurrence within 1 year of treatment. More patients had a lower body mass index in the early recurrence group than in the later recurrence group (p = 0.038). A higher number of patients in the late recurrence group underwent surgery after CRT (p = 0.036). Patients with a higher TPS were more likely to experience late recurrence than early recurrence (p = 0.001), whereas more patients with stage N3 disease were in the early recurrence group (p = 0.011). Multivariate analysis identified lower TPS expression as an independent risk factor for early recurrence after CRT. Overall survival was prolonged in the late recurrence group (p < 0.001). CONCLUSIONS: A lower TPS may be a predictor of early recurrence after CRT in patients with LA-NSCLC. These patients should be closely monitored for post-treatment recurrence.

Serum Derivatives of Reactive Oxygen Metabolites are Associated with Severity of Chronic Obstructive Pulmonary Disease and Affected by a p53 Gene Polymorphism.

Purpose: Oxidative stress is known to activate tumor suppressor p53, which inhibits cell cycle progression and induces apoptosis. Levels of p53 in lung tissues from patients with chronic obstructive pulmonary disease (COPD) are increased compared with levels in nonsmokers or smokers without emphysema. A polymorphism in p53 codon 72 (rs1042522) is associated with emphysematous changes in patients with COPD. However, whether oxidative stress in the serum is associated with the p53 polymorphism and disease severity in COPD patients is unclear. Patients and Methods: A total of 251 patients with a history of smoking more than 10 pack-years were enrolled in this study, and serum levels of derivatives of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), and d-ROMs/BAP ratio (oxidative stress index; OSI) were measured. The percent low-attenuation area (LAA%) and cross-sectional area of the erector spinae muscles (ESMCSA) at the Th12 level were calculated from chest high-resolution computed tomography images. p53 codon 72 C/G genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: In patients carrying the p53 GG genotype, LAA% was significantly higher than in those carrying the CC genotype. d-ROM levels and OSI were associated with COPD severity and correlated with airflow limitation and markers of muscle atrophy (ESMCSA and creatinine/cystatin C ratio). Associations between markers of oxidative stress and COPD severity were observed primarily in patients carrying the p53 codon 72 GG genotype. Conclusion: Susceptibility to pulmonary emphysema and responses to oxidative stress may be affected by the p53 gene polymorphism.

Laryngeal papilloma-induced chronic airway obstruction: A case report.

Laryngeal papilloma is a benign tumor characterized by minimal symptoms; however, in rare cases, it can cause airway obstruction and should be treated with caution. A 65-year-old woman presented to the clinic with a history of dyspnea for the past 20 years. Chest computed tomography revealed the presence of a tracheal diverticulum with an internal septum on the right side of the trachea at the apex of the lung. Upon examination, an otorhinolaryngologist revealed a wart-like tumor at the base of the tongue. However, it was ruled out to be the cause of dyspnea owing to the small size of the tumor. Thereafter, the patient was placed under observation. Brochoscopy was performed to investigate the tracheal diverticulum. Bronchoscopy revealed a pedunculated papilloma entering the glottis because of inhalation in the supine position, indicating a high risk of airway obstruction by the papilloma. The patient underwent papilloma resection. Papillomas must be considered in the differential diagnosis of dyspnea. The risk of airway obstruction should not be underestimated in patients with papilloma with reported history of dyspnea, even in the case of small tumors. The patient had a rare tracheal diverticulum, which further complicated the diagnosis of dyspnea.

Efficacy and predictors of rechallenge with immune checkpoint inhibitors in non-small cell lung cancer.

BACKGROUND: The efficacy of rechallenge with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients has not yet been fully clarified. This study aimed to identify the clinical characteristics of patients with NSCLC who benefited from rechallenge with ICIs. METHODS: We retrospectively reviewed the clinical records of 24 patients who were diagnosed with NSCLC and rechallenged with ICIs between August 2016 and July 2021. RESULTS: Of the 24 patients included in the study, 11 were in the responder group (45.8%) and 13 in the nonresponder group (54.2%). The number of patients who used a different ICI from that used in the initial therapy was significantly higher in the responder group than in the nonresponder group (p = 0.006). Multivariate analysis identified lung metastasis and female sex as significant independent risk factors for nonresponse to rechallenge with ICIs. Compared to the nonresponder group, the duration of treatment after rechallenge with ICIs was significantly longer in the responder group (p = 0.016), and there was a trend toward longer overall survival (p = 0.059). CONCLUSIONS: Patients with lung cancer who were rechallenged with ICIs and without progressive disease after initial ICI therapy were able to continue ICI therapy for a longer period of time. This may be associated with longer survival. Patients with lung metastases and female patients are more likely to be nonresponsive to rechallenge with ICIs. Administration of a different type of ICI from that used in the initial ICI therapy may result in disease control.

Acquired pulmonary arteriovenous malformation associated with bronchiectasis: a case report.

BACKGROUND: Pulmonary arteriovenous malformations are mostly caused by congenitally abnormal shunts between pulmonary arteries and pulmonary veins. CASE PRESENTATION: A 74-year-old Japanese woman with a history of bronchiectasis was admitted to our hospital because of dyspnea on exertion. Pulmonary angiography and reconstructed three-dimensional contrast-enhanced computed tomography images showed shunts between pulmonary arteries and pulmonary veins, indicating a diagnosis of pulmonary arteriovenous malformations. Coil embolization of the shunts was successful. CONCLUSIONS: Our findings imply that bronchiectasis can cause pulmonary arteriovenous malformations, and thus patients who present with hypoxemia with bronchiectasis should be carefully evaluated.

Risk factors for acute exacerbation in lung cancer complicated by interstitial lung disease with slight reticular shadows.

BACKGROUND: The risk of cancer treatment-related acute exacerbation (AE) in patients with lung cancer and mild interstitial lung disease (ILD) on imaging, classified as indeterminate for usual interstitial pneumonia (UIP), has not previously been clarified. METHODS: We retrospectively reviewed the clinical records of 27 patients with lung cancer and ILD who were diagnosed and treated from April 2016 to March 2021. RESULTS: Among the 27 patients, 21 were classified as indeterminate for UIP and six as UIP/probable UIP; furthermore, 10 (46.6%) and three (50%) patients from each group, respectively, developed treatment-related AEs. No significant difference was observed regarding the incidence of AEs between the two groups. However, significantly more patients in the AE group received immune checkpoint inhibitors (ICIs) compared to the non-AE group (p = 0.021). Multivariate analysis revealed that the use of ICIs was a significant independent risk factor for treatment-related AEs. CONCLUSIONS: Lung cancer patients with mild ILD suggestive of indeterminate for UIP and UIP patterns are at an increased risk for treatment-related AEs. Furthermore, ICI use is an independent risk factor for AEs in patients with lung cancer complicated by ILD, and ICIs should be used with great caution.

Relationship between clinical features and gene mutations in non-small cell lung cancer with osteoblastic bone metastasis.

OBJECTIVE: Lung cancer patients presenting with osteoblastic bone metastases at the first visit is rare. We investigated the clinical characteristics and gene mutation rate of non-small cell lung cancer patients with osteoblastic bone metastases at the time of the initial diagnosis. MATERIALS AND METHODS: We retrospectively screened newly diagnosed non-small cell lung cancer patients with osteoblastic bone metastases who presented from June 2015 to March 2021, and analyzed their clinical characteristics and status of EGFR gene mutations, EML4-ALK translocation and ROS1 rearrangements. For comparison, we collected data from patients with non-small cell lung cancer who had osteolytic bone metastases at their first visit between June 2015 and March 2021. RESULTS: Fifty patients had bone metastases at the initial diagnosis. Among them, eight patients (8/50 = 16%) had osteoblastic bone metastases, and the lung tumors in all of them were histopathologically adenocarcinomas. Among the eight cases, two were EGFR mutation-positive, none were EML4-ALK translocation-positive, two were ROS1 rearrangement-positive, and the remaining four cases were negative for all three gene mutations/rearrangements. Compared with the osteolytic bone metastasis group, the percentage of non-smokers was higher (p = 0.020) and the ROS1 rearrangement positivity rate was higher (p = 0.05) in the osteoblastic bone metastasis group. CONCLUSION: Our results indicate that osteoblastic bone metastases in NSCLC are suggestive of adenocarcinoma, and that a high proportion of these patients might be positive for ROS1 rearrangements, and hence, indicated for more aggressive diagnostic biopsies.

Serum Creatinine/Cystatin C Ratio Associated with Cross-Sectional Area of Erector Spinae Muscles and Pulmonary Function in Patients with Chronic Obstructive Pulmonary Disease.

PURPOSE: Muscle atrophy is a major clinical feature of chronic obstructive pulmonary disease (COPD) and is considered a predictor of mortality in COPD patients. Recently, the cross-sectional area (CSA) of the erector spinae muscles measured by chest computed tomography (CT) scans (ESMCSA) has been reported as a clinical parameter reflecting disease severity and future prognosis in patients with COPD. In addition, the serum creatinine (Cr)/cystatin C (CysC) ratio has been considered a quantitative marker of residual muscle mass, because serum Cr levels are affected by muscle mass, and correction by CysC counteracts the effect of renal function on serum Cr levels. The purpose of this study was to assess whether the serum Cr level corrected by serum CysC can be used as a predictive marker of pulmonary function and disease severity in patients with COPD. PATIENTS AND METHODS: A total of 99 patients without COPD and 201 patients with COPD, with a smoking history of more than 10 pack-years were enrolled in this study, and serum Cr and CysC levels were measured. On chest high-resolution CT images, %low attenuation area (LAA%) (≤960 Hounsfield units (HU)) and ESMCSA at the Th12 level were identified. RESULTS: There was a significant correlation between the ESMCSA and the Cr/CysC ratio. The Cr/CysC ratio was significantly associated with forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) values, especially in former smokers. CONCLUSION: The serum Cr/CysC ratio could be a convenient substitute for the measurement of muscle atrophy and pulmonary function testing in patients with COPD.

A case of ROS1-rearranged lung adenocarcinoma with osteoblastic bone metastasis.

A 53-year-old woman was referred to our hospital for detailed examination of abnormal chest shadows recognized on CT imaging. Transbronchial lung biopsy of a right S6 nodular shadow led to a diagnosis of lung adenocarcinoma. FDG-PET-CT showed FDG accumulation in the Th11 and L2 vertebral bodies and osteoblastic bone lesions. Since osteoblastic bone metastasis in lung cancer is extremely rare, CT-guided bone biopsy was performed. The tumor was diagnosed as ROS1-rearranged lung adenocarcinoma, for which crizotinib was administered, which led to improvement of both the primary and metastatic lesions. We report here a rare case of ROS1-rearranged lung adenocarcinoma with osteoblastic bone metastasis of lung cancer.

Primary pulmonary T-cell lymphoma with lung adenocarcinoma: a case report.

BACKGROUND: Primary pulmonary T-cell lymphoma is an extremely rare disease that is characterized by neoplastic proliferation of T-cell lymphocytes in the lung. CASE PRESENTATION: An 88-year-old Japanese woman was admitted to our hospital because of dyspnea. She was treated with antibiotics for chest x-ray findings of consolidation in the upper and middle lobes of the right lung. However, her condition worsened and progressed to respiratory failure, which led to death 14 days after admission. Autopsy of the lungs revealed both T-cell lymphoma and adenocarcinoma. CONCLUSIONS: Our patient had a rare case of primary pulmonary T-cell lymphoma with primary lung adenocarcinoma. Further evidence and accumulation of case reports are required to clarify the pathophysiology of primary pulmonary T-cell lymphoma.

ADRB2 gene polymorphism and emphysema heterogeneity can modulate bronchodilator response in patients with emphysema.

BACKGROUND: Genetic variation in the ß2-adrenergic receptor (ADRB2) gene has been thought to have an important role in the differential response to ß2-agonist therapy for asthma. However, previous studies have shown little evidence for an association between these ADRB2 variants and the bronchial dilator response (BDR) in chronic obstructive pulmonary disease (COPD) patients. This discrepancy could be explained by differences in the distribution and heterogeneity of pulmonary emphysema in COPD patients, since emphysema distribution and heterogeneity are thought to have a role in pulmonary function in COPD patients. We hypothesized that differences in emphysema distribution and heterogeneity may have masked significant alterations of the bronchodilator response among ADRB2 genotypes in COPD patients in previous studies. METHODS: The BDR (induced by 20 µg of procaterol) was measured in 211 patients who had a smoking history of more than 10 pack/years and had undergone chest high resolution computed tomography examination. A low attenuations area (<960 Hounsfield Units) was identified and the emphysema heterogeneity index (EHI%) was calculated with a range in value from -100% to 100%. ADRB2 Arg16Gly genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The BDR was augmented in patients with homogenous emphysema compared with those with upper-dominant emphysema. In patients carrying the AA genotype of ADRB2, the BDR was significantly increased in patients with upper-dominant emphysema, but not in patients with lower-dominant emphysema. CONCLUSION: Combination analysis of ADRB2 Arg16Gly polymorphism and EHI% may predict the effectiveness of ß2-adrenergic receptor agonist treatment in patients with COPD and emphysema.

Exogenous gene transfer of Rab38 small GTPase ameliorates aberrant lung surfactant homeostasis in Ruby rats.

BACKGROUND: Rab38 small GTPase regulates intracellular transport in melanocytes and alveolar type II epithelial cells. Ruby rats carrying Rab38 and other gene mutations exhibit oculocutaneous albinism, bleeding diathesis, and hence, are a rat model of human Hermansky-Pudlak syndrome (HPS). We previously showed that Long Evans Cinnamon (LEC) rats, one strain of the Ruby rats, developed aberrant lung surfactant homeostasis with remarkably enlarged lamellar bodies in alveolar type II cells. METHODS: A replication-deficient recombinant adenovirus expressing rat Rab38 (Ad-Rab38) was constructed. Alveolar type II cells were isolated from the LEC rats and tested for lung surfactant phosphatidylcholine secretion. The rats were also examined whether exogenous expression of Ad- Rab38 could rescue the altered lung surfactant homeostasis in the lungs. RESULTS: Isolated type II cells infected with Ad-Rab38 exhibited improved secretion patterns of [3H]phosphatidylcholine, i.e. increased basal hyposecretion and decreased agonist-induced hypersecretion. Endobronchial administration of Ad-Rab38 improved the morphology of type II cells and lamellar bodies, reducing their sizes close to those of wild-type rats. The increased amounts of phosphatidylcholine and surfactant protein B in the lamellar body fractions were decreased in the Ad-Rab38 infected lungs. CONCLUSIONS: These results provide strong evidence that the aberrant lung surfactant homeostasis in the LEC rats is caused by Rab38 deficit, and suggest that endobronchial delivery of the responsive transgene could be an effective method to ameliorate the abnormal lung phenotype in the animal model of HPS.

The anti-apoptotic protein L(*) of Theiler's murine encephalomyelitis virus (TMEV) contains a mitochondrial targeting signal.

L(*) protein of TMEV is out-of-frame with the viral polyprotein from an alternative initiation codon AUG, 13 nucleotides downstream from the authentic polyprotein AUG. Anti-apoptotic activity of L(*) was demonstrated by both 'loss of function' and 'gain of function' experiments. However, the precise mechanism(s) of anti-apoptotic activity of L(*) remains to be clarified. In this study, L(*) was demonstrated to be localized to mitochondria. It was also shown by the GFP fusion protein that N-terminal sequence of L(*) may contain a mitochondrial targeting signal (MTS). Surprisingly, L(*)((5-70))-GFP and L(*)((41-70))-GFP were localized to mitochondria although L(*)((1-70))-GFP was distributed in the cytosol, suggesting L(*) has an MTS between amino acid (AA) positions 41 and 70, and that L(*)((1-4)) inhibits its mitochondrial targeting. Furthermore, L(*)((1-70))-GFP was localized to the mitochondria by co-expression of L(*)((65-156)), indicating that L(*)((65-156)) suppresses the inhibition of mitochondrial targeting by L(*)((1-4)). These results suggest that the intra- or inter-molecular interaction of L(*) regulates its mitochondrial localization. It is also suggested that L(*) may inhibit the intrinsic apoptosis through the localization to mitochondria.