Predicting pathological response to neoadjuvant or conversion chemoimmunotherapy in stage IB-III non-small cell lung cancer patients using radiomic features.

BACKGROUND: To develop a radiomics model based on chest computed tomography (CT) for the prediction of a pathological complete response (pCR) after neoadjuvant or conversion chemoimmunotherapy (CIT) in patients with non-small cell lung cancer (NSCLC). METHODS: Patients with stage IB-III NSCLC who received neoadjuvant or conversion CIT between September 2019 and July 2021 at Hunan Cancer Hospital, Xiangya Hospital, and Union Hospital were retrospectively collected. The least absolute shrinkage and selection operator (LASSO) were used to screen features. Then, model 1 (five radiomics features before CIT), model 2 (four radiomics features after CIT and before surgery) and model 3 were constructed for the prediction of pCR. Model 3 included all nine features of model 1 and 2 and was later named the neoadjuvant chemoimmunotherapy-related pathological response prediction model (NACIP). RESULTS: This study included 110 patients: 77 in the training set and 33 in the validation set. Thirty-nine (35.5%) patients achieved a pCR. Model 1 showed area under the curve (AUC) = 0.65, 64% accuracy, 71% specificity, and 50% sensitivity, while model 2 displayed AUC = 0.81, 73% accuracy, 62% specificity, and 92% sensitivity. In comparison, NACIP yielded a good predictive value, with an AUC of 0.85, 81% accuracy, 81% specificity, and 83% sensitivity in the validation set. CONCLUSION: NACIP may be a potential model for the early prediction of pCR in patients with NSCLC treated with neoadjuvant/conversion CIT.

Radiomics for differentiating tumor deposits from lymph node metastasis in rectal cancer.

BACKGROUND: Tumor deposits (TDs) are not equivalent to lymph node (LN) metastasis (LNM) but have become independent adverse prognostic factors in patients with rectal cancer (RC). Although preoperatively differentiating TDs and LNMs is helpful in designing individualized treatment strategies and achieving improved prognoses, it is a challenging task. AIM: To establish a computed tomography (CT)-based radiomics model for preoperatively differentiating TDs from LNM in patients with RC. METHODS: This study retrospectively enrolled 219 patients with RC [TDs+LNM- (n = 89); LNM+ TDs- (n = 115); TDs+LNM+ (n = 15)] from a single center between September 2016 and September 2021. Single-positive patients (i.e., TDs+LNM- and LNM+TDs-) were classified into the training (n = 163) and validation (n = 41) sets. We extracted numerous features from the enhanced CT (region 1: The main tumor; region 2: The largest peritumoral nodule). After deleting redundant features, three feature selection methods and three machine learning methods were used to select the best-performing classifier as the radiomics model (Rad-score). After validating Rad-score, its performance was further evaluated in the field of diagnosing double-positive patients (i.e., TDs+LNM+) by outlining all peritumoral nodules with diameter (short-axis) > 3 mm. RESULTS: Rad-score 1 (radiomics signature of the main tumor) had an area under the curve (AUC) of 0.768 on the training dataset and 0.700 on the validation dataset. Rad-score 2 (radiomics signature of the largest peritumoral nodule) had a higher AUC (training set: 0.940; validation set: 0.918) than Rad-score 1. Clinical factors, including age, gender, location of RC, tumor markers, and radiological features of the largest peritumoral nodule, were excluded by logistic regression. Thus, the combined model was comprised of Rad-scores of 1 and 2. Considering that the combined model had similar AUCs with Rad-score 2 (P = 0.134 in the training set and 0.594 in the validation set), Rad-score 2 was used as the final model. For the diagnosis of double-positive patients in the mixed group [TDs+LNM+ (n = 15); single-positive (n = 15)], Rad-score 2 demonstrated moderate performance (sensitivity, 73.3%; specificity, 66.6%; and accuracy, 70.0%). CONCLUSION: Radiomics analysis based on the largest peritumoral nodule can be helpful in preoperatively differentiating between TDs and LNM.

Efficacy and Safety of Different Doses of Bevacizumab Combined With Pemetrexed and Platinum in First-Line Treatment of Advanced NSCLC: A Retrospective-Real World Study.

Background: Bevacizumab was demonstrated to have efficacy in patients with NSCLC. However, application of different doses of bevacizumab in different clinical trials was overlooked. This study aims to investigate the effects and safety of different doses of bevacizumab in the treatment. Methods: From January 2016 to March 2020, 79 patients with NSCLC received first-line combination treatment with chemotherapy (pemetrexed + platinum) and bevacizumab for four cycles; patients without progression after four cycles were randomly assigned to maintenance therapy with bevacizumab combined with pemetrexed, of which 57 patients received bevacizumab at a dose of 7.5 mg/kg and 22 patients at a dose of 15 mg/kg. The primary endpoint was progression-free survival, and secondary endpoints were overall response rate, disease control rate, and adverse events. Results: There was no significant difference between two groups in effectiveness; Median PFS in 7.5 mg/kg group and in 15 mg/kg group were 8.0 and 8.7 months, respectively (p = 0.663), reaching the primary endpoint. The ORR and DCR in the bevacizumab 7.5 and 15 mg/kg group were 45.46 and 86.0% vs. 50 and 90.9% showing no statistical significance (p = 0.804 and 0.717). Most of side effects were tolerable. The incidences of overall toxicities were higher in 15 mg/kg group (p = 0.001). No new safety signals were observed. Conclusion: We did not detect significant difference of efficacy and safety between 7.5 mg/kg group and 15 mg/kg group for bevacizumab administration, the cost-effectiveness of the 7.5 mg/kg group was significantly better than that of the 15 mg/kg group.

Radiomics for predicting perineural invasion status in rectal cancer.

BACKGROUND: Perineural invasion (PNI), as a key pathological feature of tumor spread, has emerged as an independent prognostic factor in patients with rectal cancer (RC). The preoperative stratification of RC patients according to PNI status is beneficial for individualized treatment and improved prognosis. However, the preoperative evaluation of PNI status is still challenging. AIM: To establish a radiomics model for evaluating PNI status preoperatively in RC patients. METHODS: This retrospective study enrolled 303 RC patients in a single institution from March 2018 to October 2019. These patients were classified as the training cohort (n = 242) and validation cohort (n = 61) at a ratio of 8:2. A large number of intra- and peritumoral radiomics features were extracted from portal venous phase images of computed tomography (CT). After deleting redundant features, we tested different feature selection (n = 6) and machine-learning (n = 14) methods to form 84 classifiers. The best performing classifier was then selected to establish Rad-score. Finally, the clinicoradiological model (combined model) was developed by combining Rad-score with clinical factors. These models for predicting PNI were compared using receiver operating characteristic curve (ROC) analysis and area under the ROC curve (AUC). RESULTS: One hundred and forty-four of the 303 patients were eventually found to be PNI-positive. Clinical factors including CT-reported T stage (cT), N stage (cN), and carcinoembryonic antigen (CEA) level were independent risk factors for predicting PNI preoperatively. We established Rad-score by logistic regression analysis after selecting features with the L1-based method. The combined model was developed by combining Rad-score with cT, cN, and CEA. The combined model showed good performance to predict PNI status, with an AUC of 0.828 [95% confidence interval (CI): 0.774-0.873] in the training cohort and 0.801 (95%CI: 0.679-0.892) in the validation cohort. For comparison of the models, the combined model achieved a higher AUC than the clinical model (cT + cN + CEA) achieved (P < 0.001 in the training cohort, and P = 0.045 in the validation cohort). CONCLUSION: The combined model incorporating Rad-score and clinical factors can provide an individualized evaluation of PNI status and help clinicians guide individualized treatment of RC patients.

Successful Treatment with Ensartinib After Alectinib-induced Hyperbilirubinemia in ALK-Positive NSCLC.

BACKGROUND: Alectinib is approved for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring ALK rearrangements. Although generally well tolerated, alectinib can cause serious or life-threatening side effects. CASE PRESENTATION: Here, we report a case of a patient with NSCLC with an EML4-ALK fusion and was treated with alectinib but who developed grade 4 hyperbilirubinemia after five months on therapy. Alectinib was discontinued, and an artificial liver support system (ALSS) was used with an impressive decline in bilirubin levels. After two months drug-free, the patient experienced disease progression. Ensartinib was initiated as second-line treatment with a best response of stable disease after three months of therapy with no evidence of hyperbilirubinemia. CONCLUSION: This is the first report of ensartinib treatment after alectinib-induced hyperbilirubinemia which was successfully relieved by ALSS treatment and targeted drug cessation.

Exosomal miR-107 antagonizes profibrotic phenotypes of pericytes by targeting a pathway involving HIF-1α/Notch1/PDGFRß/YAP1/Twist1 axis in vitro.

Microvascular pericytes have been demonstrated as an origin for myofibroblasts that produce excessive extracellular matrix (ECM) proteins such as α-smooth muscle actin (α-SMA) and type I collagen (ColIA1) and contribute to pulmonary fibrosis (PF). However, the signaling mechanism responsible for ECM production within pericytes is poorly understood. In this study, we examined exosomal miR-107 in the fibrotic phenotypes of pericytes and the pathogenesis of PF. Using RT-qPCR, MiR-107 level was compared between clinical or bleomycin-induced PF and normal pulmonary tissues. Exosomes were isolated from cultured microvascular endothelial cells (ECs) derived from either normal or PF tissues, characterized using dynamic light scattering, transmission electron microscopy, flow cytometry, Western blot, and immunofluorescence, and then applied to pericytes. The effects of exosomes or different fibrosis-related signaling molecules were examined by Western blot, and the potential regulations between the signaling molecules were identified using bioinformatic analysis and assessed by electrophoretic mobility shift assay, chromatin immunoprecipitation, luciferase assay, and RNA binding protein immunoprecipitation. MiR-107 was downregulated in clinical or experimental PF tissues and also in exosomes from PF-derived ECs. EC-derived exosomal miR-107 essentially controlled the miR-107 level and inhibited α-SMA and ColIA1 expression in pericytes. The antifibrosis effect of miR-107 was mediated through the suppression of a pathway involving HIF-1α/Notch1/PDGFRß/YAP1/Twist1, where miR-107 directly targeted HIF-1α mRNA, whereas the latter directly activated the transcriptions of both Notch1 and PDGFRß. Functionally, targeting miR-107 promoted and targeting HIF-1α abolished the fibrotic phenotypes of pericytes. Exosomal miR-107 produced by pulmonary vascular ECs may alleviate pericyte-induced fibrosis by inhibiting a signaling pathway involving HIF-1α/Notch1/PDGFRß/YAP1/Twist1.NEW & NOTEWORTHY This work reveals a novel mechanism by which pulmonary vascular endothelial cells, via regulating the transdifferentiation of microvascular pericytes into myofibroblasts, contribute to the pathogenesis of pulmonary fibrosis. Since targeting the formation of myofibroblasts may prevent the development and benefit the treatment of pulmonary fibrosis, this study provides not only mechanistic understanding but also promising therapeutic targets for pulmonary fibrosis.

Low let-7d exosomes from pulmonary vascular endothelial cells drive lung pericyte fibrosis through the TGFßRI/FoxM1/Smad/ß-catenin pathway.

The pathogenesis of pulmonary fibrosis (PF) was mediated by the progressive deposition of excessive extracellular matrix, but little is known about the regulatory mechanisms of fibrogenesis by lung pericytes. The mouse PF model was established by treatment with bleomycin, followed by isolation of exosomes from mouse broncho-alveolar lavage fluids by the centrifuge method. Relative mRNA/microRNA levels and protein expression were assessed by qRT-PCR and Western blotting, respectively. The binding of let-7d with gene promoter was validated by dual-luciferase reporter assay. Protein interactions were verified via GST pull-down and co-immunoprecipitation. Nuclear retention of Smad3 was analysed by extraction of cytoplasmic and nuclear fraction of pericytes followed by Western blotting. Association of FoxM1 with gene promoter was detected by EMSA and ChIP-PCR methods. FoxM1 expression is significantly elevated in human lung fibroblasts of PF patients and mouse PF model. The expression of let-7d is repressed in exosomes derived from broncho-alveolar lavage fluids of PF mice. Let-7d or FoxM1 knockdown suppressed the expression of FoxM1, Smad3, ß-catenin, Col1A and α-SMA expression in mouse lung pericytes under TGF-ß1 treatment. FoxM1 overexpression elevated above gene expression in mouse lung pericytes under TGF-ß1 treatment. Let-7d directly targets TGFßRI to regulate FoxM1 and downstream gene expression in mouse lung pericytes. FoxM1 directly interacts with Smad3 proteins to promote Smad3 nuclear retention and binds with ß-catenin promoter sequence to promote fibrogenesis. Exosomes with low let-7d from pulmonary vascular endothelial cells drive lung pericyte fibrosis through activating the TGFßRI/FoxM1/Smad/ß-catenin signalling pathway.

Radiomics of rectal cancer for predicting distant metastasis and overall survival.

BACKGROUND: Rectal cancer (RC) patient stratification by different factors may yield variable results. Therefore, more efficient prognostic biomarkers are needed for improved risk stratification, personalized treatment, and prognostication of RC patients. AIM: To build a novel model for predicting the presence of distant metastases and 3-year overall survival (OS) in RC patients. METHODS: This was a retrospective analysis of 148 patients (76 males and 72 females) with RC treated with curative resection, without neoadjuvant or postoperative chemoradiotherapy, between October 2012 and December 2015. These patients were allocated to a training or validation set, with a ratio of 7:3. Radiomic features were extracted from portal venous phase computed tomography (CT) images of RC. The least absolute shrinkage and selection operator regression analysis was used for feature selection. Multivariate logistic regression analysis was used to develop the radiomics signature (Rad-score) and the clinicoradiologic risk model (the combined model). Receiver operating characteristic curves were constructed to evaluate the diagnostic performance of the models for predicting distant metastasis of RC. The association of the combined model with 3-year OS was investigated by Kaplan-Meier survival analysis. RESULTS: A total of 51 (34.5%) patients had distant metastases, while 26 (17.6%) patients died, and 122 (82.4%) patients lived at least 3 years post-surgery. The values of both the Rad-score (consisted of three selected features) and the combined model were significantly different between the distant metastasis group and the non-metastasis group (0.46 ± 0.21 vs 0.32 ± 0.24 for the Rad-score, and 0.60 ± 0.23 vs 0.28 ± 0.26 for the combined model; P < 0.001 for both models). Predictors contained in the combined model included the Rad-score, pathological N-stage, and T-stage. The addition of histologic grade to the model failed to show incremental prognostic value. The combined model showed good discrimination, with areas under the curve of 0.842 and 0.802 for the training set and validation set, respectively. For the survival analysis, the combined model was associated with an improved OS in the whole cohort and the respective subgroups. CONCLUSION: This study presents a clinicoradiologic risk model, visualized in a nomogram, that can be used to facilitate individualized prediction of distant metastasis and 3-year OS in patients with RC.

Postoperative intensity-modulated radiation therapy reduces local recurrence and improves overall survival in III-N2 non-small-cell lung cancer: A single-center, retrospective study.

PURPOSE: To determine the postoperative effects of radiotherapy (PORT) on the local recurrence-free survival (LRFS) and overall survival (OS) of stage III-N2 non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: 183 patients with resected stage III-pN2 NSCLC from Hunan Cancer Hospital between 2013 and 2016 were divided into two groups for postoperative chemotherapy (POCT) (n = 105) or combination chemotherapy and radiotherapy (POCRT) (n = 78). The LRFS and OS were compared and the factors affecting local recurrence were illustrated in these two groups. The sites of failure based on the lobe of the primary tumor in two groups were described. RESULTS: PORT leads to a strikingly lower risk for local recurrence and brought superior OS benefit. For different pN2 Subclassification, Patients with multiple-station pN2 ± pN1 disease had the worst LRFS (11 months) and single-station pN2 + multiple station pN1 disease had a relatively short LRFS (24 months) in group POCT. Short LRFS is correlated with multiple-station pN2, older age (Y > 55), patients with a high positive LN ratio > 1/3 and a poor tumor histological differentiation degree. In group POCT, the most frequent failure site occurs at the ipsilateral hilum (21.0%), the bronchial stump (20.0%), followed by LNs4R (19.0%), LNs4L (18.1%), LNs7 (15.2%), most of left-sided tumors more frequently involved the contralateral mediastinum, whereas the ipsilateral recurrences dominated for right-sided tumors, especially for LNs4R. In group POCRT, the highest failure site was the bronchial stump (11.5%), followed by LNs4L (8.97%), LNs1 (7.69%), the ipsilateral hilum (6.41%) and LNs4R (6.41%). CONCLUSION: PORT remarkably reduced local recurrence and improved OS in stage III-pN2 NSCLC, especially in the multiple-station pN2 group.

Supersolidity around a Critical Point in Dipolar Bose-Einstein Condensates.

We explore spatial symmetry breaking of a dipolar Bose-Einstein condensate in the thermodynamic limit and reveal a critical point in the phase diagram at which crystallization occurs via a second-order phase transition. This behavior is traced back to the significant effects of quantum fluctuations in dipolar condensates, which moreover stabilize a new supersolid phase, namely a regular honeycomb pattern with high modulational contrast and near-perfect superfluidity.

Long-Range Interactions and Symmetry Breaking in Quantum Gases through Optical Feedback.

We consider a quasi-two-dimensional atomic Bose-Einstein condensate interacting with a near-resonant laser field that is backreflected onto the condensate by a planar mirror. We show that this single-mirror optical feedback leads to an unusual type of effective interaction between the ultracold atoms giving rise to a rich spectrum of ground states. In particular, we find that it can cause the spontaneous contraction of the quasi-two-dimensional condensate to form a self-bound one-dimensional chain of mesoscopic quantum droplets, and demonstrate that the observation of this exotic effect is within reach of current experiments.

Cavity-Assisted Single-Mode and Two-Mode Spin-Squeezed States via Phase-Locked Atom-Photon Coupling.

We propose a scheme to realize the two-axis countertwisting spin-squeezing Hamiltonian inside an optical cavity with the aid of phase-locked atom-photon coupling. By careful analysis and extensive simulation, we demonstrate that our scheme is robust against dissipation caused by cavity loss and atomic spontaneous emission, and it can achieve significantly higher squeezing than one-axis twisting. We further show how our idea can be extended to generate two-mode spin-squeezed states in two coupled cavities. Because of its easy implementation and high tunability, our scheme is experimentally realizable with current technologies.

The NF-κB p65/miR-23a-27a-24 cluster is a target for leukemia treatment.

p65 is a transcription factor that is involved in many physiological and pathologic processes. Here we report that p65 strongly binds to the miR-23a-27a-24 cluster promoter to up-regulate its expression. As bone marrow-derived cells differentiate into red blood cells in vitro, p65/miR-23a-27a-24 cluster expression increases sharply and then declines before the appearance of red blood cells, suggesting that this cluster is negatively related to erythroid terminal differentiation. Bioinformatic and molecular biology experiments confirmed that the miR-23a-27a-24 cluster inhibited the expression of the erythroid proteome and contributed to erythroleukemia progression. In addition, high level of the p65/miR-23a-27a-24 cluster was found in APL and AML cell lines and in nucleated peripheral blood cells from leukemia patients. Furthermore, anti-leukemia drugs significantly inhibited the expression of the p65/miR-23a-27a-24 cluster in leukemia cells. Administration of the p65 inhibitor parthenolide significantly improved hematology and myelogram indices while prolonging the life span of erythroleukemia mice. Meanwhile, stable overexpression of these three miRNAs in mouse erythroleukemia cells enhanced cell malignancy. Our findings thus connect a novel regulation pathway of the p65/miR-23a-27a-24 cluster with the erythroid proteome and provide an applicable approach for treating leukemia.

Stable Solitons in Three Dimensional Free Space without the Ground State: Self-Trapped Bose-Einstein Condensates with Spin-Orbit Coupling.

By means of variational methods and systematic numerical analysis, we demonstrate the existence of metastable solitons in three dimensional (3D) free space, in the context of binary atomic condensates combining contact self-attraction and spin-orbit coupling, which can be engineered by available experimental techniques. Depending on the relative strength of the intra- and intercomponent attraction, the stable solitons feature a semivortex or mixed-mode structure. In spite of the fact that the local cubic self-attraction gives rise to the supercritical collapse in 3D, and hence the setting produces no true ground state, the solitons are stable against small perturbations, motion, and collisions.

Characterization of interstitial Cajal progenitors cells and their changes in Hirschsprung's disease.

Interstitial cells of Cajal (ICC) are critical to gastrointestinal motility. The phenotypes of ICC progenitors have been observed in the mouse gut, but whether they exist in the human colon and what abnormal changes in their quantity and ultrastructure are present in Hirschsprung's disease (HSCR) colon remains uncertain. In this study, we collected the surgical resection of colons, both proximal and narrow segments, from HSCR patients and normal controls. First, we identified the progenitor of ICC in normal adult colon using immunofluorescent localization techniques with laser confocal microscopy. Next, the progenitors were sorted to observe their morphology. We further applied flow cytometry to examine the content of ICC progenitors in these fresh samples. The ultrastructural changes in the narrow and proximal parts of the HSCR colon were observed using transmission electron microscopy (TEM) and were compared with the normal adult colon. The presumed early progenitor (c-Kit(low)CD34(+)Igf1r(+)) and committed progenitor (c-Kit(+)CD34(+)Igf1r(+)) of ICC exist in adult normal colon as well as in the narrow and proximal parts of the HSCR colon. However, the proportions of mature, early and committed progenitors of ICC were dramatically reduced in the narrow segment of the HSCR colon. The proportions of mature and committed progenitors of ICC in the proximal segment of the HSCR colon were lower than in the adult normal colon. Ultrastructurally, ICC, enteric nerves, and smooth muscle in the narrow segment of the HSCR colon showed severe injury, including swollen vacuola or ted mitochondria, disappearance of mitochondrial cristae, dilated rough endoplasmic reticulum, vesiculation and degranulation, and disappearance of the caveolae on the ICC membrane surface. The contents of ICC and its progenitors in the narrow part of the HSCR colon were significantly decreased than those of adult colon, which may be associated with HSCR pathogenesis.

[Surveillance for occult HBV infection and HBsAg variants in blood donors].

Occult hepatitis B virus (HBV) infection status of blood donors in a southern city in China was investigated by immunological assays and nucleic acid testing. Overall, 17 (0.19%, 95% CI: 0.11%-0.30%) of the 9023 HBsAg negative samples were found to be positive for the presence of HBV DNA. "A" epitope sequences were obtained from 14 among them. Mutation(s) in aa124-aa147 existed in 6 (42.9%, 6/14) samples and 4 (66.7%, 4/6)were G145R mutation. Ratio of genotype C in occult donors (10/17) was statistically higher than HBs-positive donors (0/15, P<0.01), which implied that HBV genotype C leaded to occult infection more easily.

The effect of protein kinase C on voltage-gated potassium channel in pulmonary artery smooth muscle cells from rats exposed to chronic hypoxia.

BACKGROUND: Chronic hypoxia can cause pulmonary hypertension and pulmonary heart disease with high mortality. The signal transduction pathway of protein kinase C (PKC) plays an important role in chronic pulmonary hypertension. So it is necessary to investigate the effect of PKC on voltage-gated potassium (K+) channels in pulmonary artery smooth muscle cells of rats exposed to chronic hypoxia. METHODS: Male Wistar rats were randomly divided into a control group (group A) and a chronic hypoxia group (group B). Group B received hypoxia [oxygen concentration (10 +/- 1)%] eight hours per day for four consecutive weeks. Single pulmonary artery smooth muscle cells were obtained using an acute enzyme separation method. Conventional whole cell patch clamp technique was used to record resting membrane potential, membrane capacitance and voltage-gated K+ currents. The changes in voltage-gated K+ currents before and after applying paramethoxyamphetamine (PMA) (500 nmol/L), an agonist of PKC, and PMA plus carbohydrate mixture of glucose, fructose and xylitol (GFX) (30 nmol/L), an inhibitor of PKC, were compared between the two groups. RESULTS: The resting membrane potential in group B was significantly lower than that of group A: -(29.0 +/- 4.8) mV (n = 18) vs -(42.5 +/- 4.6) mV (n = 35) (P < 0.01). But there was no change in membrane capacitance between the two groups: (17.9 +/- 4.6) pF (n = 40) vs (19.7 +/- 5.8) pF (n = 31) (P > 0.05). The voltage-gated K+ currents were significantly inhibited by PMA in group A, and this effect was reversed by GFX. However, the voltage-gated K+ currents in group B were not affected by PMA. CONCLUSIONS: The resting membrane potential and voltage-gated K+ currents in pulmonary artery smooth muscle cells from rats exposed to chronic hypoxia decreased significantly. It seems that PKC has different effects on the voltage-gated K+ currents of pulmonary artery smooth muscle cells under different conditions.

[The effects of long-term application of L-arginine on K+ channel in pulmonary artery smooth muscle cells from rats exposed to chronic hypoxia].

OBJECTIVE: To investigate the effects of long-term application of L-arginine (L-Arg) on K(+) channel in pulmonary artery smooth muscle cells (PASMC) from rats exposed to chronic hypoxia. METHODS: Male Wistar rats were randomly divided into three groups: group A (control group), group B (chronic hypoxia group) and group C (chronic hypoxia plus L-Arg treatment group). The rats were exsanguinated and the intrapulmonary arteries (300 approximately 700 OD) were collected. Single PASMC was obtained by the acute enzyme separation method (collagnase Iplus papain) and the conventional whole-cell patch clamp technique was used to record resting membrane potential (Em), potassium ion currents of voltage-gated potassium channel and Ca(2+)-sensitive potassium channel. RESULTS: (1) The Em of group B [(-31 +/- 8) mV, n = 6] was significantly higher than that of group A [(-42 +/- 5) mV, n = 6, P < 0.01]. After long-term application of L-Arg, the Em of group C [(-39 +/- 4) mV, n = 6] was significantly lower than that of group B (P < 0.05). (2) The peak current at +50 mV of voltage-gated potassium channel was compared among three groups. In group B [(62.2 +/- 5.3) pA/pF, n = 6], it was significantly lower than that of group A [(121 +/- 9) pA/pF, n = 6] (P < 0.01). After long-term application of L-Arg, the peak current at +50 mV of voltage-gated potassium channel in group C [(95 +/- 3) pA/pF, n = 6] was significantly higher than that of group B (P < 0.001). (3) The peak current at +50 mV of Ca(2+)-sensitive potassium channel was compared among three groups. In group B [(74.7 +/- 4.1) pA/pF, n = 6], it was significantly higher than that of group A [(53.6 +/- 5.9) pA/pF, n = 6] (P < 0.05). After long-term application of L-Arg, the peak current at +50 mV of Ca(2+)-sensitive potassium channel in group C [(31.8 +/- 1.8) pA/pF, n = 6] was significantly lower than that of group B [(74.7 +/- 4.1) pA/pF, n = 6] (P < 0.001). CONCLUSIONS: The long-term application of L-Arg can improve the resting membrane potential of PASMCs from rats exposed to chronic hypoxia, increase the currents of voltage-gated potassium channel and decrease the currents of Ca(2+)-sensitive potassium channel. These effects are considered to be effective in improving chronic hypoxic pulmonary hypertension.