Study on the affinity sites of cadmium's binding to ligands by thermodynamics and nuclear magnetic resonance spectroscopy.

The affinity sites of cadmium (Cd(II)) when binding to cysteine (Cys) and glutathione (GSH) were studied via thermodynamics and nuclear magnetic resonance (NMR) spectroscopy methods. The results showed that the Cd(II) binding sites of Cys and GSH were -SH (exothermic), -NH2 (endothermic) and -COOH (endothermic). The thermodynamic behaviour of Cd(II) binding to Cys/GSH in boric acid and HEPES buffers differed, with the former being mainly endothermic and the latter mainly exothermic. It could be inferred that, in the boric acid system, the main binding site of Cd(II) with Cys and GSH is changed from -SH in HEPES to -COOH and -NH2 in boric acid. This was confirmed by the results of NMR experiments of Cd(II) with Cys/GSH. 1D 1H-NMR experiments showed that, after the combination of Cd(II) and Cys, the changes in the chemical shifts and peak strengths of protons near the -SH group for the reaction in HEPES were greater than when boric acid buffer was used. Changes in the chemical shift and peak strength of the -NH2 protons due to the binding of Cd(II) to GSH were evident in the boric acid buffer but not in HEPES. The screening of functional monomers is very important in the process of preparation of cadmium ion-imprinted materials. This research provides important theoretical and experimental guidance for the screening of functional monomers.

Dosimetric Comparison of Postmastectomy Radiotherapy Plans for Synchronous Bilateral Breast Cancer, Including Regional Lymph Node Irradiation.

BACKGROUND: To investigate the optimal radiotherapy plans for synchronous bilateral breast cancer (SBBC) patients receiving postmastectomy radiotherapy (PMRT), including regional lymph node irradiation (RNI). METHODS: For 10 SBBC patients who underwent bilateral mastectomy and received bilateral PMRT with RNI, 3 integrally optimized plans with a single isocenter were designed for each patient in this retrospective study: intensity-modulated radiation therapy (IMRT) with 9 fixed beams (9F-IMRT), volumetric-modulated arc therapy (VMAT) with 2 pairs of half arcs (2F-VMAT), VMAT with 2 pairs of outer tangential arcs and 1 pair of 200-degree arcs (3F-VMAT). The paired t-test (in the case of normal variables) and Friedman's test (in the case of nonnormal variables) were applied to compare the planning target volumes (PTVs) and organs at risk (OARs) values of the 3 techniques. RESULTS: The 3 techniques provided adequate target dose coverage and comparable results for PTVs. For OARs, 3F-VMAT yielded the lowest mean or median values of the left lung (15.02 ± 1.57 Gy) and right lung (14.91 ± 1.14 Gy), heart (6.19 (1.96) Gy), coronary artery (15.96 ± 5.76 Gy) and liver (8.10 ± 2.70 Gy) which were significantly different from those of 9F-IMRT and 2F-VMAT. The percentages of volume at various doses (V5, V10, V20, and V30) of 3F-VMAT plans were also lower than or comparable with those of 9F-IMRT and 2F-VMAT. The monitor units (MUs) of 3F-VMAT were 31% higher than those of 9F-IMRT and comparable with those of 2F-VMAT; however, there were time savings and halved beam-on times (BOTs) compared to 9F-IMRT. CONCLUSIONS: The 3F-VMAT plan yielded comparable target coverage compared with 9F-IMRT and 2F-VMAT, was superior in dose sparing of normal tissues and enabled shorter BOTs, improving treatment efficiency. In our research, 3F-VMAT was the optimal radiotherapy technique for SBBC patients receiving PMRT including RNI.

Dosimetric Comparison of Commonly Used Volumetric Modulated Arc Therapy Field Arrangements Based on Flattening Filter-Free Beams for Synchronous Bilateral Breast Carcinoma Radiation Therapy.

PURPOSE: Flattening filter-free (FFF)-based volumetric modulated arc therapy (VMAT) has been shown to be feasible and significantly improves treatment efficiency and lung protection for synchronous bilateral breast irradiation (SBBI). This research compared the commonly used VMAT field arrangements using FFF beams. METHODS: Twenty-eight patients underwent SBBI were retrospectively enrolled to design irradiation plans using tangential arc VMAT (taVMAT), half arc VMAT (haVMAT), and large arc VMAT (laVMAT). Dosimetric and delivery parameters of all designed plans were recorded and compared. RESULTS: Comparable target volume coverage was observed for all field arrangements. taVMAT significantly reduced the dose to spinal cord and the volume covered by 5 Gy (V5Gy) and V7Gy of the lungs while decreasing the conformity index of the target volume. It also increased the volume covered by 105% of the prescription dose (V105%) and V107% of the target volume. haVMAT considerably decreased V20 Gy and V30 Gy of the lungs, mean dose (Dmean) and V30 Gy of the heart and the liver. It also notably reduced Dmean and V40 Gy of the left anterior descending coronary artery while increasing the beam-on time. laVMAT significantly reduced the mean treatment time (range, 113-117 seconds) compared with the other field arrangements. CONCLUSIONS: There were distinct differences in various dosimetric and delivery parameters for different field arrangements, highlighting the importance of selecting the appropriate field arrangement based on specific treatment goals and considerations. This study contributes valuable insights into the use of FFF-based VMAT techniques in SBBI.

Targeting mTOR Signaling by Dietary Polysaccharides in Cancer Prevention: Advances and Challenges.

Cancer is the most serious problem for public health. Traditional treatments often come with unavoidable side effects. Therefore, the therapeutic effects of natural products with wide sources and low toxicity are attracting more and more attention. Polysaccharides have been shown to have cancer-fighting potential, but the molecular mechanisms remain unclear. The mammalian target of rapamycin (mTOR) pathway has become an attractive target of antitumor therapy research in recent years. The regulation of mTOR pathway not only affects cell proliferation and growth but also has an important effect in tumor metabolism. Recent studies indicate that dietary polysaccharides play a vital role in cancer prevention and treatment by regulating mTOR pathway. Here, the progress in targeting mTOR signaling by dietary polysaccharides in cancer prevention and their molecular mechanisms are systemically summarized. It will promote the understanding of the anticancer effects of polysaccharides and provide reference to investigators of this cutting edge field.

Error detection using EPID-based 3D in vivo dose verification for lung stereotactic body radiotherapy.

PURPOSE: To investigate the error detectability limitations of an EPID-based 3D in vivo dosimetry verification system for lung stereotactic body radiation therapy (SBRT). METHODS: Thirty errors were intentionally introduced, consisting of dynamic and constant machine errors, to simulate the possible errors that may occur during delivery. The dynamic errors included errors in the output, gantry angle and MLC positions related to gantry inertial and gravitational effects, while the constant errors included errors in the collimator angle, jaw positions, central leaf positions, setup shift and thickness to simulate patient weight loss. These error plans were delivered to a CIRS phantom using the SBRT technique for lung cancer. Following irradiation of these error plans, the dose distribution was reconstructed using iViewDose™ and compared with the no error plan. RESULTS: All errors caused by the central leaf positions, dynamic MLC errors, Jaw inwards movements, setup shifts and patient anatomical changes were successfully detected. However, dynamic gantry angle and collimator angle errors were not detected in the lung case due to the rotation-symmetric target shape. The results showed that the γmean and γpassrate indicators can detect 13 (81.3%) and 14 (87.5%) of the 16 errors respectively without including the gantry angle error, collimator angle error and output error. CONCLUSIONS: In summary, iViewDose™ is an appropriate approach for detecting most types of clinical errors for lung SBRT. However, the phantom results also showed some detectability limitations of the system in terms of dynamic gantry angle and constant collimator angle errors.

Laminarin ameliorates alcohol-induced liver damage and its molecular mechanism in mice.

Alcoholic liver disease (ALD) has become a health issue globally. Laminarin, a low molecular weight marine-derived ß-glucan, has been identified with multiple biological activities. In this study, the ameliorative effect on ALD of laminarin isolated from brown algae was investigated. Phenotypic, pathological alterations and biochemical characteristics indicated that laminarin administration (100 mg/kg/day) significantly alleviated liver injury and improved liver function in the alcohol-induced mice. Gene chip results indicated that laminarin treatment caused 52 up-regulated and 13 down-regulated genes in the hepatic tissues of alcohol-induced damage mice, and most of these genes are associated with regulation of oxidative stress (such as CYP450/glutathione-dependent antioxidation), Wnt signaling pathway, retinol metabolism, and cAMP pathway based on GO and KEGG analysis. PPI network analysis indicated that the downstream target genes lied in the hub of the net. Our experiments also confirmed the changed expressions of some target genes. Taken together, these results suggest that laminarin can ameliorate alcohol-induced damage in mice and its molecular mechanism lies in modulating anti-oxidation pathway, WNT pathway, and cAMP pathway, which regulate the expressions of downstream target genes and alleviate alcohol-induced damage. Our study provides new clue to prevent alcohol-induced damage and will be benefit to develop functional foods. PRACTICAL APPLICATIONS: This study verified the positive effect on alcoholic liver disease (ALD) of laminarin, a water-soluble brown algae-derived ß-glucan, linked by ß-(1,3) glycosidic bonds with ß-(1,6) branches. Laminarin significantly alleviated liver injury and improved liver function of ALD mice. Moreover, transcriptomics and bioinformatics analysis further revealed the gene expression patterns, hub targets, and signalings including CYP450/glutathione, Wnt, retinol metabolism, cAMP pathways regulated by laminarin. This research is the first evidence for hepatoprotective effect of laminarin against ALD and its molecular mechanism, which will be advantage to develop functional foods or adjuvant therapy of ALD.

Lymph node yield less than 12 is not a poor predictor of survival in locally advanced rectal cancer after laparoscopic TME following neoadjuvant chemoradiotherapy.

Purpose: Previous studies have confirmed that neoadjuvant chemoradiotherapy (nCRT) may reduce the number of lymph nodes retrieved in rectal cancer. However, it is still controversial whether it is necessary to harvest at least 12 lymph nodes for locally advanced rectal cancer (LARC) patients who underwent nCRT regardless of open or laparoscopic surgery. This study was designed to evaluate the relationship between lymph node yield (LNY) and survival in LARC patients who underwent laparoscopic TME following nCRT. Methods: Patients with LARC who underwent nCRT followed by laparoscopic TME were retrospectively analyzed. The relationship between LNY and survival of patients was evaluated, and the related factors affecting LNY were explored. To further eliminate the influence of imbalance of clinicopathological features on prognosis between groups, propensity score matching was conducted. Results: A total of 257 consecutive patients were included in our study. The median number of LNY was 10 (7 to 13) in the total cohort. There were 98 (38.1%) patients with 12 or more lymph nodes harvested (LNY ≥12 group), and 159 (61.9%) patients with fewer than 12 lymph nodes retrieved (LNY <12 group). There was nearly no significant difference between the two groups in clinicopathologic characteristics and surgical outcomes except that the age of LNY <12 group was older (P<0.001), and LNY <12 group tended to have more TRG 0 cases (P<0.060). However, after matching, when 87 pairs of patients obtained, the clinicopathological features were almost balanced between the two groups. After a median follow-up of 65 (54 to 75) months, the 5-year OS was 83.9% for the LNY ≥12 group and 83.6% for the LNY <12 group (P=0.893), the 5-year DFS was 78.8% and 73.4%, respectively (P=0.621). Multivariate analysis showed that only patient age, TRG score and ypN stage were independent factors affecting the number of LNY (all P<0.05). However, no association was found between LNY and laparoscopic surgery-related factors. Conclusions: For LARC patients who underwent nCRT followed by laparoscopic TME, the number of LNY less than 12 has not been proved to be an adverse predictor for long-term survival. There was no correlation between LNY and laparoscopic surgery-related factors.

Patterns and predictors of recurrence after laparoscopic resection of rectal cancer.

Purpose: This study was designed to evaluate the patterns and predictors of recurrence in patients who underwent laparoscopic resection of rectal cancer. Methods: Patients with rectal cancer receiving laparoscopic resection between April 2009 and March 2016 were retrospectively analyzed. The association of recurrence with clinicopathological characteristics was evaluated using multivariate analyses. Results: A total of 405 consecutive patients were included in our study. Within a median follow-up time of 62 months, 77 patients (19.0%) experienced disease recurrence: 10 (2.5%) had locoregional recurrence (LR), 61 (15.1%) had distant metastasis (DM), and 6 (1.5%) developed LR and DM synchronously. The lung was the most common site of metastasis. Multivariate analyses indicated that involved circumferential resection margin (CRM) was the only independent predictor for LR (OR=13.708, 95% CI 3.478-54.026, P<0.001), whereas elevated baseline level of CA19-9 (OR=3.299, 95% CI 1.461-7.449, P=0.032), advanced pN stage (OR=2.292, 95% CI 1.177-4.462, P=0.015) and harvested lymph nodes less than 12 (OR=2.418, 95% CI 1.245-4.695, P=0.009) were independently associated with DM. Patients receiving salvage surgery showed superior 3-year survival compared with palliative treatment after relapse (90.9% vs. 20.5%; P=0.017). The estimated 5-year DFS and CSS for the entire cohort was 80.2% and 83.1%, respectively. Conclusions: DM was more common than LR after laparoscopic resection of rectal cancer, and there were several clinicopathological factors related to LR and DM. Involved CRM and suboptimal lymph node yield were adverse surgery-related factors of tumor recurrence, which should be paid more attention to during the operation.

A fast, sensitive, low-cost electrochemical paper-based chip for real-time simultaneous detection of cadmium (â ¡) and lead (â ¡) via aptamer.

A novel electrochemical paper-based microfluidic chip was firstly developed to simultaneously detect cadmium (Ⅱ) and lead (Ⅱ) in vegetable and fruit samples. The patterned filter paper was prepared through the printing of three-electrode patterns on filter paper using an automatic screen-printing machine. Portable and low-cost (less than $1) electrochemical paper-based chips are prepared by filling conductive ink and hot pressing. The paper-based chip could realize signal amplification through gold nanoparticles and seed solutions. Cadmium (Ⅱ) and lead (Ⅱ) were sensitively detected by their aptamers labeled with methylene blue and ferrocene, separately. Under the optimal experimental parameters, the paper-based chip detected cadmium (Ⅱ) and lead (Ⅱ) as low as 23.31 and 46.23 pmol/L (3σ) with a wide linear range from 0.1 to 1000 nmol/L and exhibited excellent selectivity. The RSD was 6.41% (cadmium (Ⅱ)) and 4.20% (lead (Ⅱ)). Compared with other methods, the paper-based chip could complete the detection within 15 min and could be stored at -20 °C for 5 days. Furthermore, the results for vegetable and fruit samples were agreed with the results of the graphite furnace atomic absorption spectrophotometer, in which the recovery rates were 93.20%-95.80%.

Synchronous bilateral breast carcinoma irradiation: A comparative investigation between flattened and unflattened beams.

Synchronous bilateral breast carcinoma (SBBC) radiotherapy is a very complicated and time-consuming process. Considering the advantages of unflattened (FFF) beams at a high dose rate, this work investigated the feasibility of FFF beam application in SBBC radiotherapy and compared the advantages between FFF and flattened (FF) beams. CT images of 13 patients with SBBC were retrospectively collected to design intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) plans using FF and FFF beams. Dosimetric verification was applied for each plan. The target volume metrics, dose received by organs at risk (OARs), and delivery parameter of the plans were documented. All plans met the universal tolerance limits in dosimetric verification. FFF decreased the volume to receive 5 Gy (V5Gy), V7Gy, and mean dose of the left lung but slightly increased the V30Gy of the liver for VMAT and decreased the V17Gy and V20Gy of the right lung for IMRT. No remarkable differences between FF and FFF were found in the other investigated OARs and all the investigated target volume metrics. The mean treatment times of FFF were 66 and 45 s shorter than those of FF for IMRT and VMAT, respectively. FFF beams were feasible and had advantages in reducing treatment time and protecting the lung while maintaining the target volume metrics in SBBC irradiation.

The selective recognition mechanism of a novel highly hydrophobic ion-imprinted polymer towards Cd(ii) and its application in edible vegetable oil.

Edible vegetable oils are easily contaminated by heavy metals, resulting in the oxidative degradation of oils and various health effects on humans. Therefore, it is very important to develop a rapid and efficient method to extract trace heavy metals from vegetable oils. In this work, a highly hydrophobic ion-imprinted polymer (IIP) was synthesized on a novel raspberry (RS)-like particle surface. The synthesized IIP@RS was characterized and used in solid-phase extraction (SPE) for the selective and fast adsorption of Cd(ii) from vegetable oils. The results showed that IIP was successfully coated onto RS particles with a high specific surface area (458.7 m2 g-1) and uniform porous structure. The contact angle (θ) value (141.8°) of IIP@RS was close to the critical value of super-hydrophobic materials, which is beneficial to their adsorption in hydrophobic vegetable oils. The IIP@RS also exhibited excellent adsorption ability and selectivity to Cd(ii) with a maximum adsorption capacity of 36.62 mg g-1, imprinting factor of 4.31 and equilibrium adsorption rate of 30 min. According to isothermal titration calorimetry results, the recognition behavior of IIP@RS for Cd(ii) was mainly contributed by Cd(ii)-induced cavities during gel formation and coordination between Cd(ii) and -SH groups in imprinted cavities. Furthermore, the adsorption process driven by entropy and enthalpy was spontaneous at all temperatures. In real vegetable oil samples, IIP@RS-SPE adsorbed approximately 96.5-115.8% of Cd(ii) with a detection limit of 0.62 µg L-1. Therefore, IIP@RS has wide application prospects in enriching and detecting Cd(ii) from vegetable oil.

Evaluation of fixed-jaw IMRT and tangential partial-VMAT radiotherapy plans for synchronous bilateral breast cancer irradiation based on a dosimetric study.

PURPOSE: To investigate the fixed-jaw intensity-modulated radiotherapy (F-IMRT) and tangential partial volumetric modulated arc therapy (tP-VMAT) treatment plans for synchronous bilateral breast cancer (SBBC). MATERIALS AND METHOD: Twelve SBBC patients with pTis-2N0M0 stages who underwent whole-breast irradiation after breast-conserving surgery were planned with F-IMRT and tP-VMAT techniques prescribing 42.56 Gy (2.66 Gy*16f) to the breast. The F-IMRT used 8-12 jaw-fixed tangential fields with single (sF-IMRT) or two (F-IMRT) isocenters located under the sternum or in the center of the left and right planning target volumes (PTVs), and tP-VMAT used 4 tangential partial arcs with two isocenters located in the center of the left and right PTVs. Plan evaluation was based on dose-volume histogram (DVH) analysis. Dosimetric parameters were calculated to evaluate plan quality; total monitor units (MUs), and the gamma analysis for patient-specific quality assurance (QA) were also evaluated. RESULTS: For PTVs, the three plans had similar Dmean and conformity index (CI) values. F-IMRT showed a slightly better target coverage according to the V100% values and demonstrated an obvious reduction in V105% and Dmax compared with the values observed for sF-IMRT and tP-VMAT. Compared with tP-VMAT, sF-IMRT was slightly better in terms of V100% , V105% and Dmax . In addition, F-IMRT achieved the best homogeneity index (HI) values for PTVs. Concerning healthy tissue, tP-VMAT had an advantage in minimizing the high dose volume. The MUs of the tP-VMAT plan were decreased approximately 1.45 and 1 times compared with the sF-IMRT and F-IMRT plans, respectively, and all plans passed QA. For the lungs, heart and liver, F-IMRT achieved the smallest values in terms of Dmean and showed a significant difference compared with tP-VMAT. Simultaneously, sF-IMRT was also superior to tP-VMAT. For the coronary artery, tP-VMAT achieved the lowest Dmean , while the value for F-IMRT was 2.24% lower compared with sF-IMRT. For all organs at risk (OARs), tP-VMAT was superior at the high dose level. In contrast, sF-IMRT and F-IMRT were obviously superior at the low dose level. The sF-IMRT and F-IMRT plans showed consistent trends. CONCLUSION: All treatment plans for the provided techniques were of high quality and feasible for SBBC patients. However, we recommend F-IMRT with a single isocenter as a priority technique because of the tremendous advantage of local hot spot control in PTVs and the reduced dose to OARs at low dose levels. When the irradiated dose to the lungs and heart exceed the clinical restriction, two isocenter F-IMRT can be used to maximize OAR sparing. Additionally, tP-VMAT can be adopted for improving cold spots in PTVs or high-dose exposure to normal tissue when the interval between PTVs is narrow.

Long-term efficacy and safety of sirolimus therapy in patients with lymphangioleiomyomatosis.

BACKGROUND: Sirolimus has been confirmed to be effective for lymphangioleiomyomatosis (LAM), a rare multisystem neoplastic disease in women. The long-term effects of sirolimus treatment for LAM, however, are largely unknown. We aimed to analyze the long-term efficacy and safety of sirolimus therapy for LAM with 4-year follow-up. METHODS: In total, 142 sporadic LAM patients who took sirolimus for 1-4 years were retrospectively enrolled for this analysis. The variables used for analysis included pulmonary function tests, arterial blood gas analysis, 6-min walking distance (6MWD), St. George's Respiratory Questionnaires (SGRQ) and serum vascular endothelial growth factor-D (VEGF-D) levels before and after the initiation of sirolimus therapy. The rates of change (slope) in those variables were calculated, and adverse events were also analyzed. RESULTS: In total, 122, 83, 60 and 32 patients out of 142 were followed for 1, 2, 3 and 4 years respectively. Sirolimus treatment improved the change rate in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) compared with the data before treatment (FEV1, - 10 ± 15 vs. - 178 ± 36 ml/y, P <  0.001 and FVC, 54 ± 22 vs.-72 ± 68 ml/y, P < 0.05). In comparison to the baseline measurements, significant improvements were observed in FEV1 at the first year; FVC at 1-2 years; arterial oxygen levels, 6MWD, and SGRQ at 1-3 years; and VEGF-D at 1-4 years. Overall, all variables stabilized or improved during the 4 years of observation. Adverse events related to sirolimus were mild. CONCLUSION: Sirolimus therapy is effective at improving or stabilizing pulmonary function, oxygen levels, exercise capacity, and quality of life in patients with LAM for up to 4 years. VEGF-D is maintained at a lower level for 4 years after treatment. Adverse events related to sirolimus were mild.

Effect of multimodal intervention on postoperative nausea and vomiting in patients undergoing gynecological laparoscopy.

OBJECTIVE: Postoperative nausea and vomiting (PONV) is a common complication in patients undergoing gynecological laparoscopic surgery, and achieving good results is difficult with a single antiemetic method. This study investigated whether multimodal intervention can reduce PONV in patients undergoing gynecological laparoscopic surgery. METHODS: A total of 153 patients who underwent gynecological laparoscopic surgery were randomized into the control group and multimodal group. Patients in the multimodal group received dexmedetomidine 1 µg/kg intravenously 15 minutes before induction of anesthesia. A bilateral transversus abdominis plane block was performed with 0.375% ropivacaine 30 mL after induction of anesthesia. Scores of postoperative nausea and vomiting, the visual analog scale, and the Bruggemann comfort scale (BCS) were assessed 24 hours postoperatively. RESULTS: Nausea and vomiting scores were significantly lower at 2, 6, and 24 hours in the multimodal group compared with the control group. BCS scores were significantly higher at 0 to 24 hours in the multimodal group compared with the control group. CONCLUSIONS: Multimodal intervention improves PONV and increases patients' comfort. The multimodal approach can also enhance recovery after gynecological laparoscopic surgery.

Clinical characteristics in lymphangioleiomyomatosis-related pulmonary hypertension: an observation on 50 patients.

Lymphangioleiomyomatosis (LAM) is a rare diffuse cystic lung disease. Knowledge on LAM-related pulmonary hypertension (PH) is limited. This study aimed to analyze the clinical characteristics of LAM with elevated pulmonary artery pressure (PAP) and evaluate the potential efficacy of sirolimus. The study involved 50 LAM patients who underwent echocardiography. According to the tricuspid regurgitation velocity (TRV), these patients were divided into the TRV ⩽ 2.8 m/s group and TRV > 2.8 m/s group. Both groups comprised 25 females with an average age of 38.6 ± 8.1 and 41.5 ± 8.9 years. In the TRV > 2.8 m/s group, the estimated systolic PAP (SPAP) was significantly elevated (52.08 ± 12.45 mmHg vs. 30.24 ± 5.25 mmHg, P < 0.01). Linear analysis showed that SPAP was correlated with forced expiratory volume in 1 s (FEV1), diffusing capacity of the lungs for carbon monoxide, alveolar arterial oxygen gradient (PA-aO2), and 6 min walking distance (r =-0.392, -0.351, 0.450, and -0.591, respectively; P < 0.05), in which PA-aO2 was a risk factor for SPAP elevation (ß = 0.064, OR = 1.066, P < 0.05). Moreover, in 10 patients who received sirolimus therapy, SPAP decreased from 57.0 12.6 mmHg to 35.2 ± 11.1 mmHg. The study showed that LAM patients with PH exhibit poor pulmonary function and hypoxemia and may benefit from sirolimus treatment.

Retraction: PDZ-containing 1 acts as a suppressor of pancreatic cancer by regulating PTEN phosphorylation.

[This retracts the article DOI: 10.18632/oncotarget.20552.].

Functional improvements in patients with lymphangioleiomyomatosis after sirolimus: an observational study.

BACKGROUND: Sirolimus has been shown to be effective in patients with lymphangioleiomyomatosis (LAM). We wish to summarize our experience using sirolimus and its effectiveness in LAM patients. METHODS: We analyzed data from 98 patients who were diagnosed with definite or probable sporadic LAM based on the European Respiratory Society diagnosis criteria for LAM in 2010 at Peking Union Medical College Hospital and who had received sirolimus during January 2007 to June 2015. The data before and after the initiation of sirolimus therapy included pulmonary function tests, arterial blood gas analysis, 6-min walking distance (6MWD), size of chylous effusion and renal angiomyolipomas (AML), St. George's Respiratory Questionnaires (SGRQ) and vascular endothelial growth factor-D (VEGF-D) levels. Serum levels of sirolimus and adverse events were collected. RESULTS: Median follow-up was 2.5 years. Most patients had forced expiratory volume in 1 s (FEV1) values less than 70% predicted or symptomatic chylothorax. The mean changes before and after the initiation of sirolimus were - 31.12 ± 30.78 mL/month and 16.11 ± 36.00 mL/month (n = 18,p = 0.002) for FEV1 change, and - 0.55 ± 0.60 mmHg/month and 0.30 ± 1.19 mmHg/month (n = 17, p = 0.018) for PaO2 change. 6MWD improved from 358.8 ± 114.4 m to 415.6 ± 118.6 m (n = 46, p = 0.004) and SGRQ total score from 57.2 ± 21.0 to 47.5 ± 22.8 (n = 50, p < 0.001). The median VEGF-D concentration decreased to 1609.4 pg/mL from 3075.6 pg/mL after sirolimus therapy (n = 41, p < 0.001). Patients with sirolimus trough levels of 5-9.9 ng/mL had an increase in FEV1 (p < 0.05). Sixty-five percent of patients (13/20) had almost complete resolution of chylous effusions. The most frequent adverse events were mouth ulcers, menstrual disorder, hyperlipidemia and acneiform rash, all were mild. CONCLUSION: Long-term use of sirolimus is safe in patients with LAM. LAM patients with FEV1 less than 70% predicted and symptomatic chylothorax are suitable for receiving sirolimus therapy. The maintaining serum trough levels of sirolimus are recommended between 5 to 9.99 ng/mL.

PDZ-containing 1 acts as a suppressor of pancreatic cancer by regulating PTEN phosphorylation.

Phosphorylation is a recently established cause of phosphatase and tensin homolog (PTEN) gene inactivation, which leads to defect tumour-suppressor function. In pancreatic cancer, this phenomenon has not been reported. Based on database and clinical sample analyses, we found that PTEN phosphorylation occurs in pancreatic ductal adenocarcinoma patient tissues and cell lines, and we aimed to find a method for dephosphorylation. PDZ-containing 1 (PDZK1), a tumour-associated protein that shares its PDZ-binding sequence with the carboxyl-terminal domain of PTEN, was significantly down-regulated in pancreatic cancer as compared to adjacent non-tumour tissues. In vitro, PDZK1 overexpression reversed the proliferation and migration abilities of pancreatic cancer cells and led to significantly decreased PTEN phosphorylation and AKT phosphorylation by interacting with wild-type PTEN. In addition, a transcription factor-activation assay supported that PDZK1 overexpression enhanced the anti-oncogene function of PTEN by regulating the activities of its downstream transcription factors, including p53, NF-κB, and FOXO1. In vivo, nude mice stably over-expressing PDZK1 had lower tumour weights and volumes and showed significantly down-regulated PTEN phosphorylation in xenograft tumour tissues as compared to the control group. Moreover, low PDZK1 expression strongly correlated with advanced stage and poor prognosis of patients with pancreatic ductal adenocarcinoma. In conclusion, our study elucidated the tumour-suppressor role of PDZK1 in pancreatic cancer through down-regulating PTEN phosphorylation, and established PDZK1 as a potential novel prognostic marker for pancreatic cancer.

SERP1 is a novel marker of poor prognosis in pancreatic ductal adenocarcinoma patients via anti-apoptosis and regulating SRPRB/NF-κB axis.

Stress associated endoplasmic reticulum protein 1 (SERP1), can cause accumulation of unfolded proteins in ER stress. However, studies on the role of SERP1 in pancreatic ductal adenocarcinoma (PDAC) are still incomplete. The present study aimed at identifying whether SERP1 acts as a potential novel prognostic marker of PDAC, and analyzed its possible mechanism. GEO database analysis showed SERP1 was significantly upregulated in PDAC tissues, and strongly associated with advanced clinical stage of PDAC patients from TCGA database. Univariate and multivariate Cox regression analysis further revealed SERP1 high expression was an independent factor for the prognosis of PDAC. Gene set enrichment analysis (GSEA) revealed that SERP1 was mainly involved in regulating cell apoptosis and nuclear factor-κB (NF-κB) signaling pathway, and downregulated SERP1 significantly promoted PANC-1 cell apoptosis. To further explore its possible mechanism, protein-protein interaction (PPI) and gene ontology (GO) analysis showed the functions of proteins interacting with SERP1 were mainly enriched in regulating cell apoptosis, and SRP receptor ß subunit (SRPRB) was the core of the whole PPI network. The expression of SERP1 was negatively correlated with SRPRB expression. In vitro, downregulated SERP1 significantly increased SRPRB expression. Furthermore, upregulated SRPRB could increase cell apoptosis rate and decreased the expression level of NF-κB and the phosphorylation NF-κB. The above results indicated that SERP1 as a potential novel prognostic marker of PDAC probably via regulating cell apoptosis and NF-κB activation, which may be associated with SRPRB.

Downregulation of matrix metalloproteinase­19 induced by respiratory syncytial viral infection affects the interaction between epithelial cells and fibroblasts.

The present study was designed to examine the expression and function of matrix metalloproteinase­19 (MMP­19), which is downregulated following respiratory syncytial virus (RSV) infection. The diverse expression levels of MMP were examined using a designed cDNA expression array. The expression and secretion of MMP­19 was examined using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analysis and ELISA, respectively. The proliferation of epithelial cells and lung fibroblasts were examined using flow cytometry. The epithelial­mesenchymal transition (EMT) was also examined by performing western blot and RT­qPCR analyses. The results of the cDNA assay showed that infection with RSV resulted in the abnormal expression of certain metalloproteinases. Among these, the expression of MMP­19 decreased 3 and 7 days following infection. By using flow cytometric, western blot and RT­qPCR analyses, the present study demonstrated that the downregulation of MMP­19 inhibited the proliferation of epithelial cells, promoted the EMT and induced the proliferation of lung fibroblasts. Taken together, the findings of the present study suggested that the downregulation of MMP­19 following RSV infection may be associated with the development of airway hyper­responsiveness.