[Analysis of the efficacy of high tibial osteotomy combined with medial meniscus centralization in knee osteoarthritis].

OBJECTIVE: To explore the efficacy of high tibial osteotomy （HTO） combined with medial meniscus centralization in knee osteoarthritis. METHODS: A total of 26 patients who underwent surgery from October 2018 to October 2020 were reviewed. Among them, 14 patients underwent high tibial osteotomy combined with arthroscopic meniscus centralization surgery were centralized group, including 8 males and 6 females, with an average age of （50.2±1.4） years old and follow-up time of （16.8±4.0） months. Twelve patients with high tibial osteotomy were in the control group, including 6 males and 6 females, with an average age of （50.9±1.8） years and follow-up time of （19.0±4.8） months. Operation time, the knee Lysholm score, knee 2000 IKDC score, MRI, femoral tibial angle（FTA）, hip knee ankle angle （HKA）, and intraoperative and postoperative complications were recorded. RESULTS: All the incisions healed without any complication. The operation time in the centralized group was longer than that in the control group[（65.0±2.1）min vs（52.0±2.1）min, P<0.05]. The medial meniscus extrusion reduction value in the centralized group was significantly reduced compared with the control group[（2.8±1.4） mm vs （1.1±2.2） mm, P<0.05]. The FTA, HKA, knee Lyshlom score, and 2000 IKDC score between two groups were no significantly （P>0.05）. Postoperative knee Lyshlom score and knee 2000 IKDC score improved in both groups（P<0.05）. CONCLUSION: HTO combined with centralization of medial meniscus can improve the reduction of medial meniscus and improve knee function. The medium and long-term curative effect still needs long-term follow-up of more cases.

Real-world tobacco cessation practice in China: findings from the prospective, nationwide multicenter China National Tobacco Cessation Cohort Study (CNTCCS).

Background: Tobacco cessation is proven to be the most effective and cost-effective strategy for smokers to reduce their risk of smoking-related disease and premature death. Providing effective, efficient, safe, and patient-centred tobacco cessation treatment to reach those who need them is a significant challenge. To date, only a few nationwide studies in China have assessed the overall clinical care practice and treatment outcome of tobacco cessation. Methods: This a prospective, nationwide, multicenter, cohort study covering all Eastern China, Northwest China, Central China, North China, Southwest China, Northeast China, and South China. Participants who were current smokers aged 18-85 years attending clinic for smoking cessation were included. All the participants were treated with 3-month cessation treatment and followed up for 3 months. Data were collected prospectively using online system. The primary outcome was 7-day point abstinence rate at 24 weeks, validated biochemically by an expired carbon monoxide level of less than 10 ppm. The participants lost to follow-up or not providing validation were included as non-abstainers. Findings: A representative sample of 3557 participants were recruited and 2943 participants were included into this analysis. These participants had mean age of 53.05 years, and 94.8% were males, with 75.8% showing symptoms of tobacco dependence. A total of 965 (32.8%) participants were treated with Bupropion + behavioural counselling, followed by 935 (31.8%) with behavioural counselling, 778 (26.4%) with Varenicline + behavioural counselling, 135 (4.6%) with alternative treatments + behavioural counselling, and 130 (4.4%) with nicotine replacement therapy (NRT) + behavioural counselling. After 3-month treatment and 3-month follow-up, 21.74% of the participants quit smoking at 24 weeks. In the multivariable-adjusted analyses, quitting smoking was significantly associated with female, higher socioeconomic status, poor health condition, different treatment received, and less smoking intensity. The tobacco cessation treatment varied widely across different areas of China. In particular, the areas with higher usage of cessation medication were associated with better cessation treatment outcome. Interpretation: The CNTCCS is the first large-scale nationwide cohort study of smoking cessation in China. Rich data collected from this prospective cohort study provided the opportunity to evaluate the clinical practice of tobacco cessation treatment in China. Funding: Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (CAMS 2021-I2M-1-010), Heilongjiang Provincial Science and Technology Key Program (2022ZXJ03C02), and National Key R&D Program of China (grant no. 2017YFC1309400).

The Role of MMP-9 in Regulating Degradation of the Splenic Microvascular Basement Membrane Induced by High Altitude Hypoxia / Rol de la MMP-9 en la Regulación de la Degradación de la Membrana Basal Microvascular Esplénica Inducida por Hipoxia de Altura

SUMMARY: To investigate changes of MMP-9 in the rat spleen and hypoxia-induced microvascular basement membrane under high altitude hypoxia. Thirty male specific pathogen-free Sprague Dawley rats were randomly divided into control and hypoxia groups, with 15 rats in each group. The rats in the control group were placed in Dingxi City, Gansu Province (2080 m above sea level) for 30 days. Rats in the hypoxia group were raised in a hypoxic environment in Maduo County, Qinghai Province (4300 m above sea level), for 30 days to establish a hypoxic rat model. Routine blood tests, MMP-9 mRNA, MMP-9 protein, and the spleen microvascular basement membrane were detected. (1) Compared with the control group, the red blood cell count, hemoglobin, and hematocrit levels of the rats in the hypoxia group were all increased; thus, a hypoxia model was successfully established. (2) Compared with the control group, the expression of MMP-9 mRNA and protein was significantly higher in the spleen of rats in the hypoxic group, and the difference was statistically significant (P <0.05). (3) Compared with the control group, the blood vessel basement membrane in the spleen of the hypoxia group was degraded. Under natural low air pressure and high altitude conditions, the expression of MMP-9 in rat spleen tissue increases and participates in the degradation of the microvascular basement membrane.

El objetivo de este trabajo fue investigar los cambios de la MMP-9 en el bazo de la rata y la membrana basal microvascular inducida bajo hipoxia a gran altura. Treinta ratas macho Sprague Dawley, libres de patógenos específicos, se dividieron aleatoriamente en dos grupos de 15 ratas cada uno, un grupo control y un grupo hipoxia. Durante 30 días las ratas del grupo control estuvieron en la ciudad de Dingxi, provincia de Gansu (2080 m sobre el nivel del mar). Las ratas del grupo de hipoxia se criaron en un entorno hipóxico en el condado de Maduo, provincia de Qinghai (4300 m sobre el nivel del mar), durante 30 días para establecer un modelo de rata hipóxica. Se realizaron análisis de sangre de rutina, ARNm de MMP-9, proteína MMP-9 y de la membrana basal microvascular del bazo. En comparación con el grupo control, el recuento de glóbulos rojos, la hemoglobina y los niveles de hematocrito de las ratas del grupo de hipoxia aumentaron; por lo tanto, se estableció con éxito un modelo de hipoxia. En comparación con el grupo control, la expresión de ARNm y proteína de MMP-9 fue significativamente mayor en el bazo de las ratas del grupo hipóxico, siendo la diferencia estadísticamente significativa (P <0,05). En comparación con el grupo control, la membrana basal de los vasos sanguíneos estaba degradada en el bazo del grupo hipoxia. En condiciones naturales de baja presión atmosférica y gran altitud, la expresión de MMP-9 en el tejido del bazo de la rata aumenta y participa en la degradación de la membrana basal microvascular.

Mutation and Expression of Gene YY1 in Pancreatic Neuroendocrine Tumors and Its Clinical Significance.

OBJECTIVE: The clinical significance of the YY1 gene mutation and expression in pancreatic neuroendocrine tumors (PNETs) remains unknown. Therefore, this study aimed to comprehensively analyze the somatic mutation of YY1 in the different subtypes of PNETs. METHODS: A total of 143 PNETs were assessed by Sanger sequencing to identify the somatic mutation of YY1 gene in various subtypes of PNETs. YY1 protein expression was examined in 103 PNETs by immunohistochemical staining and western blot. Gene mutation and its protein expression were correlated with clinicopathologic features. RESULTS: A recurrent mutation (chr14:100743807C>G) in the YY1 gene was identified in 15 of 83 insulinomas (18%) and in only 1 of 60 noninsulinoma PNETs (1.7%) (P = .0045). The YY1 mutation was not found in MEN1-associated insulinomas. The YY1 mutation in insulinomas was correlated with older age and lower serum glucose levels (age, 57 vs 42.5 years, P = .006; blood glucose, 25.2 vs 33.6 mg/dL, P = .008). YY1 protein expression was found in 100 of 103 PNETs, although expression was weaker in metastases than in localized tumors (P = .036). The stronger expression of YY1 protein was associated with favorable disease-free survival of patients with PNETs (log-rank, P = .011; n = 70). Multivariable statistical analysis showed that YY1 protein expression could be an independent predictor of prognosis. CONCLUSION: The hotspot YY1 mutation mostly occurred in insulinomas and rarely in noninsulinoma PNETs. The stronger YY1 protein expression was correlated with the better prognosis of PNETs patients.

Sonochemical synthesis and characterization of four nanostructural nickel coordination polymers and photocatalytic degradation of methylene blue.

Four nanostructural nickel(II) coordination polymers {[Ni(ttpa)(1,4-ndc)(H2O)2]·2H2O}n (1), {[Ni(ttpa)(1,3-bda)]·2H2O·DMF}n (2·2H2O·DMF), {[Ni(ttpa)(1,4-bdc)]·H2O}n (3) and {[Ni(ttpa)(aip)(H2O)]·3H2O}n (4·3H2O) were synthesized using hydrothermal and sonochemical methods (ttpa = tris(4-(1,2,4-triazol-1-yl)phenyl)amine, 1,4-ndc = 1,4-naphthalenedicarboxylate, 1,3-bda = 1,3-benzenediacetate, 1,4-bdc = 1,4-benzenedicarboxylate, aip = 5-aminoisophthalate), and characterized by elemental analysis, IR spectra, scanning electron microscopy, single-crystal and powder X-ray diffraction analysis, optical band gaps, VB XPS spectra and luminescence. The effects of sonication power, time and frequency on the size and morphology of nano-sized 1-4 have been studied. 1 exhibits an unusual 2D + 2D → 3D inclined polycatenated motif based on the (3,3)-coordinated 63-hcb topology. 2 shows a (3,4)-coordinated 2D network of the bey topology. 3 presents a rare example of the 4-fold interpenetrating array of (3,5)-coordinated 3D network belonging to the 35T1 topology type. 4 displays an unusual 2D → 3D polythreaded network based on 2D sql networks. 1-4 exhibit luminescent emissions at 409, 399, 413 and 402 nm, respectively. 1-4 are semiconducting in nature, with Eg of 2.12 eV (1), 2.34 eV (2), 2.32 eV (3), and 2.47 eV (4). 1-4 are good catalysts for the degradation of MB under visible light irradiation. The effects of the size and morphology of nano-sized 1-4 on the photocatalytic efficiencies were studied. The higher sonication frequency obtains uniform and smaller nano-sized coordination polymers which have higher catalytic efficiencies.

[Community structure of Chironomid larvae and their indicative significance for water quality in streams of Xianju National Park, China]. / ä»™å± å›½å®¶å ¬å›­æºªæµæ‘‡èšŠå¹¼è™«ç¾¤è½ç»“æž„åŠå ¶å¯¹æ°´è´¨çš„æŒ‡ç¤ºä½œç”¨.

In August 2016, 59 sites of 13 streams in Xianju National Park were surveyed to explore the community structure of Chironomid larvae and their indicative significance for water quality. Water quality of the streams was evaluated based on Hilsenhoff biological index. The results showed that there were 37 clean sites, 19 mild polluted sites and three moderated polluted sites in Xianju National Park. We identified a total of 86 species of Chironomid larvae, belonging to 51 genera and four subfamilies, including 37 species in 19 genera of Chironominae; 35 species in 21 genera of Orthcladiinae; 12 species in 9 genera of Tanypodinae, two species in two genera of Diamesinae. Chironominae accounted for 40.3% of Chironomid larval density. Tanypodinae and Orthcladiinae were almost similar in Chironomid larval density, respectively accounted for 30% and 29.4% of the total. Diamesinae accounted for 0.3% of total Chironomid larval density. Conchapelopia sp. was the overwhelming dominant species and Polypedilum flavum, Rheocricotopus sp., Cricotupus vierriensis, Rheotanytarsus muscicola and Corynoneura carriana were the dominant species of Chironomid larvae. The result of indicator species analysis showed that Cricotupus vierriensis, Nanocladius dichromus, Tanytarsus formosanus, Tanytarsus mendex were indicator species of moderated pollution water, and that Rheocricotopus sp. was the indicator species of clean state water.

Robot-assisted percutaneous screw placement combined with pelvic internal fixator for minimally invasive treatment of unstable pelvic ring fractures.

PURPOSE: The purpose of this study was to investigate the safety and efficacy of the combination of robot-assisted percutaneous screw placement and pelvic internal fixator (INFIX) for minimally invasive treatment of unstable anterior and posterior pelvic ring injuries. METHODS: From September 2016 to June 2017, twenty-four patients with unstable anterior and posterior pelvic ring injuries were treated with TiRobot-assisted percutaneous sacroiliac cannulated screw fixation on the posterior pelvic ring combined with robot-assisted pedicle screw placement in the anterior inferior iliac spine along with INFIX on the anterior pelvic ring. The results of the treatment, including surgery duration, fluoroscopy frequency, total drilling, amount of blood loss, fracture healing time, and postoperative functional outcomes were recorded and compared with another 21 similar patients who underwent conventional manual positioning surgery. RESULTS: The TiRobot group incurred significantly shorter duration of surgery; less fluoroscopy frequency, intraoperative bleeding, and total drilling than in the conventional group (P < 0.05). Postoperative radiological follow-up showed that all screws were in the safe area and no screw penetrated the cortex. All wounds healed by primary intention and no iatrogenic damage to the blood vessels, nerves, and organs occurred. Patients showed good tolerance to INFIX and reported no discomfort. The mean follow-up duration was 5.4 months; the fractures were all healed, no loss of reduction occurred, and the mean Majeed score at the last follow-up did not show any difference. CONCLUSION: TiRobot-assisted percutaneous screw placement combined with INFIX for the anterior and posterior pelvic ring injuries is accurate, safe, less invasive, and shows satisfactory efficacy, suggesting it is a better method for minimally invasive treatment of unstable pelvic ring fractures.

Predictors of healthcare-seeking behavior among Chinese patients with irritable bowel syndrome.

AIM: To analyze predictors of healthcare-seeking behavior among Chinese patients with irritable bowel syndrome (IBS) and their satisfaction with medical care. METHODS: Participating patients met IBS Rome III criteria (excluding those with organic diseases) and were enrolled in an IBS database in a tertiary university hospital. Participants completed IBS questionnaires in face-to-face interviews. The questionnaires covered intestinal and extra-intestinal symptoms, medical consultations, colonoscopy, medications, and self-reported response to medications during the whole disease course and in the past year. Univariate associations and multivariate logistic regression were used to identify predictors for frequent healthcare-seeking behavior (≥ 3 times/year), frequent colonoscopies (≥ 2 times/year), long-term medications, and poor satisfaction with medical care. RESULTS: In total, 516 patients (293 males, 223 females) were included. Participants' average age was 43.2 ± 11.8 years. Before study enrollment, 55.2% had received medical consultations for IBS symptoms. Ordinary abdominal pain/discomfort (non-defecation) was an independent predictor for healthcare-seeking behavior (OR = 2.07, 95%CI: 1.31-3.27). Frequent colonoscopies were reported by 14.7% of patients (3.1 ± 1.4 times per year). Sensation of incomplete evacuation was an independent predictor for frequent colonoscopies (OR = 2.76, 95%CI: 1.35-5.67). During the whole disease course, 89% of patients took medications for IBS symptoms, and 14.7% reported they were satisfied with medical care. Patients with anxiety were more likely to report dissatisfaction with medical care (OR = 2.08, 95%CI: 1.20-3.59). In the past year, patients with severe (OR = 1.74, 95%CI: 1.06-2.82) and persistent (OR = 1.66, 95%CI: 1.01-2.72) IBS symptoms sought medical care more frequently. CONCLUSION: Chinese patients with IBS present high rates of frequent healthcare-seeking behavior, colonoscopies, and medications, and low satisfaction with medical care. Intestinal symptoms are major predictors for healthcare-seeking behavior.

Differences and Similarities in the Clinicopathological Features of Pancreatic Neuroendocrine Tumors in China and the United States: A Multicenter Study.

The presentation, pathology, and prognosis of pancreatic neuroendocrine tumors (PNETs) in Asian patients have not been studied in large cohorts. We hypothesized that the clinicopathological features of PNETs of Chinese patients might be different from those of US patients. The objectives of this study were to address whether PNETs in Chinese patients exhibit unique clinicopathological features and natural history, and can be graded and staged using the WHO/ENETS criteria. This is a retrospective review of medical records of patients with PNETs in multiple academic medical centers in China (7) and the United States (2). Tumor grading and staging were based on WHO/ENETS criteria. The clinicopathological features of PNETs of Chinese and US patients were compared. Univariate and multivariate analyses were performed to find associations between survival and patient demographics, tumor grade and stage, and other clinicopathological characteristics. A total of 977 (527 Chinese and 450 US) patients with PNETs were studied. In general, Chinese patients were younger than US patients (median age 46 vs 56 years). In Chinese patients, insulinomas were the most common (52.2%), followed by nonfunctional tumors (39.7%), whereas the order was reversed in US patients. Tumor grade distribution was similar in the 2 countries (G1: 57.5% vs 55.0%; G2: 38.5% vs 41.3%; and G3: 4.0% vs 3.7%). However, age, primary tumor size, primary tumor location, grade, and stage of subtypes of PNETs were significantly different between the 2 countries. The Chinese nonfunctional tumors were significantly larger than US ones (median size 4 vs 3 cm) and more frequently located in the head/neck region (54.9% vs 34.8%). The Chinese and US insulinomas were similar in size (median 1.5 cm) but the Chinese insulinomas relatively more frequently located in the head/neck region (48.3% vs 26.1%). Higher grade, advanced stage, metastasis, and larger primary tumor size were significantly associated with unfavorable survival in both countries. Several clinicopathological differences are found between Chinese and US PNETs but the PNETs of both countries follow a similar natural history. The WHO tumor grading and ENETS staging criteria are applicable to both Chinese and US patients.

TMPRSS4 promotes invasiveness of human gastric cancer cells through activation of NF-κB/MMP-9 signaling.

Transmembrane protease serine 4 (TMPRSS4) is a type-II transmembrane serine protease that is frequently upregulated in human cancers. However, little is known about the biological roles of TMPRSS4 in gastric cancer. In this study, we examined the effect of TMPRSS4 on gastric cancer cell proliferation, migration, and invasion. The expression and secretion of matrix metalloproteinase-9 (MMP-9) and activation of nuclear factor-κB (NF-κB) were determined. The involvement of NF-κB/MMP-9 signaling was checked. Our data showed that TMPRSS4 silencing significantly (P<0.05) reduced the migration and invasion of AGS and MKN-45 gastric cancer cells, without affecting cell proliferation. Overexpression of TMPRSS4 significantly promoted cell migration and invasion. The expression and secretion of MMP-9 was significantly (P<0.05) enhanced in TMPRSS4-overexpressing cells. TMPRSS4-overexpressing cells had a significantly (P<0.05) lower level of IκBα and higher level of nuclear NF-κB. Luciferase reporter assay confirmed that overexpression of TMPRSS4 resulted in a 3-5-fold increase in NF-κB-dependent luciferase activity. Downregulation of MMP-9 significantly (P<0.05) reversed the invasiveness of gastric cancer cells induced by TMPRSS4 overexpression. Moreover, pharmacological inhibition of NF-κB attenuated the invasion of TMPRSS4-overexpressing cells and the expression of MMP-9. Upregulation of TMPRSS4 enhances the invasiveness of gastric cancer cells, largely through activation of NF-κB and induction of MMP-9 expression. Our study provides the rationale for targeting TMPRSS4 in the treatment of gastric cancer.

Efficacy and safety of bevacizumab in Chinese patients with metastatic colorectal cancer.

OBJECTIVE: To evaluate the efficacy and safety of bevacizumab in the treatment of patients with metastatic colorectal cancer (mCRC). METHODS: In a single-center, observational study of 91 Chinese patients with mCRC who received bevacizumab in combination with chemotherapy was conducted. OBJECTIVE response rates (ORRs), progression-free survival (PFS), overall survival (OS) and adverse events were recorded, and the relationships between various clinical factors and PFS or OS were evaluated by Cox proportional hazards models. RESULTS: Treatment with bevacizumab and chemotherapy was effective and tolerable. Univariate analysis showed that PFS and OS were significantly associated with the Eastern Cooperative Oncology Group performance status (ECOG- PS) score, duration of bevacizumab exposure, and whether chemotherapy was continued after discontinuation of bevacizumab treatment. A multivariate analysis showed that the duration of bevacizumab exposure and whether chemotherapy was continued after discontinuation of bevacizumab were independent prognostic factors for PFS and OS. CONCLUSION: In Chinese mCRC population, the shorter the duration of exposure to bevacizumab and chemotherapy, the worse the prognosis is.

Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma.

X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tissues than that in paired non-cancer liver tissues. Adenovirus-mediated XAF1 expression (Ad5/F35-XAF1) significantly inhibited cell proliferation and induced apoptosis in HCC cells in dose- and time- dependent manners. Infection of Ad5/F35-XAF1 induced cleavage of caspase -3, -8, -9 and PARP in HCC cells. Furthermore, Ad5/F35-XAF1 treatment significantly suppressed tumor growth in a xenograft model of liver cancer cells. Western Blot and immunohistochemistry staining showed that Ad5/F35-XAF1 treatment suppressed expression of vascular endothelial growth factor (VEGF), which is associated with tumor angiogenesis, in cancer cells and xenograft tumor tissues. Moreover, Ad5/F35-XAF1 treatment prolonged the survival of tumor-bearing mice. Our results demonstrate that XAF1 inhibits tumor growth by inducing apoptosis and inhibiting tumor angiogenesis. XAF1 may be a promising target for liver cancer treatment.

[Sublingual gland amyloidosis causing obstructive sleep apnea hypopnea syndrome: a case report and review of the literatures].

OBJECTIVE: To improve the understanding of sublingual gland amyloidosis causing obstructive sleep apnea hypopnea syndrome(OSAHS). METHODS: A case of sublingual gland amyloidosis causing OSAHS diagnosed in april 2012 was reported and the related literatures were reviewed. The literature review was carried out respectively with "amyloidosis, sublingual gland, obstructive sleep apnea hypopnea syndrome", as the search terms in Wanfang Data and PubMed by November 2012. RESULTS: A case of 74 year-old male patient was admitted to the hospital because of snoring for 5 years, sleep apnea for 1 year and arousal for 1 month. After admission, polysomnography showed severe OSAHS, physical examination showed redundant the sublingual gland. Enhanced CT scanning showed soft tissue masses at the sublingual gland. Abdominal B ultrasonic and CT also showed a spaces-occupying lesion in the left retroperitoneal. B-guided core needle biopsy was performed in the left retroperitoneal. Pathology report showed amyloidosis. Subsequently, sublingual gland mass resection was performed. Pathology report after operation showed amyloid deposits staining with Congo red, which gives it a characteristic green birefringence in polarised light. Accordingly, it was diagnosed as sublingual gland amyloidosis. The symptoms of snore and sleep apnea were disappeared after operation.So far, there was no local recurrence with 10 months follow-up. A total of 3 literatures were received in Wanfang Data, including 2 of macroglossia amyloidosis causeing OSAHS case report and one of retrospective study. There were no reports about sublingual gland amyloidosis in Wanfang Data. A total of 5 literatures were received in Pubmed, including 2 of sublingual gland amyloidosis case report, 2 of macroglossia amyloidosis causeing OSAHS case report and one of retrospective study. However, there were no reports about sublingual gland amyloidosis causing OSAHS. CONCLUSIONS: Amyloidosis rarely occurred in the sublingual gland and is easy to be misdiagnosed and missed diagnosed, which can causing severe OSAHS. To make a definite diagnosis, histopathology and staining with Congo red are needed and a characteristic green birefringence in polarised light is a reliable marker for diagnosis. After sublingual gland mass resection, the patient had good prognosis.

[The expression and possible role of SENP1 in the pulmonary vascular wall of rat during the development of hypoxic pulmonary hypertension].

OBJECTIVE: To investigate the dynamic expression and role of SENP1 (SUMO-specific proteases-1) in the pulmonary vascular wall of rat during the development of hypoxic pulmonary hypertension (HPH). METHODS: Forty adult male Wistar rats were randomly divided into 5 groups (n = 8), and exposed to normoxia (Control group) or exposed to hypoxia for 3, 7, 14 or 21 d, respectively. The HPH models were established by normobaric intermittent hypoxia. Mean pulmonary arterial pressure (mPAP), right ventricle hypertrophy index (RVHI), and vessel morphometry were measured. Reverse transcriptase-polymerase chain reaction(RT-PCR) and in situ hybridization were used to determine the mRNA expression of SENP1. Immunohistochemistry and Western blot were used to determine the protein expression of SENP1. RESULTS: The hypoxic rats developed pulmonary vascular remodeling in pulmonary arterioles after 7 d of hypoxia exposure. Pulmonary vascular remodeling in pulmonary arterioles significantly increased after 14 d of hypoxia. The level of mPAP in hypoxic rats increased significantly after 7 d of hypoxia, reached its peak after 14 d of hypoxic exposure. RVHI was markedly increased after 14 d of hypoxia. In situ hybridization and immunohistochemical analysis showed that SENP1 mRNA and protein were positively stained in control. SENP1 mRNA expression had little changes after exposure to hypoxia compared with the control, however, SENP1 protein expression was declined gradually after 7 d of hypoxia. The results of RT-PCR and Western blot showed that the same dynamic expression of SENP1 mRNA and protein in lung tissues of rats. Linear correlation analysis showed that SENP1 protein were negatively correlated with mPAP, pulmonary vascular remodeling index and RVHI. CONCLUSION: Under chronic hypoxia, SENP1 protein can be degradated. The dynamic expression of SENP1 protein may play a role in implicating in the development of HPH.

[The effect of transcription factor KLF2 in expression of gamma-GCS depend on regulation by Nrf2 in lung of rats with chronic obstructive pulmonary disease].

OBJECTIVE: To study the expression of lung Krüppel-like transcription factor (KLF2/LKLF) in lung tissues of rats with chronic obstructive pulmonary disease (COPD) and the relationship between KLF2 and NF-E2-related factor 2 (Nrf2), and make further explore the effects of KLF2 on the expression of gamma-glutamylcysteine synthetase (gamma-GCS). METHODS: Twenty-two male SD rats were randomly divided into a COPD group (n = 10) and a normal control group (n = 11). The rat model of COPD established by cigarette smoking and intratracheal instillation of lipopolysaccharide (LPS), and lung tissues were obtained. The expressions of KLF2, Nrf2, gamma-GCS mRNA and protein in lung tissues were measured by immunohistochemistry (IHC), Western blot, in situ hybridization (ISH) and reverse transcription-polymerase chain reaction (RT-PCR). To explore the relationship between KLF2 and Nrf2 protein,we utilize the method of co-immunoprecipitation (CO-IP). RESULTS: IHC and Western blot showed that protein expressions of KLF2, Nrf2, gamma-GCS were higher in the lung tissues from rats with COPD than those in the control groups (all P < 0.05). The levels of KLF2, gamma-GCS mRNA were markedly increased in the COPD group (all P < 0.01) while Nrf2 mRNA expression in COPD group had no significant difference with that in control group ( P > 0.05). CO-IP result showed that KLF2 were obviously present in immunoprecipitates of Nrf2 (P < 0.01) . Linear correlation analysis showed that the level of KLF2 protein was positively correlated with the level of Nrf2 protein (P < 0.05), and KLF2, Nrf2 proteins were positively correlated with gamma-GCS mRNA and protein (all P < 0.05). CONCLUSION: The expression of KLF2 is significantly up-regulated in COPD, which maybe up-regulate gamma-GCS mRNA expression by increasing Nrf2 expression and nuclear translocation against oxidative stress.

Developments in metastatic pancreatic cancer: is gemcitabine still the standard?

In the past 15 years, we have seen few therapeutic advances for patients with pancreatic cancer, which is the fourth leading cause of cancer-related death in the United States. Currently, only about 6% of patients with advanced disease respond to standard gemcitabine therapy, and median survival is only about 6 mo. Moreover, phase III trials have shown that adding various cytotoxic and targeted chemotherapeutic agents to gemcitabine has failed to improve overall survival, except in cases in which gemcitabine combined with erlotinib show minimal survival benefit. Several meta-analyses have shown that the combination of gemcitabine with either a platinum analog or capecitabine may lead to clinically relevant survival prolongation, especially for patients with good performance status. Meanwhile, many studies have focused on the pharmacokinetic modulation of gemcitabine by fixed-dose administration, and metabolic or transport enzymes related to the response and toxicity of gemcitabine. Strikingly, a phase III trial in 2010 showed that, in comparison to gemcitabine alone, the FOLFIRINOX regimen in patients with advanced disease and good performance status, produced better median overall survival, median progression-free survival, and objective response rates. This regimen also resulted in greater, albeit manageable toxicity.

Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth.

Myeloid-derived suppressor cells (MDSC) accumulate in the spleen and tumors and contribute to tumor growth, angiogenesis, and progression. In this study, we examined the effects of curcumin on the activation and differentiation of MDSCs, their interaction with human cancer cells, and related tumor growth. Treatment with curcumin in the diet or by intraperitoneal injection significantly inhibited tumorigenicity and tumor growth, decreased the percentages of MDSCs in the spleen, blood, and tumor tissues, reduced interleukin (IL)-6 levels in the serum and tumor tissues in a human gastric cancer xenograft model and a mouse colon cancer allograft model. Curcumin treatment significantly inhibited cell proliferation and colony formation of cancer cells and decreased the secretion of murine IL-6 by MDSCs in a coculture system. Curcumin treatment inhibited the expansion of MDSCs, the activation of Stat3 and NF-κB in MDSCs, and the secretion of IL-6 by MDSCs, when MDSCs were cultured in the presence of IL-1ß, or with cancer cell- or myofibroblast-conditioned medium. Furthermore, curcumin treatment polarized MDSCs toward a M1-like phenotype with an increased expression of CCR7 and decreased expression of dectin 1 in vivo and in vitro. Our results show that curcumin inhibits the accumulation of MDSCs and their interaction with cancer cells and induces the differentiation of MDSCs. The induction of MDSC differentiation and inhibition of the interaction of MDSCs with cancer cells are potential strategies for cancer prevention and therapy.

Inhibition of matrine against gastric cancer cell line MNK45 growth and its anti-tumor mechanism.

Anti-tumor activity and mechanism of matrine is evaluated and investigated. MTT assay showed that the matrine was able to inhibit gastric cancer cell line MNK45 in a dose-dependent manner. The concentration required for 50% inhibition (IC50) was found to be 540 µg/ml. This anti-tumor function was achieved through modulation of the NF-κB, XIAP, CIAP, and p-ERK proteins expression in cell line MNK45. By western blot analysis, we found that expression of NF-κB, XIAP, CIAP, and p-ERK proteins in cell line MNK45 would vary with varying concentration of matrine. These protein interactions possibly play a pivotal role in the regulation of apoptosis, for which further detailed analyzes are need. These results overall indicate that matrine can be used as an effective anti-tumor agent in therapy of gastric cancer.

[The roles of PPAR-gamma/PGC-1alpha to Nrf2/gamma-GCS-h in lung of guinea pigs with bronchial asthma].

OBJECTIVE: To investigate the expressions of PPAR-gamma/PGC-1alpha and Nrf2/gamma-GCS-h in lung of guinea pigs with bronchial asthma, and to explore the roles of them. METHODS: Forty adult male guinea pigs were randomly divided into 4 groups: the control group (group A), asthmatic group ( group B), dexamethasone group (group C) and rogridone group (group D), 10 guinea pigs in each group. The asthmatic model was established by the ovalbumin challenge method. Expressions of PPAR-gamma/PGC-1alpha and Nrf2/gamma-GCS-h mRNA in lung tissue were assayed by in situ hybridization. Expressions of PPAR-gamma/PGC-1alpha and Nrf2/gamma-GCS-h protein were detected by immunohischemistry and by Western blot. RESULTS: In situ hybridization showed that the expressions of PPAR-gamma/PGC-1alpha and Nrf2/gamma-GCS-h mRNA in lung tissue were the lowest in group B and the comparison among groups showed statistical significant (all P < 0.01). Immunohistochemistry and Western blot indicated that the value of PPAR-gamma/PGC-1alpha and Nrf2/gamma-GCS-h protein in lung tissue were the lowest in group B, and expressed primarily in nucleus, the differences being statistically significant (all P < 0.01). There was positive correlation between PPAR-gamma and PGC-1. gamma-GCS-h mRNA also positively correlated between PPAR-gamma/PGC-1alpha and Nrf2 in nucleus, and the expression of Nrf2 was also positively correlated with PPAR-gamma/ PGC-1alpha. CONCLUSION: In acute asthmatic models induced by ovalbumin, the expressions of PPAR-alpha/PGC-1alpha and Nrf2/gamma-GCS-h were decreased, and PPARgamma/PGC-1alpha could up-regulate the expressions of Nrf2/gamma-GCS-h to increase the antioxidant defense of tissues, thus being implicated that PPARgamma/PGC-1alpha might play important roles in the pathogenesis and prevention of asthma.

The XAF1 tumor suppressor induces autophagic cell death via upregulation of Beclin-1 and inhibition of Akt pathway.

Autophagy is designated as type II programmed cell death and may confer a tumor-suppressive function. Our previous studies have shown that XIAP-associated factor 1 (XAF1) induced apoptosis and inhibited tumor growth in gastric cancer cells. In this study, we investigated the effect of XAF1 on the induction of autophagy in gastric cancer cells. We found that adenovirus vector-mediated XAF1 (adeno-XAF1) expression markedly induced autophagy, upregulated the level of Beclin-1 and inhibited phospho-Akt and phospho-p70S6K in gastric cancer cells. The downregulation of Beclin 1 or 3-methyladenine treatment suppressed adeno-XAF1-induced autophagy, but significantly enhanced adeno-XAF1-induced apoptosis. A pan-caspase inhibitor prevented adeno-XAF1-induced apoptosis, but significantly increased adeno-XAF1-induced autophagy. Furthermore, adeno-XAF1 induced autophagy in xenograft tumor and inhibited tumor growth. Our results document that adeno-XAF1 induces autophagy through upregulation of Beclin 1 expression and inhibition of Akt/p70S6K pathway, and reveal a new mechanism of XAF1 tumor suppression.