[Evaluation of safety and clinical efficacy of bilateral percutaneous kyphoplasty in treatment of osteoporotic thoraco-lumbar burst fractures].

Objective: To evaluate the safety and clinical efficacy of bilateral percutaneous kyphoplasty (PKP) in the treatment of osteoporotic vertebral burst fractures. Methods: It was a prospective study, 28 patients with osteoporotic thoraco-lumbar burst fractures who were treated in Beijing Chao-Yang Hospital from January 2021 to July 2021 were included, including 10 males and 18 females, with a median age of 73.6 years (range: 56.0-87.0 years). The X-ray radiographs, bone mineral density (BMD), CT three-dimensional reconstruction scan and MRI were taken and measured before operation to observe the fracture location and the posterior wall of the vertebral body, and further to determine the diagnosis. The X-ray radiographs and CT three-dimensional reconstruction scans were taken on the first day after operation and the last follow-up to observe whether there were bone cement leakage or not. The changes of kyphosis angle (KA), the height of anterior wall (HAW) and the height of posterior wall (HPW) before the operation, on the 1st day post operation and at the last follow-up were recorded. The visual analogue scale (VAS) of back pain and Oswestry dysfunction index (ODI) before the operation, 1 day post operation and at the last follow-up were used to evaluate the clinical effect of the operation. Results: All the patients were followed up for (12.2±6.0) months. The HAW on the 1st day post operation [(22.5±2.0) mm] was significantly increased as compared with that before the operation [(21.2±2.4) mm] (P<0.05). The HAW at the last follow-up [(18.9±1.6) mm] decreased signficantly as compared with that on the 1st day post opertion [(22.5±2.0) mm] (P<0.05). The HPW was also significantly corrected after surgery (P<0.05). At the end of the follow-up, the HPW [(27.2±1.3) mm] was comparable with that on the 1st day after surgery [(27.5±1.6) mm] (P>0.05). The KA on the 1st day after the operation (14.2°±1.5°) decreased significantly when compared with that before the operation (18.8°±1.3°) (P<0.05), but it was increased to 17.6°±1.4° at the last follow-up and was higher than that on the 1st day after the operation (P<0.05). There were bone cement leakage in 5 cases and adjacent vertebral fracture in 1 case. The VAS and ODI scores were all significantly lower on the 1st day and at last follow-up than that before the operation (all P<0.05). Conclusions: Bilateral PKP is effective, safe and reliable in the treatment of osteoporotic vertebral burst fracture. Careful evaluation of preoperative imaging data, accurate puncture and timing of bone cement injection are the key factors to ensure the success of the operation.

[Diagnosis and treatment status of perioperative anemia in patients with gastrointestinal neoplasms: a multi-center study in Hubei Province].

Objective: To investigate the incidence and treatment of perioperative anemia in patients with gastrointestinal neoplasms in Hubei Province. Methods: The clinicopathological data of 7 474 patients with gastrointestinal neoplasms in 62 hospitals in 15 cities (state) of Hubei Province in 2019 were collected in the form of network database. There were 4 749 males and 2 725 females. The median age of the patients was 62 years (range: 17 to 96 years). The hemoglobin value of the first time in hospital and the first day after operation was used as the criterion of preoperative anemia and postoperative anemia. Anemia was defined as male hemoglobin <120 g/L and female hemoglobin <110.0 g/L, mild anemia as 90 to normal, moderate anemia as 60 to <90 g/L, severe anemia as <60 g/L. The t test and χ2 test were used for inter-group comparison. Results: The overall incidence of preoperative anemia was 38.60%(2 885/7 474), and the incidences of mild anemia, moderate anemia and severe anemia were 25.09%(1 875/7 474), 11.37%(850/7 474) and 2.14%(160/7 474), respectively. The overall incidence of postoperative anemia was 61.40%(4 589/7 474). The incidence of mild anemia, moderate anemia and severe anemia were 48.73%(3 642/7 474), 12.20%(912/7 474) and 0.47%(35/7 474), respectively. The proportion of preoperative anemia patients receiving treatment was 26.86% (775/2 885), and the proportion of postoperative anemia patients receiving treatment was 14.93% (685/4 589). The proportions of preoperative anemia patients in grade ⅢA, grade ⅢB, and grade ⅡA hospitals receiving treatment were 26.12% (649/2 485), 32.32% (85/263), and 29.93% (41/137), and the proportions of postoperative anemia patients receiving treatment were 14.61% (592/4 052), 22.05% (73/331), and 9.71% (20/206). The proportion of intraoperative blood transfusion (16.74% (483/2 885) vs. 3.05% (140/4 589), χ²=434.555, P<0.01) and the incidence of postoperative complications (17.78% (513/2 885) vs. 14.08% (646/4 589), χ²=18.553, P<0.01) in the preoperative anemia group were higher than those in the non-anemia group, and the postoperative hospital stay in the preoperative anemia group was longer than that in the non-anemia group ((14.1±7.3) days vs. (13.3±6.2) days, t=5.202, P<0.01). Conclusions: The incidence of perioperative anemia in patients with gastrointestinal neoplasms is high. Preoperative anemia can increase the demand for intraoperative blood transfusion and affect the short-term prognosis of patients. At present, the concept of standardized treatment of perioperative anemia among gastrointestinal surgeons in Hubei Province needs to be improved.

Is Preexisting Cervical Degeneration a Risk Factor for Poor Prognosis in Whiplash-Associated Disorder?

BACKGROUND: The term whiplash describes the acceleration-deceleration mechanism of injury to the cervical spine. Whiplash injuries present with a variety of clinical and psychological manifestations, collectively termed as whiplash-associated disorders (WADs). Although largely self-limiting, some patients may experience long-lasting symptoms. This review aimed to summarize the current literature regarding the predictive value of cervical degeneration in the prognosis of patients with WAD. METHODS: A comprehensive search of the literature was performed. Nine studies were identified, including 894 patients, with an age range between 16 and 76 years. RESULTS: A statistically significant association was found between moderate facet joint degeneration and nonrecovery. Although no association was established between isolated disc degeneration and nonrecovery, total cervical degeneration (facet joint + disc degeneration) was shown to correlate with nonrecovery.All included studies demonstrated the lack of correlation between preexisting disc degeneration and clinical outcomes. Four studies showed a significant correlation between cervical degeneration and poor prognosis following whiplash injury. A significantly higher proportion of patients who remained symptomatic at 2 years following a whiplash injury had preexisting degenerative changes. CONCLUSIONS: This review highlights the presence of significant variability in the existing literature concerning WAD in terms of study methodology, definitions of cervical degeneration, and outcome measures. Degenerative changes of the facet joint lead to alterations in its biomechanics. Several cadaveric, biomechanical, and clinical studies have demonstrated facet joints as a source of pain in patients with chronic WAD. We present moderate evidence to suggest that preexisting facet joint degeneration is a negative prognostic indicator for long-lasting symptoms in WAD. Conversely, preexisting disc degeneration is not associated with chronicity of WAD symptoms. We propose facet joint instability due to facet joint capsule rupture as a potential mechanism for nonrecovery. Further studies are needed to inform our knowledge of the long-term sequelae of WAD among patients with preexisting cervicalspine degeneration.

[Effect of enhanced recovery after surgery for elderly patients with hemiarthroplasty for the treatment of femoral neck fracture].

Objective: To explore the clinical effect of enhanced recovery after surgery (ERAS) for the elderly patients with femoral neck fracture. Methods: A total of 92 elderly patients with femoral neck fracture who received hemiarthroplasty from July 2018 to December 2018 in Beijing Jishuitan Hospital were enrolled in this study. The average age of the participants was (75±6) years, including 31 males and 61 females, and 72(78.3%) of the patients complicated with comorbidity. According to the perioperative management method, the patients were divided into the observational group (47 cases with ERAS) and the control group (45 cases with normal management). The data related to operation, hospitalization, complication and nursing satisfaction were compared between the 2 groups. The visual analogue scale (VAS) was used for pain evaluation. The Harris scores for hip joint and EQ-5D index scores were applied to evaluate the clinical outcomes. The follow-up were performed periodically for 3 months. The measurement data in accordance with normal distribution and homogeneity of variance were compared with t test. Results: All the surgeries completed successfully and no patient died during perioperative period. Compared with the control group, the operation rate in 48 hours (χ(2)=17.781, P<0.01), bed days (Z=-4.987, P<0.01), and medical costs (Z=-4.315, P<0.01) favored that in the observational group. The incidence of complication and nursing satisfaction showed no significant difference between the two groups (31.1% vs 14.9%, 86.7% vs 95.7%, χ(2)=3.432, 1.380, both P>0.05). The perioperative VAS score was lower in the observational group. The Harris scores were higher in the observational group after 1 months (t=4.458, P<0.01), however the quality of life for 2 groups was similar at all time points (t=1.293, 1.227, both P>0.05). Conclusion: ERAS can improve hip function and reduce the hospital stays and medical costs for patients underwent HA operation.

Multifocal and multicentric breast cancer, is it time to think again?

Multifocal multicentric breast cancer has traditionally been considered a contraindication to breast conserving surgery because of concerns regarding locoregional control and risk of disease recurrence. However, the evidence supporting this practice is limited. Increasingly, many breast surgeons are advocating breast conservation in selected cases. This short narrative review summarises current evidence on the role of surgery in multifocal multicentric breast cancer and shows that when technically feasible the option of breast conservation is oncologically safe.

Commissioning and beam characterization of the first gantry-mounted accelerator pencil beam scanning proton system.

PURPOSE: To present and discuss beam characteristics and commissioning process of the first gantry-mounted accelerator single room pencil beam scanning (PBS) proton system. METHODS: The Mevion HYPERSCAN employs a design configuration with a synchrocyclotron mounted on the gantry to eliminate the traditional beamline and a nozzle that contains the dosimetry monitoring chambers, the energy modulator (Energy Selector (ES)), and an Adaptive Aperture (AA). To characterize the beam, we measured the integrated depth dose (IDDs) for 12 energies, from highest energy of 227 MeV down to 28 MeV with a range difference ~ 2 cm between the adjacent energies, using a large radius Bragg peak chamber; single-spot profiles in air at five locations along the beam central axis using radiochromic EBT3 film and cross compared with a scintillation detector; and determined the output using a densely packed spot map. To access the performance of AA, we measured interleaf leakage and the penumbra reduction effect. Monte Carlo simulation using TOPAS was performed to study spot size variation along the beam path, beam divergence, and energy spectrum. RESULTS: This proton system is calibrated to deliver 1 Gy dose at 5 cm depth in water using the highest beam energy by delivering 1 MU/spot to a 10 × 10 cm2 map with a 2.5 mm spot spacing. The spot size in air varies from 4 mm to 26 mm from 227 MeV to 28 MeV at the isocenter plane with the nozzle retracted 23.6 cm from isocenter. The beam divergence of 28 MeV beam is ~ 52.7 mrad, which is nearly 22 times that of 227 MeV proton beam. The binary design of the ES has resulted in shifts of the effective SSD toward the isocenter as the energy is modulated lower. The peaks of IDD curves have a constant 80%-80% width of 8.4 mm at all energies. The interleaf leakage of the AA is less than 1.5% at the highest energy; and the AA can reduce the penumbra by 2 mm to 13 mm for the 227 and 28 MeV energies at isocenter plane in air. CONCLUSIONS: The unique design of the HYPERSCAN proton system has yielded beam characteristics significantly different from that of other proton systems in terms of the Bragg peak shapes, spot sizes, and the penumbra sharpening effect of the AA. The combination of the ES and AA has made PBS implementation possible without using beam transport line and range shifter devices. Different considerations may be required in treatment planning optimization to account for different design and beam characteristics.

CCL22 is a biomarker of cartilage injury and plays a functional role in chondrocyte apoptosis.

BACKGROUND: Osteoarthritis (OA) is one of the leading causes of disability worldwide. Previous history of knee injury is a significant risk factor for OA. It has been established that low-level chronic inflammation plays a pivotal role in the onset and pathogenesis of OA. The primary aim of this research was to determine if a history of knee joint injury is associated with systemic inflammation. A secondary aim was to determine if systemic inflammation is related to knee pain and joint structure. METHODS: Differences in serum cytokine association networks, knee joint structural changes (MRI), and self-reported pain (i.e., Knee Injury and Osteoarthritis Outcome Score Pain subscale, KOOSPAIN and Intermittent and Constant Osteoarthritis Pain score, ICOAP) between individuals who had sustained a youth (aged 15-26 years) sport-related knee injury 3-10 years previously and age- and sex-matched controls were examined. Proteins of interest were also examined in an OA rat model. RESULTS: Cytokine association networks were found to differ significantly between study groups, yet no significant associations were found between networks and KOOSPAIN or MRI-defined OA. A group of cytokines (MCP1/CCL2, CCL22 and TNFα) were differentially associated with other cytokines between study groups. In a pre-clinical rat OA model, serum CCL22 levels were associated with pain (r = 0.255, p = 0.045) and structural changes to the cartilage. CCL22 expression was also observed in human OA cartilage and furthermore, CCL22 induced apoptosis of isolated human chondrocytes. DISCUSSION: These results suggest that CCL22 may be an early factor in the onset/pathogenic process of cartilage degeneration and/or related to pain OA.

[Association between AOX1, IRF4 methylation in peripheral blood leukocyte DNA and the risks of breast cancer: a case-control study].

Objective: To understand the relationship between AOX1, IRF4 gene methylation status in peripheral blood leukocyte DNA, as well as its interaction with environmental factors, and the risk of breast cancer. Methods: A case-control study was conducted among 401 breast cancer patients and 555 cancer-free controls selected from 2010 to 2014. Methylation sensitive-high resolution melting curve analysis was used to detect the methylation status of AOX1 and IRF4. The multiplication interaction effect between genes' methylation and environmental factors on the risk of breast cancer was analyzed by using unconditional logistic regression, and Excel software was used to analyze the additive interaction effect. Results: Individuals without AOX1 methylation had a 1.37-fold (95%CI: 1.02-1.84) higher breast cancer risk compared to individuals with AOX1 methylation. AOX1 methylation interacted with fungi intake (OR=2.06, 95%CI: 1.12-3.79) and physical activity (OR=2.18, 95%CI: 1.16-4.09) synergistically, on the risk for breast cancer, but no additive interaction effects were observed. Non-methylation of IRF4 could increase the risk for breast cancer, with statistical significance (OR=1.71, 95%CI: 0.99-7.43). Neither multiplication nor additive interactions were observed between IRF4 methylation and environmental factors. Conclusion: Non-methylation of AOX1 and IRF4 were a risk factors for breast cancer.

Surgical Management of Renal Cell Carcinoma Extending Into Venous System: A 20-Year Experience.

BACKGROUND AND AIMS: The purpose of this study is to report our 20-year experience with the surgical management of renal cell carcinoma extending into the inferior vena cava using a novel classification system. MATERIALS AND METHODS: We retrospectively reviewed the data of 103 patients (69 males, 34 females, mean age: 52.9 ± 12.6 years) with renal cell carcinoma involving the venous system treated between 1993 and 2014. The inferior vena cava tumor thrombus was classified into five levels: 0 (renal vein, n = 12), 1 (infrahepatic, n = 33), 2a (low retrohepatic, n = 26), 2b (high retrohepatic, n = 19), and 3 (supradiaphragmatic, n = 13). Clinical data were summarized, and overall survival, cancer-specific survival, and disease-free survival were examined by Cox regression analysis. RESULTS: All patients underwent radical surgery. Complete resections of the renal tumor and thrombus were achieved in 101 patients (98.1%). Two intraoperative and one postoperative in-hospital deaths (2.9%) occurred. In total, 19 patients (18.8%) had a total of 29 postoperative complications. Mean follow-up time was 46 months (range, 1-239 months). The 5- and 10-year overall survival rates were 62.9% and 56.0%, respectively. Metastasis, rather than thrombus level, was a significant risk factor associated with overall survival (hazard ratio = 4.89, 95% confidence interval: 2.24-10.67, p < 0.001). CONCLUSION: Our novel classification system can be used to select the optimal surgical approach and method for patients with renal cell carcinoma and venous thrombus. Its use is associated with prolonged survival and relatively few complications. Metastasis is an independent risk factor of overall survival.

Forced-air pre-warming prevents peri-anaesthetic hypothermia and shortens recovery in adult rats.

General anaesthesia disrupts thermoregulation in mammals, which can cause hypothermia. Decreases in core body temperature of 1℃ cause significant postoperative complications in humans, and peri-anaesthetic hypothermia in mice increases data variability, which can potentially increase animal use. In rats, the impact of different temperature management strategies on the incidence and severity of hypothermia, and the accuracy of different temperature measurement methods, is unknown. Eighteen adult male and female SD rats were block-randomized to one of three treatment groups: no-warming (NW), limited-warming (LW, heat pad during anaesthesia), and pre-warming (PW, warm air exposure before anaesthesia, followed by heat pad). Anaesthesia (isoflurane) duration was for 40 min. Core body temperature (intra-abdominal telemetric temperature capsule) was recorded during anaesthesia and recovery. During anaesthesia, rectal, skin, and tail temperatures were also recorded. In the PW group, core temperature was maintained during anaesthesia and recovery. By contrast, the NW group was hypothermic (11% temperature decrease) during anaesthesia. The LW group showed a decrease in temperature during recovery. Recovery to sternal recumbency was significantly faster in the PW (125 [70-186] s, P = 0.0003) and the LW (188 [169-420] s, P = 0.04) groups than in the NW group (525 [229-652] s). Rectal temperature underestimated core temperature (bias -0.90℃, 95% limits of agreement -0.1 to 1.9℃). Skin and tail temperatures showed wide 95% limits of agreement, spanning 6 to 15℃, respectively. The novel strategy of PW was effective at maintaining core temperature during and after anaesthesia. Rectal temperature provided an acceptable proxy for core body temperature.

Perceptions and opinions of Canadian pet owners about anaesthesia, pain and surgery in small animals.

OBJECTIVES: The aim of this study was to evaluate the perceptions and opinions of Canadian pet owners about anaesthesia, pain and surgery in dogs and cats. METHODS: Six Canadian veterinary hospitals participated. Each practice received 200 copies of a questionnaire that were distributed to pet owners. Questions regarding the use of analgesics, anaesthesia, surgery and onychectomy (cats) were included. Responses were transformed into ordinal scores and analysed with a Cochran-Mantel-Haenszel test. RESULTS: A total of 849 out of 1200 questionnaires were returned. Owners believed more frequently that analgesics are needed for surgical procedures than for the medical conditions. Owners rated as very important/important: "knowing what to expect during illness/injury/surgery" (99·3%), "being assured that all necessary analgesic drugs/techniques will be used" (98·6%), "being informed about procedures/risk" (98·5%), and having a board-certified anaesthesiologist (90·5%). Most owners agreed/partly agreed that pain impacts quality of life (94·2%), and affects their pet's behaviour (89·5%). Most respondents (69%) were women; they were significantly more concerned than men about anaesthesia, pain, cost and client-communication. Cat owners believed that analgesics were necessary for some procedures/conditions significantly more often than canine-only owners. Pet owners with previous surgery disagreed more frequently that "pain after surgery can be helpful" and that "pain in animals is easy to recognize" than those without previous surgery. Most owners think onychectomy should be banned in cats (56·4%). CLINICAL SIGNIFICANCE: This study identified important areas of client communication regarding pain and its control in pets.

Yttrium-90 radioembolization for colorectal cancer liver metastases in KRAS wild-type and mutant patients: Clinical and ccfDNA studies.

Patients with unresectable, chemo-refractory colorectal cancer liver metastases (CRCLM) have limited local treatment options. We report our institutional experience on the efficacy of resin-based yttrium-90 (90Y) radioembolization for the treatment of CRCLM and our findings on associated circulating cell-free DNA (ccfDNA) studies. A total of 58 patients treated with 90Y for CRCLM at the Medstar Georgetown University Hospital had a median survival of 6 months [95% confidence interval (CI), 4.55­7.45 months] after treatment, with a 12-month survival rate of 33%. The median survival from treatment stratified by mutational status was longer in the wild-type (WT) as compared to the KRAS mutant patients at 7 vs. 5 months, but did not achieve statistical significance (p=0.059). Median tumor local control duration after 90Y treatment was 2 months (95% CI, 0.34­3.66 months) for the entire cohort and was longer in the WT vs. the mutant patients (2 vs. 1 month, respectively, p=0.088). Plasma was prospectively collected from a subset of 9 patients both before and after single lobe treatment, and ccfDNA concentration and fragmentation index (FI) were measured using quantitative PCR and atomic-force microscopy (AFM). In the WT and KRAS mutant patients, DNA FI was reduced from a median of 0.73-0.65 after treatment. A reduction in DNA FI after single lobe treatment was associated with an improved overall survival (p=0.046). Analysis by AFM of paired pre- and post-treatment samples from KRAS mutant and WT patients revealed a larger average decrease in fragment size in the WT patients (p=0.013). 90Y radioembolization extends local control for CRCLM, however, KRAS mutant tumors may be more radio-resistant to treatment. Changes in the FI of patients following treatment were noted and may be evaluated in a larger study for relevance as a biomarker of response.

Toxicological effects of benzo[a]pyrene on DNA methylation of whole genome in ICR mice.

It has been well known that alterations in DNA methylation - an important regulator of gene transcription - lead to cancer. Therefore a change in the level of DNA methylation of whole genome has been considered as a biomarker of carcinogenesis. Previously, a large number of experimental results in genetic toxicology have showed that benzo[a]pyrene could cause DNA mutation and fragmentation. However, there was little to no studies on alterations in DNA methylation of genome directly result from exposure to benzo[a]pyrene. In this paper, possible mechanisms of alterations in whole genomic DNA methylation by benzo[a]pyrene were investigated using ICR mice after benzo[a]pyrene exposure. The blood, liver, pancreas, skin, lung and bladder of ICR mice were removed and checked after a fixed time interval (6 hours) of benzo[a]pyrene exposure, and whole genomic DNA methylation level was determined by high performance liquid chromatography (HPLC). The results exhibited tissue specificity, that is, the level of whole genomic DNA methylation decreases significantly in blood and liver, rather than pancreas, lung, skin and bladder of ICR mice. This study investigated the direct relationship between aberrant DNA methylation level and benzo[a]pyrene exposure, which might be helpful to clarify the toxicological mechanism of benzo[a]pyrene in epigenetic perspectives.

Phosphoglycerate kinase-1 is a predictor of poor survival and a novel prognostic biomarker of chemoresistance to paclitaxel treatment in breast cancer.

BACKGROUND: Phosphoglycerate kinase-1 (PGK1) has been recently documented in various malignancies; however, the molecular mechanisms of the variable PGK1 expression and its clinical significance in terms of survival status remain unclear. METHODS: Real-time quantitative PCR (real-time qPCR) and western blotting were used to verify PGK1 expression in 46 fresh breast cancer tissues and matched normal tissues. A tissue microarray (TMA) comprising 401 breast cancer tissues and 123 matched normal tissues was investigated by immunohistochemistry for PGK1 expression. Then, the correlation between PGK1 expression and the clinicopathologic features was analysed. RESULTS: PGK1 mRNA and protein expression were significantly increased in breast cancer tissues compared with that in normal breast tissues. High PGK1 expression was significantly associated with higher histologic grade (P=0.009) and positive status of ER (P=0.004), Her-2 (P=0.026) and P53 (P=0.012). High levels of PGK1 expression were associated with worse overall survival (OS, P=0.02). Furthermore, patients who underwent paclitaxel chemotherapy with high levels PGK1 expression had shorter OS than did those with low levels of PGK1 expression (P<0.001). Multivariate analysis indicated that PGK1 (P=0.001) was an independent predictor in the patients treated with paclitaxel. CONCLUSIONS: PGK1 is a prognostic biomarker of chemoresistance to paclitaxel treatment in breast cancer.

Failed back surgery syndrome: who has failed?

INTRODUCTION: Failed back surgery syndrome (FBSS) results from a cascade of medical and surgical events that lead to or leave the patient with chronic back and radicular pain. This concept is extremely difficult to understand, both for the patient and for the therapist. The difficulty is related to the connotations of failure and blame directly associated with this term. The perception of the medical situation varies enormously according to the background and medical education of the clinician who manages this type of patient. Eight health system experts (2 pain physicians, 1 orthopaedic spine surgeon, 1 neuro spine surgeon, 1 functional neurosurgeon, 1 physiatrist, 1 psychologist and one health-economic expert) were asked to define and share their specialist point of view concerning the management of postoperative back and radicular pain. Ideally, it could be proposed that the patient would derive optimal benefit from systematic confrontation of these various points of view in order to propose the best treatment option at a given point in time to achieve the best possible care pathway. CONCLUSION: The initial pejorative connotation of FBSS suggesting failure or blame must now be replaced to direct the patient and therapists towards a temporal concept focusing on the future rather than the past. In addition to the redefinition of an optimised care pathway, a consensus based on consultation would allow redefinition and renaming of this syndrome in order to ensure a more positive approach centered on the patient.

Secretory leukocyte protease inhibitor is a proliferation and survival factor for pancreatic cancer cells.

OBJECTIVES: A variety of inflammatory cytokines have been demonstrated to participate in tumorigenesis and progression. Secretory leukocyte protease inhibitor (SLPI) has been demonstrated to show a broad-spectrum of anti-inflammatory effects. This study investigates the expression of SLPI in human pancreatic cancer tissues and cells as well as its biological effects in human pancreatic cancer cells. METHODS: Reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot were used to detect SLPI mRNA and protein levels in human pancreatic cancer tissues, adjacent tissues, and pancreatic cancer Bxpc-3 and Panc-1 cells. Knockout of SLPI expression was established by recombinant viral vector expressing short hairpin RNA (shRNA) targeting SLPI. Cell viability was analyzed by MTT assay. Cell apoptosis was detected by Hochest33258 staining and flow cytometry assay. RESULTS: Higher SLPI expression was observed in pancreatic tissues, Bxpc-3 cells, and Panc-1 cells compared to the peritumoral tissues (p < 0.01). SLPI expression in Bxpc-3 and Panc-1 cells was effectively silenced by shRNA (p < 0.001). Silencing of SLPI expression significantly reduced cell viability, inhibited cell proliferation, and induced cell apoptosis (p < 0.001). CONCLUSIONS: Abnormal over-expression of SLPI in pancreatic cancer cells may be associated with the development of disease through its roles in promoting cancer cell survival and proliferation as well as anti-apoptosis. SLPI can be used as a target for developing targeted therapy of pancreatic cancer.

Functional analysis of TCF7L2 genetic variants associated with type 2 diabetes.

BACKGROUND AND AIMS: Common non-coding variations within the TCF7L2 locus have a strong influence on type 2 diabetes (T2D) susceptibility through uncharacterised mechanisms. An islet-specific functional polymorphism has been identified, although this does not explain the association between genotype and gene expression in other cell types. This study sought to identify these other functional TCF7L2 variants. METHODS AND RESULTS: Alternative splicing and gene expression from TCF7L2 was examined from peripheral blood mononuclear cells from 100 healthy Caucasians using two T2D-associated SNPs, rs7903146 and rs12255372. Electrophoretic mobility shift assays and luciferase reporter assays were performed with these SNPs and those in strong LD to determine potential SNP functionality. Individuals homozygous for rs7903146 and rs12255372 T2D risk alleles (TT/TT) expressed 2.6-fold greater levels of TCF7L2 mRNA compared to individuals homozygous for the non-risk alleles (CC/GG, p = 0.006), although differentially spliced TCF7L2 transcripts did not differ by T2D risk-associated genotype. From SNPs identified to be in strong LD with the T2D-associated SNPs, rs7903146 and rs12255372, five (rs4132670, rs4506565, rs7903146, rs7901695, rs17747324) demonstrated allele-specific binding in electrophoretic mobility shift assays (EMSA). In luciferase reporter assays, rs4132670 exhibited 1.3-fold higher levels of enhancer activity in the Huh7 cell line (p = 3.8 × 10(-5)) and 2-fold higher levels in a WiDr colon carcinoma cell line (p = 0.008). CONCLUSIONS: These results suggest that rs4132670, located in a region of chromatin accessibility, is a non-tissue-specific candidate functional SNP that has the potential to play a role in TCF7L2 gene expression and T2D risk.

Effects of genetic variation on chromatin structure and the transcriptional machinery: analysis of the IL6 gene locus.

The presence of functional regulatory polymorphism at the interleukin 6 (IL6) locus is uncertain, with many conflicting in vitro findings. To examine the in vivo effect of the three putative functional IL6 promoter variants, -174G>C, -572G>C and -6331T>C, two complementary techniques, allele-specific chromatin immunoprecipitation and allele-specific formaldehyde-assisted isolation of regulatory elements, were carried out using unrelated lymphoblast cell lines of known genotype. There were no allele-specific effects for all three single-nucleotide polymorphisms (SNPs) under basal conditions. Upon IL-1ß stimulation, however, allele-specific effects were seen for the -6331 allele, which showed both increased RNA polymerase II loading (56%, P=0.001) and increased open chromatin (59%, P=0.004) for the T allele, which is in line with previous reports of this SNP and the effects from acute inflammation. These studies highlight the importance of examining chromatin under different environmental conditions when studying the functionality of regulatory polymorphisms.

Survival from cancer in teenagers and young adults in England, 1979-2003.

Cancer is the leading cause of disease-related death in teenagers and young adults aged 13-24 years (TYAs) in England. We have analysed national 5-year relative survival among more than 30,000 incident cancer cases in TYAs. For cancer overall, 5-year survival improved from 63% in 1979-84 to 74% during 1996-2001 (P<0.001). However, there were no sustained improvements in survival over time among high-grade brain tumours and bone and soft tissue sarcomas. Survival patterns varied by age group (13-16, 17-20, 21-24 years), sex and diagnosis. Survival from leukaemia and brain tumours was better in the youngest age group but in the oldest from germ-cell tumours (GCTs). For lymphomas, bone and soft tissue sarcomas, melanoma and carcinomas, survival was not significantly associated with age. Females had a better survival than males except for GCTs. Most groups showed no association between survival and socioeconomic deprivation, but for leukaemias, head and neck carcinoma and colorectal carcinoma, survival was significantly poorer with increasing deprivation. These results will aid the development of national specialised service provision for this age group and identify areas of clinical need that present the greatest challenges.