Lead Time and Immortal Time Biases Impact the Calculation of Post-colonoscopy Colorectal Cancer Survival.

The World Endoscopy Organization (WEO) standardized the reporting of post-colonoscopy colorectal cancers (PCCRCs), which account for 7% to 10% of colorectal cancers (CRCs).1 PCCRCs are diagnosed 6 to 36 months after a false negative colonoscopy. Detected CRCs (dCRCs) are diagnosed ≤6 months after an index true positive colonoscopy.2 PCCRC prognosis is unclear, with outcomes reported as comparable,3 superior,4 or inferior5,6 to those of dCRC. Because WEO terminology defines cases relative to the index colonoscopy, conventional survival analyses of PCCRC are susceptible to lead time and immortal time biases. We evaluated the influence of these biases on mortality in a population-based retrospective cohort of 10,938 dCRCs (93.8%) and 717 PCCRCs (6.2%). This study was set within Kaiser Permanente Northern California (KPNC), a large integrated health system, whose members are similar in demographic and socioeconomic characteristics to the Northern California region.7.

Tumor resistance to anti-mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by targeting a juxtamembrane epitope.

Despite many clinical trials, CAR-T cells are not yet approved for human solid tumor therapy. One popular target is mesothelin (MSLN) which is highly expressed on the surface of about 30% of cancers including mesothelioma and cancers of the ovary, pancreas, and lung. MSLN is shed by proteases that cleave near the C terminus, leaving a short peptide attached to the cell. Most anti-MSLN antibodies bind to shed MSLN, which can prevent their binding to target cells. To overcome this limitation, we developed an antibody (15B6) that binds next to the membrane at the protease-sensitive region, does not bind to shed MSLN, and makes CAR-T cells that have much higher anti-tumor activity than a CAR-T that binds to shed MSLN. We have now humanized the Fv (h15B6), so the CAR-T can be used to treat patients and show that h15B6 CAR-T produces complete regressions in a hard-to-treat pancreatic cancer patient derived xenograft model, whereas CAR-T targeting a shed epitope (SS1) have no anti-tumor activity. In these pancreatic cancers, the h15B6 CAR-T replicates and replaces the cancer cells, whereas there are no CAR-T cells in the tumors receiving SS1 CAR-T. To determine the mechanism accounting for high activity, we used an OVCAR-8 intraperitoneal model to show that poorly active SS1-CAR-T cells are bound to shed MSLN, whereas highly active h15B6 CAR-T do not contain bound MSLN enabling them to bind to and kill cancer cells.

Retraction Note: MiR-195-5p inhibits the cell migration and invasion of cervical carcinoma through suppressing ARL2.

The article "MiR-195-5p inhibits the cell migration and invasion of cervical carcinoma through suppressing ARL2", by S.-S. Pan, H.-E. Zhou, H.-Y. Yu, L.-H. Xu, published in Eur Rev Med Pharmacol Sci 2019; 23 (24): 10664-10671-DOI: 10.26355/eurrev_201912_19764-PMID: 31858533 has been retracted by the Authors for the following reasons: The authors found some inaccuracies in the research due to the number of experiments, as well as problems in the editing process of pictures. These errors may mislead readers and affect scientific research in this field. Figures 2D and 5D have also been questioned on PubPeer in April 2023. https://www.europeanreview.org/article/19764 This manuscript has been withdrawn. The Publisher apologizes for any inconvenience this may cause.

The role of lymphocyte count in the early diagnosis of surgical site infection following posterior lumbar fusion.

OBJECTIVE: This study aimed to explore the early diagnostic value of lymphocyte count in the early diagnosis of surgical site infection (SSI) following posterior lumbar fusion. PATIENTS AND METHODS: In this study, we retrospectively analyzed the data from a total of 37 patients with lumbar SSI from Guizhou  Province Orthopaedic Hospital and Nanyang Central Hospital, 2008.1-2018.11, and 104 patients without SSI. We analyzed the C-reactive protein (CRP) level, white blood cell count (WBC) and differential count before instrumented lumbar fusion at 3 and 7 days postoperatively. The significance of the differences was evaluated by one-way ANOVA, followed by Fisher's test. The parameters mentioned above were analyzed on postoperative days 3 and 7 using the receiver operating characteristic curve and the area under the curve (AUC). Furthermore, the analyses were conducted by SPSS 22.0 software. RESULTS: The lymphocyte count in the SSI group on postoperative day 3 was significantly lower than that in the no-SSI group after surgery (p=0.000). According to the ROC curve analysis of related parameters on postoperative day 3, the AUC value of lymphocytes (0.840) was significantly larger than the AUC value of C-reactive protein (0.749). CONCLUSIONS: The lymphocyte count and C-reactive protein level on postoperative day 3 are reliable predictors of infection.

A bioinformatic analysis of the role of TP53 status on the infiltration of CD8+ T cells into the tumor microenvironment

CD8+ T cells play basic roles in the immune system in a tumor microenvironment (TME) to fight cancer. Several reports have suggested signs of the involvement of tumor protein p53 (TP53) in a complex immune system network. Moreover, our previous research indicated that TP53 orchestrates the polarization and infiltration of macrophages into the TME. In the present study, the clinical function of TP53 status (wild/mutant) in CD8+ T cell infiltration was assessed using more than 10,000 The Cancer Genome Atlas (TCGA) samples from 30 cancer types through Tumor Immune Estimation (TIMER). Our investigation revealed that CD8+ T cell infiltration was higher in head and neck squamous cell carcinoma (HNSC) and uterine corpus endometrial carcinoma (UCEC) patients with wild-type TP53 than in those with mutant TP53. Wild-type TP53 conferred a good prognosis for HNSC and UCEC (P<0.05). In contrast, CD8+ T cell infiltration in lung adenocarcinoma (LUAD) patients with wild-type TP53 was much lower than in those with mutant TP53. Notably, clinical outcomes for LUAD with wild-type TP53 were poor (P<0.05). This study was the first to provide insights into the novel association of TP53 with CD8+ T cells infiltration in the TME in patients with HNSC, LUAD, and UCEC. Therefore, TP53 status acts as a prognostic marker, and this can be used as a basis to further study the effect of targeting TP53 in these patients. Furthermore, our study found that TP53 status was a reliable predictive factor and therapeutic target in patients with HNSC and UCEC.

Systematic review with meta-analysis: the prevalence of post-colonoscopy colorectal cancers using the World Endoscopy Organization nomenclature.

INTRODUCTION: Post-colonoscopy colorectal cancers (PCCRCs) have been proposed as a performance metric for colonoscopy quality assurance programs. Previously, there was no standardised terminology or reporting methods. In 2018, the World Endoscopy Organization (WEO) advised standardised definitions and prevalence calculation methodology. AIMS: To assess PCCRC burden using WEO standardised methods, to explore causes of heterogeneity, and to review changes in prevalence over time METHODS: We updated a prior systematic review by searching Ovid MEDLINE and EMBASE databases from 1 January 2013 to 31 January 2021 to identify population-based studies (or multicentre studies representative of the local population) reporting PCCRC prevalence (PROSPERO [CRD42020183796]). Two authors independently determined study eligibility, assessed quality, and extracted data. We estimated the PCCRC 3-year prevalence using WEO-recommended methodologies and investigated between-study sources of heterogeneity. We examined changes in prevalence over time. RESULTS: Fifteen studies reporting on 25 872 PCCRC cases met eligibility criteria. Pooled PCCRC 3 year prevalence was 8.2% (95% CI = 6.9%-9.4%, I2  = 98.2%) across four European studies using WEO precise methodology. Proximal PCCRC prevalence was greater than distal (9.7% [95% CI = 7.0%-12.4%] vs 5.4% [95% CI = 2.9%-7.8%], I2  = 99.2%). Seven studies reporting PCCRC rates over time showed no consistent trend: four showed a decrease, one an increase and two were unchanged. Between-study heterogeneity was high. CONCLUSIONS: Pooled 3-year PCCRC prevalence was 8.2% (95% CI = 6.9%-9.4%). Despite WEO standardised methodology to define and calculate PCCRC rates, there was significant heterogeneity among studies. Comparing rates between populations remains challenging and additional studies are needed to better understand the global PCCRC burden to inform quality assurance programs.

Multiple vertebral compression fractures in a human immunodeficiency virus-positive patient with glucocorticoid-induced Cushing syndrome treated with percutaneous vertebroplasty: a case report.

The authors present a rare case of multiple vertebral compression fractures in a young female with iatrogenic glucocorticoid-induced Cushing syndrome and concomitant human immunodeficiency virus (HIV) infection. Both long-term steroid use and HIV infection may lead to osteopenia or even osteoporosis. Multiple vertebral fractures in young patients are very uncommon and should alert the examiner to investigate any underlying cause. Treatment choices include pharmacological agents such as bisphosphonates or parathyroid hormone and even surgical interventions such as percutaneous vertebroplasty.

Overexpression of secretory leukocyte peptidase inhibitor (SLPI) does not modulate experimental osteoarthritis but may be a biomarker for the disease.

OBJECTIVE: Osteoarthritic cartilage destruction can be regulated by the balance between proteases and anti-proteases. Here, we sought to identify novel cellular protease inhibitors associated with osteoarthritis (OA) pathogenesis. METHODS: Candidate molecules were screened from microarray data of chondrocytes treated with OA-associated catabolic factors. The functions of candidate molecules in OA pathogenesis were examined in primary-culture mouse articular chondrocytes and mouse models of OA, such as those stimulated by destabilization of the medial meniscus (DMM) or intra-articular (IA) injection of adenovirus expressing the candidate gene. The value of the selected candidate molecule as a biomarker of OA was examined by measuring its circulating levels in human and mouse blood. RESULTS: Bioinformatic analysis identified secretory leukocyte peptidase inhibitor (SLPI) as a highly upregulated cellular protease inhibitor in chondrocytes treated with pathogenic catabolic factors, including interleukin (IL)-1ß, hypoxia-inducible factor (HIF)-2α, and zinc importer ZIP8. The adenovirus-mediated overexpression of SLPI in joint tissues did not cause any OA-like change or modulate DMM- or HIF-2α-induced experimental OA in mice. SLPI also did not markedly modulate the expression of OA-associated catabolic or anabolic factors in chondrocytes. However, SLPI was specifically upregulated in OA cartilage, and the serum SLPI levels were significantly elevated in human OA patients and experimental OA mice, suggesting that SLPI may be a biomarker of OA. CONCLUSION: Although SLPI is upregulated in OA chondrocytes, it does not appear to per se modulate OA development in mice. However, it may be a potential biomarker of OA in humans and animal models.

Review of recently used techniques and materials to improve the efficiency of orally administered proteins/peptides.

OBJECTIVES: The main objective of present review is to explore and evaluate the effectiveness of recently developed methods to improve the bioavailability of orally administered biopharmaceutical drugs. METHODS: A systematic search of sciencedirect, tandfonline and Google Scholar databases based on various sets of keywords was performed. All results were evaluated based on their abstracts, and irrelevant studies were neglected during further evaluation. RESULTS: At present, biopharmaceuticals are used as injectable therapies as they are not absorbed adequately from the different routes of drug administration, particularly the oral one. Their insufficient absorption is attributed to their high molecular weight, degradation by proteolytic enzymes, high hydrophilicity and rigidity of the absorptive tissues. From industrial aspect incorporation of enzyme inhibitors (EIs) and permeation enhancers (PEs) and mucoadhesive polymers into conventional dosage forms may be the easiest way of formulation of orally administered macromolecular drugs, but the effectiveness of protection and absorption enhancement here is the most questionable. Conjugation may be problematic from regulatory aspect. Encapsulation into lipid-based vesicles sufficiently protects the incorporated macromolecule and improves intestinal uptake but have considerable stability issues. In contrast, polymeric nanocarriers may provide good stability but provides lower internalization efficacy in comparison with the lipid-based carriers. CONCLUSION: It can be concluded that the combination of the advantages of mucoadhesive polymeric and lid-based carriers in hybrid lipid/polymer nanoparticles may result in improved absorption and might represent a potential means for the oral administration of therapeutic proteins in the near future. Graphical abstract Delivery systems for oral protein daministration.

TRIM24 aggravates the progression of ovarian cancer through negatively regulating FOXM1 level.

OBJECTIVE: This study aims to uncover the biological functions of the feedback loop tripartite motif-containing 24 (TRIM24)/Forkhead Box M1 (FOXM1) in the pathological progression of ovarian cancer (OC) and the underlying mechanism. PATIENTS AND METHODS: The expression levels of TRIM24 and FOXM1 in OC tissues and cells were determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The potential correlation between TRIM24 level and clinical indexes of OC patients was analyzed. The Kaplan-Meier curves were depicted for evaluating the prognostic potentials of TRIM24 and FOXM1 in OC patients. The regulatory effects of TRIM24 and FOXM1 on proliferative, migratory, and invasive capacities of SKOV3 and OVCAR3 cells were assessed through functional experiments. The rescue experiments were performed to clarify the feedback loop TRIM24/FOXM1 in influencing the progression of OC. RESULTS: TRIM24 was upregulated in OC tissues and cells. The high level of TRIM24 was linked to higher rates of lymphatic and distant metastasis and worse survival in OC patients. The silence of TRIM24 attenuated proliferative, migratory, and invasive capacities of SKOV3 and OVCAR3 cells. FOXM1 level was negatively regulated by TRIM24, which was downregulated in OC. The low level of FOXM1 predicted worse survival in OC patients. Besides, the rescue experiments demonstrated that the feedback loop TRIM24/FOXM1 aggravated the malignant progression of OC. CONCLUSIONS: TRIM24 is upregulated in OC tissues, and closely linked to the occurrence of lymphatic and distant metastasis. Through negatively regulating FOXM1 level, TRIM24 aggravates the progression of OC.

MiR-195-5p inhibits the cell migration and invasion of cervical carcinoma through suppressing ARL2.

OBJECTIVE: MicroRNAs (miRNAs) have great effects on the progression of cervical cancer (CC). This study aimed to investigate the role of miR-195-5p in CC and to explain the regulatory mechanism between ARL2 and miR-195-5p. PATIENTS AND METHODS: Quantitative Real-Time-Polymerase Chain Reaction (qRT-PCR) was used to detect miR-195-5p levels in CC tissues and cell lines. Transwell assays for cell migration and invasion were also performed. A luciferase reporter assay was used to detect the direct target of miR-195-5p. The protein levels of ARL2 were measured by Western blot analysis. RESULTS: In CC tissues and cell lines, miR-195-5p expression was decreased. Downregulation of miR-195-5p was associated with higher FIGO stage, deep stromal invasion, and lymph node metastasis. Moreover, over-expression of miR-195-5p inhibited cell migration and invasion in CC. Furthermore, it was observed that miR-195-5p directly targeted ARL2, which affected the suppressive effect of miR-195-5p in CC. CONCLUSIONS: MiR-195-5p inhibited cell migration and invasion in CC by suppressing ARL2 expression. The miR-195/ARL2 axis may provide a pathway for cell metastasis in CC.

MicroRNA-495 inhibits the progression of non-small-cell lung cancer by targeting TCF4 and inactivating Wnt/ß-catenin pathway.

OBJECTIVE: Different effects of microRNA-495 (miR-495) on human cancers have been exhibited in recent years. However, the specific function of miR-495 remains uncertain in non-small-cell lung cancer (NSCLC). Thus, we aim to explore the role of miR-495 in NSCLC. PATIENTS AND METHODS: The expressions of miR-495 and transcription factor 4 (TCF4) were detected through quantitative Real-time polymerase chain reaction (qRT-PCR) assay. Western blot was used to measure the protein expression of relative genes. The relationship between miR-495 and TCF4 was testified by the dual-luciferase reporter gene assay. The function of miR-495 was investigated through cell counting kit-8 (CCK-8) assay and transwell assay. RESULTS: MiR-495 was downregulated in NSCLC tissues. Overexpression of miR-495 inhibited the migration, invasion and proliferation of NSCLC cells. Further, TCF4 was a direct target gene of miR-495. TCF4 was highly expressed in NSCLC tissues. In addition, miR-495 inhibited the progression of NSCLC through targeting TCF4. Furthermore, miR-495 inhibited EMT and Wnt/ß-catenin pathway in NSCLC. CONCLUSIONS: MiR-495 inhibited the progression of NSCLC by targeting TCF4 and inactivating Wnt/ß-catenin pathway.

Dietary antioxidant intake and the risk of developing Barrett's oesophagus and oesophageal adenocarcinoma.

BACKGROUND: We investigated in a cohort study, for the first time using 7-day food diaries (7-DFDs), for age-dependent inverse associations with antioxidants, which have anti-carcinogenic properties, and development of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). METHODS: A total of 24,068 well individuals completed 7-DFDs and donated blood. Vitamins C and E, carotenes, zinc and selenium intakes, and plasma vitamin C were measured. Participants were monitored for 15 years for BO and OAC. Hazard ratios (HRs) were estimated for: quintiles of intake and in participants younger and >=65 years at recruitment, the midpoint of BO peak prevalence. RESULTS: A total of 197 participants developed BO and 74 OAC. There were no significant associations between antioxidants and BO or OAC in the whole cohort or if >65 years at recruitment. In participants <65 years, for BO, there was an inverse trend across plasma vitamin C quintiles (trend HR = 0.82; 95% CI = 0.71-0.96, P = 0.01), OAC for plasma vitamin C (trend HR = 0.58; 95% CI = 0.37-0.92, P = 0.02) and for dietary vitamins C and E (trend HR = 0.71 95% CI = 0.51-0.99, P = 0.04 and trend HR = 0.70; 95% CI = 0.51-0.96; P = 0.03). CONCLUSIONS: Data supports a role for dietary antioxidants prevent BO and OAC, perhaps at the earlier stages of carcinogenesis.

Complication Follow-up With Ultrasonographic Analyses of 91 Cases With Donor Gallbladder Preservation in Living Donor Liver Transplantation of Left Lateral Sectionectomies.

BACKGROUND: Preserving the donor's gallbladder during living donor liver transplantation (LDLT) is a better method for liver transplantation surgery, but not enough is known about gallbladder complications after the operation. METHODS: We retrospectively investigated postsurgical donor gallbladder complications in clinical LDLT with gallbladder preservation. The feasibility of retaining the gallbladder during liver graft procurement is discussed. Ninety-one donors with retained gallbladder after LDLT with the hepatic left lateral sectionectomy (from June 2013 to October 2015) were retrospectively analyzed. Donors were followed for 12.6 to 40.7 months after surgery (median 26.1 months). Sonography was used to evaluate gallbladder characteristics before and after surgery. RESULTS: Gallbladder function had recovered to almost normal 1 month after transplantation. Four donors (4.40%) experienced gallbladder enlargement that resolved after 3 days. Thickening of the gallbladder wall in 31 donors (34.07%) was restored within 2 to 75 days. Biliary sludge appeared in 9 donors (9.89%); 6 of them recovered within 3 to 34 days. Three (3.30%) and 1 donor (1.10%) suffered gallstone and gallbladder polyps, respectively, which persisted until the last follow-up. CONCLUSION: The rate of postoperative complications of the gallbladder in donors was relative low. Preserving the gallbladder in liver transplantation donors during liver graft procurement is feasible and safe.

Congenital thumb anomalies and the consequences for daily life: patients' long-term experience after corrective surgery. A qualitative study.

PURPOSE: The aim of the study was to explore patients' long-term experience of a congenital hand problem, and the consequences for daily life. METHOD: Fifteen participants with a median age 24 years (17-55 years), born with thumb hypoplasia/aplasia or thumb duplication were interviewed using a semi-structured interview guide. The interviews were subjected to qualitative content analysis. RESULTS: Although the mobility and strength in the thumb/hand(s) varied within the group, hand function was generally described as good. Compensatory strategies were used to overcome practical obstacles. The emotional reactions to being visibly different from peers in early life varied from total acceptance and a sense of pride in being special, to deep distress and social withdrawal. Support from parents, teachers and others was important in facing emotional challenges and practical consequences. CONCLUSION: The present study highlights the importance of healthcare professionals addressing appearance-related concerns which may have long-term emotional and social consequences for patients born with a thumb anomaly. Implications for Rehabilitation Appearance-related concerns and need for emotional support should be fully considered throughout the rehabilitation process to prevent distress and social withdrawal. Effective problem-solving strategies, such as compensation, change in occupational performance and support from others may reduce activity limitations and participation restriction.

The Krümmel (Germany) Childhood Leukaemia Cluster: a review and update.

The debate surrounding possible adverse health effects from the civil use of nuclear power under normal operating conditions has been on-going since its introduction. It was particularly intensified by the detection of three leukaemia clusters near nuclear installations, i.e. near the reprocessing plants in Sellafield and Dounreay, UK, and near the Krümmel nuclear power plant, Germany, the last of which commenced between 1990 and 1991 and was first described in 1992; it continued until 2003, and an elevated risk up to 2005 has been reported in the literature. A number of expert commissions and working groups were set up by the governments of the German federal states of Lower Saxony and Schleswig-Holstein to investigate the possible causes of the cluster. An overview of the many risk factors that were investigated as a possible explanation of the Krümmel cluster is given here, focussing on radiation, but also including other risk factors. Further, results from related epidemiological and cytogenetic studies are described. In summary, the cause of the occurrence of the Krümmel cluster has to be considered as unknown. Further research on the causes of childhood leukaemia is needed, focussing on epigenetics and on gene-environment interaction. An update of the leukaemia incidence around the Krümmel site shows that the incidence rates are now comparable to the average rate in Germany.

Upregulation of Atrogin-1/FBXO32 is not necessary for cartilage destruction in mouse models of osteoarthritis.

OBJECTIVE: In a preliminary study, we found that recently identified catabolic regulators of osteoarthritis (OA), including hypoxia-inducible factor (HIF)-2α and members of the zinc-ZIP8-MTF1 axis, upregulate the E3 ubiquitin ligase, Atrogin-1 (encoded by Fbxo32), in chondrocytes. As the ubiquitination/proteasomal degradation pathways are tightly regulated to modulate the expression of catabolic factors in chondrocytes, we examined the in vivo functions of Atrogin-1 in mouse models of OA. METHODS: The mRNA and protein levels of Atrogin-1 and other regulators of OA were determined in primary cultured mouse chondrocytes, OA human cartilage, and OA cartilage from wild-type (WT) and Fbxo32-knockout (KO) mice subjected to destabilization of the medial meniscus or intra-articular (IA) injection of adenoviruses expressing HIF-2α (Ad-Epas1), ZIP8 (Ad-Zip8), or Atrogin-1 (Ad-Fbxo32). The effect of Atrogin-1 overexpression on the cartilage of WT mice was examined by IA injection of Ad-Fbxo32. RESULTS: Atrogin-1 mRNA levels in chondrocytes were markedly increased by treatment with interleukin-1ß, HIF-2α, and members of the zinc-ZIP8-MTF1 axis. Atrogin-1 protein levels were also increased in OA cartilage from humans and various mouse OA models. However, the forced overexpression of Atrogin-1 in chondrocytes did not modulate the expression of cartilage matrix molecules or matrix-degrading enzymes. Moreover, overexpression of Atrogin-1 in the mouse joint tissues failed to cause OA pathogenesis, and Fbxo32 knockout failed to affect post-traumatic OA cartilage destruction in mice. CONCLUSIONS: Although Atrogin-1 is upregulated in OA cartilage, overexpression of Atrogin-1 in the joint tissues or knockout of Fbxo32 does not affect OA cartilage destruction in mice.

[Registry Research Funding of the German Society of Plastic, Reconstructive and Aesthetic Surgeons (DGPRÄC) and Research Funding Report 2015/2016]. / Register Forschungsförderung der Deutschen Gesellschaft der Plastischen, Rekonstruktiven und Ästhetischen Chirurgen (DGPRÄC) und Forschungsförderungs-Bericht 2015/2016.

In addition to the impact factor, research funding also plays a central role in evaluating the academic performance and quality of a researcher, a clinic or a surgical specialty. The scope and quality of research in Plastic Surgery are usually very little known, so that even large funding institutions do not get a full view of research funding in our specialty. Therefore, sometimes traditional structures are not adapted to new needs by the developing younger surgical fields. In peer review sometimes peers are not chosen from the same surgical specialty, but from a different surgical fields being peers in large field of surgery. By this a bias can easily be generated which would not be advantageous for subspecialties such Plastic Surgery. The goal of this paper is to establish an overview in the form of a registry of the German Society of Plastic Reconstructive and Aesthetic Surgeons (DGPRÄC) in order to make the joint academic achievements more visible in the future. At the same time, a research funding report is to be published for the years 2015 and 2016.