F-box and WD repeat domain-containing 7 (FBXW7) is a cell cycle regulatory gene whose protein product ubiquitinates positive cell cycle regulators such as c-Myc, cyclin E, and c-Jun, thereby acting ...as a tumour-suppressor gene. This study focused on microRNA-223 (miR-223), which is a candidate regulator of FBXW7 mRNA. The aim of this study was to clarify the clinical significance of miR-223 and FBXW7 in oesophageal squamous cell carcinoma (ESCC) patients, and to elucidate the mechanism by which FBXW7 is regulated by miR-223.
The expression levels of miR-223 and the expression of FBXW7 protein was examined using 109 resected specimens to determine the clinicopathological significance. We also investigated the role of miR-223 in the regulation of FBXW7 expression in ESCC cell lines in an in vitro analysis.
We found that miR-223 expression was significantly higher in cancerous tissues than in the corresponding normal tissues. There was a significant inverse relationship between the expression levels of miR-223 and FBXW7 protein. Moreover, patients with high miR-223 expression demonstrated a significantly poorer prognosis than those with low expression. On the basis of a series of gain-of-function and loss-of-function studies in vitro, we identified FBXW7 as a functional downstream target of miR-223.
Our present study indicates that high expression of miR-223 had a significant adverse impact on the survival of ESCC patients through repression of the function of FBXW7.
Summary
Recently, depletion of skeletal muscle mass (sarcopenia) has been linked to poor prognosis in several types of cancers, but has not been investigated in esophageal squamous cell carcinoma ...(ESCC). This retrospective study investigates the relationship between sarcopenia and clinical outcome in ESCC patients treated by surgical resection or definitive chemoradiation therapy (dCRT). The study was retrospectively conducted in a single academic hospital in Kumamoto, Japan, and involved 325 ESCC patients (256 surgical cases and 69 dCRT cases) treated between April 2005 and April 2011. Skeletal muscle mass was quantified by radiologic measures using standard computed tomography scans. The skeletal muscle tissue in the 325 ESCC patients was distributed as follows: mean: 47.10; median: 46.88; standard deviation (SD): 7.39; range: 31.48–71.11; interquartile range, 46.29–47.90. Skeletal muscle tissue was greater in male patients than in female patients (P < 0.0001), but was independent of other clinical and tumor features. Sarcopenia was not significantly associated with overall survival (log rank P = 0.54). Lymph node involvement significantly altered the relationship between sarcopenia and survival rate (P for interaction = 0.026). Sarcopenia significantly reduced the overall survival of patients without lymph node involvement (log rank P = 0.035), but was uncorrelated with overall survival in patients with lymph involvement (log rank, P = 0.31). The anastomosis leakage rate was significantly higher in the sarcopenia group than in the non‐sarcopenia group (P = 0.032), but other surgical complications did not significantly differ between the two groups. Sarcopenia in ESCC patients without lymph node involvement is associated with poor prognosis, indicating sarcopenia as a potential biomarker for identifying patients likely to experience an inferior outcome. Moreover, sarcopenia was associated with anastomosis leakage but no other short‐term surgical outcome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
Although associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been increasingly adopted by many centres, the oncological outcome for colorectal liver ...metastases compared with that after two‐stage hepatectomy is still unknown.
Methods
Between January 2010 and June 2014, all consecutive patients who underwent either ALPPS or two‐stage hepatectomy for colorectal liver metastases in a single institution were included in the study. Morbidity, mortality, disease recurrence and survival were compared.
Results
The two groups were comparable in terms of clinicopathological characteristics. ALPPS was completed in all 17 patients, whereas the second‐stage hepatectomy could not be completed in 15 of 41 patients. Ninety‐day mortality rates for ALPPS and two‐stage resection were 0 per cent (0 of 17) versus 5 per cent (2 of 41) (P = 0·891). Major complication rates (Clavien grade at least III) were 41 per cent (7 of 17) and 39 per cent (16 of 41) respectively (P = 0·999). Overall survival was significantly lower after ALPPS than after two‐stage hepatectomy: 2‐year survival 42 versus 77 per cent respectively (P = 0·006). Recurrent disease was more often seen in the liver in the ALPPS group. Salvage surgery was less often performed after ALPPS (2 of 8 patients) than after two‐stage hepatectomy (10 of 17).
Conclusion
Although major complication and 90‐day mortality rates of ALPPS were similar to those of two‐stage hepatectomy, overall survival was significantly lower following ALPPS.
Overall survival worse after ALPPS
Background
Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that ...adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer.
Methods
This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of 1000 mg/m2, administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was overall survival, and secondary endpoints were relapse‐free survival, subgroup analysis and toxicity.
Results
Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics were well balanced between the gemcitabine and observation groups. There were no significant differences in overall survival (median 62·3 versus 63·8 months respectively; hazard ratio 1·01, 95 per cent c.i. 0·70 to 1·45; P = 0·964) and relapse‐free survival (median 36·0 versus 39·9 months; hazard ratio 0·93, 0·66 to 1·32; P = 0·693). There were no survival differences between the two groups in subsets stratified by lymph node status and margin status. Although haematological toxicity occurred frequently in the gemcitabine group, most toxicities were transient, and grade 3/4 non‐haematological toxicity was rare.
Conclusion
The survival probability in patients with resected bile duct cancer was not significantly different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration number: UMIN 000000820 (http://www.umin.ac.jp/).
No advantage
Background
Immune checkpoint inhibitors, such as antibody against programmed cell death protein (PD‐1), have demonstrated antitumour effects in patients with malignancies, including oesophageal ...cancer. A lymphocytic reaction observed by pathological examination is a manifestation of the host immune response to tumour cells. It was hypothesized that a stronger lymphocytic reaction to tumours might be associated with favourable prognosis in oesophageal cancer.
Methods
Using a database of resected oesophageal cancers, four morphological components of lymphocytic reactions (peritumoral, intranest, lymphoid and stromal) to tumours were evaluated in relation to clinical outcome, PD‐1 expression by immunohistochemistry and total lymphocyte count in blood.
Results
Resected oesophageal cancer specimens from 436 patients were included in the study. Among the four morphological components, only peritumoral reaction was associated with patient prognosis (multivariable P for trend <0·001); patients with a higher peritumoral reaction had significantly longer overall survival than those with a lower reaction (multivariable hazard ratio 0·48, 95 per cent c.i. 0·34 to 0·67). The prognostic effect of peritumoral reaction was not significantly modified by other clinical variables (all P for interaction >0·050). Peritumoral reaction was associated with total lymphocyte count in the blood (P < 0·001), supporting the relationship between local immune response and systemic immune competence. In addition, higher morphological peritumoral reaction was associated with high PD‐1 expression on lymphocytes in tumours (P = 0·034).
Conclusion
These findings should help to improve risk‐adapted therapeutic strategies and help stratify patients in the future clinical setting of immunotherapy for oesophageal cancer.
Antecedentes
Los inhibidores de los puntos de control inmunitario (checkpoints) (p.ej. los anticuerpos anti‐PD‐1) han demostrado efectos antitumorales en pacientes con tumores malignos, incluido el cáncer de esófago. La reacción linfocítica detectada en estudios anatomopatológicos es una manifestación de la respuesta inmune del huésped a las células tumorales. Se estableció la hipótesis de que una mayor reacción linfocítica a los tumores podría asociarse con un mejor pronóstico en el cáncer de esófago.
Métodos
Usando una base de datos de 436 cánceres de esófago resecados, se evaluaron cuatro componentes morfológicos (peritumoral, intra‐epitelial, linfoide y estromal) de las reacciones linfocíticas a tumores en relación con los resultados clínicos, la expresión inmunohistoquímica de PD‐1 y el recuento total de linfocitos en sangre.
Resultados
De los cuatro componentes, solamente la reacción peritumoral se asoció con el pronóstico del paciente (P multivariable para tendencia < 0,001): los pacientes con mayor reacción peritumoral presentaron una supervivencia global significativamente más prolongada que aquellos pacientes con menor reacción peritumoral (cociente de riesgos instantáneos multivariable, hazard ratio, HR: 0,48; i.c. del 95%: 0,34 –0,67; P <0,001). El efecto pronóstico de la reacción peritumoral no se modificó significativamente por otras variables clínicas (todas las P para la interacción > 0,05). La reacción peritumoral se asoció con el recuento total de linfocitos en la sangre (P < 0,001), lo que respalda la relación entre la respuesta inmune local y la competencia inmune sistémica. Además, una elevada reacción morfológica peritumoral se asoció con una alta expresión de PD‐1 en linfocitos tumorales (P = 0,034).
Conclusión
Estos hallazgos deberían ayudar a mejorar las estrategias terapéuticas adaptadas al riesgo y contribuir a estratificar a los pacientes en el entorno clínico futuro de la inmunoterapia para los pacientes con cáncer de esófago.
Among four components of lymphocytic reactions, only peritumoral reaction was associated with patient prognosis in 436 patients with oesophageal cancer, suggesting higher peritumoral reaction as a prognostic marker. Peritumoral reaction was associated with total lymphocytes in the blood and programmed cell death protein 1 (PD‐1) expression on lymphocytes in tumours.
Will guide future immunotherapy
While statin intake has been proven to reduce the risk of colorectal cancer (CRC), the mechanism of antitumor effects and clinical significance in survival benefits remain unclear. Statin‐induced ...antiproliferative effects and its underlying mechanism were examined using six CRC cell lines. Statins except pravastatin showed antiproliferative effects (simvastatin ≥ fluvastatin > atorvastatin) even though both of simvastatin and pravastatin could activate mevalonate pathways, suggesting the statin‐mediated antiproliferative effects depended on non‐mevalonate pathway. Indeed, statin induced p27KIP1 expression by downregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2), which acts as an epigenetic gene silencer. Additionally, the use of simvastatin plus classII histone deacetylase (HDAC) inhibitor (MC1568) induced further overexpression of p27KIP1 by inhibiting HDAC5 induction originated from downregulated EZH2 in CRC cells and synergistically led to considerable antiproliferative effects. In the clinical setting, Statin intake (except pravastatin) displayed the downregulated EZH2 expression and inversely upregulated p27KIP1 expression in the resected CRC by immunohistochemical staining and resulted in the significantly better prognoses both in overall survival (p = 0.02) and disease free survival (p < 0.01) compared to patients without statin intake. Statins may inhibit tumor progression via an EZH2‐mediated epigenetic alteration, which results in survival benefits after resected CRC. Furthermore, statin plus classII HDAC inhibitor could be a novel anticancer therapy by their synergistic effects in CRC.
What's new?
Although statin use is associated with reduced colorectal cancer risk, the mechanism by which the drugs exert antitumor effects and their benefits for survival remain unclear. Here, experimental and clinical statin‐associated anticancer effects were found to differ for different kinds of statins. For example, while both simvastatin and pravastatin activated the mevalonate pathway in colon cancer cells, of the two drugs, only simvastatin displayed non‐mevalonate‐pathway antiproliferative effects via induction of p27KIP1 and epigenetic silencing by enhancer of zeste homolog 2 (EZH2). Statin‐induced downregulation of EZH2 and upregulation of p27KIP1 was associated with improved overall and disease‐free survival.
IntroductionSchizophrenia, a chronic and complex psychiatric pathology, can be isolated. However, it may have other comorbidities and thus be accompanied by addictive behaviors complicating their ...management.Objectivesto estimate the prevalence and identify the characteristics of addictive behavior among patients with schizophrenia.MethodsA retrospective study of 151 patients with schizophrenia and hospitalized in the psychiatry department of the Taher Sfar university hospital in Mahdia from January 2017 to December 2021.ResultsThe mean age of the patients was 39.8 ± 11.23 years with a predominance of age group 36-45 years (38.4%). All of the patients were males . Three quarters of patients (75.5%) were users of psychoactive substances (PSA): nearly three quarters (72.8%) dependent on tobacco, more than a third (39.7%) dependent on alcohol, more a quarter (29.1%) dependent on cannabis and almost a quarter (26.5%) dependent on other SPA. In more than half of the cases (54.4%), the age at which SPA consumption began was between 16 and 25. SPA use preceded the onset of schizophrenia in 62.3% of case. The relationship with the entourage was marked by hetero-aggressiveness in 77.5% of the patients, a withdrawal from the entourage for 16.6% of the patients and a conflict for 5.3% of the patients. The impact on the relationship with oneself was marked by self-aggressiveness in 18.5% of patients. Regarding professional impact, three quarters of patients (76.1%) had to stop working. The majority of patients (84.1%) continued their usual treatment, while 15.2% of patients stopped it. In only one patient increased doses were necessary.ConclusionsSubjects suffering from schizophrenia are particularly vulnerable to addictions, mainly to tobacco and alcohol. They are therefore a group at greater risk of harmful effects of psychoactive substances and at worsening the clinical course of their psychiatric illness. Screening and treatment measures their addictive behaviors early on, even before schizophrenia sets in, should be offered.Disclosure of InterestNone Declared
The inactivation of the Hippo pathway lead to TAZ (PDZ-binding motif)/YAP (yes-associated protein) overexpression, and is associated with worse prognostic outcomes in various cancers including ...hepatocellular carcinoma (HCC). Although there are several reports of microRNA (miR) targeting for YAP, miR targeting for TAZ remains unclear. The aim of this study is to identify the miR targeting TAZ expression in HCC.
MicroRNA expression was analysed using the Human miFinder 384HC miScript miR PCR array, and was compared between low and high TAZ expression cell lines. Then, we extracted miR-9-3p as a tumour-suppressor miR targeting TAZ. We examined the functional role of miR-9-3p using miR-9-3p mimic and inhibitor in HCC cell lines).
In HCC cell lines and HCC clinical samples, there was the inverse correlation between miR-9-3p and TAZ expressions. TAZ expression was induced by treatment of miR-9-3p inhibitor and was downregulated by treatment of miR-9-3p mimic. Treatment of miR-9-3p mimic inhibited cell proliferative ability with downregulated phosphorylations of Erk1/2, AKT, and β-catenin in HLF. Inversely, treatment of miR-9-3p inhibitor accelerated cell growth compared with control in HuH1.
MicroRNA-9-3p was identified as the tumour-suppressor miR targetting TAZ expression in HCC cells.
Using a novel Genetic Algorithm-based Compressive Learning (GACL), a compressed domain-learning framework is proposed that is implemented on the Haar wavelet approximation coefficient images of the ...standard kaggle RGB cat dog dataset with every images resized to <inline-formula> <tex-math notation="LaTeX">256 \times 256\,\,\times3 </tex-math></inline-formula>. The compressive sensing (CS) measurements on the selected dataset is achieved by using a simple reduced pixel scheme by retaining only <inline-formula> <tex-math notation="LaTeX">\mathrm {P\%} </tex-math></inline-formula> of the pixels of the approximation coefficient images and forcing the remaining pixels to 0 using the Primitive Walsh Hadamard (PWH) binary mask and the masked images are used for further learning. A numerical experiment is conducted to analyze the image classification performance of deep convolution neural network (DCNN) learning on compressive sensing (CS) measurements of wavelet approximation coefficient image of the selected dataset. The unmasked wavelet approximation coefficients images are of size only one fourth of the original image, but they visually resembles the original image. The numerical experiment shows that when learning is done on this unmasked wavelet approximation coefficient images a training accuracy of 97% and validation accuracy of 77% are achieved which is remarkable and as good as using the complete spatial domain image. It is found from numerical experiment that, when PWH masking with <inline-formula> <tex-math notation="LaTeX">P=10 </tex-math></inline-formula> is applied only to the test images the validation accuracy falls up to 58% and this fall is due to the fact that the training is done on unmasked images and tested on masked images. On the other hand in a compressive learning framework the DCNN is trained using masked images and when tested using masked images the validation accuracy rises up to 62% due to the fact both the trained images and test images are masked. Further, it is demonstrated that the best PWH masks can be learned by GACL in which the training accuracy increases up to 89% when vertical cross over is used in GACL and increases up to 96% when diagonal crossover is used in GACL. in this case of GACL using diagonal crossover, the 96% of training accuracy using only (10/4 = 2.5) 2.5% of the image is very remarkable and stand as proof of concept to implement compressive learning framework which need very less pixel thus very less measurement rate (MR) both in training and testing phase minimizing the bandwidth and storing requirement in applications related to IoT and cloud solutions. The average SSIM (<inline-formula> <tex-math notation="LaTeX">S_{\text {avg}} </tex-math></inline-formula>) and average PSNR (<inline-formula> <tex-math notation="LaTeX">{\text {PSNR}}_{\text {avg}} </tex-math></inline-formula>) are used as quality measurements, which reduce as P reduces, and it is demonstrated that the average SSIM and average PSNR improves when GACL is used to learn the mask, which is the key reason for the performance improvement.
Intraductal papillary mucinous neoplasm (IPMN), the most common pancreatic cystic neoplasm, is known to progress to invasive ductal adenocarcinoma. IPMNs commonly harbor activating somatic mutations ...in GNAS and KRAS, primarily GNAS(R201H) and KRAS(G12D). GNAS encodes the stimulatory G-protein α subunit (Gsα) that mediates a stimulatory signal to adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP), subsequently activating cAMP-dependent protein kinase A. The GNAS(R201H) mutation results in constitutive activation of Gsα. To study the potential role of GNAS in pancreatic tumorigenesis in vivo, we generated lines of transgenic mice in which the transgene consisted of Lox-STOP-Lox (LSL)-GNAS(R201H) under the control of the CAG promoter (Tg(CAG-LSL-GNAS)). These mice were crossed with pancreatic transcription factor 1a (Ptf1a)-Cre mice (Ptf1a(Cre/+)), generating Tg(CAG-LSL-GNAS);Ptf1a(Cre/+) mice. This mouse line showed elevated cAMP levels, small dilated tubular complex formation, loss of acinar cells and fibrosis in the pancreas; however, no macroscopic tumorigenesis was apparent by 2 months of age. We then crossed Tg(CAG-LSL-GNAS);Ptf1a(Cre/+) mice with LSL-Kras(G12D) mice, generating Tg(CAG-LSL-GNAS);LSL-Kras(G12D);Ptf1a(Cre/+) mice. We used these mice to investigate a possible cooperative effect of GNAS(R201H) and Kras(G12D) in pancreatic tumorigenesis. Within 5 weeks, Tg(CAG-LSL-GNAS);LSL-Kras(G12D);Ptf1a(Cre/+) mice developed a cystic tumor consisting of marked dilated ducts lined with papillary dysplastic epithelia in the pancreas, which closely mimicked the human IPMN. Our data strongly suggest that activating mutations in GNAS and Kras cooperatively promote murine pancreatic tumorigenesis, which recapitulates IPMN. Our mouse model may serve as a unique in vivo platform to find biomarkers and effective drugs for diseases associated with GNAS mutations.
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