NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome has recently become an intriguing target of several chronic and viral diseases. Here, we argue that targeting NLRP3 inflammasome ...could be a strategy to prevent cardiovascular outcomes fulminant myocarditis, heart failure, venous thromboembolism (VTE) and acute respiratory distress syndrome (ARDS) in patients with SARS-CoV-2 infection. We discuss the rationale for NLRP3 targeting in clinical trials as an effective therapeutic strategy aimed to improve prognosis of COVID-19, analyzing the potential of two therapeutic options (tranilast and OLT1177) currently available in clinical practice.
Midface Lift: Our Current Approaches Botti, G.; Botti, C.
Handchirurgie, Mikrochirurgie, plastische Chirurgie,
08/2014, Volume:
46, Issue:
4
Journal Article
Open access
Abstract
In the last few years, surgery of the ageing face seems to have shifted from tissue uplifting and tightening to mere filling. We do not agree with this trend. We are positive that ageing ...brings about 2 basic phenomena: on one hand bone and fat volume reduction, whilst on the other a deterioration of the skin lining (elastosis) leading to an increase in its compliance and extension. We therefore deem of the utmost importance to couple soft tissue filling with indispensable tightening and repositioning together with resection of overabundant skin. For what concerns the mid-face area in particular, we suggest to resort to 3 different lifting techniques, according to the kind of defect to be treated. It is important to take the right pulling vector into consideration as well as the need of skin excess removal. The procedures can be tailored to suit any peculiar need such as malar bag, lower lid border malposition, tear trough deformity, etc. Different cases will be taken into consideration as examples of the various indications and techniques.
Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. However, their efficacy is ...thought to be limited by feedback loops and crosstalk with other pathways leading to the development of drug resistance. As CXCR4-CXCL12-CXCR7 axis has been described to have a crucial role in renal cancer; the crosstalk between the mTOR pathway and the CXCR4-CXCL12-CXCR7 chemokine receptor axis has been investigated in human renal cancer cells. In SN12C and A498, the common CXCR4-CXCR7 ligand, CXCL12, and the exclusive CXCR7 ligand, CXCL11, activated mTOR through P70S6K and 4EBP1 targets. The mTOR activation was specifically inhibited by CXCR4 antagonists (AMD3100, anti-CXCR4-12G5 and Peptide R, a newly developed CXCR4 antagonist) and CXCR7 antagonists (anti-CXCR7-12G8 and CCX771, CXCR7 inhibitor). To investigate the functional role of CXCR4, CXCR7 and mTOR in human renal cancer cells, both migration and wound healing were evaluated. SN12C and A498 cells migrated toward CXCL12 and CXCL11; CXCR4 and CXCR7 inhibitors impaired migration and treatment with mTOR inhibitor, RAD001, further inhibited it. Moreover, CXCL12 and CXCL11 induced wound healing while was impaired by AMD3100, the anti CXCR7 and RAD001. In SN12C and A498 cells, CXCL12 and CXCL11 promoted actin reorganization characterized by thin spikes at the cell periphery, whereas AMD3100 and anti-CXCR7 impaired CXCL12/CXCL11-induced actin polymerization, and RAD001 treatment further reduced it. In addition, when cell growth was evaluated in the presence of CXCL12, CXCL11 and mTOR inhibitors, an additive effect was demonstrated with the CXCR4, CXCR7 antagonists and RAD001. RAD001-resistant SN12C and A498 cells recovered RAD001 sensitivity in the presence of CXCR4 and CXCR7 antagonists. In conclusion, the entire axis CXCR4-CXCL12-CXCR7 regulates mTOR signaling in renal cancer cells offering new therapeutic opportunities and targets to overcome resistance to mTOR inhibitors.
Evidence on adjuvant chemotherapy for elderly early breast cancer patients is poor, due to the low number of phase 3 trials. ELDA shows that weekly docetaxel does not prolong DFS compared with ...standard CMF and worsens quality of life. Non-hematological toxicity is worse with weekly docetaxel. Age, comorbidities and functioning geriatric scales may be predictive of non-hematological side effects.
Evidence on adjuvant chemotherapy in older women with breast cancer is poor. We tested whether weekly docetaxel is more effective than standard chemotherapy.
We carried out a multicenter, randomized phase III study. Women aged 65–79, operated for breast cancer, with average to high risk of recurrence, were allocated 1 : 1 to CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m², days 1, 8) or docetaxel (35 mg/m2 days 1, 8, 15) every 4 weeks, for four or six cycles according to hormone receptor status. Primary end point was disease-free survival (DFS). A geriatric assessment was carried out. Quality of life (QoL) was assessed with EORTC C-30 and BR-23 questionnaires.
From July 2003 to April 2011, 302 patients were randomized and 299 (152 allocated CMF and 147 docetaxel) were eligible. After 70-month median follow-up, 109 DFS events were observed. Unadjusted hazard ratio (HR) of DFS for docetaxel versus CMF was 1.21 95% confidence interval (CI) 0.83–1.76,P = 0.32; DFS estimate at 5 years was 0.69 with CMF and 0.65 with docetaxel. HR of death was 1.34 (95% CI 0.80–2.22,P = 0.26). There was no interaction between treatment arms and geriatric scales measuring patients' ability or comorbidities. Hematological toxicity, mucositis and nausea were worse with CMF; allergy, fatigue, hair loss, onychopathy, dysgeusia, diarrhea, abdominal pain, neuropathy, cardiac and skin toxicity were worse with docetaxel. One death was attributed to CMF and two to docetaxel. Increasing age, impairment in instrumental daily living activities, number of comorbidities and docetaxel treatment were independently associated with severe nonhematological toxicity. QoL was worse with docetaxel for nausea-vomiting, appetite loss, diarrhea, body image, future perspective, treatment side-effects and hair loss items.
Weekly docetaxel is not more effective than standard CMF as adjuvant treatment of older women with breast cancer and worsens QoL and toxicity.
NCT00331097.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Objective Human papillomavirus (HPV) genotypes have been extensively studied in uterine cervix squamous cell carcinoma and HPV16 variants have been found to be associated with increased ...cancer risk, but few reports have been published on genotype distribution and HPV16 variant prevalence in adenocarcinoma tumors. The objective of this study was to analyze viral genotypes and HPV16 intratypic variants in cervical adenocarcinoma and squamous cell carcinoma of Italian women. Methods A total of 39 invasive adenocarcinoma and 132 squamous cell carcinoma were reviewed and classified according to the modified WHO classification. HPV sequences were detected by nested PCR, using the broad spectrum consensus–primer pairs MY09/MY11 and the GP5+/GP6+ system, and genotyped by nucleotide sequence analysis. The HPV16-positive cases were amplified with E6-specific oligonucleotides and amplimers subjected to direct nucleotide sequence for variant identification. Results The prevalence rate of any HPV infection was 72% in adenocarcinoma, and 85% in cervical squamous cell carcinoma. Among the 140 HPV-positive cancer cases, a total of nine mucosal HPV genotypes (HPV16, 18, 31, 33, 35, 39, 45, 58, 82) epidemiologically classified as carcinogenic or probably carcinogenic viruses were identified. The HPV type 16 was the most common viral type representing 64% and 73% of all infections in adenocarcinoma and squamous cell carcinoma, respectively. The E6 nucleotide sequence analysis of HPV16 isolates allowed the identification of Asian American (AA) variants in 33% of adenocarcinoma and in 20% of squamous cell carcinoma suggesting their stronger association with cancer of glandular origin. Conclusion These results suggest that HPV16 has a high prevalence in both invasive adenocarcinoma and squamous cell carcinoma from Italian patients. Moreover this study confirms previous observations, summarized in a systematic review of the literature, on the increased cancer risk of HPV16 AA class in adenoglandular cancer, possibly related to their more oncogenic behavior compared to HPV16 European variants.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mollo A, Botti G, Prinicipi Goldoni N, Randellini E, Paragliola R, Chazine M, Ounsi HF, Grandini S. Efficacy of two Ni‐Ti systems and hand files for removing gutta‐percha from root canals. ...International Endodontic Journal, 45, 1–6, 2012.
Aim To compare the effectiveness of two Ni‐Ti systems and hand files for removing gutta‐percha and sealer from root canals.
Methodology The root canals of 60 single‐rooted human teeth were prepared, filled with gutta‐percha and sealer (Pulp Canal Sealer; SybronEndo, Orange, CA, USA). Specimens were then divided into three groups (n = 20), and root filling material was removed using MTwo Retreatment Files (group 1); R‐Endo (group 2); K‐files and Gates‐Glidden drills (group 3). After retreatment, the efficacy of each technique was assessed using radiographs that were later digitized and the images analysed using AutoCAD 2004. The percentage of residual gutta‐percha was calculated for the whole canal as well as for the coronal, middle and apical thirds. Time required, apically extruded debris and the number of fractured instruments were also recorded. Data were statistically analysed using Kruskal–Wallis and Mann–Whitney U‐tests.
Results All instrumentation techniques left gutta‐percha and sealer remnants inside the root canals. Ni‐Ti systems were significantly faster (P < 0.05) than the manual technique and significantly more effective (P < 0.05) in removing gutta‐percha particularly from the middle and apical thirds of the root canal. R‐Endo instrumentation was significantly more effective (P < 0.05) than MTwo retreatment files in removing gutta‐percha from the middle and apical thirds. R‐Endo instruments were associated with the least number of cases of apical extrusion. One MTwo instrument fractured.
Conclusions The Ni‐Ti systems were more effective and faster than hand files, although all techniques left gutta‐percha and sealer remnants on the root canals.
Full text
Available for:
BFBNIB, CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Genito-urinary malignancies (prostate, bladder, renal and testicular cancers) rank high among human tumors with an incidence that varies with age and organ involvement. Prostate cancer is the most ...commonly detected male cancer followed by bladder and kidney cancers, less frequent in women. Testicular cancer, although rare, is the most frequent cancer in males under 35. The majority of oncogenic and tumor suppressor signaling pathways involved with urogenital cancers converge on sets of transcription factors that ultimately control gene expression resulting in tumor formation and metastatic progression. The activity of these transcription factors is modulated by multiple mechanisms spanning from transcriptional regulation, deregulation of the splicing, maturation, export and location of mRNAs, protein synthesis and post-translational modifications. The recent involvement of the epigenitic mechanisms in the generation and the evolution of cancer has produced a great deal of interest. This is related to the possibility that revealing these mechanisms able to regulate the cell memory program (the gene systems polycomb, trithorax and HOX) may generate important biological and therapeutic achievements. The HOX gene network is the only physically and functionally identifiable transcription factor network located in the human genome controlling crucial cellular processes. Here we describe the implication of the HOX genes in the urogenital embryonic development and cancers. We further highlight the mechanisms uncovered along these processes and involving the HOX genes. Finally, we foresee the specific targeting of HOX genes and in general the cell memory gene program in the therapeutic setting of urogenital malignancies due to their upstream location in these stepwise cell processes and their early deregulation in cancer evolution.
We investigated pretreatment fasting glucose as a predictor of patients’ important outcomes in breast and colorectal cancers undergoing targeted therapies.
In a historic cohort of 202 breast and 218 ...colorectal cancers treated with targeted agents from 1998 to 2009, we used the Kaplan–Meier method and the log-rank test to estimate survival through tertiles of fasting glucose and the Cox proportional hazards model for multivariate analysis stratified by primary site of cancer and including gender, age and body mass index.
The median follow-up was 20 months (1–128). At 60 months, 65% of patients in the lowest tertile of fasting glucose did not experiment disease progression compared with 34% in the highest tertile (P = 0.001). Seventy-six percent of females in the lowest tertile showed no progression compared with 49% in the top tertiles (P = 0.015). In multivariate analysis, fasting glucose was a significant predictor of time to disease progression only in breast cancer patients in the first tertile compared with the third (P = 0.017).
We found evidence of a predictive role of pretreatment fasting glucose in the development of resistance in breast cancer patients treated with targeted agents. Prospective studies are warranted to confirm our findings.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Epigenetic DNA methylations plays an important role in oral carcinogenesis. The soluble frizzled receptor protein (SFRP) family together with WIF-1 and DKK-3 encodes antagonists of the WNT pathway. ...Silencing of these genes leads to constitutive WNT signalling. Because aberrant expression of beta-catenin might be associated with the epigenetic inactivation of WNT inhibitors, we analyzed, in a collection of primary OSCC with matched normal oral mucosa, the methylation status of a complete panel of genes, SFRP-1, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3, that are involved directly and indirectly in WNT pathway, in order to demonstrate WNT-pathway activation in the absence of beta-catenin and/or APC/Axin mutations during oral carcinogenesis. Methylation-specific PCR (MSP) was performed to study inactivation of SFRP-1, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3 genes in 37 cases of paraffin embedded oral cancer. This study showed that the methylation is an important epigenetic alteration in oral cancer. In particular, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3 revealed methylation status of their promoter in OSCC, whereas SFRP-1 showed demethylation in cancer. Fisher's exact test revealed statistically significant results (p<0.05) for all genes. The Wald test confirmed the statistically significant association between SFRP2-4-5 gene methylation and OSCC (p<0.05). SFRP-1 was also characterized by a different statistically significant epigenetic behaviour, because of it was demethylated in cancer (p<0.05). Statistical regression test showed high levels of sensitivity, specificity and accuracy for SFRP genes, while WIF-1 and DKK-3 have reportedly high specificity, moderate accuracy but low sensitivity. This study suggests that a cause of catenin delocalization in oral cancer could be due to WNT pathway activation, by epigenetic alterations of SFRP, WIF-1 and DKK-3 genes.
PDF
