To assess the effectiveness and the safety of radio-frequency thermal ablation (RFTA) in patients with hepatocellular carcinoma (HCC) ≤5
cm in compensated cirrhosis.
A cohort of 202 consecutive ...patients (165 Child-Pugh class A and 37 class B) was prospectively assessed. A single lesion was observed in 160/202 (79.2%), two lesions in 29/202 (14.3%), and three lesions in 13/202 (6.4%) of patients.
Sixty-seven patients died. Survival rates were 80% at 12 months, 67% at 24 months and 57% at 30 months (Child-Pugh A 59% and Child-Pugh B 48%). By Cox regression analysis, survival was independently predicted by serum albumin levels ≥35
g/L, platelet count ≥100.000/mmc, tumor size ≤3
cm, complete response at 1 month and Barcelona Clinic Liver Cancer (BCLC) staging classification. Overall recurrence rates were 22, 38, and 44% at 12, 24, and 30 months, respectively. One procedure-related death occurred. The proportion of major complications after treatment was 3.9%.
A complete response after RFTA significantly increases survival. The longest survival is obtained in the presence of HCC ≤3
cm and of higher baseline albumin levels and platelet counts. BCLC staging classification is able to discriminate patients with good or poor prognosis.
Mutations at the TP53 gene are readily detected (approximately 50–75%) in pancreatic ductal adenocarcinoma (PDAC) patients. TP53 was previously thought to be a difficult target as it is often ...mutated, deleted or inactivated on both chromosomes in certain cancers. In the following study, the effects of restoration of wild-type (WT) TP53 activity on the sensitivities of MIA-PaCa-2 pancreatic cancer cells to the MDM2 inhibitor nutlin-3a in combination with chemotherapy, targeted therapy, as well as, nutraceuticals were examined. Upon introduction of the WT-TP53 gene into MIA-PaCa-2 cells, which contain a TP53 gain of function (GOF) mutation, the sensitivity to the MDM2 inhibitor increased. However, effects of nutlin-3a were also observed in MIA-PaCa-2 cells lacking WT-TP53, as upon co-treatment with nutlin-3a, the sensitivity to certain inhibitors, chemotherapeutic drugs and nutraceuticals increased. Interestingly, co-treatment with nutlin-3a and certain chemotherapeutic drug such as irinotecan and oxaliplatin resulted in antagonistic effects in cells both lacking and containing WT-TP53 activity. These studies indicate the sensitizing abilities that WT-TP53 activity can have in PDAC cells which normally lack WT-TP53, as well as, the effects that the MDM2 inhibitor nutlin-3a can have in both cells containing and lacking WT-TP53 to various therapeutic agents.
Chronic kidney disease is a risk factor for oral diseases, which may be associated with premature death. We evaluated the risk of all-cause and cardiovascular mortality associated with oral mucosal ...lesions in adults with kidney failure treated with long-term haemodialysis.
Oral mucosal lesions (herpes, ulceration, neoformation, white lesion, red lesion, oral candidiasis, geographical tongue, petechial lesions, and fissured tongue) were evaluated within the Oral Diseases in Haemodialysis (ORAL-D) study, a multinational cohort study of 4726 haemodialysis adults. We conducted cox regression analyses adjusted for demographic and clinical variables to evaluate the association with all-cause and cardiovascular mortality.
Overall, 4205 adults (mean age 61.6 ± 15.6 years) underwent oral mucosal examination with 40% affected by at least one lesion. The prevalence of oral lesions was (in order of frequency): oral herpes 0.5%, mucosal ulceration 1.7%, neoformation 2.0%, white lesion 3.5%, red lesion 4.0%, oral candidiasis 4.6%, geographical tongue 4.9%, petechial lesions 7.9%, and fissured tongue 10.7%. During median follow-up of 3.5 years, 2114 patients died (1013 due to cardiovascular disease). No association was observed between any individual oral lesion and all-cause or cardiovascular mortality when adjusted for comorbidities, except for oral candidiasis, which was associated with all-cause mortality (adjusted hazard ratio 1.37, 95% CI 1.00 to 1.86) and cardiovascular mortality (adjusted hazard ratio 1.64, 95% CI 1.09 to 2.46).
Oral mucosal lesions are prevalent in haemodialysis patients. Oral candidiasis appears to be a risk factor for death due to cardiovascular diseases.
In patients with COVID-19 respiratory failure, controlled mechanical ventilation (CMV) is often necessary during the acute phases of the disease. Weaning from CMV to pressure support ventilation ...(PSV) is a key objective when the patient's respiratory functions improve. Limited evidence exists regarding the factors predicting a successful transition to PSV and its impact on patient outcomes.
Retrospective observational cohort study.
Twenty-four Italian ICUs from February 2020 to May 2020.
Mechanically ventilated ICU patients with COVID-19-induced respiratory failure.
The transition period from CMV to PSV was evaluated. We defined it as "failure of assisted breathing" if the patient returned to CMV within the first 72 hours.
Of 1260 ICU patients screened, 514 were included. Three hundred fifty-seven patients successfully made the transition to PSV, while 157 failed. Pao
/Fio
ratio before the transition emerged as an independent predictor of a successful shift (odds ratio 1.00; 95% CI, 0.99-1.00;
= 0.003). Patients in the success group displayed a better trend in Pao
/Fio
, Paco
, plateau and peak pressure, and pH level. Subjects in the failure group exhibited higher ICU mortality (hazard ratio 2.08; 95% CI, 1.42-3.06;
< 0.001), an extended ICU length of stay (successful vs. failure 21 ± 14 vs. 27 ± 17 d;
< 0.001) and a longer duration of mechanical ventilation (19 ± 18 vs. 24 ± 17 d,
= 0.04).
Our study emphasizes that the Pao
/Fio
ratio was the sole independent factor associated with a failed transition from CMV to PSV. The unsuccessful transition was associated with worse outcomes.
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy. Approximately 85% of pancreatic cancers are classified as PDACs. The survival of PDAC patients is very poor and only 5–10% ...of patients survive 5 years after diagnosis. Mutations at the KRAS and TP53 gene are frequently observed in PDAC patients. The PANC-28 cell line lacks wild-type (WT) TP53. In the following study, we have investigated the effects of restoration of WT TP53 activity on the sensitivity of PANC-28 pancreatic cancer cells to various drugs which are used to treat PDAC patients as well as other cancer patients. In addition, we have examined the effects of signal transduction inhibitors which target critical pathways frequently deregulated in cancer. The effects of the anti-diabetes drug metformin and the anti-malarial drug chloroquine were also examined as these drugs may be repurposed to treat other diseases. Finally, the effects of certain nutraceuticals which are used to treat various ailments were also examined. Introduction of WT-TP53 activity in PANC-28 PDAC cells, can increase their sensitivity to various drugs. Attempts are being made clinically to increase TP53 activity in various cancer types which will often inhibit cell growth by multiple mechanisms.
IntroductionAndrogen receptor (AR) expression in breast cancer growth and progression appears to be clinically relevant and disease context specific. In oestrogen receptor (ER)α-positive primary ...breast cancers, AR positivity correlates with lower tumour grade and a better clinical outcome. These clinical-pathological findings mirror the capability of androgens to counteract ERα-dependent proliferation in both normal mammary epithelium and ERα-positive breast cancer preclinical models in which androgen/AR-dependent pro-apoptotic effects have been also evidenced.Here we report a novel additional mechanism underlining the protective, anti-proliferative role exerted by AR signalling. This mechanism involves modulation of the expression, cellular distribution and function of BAD, a pro-apoptotic member of the Bcl-2 family proteins, whose expression is related to a significantly better disease free survival in (ER)α-positive human breast cancers.Material and methodsMCF-7, TD47D, ZR-75 breast cancer cells; qReal Time PCR; western blotting (WB); immunofluorescence analysis (IF); immunoprecipitation assay (IP); DNA affinity precipitation assay; Chromatin Immunoprecipitation Assay.Results and discussionsThe expression of a panel of pro/anti-apoptotic proteins was investigated in cellular protein lysates from ERα/AR-positive MCF-7 cells cultured for 1, 3 and 6 days under androgen treatment. The expression of the anti-apoptotic Bcl-2 protein, or the pro-apoptotic BID and BAX remained unchanged, while a sustained increase in the expression of the pro-apoptotic BAD could be observed, reducing the Bcl-2/BAD ratio and, thus, shifting the delicate balance between inhibitors and inducers of cell death. Interestingly, androgens induced a marked BAD levels increase into the nuclear compartment in ERα/AR-positive MCF-7, T47D and ZR-75 as well as in ERα negative/AR-positive SKBR3 cells. The androgen-regulated intracellular localization of BAD involved an AR/BAD physical interaction, suggesting a nuclear role for BAD upon androgen stimulation. Indeed, androgens induced both AR and BAD recruitment at a AP-1 and at a ARE site within the cyclin D1 promoter region, contributing to explain the anti-proliferative effect of androgens in breast cancer cells.ConclusionWe defined a novel mechanism by which androgens modulate BAD expression and force its ability to act as a cell cycle inhibitor through modulation of cyclin D1 gene transcriptional activity, strengthening the protective role of androgen signalling in estrogen-responsive breast cancer.
IntroductionProgesterone Receptor (PR) positivity is associated with a good prognosis and better response to breast cancer treatment. Conversely, cyclin D1 (CD1) is retained a marker of poor outcome ...since it has been associated with breast cancer metastasis in clinical studies.Material and methods17-Hydroxyprogesterone (OHPg) was from Sigma-Aldrich. Antibodies and Protein A/GPLUS-Agarose were from Santa Cruz Biotechnology. T47-D, MCF-7 and MDA-MB-231 human breast cancer cells from the American Type Culture Collection; Total real-time RT-PCR assay; Western blotting and immunoprecipitation; Transfections and luciferase assays; Lipid-Mediated Transfection of siRNA Duplexes; Chromatin immunoprecipitation (ChIP) assays and realtime ChIP; Wound-healing assays; Transmigration assays; Cell invasion assay; Phalloidin staining.Results and discussionsHerein we provide evidences that OHPg through PR-B isoform, reduces motility and invasion of T47-D and MCF-7 breast cancer cells, by targeting the cytoplasmic CD1. Specifically, OHPg reduces CD1 expression through a transcriptional mechanism due to the occupancy of CD1 promoter at a canonical half progesterone responsive element by PR-B. This allows the recruitment of HDAC1 influencing a less permissive chromatin conformation for gene transcription and the release of RNA Pol II. CD1 has an active role in the control of cell migration and metastasis through the interaction with key components of focal adhesion such as Paxillin (Pxn). In untreated T47-D and MCF-7 cells a specific co-immunoprecipitation of endogenous cytoplasmic CD1 with Pxn was detected. Interestingly, OHPg exposure reduced the interaction between these proteins although total Pxn expression was substantially unaffected. Moreover a concomitant reduction of p-Pxn levels was observed and these effects were required for OHPg/PR-B dependent delay in cell invasion, as evidenced by assays carried out with the phoshomimetic mutants of Pxn.ConclusionCollectively these findings support the importance of PR-B expression in breast cancer cells behaviour, suggesting potentiating of PR-B signalling as a prospective useful strategy to restrict breast tumour cells invasion and metastasis.
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