Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium-Chrysin Polyurea Dendrimer Nanoformulation

The research was funded by iNOVA4Health UID/Multi/04462, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência (FCT-MCTES), through national funds, and co-funded by FEDER under the PT2020 Partnership Agreement. We also acknowledge funding from FCT-MCTES through project DREAM PTDC/MEC-ONC/29327/2017.Ovarian cancer is the main cause of death from gynecological cancer, with its poor prognosis mainly related to late diagnosis and chemoresistance (acquired or intrinsic) to conventional alkylating and reactive oxygen species (ROS)-generating drugs. We and others reported that the availability of cysteine and glutathione (GSH) impacts the mechanisms of resistance to carboplatin in ovarian cancer. Different players in cysteine metabolism can be crucial in chemoresistance, such as the cystine/glutamate antiporter system Xc (xCT) and the H2S-synthesizing enzyme cystathionine β-synthase (CBS) in the pathway of cysteine catabolism. We hypothesized that, by disrupting cysteine metabolic flux, chemoresistance would be reverted. Since the xCT transporter is also able to take up selenium, we used selenium-containing chrysin (SeChry) as a plausible competitive inhibitor of xCT. For that, we tested the effects of SeChry on three different ovarian cancer cell lines (ES2, OVCAR3, and OVCAR8) and in two non-malignant cell lines (HaCaT and HK2). Results showed that, in addition to being highly cytotoxic, SeChry does not affect the uptake of cysteine, although it increases GSH depletion, indicating that SeChry might induce oxidative stress. However, enzymatic assays revealed an inhibitory effect of SeChry toward CBS, thus preventing production of the antioxidant H2S. Notably, our data showed that SeChry and folate-targeted polyurea dendrimer generation four (SeChry@PUREG4-FA) nanoparticles increased the specificity for SeChry delivery to ovarian cancer cells, reducing significantly the toxicity against non-malignant cells. Collectively, our data support SeChry@PUREG4-FA nanoparticles as a targeted strategy to improve ovarian cancer treatment, where GSH depletion and CBS inhibition underlie SeChry cytotoxicity.publishersversionpublishe

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

xCT (SLC7A11)- Antiporter system role in ovarian cancer chemoresistance.

Ovarian cancer is the main cause of death among gynaecologic diseases and the most wide-spread malignancy in women over 40 years of age after breast cancer. The causes of that situa-tion are substantially three: the histological and molecular heterogeneity; the late diagnosis and detection and finally chemoresistance. Epithelial ovarian cancer, called carcinomas, is the most common (85-90%) and comprehend two different histotypes based on their type of chemoresistance: ovarian serous carcinoma (OSC) characterized by an acquired chemo-resistance and ovarian clear cell carcinoma (OCCC) that shows an intrinsic form of chemo-resistance. Considering that chemoresistance is the reduction of the efficiency of chemotherapy and that glutathione (GSH) is able to nick platinum-based drug effectiveness, the main role of GSH and cysteine (rate-limiting substrate for GSH synthesis), in ovarian cancer, was hypothe-sized. Since the main role of xCT/SLC7A11 in cyst(e)ine transport, we decided to investigate the role of that protein in ovarian cancer chemoresistance using three ovarian cancer cell lines (ES2, OVCAR3 and OVCAR8), upon exposure to cysteine and cisplatin. Therefore, sustaining the idea that NF E2 Relator Factor 2 (NRF2) was able to regulate the xCT/SLC7A11 transcription (in stressful conditions) by binding ARE enhancer sequence in xCT/SLC7A11 promoter, the cells were exposed to Selenium-containing Chrysin (SeChry) that was reported to largely impact xCT expression. Our results, confirmed the role of cysteine in the protection against the damages caused by platinum drugs and the role of xCT in the transport of cysteine, enhancing chemo-resistance. Concerning SeChry impacts NRF2 binding xCT/SLC7A11 promoter, the results preliminarily showed that NRF2 has a role in xCT/SLC7A11 expression in OVCAR3 cells exposed to SeChry. The results of that thesis have contributed to publish an article on Nutrients: “Targeting Gluta-thione and Cystathione β-Synthase in Ovarian Cancer Treatment by Selenium-Chrysin Polyurea Dendrimer Nanoformulation”

Long-term follow-up after endoscopic forceps biopsies for early stage duodenal carcinoid: case report and review of endoscopic treatments

IF 4.07

Long-Term oncologic results and complications after preoperative chemoradiotherapy for rectal cancer: a Single-Institution experience after a median Follow-Up of 95 months.

Background This study sought to evaluate the long-term outcome and complications, and occurrence of second malignancy after preoperative chemoradiotherapy (pCRT) for rectal cancer. Methods One hundred twenty-three consecutive patients (78 men, 45 women) with locally advanced mid-low rectal cancer underwent pCRT between 1994 and 2002. Patients were followed up by one surgeon with a standard protocol, and data were prospectively recorded in a dedicated database. No patient was lost to follow-up. Complications were defined as late if they occurred >6 months after surgery. Overall and disease-free survival were calculated by the Kaplan-Meier method. Results Of 123 patients, 111 underwent an R0 procedure. The rate of pathologic complete response was 16% (n = 20 patients). At a median follow-up of 95 (range, 56–160) months, 50 late complications occurred in 41 patients, 21 of whom required surgery. In seven cases, the complications were clearly CRT related and were significantly associated with the total dose of radiation delivered (P < .05). The estimated 5- and 10-year overall survival was 76% and 67%, respectively. The estimated 5- and 10-year disease-free survival was 83% and 82%, respectively. In 18 of 19 patients who experienced recurrence (local, n = 3; distant, n = 16), it occurred within 48 months from surgery. The most frequent site of metastasis as first site of recurrence was the lung (9 of 19). The most frequent second primary malignancy was lung cancer (3 of 8). Conclusions Despite satisfactory oncological outcome, late morbidity after pCRT is relevant and related to the radiotherapy dose used. Most recurrences and second malignancies were located in the lung

Rectum-sparing surgery may be appropriate for biallelic MutYH-associated polyposis.

Abstract PURPOSE: The risk of cancer or severe polyposis of the rectal stump after total colectomy for MutYH-associated polyposis is scarcely defined. To evaluate this risk, we describe the findings of endoscopic surveillance of the rectal stump in a series of patients with biallelic MutYH mutations and polyposis. METHODS: This is a retrospective, observational, multicenter case series derived from 2 familial cancer registries. Biallelic, germ-line MutYH mutations were found in 14 patients with no adenomatous polyposis coli gene mutations. Eleven of them underwent total colectomy with ileorectal anastomosis and yearly proctoscopic surveillance thereafter. Phenotype and histology of rectal polyps were recorded at diagnosis and during follow-up. Development of adenomas and carcinomas during endoscopic surveillance of the rectal stump was observed. RESULTS: At diagnosis, 6 patients had attenuated polyposis (10-100 adenomas), 5 patients had classical polyposis, 8 patients had colon carcinoma, and no patient had rectal carcinoma. The mean number of rectal polyps at diagnosis was 2.64 \ub1 2.11 (range, 0-6). No patients had rectal cancer. The most frequent MutYH mutations were Y165C/Y165C and G382D/G382D in 6 and 2 patients, respectively. During surveillance of the rectal stump after surgery (median duration, 5 y; range, 2-23 y), no patient developed rectal cancer. The mean number of adenomas per proctoscopy was 1.23 \ub1 2.19 (range, 0-10 adenomas per proctoscopy). This study was limited by the small size and retrospective nature of the case series. CONCLUSION: Total colectomy with ileorectal anastomosis may be appropriate for patients with MutYH-associated polyposis, provided that they have no rectal cancer or severe rectal polyposis at presentation and that they undergo yearly endoscopic surveillance thereafter

Proximal colon cancer in patients aged 51-60 years of age should be tested for microsatellites instability. A comment on the Revised Bethesda Guidelines.

IF: 1,918 Abstract: Purpose The Bethesda guidelines suggest to perform microsatellite instability (MSI) test in early onset rectal cancer and not in patients > 50 years with proximal colon cancer. The aim of the study was to evaluate whether the risk of high MSI (MSI-H) is greater in proximal colon cancer of patients 51-60 years old than in early-onset rectal cancer. Methods Consecutive colorectal cancer (CRC) patients were evaluated. Tumor location, cancer family history, MSI status and histology were recorded. Mutations in MLH1/MSH2 were investigated in MSI-H tumors. Patients were subdivided into groups: group A, proximal colon cancer patients 51-60 years old and groups B, C and D, patients <= 50 years old, with rectal cancer, proximal and distal colon cancer, respectively. Results Out of 409 CRC patients evaluated, 48 (12%) showed tumors with MSI-H. No MSI-H tumors were found in distal and rectal tumors of patients at sixth decade of life. Group A included 27 patients, eight (29.7%) MSI-H cancers, four missense mutations in MLH1/MSH2; groups B, C and D included 26, 11 and 11 patients with two (7.7%), two (18%) and two (18%) MSI-H cancers, respectively. One missense mutation on MSH2 in group B, one pathogenetic mutation on MSH1 in group C and one pathogenetic mutation on MSH2 in group D were found. Tumors of group A showed an increased probability to have MSI-H if compared to those of group B (OD=4.907, p=0.043). Conclusions The Bethesda criteria should be broadened to include patients 51-60 years old with proximal colon cancer