Morphological characteristics of non-carious cervical lesions. A systematic review.

OBJECTIVES: This systematic review assessed the morphological characteristics of non-carious cervical lesions (NCCL), among clinical and ex-vivo studies assessed by observational and imaging methods. DESIGN: The search strategy was conducted on four online databases (MEDLINE, Embase, Scopus and Web of Science) and grey literature (Google Scholar and OpenGrey). The study selection was performed by three reviewers from March to September (2023). The eligibility criteria were established according to the PICO strategy and included NCCL, morphological characteristics and clinical and ex-vivo study designs. The data extraction considered general data that identifies the study, evaluation method, parameter to assess the outcome and the main results for each study. The risk of bias was evaluated using Joanna Briggs Institute critical appraisal tool, and a personalized tool. RESULTS: The search resulted in 252 studies. A total of 14 studies were included. Prevalence of NCCLs ranged from 3.5 %to 77.78 % with a higher presence in premolars. Common characteristics were wear facets, occluded tubules or cracks, occlusal stress, scratch marks, dimples and craters, structure loss, and dentin sclerosis, which appear more often on buccal surface and were generally classified as wedge-shaped, saucer-shaped. Etiological hypothesis was mainly related to multifactorial factors. In most of the studies, the risk of bias was classified as high. CONCLUSIONS: The morphological characteristics of NCCL showed a wide range of descriptions regarding appearance, prevalence, lesion-related measures, and macro and microscopic descriptions.

Maternal Hypertriglyceridemia in Gestational Diabetes: A New Risk Factor?

Elevated maternal triglycerides (TGs) have been associated with excessive fetal growth. However, the role of maternal lipid profile is less studied in gestational diabetes mellitus (GDM). We aimed to study the association between maternal lipid profile in the third trimester and the risk for large-for-gestational-age (LGA) newborns in women with GDM. We performed an observational and retrospective study of pregnant women with GDM who underwent a lipid profile measurement during the third trimester. We applied a logistic regression model to assess predictors of LGA. A total of 100 singleton pregnant women with GDM and third-trimester lipid profile evaluation were included. In the multivariate analysis, pre-pregnancy BMI (OR 1.19 (95% CI 1.03-1.38), p = 0.022) and hypertriglyceridemia (OR 7.60 (1.70-34.10), p = 0.008) were independently associated with LGA. Third-trimester hypertriglyceridemia was found to be a predictor of LGA among women with GDM, independently of glycemic control, BMI, and pregnancy weight gain. Further investigation is needed to confirm the role of TGs in excessive fetal growth in GDM pregnancies.

Clinical utility of rapid shallow breathing index in predicting successful weaning: secondary analysis of the COBRE-US trial.

OBJECTIVE: To assess the predictive capacity of the Rapid Shallow Breathing Index (RSBI) for success in spontaneous breathing trials (SBT) and extubation in critically ill patients. We evaluated the association between RSBI, duration of mechanical ventilation, and ventilator-free time at 28 days. DESIGN: Prospective multicenter observational study. Secondary analysis of the COBRE-US study. SETTING: Intensive care unit (ICU). PATIENTS OR PARTICIPANTS: 367 patients in the ICU receiving invasive mechanical ventilation. INTERVENTIONS: Assessment of RSBI at the end of SBT. MAIN VARIABLES OF INTEREST: RSBI, SBT, duration of mechanical ventilation, and ventilator-free time at 28 days were evaluated. RESULTS: 367 patients in the ICU under invasive mechanical ventilation were evaluated, of whom 59.7% were male with a median age of 61 years (IQR: 49-72). A total of 456 SBT were conducted with a success rate of 76.5%. RSBI had a ROC-curve of 0.53 for SBT success and a ROC-curve of 0.48 for extubation. The Spearman correlation coefficient between RSBI and duration of ventilation was 0.117 (p = 0.026), while for ventilator-free time at 28 days, it was -0.116 (p = 0.028). CONCLUSIONS: RSBI was not associated with success in SBT or extubation, regardless of the cutoff point used. Correlation analyses showed weak associations between RSBI and both the duration of ventilation and ventilator-free time at 28 days.

Assessing the reproducibility and predictive value of objective cough measurement for successful withdrawal of invasive ventilatory support in adult patients.

BACKGROUND: Utilizing clinical tests, such as objective cough measurement, can assist in predicting the success of the weaning process in critically ill patients. METHODS: A multicenter observational analytical study was conducted within a prospective cohort of patients recruited to participate in COBRE-US. We assessed the capability of objective cough measurement to predict the success of the spontaneous breathing trial (SBT) and extubation. Intra- and inter-observer reproducibility of the cough test and was evaluated using the intraclass correlation coefficient (ICC) and Cohen's weighted kappa. We used receiver operating characteristic curves (ROC-curve) to evaluate the predictive ability of objective cough measurement. RESULTS: We recruited 367 subjects who were receiving invasive mechanical ventilation. A total of 451 objective cough measurements and 456 SBTs were conducted. A significant association was found between objective cough measurement and successful SBT (OR: 1.68; 95% CI 1.48-1.90; p = 0.001). The predictive capability of the objective cough test for SBT success had a ROC-curve of 0.58 (95% CI: 0.56-0.61). Objective cough measurement to predict successful extubation had a ROC-curve of 0.61 (95% CI: 0.56-0.66). The intraobserver reproducibility exhibited an ICC of 0.94 (95% CI: 0.89-0.96; p < 0.001), while the interobserver reproducibility demonstrated an ICC of 0.72 (95% CI: 0.51-0.85; p < 0.001). The intraobserver agreement, assessed using Cohen's weighted kappa was 0.94 (95% CI: 0.93-0.99; p < 0.001), whereas the interobserver agreement was 0.84 (95% CI: 0.67 - 0.10; p < 0.001). CONCLUSIONS: The objective measurement of cough using the method employed in our study demonstrates nearly perfect intra-observer reproducibility and agreement. However, its ability to predict success or failure in the weaning process is limited.

Efficacy and safety of SGLT2 inhibitors in individuals with type 1 diabetes under continuous subcutaneous insulin infusion: a real-world study.

Objective. Adjuvant therapy with sodium-glucose cotransport 2 inhibitors (SGLT2i) in type 1 diabetes (T1D) is associated with an improvement in glycemic control, but increases the risk of diabetic ketoacidosis (DKA). However, real-life studies in individuals with T1D under continuous subcutaneous insulin infusion (CSII) are still scarce. We present the first real-life study performed in patients with T1D exclusively treated with CSII. The aim of the present study was to assess the metabolic impact and safety of SGLT2i in T1D individuals under CSII. Methods. Retrospective study includes 34 T1D adult individuals under CSII, who started SGLT2i until 30th June 2021. Data regarding the glycemic control and acute diabetes complications at the moment of introduction of SGLT2i and after 3, 6, and 12 months of use were collected. Results. Twenty-three individuals were included. Comparing with the moment of SGLT2i introduction after 3, 6, and 12 months of use, there was a statistically significant increase of time in range (TIR) (∆T3M=12.8%; ∆T6M=11.5%; ∆T12M=11.1%), and a decrease in time above range (∆T3M=13.6%; ∆T6M=11.9%; ∆T12M=10.5%). There were no significant differences in time below the range. Mean glucose and mean glucose management indicator significantly reduced in the 3 evaluated moments. A significant reduction in median weight was also observed (∆T6M=2 kg; ∆T12M=4.5 kg). Two patients (8.7%) developed mild euglycemic DKA during SGLT2i treatment, both were women and had body mass index (BMI) <27 kg/m2. One of them had a total daily insulin dose (TDDI) reduction of 26.9% after 3 months of use. Conclusions. The use of SGLT2i, as an adjuvant treatment in T1D individuals under CSII, was associated with a significant increase of TIR without increasing time in hypoglycemia. It also had a weight benefit. Careful use in selected participants is necessary to reduce the occurrence of DKA.

A bibliometric analysis and literature review on emotional skills.

The content, management, and implementation of social skills have been developed since the end of the 20th century as a model of capabilities. Thus, as human beings develop and train their basic cognitive and perceptual-motor functions, they increase their ability to solve and cope with difficulties. This article aims to present a bibliometric and systematic review of social skills, using query sources in databases such as Web of Science (WoS) and Scopus between the years 2000 and 2022, with platforms such as Bibliometrix and Gephi. This search yielded a total of 233 records in WoS and 250 records in Scopus that were merged and, after eliminating 143 duplicate data, were consolidated into 340 records that enclose the academic production of 20 years. Through scientific mapping, the main authors, journals, and countries in this field were determined; similarly, the most relevant studies were classified into three categories, namely, classic, structural, and perspectives, which were represented by means of the metaphor of the tree of science. In addition, a program for further studies was planned, such as in-depth qualitative research measuring observationally and directly taking into account emotional expressiveness, emotional understanding, emotion regulation, and behavior, and the impact of social skills training on social problem-solving. Finally, another important aspect to mention is that this research work is useful for the scientific academic community in many areas of knowledge such as psychology, education, and managers of educational institutions.

Improvement of the In Vitro Cytotoxic Effect on HT-29 Colon Cancer Cells by Combining 5-Fluorouacil and Fluphenazine with Green, Red or Brown Propolis.

Cancer is regard as one of the key factors of mortality and morbidity in the world. Treatment is mainly based on chemotherapeutic drugs that, when used in targeted therapies, have serious side effects. 5-fluorouracil (5-FU) is a drug commonly used against colorectal cancer (CRC), despite its side effects. Combination of this compound with natural products is a promising source in cancer treatment research. In recent years, propolis has become the subject of intense pharmacological and chemical studies linked to its diverse biological properties. With a complex composition rich in phenolic compounds, propolis is described as showing positive or synergistic interactions with several chemotherapeutic drugs. The present work evaluated the in vitro cytotoxic activity of the most representative propolis types, such as green, red and brown propolis, in combination with chemotherapeutic or CNS drugs on HT-29 colon cancer cell lines. The phenolic composition of the propolis samples was evaluated by LC-DAD-ESI/MSn analysis. According to the type of propolis, the composition varied; green propolis was rich in terpenic phenolic acids and red propolis in polyprenylated benzophenones and isoflavonoids, while brown propolis was composed mainly of flavonoids and phenylpropanoids. Generally, for all propolis types, the results demonstrated that combing propolis with 5-FU and fluphenazine successfully enhances the in vitro cytotoxic activity. For green propolis, the combination demonstrated an enhancement of the in vitro cytotoxic effect compared to green propolis alone, at all concentrations, while for brown propolis, the combination in the concentration of 100 µg/mL gave a lower number of viable cells, even when compared with 5-FU or fluphenazine alone. The same was observed for the red propolis combination, but with a higher reduction in cell viability. The combination index, calculated based on the Chou-Talalay method, suggested that the combination of 5-FU and propolis extracts had a synergic growth inhibitory effect in HT-29 cells, while with fluphenazine, only green and red propolis, at a concentration of 100 µg/mL, presented synergism.

Bone mineral density progression following long-term simultaneous pancreas-kidney transplantation in type-1 diabetes.

INTRODUCTION: Simultaneous pancreas-kidney transplantation (SPKT) has demonstrated favorable impact on the progression of chronic complications in type-1 diabetes (T1D) and terminal chronic kidney disease (CKD). However, some CKD mineral and bone disorders (CKD-MBD) may persist, even after transplantation. There are only a few studies addressing the long-term progression of bone mineral density (BMD) in these patients. Our aim was to assess baseline BMD and long-term progression and consequences in patients with T1D undergoing SPKT. METHODS: A retrospective cohort included patients undergoing SPKT in our tertiary center between 2000 and 2017. BMD progression was assessed on dual X-ray absorptiometry (DXA). Only patients with baseline data and a minimum follow-up of 2 years were included. RESULTS: Seventy-three patients were included, 53.4% male, with a median age at SPKT of 35 years (interquartile range [IQR] 31; 39). At transplantation, the median T-scores for the lumbar spine (LS) and femoral neck (FN) were -1.6 (IQR -2.6; -1.1) and --2.1 (IQR -2.7; -1.6), respectively. Seventy-five percent of patients presented low BMD (osteopenia or osteoporosis) in the LS and 90% in the FN, with 33% osteoporosis in the LS and 36% in the FN. On multivariate analysis, male gender (odds ratio [OR] 10.82, 95% confidence interval (CI) 2.88-40.70) and low body-mass index (BMI) (OR 0.73, 95% CI 0.55-0.97) were significantly associated with lumbar but not femoral osteoporosis. At long-term follow-up, BMD significantly improved in the LS (ΔT-score +0.41, P<0.001) and FN (ΔT-score +0.29, P=0.01), at a median 4 years after SPKT. Twelve (16.4%) and 9 (12.3%) patients showed persistent FN and LS osteoporosis, respectively. Multivariate linear regression showed that high BMI was predictive of improvement in BMD. CONCLUSIONS: This study demonstrated severe skeletal fragility in T1D patients with terminal CKD undergoing SPKT, more than a quarter of whom showed osteoporosis. The significant improvement in BMD may result from metabolic correction by SPKT and from physiological skeleton mineralization, which continues in this age group. BMD progression was positively associated with BMI, due to improved nutritional balance after transplantation.

Maturity-onset diabetes of the young in a large Portuguese cohort.

AIMS: Monogenic forms of diabetes that develop with autosomal dominant inheritance are classically aggregated in the Maturity-Onset Diabetes of the Young (MODY) categories. Despite increasing awareness, its true prevalence remains largely underestimated. We describe a Portuguese cohort of individuals with suspected monogenic diabetes who were genetically evaluated for MODY-causing genes. METHODS: This single-center retrospective cohort study enrolled patients with positive genetic testing for MODY between 2015 and 2021. Automatic sequencing and, in case of initial negative results, next-generation sequencing were performed. Their clinical and molecular characteristics were described. RESULTS: Eighty individuals were included, 55 with likely pathogenic/pathogenic variants in one of the MODY genes and 25 MODY-positive family members, identified by cascade genetic testing. The median age at diabetes diagnosis was 23 years, with a median HbA1c of 6.5%. The most frequently mutated genes were identified in HNF1A (40%), GCK (34%) and HNF4A (13%), followed by PDX1, HNF1B, INS, KCNJ11 and APPL1. Thirty-six unique variants were found (29 missense and 7 frameshift variants), of which ten (28%) were novel. CONCLUSIONS: Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of its subtypes, leading to more personalized treatment and follow-up strategies.

Investigation of the Anticancer and Drug Combination Potential of Brominated Coelenteramines toward Breast and Prostate Cancer.

Cancer is a very challenging disease to treat, both in terms of therapeutic efficiency and harmful side effects, which continues to motivate the pursuit for novel molecules with potential anticancer activity. Herein, we have designed, synthesized, and evaluated the cytotoxicity of different brominated coelenteramines, which are metabolic products and synthesis precursors of the chemi-/bioluminescent system of marine coelenterazine. The evaluation of the anticancer potential of these molecules was carried out for both prostate and breast cancer, while also exploring their potential for use in combination therapy. Our results provided further insight into the structure-activity relationship of this type of molecule, such as their high structural specificity, as well highlighting the 4-bromophenyl moiety as essential for the anticancer activity. The obtained data also indicated that, despite their similarity, the anticancer activity displayed by both brominated coelenteramines and coelenterazines should arise from independent mechanisms of action. Finally, one of the studied coelenteramines was able to improve the profile of a known chemotherapeutic agent, even at concentrations in which its anticancer activity was not relevant. Thus, our work showed the potential of different components of marine chemi-/bioluminescent systems as novel anticancer molecules, while providing useful information for future optimizations.

Novel Strategies for Cancer Combat: Drug Combination Using Repurposed Drugs Induces Synergistic Growth Inhibition of MCF-7 Breast and HT-29 Colon Cancer Cells.

Our group developed a new model of drug combination consisting of the use of antineoplastic drugs and different repurposed drugs, having demonstrated that antimalarial and central nervous system (CNS) drugs have a promising anticancer profile as standalone agents, as well as in combined regimens. Here, we evaluated the anticancer profiles of two different CNS drugs (edaravone and quetiapine), both alone and in combination with antineoplastic agents for breast and colon cancer, to explore whether these repurposed drugs could synergistically enhance the anticancer potential of chemotherapeutic drugs. We also developed a new model of combination using two repurposed drugs, to explore whether this model of combination could also be suitable for application in breast and colon cancer therapy. MCF-7 and HT-29 cancer cells were incubated for 48 h with each individual drug (0.01-100 µM) to determine their IC50. Cells were then treated with the IC50 value for doxorubicin or paclitaxel (MCF-7) or 5-fluorouracil (HT-29) and combined with increasing concentrations of edaravone or quetiapine for 48 h. Both cell lines were also treated with a combination of two antimalarial drugs (mefloquine and pyronaridine) or two CNS drugs (fluphenazine and sertraline) for 48 h. We found that the use of quetiapine in combined therapies seems to synergistically enhance the anticancer activity of doxorubicin for the management of breast cancer. Both CNS drugs significantly improved the cytotoxic potential of 5-fluorouracil in HT-29 cells, with quetiapine synergistically interacting with the antineoplastic drug in this drug combination. Regarding the combination of repurposed drugs, only found one synergic combination regimen (sertraline IC50 plus variable concentrations of fluphenazine) with anticancer potential against HT-29 colon cancer cells was found. Taken together, these results suggest that quetiapine and edaravone can be used as adjuvant agents in chemotherapy for colon cancer. It was also found that the combination of repurposed drugs, specifically the CNS drugs sertraline and fluphenazine, may have an interesting profile for application in colon cancer novel therapies.

Antipsychotic Drug Fluphenazine against Human Cancer Cells.

Drug repurposing is a strategy that can speed up and find novel clinical uses for already-approved drugs for several diseases, such as cancer. This process is accelerated compared to the development of new drugs because these compounds have already been tested in clinical trials and data related to their pharmacokinetics is already described, reducing the costs and time associated with the development of new anticancer therapeutics. Several studies suggest that the repurposing of fluphenazine for cancer therapy may be a promising approach, as this drug proved to reduce the viability of diverse cancer cell lines. In this review, intensive research of the literature was performed related to the anticancer potential of fluphenazine in different human cancer cells. We have found several research articles on the cytotoxic effect of fluphenazine in lung, breast, colon, liver, brain, leukemia, oral, ovarian, and skin cancer and have summarized the main findings in this review. Taken together, these findings suggest that fluphenazine may regulate the cell cycle, reduce cell proliferation, and cause apoptosis in several types of cancer cells, besides being an established calmodulin inhibitor. It was also found that this drug is able to target cancer-related proteins, such as ABCB1 and P-glycoprotein as well as to regulate the Akt and Wnt signaling pathways. Some studies also refer this drug causes DNA alterations and interferes with cell invasion and migration ability as well as with ROS generation. Collectively, these results imply that fluphenazine may be a favorable compound for further research in oncologic therapy.

Combination of Antimalarial and CNS Drugs with Antineoplastic Agents in MCF-7 Breast and HT-29 Colon Cancer Cells: Biosafety Evaluation and Mechanism of Action.

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC50). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action.

Antidepressant Drug Sertraline against Human Cancer Cells.

The use of FDA-approved drugs for new indications represents a faster and more economical way to find novel therapeutic agents for cancer therapy, compared to the development of new drugs. Repurposing drugs is advantageous in a pharmacological context since these drugs already have extensive data related to their pharmacokinetics, facilitating their approval process for different diseases. Several studies have reported the promising anticancer effects of sertraline, both alone and combined, in different types of cancer cell lines. Here, we performed a literature review on the anticancer potential of sertraline against different human cancer cells, more specifically in lung, colorectal, breast, hepatocellular, leukemia, brain, skin, oral, ovarian, and prostate cancer. Taken together, these findings suggest that sertraline decreases cell viability, proliferation, migration, and invasion, induces apoptosis, and causes cell cycle arrest in different types of cancer cells, besides being an established P-glycoprotein modulator. It was also found that this drug is able to modulate autophagy, cause DNA fragmentation, and induce radical oxygen species (ROS) formation. Moreover, it was found this drug targets important cellular pathways involved in tumorigeneses such as the TNF-MAP4K4-JNK pathway, the antiapoptotic pathway PI3K/Akt/mTOR, and the AMPK/mTOR axis. This drug also interferes with the TCTP/P53 feedback loop and with the cytosolic free Ca2+ levels. Together, these results suggest that sertraline may be a promising compound for further evaluation in novel cancer therapies.

Papillary thyroid carcinoma: the impact of histologic vascular invasion.

OBJECTIVE: The American Thyroid Association (ATA) recurrence risk prediction system considers vascular invasion (VI) as a relative indicator for adjuvant radioactive iodine (RAI) treatment, nevertheless VI final role in PTC management is yet to be defined. This study aims to assess the impact of histologic VI in PTC. METHODS: A retrospective study with PTC patients admitted in our Thyroid Cancer Unit, between January 1960 and December 2016 was performed. We reviewed 905 patient records with 275 having full information about VI on their pathological reports. Demographic and clinical variables were obtained, and univariate/multivariate analysis was performed in order to obtain potential predictive prognostic factors. RESULTS: Fifty-one out 275 patients presented VI (18.5%; 95% CI 14.4 - 23.6%), these individuals had larger tumors (median 19mm vs 12 mm, p < 0.001) with more frequent extraglandular invasion (54.0% vs 17.1%, p<0.001), regional lymph nodes involvement (29.8% vs 12.6%, p = 0.003)and distant metastasis (10.9% vs 1.9%, p = 0.003) at diagnosis. Vascular invasion was an independent predictor for regional lymph node and/or distant metastasis at diagnosis [OR 2.93 (IC95% 1.16 - 7.41, p = 0.008)]. After a median follow-up time was 68.5 months patients with VI presented higher rates of local recurrence and lymph node metastasis recurrence. CONCLUSIONS: In this study, the presence of VI in PTC is associated to higher rate of lymph node and distant metastasis at diagnosis. Its presence should be probably considered an adverse prognostic factor in PTC, perhaps justifying more aggressive therapeutic and follow-up approaches in such cases.

Pitavastatin and Ivermectin Enhance the Efficacy of Paclitaxel in Chemoresistant High-Grade Serous Carcinoma.

Chemotherapy is a hallmark in high-grade serous carcinoma management; however, chemoresistance and side effects lead to therapeutic interruption. Combining repurposed drugs with chemotherapy has the potential to improve antineoplastic efficacy, since drugs can have independent mechanisms of action and suppress different pathways simultaneously. This study aimed to explore whether the combination of Paclitaxel with repurposed drugs led to a therapeutic benefit. Thus, we evaluated the cytotoxic effects of Paclitaxel alone and in combination with several repurposed drugs (Pitavastatin, Metformin, Ivermectin, Itraconazole and Alendronate) in two tumor chemoresistant (OVCAR8 and OVCAR8 PTX R P) and a non-tumoral (HOSE6.3) cell lines. Cellular viability was assessed using Presto Blue assay, and the synergistic interactions were evaluated using Chou-Talalay, Bliss Independence and Highest Single Agent reference models. The combination of Paclitaxel with Pitavastatin or Ivermectin showed the highest cytotoxic effect and the strongest synergism among all combinations for both chemoresistant cell lines, resulting in a chemotherapeutic effect superior to both drugs alone. Almost all the repurposed drugs in combination with Paclitaxel presented a safe pharmacological profile in non-tumoral cells. Overall, we suggest that Pitavastatin and Ivermectin could act synergistically in combination with Paclitaxel, being promising two-drug combinations for high-grade serous carcinoma management.

Non-thyroidal second primary malignancy in papillary thyroid cancer patients.

Introduction: The occurrence of non-thyroidal second primary malignancy (NTSPM) in patients with papillary thyroid cancer (PTC) is well documented, but epidemiological data are conflicting. Objective: The aim of this study was to evaluate the incidence of NTSPM in a large series of patients with PTC and to assess its potential risk factors. Methods: Single-center cohort study with retrospective data collection conducted on consecutive PTC patients diagnosed from 1988 to 2018 with a minimum follow-up time of 2 years. NTSPM was defined as any primary malignancy with histological confirmation occurring in an anatomical site other than the thyroid. According to the timing of occurrence, NTSPM were subdivided into anachronous, synchronous or metachronous (diagnosed >6 months before, within 6 months and >6 months after PTC diagnosis, respectively). Results: We included 773 individuals (83.3% females), median age at PTC diagnosis was 47.0 (IQR: 37.0-58.0) years and median follow-up time was 9.9 (6.2-16.3) years. Incidence of NTSPM was 15.5% (n = 120) and its standard incidence ratio (SIR) was higher when compared to the general population (SIR: 2.70). Family history of malignancy and younger age at diagnosis were associated respectively with 206 and 4% increased risk of developing metachronous neoplasia (HR: 2.06 (95% CI: 1.10-3.86) and 1.04 (95% CI: 1.02-1.05), respectively). Conclusion: In our series, the occurrence of NTSPM was not uncommon and its incidence was higher compared to the general population. First-degree family history of malignancy was a strong risk factor for multiple primary malignancies.

New Peptide Functionalized Nanostructured Lipid Carriers with CNS Drugs and Evaluation Anti-proliferative Activity.

Nanoparticulate systems have been widely investigated as delivery vectors for efficient drug delivery in different diseases. Nanostructured lipid carriers (NLC) are composed of both solid and liquid lipids (glyceryl dibehenate and diethylene glycol monoethyl ether) and have demonstrated enhanced biological compatibility and increased drug loading capability. Furthermore, the use of peptides, in particular cell-penetrating peptides, to functionalize nanoparticles and enhance cell membrane permeation was explored in this paper. In this paper, we described the synthesis of a new conjugated of tranylcypromine with MAP. In addition, taking into consideration our previous results, this study developed different NLCs loaded with three central nervous system (CNS) drugs (tacrine (TAC), rasagiline (RAS), and tranylcypromine (TCP)) functionalized with model amphipathic peptide (MAP) and evaluated their activity against cancer cells. Particle size analysis demonstrated NLC presented less than 200 nm and a polydispersity index less than 0.3. Moreover, in vitro results showed that conjugation of MAP with drugs led to a higher decrease in cell viability of a neuroblastoma cell line and Caco-2 cell line, more than MAP alone. Furthermore, NLC encapsulation contributed to higher cellular delivery and enhanced toxic activity at lower concentrations when compared with free or co-administration drug-MAP conjugate.

MODY probability calculator utility in individuals' selection for genetic testing: Its accuracy and performance.

INTRODUCTION: MODY probability calculator (MPC) represents an easy-to-use tool developed by Exeter University to help clinicians prioritize which individuals should be oriented to genetic testing. We aimed to assess the utility of MPC in a Portuguese cohort with early-onset monogenic diabetes. METHODS: This single-centre retrospective study enrolled 132 participants submitted to genetic testing between 2015 and 2020. Automatic sequencing and, in case of initial negative results, generation sequencing were performed. MODY probability was calculated using the probability calculator available online. Positive and negative predictive values (PPV and NPV, respectively), accuracy, sensitivity and specificity of the calculator were determined for this cohort. RESULTS: Seventy-three individuals were included according to inclusion criteria: 20 glucokinase (GCK-MODY); 16 hepatocyte nuclear factor 1A (HNF1A-MODY); 2 hepatocyte nuclear factor 4A (HNF4A-MODY) and 35 DM individuals with no monogenic mutations found. The median probability score of MODY was significantly higher in monogenic diabetes-positive subgroup (75.5% vs. 24.2%, p < .001). The discriminative accuracy of the calculator, as expressed by area under the curve, was 75% (95% CI: 64%-85%). In our cohort, the best cut-off value for the MODY calculator was found to be 36%, with a PPV of 74.4%, NPV of 73.5% and corresponding sensitivity and specificity of 76.2% and 71.4%, respectively. CONCLUSIONS: In a highly pre-selected group of probands qualified for genetic testing, the Exeter MODY probability calculator provided a useful tool in individuals' selection for genetic testing, with good discrimination ability under an optimal probability cut-off of 36%. Further geographical and population adjustments are warranted for general use.

Evaluation of synergism in drug combinations and reference models for future orientations in oncology.

Current cancer therapy includes a variety of strategies that can comprise only one type of treatment or a combination of multiple treatments. Chemotherapy is still the gold standard for cancer therapy, though sometimes associated with undesired side effects and the development of drug resistance. For this reason, drug combination is an approach that has been proposed to overcome the problems related to monotherapy and several studies have already demonstrated the superiority of combined therapies compared to monotherapy. The main goal when designing and evaluating drug combinations is to achieve synergistic effects by demonstrating that the combined effects are greatly superior to the expected from the additive effects of the single drugs, allowing for dosage reduction and therefore decreasing toxicity. Nevertheless, synergism quantification is not a simple task due to the different definitions of additivity and over the years several reference models have been proposed based on different assumptions and with different mathematical frameworks. In this review, we begin to cover the available treatment options for cancer therapy, with emphasis on the importance of drug combinations in cancer therapy. We next describe the classical reference models that have been proposed for synergism evaluation, usually classified as effect-based and dose-effect based methods, with a brief analysis of the current limitations of these models. We also describe here the novel methods for the accurate quantification of drug interactions in combined treatments. At the end of this manuscript, we covered some of the most recent preclinical and clinical combination studies that reflect the importance of the appropriate, accurate and precise application of the concepts and methodologies here described for the evaluation of synergism.