Antimicrobial and antibiofilm effect of promethazine on bacterial isolates from canine otitis externa: an in vitro study.

Otitis externa is an inflammatory disease of the external ear canal of complex and multifactorial etiology associated with recurrent bacterial infection. This study aimed to assess the antimicrobial and antibiofilm activity of promethazine against bacterial isolates from dogs with otitis externa, as well as the effect of this compound on the dynamics of biofilm formation over 120 h. Planktonic bacterial susceptibility to promethazine was evaluated to determine the minimum inhibitory concentrations (MIC). The minimum biofilm eradication concentration (MBEC) was also determined by broth microdilution. To evaluate the effect on biofilm growth, promethazine was tested at three concentrations MIC, MIC/2 and MIC/8, with daily readings at 48, 72, 96 and 120 h. The MICs of promethazine ranged from 48.83 to 781.25 µg mL-1. Promethazine significantly (P < 0.05) reduced mature biofilm biomass, with MBECs ranging from 48.8 to 6250 µg mL-1 and reduced (P < 0.01) biofilm formation for up to the 120-h, at concentrations corresponding to the MIC obtained against each isolate. Promethazine was effective against microorganisms associated with canine otitis externa. The data suggest that promethazine presents antimicrobial and antibiofilm activity and is a potential alternative to treat and prevent recurrent bacterial otitis in dogs. These results emphasize the importance of drug repurposing in veterinary otology as an alternative to reduce antimicrobial resistance.

Decreased Nuclear Immunoexpression of ING3 is a Frequent Event in Lip Carcinogenesis.

PURPOSE: Evaluate the immunohistochemical expression of the ING3 in actinic cheilitis and squamous cell carcinoma of the lower lip. METHODS: Forty-five specimens of actinic cheilitis and 48 specimens of squamous cell carcinoma of the lower lip were submitted to immunohistochemical detection of ING3. The protein expression in different cellular sublocations was compared between the two groups, and associations with the clinicopathological variables were analyzed. A significance level of 5% was adopted for all tests. RESULTS: Deaths were significantly more frequent in tumors with a high histopathological risk score (p < 0.05). In actinic cheilitis, significant differences were found in the nucleus-cytoplasmic expression of ING3 and expression restricted to the cytoplasm with binary histopathological grading (p < 0.05). In squamous cell carcinoma of the lower lip, there was no statistically significant difference when comparing ING3 expressions with clinical and morphological parameters (p > 0.05). Nucleo-cytoplasmic ING3 expression was significantly lower in squamous cell carcinoma of the lower lip when compared to actinic cheilitis (p < 0.05) and the expression restricted to the cytoplasm was significantly higher in squamous cell carcinoma of the lower lip (p < 0.05). CONCLUSION: The results of this study suggest that there is a marked decrease in the nuclear expression of ING3 as malignant progression occurs, indicating an impaired tumor suppressor function of this protein in actinic cheilitis and squamous cell carcinoma of the lower lip.

Gaucher disease in Brazil: a comprehensive 16 year retrospective study on survival, cost, and treatment insights.

Background: Gaucher's disease (GD), a lysosomal storage disorder, poses significant treatment challenges. This 23-year study assesses survival rates and treatment efficacy in Brazilian GD patients, integrating data from a 16-year cohort (2000-2015) and the TABNET/DATASUS medicines distribution data (1999-2022). Objective: To investigate the survival of GD patients in Brazil, identifying key risk factors and evaluating the impact of treatments funded by the Brazilian National Health System (SUS). Methodology: A 16-year retrospective cohort study was conducted using the National Database of SUS. Patients diagnosed with GD and treated with Enzyme Replacement Therapy (ERT) or Substrate Synthesis Inhibition (SSI) from 2000 to 2015 were included. Survival analysis was performed using Kaplan-Meier method and Cox proportional hazards model. The data from TABNET/DATASUS system from 1999 to 2022 was used to assess the trend in drug distribution beyond the main cohort. Results: The study included 1,234 patients. Survival rates at 5 and 10 years were 93.2% and 88.5%, respectively, with age and comorbidities like diabetes, cardiovascular diseases, and Parkinson's disease significantly affecting survival. Patients who received doses lower than DDD (n = 880) demonstrated a survival probability of 91.8%. In contrast, those with doses equal to the DDD (n = 15) showed a 100% survival probability, as no events were observed in this group. The greater than DDD group (n = 339) exhibited a survival probability of 81%. A log-rank test indicated a borderline statistical significance (p = 0.058) in the survival distributions among the different DDD adherence, with the lower dose group showing a favorable trend. Conclusion: This study provides insights into the survival rates and associated risk factors for GD patients in Brazil, contributing to the global understanding of GD and its management. While we acknowledge the inherent limitations of relying largely on electronic medical records and categorical codes, our findings underscore the need for early diagnosis, timely initiation of treatment, effective management of comorbidities, and personalized dosing strategies to improve patient outcomes. Future studies should aim to incorporate clinical verification of electronic data to further enhance the reliability and applicability of these findings.

Latin American Challenges and Recommendations for Poly Adenosine Diphosphate Ribose Polymerase Inhibitor Treatment in Metastatic Castration Resistant Prostate Cancer: An Expert Overview.

In Latin America, prostate cancer is the third most common cancer overall and the most common in men, with the highest mortality rate of all cancers. In 2022, there were approximately 22,985 new prostate cancer cases and 61,056 deaths from prostate cancer in the region. Patients with metastatic disease that is resistant to cure by castration now have multiple therapeutic options, including poly-ADP ribose polymerase inhibitors. These treatment advances present new challenges, such as developing monitoring protocols for early detection of disease progression to castration resistance. The Americas Health Foundation organized a 3-day meeting with 8 regional oncologists and pathologists to create a paper on metastatic castration-resistant prostate cancer diagnosis and therapy, including the new poly-ADP ribose polymerase inhibitors. The panel examined metastatic castration-resistant prostate cancer in Latin America and recommended ways to improve patient care using published literature and their expertise. Gene mutations play an important role in prostate cancer development. Precision medicine innovations highlight the importance of genotyping DNA variants and tumor biomarkers for targeted treatment. Access to appropriate genetic testing is difficult, medications are available but expensive, and there is a lack of infrastructure and regulatory frameworks that prevent patients from benefiting from innovative therapies. The panel recommends developing a population database and biobank and creating tumor tissue collection, processing, and storage facilities. Multi-stakeholder collaboration is needed to integrate the information gathered, train staff, select target populations, improve patient accessibility, and reduce the cost burden of drugs, genetic counselors, and cancer geneticists in Latin America. Collaboration is essential among healthcare professionals, policymakers, patient advocacy groups, pharmaceutical companies, and international organizations to address these challenges and needs in Latin America.

STAT3 and the STAT3­regulated inhibitor of apoptosis protein survivin as potential therapeutic targets in colorectal cancer (Review).

Colorectal cancer (CRC) is one of the leading types of cancer worldwide. CRC development has been associated with the constitutive activation of signal transducer and activator of transcription 3 (STAT3). STAT3 is a master regulator of inflammation during cancer-associated colitis, and becomes upregulated in CRC. In CRC, STAT3 is activated by IL-6, among other pro-inflammatory cytokines, inducing the expression of target genes that stimulate proliferation, angiogenesis and the inhibition of apoptosis. One of the main STAT3-regulated inhibitors of apoptosis is survivin, which is a bifunctional protein that regulates apoptosis and participates in cell mitosis. Survivin expression is normally limited to foetal tissue; however, survivin is also upregulated in tumours. In silico and experimental analyses have shown that the STAT3 interactome is relevant during CRC progression, and the constitutive STAT3-survivin axis participates in development of the tumour microenvironment and response to therapy. The presence of a STAT3-survivin axis has been documented in CRC cohorts, and the expression of these molecules is associated with poor prognosis and a higher mortality rate in patients with CRC. Thus, STAT3, survivin, and the upstream activators IL-6 and IL-6 receptor, are considered therapeutic targets for CRC. Efforts to develop drugs targeting the STAT3-survivin axis include the evaluation of phytochemical compounds, small molecules and monoclonal antibodies. In the present review, the expression, function and participation of the STAT3-survivin axis in the progression of CRC were investigated. In addition, an update on the pre-clinical and clinical trials evaluating potential treatments targeting the STAT3-survivin axis is presented.

Analysis of genomic alternations in epidermal growth factor receptor (EGFR)-T790M-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib therapy.

BACKGROUND AND OBJECTIVES: Genomic alterations after resistance to osimertinib therapy in advanced T790M-mutated non-small cell lung cancer (NSCLC) are complex and poorly understood. In this study, we aimed to detect these genomic alternations via comprehensive next-generation sequencing (NGS) of tissue and liquid biopsies. PATIENTS AND METHODS: From September 2020 to June 2021, 31 stage IIIB/IV T790M-mutated NSCLC patients who exhibited progressive disease after osimertinib therapy and provided written informed consent were recruited. Liquid and tissue biopsy samples for NGS testing were collected from 31 and 18 patients, respectively. Eighteen study patients had paired NGS data from tissue and liquid biopsies. RESULTS: With respect to the T790M mutation status, the preservation and loss rates were 33% and 67%, respectively, in both liquid and tissue biopsy samples. Five patients (16.1%) had the C797S mutation (4 liquid samples and 1 tissue sample). Two (6.5%) had MET mutations, 3 (9.7%) had BRAF-V600E mutations, and 1 (3.2%) had a KRAS-G12C mutation. Among the 18 patients who underwent tissue rebiopsies, those with preserved T790M mutation had significantly longer progression-free survival (PFS) with osimertinib therapy than those with T790M mutation loss (10.8 vs. 5.0 months, P = 0.045). Among all patients, those with T790M mutation loss in liquid biopsy samples had longer PFS after osimertinib therapy (10.8 vs. 7.5 months, P = 0.209) and postprogression survival (17.7 vs. 9.6 months, P = 0.132) than those with preserved T790M mutation based on liquid biopsies. CONCLUSIONS: NGS using either tissue or liquid biopsy samples from advanced T790M-mutated NSCLC patients with acquired resistance to osimertinib therapy can detect various genomic alternations. Future studies focusing on subsequent tailored therapies on the basis of NGS results are warranted.

Baloxavir Resistance Markers in Influenza A and B Viruses in the Americas.

Aim: Influenza control demands multifaceted strategies, including antiviral drugs. Baloxavir, a recent addition to influenza treatment, acts as an inhibitor of the Polymerase acid (PA) component of the viral polymerase. However, mutations associated with resistance have been identified. Purpose: This study analyzed PA gene sequences of influenza A and B viruses (IAV and IBV, respectively) reported in the Americas, retrieved from databases published until May 2023, to identify primary markers of resistance to baloxavir. Patients and Methods: PA gene sequences were obtained from the GISAID and NCBI databases, focusing on countries in the Americas with 500 or more sequences for IAV, and 50 or more sequences for IBV. Results: Of the 58,816 PA sequences analyzed for IAV, only 55 (0.1%) harbored resistance markers, representing approximately 1 in 1000 occurrence. The most frequent markers were I38V (21 cases) and I38M (7 cases) at position 38 of PA, followed by E199G (9 cases) at position 199. For IBV, 14,684 sequences were analyzed, of which only eight presented a resistance marker (0.05%). Five sequences had the M34I marker, while the remaining three had the I38V marker. While frequency of resistance markers in PA is comparable to other regions, these results highlight the need for enhanced sequencing efforts, particularly in Latin America. Such efforts would serve to intensify influenza surveillance and inform public health interventions. Conclusion: While baloxavir demonstrates efficacy against influenza, resistance markers have been identified, including pre-existing ones. Our study adds eight (IAV: six and IBV: two) new spontaneously occurring substitutions to the existing literature, highlighting the need for continued surveillance. Among these, I38M stands out due to its significant tenfold reduction in drug susceptibility. Therefore, vigilant monitoring of these resistance markers in IAV and IBV remains crucial for maintaining baloxavir's effectiveness and informing future public health interventions.

The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells.

The central role of the control of apoptosis in the pathophysiology of Philadelphia chromosome-negative myeloproliferative neoplasms has recently been reinforced in genetic and pharmacological studies. The inhibitor of apoptosis protein family has eight members and plays an important role in apoptosis, with the most studied being survivin (BIRC5) and X-linked inhibitor of apoptosis (XIAP). YM155 is a small molecule with antineoplastic potential that has been described as a suppressant of survivin and XIAP. In the present study, BIRC5 expression was significantly increased in primary myelofibrosis patients compared to healthy donors. On the other hand, XIAP expression was reduced in myeloproliferative neoplasms patients. In JAK2V617F cells, YM155 reduces cell viability and autonomous clonal growth and induces apoptosis, cell cycle arrest, and autophagy. HEL cells that show greater malignancy are more sensitive to the drug than SET2 cells. In the molecular scenario, YM155 modulates apoptosis-, cell cycle-, DNA damage- and autophagy-related genes. Protein expression analysis corroborates the observed cellular phenotype and exploratory gene expression findings. In summary, our results indicate that survivin/BIRC5 and XIAP are differently expressed in myeloproliferative neoplasms and YM155 has multiple antineoplastic effects on JAK2V617F cells suggesting that inhibitor of apoptosis proteins may be a target for pharmacological interventions in the treatment of these diseases.

Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors.

INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.

Oral Janus Kinase Inhibitors in Pediatric Atopic Dermatitis.

PURPOSE OF REVIEW: To analyze the efficacy and safety of Janus kinase inhibitors (JAKi) in the treatment of pediatric AD. RECENT FINDINGS: Adolescents with moderate and severe atopic dermatitis (AD) need systemic therapies, as stated several recent practice guidelines. (JAKi) have shown their efficacy in the treatment of adult AD, however, there is a lack of information concerning efficacy and safety of their use in pediatric AD. We found that the JAKi's abrocitinib (ABRO), baricitinib (BARI), and upadacitinib (UPA), are all an effective treatment option with a very fast onset of action for adolescents with moderate-to-severe AD. BARI was not effective in children between 2 and 10 years with moderate-to-severe AD. Fortunately, major safety issues with JAKi in adolescents with AD have not been documented in the trials, so far, contrasting with the reports in adults with AD, where these events have very rarely occurred. There are some reports of herpes zoster (HZ) infection in adolescents on JAKi, but it is not a major safety concern. Acne is a relatively common AE with UPA in adolescents; however, it is responsive to standard treatment. This review will help the clinician to choose among the JAKi according to the needs and clinical features of patients with moderate and severe AD. In the following years, with the advent of new biologicals and JAKi, these therapies will fall into place in each phase of the evolution of patients with AD.

A Novel Kunitz Trypsin Inhibitor from Enterolobium gummiferum Seeds Exhibits Antibiofilm Properties against Pathogenic Yeasts.

Plant peptidase inhibitors play crucial roles in plant defence mechanisms and physiological processes. In this study, we isolated and characterised a Kunitz trypsin inhibitor from Enterolobium gummiferum seeds named EgPI (E. gummiferum peptidase inhibitor). The purification process involved two chromatography steps using size exclusion and hydrophobic resins, resulting in high purity and yield. EgPI appeared as a single band of ~20 kDa in SDS-PAGE. Under reducing conditions, the inhibitor exhibited two polypeptide chains, with 15 and 5 kDa. Functional characterisation revealed that EgPI displayed an inhibition stoichiometry of 1:1 against trypsin, with a dissociation constant of 8.4 × 10-9 mol·L-1. The amino-terminal sequencing of EgPI revealed the homology with Kunitz inhibitors. Circular dichroism analysis provided insights into the secondary structure of EgPI, which displayed the signature typical of Kunitz inhibitors. Stability studies demonstrated that EgPI maintained the secondary structure necessary to exhibit its inhibitory activity up to 70 °C and over a pH range from 2 to 8. Microbiological screening revealed that EgPI has antibiofilm properties against pathogenic yeasts at 1.125 µmol·L-1, and EgPI reduced C. albicans biofilm formation by 82.7%. The high affinity of EgPI for trypsin suggests potential applications in various fields. Furthermore, its antibiofilm properties recommended its usefulness in agriculture and antimicrobial therapy research, highlighting the practical implications of our research.

Synthesis, in vitro and in silico evaluation of gallamide and selenogallamide derivatives as inhibitors of the SARS-CoV-2 main protease.

The present work reports the inhibitory effect of amides derived from gallic acid (gallamides) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro), along with cytotoxicity evaluation and molecular docking studies. In addition to gallamides, other relevant compounds were also synthesized and evaluated against Mpro, making a total of 25 compounds. Eight compounds presented solubility issues during the inhibitory assay and one showed no inhibitory activity. Compounds 3a, 3b, and 3f showed the highest enzymatic inhibition with IC50 = 0.26 ± 0.19 µM, 0.80 ± 0.38 µM, and 2.87 ± 1.17 µM, respectively. Selenogallamide 6a exhibited IC50 values of 5.42 ± 2.89 µM and a comparison with its nonselenylated congener 3c shows that the insertion of the chalcogen moiety improved the inhibitory capacity of the compound by approximately 10 times. Regarding the cellular toxicity in THP-1 and Vero cells, compounds 3e and 3g, showed moderate cytotoxicity in Vero cells, while for THP-1 both were nontoxic, with CC50 > 150 µM. Derivative 3d showed moderate cytotoxicity against both cell lines, whereas 6d was moderatly toxic to THP-1. Other compounds analyzed do not induce substantial cellular toxicity at the concentrations tested. The molecular docking results for compounds 3a, 3b, and 3f show that hydrogen bonding interactions involving the hydroxyl groups (OH) of the gallate moiety are relevant, as well as the carbonyl group.

The Repurposing of FDA-Approved Drugs as FtsZ Inhibitors against Mycobacterium tuberculosis: An In Silico and In Vitro Study.

Mycobacterium tuberculosis (Mtb), the causative pathogen of tuberculosis, remains one of the leading causes of death from a single infectious agent. Furthermore, the growing evolution to multi-drug-resistant (MDR) strains requires de novo identification of drug targets for evaluating candidates or repurposing drugs. Hence, targeting FtsZ, an essential cell division protein, is a promising target. METHODS: Using an in silico pharmacological repositioning strategy, four FDA-based drugs that bind to the catalytic site FtsZ were selected. The Alamar Blue colorimetric assay was used to assess antimicrobial activity and the effect of drugs on Mtb growth through growth curves. Bacterial load was determined with an in vitro infection model using colony-forming units (CFU)/mL, and cytotoxicity on human monocyte-derived macrophages (MDMhs) was assessed by flow cytometry. RESULTS: Paroxetine and nebivolol exhibited antimycobacterial activity against both reference TB and MDR strains at a concentration of 25 µg/mL. Furthermore, both paroxetine and nebivolol demonstrated a significant reduction (p < 0.05) in viable bacteria compared to the untreated group in the in vitro infection model. CONCLUSIONS: Collectively, our findings demonstrate that the use of paroxetine and nebivolol is a promising strategy to help in the control of tuberculosis infection.

Evaluation of Cytotoxicity and Acute Oral Toxicity of Saline Extract and Protein-Rich Fraction from Moringa oleifera Lam. Leaves.

Moringa oleifera Lam. (horseradish tree) leaves demonstrate high nutritional value, are rich in proteins, and are widely used in folk medicine and food. This study investigated the presence of secondary metabolites and antinutritional proteins in leaf extract (LE) and the protein-rich fraction (PRF) derived from M. oleifera leaves, as well as the cytotoxicity to human cells, hemolytic activity, and in vivo acute toxicity and genotoxicity in mice. The flavonoids rutin and vitexin as well as trypsin inhibitors and lectins were detected in LE and PRF. Neither sample demonstrated toxicity against human peripheral blood mononuclear cells and both showed low hemolytic action. In vivo, LE and PRF did not show antinutritional effects and caused no death. The hematological parameters of the animals in the treated group were similar to those of the control. A significant increase in the serum levels of alanine aminotransferase and a discrete leukocyte infiltration with cytoplasmic vacuolization of the hepatocytes in the liver were detected in LE-treated animals. The preparations were not genotoxic or mutagenic. This study shows that LE and PRF are not antinutritional agents and presented low acute toxicity and no genotoxicity or mutagenicity. The present study contributes to the determination of the safety of using M. oleifera leaf proteins.

The use of phosphodiesterase inhibitors in the treatment of female sexual dysfunction: scoping review.

Objective: The purpose of this study was to analyze the available evidence regarding the efficacy of iPDE5 in the treatment of female sexual dysfunction (FSD). Methods: A comprehensive literature search was conducted in March 2023 through the main scientific databases. Results: A total of 53 articles were identified, out of which, 6 met the predefined inclusion criteria. All of these were randomized controlled trials. Among the included studies, 4 demonstrated the effectiveness of sildenafil in improving sexual response and addressing FSD, while 2 studies failed to establish its efficacy in this context. Conclusion: Overall, the efficacy of sildenafil in the treatment of FSD remains controversial and inconclusive based on the available evidence. Further research is necessary to clarify the therapeutic potential of iPDE5 in addressing FSD and to better understand the factors that influence treatment outcomes.

The Antidepressant- and Anxiolytic-Like Effects of the Phosphodiesterase Type-5 Inhibitor Tadalafil are Associated with the Modulation of the Gut-Brain Axis During CNS Autoimmunity.

Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.

Clinical predictive factors of the efficacy of immune checkpoint inhibitors and kinase inhibitors in advanced hepatocellular cancer.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive tumor associated with significant morbidity and mortality rates. Combination therapy with immune checkpoint inhibitors (ICIs) and kinase inhibitors has emerged as a promising strategy for liver cancer treatment in recent years. However, the clinical factors predicting the outcomes of combination therapy in patients with advanced liver cancer remain uncertain. Therefore, this study investigated the relationships between clinical predictors and the efficacy of ICI plus kinase inhibitor therapy to personalize treatment plans. METHODS: We retrospectively enrolled 98 patients who received combination treatment with ICIs and kinase inhibitors for advanced HCC. Based on blood lipid levels and other clinical factors prior to treatment, we investigated potential biomarkers that could predict treatment responses in this patient population. RESULTS: Mean progression-free survival (PFS) and overall survival (OS) in this cohort were 10.1 and 17.2 months, respectively. Via multivariate analysis, the absence of extrahepatic metastasis, the absence of portal vein thrombosis (PVT), neutrophil-to-lymphocyte ratio (NLR) < 3.225, platelet-to-lymphocyte ratio (PLR) < 140.75, and prognostic nutritional index (PNI) ≥ 37.25 were identified as independent predictors of improved PFS. Factors associated with better OS included PLR < 140.75 and total cholesterol (TC) < 3.46 mmol/L. Univariate analysis identified significant associations of Eastern Cooperative Oncology Group performance status (ECOG PS), hepatitis B virus (HBV) DNA levels, Child-Pugh classification, alpha-fetoprotein (AFP), TC, and the receipt of regorafenib with PFS. Additionally, ECOG PS, Child-Pugh classification, AFP, PVT, NLR, PNI, and the receipt of regorafenib were significantly associated with OS. CONCLUSIONS: PLR and TC were potential clinical predictive factors for survival outcomes in patients with advanced HCC who received ICI/kinase inhibitor combination therapy. It is important to know the clinical characteristics of patients prior to treatment initiation to optimize outcomes.

Importance of Testing for ROS1 Rearrangements in Non-Small Cell Lung Cancer in the Era of Targeted Therapy in a Latin American Country.

Purpose: Lung cancer is the leading cause of cancer-related deaths worldwide. However, with the optimization of screening strategies and advances in treatment, mortality has been decreasing in recent years. In this study, we describe non-small cell lung cancer patients diagnosed between 2021 and 2022 at a high-complexity hospital in Latin America, as well as the immunohistochemistry techniques used to screen for ROS1 rearrangements, in the context of the recent approval of crizotinib for the treatment of ROS1 rearrangements in non-small cell lung cancer in Colombia. Methods: A descriptive cross-sectional study was conducted. Sociodemographic, clinical, and molecular pathology information from non-small cell lung cancer individuals who underwent immunohistochemistry to detect ROS1 rearrangements between 2021 and 2022 at Fundación Valle del Lili (Cali, Colombia) was recorded. The clinical outcomes of confirmed ROS1 rearrangements in non-small cell lung cancer patients were reported. Results: One hundred and thirty-six patients with non-small cell lung cancer were included. The median age at diagnosis was 69.8 years (interquartile range 61.9-77.7). At diagnosis, 69.8% (n = 95) were at stage IV. ROS1 immunohistochemistry was performed using the monoclonal D4D6 antibody clone in 54.4% (n = 74) of the cases, while 45.6% (n = 62) were done with the monoclonal SP384 antibody clone. Two patients were confirmed to have ROS1 rearrangements in non-small cell lung cancer using next-generation sequencing and received crizotinib. On follow-up at months 5.3 and 7.0, one patient had a partial response, and the other had oligo-progression, respectively. Conclusion: Screening for ROS1 rearrangements in non-small cell lung cancer is imperative, as multiple prospective studies have shown improved clinical outcomes with tyrosine kinase inhibitors. Given the recent approval of crizotinib in Colombia, public health policies must be oriented toward early detection of driver mutations and prompt treatment. Additionally, future approvals of newly tested tyrosine kinase inhibitors should be anticipated.

Eligibility of sodium-glucose cotransporter-2 inhibitors in heart failure with preserved ejection fraction: Insights from the Colombian heart failure registry (RECOLFACA).

Background: The value of Sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitor) therapy in individuals with heart failure with preserved EF (HFpEF) was unknown until the EMPEROR-Preserved trial. We aimed to assess the proportion of patients with HFpEF that are eligible for empagliflozin therapy within the Colombian Heart Failure Registry (RECOLFACA). Methods: RECOLFACA enrolled adult patients with a HF diagnosis during 2017-2019 from 60 medical centers in Colombia. Criteria of the EMPEROR-Preserved Trial were used to recruit participants. The main outcome was individual eligibility with N-terminal pro-B-type natriuretic peptide (NT-proBNP) criteria, while the secondary outcome was eligibility without NT-proBNP data. Results: RECOLFACA had 799 patients with HFpEF (mean age70.7 ± 13.5; 50.7 % males). According to the major selection criteria of the EMPEROR Preserved Trial, 73.7 % patients would be eligible for empagliflozin therapy initiation when considering the NT-proBNP threshold. The NT-proBNP threshold represented the main determinant of ineligibility in patients with this biomarker measure (13.6 %; n = 16). In patients without NT-proBNP data, the main reasons for exclusion were the diagnosis of symptomatic hypotension or a systolic blood pressure below 100 mmHg (7.5 %), having an eGFR < 20 ml/min/1.73 m2 (4.3 %), and haemoglobin < 9 g/dl (3.1 %). Excluding NT-proBNP criteria increased empagliflozin eligibility to 80.6 %. Conclusion: Most patients with HFpEF from RECOLFACA are potential candidates for empagliflozin therapy initiation according to the EMPEROR-Preserved trial criteria. These findings favor the utilization of SGLT-2 inhibitor medications in daily medical practice, which may further decrease morbidity and mortality in HF patients, regardless of their EF classification.