Dual FGFR-targeting and pH-activatable ruthenium-peptide conjugates for targeted therapy of breast cancer.

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.

The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of commonly targeted receptors. Unspecific chemotherapy is currently the main therapeutic option, with poor results. Another major challenge is the frequent appearance of brain metastasis (BM) associated with a significant decrease in patient overall survival. The treatment of BM is even more challenging due to the presence of the blood-brain barrier (BBB). Here, we present a dual-acting peptide (PepH3-vCPP2319) designed to tackle TNBC/BM, in which a TNBC-specific anticancer peptide (ACP) motif (vCPP2319) is joined to a BBB peptide shuttle (BBBpS) motif (PepH3). PepH3-vCPP2319 demonstrated selectivity and efficiency in eliminating TNBC both in monolayers (IC50≈5.0 µM) and in spheroids (IC50≈25.0 µM), with no stringent toxicity toward noncancerous cell lines and red blood cells (RBCs). PepH3-vCPP2319 was also able to cross the BBB in vitro and penetrate the brain in vivo, and was stable in serum with a half-life above 120 min. Tumor cell-peptide interaction is fast, with quick peptide internalization via clathrin-mediated endocytosis without membrane disruption. Upon internalization, the peptide is detected in the nucleus and the cytoplasm, indicating a multi-targeted mechanism of action that ultimately induces irreversible cell damage and apoptosis. In conclusion, we have designed a dual-acting peptide capable of brain penetration and TNBC cell elimination, thus expanding the drug arsenal to fight this BC subtype and its BM.

Comparative morphology of eggs of Rhodnius domesticus Neiva & Pinto, Rhodnius neglectus Lent and Rhodnius prolixus Stål (Hemiptera: Reduviidae: Triatominae).

Rhodnius species are potential vectors of the etiological agent of Chagas disease (CD), the protozoan Trypanosoma cruzi. CD impacts around seven million people in Latin America, resulting in approximately fourteen thousand deaths per year. Several species of Rhodnius are notable not only for their epidemiological relevance, but also for the challenging distinction between their species. Rhodnius has twenty species, each with its specific epidemiological importance. Rhodnius neglectus and Rhodnius prolixus are found with colonies in domiciliary environments. The observation of eggs in human dwellings signals the colonization process of these insects, increasing the risk of contamination of the population, since correct identification of eggs is necessary to help more effective vector control programs. Here we highlight diagnostic characters of eggs for these three species.

Taxonomic reassessment of Rhodnius zeledoni Jurberg, Rocha & Galvão: a morphological and morphometric analysis comparing its taxonomic relationship with Rhodnius domesticus Neiva & Pinto.

BACKGROUND: Rhodnius zeledoni was described from a single specimen. Since its description, doubts have arisen regarding the taxonomic status of this species in relation to Rhodnius domesticus. METHODS: The present study reviewed and compared R. zeledoni with R. domesticus based on morphological analysis and head geometric morphometrics. RESULTS: Our analysis revealed the absence of distinctive diagnostic characters between the two species at specific levels. Rhodnius zeledoni and R. domesticus show morphological and morphometric similarity, with only minor differences in coloration observed between them. Contrary to previous statements, our analysis showed that R. zeledoni and R. paraensis are not closely related species, not corroborating previous studies with such an assumption. CONCLUSIONS: Therefore, we formally propose R. zeledoni as a junior synonym of R. domesticus.

Compulsory treatment in Portuguese-speaking countries: An analysis and comparison of the legal framework.

BACKGROUND: Compulsory treatment involves the hospital admission of individuals with mental disorders in appropriate facilities through judicial decisions. However, limited information is available regarding the similarities and differences in compulsory treatment legislation in Portuguese-speaking countries. AIMS: To analyse the commonalities and differences in compulsory treatment legislation in Portuguese-speaking countries, where Portuguese is the primary official language, including Angola, Brazil, Cape Verde, East Timor, Guinea-Bissau, Mozambique, Portugal, and São Tomé and Príncipe. METHODS: A comparative analysis of the specific legislation on compulsory treatment in Portuguese-speaking countries was conducted. National development plans were analysed in countries lacking legislation. A purposive sampling of mental health professionals was contacted to gather information on the countries under study. RESULTS: Among the eight Portuguese-speaking countries examined, specific legislation regarding compulsory treatment was found only in Brazil, Cape Verde, and Portugal. These countries, with the lowest poverty rates, exhibited a notable degree of homogeneity in the criteria supporting compulsory treatment, ensuring the protection of individual rights. In contrast, in Angola, East Timor, Guinea-Bissau, Mozambique, and São Tomé and Príncipe, compulsory treatment primarily relies on mental health development plans, resulting in significant variations in the presented criteria. CONCLUSIONS: The significant disparities in compulsory treatment policies among Portuguese-speaking countries, with only Brazil, Cape Verde, and Portugal having specific legislation, underscore the need for a collective effort to establish more consistent procedures and safeguard individual rights.

Lung abscess in a non-compliant patient with Crohn's disease.

A 66-year-old man was admitted to the emergency department due to malaise, fatigue and anorexia for the last 2 weeks. He presented no fever, no respiratory or gastrointestinal symptoms. The patient had been previously diagnosed with Crohn's Disease (CD) (A2L1L4B1 of Montreal Classification) 10 years before, when he presented complaints of watery diarrhea and unexplained weight loss. Despite refusing to start treatment, in the last staging exams performed 5 years before the admission (colonoscopy and magnetic resonance imaging) the patient was in deep remission. Nevertheless, he frequently missed his medical appointments and his disease had not been monitored since then. He denied previous use of corticosteroids, past abdominal surgery or previous CD related hospital admissions. He also denied smoking habits or chronic lung disease.

Organ damage is a major determinant of work productivity impairment in Behçet's Syndrome: a post-hoc analysis of the BODI validation study.

OBJECTIVES: To evaluate the prevalence, magnitude, and potential determinants of work productivity impairment in patients with Behçet's Syndrome (BS), focusing on the role of irreversible organ damage. METHODS: A post-hoc analysis of the BS overall damage index (BODI) prospective validation study was performed. Demographics and clinical features were recorded in all patients. The Work Productivity and Activity Impairment: General Health (WPAI: GH) questionnaire was administered to assess the work limitation and the BODI to measure organ damage. The independent effect of BS features on WPAI: GH outcomes was evaluated by regression analysis. RESULTS: Out of 148 patients, 34.5% were unemployed, with age (OR 1.035) and BODI score (OR 1.313 for 1-unit increase) as the only factors significantly (p< 0.05) associated with the unemployment state. An overall work impairment was reported in about 64.2% of the employed patients. Indeed, 22.7% reported missing work h due to their health (absenteeism), with a mean time loss of 34.4%; whereas 60.2% declared a reduced performance at work because of their health (presenteeism), with a mean productivity impairment of 45.4%. Ocular damage was associated with absenteeism (ß 0.225); female sex (ß 0.260), physician global assessment of disease activity (ß 0.502) and an increased BODI score (ß 0.166 for 1-point increase) with presenteeism; fibromyalgia (ß 0.246), physician global assessment (ß 0.469), and musculoskeletal damage (ß 0.325) with overall work impairment. CONCLUSIONS: Disease activity and organ damage accrual remarkably affect work productivity in BS patients. Achieving remission and preventing damage accrual are crucial and complementary objectives.

Are sarcopenia, frailty and malnutrition prognostic markers of liver disease decompensation in the ambulatory setting? - A prospective cohort study.

BACKGROUND: Sarcopenia, frailty and malnutrition are associated with adverse outcomes in liver cirrhosis. Studies assessing the prognostic value of these conditions in ambulatory patients with cirrhosis are scarce. METHODS: A prospective cohort study was conducted, with consecutive inclusion of all patients with cirrhosis observed in the Hepatology outpatient clinic of a Portuguese tertiary centre. At study enrolment, evaluation of muscle mass (ultrasound quadriceps femoris thickness), muscle strength (handgrip dynamometry) and nutritional status (Patient-Generated Subjective Global Assessment Short Form) was held. Follow-up ended upon the occurrence of a composite endpoint, comprising liver decompensation events and liver-related death, or last medical appointment/non-liver related death before the end of the study. The prognostic value of anthropometrical parameters and nutritional status in the composite endpoint was assessed using a multivariate Cox regression analysis, adjusted for several confounders. RESULTS: Ninety patients were enrolled (80% male), with a mean age of 63.5±10.5 years. The median follow-up was 30 (interquartile range 38) weeks, during which 12 patients reached the composite endpoint. These patients presented a lower mean handgrip strength [23.1±6.41 vs 30.3±10.4 Kg, p=0.04], compared to patients who did not reach the composite endpoint. On Cox regression multivariate analysis, however, no independent predictors of the composite endpoint were found, apart from previous decompensation episodes. CONCLUSION: In this study, muscle strength was lower in the group of patients with cirrhosis who presented a liver-related event. Handgrip strength might be a promising tool in the ambulatory setting to identify patients at risk of liver decompensation and liver-related death in the short term.

Effective submucosal tunneling endoscopic resection (STER) of a giant esophageal leiomyoma / Tunelización submucosa eficaz resección endoscópica (STER) de un esófago gigante leiomioma

We report the successful removal of a giant esophageal leiomyoma using submucosal tunneling endoscopic resection in a 37-year-old woman with significant dysphagia.(AU)

Exploiting click-chemistry: backbone post-functionalisation of homoleptic gold(I) 1,2,3-triazole-5-ylidene complexes.

The synthesis of a homoleptic azide-functionalised Au(I) bis-1,2,3-triazole-5-ylidene complex is reported, starting from a backbone-modified 1,2,3-triazolium salt ligand precursor. The incorporated azide handle allows for a straightforward modification of the complex according to click-chemistry protocols without impacting the steric shielding around the metal center, demonstrating the superiority of the presented triazole ligand framework over imidazole based systems. Employing the SPAAC and the CuAAC reactions, post-modification of the complex is facilitated with two model substrates, while retaining very high antiproliferative activity (nanomolar range IC50 values) in A2780 and MCF-7 human cancer cells.

Microbial production of the plant flavanone hesperetin from caffeic acid.

OBJECTIVE: Hesperetin is an important O-methylated flavonoid produced by citrus fruits and of potential pharmaceutical relevance. The microbial biosynthesis of hesperetin could be a viable alternative to plant extraction, as plant extracts often yield complex mixtures of different flavonoids making it challenging to isolate pure compounds. In this study, hesperetin was produced from caffeic acid in the microbial host Escherichia coli. We combined a previously optimised pathway for the biosynthesis of the intermediate flavanone eriodictyol with a combinatorial library of plasmids expressing three candidate flavonoid O-methyltransferases. Moreover, we endeavoured to improve the position specificity of CCoAOMT7, a flavonoid O-methyltransferase from Arabidopsis thaliana that has been demonstrated to O-methylate eriodictyol in both the para- and meta-position, thus leading to a mixture of hesperetin and homoeriodictyol. RESULTS: The best performing flavonoid O-methyltransferase in our screen was found to be CCoAOMT7, which could produce up to 14.6 mg/L hesperetin and 3.8 mg/L homoeriodictyol from 3 mM caffeic acid in E. coli 5-alpha. Using a platform for enzyme engineering that scans the mutational space of selected key positions, predicting their structures using homology modelling and inferring their potential catalytic improvement using docking simulations, we were able to identify a CCoAOMT7 mutant with a two-fold higher position specificity for hesperetin. The mutant's catalytic activity, however, was considerably diminished. Our findings suggest that hesperetin can be created from central carbon metabolism in E. coli following the introduction of a caffeic acid biosynthesis pathway.

Small-Bowel Angioectasias: Are They Responsible for a Real Impact on Survival?

Introduction: This study aimed to evaluate the effect of small-bowel angioectasia on survival, given the hypothesis that angioectasia might be an independent risk factor of frailty and poor outcomes. Methods: In this retrospective cohort study, all patients undergoing small-bowel capsule endoscopy between 2010 and 2013 for obscure gastrointestinal bleeding from a Portuguese tertiary centre were included. Follow-up started after capsule endoscopy and ended upon death or end of the study (November 2020). Survival analysis was performed using a Cox proportional-hazards model, in order to analyse the effect of small-bowel angioectasia on survival as well as potentially confounding factors (age, vascular diseases and chronic kidney disease). Results: A total of 176 patients were included in this study (50.6% male), with a median age of 68.5 years (IQR 24). The median follow-up was 7 years (IQR 4), during which 67 (38.1%) patients died. Seventy-three (41.5%) patients had at least one small-bowel angioectasia on capsule endoscopy. On multivariate Cox regression analysis, only age, peripheral arterial disease, history of previous mesenteric ischaemia and chronic kidney disease were independent risk factors of death. The presence of small-bowel angioectasia did not affect survival in this analysis (HR 1.30; 95% CI 0.75-2.23; p = 0.35). Conclusion: In this retrospective cohort study, some comorbidities and age were independent predictors of poor survival. The presence of small-bowel angioectasia per se did not affect survival.

Introdução: Este estudo pretendeu avaliar a influência das angiectasias do intestino delgado na sobrevida, dada a hipótese de que as angiectasias pudessem constituir um fator de risco independente para fragilidade e outcomes adversos. Métodos: Os autores incluíram neste estudo de coorte retrospetivo todos os doentes submetidos a cápsula endoscópica entre 2010 e 2013 por hemorragia digestiva obscura num centro português terciário. O followup iniciou-se após a realização da cápsula e terminou aquando da morte ou fim do estudo (Novembro de 2020). A análise da sobrevida foi realizada através de um modelo de regressão de Cox, no sentido de analisar o efeito na sobrevida das angiectasias do intestino delgado e de potenciais fatores confundidores (idade, doenças vasculares e doença renal crónica). Resultados: Neste estudo foram incluídos 176 doentes (50.6% do sexo masculino), com uma idade mediana de 68.5 anos (IQR 24). O tempo de follow-up mediano foi de 7 anos (IQR 4), durante o qual se verificaram 67 (38.1%) óbitos. 73 (41.5%) dos doentes apresentavam pelo menos uma angiectasia no intestino delgado. Na análise de sobrevida, apenas a idade, doença arterial periférica, história prévia de isquemia mesentérica e doença renal crónica foram fatores de risco independentes de mortalidade. A presença de angiectasias no intestino delgado não afetou a sobrevida nesta amostra (HR 1,30; 95% CI 0,75­2,23; p = 0.35). Conclusão: Neste estudo de coorte retrospetivo, algumas co-morbilidades e a idade foram fatores de risco independentes de mortalidade. A presença de angiectasias no intestino delgado, per se, não afetou a sobrevida.

External quality assessment of the entomological identification of triatomines in the network of public laboratories in Rondônia, Brazil.

BACKGROUND: An external quality assessment on the identification of triatomines within the laboratory network in the state of Rondônia. METHODS: Seven laboratories participated in this evaluation. Each was provided with support materials and nine insects from the Hemiptera order for identification. RESULTS: All samples were accurately identified at the species level. However, correct sex identification was achieved for only 79% of the samples. The most significant challenges were encountered in determining the sex of predators, phytophagous species, Rhodnius robustus, and Rhodnius pictipes. CONCLUSIONS: The identified shortcomings can inform enhancements in vector control programs for Chagas disease.

Capsule Enteroscopy Using the Mirocam® versus OMOM® Systems: A Matched Case-Control Study.

Although several devices are available for small bowel capsule endoscopy, few studies have compared their visualization quality and diagnostic yield, despite users reporting subjective differences between them. This study aims to compare two widely used systems (Mirocam® MC1600 and OMOM® HD). Patients who underwent OMOM® HD capsule enteroscopy between August 2022 and February 2023 were prospectively included consecutively (cases). Controls were retrospectively selected from a database of patients who underwent Mirocam® MC1600 enteroscopy between March 2018 and July 2022 in a 1:1 ratio. Controls were matched for potential confounders (age, sex, indication, hospitalization, comorbidities, and opioid prescription). The small bowel cleanliness (global and divided by tertiles), the diagnostic yield (positive findings) and the transit times (TT) were compared. Overall, 214 patients were included (107:107). Global bowel preparation was similar between the OMOM® and Mirocam® groups. However, the average scores for each tertile were significantly higher when the OMOM® HD capsule was used (p < 0.05). Small bowel TT was shorter for OMOM® HD (265 ± 118 versus 307 ± 87 min, p = 0.020), while the diagnostic yield (55.0%) and relative distribution of lesions were similar. This study suggests that capsule characteristics, namely resolution, and illumination, systematically interfere with the perception of preparation quality. However, this did not affect the diagnostic yield.

Concordance of Dye-Spraying Chromoendoscopy and Virtual Chromoendoscopy for Colonic Dysplasia Detection in Longstanding Inflammatory Bowel Disease.

BACKGROUND/AIMS: In the past, dye-spraying chromoendoscopy was the technique of choice for colonic surveillance in patients with long-standing extensive inflammatory bowel disease. Recent evidence suggests that virtual chromoendoscopy is an equally acceptable technique. MATERIALS AND METHODS: Eleven gastroenterologists were given a survey with 20 pairs of pictures from inflammatory bowel disease surveillance colonoscopies (10 with nondysplastic lesions, 5 with dysplastic lesions, and 5 with no lesions). Each pair contained the same image captured during colonoscopy using indigo carmine and narrow-band imaging. For each picture, the gastroenterologist assessed the presence/absence of lesion and, when a lesion was identified, assessed the presence/absence of dysplasia and delineated its margins. To compare lesion and dysplasia detection between techniques, sensitivity, specificity, and interobserver agreement were calculated. The chi-square test was used to assess the accuracy of margins delineation. RESULTS: When assessing lesion and dysplasia detection, similar sensitivity and specificity values were obtained for both techniques. Interobserver agreement analysis revealed that dye-spraying chromoendoscopy and virtual chromoendoscopy had a moderate agreement in lesion detection but, for dysplasia detection, dye-spraying chromoendoscopy had a slight agreement [K = 0.11 (0.03-0.18), P < .01] and virtual chromoendoscopy a fair agreement [K = 0.30 (0.22-0.37), P < .01]. Margin delineation was similar between techniques. CONCLUSION: Sensitivity and specificity for lesion and dysplasia detection, as well as the accuracy of margins delineation, were similar between dye-spraying chromoendoscopy and virtual chromoendoscopy. Interobserver agreement for dysplasia detection was suboptimal in both techniques; however, it was superior when using virtual chromoendoscopy. These findings suggest that virtual chromoendoscopy constitutes a valid alternative for dysplasia screening in inflammatory bowel disease.

Effective submucosal tunneling endoscopic resection (STER) of a giant esophageal leiomyoma.

We report the successful removal of a giant esophageal leiomyoma using submucosal tunneling endoscopic resection in a 37-year-old woman with significant dysphagia.