Necrotizing mesenteric vasculitis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder which may affect the gastrointestinal system. Half of the patients with SLE experience gastrointestinal symptoms, with the most common being nausea, vomiting, anorexia, and abdominal pain. Mesenteric vasculitis is a severe and rare complication of SLE and one of the most frequent causes of severe acute abdominal pain. The authors present a case of a 57-year-old woman with SLE who was diagnosed with necrotizing mesenteric vasculitis following a urinary septic shock. The patient was treated with high-dose corticosteroid therapy and cyclophosphamide, with resolution of the clinical picture.

Predictors of damage accrual and its impact on health-related quality of life of thrombotic antiphospholipid syndrome: Independent validation of the damage index for antiphospholipid syndrome (DIAPS).

OBJECTIVES: We aim to independently assess the validity of the damage index for antiphospholipid syndrome (DIAPS) in thrombotic antiphospholipid syndrome (APS) patients by exploring the prevalence and risk factors of organ damage and evaluating its impact on health-related quality of life (HR-QoL). METHODS: Cross-sectional study including all thrombotic APS patients (Sydney criteria) attending a Portuguese tertiary centre. Damage was assessed using the DIAPS, and HR-QoL using the 3- and 5-level EuroQol HR-QoL (EQ-D5-3L and 5L), and Visual Analogue Scale (VAS) applied via a phone questionnaire. Spearman's correlation between DIAPS and the HR-QoL scales was performed. Risk factors for damage accrual and HR-QoL impairment were explored using univariate and multivariate logistic regression. RESULTS: Among the 108 patients (female, 65.7%; white, 90.7%; primary APS, 75.9%; median disease duration, 6 years), damage (DIAPS≥1) developed in 48.2% of patients (mean ± SD DIAPS, 3.08 ± 1.83). DIAPS's neuropsychiatric domain was the most affected (24.2%), followed by the peripheral vascular domain (20.3%). No clinical, demographic nor laboratory parameters were significantly associated with damage. Regarding HR-QoL, pain/discomfort, anxiety/depression and usual activities domains were the most frequently impaired in both scales. DIAPS's domains correlated similarly with the EQ-5D-3L and 5L scales' individual domains. Female sex, medical disorders, secondary APS and type of presenting thrombosis (arterial) increased the risk of HR-QoL impairment. Total DIAPS was associated with higher odds of mobility, self-care and pain/discomfort impairment in both EQ-5D-3L and 5L scales but lost its independent risk in multivariable analysis. CONCLUSION: This external validation of DIAPS reinforces the ability of the score to correlate with HR-QoL while also highlighting risk factors for HR-QoL impairment other than damage accrual.

Stroma-infiltrating T cell spatiotypes define immunotherapy outcomes in adolescent and young adult patients with melanoma.

The biological underpinnings of therapeutic resistance to immune checkpoint inhibitors (ICI) in adolescent and young adult (AYA) melanoma patients are incompletely understood. Here, we characterize the immunogenomic profile and spatial architecture of the tumor microenvironment (TME) in AYA (aged ≤ 30 years) and older adult (aged 31-84 years) patients with melanoma, to determine the AYA-specific features associated with ICI treatment outcomes. We identify two ICI-resistant spatiotypes in AYA patients with melanoma showing stroma-infiltrating lymphocytes (SILs) that are distinct from the adult TME. The SILhigh subtype was enriched in regulatory T cells in the peritumoral space and showed upregulated expression of immune checkpoint molecules, while the SILlow subtype showed a lack of immune activation. We establish a young immunosuppressive melanoma score that can predict ICI responsiveness in AYA patients and propose personalized therapeutic strategies for the ICI-resistant subgroups. These findings highlight the distinct immunogenomic profile of AYA patients, and individualized TME features in ICI-resistant AYA melanoma that require patient-specific treatment strategies.

Aggressiveness in systemic anticancer therapy at the end of life in an oncology center.

Introduction: An increasing aggressiveness in cancer treatment at the end of life (EoL) has been reported in several, but not all, countries. This study aimed to see how aggressive cancer treatment is at the EoL in an oncology center. Methods: Retrospective study of patients 18 years or older with a solid cancer diagnosis who died in 2017. The focus was systemic anticancer therapy (SACT), excluding hormonotherapy. Results: In 2017, 2024 patients with solid tumors died. Of those patients, 1262 (62%) were male, and the median age was 69 (range 19-97) years. The most frequent primary cancer was lung cancer, followed by colorectal and stomach cancers, and 740 (37%) patients had metastatic disease. The median interval between SACT and death was 61 days. Of the patients undergoing SACT, 216 (27%) did it in the last month of life, 174 (22%) between 8 and 30 days from death, and 42 (5%) in the last week. On multivariable analysis, head and neck, colorectal, breast, and melanoma primaries; age group (older than 65 years); and metastatic disease had statistical significance associated with SACT. Of these variables, only metastatic disease is more likely to undergo SACT. Conclusion: This study confirms the relatively frequent aggressiveness in cancer treatment at the EoL. Taking into consideration previously published data, it can be tentatively concluded that the use of SACT increased in the last month and the last week of life.

Blockage of aquaporin-3 peroxiporin activity by organogold compounds affects melanoma cell adhesion, proliferation and migration.

Aquaporin-3 (AQP3) is a membrane channel with dual aquaglyceroporin/peroxiporin activity, facilitating the diffusion of water, glycerol and H2 O2 across cell membranes. AQP3 shows aberrant expression in melanoma and its role in cell adhesion, migration and proliferation is well described. Gold compounds were shown to modulate AQP3 activity with reduced associated toxicity, making them promising molecules for cancer therapy. In this study, we validated the phenotype resulting from AQP3-silencing of two melanoma cell lines, MNT-1 and A375, which resulted in decreased H2 O2 permeability. Subsequently, the AQP3 inhibitory effect of a new series of organogold compounds derived from Auphen, a potent AQP3 inhibitor, was first evaluated in red blood cells (RBCs) that highly express AQP3, and then in HEK-293T cells with AQP3 overexpression to ascertain the compounds' specificity. The first screening in RBCs unveiled two organogold compounds as promising blockers of AQP3 permeability. Moderate reduction of glycerol permeability but drastic inhibition of H2 O2 permeability was detected for some of the gold derivatives in both AQP3-overexpressing cells and human melanoma cell lines. Additionally, all compounds were effective in impairing cell adhesion, proliferation and migration, although in a cell type-dependent manner. In conclusion, our data show that AQP3 peroxiporin activity is crucial for melanoma progression and highlight organogold compounds as promising AQP3 inhibitors with implications in melanoma cell adhesion, proliferation and migration, unveiling their potential as anticancer drugs against AQP3-overexpressing tumours. KEY POINTS: AQP3 affects cellular redox balance. Gold compounds inhibit AQP3 permeability in melanoma cells. AQP3 is involved in cell adhesion, proliferation and migration of melanoma. Blockage of AQP3 peroxiporin activity impairs melanoma cell migration. Gold compounds are potential anticancer drug leads for AQP3-overexpressing cancers.

First-line chemoimmunotherapy and immunotherapy in patients with non-small cell lung cancer and brain metastases: a registry study.

Introduction: Brain metastases commonly occur in patients with non-small cell lung cancer (NSCLC). Standard first-line treatment for NSCLC, without an EGFR, ALK or ROS1 mutation, is either chemoimmunotherapy or anti-PD-1 monotherapy. Traditionally, patients with symptomatic or untreated brain metastases were excluded from the pivotal clinical trials that established first-line treatment recommendations. The intracranial effectiveness of these treatment protocols has only recently been elucidated in small-scale prospective trials. Methods: Patients with NSCLC and brain metastases, treated with first-line chemoimmunotherapy or anti-PD-1 monotherapy were selected from the Australian Registry and biObank of thoracic cancers (AURORA) clinical database covering seven institutions. The primary outcome was a composite time-to-event (TTE) outcome, including extracranial and intracranial progression, death, or need for local intracranial therapy, which served as a surrogate for disease progression. The secondary outcome included overall survival (OS), intracranial objective response rate (iORR) and objective response rate (ORR). Results: 116 patients were included. 63% received combination chemoimmunotherapy and 37% received anti-PD-1 monotherapy. 69% of patients received upfront local therapy either with surgery, radiotherapy or both. The median TTE was 7.1 months (95% CI 5 - 9) with extracranial progression being the most common progression event. Neither type of systemic therapy or upfront local therapy were predictive of TTE in a multivariate analysis. The median OS was 17 months (95% CI 13-27). Treatment with chemoimmunotherapy was predictive of longer OS in multivariate analysis (HR 0.35; 95% CI 0.14 - 0.86; p=0.01). The iORR was 46.6%. The iORR was higher in patients treated with chemoimmunotherapy compared to immunotherapy (58% versus 31%, p=0.01). The use of chemoimmunotherapy being predictive of iORR in a multivariate analysis (OR 2.88; 95% CI 1.68 - 9.98; p=0.04). Conclusion: The results of this study of real-world data demonstrate the promising intracranial efficacy of chemoimmunotherapy in the first-line setting, potentially surpassing that of immunotherapy alone. No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.

Is it possible to identify physical-motor profiles of preschool children on their association with selected biosocial factors?

Biosocial factors play a crucial role in the physical-motor development (PMD) of children during the preschool age. The present study aims to identify physical-motor profiles throughout preschool age (3-6 years) and explore associations between profiles and selected biosocial factors such as age, sex, prematurity, weight, height, BMI, and participation in extracurricular physical activities. Data from 412 typically developing children (46.6% girls and 53.4% boys), aged 35-71 months (M = 51.21, SD = 10.47) was collected using the Psychomotor Activities Checklist and specifically the scale of Psycho-Motor Aspects. Cluster analysis made it possible to define four different childhood PMD profiles. High PMD; High PMD except left laterality; medium-low PMD; and low PMD. High PMD profile includes older children, with anthropometric measurements closer to the WHO recommendations, fewer preterm children, and greater participation in extracurricular physical activities. Low PMD profile includes younger children, with weight slightly above and height slightly below the WHO recommendations and low participation in extracurricular physical activities. This study allows us to identify specific trends that may be decisive for the motor development of children throughout preschool age, highlighting selected biological variables and participation in extracurricular physical activities.

Seasonal patterns of toxicity in melanoma patients treated with combination anti-PD-1 and anti-CTLA-4 immunotherapy.

BACKGROUND: Immune checkpoint inhibitors are frequently associated with the development of immunotherapy-related adverse events (irAEs). The exact etiology, including the role of environmental factors, remains incompletely understood. METHODS: We analyzed the records of 394 melanoma patients from three centers (northern and southern hemisphere). Patients had received at least one cycle of anti-PD-1/anti-CTLA-4 with a minimum follow-up of 3 months. We study the distribution and time to irAEs onset throughout the calendar year. RESULTS: 764 irAEs were recorded; the most frequent were skin rash (35%), hepatitis (32%) and colitis (30%). The irAEs incidence was the highest in autumn and winter, and the ratio for the 'number of irAEs' per 'therapies commenced' was the highest in winter and lowest in summer (2.4 and 1.7, respectively). Season-specific patterns in the time of irAEs onset were observed for pneumonitis (shorter time to onset in autumn, p = 0.025), hepatitis (shorter time to onset in spring, p = 0.016) and sarcoid-like immune reaction (shorter time to onset in autumn, p = 0.041). Season-specific patterns for early-onset irAEs were observed for hepatitis (spring, p = 0.023) and nephritis (summer, p = 0.017). Early-onset pneumonitis was more frequent in autumn-winter (p = 0.008) and early-onset nephritis in spring-summer (p = 0.004). CONCLUSIONS: Environmental factors that are associated with particular seasons may contribute to the development of certain irAEs and suggest the potential effect of environmental triggers. The identification of these factors may enhance preventive and therapeutic strategies to reduce the morbidity of irAEs.

Impact of washing and freezing on nutritional composition, bioactive compounds, antioxidant activity and microstructure of mango peels.

Mango peels are widely produced and highly perishable. Disinfectant washing and freezing are among the most used methods to preserve foods. However, their impact on products' properties is conditioned by the foods' features. This study evaluated for the first time the phytochemical composition, antioxidant activity, and microstructure of mango peels washed with peracetic acid (27 mg/mL for 19 min) and frozen at -20 °C for 30 days. Washing decreased the content of vitamin C (-7%), penta-O-galloyl-ß-d-glucose (-23 %), catechin (-30 %), and lutein (-24 %), but the antioxidant activity was preserved. Freezing changed mango peels' microstructure, increased free phenolic compounds, namely acid gallic (+36 %) and catechin (+51 %), but reduced bound phenolic compounds (-12 % to -87 %), bound phenolic compounds' antioxidant activity (-51 % to -72 %), and violaxanthin (-51 %). Both methods were considered adequate to conserve mango peels since fiber and the main bioactive compounds (free mangiferin, free gallic acid, and ß-carotene) remained unchanged or increased.

Combined immunotherapy in melanoma patients with brain metastases: A multicenter international study.

BACKGROUND: Ipilimumab plus nivolumab (COMBO) is the standard treatment in asymptomatic patients with melanoma brain metastases (MBM). We report a retrospective study aiming to assess the outcome of patients with MBM treated with COMBO outside clinical trials. METHODS: Consecutive patients treated with COMBO have been included. Demographics, steroid treatment, Central Nervous System (CNS)-related symptoms, BRAF status, radiotherapy or surgery, response rate (RR), progression-free (PFS) and overall survival (OS) have been analyzed. RESULTS: 376 patients were included: 262 received COMBO as first-line and 114 as a subsequent line of therapy, respectively. In multivariate analysis, Eastern Cooperative Oncology Group (ECOG) (≥1 vs 0) [HR 1.97 (1.46-2.66)], extracerebral metastases [HR 1.92 (1.09-3.40)], steroid use at the start of COMBO [HR 1.59 (1.08-2.38)], CNS-related symptoms [HR 1.59 (1.08-2.34)], SRS (Stereotactic radiosurgery) [HR 0.63 (0.45-0.88)] and surgery [HR 0.63 (0.43-0.91)] were associated with OS. At a median follow-up of 30 months, the median OS (mOS) in the overall population was 21.3 months (18.1-24.5), whilst OS was not yet reached in treatment-naive patients, steroid-free at baseline. In patients receiving COMBO after BRAF/MEK inhibitors(i) PFS at 1-year was 15.7%. The dose of steroids (dexamethasone < vs ≥ 4 mg/day) was not prognostic. SRS alongside COMBO vs COMBO alone in asymptomatic patients prolonged survival. (p = 0.013). Toxicities were consistent with previous studies. An independent validation cohort (n = 51) confirmed the findings. CONCLUSIONS: Our results demonstrate remarkable long-term survival in treatment-naïve, asymptomatic, steroid-free patients, as well as in those receiving SRS plus COMBO. PFS and OS were poor in patients receiving COMBO after progressing to BRAF/MEKi.

Validation and Cultural Adaptation of the Problem Areas in Diabetes-5 (PAID-5) Scale to European Portuguese.

INTRODUCTION: Diabetes distress syndrome (DDS) can lead to poor outcomes and should be assessed with adapted and validated tools. One of these tools is the Problem Areas in Diabetes (PAID) scale, which assesses diabetes distress in people suffering from diabetes (PsD). A short five-item form, PAID-5, is an easier and quicker alternative to be used in clinical and research practices, than the previous one with 20-items and has been validated by the original authors. This study intended to perform the cultural adaptation and validation of the PAID-5 scale in European Portuguese. METHODS: To create the Portuguese version of PAID-5, translation-back translation, a clinical review, and a cognitive debriefing panel were performed. A convenience sample of 90 PsD was studied in three primary healthcare units for reliability and validity tests. Reliability was studied by the internal consistency (Cronbach's alpha) and the interval coefficient correlation (ICC) under a test-retest design. Structural validity was studied by principal component analysis. The construct validity was tested by the sensitivity of the PAID-5 total score with age, most recent HbA1c test, and socioeconomic class by the Socio-Economic Deprivation Index (SEDI). Criterion validity was tested by correlating the PAID-5 total score with the psychological distress questions of the Diabetes Health Profile 18 Questions (DHP-PDQ). RESULTS: A Cronbach's alpha coefficient value of 0.905 and an ICC of 0.905 were computed. In a sample of n = 90 PsD, 55.6% were males, 63.3% aged 65 years or more, SEDI was 5.2 ± 0.8 [3 to 6], 44.4% studied for less than 4 years, and 18.9% were living alone. The Spearman correlation between PAID-5 and DHP-PDQ total scores was ρ = 0.382, p < 0.001, between PAID-5 total score and age was ρ = -0.207, p = 0.050 and between PAID-5 total score and most recent HbA1c knowledge was ρ = 0.275, p = 0.040. There was no significant relationship between PAID-5 total score and SEDI ρ = 0.080, p = 0.452. CONCLUSION: DDS can now be assessed in the Portuguese context, accounting for better intervention by primary care teams. PAID-5 has good psychometric properties and is a reliable scale to identify diabetes-specific distress in the Portuguese diabetic population.

The Pharmacological Effect of Hemin in Inflammatory-Related Diseases: Protocol for a Systematic Review.

BACKGROUND: Hemin is a commonly used drug in the treatment of acute attacks of porphyria, due to its capability of restoring normal levels of hemoproteins and respiratory pigments. In addition, this drug has demonstrated the capacity to induce the heme oxygenase (HO) enzyme. At the moment, there are 3 known HO isoenzymes in mammals: HO-1, HO-2, and HO-3. The first of these shows cytoprotective, antioxidant, and anti-inflammatory effects. Currently, medicines used in inflammatory disorders have increased toxicity, especially over longer time frames, which highlights the need to investigate new, safer options. Indeed, the current nonclinical evidence demonstrates the potential that hemin has a significant anti-inflammatory effect in several animal models of inflammation-related diseases, such as experimental colitis, without significant side effects. However, the underlying mechanism(s) are still not fully understood. In addition, past nonclinical studies have applied different therapeutic regimens, making it relatively difficult to understand which is optimal. According to the literature, there is a lack of review articles discussing this topic, highlighting the need for a summary and analysis of the available preclinical evidence to elucidate the abovementioned issues. Therefore, a qualitative synthesis of the current evidence is essential for the research and medical communities. OBJECTIVE: This systematic review aims to summarize and analyze currently available nonclinical data to ascertain the potential anti-inflammatory effect of hemin in animal models. METHODS: Throughout the development of this protocol, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The comprehensive search strategy will be carried out in MEDLINE (PubMed), Web of Science, and Scopus without any filters associated with publication date. Only in vivo, nonclinical studies that evaluated the potential anti-inflammatory effect of hemin will be included. The evaluated outcomes will be the observed clinical signs, inflammatory and other biochemical markers, and macroscopic and microscopic evaluations. To analyze the potential risk of bias, we will use the risk of bias tool developed by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE). RESULTS: Currently, it is not possible to disclose any results since the project is still in initial steps. More specifically, we are currently engaged in the identification of eligible articles through the application of the inclusion and exclusion criteria. The work was initiated in April 2023, and it is expected to be finished at the end of 2023. CONCLUSIONS: Concerning the major gap in the literature regarding the underlying mechanism(s) and treatment-related properties, this systematic review will be essential to clearly summarize and critically analyze the nonclinical data available, promoting a clearer vision of the potential anti-inflammatory effect of hemin. TRIAL REGISTRATION: PROSPERO CRD42023406160; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=406160. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/48368.

VEGF Inhibitors Improve Survival Outcomes in Patients with Liver Metastases across Cancer Types-A Meta-Analysis.

BACKGROUND: Liver metastases are associated with poor prognosis across cancers. Novel treatment strategies to treat patients with liver metastases are needed. This meta-analysis aimed to assess the efficacy of vascular endothelial growth factor inhibitors in patients with liver metastases across cancers. METHODS: A systematic search of PubMed, Cochrane CENTRAL, and Embase was performed between January 2000 and April 2023. Randomized controlled trials of patients with liver metastases comparing standard of care (systemic therapy or best supportive care) with or without vascular endothelial growth factor inhibitors were included in the study. Outcomes reported included progression-free survival and overall survival. RESULTS: A total of 4445 patients with liver metastases from 25 randomized controlled trials were included in this analysis. The addition of vascular endothelial growth factor inhibitors to standard systemic therapy or best supportive care was associated with superior progression-free survival (HR = 0.49; 95% CI, 0.40-0.61) and overall survival (HR = 0.83; 95% CI, 0.74-0.93) in patients with liver metastases. In a subgroup analysis of patients with versus patients without liver metastases, the benefit with vascular endothelial growth factor inhibitors was more pronounced in the group with liver metastases (HR = 0.44) versus without (HR = 0.57) for progression-free survival, but not for overall survival. CONCLUSION: The addition of vascular endothelial growth factor inhibitors to standard management improved survival outcomes in patients with liver metastasis across cancers.

Previous exposure to Spike-providing parental strains confers neutralizing immunity to XBB lineage and other SARS-CoV-2 recombinants in the context of vaccination.

The emergence of SARS-CoV-2 recombinants is of particular concern as they can result in a sudden increase in immune evasion due to antigenic shift. Recent recombinants XBB and XBB.1.5 have higher transmissibility than previous recombinants such as "Deltacron." We hypothesized that immunity to a SARS-CoV-2 recombinant depends on prior exposure to its parental strains. To test this hypothesis, we examined whether Delta or Omicron (BA.1 or BA.2) immunity conferred through infection, vaccination, or breakthrough infection could neutralize Deltacron and XBB/XBB.1.5 recombinants. We found that Delta, BA.1, or BA.2 breakthrough infections provided better immune protection against Deltacron and its parental strains than did the vaccine booster. None of the sera were effective at neutralizing the XBB lineage or its parent BA.2.75.2, except for the sera from the BA.2 breakthrough group. These results support our hypothesis. In turn, our findings underscore the importance of multivalent vaccines that correspond to the antigenic profile of circulating variants of concern and of variant-specific diagnostics that may guide public health and individual decisions in response to emerging SARS-CoV-2 recombinants.

Classification of the tumor immune microenvironment and associations with outcomes in patients with metastatic melanoma treated with immunotherapies.

BACKGROUND: Tumor microenvironment (TME) characteristics are potential biomarkers of response to immune checkpoint inhibitors in metastatic melanoma. This study developed a method to perform unsupervised classification of TME of metastatic melanoma. METHODS: We used multiplex immunohistochemical and quantitative pathology-derived assessment of immune cell compositions of intratumoral and peritumoral regions of metastatic melanoma baseline biopsies to classify TME in relation to response to anti-programmed cell death protein 1 (PD-1) monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 (ipilimumab (IPI)+PD-1). RESULTS: Spatial profiling of CD8+T cells, macrophages, and melanoma cells, as well as phenotypic PD-1 receptor ligand (PD-L1) and CD16 proportions, were used to identify and classify patients into one of three mutually exclusive TME classes: immune-scarce, immune-intermediate, and immune-rich tumors. Patients with immune-rich tumors were characterized by a lower proportion of melanoma cells and higher proportions of immune cells, including higher PD-L1 expression. These patients had higher response rates and longer progression-free survival (PFS) than those with immune-intermediate and immune-scarce tumors. At a median follow-up of 18 months (95% CI: 6.7 to 49 months), the 1-year PFS was 76% (95% CI: 64% to 90%) for patients with an immune-rich tumor, 56% (95% CI: 44% to 72%) for those with an immune-intermediate tumor, and 33% (95% CI: 23% to 47%) for patients with an immune-scarce tumor. A higher response rate was observed in patients with an immune-scarce or immune-intermediate tumor when treated with IPI+PD-1 compared with those treated with PD-1 alone. CONCLUSIONS: Our study provides an automatic TME classification method that may predict the clinical efficacy of immunotherapy for patients with metastatic melanoma.

A paradox of bacterial persistence and antibiotic resistance: chloramphenicol acetyl transferase as a double barrel shot gun.

The problematic microbial resistance to antibiotics has led to an increasing interest in bacterial persistence and its impact on infection. Nonetheless, these two mechanisms are often assessed in independent studies, and there is a lack of knowledge about their relation or possible interactions, both at cellular and population levels. This work shows evidence that the insertion of the resistance gene Chloramphenicol Acetyl Transferase (cat) together with its cognate antibiotic chloramphenicol (CAM), is capable to modulate Salmonella Typhimurium persistence to several antibiotics and decrease its survival. This effect is independent of the antibiotics' mechanisms of action or the locus of cat. RelA [p(ppGpp) syntetase] has been shown to be involved in persistence. It was recently proposed that RelA [(p)ppGpp synthetase], binds to uncharged tRNAs, forming RelA.tRNA complexes. These complexes bind to vacant A-sites in the ribosome, and this mechanism is essential for the activation of RelA. In this study, we propose that the antibiotic chloramphenicol blocks the A-site of the ribosome, hindering the binding of RelA.tRNA complexes to the ribosome thus preventing the activation of RelA and (p)ppGpp synthesis, with a consequent decrease in the level of persistence of the population. Our discovery that the concomitant use of chloramphenicol and other antibiotics in chloramphenicol resistant bacteria can decrease the persister levels can be the basis of novel therapeutics aiming to decrease the persisters and recalcitrant infections.

Colorectal cancer cell exosome and cytoplasmic membrane for homotypic delivery of therapeutic molecules.

Colorectal cancer (CRC) is one of the most common causes of death in the world. The multi-drug resistance, especially in metastatic colorectal cancer, drives the development of new strategies that secure a positive outcome and reduce undesirable side effects. Nanotechnology has made an impact in addressing some pharmacokinetic and safety issues related to administration of free therapeutic agents. However, demands of managing complex biointerfacing require equally complex methods for introducing stimuli-responsive or targeting elements. In order to procure a more efficient solution to the overcoming of biological barriers, the physiological functions of cancer cell plasma and exosomal membranes provided the source of highly functionalized coatings. Biomimetic nanovehicles based on colorectal cancer (CRC) membranes imparted enhanced biological compatibility, immune escape and protection to diverse classes of therapeutic molecules. When loaded with therapeutic load or used as a coating for other therapeutic nanovehicles, they provide highly efficient and selective cell targeting and uptake. This review presents a detailed overview of the recent application of homotypic biomimetic nanovehicles in the management of CRC. We also address some of the current possibilities and challenges associated with the CRC membrane biomimetics.

Cytomegalovirus and rheumatic diseases: cases-based review.

Cytomegalovirus (CMV) infection is a common and typically benign disease in immunocompetent individuals. However, immunocompromised patients are at a greater risk of reactivation, leading to more severe outcomes. Patients with rheumatic diseases have a particularly high risk of opportunistic infections due to both the inherent immunosuppressive state conveyed by the disease itself and the use of potent immunosuppressant drugs, such as glucocorticoids, cyclophosphamide, and rituximab. Limited data are available regarding prophylactic or preemptive treatment of CMV infection in patients with rheumatic diseases. In this article the authors present two cases of rheumatic conditions complicated by CMV infection. The first case describes a patient with eosinophilic granulomatosis with polyangiitis, previously treated with glucocorticoids and cyclophosphamide, who developed CMV colitis with bowel perforation. The second case involves a woman with systemic lupus erythematosus who was diagnosed with CMV meningitis. Both cases reinforce the importance of establishing guidelines for surveillance and prophylaxis of CMV infection in these patients.

Lag-3 expression and clinical outcomes in metastatic melanoma patients treated with combination anti-lag-3 + anti-PD-1-based immunotherapies.

Lymphocyte-activation gene-3 (LAG-3), an immune checkpoint receptor, negatively regulates T-cell function and facilitates immune escape of tumors. Dual inhibition of LAG-3 and programmed cell death receptor-1 (PD-1) significantly improved progression-free survival (PFS) in metastatic melanoma patients compared to anti-PD-1 therapy alone. Investigating the utility of LAG-3 expression as a biomarker of response to anti-LAG-3 + anti-PD-1 immunotherapy is of great clinical relevance. This study sought to evaluate the association between baseline LAG-3 expression and clinical outcomes following anti-LAG-3 and anti-PD-1-based immunotherapy in metastatic melanoma. LAG-3 immunohistochemistry (clone D2G4O) was performed on pre-treatment formalin-fixed, paraffin-embedded metastatic melanoma specimens from 53 patients treated with combination anti-LAG-3 + anti-PD-1-based therapies. Eleven patients had received prior anti-PD-1-based treatment. Patients were categorized as responders (complete/partial response; n = 36) or non-responders (stable/progressive disease; n = 17) based on the Response Evaluation Criteria in Solid Tumours (RECIST). Tumor-infiltrating lymphocytes (TILs) were scored on hematoxylin and eosin-stained sections. LAG-3 expression was observed in 81% of patients, with staining in TILs and dendritic cells. Responders displayed significantly higher proportions of LAG-3+ cells compared to non-responders (P = .0210). LAG-3 expression positively correlated with TIL score (P < .01). There were no significant differences in LAG-3 expression between different sites of metastases (P > .05). Patients with ≥ 1% LAG-3+ cells in their tumors had significantly longer PFS compared to patients with < 1% LAG-3 expression (P = .0037). No significant difference was observed in overall survival between the two groups (P = .1417). Therefore, the assessment of LAG-3 expression via IHC warrants further evaluation to determine its role as a predictive marker of response and survival in metastatic melanoma.