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We present the case of a 62-year-old man with a history of celiac disease and IgA deficiency, following a strict gluten-free diet that was admitted to our hospital for recurrent abdominal pain, fatigue and melena. Esophagogastroduodenoscopy and colonoscopy with biopsies were normal. A video-capsule endoscopy was performed and revealed a sub-stenosing, vegetating, and bleeding lesion in the first jejunal loop. He underwent laparotomic surgery with resection of the involved segment with loco-regional lymphadenectomy. The pathological report described a poorly differentiated adenocarcinoma of the jejunum, stage IIIA (pT3pN1). Analysis of next-generation sequencing (NGS) of DNA on the surgical sample revealed a likely pathogenetic variant in exon 15 of the DDR2 gene (c.2003G > A) and a TP53 non-frame-shift deletion (c.585_602del). Considering the risk of recurrence, he was candidate to 6 months of adjuvant chemotherapy with platinum salt and fluoropyrimidine. Thirty-eight months after the diagnosis, the patient is still disease free and in good clinical condition. This is the first described case of SBA with DDR2 mutation. Considering the limited therapeutic options beyond surgery for SBA, molecular analyses could become promising for the search for potential targetable alterations for treatments with new available drugs. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced solid cancers. Resistance to ICIs, both primary and secondary, poses challenges, with early mortality (EM) within 30–90 days indicating a lack of benefit. Prognostic factors for EM, including the lung immune prognostic index (LIPI), remain underexplored. Methods: We performed a retrospective, observational study including patients affected by advanced solid tumors, treated with ICI as single agent or combined with other agents. Logistic regression models identified factors associated with EM and 90-day progression risks. A nomogram for predicting 90-day mortality was built and validated within an external cohort. Results: In total, 637 patients received ICIs (single agent or in combination with other drugs) for advanced solid tumors. Most patients were male (61.9%), with NSCLC as the prevalent tumor (61.8%). Within the cohort, 21.3% died within 90 days, 8.4% died within 30 days, and 34.5% experienced early progression. Factors independently associated with 90-day mortality included ECOG PS 2 and a high/intermediate LIPI score. For 30-day mortality, lung metastasis and a high/intermediate LIPI score were independent risk factors. Regarding early progression, high/intermediate LIPI score was independently associated. A predictive nomogram for 90-day mortality combining LIPI and ECOG PS achieved an AUC of 0.76 (95% CI 0.71–0.81). The discrimination ability of the nomogram was confirmed in the external validation cohort (n = 255) (AUC 0.72, 95% CI 0.64–0.80). Conclusion: LIPI and ECOG PS independently were able to estimate 90-day mortality, with LIPI also demonstrating prognostic validity for 30-day mortality and early progression. [ABSTRACT FROM AUTHOR]

The aim of this work is an intra- and interlinguistic reflection on the expressions relating to the semantic field of DISABILITY1 in the main Italian and German lexicographic resources as well as in the two laws regulating and guaranteeing the right to participation of disabled people and promoting their integration in Italy and Germany, respectively (the "Legge-quadro per l'assistenza, l'integrazione sociale e i diritti delle persone handicappate" of the 5th february 1992 n. 104 and the "Gesetz zur Stärkung der Teilhabe und Selbsbestimmung von Menschen mit Behinderungen"). First, the general and specialised Italian and German monolingual lexicographic resources will be taken into account in order to draw preliminary conclusions concerning the lexicographical landscape (Section 2). After a description of the theoretical framework, the use of these expressions in the two legislative texts will be analysed by means of corpus linguistic tools. In particular, the focus will be put on the most frequent and most typical lexemes of the two compiled corpora (LQH and BTHG) and a selection of those will be examined according to their collocational structures (Section 3). As a result, a general picture of terminology related to the sematic field of DISABILITY in both languages will be given and contrastive reflections, serving as a starting point for subsequent and broader analyses, will be formulated. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have revolutionized cancer treatment, but they are associated with a range of immune-related adverse events (irAEs), and emerging evidence suggests significant sex differences in the incidence, type, and severity of these toxicities, suggesting an influential factor and understanding sex-related differences in irAEs as crucial for optimizing patient care and improving clinical outcomes. In MOUSEION-07 study, we aimed to assess the association between sex and treatment-related adverse events in cancer patients treated with immunotherapy through a large up-to-date meta-analysis of available clinical trials. The present systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis. The protocol was registered with PROSPERO no. CRD42024549518. Sixteen studies encompassing a total of 4658 patients were included, and 2133 adverse effects were highlighted. The analysis observed a not statistically significant difference in terms of immune-related adverse events (irAEs) between males and females (Odds Ratio 1.19; CI 0.88–1.63) and revealed the presence of publication bias (β = −2.53; 95% CI = [−4.03; −1.04]; P = 0.006). Sex differences in immunotherapy-related adverse events are a significant factor in cancer treatment, necessitating a personalized approach to patient care. Further research is needed to fully understand the mechanisms driving these differences and to develop optimized strategies for monitoring and managing irAEs in both females and males. [ABSTRACT FROM AUTHOR]

Background With aging of the population and improvements in diagnosis, treatment, and supportive care, the number of cancer survivors in the United States has increased; updated prevalence estimates are needed. Methods Cancer prevalence on January 1, 2022, was estimated using the Prevalence Incidence Approach Model, utilizing incidence, survival, and mortality. Prevalence by age decade, sex, and time from diagnosis was calculated. The percentage of cancer survivors in the projected US population by age and sex was calculated as the ratio of the sex-specific projected prevalence to the sex-specific projected US population. Results There were an estimated 18.1 million US cancer survivors as of January 1, 2022. From 2022 to 2030, the number of US cancer survivors is projected to increase to 21.6 million; by 2040, the number is projected to be 26 million. Long-term survivors are highly prevalent; in 2022, 70% of cancer survivors had lived 5 years or more after diagnosis, and 11% of cancer survivors had lived 25 years or more after diagnosis. Among all US females aged 40-54 years, 3.6% were cancer survivors; among females aged 65-74 years, 14.5% were cancer survivors; among females aged 85 years and older, 36.4% were cancer survivors. Among all US males aged 40-54 years, 2.1% were cancer survivors; among males aged 65-74 years, 16% were cancer survivors; and among those aged 85 years and older, 48.3% were cancer survivors. Conclusions Cancer survivors are growing in number. In the United States, most cancer survivors are long-term and very long-term survivors, representing a substantial proportion of the US population. [ABSTRACT FROM AUTHOR]

Introduction: This study investigated the interaction with membrane mimetic systems (LUVs), bacterial membranes, the CD spectra, and the bactericidal activity of two designed trematocine mutants, named Trem-HK and Trem-HSK. Mutants were constructed from the scaffold of Trematocine (Trem), a natural 22-amino acid AMP from the Antarctic fish Trematomus bernacchii, aiming to increase their positive charge. Methods: The selectivity of the designed AMPs towards bacterial membranes was improved compared to Trematocine, verified by their interaction with different LUVs and their membranolytic activity. Additionally, their a-helical conformation was not influenced by the amino acid substitutions. Our findings revealed a significant enhancement in antibacterial efficacy against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae family) pathogens for both Trem-HK and Trem-HSK. Results: Firstly, we showed that the selectivity of the two new designed AMPs towards bacterial membranes was greatly improved compared to Trematocine, verifying their interaction with different LUVs and their membranolytic activity. We determined that their a-helical conformation was not influenced by the amino acid substitutions. We characterized the tested bacterial collection for resistance traits to different classes of antibiotics. The minimum inhibitory and bactericidal concentration (MIC and MBC) values of the ESKAPE collection were reduced by up to 80% compared to Trematocine. The bactericidal concentrations of Trematocine mutants showed important membranolytic action, evident by scanning electron microscopy, on all tested species. We further evaluated the cytotoxicity and hemolytic activity of the mutants. At 2.5 µM concentration, both mutants demonstrated low cytotoxicity and hemolysis, indicating selectivity towards bacterial cells. However, these effects increased at higher concentrations. Discussion: Assessment of in vivo toxicity using the Galleria mellonella model revealed no adverse effects in larvae treated with both mutants, even at concentrations up to 20 times higher than the lowest MIC observed for Acinetobacter baumannii, suggesting a high potential safety profile for the mutants. This study highlights the significant improvement in antibacterial efficacy achieved by increasing the positive charge of Trem-HK and Trem-HSK. This improvement was reached at the cost of reduced biocompatibility. Further research is necessary to optimize the balance between efficacy and safety for these promising AMPs. [ABSTRACT FROM AUTHOR]

Platelets are critical mediators of hemostasis and thrombosis. Platelets circulate as discs in their resting form but change shape rapidly upon activation by vascular damage and/or soluble agonists such as thrombin. Platelet shape change is driven by a dynamic remodeling of the actin cytoskeleton. Actin filaments interact with the protein myosin, which is phosphorylated on the myosin light chain (MLC) upon platelet activation. Actin-myosin interactions trigger contraction of the actin cytoskeleton, which drives platelet spreading and contractile force generation. Filamin A (FLNA) is an actin cross-linking protein that stabilizes the attachment between subcortical actin filaments and the cell membrane. In addition, FLNA binds multiple proteins and serves as a critical intracellular signaling scaffold. Here, we used platelets from mice with a megakaryocyte/platelet-specific deletion of FLNA to investigate the role of FLNA in regulating platelet shape change. Relative to controls, FLNA-null platelets exhibited defects in stress fiber formation, contractile force generation, and MLC phosphorylation in response to thrombin stimulation. Blockade of Rho kinase (ROCK) and protein kinase C (PKC) with the inhibitors Y27632 and bisindolylmaleimide (BIM), respectively, also attenuated MLC phosphorylation; our data further indicate that ROCK and PKC promote MLC phosphorylation through independent pathways. Notably, the activity of both ROCK and PKC was diminished in the FLNA-deficient platelets. We conclude that FLNA regulates thrombin-induced MLC phosphorylation and platelet contraction, in a ROCK- and PKC-dependent manner. [ABSTRACT FROM AUTHOR]

This article discusses the immunophenotypical assessment of post-chemotherapy glandular tumors of germ cell origin. These tumors can exhibit a range of morphologies, including sarcomatoid and glandular tumors. Historically, these malignancies were thought to arise from postpubertal-type teratoma, but recent studies suggest that adenocarcinomas may arise from postpubertal-type yolk sac tumors (YST). The study found that the expression of transcription factors FOXA2 and HNF1β can help elucidate the origin of these tumors within the spectrum of glandular YST and somatic-type adenocarcinomas (STAs). Further research is needed to fully understand the development and progression of these tumors. [Extracted from the article]

Immune checkpoint inhibitors (ICI) have become the cornerstone of treatment in renal cell carcinoma (RCC), for both metastatic disease and in an adjuvant setting. However, an adaptive resistance from cancer cells may arise during ICI treatment, therefore many studies are focusing on additional immune checkpoint inhibitor pathways. Promising targets of immunotherapeutic agents under investigation include T cell immunoglobulin and ITIM domain (TIGIT), immunoglobulin-like transcript 4 (ILT4), lymphocyte activation gene-3 (LAG-3), vaccines, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and chimeric antigen receptor (CAR) T cells. In this review of the literature, we recollect the current knowledge of the novel treatment strategies in the field of immunotherapy that are being investigated in RCC and analyze their mechanism of action, their activity and the clinical studies that are currently underway. [ABSTRACT FROM AUTHOR]

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The aim of the present in vitro comparative study is to validate a novel composite polymer, named "ONLY", developed to overcome the mechanical drawbacks of conventional, metal-reinforced poly(methyl methacrylate) (PMMA) interim restoration. Ten interim restorations were designed and fabricated (five in the composite "ONLY" group, and five in the metal-reinforced PMMA group). All the samples were screwed into the prototype models, simulating a complete edentulous mandible rehabilitated with six straight implants. Outcome measures were break point (load, N) and displacement (mm) through a static compression test, and material behavior through a dynamic cyclic test method (fatigue test). A total of 20 samples were tested (10 for static and 10 for dynamic). In each group, five samples (test and control) were used. All the specimens completed the mechanical tests, as planned. There was no statistically significant difference between groups for any test. In the test group, the break point was 1953.19 ± 543.73 N, while it was 2031.10 ± 716.68 N in the control group (p = 0.775). The displacement was 1.89 ± 0.34 mm in the test group and 1.98 ± 0.75 mm in the control group (p = 0.763). Using the dynamic cyclic test method, in the control group the mean load was 2504.60 ± 972.15 N, while in the test group the mean load was 3382.00 ± 578.50 N. The difference between groups was 877.40 ± 579.30 N (p value = 0.121). Within the limitations of this in vitro study, the novel composite polymer can be used to immediately load dental implants. Further clinical research is needed to confirm these preliminary results. [ABSTRACT FROM AUTHOR]

This article, published in the journal Histopathology, discusses the immunophenotypical assessment of post-chemotherapy glandular tumors of germ cell origin. These tumors can exhibit a range of morphologies, including sarcomatoid and glandular tumors. The study examines the expression of various markers, including FOXA2 and HNF1β, in a series of cases. The results suggest that these tumors originate from glandular yolk sac tumors (GYST) and should be interpreted as such. However, there is some overlap with somatic-type adenocarcinomas (STAs), and further research is needed to fully understand the origin and development of these tumors. [Extracted from the article]

Purpose: To describe the characteristics of National Institutes of Health (NIH) cancer survivorship grants funded over the past 5 years and identify gap areas for future efforts and initiatives. Methods: Research project grants (RPG) funded during Fiscal Year (FY) 2017 to 2021 focused on cancer survivorship were identified using a text mining algorithm of words from the NIH Research, Condition, and Disease Categorization (RCDC) thesaurus with survivorship-relevant terms. The title, abstract, specific aims, and public health relevance section of each grant were reviewed for eligibility. Grants meeting the eligibility criteria were double coded to extract study characteristics (e.g., grant mechanism, study design, study population). Results: A total of 586 grants were funded by 14 NIH Institutes from FY2017 to FY2021, and the number of newly funded grants increased each FY, from 68 in 2017 to 105 in 2021. Approximately 60% of all grants included an intervention study, and interventions most often focused on psychosocial or supportive care (32.0%). The most common primary focus of the grants was late- and long-term effects of cancer treatment (46.6%), and least often financial hardship. Conclusions: The results of this portfolio analysis indicate overall growth in the number and breadth of grants over the last five years, although notable gaps persist. Implications for Cancer Survivors: This review of current NIH grants suggests a need for expanded research to understand and address survivor needs to ensure that the over 18 million cancer survivors in the United States have optimal quality of life and health outcomes. [ABSTRACT FROM AUTHOR]

Upper tract urothelial carcinoma (UTUC) accounts for the 5–10% of all urothelial carcinomas (UCs). In this analysis, we reported the real-world data from the ARON-2 study (NCT05290038) on the efficacy of pembrolizumab in patients with UTUC who recurred or progressed after platinum-based chemotherapy. Medical records of patients with metastatic UTUC treated with pembrolizumab as second-line therapy were reviewed from 34 institutions in 14 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. 235 patients were included in our analysis. Median OS was 8.6 months (95% CI 6.6–12.1), the 1 year OS rate was 43% while the 2 years OS rate 29%. The median PFS was 5.1 months (95% CI 3.9–6.9); 46% of patients were alive at 6 months, 34% at 12 months and 25% at 24 months. According to RECIST 1.1, 18 patients (8%) experienced complete response (CR), 57 (24%) partial response (PR), 44 (19%) stable disease (SD), and 116 (49%) progressive disease (PD), with an ORR of 32%. Our study confirms the effectiveness of pembrolizumab in patients pretreated with a platinum-based combination, irrespective of their sensitivity to the first-line treatment and of their histology. In addition, we emphasized the limited benefit of the treatment with pembrolizumab in patients with hepatic metastases and poor ECOG performance status. [ABSTRACT FROM AUTHOR]

Background: Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment. Materials and methods: A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses. Results: A total of 571 patients with a median age of 61 years (range 17–85) were included in the analysis. With a median follow-up of 22.1 (1.0–89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders. Conclusion: This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

This paper describes technical details and new scientific opportunities offered by the new High Power Laser Facility at the ESRF, opened to users since 2022. This facility enables laser-induced dynamic compression experiments probed by ultra-fast X-ray Absorption Spectroscopy at beamline ID24-ED. This capability allows to reach and probe more extreme pressure and temperature states and higher strain rates with respect to static compression, addressing open questions in fundamental, planetary and material science. [ABSTRACT FROM AUTHOR]

Since retrofitting existing natural gas-fired (NGF) power plants is an essential strategy for enhancing their efficiency and controlling greenhouse gas emissions, this paper compares the carbon footprint of natural gas-fired power generation from an NGF power plant in Brazil (BR-NGF) with and without retrofitting. The former scenario entails retrofitting the BR-NGF power plant with combined-cycle gas turbine (CCGT) technology. In contrast, the latter involves continuing the BR-NGF power plant operation with open-cycle gas turbine (OCGT) technology. Our analysis considers the BR-NGF power plant's life cycle (construction, operation, and decommissioning) and the natural gas' life cycle (natural gas extraction and processing, liquefaction, liquefied natural gas transportation, regasification, and combustion). Moreover, it is based on data from primary and secondary sources, mainly the Ecoinvent database and the ReCiPe 2016 method. For OCGT, the results showed that the BR-NGF power plant and the natural gas life cycles are responsible for 620.87 gCO2eq./kWh and 178.58 gCO2eq./kWh, respectively. For CCGT, these values are 450.04 gCO2eq./kWh and 129.30 gCO2eq./kWh. Our findings highlight the relevance of the natural gas' life cycle, signaling additional opportunities for reducing the overall carbon footprint of natural gas-fired power generation. [ABSTRACT FROM AUTHOR]

PURPOSE: People with advanced or metastatic cancer and their caregivers may have different care goals and face unique challenges compared with those with early-stage disease or those nearing the end of life. These Multinational Association for Supportive Care in Cancer (MASCC)-ASCO standards and practice recommendations seek to establish consistent provision of quality survivorship care for people affected by advanced or metastatic cancer. METHODS: A MASCC-ASCO expert panel was formed. Standards and recommendations relevant to the provision of quality survivorship care for people affected by advanced or metastatic cancer were developed through conducting (1) a systematic review of unmet supportive care needs; (2) a scoping review of cancer survivorship, supportive care, and palliative care frameworks and guidelines; and (3) an international modified Delphi consensus process. RESULTS: A systematic review involving 81 studies and a scoping review of 17 guidelines and frameworks informed the initial standards and recommendations. Subsequently, 77 experts (including eight people with lived experience) across 33 countries (33% were low- to middle-resource countries) participated in the Delphi study and achieved ≥94.8% agreement for seven standards, (1) Person-Centered Care; (2) Coordinated and Integrated Care; (3) Evidence-Based and Comprehensive Care; (4) Evaluated and Communicated Care; (5) Accessible and Equitable Care; (6) Sustainable and Resourced Care; and (7) Research and Data-Driven Care, and ≥84.2% agreement across 45 practice recommendations. CONCLUSION: Standards of survivorship care for people affected by advanced or metastatic cancer are provided. These MASCC-ASCO standards support optimization of health outcomes and care experiences by providing guidance to stakeholders (health care professionals, leaders, and administrators; governments and health ministries; policymakers; advocacy agencies; cancer survivors and caregivers). Practice recommendations may be used to facilitate future research, practice, policy, and advocacy efforts. Additional information is available at www.mascc.org, www.asco.org/standards and www.asco.org/survivorship-guidelines. [ABSTRACT FROM AUTHOR]

Milk and its derivatives are included in a balanced diet of humans as excellent sources of proteins, vitamins, and essential minerals that are functional nutrients. Knowledge about the nutritional benefits or harms due to milk consumption has been expanding in recent years. We previously explored, in rodent models, the metabolic effects of isoenergetic intake of milk derived from cows, donkeys, or humans, while the impact of goat's milk intake has remained unexplored. The aim of this work was to investigate, in an animal model, the effects of dietary supplementation with goat's milk on energy homeostasis and inflammatory state, focusing on the modulation of mitochondrial functions in most metabolically active organs, such as skeletal muscle and the liver. In addition, we highlighted a link between nutrient intake, substrate metabolism, and the orexinergic system. Our results indicate that goat milk improves mitochondrial oxidative capacity and reduces inflammation and oxidative stress in both organs. Notably, goat milk lowers the circulating levels of Orexin-A, a neuropeptide that plays a crucial role in regulating peripheral energy balance and central nervous system mechanisms. These data provide the first evidence that the anti-inflammatory and antioxidant effects of goat milk are mediated by the modulation of mitochondrial functions and orexinergic signaling. [ABSTRACT FROM AUTHOR]

Whereas principles of communicative efficiency and legal doctrine dictate that laws be comprehensible to the common world, empirical evidence suggests legal documents are largely incomprehensible to lawyers and laypeople alike. Here, a corpus analysis (n = 59 million words) first replicated and extended prior work revealing laws to contain strikingly higher rates of complex syntactic structures relative to six baseline genres of English. Next, two preregistered text generation experiments (n = 286) tested two leading hypotheses regarding how these complex structures enter into legal documents in the first place. In line with the magic spell hypothesis, we found people tasked with writing official laws wrote in a more convoluted manner than when tasked with writing unofficial legal texts of equivalent conceptual complexity. Contrary to the copy-and-edit hypothesis, we did not find evidence that people editing a legal document wrote in a more convoluted manner than when writing the same document from scratch. From a cognitive perspective, these results suggest law to be a rare exception to the general tendency in human language toward communicative efficiency. In particular, these findings indicate law's complexity to be derived from its performativity, whereby low-frequency structures may be inserted to signal law's authoritative, world-state-altering nature, at the cost of increased processing demands on readers. From a law and policy perspective, these results suggest that the tension between the ubiquity and impenetrability of the law is not an inherent one, and that laws can be simplified without a loss or distortion of communicative content. [ABSTRACT FROM AUTHOR]

Introduction: This study investigated the interaction with membrane mimetic systems (LUVs), bacterial membranes, the CD spectra, and the bactericidal activity of two designed trematocine mutants, named Trem-HK and Trem-HSK. Mutants were constructed from the scaffold of Trematocine (Trem), a natural 22-amino acid AMP from the Antarctic fish Trematomus bernacchii, aiming to increase their positive charge. Methods: The selectivity of the designed AMPs towards bacterial membranes was improved compared to Trematocine, verified by their interaction with different LUVs and their membranolytic activity. Additionally, their α-helical conformation was not influenced by the amino acid substitutions. Our findings revealed a significant enhancement in antibacterial efficacy against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae family) pathogens for both Trem-HK and Trem-HSK. Results: Firstly, we showed that the selectivity of the two new designed AMPs towards bacterial membranes was greatly improved compared to Trematocine, verifying their interaction with different LUVs and their membranolytic activity. We determined that their α-helical conformation was not influenced by the amino acid substitutions. We characterized the tested bacterial collection for resistance traits to different classes of antibiotics. The minimum inhibitory and bactericidal concentration (MIC and MBC) values of the ESKAPE collection were reduced by up to 80% compared to Trematocine. The bactericidal concentrations of Trematocine mutants showed important membranolytic action, evident by scanning electron microscopy, on all tested species. We further evaluated the cytotoxicity and hemolytic activity of the mutants. At 2.5 μM concentration, both mutants demonstrated low cytotoxicity and hemolysis, indicating selectivity towards bacterial cells. However, these effects increased at higher concentrations. Discussion: Assessment of in vivo toxicity using the Galleria mellonella model revealed no adverse effects in larvae treated with both mutants, even at concentrations up to 20 times higher than the lowest MIC observed for Acinetobacter baumannii, suggesting a high potential safety profile for the mutants. This study highlights the significant improvement in antibacterial efficacy achieved by increasing the positive charge of Trem-HK and Trem-HSK. This improvement was reached at the cost of reduced biocompatibility. Further research is necessary to optimize the balance between efficacy and safety for these promising AMPs. [ABSTRACT FROM AUTHOR]

Background Communities and researchers have called for a paradigm shift from describing health disparities to a health equity research agenda that addresses structural drivers. Therefore, we examined whether the cancer survivorship research portfolio has made this shift. Methods We identified grants focused on populations experiencing health disparities from the National Institutes of Health (NIH) Cancer Survivorship Research Portfolio (N  =   724), Fiscal Years 2017–2022. Grant characteristics were abstracted, drivers of health disparities were mapped onto the levels and domains of influence, and opportunities for future research were identified. Results A total of 147 survivorship grants focused on health disparities were identified, of which 73.5% of grants focused on survivors from racial and ethnic minoritized groups, 25.9% living in rural areas, 24.5% socioeconomically disadvantaged, and 2.7% sexual and gender minority groups. Study designs were 51.0% observational; 82.3% of grants measured or intervened on at least 1 individual-level of influence compared to higher levels of influence (32.7% interpersonal, 41.5% institutional and community, and 12.2% societal). Behavioral and health care system domains of influence were commonly represented, especially at the individual level (47.6% and 36.1%, respectively). Less frequently represented was the physical and built environment (12.2%). Conclusions NIH-funded cancer survivorship research on health disparities is still focused on individual level of influence. However, the proportion of grants examining structural and social drivers as well as the mechanisms that drive disparities in health care and health outcomes among cancer survivors have increased over time. Gaps in funded research on specific populations, cancer types, and focus areas of survivorship science were identified and warrant priority. [ABSTRACT FROM AUTHOR]

Research into novel anti-Helicobacter pylori agents represents an important approach for the identification of new treatments for chronic gastritis and peptic ulcers, which are associated with a high risk of developing gastric carcinoma. In this respect, two series of azobenzenesulfonamides were designed, synthesized, and tested against a large panel of human and bacterial CAs to evaluate their inhibitory activity. In addition, computational studies of the novel primary benzenesulfonamides (4a–j) were performed to predict the putative binding mode to both HpCAs. Then, the antimicrobial activity versus H. pylori of the two series was also studied. The best-in-class compounds were found to be 4c and 4e among the primary azobenzenesulfonamides and 5c and 5f belonging to the secondary azobenzenesulfonamides series, showing themselves to exert a promising anti-H. pylori activity, with MIC values of 4–8 μg/mL and MBCs between 4 and 16 μg/mL. Moreover, the evaluation of their toxicity on a G. mellonella larva in vivo model indicated a safe profile for 4c,e and 5c,f. The collected results warrant considering these azobenzenesulfonamides as an interesting starting point for the development of a new class of anti-H. pylori agents. [ABSTRACT FROM AUTHOR]

Purpose: To develop United States (US) standards for survivorship care that informs (1) essential health system policy and process components and (2) evaluation of the quality of survivorship care. Methods: The National Cancer Institute and the Department of Veterans Affairs led a review to identify indicators of quality cancer survivorship care in the domains of health system policy, process, and evaluation/assessment. A series of three virtual consensus meetings with survivorship care and research experts and advocates was conducted to rate the importance of the indicators and refine the top indicators. The final set of standards was developed, including ten indicators in each domain. Results: Prioritized items were survivor-focused, including processes to both assess and manage physical, psychological, and social issues, and evaluation of patient outcomes and experiences. Specific indicators focused on developing a business model for sustaining survivorship care and collecting relevant business metrics (e.g., healthcare utilization, downstream revenue) to show value of survivorship care to health systems. Conclusions: The National Standards for Cancer Survivorship Care can be used by health systems to guide development of new survivorship care programs or services or to assess alignment and enhance services in existing survivorship programs. Given the variety of settings providing care to survivors, it is necessary for health systems to adapt these standards based on factors including age-specific needs, cancer types, treatments received, and health system resources. Implications for Cancer Survivors: With over 18 million cancer survivors in the United States, many of whom experience varied symptoms and unmet needs, it is essential for health systems to have a comprehensive strategy to provide ongoing care. The US National Standards for Survivorship Care should serve as a blueprint for what survivors and their families can anticipate after a cancer diagnosis to address their needs. [ABSTRACT FROM AUTHOR]

Among the non-communicable neurological diseases, epilepsy is characterized by abnormal brain activity with several peripheral implications. The role of peripheral inflammation in the relationship between seizure development and nonalcoholic fatty liver disease based on sex difference remains still overlooked. Severe early-life infections lead to increased inflammation that can aggravate epilepsy and hepatic damage progression, both related to increased odds of hospitalization for epileptic patients with liver diseases. Here, we induced a post-natal-day 3 (PND3) infection by LPS (1 mg/kg, i.p.) to determine the hepatic damage in a genetic model of young epileptic WAG/Rij rats (PND45). We evaluated intra- and inter-gender differences in systemic and liver inflammation, hepatic lipid dysmetabolism, and oxidative damage related to mitochondrial functional impairment. First, epileptic rats exposed to LPS, regardless of gender, displayed increased serum hepatic enzymes and altered lipid profile. Endotoxin challenge triggered a more severe inflammatory and immune response in male epileptic rats, compared to females in both serum and liver, increasing pro-inflammatory cytokines and hepatic immune cell recruitment. Conversely, LPS-treated female rats showed significant alterations in systemic and hepatic lipid profiles and reduced mitochondrial fatty acid oxidation. The two different sex-dependent mechanisms of LPS-induced liver injury converge in increased ROS production and related mitochondrial oxidative damage in both sexes. Notably, a compensatory increase in antioxidant defense was evidenced only in female rats. Our study with a translational potential demonstrates, for the first time, that early post-natal infections in epileptic rats induced or worsened hepatic disorders in a sex-dependent manner, amplifying inflammation, lipid dysmetabolism, and mitochondrial impairment. [ABSTRACT FROM AUTHOR]

Background: Immune-checkpoint inhibitors (ICIs) have significantly improved metastatic renal cell carcinoma (mRCC) prognosis, although their efficacy in patients with bone metastases (BMs) remains poorly understood. We investigated the prognostic role of natremia in pretreated RCC patients with BMs receiving immunotherapy. Materials and Methods: This retrospective multicenter study included RCC patients with BMs receiving nivolumab as second-line therapy or beyond. Inclusion criteria involved baseline sodium levels (pre-ICI) and sodium levels after 4 weeks of nivolumab initiation (post-ICI). The population was divided into two groups based on the median value, and response rates, progression-free survival (PFS), and overall survival (OS) were assessed. Results: Among 120 eligible patients, those with pre-treatment sodium levels =140 mEq/L showed longer OS (18.7 vs. 12.0 months, p=0.04). Pre-treatment sodium levels =140 mEq/L were associated with better OS compared to levels <140 mE/L (18.7 vs. 12.0, p=0.04). Post-treatment sodium levels =140mEq/L were associated with improved PFS (9.6 vs. 3.2 months) and OS (25.1 vs. 8.8 months) (p=0.05 and p<0.01, respectively). Patients with consistent sodium levels =140 mEq/L at both time points exhibited the best outcomes compared to those with lower values (PFS 11.5 vs. 3.3 months and OS 42.2 vs. 9.0 months, respectively, p<0.01). Disease control rate was significantly higher in the latter group (p<0.01). Multivariate analysis confirmed the prognostic significance of sodium levels. Conclusion: Elevated sodium levels (=140 mEq/L) pre- and post-ICI treatment correlate with better survival outcomes in mRCC patients with BMs. This finding suggests sodium level assessment as a potential prognostic factor in these patients and warrants further investigation, particularly in combination immunotherapy settings. [ABSTRACT FROM AUTHOR]

Cannabis sativa L. is a plant that has been cultivated since ancient times thanks to its various uses. Even its extraction products, such as essential oil and hydrolate, having a varied chemical composition and rich in bioactive components, find wide use in different sectors, gathering ever-increasing interest over time. In this work, the essential oil of Cannabis sativa L. cv. Carmagnola was characterized by using Gas Chromatography/Mass Spectrometry (GC/MS) and, for the first time, the chemical profile of the hydrolate was also described through different analytical techniques such as Large-Volume Injection Gas Chromatography/Mass Spectrometry (LVI-GC/MS) and Direct Immersion-Solid Phase Microextraction-Gas Chromatography/Mass spectrometry (DI-SPME-GC/MS), in order to provide a more complete compositional profile. The results of the analyses conducted on the hydrolate highlighted a high content of α-terpineol; on the other side, in the essential oil, a prevalence of monoterpenes, with α-pinene and limonene as the characterizing components, was detected. Both matrices were also investigated to evaluate their cytotoxic activity by using a panel of cancer cell lines derived from different histotypes such as melanoma (A375, LOX IMVI), non-small cell lung cancer (H1299, A549), colon (HT29) and pancreatic (L3.6) cancer cell lines. The obtained data demonstrated that essential oil was more effective than hydrolate in terms of reduction in cell viability. [ABSTRACT FROM AUTHOR]

Human language is expressive because it is compositional: The meaning of a sentence (semantics) can be inferred from its structure (syntax). It is commonly believed that language syntax and semantics are processed by distinct brain regions. Here, we revisit this claim using precision fMRI methods to capture separation or overlap of function in the brains of individual participants. Contrary to prior claims, we find distributed sensitivity to both syntax and semantics throughout a broad frontotemporal brain network. Our results join a growing body of evidence for an integrated network for language in the human brain within which internal specialization is primarily a matter of degree rather than kind, in contrast with influential proposals that advocate distinct specialization of different brain areas for different types of linguistic functions. [ABSTRACT FROM AUTHOR]

Background: Hemodynamic classification of pulmonary hypertension (PH) has important clinical implications. However, only a few echocardiographic variables have been used to hemodynamically classify PH in dogs. Objective: To evaluate the echocardiographic pulmonary to left atrial ratio index (ePLAR) in dogs with PH. Animals: Forty‐six dogs with intermediate to high probability of PH. Methods: Cross‐sectional study. Variables were compared between dogs with precapillary PH [PrePH (n = 24)] vs postcapillary PH [PostPH (n = 22)], and with combined PH [CombPH (n = 14)] vs isolated PH [IsoPH (n = 8)] using the t‐, Mann‐Whitney, Pearson's Chi, or Fisher's exact test. The receiver operating characteristic curve and Youden index were used to identify the optimal ePLAR cutoff value to differentiate among the groups, intraclass correlation coefficients (ICC) were used to determine the reliability of measurements. Results: The mean (SD) ePLAR of the PrePH was higher than that of the PostPH group [0.36 (0.13) vs 0.26 (0.09), respectively; P =.005]. The median (interquartile range) ePLAR of the CombPH was higher than that of the IsoPH subgroup [0.29 (0.24‐0.38), vs 0.20 (0.16‐0.23), respectively; P =.001]. The best cutoff value of ePLAR for identifying IsoPH was <0.245 [AUC at cutoff point = 0.86; sensitivity (95% confidence interval [CI]) = 0.71 (0.47‐0.95); specificity (95% CI) = 1 (0.76‐1)]. The ICC analysis indicated a high degree of reliability. Conclusions and Clinical Importance: ePLAR can be considered a valid noninvasive variable to hemodynamically classify PH in dogs with an intermediate to high probability of PH. Assessment of ePLAR can be useful in the therapeutic management of PH in dogs. [ABSTRACT FROM AUTHOR]

For children living in the urban slums of Nairobi (Kenya), primary health conditions are not guaranteed, and oral diseases add further concern at social and institutional levels beyond the general poverty conditions. This study aims at determining the factors that influence the oral health status of children living in Nairobi slums. A cross-sectional study on school-aged subjects was conducted in June 2022 in three urban slum areas of Nairobi through a pediatric dental screening. The PI (Plaque Index), CPITN (Community Periodontal Index of Treatment Needs), and dmft (decayed, missing, and filled teeth index—deciduous) were considered as primary outcomes of dental health. Multivariate statistical analysis, based on ordinal and zero-inflated negative binomial regression models, was conducted to identify determinants of the oral outcomes in a wide set of potential predictors. A sample of 359 children aged 2–17 was examined. The PI was significantly associated with age, the type of bite, and the use of a toothbrush. The CPITN is influenced by different types of malocclusions, abnormal frenulum, dental trauma, and fluorosis. Dietary habits were found to significantly impact the susceptibility to dental caries. Fluorosis and a dental visit in the last year were highlighted as risk and protective factors, respectively, against higher rates of caries. The oral health features of children living in Nairobi slums are differently affected by socio-demographic conditions, dietary habits, dental characteristics, and oral care practices. [ABSTRACT FROM AUTHOR]

The olive oil industry recently introduced a novel multi-phase decanter with the "Leopard DMF" series, which gives a by-product called pâté, made up of pulp and olive wastewater with a high content of phenolic substances and without pits. This study aims to create a new culture medium, the Olive Juice Broth (OJB), from DMF pâté, and apply it to select bacteria strains able to survive and degrade the bitter substances normally present in the olive fruit. Thirty-five different bacterial strains of Lactiplantibacillus plantarum from the CREA-IT.PE Collection of Microorganisms were tested. Seven strains characterized by ≥50% growth in OJB (B31, B137, B28, B39, B124, B130, and B51) showed a degradation of the total phenolic content of OJB ≥ 30%. From this set, L. plantarum B51 strain was selected as a starter for table olive production vs. spontaneous fermentation. The selected inoculant effectively reduced the debittering time compared to spontaneous fermentation. Hydroxytyrosol, derived from oleuropein and verbascoside degradation, and tyrosol, derived from ligstroside degradation, were produced faster than during spontaneous fermentation. The OJB medium is confirmed to be useful in selecting bacterial strains resistant to the complex phenolic environment of the olive fruit. [ABSTRACT FROM AUTHOR]

Purpose: People with advanced or metastatic cancer and their caregivers may have different care goals and face unique challenges compared to those with early-stage disease or those nearing the end-of-life. These MASCC-ASCO standards and practice recommendations seek to establish consistent provision of quality survivorship care for people affected by advanced or metastatic cancer. Methods: An expert panel comprising MASCC and ASCO members was formed. Standards and recommendations relevant to the provision of quality survivorship care for people affected by advanced or metastatic cancer were developed through conducting: (1) a systematic review of unmet supportive care needs; (2) a scoping review of cancer survivorship, supportive care, and palliative care frameworks and guidelines; and (3) an international modified Delphi consensus process. Results: A systematic review involving 81 studies and a scoping review of 17 guidelines and frameworks informed the initial standards and recommendations. Subsequently, 77 experts (including 8 people with lived experience) across 33 countries (33% were low-to-middle resource countries) participated in the Delphi study and achieved ≥ 94.8% agreement for seven standards (1. Person-Centred Care; 2. Coordinated and Integrated Care; 3. Evidence-Based and Comprehensive Care; 4. Evaluated and Communicated Care; 5. Accessible and Equitable Care; 6. Sustainable and Resourced Care; 7. Research and Data-Driven Care) and ≥ 84.2% agreement across 45 practice recommendations. Conclusion: Standards of survivorship care for people affected by advanced or metastatic cancer are provided. These MASCC-ASCO standards will support optimization of health outcomes and care experiences by providing guidance to stakeholders in cancer care (healthcare professionals, leaders, and administrators; governments and health ministries; policymakers; advocacy agencies; cancer survivors and caregivers. Practice recommendations may be used to facilitate future research, practice, policy, and advocacy efforts. [ABSTRACT FROM AUTHOR]

Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords. In this study, we investigated the in vitro binding and functional activities to the human MOR and the in vivo pharmacology of LENART01 in mice after subcutaneous administration. In vitro binding assays showed LENART01 to bind and be selective to the human MOR over the other opioid receptor subtypes and delta, kappa and nociceptin receptors. In the [35S]GTPγS binding assay, LENART01 acted as a potent and full agonist to the human MOR. In mice, LENART01 produced dose-dependent antinociceptive effects in formalin-induced inflammatory pain, with increased potency than morphine. Antinociceptive effects were reversed by naloxone, indicating MOR activation in vivo. Behavioral studies also demonstrated LENART01's properties to induce less adverse effects without locomotor dysfunction and withdrawal syndrome compared to conventional opioid analgesics, such as morphine. LENART01 is the first peptide-based MOR-D2R ligand known to date and the first dual MOR-dopamine D2R ligand for which in vivo pharmacology is reported with antinociceptive efficacy and reduced opioid-related side effects. Our current findings may pave the way to new pain therapeutics with limited side effects in acute and chronic use. [ABSTRACT FROM AUTHOR]

Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47–0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39–0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling. [ABSTRACT FROM AUTHOR]

Permanent epigenetic silencing using programmable editors equipped with transcriptional repressors holds great promise for the treatment of human diseases1–3. However, to unlock its full therapeutic potential, an experimental confirmation of durable epigenetic silencing after the delivery of transient delivery of editors in vivo is needed. To this end, here we targeted Pcsk9, a gene expressed in hepatocytes that is involved in cholesterol homeostasis. In vitro screening of different editor designs indicated that zinc-finger proteins were the best-performing DNA-binding platform for efficient silencing of mouse Pcsk9. A single administration of lipid nanoparticles loaded with the editors’ mRNAs almost halved the circulating levels of PCSK9 for nearly one year in mice. Notably, Pcsk9 silencing and accompanying epigenetic repressive marks also persisted after forced liver regeneration, further corroborating the heritability of the newly installed epigenetic state. Improvements in construct design resulted in the development of an all-in-one configuration that we term evolved engineered transcriptional repressor (EvoETR). This design, which is characterized by a high specificity profile, further reduced the circulating levels of PCSK9 in mice with an efficiency comparable with that obtained through conventional gene editing, but without causing DNA breaks. Our study lays the foundation for the development of in vivo therapeutics that are based on epigenetic silencing.Experiments in mice show that designed epigenome editors that contain domains of transcriptional repressors can enable stable epigenetic silencing of Pcsk9, a gene with a role in cholesterol homeostasis, without inducing DNA breaks. [ABSTRACT FROM AUTHOR]

Metabolism and immunity are crucial monitors of the whole-body homeodynamics. All cells require energy to perform their basic functions. One of the most important metabolic skills of the cell is the ability to optimally adapt metabolism according to demand or availability, known as metabolic flexibility. The immune cells, first line of host defense that circulate in the body and migrate between tissues, need to function also in environments in which nutrients are not always available. The resilience of immune cells consists precisely in their high adaptive capacity, a challenge that arises especially in the framework of sustained immune responses. Pubmed and Scopus databases were consulted to construct the extensive background explored in this review, from the Kennedy and Lehninger studies on mitochondrial biochemistry of the 1950s to the most recent findings on immunometabolism. In detail, we first focus on how metabolic reconfiguration influences the action steps of the immune system and modulates immune cell fate and function. Then, we highlighted the evidence for considering mitochondria, besides conventional cellular energy suppliers, as the powerhouses of immunometabolism. Finally, we explored the main immunometabolic hubs in the organism emphasizing in them the reciprocal impact between metabolic and immune components in both physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

The detection of temperature by the human sensory system is life-preserving and highly evolutionarily conserved. Platelets are sensitive to temperature changes and are activated by a decrease in temperature, akin to sensory neurons. However, the molecular mechanism of this temperature-sensing ability is unknown. Yet, platelet activation by temperature could contribute to numerous clinical sequelae, most importantly to reduced quality of ex vivo-stored platelets for transfusion. In this multidisciplinary study, we present evidence for the expression of the temperature-sensitive ion channel transient receptor potential cation channel subfamily member 8 (TRPM8) in human platelets and precursor cells. We found the TRPM8 mRNA and protein in MEG-01 cells and platelets. Inhibition of TRPM8 prevented temperature-induced platelet activation and shape change. However, chemical agonists of TRPM8 did not seem to have an acute effect on platelets. When exposing platelets to below-normal body temperature, we detected a cytosolic calcium increase which was independent of TRPM8 but was completely dependent on the calcium release from the endoplasmic reticulum. Because of the high interindividual variability of TRPM8 expression, a population-based approach should be the focus of future studies. Our study suggests that the cold response of platelets is complex and TRPM8 appears to play a role in early temperature-induced activation of platelets, while other mechanisms likely contribute to later stages of temperature-mediated platelet response. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to describe the patterns of palliative intent treatment and/or palliative care (PC) delivery among a population-based sample of individuals diagnosed with advanced nonsmall cell lung cancer (NSCLC) or advanced melanoma. Methods: Data from 655 advanced-stage melanoma patients and 2688 advanced-stage NSCLC patients included in the National Cancer Institute's 2017/2018 Patterns of Care study were analyzed. Bivariate and multivariate logistic regression analyses examined factors associated with (1) receipt of PC (including palliative surgery, radiation, and/or systemic therapy after cancer diagnosis, and PC consultations); and (2) timing from diagnosis to receipt of PC. Proportional hazards models also examined factors associated with timing of receipt of PC after diagnosis. Results: A total of 23.5% of those with melanoma and 52.6% of those with NSCLC received some type of PC. For melanoma, stage 4 (vs. stage 3) was associated with higher receipt of PC and receipt within three months of diagnosis. For NSCLC, stage 4 (vs. stage 3) and a diagnosis of depression or psychosocial distress within three months of diagnosis were significantly associated with receipt of PC and receipt within three months of diagnosis. Conclusion: Study findings indicate that those with advanced-stage cancer or who report distress are more likely to receive palliative intent treatment and/or PC. Given that individuals with advanced cancers are living longer and often experience long-lasting symptoms, it is critical to identify and overcome barriers for broadly delivering comprehensive palliative and supportive care. [ABSTRACT FROM AUTHOR]

Several studies have shown the effects of e-cigarettes in adults. Nowadays, few data are available in the pediatric population. This study aims to assess the relationship between asthma exacerbations and home exposure to e-cigarettes. We conducted a pilot, retrospective, monocenter, observational study. Demographic and clinical data were collected, including number of asthma exacerbations, need for rescue therapy and/or therapeutic step-up, and Asthma Control Test (ACT) and children-Asthma Control Test (c-ACT) scores. The cohort consisted of 54 patients (5–17 years old), divided into two groups: A, including patients exposed to e-cigarette aerosols; B, including unexposed patients. The statistical analysis showed no relevant variation in the number of asthma symptomatic days and need for rescue therapy in group A versus group B (p = 0.27 and 0.19, respectively). There were no statistically significant variations when also considering the number of patients who needed a therapeutic step-up (p = 0.3). The mean values of ACT and c-ACT were, respectively, 17.2 ± 7.6 and 18.3 ± 5.6 in group A and 19.6 ± 3.8 and 14.6 ± 5.8 in group B (p = 0.3 and 0.4, respectively). Although we did not find a statistically significant correlation between second-hand e-cigarette exposure and asthma exacerbations, our findings suggest that asthmatic children exposed second-hand to e-cigarettes may have increased risk of asthma symptomatic days. Future research is warranted. [ABSTRACT FROM AUTHOR]

We propose a novel method for assessing metabolic flexibility (MF) through indirect calorimetry. A total of twenty healthy volunteers (10 females; 10 males) aged 45–65 were categorized into a Low-Intensity activity group (LI, 0–1 session of 1 h per week) and a High-Intensity activity group (HI, 5–6 sessions of 2 h per week). Volunteers underwent a stepwise exercise test on a cycle ergometer, connected to a calorimeter, to examine respiratory gas exchange to evaluate peak fatty acid Oxidation (PFO) and peak carbohydrate oxidation (PCO). Circulating peroxisome proliferator-activated receptor α (PPARα) biomarkers, docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA) ratio and N-oleoylethanolamine (OEA), and the endocannabinoid- 2-arachidonoylglycerol (2-AG), were evaluated. We developed two MF parameters: the MF index (MFI), calculated by the product of PFO normalized per kg of fat-free mass (FFM) and the percentage of VO2max at PFO, and the peak energy substrates' oxidation (PESO), computed by summing the kilocalories from the PFO and PCO, normalized per kg FFM. The MFI and PESO were significantly different between the HI and LI groups, showing strong correlations with the circulating bioactive substances. Higher DHA/EPA ratio (p ≤ 0.05) and OEA (p ≤ 0.01), but lower 2-AG levels (p ≤ 0.01) were found in the HI group. These new parameters successfully established a functional link between MF and the balance of PPARα/endocannabinoid systems. [ABSTRACT FROM AUTHOR]

The recent uptick in the approval of ex vivo cell therapies highlights the relevance of lentivirus (LV) as an enabling viral vector of modern medicine. As labile biologics, however, LVs pose critical challenges to industrial biomanufacturing. In particular, LV purification—currently reliant on filtration and anion‐exchange or size‐exclusion chromatography—suffers from long process times and low yield of transducing particles, which translate into high waiting time and cost to patients. Seeking to improve LV downstream processing, this study introduces peptides targeting the enveloped protein Vesicular stomatitis virus G (VSV‐G) to serve as affinity ligands for the chromatographic purification of LV particles. An ensemble of candidate ligands was initially discovered by implementing a dual‐fluorescence screening technology and a targeted in silico approach designed to identify sequences with high selectivity and tunable affinity. The selected peptides were conjugated on Poros resin and their LV binding‐and‐release performance was optimized by adjusting the flow rate, composition, and pH of the chromatographic buffers. Ligands GKEAAFAA and SRAFVGDADRD were selected for their high product yield (50%–60% of viral genomes; 40%–50% of HT1080 cell‐transducing particles) upon elution in PIPES buffer with 0.65 M NaCl at pH 7.4. The peptide‐based adsorbents also presented remarkable values of binding capacity (up to 3·109 TU per mL of resin, or 5·1011 vp per mL of resin, at the residence time of 1 min) and clearance of host cell proteins (up to a 220‐fold reduction of HEK293 HCPs). Additionally, GKEAAFAA demonstrated high resistance to caustic cleaning‐in‐place (0.5 M NaOH, 30 min) with no observable loss in product yield and quality. [ABSTRACT FROM AUTHOR]

Objective: Recent studies have pointed to neuroinflammation and neurotrophic factors as crucial mediators in the pathophysiology origins of mood disorders. The aim of this review is to assess the potential association between cognitive impairment, brain imaging abnormalities, and inflammatory biomarkers in patients affected by bipolar disorder (BD). Method: Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, we systematically searched PubMed, Google Scholar, Scopus, and Web of Science databases, with no year restriction, up until August 2023, for human studies that examined the relationship between inflammatory markers and cognitive impairment in BD patients. Studies based on neuroimaging, such as MRI, DTI, and fMRI, were also included, along with those examining the moderating role of specific inflammatory markers in the alteration of the brain. Results: 59 human clinical studies satisfied the criteria for consideration. Most of the studies reviewed concur that inflammatory state, measured by peripheral blood levels of CRP and cytokines, constitutes an important contributor to cognitive impairment observed in patients with BD. Robust evidence indicates an association between cognitive impairment and CRP, IL-1RA, IL-6, and TNF-a with its receptors, whereas there is no convincing evidence for the involvement of other neuroinflammatory biomarkers. Neuroimaging studies suggest that brain structural/functional abnormalities seen in BD could also be linked to a neuroinflammatory condition. Conclusions: Current data provide evidence of a link between cognitive impairments observed in BD patients and mechanisms of neuroinflammation. Emerging evidence indicates that systemic inflammation might also play an important role in the deterioration of brain structures critical to cognitive functions in patients with BD. The convergence of findings across these studies strengthens our understanding of the complex neurobiological underpinnings of these disorders. Identification of BD specific inflammatory markers may be of assistance for future early therapeutic interventions. [ABSTRACT FROM AUTHOR]

Purpose: This study describes financial toxicity (FT) reported by people with metastatic cancer, characteristics associated with FT, and associations between FT and compensatory strategies to offset costs. Methods: Cancer Support Community’s Cancer Experience Registry data was used to identify respondents with a solid tumor metastatic cancer who completed the Functional Assessment of Chronic Illness Therapy COmprehensive Score for Financial Toxicity (FACIT-COST) measure. Multivariable logistic regression analyses examined associations between respondent characteristics and FT, and FT and postponing medical visits, nonadherence to medications, and postponing supportive and/or psychosocial care. Results: 484 individuals were included in the analysis; the most common cancers included metastatic breast (31%), lung (13%), gynecologic (10%), and colorectal (9%). Approximately half of participants (50.2%) reported some degree of FT. Those who were non-Hispanic White, Hispanic, or multiple races (compared to non-Hispanic Black), and who reported lower income, less education, and being less than one year since their cancer diagnosis had greater odds of reporting FT. Individuals with any level of FT were also more likely to report postponing medical visits (Adjusted Odds Ratio [OR] 2.58; 95% Confidence Interval [CI] 1.45–4.58), suboptimal medication adherence (Adjusted OR 5.05; 95% CI 2.77–9.20) and postponing supportive care and/or psychosocial support services (Adjusted OR 4.16; 95% CI 2.53–6.85) compared to those without FT. Conclusions: With increases in the number of people living longer with metastatic cancer and the rising costs of therapy, there will continue to be a need to systematically screen and intervene to prevent and mitigate FT for these survivors. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries lead to severe functional impairments and long recovery times, with limited effectiveness and accessibility of current treatments. This has increased interest in natural bioactive compounds, such as ursolic acid (UA). Our study evaluated the effect of an oleolyte rich in UA from white grape pomace (WGPO) on neuronal regeneration in mice with induced sciatic nerve resection, administered concurrently with the induced damage (the WGPO group) and 10 days prior (the PRE-WGPO group). The experiment was monitored at two-time points (4 and 10 days) after injury. After 10 days, the WGPO group demonstrated a reduction in muscle atrophy, evidenced by an increased number and diameter of muscle fibers and a decreased Atrogin-1 and Murf-1 expression relative to the denervated control. It was also observed that 85.7% of neuromuscular junctions (NMJs) were fully innervated, as indicated by the colocalization of α-bungarotoxin and synaptophysin, along with the significant modulation of Oct-6 and S-100. The PRE-WGPO group showed a more beneficial effect on nerve fiber reformation, with a significant increase in myelin protein zero and 95.2% fully innervated NMJs, and a pro-hypertrophic effect in resting non-denervated muscles. Our findings suggest WGPO as a potential treatment for various conditions that require the repair of nerve and muscle injuries. [ABSTRACT FROM AUTHOR]

The design and development of hybrid compounds as a new class of drug candidates remains an excellent opportunity to improve the pharmacological properties of drugs (including enzymatic stability, efficacy and pharmacokinetic and pharmacodynamic profiles). In addition, considering various complex diseases and/or disorders, the conjugate chemistry approach is highly acceptable and justified. Opioids have long been recognized as the most potent analgesics and serve as the basic pharmacophore for potent hybrid compounds that may be useful in pain management. However, a risk of tolerance and physical dependence exists. Since dopamine receptors have been implicated in the aforementioned adverse effects of opioids, the construction of a hybrid with dual action at opioid and dopamine receptors is of interest. Herein, we present nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation results for LENART01, an opioid–ranatensin hybrid peptide. Apart from molecular docking, protein–ligand interactions were also assessed in vitro using a receptor binding assay, which proved LENART01 to be bound to mu-opioid and dopamine receptors, respectively. [ABSTRACT FROM AUTHOR]