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Gurjyot K Doshi,1 Abhijeet Bhanegaonkar,2 Mairead Kearney,3 Murtuza Bharmal,2 Paul Cislo,4 Ruth Kim,4 Marley Boyd,5 Kathleen M Aguilar,5 Hemant Phatak2 1Texas Oncology, Houston, TX, USA; 2EMD Serono Research & Development Institute, Inc., Rockland, MA, USA; an affiliate of Merck KGaA, Darmstadt, Germany; 3Merck KGaA, Darmstadt, Germany; 4Pfizer Inc., New York, NY, USA; 5Data, Evidence and Insights, McKesson Life Sciences, The US Oncology Network, The Woodlands, TX, USACorrespondence: Abhijeet BhanegaonkarDirector, US Health Economics and Outcomes Research – Oncology, North America Medical Affairs, EMD Serono, Inc., One Technology Place, Rockland, MA 02370, USATel +1 781-681-2483Email abhijeet.bhanegaonkar@emdserono.comPurpose: Clinical trial evidence has affirmed the role for immuno-oncology (IO) treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). This Study informing treatment Pathway dEcision in bladder cAnceR (SPEAR-Bladder) aimed to provide insight into the optimal sequencing of IO treatments among la/mUC patients treated in the US Oncology Network.Patients and Methods: This was a retrospective analysis of adult patients with la/mUC who initiated first-line chemotherapy followed by either IO therapy (C-IO subgroup) or chemotherapy (C-C subgroup) between 01/01/2015 and 04/30/2017 and included a potential follow-up period through 06/30/2017. Data were sourced from iKnowMed electronic health records. Patient and treatment characteristics were assessed descriptively, with Kaplan–Meier methods used to evaluate time-to-event outcomes, including overall survival (OS).Results: A total of 117 patients were included in this analysis (median age 69 years, 74.4% male, 88.0% Caucasian): 79 and 38 patients were in the C-IO and C-C subgroups, respectively. The median OS was 19.2 months among patients who received the C-IO sequence and 11.9 months among those who received the C-C treatment sequence.Conclusion: These results suggest that patients who received the C-IO treatment sequence had notable improvement in OS compared with those who received the C-C sequence. In light of the rapidly evolving therapeutic landscape, further investigation will be required to determine how best to select the optimal therapeutic regimen and sequencing for patients with la/mUC.Keywords: urothelial carcinoma, SPEAR-Bladder, real-world clinical outcomes, treatment sequencing, retrospective, community oncology setting

1. The host species used by a herbivorous insect may impose different selective pressures promoting host race formation, yet the presence of plasticity can potentially constrain host race formation. 2. The goal of this study is to determine if there is phenotypic plasticity in life history traits of Brevicoryne brassicae in response to host and nutritional quality of two host species, Brassica oleraceae and Brassica campestris, and to what extent there are genetic differences among genotypes in plasticity. 3. Plants of B. oleraceae and B. campestris were fertilised with three different nitrogen doses (with nutritive solutions of 50, 200 and 400 ppm of soluble nitrogen) to produce plants with different nutritional qualities. Eight clones of B. brassicae were reared on those plants, and days to reproduction (DTR), number of nymphs, and fitness ( rm) were recorded. 4. A significant genotype × host interaction was detected in days to reproduction. Genotype × nitrogen interaction (plasticity) was detected in the number of nymphs when aphids were raised on B. campestris. Aphids showed plasticity in DTR and marginal plasticity in rm in reaction to the varying nitrogen content of B. oleraceae. 5. The phenotypic plasticity to fine-scale variation of host (nutritional quality) documented here may be an important source of phenotypic variation and may potentially constrain host race formation. [ABSTRACT FROM AUTHOR]

The ability to label proteins by fusion with genetically encoded fluorescent proteins is a powerful tool for understanding dynamic biological processes. However, current approaches for expressing fluorescent protein fusions possess drawbacks, especially at the whole organism level. Expression by transgenesis risks potential overexpression artifacts while fluorescent protein insertion at endogenous loci is technically difficult and, more importantly, does not allow for tissue-specific study of broadly expressed proteins. To overcome these limitations, we have adopted the split fluorescent protein system mNeonGreen2 1-10/11 (split-mNG2) to achieve tissue-specific and endogenous protein labeling in zebrafish. In our approach, mNG2 1-10 is expressed under a tissue-specific promoter using standard transgenesis while mNG2 11 is inserted into protein-coding genes of interest using CRISPR/Cas-directed gene editing. Each mNG2 fragment on its own is not fluorescent, but when co-expressed the fragments self-assemble into a fluorescent complex. Here, we report successful use of split-mNG2 to achieve differential labeling of the cytoskeleton genes tubb4b and krt8 in various tissues. We also demonstrate that by anchoring the mNG2 1-10 component to specific cellular compartments, the split-mNG2 system can be used to manipulate protein localization. Our approach should be broadly useful for a wide range of applications., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The clinical outcome of patients with muscle-invasive bladder cancer (MIBC) is poor despite the approval of neoadjuvant chemotherapy or immunotherapy to improve overall survival after cystectomy. MIBC subtypes, immune, transcriptome, metabolomic signatures, and mutation burden have the potential to predict treatment response but none have been incorporated into clinical practice, as tumor heterogeneity and lineage plasticity influence their efficacy. Using the PRISMA statement, we conducted a systematic review of the literature, involving 135 studies published within the last five years, to identify studies reporting on the prognostic value of protein-based biomarkers for response to neoadjuvant therapy in patients with MIBC. The studies were grouped based on biomarkers related to molecular subtypes, cancer stem cell, actin-cytoskeleton, epithelial-mesenchymal transition, apoptosis, and tumor-infiltrating immune cells. These studies show the potential of protein-based biomarkers, especially in the spatial context, to reduce the influence of tumor heterogeneity on a biomarker's prognostic capability. Nevertheless, currently, there is little consensus on the methodology, reagents, and the scoring systems to allow reliable assessment of the biomarkers of interest. Furthermore, the small sample size of several studies necessitates the validation of potential prognostic biomarkers in larger multicenter cohorts before their use for individualizing neoadjuvant therapy regimens for patients with MIBC.

Poly(3-hydroxybutyrate- co -3-hydroxyvalerate) (PHBV) is a very promising biodegradable copolyester of high interest in food packaging. Its inherent brittleness and narrow processing window make it necessary to blend it with flexible biopolyesters, such as poly(butylene succinate- co -adipate) (PBSA). However, the resultant biopolyester blends are thermodynamically immiscible, which impairs their performance and limits their applications. This study is the first to explore the use of poly(butylene succinate- co -adipate) grafted with maleic anhydride (PBS- g -MAH) as a novel reactive additive to compatibilize PHBV/PBSA blends. The compatibilizer was prepared by a reactive melt-mixing process of PBSA and maleic anhydride (MAH) using dicumyl peroxide (DCP) as an organic radical initiator, achieving a grafting degree (G d ) of 5.4%. Biopolyester blend films were thereafter prepared via cast extrusion and their morphological, thermal, mechanical, and barrier properties were characterized. Compatibilization by PBSA- g -MAH was confirmed by observing an improved phase interaction and lower dispersed domain sizes in the blends with 15 wt% PBSA. These compatibilized PHBV/PBSA blends were thermally stable up to 285 °C, showed enhanced ductility and toughness, as well as providing an improved barrier against water and limonene vapors and oxygen. These findings suggest that the use of MAH-grafted biopolyesters can represent an effective strategy to improve the properties of biopolyester blends and open up new opportunities for the application of PHBV-based formulations for food packaging.

Currently, the global lifespan has increased, resulting in a higher proportion of the population over 65 years. Changes that occur in the lung during aging increase the risk of developing acute and chronic lung diseases, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer. During normal tissue homeostasis, cell proliferation and apoptosis create a dynamic balance that constitutes the physiological cell turnover. In basal conditions, the lungs have a low rate of cell turnover compared to other organs. During aging, changes in the rate of cell turnover in the lung are observed. In this work, we review the literature that evaluates the role of molecules involved in cell proliferation and apoptosis in lung aging and in the development of age-related lung diseases. The list of molecules that regulate cell proliferation, apoptosis, or both processes in lung aging includes TNC, FOXM1, DNA-PKcs, MicroRNAs, BCL-W, BCL-XL, TCF21, p16, NOX4, NRF2, MDM4, RPIA, DHEA, and MMP28. However, despite the studies carried out to date, the complete signaling pathways that regulate cell turnover in lung aging are still unknown. More research is needed to understand the changes that lead to the development of age-related lung diseases.

Objective: We present results from a 2-site, randomized clinical trial to assess the efficacy of a brief intervention (As Safe As Possible [ASAP]), a safety plan phone application (BRITE), and their combination on suicide attempts, suicidal ideation, non-suicidal self-injury, re-hospitalizations. and suicidal events among adolescents., Method: Adolescents (n= 240; 12-17 years of age) who were hospitalized for suicidal ideation with plan and/or intent, and/or suicide attempt, were assigned to 1 of 4 treatment conditions in a 2 by 2 design: ASAP+BRITE app+treatment as usual (TAU); (2) BRITE+TAU; (3) ASAP+TAU; and (4) TAU alone. Independent evaluators assessed suicidal ideation and behavior at 4, 12, and 24 weeks using the Columbia-Suicide Severity Rating Scale (C-SSRS) and re-hospitalization using the Child and Adolescent Services Assessment (CASA)., Results: No group differences were found on primary outcomes, except that ASAP participants were less likely to be re-hospitalized over 6 months (15.6%, vs 26.5%, p = .046). Participants hospitalized for an attempt and assigned to BRITE had a lower rate of subsequent attempts (odds ratio [OR] = 0.16, p = .01) and a greater time to attempt (hazard ratio [HR] = 0.20, p = .02). ASAP+BRITE, albeit not statistically significant, was most consistently associated with a reduction (60% reduction) in suicide attempts., Conclusion: ASAP, BRITE, and their combination are equally effective at decreasing risk for suicidal events 6 months post hospital discharge among suicidal adolescents; the ASAP intervention (with or without BRITE) was associated with lower rates of re-hospitalization. The BRITE app in youth hospitalized for suicide attempt had promising outcomes in regard to future attempts., Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. The research was performed with permission from the University of Pittsburgh Institutional Review Board and the University of Texas Institutional Review Board. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work., Clinical Trials Registration Information: Establishing Efficacy of an Inpatient Intervention and Phone App to Reduce Suicidal Risk (ASAP+BRITE); https://clinicaltrials.gov/study/; NCT03825588., (Copyright © 2024 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives and Scope: Primary mitochondrial diseases (PMDs) are rare genetic disorders resulting from mutations in genes crucial for effective oxidative phosphorylation (OXPHOS) that can affect mitochondrial function. In this review, we examine the bioenergetic alterations and oxidative stress observed in cellular models of primary mitochondrial diseases (PMDs), shedding light on the intricate complexity between mitochondrial dysfunction and cellular pathology. We explore the diverse cellular models utilized to study PMDs, including patient-derived fibroblasts, induced pluripotent stem cells (iPSCs) and cybrids. Moreover, we also emphasize the connection between oxidative stress and neuroinflammation., Insights: The central nervous system (CNS) is particularly vulnerable to mitochondrial dysfunction due to its dependence on aerobic metabolism and the correct functioning of OXPHOS. Similar to other neurodegenerative diseases affecting the CNS, individuals with PMDs exhibit several neuroinflammatory hallmarks alongside neurodegeneration, a pattern also extensively observed in mouse models of mitochondrial diseases. Based on histopathological analysis of postmortem human brain tissue and findings in mouse models of PMDs, we posit that neuroinflammation is not merely a consequence of neurodegeneration but a potential pathogenic mechanism for disease progression that deserves further investigation. This recognition may pave the way for novel therapeutic strategies for this group of devastating diseases that currently lack effective treatments., Summary: In summary, this review provides a comprehensive overview of bioenergetic alterations and redox imbalance in cellular models of PMDs while underscoring the significance of neuroinflammation as a potential driver in disease progression., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Mercury (Hg) is one of the toxic metals of global and environmental concern, with aquatic Hg cycling being central in determining the production of highly toxic methylmercury and the air-water Hg exchange influencing the long-range intercontinental atmospheric Hg transport. Both inorganic and organic forms of Hg can be bound by suspended particles, including inorganic minerals (in particular metal oxides/sulfides) and particulate organic matter. Photochemical transformation is a critical process in surface water, and the role of suspended particles in Hg redox photoreactions has increasingly emerged, albeit in limited studies in comparison to extensive studies on aqueous (homogeneous) photoreactions of Hg. The lack of understanding of what roles suspended particles play might result in inaccurate estimation of how Hg species transform and/or cycle in the environment. In view of this gap, this paper critically reviews and synthesizes information on the studies conducted on different natural surface waters with respect to the potential roles of suspended particles on Hg photo-redox reactions. It robustly discusses the various possible pathways and/or mechanisms of particle-mediated Hg (II) reduction, in enhancing or lowering the production of dissolved gaseous mercury. These processes include photo hole-electron pair formation and reactive oxygen species generation from particle excitation and their involvement in Hg photoreduction, in addition to the light attenuation effect of particles. This paper highlights the necessity of future studies exploiting these particles-mediated Hg photoreactions pathways and the implications of including these heterogeneous photoreactions (together with particulate elemental Hg species) on the air-water Hg exchange estimation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Kodamaea ohmeri is an environmental yeast considered a rare emerging pathogen. In clinical settings, the correct identification of this yeast is relevant because some isolates are associated with resistance to antifungals. There is a lack of available data regarding the geographical distribution, virulence, and drug resistance profile of K. ohmeri . To contribute to the knowledge of this yeast, this study aimed to describe in depth three isolates of K. ohmeri associated with fungemia in Honduras. The identification of the isolates was carried out by sequencing the ribosomal ITS region. In addition, the susceptibility profile to antifungals was determined, and some properties associated with virulence were evaluated (exoenzyme production, biofilm formation, cell adhesion, and invasion). The isolates showed strong protease, phospholipase, and hemolysin activity, in addition to being biofilm producers. Adherence and invasion capacity were evident in the HeLa and Raw 264.7 cell lines, respectively. This study expands the understanding of the underlying biological traits associated with virulence in K. ohmeri , and it is the first report of the detection and identification of K. ohmeri in Honduras as a cause of human infection.

The paucity of preclinical models that recapitulate COVID-19 pathology without requiring SARS-COV-2 adaptation and humanized/transgenic mice limits research into new therapeutics against the frequently emerging variants-of-concern. We developed virus-free models by C57BL/6 mice receiving oropharyngeal instillations of a SARS-COV-2 ribo-oligonucleotide common in all variants or specific to Delta/Omicron variants, concurrently with low-dose bleomycin. Mice developed COVID-19-like lung pathologies including ground-glass opacities, interstitial fibrosis, congested alveoli, and became moribund. Lung tissues from these mice and bronchoalveolar lavage and lung tissues from patients with COVID-19 showed elevated levels of hyaluronic acid (HA), HA-family members, an inflammatory signature, and immune cell infiltration. 4-methylumbelliferone (4-MU), an oral drug for biliary-spasm treatment, inhibits HA-synthesis. At the human equivalent dose, 4-MU prevented/inhibited COVID-19-like pathologies and long-term morbidity; 4-MU and metabolites accumulated in mice lungs. Therefore, these versatile SARS-COV-2 ribo-oligonucleotide oropharyngeal models recapitulate COVID-19 pathology, with HA as its critical mediator and 4-MU as a potential therapeutic for COVID-19., Competing Interests: None., (© 2024 The Authors.)

Background: Mitochondrial diseases (MDs) are genetic disorders characterized by dysfunctions in mitochondria. Clinical data suggest that additional factors, beyond genetics, contribute to the onset and progression of this group of diseases, but these influencing factors remain largely unknown. Mounting evidence indicates that immune dysregulation or distress could play a role. Clinical observations have described the co-incidence of infection and the onset of the disease as well as the worsening of symptoms following infection. These findings highlight the complex interactions between MDs and immunity and underscore the need to better understand their underlying relationships., Results: We used Ndufs4 KO mice, a well-established mouse model of Leigh syndrome (one of the most relevant MDs), to test whether chronic induction of a neuroinflammatory state in the central nervous system before the development of neurological symptoms would affect both the onset and progression of the disease in Ndufs4 KO mice. To this aim, we took advantage of the GFAP-IL6 mouse, which overexpresses interleukin-6 (IL-6) in astrocytes and produces chronic glial reactivity, by generating a mouse line with IL-6 overexpression and NDUFS4 deficiency. IL-6 overexpression aggravated the mortality of female Ndufs4 KO mice but did not alter the main motor and respiratory phenotypes measured in any sex. Interestingly, an abnormal region-dependent microglial response to IL-6 overexpression was observed in Ndufs4 KO mice compared to controls., Conclusion: Overall, our data indicate that chronic neuroinflammation may worsen the disease in Ndufs4 KO female mice, but not in males, and uncovers an abnormal microglial response due to OXPHOS dysfunction, which may have implications for our understanding of the effect of OXPHOS dysfunction in microglia., (© 2023. The Author(s).)

Objective: To compare vestibular outcomes in cochlear implant (CI) surgery, between robotic-assisted insertion of the electrodes versus manual insertion., Methods: We performed a monocentric retrospective study. From March 2021, the robotic system RobOtol© was used for all CI cases. We compared this robotic-assisted insertion group with a manual insertion group of patients who received a CI between July 2020 and March 2021. Primary objective was vestibular outcome. We used objective vestibular function tests: caloric testing, Vestibular Evoked Myogenic Potential (VEMP), and Video Head Impulse Test (VHIT). Secondary objectives were postoperative complications including patient-reported postoperative vertigo., Results: We found no statistically significant difference between the two groups in terms of caloric testing, VEMP or VHIT outcomes. In patient-reported outcomes, there was significantly more vertigo in the manual insertion group compared with robotic-assisted insertion., Conclusion: It is hypothesized that a non-traumatic insertion would cause less vestibular dysfunction postoperatively. Larger prospective studies are required to determine whether robotic-assisted CI insertion has a significant impact on vestibular outcomes in CI surgery.

In the quest for improving the clinical outcome of patients with metastatic genitourinary cancers, including metastatic renal cell carcinoma (mRCC), the emphasis often is on finding new targeted therapies. However, two studies by Jordan et al. (Oncogenesis 2020) and Wang et al. (Cancer Cell Int 2022) demonstrate the feasibility of improving the efficacy of a modestly effective drug Sorafenib against mRCC by attacking a mechanism hijacked by RCC cells for inactivating Sorafenib. The studies also identified hyaluronic acid synthase -3 (HAS3) as a bonafide target of Sorafenib in RCC cells. The studies demonstrate that an over-the-counter drug Hymecromone (4-methylumbelliferone) blocks inactivation of Sorafenib in RCC cells and improves its efficacy against mRCC through the inhibition of HAS3 expression and HA signaling. In the broader context, improving the efficacy of "old and failed drugs" that have favorable safety profiles should increase the availability of effective treatments for patients with advanced cancers., Competing Interests: Competing Interests The authors declare no conflict of interest.

Biocircularity could play a key role in the circular economy, particularly in applications where organic recycling (composting) has the potential to become a preferred waste management option, such as food packaging. The development of fully biobased and biodegradable composites could help reduce plastic waste and valorize agro-based residues. In this study, extruded films made of composites of polyhydroxybutyrate-co-valerate (PHBV) and lignocellulosic fibers, namely almond shell (AS) and Oryzite ® (OR), a polymer hybrid composite precursor, have been investigated. Scanning electron microscopy (SEM) analysis revealed a weak fiber-matrix interfacial interaction, although OR composites present a better distribution of the fiber and a virtually lower presence of "pull-out". Thermogravimetric analysis showed that the presence of fibers reduced the onset and maximum degradation temperatures of PHBV, with a greater reduction observed with higher fiber content. The addition of fibers also affected the melting behavior and crystallinity of PHBV, particularly with OR addition, showing a decrease in crystallinity, melting, and crystallization temperatures as fiber content increased. The mechanical behavior of composites varied with fiber type and concentration. While the incorporation of AS results in a reduction in all mechanical parameters, the addition of OR leads to a slight improvement in elongation at break. The addition of fibers improved the thermoformability of PHBV. In the case of AS, the improvement in the processing window was achieved at lower fiber contents, while in the case of OR, the improvement was observed at a fiber content of 20%. Biodisintegration tests showed that the presence of fibers promoted the degradation of the composites, with higher fiber concentrations leading to faster degradation. Indeed, the time of complete biodisintegration was reduced by approximately 30% in the composites with 20% and 30% AS.

Evidence points to a direct relationship between nutritional quality and food expenditure. However, food expenditure is highly susceptible to changes, and nutritional quality of household food presents limited evidence. The aim of this study was to assess the relationship between nutritional quality available and total food expenditure in Peruvian households, and whether there were differences by area (urban and rural) and between years of the COVID-19 pandemic. For this, we used Peru's National Household Survey (ENAHO) from 2019 and 2020. We assessed total food expenditure in US dollars per day, whereas household nutritional quality available was assessed based on dietary diversity and compliance with the household calorie requirements, percentage of food expenditure, and potential confounders. We used the Student's t-test, analysis of variance (ANOVA), linear regression, and the Wald test to assess the interaction effect. Households with adequate total/partial nutritional quality available by area were found to spend, on average, USD 2.00 more in urban than in rural areas and, by year, they presented 7.1% more percentage of food expenditure in 2020 than in 2019. Despite associations existing between nutritional quality available and total food expenditure by year and study area, the effect modification was only present by study area. In multivariable model, households with adequate total/partial nutritional quality available consistently presented a lower total food expenditure by year, with a lower total food expenditure in urban areas. An inverse relationship was found between nutritional quality available and total food expenditure, in contrast to the direct relationship of studies assessing dietary cost and nutritional quality. Our results reflect the nutritional deficit in the food purchases of Peruvian households.

Poly(3-hydroxybutyrate- co -3-hydroxyvalerate) (PHBV) has gained attention as a possible substitute for conventional polymers that could be integrated into the organic recycling system. Biocomposites with 15% of pure cellulose (TC) and woodflour (WF) were prepared to analyze the role of lignin on their compostability (58 °C) by tracking the mass loss, CO 2 evolution, and the microbial population. Realistic dimensions for typical plastic products (400 µm films), as well as their service performance (thermal stability, rheology), were taken into account in this hybrid study. WF showed lower adhesion with the polymer than TC and favored PHBV thermal degradation during processing, also affecting its rheological behavior. Although all materials disintegrated in 45 days and mineralized in less than 60 days, lignin from woodflour was found to slow down the bioassimilation of PHBV/WF by limiting the access of enzymes and water to easier degradable cellulose and polymer matrix. According to the highest and the lowest weight loss rates, TC incorporation allowed for higher mesophilic bacterial and fungal counts, while WF seemed to hinder fungal growth. At the initial steps, fungi and yeasts seem to be key factors in facilitating the later metabolization of the materials by bacteria.