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Moraima Morales-Cruz,1,* Yamixa Delgado,2,* Betzaida Castillo,3 Cindy M Figueroa,4 Anna M Molina,1 Anamaris Torres,2 Melissa Milián,2 Kai Griebenow1,* 1Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, PR, USA; 2Department of Biochemistry & Pharmacology, San Juan Bautista School of Medicine, Caguas, PR, USA; 3Department of Chemistry, University of Puerto Rico, Humacao Campus, Humacao, PR, USA; 4Department of Math and Sciences, Polytechnic University of Puerto Rico, San Juan, PR, USA*These authors contributed equally to this workCorrespondence: Yamixa Delgado PO Box 4968 Caguas, PR 00726-4968, USATel +1 787 743 3038Fax +1 787 746 3093Email ydelgado@sanjuanbautista.edu Kai Griebenow 17 Ave Universidad STE 1701, San Juan, PR 00925-2537, USATel +1 787 764 0000Fax +1 787 746 3093Email kai.griebenow@upr.eduAbstract: Cancer is the second largest cause of death worldwide with the number of new cancer cases predicted to grow significantly in the next decades. Biotechnology and medicine can and should work hand-in-hand to improve cancer diagnosis and treatment efficacy. However, success has been frequently limited, in particular when treating late-stage solid tumors. There still is the need to develop smart and synergistic therapeutic approaches to achieve the synthesis of strong and effective drugs and delivery systems. Much interest has been paid to the development of smart drug delivery systems (drug-loaded particles) that utilize passive targeting, active targeting, and/or stimulus responsiveness strategies. This review will summarize some main ideas about the effect of each strategy and how the combination of some or all of them has shown to be effective. After a brief introduction of current cancer therapies and their limitations, we describe the biological barriers that nanoparticles need to overcome, followed by presenting different types of drug delivery systems to improve drug accumulation in tumors. Then, we describe cancer cell membrane targets that increase cellular drug uptake through active targeting mechanisms. Stimulus-responsive targeting is also discussed by looking at the intra- and extracellular conditions for specific drug release. We include a significant amount of information summarized in tables and figures on nanoparticle-based therapeutics, PEGylated drugs, different ligands for the design of active-targeted systems, and targeting of different organs. We also discuss some still prevailing fundamental limitations of these approaches, eg, by occlusion of targeting ligands.Keywords: active targeting, drug delivery systems, EPR effect, nanoparticles, passive targeting, stimulus-responsive targeting

Single-case design research studies have historically used external observers to collect time series data that may be used to evaluate intervention effectiveness; however, single-case interventions implemented in educational settings may use the person implementing the intervention (e.g., teacher) to collect data in order to maximize feasibility. The implementer's knowledge of intervention goals and phase has the potential to influence assessment of dependent variables, particularly when ratings involving some degree of judgment (e.g., Direct Behavior Rating-Single Item Scales [DBR-SIS]) are used. Given the potential for rater effects and expectancy to influence data collection, this study sought to determine whether DBR-SIS measuring social skills collected in vivo by interventionists with full knowledge of intervention goals and phase were equivalent to data collected by external raters masked to intervention phase. Results indicated in vivo DBR-SIS differed from those completed by masked external raters, which has the potential to result in different conclusions regarding intervention effectiveness. The potential for negative effects resulting from sole reliance on in vivo ratings conducted by an interventionist may be mitigated by including additional data streams collected by external personnel masked to intervention phase or by using effect sizes that account for baseline trends. Implications for training and practice are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: The early stages of the COVID-19 pandemic overwhelmed general hospitals in Spain. In response, a dedicated hospital for COVID-19 care, the Hospital de Emergencias Enfermera Isabel Zendal (HEEIZ), was established. This study aimed to compare clinical outcomes of COVID-19 patients treated at the specialized HEEIZ with those at conventional general hospitals (CGHs) in Madrid, Spain., Methods: The study was a prospective, observational cohort study including COVID-19 patients admitted to the HEEIZ and 14 CGHs (December 2020 to August 2021). Patients were assigned based on hospital preference. Clinical data were collected and analyzed using multivariate regression to assess primary and secondary outcomes, including hospital mortality, need of invasive mechanical ventilation (IMV), and pharmacological treatments., Results: The HEEIZ cohort ( n = 2997) was younger and had lower Charlson comorbidity scores than the CGH cohort ( n = 1526). Adjusted HEEIZ hospital mortality was not significantly higher compared with CGHs (OR: 1.274; 95% CI: 0.781-2.079; p = 0.332)., Conclusions: During the study period, patients admitted to the HEEIZ showed no significant differences in clinical outcomes, compared with patients admitted at CGHs. These results might support the use of specialized centers in managing pandemic surges, allowing CGHs to handle other needs.

Chronic inflammation drives the growth of colorectal cancer through the dysregulation of molecular pathways within the immune system. Infiltration of immune cells, such as macrophages, into tumoral regions results in the release of proinflammatory cytokines (IL-6; IL-17; TNF-α), fostering tumor proliferation, survival, and invasion. Tumors employ various mechanisms to evade immune surveillance, effectively 'cloaking' themselves from detection and subsequent attack. A comprehensive understanding of these intricate molecular interactions is paramount for advancing novel strategies aimed at modulating the immune response against cancer.

Background: Around 10% of people infected by SARS-COV-2 report symptoms that persist longer than 3 months. Little has been reported about sex differences in symptoms and clustering over time of non-hospitalised patients in primary care settings., Methods: This is a descriptive study of a cohort of mainly non-hospitalized patients with a persistence of symptoms longer than 3 months from the clinical onset in co-creation with the Long Covid Catalan affected group using an online survey. Recruitment was from March 2020 to June 2021. Exclusion criteria were being admitted to an ICU, < 18 years of age and not living in Catalonia. We focused on 117 symptoms gathered in 18 groups and performed cluster analysis over the first 21 days of infection, at 22-60 days, and ≥ 3 months., Results: We analysed responses of 905 participants (80.3% women). Median time between symptom onset and the questionnaire response date was 8.7 months. General symptoms (as fatigue) were the most prevalent with no differences by sex, age, or wave although its frequency decreased over time (from 91.8 to 78.3%). Dermatological (52.1% in women, 28.5% in men), olfactory (34.9% women, 20.9% men) and neurocognitive symptoms (70.1% women, 55.8% men) showed the greatest differences by sex. Cluster analysis showed five clusters with a predominance of Taste & smell (24.9%) and Multisystemic clusters (26.5%) at baseline and &#95;Multisystemic (34.59%) and Heterogeneous (24.0%) at ≥3 months. The Multisystemic cluster was more prevalent in men. The Menstrual cluster was the most stable over time, while most transitions occurred from the Heterogeneous cluster to the Multisystemic cluster and from Taste & smell to Heterogeneous., Conclusions: General symptoms were the most prevalent in both sexes at three-time cut-off points. Major sex differences were observed in dermatological, olfactory and neurocognitive symptoms. The increase of the Heterogeneous cluster might suggest an adaptation to symptoms or a non-specific evolution of the condition which can hinder its detection at medical appointments. A carefully symptom collection and patients' participation in research may generate useful knowledge about Long Covid presentation in primary care settings., (© 2024. The Author(s).)

Cancer is one of the world's most significant health problems today. Currently, breast cancer has globally surpassed lung cancer as the most commonly diagnosed cancer in women. In 2020, an estimated 2,261,419 new cases were diagnosed in women worldwide. Therefore, there is a need to understand the processes that can help us better treat this disease. In recent years, research in the fight against cancer has often been based on two treatment modalities. One of them is the use of protein kinase inhibitors, which have been instrumental in the development of new therapeutic strategies. Another crucial route is the use of immunotherapy, which has been touted as a great promise for cancer treatment. Protein kinase alterations can interfere with the effectiveness of other treatments, such as immunotherapy. In this review, we will analyze the role played by protein kinase alterations in breast cancer and their possible impact on the effectiveness of the response to immunotherapy treatments.

Background: Worldwide, an estimated 4·4 million newborn deaths and stillbirths occurred in 2020, and 98% of these deaths occurred in low-income and middle-income countries (LMICs). We aimed to analyse new research grants for newborns and stillbirth awarded by major funders in 2019-20, and all research funding allocated to LMIC-based institutions in 2011-20., Methods: For this systematic analysis, we searched Dimensions, the world's largest research funding database, for grants relevant to neonatal and stillbirth research. Included grants were categorised by in-depth content analysis, with descriptive quantitative analyses by funder and recipient countries, research pipeline, topic, and year., Findings: Globally, in 2019-20, major funders awarded a mean annual total of US$577·1 million per year for newborn and stillbirth research (mean total of 550 grants per year). $166·3 million (28·8%) of $577·1 million was directed to small and vulnerable newborn research, but only $8·4 million (1·5%) was directed to stillbirth research. The majority of funding, $537·0 million (93·0%), was allocated to organisations based in high-income countries. Between 2011 and 2020, LMIC-based recipients were named on 1985 grants from all funders worth $486·7 million, of which $73·1 million (15·0%) was allocated to small and vulnerable newborn research and $12·0 million (2·5%) was allocated to stillbirth research. Most LMIC funding supported preclinical or observational studies ($236·8 million [48·7%] of $486·7 million), with implementation research receiving only $13·9 million (2·9%)., Interpretation: Although investment in research related to neonatal health and stillbirths has increased between 2011 and 2020, there are marked disparities in distribution geographically, between major causes of mortality, and among research pipeline types. Stillbirth research received minimal funding in both high-income countries and LMICs, despite a similar number of deaths compared with neonates. Direct investment in LMIC-led research, especially for implementation research, could accelerate the slow global progress on stillbirth prevention and newborn survival., Funding: None., Translations: For the French, German and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The study of the effects of the magnetic field (MF) on living matter continues to be a dilemma. Until now, the interaction mechanisms of MF with living matter that explain the observed phenomena are unknown. Despite the existing literature and the multiple effects described to date, there are few published articles that study the combined effect of MF with other physical agents during the cellular aging process. In this sense, the aim of this work is to study whether low frequency and intensity pulsed and sinusoidal MF exposure produce alterations in the cell killing effect of ultraviolet C (UVC) radiation and thermal shock during the chronological aging of S. cerevisiae. Yeast cells were exposed to 2.45 mT (50 Hz) sinusoidal MF and 1.5 mT (25 Hz) pulsed MF, during 40 days of aging, in combination with UVC radiation (50 J/m 2 ) and/or thermal shock (52°C). Cell survival was evaluated by clonogenic assay. The exposure of yeast to pulsed MF produces an acceleration of aging, which is not observed in cells exposed to sinusoidal MF. The pulsed MF modifies the cellular response to damaging agents only in aged S. cerevisiae cells. In this sense, the pulsed MF applied increases the damage induced by UVC radiation and by thermal shock. In contrast, the sinusoidal MF used has no effect., (© 2023. The Author(s).)

Several studies have shown an increased prevalence of anxiety, depression and suicidal ideation in the general population in relation to the COVID-19 pandemic.

The repair of the damage produced to the genome and proteome by the action of ionizing radiation, oxidizing agents, and during aging is important to maintain cellular homeostasis. Many of the metabolic pathways influence multiple processes. In this way, this work aims to study the relationship between resistance/response to ionizing radiation, cellular aging, and the response mechanisms to oxidative stress, free radicals, reactive oxygen species (ROS), and antioxidant activity in the yeast S. cerevisiae . Systems biology allows us to use tools that reveal the molecular mechanisms common to different cellular response phenomena. The results found indicate that homologous recombination, non-homologous end joining, and base excision repair pathways are the most important common processes necessary to maintain cellular homeostasis. The metabolic routes of longevity regulation are those that jointly contribute to the three phenomena studied. This study proposes eleven common biomarkers for response/resistance to ionizing radiation and aging (EXO1, MEC1, MRE11, RAD27, RAD50, RAD51, RAD52, RAD55, RAD9, SGS1, YKU70) and two biomarkers for response/resistance to radiation and oxidative stress, free radicals, ROS, and antioxidant activity (NTG1, OGG1). In addition, it is important to highlight that the HSP104 protein could be a good biomarker common to the three phenomena studied.

Background: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment., Methods: A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival., Discussion: The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions., Trial Registration: ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The Olami, Feder and Christensen (OFC) spring-block model has proven to be a powerful tool for analyzing and comparing synthetic and real earthquakes. This work proposes the possible reproduction of Utsu's law for earthquakes in the OFC model. Based on our previous works, several simulations characterizing real seismic regions were performed. We located the maximum earthquake in these regions and applied Utsu's formulae to identify a possible aftershock area and made comparisons between synthetic and real earthquakes. The research compares several equations to calculate the aftershock area and proposes a new one with the available data. Subsequently, the team performed new simulations and chose a mainshock to analyze the behavior of the surrounding events, so as to identify whether they could be catalogued as aftershocks and relate them to the aftershock area previously determined using the formula proposed. Additionally, the spatial location of those events was considered in order to classify them as aftershocks. Finally, we plot the epicenters of the mainshock, and the possible aftershocks comprised in the calculated area resembling the original work of Utsu. Having analyzed the results, it is likely to say that Utsu's law is reproducible using a spring-block model with a self-organized criticality (SOC) model.

With the spring-block model proposed by Olami, Feder, and Christensen (OFC), we obtained a time series of synthetic earthquakes with different values of the conservation level (β), which measures the fraction of the energy that a relaxing block passes to its neighbors. The time series have multifractal characteristics, and we analyzed them with the Chhabra and Jensen method. We calculated the width, symmetry, and curvature parameters for each spectrum. As the value of conservation level increases, the spectra widen, the symmetric parameter increases, and the curvature around the maximum of the spectra decreases. In a long series of synthetic seismicity, we located earthquakes of the greatest magnitude and built overlapping windows before and after them. For the time series in each window, we performed multifractal analysis to obtain multifractal spectra. We also calculated the width, symmetry, and curvature around the maximum of the multifractal spectrum. We followed the evolution of these parameters before and after large earthquakes. We found that the multifractal spectra had greater widths, were less skewed to the left, and were very pointed around the maximum before rather than after large earthquakes. We studied and calculated the same parameters and found the same results in the analysis of the Southern California seismicity catalog. This suggests that there seems to be a process of preparation for a great earthquake and that its dynamics are different from the one that occurs after this mainshock based on the behavior of the parameters mentioned before.

Inflammatory bowel diseases (IBDs) are characterized by abnormal, non-antigen specific chronic inflammation of unknown etiology. Genome-wide association studies show that many IBD genetic susceptibility loci map to immune function genes and compelling evidence indicate that environmental factors play a critical role in IBD pathogenesis. Clinical and experimental evidence implicate the pro-inflammatory cytokine IL-15 in the pathogenesis of IBD. IL-15 and IL-15α expression is increased in the inflamed mucosa of IBD patients. IL-15 contributes to the maintenance of different cell subsets in the intestinal mucosa. However, very few studies have addressed the role of IL-15 in pre-clinical models of colitis. In this study, we use three well-characterized models of experimental colitis to determine the contribution of IL-15 to pathological intestinal inflammation., (© 2022 American Association for Anatomy.)

In response to the largest recorded monkeypox virus outbreak outside of endemic Central and Western Africa, the East African Community (EAC), in cooperation with the Bernhard-Nocht- Institute for Tropical Medicine, coordinated an emergency monkeypox diagnostic training for the East African Region. As of June 2022, the Democratic Republic of Congo reported a steady increase of suspected monkeypox cases, increasing the risk of spill-over into the remaining six EAC Partner States. Within the existing EAC Mobile Laboratories project, laboratory experts of the National Public Health Laboratories of the remaining six EAC Partner States (Burundi, Rwanda, Tanzania, Kenya, Uganda, and South Sudan) participated in the workshop and were trained in the reception of suspect samples, DNA extraction and diagnosis using real-time polymerase chain reaction (RT-PCR). The EAC region is now equipped with the tools to prepare and rapidly respond to any emerging monkeypox outbreak., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest., (©Copyright: the Author(s).)

Background: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression., Methods: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025., Discussion: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents., Trial Registration: EU CT-Number: 2022-500024-30-00., (© 2023. The Author(s).)

Mindfulness-based interventions (MBIs) have been evaluated in terms of efficacy; however, little is known about implementation factors of MBIs in schools . The purpose of the current study was to systematically review MBI studies published in school psychology journals. This systematic review examined peer-reviewed MBI literature in nine school psychology journals from 2006 to 2020 to examine prevalence of MBI intervention studies, specific techniques taught in MBIs, if and how fidelity of MBI implementation was evaluated, and how mindfulness skills were measured for youth participating in MBIs. A total of 46 articles (out of 4415) were related to mindfulness and 23 articles (0.52%) focused on the implementation of MBIs in schools. Nine different mindfulness techniques were implemented as part of MBIs in studies with some of the most common including awareness, breathing, and meditation. This study also found scarce evidence of implementation fidelity, and limited use of mindfulness measures within MBI studies. Future research and limitations are also discussed., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to California Association of School Psychologists 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: Many articles describe the effects of extremely low-frequency magnetic fields (MFs) on DNA damage induction. However, the mechanism of MF interaction with living matter is not yet known with certainty. Some works suggest that MF could induce an increase in the efficacy of reactive oxygen species (ROS) production. This work investigates whether pulsed MF exposure produces alterations in genomic DNA damage induced by co-exposure to DNA damaging agents (bleomycin and methyl methanesulfonate (MMS))., Materials and Methods: Genomic DNA, prepared from S. cerevisiae cultures, was exposed to pulsed MF (1.5 mT peak, 25 Hz) and MMS (0-1%) (15-60 min), and to MF and bleomycin (0-0.6 IU/mL) (24-72 h). The damage induced to DNA was evaluated by electrophoresis and image analysis., Results: Pulsed MF induced an increment in the level of DNA damage produced by MMS and bleomycin in all groups at the exposure conditions assayed., Conclusions: Pulsed MF could modulate the cytotoxic action of MMS and bleomycin. The observed effect could be the result of a multifactorial process influenced by the type of agent that damages DNA, the dose, and the duration of the exposure to the pulsed MF.

The response of plants to magnetic fields (MF) is not fully understood. This work studies the effects of pulsed MF on the germination and growth of Allium cepa roots. Onions were exposed to 25Hz, 1.5mT, 33h. Pulsed MF was generated by a Helmholtz-type equipment that generated rectangular voltage pulses. The results showed that fewer roots grew in the specimens exposed to pulsed MF (14±6 roots on day 1 to 21±8 on day 4) than in the control groups (32±17 to 48±23) (p<0.05 Friedman). Control specimens showed a root mean length of 7±4 mm (day 1) and 24±10 mm (day 4). The specimens treated with pulsed MF showed a length of 4±2 mm (day 1), reaching 18±9 mm on day 4 (p<0.001 ANOVA). In conclusion, the exposure of Allium cepa specimens to 25Hz, 1.5mT pulsed MF during 33h produces a decrease in the germination and growth of roots.

Background and Aims: Ageing is a multifactorial degenerative process which causes a decrease in the cellular capacity for repair and adaptation to external stressors. In this way, it is important to maintain the proper balance of the proteome. Heat shock proteins (HSP) will intervene in this balance, which are responsible for the correct assembly, folding and translocation of other proteins when cells are subjected to stressors. This type of protein is overexpressed in human tumor cells, while its deficit, both in function and quantity, contributes to ageing processes. The present work aims to analyze the response of cells from studies carried out in normal and tumor cells that are subjected to stressors., Methods and Results: A PubMed search was performed using the keywords "cell ageing, cell longevity, resistance, HSP, heat shock proteins, thermal shock proteins". This search generated 212 articles. Subsequently, a series of inclusion and exclusion criteria were applied to select the articles of interest to be evaluated. Normal cells subjected to external stressors at low doses increase the number of HSP, causing them to become more resistant. In addition, tumor cells expressing high levels of HSP show greater resistance to treatment and increased cell replication. HSP intervene in the cellular resistance of both normal and tumor cells., Conclusions: In the case of normal cells, the increase in HSP levels makes them respond effectively to an external stressor, increasing their resistance and not causing cell death. In the case of tumor cells, there is an increase in resistance to treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The non-randomised, open-label, phase IIIb/IV multicohort CheckMate 920 trial explored the safety and efficacy with a less frequent, but continual nivolumab plus ipilimumab (NIVO+IPI) dosing regimen (cohort 1) to determine whether this modification could potentially retain efficacy benefits while improving on the manageable safety profile previously observed with this combination in patients with advanced renal cell carcinoma (aRCC)., Setting: Patients were enrolled from 48 largely community-based sites in the USA., Participants: 106 patients with previously untreated, predominantly clear cell aRCC received treatment., Interventions: Patients received NIVO 6 mg/kg plus IPI 1 mg/kg on day 1 of the first week of each 8-week cycle; the combination alternated with NIVO 480 mg monotherapy on day 1 of the fifth week of each 8-week cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or study end. The maximum treatment duration was 2 years. The primary endpoint was the incidence of high-grade (grade 3/4 and grade 5) immune-mediated adverse events (IMAEs) within 100 days of the last dose. Select secondary endpoints included time to onset and resolution of high-grade IMAEs, progression-free survival (PFS) and objective response rate (ORR). The incidence of treatment-related adverse events and the overall survival (OS) were the exploratory endpoints., Results: The most common grade 3/4 IMAEs were diarrhoea/colitis (7.5%) and rash (6.6%) and no grade 5 IMAEs occurred, with a minimum follow-up of 28.5 months. The median PFS was 4.8 (95% CI 3.0 to 8.3) months, the ORR in evaluable patients (n=96) was 34.4% (95% CI 25.0 to 44.8), and the median OS was not reached (95% CI 24.8 months to not estimable)., Conclusions: While no new safety signals were reported with less frequent, but continual NIVO+IPI dosing in CheckMate 920, the modified regimen was not associated with clinical benefits relative to the approved NIVO+IPI dose. These results support the continued use of the currently approved NIVO+IPI combination dosing schedule for patients with aRCC., Trial Registration Number: NCT02982954., Competing Interests: Competing interests: DJG reports consulting or advisory roles from Bayer, Exelixis, Pfizer, Sanofi, Astellas Pharma, Innocrin Pharma, Bristol Myers Squibb (BMS), Genentech, Janssen, Merck Sharp & Dohme, Myovant Sciences, AstraZeneca, Michael J Hennessy Associates, Vizuri and Constellation Pharmaceuticals; leadership from Capio Biosciences; speakers bureau from Sanofi, Bayer and Exelixis; travel, accommodations and expenses from Bayer, Exelixis, Merck, Pfizer, Sanofi, Janssen Oncology and UroToday; honoraria from Sanofi, Bayer, Exelixis, EMD Serono, OncLive, Pfizer, UroToday, Acceleron Pharma, American Association for Cancer Research, Axess Oncology, Janssen Oncology and Millennium Medical Publishing; and research funding (all institution) from Exelixis, Janssen Oncology, Novartis, Pfizer, Astellas Pharma, BMS, Acerta Pharma, Bayer, Dendreon, Innocrin Pharma, Calithera Biosciences and Sanofi/Aventis. DRS reports consulting or advisory roles (all institution) from Amgen, AstraZeneca, BMS, Curio Science, EMD Serono, Evidera, Exelixis, GlaxoSmithKline, Intellisphere, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Mirati Therapeutics, Molecular Templates, Novartis, Novocure, Pfizer, Puma Biotechnology, Regeneron Pharmaceuticals, Roche/Genentech and Sanofi/Aventis; and research funding (all institution) from Aeglea BioTherapeutics, Agios, Apollomics, Arcus, Arrys Therapeutics, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech RNA Pharmaceuticals, Blueprint Medicine, Boehringer Ingelheim, BMS, Calithera, Celgene, Celldex, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, EMD Serono, Evelo Biosciences, G1 Therapeutics, Roche/Genentech, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Incyte, ImmunoGen, Ipsen, Janssen, Kronos Bio, Lilly, Loxo Oncology, MacroGenics, MedImmune, Merck, Molecular Partners, Molecular Template, Nektar, Neon Therapeutics, Novartis, Novocure, Oncologie, Pfizer, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics, Transgene, UT Southwestern and Verastem. LNG reports employment from Florida Medical Clinic; leadership from Florida Cancer Specialists; honoraria from Ameris Pharma; consulting or advisory role from Janssen Oncology; and speakers bureau from Myriad Genetics. STK has no conflicts of interests to disclose. AMM reports consulting or advisory roles from Exelixis, Janssen and Eisai; and honoraria from the American Society of Clinical Oncology. JY reports consulting or advisory roles from BMS, Janssen and Lantheus. ARK reports remuneration for a consulting or advisory roles from Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, BMS and EMD Serono; speakers bureau from Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/Roche, Eisai, AstraZeneca, BMS, Amgen, Exelixis, EMD Serono, Merck and Seattle Genetics/Astellas; travel, accommodations and expenses from Genentech, Prometheus, Astellas Medivation, Janssen, Eisai, Bayer, Pfizer, Novartis, Exelixis and AstraZeneca; stock ownership from ECOM Medical; and research funding (all institution) from Genentech, Exelixis, Janssen, AstraZeneca, Bayer, BMS, Eisai, MacroGenics, Astellas Pharma, BeyondSpring Pharmaceuticals, BioClin Therapeutics, Clovis Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics and Epizyme. HM has no conflicts of interests to disclose. NT reports consulting or advisory roles from Amgen, IntrinsiQ and Foundation Medicine. SST reports consulting or advisory roles from Merck, Intellisphere, Natera, BMS and Exelixis; patent pending (institution); and research funding (all institution) from Genentech, BMS, Merck, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis and Clinigen Group. JZ reports employment and stock ownership from BMS. MA reports employment from BMS. JLJ reports employment and stock ownership from BMS. TEH reports employment from Texas Oncology; consulting or advisory roles from Bayer/Onyx, Pfizer, Novartis, Astellas Pharma, Johnson & Johnson, BMS, Eisai and Exelixis; speakers bureau from Pfizer, Johnson & Johnson, Eisai, Exelixis, Astellas Pharma and BMS; honoraria from Pfizer, Astellas Pharma, BMS, Exelixis, Eisai, Novartis, Johnson & Johnson and Bayer/Onyx; and research funding (all institution) from Pfizer, Johnson & Johnson, Exelixis, Eisai and BMS., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. 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Purpose: To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC)., Methods: An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations., Results: The panel considered peer-reviewed reports published in English., Recommendations: The diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis. The International Metastatic RCC Database Consortium risk criteria should be used to inform treatment. Cytoreductive nephrectomy may be offered to select patients with kidney-in-place and favorable- or intermediate-risk disease. For those who have already had a nephrectomy, an initial period of active surveillance may be offered if they are asymptomatic with a low burden of disease. Patients with favorable-risk disease who need systemic therapy may be offered an immune checkpoint inhibitor (ICI) in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI); patients with intermediate or poor risk should be offered a doublet regimen (no recommendation was provided between ICIs or an ICI in combination with a VEGFR TKI). For select patients, monotherapy with either an ICI or a VEGFR TKI may be offered on the basis of comorbidities. Interleukin-2 remains an option, although selection criteria could not be identified. Recommendations are also provided for second- and subsequent-line therapy as well as the treatment of bone metastases, brain metastases, or the presence of sarcomatoid features. Participation in clinical trials is highly encouraged for patients with metastatic ccRCC.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

This study evaluates the DNA damage induced by pulsed magnetic field (MF) on S. cerevisiae cells exposed during chronological aging. Samples were exposed to 25 Hz pulsed MF (1.5mT, 8 h/day) while cells were aging chronologically. Clonogenic drop test was used to study cellular survival and the mutation frequency was evaluated by scoring the spontaneous revertant mutants. DNA damage analysis was performed after aging by electrophoresis and image analysis. Yeast cells aged during 40 days of exposure showing that pulsed MF exposure induced a premature aging. In addition, a gradual increase in spontaneous mutants was found in pulsed MF samples in relation to unexposed controls. An increase in DNA degradation, over the background level in relation to controls, was observed at the end of the exposure period. In conclusion, exposure of S. cerevisiae cells to pulsed MF during chronological aging could induce genomic DNA damage.

Primary clear cell renal cell carcinoma (ccRCC) has been previously characterized, but the genomic landscape of metastatic ccRCC is largely unexplored. Here, we performed whole exome sequencing (WES) in 68 samples from 44 patients with ccRCC, including 52 samples from a metastatic site. SETD2, PBRM1, APC and VHL were the most frequently mutated genes in the metastatic ccRCC cohort. RBM10 and FBXW7 were also among the 10 most frequently mutated genes in metastatic tissues. Recurrent somatic copy number variations (CNV) were observed at the previously identified regions 3p25, 9p21 and 14q25, but also at 6p21 (CDKN1A) and 13q14 (RB1). No statistically significant differences were found between samples from therapy-naïve and pretreated patients. Clonal evolution analyses with multiple samples from 13 patients suggested that early appearance of CNVs at 3p25, 9p21 and 14q25 may be associated with rapid clinical progression. Overall, the genomic landscapes of primary and metastatic ccRCC seem to share frequent CNVs at 3p25, 9p21 and 14q25. Future work will clarify the implication of RBM10 and FBXW7 mutations and 6p21 and 13q14 CNVs in metastatic ccRCC., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The self-organized critical (SOC) spring-block models are accessible and powerful computational tools for the study of seismic subduction. This work aims to highlight some important findings through an integrative approach of several actual seismic properties, reproduced by using the Olami, Feder, and Christensen (OFC) SOC model and some variations of it. A few interesting updates are also included. These results encompass some properties of the power laws present in the model, such as the Gutenberg-Richter (GR) law, the correlation between the parameters a and b of the linear frequency-magnitude relationship, the stepped plots for cumulative seismicity, and the distribution of the recurrence times of large earthquakes. The spring-block model has been related to other relevant properties of seismic phenomena, such as the fractal distribution of fault sizes, and can be combined with the work of Aki, who established an interesting relationship between the fractal dimension and the b -value of the Gutenberg-Richter relationship. Also included is the work incorporating the idea of asperities, which allowed us to incorporate several inhomogeneous models in the spring-block automaton. Finally, the incorporation of a Ruff-Kanamori-type diagram for synthetic seismicity, which is in reasonable accordance with the original Ruff and Kanamori diagram for real seismicity, is discussed.

Background: Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long-term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954) evaluated the safety and efficacy of NIVO + IPI in a cohort that included patients with aRCC and brain metastases, as reported here., Methods: Patients with previously untreated aRCC and asymptomatic brain metastases received NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × 4 followed by NIVO 480 mg every 4 weeks. The primary end point was the incidence of grade ≥3 immune-mediated adverse events (imAEs) within 100 days of the last dose of study drug. Key secondary end points were progression-free survival and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (both determined by the investigator). Exploratory end points included overall survival, among others., Results: After a minimum follow-up of 24.5 months (N = 28), no grade 5 imAEs occurred. The most common grade 3 and 4 imAEs were diarrhea/colitis (n = 2; 7%) and hypophysitis, rash, hepatitis, and diabetes mellitus (n = 1 each; 4%). The objective response rate was 32% (95% CI, 14.9%-53.5%) with a median duration of response of 24.0 months; 4 of 8 responders remained without reported progression. Seven patients (25%) had intracranial progression. The median progression-free survival was 9.0 months (95% CI, 2.9-12.0 months), and the median overall survival was not reached (95% CI, 14.1 months to not estimable)., Conclusions: In patients who had previously untreated aRCC and brain metastases-a population with a high unmet medical need that often is underrepresented in clinical trials-the approved regimen of NIVO + IPI followed by NIVO showed encouraging antitumor activity and no new safety signals., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Targeted sequencing of circulating tumour DNA (ctDNA) is a promising tool to monitor dynamic changes in the variant allele frequencies (VAF) of genomic alterations and predict clinical outcomes in patients with advanced urothelial carcinoma (UC)., Methods: We performed targeted sequencing of 182 serial ctDNA samples from 53 patients with advanced UC., Results: Serial ctDNA-derived metrics predicted the clinical outcomes in patients with advanced UC. Combining serial ctDNA aggregate VAF (aVAF) values with clinical factors, including age, sex, and liver metastasis, improved the performance of prognostic models. An increase of the ctDNA aVAF by ≥1 in serial ctDNA samples predicted disease progression within 6 months in 90% of patients. The majority of patients with aVAFs ≤0.7 in three consecutive ctDNA samples achieved durable clinical responses (≥6 months)., Conclusions: Serial ctDNA analysis predicts disease progression and enables dynamic monitoring to guide precision medicine in patients with advanced UC., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC)., Methods and Materials: Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall survival (OS). A survey of treating physicians assessed reasons for treatment initiations and discontinuations., Results: Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8-not reached] months) versus pazopanib (39.0 [29.7-50.9] months) and sunitinib 26.2 [19.9-61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs. 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection., Conclusion: The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Renal replacement therapy (RRT) in cirrhotic patients encompasses a number of issues related to the particular characteristics of this population, especially in the intensive care unit (ICU) setting. The short-term prognosis of cirrhotic patients with acute kidney injury is poor, with a mortality rate higher than 65% in patients with RRT requirement, raising questions about the futility of its initiation. Regarding the management of the RRT itself, there is still no consensus with respect to the modality (continuous versus intermittent) or the anticoagulation required to improve the circuit life, which is shorter than similar at-risk populations, despite the altered haemostasis in traditional coagulation tests frequently found in these patients. Furthermore, volume management is one of the most complex issues in this cohort, where tools used for ambulatory dialysis have not yet been successfully reproducible in the ICU setting. This review attempts to shed light on the management of acute RRT in the critically ill cirrhotic population based on the current evidence and the newly available tools. We will discuss the timing of RRT initiation and cessation, the modality, anticoagulation and fluid management, as well as the outcomes of the RRT in this population, and provide a brief review of the albumin extracorporeal dialysis from the point of view of a nephrologist., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Purpose: The aim of this work is to review the published studies on radiation resistance mechanisms and molecular markers involved in different tumors. The revision has been focused in the last 5 years (2016-2021)., Conclusions: Radioresistance is a cause of concern as it causes failure of radiation therapy and subsequent tumor relapse. Combination chemotherapy and radiation therapy are clinically successful in treating many types of tumors. Despite continued improvements in cancer treatment, locoregional recurrence or metastatic spread continues to occur in a high proportion of patients after being treated with radiation therapy or combination treatments. There is strong evidence that cancer stem cells contribute to radiation resistance, contributing to treatment failure. The mechanisms of radiation resistance in different tumors are not fully understood. A better understanding of cancer stem cells and the associated signaling pathways that regulate radiation resistance will open up new strategies for treating cancer by radiation therapy. Radiation can damage malignant cells mainly by the induction of DNA double-strand breaks. However, in some tumors appear resistant cells that repopulate the tumor following therapy leading over time to the failure of the treatment. Native mechanisms and induced pathways are the cause of radiation resistance. It has been described that numerous molecular markers acting through numerous mechanisms of action involved in radiation resistance, such as apoptosis resistance, alterations of cell growth, proliferation and DNA repair, hypoxia, increase in invasiveness and migration capacity, cell cycle alterations, and expression of heat shock proteins, among others. Therefore, resistance to radiation is a multifactorial phenomenon that, in different cell types, occurs through different regulatory mechanisms in which different molecules intervene. Resistance can be acquired by altering different regulatory pathways in different tumors. The knowledge of radiation resistance markers could help in the classification and treatment of patients with more aggressive tumors.

In spite of the low frequency of COVID-19 associated bacterial coinfections, the rate of empiric antibiotic use varies between 70% and 90%. The primary objective of this study was to evaluate the impact of an antimicrobial stewardship program (ASP) on COVID-19 patients. The study design was an interrupted time series, assessing prevalence of antibiotic use, adequacy of treatment and antimicrobial consumption in adult patients hospitalized with COVID before the COVID-ASP implementation in June 2020, and on three subsequent periods (P2 in August 2020, P3 in October 2020 and P4 in June 2021). One hundred and one patients were included. Moderate and severe disease was more frequent in P2, P3, and P4 periods (p < 0.001). After the implementation we observed a significant reduction on ATM use (61% vs. 41% vs. 31.1% vs. 8.1%, p < 0.001), and macrolid combination therapy (17.3% vs. 19.2% vs. 10.8% vs. 1.4%, p = 0.03), and an increase of adequate use (37.5% vs. 46.9% vs. 69.9% vs. 66.6%, p = 0.039). Antimicrobial consumption by period in days of therapy (DOT)/1000 patient-day was 347.9 vs. 272.8 vs. 134.29 vs. 43.6 (p <0.001). We did not find any difference in intensive care unit transfer or mortality. COVID-ASP implementation was an effective strategy to reduce antimicrobial consumption and optimize antibiotic indications without affecting morbidity or mortality.

Due to the massive increase in non-ionizing radiation emitting devices, the social concern about the possible malignancy to its exposure has increased the research interest. The International Commission on Non-Ionizing Radiation Protection (ICNIRP) included the radiofrequency electromagnetic field (RF-EMF) of mobile phones on the category 2B as 'possibly' carcinogenic to humans. Epidemiological studies noticed a causal association between the exposure to RF-EMF and the incidence of brain neoplasm in different populations, since this is the organ with the highest specific absorption rate. The fact that so many of the ipsilateral tumors found are statistically significant with RF-EMF exposure provides weight suggesting causality. In this way, the higher the exposure (ipsilateral vs contralateral), the longer the cumulative exposure (hours of exposure) and the longer the latency (beyond 10 years); the greater the risk. In addition, considering together all of these parameters suggest a strong causality.

Background: Characterization of circulating tumor DNA (ctDNA) has been integrated into clinical practice. Although labs have standardized validation procedures to develop single locus tests, the efficacy of on-site plasma-based next-generation sequencing (NGS) assays still needs to be proved., Materials and Methods: In this retrospective study, we profiled DNA from matched tissue and plasma samples from 75 patients with cancer. We applied an NGS test that detects clinically relevant alterations in 33 genes and microsatellite instability (MSI) to analyze plasma cell-free DNA (cfDNA)., Results: The concordance between alterations detected in both tissue and plasma samples was higher in patients with metastatic disease. The NGS test detected 77% of sequence alterations, amplifications, and fusions that were found in metastatic samples compared with 45% of those alterations found in the primary tumor samples (p = .00005). There was 87% agreement on MSI status between the NGS test and tumor tissue results. In three patients, MSI-high ctDNA correlated with response to immunotherapy. In addition, the NGS test revealed an FGFR2 amplification that was not detected in tumor tissue from a patient with metastatic gastric cancer, emphasizing the importance of profiling plasma samples in patients with advanced cancer., Conclusion: Our validation experience of a plasma-based NGS assay advances current knowledge about translating cfDNA testing into clinical practice and supports the application of plasma assays in the management of oncology patients with metastatic disease. With an in-house method that minimizes the need for invasive procedures, on-site cfDNA testing supplements tissue biopsy to guide precision therapy and is entitled to become a routine practice., Implications for Practice: This study proposes a solution for decentralized liquid biopsy testing based on validation of a next-generation sequencing (NGS) test that detects four classes of genomic alterations in blood: sequence mutations (single nucleotide substitutions or insertions and deletions), fusions, amplifications, and microsatellite instability (MSI). Although there are reference labs that perform single-site comprehensive liquid biopsy testing, the targeted assay this study validated can be established locally in any lab with capacity to offer clinical molecular pathology assays. To the authors' knowledge, this is the first report that validates evaluating an on-site plasma-based NGS test that detects the MSI status along with common sequence alterations encountered in solid tumors., (© 2021 AlphaMed Press.)

Human exposure to bisphenol-A (BPA) is largely unavoidable because BPA is an environmental contaminant found in soil, water, food and indoor dust. The safety of authorized BPA amounts in consumer products is under question because new studies have reported adverse effects of BPA at doses far below that previously established by the NOAEL (50 μg/kg per day). To protect public health, the consequences of low-dose BPA exposure in different organs and organismal functions must be further studied to generate relevant data. This study attempted to investigate the effects and potential molecular mechanisms of short-term exposure to 1 μg/L BPA on zebrafish ovarian follicular development. We observed only minor changes at the histopathological level with a small (3 %) increase in follicular atresia. However, a shotgun proteomics approach indicated deep alterations in BPA-exposed ovarian cells, including induction of the oxidative stress response, metabolic shifts and degradome perturbations, which could drive oocytes towards premature maturation. Based on these results, it could be suggested that inadvertent exposure to small concentrations of BPA on a continuous basis causes alteration in biological processes that are essential for healthy reproduction., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bisphenol A (BPA) is used to produce plastic and plastic derived products in multitude of daily utensils, being one of the industrial compounds most widely used. This endocrine disrupting chemical (EDCs) is a well-known environmental pollutant released into the aquatic environment from industrial wastewater, sewage sludge or landfill leachate. Aromatases are considered potential targets of EDCs with characteristics that make them suitable biomarkers of exposure to their effects. The main objective of our study was to evaluate the expression of cyp19a aromatase as a toxicological endpoint after BPA exposure through the identification and assessment of alterations of the main cells responsible for cyp19a1a and cyp19a1b expression in the zebrafish ovary and brain using different concentrations of BPA in water. Immunohistochemistry was used to analyze the expression of these enzymes in female zebrafish exposed and not exposed to different concentrations of BPA (1, 10, 100 and 1000 μg / L) in water (n = 6/group) for 14 days. The results obtained in this study showed that the cyp19a aromatase system, involved in the synthesis of steroid compounds, is specially located in distinct oocyte stages in the ovary (cyp19a1a) and in radial glial cells of the brain (cyp19a1b). An overexpression of these aromatases was observed after BPA exposure in zebrafish, peaking from a concentration of 10 µg/L and showing to be good biomarkers of exposure to identify the early effects of low BPA concentrations. To our knowledge, this study is the first to localize and quantify the expression of cyp19a1a and cyp19a1b in the cells of brain and ovary after fish exposure to different BPA concentrations in water., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy., Objective: To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC., Design, Setting, and Participants: This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease., Intervention: Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily., Outcome Measurements and Statistical Analysis: The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method., Results and Limitations: The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12-45). Median PFS was 9.2 mo (95% CI 5.5-not estimable), and median OS was 15.6 mo (95% CI 9.2-not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design., Conclusions: Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination., Patient Summary: We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects., Clinical Registration: This trial is registered at ClinicalTrials.Gov as NCT02915783., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature., Methods: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ 2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival., Results: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST., Conclusions: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Introduction: Alexithymia is the difficulty in identifying and describing feelings. Several studies have suggested that chronic pain can be linked to alexithymia. The aims of this study were to determine the presence of alexithymia in a sample of Mexican individuals who attended public health services, to assess if alexithymia is higher in medically ill individuals with pain than in those without pain, and to determine which alexithymia dimensions are more affected by the presence of pain., Methods: Demographic and clinical features were evaluated in 250 Mexican outpatients of the General Hospital of Comalcalco, Tabasco. Pain was evaluated using the Visual Analogue Scale for Pain Assessment (VAS-P) and alexithymia was evaluated using the Toronto Alexithymia Scale (TAS-20)., Results: 38.8% of the sample was identified with probable/definite alexithymia and up to 61.2% of individuals were currently experiencing pain. Individuals with pain exhibited higher scores in the TAS-20 dimensions: difficulty describing feelings (p = 0.02), difficulty identifying feelings (p < 0.001) and higher total TAS-20 score (p < 0.001). Also, Probable/definite alexithymia was more frequently reported in individuals with pain (49% vs. 21.6%, p < 0.001)., Conclusions: Our results show that a large proportion of individuals who attend public health services in a Mexican population present pain. We also identified that pain could be associated with alexithymia, in particular with a difficulty in describing and identifying feelings. An early identification and treatment of alexithymia could help in reducing the clinical burden of chronic pain in Mexican outpatients.

Background: Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) has demonstrated efficacy and tolerability with a dose-response effect in phase I/II trials in men with metastatic castration-resistant prostate cancer (mCRPC). The need for positive PSMA imaging before PSMA-TRT to select patients is largely practiced, but its utility is not proven. Given target heterogeneity, developing a biomarker to identify the optimal patient population remains an unmet need. The aim of this study was to assess PSMA uptake by imaging and response to PSMA-TRT., Methods: We performed an analysis of men with mCRPC enrolled in sequential prospective phase I/II trials of PSMA-TRT. Each patient had baseline PSMA imaging by planar 111 In and/or 177 Lu SPECT (N = 171) or 68 Ga-PSMA-11 PET/CT (N = 44), but the results were not used to include/exclude treatment. Semiquantitative imaging scores (IS) on a 0-4 scale were assigned based on PSMA uptake in tumors compared to liver uptake. We compared the ≥50% PSA decline response proportions between low (0-1) and high (2-4) PSMA IS using the χ 2 -test. We used multivariable logistic regression analysis to understand the relationship between independent and dependent variables, including IS, radionuclide activity (dose) administered, CALGB (Halabi) prognostic risk score, prior taxane use., Results: 215 men with progressive mCRPC received PSMA-TRT as follows: 177 Lu-J591 (n = 137), 177 Lu-PSMA-617 (n = 44), 90 Y-J591 (n = 28), 177 Lu-J591 +  177 Lu-PSMA-617 (n = 6). High PSMA expression (IS 2-4) was found in 160 (74.4%) patients and was significantly associated with more frequent ≥ 50% PSA reduction (26.2 vs. 7.3%, p = .006). On multivariate logistic regression analysis, higher IS was associated with a ≥50% decrease in PSA, even after accounting for CALGB (Halabi) prognostic score, the dose administered, and previous taxane use (OR, 4.72; 95% CI, 1.71-16.85; p = .006). Patients with low PSMA expression (N = 55, 24.7%) were less likely to respond. Thirteen of 26 (50%) with no PSMA uptake (IS = 0) had post-PSMA-TRT PSA decline with 2 (7.7%) having ≥ 50% PSA declines., Conclusion: Collectively, the data provide evidence in favor of the hypothesis that patients with high PSMA uptake and high administered radionuclide dose correlate with a higher chance of response., (© 2021 Wiley Periodicals LLC.)

The aim of this study is to select a cisplatin-resistant Saccharomyces cerevisiae strain to look for new molecular markers of resistance and the identification of mechanisms/interactions involved. A resistant strain was obtained after 80 days of cisplatin exposure. Then, total protein extraction, purification, and identification were carried out, in wild-type (wt) and resistant strains, by tandem mass spectrometry using a "nano HPLC-ESI-MS/MS" ion trap system. The increase in the exponentially modified protein abundance index (emPAI) (resistant vs wt strains) was calculated to study the increase in protein expression. "Genemania" software ( http://www.Genemania.org/ ) was used to compare the effects, functions, and protein interactions. KEGG tool was used for metabolic pathway analysis. Data are available via ProteomeXchange with identifier PXD020665. The cisplatin-resistant strain showed 2.5 times more resistance than the wt strain for the inhibitory dose 50% (ID50) value (224 μg/ml vs 89.68 μg/ml) and 2.78 times more resistant for the inhibitory dose 90% (ID90) value (735.2 μg/ml vs 264.04 μg/ml). Multiple deregulated proteins were found in the glutathione and carbon metabolism, oxidative phosphorylation, proteasome, glycolysis and gluconeogenesis, glyoxylate metabolism, fatty acid degradation pathway, citric acid cycle, and ribosome. The most overexpressed proteins in the cisplatin-resistant strain were related to growth and metabolism (QCR2, QCR1, ALDH4, ATPB, ATPA, ATPG, and PCKA), cell structure (SCW10), and thermal shock (HSP26). The results suggest that these proteins could be involved in cisplatin resistance. The resistance acquisition process is complex and involves the activation of multiple mechanisms that interact together. KEY POINTS: • Identification of new proteins/genes related to cisplatin resistance • Increased expression of QCR2/QCR1/ALDH4/ATPB/ATPA/SCW10/HSP26/ATPG and PCKA proteins • Multiple molecular mechanisms that interact together are involved in resistance.

Phenolic compounds have antioxidant and anti-inflammatory properties and may prevent inflammation and oxidative stress as well as help the athletes to recover from exercise-induced muscle damage (EIMD). Tart cherry (TC) and pomegranate (PG) are two fruits with high content of polyphenols. Their antioxidant and anti-inflammatory properties have recently attracted substantial interest for their potential to reduce strength loss and promote recovery from EIMD. The aims of this review are (1) to summarise the effects of tart cherry and pomegranate supplementation on oxidative stress, inflammation and recovery, and (2) to outline the differences found in supplementation with tart cherries or pomegranates. SPORTDiscus, PubMed, Web of Science and Scopus were searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis and 25 studies were included. The existing evidence suggests that both types of supplementation are good strategies to accelerate recovery of functional performance variables, perceptual variables and inflammation but PG supplementation shows better recovery of oxidative stress. However, positive effects are more likely: 1) when supplementation starts some days before muscle damage is induced and finishes some days after, for a total period of at least 8/10 days, 2) with pronounced muscle damage of the muscles involved, and 3) when total phenolic content is at least 1000 mg/day. This review may help to optimise TC or PG supplementation practice to improve post-exercise recovery., (Copyright © 2020 Termedia.)