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BackgroundCOVID-19 is a complex multisystem disease, frequently associated with kidney injury. Since the beginning of the COVID-19 pandemic, we observed a striking increase in the incidence of acute tubulointerstitial nephritis (aTIN) without or with uveitis (TINUs) among children. This prompted us to examine whether SARS-CoV-2 might be the underlying trigger.MethodsWe conducted a French nationwide retrospective cohort study. We included all consecutive children diagnosed with aTIN or TINUs of undetermined cause between April-2020 and March-2021. SARS-CoV-2 antibody responses were tested by a luciferase immunoprecipitation system and compared to age-matched controls. Immunohistochemistry, immunofluorescence and molecular microbiology analyses were performed on kidney biopsies.ResultsForty-eight children were included with a median age at diagnosis of 14.7 years (9.4-17.6). aTIN and TINUs incidence rates increased 3-fold and 12-fold, respectively, compared to pre-pandemic years. All patients had impaired kidney function with a median eGFR of 31.9 ml/min/1.73m² at diagnosis. Kidney biopsies showed lesions of acute tubulointerstitial nephritis and 25% of patients had fibrosis. No patient had concomitant acute COVID-19. All 16 children tested had high anti-N IgG titers and one had anti-S IgGs. Next-generation sequencing failed to detect any infectious agents in kidney biopsies. However, SARS-CoV-2 RNA was detected by PCR in two kidney samples supporting a potential direct link between SARS-CoV-2 and aTIN/TINUs.ConclusionsWe describe a novel form of post-acute COVID-19 syndrome in children, unique in its exclusive kidney and eye involvement, and its distinctive anti-SARS-CoV-2 N+/S-serological profile. Our results support a causal association linking SARS-CoV-2 infection to this newly-reported burst of renal/eye inflammation.

Purpose In selected ADPKD patients, a nephrectomy is required in the work-up for a kidney transplantation. Because the impact of this procedure is unknown, we investigated the effect of pre-transplantation nephrectomy on quality of life in this group. Methods In this retrospective cohort study all ADPKD patients, ≥ 18 years, who received a kidney transplantation in 2 ADPKD expertise centers between January 2000 and January 2016, were asked to participate. Quality of life was assessed using three validated questionnaires on three time points. Nephrectomy was performed in preparation for transplantation. Results Two hundred seventy-six ADPKD patients (53 ± 9 years, 56.2% male) were included. 98 patients (35.5%) underwent native nephrectomy in preparation for transplantation, of which 43 underwent bilateral nephrectomy. Pre-transplantation, ADPKD-IS scores were worse in the nephrectomy group vs. no-nephrectomy group (physical: 2.9 vs. 2.3, p p = 0.03; fatigue: 3.0 vs. 2.3, p = 0.01). Post-transplantation and post-nephrectomy, ADPKD-IS scores improved significantly in both groups, with a significantly higher improvement in the nephrectomy group. During follow-up, all scores were still better compared to pre-transplantation. Observed physical QoL (ADPKD-IS physical 1.3 vs. 1.7, p = 0.04; SF-36 physical 50.0 vs. 41.3, p = 0.03) was better post-transplantation after bilateral nephrectomy compared to unilateral nephrectomy. In retrospect, 19.7% of patients would have liked to undergo a nephrectomy, while the decision not to perform nephrectomy was made by the treating physician. Conclusion This study shows that pre-transplantation nephrectomy improves quality of life in selected ADPKD patients. Bilateral nephrectomy may be preferred, although the risk of additional complications should be weighted.

OBJECTIVE: We evaluated the public health impact and return on investment of Belgium's pediatric immunization program (PIP) from both healthcare-sector and societal perspectives. METHODS: We developed a decision analytic model for 6 vaccines routinely administered in Belgium for children aged 0-10 years: DTaP-IPV-HepB-Hib, DTaP-IPV, MMR, PCV, rotavirus, and meningococcal type C. We used separate decision trees to model each of the 11 vaccine-preventable pathogens: diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type b, measles, mumps, rubella, Streptococcus pneumoniae, rotavirus, and meningococcal type C; hepatitis B was excluded because of surveillance limitations. The 2018 birth cohort was followed over its lifetime. The model projected and compared health outcomes and costs with and without immunization (based on vaccine-era and pre-vaccine era disease incidence estimates, respectively), assuming that observed reductions in disease incidence were fully attributable to vaccination. For the societal perspective, the model included productivity loss costs associated with immunization and disease in addition to direct medical costs. The model estimated discounted cases averted, disease-related deaths averted, life-years gained, quality-adjusted life-years gained, costs (2020 euros), and an overall benefit-cost ratio. Scenario analyses considered alternate assumptions for key model inputs. RESULTS: Across all 11 pathogens, we estimated that the PIP prevented 226,000 cases of infections and 200 deaths, as well as the loss of 7,000 life-years and 8,000 quality-adjusted life-years over the lifetime of a birth cohort of 118,000 children. The PIP was associated with discounted vaccination costs of €91 million from the healthcare-sector perspective and €122 million from the societal perspective. However, vaccination costs were more than fully offset by disease-related costs averted, with the latter amounting to a discounted €126 million and €390 million from the healthcare-sector and societal perspectives, respectively. As a result, pediatric immunization was associated with overall discounted savings of €35 million and €268 million from the healthcare-sector and societal perspectives, respectively; every €1 invested in childhood immunization resulted in approximately €1.4 in disease-related cost savings to the health system and €3.2 in cost savings from a societal perspective for Belgium's PIP. Estimates of the value of the PIP were most sensitive to changes in input assumptions for disease incidence, productivity losses due to disease-related mortality, and direct medical disease costs. CONCLUSION: Belgium's PIP, which previously had not been systematically assessed, provides large-scale prevention of disease-related morbidity and premature mortality, and is associated with net savings to health system and society. Continued investment in the PIP is warranted to sustain its positive public health and financial impact. ispartof: Frontiers In Public Health vol:11 ispartof: location:Switzerland status: Published online

Use of pharmaceutical products has seen a tremendous increase in the recent decades. It has been observed that more than thirty million tons of pharmaceuticals are consumed worldwide. The used pharmaceutical products are not completely metabolized in human and animal body. Therefore, they are excreted to the environment and remain there as persistent organic chemicals. These compounds emerge as toxic contaminants in water and affect the human metabolism directly or indirectly. This literature review is an endeavour to understand the origin, applications and current advancement in the removal of pharmaceuticals from the environment. It discusses about the pharmaceuticals used in medical applications such diagnosis and disease treatment. In addition, it discusses about the recent approaches applied in pharmaceutical removal including microbial fuel cells, biofiltration, and bio nanotechnology approaches. Moreover, the challenges associated with pharmaceutical removal are presented considering biological and environmental factors. The review suggest the potential recommendations on pharmaceutical removal., The corresponding author Prof. Vinay Kumar is thankful to all the co-authors for their collaborative efforts in writing this paper. This work was supported by Department of Community Medicine, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India.

The whole world had suffered the Covid-19 pandemic and most countries had practiced social distancing and Movement Control Orders (MCO) for a variable duration on time. Because of MCO, educational institutions including universities had to shift to online learning. This dramatic change in the mode of learning is expected to affect the students’ academic performance. This research aimed to explore the students’ reflection regarding the online mode of learning and to detect if this affected their academic performance. A cross-sectional study has been implemented among students of the International Medical School, Management and Science University, Malaysia through an online questionnaire distributed in April 2020 investigating the students’ demographic characteristics and the effectiveness of online learning from their point of view. The results regarding the students’ perception of the effectiveness of online learning, showed that 30.4% of the students agreed that the discussion during online learning was depth and comprehensive. 41.8% of the students agreed that they had discussed more and used more resources during online learning. 23.2% of the students agreed that they learned better through online learning while 19.6% agreed that they learned better through online learning. Regarding participation and interaction during online learning, 25.8% agreed on that online learning promotes more participation and interaction while 42.3% of the students agreed that it was difficult for them to ask and to answer questions through online learning. 45.9% of the students suffered technical issues during the online learning session, and 33.5% of the students required more budget for internet connection. 41.8% agreed that there was an increased distraction during the online session. And 35.1% of the students agreed that it was harder for them to be motivated during the online session. These results are representing this period of time which is one month after the start of MCO, and more research is needed to be implemented after the students get used to the new normal mode of learning.

There is currently an urgent demand to reuse waste heat from industrial processes with approaches that require minimal investment and low cost of operation. Thermoacoustic generator (TAG) is a device that converts heat energy into useful work through the use of acoustic wave, porous media (honeycomb ceramic celcor) and heat exchangers that are all enclosed in a custom-defined resonator. This paper reports the basic design of thermoacoustic generator that is tested using a design software known as a Design Environmental for Low-amplitude Thermoacoustic Energy Conversion (DeltaEC). Many studies have highlighted the relationships between the geometry of the stack and the performance of the device. In this study, attention is given on the impact of the length of stack which was found to be the best at a length of 0.6 m when the frequency of the flow is at 127.4 Hz. Performance indicators like the acoustic power and the temperature difference across the stack have been used to analyse the results. The result shows that the highest acoustic power can be achieved when the generator that work with air at an atmospheric pressure is designed with a resonator of 2.14 m long and a stack with a length of 0.6 m. The maximum value for acoustic power is predicted to be as much as 24.01 kW.

Agriculture intensification is increasing due to food demand and consumption patterns. Intensive agriculture is based on management that promotes the maximum profit per unit of area and involves agrochemicals, irrigation and heavy machinery. The purpose is to have high crop yields and livestock productivity. This practice's implications are increasing soil degradation and the loss of ecological functions and consequently to the detriment of ecosystem condition and services. Intensive agriculture practices are related to high erosion rates, soil compaction, pollution (e.g., pesticides, herbicides, heavy metals, pharmaceuticals), nitrification and acidification, loss of fertility and productivity, desertification, diffuse pollution, ground and surface water contamination, land fragmentation, loss of biodiversity, greenhouse gases emission, air pollution and ultimately human impact. All these effects contribute dramatically to global environmental change. Soils are the base of life. Therefore, such intensive use will induce rapid degradation. This is a global reality. Shreds of evidence from the world are plentiful: Tropical rainforests destruction in Amazonia, Congo Basin and southeast Asia due to the establishment of agriculture plantations or livestock farms, irrigation in semi-arid or arid areas of central Asia and Saudi Arabia and acidification in Northeast Europe. All these forms of soil degradation have negative implications on soil ecosystem services. For instance, agriculture intensification affects multiple regulating ecosystem services. The soil loses the capacity to regulate erosion, floods, water purification, and carbon storage, contribute to microclimate regulation, and combat pests and diseases. It also hampers the soil's capacity to supply fodder, water, wild food and medicinal plants. Although crop yields may increase, intensive agriculture practices are not sustainable since they contribute to soil degradation. Without any intervention (e.g., fertilization), there will be a loss of fertility, and yields may be reduced. Also, diffuse pollution from agriculture contributes to surface water bodies' loss of biodiversity and ecosystem services. These areas are also key for food provisioning. Intensive agriculture also dramatically impacts cultural ecosystem services such as landscape aesthetics, recreation and heritage. We have many challenges ahead regarding the impacts of agriculture intensification, and it is key to halt and reduce their impacts on ecosystem services. We live in challenging times when food security needs to be ensured for a growing global population. How we can balance between food production and soil degradation? What practices are more adjusted in each context to ensure the sustainability of agroecosystems? These are key questions that need to be answered. Bottom line is that we need to develop practices to follow a sustainable path, instead of exhausting the ecosystems and their services at a dramatic pace. AcknowledgementsWe would like to acknowledge the support of the project Enhancing ecoSysteM sERvices mApping for poLicy and Decision mAking (SELINA), financed by the European Union’s Horizon Europe research and innovation programme under grant agreement No 101060415.

A comprehensive characterisation of extreme sea levels at different spatio-temporal scales is presented for the Western Mediterranean. The classical view of extreme sea levels as a consequence of the concurrence of storm events and high tides may lead to an incomplete picture for the Mediterranean coasts, where the tidal regime is small and processes operating at high frequencies can contribute significantly to extreme levels. Our approach bases on the analysis of tide gauge records with a high sampling frequency (1 minute), in order to consider other contributors beyond storm surges and tides. To have a basin-scale view, we first analyse the tide gauges operated by Puertos del Estado, which are distributed over all the Spanish Mediterranean coasts and cover at least from 2010 to 2022. Next, we focus on a more reduced domain to take advantage of the unprecedented spatio-temporal resolution of the VENOM tide gauge network, opering since 2020 in the Balearic archipelago. Last, we analyse the role of waves in local extreme sea level events by propagating waves towards the coast in the Bay of Palma. The wave run-up estimates are calculated considering the type of coastal protection and are used to simulate the potential flooding that could occur in the future under an unfavourable climate change scenario. Our results highlight the importance of high-frequency sea level records to study extreme events, and the key role of processes such as meteotsunamis and waves in the occurrence of extreme sea levels.

Gene therapeutics; Gold nanoparticles; Safety Terapia génica; Nanopartículas de oro; Seguridad Teràpia gènica; Nanopartícules d'or; Seguretat Introduction: Gene therapy holds promise to cure various diseases at the fundamental level. For that, efficient carriers are needed for successful gene delivery. Synthetic ‘non-viral’ vectors, as cationic polymers, are quickly gaining popularity as efficient vectors for transmitting genes. However, they suffer from high toxicity associated with the permeation and poration of the cell membrane. This toxic aspect can be eliminated by nanoconjugation. Still, results suggest that optimising the oligonucleotide complexation, ultimately determined by the size and charge of the nanovector, is not the only barrier to efficient gene delivery. Methods: We herein develop a comprehensive nanovector catalogue comprising different sizes of Au NPs functionalized with two different cationic molecules and further loaded with mRNA for its delivery inside the cell. Results and Discussion: Tested nanovectors showed safe and sustained transfection efficiencies over 7 days, where 50 nm Au NPs displayed the highest transfection rates. Remarkably, protein expression was increased when nanovector transfection was performed combined with chloroquine. Cytotoxicity and risk assessment demonstrated that nanovectors are safe, ascribed to lesser cellular damage due to their internalization and delivery via endocytosis. Obtained results may pave the way to design advanced and efficient gene therapies for safely transferring oligonucleotides. We acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (RTI2018-099965-B-I00, AEI/FEDER,UE) proyectos de I+D+i de programación conjunta internacional MCIN/AEI (CONCORD, PCI2019-103436) cofunded by the European Union and Generalitat de Catalunya (2017-SGR-1431). ICN2 is supported by the Severo Ochoa program from Spanish MINECO (SEV-2017-0706) and is funded by the CERCA Programme/Generalitat de Catalunya.

PDF file - 41KB, Dose response curve of PTX in MDA-MB-231 cells alone or in combination with E-3810, sunitinb and brivanib.

The DNA damage response (DDR) kinases ATR, Chk1, and Wee1 play vital roles in the response to replication stress and in maintaining cancer genomic stability. Inhibitors of these kinases are currently under clinical investigation. Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are aggressive lymphomas whose clinical outcome is still largely unsatisfactory. These cell lymphoma subtypes are highly dependent on both Chk1 and Wee1 for survival. We investigated the activity of the ATR inhibitor AZD6738 as single agent and in combination with either Chk1 (AZD6738) or Wee1 (AZD1775) inhibitors in several preclinical models of MCL and DLBCL. This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, and validation experiments on in vivo models. Cellular and molecular mechanisms of the observed synergistic effect as well as pharmacodynamic analysis of in vivo samples were studied. AZD6738 exerted a strong synergistic cytotoxic effect in combination with both AZD7762 and AZD1775 in the 2 lymphoma subtypes regardless of their TP53, MYC, and ATM mutational status. These DDR inhibitor combinations, similarly to the Chk1/Wee1 inhibitor combination, caused a marked S-phase delay, with an increase in cyclin-dependent kinases (CDK) activity, increased DNA damage, and decreases in Wee1, MYC, and RRM2 protein levels. The synergistic in vitro activity translated to striking in vivo antitumor activity. DDR–DDR inhibitor combinations could potentially offer promising novel therapeutic strategies for patients with B-cell lymphoma.

PDF file - 51KB, Body weights of MDA-MB-231 bearing mice treated with E-3810, 5FU, DDP and their combinations.

PDF file - 63KB, Circulating factors in plasma of mice bearing MDA-MB-231 tumors untreated or treated with E-3810 (E), brivanib (B), sunitinib (S), paclitaxel (PTX) and their combinations as described in Material amd Methods.

PDf file - 30KB, Survival curves of MDA-MB-231 bearing mice treated with E-3810, PTX and their combination.

GSEA of transcripts upregulated in cells with low sensitivity (non-responders) to AZD6738.

Primers used for real-time PCR on cDNA

GSEA of transcripts upregulated in cells with high sensitivity (responders) to AZD6738.

Supplementary Figure 1. Correlation analysis among the different drug IC50s; Supplementary Figure 2. AZD6738 IC50 in all the 36 B-cell lymphoma cells and their molecular characteristics; Supplementary Figure 3: Cell cycle and DNA damage protein levels in the different cell lines under study; Supplementary Figure 4: Correlation between drug IC50s and biomarkers of response; Supplementary Figure 5: Cell cycle perturbation induced by single and combined treatments with the inhibitors; Supplementary Figure 6: Biparametric analysis of pS10-Histone H3 and DNA in OCILY-7 cells untreated or 8, 24 and 48 h after treatment with the drug either singly or combined. Caspase-3 activity assay 8, 24 and 48h after treatment with the three drugs either singly or combined Real time PCR showing Myc, Wee1 and RRM2 expression levels after 24 and 48h of treatment with the drugs either singly or combined; Supplementary Figure 7: Body weights of mice transplanted with OCILY-7 xonografts treated or not with the single agents and with the combination. Tumor growth curves in OCILY-7 xenograft transplanted mice untreated or treated at a late stage; Supplementary Figure 8: Antitumor activity and pharmacodimamic markers of single and combined agents in JEKO1 xenografts

PDF file - 101KB

Supplementary Material and Methods

Supplementary Figure 5. Pearson's correlation coefficient across all EOCs.

Supplementary Figure 3. Comparative immunohistochemical analysis of xenografts at different passages.

Supplementary Figure 1. Histologic characteristics of the original patient tumors and corresponding EOC-xenografts.

Supplementary Table 1 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Supplementary Figure 2. Comparative immuno-histologic analysis of patient tumor and the corresponding xenograft.

Supplementary Figure 4. Gene copy number in patient and xenograft

Supplementary Figures 1-4 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Supplementary Information

Supplementary Table 2 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Supplementary Methods, Figure Legends 1-4 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

BackgroundIntra-articular (IA) combined with intra-osseous (IO) infiltration of plasma rich in growth factors (PRGF) have been proposed as an alternative approach to treat patients with severe osteoarthritis (OA) and subchondral bone damage. The aim of the study is to evaluate the efficacy of IO injections of PRGF to treat acute full depth chondral lesion in a rabbit model by using two histological validated scales (OARSI and ICRS II).MethodologyA total of 40 rabbits were included in the study. A full depth chondral defect was created in the medial femoral condyle and then animals were divided into 2 groups depending on the IO treatment injected on surgery day: control group (IA injection of PRGF and IO injection of saline) and treatment group (IA combined with IO injection of PRGF). Animals were euthanized 56 and 84 days after surgery and the condyles were processed for posterior histological evaluation.ResultsBetter scores were obtained in treatment group in both scoring systems at 56- and 84-days follow-up than in control group. Additionally, longer-term histological benefits have been obtained in the treatment group.ConclusionsThe results suggests that IO infiltration of PRGF enhances cartilage and subchondral bone healing more than the IA-only PRGF infiltration and provides longer-lasting beneficial effects.

Cyclin-dependent kinase 12 (CDK12) is a serine/threonine kinase involved in the regulation of RNA polymerase II and in the transcription of a subset of genes involved in the DNA damage response. CDK12 is one of the most mutated genes in ovarian carcinoma. These mutations result in loss-of-function and can predict the responses to PARP1/2 inhibitor and platinum. To investigate the role of CDK12 in ovarian cancer, CRISPR/Cas9 technology was used to generate a stable CDK12 knockout (KO) clone in A2780 ovarian carcinoma cells. This is the first report on a CDK12 null cell line. The clone had slower cell growth and was less clonogenic than parental cells. These data were confirmed in vivo, where CDK12 KO transplanted cells had a much longer time lag and slightly slower growth rate than CDK12-expressing cells. The slower growth was associated with a higher basal level of apoptosis, but there were no differences in the basal level of autophagy and senescence. While cell cycle distribution was similar in parental and knockout cells, there was a doubling in DNA content, with an almost double modal number of chromosomes in the CDK12 KO clone which, however did not display any increase in γH2AX, a marker of DNA damage. We found partial down-regulation of the expression of DNA repair genes at the mRNA level and, among the down-regulated genes, an enrichment in the G2/M checkpoint genes. Although the biological features of CDK12 KO cells are compatible with the function of CDK12, contrary to some reports, we could not find any difference in the sensitivity to cisplatin and olaparib between wild-type and CDK12 KO cells.

Biocompatible nanoparticles have been increasingly used in a variety of medical applications, including photodynamic therapy. Although the impact of synthesis parameters and purification methods is reported in previous studies, it is still challenging to produce a reliable protocol for the fabrication, purification, and characterization of nanoparticles in the 200-300 nm range that are highly monodisperse for biomedical applications.We investigated the synthesis of chitosan nanoparticles in the 200-300 nm range by evaluating the chitosan to sodium tripolyphosphate (TPP) mass ratio and acetic acid concentration of the chitosan solution. Chitosan nanoparticles were also crosslinked to rose bengal and incubated with human breast cancer cells (MCF-7) to test photodynamic activity using a green laser (λ = 532 nm, power = 90 mW).We established a simple protocol to fabricate and purify biocompatible nanoparticles with the most frequent size occurring between 200 and 300 nm. This was achieved using a chitosan to TPP mass ratio of 5:1 in 1% v/v acetic acid at a pH of 5.5. The protocol involved the formation of nanoparticle coffee rings that showed the particle shape to be spherical in the first approximation. Photodynamic treatment with rose bengal-nanoparticles killed ~98% of cancer cells.A simple protocol was established to prepare and purify spherical and biocompatible chitosan nanoparticles with a peak size of ~200 nm. These have remarkable antitumor activity when coupled with photodynamic treatment.

Immigrant communities in Chile face barriers to their integration, in the form of discrimination and social exclusion. Psychology of liberation claims that, when minority groups experience oppressing conditions, community engagement can be a path toward integration. Nevertheless, community participation has been mainly studied in North America and Europe. Through a concurrent nested mixed-method design, this study explores the relation between community engagement and perception of integration of Peruvian immigrants in Santiago de Chile. One hundred and ten Peruvians (age range 19 to 52 years), engaged in migrant organizations (MOs), completed a self-report questionnaire that aims to identify the predictors of integration based on psychosocial perspective (education), acculturation (national identity and ethnic identity), and liberation psychology literature (perceived institutional sensitivity, knowledge of the Chilean culture and laws). Additionally, 18 Peruvian leaders (ages 31 to 56 years) were interviewed in order to explore intergroup relations and organizational strategies that their MOs use to enhance integration. An interesting and novel finding points to the role of a Latin-American identity that appears to have potential negative consequences in maintaining the status quo for the social exclusion that Peruvians currently face.

PurposeThe DNA damage response (DDR) is the cellular process devoted to the preservation of an intact genome. The DDR is often deregulated in lymphoma cells due to high levels of DNA damage, tumor suppressor inactivation, increased replication stress observed after oncogene activation, or high amounts of reactive oxygen species. The ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial factor of DDR in the response to DNA single strand breaks. ATR inhibitors are a class of agents that have shown considerable clinical potential in this context.Experimental DesignWe characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a panel of lymphoma cell lines. Furthermore, we evaluated the activity of elimusertib in combination with the clinically approved PI3K inhibitor copanlisib inin vitroandin vivolymphoma models.ResultsElimusertib exhibitedin vitroactivity across a variety of lymphoma subtypes which was associated with expression of genes related to replication stress. Elimusertib also demonstrated wide-spread anti-tumor activity that was stronger compared to ceralasertib, another ATR inhibitor, in several tumor models. This activity was present in both DDR-proficient and DDR-deficient lymphoma models. Furthermore, elimusertib had synergistic antitumor activity in combination with copanlisib.ConclusionsPotent antitumor activity of elimusertib was demonstrated in several lymphoma models which is associated with high expression of gene transcripts coding for proteins that are involved in DDR and cell cycle regulation. Combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib had synergistic efficacy providing a potential new treatment option for lymphoma patients.Translational relevanceThe DNA damage response (DDR) is often deregulated in lymphoma cells. Here, we characterized the activity of elimusertib, an inhibitor of the ataxia telangiectasia and Rad3-related kinase (ATR) that is involved in the DDR. Elimusertib was demonstrated to exhibit anti-lymphoma activity across several lymphoma cell lines and tumor models. Copanlisib is an inhibitor of PI3K kinase family which has also shown activity in various lymphomas. Combined treatment with elimusertib and copanlisib resulted in a synergistic antitumor effect in lymphoma models. The combination of elimusertib and copanlisib could potentially constitute a new chemotherapy-free treatment option for lymphomas.

BH3 mimetics, targeting Bcl-2 family anti-apoptotic proteins, represent a promising therapeutic opportunity in tumors. ABT-199, the first specific Bcl-2 inhibitor, has been approved by FDA for treating several hematological malignancies. We have recently discovered IS21, a novel pan BH3 mimetic with preclinical anti-tumor activity in different cancers. This study aimed to evaluate the efficacy of different BH3 mimetics both as single agents, in a panel of different tumor cell histotypes, and in combination with the currently used target therapy in ovarian cancer and melanoma. Our results demonstrate that IS21 reduced the viability of T-cell acute lymphoblastic leukemia, melanoma, lung, pancreatic and ovarian cancer cell lines, and that Bcl-xL and Mcl-1 protein levels were markers of IS21 sensitivity in melanoma and ovarian cancer, respectively. Exploring the IS21 mechanism of action, we reported that IS21 activity was dependent on BAX and BAK proteins, and complexes between Bcl-2 and Bcl-xL proteins and their main binding partners were reduced by IS21. In combination experiments, BH3 mimetics sensitized ovarian cancer cells to the treatment with PARP inhibitors, while IS21 and ABT-199 synergized with MAPK inhibitors in melanoma models both in vitro and in vivo. Through different methodological approaches, we evidenced that the potentiating effect of BH3 mimetics was related to enhancement of apoptotic pathway, both in melanoma and ovarian cancer. In conclusion, our data suggest the use of inhibitors of the anti-apoptotic proteins as a possible therapeutic strategy to enhance the efficacy of target therapy in ovarian cancer and melanoma.

We explore novel examples of RG flows preserving a non-invertible duality symmetry. Our main focus is on $\mathcal{N}=1$ quadratic superpotential deformations of 4d $\mathcal{N}=4$ super-Yang-Mills theory with gauge algebra $\mathfrak{su}(N)$. A theory that can be obtained in this way is the so-called $\mathcal{N}=1^*$ SYM where all adjoint chiral multiplets have a mass. Such IR theory exhibits a rich structure of vacua which we thoroughly examine. Our analysis elucidates the physics of spontaneous breaking of self-duality symmetry occurring in the degenerate gapped vacua. The construction can be generalized, taking as UV starting point a theory of class $\mathcal{S}$, to demonstrate how non-invertible duality symmetries exist in a variety of $\mathcal{N}=1$ SCFTs. We finally apply this understanding to prove that the conifold theory has a non-invertible duality symmetry., Comment: 48 pages + appendices