A combination of protein phosphatase 2A inhibition and checkpoint immunotherapy: a perfect storm.

Immune checkpoint blockade has emerged as a potent new tool in the war on cancer. However, only a subset of cancer patients benefit from this therapeutic modality, sparking a search for combination therapies to increase the fraction of responding patients. We argue here that inhibition of protein phosphatase 2A (PP2A) is a promising approach to increase responses to immune checkpoint blockade and other therapies that rely on the presence of tumor-reactive T cells. Inhibition of PP2A increases neoantigen expression on tumor cells, activates the cGAS/STING pathway, suppresses regulatory T cells, and increases cytotoxic T cell activation. In preclinical models, inhibition of PP2A synergizes with immune checkpoint blockade and emerging evidence indicates that patients who have tumors with mutations in PP2A respond better to immune checkpoint blockade. Therefore, inhibition of PP2A activity may be an effective way to sensitize cancer cells to immune checkpoint blockade and cell-based therapies using tumor-reactive T cells.

Unraveling the structural aspects of microwave-assisted OrganoCat-based coconut shell lignins: An eco-friendly route for obtaining bio-based antioxidants.

New routes for biomass valorization have been developing by the scientific community. The aim of this work was developing a novel OrganoCat-based protocol and deeply understand the structure of the obtained lignins. Microwave-assisted OrganoCat-based process was performed using a biphasic system (ethyl acetate and oxalic acid or HCl) at mild conditions. OrganoCat-based lignins (OCLs) were characterized by compositional analysis, FTIR, 1H, 13C, 1H13C HSQC, 31P NMR, TGA and GPC. The solubility of OCLs in different organic solvents and their antioxidant capacity against DPPH were investigated. The spectroscopic analyses showed that OCLs have high residual extractives and the lignin motifs were preserved. OCLs have presented lower thermal stability than MWL, but showed great antioxidant activities and high solubility in a wide range of organic solvents. A novel biorefinery protocol yielded coconut shell lignins with peculiar structural and compositional features and several technological applications through an eco-friendly, sustainable and relatively low-cost biphasic pulping process.

The case for therapeutic overactivation of oncogenic signaling as a potential cancer treatment strategy.

Most targeted cancer drugs inhibit the oncogenic signals to which cancer cells are addicted. We discuss here a counterintuitive approach to cancer therapy, which consists of deliberate overactivation of the oncogenic signals to overload the stress responses of cancer cells. We discuss why such overactivation of oncogenic signaling, combined with perturbation of the stress response pathways, can be potentially effective in killing cancer cells, aiming to inspire further discussion and consideration.

Sodium overload during postnatal phases impairs diastolic function and exacerbates reperfusion arrhythmias in adult rats.

Sodium overload during childhood impairs baroreflex sensitivity and increases arterial blood pressure and heart rate in adulthood; these effects persist even after high-salt diet (HSD) withdrawal. However, the literature lacks details on the effects of HSD during postnatal phases on cardiac ischemia/reperfusion responses in adulthood. The current study aimed to elucidate the impact of HSD during infancy adolescence on isolated heart function and cardiac ischemia/reperfusion responses in adulthood. Male 21-day-old Wistar rats were treated for 60 days with hypertonic saline solution (NaCl; 0.3M; experimental group) or tap water (control group). Subsequently, both groups were maintained on a normal sodium diet for 30 days. Subsequently, the rats were euthanized, and their hearts were isolated and perfused according to the Langendorff technique. After 30 min of the basal period, the hearts were subjected to 20 min of anoxia, followed by 20 min of reperfusion. The basal contractile function was unaffected by HSD. However, HSD elevated the left ventricular end-diastolic pressure during reperfusion (23.1 ± 5.2 mmHg vs. 11.6 ± 1.4 mmHg; p < 0.05) and increased ectopic incidence period during reperfusion (208.8 ± 32.9s vs. 75.0 ± 7.8s; p < 0.05). In conclusion, sodium overload compromises cardiac function after reperfusion events, diminishes ventricular relaxation, and increases the severity of arrhythmias, suggesting a possible arrhythmogenic effect of HSD in the postnatal phases.

The phosphatase inhibitor LB-100 creates neoantigens in colon cancer cells through perturbation of mRNA splicing.

Perturbation of protein phosphorylation represents an attractive approach to cancer treatment. Besides kinase inhibitors, protein phosphatase inhibitors have been shown to have anti-cancer activity. A prime example is the small molecule LB-100, an inhibitor of protein phosphatases 2A/5 (PP2A/PP5), enzymes that affect cellular physiology. LB-100 has proven effective in pre-clinical models in combination with immunotherapy, but the molecular underpinnings of this synergy remain understood poorly. We report here a sensitivity of the mRNA splicing machinery to phosphorylation changes in response to LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. Altered phosphorylation endows LB-100-treated colorectal adenocarcinoma cells with differential splicing patterns. In PP2A-inhibited cells, over 1000 events of exon skipping and intron retention affect regulators of genomic integrity. Finally, we show that LB-100-evoked alternative splicing leads to neoantigens that are presented by MHC class 1 at the cell surface. Our findings provide a potential explanation for the pre-clinical and clinical observations that LB-100 sensitizes cancer cells to immune checkpoint blockade.

Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor-suppressive resistance. Significance: A therapy consisting of deliberate hyperactivation of oncogenic signaling combined with perturbation of the stress responses that result from this is very effective in animal models of colon cancer. Resistance to this therapy is associated with loss of oncogenic signaling and reduced oncogenic capacity, indicative of tumor-suppressive drug resistance.

Small-molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in KRAS-mutant cancers.

The Kirsten rat sarcoma viral oncogene homologue KRAS is among the most commonly mutated oncogenes in human cancers, thus representing an attractive target for precision oncology. The approval for clinical use of the first selective inhibitors of G12C mutant KRAS therefore holds great promise for cancer treatment. However, despite initial encouraging clinical results, the overall survival benefit that patients experience following treatment with these inhibitors has been disappointing to date, pointing toward the need to develop more powerful combination therapies. Here, we show that responsiveness to KRASG12C and pan-RAS inhibitors in KRAS-mutant lung and colon cancer cells is limited by feedback activation of the parallel MAP2K4-JNK-JUN pathway. Activation of this pathway leads to elevated expression of receptor tyrosine kinases that reactivate KRAS and its downstream effectors in the presence of drug. We find that the combination of sotorasib, a drug targeting KRASG12C, and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of KRASG12C-mutant lung and colon cancer cells. Moreover, combining HRX-0233 and sotorasib is well-tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung cancer cells, suggesting a therapeutic strategy for KRAS-driven cancers.

Potential of NIR spectroscopy for predicting cellulose nanofibril quality in commercial bleached Kraft pulp of Eucalyptus.

Multivariate models were developed to classify cellulose nanofibril (CNF) fibrillation by a quality index from near infrared (NIR) spectra. Commercial pulps of Eucalyptus spp. were used to produce cellulose nanofibrils by means of a fibrillator mill. After each of the five passes through the mill, samples were collected and analyzed for energy consumption and fiber classification. As a standard, pulps were oxidized with TEMPO reagent followed by a single pass through the mill to compare the resulting quality of CNFs produced by each method. NIR spectra of CNFs were associated with quality indices determined by conventional laboratory analyses that included morphology, turbidity, mechanical properties, X-ray diffraction and quality index measurements. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were applied to the spectral and experimental data. Fibrillator milling to obtain CNFs was efficient and resulted in gel formation following the third pass through the mill. NIR spectroscopy combined with PLS-DA was used successfully to create a model to classify quality of CNFs with 96 % certainty in 3 wt% solutions. These findings suggest that NIR spectroscopy holds promise for estimating CNF quality in suspension, particularly in real-time industrial applications where reliable estimates are crucial.

Utilization of rice production residues as a reinforcing agent in bioadhesives based on polyphenols extracted from the bark of trees from the Brazilian Cerrado biome.

The scarcity of nonrenewable resources and the increase in environmental pollution have intensified the search for materials that exhibit specific characteristics and are nontoxic, renewable, and sustainable. Thus, the objective of this work was to produce natural polyphenol adhesives reinforced with rice husk and its ash to increase the mechanical resistance and moisture resistance of the glue line in wood bonded joints. Polyphenols were extracted from the bark of Stryphnodendron adstringens (Mart.) Coville (barbatimão). Adhesives were produced with a 50 % solid and 50 % liquid composition. Rice husk and husk ash underwent X-ray fluorescence analysis (XRF). Adhesives and reinforcement material were characterized by Fourier transform infrared (FTIR) and thermogravimetric analyses (TGA). The adhesives were glued in a mechanical press in specimens made of Pinus elliottii, which were subjected to shear testing of the wet and dry glue line. As a result, the chemical components present in rice husk and its ash positively influenced the properties of the adhesives. The mechanical glue line shear test showed that the adhesive reinforced with rice husk ash did not show a statistically significant difference. However, natural adhesives based on polyphenols from barbatimão strengthened with rice husk and ash showed improved properties, demonstrating how much it pays to use the residue of rice production to reinforce the matrix of tannin adhesives. Thus, it can be determined that reinforcement with rice husk and ash is efficient in improving some properties of natural adhesives based on polyphenols.

Tonsils are major sites of persistence of SARS-CoV-2 in children.

In the present study, we show that SARS-CoV-2 can infect palatine tonsils, adenoids, and secretions in children without symptoms of COVID-19, with no history of recent upper airway infection. We studied 48 children undergoing tonsillectomy due to snoring/OSA or recurrent tonsillitis between October 2020 and September 2021. Nasal cytobrushes, nasal washes, and tonsillar tissue fragments obtained at surgery were tested by RT-qPCR, immunohistochemistry (IHC), flow cytometry, and neutralization assay. We detected the presence of SARS-CoV-2 in at least one specimen tested in 27% of patients. IHC revealed the presence of the viral nucleoprotein in epithelial surface and in lymphoid cells in both extrafollicular and follicular regions, in adenoids and palatine tonsils. Also, IHC for the SARS-CoV-2 non-structural protein NSP-16 indicated the presence of viral replication in 53.8% of the SARS-CoV-2-infected tissues. Flow cytometry showed that CD20+ B lymphocytes were the most infected phenotypes, followed by CD4+ lymphocytes and CD123 dendritic cells, CD8+ T lymphocytes, and CD14+ macrophages. Additionally, IF indicated that infected tonsillar tissues had increased expression of ACE2 and TMPRSS2. NGS sequencing demonstrated the presence of different SARS-CoV-2 variants in tonsils from different tissues. SARS-CoV-2 antigen detection was not restricted to tonsils but was also detected in nasal cells from the olfactory region. Palatine tonsils and adenoids are sites of prolonged RNA presence by SARS-CoV-2 in children, even without COVID-19 symptoms. IMPORTANCE This study shows that SRS-CoV-2 of different lineages can infect tonsils and adenoids in one quarter of children undergoing tonsillectomy. These findings bring advancement to the area of SARS-CoV-2 pathogenesis, by showing that tonsils may be sites of prolonged infection, even without evidence of recent COVID-19 symptoms. SARS-CoV-2 infection of B and T lymphocytes, macrophages, and dendritic cells may interfere with the mounting of immune responses in these secondary lymphoid organs. Moreover, the shedding of SARS-CoV-2 RNA in respiratory secretions from silently infected children raises concern about possible diagnostic confusion in the presence of symptoms of acute respiratory infections caused by other etiologies.

Bone health education programs for older people: an integrative review. / Programas de educação sobre saúde óssea para idosos: uma revisão integrativa.

Osteoporosis is a systemic disease characterized by a reduction in bone mineral density. The dissemination of knowledge about the disease can be a viable alternative for promoting preventive behavior and self-care. This study sought to identify the main characteristics of bone health programs for older persons. We conducted an integrative review, searching for studies published between 2011 and 2022 in the CAPES periodicals database, Web of Science, PubMed, and Google Scholar using English descriptors. A total of 10,093 studies were retrieved, seven of which were selected after applying the inclusion criteria. The findings show that bone health education programs aim to empower older people by increasing knowledge about the disease and raising awareness about calcium and vitamin D intake, osteoporosis medications, and the importance of changing habits and exercise. Programs generally consist of group or individual meetings, with sessions lasting 50 to 60 minutes. Class sizes may be limited or unrestricted. Follow-up during the educational process was also found to be important. Tailoring topics to the reality and interests of participants appears to be another positive way of promoting the adoption of self-care practices.

A osteoporose é uma doença sistêmica caracterizada pela redução da densidade mineral óssea. A difusão do conhecimento sobre à doença, pode ser uma alternativa viável para atitudes preventivas e de autocuidado. Dessa forma, esse artigo procura identificar como são os programas sobre saúde óssea para idosos. Trata-se de uma revisão integrativa de estudos publicados entre 2011 e 2022 nas bases de dados Periódicos Capes, Web of Science, PubMed e Google Scholar em inglês. Foram encontrados 10.093 estudos, sendo selecionados 7 depois dos critérios de inclusão. Foi possível verificar que os programas de educação para saúde óssea possuem o objetivo de empoderar o idoso pelo aumento do conhecimento sobre a doença, conscientizar sobre o consumo de cálcio e vitamina D ou de medicamentos para osteoporose, mudanças de hábitos e a prática de exercícios físicos. Os programas geralmente são realizados com reuniões em grupo ou individualizados, com sessões de 50 a 60 minutos, podendo ou não, delimitar o número de indivíduos em cada uma delas. Nota-se que acompanhar a evolução do processo educativo também é importante. A contextualização dos temas junto a realidade e interesse dos idosos, parece ser outra forma positiva para despertar atitudes de autocuidado.

Programas de educação sobre saúde óssea para idosos: uma revisão integrativa / Bone health education programs for older people: an integrative review

Resumo A osteoporose é uma doença sistêmica caracterizada pela redução da densidade mineral óssea. A difusão do conhecimento sobre à doença, pode ser uma alternativa viável para atitudes preventivas e de autocuidado. Dessa forma, esse artigo procura identificar como são os programas sobre saúde óssea para idosos. Trata-se de uma revisão integrativa de estudos publicados entre 2011 e 2022 nas bases de dados Periódicos Capes, Web of Science, PubMed e Google Scholar em inglês. Foram encontrados 10.093 estudos, sendo selecionados 7 depois dos critérios de inclusão. Foi possível verificar que os programas de educação para saúde óssea possuem o objetivo de empoderar o idoso pelo aumento do conhecimento sobre a doença, conscientizar sobre o consumo de cálcio e vitamina D ou de medicamentos para osteoporose, mudanças de hábitos e a prática de exercícios físicos. Os programas geralmente são realizados com reuniões em grupo ou individualizados, com sessões de 50 a 60 minutos, podendo ou não, delimitar o número de indivíduos em cada uma delas. Nota-se que acompanhar a evolução do processo educativo também é importante. A contextualização dos temas junto a realidade e interesse dos idosos, parece ser outra forma positiva para despertar atitudes de autocuidado.

Abstract Osteoporosis is a systemic disease characterized by a reduction in bone mineral density. The dissemination of knowledge about the disease can be a viable alternative for promoting preventive behavior and self-care. This study sought to identify the main characteristics of bone health programs for older persons. We conducted an integrative review, searching for studies published between 2011 and 2022 in the CAPES periodicals database, Web of Science, PubMed, and Google Scholar using English descriptors. A total of 10,093 studies were retrieved, seven of which were selected after applying the inclusion criteria. The findings show that bone health education programs aim to empower older people by increasing knowledge about the disease and raising awareness about calcium and vitamin D intake, osteoporosis medications, and the importance of changing habits and exercise. Programs generally consist of group or individual meetings, with sessions lasting 50 to 60 minutes. Class sizes may be limited or unrestricted. Follow-up during the educational process was also found to be important. Tailoring topics to the reality and interests of participants appears to be another positive way of promoting the adoption of self-care practices.

Transmastoid/Infralabyrinthine Approach to the Jugular Foramen: 2-Dimensional Operative Video.

INDICATIONS CORRIDOR AND LIMITS OF EXPOSURE: This approach is intended for tumors centered in the jugular foramen with extensions between intracranial and extracranial spaces, possible spread to the middle ear, and variable bony destruction. 1,2. ANATOMIC ESSENTIALS NEED FOR PREOPERATIVE PLANNING AND ASSESSMENT: Jugular foramen paragangliomas are complex lesions that usually invade and fill related venous structures. They present complex relationships with skull base neurovascular structures as internal carotid artery, lower cranial nerves (CNs), middle ear, and mastoid segment of facial nerve. In this way, it is essential to perform an adequate preoperative vascular study to evaluate sinus patency and the tumor blood supply, besides a computed tomography scan to depict bone erosion. ESSENTIAL STEPS OF THE PROCEDURE: Mastoidectomy through an infralabyrinthine route up to open the lateral border of jugular foramen, allowing exposure from the sigmoid sinus to internal jugular vein. Skeletonization of facial canal without exposure of facial nerve is performed and opening of facial recess to give access to the middle ear in way of a fallopian bridge technique. 2-10. PITFALLS/AVOIDANCE OF COMPLICATIONS: If there is preoperative preservation of lower CN function, it is important to not remove the anteromedial wall of the internal jugular vein and jugular bulb. In addition, facial nerve should be exposed just in case of preoperative facial palsy to decompress or reconstruct the nerve. VARIANTS AND INDICATIONS FOR THEIR USE: Variations are related mainly with temporal bone drilling depending on the extensions of the lesion, its source of blood supply, and preoperative preservation of CN function.Informed consent was obtained from the patient for the procedure and publication of his image.Anatomy images were used with permission from:• Ceccato GHW, Candido DNC, and Borba LAB. Infratemporal fossa approach to the jugular foramen. In: Borba LAB and de Oliveira JG. Microsurgical and Endoscopic Approaches to the Skull Base. Thieme Medical Publishers. 2021.• Ceccato GHW, Candido DNC, de Oliveira JG, and Borba LAB. Microsurgical Anatomy of the Jugular Foramen. In: Borba LAB and de Oliveira JG. Microsurgical and Endoscopic Approaches to the Skull Base. Thieme Medical Publishers. 2021.

Effect of different pre-treatments on the redispersion capacity of spray-dried microfibrillated cellulose: Elaboration and characterization of biofilms.

This study aimed to evaluate the influence of the addition of the cationic surfactant cetyltrimethylammonium bromide (CTAB) in microfibrillated cellulose (MFC/CNFs) suspensions submitted to different pretreatments to produce redispersible spray-dried (SD) MFC/CNFs. Suspensions pretreated with 5 % and 10 % sodium silicate and oxidized with 2,2,6,6,-tetramethylpiperidinyl-1-oxyl (TEMPO) were modified with CTAB surfactant and subsequently dried by SD. The SD-MFC/CNFs aggregates were redispersed by ultrasound to produce cellulosic films by the casting method. In summary, the results demonstrated that the addition of CTAB surfactant to the TEMPO-oxidized suspension was critical to achieving the most effective redispersion. The experimental results obtained using micrographs, optical (UV-Vis), mechanical, water vapor barrier properties, and the quality index confirmed that the addition of CTAB to the TEMPO-oxidized suspension favored the redispersion of spray-dried aggregates, development of cellulosic films with attractive properties, offering possibilities for the elaboration of new products, for example, in the production of bionanocomposites with higher mechanical performance. This research brings interesting insights into the redispersion and application of SD-MFC/CNFs aggregates, strengthening the commercialization of MFC/CNFs for industrial use.

Substitution of petrochemical compounds for polyphenols of natural origin reinforced with cellulose nanofibrils to formulate adhesives for wood bonding.

Vegetable tannins are excellent options to produce adhesives for the panel industry since they have the capacity to reduce formaldehyde emissions and are derived from renewable sources. They also allow for the possibility of increasing the resistance of the glue line through the use of natural reinforcements such as cellulose nanofibrils. Condensed tannins, polyphenols isolated from tree bark, are widely studied for the production of natural adhesives as an alternative to commercial synthetic adhesives. So, the purpose of our research is to show a natural adhesive alternative for wood bonding. Therefore, the objective of the study was to evaluate the quality of tannin adhesives of different species reinforced with different nanofibrils and thus predict which adhesive is the most promising at different concentrations of reinforcement and with different types of polyphenols. To meet this objective, polyphenols were extracted from the bark, nanofibrils were obtained, and both processes followed the current standards. Then, the adhesives were produced, their properties were characterized, and they were chemically analyzed via Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). A mechanical shear analysis of the glue line was also performed. According to the results, the addition of cellulose nanofibrils affected the physical properties of the adhesives, mostly the content of solids and the gel time. In the FTIR spectra, the OH band of the 5% Pinus and 5% Eucalyptus (EUC) TEMPO in the barbatimao adhesive and the 5% EUC of the cumate red adhesive were reduced, possibly due to their higher moisture resistance. Mechanical tests of the glue line showed that barbatimao with 5% Pinus and cumate red with 5% EUC performed best in the dry and wet shear tests. The control was the best-performing sample in the test of the commercial adhesives. The cellulose nanofibrils used as reinforcement did not change the thermal resistance of the adhesives. Therefore, the addition of cellulose nanofibrils to these tannins is an interesting means of increasing the mechanical strength, as occurred in commercial adhesive with 5% EUC. Thus, the physical and mechanical properties of tannin adhesives were better with reinforcement, making it possible to expand the use of these adhesives in the panel industry. At the industrial level, it is important to replace synthetic products with natural ones. Besides environmental and health issues, there is the question of the value of petroleum-based products, which have been widely studied so that they can be replaced.

Post-partum depression: From clinical understanding to preclinical assessments.

Post-partum depression (PPD) with varying clinical manifestations affecting new parents remains underdiagnosed and poorly treated. This minireview revisits the pharmacotherapy, and relevant etiological basis, capable of advancing preclinical research frameworks. Maternal tasks accompanied by numerous behavioral readouts demand modeling different paradigms that reflect the complex and heterogenous nature of PPD. Hence, effective PPD-like characterization in animals towards the discovery of pharmacological intervention demands research that deepens our understanding of the roles of hormonal and non-hormonal components and mediators of this psychiatric disorder.

Mandacaru cactus as a source of nanofibrillated cellulose for nanopaper production.

In this work, nanofibrillated cellulose (NFC) was extracted from cactus Cereus jamacaru DC. (mandacaru) for nanopaper production. The technique adopted includes alkaline treatment, bleaching, and grinding treatment. The NFC was characterized according to its properties and scored based on a quality index. Particle homogeneity, turbidity, and microstructure of the suspensions were evaluated. Correspondingly, the optical and physical-mechanical properties of the nanopapers were investigated. The chemical constituents of the material were analyzed. The sedimentation test and the zeta potential analyzed the stability of the NFC suspension. The morphological investigation was performed using environmental scanning electron microscopy (ESEM) and transmission electron microscopy (TEM). X-ray diffraction (XRD) analysis revealed that Mandacaru NFC has high crystallinity. Thermogravimetric analysis (TGA) and mechanical analysis were also used and revealed good thermal stability and good mechanical properties of the material. Therefore, the application of mandacaru is interesting in sectors such as packaging and electronic device development, as well as in composite materials. Given its score of 72 points on a quality index, this material was presented as an attractive, facile, and innovative source for obtaining NFC.

Comparison of pre-treatments mediated by endoglucanase and TEMPO oxidation for eco-friendly low-cost energy production of cellulose nanofibrils.

Specific kinds of enzymes have been used as an eco-friendly pre-treatment for mechanical extraction of cellulose nanofibrils (CNFs) from vegetal pulps. Another well-established pre-treatment is the 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-mediated oxidation, which has gained considerable attention. Pre-treatments assist in fiber swelling, facilitating mechanical fibrillation, and reducing energy consumption; however, some of these methods are extremely expensive. This work aimed to evaluate the influence of enzymatic pre-treatment with endoglucanase on the energy consumption during mechanical fibrillation of cellulose pulps. Bleached pulps from Eucalyptus sp. and Pinus sp. were pre-treated with endoglucanase enzyme compared to TEMPO-meditated oxidation. Average diameters of CNFs pre-treated with enzymes were close to that found for TEMPO-oxidized nanofibrils (TOCNFs). Results showed that enzymatic pre-treatment did not significantly modify the pulp chemical and morphological characteristics with efficient stabilization of the CNFs suspension at higher supernatant turbidity. Energy consumption of pulps treated with endoglucanase enzymes was lower than that shown by pulps treated with TEMPO, reaching up to 58% of energy savings. The enzyme studied in the pulp treatment showed high efficiency in reducing energy consumption during mechanical fibrillation and production of films with high mechanical quality, being an eco-friendly option for pulp treatment.

cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis.

Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies; however, this remains challenging due to a lack of broadly acting senolytic drugs. Using CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify loss of the death receptor inhibitor cFLIP as a common vulnerability of senescent cancer cells. Senescent cells are primed for apoptotic death by NF-κB-mediated upregulation of death receptor 5 (DR5) and its ligand TRAIL, but are protected from death by increased cFLIP expression. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of a variety of senescent cancer cells. Moreover, senescent cells sensitize adjacent non-senescent cells to killing by DR5 agonist through a bystander effect mediated by secretion of cytokines. We validate this 'one-two punch' cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.