Enhancing chimeric antigen receptor T cell therapy by modulating the p53 signaling network with Δ133p53α.

Chimeric antigen receptor (CAR) T cell dysfunction is a major barrier to achieving lasting remission in hematologic cancers, especially in chronic lymphocytic leukemia (CLL). We have shown previously that Δ133p53α, an endogenous isoform of the human TP53 gene, decreases in expression with age in human T cells, and that reconstitution of Δ133p53α in poorly functional T cells can rescue proliferation [A. M. Mondal et al., J. Clin. Invest. 123, 5247-5257 (2013)]. Although Δ133p53α lacks a transactivation domain, it can form heterooligomers with full-length p53 and modulate the p53-mediated stress response [I. Horikawa et al., Cell Death Differ. 24, 1017-1028 (2017)]. Here, we show that constitutive expression of Δ133p53α potentiates the anti-tumor activity of CD19-directed CAR T cells and limits dysfunction under conditions of high tumor burden and metabolic stress. We demonstrate that Δ133p53α-expressing CAR T cells exhibit a robust metabolic phenotype, maintaining the ability to execute effector functions and continue proliferating under nutrient-limiting conditions, in part due to upregulation of critical biosynthetic processes and improved mitochondrial function. Importantly, we show that our strategy to constitutively express Δ133p53α improves the anti-tumor efficacy of CAR T cells generated from CLL patients that previously failed CAR T cell therapy. More broadly, our results point to the potential role of the p53-mediated stress response in limiting the prolonged antitumor functions required for complete tumor clearance in patients with high disease burden, suggesting that modulation of the p53 signaling network with Δ133p53α may represent a translationally viable strategy for improving CAR T cell therapy.

Exercise training adaptations in liver glycogen and glycerolipids require hepatic AMP-activated protein kinase in mice.

Regular exercise elicits adaptations in glucose and lipid metabolism that allow the body to meet energy demands of subsequent exercise bouts more effectively and mitigate metabolic diseases including fatty liver. Energy discharged during the acute exercise bouts that comprise exercise training may be a catalyst for liver adaptations. During acute exercise, liver glycogenolysis and gluconeogenesis are accelerated to supply glucose to working muscle. Lower liver energy state imposed by gluconeogenesis and related pathways activates AMP-activated protein kinase (AMPK), which conserves ATP partly by promoting lipid oxidation. This study tested the hypothesis that AMPK is necessary for liver glucose and lipid adaptations to training. Liver-specific AMPKα1α2 knockout (AMPKα1α2fl/fl+AlbCre) mice and littermate controls (AMPKα1α2fl/fl) completed sedentary and exercise training protocols. Liver nutrient fluxes were quantified at rest or during acute exercise following training. Liver metabolites and molecular regulators of metabolism were assessed. Training increased liver glycogen in AMPKα1α2fl/fl mice, but not in AMPKα1α2fl/fl+AlbCre mice. The inability to increase glycogen led to lower glycogenolysis, glucose production, and circulating glucose during acute exercise in trained AMPKα1α2fl/fl+AlbCre mice. Deletion of AMPKα1α2 attenuated training-induced declines in liver diacylglycerides. In particular, training lowered the concentration of unsaturated and elongated fatty acids comprising diacylglycerides in AMPKα1α2fl/fl mice, but not in AMPKα1α2fl/fl+AlbCre mice. Training increased liver triacylglycerides and the desaturation and elongation of fatty acids in triacylglycerides of AMPKα1α2fl/fl+AlbCre mice. These lipid responses were independent of differences in tricarboxylic acid cycle fluxes. In conclusion, AMPK is required for liver training adaptations that are critical to glucose and lipid metabolism.NEW & NOTEWORTHY This study shows that the energy sensor and transducer, AMP-activated protein kinase (AMPK), is necessary for an exercise training-induced: 1) increase in liver glycogen that is necessary for accelerated glycogenolysis during exercise, 2) decrease in liver glycerolipids independent of tricarboxylic acid (TCA) cycle flux, and 3) decline in the desaturation and elongation of fatty acids comprising liver diacylglycerides. The mechanisms defined in these studies have implications for use of regular exercise or AMPK-activators in patients with fatty liver.

Disruption of hepatic mitochondrial pyruvate and amino acid metabolism impairs gluconeogenesis and endurance exercise capacity in mice.

Exercise robustly increases the glucose demands of skeletal muscle. This demand is met by not only muscle glycogenolysis but also accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose. Herein, we examined the effects of interrupting hepatic gluconeogenic efficiency and capacity on exercise performance by deleting mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in the liver of mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or postexercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in hepatocytes (double knockout, DKO) reached exhaustion faster and exhibited lower circulating glucose during and after exercise. Use of 2H/1³C metabolic flux analyses demonstrated that DKO mice exhibited lower endogenous glucose production owing to decreased glycogenolysis and gluconeogenesis at rest and during exercise. Decreased gluconeogenesis was accompanied by lower anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings demonstrate that the transition of the liver to the gluconeogenic mode is critical for preventing hypoglycemia and sustaining performance during exercise. The results also illustrate the need for interorgan cross talk during exercise as described by the Cahill and Cori cycles.NEW & NOTEWORTHY Martino and colleagues examined the effects of inhibiting hepatic gluconeogenesis on exercise performance and systemic metabolism during treadmill exercise in mice. Combined inhibition of gluconeogenesis from lactate/pyruvate and alanine impaired exercise endurance and led to hypoglycemia during and after exercise. In contrast, suppressing either pyruvate-mediated or alanine-mediated gluconeogenesis alone had no effect on these parameters. These findings provide new insight into the molecular nodes that coordinate the metabolic responses of muscle and liver during exercise.

The landscape of etiological patterns of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in Thailand.

Thailand is among countries with the highest global incidence and mortality rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). While viral hepatitis and liver fluke infections have been associated with HCC and iCCA, respectively, other environmental risk factors, overall risk factor commonality and combinatorial roles, and effects on survival have not been systematically examined. We conducted a TIGER-LC consortium-based population study covering all high-incidence areas of both malignancies across Thailand: 837 HCC, 1474 iCCA, and 1112 controls (2011-2019) were comprehensively queried on lifelong environmental exposures, lifestyle, and medical history. Multivariate logistic regression and Cox proportional hazards analyses were used to evaluate risk factors and associated survival patterns. Our models identified shared risk factors between HCC and iCCA, such as viral hepatitis infection, liver fluke infection, and diabetes, including novel and shared associations of agricultural pesticide exposure (OR range of 1.50; 95% CI: 1.06-2.11 to 2.91; 95% CI: 1.82-4.63) along with vulnerable sources of drinking water. Most patients had multiple risk factors, magnifying their risk considerably. Patients with lower risk levels had better survival in both HCC (HR 0.78; 95% CI: 0.64-0.96) and iCCA (HR 0.84; 95% CI: 0.70-0.99). Risk factor co-exposures and their common associations with HCC and iCCA in Thailand emphasize the importance for future prevention and control measures, especially in its large agricultural sector. The observed mortality patterns suggest ways to stratify patients for anticipated survivorship and develop plans to support medical care of longer-term survivors, including behavioral changes to reduce exposures.

Photochemical Povarov-type Reactions: Electron Donor-Acceptor Photoactivation by Visible Light.

This report investigates the mechanism of photochemical Povarov-type reactions of N,N-dialkylanilines and maleimides in polar solvents (DMF or dioxane) in the presence of light. Fundamental aspects of the electron donor-acceptor (EDA) photoactivation pathway proposed to underpin this chemistry are examined through integrated experimental and computational studies. This approach provided evidence supporting the involvement of an EDA complex in facilitating this chemistry via a reaction mechanism that does not involve a triplet manifold. Most notably, our findings indicate that relying solely on UV-vis absorption spectroscopic data to either account for or predict reactivity in synthetic experiments may not always provide the complete picture. More specifically, this relates to considering UV-vis absorption spectroscopic data, calculated values for association constants (KEDA) and molar extinction coefficients (ε), with the reactivity observed in associated synthetic reactions in practice.

Challenges and gaps in immunosafety evaluation of therapeutics: An IQ DruSafe survey.

Immunotoxicology/immunosafety science is rapidly evolving, with novel modalities and immuno-oncology among the primary drivers of new tools and technologies. The Immunosafety Working Group of IQ/DruSafe sought to better understand some of the key challenges in immunosafety evaluation, gaps in the science, and current limitations in methods and data interpretation. A survey was developed to provide a baseline understanding of the needs and challenges faced in immunosafety assessments, the tools currently being applied across the industry, and the impact of feedback received from regulatory agencies. This survey also focused on current practices and challenges in conducting the T-cell-dependent antibody response (TDAR) and the cytokine release assay (CRA). Respondents indicated that ICH S8 guidance was insufficient for the current needs of the industry portfolio of immunomodulators and novel modalities and should be updated. Other challenges/gaps identified included translation of nonclinical immunosafety assessments to the clinic, and lack of relevant nonclinical species and models in some cases. Key areas of emerging science that will add future value to immunotoxicity assessments include development of additional in vitro and microphysiological system models, as well as application of humanized mouse models. Efforts are ongoing in individual companies and consortia to address some of these gaps and emerging science.

Contamination of depressional wetlands in the Mpumalanga Lake District of South Africa near a global emission hotspot.

The Mpumalanga Lake District (MLD) of South Africa hosts a regionally unique cluster of water bodies of great importance for wetland biodiversity. It is also located close to a global hotspot for coal-fired power station emissions but the local impacts from these sources of pollution are poorly understood. Sediment cores from three contrasting wetlands were 210Pb dated and analysed for a range of contaminants linked to fossil fuel combustion, including trace elements, Hg, sulphur and spheroidal carbonaceous fly-ash particles (SCPs). At the two sites with pre-industrial (1900) baseline sediments, Pb, Zn and especially Cr concentrations and fluxes showed significant increases in the impact period (post-1975). Mercury showed the greatest proportional increase in flux (>4-fold) of all trace metals. Mercury and sulphur concentrations and fluxes showed highly significant correlations with emissions over the corresponding periods, while SCPs in sediments also closely tracked emissions. In a global context, levels of sediment contamination are relatively minor compared with other heavily industrialised regions, with only Cr exceeding the sediment Probable Effects Concentration for biological impact post-1975. Despite the relatively large increases in Hg, concentrations do not reach the Threshold Effects Concentration. The unexpectedly low levels of contamination may be due to i) low levels of many trace contaminants in South African coals compared to global averages, ii) prevailing recirculation patterns which transport pollution away from the study area during the wet season, minimising wet deposition, and iii) pollutant remobilisation through desiccation of wetlands or volatilization. The effects of hydrology and sediment accumulation rates lead to differential transport and preservation of organic-associated and more volatile contaminants (e.g. Hg, S) relative to non-volatile trace elements in wetlands of the MLD. The greatest fluxes of Hg and S are recorded in the site with the highest catchment: lake area ratio, lowest salinity and greatest sediment organic matter content.

Acridine-based copper(I) PNP pincer complexes: catalysts for alkyne hydroboration and borylation of aryl halides.

PNP pincers represent some of the most well-studied ligand systems in coordination chemistry owing to their high thermal and chemical stability, and the predictable metal coordination geometries of associated metal complexes. Examples of first-row transition metal complexes bearing acridine-based PNP pincer ligands are extremely rare. This study reports the preparation and structural authentication of acridine-based copper(I) PNP complexes, which reveal the profound effects that the steric bulk of methylene-tethered P-substituents has on metal centre coordination number and geometry. The capacity of these systems to mediate copper-catalysed alkyne hydroboration and the borylation of aryl halides is also investigated.

Correction: Acridine-based copper(I) PNP pincer complexes: catalysts for alkyne hydroboration and borylation of aryl halides.

Correction for 'Acridine-based copper(I) PNP pincer complexes: catalysts for alkyne hydroboration and borylation of aryl halides' by Angus Olding et al., Dalton Trans., 2024, 53, 4471-4478, https://doi.org/10.1039/D3DT04269C.

Distinct functions of wild-type and R273H mutant Δ133p53α differentially regulate glioblastoma aggressiveness and therapy-induced senescence.

Despite being mutated in 92% of TP53 mutant cancers, how mutations on p53 isoforms affect their activities remain largely unknown. Therefore, exploring the effect of mutations on p53 isoforms activities is a critical, albeit unexplored area in the p53 field. In this article, we report for the first time a mutant Δ133p53α-specific pathway which increases IL4I1 and IDO1 expression and activates AHR, a tumor-promoting mechanism. Accordingly, while WT Δ133p53α reduces apoptosis to promote DNA repair, mutant R273H also reduces apoptosis but fails to maintain genomic stability, increasing the risks of accumulation of mutations and tumor's deriving towards a more aggressive phenotype. Furthermore, using 2D and 3D spheroids culture, we show that WT Δ133p53α reduces cell proliferation, EMT, and invasion, while the mutant Δ133p53α R273H enhances all three processes, confirming its oncogenic potential and strongly suggesting a similar in vivo activity. Importantly, the effects on cell growth and invasion are independent of mutant full-length p53α, indicating that these activities are actively carried by mutant Δ133p53α R273H. Furthermore, both WT and mutant Δ133p53α reduce cellular senescence in a senescence inducer-dependent manner (temozolomide or radiation) because they regulate different senescence-associated target genes. Hence, WT Δ133p53α rescues temozolomide-induced but not radiation-induced senescence, while mutant Δ133p53α R273H rescues radiation-induced but not temozolomide-induced senescence. Lastly, we determined that IL4I1, IDO1, and AHR are significantly higher in GBMs compared to low-grade gliomas. Importantly, high expression of all three genes in LGG and IL4I1 in GBM is significantly associated with poorer patients' survival, confirming the clinical relevance of this pathway in glioblastomas. These data show that, compared to WT Δ133p53α, R273H mutation reorientates its activities toward carcinogenesis and activates the oncogenic IL4I1/IDO1/AHR pathway, a potential prognostic marker and therapeutic target in GBM by combining drugs specifically modulating Δ133p53α expression and IDO1/Il4I1/AHR inhibitors.

Hyperventilation During Manual Ventilation Can Be Reduced Using a Novel Ventilator but Not With Education Interventions.

INTRODUCTION: Traumatic brain injury (TBI) is the leading cause of combat casualties in modern war with an estimated 20% of casualties experiencing head injury. Since the release of the Brain Trauma Foundation's Guidelines for the Management of Severe Traumatic Brain Injury in 1995, recommendations for management of TBI have included the avoidance of routine hyperventilation. However, both published and anecdotal data suggest that many patients with TBI are inappropriately ventilated during transport, thereby increasing the risk of morbidity and mortality from secondary brain injury. MATERIALS AND METHODS: Enlisted Air Force personnel with prior emergency medical technician training completing a 3-week trauma course were evaluated on their ability to provide manual ventilation. Participants provided manual ventilation using either an in-situ endotracheal tube (ETT) or standard face mask on a standardized simulated patient manikin with TBI on the first and last days of the course. Manual ventilation was provided via a standard manual ventilator and a novel manual ventilator designed to limit tidal volume (VT) and respiratory rate (RR). Participants were given didactic and hands-on training on the third day of the course. Half of the participants were given simulator feedback during the hands-on training. All students provided 2 minutes of manual ventilation with each respirator. Data were collected on the breath-to-breath RR, VT, and peak airway pressures generated by the participant for each trial and were averaged for each trial. A minute ventilation (MV) was then derived from the calculated RR and VT. RESULTS: One hundred fifty-six personnel in the trauma course were evaluated in this study. Significant differences were found in the participant's performance with manual ventilation with the novel compared to the traditional ventilator. Before training, MV with the novel ventilator was less than with the traditional ventilator by 2.1 ± 0.4 L/min (P = .0003) and 1.6 ± 0.5 L/min (P = .0489) via ETT and face mask, respectively. This effect persisted after training with a difference between the devices of 1.8 ± 0.4 L/min (P = .0069) via ETT. Both traditional education interventions (didactics with hands-on training) and simulator-based feedback did not make a significant difference in participant's performance in delivering MV. CONCLUSIONS: The use of a novel ventilator that limits RR and VT may be useful in preventing hyperventilation in TBI patients. Didactic education and simulator-based feedback training may not have significant impact on improving ventilation practices in prehospital providers.

Gender-based heterogeneity of FAHFAs in trained runners.

Fatty acid esters of hydroxy fatty acid (FAHFA) are anti-diabetic and anti-inflammatory lipokines. Recently FAHFAs were also found to predict cardiorespiratory fitness in a cross-sectional study of recreationally trained runners. Here we report the influences of body composition and gender on static FAHFA abundances in circulation. We compared the association between circulating FAHFA concentrations and body composition, determined by dual x-ray absorptiometry, in female recreational runners who were lean (BMI < 25 kg/m2, n = 6), to those who were overweight (BMI ≥ 25 kg/m2, n = 7). To characterize the effect of gender we also compared circulating FAHFAs in lean male recreational runners (n = 8) to recreationally trained lean female (n = 6) runner group. Circulating FAHFAs were increased in females in a manner that was modulated by specific adipose depot sizes, blood glucose, and lean body mass. As expected, circulating FAHFAs were diminished in the overweight group, but strikingly, within the lean cohort, increases in circulating FAHFAs were promoted by increased fat mass, relative to lean mass, while the overweight group showed a significantly attenuated relationship. These studies suggest multimodal regulation of circulating FAHFAs and raise hypotheses to test endogenous FAHFA dynamic sources and sinks in health and disease, which will be essential for therapeutic target development. Baseline circulating FAHFA concentrations could signal sub-clinical metabolic dysfunction in metabolically healthy obesity.

Prognostic Significance of CD163+ and/or CD206+ Tumor-Associated Macrophages Is Linked to Their Spatial Distribution and Tumor-Infiltrating Lymphocytes in Breast Cancer.

Tumor-associated macrophages (TAMs) is a key element in the breast tumor microenvironment. CD163 and CD206 have been utilized for TAM identification, but the clinical implications of TAMs identified by these markers have not been thoroughly explored. This study conducted a comparative analysis of CD163 and CD206 TAMs using digital image analysis, focusing on their spatial distribution and prognostic significance in relation to tumor-infiltrating lymphocytes (TILs). Distinct clinico-pathological and prognostic characteristics were noted between the two types of TAMs. CD163 TAMs were linked to high-grade tumors (p = 0.006), whereas CD206 TAMs were associated with a higher incidence of nodal metastasis (p = 0.033). CD206 TAMs were predominantly found in the stroma, with more cases being stromal CD206-high (sCD206-high) than tumoral CD206-high (tCD206-high) (p = 0.024). Regarding prognostication, patients stratified according to stromal and tumoral densities of CD163 showed different disease-free survival (DFS) time. Specifically, those that were sCD163-low but tCD163-high exhibited the poorest DFS (chi-square = 10.853, p = 0.013). Furthermore, a high sCD163-to-stromal-TILs ratio was identified as an independent predictor of unfavorable survival outcomes (DFS: HR = 3.477, p = 0.018). The spatial distribution and interactions with TILs enhanced the prognostic value of CD163 TAMs, while CD206 TAMs appeared to have limited prognostic utility in breast cancer cases.

Acidovorax temperans skews neutrophil maturation and polarizes Th17 cells to promote lung adenocarcinoma development.

Change within the intratumoral microbiome is a common feature in lung and other cancers and may influence inflammation and immunity in the tumor microenvironment, affecting growth and metastases. We previously characterized the lung cancer microbiome in patients and identified Acidovorax temperans as enriched in tumors. Here, we instilled A. temperans in an animal model driven by mutant K-ras and Tp53. This revealed A. temperans accelerates tumor development and burden through infiltration of proinflammatory cells. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic phenotype with increased cytokine signaling, with a global shift away from IL-1ß signaling. Neutrophil to monocyte and macrophage signaling upregulated MHC II to activate CD4+ T cells, polarizing them to an IL-17A+ phenotype detectable in CD4+ and γδ populations (T17). These T17 cells shared a common gene expression program predictive of poor survival in human LUAD. These data indicate bacterial exposure promotes tumor growth by modulating inflammation.

Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Nonsmokers and Tobacco Smokers.

PURPOSE: Nonsmokers account for 10% to 13% of all lung cancer cases in the United States. Etiology is attributed to multiple risk factors including exposure to secondhand smoking, asbestos, environmental pollution, and radon, but these exposures are not within the current eligibility criteria for early lung cancer screening by low-dose CT (LDCT). EXPERIMENTAL DESIGN: Urine samples were collected from two independent cohorts comprising 846 participants (exploratory cohort) and 505 participants (validation cohort). The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA), were analyzed and quantified using liquid chromatography-mass spectrometry to determine if nonsmoker cases can be distinguished from sex and age-matched controls in comparison with tobacco smoker cases and controls, potentially leading to more precise eligibility criteria for LDCT screening. RESULTS: Urinary levels of CR and NANA were significantly higher and comparable in nonsmokers and tobacco smoker cases than population controls in both cohorts. Receiver operating characteristic analysis for combined CR and NANA levels in nonsmokers of the exploratory cohort resulted in better predictive performance with the AUC of 0.94, whereas the validation cohort nonsmokers had an AUC of 0.80. Kaplan-Meier survival curves showed that high levels of CR and NANA were associated with increased cancer-specific death in nonsmokers as well as tobacco smoker cases in both cohorts. CONCLUSIONS: Measuring CR and NANA in urine liquid biopsies could identify nonsmokers at high risk for lung cancer as candidates for LDCT screening and warrant prospective studies of these biomarkers.

Identification of intracellular bacteria from multiple single-cell RNA-seq platforms using CSI-Microbes.

The study of the tumor microbiome has been garnering increased attention. We developed a computational pipeline (CSI-Microbes) for identifying microbial reads from single-cell RNA sequencing (scRNA-seq) data and for analyzing differential abundance of taxa. Using a series of controlled experiments and analyses, we performed the first systematic evaluation of the efficacy of recovering microbial unique molecular identifiers by multiple scRNA-seq technologies, which identified the newer 10x chemistries (3' v3 and 5') as the best suited approach. We analyzed patient esophageal and colorectal carcinomas and found that reads from distinct genera tend to co-occur in the same host cells, testifying to possible intracellular polymicrobial interactions. Microbial reads are disproportionately abundant within myeloid cells that up-regulate proinflammatory cytokines like IL1Β and CXCL8, while infected tumor cells up-regulate antigen processing and presentation pathways. These results show that myeloid cells with bacteria engulfed are a major source of bacterial RNA within the tumor microenvironment (TME) and may inflame the TME and influence immunotherapy response.

Cell Context Is the Third Axis of Synergy for the Combination of ATR Inhibition and Cisplatin in Ewing Sarcoma.

PURPOSE: The importance of cellular context to the synergy of DNA damage response (DDR)-targeted agents is important for tumors with mutations in DDR pathways, but less well-established for tumors driven by oncogenic transcription factors. In this study, we exploit the widespread transcriptional dysregulation of the EWS-FLI1 transcription factor to identify an effective DDR-targeted combination therapy for Ewing sarcoma. EXPERIMENTAL DESIGN: We used matrix drug screening to evaluate synergy between a DNA-PK inhibitor (M9831) or an ATR inhibitor (berzosertib) and chemotherapy. The combination of berzosertib and cisplatin was selected for broad synergy, mechanistically evaluated for Ewing sarcoma selectivity, and optimized for in vivo schedule. RESULTS: Berzosertib combined with cisplatin demonstrates profound synergy in multiple Ewing sarcoma cell lines at clinically achievable concentrations. The synergy is due to loss of expression of the ATR downstream target CHEK1, loss of cell-cycle check-points, and mitotic catastrophe. Consistent with the goals of the project, EWS-FLI1 drives the expression of CHEK1 and five other ATR pathway members. The loss of CHEK1 expression is not due to transcriptional repression and instead caused by degradation coupled with suppression of protein translation. The profound synergy is realized in vivo with a novel optimized schedule of this combination in subsets of Ewing sarcoma models, leading to durable complete responses in 50% of animals bearing two different Ewing sarcoma xenografts. CONCLUSIONS: These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule. See related commentary by Ohmura and Grünewald, p. 3358.

Pan-viral serology uncovers distinct virome patterns as risk predictors of hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

This study evaluates the pan-serological profiles of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) compared to several diseased and non-diseased control populations to identify risk factors and biomarkers of liver cancer. We used phage immunoprecipitation sequencing, an anti-viral antibody screening method using a synthetic-phage-displayed human virome epitope library, to screen patient serum samples for exposure to over 1,280 strains of pathogenic and non-pathogenic viruses. Using machine learning methods to develop an HCC or iCCA viral score, we discovered that both viral scores were positively associated with several liver function markers in two separate at-risk populations independent of viral hepatitis status. The HCC score predicted all-cause mortality over 8 years in patients with chronic liver disease at risk of HCC, while the viral hepatitis status was not predictive of survival. These results suggest that non-hepatitis viral infections may contribute to HCC and iCCA development and could be biomarkers in at-risk populations.

Various pyrethroids on bednets and curtains

Verandah trap huts in Tanzania village were used to assess the effectiveness if impregnated bednets and curtains in preventing hut entry and feeding by, and in killing of, Anopheles gambiae and An. funestus. Permethrin, deltamethrin, lambdacyhalothrin and pyrethrum were used for impregnation of damaged or undamaged bednets, sisal eaves curtains or bed curtains made of polypropylene fibre. The performance of the synthetic pyrethroids did not differ statistically significantly, except that on a damage net permethrin was better at preventing feeding. sisal eaves curtains deterred mosquitoes from hut entry but did not kill those that had entered. In assessing damaged nets and curtains it must be recognised that anything less than the best vector control may have no appreciable impact on holoendemic malaria