Plasticity in the Functional Properties of NMDA Receptors Improves Network Stability during Severe Energy Stress.

Brain energy stress leads to neuronal hyperexcitability followed by a rapid loss of function and cell death. In contrast, the frog brainstem switches into a state of extreme metabolic resilience that allows them to maintain motor function during hypoxia as they emerge from hibernation. NMDA receptors (NMDARs) are Ca2+-permeable glutamate receptors that contribute to the loss of homeostasis during hypoxia. Therefore, we hypothesized that hibernation leads to plasticity that reduces the role of NMDARs within neural networks to improve function during hypoxia. To test this, we assessed a circuit with a large involvement of NMDAR synapses, the brainstem respiratory network of female bullfrogs, Lithobates catesbeianus Contrary to our expectations, hibernation did not alter the role of NMDARs in generating network output, nor did it affect the amplitude, kinetics, and hypoxia sensitivity of NMDAR currents. Instead, hibernation strongly reduced NMDAR Ca2+ permeability and enhanced desensitization during repetitive stimulation. Under severe hypoxia, the normal NMDAR profile caused network hyperexcitability within minutes, which was mitigated by blocking NMDARs. After hibernation, the modified complement of NMDARs protected against hyperexcitability, as disordered output did not occur for at least one hour in hypoxia. These findings uncover state-dependence in the plasticity of NMDARs, whereby multiple changes to receptor function improve neural performance during metabolic stress without interfering with their normal role during healthy conditions.

Sodium-glucose cotransporter 2 inhibition in primary and secondary glomerulonephritis.

BACKGROUND: The role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the management glomerular/systemic autoimmune diseases with proteinuria in real-world clinical settings is unclear. METHODS: This is a retrospective, observational, international cohort study. Adult patients with biopsy-proven glomerular diseases were included. The main outcome was the percentage reduction in 24-h proteinuria from SGLT2i initiation to 3, 6, 9 and 12 months. Secondary outcomes included percentage change in estimated glomerular filtration rate (eGFR), proteinuria reduction by type of disease and reduction of proteinuria ≥30% from SGLT2i initiation. RESULTS: Four-hundred and ninety-three patients with a median age of 55 years and background therapy with renin-angiotensin system blockers were included. Proteinuria from baseline changed by -35%, -41%, -45% and -48% at 3, 6, 9 and 12 months after SGLT2i initiation, while eGFR changed by -6%, -3%, -8% and -10.5% at 3, 6, 9 and 12 months, respectively. Results were similar irrespective of the underlying disease. A correlation was found between body mass index (BMI) and percentage proteinuria reduction at last follow-up. By mixed-effects logistic regression model, serum albumin at SGLT2i initiation emerged as a predictor of ≥30% proteinuria reduction (odds ratio for albumin <3.5 g/dL, 0.53; 95% CI 0.30-0.91; P = .02). A slower eGFR decline was observed in patients achieving a ≥30% proteinuria reduction: -3.7 versus -5.3 mL/min/1.73 m2/year (P = .001). The overall tolerance to SGLT2i was good. CONCLUSIONS: The use of SGLT2i was associated with a significant reduction of proteinuria. This percentage change is greater in patients with higher BMI. Higher serum albumin at SGLT2i onset is associated with higher probability of achieving a ≥30% proteinuria reduction.

Characterisation of Aberrant Metabolic Pathways in Hepatoblastoma Using Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS).

Hepatoblastoma (HB) is a rare childhood tumour with an evolving molecular landscape. We present the first comprehensive metabolomic analysis using untargeted and targeted liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS) of paired tumour and non-tumour surgical samples in HB patients (n = 8 pairs). This study demonstrates that the metabolomic landscape of HB is distinct from that of non-tumour (NT) liver tissue, with 35 differentially abundant metabolites mapping onto pathways such as fatty acid transport, glycolysis, the tricarboxylic acid (TCA) cycle, branched-chain amino acid degradation and glutathione synthesis. Targeted metabolomics demonstrated reduced short-chain acylcarnitines and a relative accumulation of branched-chain amino acids. Medium- and long-chain acylcarnitines in HB were similar to those in NT. The metabolomic changes reported are consistent with previously reported transcriptomic data from tumour and non-tumour samples (49 out of 54 targets) as well as metabolomic data obtained using other techniques. Gene set enrichment analysis (GSEA) from RNAseq data (n = 32 paired HB and NT samples) demonstrated a downregulation of the carnitine metabolome and immunohistochemistry showed a reduction in CPT1a (n = 15 pairs), which transports fatty acids into the mitochondria, suggesting a lack of utilisation of long-chain fatty acids in HB. Thus, our findings suggest a reduced metabolic flux in HB which is corroborated at the gene expression and protein levels. Further work could yield novel insights and new therapeutic targets.

Computational drug prediction in hepatoblastoma by integrating pan-cancer transcriptomics with pharmacological response.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the predominant form of pediatric liver cancer, though it remains exceptionally rare. While treatment outcomes for children with HB have improved, patients with advanced tumors face limited therapeutic choices. Additionally, survivors often suffer from long-term adverse effects due to treatment, including ototoxicity, cardiotoxicity, delayed growth, and secondary tumors. Consequently, there is a pressing need to identify new and effective therapeutic strategies for patients with HB. Computational methods to predict drug sensitivity from a tumor's transcriptome have been successfully applied for some common adult malignancies, but specific efforts in pediatric cancers are lacking because of the paucity of data. APPROACH AND RESULTS: In this study, we used DrugSense to assess drug efficacy in patients with HB, particularly those with the aggressive C2 subtype associated with poor clinical outcomes. Our method relied on publicly available collections of pan-cancer transcriptional profiles and drug responses across 36 tumor types and 495 compounds. The drugs predicted to be most effective were experimentally validated using patient-derived xenograft models of HB grown in vitro and in vivo. We thus identified 2 cyclin-dependent kinase 9 inhibitors, alvocidib and dinaciclib as potent HB growth inhibitors for the high-risk C2 molecular subtype. We also found that in a cohort of 46 patients with HB, high cyclin-dependent kinase 9 tumor expression was significantly associated with poor prognosis. CONCLUSIONS: Our work proves the usefulness of computational methods trained on pan-cancer data sets to reposition drugs in rare pediatric cancers such as HB, and to help clinicians in choosing the best treatment options for their patients.

Racial disparities in treatment and outcomes between non-Hispanic Black and non-Hispanic White women with nonmetastatic inflammatory breast cancer.

PURPOSE: The incidence rate of inflammatory breast cancer (IBC) is higher among non-Hispanic Black (NHB) than non-Hispanic White (NHW) women. We examined the differences in treatment and outcomes between NHB and NHW women with IBC, accounting for demographic, clinicopathological, and socioeconomic factors. METHODS: We collected data from the Surveillance, Epidemiology, and End Results database for NHB and NHW women with IBC diagnosed between 2010-2016. We analyzed the odds of receiving chemotherapy, radiation, and surgery between NHB and NHW women. We evaluated overall survival (OS) with Kaplan-Meier methods and Cox proportional hazards methods. Competing risk analysis was used to compare the risk of breast cancer death between NHB and NHW women. We also evaluated the magnitude of survival disparities within the strata of demographic, socioeconomic, and treatment factors. RESULTS: Among 1,652 NHW and 371 NHB women with IBC, the odds of receiving chemotherapy, surgery, and radiation were similar for NHB and NHW. After 39-month follow-up, the median OS was 40 and 81 months for NHB and NHW, respectively (p < 0.0001). The risk of breast cancer death was higher for NHB than NHW women (5-year risk of breast cancer death, 51% vs. 35%, p < 0.0001). CONCLUSION: After adjustment for demographic, clinicopathological, and socioeconomic factors; NHB women with IBC had similar odds of receiving surgery, chemotherapy, and radiation therapy, but were more likely to die of the disease compared to their NHW counterparts. Our findings suggest the presence of masked tumor biology, treatment, or socioeconomic factors associated with race that can lead to worse IBC outcomes.

Identification of IGF2 as Genomic Driver and Actionable Therapeutic Target in Hepatoblastoma.

Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens. In this study, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in preclinical models of HB. Paired tumor and adjacent tissues from 31 HBs and a validation set of 50 HBs were analyzed using RNA-seq, SNP, and methylation arrays. IGF2 overexpression was identified as the top targetable HB driver, present in 71% of HBs (22/31). IGF2high tumors displayed progenitor cell features and shorter recurrence-free survival. IGF2 overexpression was associated in 91% of cases with fetal promoter hypomethylation, ICR1 deregulation, 11p15.5 loss of heterozygosity or miR483-5p overexpression. The antitumor effect of xentuzumab (a monoclonal antibody targeting IGF1/2) alone or in combination with the conventional therapeutic agent cisplatin was assessed in HB cell lines, in PDX-derived HB organoids and in a xenograft HB murine model. The combination of xentuzumab with cisplatin showed strong synergistic antitumor effects in organoids and in IGF2high cell lines. In mice (n = 55), the combination induced a significant decrease in tumor volume and improved survival compared with cisplatin alone. These results suggest that IGF2 is an HB actionable driver and that, in preclinical models of HB, the combination of IGF1/2 inhibition with cisplatin induces superior antitumor effects than cisplatin monotherapy. Overall, our study provides a rationale for testing IGF2 inhibitors in combination with cisplatin in HB patients with IGF2 overexpression.

Plasticity in the functional properties of NMDA receptors improves network stability during severe energy stress.

Brain energy stress leads to neuronal hyperexcitability followed by a rapid loss of function and cell death. In contrast, the frog brainstem switches into a state of extreme metabolic resilience that allows them to maintain motor function during hypoxia as they emerge from hibernation. NMDA receptors (NMDARs) are Ca2+-permeable glutamate receptors that contribute to the loss of homeostasis during hypoxia. Therefore, we hypothesized that hibernation leads to plasticity that reduces the role of NMDARs within neural networks to improve function during energy stress. To test this, we assessed a circuit with a large involvement of NMDAR synapses, the brainstem respiratory network of female bullfrogs, Lithobates catesbeianus. Contrary to our expectations, hibernation did not alter the role of NMDARs in generating network output, nor did it affect the amplitude, kinetics, and hypoxia sensitivity of NMDAR currents. Instead, hibernation strongly reduced NMDAR Ca2+ permeability and enhanced desensitization during repetitive stimulation. Under severe hypoxia, the normal NMDAR profile caused network hyperexcitability within minutes, which was mitigated by blocking NMDARs. After hibernation, the modified complement of NMDARs protected against hyperexcitability, as disordered output did not occur for at least one hour in hypoxia. These findings uncover state-dependence in the plasticity of NMDARs, whereby multiple changes to receptor function improve neural performance during energy stress without interfering with its normal role during healthy activity.

Racial disparities in overall survival after the introduction of cyclin-dependent kinase 4/6 inhibitors for patients with hormone receptor-positive, HER2-negative metastatic breast cancer.

PURPOSE: CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have improved HR + /HER2- metastatic breast cancer (MBC) outcomes. However, it is still unclear whether the response to CDK4/6i is similar for all races. Therefore, we aimed to assess overall survival (OS) trends stratified by race in patients with HR + /HER2- MBC after the approval of CDK4/6i, as part of the standard of care, in 2015. METHODS: We performed a population-based study using the SEER database. Patients with HR + /HER2- MBC were divided into two time-based cohorts: 1) pre-CDK4/6i era (diagnosed in 2011-2013) and 2) post-CDK4/6i era (diagnosed in 2015-2017). We used propensity score matching and identified 2,684 patients in each cohort that matched in several characteristics. Kaplan-Meier methods were used to estimate 2-year OS. Association between cohort and OS was evaluated using marginal Cox proportional hazards models with robust sandwich variance estimator. We conducted competing risk analysis to estimate the risk of breast cancer death in both cohorts. RESULTS: The 2-year OS rate was 65% for the post-CDK4/6i era and 62% for the pre-CDK4/6i era (stratified log-rank p = 0.025). The 2-year OS for non-Hispanic White (NHW) patients improved in the post-CDK4/6i era compared to the pre-CDK4/6i era (67% vs. 63%, p = 0.033). However, OS did not improve for non-Hispanic Black (NHB) (54% vs. 54%, p = 0.876) or Hispanic (67% vs. 65%, p = 0.617) groups. The risk of breast cancer death decreased in the post-CDK4/6i era as compared to the pre-CDK4/6i era (2-year risk of breast cancer death: 33% vs. 30%, p = 0.015); however, this effect was observed only in NHW (sHR 0.84, p = 0.005) women, but not in NHB (sHR 0.94, p = 0.630) or Hispanic (sHR 0.91, p = 0.550) women. CONCLUSIONS: Our study confirms that outcomes for HR + /HER2- MBC have improved after CDK4/6i were introduced in 2015. However, this effect is primarily driven by the improved OS in NHW patients, without significant improvement in OS in NHB or Hispanics.

Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma.

Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin, the current treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony and tumor spheroid formation capabilities, cell cycle arrest, and induction of apoptosis of hepatoblastoma cells. Mechanistically, mebendazole causes blockage of microtubule formation and transcriptional downregulation of genes encoding the unwindosome, which are highly expressed in chemoresistant tumors. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model without side effects. In conclusion, our results strongly support the clinical use of mebendazole in the treatment of chemoresistant hepatoblastoma and highlight the potential theranostic value of unwindosome-associated genes.

MacroH2As regulate enhancer-promoter contacts affecting enhancer activity and sensitivity to inflammatory cytokines.

MacroH2A histone variants have a function in gene regulation that is poorly understood at the molecular level. We report that macroH2A1.2 and macroH2A2 modulate the transcriptional ground state of cancer cells and how they respond to inflammatory cytokines. Removal of macroH2A1.2 and macroH2A2 in hepatoblastoma cells affects the contact frequency of promoters and distal enhancers coinciding with changes in enhancer activity or preceding them in response to the cytokine tumor necrosis factor alpha. Although macroH2As regulate genes in both directions, they globally facilitate the nuclear factor κB (NF-κB)-mediated response. In contrast, macroH2As suppress the response to the pro-inflammatory cytokine interferon gamma. MacroH2A2 has a stronger contribution to gene repression than macroH2A1.2. Taken together, our results suggest that macroH2As have a role in regulating the response of cancer cells to inflammatory signals on the level of chromatin structure. This is likely relevant for the interaction of cancer cells with immune cells of their microenvironment.

Racial disparities in neutrophil counts among patients with metastatic breast cancer during treatment with CDK4/6 inhibitors.

PURPOSE: The three CDK4/6 inhibitors (CDK4/6i) approved for use in HR-positive/HER2-negative metastatic breast cancer (MBC), palbociclib, ribociclib, and abemaciclib, are generally well tolerated; however, neutropenia is a common toxicity. Within the general population, neutropenia has been shown to be more common in individuals of African descent. The landmark CDK4/6i trials in MBC lacked racial diversity in their patient populations. We aimed to assess the toxicity profiles of CDK4/6is in a racially diverse population. METHODS: We conducted a retrospective study at Montefiore Medical Center in patients with HR-positive/HER2-negative MBC prescribed CDK4/6i as first or subsequent line therapy between January 2015 and April 2020. Baseline characteristics and laboratory data at various treatment timepoints were collected. RESULTS: The final analysis included 182 patients, of whom 46% were Black. Baseline absolute neutrophil count (ANC) was lower in the Black vs. Non-Black cohort (p = 0.001) but the change in ANC from baseline (delta-ANC) was smaller in the Black cohort, and the ANC at different treatment timepoints was similar between groups. There was no difference in the rate of infection or number of dose delays/reductions between racial groups. We did not find any difference in PFS between Black and Non-Black groups, regardless of the presence of CDK4/6i-induced neutropenia. CONCLUSION: We analyzed toxicity profiles of 182 patients with HR-positive/HER2-negative MBC treated with CDK4/6i. Despite the lower baseline ANC seen in our Black cohort, treatment toxicities were similar between racial groups. Long-term outcomes with CDK4/6i therapy, measured by PFS, were similar between Black vs. Non-Black patients.

LIM Homeobox-2 Suppresses Hallmarks of Adult and Pediatric Liver Cancers by Inactivating MAPK/ERK and Wnt/Beta-Catenin Pathways.

Introduction: Hepatocellular carcinoma and hepatoblastoma are two liver cancers characterized by gene deregulations, chromosomal rearrangements, and mutations in Wnt/beta-catenin (Wnt) pathway-related genes. LHX2, a transcriptional factor member of the LIM homeobox gene family, has important functions in embryogenesis and liver development. LHX2 is oncogenic in many solid tumors and leukemia, but its role in liver cancer is unknown. Methods: We analyzed the expression of LHX2 in hepatocellular carcinoma and hepatoblastoma samples using various transcriptomic datasets and biological samples. The role of LHX2 was studied using lentiviral transduction, in vitro cell-based assays (growth, migration, senescence, and apoptosis), molecular approaches (phosphokinase arrays and RNA-seq), bioinformatics, and two in vivo models in chicken and Xenopus embryos. Results: We found a strong connection between LHX2 downregulation and Wnt activation in these two liver cancers. In hepatoblastoma, LHX2 downregulation correlated with multiple poor outcome parameters including higher patient age, intermediate- and high-risk tumors, and low patient survival. Forced expression of LHX2 reduced the proliferation, migration, and survival of liver cancer cells in vitro through the inactivation of MAPK/ERK and Wnt signals. In vivo, LHX2 impeded the development of tumors in chick embryos and repressed the Wnt pathway in Xenopus embryos. RNA-sequencing data and bioinformatic analyses confirmed the deregulation of many biological functions and molecular processes associated with cell migration, cell survival, and liver carcinogenesis in LHX2-expressing hepatoma cells. At a mechanistic level, LHX2 mediated the disassembling of beta-catenin/T-cell factor 4 complex and induced expression of multiple inhibitors of Wnt (e.g., TLE/Groucho) and MAPK/ERK (e.g., DUSPs) pathways. Conclusion: Collectively, our findings demonstrate a tumor suppressive function of LHX2 in adult and pediatric liver cancers.

Standardised packs and larger health warnings: visual attention and perceptions among Colombian smokers and non-smokers.

AIMS: To measure how cigarette packaging (standardised packaging and branded packaging) and health warning size affect visual attention and pack preferences among Colombian smokers and non-smokers. DESIGN: To explore visual attention, we used an eye-tracking experiment where non-smokers, weekly smokers and daily smokers were shown cigarette packs varying in warning size (30%-pictorial on top of the text, 30%-pictorial and text side-by-side, 50%, 70%) and packaging (standardised packaging, branded packaging). We used a discrete choice experiment (DCE) to examine the impact of warning size, packaging and brand name on preferences to try, taste perceptions and perceptions of harm. SETTING: Eye-tracking laboratory, Universidad Nacional de Colombia, Bogotá, Colombia. PARTICIPANTS: Participants (n = 175) were 18 to 40 years old. MEASUREMENTS: For the eye-tracking experiment, our primary outcome measure was the number of fixations toward the health warning compared with the branding. For the DCE, outcome measures were preferences to try, taste perceptions and harm perceptions. FINDINGS: We observed greater visual attention to warning labels on standardised versus branded packages (F[3,167] = 22.87, P < 0.001) and when warnings were larger (F[9,161] = 147.17, P < 0.001); as warning size increased, the difference in visual attention to warnings between standardised and branded packaging decreased (F[9,161] = 4.44, P < 0.001). Non-smokers visually attended toward the warnings more than smokers, but as warning size increased these differences decreased (F[6,334] = 2.92, P = 0.009). For the DCE, conditional trials showed that increasing the warning size from 30% to 70% reduced preferences to try (odds ratio [OR] = 0.48, 95% CI = [0.42,0.54], P < 0.001), taste perceptions (OR = 0.61, 95% CI = [0.54,0.68], P < 0.001); and increased harm perceptions (OR = 0.78, 95% CI = [0.76,0.80], P < 0.001). Compared with branded packaging, standardised packaging reduced our DCE outcome measures with ORs ranging from OR = 0.25 (95% CI = [0.17,0.38], P < 0.001) to OR = 0.79 (95% CI = [0.67,0.93], P < 0.001) across two brands. These effects were more pronounced among non-smokers, males and younger participants. Unconditional trials showed similar results. CONCLUSIONS: Standardised cigarette packaging and larger health warnings appear to decrease positive pack perceptions and have the potential to reduce the demand for cigarette products in Colombia.

Iron status in late pregnancy is inversely associated with birth weight in Colombia.

OBJECTIVE: Gestational anaemia (GA) is common in developing countries. This study assessed the relationship of late GA and negative perinatal outcomes in participants recruited in a reference maternity unit of the Caribbean region of Colombia. DESIGN: Prospective analytical birth cohort study. Maternal Hb and serum ferritin (SF) levels were measured. GA was defined as Hb levels <6·82 mmol/l (<11 g/dl), SF depletion as SF levels <12 µg/l. Birth outcomes such as low birth weight (LBW), preterm birth (PB) and small for gestational age (SGA) were examined. SETTING: Mothers in the first stage of labour, living in urban or rural areas of Bolívar, were enrolled in an obstetrical centre located in Cartagena, Colombia. Blood and stool samples were taken prior delivery. Maternal blood count, SF levels and infant anthropometric data were recorded for analysis. PARTICIPANTS: 1218 pregnant women aged 18-42 years and their newborns. RESULTS: Prevalence of GA and SF depletion was 41·6 % and 41·1 %, respectively. GA was positively associated with poverty-related sociodemographic conditions. Prenatal care attendance lowered the risk of PB, LBW and SGA. Birth weight was inversely associated with Hb levels, observing a -36·8 g decrease in newborn weight per 0·62 mmol/l (or 1 g/dl) of maternal Hb. SF depletion, but not anaemia, was associated with PB. SGA outcome showed a significant association with anaemia, but not a significant relationship with SF depletion. CONCLUSIONS: Birth weight and other-related perinatal outcomes are negatively associated with Hb and SF depletion. Prenatal care attendance reduced the risk of negative birth outcomes.

Simulations of breakthrough curves for fixed-bed column adsorption of cobalt (II) ions on spent tealeaves.

The objective of this study is to model the breakthrough adsorption curves of Co (II) ions using spent tealeaves in fixed-bed column experiments. Spent leaves of green tea (GT), peppermint tea (PM) and chamomile (CM) were packed in glass columns with a diameter of 2 cm and height of 15 cm, and used as filters for the removal of the pollutant. Aqueous solutions of cobalt (II) ions (100 mg/L) at pH 6 were prepared and pumped against gravity through the columns at a uniform flow rate of 5 mL/min. Breakthrough curves were fitted for the residual concentration data using the Thomas, Yoon-Nelson, and Clark models, with added empirical terms to delineate the lower tail of the breakthrough curve. These mathematical models were successfully linearized using the natural logarithm for parameter estimation. The results reveal that the Co (II) adsorption fits all three models for all the adsorbents. The Thomas model indicated that the calculated adsorption capacities followed the trend: PM > GT > CM with values of 59.7, 25.2, and 24.9 mg/g respectively. Moreover, CM showed the highest adsorption rates with all the mathematical models, whereas Yoon-Nelson theory provided evidence that PM has the longest 50% adsorption breakthrough among the adsorbents. Lastly, morphological and textural studies indicate that all spent leaves are good candidates as adsorbents due to their high surface heterogeneity. This study proposes the use of spent tealeaves as Co (II) adsorbents because they are inexpensive and environmentally beneficial.

Hybrid Gold(I) NHC-Artemether Complexes to Target Falciparum Malaria Parasites.

The emergence of Plasmodium falciparum parasites, responsible for malaria disease, resistant to antiplasmodial drugs including the artemisinins, represents a major threat to public health. Therefore, the development of new antimalarial drugs or combinations is urgently required. In this context, several hybrid molecules combining a dihydroartemisinin derivative and gold(I) N-heterocyclic carbene (NHC) complexes have been synthesized based on the different modes of action of the two compounds. The antiplasmodial activity of these molecules was assessed in vitro as well as their cytotoxicity against mammalian cells. All the hybrid molecules tested showed efficacy against P. falciparum, in a nanomolar range for the most active, associated with a low cytotoxicity. However, cross-resistance between artemisinin and these hybrid molecules was evidenced. These results underline a fear about the risk of cross-resistance between artemisinins and new antimalarial drugs based on an endoperoxide part. This study thus raises concerns about the use of such molecules in future therapeutic malaria policies.

An Artemisinin-Derivative-(NHC)Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of NRF2 Transcriptional Activity.

A family of hybrid complexes combining two biologically active motifs, an artemisinin derivative and a cationic bis(NHC)-gold(I) unit, has been synthesized. One of these complexes, 2 a, has been analyzed by single-crystal X-ray diffraction. 2 a shows strong anticancer activities on a large panel of human cancer cell models (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias) with GI50 values in the nm range, together with a high selectivity. An original and distinctive mechanism of action, that is, through inhibition of the redox antioxidant NRF2 transcription factor (strongly associated with aggressiveness and resistance to cancer therapies) has been evidenced. 2 a could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is linked to primary and acquired drug resistance. 2 a also inhibited NF-κB and HIF transcriptional activities, which are also associated with progression and resistance in cancer. Our findings provide evidence that hybrid (NHC)gold(I) compounds represent a new class of organometallic hybrid molecules that may yield new therapeutic agents.

m-SFT: A Novel Mobile Health System to Assess the Elderly Physical Condition.

The development of innovative solutions that allow the aging population to remain healthier and independent longer is essential to alleviate the burden that this increasing segment of the population supposes for the long term sustainability of the public health systems. It has been claimed that promoting physical activity could prevent functional decline. However, given the vulnerability of this population, the activity prescription requires to be tailored to the individual's physical condition. We propose mobile Senior Fitness Test (m-SFT), a novel m-health system, that allows the health practitioner to determine the elderly physical condition by implementing a smartphone-based version of the senior fitness test (SFT). The technical reliability of m-SFT has been tested by carrying out a comparative study in seven volunteers (53-61 years) between the original SFT and the proposed m-health system obtaining high agreement (intra-class correlation coefficient (ICC) between 0.93 and 0.99). The system usability has been evaluated by 34 independent health experts (mean = 36.64 years; standard deviation = 6.26 years) by means of the System Usability Scale (SUS) obtaining an average SUS score of 84.4 out of 100. Both results point out that m-SFT is a reliable and easy to use m-health system for the evaluation of the elderly physical condition, also useful in intervention programs to follow-up the patient's evolution.

Urinary bladder agenesis and renal hypoplasia potentially related to in utero Zika virus infection.

This case report describes the clinical findings of a 22-year-old pregnant woman with confirmed Zika virus infection, at 16 weeks of gestation, in Sucre, Colombia. Her ultrasound revealed severe oligohydramnios, intrauterine growth restriction, and a complete absence of the urinary bladder of the fetus. The poor prognosis led to the decision to terminate the pregnancy. Autopsy of the fetus revealed severe bilateral renal hypoplasia.