A bone marrow niche-derived molecular switch between osteogenesis and hematopoiesis.

Hematopoietic stem cells (HSCs) reside and are maintained in specialized microenvironments within the bone marrow known as niches, which are comprised of various cell types. Among them, leptin receptor (LepR)-expressing CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells are known to create a niche for HSCs and at the same time to give rise to osteoblasts. These two functions of CAR/LepR+ cells appear to be tightly but inversely regulated to ensure adequate physical space for HSCs. However, how osteogenesis is prevented in CAR cells to maintain spaces available for HSCs and hematopoiesis remains unclear. In this issue of Genes & Development, Seike and colleagues (pp. 359-372) report that the transcription factor early B-cell factor (Ebf3) is preferentially expressed by CAR/LepR+ cells and inhibits CAR cell differentiation into osteoblasts while at the same time maintaining self-renewal of CAR/LepR+ cells. Using conditional knockout and retroviral systems, the investigators show that loss of Ebf3 in CAR cells impairs HSC numbers and leads to osteosclerosis. This study provides novel insights into transcriptional requirements for CAR cell bone formation by identifying Ebf3 as a niche factor secreted from CAR/Lepr+ cells that regulates the interplay between osteogenesis and hematopoiesis.

From Sea Sponge to Clinical Trials: Starting the Journey of the Novel Compound PM742.

PM742 (1), a new chemical entity, has been isolated from the sponge Discodermia du Bocage collected in the Pacific Ocean. This compound showed strong in vitro cytotoxicity against several human tumor cell lines as well as a tubulin depolymerization mechanism of action, which led us to conduct an extensive Structure-Activity-Relationship study through the synthesis of different analogs. As a result, a derivatively named PM534 (2) is currently in its first human Phase I clinical trial. Herein, we present a comprehensive review of the isolation, structural elucidation, and antitumor activities of the parent compound PM742.

Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation.

How commensal microbiota contributes to immune cell homeostasis at barrier surfaces is poorly understood. Lamina propria (LP) T helper 17 (Th17) cells participate in mucosal protection and are induced by commensal segmented filamentous bacteria (SFB). Here we show that MHCII-dependent antigen presentation of SFB antigens by intestinal dendritic cells (DCs) is crucial for Th17 cell induction. Expression of MHCII on CD11c(+) cells was necessary and sufficient for SFB-induced Th17 cell differentiation. Most SFB-induced Th17 cells recognized SFB in an MHCII-dependent manner. SFB primed and induced Th17 cells locally in the LP and Th17 cell induction occurred normally in mice lacking secondary lymphoid organs. The importance of other innate cells was unveiled by the finding that MHCII deficiency in group 3 innate lymphoid cells (ILCs) resulted in an increase in SFB-independent Th17 cell differentiation. Our results outline the complex role of DCs and ILCs in the regulation of intestinal Th17 cell homeostasis.

Effectiveness of Gold Nanorods of Different Sizes in Photothermal Therapy to Eliminate Melanoma and Glioblastoma Cells.

Gold nanorods are the most commonly used nanoparticles in photothermal therapy for cancer treatment due to their high efficiency in converting light into heat. This study aimed to investigate the efficacy of gold nanorods of different sizes (large and small) in eliminating two types of cancer cell: melanoma and glioblastoma cells. After establishing the optimal concentration of nanoparticles and determining the appropriate time and power of laser irradiation, photothermal therapy was applied to melanoma and glioblastoma cells, resulting in the highly efficient elimination of both cell types. The efficiency of the PTT was evaluated using several methods, including biochemical analysis, fluorescence microscopy, and flow cytometry. The dehydrogenase activity, as well as calcein-propidium iodide and Annexin V staining, were employed to determine the cell viability and the type of cell death triggered by the PTT. The melanoma cells exhibited greater resistance to photothermal therapy, but this resistance was overcome by irradiating cells at physiological temperatures. Our findings revealed that the predominant cell-death pathway activated by the photothermal therapy mediated by gold nanorods was apoptosis. This is advantageous as the presence of apoptotic cells can stimulate antitumoral immunity in vivo. Considering the high efficacy of these gold nanorods in photothermal therapy, large nanoparticles could be useful for biofunctionalization purposes. Large nanorods offer a greater surface area for attaching biomolecules, thereby promoting high sensitivity and specificity in recognizing target cancer cells. Additionally, large nanoparticles could also be beneficial for theranostic applications, involving both therapy and diagnosis, due to their superior detection sensitivity.

Multi-joint isometric measurement for the evidence-based assessment of upper limb strength impairment in wheelchair athletes with different health conditions: a preliminary study.

The present study presents a novel specific multi-joint isometric test to assess upper limb strength impairment for evidence-based classification in wheelchair sports. Sixteen wheelchair athletes participated in this study and were classified according to their type of physical impairment and health condition as follows: athletes with neurological impairment (ANI, n = 5) and athletes with impaired muscle power (IMP, n = 11). In addition, six non-disabled participants formed a control group (CG, n = 6). All the participants performed the isometric propulsion strength test (IPST), evaluating pushing and pulling actions, and two wheelchair performance tests. Excellent relative intra-session reliability scores were obtained for strength values for the ANI, IMP and CG groups (0.90 < ICC < 0.99) and absolute reproducibility showed acceptable scores of SEM (< 9.52%) for IPST pushing action. The ANI had significantly lower scores in strength and wheelchair performance than the IMP and the CG, while no differences were found between the IMP and the non-disabled participants. In addition, no correlations were found for wheelchair athletes between the isometric upper limb strength measure and wheelchair performance. Our findings suggest that the IPST is a valid test for strength measurement in upper limb impairment wheelchair athletes with different health conditions, which must be used in combination with a performance test to obtain a holistic assessment of this population.

The effectiveness of a "EspaiJove.net"- a school-based intervention programme in increasing mental health knowledge, help seeking and reducing stigma attitudes in the adolescent population: a cluster randomised controlled trial.

BACKGROUND: The aim of this study is to evaluate the short- and long-term effects of the universal mental health literacy intervention "EspaiJove.net" in increasing mental health knowledge, help seeking and reducing stigma attitudes in the adolescent population. We also examine whether these effects depend on the intervention intensity.  METHODS: A clustered school-based randomised controlled trial (cRCT) design. SUBJECTS: 1,298 secondary pupils aged 13 and 14 were recruited from 18 schools in Barcelona (Spain) between September 2016 and January 2018. INTERVENTION: Three programmes were assessed: 1) Sensitivity Programme (SP; 1 h); 2) Mental Health Literacy (MHL; 6 h); 3) MHL plus a first-person Stigma Reduction Programme (MHL + SR; 7 h); 4) Control group (CG): waiting list. OUTCOME MEASURES: 1) MHL: EspaiJove.net EMHL Test (First part and Second Part); 2) Stigma: RIBS and CAMI; 3) Help-seeking and use of treatment: GHSQ. ANALYSIS: The data was collected at baseline, post-intervention and 6 and 12 months later. An intention-to-treat analysis and imputation method was used to analyse the missing data. Intervention effects were analysed using multilevel modelling. RESULTS: One thousand thirty-two students were included (SP = 225; MHL = 261; MHL + SR = 295 and CG = 251). The MHL and MHL + SR interventions showed short- and long-term an increase in knowledge compared to SP and CG, but no significant change post-intervention or over time (First part p = 0.52 and Second part p = 0.62) between intervention groups and CG. No significant changes were found in stigma scores post-intervention or over time (CAMI p = 0.61 and RIBS p = 0.98) or in help-seeking scores (parent p = 0.69; teacher p = 0.23 and healthcare professional p = 0.75). The MHL + SR intervention was the best valued and recommended (p < 0.005). CONCLUSIONS: The three interventions of the EspaiJove.net programme (SP, MHL and MHL + SR) seem not to be effective in terms MHL, Stigma and help-seeking behaviours. The contact with a person who has experimented mental illness first-hand did not reduce stigma attitudes. Further research should deal with the heterogeneity of MHL interventions (concept, duration and measures) and identify which components of stigma interventions are effective. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03215654 (registration date 12 July 2017).

Identification of Human Pathological Mitral Chordae Tendineae Using Polarization-sensitive Optical Coherence Tomography.

Defects of the mitral valve complex imply heart malfunction. The chordae tendineae (CTs) are tendinous strands connecting the mitral and tricuspid valve leaflets to the papillary muscles. These CTs are composed of organized, wavy collagen bundles, making them a strongly birefringent material. Disorder of the collagen structure due to different diseases (rheumatic, degenerative) implies the loss or reduction of tissue birefringence able to be characterized with Polarization Sensitive Optical Coherence Tomography (PS-OCT). PS-OCT is used to discriminate healthy from diseased chords, as the latter must be excised and replaced in clinical conventional interventions. PS-OCT allows to quantify birefringence reduction in human CTs affected by degenerative and rheumatic pathologies. This tissue optical property is proposed as a diagnostic marker for the identification of degradation of tendinous chords to guide intraoperative mitral valve surgery.

Binding of eEF1A2 to the RNA-dependent protein kinase PKR modulates its activity and promotes tumour cell survival.

BACKGROUND: Through several not-fully-characterised moonlighting functions, translation elongation factor eEF1A2 is known to provide a fitness boost to cancer cells. Furthermore, eEF1A2 has been demonstrated to confer neoplastic characteristics on preneoplastic, nontumourigenic precursor cells. We have previously shown that eEF1A2 is the target of plitidepsin, a marine drug currently in development for cancer treatment. Herein, we characterised a new signalling pathway through which eEF1A2 promotes tumour cell survival. METHODS: Previously unknown binding partners of eEF1A2 were identified through co-immunoprecipitation, high-performance liquid chromatography-mass spectrometry and proximity ligation assay. Using plitidepsin to release eEF1A2 from those protein complexes, their effects on cancer cell survival were analysed in vitro. RESULTS: We uncovered that double-stranded RNA-activated protein kinase (PKR) is a novel eEF1A2-interacting partner whose pro-apoptotic effect is hindered by the translation factor, most likely through sequestration and inhibition of its kinase activity. Targeting eEF1A2 with plitidepsin releases PKR from the complex, facilitating its activation and triggering a mitogen-activated protein kinase signalling cascade together with a nuclear factor-κB-dependent activation of the extrinsic apoptotic pathway, which lead to tumour cell death. CONCLUSIONS: Through its binding to PKR, eEF1A2 provides a survival boost to cancer cells, constituting an Achilles heel that can be exploited in anticancer therapy.

Plocabulin, a novel tubulin-binding agent, inhibits angiogenesis by modulation of microtubule dynamics in endothelial cells.

BACKGROUND: Vascular supply of tumors is one of the main targets for cancer therapy. Here, we investigated if plocabulin (PM060184), a novel marine-derived microtubule-binding agent, presents antiangiogenic and vascular-disrupting activities. METHODS: The effects of plocabulin on microtubule network and dynamics were studied on HUVEC endothelial cells. We have also studied its effects on capillary tube structures formation or destabilization in three-dimensional collagen matrices. In vivo experiments were performed on different tumor cell lines. RESULTS: In vitro studies show that, at picomolar concentrations, plocabulin inhibits microtubule dynamics in endothelial cells. This subsequently disturbs the microtubule network inducing changes in endothelial cell morphology and causing the collapse of angiogenic vessels, or the suppression of the angiogenic process by inhibiting the migration and invasion abilities of endothelial cells. This rapid collapse of the endothelial tubular network in vitro occurs in a concentration-dependent manner and is observed at concentrations lower than that affecting cell survival. The in vitro findings were confirmed in tumor xenografts where plocabulin treatment induced a large reduction in vascular volume and induction of extensive necrosis in tumors, consistent with antivascular effects. CONCLUSIONS: Altogether, these data suggest that an antivascular mechanism is contributing to the antitumor activities of plocabulin.

Normal hematopoiesis and lack of ß-catenin activation in osteoblasts of patients and mice harboring Lrp5 gain-of-function mutations.

Osteoblasts are emerging regulators of myeloid malignancies since genetic alterations in them, such as constitutive activation of ß-catenin, instigate their appearance. The LDL receptor-related protein 5 (LRP5), initially proposed to be a co-receptor for Wnt proteins, in fact favors bone formation by suppressing gut-serotonin synthesis. This function of Lrp5 occurring in the gut is independent of ß-catenin activation in osteoblasts. However, it is unknown whether Lrp5 can act directly in osteoblast to influence other functions that require ß-catenin signaling, particularly, the deregulation of hematopoiesis and leukemogenic properties of ß-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5 mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate ß-catenin signaling in osteoblasts. Consistent with a lack of ß-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation of ß-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM patients showed normal hematopoiesis, normal percentage of myeloid cells, and lack of anemia. We conclude that Lrp5 GOF mutations do not activate ß-catenin signaling in osteoblasts. As a result, myeloid lineage differentiation is normal in HBM patients and mice. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

Effects of mindfulness-based interventions on biomarkers in healthy and cancer populations: a systematic review.

BACKGROUND: Only a small number of articles have investigated the relationship between mindfulness-based interventions (MBIs) and biomarkers. The aim of this systematic review was to study the effect of MBIs on specific biomarkers (cytokines, neuropeptides and C-reactive protein (CRP)) in both healthy subjects and cancer patients. METHODS: A search was conducted using PubMed, EMBASE, PsycINFO and the Cochrane library between 1980 and September 2016. RESULTS: A total of 13 studies with 1110 participants were included. In the healthy population, MBIs had no effect on cytokines, but were found to increase the levels of the neuropeptide insulin-like growth factor 1 (IGF-1). With respect to neuropeptide Y, despite the absence of post-intervention differences, MBIs may enhance recovery from stress. With regard to CRP, MBIs could be effective in lower Body Mass Index (BMI) individuals. In cancer patients, MBIs seem to have some effect on cytokine levels, although it was not possible to determine which specific cytokines were affected. One possibility is that MBIs might aid recovery of the immune system, increasing the production of interleukin (IL)-4 and decreasing interferon gamma (IFN-γ). CONCLUSIONS: MBIs may be involved in changes from a depressive/carcinogenic profile to a more normalized one. However, given the complexity and different contexts of the immune system, and the fact that this investigation is still in its preliminary stage, additional randomized controlled trials are needed to further establish the impact of MBI programmes on biomarkers in both clinical and non-clinical populations.

Gene expression profile of angiogenic factors in pulmonary arteries in COPD: relationship with vascular remodeling.

Pulmonary vessel remodeling in chronic obstructive pulmonary disease (COPD) involves changes in smooth muscle cell proliferation, which are highly dependent on the coordinated interaction of angiogenic-related growth factors. The purpose of the study was to investigate, in isolated pulmonary arteries (PA) from patients with COPD, the gene expression of 46 genes known to be modulators of the angiogenic process and/or involved in smooth muscle cell proliferation and to relate it to vascular remodeling. PA segments were isolated from 29 patients and classified into tertiles, according to intimal thickness. After RNA extraction, the gene expression was assessed by RT-PCR using TaqMan low-density arrays. The univariate analysis only showed upregulation of angiopoietin-2 (ANGPT-2) in remodeled PA (P < 0.05). The immunohistochemical expression of ANGPT-2 correlated with intimal enlargement (r = 0.42, P < 0.05). However, a combination of 10 factors in a multivariate discriminant analysis model explained up to 96% of the classification of the arteries. A network analysis of 46 genes showed major decentralization. In this network, the metalloproteinase-2 (MMP-2) was shown to be the bridge between intimal enlargement and fibrogenic factors. In COPD patients, plasma levels of ANGPT-2 were higher in current smokers or those with pulmonary hypertension. We conclude that an imbalance in ANGPT-2, combined with related factors such as VEGF, ß-catenin, and MMP-2, may partially explain the structural derangements of the arterial wall. MMP-2 may act as a bridge channeling actions from the main fibrogenic factors.

Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts.

The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.

Polymorphisms in miRNA processing genes and their role in osteosarcoma risk.

BACKGROUND: The possible associations between genetic variants and osteosarcoma risk have been analyzed without conclusive results. Those studies were focused mainly on genes of biologically plausible pathways. However, recently, another pathway has acquired relevance in cellular transformation and tumorigenesis, the microRNA (miRNA) processing pathway. Dysregulation of the expression levels of genes in this pathway has been described in cancer. Consequently, single nucleotide polymorphisms (SNPs) in genes that codify for proteins involved in the miRNA processing pathway may affect miRNAs, and therefore their target genes, which might be associated with cancer development and progression. The aim of this study was to evaluate whether SNPs in miRNA processing genes confer predisposition to osteosarcoma. PROCEDURE: We analyzed 72 SNPs in 21 miRNA processing genes in a total of 99 osteosarcoma patients and 387 controls. RESULTS: A total of three SNPs were associated with osteosarcoma susceptibility. Interestingly, these SNPs were located in miRNA processing genes (CNOT1, CNOT4 and SND1) which are part of the RISC complex. Among them, the association of rs11866002 in CNOT1 was nearly significant after Bonferroni correction. CONCLUSIONS: This study suggests that SNPs in RISC complex genes may be involved in osteosarcoma susceptibility, especially rs11866002 in CNOT1.

Identity development and adjustment during emerging adulthood from a gender perspective.

Identity development is a key task during emerging adulthood. The goals of the present study are to validate the Spanish version of the Dimensions of Identity Development Scale (DIDS) and to explore the relationship between identity dimensions and adjustment (flourishing and distress), from a gender perspective. The sample comprised 1502 Spanish university students (60.1% women). The results reveal that the DIDS is valid in the Spanish context and that significant gender differences were observed in some dimensions of identity development, with men scoring higher for identification with commitment and women scoring higher for exploration in depth and ruminative exploration. Finally, both dimensions of commitment and ruminative exploration had a stronger effect on men's than on women's adjustment, suggesting that the integration of the self has more impact on men's outcomes than on women's. These findings highlight the need to include the gender perspective in all future research in order to gain deeper insight into the relationship between the identity development process and adjustment during emerging adulthood.

Depression, Anxiety, and Stress Among Emerging Adult Undergraduates: A Longitudinal and Two-Cohort Study.

Mental disorders constitute one of the population's principal health problems, especially among undergraduates. This quantitative study compared levels of depression, anxiety, and stress in a sample of emerging adult university undergraduates from a gender perspective (1) during the initial and intermediate years of emerging adulthood and (2) in two different cohorts. A total of 383 Spanish emerging adult university undergraduates were monitored longitudinally (2015-2018) and two cohorts were compared (2015-2020). Participants completed the validated Spanish version of the Depression Anxiety Stress Scale-21. Mean-level and rank-order stability was found across the two waves of the longitudinal study in relation to levels of depression, anxiety, and stress. Significant differences were found between the two cohorts, indicating higher levels of psychological distress in 2020 than in 2015. Women were found to have higher levels of psychological distress, particularly stress, than men in both waves and cohorts. Results are discussed in relation to the negative effects of the COVID-19 health crisis on the emotional health of emerging adults. The present study highlights the need to establish measures designed to improve the mental health of emerging adults, which was more severely affected by the COVID-19 crisis than by the aftermath of the 2008 financial crisis. It also underscores the need to develop interventions designed to alleviate the greater degree of stress suffered by women.

Thrombotic microangiopathy (TMA) associated with pregnancy: role of the clinical laboratory in differential diagnosis.

Objectives: Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia, microangiopathic hemolytic anemia and target organ damage. Pregnancy is associated with several forms of TMA, including preeclampsia (PE), HELLP syndrome, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). When HUS is secondary to a deregulation of the alternative complement pathway, it is known as atypical HUS (aHUS). Differential diagnosis is challenging, as these forms share clinical characteristics. However, early diagnosis is crucial for a specific treatment to be established and improve prognosis. Case presentation: We present the case of a 43 year-old primiparous woman admitted to hospital for an urgent C-section at 33 gestational weeks due to a diagnosis of severe preeclampsia and fetal distress. In the immediate postpartum, the patient developed acute liver failure and anuric renal failure in the context of the HELLP syndrome, anemia, thrombocytopenia, arterial hypertension (HTN) and neurological deficit. TMA study and differential diagnosis confirmed pregnancy-associated aHUS. Treatment with eculizumab was initiated, with good response and progressive improvement of clinical and analytical parameters. Conclusions: aHUS is a rare multifactorial disease that used to be associated with high mortality rates before the advent of eculizumab. Due to challenging diagnosis, the clinical laboratory plays a major role in the differential diagnosis and management of the disease.

CAR-T lymphocyte-based cell therapies; mechanistic substantiation, applications and biosafety enhancement with suicide genes: new opportunities to melt side effects.

Immunotherapy has made significant strides in cancer treatment with strategies like checkpoint blockade antibodies and adoptive T cell transfer. Chimeric antigen receptor T cells (CAR-T) have emerged as a promising approach to combine these strategies and overcome their limitations. This review explores CAR-T cells as a living drug for cancer treatment. CAR-T cells are genetically engineered immune cells designed to target and eliminate tumor cells by recognizing specific antigens. The study involves a comprehensive literature review on CAR-T cell technology, covering structure optimization, generations, manufacturing processes, and gene therapy strategies. It examines CAR-T therapy in haematologic cancers and solid tumors, highlighting challenges and proposing a suicide gene-based mechanism to enhance safety. The results show significant advancements in CAR-T technology, particularly in structure optimization and generation. The manufacturing process has improved for broader clinical application. However, a series of inherent challenges and side effects still need to be addressed. In conclusion, CAR-T cells hold great promise for cancer treatment, but ongoing research is crucial to improve efficacy and safety for oncology patients. The proposed suicide gene-based mechanism offers a potential solution to mitigate side effects including cytokine release syndrome (the most common toxic side effect of CAR-T therapy) and the associated neurotoxicity.

PM534, an Optimized Target-Protein Interaction Strategy through the Colchicine Site of Tubulin.

Targeting microtubules is the most effective wide-spectrum pharmacological strategy in antitumoral chemotherapy, and current research focuses on reducing main drawbacks: neurotoxicity and resistance. PM534 is a novel synthetic compound derived from the Structure-Activity-Relationship study on the natural molecule PM742, isolated from the sponge of the order Lithistida, family Theonellidae, genus Discodermia (du Bocage 1869). PM534 targets the entire colchicine binding domain of tubulin, covering four of the five centers of the pharmacophore model. Its nanomolar affinity and high retention time modulate a strikingly high antitumor activity that efficiently overrides two resistance mechanisms in cells (detoxification pumps and tubulin ßIII isotype overexpression). Furthermore, PM534 induces significant inhibition of tumor growth in mouse xenograft models of human non-small cell lung cancer. Our results present PM534, a highly effective new compound in the preclinical evaluation that is currently in its first human Phase I clinical trial.

miR-127-5p targets the 3'UTR of human ß-F1-ATPase mRNA and inhibits its translation.

The mitochondrial H(+)-ATP synthase is a bottleneck component in the provision of metabolic energy by oxidative phosphorylation. The expression of its catalytic subunit (ß-F1-ATPase) is stringently controlled at post-transcriptional levels during oncogenesis, the cell cycle and in development. Here we show that miR-127-5p targets the 3'UTR of ß-F1-ATPase mRNA (ß-mRNA) significantly reducing its translational efficiency without affecting ß-mRNA abundance. Despite the reduced expression of ß-F1-ATPase in most human carcinomas, we observed no expression of miR-127-5p in different human cancer cell lines, minimizing the potential role of miR-127-5p as a regulator of the bioenergetic activity of mitochondria in cancer. In contrast, miR-127-5p is highly over-expressed in the human fetal liver. Consistent with previous findings in the rat, the expression of ß-F1-ATPase in the human liver also seems to be controlled at post-transcriptional levels during development, what might suggest a role for miR-127-5p in controlling ß-mRNA translation and thus in defining the bioenergetic activity of human liver mitochondria. Moreover, immunolocalization techniques and subcellular fractionation experiments using different antibodies against ß-F1-ATPase reveal that the ectopic expression of ß-F1-ATPase at the cell surface of the hepatocytes and HepG2 cells is negligible or stands for scrutiny.