Explore the vast range of titles available.

Systemic toxicity and tumor cell resistance still limit the efficacy of chemotherapy in colorectal cancer. Therefore, alternative treatments are desperately needed. The thiazolide Nitazoxanide (NTZ) is an FDA-approved drug for the treatment of parasite-mediated infectious diarrhea with a favorable safety profile. Interestingly, NTZ and the thiazolide RM4819—its bromo-derivative lacking antibiotic activity—are also promising candidates for cancer treatment. Yet the exact anticancer mechanism(s) of these compounds still remains unclear. In this study, we systematically investigated RM4819 and NTZ in 2D and 3D colorectal cancer culture systems. Both compounds strongly inhibited proliferation of colon carcinoma cell lines by promoting G1 phase cell cycle arrest. Thiazolide-induced cell cycle arrest was independent of the p53/p21 axis, but was mediated by inhibition of protein translation via the mTOR/c-Myc/p27 pathway, likely caused by inhibition of mitochondrial respiration. While both thiazolides demonstrated mitochondrial uncoupling activity, only RM4819 inhibited the mitochondrial respiratory chain complex III. Interestingly, thiazolides also potently inhibited the growth of murine colonic tumoroids in a comparable manner with cisplatin, while in contrast to cisplatin thiazolides did not affect the growth of primary intestinal organoids. Thus, thiazolides appear to have a tumor-selective antiproliferative activity, which offers new perspectives in the treatment of colorectal cancer.

Interactions of long non-coding RNAs (lncRNA) with proteins play important roles in the regulation of many cellular processes. PANDAR ( P romotor of CDKN1A An tisense D NA damage A ctivated R NA) is a lncRNA that is transcribed in a p53-dependent manner from the CDKN1A promoter and is involved in the regulation of proliferation and senescence. Overexpression of PANDAR has been observed in several tumor species and correlated with a poor prognosis for patient survival rate. Depending on the cellular state, PANDAR is known to interact with proteins such as the nuclear transcription factor Y subunit A (NF-YA) and the scaffold attachment factor A (SAF-A). However, a comprehensive analysis of the PANDAR interactome was missing so far. Therefore, we applied peptide nucleic acid (PNA)-based pull-downs combined with quantitative mass spectrometry to identify new protein binding partners. We confirmed potential candidates like U2AF65 and PTBP1, known to be involved in RNA processing. Furthermore, we observed that overexpression of PANDAR leads to a reduced level of the short pro-apoptotic BCL-X splice variant ( BCL-XS ) which is regulated by PTBP1. Simultaneous overexpression of PTBP1 was able to rescue this effect. Overall, our data suggest a role for PANDAR in the regulation of splicing events via its interaction partner PTBP1.

This paper summarizes the first results from isolated droplet combustion experiments performed on the International Space Station (ISS). The long durations of microgravity provided in the ISS enable the measurement of droplet and flame histories over an unprecedented range of conditions. The first experiments were with heptane and methanol as fuels, initial droplet droplet diameters between 1.5 and 5.0 m m , ambient oxygen mole fractions between 0.1 and 0.4, ambient pressures between 0.7 and 3.0 a t m and ambient environments containing oxygen and nitrogen diluted with both carbon dioxide and helium. The experiments show both radiative and diffusive extinction. For both fuels, the flames exhibited pre-extinction flame oscillations during radiative extinction with a frequency of approximately 1 H z . The results revealed that as the ambient oxygen mole fraction was reduced, the diffusive-extinction droplet diameter increased and the radiative-extinction droplet diameter decreased. In between these two limiting extinction conditions, quasi-steady combustion was observed. Another important measurement that is related to spacecraft fire safety is the limiting oxygen index (LOI), the oxygen concentration below which quasi-steady combustion cannot be supported. This is also the ambient oxygen mole fraction for which the radiative and diffusive extinction diameters become equal. For oxygen/nitrogen mixtures, the LOI is 0.12 and 0.15 for methanol and heptane, respectively. The LOI increases to approximately 0.14 (0.14 O 2 /0.56 N 2 /0.30 C O 2 ) and 0.17 (0.17 O 2 /0.63 N 2 /0.20 C O 2 ) for methanol and heptane, respectively, for ambient environments that simulated dispersing an inert-gas suppressant (carbon dioxide) into a nominally air (1.0 a t m ) ambient environment. The LOI is approximately 0.14 and 0.15 for methanol and heptane, respectively, when helium is dispersed into air at 1 atm. The experiments also showed unique burning behavior for large heptane droplets. After the visible hot flame radiatively extinguished around a large heptane droplet, the droplet continued to burn with a cool flame. This phenomena was observed repeatably over a wide range of ambient conditions. These cool flames were invisible to the experiment imaging system but their behavior was inferred by the sustained quasi-steady burning after visible flame extinction. Verification of this new burning regime was established by both theoretical and numerical analysis of the experimental results. These innovative experiments have provided a wealth of new data for improving the understanding of droplet combustion and related aspects of fire safety, as well as offering important measurements that can be used to test sophisticated evolving computational models and theories of droplet combustion.

The Fourier harmonics,$$v_2$$v 2 and$$v_3$$v 3 of negative pions are measured at center-of-mass energy per nucleon pair of$$\\sqrt{s_{\\textrm{NN}}}$$s NN = 17.3 GeV around midrapidity by the CERES/NA45 experiment at the CERN SPS in 0–30% central PbAu collisions with a mean centrality of 5.5%. The analysis is performed in two centrality bins as a function of the transverse momentum$$\\mathrm {p_{\\textrm{T}}}$$p T from 0.05 GeV/ c to more than 2 GeV/ c . This is the first measurement of the$$v^{1/3}_{3}/v^{1/2}_{2}$$v 3 1 / 3 / v 2 1 / 2 ratio as a function of transverse momentum at SPS energies, that reveals, independently of the hydrodynamic models, hydrodynamic behavior of the formed system. For$$\\mathrm {p_{\\textrm{T}}}$$p T above 0.5 GeV/ c , the ratio is nearly flat in accordance with the hydrodynamic prediction and as previously observed by the ATLAS and ALICE experiments at the much higher LHC energies. The results are also compared with the SMASH-vHLLE hybrid model predictions, as well as with the SMASH model applied alone.

The Fourier harmonics, v 2 and v 3 of negative pions are measured at center-of-mass energy per nucleon pair of s NN = 17.3 GeV around midrapidity by the CERES/NA45 experiment at the CERN SPS in 0–30% central PbAu collisions with a mean centrality of 5.5%. The analysis is performed in two centrality bins as a function of the transverse momentum p T from 0.05 GeV/ c to more than 2 GeV/ c . This is the first measurement of the v 3 1 / 3 / v 2 1 / 2 ratio as a function of transverse momentum at SPS energies, that reveals, independently of the hydrodynamic models, hydrodynamic behavior of the formed system. For p T above 0.5 GeV/ c , the ratio is nearly flat in accordance with the hydrodynamic prediction and as previously observed by the ATLAS and ALICE experiments at the much higher LHC energies. The results are also compared with the SMASH-vHLLE hybrid model predictions, as well as with the SMASH model applied alone.

Pneumocystis jirovecii is the most common cause of fungal pneumonia in children under the age of 2 years. However, the inability to culture and propagate this organism has hampered the acquisition of a fungal genome as well as the development of recombinant antigens to conduct seroprevalence studies. In this study, we performed proteomics on Pneumocystis-infected mice and used the recent P. murina and P. jirovecii genomes to prioritize antigens for recombinant protein expression. We focused on a fungal glucanase due to its conservation among fungal species. We found evidence of maternal IgG to this antigen, followed by a nadir in pediatric samples between 1 and 3 months of age, followed by an increase in prevalence over time consistent with the known epidemiology of Pneumocystis exposure. Moreover, there was a strong concordance of anti-glucanase responses and IgG against another Pneumocystis antigen, PNEG_01454. Taken together, these antigens may be useful tools for Pneumocystis seroprevalence and seroconversion studies.

Background: Sialophorin is a transmembrane sialoglycoprotein. Normally, the molecule is only produced by white blood cells where it regulates functions such as intercellular adhesion, intracellular signalling, apoptosis, migration and proliferation. Methods: Normal breast tissue and primary breast tumours were analysed by immunohistochemistry for sialophorin expression. The sialophorin-positive breast cancer cell line MCF7 was engineered to stably express either non-targeted or sialophorin-targeted small interfering RNA (siRNA). Assays were then performed in vitro to assess apoptosis, intracellular adhesion, transendothelial migration and cytotoxicity. An orthotopic mouse model assayed ability to produce tumours in vivo . Results: Normal breast epithelial cells exhibit expression of the N-terminal domain of sialophorin in the cytoplasm but not the nucleus. The majority of these normal cells are also negative for expression of the C-terminal domain. In contrast, malignant breast epithelial cells exhibit N-terminal expression both in the cytoplasm and nucleus and the majority express the C-terminus in the nucleus. Using differential patterns of intracellular expression of the N and C termini of sialophorin, we define six subtypes of breast cancer that are independent of histological and receptor status classification. Targeting sialophorin with siRNA resulted in the MCF7 breast cancer cell line exhibiting increased homotypic adhesion, decreased transendothelial migration, increased susceptibility to apoptosis, increased vulnerability to lysis by natural killer cells and decreased ability to produce tumours in mice. Conclusion: Our results indicate that intracellular patterns of sialophorin expression define a new molecular classification of breast cancer and that sialophorin represents a novel therapeutic target.

Congenital cytomegalovirus (cCMV) is the leading cause of nongenetic congenital hearing loss in much of the world and a leading cause of neurodevelopmental disabilities. Infected babies can be born to women who are seropositive and seronegative prior to pregnancy, and the incidence is approximately 0.6%-0.7% in the United States. Symptoms vary from mild to severe, and hearing loss can be delayed in onset and progressive. We reviewed the literature to summarize the epidemiology, clinical manifestations, diagnosis, treatment, and future directions of cCMV. The best way to diagnose the infection is with polymerase chain reaction of urine or saliva within 3 weeks after birth, followed by a repeat confirmatory test if positive. Moderately to severely symptomatic neonates should be treated for 6 months with valganciclovir, and some practitioners also choose to treat infants who have isolated hearing loss only. Treatment is not recommended for asymptomatic infants. All infected infants should be screened for hearing loss and neurodevelopmental sequelae. Universal and targeted screening may be cost effective. Currently, no vaccine is commercially available, although multiple candidates are under study. Congenitally acquired cytomegalovirus is found in all communities around the world with a disease burden that is greater than many other well-known diseases. Advances are being made in prevention and treatment; however, improved awareness of the disease among clinicians and patients is needed.

The addition of olanzapine to a neurokinin receptor blocker, a serotonin receptor blocker, and dexamethasone markedly improved the control of nausea and vomiting in previously untreated patients receiving highly emetogenic chemotherapy. Chemotherapy-induced nausea and vomiting are associated with a significant deterioration in quality of life and are perceived by patients as major adverse effects of cancer treatment. 1 The use of 5-hydroxytryptamine type 3 (5-HT 3 ) receptor antagonists, 2 dexamethasone, 2 and neurokinin-1 (NK 1 ) receptor antagonists 3 – 9 has significantly improved the control of this troublesome side effect. International guidelines 10 – 12 recommend combinations of these agents to prevent chemotherapy-induced nausea and vomiting in patients receiving moderately or highly emetogenic chemotherapy. Nonetheless, nausea remains a major problem for many patients. 1 , 2 Olanzapine is approved by the Food and Drug Administration (FDA) as an . . .

Congenital cytomegalovirus (CMV) infection is the leading non-genetic cause of infant hearing loss worldwide, and a significant cause of neurodevelopmental disabilities. Reliance on polymerase chain reaction (PCR) for CMV DNA testing hampers diagnostic and research efforts in low-resource settings and universal screening implementation in high-resource settings. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein (Cas) detection and recombinase polymerase amplification (RPA) can be used together for low-cost viral detection. Here we describe an adaptable RPA-Cas12a assay for CMV DNA quantification based on the WHO international standard. Adequate quantification accuracy was achieved with contrived CMV samples but performance with Sierra Leonean infant saliva remains suboptimal. While improved quantification accuracy will require further optimization, our assay achieves screening test requirements, including > 80% sensitivity/specificity, quicker and more economically than PCR. This work highlights RPA-Cas12a-based assays for DNA quantification and suggests a path towards increased congenital CMV screening using PCR and RPA-Cas12a synergistically.