Categorical Dimensions of Human Odor Descriptor Space Revealed by Non-Negative Matrix Factorization

In contrast to most other sensory modalities, the basic perceptual dimensions of olfaction remain unclear. Here, we use non-negative matrix factorization (NMF) – a dimensionality reduction technique – to uncover structure in a panel of odor profiles, with each odor defined as a point in multi-dimensional descriptor space. The properties of NMF are favorable for the analysis of such lexical and perceptual data, and lead to a high-dimensional account of odor space. We further provide evidence that odor dimensions apply categorically. That is, odor space is not occupied homogenously, but rather in a discrete and intrinsically clustered manner. We discuss the potential implications of these results for the neural coding of odors, as well as for developing classifiers on larger datasets that may be useful for predicting perceptual qualities from chemical structures

Quality of life in metastatic pancreatic cancer patients receiving liposomal irinotecan plus 5-fluorouracil and leucovorin

Abstract Background The NAPOLI-1 study (NCT01494506) reported that liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) improved overall survival vs 5-FU/LV with manageable toxicity in patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy. Yet, clinicians need treatment strategies that also maintain the patient's health-related quality of life (HRQOL). Here, we report the HRQOL data. Methods Patients completed the European Organisation for Research and Treatment of Cancer QOL core questionnaire C30 (EORTC QLQ-C30) at baseline, every 6 weeks, and at 30 days after discontinuation of study treatment. Patient-reported outcomes (PROs) were scored according to EORTC guidelines. nal-IRI+5-FU/LV HRQOL was compared with 5-FU/LV. The PRO population comprised intent-to-treat patients who completed baseline and at least one subsequent assessment on the EORTC QLQ-C30. Data were also analysed for missingness. Results Of 236 patients in the intent-to-treat population, 128 (54.2%) comprised the PRO population (71 in the nal-IRI+5-FU/LV arm; 57 the in 5-FU/LV arm). Of the remaining 108 patients (45.8%) not included in the PRO population, most progressed rapidly, making participation difficult. Median change from baseline was ≤10 points at weeks 6 and 12 in global health status or functional and symptom scale scores, except for fatigue, which deteriorated by 11.1 points with nal-IRI+5-FU/LV but did not change vs 5-FU/LV. The proportion of patients whose HRQOL improved or deteriorated was not significantly different between the arms. Conclusion In the NAPOLI-1 study, HRQOL was maintained with nal-IRI+5-FU/LV in patients with metastatic pancreatic adenocarcinoma previously treated with a gemcitabine-based regimen, while survival was significantly extended

A RAS-Independent Biomarker Panel to Reliably Predict Response to MEK Inhibition in Colorectal Cancer

Background: In colorectal cancer (CRC), mutations of genes associated with the TGF-β/BMP signaling pathway, particularly affecting SMAD4, are known to correlate with decreased overall survival and it is assumed that this signaling axis plays a key role in chemoresistance. Methods: Using CRISPR technology on syngeneic patient-derived organoids (PDOs), we investigated the role of a loss-of-function of SMAD4 in sensitivity to MEK-inhibitors. CRISPR-engineered SMAD4R361H PDOs were subjected to drug screening, RNA-Sequencing, and multiplex protein profiling (DigiWest®). Initial observations were validated on an additional set of 62 PDOs with known mutational status. Results: We show that loss-of-function of SMAD4 renders PDOs sensitive to MEK-inhibitors. Multiomics analyses indicate that disruption of the BMP branch within the TGF-β/BMP pathway is the pivotal mechanism of increased drug sensitivity. Further investigation led to the identification of the SFAB-signature (SMAD4, FBXW7, ARID1A, or BMPR2), coherently predicting sensitivity towards MEK-inhibitors, independent of both RAS and BRAF status. Conclusion: We identified a novel mutational signature that reliably predicts sensitivity towards MEK-inhibitors, regardless of the RAS and BRAF status. This finding poses a significant step towards better-tailored cancer therapies guided by the use of molecular biomarkers

Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer

Purpose: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. Experimental Design: In ARMOR1, 49 patients received increasing doses (650–2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700–3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. Results: In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. Conclusions: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition

Gel–Polymer Electrolytes Based on Poly(Ionic Liquid)/Ionic Liquid Networks

The use of electrically charged, polymerized ionic liquids (polyILs) offers opportunities for the development of gel–polymer electrolytes (GPEs), but the rational design of such systems is in its infancy. In this work, we compare the properties of polyIL/IL GPEs based on 1-butyl-3-(4-vinylbenzyl)imidazolium bis(trifluromethanesulfonyl)imide containing trapped ammonium-based protic ionic liquids (ILs) with an analogous series based on the electrically neutral host polymer 1-(4-vinylbenzyl)imidazole. The materials are synthesized by photopolymerizing ionic and neutral monomers in the presence of diethylmethylammonium trifluoromethanesulfonate, [dema][TfO], diethylmethylammonium trifluoroacetate, [dema][TFAc], and diethylmethylammonium bis[trifluoromethanesulfonyl]imide, [dema][Tf2N], respectively. The resulting materials are characterized using electron microscopy, infrared spectroscopy, thermal analysis, Raman spectroscopy, and AC-impedance analysis. Spectroscopic analysis confirms that the ILs are distributed throughout the polymers, unless the GPE also contains poly(diallyldimethylammonium) bis[trifluoromethanesulfonyl]imide, when separation of the components occurs. The polyIL/IL GPEs are more electrochemically and thermally stable, and up to six times more conductive, than the materials based on the neutral host. As a proof-of-concept demonstration, we show that polyIL/IL gels can be 3D printed using readily available 3D-printing hardware

Acetic Acid Bacteria: Physiology and Carbon Sources Oxidation

Acetic acid bacteria (AAB) are obligately aerobic bacteria within the family Acetobacteraceae, widespread in sugary, acidic and alcoholic niches. They are known for their ability to partially oxidise a variety of carbohydrates and to release the corresponding metabolites (aldehydes, ketones and organic acids) into the media. Since a long time they are used to perform specific oxidation reactions through processes called “oxidative fermentations”, especially in vinegar production. In the last decades physiology of AAB have been widely studied because of their role in food production, where they act as beneficial or spoiling organisms, and in biotechnological industry, where their oxidation machinery is exploited to produce a number of compounds such as l-ascorbic acid, dihydroxyacetone, gluconic acid and cellulose. The present review aims to provide an overview of AAB physiology focusing carbon sources oxidation and main products of their metabolism

Rectal Carriage of Extended-Spectrum Beta-Lactamase-Producing Gram-Negative Bacilli in Community Settings in Madagascar

BACKGROUND: Extended-spectrum ß-lactamase-producing Enterobacteria (ESBL-PE) emerged at the end of the 1980s, causing nosocomial outbreaks and/or hyperendemic situations in hospitals and long-term care facilities. In recent years, community-acquired infections due to ESBL-PE have spread worldwide, especially across developing countries including Madagascar. OBJECTIVES: This study aimed to determine the prevalence and risk factors of intestinal carriage of ESBL-PE in the community of Antananarivo. METHODS: Non-hospitalized patients were recruited in three health centers in different socio economic settings. Fresh stool collected were immediately plated on Drigalski agar containing 3 mg/liter of ceftriaxone. Gram-negative bacilli species were identified and ESBL production was tested by a double disk diffusion (cefotaxime and ceftazidime +/- clavulanate) assay. Characterization of ESBLs were perfomed by PCR and direct sequencing . Molecular epidemiology was analysed by Rep-PCR and ERIC-PCR. RESULTS: 484 patients were screened (sex ratio  = 1.03, median age 28 years). 53 ESBL-PE were isolated from 49 patients (carrier rate 10.1%). The isolates included Escherichia coli (31), Klebsiella pneumoniae (14), Enterobacter cloacae (3), Citrobacter freundii (3), Kluyvera spp. (1) and Pantoae sp.(1). In multivariate analysis, only the socioeconomic status of the head of household was independently associated with ESBL-PE carriage, poverty being the predominant risk factor. CONCLUSIONS: The prevalence of carriage of ESBL in the community of Antananarivo is one of the highest reported worldwide. This alarming spread of resistance genes should be stopped urgently by improving hygiene and streamlining the distribution and consumption of antibiotics

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue lacking visible organization. We sought to define transcriptional states of colorectal cancer cells and signals controlling their development by performing single-cell transcriptome analysis of tumors and matched non-cancerous tissues of twelve colorectal cancer patients. We defined patient-overarching colorectal cancer cell clusters characterized by differential activities of oncogenic signaling pathways such as mitogen-activated protein kinase and oncogenic traits such as replication stress. RNA metabolic labeling and assessment of RNA velocity in patient-derived organoids revealed developmental trajectories of colorectal cancer cells organized along a mitogen-activated protein kinase activity gradient. This was in contrast to normal colon organoid cells developing along graded Wnt activity. Experimental targeting of EGFR-BRAF-MEK in cancer organoids affected signaling and gene expression contingent on predictive KRAS/BRAF mutations and induced cell plasticity overriding default developmental trajectories. Our results highlight directional cancer cell development as a driver of non-genetic cancer cell heterogeneity and re-routing of trajectories as a response to targeted therapy