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Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.

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Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax.

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Oral squamous cell carcinoma (OSCC) is a frequent human malignancy that demonstrates a range of genetic and epigenetic alterations. Histone deacetylases (HDACs) are key epigenetic regulators of cell-cycle progression, differentiation and apoptosis and their dysregulation is implicated in cancer development. HDACs are promising targets for anticancer therapy through the utilisation of HDAC inhibitors (HDACis). OSCC cells have been shown to have low levels of histone acetylation, suggesting that HDACis may produce beneficial effects in patients with OSCC. Valproic acid (VPA) is a class I and IIa HDACi and, therefore, may be useful in anticancer therapy. VPA has been reported as a chemo-preventive epigenetic agent in individuals with high-risk oral dysplasia (OD) and thus associated with a reduced risk of HNSCC. It is hypothesised that HDAC inhibition by VPA triggers a change in the expression levels of different HDAC family gene-members. The present review summarises the current literature on HDAC expression changes in response to VPA in oral cancer patients and in vitro studies in an effort to better understand the potential epigenetic impact of VPA treatment. The present review outlined the need for exploring supportive evidence of the chemo-preventive role played by VPA-based epigenetic modification in treating oral pre-cancerous lesions and, thus, providing a novel tolerable chemotherapeutic strategy for patients with oral cancer.

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Objective: Speech tests assess the ability of people with hearing loss to comprehend speech with a hearing aid or cochlear implant. The tests are usually at the word or sentence level. However, few tests analyze errors at the phoneme level. So, there is a need for an automated program to visualize in real time the accuracy of phonemes in these tests. Method: The program reads in stimulus-response pairs and obtains their phonemic representations from an open-source digital pronouncing dictionary. The stimulus phonemes are aligned with the response phonemes via a modification of the Levenshtein Minimum Edit Distance algorithm. Alignment is achieved via dynamic programming with modified costs based on phonological features for insertion, deletions and substitutions. The accuracy for each phoneme is based on the F1-score. Accuracy is visualized with respect to place and manner (consonants) or height (vowels). Confusion matrices for the phonemes are used in an information transfer analysis of ten phonological features. A histogram of the information transfer for the features over a frequency-like range is presented as a phonemegram. Results: The program was applied to two datasets. One consisted of test data at the sentence and word levels. Stimulus-response sentence pairs from six volunteers with different degrees of hearing loss and modes of amplification were analyzed. Four volunteers listened to sentences from a mobile auditory training app while two listened to sentences from a clinical speech test. Stimulus-response word pairs from three lists were also analyzed. The other dataset consisted of published stimulus-response pairs from experiments of 31 participants with cochlear implants listening to 400 Basic English Lexicon sentences via different talkers at four different SNR levels. In all cases, visualization was obtained in real time. Analysis of 12,400 actual and random pairs showed that the program was robust to the nature of the pairs. Conclusion: It is possible to automate the alignment of phonemes extracted from stimulus-response pairs from speech tests in real time. The alignment then makes it possible to visualize the accuracy of responses via phonological features in two ways. Such visualization of phoneme alignment and accuracy could aid clinicians and scientists.

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The effects of feeding essential oils and(or) benzoic acid to finishing steers on fatty acid profile and oxidative stability (color and lipid oxidation) of beef longissimus thoracis steaks and ground beef was determined in this study. Beef was procured from crossbred beef steers (n = 63) fed one of five dietary treatments: (1) control (no antibiotics fed); (2) monensin/tylosin (monensin supplemented at 33 mg/kg [DM basis]; tylosin supplemented at 11 mg/kg [DM basis]); (3) essential oils (supplemented at 1.0 g/steer/day); (4) benzoic acid (supplemented at 0.5% [DM basis]); and (5) combination (essential oils supplemented at 1.0 g/steer/day and benzoic acid supplemented at 0.5% [DM basis]). Although no improvements in shelf life stability were observed, feeding finishing cattle essential oils and(or) benzoic acid did not have detrimental impacts on beef color stability and lipid oxidation over a simulated retail display period.

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Quality of the dietary protein in foods rather than amount of dietary protein may be of greater importance from a human health and wellness standpoint. Various systems are in place to determine the value of dietary protein. Protein digestibility-corrected amino acid score (PDCAAS) and digestible indispensable amino acid score (DIAAS) are the two major protein standards used to determine the completeness of proteins by their unique concentration and digestibility of indispensable amino acids. The purpose of this review was to provide a comprehensive comparison of the amino acid concentration of high protein foods and provide the current status of the use and practicality of the PDCAAS and DIAAS system. This review builds upon previous research analyzing the total nutrient density of protein-rich foods and expands scientific research investigating the quality of proteins. In summary, the average sum of indispensable amino acids for meat and fish products is much more consistent than that of non-meat and plant-based food products. However, some non-meat products have relatively similar amounts of indispensable amino acids on a similar serving size basis. The overwhelming aspect of determining protein quality is that greater research is needed to determine protein digestibility of food products.

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This study was to evaluate the mechanistic effect of protein to help better interpret the permeability results for compounds with low mass balance in Caco-2 permeability assay. The absorptive or bi-directional permeability of lipophilic compounds with mass balance were measured across Caco-2 cell monolayers as well as the empty transport devices with or without protein (4% bovine serum albumin, BSA) added to the receiver side. The results from empty transport device study indicated that the filter membrane is a permeability barrier for the low mass balance compounds and protein increases permeability by improving the compound diffusivity through the filter membrane. Caco-2 permeability measured with protein provided better absorption projection. Assuming the amount of compound associated with cells as transported did not correlate with absorption. For efflux substrate identification using Caco-2 bi-directional permeability assay, protein at the receiver side had no significant effect on the conclusion regarding the tested compounds as efflux substrate but increased the permeability measurement from both transport directions. In conclusions, Caco-2 permeability results measured using protein-containing buffer at the receiver side for low mass balance compound seems to provide better correlation with in vivo absorption. The fact that protein at receiver side has minimal effect on efflux substrate identification provides scientific basis for further specific transporter characterization (such as P-gp or BCRP) using specific inhibitors, in which same concentration of inhibitor is used in both sides of the Caco-2 cell system and protein for optimal permeability assessment has to be avoided.

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