Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. Although promising new therapies for this incurable disease are being tested in clinical trials, the therapeutic relevance of metabolic rewiring in chronic lymphocytic leukemia (CLL) is poorly understood. The aim of this study was to identify targetable metabolic differences in primary CLL lymphocytes by the use of Dasatinib. Dasatinib is a multi-tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML) and is being tested in clinical trials for several cancers including CLL. This drug has been shown to be beneficial to CML patients suffering from diabetes by reducing their glucose plasma levels. In keeping with this previous observation, we report that Dasatinib induced glucose use while reducing lactate production, suggesting that this tyrosine kinase inhibitor decreases aerobic glycolysis and shifts glucose use in primary CLL lymphocytes. Our results suggest that primary CLL lymphocytes (independently of traditional prognostic factors) can be stratified in two subsets by their sensitivity to Dasatinib in vitro. Increased glucose use induced by Dasatinib or by inhibition of mitochondrial respiration was not sufficient to sustain survival and ATP levels in CLL samples sensitive to Dasatinib. The two subsets of primary CLL lymphocytes are characterized as well by a differential dependency on mitochondrial respiration and the use of anabolic or catabolic processes to cope with induced metabolic/energetic stress. Differential metabolic reprogramming between subsets is supported by the contrasting effect on the survival of Dasatinib treated CLL lymphocytes with pharmacological inhibition of two master metabolic regulators (mTorc1 and AMPK) as well as induced autophagy. Alternative metabolic organization between subsets is further supported by the differential basal expression (freshly purified lymphocytes) of active AMPK, regulators of glucose metabolism and modulators of AKT signaling. The contrasting metabolic features revealed by our strategy could be used to metabolically target CLL lymphocyte subsets creating new therapeutic windows for this disease for mTORC1 or AMPK inhibitors. Indeed, we report that Metformin, a drug used to treat diabetes was selectively cytotoxic to Dasatinib sensitive samples. Ultimately, we suggest that a similar strategy could be applied to other cancer types by using Dasatinib and/or relevant tyrosine kinase inhibitors.

Vertebrate cell surfaces exhibit intricate arrangements of glycosaminoglycan polymers, which are primarily linked to lipids and proteins. Numerous soluble secreted proteins are also decorated with either individual sugar molecules or their polymers. The carbohydrate polymers commonly possess terminal nine-carbon sugars, known as sialic acids. Due to their widespread distribution and strategic positioning, sialic acids play a crucial role in mediating and regulating a wide range of physiologic processes and pathologic conditions. Human- or animal-based investigations predominantly concentrate on the effects of sialic acids during infections, inflammations, vascular disorders, or cancers. Further investigations encompass a variety of applications, including cell–cell interactions, signaling, host–pathogen interactions, and other biological functions associated with nutrition, metabolism, or genetic disorders. Nevertheless, future mechanistic investigations are needed to clarify the specific roles of sialic acids in these varied contexts, so that more effective interventions may be developed.

N-Acetyl-D-mannosamine (ManNAc) and N-acetylneuraminic acid (Neu5Ac) are important components of glycosylation, affecting numerous physiologic processes. The effects of age, body mass index (BMI), race, or sex on serum levels of ManNAc and Neu5Ac are poorly understood. However, these associations are of substantial interest. Simultaneous quantification of ManNAc and Neu5Ac, using liquid chromatography tandem mass spectrometry (LC-MS/MS), was developed and validated for human serum samples. This method has high sensitivity, specificity, and reproducibility, with limits of detection as low as 1.02 ng/mL for ManNAc or 1.14 ng/mL for Neu5Ac. A set of 155 serum samples from the Adventist Health Study 2 (AHS-2) cohort was analyzed. Concentrations of conjugated Neu5Ac were 35.1 ± 9.4 µg/mL and 33.0 ± 9.5 µg/mL in black and white participants, respectively. Conjugated and total Neu5Ac levels were significantly higher in women, with p-values of 0.029 and 0.026, respectively. The free forms of Neu5Ac were 594 ± 421 ng/mL and 439 ± 168 ng/mL in black and white participants, respectively. Similarly, conjugated and total ManNAc levels were higher in black participants, at 1.81 ± 0.81 µg/mL and 1.90 ± 0.83 µg/mL, compared to 1.32 ± 0.52 µg/mL and 1.41 ± 0.53 µg/mL in white participants (both cases, p < 0.001). Free ManNAc was 93.1 ± 36.2 ng/mL in black and 89 ± 20.2 ng/mL in white participants. Subjects with higher BMI tend to have higher free ManNAc (p = 0.041). Furthermore, older subjects tend to have higher free (p ≤ 0.001) and total (p = 0.045) ManNAc. The improved LC-MS/MS quantification method should facilitate further investigations.

Toll-like receptors (TLRs) may be involved both in the initial failure of viral clearance and in the subsequent development of severe clinical manifestations of COVID-19, essentially ARDS (acute respiratory distress syndrome) with fatal respiratory failure. We present the gene expression of TLR 3, 4, and 7 in nasopharyngeal total RNA samples from 150 individuals positive for SARS Cov2 (DET) by molecular techniques of isothermal amplification (Neokit SA) and 152 SARS Cov2 non detectable (ND) ambulatory and hospitalized patients with a non-defined respiratory disease, and we compared with the symptomatology developed by all those patients. We analyzed 4 cohorts: 1-SARS Cov2 genome detected patients with severe to high symptomatology (n=107); 2-SARS Cov2 genome detected patients low to mild symptomatology (n=43); 3-SARS Cov2 genome non detected patients with severe to high symptomatology (n=109); and 4-SARS Cov2 genome non detected patients low to mild symptomatology (n=41). Our results not only contradict few previous study, it also corrects for sample size bias, showing no significant differences of expression for TLR3, TLR4 and TLR7 between SARS Cov2 DET and ND total cohort of patients (Non Paired T –Test p Value>0.1). When compared severity of symptoms -presence of symptoms from the COVID-19 12 WHO diagnosis symptoms- and gene expression, here we found significant positive correlation between severe symptomatology, and the number of symptoms and death for TLR4 and TLR7 for both DET and ND COVID-19 patients. When the cohort was construct with low/middle and severe symptoms, the Correlation Coefficient showed that expression of TLR4 and TLR7 was significantly amplified in those ND patients with severe symptomatology ( p Value = 0.00311) as well as for TLR3 in ND low to mild symptoms cohort of patients. We also showed and discussed the results obtained of these genes expression and the sex and age of patients. In summary, our data suggest that although our innate immune system with TLRs contributes to the elimination of viruses, it can also be associated with harm to the host due to persistent inflammation and tissue destruction. We confirmed that principally TLR4 and TLR7 could be involved not only in the pathogenesis of COVID□19 but also in other respiratory diseases with same symptomatology. We agree with previous studies that treatments focus on TLR4 and TLR7 expression in inflammatory respiratory diseases could be a start point against severe symptoms development.

ESSIAC tea is a traditional multi-herb infusion or decoction widely used by cancer patients as a complementary therapy. Originally employed in traditional Ojibwa medicine, it was later reformulated by a Canadian nurse. The classic ESSIAC infusion contains four main botanicals: burdock root (Arctium lappa), Turkish rhubarb root (Rheum palmatum), sheep sorrel (Rumex acetosella), and slippery elm bark (Ulmus rubra). Commercial variations (e.g., FlorEssence® and Genuine ESSIAC™) expand this list to include blessed thistle (Cnicus benedictus), kelp (edible Laminaria seaweeds), red clover (Trifolium pratense), and watercress (Nasturtium officinale). Although they are commercially available, human safety data are limited. We conducted an exploratory analysis registered at the Central Ethics Entre Ríos Provincial Committee Board, of the Provincial Minister, and Ethical Committee of CCT-CONICET Santa Fe (Committee Ref #: CES-00641) to evaluate the safety and DNA‐protective effects by comet assay of an 8-herb tea in healthy adults and compared it to a traditional infusion of mate cocido, of Ilex paraguariensis. Participants consumed 200 mL/day for 6 weeks; pre- and post-assessments included blood chemistry and an alkaline comet assay. Twenty‑four participants completed the study (12 per arm). Adherence was high, and no serious adverse events occurred. Laboratory indices remained within reference ranges in both groups, as well as for DNA damage, as the percent DNA comet tail declined from week 0 or baseline in both arms. Overall, daily ESSIAC tea was well tolerated and did not adversely affect laboratory indices. The observed genoprotective trend in both groups is consistent with the antioxidant phytochemicals present in the herbal infusion. These results support the safety of ESSIAC tea and justify larger trials to assess its complementary roles.