Cold atmospheric plasma enhances morphological and biochemical attributes of tomato seedlings.

Cold atmospheric plasma (CAP) is a physical technology with notable effects on living organisms. In the present study, tomato seeds (Solanum lycopersicum var. Bassimo Mill.) were exposed to CAP for various time intervals, ranging from 1 to 5 min, in both continuous and intermittent periods, and were compared with a control group that received no CAP treatment. Seedlings grown from treated seeds exhibited improvements in levels of growth traits, photosynthetic pigments, and metabolite contents when compared to the control group. Seedlings from seeds treated with S04 displayed significant increases in shoot and root lengths, by 32.45% and 20.60% respectively, compared to the control group. Moreover, seedlings from seeds treated with S01 showed a 101.90% increase in total protein, whereas those treated with S02 experienced a 119.52% increase in carbohydrate content. These findings highlight the substantial improvements in growth characteristics, photosynthetic pigments, and metabolite levels in seedlings from treated seeds relative to controls. Total antioxidant capacity was boosted by CAP exposure. The activities of enzymes including superoxide dismutase, catalase, and peroxidases were stimulated by S02 and exceeded control treatment by (177.48%, 137.41%, and 103.32%), respectively. Additionally, exposure to S04 increased the levels of non-enzymatic antioxidants like flavonoids, phenolics, saponins, and tannins over the control group (38.08%, 30.10%, 117.19%, and 94.44%), respectively. Our results indicate that CAP-seed priming is an innovative and cost-effective approach to enhance the growth, bioactive components, and yield of tomato seedlings.

Carcinogenesis and Prognostic Utility of Arginine Methylation-Related Genes in Hepatocellular Cancer.

Protein arginine methylation is among the most important post-translational modifications and has been studied in cancers such as those of the lung and breast. However, comparatively less has been investigated regarding hepatocellular carcinoma, with an annual incidence of almost one million cases. Through using in silico methods, this study examined arginine methylation-related gene expression and methylation levels, and alongside network and enrichment analysis attempted to find how said genes can drive tumorigenesis and offer possible therapeutic targets. We found a robust relationship among the selected methylation genes, with ⅞ showing prognostic value regarding overall survival, and a medley of non-arginine methylation pathways also being highlighted through the aforementioned analysis. This study furthers our knowledge of the methylation and expression patterns of arginine histone methylation-related genes, offering jumping points for further wet-lab studies.

Regulation of SELENOF translation by eIF4a3: Possible role in prostate cancer progression.

The levels of the SELENOF selenoprotein are dramatically reduced in prostate cancer compared to adjacent benign tissue and reducing SELENOF in prostate epithelial cells results in the acquisition of features of the transformed phenotype. It was hypothesized that the aberrant increase in the eiF4a3 translation factor, which has an established role in RNA splicing and the regulation of selenoprotein translation, contributes to the lower levels of SELENOF. Using the available databases, eIF4a3 messenger RNA (mRNA) levels are elevated in prostate cancer compared to normal tissue as is the hypomethylation of the corresponding gene. Using a prostate cancer tissue microarray, we established that eiF4a3 levels are higher in prostate cancer tissue. Ectopic expression of eIF4a3 in prostate cancer cells reduced SELENOF levels and attenuated the readthrough of the UGA codon using a specialized reporter construct designed to examine UGA decoding, with the opposite effects observed using eIF4a3 knock-down constructs. Direct binding of eIF4a3 to the regulatory regions of SELENOF mRNA was established with pull-down experiments. Lastly, we show that an eIF4a3 inhibitor, eIF4a3-IN-2, increases SELENOF levels, UGA readthrough, and reduces binding of eIF4a3 to the SELENOF mRNA 3'-UTR in exposed cells. These data establish eIF4a3 as a likely prostate cancer oncogene and a regulator of SELENOF translation.

Associations of selenoprotein expression and gene methylation with the outcome of clear cell renal carcinoma.

Selenoproteins are a ubiquitous class of proteins defined by having a selenocysteine amino acid residue. While many of the selenoproteins have been well characterized with important roles in oxidation-reduction reactions and hormone synthesis among others, there exist some whose biological roles are not as well understood as denoted by the "SELENO" root. In this study, we explored associations between the reported RNA levels of "SELENO" proteins and clear cell renal cell carcinoma (ccRCC), the most common subtype of renal carcinoma in the US. Utilizing The Cancer Genome Atlas (TCGA) alongside other in silico tools, we discovered higher mRNA expression of Selenoprotein I, T, and P was associated with better overall survival outcomes and differential expression of other selenoproteins based on tumor stage. Additionally, we uncovered relative hypomethylation among selenoproteins in primary ccRCC tumor samples compared to normal tissue. Network and enrichment analysis showed numerous genes through which selenoproteins may modulate cancer progression and outcomes such as DERL1, PNPLA2/3, MIEN1, and FOXO1 which have been well-described in other cancers. In light of our findings highlighting an association of selenoprotein methylation and expression patterns with ccRCC outcome, further wet lab research is warranted.

Increased Glucagon Immunoreactivity in a Rat Model of Diet-induced Obesity following Sleeve Gastrectomy.

OBJECTIVE: Bariatric surgery is currently the most effective treatment for obesity, and procedures such as Roux-en Y gastric bypass and sleeve gastrectomy (SG) also result in rapid improvements in insulin sensitivity and glucose tolerance. In addition, these procedures cause changes in the secretion of various gut-derived hormones. The role these hormones play in the mechanism of the beneficial effects of bariatric surgery is still debated, but nonetheless, their importance provides inspiration for novel obesity-targeted pharmacotherapies. METHODS: Male Sprague Dawley rats were fed either regular chow or a cafeteria diet to induce obesity. A sub-group of the obese animals then underwent either sham surgery or SG. RESULTS: Following a 4-week recovery period, SG rats weighed significantly less than obese or sham-operated rats. Improvements in glucose tolerance and insulin sensitivity also occurred in the SG group, but these were not always statistically significant. We measured the intracellular lipid content of liver samples and found that obese rats showed signs of non-alcoholic fatty liver disease, which were significantly ameliorated by SG. There were significantly higher glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses to a standard mixed meal in the SG group, as well as paradoxically higher glucagon secretion. CONCLUSION: These data highlight the need for more specific anti-glucagon antibodies to characterize the changes in proglucagon-derived peptide concentrations that occur following SG. Further studies are required to determine whether these peptides contribute to the therapeutic effects of SG.

Pyruvate produced by Brugia spp. via glycolysis is essential for maintaining the mutualistic association between the parasite and its endosymbiont, Wolbachia.

Human parasitic nematodes are the causative agents of lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness), diseases that are endemic to more than 80 countries and that consistently rank in the top ten for the highest number of years lived with disability. These filarial nematodes have evolved an obligate mutualistic association with an intracellular bacterium, Wolbachia, a symbiont that is essential for the successful development, reproduction, and survival of adult filarial worms. Elimination of the bacteria causes adult worms to die, making Wolbachia a primary target for developing new interventional tools to combat filariases. To further explore Wolbachia as a promising indirect macrofilaricidal drug target, the essential cellular processes that define the symbiotic Wolbachia-host interactions need to be identified. Genomic analyses revealed that while filarial nematodes encode all the enzymes necessary for glycolysis, Wolbachia does not encode the genes for three glycolytic enzymes: hexokinase, 6-phosphofructokinase, and pyruvate kinase. These enzymes are necessary for converting glucose into pyruvate. Wolbachia, however, has the full complement of genes required for gluconeogenesis starting with pyruvate, and for energy metabolism via the tricarboxylic acid cycle. Therefore, we hypothesized that Wolbachia might depend on host glycolysis to maintain a mutualistic association with their parasitic host. We did conditional experiments in vitro that confirmed that glycolysis and its end-product, pyruvate, sustain this symbiotic relationship. Analysis of alternative sources of pyruvate within the worm indicated that the filarial lactate dehydrogenase could also regulate the local intracellular concentration of pyruvate in proximity to Wolbachia and thus help control bacterial growth via molecular interactions with the bacteria. Lastly, we have shown that the parasite's pyruvate kinase, the enzyme that performs the last step in glycolysis, could be a potential novel anti-filarial drug target. Establishing that glycolysis is an essential component of symbiosis in filarial worms could have a broader impact on research focused on other intracellular bacteria-host interactions where the role of glycolysis in supporting intracellular survival of bacteria has been reported.

Improved Sleep Quality Improves Blood Pressure Control among Patients with Chronic Kidney Disease: A Pilot Study.

BACKGROUND: Despite the abundance of data documenting the consequences of poor sleep quality on blood pressure (BP), no previous study to our knowledge has addressed the impact of sleep improvement on resistant hypertension among patients with chronic kidney disease (CKD). METHODS: The aim of this pilot study was to determine whether improved sleep quality and duration will improve BP control in patients with resistant hypertension and CKD. It was a prospective single-center cohort study that involved 30 hypertensive subjects with CKD presenting with primary resistant hypertension and poor sleep quality or duration <6 h/night. Sleep quality and duration were modified using either sleep hygiene education alone or adding sleep medication. The cohort's BP was followed every 3 months for 6-month duration. The average home and clinic BPs were collected at each follow-up visit. The primary outcome baseline change in systolic BP (SBP) and diastolic BP (DBP; home and clinic) at 3 and 6 months after documented sleep improvement. Secondary outcomes included change from baseline in mean arterial pressure, and delta SBP after sleep improvement. RESULTS: African American patients represented 50% of the cohort. All patients had evidence of CKD with GFR ≤60 mL/min and were obese with 40% having type 2 diabetes mellitus. The primary endpoint of change in clinic SBP and DBP was significantly reduced at 3 months, baseline 156 ± 15/88 ± 8 vs. 3 months 125 ± 14/73 ± 7 (p < 0.0001). This difference persisted at 6 months. However, there was no further reduction in-home or clinic BPs between the 3- and 6-month periods. Home and clinic average delta SBP change at 3 months from baseline was -34.4 ± 15 and -30.8 ± 19 mm Hg respectively. Delta SBP change was associated with sleep improvement of >6 h/night, that is, gaining an extra 3-4 h' sleep duration, home; R2 = 0.66, p < 0.0001 and clinic; R2 = 0.49, p < 0.0001. CONCLUSION: Optimizing sleep quality and duration to >6 h/night improved BP control and was associated with a significant delta change in SBP within 3 months of follow-up. Physicians should obtain a sleep history in patients with CKD who present with resistant hypertension.

Evolution of Patiromer Use: a Review.

PURPOSE OF REVIEW: The purpose of this review is to present data from clinical trials that resulted in the key data supporting the use of patiromer as a potassium binder in clinical practice today. RECENT FINDINGS: In addition to trials that support the current Food and Drug Administration label and published over the past 3 years, the recently published Spironolactone With Patiromer in the Treatment of Resistant Hypertension in Chronic Kidney Disease (AMBER) trial provides clear benefits of patiromer use in a group of resistant hypertension patients. The AMBER was a phase 2, multicenter, randomized, double-blind, parallel-group, placebo-controlled study that evaluated 295 participants stratified by local serum potassium measurement (4.3 to < 4.7 mmol/L vs 4.7 to 5.1 mmol/L) and history of diabetes and chronic kidney disease. The focus was on enabling participants with resistant hypertension to achieve blood pressure goals by using spironolactone. Additionally, the ongoing Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure (DIAMOND) trial is designed to demonstrate how patiromer is an "enabler" of therapies that are needed to either control resistant hypertension or reduce mortality in heart failure but generate hyperkalemia. These and other studies are discussed in detail. Patiromer is one of two new potassium binders that are far better tolerated than the previous agent and can be given chronically to participants who need life-saving therapies but have elevations of potassium into a dangerous range as a consequence.

The Management of Hypertension in 2018: What Should the Targets Be?

PURPOSE OF REVIEW: To provide an overview of the different guidelines for hypertension management from around the world. RECENT FINDINGS: The guidelines discussed include those from the United States (US), Europe, Canada, and Latin America. All guidelines except the US define hypertension as > 140/90 mmHg, and the US defines it as > 130/80 mmHg. In general, all guidelines except those from the US emphasize lifestyle modification as the cornerstone of initial therapy given blood pressure levels < 140/90 mmHg. The US emphasizes lifestyle modification at all BP levels starting at 130/80 mmHg. Additionally, all guidelines emphasize the need to assess cardiovascular risk with the Canadian guidelines indicating that a high cardiovascular risk person should have a goal of < 130/80 mmHg. All agree on the proper method of blood pressure measurement techniques and importance of home blood pressure. All support use combination therapy with the European guideline emphasizing initial therapy should be a combination pill. All guidelines stress the importance of patient adherence to maintain blood pressure control. All guidelines emphasize lifestyle modification, need for home blood pressure measurement, as well as use of proper techniques to measure blood pressure. The fundamental difference between US and all other guidelines is the definition of hypertension, > 130/80 mmHg in US and > 140/90 mmHg in the rest of the world.

Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras.

K-Ras mutations are frequent in colorectal cancer (CRC), albeit K-Ras is the only Ras isoform that can elicit apoptosis. Here, we show that mutant K-Ras directly binds to the tumor suppressor RASSF1A to activate the apoptotic MST2-LATS1 pathway. In this pathway LATS1 binds to and sequesters the ubiquitin ligase Mdm2 causing stabilization of the tumor suppressor p53 and apoptosis. However, mutant Ras also stimulates autocrine activation of the EGF receptor (EGFR) which counteracts mutant K-Ras-induced apoptosis. Interestingly, this protection requires the wild-type K-Ras allele, which inhibits the MST2 pathway in part via AKT activation. Confirming the pathophysiological relevance of the molecular findings, we find a negative correlation between K-Ras mutation and MST2 expression in human CRC patients and CRC mouse models. The small number of tumors with co-expression of mutant K-Ras and MST2 has elevated apoptosis rates. Thus, in CRC, mutant K-Ras transformation is supported by the wild-type allele.

Design, synthesis, analgesic, anti-inflammatory activity of novel pyrazolones possessing aminosulfonyl pharmacophore as inhibitors of COX-2/5-LOX enzymes: Histopathological and docking studies.

A series of newly synthesized 4-aryl-hydrazonopyrazolones were designed and their structures were confirmed by spectral and elemental analyses. All synthesized compounds were evaluated for their in vitro COXs, 5-LOX inhibition, in vivo analgesic and anti-inflammatory activities. Compounds 5d, 5f and 5i were found to be the most potent COX-2/5-LOX inhibitors with superior COX-2 selectivity index values (SI = 5.29-5.69) to reference standard celecoxib (SI = 3.52). Four compounds; 5b, 5c, 5d and 5f showed excellent anti-inflammatory activity (% edema inhibition = 72.72-54.54%) and perfect ED50 values (ED50 = 0.044-0.104 mmol/kg) relative to celecoxib (ED50 = 0.032 mmol/kg). To explore the most active compounds, ulcerogenic effect on stomach in comparison with indomethacin and celecoxib in addition to histopathological investigations were performed. Compound 5f showed better gastric profile (UI = 2.33) than celecoxib (UI = 3.00). Also, 5f caused 50% increase in thermal pain threshold close to reference drug indomethacin (53.13%). Docking study of all the target compounds into COX-2 and 5-LOX active sites was performed to rational their anti-inflammatory activities.

Non-acidic 1,3,4-trisubstituted-pyrazole derivatives as lonazolac analogs with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile.

Twelve new compounds of 1,3,4-trisubstituted-pyrazole derivatives possessing two cyclooxygenase-2 (COX-2) pharmacophoric moieties (SO2Me or/and SO2NH2) 11a-c, 12a-c, 13a-c and 14a-c were designed and synthesized to be evaluated for their COX inhibition, anti-inflammatory activity, ulcerogenic liability. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. The bisaminosulphonyl derivatives (14a-c) were the most COX-2 selective compounds (S.I. = 9.87, 9.50 and 9.22 respectively) and showed good anti-inflammatory potency (ED50 = 15.06, 42.51 and 50.43 µmol/kg respectively) in comparison with celecoxib (COX-2 S.I. = 8.61, ED50 = 82.2 µmol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexes = 2.72-3.72) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.93). In addition, to explain the preferential (COX-2) inhibitory and selectivity, the designed compounds were subjected to molecular docking studies. It was found that compound 14c with the highest COX-2 activity and selectivity exhibited a binding pattern and interactions similar to that of celecoxib with formation of more hydrogen-bond features.

Quantification of furosemide in camel plasma by high resolution mass spectrometry, application on pharmacokinetics.

We developed and validated a high-resolution liquid chromatography mass spectrometry method for the quantification of furosemide in camel plasma which was used for a pharmacokinetic study in camels. Plasma samples were extracted by supported liquid extraction and furosemide and internal standard (furosemide-D5) were separated on a an Agilent Zorbax XDB C18 column (50 × 2.1 mm i.d., 3.5 µm). Data was acquired in full-scan mode over a mass range of 200-400 Da in negative electrospray mode at a resolution of 70,000. Linear calibration curves were obtained over the concentration ranges of 1.0-10,000 ng/mL. The validated method was then successfully applied in evaluating the pharmacokinetics and metabolites of furosemide in six camels (Camelus dromedarus) and we were able to advice on a withdrawal time of furosemide treatment before racing.

Cyclooxygenase-2 and 15-lipoxygenase inhibition, synthesis, anti-inflammatory activity and ulcer liability of new celecoxib analogues: Determination of region-specific pyrazole ring formation by NOESY.

Two new series of 1,5-diaryl pyrazoline (3a-f) and 1,5-diaryl pyrazole (5a and 5b) were designed as both COX-2 and 15-LOX inhibitors. All the prepared compounds were fully characterized by all spectral and element analysis. Their anti-inflammatory activity and ulcer index were included. Pyrazoline 3f is the most effective with IC50=1.14 and 4.7µM against COX-2 and 15-LOX respectively, and more potent than celecoxib and meclofenamate references. In addition 3a, 3b, 5a, and 5b were safer with low ulcer index than celecoxib. Docking study was performed for the most active compounds such as 2b, 3a, and 3f on COX-2 and 15-LOX enzymes.

Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of new 1,5-diarylpyrazole derivatives.

A new series of 1,5-diarylpyrazoles 10a-l was designed and synthesized for evaluation as COX inhibitors and as anti-inflammatory agents. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Compound 10e was the most COX-2 selective compound (S.I. = 10.67) and the most potent anti-inflammatory derivative (ED50 = 46 µmol/kg) which is approximately 11-folds more potent than ibuprofen (ED50 = 499 µmol/kg) and had 2/3 potency of celecoxib (ED50 = 31 µmol/kg). All compounds were less ulcerogenic (ulcer indexes = 1.20-4.61) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.90).

Big data: survey, technologies, opportunities, and challenges.

Big Data has gained much attention from the academia and the IT industry. In the digital and computing world, information is generated and collected at a rate that rapidly exceeds the boundary range. Currently, over 2 billion people worldwide are connected to the Internet, and over 5 billion individuals own mobile phones. By 2020, 50 billion devices are expected to be connected to the Internet. At this point, predicted data production will be 44 times greater than that in 2009. As information is transferred and shared at light speed on optic fiber and wireless networks, the volume of data and the speed of market growth increase. However, the fast growth rate of such large data generates numerous challenges, such as the rapid growth of data, transfer speed, diverse data, and security. Nonetheless, Big Data is still in its infancy stage, and the domain has not been reviewed in general. Hence, this study comprehensively surveys and classifies the various attributes of Big Data, including its nature, definitions, rapid growth rate, volume, management, analysis, and security. This study also proposes a data life cycle that uses the technologies and terminologies of Big Data. Future research directions in this field are determined based on opportunities and several open issues in Big Data domination. These research directions facilitate the exploration of the domain and the development of optimal techniques to address Big Data.

Gender-associated genomic differences in colorectal cancer: clinical insight from feminization of male cancer cells.

Gender-related differences in colorectal cancer (CRC) are not fully understood. Recent studies have shown that CRC arising in females are significantly associated with CpG island methylator phenotype (CIMP-high). Using array comparative genomic hybridization, we analyzed a cohort of 116 CRCs (57 males, 59 females) for chromosomal copy number aberrations (CNA) and found that CRC in females had significantly higher numbers of gains involving chromosome arms 1q21.2-q21.3, 4q13.2, 6p21.1 and 16p11.2 and copy number losses of chromosome arm 11q25 compared to males. Interestingly, a subset of male CRCs (46%) exhibited a "feminization" phenomenon in the form of gains of X chromosomes (or an arm of X) and/or losses of the Y chromosome. Feminization of cancer cells was significantly associated with microsatellite-stable CRCs (p-value 0.003) and wild-type BRAF gene status (p-value 0.009). No significant association with other clinicopathological parameters was identified including disease-free survival. In summary, our data show that some CNAs in CRC may be gender specific and that male cancers characterized by feminization may constitute a specific subset of CRCs that warrants further investigation.

Effectiveness of some plant extracts in biocontrol of induced onion basal rot disease in greenhouse conditions.

One of Egypt's most notable and historically significant vegetable crops is the Liliaceae plant, Allium cepa L. In this study, the effectiveness of methanolic extracts of Artemisia absinthium leaves, Calotropis procera latex, Moringa oleifera seeds, and Syzygium aromaticum clove was investigated in vitro and, in a greenhouse, setting against Fusarium oxysporum, the pathogen that causes onion basal rot in Assiut Governorate, Egypt. The S. aromaticum extract exhibited the inhibition peak (63.3%), whereas the A. absinthium extract had the lowest inhibition impact against F. oxysporum growth (41.1%). The gas chromatography-mass spectroscopy (GC-MS) analysis revealed that 82 important compounds, with abundances ranging from low to high, were present in the tested S. aromaticum's methanolic extract. The primary components were acetaldehyde, hydroxy- and 2-propanone, 1,1,3,3-tetrachloro-(42.71%), 1,2-ethanediol, and methyl alcohol (34.01%). In comparison to the infected control, the disease severity was significantly reduced by 20% with the use of a plant extracts mixture and Dovex 50% and increased by 62.22% with the use of an extract from A. absinthium. When compared to the infected control, onion plant fresh weight and dry weight were considerably higher under the clove extract therapy. The plant extracts used in this study's testing contain a number of active ingredients, including amino acids, vitamins, minerals, antioxidants, and enzymes, which is probably why they have such positive impacts. The application of a combination of plant extracts was suggested as a feasible strategy for improving the growth and productivity of onion plants by the study's findings. More research is needed to comprehend the mechanisms by which plant extracts promote plant development and to optimize the concentration and timing of administration.

The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell-Mediated Killing of AML Leukemic Stem Cells.

The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging designed ankyrin repeat protein (DARPin) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell-mediated killing of AML cells coexpressing at least two of the antigens. In vitro, MP0533 induced selective T cell-mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen-targeting T-cell engagers. In xenograft AML mice models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity toward LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with a high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).