The landscape of novel strategies for acute myeloid leukemia treatment: Therapeutic trends, challenges, and future directions.

Acute myeloid leukemia (AML) is a highly heterogeneous subtype of hematological malignancies with a wide spectrum of cytogenetic and molecular abnormalities, which makes it difficult to manage and cure. Along with the deeper understanding of the molecular mechanisms underlying AML pathogenesis, a large cohort of novel targeted therapeutic approaches has emerged, which considerably expands the medical options and changes the therapeutic landscape of AML. Despite that, resistant and refractory cases caused by genomic mutations or bypass signalling activation remain a great challenge. Therefore, discovery of novel treatment targets, optimization of combination strategies, and development of efficient therapeutics are urgently required. This review provides a detailed and comprehensive discussion on the advantages and limitations of targeted therapies as a single agent or in combination with others. Furthermore, the innovative therapeutic approaches including hyperthermia, monoclonal antibody-based therapy, and CAR-T cell therapy are also introduced, which may provide safe and viable options for the treatment of patients with AML.

Carrageenan in meat: improvement in lipid metabolism due to Sirtuin1-mediated fatty acid oxidation and inhibited lipid bioavailability.

Kappa-carrageenan (κ-CGN) is widely used in the meat industry. However, its impact on the host metabolism is less revealed. The current study investigated the effect of κ-CGN in pork-based diets on the lipid metabolism of male C57BL/6J mice. The κ-CGN supplement significantly suppressed the increase in body weight by 6.79 g on an average. Supplement of κ-CGN in high-fat diets significantly upregulated the genes and protein expression of Sirtuin1, which was accompanied by the increased gene expression of downstream fatty acids oxidation (Cpt1a and Acadl). The sirtuin1-mediated improvement of lipid metabolism was negatively associated with the levels of bile acids, especially for deoxycholic acid, 3ß-cholic acid, glycodeoxycholic acid and glycolithocholic acid. Moreover, κ-CGN in high-fat diets inhibited lipid digestion and absorption, being associated with the decrease in lipid accumulation and improved serum lipid profile. These results highlighted the role of κ-CGN in alleviating diet-induced adiposity by promoting energy expenditure and suppressing the bioavailability of ingested lipids.

Bile Acid Derivatives Effectively Prevented High-Fat Diet-Induced Colonic Barrier Dysfunction.

SCOPE: Bile acids (BAs) have recently emerged as important regulators of many physiological and pathological processes. However, the change of colonic BAs induced by high-fat diet (HFD) and their effects on colonic barrier function remain to be further elucidated. METHODS AND RESULTS: C57BL/6 mice are divided into two groups and feed 12 weeks with diets differing for fat content. Higher levels of serum diamine oxidase (DAO) activity, endotoxin (ET), and d-lactate (d-LA) are observed in HFD-fed mice, indicating an increase in intestinal permeability. Real-time quantitative PCR and western blot analyses demonstrate that HFD downregulates tight junction proteins (TJs, including zonula-occludens 1 [ZO-1], Occludin, and Claudin1) and Muc2 expression in the colon. The colonic BA profiles are analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). HFD induces an increase in primary BAs but a decrease in secondary BAs. In human colonic cell line Caco-2, secondary BAs (deoxycholic acid [DCA], lithocholic acid [LCA], their 3-oxo- and iso- derivates) upregulate the expression of TJs and counteract DSS-induced increase in intestinal permeability at physiological concentrations. IsoDCA and isoLCA are the most effective ones. Moreover, supplementation of isoDCA or isoLCA also effectively prevents HFD-induced colonic barrier dysfunction in mice. CONCLUSION: These results demonstrate that secondary BAs (especially isomerized derivatives) may be important protectors for the colonic barrier function.

Hyperthermia promotes degradation of the acute promyelocytic leukemia driver oncoprotein ZBTB16/RARα.

The acute promyelocytic leukemia (APL) driver ZBTB16/RARα is generated by the t(11;17) (q23;q21) chromosomal translocation, which is resistant to combined treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) or conventional chemotherapy, resulting in extremely low survival rates. In the current study, we investigated the effects of hyperthermia on the oncogenic fusion ZBTB16/RARα protein to explore a potential therapeutic approach for this variant APL. We showed that Z/R fusion protein expressed in HeLa cells was resistant to ATO, ATRA, and conventional chemotherapeutic agents. However, mild hyperthermia (42 °C) rapidly destabilized the ZBTB16/RARα fusion protein expressed in HeLa, 293T, and OCI-AML3 cells, followed by robust ubiquitination and proteasomal degradation. In contrast, hyperthermia did not affect the normal (i.e., unfused) ZBTB16 and RARα proteins, suggesting a specific thermal sensitivity of the ZBTB16/RARα fusion protein. Importantly, we found that the destabilization of ZBTB16/RARα was the initial step for oncogenic fusion protein degradation by hyperthermia, which could be blocked by deletion of nuclear receptor corepressor (NCoR) binding sites or knockdown of NCoRs. Furthermore, SIAH2 was identified as the E3 ligase participating in hyperthermia-induced ubiquitination of ZBTB16/RARα. In short, these results demonstrate that hyperthermia could effectively destabilize and subsequently degrade the ZBTB16/RARα fusion protein in an NCoR-dependent manner, suggesting a thermal-based therapeutic strategy that may improve the outcome in refractory ZBTB16/RARα-driven APL patients in the clinic.

Oral arsenic and retinoic acid for high-risk acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has become curable over 95% patients under a complete chemo-free treatment with all-trans retinoic acid (ATRA) and arsenic trioxide in low-risk patients. Minimizing chemotherapy has proven feasible in high-risk patients. We evaluated oral arsenic and ATRA without chemotherapy as an outpatient consolidation therapy and no maintenance for high-risk APL. We conducted a multicenter, single-arm, phase 2 study with consolidation phases. The consolidation therapy included Realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen for 4 cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary end point was the disease-free survival (DFS). Secondary end points included measurable resident disease, overall survival (OS), and safety. A total of 54 participants were enrolled at seven centers from May 2019. The median age was 40 years. At the median follow-up of 13.8 months (through April 2022), estimated 2-year DFS and OS were 94% and 100% in an intention-to-treat analysis. All the patients achieved complete molecular remission at the end of consolidation phase. Two patients relapsed after consolidation with a cumulative incidence of relapse of 6.2%. The majority of adverse events were grade 1-2, and only three grade 3 adverse events were observed. Oral arsenic plus ATRA without chemotherapy was active as a first-line consolidation therapy for high-risk APL.Trial registration: chictr.org.cn number, ChiCTR1900023309.

Reconsidering Meat Intake and Human Health: A Review of Current Research.

Meat consumption is gradually increasing and its impact on health has attracted widespread attention, resulting in epidemiological studies proposing a reduction in meat and processed meat intake. This review briefly summarizes recent advances in understanding the effects of meat or processed meat on human health, as well as the underlying mechanisms. Meat consumption varies widely among individuals, populations, and regions, with higher consumption in developed countries than in developing countries. However, increasing meat consumption may not be the main cause of increasing incidence of chronic disease, since the development of chronic disease is a complex physiological process that involves many factors, including excessive total energy intake and changes in food digestion processes, gut microbiota composition, and liver metabolism. In comparison, unhealthy dietary habits and a sedentary lifestyle with decreasing energy expenditure are factors more worthy of reflection. Meat and meat products provide high-value protein and many key essential micronutrients. In short, as long as excessive intake and overprocessing of meats are avoided, meat remains an indispensable source of nutrition for human health.

Early Death and Survival of Patients With Acute Promyelocytic Leukemia in ATRA Plus Arsenic Era: A Population-Based Study.

Most randomized trials for acute promyelocytic leukemia (APL) have investigated highly selected patients under idealized conditions, and the findings need to be validated in the real world. We conducted a population-based study of all APL patients in Zhejiang Province, China, with a total population of 82 million people, to assess the generalization of all-trans retinoic acid (ATRA) and arsenic as front-line treatment. The outcomes of APL patients were also analyzed. Between January 2015 and December 2019, 1,233 eligible patients were included in the final analysis. The rate of ATRA and arsenic as front-line treatment increased steadily from 66.2% in 2015 to 83.3% in 2019, with no difference among the size of the center (≥5 or <5 patients per year, p = 0.12) or age (≥60 or <60 years, p = 0.35). The early death (ED) rate, defined as death within 30 days after diagnosis, was 8.2%, and the 3-year overall survival (OS) was 87.9% in the whole patient population. Age (≥60 years) and white blood cell count (>10 × 109/L) were independent risk factors for ED and OS in the multivariate analysis. This population-based study showed that ATRA and arsenic as front-line treatment are widely used under real-world conditions and yield a low ED rate and a high survival rate, which mimic the results from clinical trials, thereby supporting the wider application of APL guidelines in the future.

Oral Realgar-Indigo Naturalis Formula Plus Retinoic Acid for Acute Promyelocytic Leukemia.

Treatment paradigm of acute promyelocytic leukemia (APL) is by no mean the most remarkable story of cancer therapy. Recently, the advent of oral arsenic formulations (oral-arsenic trioxide and Realgar-Indigo Naturalis formula (RIF)) based regimens may provide a therapeutic advance by curing APL with two oral agents. Indeed, the oral RIF plus all-trans-retinoic acid (ATRA) without chemotherapy display highly efficacy in patients with APL. The safety profile of RIF plus ATRA make possible to treat APL patients in a home-based manner during postremission therapy. To our knowledge, RIF was the first commercially available oral arsenic agent approved in China. The RIF plus ATRA regimens are becoming a preferred frontline care for APL in China. In this review, we will discuss the history, current evidences and challengers of RIF-based strategies in APL. More and more APL patients may enjoy a cure with a normal quality-of-life after induction in the near future.

A Short-Term Feeding of Dietary Casein Increases Abundance of Lactococcus lactis and Upregulates Gene Expression Involving Obesity Prevention in Cecum of Young Rats Compared With Dietary Chicken Protein.

Casein and chicken are assessed to contain high quality proteins, which are essential for human health. Studies have shown that ingestion of the two dietary proteins resulted in distinct effects on physiology, liver transcriptome and gut microbiota. However, its underlying mechanism is not fully understood, in particular for a crosstalk between gut microbiota and host under a specific diet intervention. We fed young rats with a casein or a chicken protein-based diet (CHPD) for 7 days, and characterized cecal microbiota composition and cecal gene expression. We found that a short-term intervention with a casein-based diet (CAD) induced a higher relative abundance of beneficial bacterium Lactococcus lactis as well as Bifidobacterium pseudolongum, which upregulated galactose metabolism of the microbiome compared with a CHPD. The CAD also upregulated gene expression involved in obesity associated pathways (e.g., Adipoq and Irs1) in cecal tissue of rats. These genes and the bacterial taxon were reported to play an important role in protecting development of obesity. Furthermore, the differentially represented bacterial taxon L. lactis was positively associated with these differentially expressed genes in the gut tissue. Our results provide a new insight into the crosstalk between gut microbiota and host in response to dietary proteins, indicating a potential mechanism of obesity prevention function by casein.

Effects of Dietary Protein from Different Sources on Biotransformation, Antioxidation, and Inflammation in the Rat Liver.

In this work, the effects of different sources of meat protein on liver metabolic enzymes were investigated. Rats were fed for 90 days with semisynthetic diets in which casein was fully replaced by isolated soybean, fish, chicken, pork, or beef proteins. Then, liver proteomics was performed using iTRAQ and LC-ESI-MS/MS. The results indicated that intake of meat protein diets significantly reduced the protein levels of CYP450s, GSTs, UGTs, and SULTs compared to those of the casein and soybean protein diet groups. The total antioxidant capacity and lipid peroxidation values did not differ between four meat protein diet groups and the casein diet group. However, GSH activity in the fish, chicken, and beef protein groups was significantly higher than those of the casein and soybean protein groups. The beef protein diet significantly upregulated the expression of immune-related proteins. The Keap1-Nrf2-ARE signaling pathway was suggested to involve the diet-mediated regulation of biotransformation, inflammation, and redox status.

Improved long-term survival in all Sanz risk patients of newly diagnosed acute promyelocytic leukemia treated with a combination of retinoic acid and arsenic trioxide-based front-line therapy.

Limited data was available for long-term follow-up in newly diagnosed acute promyelocytic leukemia (APL) patients treated with all-trans-retinoic acid (ATRA) plus intravenously arsenic trioxide (ATO)-based front-line therapy. The aim of this work was to retrospectively analyze the long-term survival rate and frequency of therapy-related myeloid neoplasia (t-MN) occurring in a large cohort of APL patients. A total of 760 newly diagnosed patients with APL between January 1999 and May 2016 were evaluated. The early death rate was 9.2% (70/760). Of the remaining 690 patients with complete remission, patients were grouped according to front-line regimens: ATRA plus ATO with or without chemotherapy (ATO group) and ATRA with chemotherapy (non-ATO group). The median duration of follow-up was 7.5 years (1.0-18.3 years). ATO group showed significant superior 10-year estimated relapse-free survival (RFS) up to 90.3% comparing with 65.5% in the non-ATO group (P < 0.0001). In addition, the 10-year estimated overall survival (OS) was 93.9% for patients in the ATO group and 89.1% for those in the non-ATO group (P = 0.03). In the subgroup analysis, the RFS rate was also higher in ATO group comparing with non-ATO group in both low-to-intermediate-risk (94.2% vs 64.6%, P < 0.0001) and high-risk subgroup (89.6% vs 74.7%, P = 0.04). Notably, the 3-year RFS and OS rates in the chemotherapy-free subgroup of the low-to-intermediate-risk patients (n = 88) were 100% and 100%, respectively. In the entire cohort, a total of 10 patients developed secondary malignant neoplasms, including 7 patients with therapy-related myeloid neoplasms (t-MN). The estimated 5-year cumulative incidence risk of t-MN in the ATO and non-ATO groups was 1.0% and 0.4%, respectively (P = 0.34). Thus, our data revealed that the long-term outcome of patients treated with ATRA plus ATO-based regimens was associated with continuing high efficacy in all Sanz risk patients with newly diagnosed APL.

Intake of Fish Oil Specifically Modulates Colonic Muc2 Expression in Middle-Aged Rats by Suppressing the Glycosylation Process.

SCOPE: Dietary fats have been shown to affect gut microbiota composition and aging gene expression of middle-aged rats at a normal dose, but little is known about such an effect on gut barrier. In this study, the changes in colonic Muc2 expression are investigated and the underlying mechanism is also proposed. METHODS AND RESULTS: 36 middle-aged Sprague-Dawley rats are assigned to one of the diets containing soybean oil, lard, or fish oil (4%). The rats are fed for 5 weeks and then goblet cells, Muc2 expression, and inflammatory cytokines in the colon are measured. Proteome analysis is performed. Compared with the lard and soybean oil diet groups, intake of fish oil decreases the number of goblet cells, and inhibits Muc2 and TLRs expression in the colon of middle-aged rats, which would impair mucus barrier. Several key enzymes involved in glycosylation process, including Agr2, Gale, Gne, Pmm2, Pdxdc1, Plch1, Pfkp, Cmpk1, and Rexo2, show the lowest abundance in the fish oil diet group. CONCLUSION: Intake of fish oil at a normal dose downregulates colonic Muc2 expression. This negative effect of fish oil may involve the suppression of mucin glycosylation process.

Effectivity of a modified Sanz risk model for early death prediction in patients with newly diagnosed acute promyelocytic leukemia.

Early death is the main obstacle for the cure of patients with acute promyelocytic leukemia (APL). We have analyzed risk factors of early death from 526 consecutive newly diagnosed APL patients between 2004 and 2016. The overall incidence of early death was 7.2% (38/526). The peak hazard of early death occurred in the first 0-3 days. Multivariate logistic analysis demonstrated white blood cell (WBC) counts [odds ratio (OR) = 1.039; 95% confidence interval (CI): 1.024-1.055; P < 0.001], age (OR = 1.061; 95% CI: 1.025-1.099; P = 0.001) and platelet counts (OR = 0.971; 95% CI: 0.944-0.999; P = 0.038) were independent risk factors for early death. Furthermore, receiver-operator characteristic (ROC) curve analyses revealed a simple WBC/platelet ratio was significantly more accurate in predicting early death [areas under the ROC curve (AUC) = 0.842, 95% CI: 0.807-0.872) than WBC counts (AUC = 0.793; 95% CI: 0.756-0.827) or Sanz score (AUC = 0.746; 95% CI: 0.706-0.783). We stratified APL patients into four risk subgroups: low risk (WBC ≤ 10 × 109/L, platelet >40 × 109/L), intermediate risk (WBC/platelet <0.2 and age ≤ 60, not in low risk), high risk (WBC/platelet ≥0.2 or age > 60, not in low and ultra-high risk) and ultra-high risk (WBC > 50 × 109/L), the early death rates were 0, 0.6, 12.8, and 41.2%, respectively. In conclusion, we proposed a modified Sanz risk model as a useful predictor of early death risk in patients with APL.

Fish oil diet may reduce inflammatory levels in the liver of middle-aged rats.

The impact of dietary soybean oil, lard and fish oil on physiological responses in middle age is little studied. In this study, we investigated the changes of oxidative stress, inflammatory cytokines, telomere length, and age-related gene expression in the liver of middle-aged rats in response to the above three fat diets. Male Sprague Dawley rats (12 months old) were fed AIN-93M diets for 3 months, in which soybean oil was equivalently replaced by lard or fish oil. As compared to the lard diet, intake of fish oil diet significantly decreased body weight gain, white blood cell count, and levels of hepatic triacylglycerol, total cholesterol, fat accumulation, low-density lipoprotein, oxidative stress and inflammatory cytokines (P < 0.05), but increased telomere length (P < 0.05). On the other hand, lard diet and soybean oil diet showed great similarity in the above variables. PCR array analysis further indicated that fish oil diet significantly down-regulated gene expression related to inflammatory response, apoptosis, DNA binding, proteostasis and telomere attrition. Differentially expressed genes were enriched in the complement and coagulation cascades pathways. Such physiological and molecular responses could be due to different fatty acid composition in fish oil, lard and soybean oil.

Efficacy and prognostic factors of imatinib plus CALLG2008 protocol in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia (ALL). We retrospectively analyzed 153 newly diagnosed adult patients with Philadelphia chromosome (Ph)-positive ALL enrolled into imatinib (400 mg/d) plus CALLG2008 regimen between 2009 and 2015. The median age was 40 years (range, 18-68 years), with 81 (52.3%) males. The overall hematologic complete remission (CR) rate was 96.7% after induction. With a median follow-up of 24.2 months, the estimated 3-year overall survival (OS) and event-free survival (EFS) rates were 49.5%(95%confidence interval (CI): 38.5%-59.5%) and 49.2% (95% CI: 38.3%-59.2%), respectively. Fifty-eight (36 with haploidentical donor) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first CR. Among the patients in CR1 after induction, both the 3-year OS and EFS were significantly better in the allo-HSCT group than in the without allo-HSCT group (73.2%, 95% CI: 58.3%-83.5% vs. 22.2%, 95% CI: 8.7%-39.6% and 66.5%, 95% CI: 50.7%-78.2% vs. 16.1%, 95% CI: 5.1%-32.7%, respectively). Multivariate analysis showed that allo-HSCT and achievement of major molecular response were associated with favorable OS or EFS independently. Interestingly, in the allo-HSCT cohort, the donor type (haploidentical versus matched donors) had no significant impact on EFS or OS. All these results suggested that imatinib plus CALLG2008 was an effective protocol for Ph-positive ALL. Haploidentical donors can also be a reasonable alternative expedient donor pool.

All-Trans Retinoic Acid plus Arsenic Trioxide versus All-Trans Retinoic Acid plus Chemotherapy for Newly Diagnosed Acute Promyelocytic Leukemia: A Meta-Analysis.

BACKGROUND: Recently, the all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) protocol has become a promising first-line therapeutic approach in patients with newly diagnosed acute promyelocytic leukemia (APL), but its benefits compared with standard ATRA plus chemotherapy regimen needs to be proven. Herein, we conducted a meta-analysis comparing the efficacy of ATRA plus ATO with ATRA plus chemotherapy for adult patients with newly diagnosed APL. METHODS: We systematically searched biomedical electronic databases and conference proceedings through February 2016. Two reviewers independently assessed all studies for relevance and validity. RESULTS: Overall, three studies were eligible for inclusion in this meta-analysis, which included a total of 585 patients, with 317 in ATRA plus ATO group and 268 in ATRA plus chemotherapy group. Compared with patients who received ATRA and chemotherapy, patients who received ATRA plus ATO had a significantly better event-free survival (hazard ratio [HR] = 0.38, 95% confidence interval [CI]: 0.22-0.67, p = 0.009), overall survival (HR = 0.44, 95% CI: 0.24-0.82, p = 0.009), complete remission rate (relative risk [RR] = 1.05; 95% CI: 1.01-1.10; p = 0.03). There were no significant differences in early mortality (RR = 0.48; 95% CI: 0.22-1.05; p = 0.07). CONCLUSION: Thus, this analysis indicated that ATRA plus ATO protocol may be preferred to standard ATRA plus chemotherapy protocol, particularly in low-to-intermediate risk APL patients. Further larger trials were needed to provide more evidence in high-risk APL patients.

Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients.

The aim of the study is to better understand the mechanism of relapse and acquired clinical resistance to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Thirty relapsed acute promyelocytic leukemia (APL) patients were followed. Fifteen patients experienced two or more relapses; nine patients had clinical resistance to ATO-based therapy. The frequency and clinical significance of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) mutational status using Sanger sequencing were evaluated. Overall, eight different types of mutations in the RARA region (V218D, R272Q, T278A, T291I, N299D, R294W, A300G, and L220_F228delinsP) were identified in 11 patients. Eight missense mutations (L211P, C213R, S214L, A216V, L217F, D219H, S221G, and D241G) were found in the PML portion of PML-RARA in 14 patients, with A216V as the predominant mutation. Eight patients were found to harbor both PML and RARA mutations over the course of the disease. The PML-region mutations were associated with response to ATO-based therapy (P < 0.0001), number of relapses (P = 0.001), and early relapse (P = 0.013). Notably, one case sampled at nine different time points showed alternating clonal dominance over the course of treatment. This study demonstrated frequent mutations of PML-RARA and supported a clonal selection model in relation to APL relapse and ATO resistance.

Prognostic factors of patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide-based frontline therapy.

Prognostic factors for patients with acute promyelocytic leukemia (APL) treated in the context of arsenic trioxide (ATO)-based frontline regimes have not been established clearly. We retrospectively analyzed the clinical features, immunophenotypes, Fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD), and outcomes of 184 consecutive newly diagnosed APL patients treated by intravenous ATO-based therapy. The median age was 40 years (14-77 years). The early death rate was 4.9% (9/184 patients). With a median follow-up time of 36 months (9-74 months), the 3-year relapse-free survival (RFS) and overall survival (OS) were 93.3% and 92.2%, respectively. Interestingly, there was no meaningful association between 3-year RFS and initial white blood cell count, FLT3-ITD status, or type of PML-RARA isoforms. In multivariable analysis, the CD56 expression was the only independent risk factor in terms of RFS (hazard ratio, 4.70; P=0.005). These results suggested that ATO-based therapy may ameliorate the unfavorable influence of previously known high-risk features; moreover, CD56 expression remains to be a potentially unfavorable prognostic factor in APL patients.