Episodes of acute methotrexate-related neurotoxicity linked to compromised long-term neurocognitive function.

Methotrexate is a critical component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but is associated with neurotoxicity. Information on long-term outcomes following an acute neurotoxic event is limited. Therefore, this report compares neurocognitive performance more than 12 months post diagnosis (mean = 4 years) between ALL patients with (n = 25) and without (n = 146) a history of acute neurotoxicity. Compared to children with no documented on-treatment neurotoxic event, children who experienced a neurotoxic event during treatment exhibited poorer performance on measures of fine motor function (p = .02) and attention (p = .02). Children with ALL who experience acute neurotoxicity may be candidates for early neuropsychological screening and intervention.

Cognitive flexibility impairment in temporal lobe epilepsy: The impact of epileptic foci lateralization on executive functions.

INTRODUCTION: Temporal Lobe Epilepsy (TLE) has been associated with memory impairments, which are typically linked to hippocampal and mesial temporal cortex lesions. Considering the presence of extensive bidirectional frontotemporal connections, it can be hypothesized that executive dysfunction in TLE is modulated by the lateralization of the epileptic foci. MATERIAL AND METHODS: A comprehensive neuropsychological executive functions protocol was administered to 63 participants, including 42 individuals with temporal lobe epilepsy (20 with right-TLE and 22 with left-TLE) and 21 healthy controls aged 20-49. RESULTS: The results indicate that TLE patients exhibit poorer executive performance compared to healthy controls in working memory (F(2,60) = 4.18, p <.01), planning (F(2,60) = 4.71, p <.05), set shifting (F(2,60) = 10.1, p <.001), phonetic verbal fluency (F(2,60) = 11.71, p <.01) and semantic verbal fluency (F(2,60) = 9.61, p <.001. No significant differences were found in cognitive inhibition. Furthermore, right-TLE patients showed lower performance than left-TLE in set shifting (F(1,61) = 6.45, p <.05), while no significant differences were observed in working memory, planning, inhibition, and verbal fluency. CONCLUSIONS: This research emphasize the importance of considering the lateralization of the temporal lobe focus to achieve a more accurate neuropsychological characterization. The cognitive differences between left and right TLE patients highlight the need for individualized approaches in their treatment and care.

Study on manipulation of ruminal fermentation using a bioelectrochemical system.

The purpose of this work was to develop a two-chamber bioelectrochemical cell to modify the metabolic activity of rumen microorganisms by applying an electric potential to the ruminal liquid. Carbohydrate fermentation changes were evaluated along with a molecular characterization by DNA sequencing of the ruminal microbial community. We observed that an electrochemical stimulation potential of 0.75 V enhanced basal acetate, propionate, and butyrate production by 71%, 86%, and 63%, respectively, with no detectable effects on grass substrate disappearance. The applied electric potential also led to changes in the volatile fatty acids production but not on the core microbiome.

Defining the Resident Continuity Clinic Panel Along Patient Outcomes: a Health Equity Opportunity.

BACKGROUND: Continuity clinics are a critical component of outpatient internal medicine training. Little is known about the population of patients cared for by residents and how these physicians perform. OBJECTIVES: To compare resident and faculty performance on standard population health measures. To identify potential associations with differences in performance, specifically medical complexity, psychosocial vulnerability, and rates of patient loss. SETTING AND PARTICIPANTS: Large academic primary care clinic caring for 40,000 patients. One hundred ten internal medicine residents provide primary care for 9,000 of these patients; the remainder are cared for by faculty. STUDY DESIGN: Descriptive analysis using review of the medical record and hospital administrative data. MAIN MEASURES: We compared resident and faculty performance on standard population health measures, including cancer screening rates, chronic disease care, acute and chronic medical complexity, psychosocial vulnerability, and rates of patient loss. We evaluated the success of resident transition by measuring rates of kept continuity visits 18 months after graduation. KEY RESULTS: Performance on all clinical outcomes was significantly better for faculty compared to residents. Despite similar levels of medical complexity compared to faculty patients, resident patients had significantly higher levels of psychosocial vulnerability across all measured domains, including health literacy, economic vulnerability, psychiatric illness burden, high-risk behaviors, and patient engagement. Resident patients experienced higher rates of patient loss than faculty patients (38.5 vs. 18.8%) with only 46.5% of resident patients with a kept continuity appointment in the practice 18 months after graduation. CONCLUSIONS: In this large academic practice, resident performance on standard population health measures was significantly lower than faculty. This may be explained in part by the burden of psychosocial vulnerability of their patients and systems that do not effectively transition patients after graduation. These findings present an opportunity to improve structural equity for these vulnerable patients and developing physicians.

Biotechnological processes to obtain bioactive secondary metabolites from some Mexican medicinal plants.

The consumption of medicinal plants has increased in recent decades due to the fact that they biosynthesize compounds with many biological activities; thus, some plant species with biological potential are being utilized as raw material by the industries for preparation of drugs, phytodrugs, or food supplements. This has the consequence of overexploitation and deforestation, which endangers plant species-of-interest. In recent years, alternatives have been sought to eradicate this problem. A solution that was given and is maintained is plant biotechnology, which favors the production of secondary metabolites (SMt) with important biological activity. Plant biotechnology allows us to increase the yield of a compound-of-interest, reduces its production times and costs, and allows constant and controlled production of the raw material, while aiding in the protection of medicinal plants that are found in danger of extinction. In the scientific literature, procuring the SMt by means of biotechnological processes is described, highlighting the study of five species from Mexican traditional medicine (Lopezia racemosa, Galphimia glauca, Cnidoscolus chayamansa, and Buddleja cordata), and the main biological activities are as follows: anti-inflammatory, hepatoprotector, neuroprotector, anxiolytic, antitumoral, antibacterial, and antioxidant, among others. KEY POINTS: • Secondary metabolites produce by biotechnology processes • Active secondary metabolites isolated from Mexican medicinal plants • Recent advances on the production of some bioactive secondary metabolites.

Effectiveness of Prone Positioning in Nonintubated Intensive Care Unit Patients With Moderate to Severe Acute Respiratory Distress Syndrome by Coronavirus Disease 2019.

BACKGROUND: In the treatment for severe acute respiratory distress syndrome (ARDS) from coronavirus disease 2019 (COVID-19), the World Health Organization (WHO) recommends prone positioning (PP) during mechanical ventilation for periods of 12-16 h/d to potentially improve oxygenation and survival. In this prospective observational study, we evaluated the ability of long PP sessions to improve oxygenation in awake intensive care unit (ICU) patients with moderate or severe ARDS due to COVID-19. METHODS: The study was approved by the ethics committee of Galicia (code No. 2020-188), and all patients provided informed consent. In this case series, awake patients with moderate or severe ARDS by COVID-19 admitted to the ICU at University Hospital of Santiago from March 21 to April 5, 2020 were prospectively analyzed. Patients were instructed to remain in PP as long as possible until the patient felt too tired to maintain that position. Light sedation was administered with dexmedetomidine. The following information was collected: number and duration of PP sessions; tissue O2 saturation (StO2) and blood gases before, during, and following a PP session; need of mechanical ventilation; duration of ICU admission; and ICU outcome. Linear mixed-effects models (LMM) were fit to estimate changes from baseline with a random effect for patient. RESULTS: Seven patients with moderate or severe ARDS by COVID-19 were included. All patients received at least 1 PP session. A total of 16 PP sessions were performed in the 7 patients during the period study. The median duration of PP sessions was 10 hours. Dexmedetomidine was used in all PP sessions. Oxygenation increased in all 16 sessions performed in the 7 patients. The ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FIO2) significantly increased during PP (change from baseline 110 with 97.5% confidence interval [CI], 19-202) and, after PP, albeit not significantly (change from baseline 38 with 97.5% CI, -9.2 to 85) compared with previous supine position. Similarly, tissue oxygenation underwent a small improvement during PP (change from baseline 2.6% with 97.5% CI, 0.69-4.6) without significant changes after PP. Two patients required intubation. All patients were discharged from the ICU. CONCLUSIONS: We found that PP improved oxygenation in ICU patients with COVID-19 and moderate or severe ARDS. PP was relatively well tolerated in our patients and may be a simple strategy to improve oxygenation trying to reduce the number of patients in mechanical ventilation and the length of stay in the ICU, especially in COVID-19 pandemic.

Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children.

BACKGROUND: After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline. METHODS: We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30-90 ml/min per 1.73 m2 and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD. RESULTS: Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m2), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly. CONCLUSIONS: Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.

Single and Combined Effects of Cypermethrin and UVR Pre-Exposure in the Microalgae Phaeodactylum Tricornutum.

Coastal marine microalgae are exposed to anthropogenic pollutants, including pesticides from aquaculture/agriculture/household uses. Some microalgae species, such as Phaeodactylum tricornutum, can induce and accumulate UV-absorbing compounds (UACs) upon ultraviolet radiation (UVR) exposure to prevent deleterious effects. Tolerance mechanisms activated by natural stressors might also protect organisms from anthropogenic stressors. This work assesses the effects of the insecticide cypermethrin (Cyp) and UVR in the marine microalgae P tricornutum. Considering the pro-oxidant properties of both stressors and UACs' induction in P tricornutum, lethal and sublethal effects of Cyp were tested in cultures with and without UVR acclimation. After a 24-h exposure to 10 µg L-1 of technical Cyp or culture medium, UACs, growth, glutathione-S-transferase activity (GST), sulfhydryl groups (SH-g), and lipid peroxidation (LPO) were analyzed. Results showed differences in terms of growth between Cyp and Cyp + UVR pre-exposure. UACs' content was induced after UVR acclimation and diminished after 24 h of growth in control and UVR pre-treated cultures, while levels remained constant under Cyp exposure. A single Cyp exposure exerted GST induction, SH-g depletion, and LPO increments. In UVR-acclimatized treatments, oxidative stress responses showed similar or more pronounced effects than the single chemical exposure, suggesting a potential additive effect of the UVR acclimation. The contrasting effects of Cyp + UVR observed between growth and biochemical responses suggest different compensatory mechanisms that need to be further investigated. Also, it highlights the need to include both lethal and sublethal endpoints to understand microalgae's tolerance and its significance in the multiple stressors' context.

Evaluation of bioremediation strategies for treating recalcitrant halo-organic pollutants in soil environments.

The aim of this study was to investigate the bioremediation potential of polychlorinated biphenyls (PCBs) in soil, mimicking three strategies: (a) mycoaugmentation: by the addition of Trametes sanguinea and Pleurotus sajor-caju co-cultures immobilized on sugarcane bagasse; (b) biostimulation: by supplementation of sugarcane bagasse; and (c) natural attenuation: no amendments. The experiments were done in microcosms using Ultisol soil. Remediation effectiveness was assessed based on pollutants content, soil characteristics, and ecotoxicological tests. Biostimulation and mycoaugmentation demonstrated the highest PCBs-removal (approx. 90%) with a significant toxicity reduction at 90 d. The studied strains were able to survive during the incubation period in non-sterilized soil. Laccase, manganese-peroxidase and endoxylanase activities increased significantly in co-cultures after 60 d. Sugarcane bagasse demonstrated to be not only a suitable support for fungal immobilization but also an efficient substrate for fungal colonization of PCBs-contaminated soils. Mycoaugmentation and biostimulation with sugarcane bagasse improved oxidable organic matter and phosphorous contents as well as dehydrogenase activity in soil. Therefore, biostimulation with sugarcane bagasse and mycoaugmentation applying dual white-rot fungal cultures constitute two efficient bioremediation alternatives to restore PCBs-contaminated soils.

Assessment of Organochlorine Pesticides in Phreatic Aquifer of Pampean Region, Argentina.

This work evaluates the factors affecting the presence of organochlorine pesticides in Pampeano aquifer in the Quequén Grande River watershed, Buenos Aires Province, Argentina. Eighteen sampling sites were selected in order to have representatives of different type of wells and types of soil. Among the analyzed compounds, endosulfan showed the highest concentrations (4.75 ng l- 1 mean), which could be related to use in the recent past. Others important pesticides groups detected were HCHs (1.1 ng l- 1 mean) and heptachlors (2.17 ng l- 1mean). The analysis of the results show that the thickness of the unsaturated zone is the main factor related to the concentrations of pesticides and there were no differences according to wells or soil types. Although agricultural use of most OCPs has been banned in Argentina from more than 30 years ago, their residues are still detected in groundwater of the region, indicating their high persistence.

Evaluation of kidney injury biomarkers in an adult Mexican population environmentally exposed to fluoride and low arsenic levels.

Fluoride (F) is a toxicant widely distributed in the environment. Experimental studies have shown kidney toxicity from F exposure. However, co-exposure to arsenic (As) has not been considered, and epidemiological information remains limited. We evaluated the association between F exposure and urinary kidney injury biomarkers and assessed As co-exposure interactions. A cross-sectional study was conducted in 239 adults (18-77 years old) from three communities in Chihuahua, Mexico. Exposure to F was assessed in urine and drinking water, and As in urine samples. We evaluated the urinary concentrations of albumin (ALB), cystatin-C (Cys-C), kidney injury molecule 1 (KIM-1), clusterin (CLU), osteopontin (OPN), and trefoil factor 3 (TFF-3). The estimated glomerular filtration rate (eGFR) was calculated using serum creatinine (Creat) levels. We observed a positive correlation between water and urine F concentrations (ρ = 0.7419, p < 0.0001), with median values of 1.5 mg/L and 2 µg/mL, respectively, suggesting that drinking water was the main source of F exposure. The geometric mean of urinary As was 18.55 ng/mL, approximately 39% of the urine samples had As concentrations above the human biomonitoring value (15 ng/mL). Multiple linear regression models demonstrated a positive association between urinary F and ALB (ß = 0.56, p < 0.001), Cys-C (ß = 0.022, p = 0.001), KIM-1 (ß = 0.048, p = 0.008), OPN (ß = 0.38, p = 0.041), and eGFR (ß = 0.49, p = 0.03); however, CLU (ß = 0.07, p = 0.100) and TFF-3 (ß = 1.14, p = 0.115) did not show significant associations. No interaction with As exposure was observed. In conclusion, F exposure was related to the urinary excretion of early kidney injury biomarkers, supporting the hypothesis of the nephrotoxic role of F exposure.

Phosphine/Sulfoxide-Supported Carbon(0) Complex.

A new carbon(0) complex 2 with two different L ligands, a phosphine and a sulfoxide, was synthesized and fully characterized. This new type of carbone exhibits excellent coordination ability, in contrast to the related phosphine/sulfide-supported carbon(0) complexes. Several organometallic complexes were isolated and, of special interest, the νav (CO) value of RhI -dicarbonyl complex indicates that 2 has a donor capability superior to classical NHCs.

DDTs-induced antioxidant responses in plants and their influence on phytoremediation process.

Phytoremediation is a low cost technology based on the use of plants to remove a wide range of pollutants from the environment, including the insecticide DDT. However, some pollutants are known to enhance generation of reactive oxygen species (ROS), which can generate toxic effects on plants affecting the phytoremediation efficiency. This study aims to analyze the potential use of antioxidant responses as a measure of tolerance to select plants for phytoremediation purposes. Tomato and zucchini plants were grown for 15 days in soils contaminated with DDTs (DDT + DDE + DDD). Protein content, glutathione-S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx) and catalase (CAT) activities were measured in plant tissues. Exposure to DDTs did not affect protein content or CAT activity in any of the species. GST, GR and GPx activity showed different responses in exposed and control tomato plants. After DDTs exposure, tomato showed increased GR and GPX activity in stems and leaves, respectively, and a decrease in the GST activity in roots. As no effects were observed in zucchini, results suggest different susceptibility and/or defense mechanisms involved after pesticide exposure. Finally, both species differed also in terms of DDTs uptake and translocation. The knowledge about antioxidant responses induced by pesticides exposure could be helpful for planning phytoremediation strategies and for the selection of tolerant species according to particular scenarios.

Identification, Confirmation, and Replication of Novel Urinary MicroRNA Biomarkers in Lupus Nephritis and Diabetic Nephropathy.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing, leading to significant morbidity and mortality. Kidney biopsy remains the gold standard for diagnosing the underlying etiology of CKD, but the procedure carries complication risks. The aim of this study was to identify novel noninvasive biomarkers correlating with kidney function and histopathology in biopsy-proven CKD patients. METHODS: We profiled 2402 urinary microRNAs (miRNAs) to identify and confirm differentially expressed miRNAs associated with kidney function and histopathology in patients with diabetic nephropathy (n = 58) or lupus nephritis (n = 89), important etiologies of CKD, compared with healthy controls (n = 93 and 119, respectively). Top performing miRNAs were then measured in 2 independent multi-institutional cohorts of patients with diabetes mellitus with (n = 74) or without nephropathy (n = 71) and systemic lupus erythematosus with (n = 86) or without (n = 37) nephritis. RESULTS: In patients with diabetic nephropathy, miR-2861, miR-1915-3p, and miR-4532 were down-regulated (>10-fold, P < 0.0001) and were associated with estimated glomerular filtration rate (P < 0.01) and interstitial fibrosis/tubular atrophy (P < 0.05). The c-statistics for miR-2861, miR-1915-3p, and miR-4532 were 0.91, 0.86, and 0.85, respectively. In lupus nephritis patients, miR-3201 and miR-1273e were down-regulated (>3-fold, P < 0.0001) and associated with endocapillary glomerular inflammation (P < 0.01), with c-statistics of 0.97 and 0.91, respectively. CONCLUSIONS: We have identified novel miRNAs that correlate with histopathological lesions and functional markers of kidney damage to facilitate sensitive, specific, and noninvasive detection of diabetic nephropathy and lupus nephritis.

Evaluation of kidney injury biomarkers in rat amniotic fluid after gestational exposure to cadmium.

Cadmium is a well-characterized nephrotoxic agent that is also capable of accumulating and diffusing across the placenta; however, only a few studies have addressed its effects over fetal kidneys and none of them has used a panel of sensitive and specific biomarkers for the detection of kidney injury. The goal of this study was to determine cadmium renal effects in rat fetuses by the quantification of early kidney injury biomarkers. Pregnant Wistar rats were exposed by inhalation to an isotonic saline solution or to CdCl2 solution (DDel =1.48 mg Cd kg(-1) day(-1) ) during gestational days (GD) 8-20. On GD 21, dams were euthanized and samples obtained. Kidney injury biomarkers were quantified in amniotic fluid samples and fetal kidneys were microscopically evaluated to search for histological alterations. Our results showed that cadmium exposure significantly raised albumin, osteopontin, vascular endothelial growth factor and tissue inhibitor of metalloproteinases-1 levels in amniotic fluid, whereas it decreased creatinine. Clusterin, calbindin and IFN-inducible protein 10 did not show any change. Accordingly, histological findings showed tubular damage and precipitations in the renal pelvis. In conclusion, gestational exposure to cadmium induces structural alterations in fetal renal tissue that can be detected by some kidney injury biomarkers in amniotic fluid samples. Copyright © 2016 John Wiley & Sons, Ltd.

Sub-chronic exposure to fluoride impacts the response to a subsequent nephrotoxic treatment with gentamicin.

Fluoride is an important groundwater contaminant, and more than 200 million people are exposed to high fluoride levels in drinking water, the major source of fluoride exposure. Exposure above 2 ppm of fluoride is associated with renal impairment in humans. In rats, moderate levels of fluoride induce kidney injury at early stages in which the glomerular filtration rate (GFR) is not altered. In the present study, we investigated if sub-nephrotoxic stimulus induced by fluoride might impact the response to a subsequent nephrotoxic treatment with gentamicin. Male Wistar rats (~21 days) were exposed to 0, 15 or 50 ppm of fluoride through drinking water during 40 days. Afer that, rats were co-exposed to gentamicin (40 mg kg(-1) day(-1), 7 days). Gentamicin induced a marked decrease in the GFR and an increase in urinary levels as well as the protein and mRNA expression of biomarkers of early kidney injury, such as Kim-1. Interestingly, gentamicin nephrotoxicity was less pronounced in groups previously exposed to fluoride than in the group only treated with gentamicin. Fluoride induced Hsp72, a cytoprotective molecule, which might have improved the response against gentamicin. Moreover, fluoride decreased the expression of megalin, a molecule necessary for internalization of gentamicin into the proximal tubule, potentially reducing gentamicin accumulation. The present results suggest that fluoride reduced gentamicin-induced nephrotoxicity by inducing a compensatory response carried out by Hsp72 and by decreasing gentamicin accumulation. These findings should not be interpreted to suggest that fluoride is a protective agent as megalin deficiency could lead to serious adverse effects on the kidney physiology.

Antioxidant responses in soybean and alfalfa plants grown in DDTs contaminated soils: Useful variables for selecting plants for soil phytoremediation?

Phytoremediation is a low-cost alternative technology based on the use of plants to remove pollutants from the environment. Persistent organic pollutants such as DDTs with a long half-life in soils are attractive candidates for remediation. This study aimed to determine the potential of antioxidant response use in the evaluation of plants' tolerance for selecting species in phytoremediation purposes. Alfalfa and soybean plants were grown in DDT contaminated soils. After 60days, growth, protein content, antioxidant capacity, GST activity, concentration of proteic and non-proteic thiol groups, chlorophyll content and carotenoid content were measured in plant tissues. Results showed no effect on alfalfa or soybean photosynthetic pigments but different responses in the protein content, antioxidant capacity, GST activity and thiol groups on roots, stems and leaves, indicating that DDTs affected both species. Soybean showed higher susceptibility than alfalfa plants due to the lower antioxidant capacity and GST activity in leaves, in spite of having the lowest DDT accumulation. This study provides new insights into the role of oxidative stress as an important component of the plant's response to DDT exposure.

Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation.

BACKGROUND: Chronic myeloid leukemia (CML) is a hematological disorder that in rare cases, mainly in CML neutrophilic, presents the e19a2 rearrangement. The encoded product is a 230-KDa protein. Despite the remarkable responses to treatment of most patients, a small but significant fraction of them develop clinical resistance to the tyrosine kinase inhibitors (TKIs). The most common mechanism of resistance is point mutations in the ABL1 kinase domain. The recently approved third-generation TKI ponatinib demonstrated remarkable activity in patients with multi-TKI-resistant disease. Particularly impressive was its efficacy in patients with T315I mutation that is resistant to all other TKIs. METHODS: Qualitative PCR was carried out by multiplex approach. Relative transcripts quantification was performed by one-step real-time PCR, with a specific Taqman probe and primers for the e19a2 rearrangement. We carried out a mutational screening by high-resolution melting, and the mutation was identified by Sanger method. The mutation burden was quantified by quantitative PCR using allele-specific primers. RESULTS: In a patient with CML, we identified a PCR product corresponding to e19a2 rearrangement harboring T315I mutation. At the time of mutational analysis, during dasatinib treatment, the T315I clone was 100% and the quantification of BCR-ABL1 was 18%. After ponatinib therapy, the T315I mutation burden decreased down to undetectable levels and the BCR-ABL1 transcripts showed a very low value (0.011%). CONCLUSIONS: Here, we report the hematological, cytogenetic, and molecular response of a patient with refractory CML in chronic phase with e19a2 transcripts, carrying T315I mutation that was successfully treated with ponatinib.