B-acute Lymphoblastic Leukemia Research Articles

Application and prognostic relevance of CD34 detection in immunophenotyping of pediatric acute B lymphoblastic leukemia.

We aimed to investigate the application of CD34 detection in immunophenotypic discrimination and its prognostic relevance in children with acute B-lymphoblastic leukemia (B-ALL). A retrospective analysis was conducted on clinical follow-up data of 105 children with newly diagnosed B-ALL treated at our hospital from January 2022 to December 2023. Based on the expression of CD34 in the bone marrow, patients were divided into a CD34 positive group (positive cells ≥10%) and a CD34 negative group (positive cells <10%). The study compared the positive rates of common leukemia cell antigens, clinical characteristics, initial treatment responses, and long-term follow-up outcomes between the two groups. Among all 105 B-ALL cases, 87 children (82.9%) had bone marrow CD34 positive cells ≥10%, classified into the CD34 positive group, while the remaining 18 children (17.1%) had bone marrow CD34 positive cells <10%, classified into the CD34 negative group. The CD34 positive group exhibited significantly higher positive rates of CD13 expression, standard-risk B-ALL, and risk stratification than the CD34 negative group. In contrast, the proportions of early pre-B-ALL, E2A-PBX1 fusion gene, and MLL-AF4 fusion gene were significantly lower in the CD34 negative group, with statistically significant differences (p<0.05). No significant differences were found in the positive rates of leukemia cell antigens such as CD10, CD19, CD20, CD22, CD79a, CD13, CD33, and CD38 between the two groups (p>0.05). The occurrence rates of minimal residual disease (MRD) and relapse after induction chemotherapy in the CD34 positive group were significantly lower than those in the CD34 negative group (p<0.05). However, the sensitivity to the first prednisone treatment and bone marrow treatment efficacy on the 19th and 33rd days after chemotherapy showed no significant differences between the groups (p>0.05). A higher positive rate of bone marrow CD34 expression in children with B-ALL is associated with a favorable prognosis. Children with negative CD34 expression are relatively more prone to MRD and tumor relapse after chemotherapy.

CAR-T CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA

The treatment outcomes of patients with chronic lymphocytic leukemia (CLL) have considerably improved with the introduction of targeted therapies based on Bruton kinase inhibitors (BTKIs), venetoclax, and anti-CD20 monoclonal antibodies. However, despite these consistent improvements, patients who become resistant to these agents have poor outcomes and need new and more productive therapeutic strategies. Among these new treatments, a potentially curative approach consists of the use of chimeric antigen receptor T (CAR-T) cell therapy, which achieved remarkable success in various B-cell malignancies, including B-cell Non-Hodgkin Lymphomas (NHLs) and B-acute lymphoblastic Leukemia (ALL). However, although CAR-T cells were initially used for the treatment of CLL, their efficacy in CLL patients was lower than in other B-cell malignancies. This review analyses the possible mechanisms of these failures. It highlights some recent developments that could offer the perspective of the incorporation of CAR-T cells in treatment protocols for relapsed/refractory CLL patients. Keywords: Chronic Lymphoid Leukemia; CLL; CAR-T Cells; Relapsed/resistant CLL:

Infectious complications in pediatric patients undergoing CD19+CD22+ chimeric antigen receptor T-cell therapy for relapsed/refractory B-lymphoblastic leukemia

Chimeric antigen receptor T-cell (CAR-T) therapy is effective in the treatment of relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL); however, patients who receive CAR-T therapy are predisposed to infections, with considerable detrimental effects on long-term survival rates and the quality of life of patients. This study retrospectively analyzed infectious complications in 79 pediatric patients with R/R B-ALL treated with CAR-T cells at our institution. Overall, 53 patients developed 88 infections. Nine patients experienced nine infections during lymphodepletion chemotherapy, 35 experienced 41 infections during the early phase (days 0–+ 30 after infusion), and 29 experienced 38 infections during the late phase (day + 31–+ 90 after infusion). Pathogens were identified in 31 infections, including 23 bacteria, seven viruses, and one fungus. Four patients were admitted to the intensive care unit for infection and one died. In a univariate analysis, there were ten factors associated with infection, including tumor load, lymphodepleting chemotherapy, neutrophil deficiency and lymphocyte reduction, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), etc. In a multivariate analysis, CRS ≥ grade 3 was identified as a risk factor for infection (hazard ratio = 2.41, 95% confidence interval: 1.08–5.36, P = 0.031). Therefore, actively reducing the CRS grade may decrease the risk of infection and improve the long-term quality of life of these patients.

Investigates the genetic types of acute lymphoblastic leukemia in full remission Indonesian patients: a cross-sectional analysis

Acute lymphoblastic leukemia (ALL) is most common in children, especially those aged 1–4 years old, and the second most common acute leukemia in adults. The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes recent clinical, cytogenetic, and molecular data. Transcriptome sequencing (RNA-seq) was performed on 200 bone marrow specimens using TruSeq library preparation and HiSeq 2000/2500 or NovaSeq 6000 sequencers (Illumina). The purpose of this study was to define the frequency of chromosomal abnormalities of ALL patients in adults and children in Indonesian patients after full remission for international collaboration has improved and advanced the diagnosis and treatment of ALL in Indonesia. Our resulting data showed that the most common structural abnormality was t(9;22) in 15% of the patients. The frequency of genetic abnormalities was 69 % and 60% for numerical and/or structural in the B-ALL and T-ALL patients, respectively. The adults had a higher incidence of t(9;22) and a lower incidence of hyperdiploid than children. In conclusion: The results of this study molecular subtypes differ strikingly in their responses to treatment that needs more assessment.

The CAR T-cell race: The rules of the game.

The management of paediatric patients with refractory acute lymphoblastic leukaemia eligible for the CAR T cell product tisagenlecleucel involves multiple decision points between the process of patient referral to product infusion. How to address the individual patient's circumstances, optimize apheresis yields and, above all, plan the best bridging chemotherapy is clearly detailed in these comprehensive and practical recommendations by Kumar Mishra and colleagues. Commentary on: Mishra etal. Practice guideline: Preparation for CAR T-cell therapy in children and young adults with B-acute lymphoblastic leukaemia. Br J Haematol 2024;204:1687-1696.

IKZF1plus is a frequent biomarker of adverse prognosis in Mexican pediatric patients with B-acute lymphoblastic leukemia.

Recurrent genetic alterations contributing to leukemogenesis have been identified in pediatric B-cell Acute Lymphoblastic Leukemia (B-ALL), and some are useful for refining classification, prognosis, and treatment selection. IKZF1plus is a complex biomarker associated with a poor prognosis. It is characterized by IKZF1 deletion coexisting with PAX5, CDKN2A/2B, or PAR1 region deletions. The mutational spectrum and clinical impact of these alterations have scarcely been explored in Mexican pediatric patients with B-ALL. Here, we report the frequency of the IKZF1plus profile and the mutational spectrum of IKZF1, PAX5, CDKN2A/2B, and ERG genes and evaluate their impact on overall survival (OS) in a group of patients with B-ALL. A total of 206 pediatric patients with de novo B-ALL were included. DNA was obtained from bone marrow samples at diagnosis before treatment initiation. A custom-designed next-generation sequencing panel was used for mutational analysis. Kaplan-Meier analysis was used for OS estimation. We identified the IKZF1plus profile in 21.8% of patients, which was higher than that previously reported in other studies. A significantly older age (p=0.04), a trend toward high-risk stratification (p=0.06), and a decrease in 5-year Overall Survival (OS) (p=0.009) were observed, although heterogeneous treatment protocols in our cohort would have impacted OS. A mutation frequency higher than that reported was found for IKZF1 (35.9%) and CDKN2A/2B (35.9%) but lower for PAX5 (26.6%). IKZF1MUT group was older at diagnosis (p=0.0002), and most of them were classified as high-risk (73.8%, p=0.02), while patients with CDKN2A/2BMUT had a higher leukocyte count (p=0.01) and a tendency toward a higher percentage of blasts (98.6%, >50% blasts, p=0.05) than the non-mutated patients. A decrease in OS was found in IKZF1MUT and CDKN2A/2BMUT patients, but the significance was lost after IKZF1plus was removed. Our findings demonstrated that Mexican patients with B-ALL have a higher prevalence of genetic markers associated with poor outcomes. Incorporating genomic methodologies into the diagnostic process, a significant unmet need in low- and mid-income countries, will allow a comprehensive identification of relevant alterations, improving disease classification, treatment selection, and the general outcome.

Chemotherapy-initiated cysteine-rich protein 61 decreases acute B-lymphoblastic leukemia chemosensitivity

PurposeChemoresistance is a major challenge for acute lymphoblastic leukemia (ALL) treatment. Cysteine-rich protein 61 (Cyr61) plays an important role in drug resistance modulation of tumor cells, and Cyr61 levels are increased in the bone marrow of patients with ALL and contribute to ALL cell survival. However, the effect of Cyr61 on B cell acute lymphoblastic leukemia (B-ALL) cell chemosensitivity and the regulatory mechanisms underlying Cyr61 production in bone marrow remain unknown.MethodsNalm-6 and Reh human B-ALL cell lines were used in this study. Cyr61 levels were assessed using quantitative real-time PCR (qRT-PCR), western blot analysis, and enzyme-linked immunosorbent assay. The effect of Cyr61 on B-ALL cell chemosensitivity to daunorubicin (DNR) was evaluated using cell viability and flow cytometry analyses. The regulatory mechanisms of Cyr61 production in bone marrow were examined using qRT-PCR and western blot analysis.ResultsCyr61 knockdown and overexpression increased and decreased the chemosensitivity of B-ALL cells to DNR, respectively. Cyr61 attenuated chemotherapeutic drug-induced apoptosis by upregulating B cell lymphoma-2. Notably, DNR induced DNA damage response and increased Cyr61 secretion in B-ALL cells through the ataxia telangiectasia mutated (ATM)-dependent nuclear factor kappa B pathway.ConclusionDNR induces Cyr61 production in B-ALL cells, and increased Cyr61 levels reduce the chemosensitivity of B-ALL cells. Consequently, targeting Cyr61 or related ATM signaling pathway may present a promising treatment strategy to enhance the chemosensitivity of patients with B-ALL.

Abstract 645: A systems biology approach uncovers the anticancer mechanisms of curcumin

Abstract Introduction: Curcumin, the active ingredient of turmeric, generates reactive oxygen species, increases p53 expression, inhibits NFⲕB signaling, and can induce apoptosis. Despite these potential anticancer effects, there has not yet been a systematic analysis of the effects of curcumin on a large panel of cancer cell lines. We hypothesized that curcumin has differential effects based on the specific cell line and its tissue of origin. This study assessed curcumin’s anticancer properties via cell survival assays and gene expression analyses. Methods: Cell survival assays were performed by the CTD2 Centre at the Broad Institute. 860 human cancer cell lines were seeded into 1536-well plates, and 24 hours after plating, either DMSO control or curcumin was added to the wells at 16 different concentrations by serial dilution. 72 hours later, cellular ATP levels were measured with CellTiter-Glo as an indication of cell survival. For gene expression analysis, the L1000 assay from the Broad Institute was used. 9 core cell lines were treated with 10 µM of curcumin in 384-well plates. After 6 and 24 hours of incubation, a gene expression signature was identified with the Affymetrix GeneChip HG-U133 Plus 2.0 Array. This signature was compared against signatures from other small molecule and genetic perturbations contained in the CMap database. Afterwards, connectivity scores (incorporating an enrichment score, nominal p-value, and false discovery rate) were used to rank the L1000 signatures by similarity to the signature induced by curcumin. Results: Curcumin was most potent against SEM (IC50 = 1.00 µM; B-acute lymphoblastic leukemia), RPMI-8226 (IC50= 1.62 µM; myeloma), and SCC-4 (IC50 = 1.81 µM; squamous cell carcinoma) cell lines. Lymphoid and peripheral nervous system cancers were generally the most sensitive to curcumin, whereas prostate cancers were the least sensitive. Curcumin-induced gene expression changes resembled GPR87 and PRKRA knockdowns, which are associated with reductions in cancer cell survival, chemoresistance, and proliferation in various cancer cell lines. However, these transcriptomic changes also resembled CERS2 downregulation, which is associated with increased cell migration. In vitro, curcumin treatment mimicked 2’,5’-dideoxyadenosine, BMS-299897, and eudesmic acid administration. Conclusion: Curcumin induces changes in cell survival and gene expression that support its anticancer properties in a variety of cancer cell lines. However, separating these effects from CERS2 downregulation may be an important component of future translational research for curcumin and its analogs. Citation Format: Adin Aggarwal, Jacqueline H. Law, Clement Lo, Kenneth W. Yip. A systems biology approach uncovers the anticancer mechanisms of curcumin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 645.

Practice guideline: Preparation for CAR T-cell therapy in children and young adults with B-acute lymphoblastic leukaemia.

The objective of this guideline, prepared by the ALL subgroup of the Advanced Cell Therapy Sub-Committee of BSBMTCT (British Society of Blood and Marrow Transplantation), is to provide healthcare professionals with practical guidance on the preparation of children and young adults with B-acute lymphoblastic leukaemia from the point of referral to that of admission for CAR T-cell treatment. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate the levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org.

Refining risk stratification in paediatric B-acute lymphoblastic leukaemia: Combining IKZF1plus and Day 15 MRD positivity.

This study investigates the potential utility of IKZF1 deletion as an additional high-risk marker for paediatric acute lymphoblastic leukaemia (ALL). The prognostic impact of IKZF1 status, in conjunction with minimal/measurable residual disease (MRD), was evaluated within the MRD-guided TPOG-ALL-2013 protocol using 412 newly diagnosed B-ALL patients aged 1-18. IKZF1 status was determined using multiplex ligation-dependent probe amplification. IKZF1 deletions, when co-occurring with CDKN2A, CDKN2B, PAX5 or PAR1 region deletions in the absence of ERG deletions, were termed IKZF1plus. Both IKZF1 deletion (14.6%) and IKZF1plus (7.8%) independently predicted poorer outcomes in B-ALL. IKZF1plus was observed in 4.1% of Philadelphia-negative ALL, with a significantly lower 5-year event-free survival (53.9%) compared to IKZF1 deletion alone (83.8%) and wild-type IKZF1 (91.3%) (p < 0.0001). Among patients with Day 15 MRD ≥0.01%, provisional high-risk patients with IKZF1plus exhibited the worst outcomes in event-free survival (42.0%), relapse-free survival (48.0%) and overall survival (72.7%) compared to other groups (p < 0.0001). Integration of IKZF1plus and positive Day 15 MRD identified a subgroup of Philadelphia-negative B-ALL with a 50% risk of relapse. This study highlights the importance of assessing IKZF1plus alongside Day 15 MRD positivity to identify patients at increased risk of adverse outcomes, potentially minimizing overtreatment.

Aetio-pathological profile of anaemic children belonging to upper socioeconomic society in a tertiary care hospital of North India

Introduction: Anaemia is a major public health problem especially in the preschool age group. It is rampant even in children of upper and middle classes of the society.Objectives: To study the aetio-pathology of anaemia in children belonging to upper and upper middle socio-economic scale and to correlate it with their nutritional status. Method: It was a cross-sectional descriptive study on 165 preschool children aged 6-59 months who presented with pallor on clinical examination. They were advised to undergo a complete haemogram and further specific tests as required. Results: The most common cause of anaemia was nutritional, including iron deficiency (92%), combined iron and B12 deficiency (2%) and isolated B12 deficiency (0.6%). Thalassaemia was the next common cause (3%) followed by B-acute lymphoblastic leukaemia (1%) and microangiopathic haemolytic anaemia (0.6%). Maternal education and nutritional awareness had positive correlation with anaemia. Majority of children were normally nourished despite being anaemic, However, undernourished children were more severely anaemic. Conclusions: Nutritional anaemia is the commonest cause of anaemia even in children belonging to higher socio-economic classes.

Lineage Switching from Acute Myeloid Leukemia associated with Systemic Mastocytosis to B-Acute Lymphoblastic Leukemia: A Diagnostic Dilemma

Relapse acute leukemia is defined as the reappearance of more than 5% blast in the bone marrow. In most instances, blast expresses the specific lineage (myeloid or lymphoid), similar to a diagnosis. However, it rarely converts to a different lineage, either myeloid shifting to lymphoid or vice versa, during relapse. Thus, it is labelled as switching lineage acute leukemia, after excluding the criteria for mixed phenotypic acute leukemia, which can be a challenge to diagnose. We describe a 24-year-old gentleman with a known case of acute myeloid leukemia associated with systemic mastocytosis (SM); eight months later and after two complete cycles of chemotherapy, relapse occurred with a switched lineage to B-acute lymphoblastic leukemia. The laboratory investigation approaches and the challenges in the diagnosis are also discussed in this case report

Charting a path through resistance: HDAC inhibitors for TP53-mutated B-acute lymphoblastic leukemia.

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Double Philadelphia chromosome: a rare and sole abnormality in pediatric B-acute lymphoblastic leukemia.

The present study describes a 7-year-old male child who had attended the Pediatric Oncology Clinic of the Regional Cancer Centre, Thiruvananthapuram, Kerala, India, and was pathologically confirmed to have B-Acute Lymphoblastic Leukemia (B-ALL). Conventional cytogenetics analysis at diagnosis showed the presence of a double Philadelphia chromosome and the karyotype of the case was 47, XY, t(9;22)(q34;q11.2), + der(22)t(9;22). FISH, done as a molecular confirmation of the translocation, t(9;22)(q34;q11.2), and this case showed an additional fusion signal that confirms the presence of double Ph. As far as we are aware, this represents the initial and only occurrence of an abnormality report regarding the double Philadelphia chromosome in pediatric B-ALL within India. The double Philadelphia chromosome in B-ALL has a very poor prognosis despite aggressive treatment with chemotherapy. This study reveals the importance of conventional and molecular cytogenetic analysis in risk stratification and prognosis prediction of pediatric B-ALL. The risk stratification based on the conventional and molecular cytogenetic analysis may be taken into consideration for deciding the treatment strategy for each patient.

Evaluating the Prognostic Utility of CAR-Hematotox Score in Predicting CAR T-Cell Toxicities in Children and Young Adults with R/R B- Acute Lymphoblastic Leukemia (B-ALL)

Evaluating the Prognostic Utility of CAR-Hematotox Score in Predicting CAR T-Cell Toxicities in Children and Young Adults with R/R B- Acute Lymphoblastic Leukemia (B-ALL)

Correlation of flow cytometric measurable residual disease (FC-MRD) with molecular MRD and clinical outcome at one year in adult B-acute lymphoblastic leukaemia (B-ALL) and acute myeloid leukaemia (AML)

Correlation of flow cytometric measurable residual disease (FC-MRD) with molecular MRD and clinical outcome at one year in adult B-acute lymphoblastic leukaemia (B-ALL) and acute myeloid leukaemia (AML)

Risk Factors for Hematotoxicity Following Tisagenlecleucel for Pediatric B-Acute Lymphoblastic Leukemia

Risk Factors for Hematotoxicity Following Tisagenlecleucel for Pediatric B-Acute Lymphoblastic Leukemia

Deciphering stage 0 hematogones by flow cytometry in follow-up bone marrow samples of pediatric B-Acute lymphoblastic leukemia cases: A potential mimicker of residual disease after anti CD19 therapy.

CD19 is frequently targeted for immunotherapy in B cell malignancies, which may result in loss of CD19 expression in leukemic cells as an escape mechanism. Stage 0 hematogones (Hgs) are normal CD19-negative very early B cell precursors that can be potentially mistaken for CD19 negative residual leukemic cells by flow cytometry (FCM) in B cell acute lymphoblastic leukemia (BCP-ALL) cases treated with anti CD19 therapy. Our main objective was to characterize and study the incidence of stage 0 hematogones in follow-up bone marrow samples of pediatric BCP-ALL cases. We analyzed the flow cytometry standard files of 61 pediatric BCP-ALL cases treated with conventional chemotherapy and targeted anti-CD19 therapy, for identifying the residual disease and normal B cell precursors including stage 0 Hgs. A non-CD19 alternate gating strategy was used to isolate the B cells for detecting the residual disease and stage 0 Hgs. The stage 0 Hgs were seen in 95% of marrow samples containing CD19+ Hgs. When compared with controls and posttransplant marrow samples, the fraction of stage 0 Hgs was higher in patients receiving anti CD19 therapy (p = 0.0048), but it was not significant when compared with patients receiving chemotherapy (p = 0.1788). Isolated stage 0 Hgs are found in samples treated with anti-CD19 therapy simulating CD19 negative residual illness. Our findings aid in understanding the stage 0 Hgs and its association with CD19+ Hgs in anti CD19 therapy and conventional chemotherapy. This is crucial as it can be potentially mistaken for residual disease in patients treated with anti CD19 therapy.

Subclassification of B-acute lymphoblastic leukemia according to age, immunophenotype and microenvironment, predicts MRD risk in Mexican children from vulnerable regions.

The decisive key to disease-free survival in B-cell precursor acute lymphoblastic leukemia in children, is the combination of diagnostic timeliness and treatment efficacy, guided by accurate patient risk stratification. Implementation of standardized and high-precision diagnostic/prognostic systems is particularly important in the most marginalized geographic areas in Mexico, where high numbers of the pediatric population resides and the highest relapse and early death rates due to acute leukemias are recorded even in those cases diagnosed as standard risk. By using a multidimensional and integrated analysis of the immunophenotype of leukemic cells, the immunological context and the tumor microenvironment, this study aim to capture the snapshot of acute leukemia at disease debut of a cohort of Mexican children from vulnerable regions in Puebla, Oaxaca and Tlaxcala and its potential use in risk stratification. Our findings highlight the existence of a distinct profile of ProB-ALL in children older than 10 years, which is associated with a six-fold increase in the risk of developing measurable residual disease (MRD). Along with the absence of CD34+ seminal cells for normal hematopoiesis, this ProB-ALL subtype exhibited several characteristics related to poor prognosis, including the high expression level of myeloid lineage markers such as MPO and CD33, as well as upregulation of CD19, CD34, CD24, CD20 and nuTdT. In contrast, it showed a trend towards decreased expression of CD9, CD81, CD123, CD13, CD15 and CD21. Of note, the mesenchymal stromal cell compartment constituting their leukemic niche in the bone marrow, displayed characteristics of potential suppressive microenvironment, such as the expression of Gal9 and IDO1, and the absence of the chemokine CXCL11. Accordingly, adaptive immunity components were poorly represented. Taken together, our results suggest, for the first time, that a biologically distinct subtype of ProB-ALL emerges in vulnerable adolescents, with a high risk of developing MRD. Rigorous research on potential enhancing factors, environmental or lifestyle, is crucial for its detection and prevention. The use of the reported profile for early risk stratification is suggested.

CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia.

Treatment of refractory and relapsed (R/R) B acute lymphoblastic leukemia (B-ALL) is an unmet medical need in both children and adults. Studies carried out in the last two decades have shown that autologous T cells engineered to express a chimeric antigen receptor (CAR-T) represent an effective technique for treating these patients. Antigens expressed on B-cells, such as CD19, CD20, and CD22, represent targets suitable for treating patients with R/R B-ALL. CD19 CAR-T cells induce a high rate (80-90%) of complete remissions in both pediatric and adult R/R B-ALL patients. However, despite this impressive rate of responses, about half of responding patients relapse within 1-2 years after CAR-T cell therapy. Allo-HSCT after CAR-T cell therapy might consolidate the therapeutic efficacy of CAR-T and increase long-term outcomes; however, not all the studies that have adopted allo-HSCT as a consolidative treatment strategy have shown a benefit deriving from transplantation. For B-ALL patients who relapse early after allo-HSCT or those with insufficient T-cell numbers for an autologous approach, using T cells from the original stem cell donor offers the opportunity for the successful generation of CAR-T cells and for an effective therapeutic approach. Finally, recent studies have introduced allogeneic CAR-T cells generated from healthy donors or unmatched, which are opportunely manipulated with gene editing to reduce the risk of immunological incompatibility, with promising therapeutic effects.