Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia.

Dasatinib is effective treatment for Philadelphia chromosome-positive (Ph+) acute leukemia but some patients develop resistance. Combination treatment with dasatinib and asciminib, an allosteric inhibitor of BCR::ABL1, may deepen responses and prevent the emergence of dasatinib-resistant clones. In this phase 1 study (NCT03595017), 24 adults with Ph+ acute lymphoblastic leukemia (ALL, n=22; p190, n=16; p210, n=6) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC, n=2) were treated with escalating daily doses of asciminib in combination with dasatinib 140 mg daily plus prednisone 60 mg/m2 daily to determine the maximum tolerated dose (MTD). After a 28-day induction, dasatinib and asciminib continued indefinitely or until hematopoietic stem cell transplant. The median age was 64.5 years (range, 33-85; 50% ³65). The recommended phase 2 dose of asciminib was 80 mg daily in combination with dasatinib and prednisone. The dose limiting toxicity at 160 mg daily was asymptomatic grade 3 pancreatic enzyme elevation without symptomatic pancreatitis. There were no vaso-occlusive events. Among patients with de novo ALL, the complete hematologic remission rate at day 28 and 84 was 84% and 100%, respectively. At day 84, 100% of patients achieved complete cytogenetic remission, 89% achieved measurable residual disease negativity (<0.01%) by multicolor flow cytometry, and 74% and 26% achieved BCR::ABL1 RT-PCR <0.1% and <0.01%. Dual BCR::ABL1 inhibition with dasatinib and asciminib is safe with encouraging activity in patients with de novo Ph+ ALL. ClinicalTrials.gov NCT02081378.

Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia.

Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected. Black patients with myelodysplasia-related AML were younger than white patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable analyses of Black patients, NPM1 and NRAS mutations were associated with inferior disease-free and IDH1 and IDH2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic risk stratification changed risk group assignment for one-third of Black patients and improved their outcome prediction.

Rare photos reveal North Korea's nuclear program.

Nation appears to have upgraded its bombmaking capacity, experts say.

PTPN11 Mutation Clonal Hierarchy in Acute Myeloid Leukemia.

Mutations in protein tyrosine phosphatase non-receptor type 11 ( PTPN11 ) have been considered late acquired mutations in acute myeloid leukemia (AML) development. To interrogate the ontogeny of PTPN11 mutations, we utilized single-cell DNA sequencing and identified that PTPN11 mutations can occur as initiating events in some AML patients when accompanied by strong oncogenic drivers, commonly NPM1 mutations. The co-driver role of PTPN11 mutations was confirmed in a novel murine model that exhibits an AML phenotype with early expansion of a diverse set of variably differentiated myeloid cells that engrafted into immunodeficient and immunocompetent mice. This immune diversity was reconstituted from early precursor cells when engrafted into immunodeficient mice. Moreover, immune diversity was also observed in the blast component of patient samples with NPM1 and PTPN11 mutations, providing novel antigen targets for immune based approaches in this subset of AML that is resistant to multiple targeted therapies.

Melanopsin in the human and chicken choroid.

The choroid embedded in between retina and sclera is essential for retinal photoreceptor nourishment, but is also a source of growth factors in the process of emmetropization that converts retinal visual signals into scleral growth signals. Still, the exact control mechanisms behind those functions are enigmatic while circadian rhythms are involved. These rhythms are attributed to daylight influences that are melanopsin (OPN4) driven. Recently, OPN4-mRNA has been detected in the choroid, and while its origin is unknown we here seek to identify the underlying structures using morphological methods. Human and chicken choroids were prepared for single- and double-immunohistochemistry of OPN4, vasoactive intestinal peptide (VIP), substance P (SP), CD68, and α-smooth muscle actin (ASMA). For documentation, light-, fluorescence-, and confocal laser scanning microscopy was applied. Retinal controls proved the reliability of the OPN4 antibody in both species. In humans, OPN4 immunoreactivity (OPN4-IR) was detected in nerve fibers of the choroid and adjacent ciliary nerve fibers. OPN4+ choroidal nerve fibers lacked VIP, but were co-localized with SP. OPN4-immunoreactivity was further detected in VIP+/SP + intrinsic choroidal neurons, in a hitherto unclassified CD68-negative choroidal cell population thus not representing macrophages, as well as in a subset of choroidal melanocytes. In chicken, choroidal nerve fibers were OPN4+, and further OPN4-IR was detected in clustered suprachoroidal structures that were not co-localized with ASMA and therefore do not represent non-vascular smooth-muscle cells. In the choroidal stroma, numerous cells displayed OPN4-IR, the majority of which was VIP-, while a few of those co-localized with VIP and were therefore classified as avian intrinsic choroidal neurons. OPN4-immunoreactivity was absent in choroidal blood vessels of both species. In summary, OPN4-IR was detected in both species in nerve fibers and cells, some of which could be identified (ICN, melanocytes in human), while others could not be classified yet. Nevertheless, the OPN4+ structures described here might be involved in developmental, light-, thermally-driven or nociceptive mechanisms, as known from other systems, but with respect to choroidal control this needs to be proven in upcoming studies.

Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101).

PURPOSE: Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A-rearranged (KMT2Ar) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia. METHODS: AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 (NPM1) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m2 if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar. The separate NPM1 cohort of the trial is ongoing. RESULTS: From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% (P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease. CONCLUSION: Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.

Stunning 3D chromosomes preserved in thawed mammoths.

"New type of fossil" may boost efforts to bring beasts back.

Diurnal gene expression patterns in retina and choroid distinguish myopia progression from myopia onset.

The world-wide prevalence of myopia (nearsightedness) is increasing, but its pathogenesis is incompletely understood. Among many putative mechanisms, laboratory and clinical findings have implicated circadian biology in the etiology of myopia. Consistent with a circadian hypothesis, we recently reported a marked variability in diurnal patterns of gene expression in two crucial tissues controlling post-natal refractive development - the retina and choroid-at the onset of form-deprivation myopia in chick, a widely studied and validated model. To extend these observations, we assayed gene expression by RNA-Seq in retina and choroid during the progression of established unilateral form-deprivation myopia of chick. We assayed gene expression every 4 hours during a single day from myopic and contralateral control eyes. Retinal and choroidal gene expression in myopic vs. control eyes during myopia progression differed strikingly at discrete times during the day. Very few differentially expressed genes occurred at more than one time in either tissue during progressing myopia. Similarly, Gene Set Enrichment Analysis pathways varied markedly by time during the day. Some of the differentially expressed genes in progressing myopia coincided with candidate genes for human myopia, but only partially corresponded with genes previously identified at myopia onset. Considering other laboratory findings and human genetics and epidemiology, these results further link circadian biology to the pathogenesis of myopia; but they also point to important mechanistic differences between the onset of myopia and the progression of established myopia. Future laboratory and clinical investigations should systematically incorporate circadian mechanisms in studying the etiology of myopia and in seeking more effective treatments to normalize eye growth in children.

Subunit-specific analysis of cohesin-mutant myeloid malignancies reveals distinct ontogeny and outcomes.

Mutations in the cohesin complex components (STAG2, RAD21, SMC1A, SMC3, and PDS5B) are recurrent genetic drivers in myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Whether the different cohesin subunit mutations share clinical characteristics and prognostic significance is not known. We analyzed 790 cohesin-mutant patients from the Dana-Farber Cancer Institute (DFCI) and the Munich Leukemia Laboratory (MLL), 390 of which had available outcome data, and identified subunit-specific clinical, prognostic, and genetic characteristics suggestive of distinct ontogenies. We found that STAG2 mutations are acquired at MDS stage and are associated with secondary AML, adverse prognosis, and co-occurrence of secondary AML-type mutations. In contrast, mutations in RAD21, SMC1A and SMC3 share features with de novo AML with better prognosis, and co-occurrence with de novo AML-type lesions. The findings show the heterogeneous nature of cohesin complex mutations, and inform clinical and prognostic classification, as well as distinct biology of the cohesin complex.

Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults.

BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission. METHODS: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point. RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group. CONCLUSIONS: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).

"The reasons you believe ": An exploratory study of text driven evidence gathering and prediction from first responder records justifying state authorised intervention for mental health episodes.

Objective First responders' mandatory reports of mental health episodes requiring emergency hospital care contain rich information about patients and their needs. In Queensland (Australia) much of the information contained in Emergency Examination Authorities (EEAs) remains unused. We propose and demonstrate a methodology to extract and translate vital information embedded in reports like EEAs and to use it to investigate the extreme propensity of incidence of serious mental health episodes. Methods The proposed method integrates clinical, demographic, spatial and free text information into a single data collection. The data is subjected to exploratory analysis for spatial pattern recognition leading to an observational epidemiology model for the association of maximum spatial recurrence of EEA episodes. Results Sentiment analysis revealed that among EEA presentations hospital and health service (HHS) region #4 had the lowest proportion of positive sentiments (18 %) compared to 33 % for HHS region #1 pointing to spatial differentiation of sentiments immanent in mandated free text which required more detailed analysis. At the postcode geographical level, we found that variation in maximum spatial recurrence of EEAs was significantly positively associated with spatial range of sentiments (0.29, p < 0.001) and the postcode-referenced sex ratio (0.45, p = 0.01). The volatility of sentiments significantly correlated with extremes of recurrence of EEA episodes. The predicted (probabilistic) incidence rate when mapped reflected this correlation. Conclusions The paper demonstrates the efficacy of integrating, machine extracted, human sentiments (as potential surrogates) with conventional exposure variables for evidence-based methods for mental health spatial epidemiology. Such insights from informatics-driven epidemiological observations may inform the strategic allocation of health system resources to address the highest levels of need and to improve the standard of care for mental patients while also enhancing their safe and humane treatment and management.

Introducing a Remote Patient Monitoring Usability Impact Model to Overcome Challenges.

Telehealth and remote patient monitoring (RPM), in particular, have been through a massive surge of adoption since 2020. This initiative has proven potential for the patient and the healthcare provider in areas such as reductions in the cost of care. While home-use medical devices or wearables have been shown to be beneficial, a literature review illustrates challenges with the data generated, driven by limited device usability. This could lead to inaccurate data when an exam is completed without clinical supervision, with the consequence that incorrect data lead to improper treatment. Upon further analysis of the existing literature, the RPM Usability Impact model is introduced. The goal is to guide researchers and device manufacturers to increase the usability of wearable and home-use medical devices in the future. The importance of this model is highlighted when the user-centered design process is integrated, which is needed to develop these types of devices to provide the proper user experience.

Intensive induction chemotherapy vs hypomethylating agents in combination with venetoclax in NPM1-mutant AML.

ABSTRACT: Although intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remission among older patients with nucleophosmin 1 (NPM1) mutations. Whether IC or HMA/VEN is superior in patients aged ≥60 years with NPM1-mutant AML is unknown. We performed an international, multicenter retrospective cohort study of 221 patients (147 IC and 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR) (defined as CR + CR with incomplete count recovery) rate was similar for IC and HMA/VEN (cCR, 85% vs 74%; P = .067). Although overall survival (OS) was favorable with IC in unselected patients compared with HMA/VEN (24-month OS, 59% [95% confidence interval (CI), 52-69%] vs 38% [95% CI, 27-55%]; P = .013), it was not statistically different among patients aged 60-75 years (60% [95% CI, 52-70%] vs 44% [95% CI, 29-66%]; P = .069) and patients who received an allogeneic stem cell transplant (70% [95% CI, 58-85%] vs 66% [95% CI, 44-100%]; P = .56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS, 65% [95% CI, 56-74%] with IC vs 40% [95% CI, 26-60%] with HMA/VEN; P = .009) and without FLT3 internal tandem duplication mutations might benefit from IC compared with HMA/VEN (24-month OS, 68% [95% CI, 59-79%] vs 43% [95% CI, 29-63%]; P = .008). In multivariable analysis, OS was not statistically different between patients treated with IC and HMA/VEN (hazard ratio for death with HMA/VEN vs IC, 0.71; 95% CI, 0.40-1.27; P = .25).

The inflamed brain.

Autoimmune conditions underlie some cases of psychosis. Scientists are expanding their search for patients, who often benefit from treatment.

Introducing the Pi-CON Methodology to Overcome Usability Deficits during Remote Patient Monitoring.

The adoption of telehealth has soared, and with that the acceptance of Remote Patient Monitoring (RPM) and virtual care. A review of the literature illustrates, however, that poor device usability can impact the generated data when using Patient-Generated Health Data (PGHD) devices, such as wearables or home use medical devices, when used outside a health facility. The Pi-CON methodology is introduced to overcome these challenges and guide the definition of user-friendly and intuitive devices in the future. Pi-CON stands for passive, continuous, and non-contact, and describes the ability to acquire health data, such as vital signs, continuously and passively with limited user interaction and without attaching any sensors to the patient. The paper highlights the advantages of Pi-CON by leveraging various sensors and techniques, such as radar, remote photoplethysmography, and infrared. It illustrates potential concerns and discusses future applications Pi-CON could be used for, including gait and fall monitoring by installing an omnipresent sensor based on the Pi-CON methodology. This would allow automatic data collection once a person is recognized, and could be extended with an integrated gateway so multiple cameras could be installed to enable data feeds to a cloud-based interface, allowing clinicians and family members to monitor patient health status remotely at any time.

Synergy between BRD9- and IKZF3-Targeting as a Therapeutic Strategy for Multiple Myeloma.

Progress in the treatment of multiple myeloma (MM) has resulted in improvement in the survival rate. However, there is still a need for more efficacious and tolerated therapies. We and others have shown that bromodomain-containing protein 9 (BRD9), a member of the non-canonical SWI/SNF chromatin remodeling complex, plays a role in MM cell survival, and targeting BRD9 selectively blocks MM cell proliferation and synergizes with IMiDs. We found that synergy in vitro is associated with the downregulation of MYC and Ikaros proteins, including IKZF3, and overexpression of IKZF3 or MYC could partially reverse synergy. RNA-seq analysis revealed synergy to be associated with the suppression of pathways associated with MYC and E2F target genes and pathways, including cell cycle, cell division, and DNA replication. Stimulated pathways included cell adhesion and immune and inflammatory response. Importantly, combining IMiD treatment and BRD9 targeting, which leads to the downregulation of MYC protein and upregulation of CRBN protein, was able to override IMiD resistance of cells exposed to iberdomide in long-term culture. Taken together, our results support the notion that combination therapy based on agents targeting BRD9 and IKZF3, two established dependencies in MM, represents a promising novel therapeutic strategy for MM and IMiD-resistant disease.

Cognitive and physiological evaluation of virtual reality training in nursing.

Virtual reality (VR) has increasingly been used in several disciplines, including nursing, a profession in high demand that is now facing a shortage. This study investigated the effectiveness and efficacy of VR hybrid training over traditional training (TR) methods. Sixteen college students were recruited and randomly assigned to get 100% TR or 50% TR and 50% VR (VR50). Participants attended a three-day program with a registered nurse, consisting of lectures and practical lab sessions. Participants' performance, training time, cognitive development, physical development, mental workload, user experience, Students' Satisfaction and Self-Confidence, and team learning were evaluated. The results showed that the VR50 performed as well as, and sometimes even better than the TR group (p-value = 0.043). VR50 group significantly had higher cognitive development and found VR easy to use and attractive (p-value < 0.05). VR-integrated training makes nurses' training more affordable and accessible while providing instant and relevant feedback.Practitioner Summary: This study assessed employment-integrated virtual training in nursing, particularly peri-care, by comparing the performance, cognitive, physical, and mental workload of traditional and integrated VR training groups. The findings of this study provide significant support for incorporating VR training into educational settings.