Precise prediction of cerebrospinal fluid amyloid beta protein for early Alzheimer's disease detection using multimodal data.

Alzheimer's disease (AD) constitutes a neurodegenerative disorder marked by a progressive decline in cognitive function and memory capacity. The accurate diagnosis of this condition predominantly relies on cerebrospinal fluid (CSF) markers, notwithstanding the associated burdens of pain and substantial financial costs endured by patients. This study encompasses subjects exhibiting varying degrees of cognitive impairment, encompassing individuals with subjective cognitive decline, mild cognitive impairment, and dementia, constituting a total sample size of 82 participants. The primary objective of this investigation is to explore the relationships among brain atrophy measurements derived from magnetic resonance imaging, atypical electroencephalography (EEG) patterns, behavioral assessment scales, and amyloid ß-protein (Aß) indicators. The findings of this research reveal that individuals displaying reduced Aß1-42/Aß-40 levels exhibit significant atrophy in the frontotemporal lobe, alongside irregularities in various parameters related to EEG frequency characteristics, signal complexity, inter-regional information exchange, and microstates. The study additionally endeavors to estimate Aß1-42/Aß-40 content through the application of a random forest algorithm, amalgamating structural data, electrophysiological features, and clinical scales, achieving a remarkable predictive precision of 91.6%. In summary, this study proposes a cost-effective methodology for acquiring CSF markers, thereby offering a valuable tool for the early detection of AD.

An ensemble learning model for continuous cognition assessment based on resting-state EEG.

One critical manifestation of neurological deterioration is the sign of cognitive decline. Causes of cognitive decline include but are not limited to: aging, cerebrovascular disease, Alzheimer's disease, and trauma. Currently, the primary tool used to examine cognitive decline is scale. However, scale examination has drawbacks such as its clinician subjectivity and inconsistent results. This study attempted to use resting-state EEG to construct a cognitive assessment model that is capable of providing a more scientific and robust evaluation on cognition levels. In this study, 75 healthy subjects, 99 patients with Mild Cognitive Impairment (MCI), and 78 patients with dementia were involved. Their resting-state EEG signals were collected twice, and the recording devices varied. By matching these EEG and traditional scale results, the proposed cognition assessment model was trained based on Adaptive Boosting (AdaBoost) and Support Vector Machines (SVM) methods, mapping subjects' cognitive levels to a 0-100 test score with a mean error of 4.82 (<5%). This study is the first to establish a continuous evaluation model of cognitive decline on a large sample dataset. Its cross-device usability also suggests universality and robustness of this EEG model, offering a more reliable and affordable way to assess cognitive decline for clinical diagnosis and treatment as well. Furthermore, the interpretability of features involved may further contribute to the early diagnosis and superior treatment evaluation of Alzheimer's disease.

Mechanisms underlying therapeutic resistance of tyrosine kinase inhibitors in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a malignant clonal disease involving hematopoietic stem cells that is characterized by myeloid cell proliferation in bone marrow and peripheral blood, and the presence of the Philadelphia (Ph) chromosome with BCR-ABL fusion gene. Treatment of CML has dramatically improved since the advent of tyrosine kinase inhibitors (TKI). However, there are a small subset of CML patients who develop resistance to TKI. Mutations in the ABL kinase domain (KD) are currently recognized as the leading cause of TKI resistance in CML. In this review, we discuss the concept of resistance and summarize recent advances exploring the mechanisms underlying CML resistance. Overcoming TKI resistance appears to be the most successful approach to reduce the burden of leukemia and enhance cures for CML. Advances in new strategies to combat drug resistance may rapidly change the management of TKI-resistant CML and expand the prospects for available therapies.

A Real-Time Non-Implantation Bi-Directional Brain-Computer Interface Solution Without Stimulation Artifacts.

The non-implantation bi-directional brain-computer interface (BCI) is a neural interface technology that enables direct two-way communication between the brain and the external world by both "reading" neural signals and "writing" stimulation patterns to the brain. This technology has vast potential applications, such as improving the quality of life for individuals with neurological and mental illnesses and even expanding the boundaries of human capabilities. Nonetheless, non-implantation bi-directional BCIs face challenges in generating real-time feedback and achieving compatibility between stimulation and recording. These issues arise due to the considerable overlap between electrical stimulation frequencies and electrophysiological recording frequencies, as well as the impediment caused by the skull to the interaction of external and internal currents. To address those challenges, this work proposes a novel solution that combines the temporal interference stimulation paradigm and minimally invasive skull modification. A longitudinal animal experiment has preliminarily validated the feasibility of the proposed method. In signal recording experiments, the average impedance of our scheme decreased by 4.59 kΩ , about 67%, compared to the conventional technique at 18 points. The peak-to-peak value of the Somatosensory Evoked Potential increased by 8%. Meanwhile, the signal-to-noise ratio of Steady-State Visual Evoked Potential increased by 5.13 dB, and its classification accuracy increased by 44%. The maximum bandwidth of the resting state rose by 63%. In electrical stimulation experiments, the signal-to-noise ratio of the low-frequency response evoked by our scheme rose by 8.04 dB, and no stimulation artifacts were generated. The experimental results show that signal quality in acquisition has significantly improved, and frequency-band isolation eliminates stimulation artifacts at the source. The acquisition and stimulation pathways are real-time compatible in this non-implantation bi-directional BCI solution, which can provide technical support and theoretical guidance for creating closed-loop adaptive systems coupled with particular application scenarios in the future.

Transfusion-dependent non-severe aplastic anemia: characteristics and outcomes in the clinic.

Transfusion-dependent non-severe aplastic anemia (TD-NSAA) is a rare condition of bone marrow failure that can persist for a long time or develop into severe aplastic anemia (SAA). Little is known about the clinical and laboratory characteristics, and disease prognosis and outcomes in TD-NSAA patients. The clinical and laboratory data of 124 consecutive TD-NSAA patients in the Chinese Eastern Collaboration Group of Anemia from December 2013 and January 2017 were analyzed retrospectively. In 124 TD-NSAA patients, the median age was 32 years (range: 3-80) and the median disease course was 38 months (range: 3-363). Common complications were iron overload (53/101, 52.5%), liver and kidney dysfunction (42/124, 33.9%), diabetes mellitus/impaired glucose tolerance (24/124, 19.4%), and severe infection (29 cases, 23.4%). 58% of patients (57/124) developed severe aplastic anemia with a median progression time of 24 months (range: 3-216). Patients with absolute neutrophil count (ANC) <0.5×109/L, severe infection, or iron overload had a higher probability of progression to SAA (P=0.022, P=0.025, P=0.001). Patients receiving antithymocyte globulin (ATG) plus Cyclosporin A (CsA) had a higher overall response rate compared to those receiving CsA alone (56.7% vs 19.3%, P < 0.001). The addition of ATG was the favorable factor for efficacy (P=0.003). Fourteen patients developed secondary clonal hematologic disease: eleven patients with paroxysmal nocturnal hemoglobinuria, two patients with myelodysplastic syndromes, and one patient with acute myeloid leukemia, respectively. Ten patients (8.1%) died with a median follow-up of 12 months (range: 3- 36 months). Patients with TD-NSAA usually have a prolonged course of disease, and are prone to be complicated with important organ damage and disease progression to SAA. Intensive immunosuppressive therapy based on ATG might be an appropriate approach for TD-NSAA. Clinical trial registration: http://www.chictr.org.cn/edit.aspx?pid=125480&htm=4, identifier ChiCTR2100045895.

Measurable residual disease detected by flow cytometry independently predicts prognoses of NPM1-mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) with NPM1 mutation is a distinct genetic entity with favorable outcomes. Nevertheless, emerging evidence suggests that NPM1-mutated AML is still a highly heterogeneous disorder. In this study, 266 patients with AML with NPM1 mutations were retrospectively analyzed to evaluate the associations between variant allele frequency (VAF) of NPM1 mutations, co-mutated genes, measurable residual disease (MRD), and patient outcomes. Multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (RT-PCR) were used for monitoring MRD. Ultimately, 106 patients were included in the long-term follow-up period. Patients with high NPM1 VAF (≥ 42.43%) had poorer 2-year relapse-free survival (RFS) (55.7% vs. 70.2%, P = 0.017) and overall survival (OS) (63.7% vs. 82.0%, P = 0.027) than those with low VAF. DNMT3A mutations negatively influenced the outcomes of patients with NPM1 mutations. Patients with high DNMT3A VAF or NPM1/DNMT3A/FLT3-ITD triple mutations had shorter RFS and significantly lower OS than that in controls. After two cycles of chemotherapy, patients with positive MFC MRD results had lower RFS (MRD+ vs. MRD-:44.9% vs. 67.6%, P = 0.007) and OS (61.5% vs. 76.6%, P = 0.011) than those without positive MFC MRD results. In multivariate analysis, high NPM1 VAF (hazard ratio [HR] = 2.045; P = 0.034) and positive MRD after two cycles of chemotherapy (HR = 3.289; P = 0.003) were independent risk factors for RFS; MRD positivity after two cycles of chemotherapy (HR = 3.293; P = 0.008) independently predicted the OS of the patients. These results indicate that VAF of both NPM1 gene itself or certain co-occurring gene pre-treatment and MRD post-treatment are potential markers for restratifying the prognoses of patients AML having NPM1 mutations.

A Binocular Vision SSVEP Brain-Computer Interface Paradigm for Dual-Frequency Modulation.

OBJECTIVE: This study presents a novel brain-computer interface paradigm of dual-frequency modulated steady-state visual evoked potential (SSVEP), aiming to suppress the unpredictable intermodulation components in current applications. This paradigm is especially suitable for training-free scenarios. APPROACH: This study built a dual-frequency binocular vision SSVEP brain-computer interface system using circularly polarized light technology. Two experiments, including a 6-target offline experiment and a 40-target online experiment, were taken with this system. Meanwhile, an improved algorithm filter bank dual-frequency canonical correlation analysis (FBDCCA) was presented for the dual-frequency SSVEP paradigm. MAIN RESULTS: Energy analysis was conducted for 9 subjects in the 6-target dual-frequency offline experiment, among which the signal-to-noise ratio of target frequency components have increased by 2 dB compared to the one of unpredictable intermodulation components. Subsequently, the online experiment with 40 targets was conducted with 12 subjects. With this new dual-frequency paradigm, the online training-free experiment's average information transmission rate (ITR) reached 104.56 ± 15.74 bits/min, which was almost twice as fast as the current best dual-frequency paradigm. And the average information transfer rate for offline training analysis of this new paradigm was 180.87 ± 17.88 bits/min. SIGNIFICANCE: These results demonstrate that this new dual-frequency SSVEP brain-computer interface paradigm can suppress the unpredictable intermodulation harmonics and generate higher quality responses while completing dual-frequency encoding. Moreover, its performance shows high ITR in applications both with and without training. It is thus believed that this paradigm is competent for achieving large target numbers in brain-computer interface systems and has more possible practices.

Somatic Mutation of PRKAR1A in Four Cases of Sporadic Cardiac Myxoma.

BACKGROUND: Inactivating mutations of the protein kinase A regulatory subunit 1 alpha (PRKAR1A) gene have been reported in familial cardiac myxoma. However, the role of PRKAR1A mutation in sporadic cardiac myxoma remains unknown. METHODS: Targeted next-generation sequencing (NGS) was performed to identify mutations with the PRKAR1A gene in seven cases of sporadic cardiac myxomas. Sanger sequencing of DNA from cardiac myxoma specimens and matched peripheral blood samples was performed to verify the identified mutations. RESULTS: Targeted NGS of myxoma DNA revealed 232 single nucleotide variants in 141 genes and 38 insertion-deletion mutations in 13 genes. Six PRKAR1A mutations were identified in four of the seven cardiac myxoma cases, and thus, the PRKAR1A inactivating mutation rate was 57.2% (4/7, 95% CI=0.44-0.58, P<0.05). The PRKAR1A variants identified by Sanger sequencing analysis were consistent with those from the NGS analysis for the four myxoma specimens. All of the pathogenic PRKAR1A mutations led to premature termination of PRKAR1A, except for one synonymous mutation. Moreover, none of the nonsense and missense mutations found in the myxoma specimens were found in the matched peripheral blood samples. CONCLUSION: Pathogenic mutations of the PRKAR1A gene were identified in tumor specimens from four cases of sporadic cardiac myxoma, and the absence of these mutations in peripheral blood samples demonstrated that they were somatic mutations.

Minimally Invasive Local-Skull Electrophysiological Modification With Piezoelectric Drill.

The research on non-invasive BCI is nowadays hitting the bottleneck due to the humble quality of scalp EEG signals. Whereas invasive solutions that offer higher signal quality in contrast are suffocated in their spreading because of the potential surgical complication and health risks caused by electrode implantation. Therefore, it puts forward a necessity to explore a scheme that could both collect high-quality EEG signals and guarantee high-level operation safety.This study proposed a Minimally Invasive Local-skull Electrophysiological Modification method to improve scalp EEG signals qualities at specific brain regions. Six eight-month-old SD rats were used for in vivo verification experiment. A hole with a diameter of about 500 micrometers was drilled in the skull above the visual cortex of rats. Significant changes in rsEEG and SSVEP signals before and after modification were observed. After modification, the skull impedance of rats decreases by about 84 %, the average maximum bandwidth of rsEEG increase by 57 %, and the broadband SNR of SSVEP is increased by 5.13 dB. The time of piezoelectric drilling operation is strictly controlled under 30 seconds for each rat to prevent possible brain damage from overheating. Compared with traditional invasive procedures such as ECoG, Minimally Invasive Local-skull Electrophysiological Modification operation time is shorter and no electrode implantation is needed while it remarkably boosts the scalp EEG signal quality. This technical solution has the potential to replace the use of ECoG in certain application scenarios and further invigorate studies in the field of scalp EEG in the future.

LINC00702-mediated DUSP1 transcription in the prevention of bladder cancer progression: Implications in cancer cell proliferation and tumor inflammatory microenvironment.

BACKGROUND: Long noncoding RNAs (lncRNAs) can mediate the biological processes during tumorigenesis which may be affected by tumor associated macrophages (TAMs). Hence, we aim to identify the functionality of LINC00702 in regulation of bladder cancer cells and M2-TAMs. METHODS: After induction of M2-TAMs from THP-1 monocyte, we evaluated effects of LINC00702 on bladder cancer cells and M2-TAMs, which were validated in a xenograft tumor mouse model. RESULTS: Low LINC00702 expression was determined in bladder cancer tissues. LINC00702 could promote DUSP1 transcription by recruiting JUND to its promoter. Ectopic LINC00702 expression suppressed the bladder cancer cell proliferation and secretion of inflammatory cytokines by M2-TAMs through up-regulation of DUSP1. The anti-tumor activity of LINC00702 was ultimately validated in vivo. CONCLUSION: LINC00702 promoted DUSP1 by recruiting JUND to inhibit the proliferation of bladder cancer cells and the secretion of inflammatory factors, thus modulating bladder cancer inflammatory microenvironment.

Neurofeedback Training of the Control Network in Children Improves Brain Computer Interface Performance.

In the past 20 years, neural engineering has made unprecedented progress in the interpretation of brain information (e.g., brain-computer interfaces) and in neuromodulation (e.g., electromagnetic stimulation and neurofeedback). However, there has been little research aiming to improve the performance of brain-computer interfaces (BCIs) using neuromodulation. The present study presents a novel design for a neurofeedback training (NFT) method to improve the operation of a steady-state visual evoked potential (SSVEP)-based BCI and further explores its underlying mechanisms. The use of NFT to upregulate alpha-band power in the user's parietal lobe is presented in this study as a new neuromodulation method to improve SSVEP-based BCI in this study. After users completed this NFT intervention, the signal-to-noise ratio (SNR), accuracy, and information transfer rate (ITR) of the SSVEP-based BCI were increased by 5.8%, 4.7%, and 15.6%, respectively. However, no improvement was observed in the control group in which the subjects did not participate in NFT. Moreover, a general reinforcement of the information flow from the parietal lobe to the occipital lobe was observed. Evidence from a network analysis and an attention test further indicates that NFT improves attention by developing the control capacity of the parietal lobe and then enhances the above SSVEP indicators. Upregulating the amplitude of parietal alpha oscillations using NFT significantly improves the SSVEP-based BCI performance by modulating the control network. The study validates an effective neuromodulation method and possibly contributes to explaining the function of the parietal lobe in the control network.

Development of a myelodysplastic/myeloproliferative neoplasm-unclassifiable in a patient with acute myeloid leukemia: a case report and literature review.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are a heterogeneous group of hematologic malignancies characterized by dysplastic and myeloproliferative overlapping features in the bone marrow and blood. The occurrence of the disease is related to age, prior history of MPN or MDS, and recent cytotoxic or growth factor therapy, but it rarely develops after acute myeloid leukemia (AML). We report a rare case of a patient diagnosed with AML with t(8; 21)(q22; q22) who received systematic chemotherapy. After 4 years of follow-up, MDS/MPN-unclassifiable occurred without signs of primary AML recurrence.

Inverse design of the thermal environment in an airplane cockpit using the adjoint method with the momentum method.

Currently, the thermal environment in airplane cockpits is unsatisfactory and pilots often complain about a strong draft sensation in the cockpit. It is caused by the unreasonable air supply diffusers design. One of the best approaches to design a better cockpit environment is the adjoint method. The method can simultaneously and efficiently identify the number, size, location, and shape of air supply inlets, and the air supply parameters. However, the real air diffuser needed to design often have grilles, especially in the airplane cockpit, and the current method can only design the inlet as an opening. This study combined the adjoint method with the momentum method to directly identify the optimal air supply diffusers with grilles to create optimal thermal environment in an airplane cockpit (1) under ideal conditions and (2) with realistic constraints. Under the ideal conditions, the resulting design provides an optimal thermal environment for the cockpit, but it might not be feasible in practice. The design with realistic constraints provides acceptable thermal comfort in the cockpit, but it is not optimal. Thus, there is an engineering trade-off between design feasibility and optimization. All in all, the adjoint method with the momentum method can be effectively used to identify real air supply diffusers.

Successful treatment of a patient with NSCLC carrying uncommon compound EGFR G719X and S768I mutations using osimertinib: A case report.

The discovery of epidermal growth factor receptor (EGFR) somatic mutations and the availability of tyrosine kinase inhibitors (TKIs) as targeted therapies have altered the therapeutic prospects of advanced non-small-cell lung cancer (NSCLC). G719X and S768I are uncommon mutations, and they often exist as compound mutations. A few reports have described the efficacy of first- and second-generation EGFR-TKIs. However, the efficacy of osimertinib in patients with these uncommon compound mutations is unknown. In this study, we reported the postoperative outcome of a patient with NSCLC and uncommon compound EGFR G719X and S768I mutations. After postoperative recurrence, the patient was treated with osimertinib, and an excellent and long-lasting clinical response was achieved. The patient has taken osimertinib for 31.0 months and exhibited a partial response, and her follow-up is ongoing.

Imatinib therapy in acute myeloid leukemia with DEK-NUP214 and FIP1L1-PDGFRA rearrangement: A case report.

The fusion product of FIP1-like-1 (FIP1L1) and platelet-derived growth factor receptor α (PDGFRA) gene rearrangement is a tyrosine kinase oncoprotein sensitive to imatinib. This gene rearrangement characterizes a novel clinico-biological class of myeloid and lymphoid neoplasms with eosinophilia and PDGFRA abnormalities. The DEK proto-oncogene (DEK) and nucleoporin 214 (NUP214) rearrangement is rare in patients with acute myeloid leukemia (AML); therefore, the coexistence of DEK-NUP214 and FIP1L1-PDGFRA rearrangements in patients with AML is extremely rare. The present study presents a rare relapse case of a patient with AML with DEK-NUP214 and FIP1L1-PDGFRA rearrangements, without marked eosinophilia in the peripheral blood or bone marrow. Low-dose imatinib monotherapy without intensive chemotherapy was used to achieve complete hematological remission.

Minimal residual disease may be an early prognostic indicator for newly diagnosed acute myeloid leukemia patients induced by decitabine-based chemotherapy.

Objectives: To analyze the efficacy and safety of decitabine combined with low/reduced-dose chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients unfit for intensive therapy and to investigate the early prognostic indicators for these patients. Methods: The eligible patients treated with decitabine-based chemotherapy were retrospectively analyzed. Responses and long-term survival were calculated and their correlation with clinical characteristics was analyzed. Minimal residual disease (MRD) detected by flow cytometry (FCM) after the induction therapy was measured, and the association with prognosis was explored. Results: Fifty-five newly diagnosed AML patients were enrolled. The overall response rate (ORR) was 80.0%, with a complete remission (CR) rate of 63.64% and partial remission (PR) rate of 16.36%. Grade 4 hematological toxicity was common, and the incidence of infections was 83.64%, with 18.18% of patients suffered from severe infections. No serious bleeding or non-hematological adverse events occurred. Treatment-related mortality was 3.64%. The median overall survival (OS) and disease-free survival (DFS) were 17.0 (13.7-20.3) months and 17.0 (10.2-23.8) months, respectively. Multivariate analysis showed that an advanced age (≥ 60 years) and higher MRD (≥ 1.34%) after induction therapy were adverse prognostic factors for patients who had achieved CR. Conclusions: Decitabine-based chemotherapy may be a suitable therapeutic alternative for newly diagnosed AML patients who are unfit for intensive chemotherapy. An advanced age (≥ 60 years) and higher MRD (≥ 1.34%) were considered adverse prognostic factors.

CSF3R mutations were associated with an unfavorable prognosis in patients with acute myeloid leukemia with CEBPA double mutations.

The aim of this study was to explore the clinical features and prognostic significance of CSF3R mutations in AML patients with CEBPA double mutations (CEBPAdm). One hundred one AML patients with CEBPAdm were retrospectively analyzed in this study. Mutation status of CSF3R gene, clinical features, and long-term outcomes were analyzed. The frequency of CSF3R mutations in patients with CEBPAdm was 19.80% (20/101). Patients with CSF3R mutations were associated with a lower platelet (u = 2.728, P = 0.006) and higher leukocytes (u = 3.178, P = 0.001) compared with those with wide-type CSF3R gene. The 5-year relapse-free survival (RFS) was 18.7% in patients with CSF3R mutations, which was significantly lower than those with wide-type CSF3R (31.8%) (P = 0.015). The 5-year overall survival (OS) was also significantly different between patients with and without CSF3R mutations (17.5% versus 57.4%, P = 0.019). The prevalence of CSF3R mutations was high in AML patients with CEBPAdm, which indicated a poor prognosis, and CSF3R mutations may be a new potential candidate for prognostically re-stratifying AML patients with CEBPAdm.

Long noncoding RNAs and their epigenetic function in hematological diseases.

Recent discoveries demonstrate the importance of long noncoding RNA (lncRNA) in the regulation of multiple major processes impacting development, differentiation, and metastasis of hematological diseases through epigenetic mechanisms. In contrast to genetic changes, epigenetic modification does not modify genes but is frequently reversible, thus providing opportunities for targeted treatment using specific inhibitors. In this review, we will summarize the function and epigenetic mechanism of lncRNA in malignant hematologic diseases.

Targeting the IGF1R Pathway in Breast Cancer Using Antisense lncRNA-Mediated Promoter cis Competition.

Aberrant insulin-like growth factor I receptor (IGF1R) signaling pathway serves as a well-established target for cancer drug therapy. The intragenic antisense long noncoding RNA (lncRNA) IRAIN, a putative tumor suppressor, is downregulated in breast cancer cells, while IGF1R is overexpressed, leading to an abnormal IGF1R/IRAIN ratio that promotes tumor growth. To precisely target this pathway, we developed an "antisense lncRNA-mediated intragenic cis competition" (ALIC) approach to therapeutically correct the elevated IGF1R/IRAIN bias in breast cancer cells. We used CRISPR-Cas9 gene editing to target the weak promoter of IRAIN antisense lncRNA and showed that in targeted clones, intragenic activation of the antisense lncRNA potently competed in cis with the promoter of the IGF1R sense mRNA. Notably, the normalization of IGF1R/IRAIN transcription inhibited the IGF1R signaling pathway in breast cancer cells, decreasing cell proliferation, tumor sphere formation, migration, and invasion. Using "nuclear RNA reverse transcription-associated trap" sequencing, we uncovered an IRAIN lncRNA-specific interactome containing gene targets involved in cell metastasis, signaling pathways, and cell immortalization. These data suggest that aberrantly upregulated IGF1R in breast cancer cells can be precisely targeted by cis transcription competition, thus providing a useful strategy to target disease genes in the development of novel precision medicine therapies.