A Case of Relapsed/Refractory CD56-Positive Acute Promyelocytic Leukemia, in Which Complete Molecular Remission Was Achieved Following Combination Therapy with Venetoclax and Azacitidine.

An 84-year-old woman was diagnosed as having acute promyelocytic leukemia(APL)in July Year X-3. The test for promyelocytic leukemia- retinoic acid receptor alpha(PML-RARA)mRNA was positive, while that for CD56 was negative. Since her white blood cell( WBC) count was <3,000/µL, with a count of APL cells of <1,000/µL, she was started on monotherapy with all-trans retinoic acid(ATRA). In September Year X-3, complete hematological remission(CHR)was confirmed. she refused to provide consent for receiving consolidation therapy. In February Year X-2, hematological relapse occurred. She was started on re-induction therapy with arsenite(ATO), and in June Year X-2, complete molecular remission(CMR)was achieved. She was started on post-remission therapy with ATO. In August Year X-1, she developed molecular relapse and was started on tamibarotene(Am80). In October Year X-1, hematological relapse was detected, and the test for CD56 was positive. She was started on combined venetoclax(VEN)+azacitidine(AZA)(VEN+AZA). After completion of 1 course of treatment, CMR was achieved, but she developed hematological relapse after 5 courses of treatment. She died of gastrointestinal hemorrhage. This is considered a valuable case for accumulating information on the treatment of CD56-positive APL resistant to ATRA and ATO.

Gilteritinib Monotherapy as a Transplant Bridging Option for a Patient with FLT3-Mutated Acute Promyelocytic Leukemia Who Developed a Second Relapse after All-Trans Retinoic Acid + Chemotherapy, Arsenic Trioxide, and High-Dose Cytarabine Therapy.

We report a case of FLT3-mutated APL who developed disease relapse despite all-trans retinoic acid (ATRA) + chemotherapy, and re-induction chemotherapy with arsenic trioxide (ATO) and high-dose (HD) cytarabine (Ara-C) therapy failed to yield complete remission. Because the leukemic cells were resistant to all the aforementioned therapies, we started the patient on monotherapy with gilteritinib, a selective FLT3-inhibitor, as an alternative re-induction treatment option rather than further intensive chemotherapy. The patient showed complete hematologic remission in response to this therapy. This case serves as supporting evidence for the use of single-agent therapy with gilteritinib as a bridge to transplantation in patients with refractory FLT3-mutated APL.

A Case of Immune Thrombocytopenia Occurring after Radiotherapy plus Atezolizumab Treatment for Bladder Cancer.

An 84-year-old female developed gross hematuria. She was diagnosed as urinary bladder carcinoma. She was initiated on concurrent atezolizumab plus radiation(a phase Ⅱ clinical trial)(jRCT2031180060). After 8 cycles of atezolizumab, complete response was confirmed. Maintenance atezolizumab treatment was started. Platelet(Plt)count decreased, there was no rechallenge with atezolizumab. Bone marrow examination revealed normal. Plt count recovered. Plt count decreased again. The serum levels of interleukin-6(IL-6)were elevated. She was diagnosed as having immune thrombocytopenia. She was started on treatment with prednisolone(PSL)at dose of 20 mg/day. Plt count was increased.

Long-term follow-up after R-High CHOP/CHASER/LEED with Auto-PBSCT in untreated mantle cell lymphoma-Final analysis of JCOG0406.

Progression-free survival after R-High CHOP/CHASER/LEED with auto-PBSCT in untreated mantle cell lymphoma in JCOG0406 study. A continuous pattern of relapse was observed.

A Case of Diffuse Large B-Cell Lymphoma Complicated by Helicobacter Pylori-Negative Russell Body Gastritis.

A 76-year-old woman with a past history of diabetes mellitus and Hashimoto's disease, in regard to her personal history, she did not smoke or drink alcohol. In March, year X-1, she became aware of cervical lymphadenopathy. Based on the findings of lymph node biopsy, she was diagnosed as having diffuse large B-cell lymphoma(DLBCL). An upper gastrointestinal endoscopy(U-GIE)revealed white granular prominences in the gastric fornix, and biopsy of these lesions revealed the diagnosis of Russell body gastritis(RBG). Neither lymphoma infiltration nor other malignant findings were found. Diagnostic tests for Helicobacter pylori were negative. The clinical stage of the DLBCL was determined as stage ⅢA, and the International Prognostic Index was"high intermediate". She received 6 cycles of R-CHOP therapy, with concomitant use of a proton pump inhibitor. Complete remission was confirmed in November, year X-1. An U-GIE performed again no longer showed the white granular prominences in the gastric fornix. The present report is the first of DLBCL complicated by RBG; our findings suggested that the two diseases were associated with each other.

Neuropilin-1 Mediates SARS-CoV-2 Infection of Astrocytes in Brain Organoids, Inducing Inflammation Leading to Dysfunction and Death of Neurons.

Coronavirus disease 2019 (COVID-19) is frequently associated with neurological deficits, but how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces these effects remains unclear. Here, we show that astrocytes are readily infected by SARS-CoV-2, but surprisingly, neuropilin-1, not angiotensin-converting enzyme 2 (ACE2), serves as the principal receptor mediating cell entry. Infection is further positively modulated by the two-pore segment channel 2 (TPC2) protein that regulates membrane trafficking and endocytosis. Astrocyte infection produces a pathological response closely resembling reactive astrogliosis characterized by elevated type I interferon (IFN) production, increased inflammation, and the decreased expression of transporters of water, ions, choline, and neurotransmitters. These combined events initiated within astrocytes produce a hostile microenvironment that promotes the dysfunction and death of uninfected bystander neurons. IMPORTANCE SARS-CoV-2 infection primarily targets the lung but may also damage other organs, including the brain, heart, kidney, and intestine. Central nervous system (CNS) pathologies include loss of smell and taste, headache, delirium, acute psychosis, seizures, and stroke. Pathological loss of gray matter occurs in SARS-CoV-2 infection, but it is unclear whether this is due to direct viral infection, indirect effects associated with systemic inflammation, or both. Here, we used induced pluripotent stem cell (iPSC)-derived brain organoids and primary human astrocytes from the cerebral cortex to study direct SARS-CoV-2 infection. Our findings support a model where SARS-CoV-2 infection of astrocytes produces a panoply of changes in the expression of genes regulating innate immune signaling and inflammatory responses. The deregulation of these genes in astrocytes produces a microenvironment within the CNS that ultimately disrupts normal neuron function, promoting neuronal cell death and CNS deficits.

Self-supervised deep learning encodes high-resolution features of protein subcellular localization.

Explaining the diversity and complexity of protein localization is essential to fully understand cellular architecture. Here we present cytoself, a deep-learning approach for fully self-supervised protein localization profiling and clustering. Cytoself leverages a self-supervised training scheme that does not require preexisting knowledge, categories or annotations. Training cytoself on images of 1,311 endogenously labeled proteins from the OpenCell database reveals a highly resolved protein localization atlas that recapitulates major scales of cellular organization, from coarse classes, such as nuclear and cytoplasmic, to the subtle localization signatures of individual protein complexes. We quantitatively validate cytoself's ability to cluster proteins into organelles and protein complexes, showing that cytoself outperforms previous self-supervised approaches. Moreover, to better understand the inner workings of our model, we dissect the emergent features from which our clustering is derived, interpret them in the context of the fluorescence images, and analyze the performance contributions of each component of our approach.

OpenCell: Endogenous tagging for the cartography of human cellular organization.

Elucidating the wiring diagram of the human cell is a central goal of the postgenomic era. We combined genome engineering, confocal live-cell imaging, mass spectrometry, and data science to systematically map the localization and interactions of human proteins. Our approach provides a data-driven description of the molecular and spatial networks that organize the proteome. Unsupervised clustering of these networks delineates functional communities that facilitate biological discovery. We found that remarkably precise functional information can be derived from protein localization patterns, which often contain enough information to identify molecular interactions, and that RNA binding proteins form a specific subgroup defined by unique interaction and localization properties. Paired with a fully interactive website (opencell.czbiohub.org), our work constitutes a resource for the quantitative cartography of human cellular organization.

DaXi-high-resolution, large imaging volume and multi-view single-objective light-sheet microscopy.

The promise of single-objective light-sheet microscopy is to combine the convenience of standard single-objective microscopes with the speed, coverage, resolution and gentleness of light-sheet microscopes. We present DaXi, a single-objective light-sheet microscope design based on oblique plane illumination that achieves: (1) a wider field of view and high-resolution imaging via a custom remote focusing objective; (2) fast volumetric imaging over larger volumes without compromising image quality or necessitating tiled acquisition; (3) fuller image coverage for large samples via multi-view imaging and (4) higher throughput multi-well imaging via remote coverslip placement. Our instrument achieves a resolution of 450 nm laterally and 2 µm axially over an imaging volume of 3,000 × 800 × 300 µm. We demonstrate the speed, field of view, resolution and versatility of our instrument by imaging various systems, including Drosophila egg chamber development, zebrafish whole-brain activity and zebrafish embryonic development - up to nine embryos at a time.

Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma Associated with Nephrotic Syndrome during Hemodialysis, Treated Successfully with Tirabrutinib.

A 74-year-old woman was diagnosed with Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) in X-18. Fludarabine plus rituximab (FR) was started, and she showed remission. In July X-7, the serum creatinine (Cr) level increased to 1.67 mg/dL, and bendamustine plus rituximab (BR) was started. By November X-7, the Cr level had increased to 8.41 mg/dL, so she was started on hemodialysis (HD). In September X-1, she developed nephrotic syndrome. She was started on tirabrutinib at 480 mg. In July X, her nephrotic syndrome had improved, and a complete response (CR) was achieved. This is the first case of the administration of tirabrutinib in a patient undergoing HD.

ZAF, the first open source fully automated feeder for aquatic facilities.

In the past few decades, aquatic animals have become popular model organisms in biology, spurring a growing need for establishing aquatic facilities. Zebrafish are widely studied and relatively easy to culture using commercial systems. However, a challenging aspect of maintaining aquatic facilities is animal feeding, which is both time- and resource-consuming. We have developed an open-source fully automatic daily feeding system, Zebrafish Automatic Feeder (ZAF). ZAF is reliable, provides a standardized amount of food to every tank, is cost-efficient and easy to build. The advanced version, ZAF+, allows for the precise control of food distribution as a function of fish density per tank, and has a user-friendly interface. Both ZAF and ZAF+ are adaptable to any laboratory environment and facilitate the implementation of aquatic colonies. Here, we provide all blueprints and instructions for building the mechanics, electronics, fluidics, as well as to setup the control software and its user-friendly graphical interface. Importantly, the design is modular and can be scaled to meet different user needs. Furthermore, our results show that ZAF and ZAF+ do not adversely affect zebrafish culture, enabling fully automatic feeding for any aquatic facility.

Basic locomotor muscle synergies used in land walking are finely tuned during underwater walking.

Underwater walking is one of the most common hydrotherapeutic exercises. Therefore, understanding muscular control during underwater walking is important for optimizing training regimens. The effects of the water environment on walking are mainly related to the hydrostatic and hydrodynamic theories of buoyancy and drag force. To date, muscular control during underwater walking has been investigated at the individual muscle level. However, it is recognized that the human nervous system modularly controls multiple muscles through muscle synergies, which are sets of muscles that work together. We found that the same set of muscle synergies was shared between the two walking tasks. However, some task-dependent modulation was found in the activation combination across muscles and temporal activation patterns of the muscle synergies. The results suggest that the human nervous system modulates activation of lower-limb muscles during water walking by finely tuning basic locomotor muscle synergies that are used during land walking to meet the biomechanical requirements for walking in the water environment.

Effort-dependent effects on uniform and diverse muscle activity features in skilled pitching.

How do skilled players change their motion patterns depending on motion effort? Pitchers commonly accelerate wrist and elbow joint rotations via proximal joint motions. Contrastingly, they show individually different pitching motions, such as in wind-up or follow-through. Despite the generality of the uniform and diverse features, effort-dependent effects on these features are unclear. Here, we reveal the effort dependence based on muscle activity data in natural three-dimensional pitching performed by skilled players. We extract motor modules and their effort dependence from the muscle activity data via tensor decomposition. Then, we reveal the unknown relations among motor modules, common features, unique features, and effort dependence. The current study clarifies that common features are obvious in distinguishing between low and high effort and that unique features are evident in differentiating high and highest efforts.

Specific Brain Reorganization Underlying Superior Upper Limb Motor Function After Spinal Cord Injury: A Multimodal MRI Study.

BACKGROUND: We recently discovered that individuals with complete spinal cord injury (SCI) have a higher grip force control ability in their intact upper limbs than able-bodied subjects. However, the neural basis for this phenomenon is unknown. OBJECTIVE: This study aimed to investigate the neural basis of the higher grip force control in the brains of individuals with SCI using multimodal magnetic resonance imaging (MRI). METHODS: Eight SCI subjects and 10 able-bodied subjects performed hand grip force control tasks at 10%, 20%, and 30% of their maximal voluntary contraction during functional MRI (fMRI). Resting-state fMRI and T1-weighted structural images were obtained to investigate changes in brain networks and structures after SCI. RESULTS: SCI subjects showed higher grip force steadiness than able-bodied subjects (P < .05, corrected), smaller activation in the primary motor cortex (P < .05, corrected), and deactivation of the visual cortex (P < .001, uncorrected). Furthermore, SCI subjects had stronger functional connectivity between the superior parietal lobule and the left primary motor cortex (P < .001, uncorrected), as well as larger gray matter volume in the bilateral superior parietal lobule (P < .001, uncorrected). CONCLUSIONS: The structural and functional reorganization observed in the superior parietal lobule of SCI subjects may represent the neural basis underlying the observed higher grip force control, and is likely responsible for the smaller activation in the primary motor cortex observed in these individuals. These findings could have applications in the fields of neurorehabilitation for improvement of intact limb functions after SCI.

Influence of Release Parameters on Pitch Location in Skilled Baseball Pitching.

This study explored the mechanical factors that determine accuracy of a baseball pitching. In particular, we focused on the mechanical parameters at ball release, referred to as release parameters. The aim was to understand which parameter has the most deterministic influence on pitch location by measuring the release parameters during actual pitching and developing a simulation that predicts the pitch location from given release parameters. By comparing the fluctuation of the simulated pitch location when varying each release parameter, it was found that the elevation pitching angle and speed significantly influenced the vertical pitch location, and the azimuth pitching angle significantly influenced the horizontal pitch location. Moreover, a regression model was obtained to predict the pitch location, and it became clear that the significant predictors for the vertical pitch location were the elevation pitching angle, the speed, and spin axis, and those for the horizontal pitch location were the azimuth pitching angle, the spin axis, and horizontal release point. Therefore, it was suggested that the parameter most affecting pitch location weas pitching angle. On the other hand, multiple regression analyses revealed that the relation between release parameters varied between pitchers. The result is expected to contribute to an understanding of the mechanisms underlying accurate ball control skill in baseball pitching.

Cross-sectional comparison of the probabilistic structure in the distribution of pitching location among baseball pitchers of different ages.

The present study was a cross-sectional comparison of probabilistic structure in the distribution of pitching location among baseball pitchers of various age groups (25 elementary school (ES), 20 junior high school (JH), 15 high school (HS), and 18 college students (CL)). In the results, despite the general age-dependent variations in pitching precision, the difference was reflected not only in error 'size' but also in the 'shape' of error as it was shown by fitting 95% confidence ellipse to the two dimensional distribution of pitch location. While the precision measure as a reflection of trial-by-trial variability of release timing (major axis length of the ellipse) was constant, minor axis length of the ellipse as a reflection of variability in the pitching form of each participant demonstrated significant differences among the groups. In the ES group particularly, the trial-by-trial variability in the trajectory angle of the throwing arm was significantly correlated with the minor axis length; this correlation was far greater than those in older groups. The present study is the first to demonstrate the detailed structure of the variability of pitching location of baseball dependent on age.

R-CHOP-14 versus R-CHOP-14/CHASER for upfront autologous transplantation in diffuse large B-cell lymphoma: JCOG0908 study.

The efficiency of upfront consolidation with high-dose chemotherapy/autologous stem-cell transplantation (HDCT/ASCT) for newly diagnosed high-risk diffuse large B-cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high-risk DLBCL patients having an age-adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R-CHOP-14 (arm A) or 3 cycles of R-CHOP-14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2-y progression-free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow-up of 40.3 mo, 2-y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%-81.2%) and 66.7% (95% CI: 48.8%-79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%-85.7%) and 83.3% (95% CI: 66.6%-92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non-hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R-CHOP-14 showed higher 2-y PFS and less toxicity compared with R-CHOP-14/CHASER in patients with high-risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN-CTR, UMIN000003823).

Raman image-activated cell sorting.

The advent of image-activated cell sorting and imaging-based cell picking has advanced our knowledge and exploitation of biological systems in the last decade. Unfortunately, they generally rely on fluorescent labeling for cellular phenotyping, an indirect measure of the molecular landscape in the cell, which has critical limitations. Here we demonstrate Raman image-activated cell sorting by directly probing chemically specific intracellular molecular vibrations via ultrafast multicolor stimulated Raman scattering (SRS) microscopy for cellular phenotyping. Specifically, the technology enables real-time SRS-image-based sorting of single live cells with a throughput of up to ~100 events per second without the need for fluorescent labeling. To show the broad utility of the technology, we show its applicability to diverse cell types and sizes. The technology is highly versatile and holds promise for numerous applications that are previously difficult or undesirable with fluorescence-based technologies.

Intelligent classification of platelet aggregates by agonist type.

Platelets are anucleate cells in blood whose principal function is to stop bleeding by forming aggregates for hemostatic reactions. In addition to their participation in physiological hemostasis, platelet aggregates are also involved in pathological thrombosis and play an important role in inflammation, atherosclerosis, and cancer metastasis. The aggregation of platelets is elicited by various agonists, but these platelet aggregates have long been considered indistinguishable and impossible to classify. Here we present an intelligent method for classifying them by agonist type. It is based on a convolutional neural network trained by high-throughput imaging flow cytometry of blood cells to identify and differentiate subtle yet appreciable morphological features of platelet aggregates activated by different types of agonists. The method is a powerful tool for studying the underlying mechanism of platelet aggregation and is expected to open a window on an entirely new class of clinical diagnostics, pharmacometrics, and therapeutics.

Platelets are small cells in the blood that primarily help stop bleeding after an injury by sticking together with other blood cells to form a clot that seals the broken blood vessel. Blood clots, however, can sometimes cause harm. For example, if a clot blocks the blood flow to the heart or the brain, it can result in a heart attack or stroke, respectively. Blood clots have also been linked to harmful inflammation and the spread of cancer, and there are now preliminary reports of remarkably high rates of clotting in COVID-19 patients in intensive care units. A variety of chemicals can cause platelets to stick together. It has long been assumed that it would be impossible to tell apart the clots formed by different chemicals (which are also known as agonists). This is largely because these aggregates all look very similar under a microscope, making it incredibly time consuming for someone to look at enough microscopy images to reliably identify the subtle differences between them. However, finding a way to distinguish the different types of platelet aggregates could lead to better ways to diagnose or treat blood vessel-clogging diseases. To make this possible, Zhou, Yasumoto et al. have developed a method called the "intelligent platelet aggregate classifier" or iPAC for short. First, numerous clot-causing chemicals were added to separate samples of platelets taken from healthy human blood. The method then involved using high-throughput techniques to take thousands of images of these samples. Then, a sophisticated computer algorithm called a deep learning model analyzed the resulting image dataset and "learned" to distinguish the chemical causes of the platelet aggregates based on subtle differences in their shapes. Finally, Zhou, Yasumoto et al. verified iPAC method's accuracy using a new set of human platelet samples. The iPAC method may help scientists studying the steps that lead to clot formation. It may also help clinicians distinguish which clot-causing chemical led to a patient's heart attack or stroke. This could help them choose whether aspirin or another anti-platelet drug would be the best treatment. But first more studies are needed to confirm whether this method is a useful tool for drug selection or diagnosis.