Homoharringtonine synergizes with venetoclax in early T cell progenitor acute lymphoblastic leukemia: Bench and bed.

BACKGROUND: Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a poor prognosis. To find a cure, we examined the synergistic effect of homoharringtonine (HHT) in combination with the BCL-2 inhibitor venetoclax (VEN) in ETP-ALL. METHODS: Using in vitro cellular assays and ETP-ALL xenograft models, we first investigated the synergistic activity of HHT and VEN in ETP-ALL. Next, to explore the underlying mechanism, we employed single-cell RNA sequencing of primary ETP-ALL cells treated with HHT or VEN alone or in combination and validated the results with western blot assays. Based on the promising preclinical results and given that both drugs have been approved for clinical use, we then assessed this combination in clinical practice. FINDINGS: Our results showed that HHT synergizes strongly with VEN both in vitro and in vivo in ETP-ALL. Mechanistic studies demonstrated that the HHT/VEN combination concurrently downregulated key anti-apoptotic proteins, i.e., MCL1, leading to enhanced apoptosis. Importantly, the clinical results were very promising. Six patients with ETP-ALL with either refractory/relapsed (R/R) or newly diagnosed disease were treated with an HHT/VEN-based regimen. All patients achieved complete remission (CR) after only one cycle of treatment. CONCLUSIONS: Our findings demonstrate that a combination of HHT/VEN is effective on ETP-ALL and represents the "backbone" of a promising and safe regimen for newly diagnosed and R/R patients with ETP-ALL. FUNDING: This work was funded by the National Cancer Institute, Gehr Family Foundation, George Hoag Family Foundation, National Natural Science Foundation of China, and Key Research and Development Program of Zhejiang Province of China.

Path analysis of self-care amongst community-dwelling pre-ageing and older adults with chronic diseases: A salutogenic model.

With the trend towards ageing population globally, the salutogenic model can be integrated in interventions for pre-ageing and older adults to better support healthy ageing. However, there is limited research examining the salutogenic model's pathway amongst pre-ageing and older adults. Hence, this study aims to investigate pathways of the salutogenic model amongst pre-ageing and older adults with chronic diseases. Two hundred and eight pre-ageing and older adults were recruited from 11 Senior Activity Centres in Singapore. Data was collected using a self-reported questionnaire and analysed using path analyses. The indirect pathway from Subjective Cognitive Complaints to self-care abilities via sense of coherence and health practices were significant. Participants with higher sense of coherence may have increased capacities to execute more complex forms of self-care. Future interventions integrating the salutogenic model could enhance pre-ageing and older adults' self-care abilities to cope with chronic diseases and contribute to healthy ageing.

Seroprevalence of anti-diphtheria toxoid antibody and implications for vaccination policy in Vietnam's South-central coast: a cross-sectional study.

BACKGROUND: Diphtheria is a re-emerging infectious disease and public health concern worldwide and in Vietnam with increasing cases in recent years. This study aimed to assess the anti-diphtheria toxoid antibodies status in Khanh Hoa Province and identify factors contributing to the vaccination policy in the south-central coast of Vietnam. METHODS: This was a cross-sectional study to evaluate the seroprevalence of anti-diphtheria toxoid antibodies among 1,195 participants, aged 5 - 40 years in Khanh Hoa Province, Vietnam. Immunoglobulin G antibody levels against diphtheria were detected using a commercial anti-diphtheria toxoid enzyme-linked immunosorbent assay (SERION ELISA classic Diphtheria Immunoglobulin G) and were categorized following the World Health Organization guidelines. RESULTS: The mean anti-diphtheria toxoid antibody levels were 0.07 IU/ml (95% Confidence Interval: 0.07-0.08). Anti-diphtheria toxoid antibody levels were found to be associated with age and history of diphtheria vaccination. The 5-15 years age group had the highest levels (0.09 IU/ml), while the older age group had the lowest antibody level (p < 0.001). Individuals who received three doses (adjusted Odds ratio: 2.34, 95%CI: 1.35 - 4.07) or 4+ doses (adjusted Odds ratio: 2.45, 95%CI: 1.29 - 4.64) had a higher antibody level compared to those who received only one dose regardless of age. CONCLUSION: It is crucial to promote routine vaccination coverage to over 95% for children under one year of age with three primary doses of the diphtheria-containing vaccine, including additional doses at 18 months and 7 years of age. Booster doses should be promoted and administered to adolescents and adults every 10 years.

IL1RAP-specific T cell engager depletes acute myeloid leukemia stem cells.

BACKGROUND: The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML. METHODS: Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples. RESULTS: IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002). CONCLUSIONS: The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.

Community-acquired necrotizing pneumonia caused by methicillin-resistant Staphylococcus aureus in a healthy pregnant woman after being infected with influenza A: A case report for early warning.

A previously healthy woman, 5 weeks pregnant, was admitted to the intensive care unit in critical condition for septic shock and acute respiratory distress syndrome due to methicillin-resistant Staphylococcus aureus (MRSA) after being infected with Influenza for 3 days. The patient in this case suffered from severe sequelae due to necrotizing pneumonia and later died on the 20th day after admission. We would like to remind clinicians to be aware of this rare but serious diagnosis. The key is to begin appropriate treatment immediately because MRSA necrotizing pneumonia is mediated by toxins and once the toxins are released they cannot be limited by antibiotic treatments. Necrotizing pneumonia related to MRSA should be considered in young patients with pneumonia, sepsis, and neutropenia following seasonal influenza infection with rapidly progressive symptoms.

Homoharringtonine Inhibits the NOTCH/MYC Pathway and Exhibits Anti-Tumor Effects in T-Cell Acute Lymphoblastic Leukemia.

We report on the antileukemic activity of homoharringtonine (HHT) in T-ALL. We showed that HHT inhibited NOTCH/MYC pathway and induced a significantly longer survival in T-ALL mouse and patient-derived xenograft models, therefore supporting HHT as a promising agent for T-ALL.

Assessment of microplastic presence in coastal environments and organisms of Da Nang, Vietnam.

This study investigates the presence of microplastics (MPs) in seawater, sediments, and organisms along the coastal areas of Da Nang, Vietnam. The results obtained revealed MP concentrations ranging from 111 to 304 MPs/L in seawater and 2267 to 4600 MPs/kg in sediment. In organisms such as oysters, mussels, crabs, snails, and fish, MP levels ranged from 1.8 to 17.3 MPs/g (wet weight). Fiber MPs were found to be predominant across seawater, sediment, and organisms. The study identified eight, ten, and eleven types of MPs in seawater, sediment, and organisms, respectively, with Nylon, Polytetrafluoroethylene (PTFE), and Ethylene vinyl alcohol (EVOH) being the most prevalent. Notably, MP concentrations were significantly higher in benthic organisms such as oysters, mussels, and crabs compared to fish (t-test, p < 0.05), suggesting habitat dependency. Similar concentrations, shapes, and types of MPs in seawater, sediments, and organisms demonstrate a tendency for MP accumulation in aquatic organisms within the marine environment.

Magnetic sensitivity enhancement via polarimetric excitation and detection of an ensemble of NV centers.

The negatively charged nitrogen-vacancy center (NV) presents remarkable spin-dependent optical properties that make it an interesting tool for magnetic field sensing. In this paper we exploit the polarization properties of the NV center absorption and emission processes to improve the magnetic sensitivity of an ensemble of NV centers. By simply equipping the experimental set-up of a half-wave plate in the excitation path and a polarizer in the detection path we demonstrate an improvement larger than a factor of two on the NV center magnetic sensitivity.

Fatal Septic Shock Due to Aeromonas Hydrophila in a Cirrhotic Patient; a Case Report.

Aeromonas hydrophila has been identified as a causative agent of necrotizing fasciitis and myonecrosis, with most reported cases having a connection to aquatic-related trauma. Cases without such trauma history are rare in existing literature. Here, we present the case of a 56-year-old cirrhotic patient who lacked any prior aquatic-related trauma and arrived at the emergency department in a state of septic shock. The suspected route of entry was through necrotizing fasciitis and myonecrosis in his left forearm. Unfortunately, the patient succumbed to multi-organ failure and passed away within 12 hours of admission to the emergency department.

8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia.

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

Antimicrobial resistance profile in Salmonella enterica serovar Choleraesuis isolates from diseased pigs in Taiwan.

This study investigated antimicrobial resistance in Salmonella enterica serovar Choleraesuis (S. Choleraesuis) isolates from diseased pigs in Taiwan (2015-2020). Among 272 isolates, florfenicol (96.7%), enrofloxacin (96.3%), doxycycline (91.2%), gentamicin (84.6%), and tiamulin (80.5%) exhibited high resistance. 99.3% of the isolates were resistant to at least one antibiotic, and 97.8% of the isolates were multidrug resistant. This study illustrated that S. Choleraesuis isolates exhibited high resistance to antimicrobials currently used in the Taiwanese swine industry.

OUTCOME OF SHOULDER HEMIARTHROPLASTY FOR COMPLEX PROXIMAL HUMERAL FRACTURE IN VIETDUC UNIVERSITY HOSPITAL.

ABSTRACTS: Translational Study Introduction: The proximal humeral fracture accounts for 4-5% of all fractures1 and traffic accidents are often the main cause of this injury in Vietnam. Shoulder hemiarthroplasty is a suitable option in treating a complex proximal humeral fracture, especially in the elderly, and improves quality of life. This study describes clinical and radiographic characteristics of complex proximal humerus fractures and evaluates the results of shoulder hemiarthroplasty for this type of fracture at Viet Duc University Hospital Materials and methods: A retrospective study of 78 cases with complex proximal humeral fractures underwent shoulder hemiarthroplasty in Viet Duc University Hospital from January 2017 to December 2021. RESULTS: Traffic accidents (42 cases, 53.8%); daily-life accidents (34 cases, 43.6%), other causes were less common (2 cases, 2.6%). 74.4% of the patients had no pain, 17.4% mild pain, 7.7% moderate pain, and no patients suffered from severe pain that required regular narcotic analgesics. The mean postoperative Constant score was 67.45 ± 13.20. CONCLUSION: In Viet Nam, the most common cause of injury was a traffic accident, primarily occurring in young males with complex proximal humerus fractures, shoulder hemiarthroplasty for complex proximal humerus fractures improves postoperative pain and shoulder function.

Aortic Balloon Occlusion in Repair of Ruptured Abdominal Aortic Aneurysm.

This case report details a novel technique implemented in Vietnam. When full equipment is unavailable, we adapt it by using aortic balloon occlusion to enhance the patient's hemodynamics and mitigate the risk of intraprocedural exsanguination. This approach effectively addresses the rupture of abdominal aortic aneurysms in patients with unstable hemodynamic conditions.

Ultrahigh peroxidase-like catalytic performance of Cu-N4 and Cu-N4S active sites-containing reduced graphene oxide for sensitive electrochemical biosensing.

Carbon-based nanozymes possessing peroxidase-like activity have attracted significant interest because of their potential to replace native peroxidases in biotechnology. Although various carbon-based nanozymes have been developed, their relatively low catalytic efficiency needs to be overcome to realize their practical utilization. Here, inspired by the elemental uniqueness of Cu and the doped elements N and S, as well as the active site structure of Cu-centered oxidoreductases, we developed a new carbon-based peroxidase-mimicking nanozyme, single-atom Cu-centered N- and S-codoped reduced graphene oxide (Cu-NS-rGO), which preserved many Cu-N4 and Cu-N4S active sites and showed dramatically high peroxidase-like activity without any oxidase-like activity, yielding up to 2500-fold higher catalytic efficiency (kcat/Km) than that of pristine rGO. The high catalytic activity of Cu-NS-rGO might be attributed to the acceleration of electron transfer from Cu single atom as well as synergistic effects from both Cu-N4 and Cu-N4S active sites, which was theoretically confirmed by Gibbs free energy calculations using density functional theory. The prepared Cu-NS-rGO was then used to construct an electrochemical bioassay system for detecting choline and acetylcholine by coupling with the corresponding oxidases. Using this system, both target molecules were selectively determined with high sensitivity that was sufficient to clinically determine their levels in physiological fluids. Overall, this study will facilitate the development of nanocarbon-based nanozymes and their electrochemical biosensing applications, which can be extended to the development of miniaturized devices in point-of-care testing environments.

Tuning interfacial oxygen vacancy level of bismuth oxybromide to enhance photocatalytic degradation of bisphenol A.

Oxygen vacancies (OVs) have garnered significant interest for their role as active sites, enhancing the catalytic efficiency of various catalysts. Despite their widespread application in environmental purification processes, the generation of OVs conventionally depends on high-temperature conditions and strong reducing agents for the extraction of surface partial oxygen atoms from catalysts. In this work, bismuth oxybromide (BiOBr) nanosheets with varying levels of OVs were synthesized via a simple and effective solvothermal method. This novel method affords precise control over the conduction band (CB) and valence band (VB) positions of BiOBr. The presence of different OVs exhibited varying photocatalytic efficiencies in the degradation of bisphenol A (BPA) under visible light irradiation, with higher levels of OVs resulting in superior photocatalytic performance. Furthermore, radical scavenger experiments demonstrated that superoxide oxides (O2•-) and holes (h+) were the primary reactive oxygen species for BPA degradation. Additionally, BiOBr-OVs exhibited excellent anti-interference and stability in water matrices containing diverse inorganic anions and organic compounds. This work provides a simple and effective approach for the fine-regulating of catalysts through interfacial defect engineering, paving the way for their practical application in environmental decontamination.

Morphological Characteristics of the Vietnamese Adult Human Acetabulum Using Multiplanar Reconstruction Computed Tomography in Total Hip Replacement Surgery.

Background: The anatomical parameters of the acetabulum vary among races and geographical regions. Multislice Computed Tomography (CT) has proven to be a practical approach to assess morphological parameters of the acetabulum. The purpose of this study was to explore morphological characteristics of the acetabulum measured by CT scans in Vietnamese adults. Methods: Thirty-five consecutive patients aged 18 years and older received indications and eligibility for total hip replacement surgery. Sixty-three acetabulum were examined with multislice computed tomographic system (CT) with multiplanar reconstruction (MPR). Measured morphometric parameters of acetabulum included acetabular inclination angle (AIA), acetabular anteversion angle (AAA), acetabular angle of sharp (AAS), sagittal acetabular angle (SAA), acetabular horizontal offset (AHO), transverse acetabular ligament anteversion (TALA), transverse acetabular ligament inclination (TALI), acetabular depth (ADe), acetabular depth ratio (ADr) and acetabular diameter (ADi). Results: The mean values of acetabular diameter, femoral head diameter, AIA, AAA, AAS, SAA, TALA, TALI, AHO, ADe, ADr were 50.22±3.56 mm, 43.54±3.68 mm, 40.27±5.09 mm, 13.30±5.54 mm, 39.46±5.41 mm, 26.38±9.01 mm, 9.49±3.92 mm, 47.70±6.73 mm, 3.06±0.37 mm, 18.62±2.95 mm and 309.60±41.87 mm. Conclusion: Our initial data has showed morphological characteristics of the acetabulum in Vietnamese adults, different from the populations from other parts of world. Also, significant correlation between the orientation of the acetabulum and the transverse acetabular ligament was documented.

The mouse retinal pigment epithelium mounts an innate immune defense response following retinal detachment.

The retinal pigment epithelium (RPE) maintains photoreceptor viability and function, completes the visual cycle, and forms the outer blood-retinal barrier (oBRB). Loss of RPE function gives rise to several monogenic retinal dystrophies and contributes to age-related macular degeneration. Retinal detachment (RD) causes separation of the neurosensory retina from the underlying RPE, disrupting the functional and metabolic relationships between these layers. Although the retinal response to RD is highly studied, little is known about how the RPE responds to loss of this interaction. RNA sequencing (RNA-Seq) was used to compare normal and detached RPE in the C57BL6/J mouse. The naïve mouse RPE transcriptome was compared to previously published RPE signature gene lists and from the union of these 14 genes (Bmp4, Crim1, Degs1, Gja1, Itgav, Mfap3l, Pdpn, Ptgds, Rbp1, Rnf13, Rpe65, Slc4a2, Sulf1 and Ttr) representing a core signature gene set applicable across rodent and human RPE was derived. Gene ontology enrichment analysis (GOEA) of the mouse RPE transcriptome identified expected RPE features and functions, such as pigmentation, phagocytosis, lysosomal and proteasomal degradation of proteins, and barrier function. Differentially expressed genes (DEG) at 1 and 7 days post retinal detachment (dprd) were defined as mRNA with a significant (padj≤0.05) fold change (FC) of 0.67 ≥ FC ≥ 1.5 in detached versus naïve RPE. The RPE transcriptome exhibited dramatic changes at 1 dprd, with 2297 DEG identified. The KEGG pathways and biological process GO groups related to innate immune responses were significantly enriched. Lipocalin 2 (Lcn2) and several chemokines were upregulated, while numerous genes related to RPE functions, such as pigment synthesis, visual cycle, phagocytosis, and tight junctions were downregulated at 1 dprd. The response was largely transient, with only 18 significant DEG identified at 7 dprd, including upregulation of complement gene C4b. Validation studies confirmed RNA-Seq results. Thus, the RPE quickly downregulates cell-specific functions and mounts an innate immune defense response following RD. Our data demonstrate that the RPE contributes to the inflammatory response to RD and may play a role in attraction of immune cells to the subretinal space.

A revised phylogeny of Boletaceae using whole genome sequences.

The porcini mushroom family Boletaceae is a diverse, widespread group of ectomycorrhizal (ECM) mushroom-forming fungi that so far has eluded intrafamilial phylogenetic resolution based on morphology and multilocus data sets. In this study, we present a genome-wide molecular data set of 1764 single-copy gene families from a global sampling of 418 Boletaceae specimens. The resulting phylogenetic analysis has strong statistical support for most branches of the tree, including the first statistically robust backbone. The enigmatic Phylloboletellus chloephorus from non-ECM Argentinian subtropical forests was recovered as a new subfamily sister to the core Boletaceae. Time-calibrated branch lengths estimate that the family first arose in the early to mid-Cretaceous and underwent a rapid radiation in the Eocene, possibly when the ECM nutritional mode arose with the emergence and diversification of ECM angiosperms. Biogeographic reconstructions reveal a complex history of vicariance and episodic long-distance dispersal correlated with historical geologic events, including Gondwanan origins and inferred vicariance associated with its disarticulation. Together, this study represents the most comprehensively sampled, data-rich molecular phylogeny of the Boletaceae to date, establishing a foundation for future robust inferences of biogeography in the group.

Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity.

Current anticancer therapies cannot eliminate all cancer cells, which hijack normal arginine methylation as a means to promote their maintenance via unknown mechanisms. Here we show that targeting protein arginine N-methyltransferase 9 (PRMT9), whose activities are elevated in blasts and leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic type I interferon (IFN)-associated immunity. PRMT9 ablation in AML cells decreased the arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cyclic GMP-AMP synthase, which underlies the type I IFN response. Genetically activating cyclic GMP-AMP synthase in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-programmed cell death protein 1 in eradicating AML. Overall, we conclude that PRMT9 functions in survival and immune evasion of both LSCs and non-LSCs; targeting PRMT9 may represent a potential anticancer strategy.

P T-symmetry breaking in dual-core phosphate-glass photonic crystal fibers.

We investigate the properties of a soft glass dual-core photonic crystal fiber for application in multicore waveguiding with balanced gain and loss. Its base material is a phosphate glass in a P2O5-Al2O3-Yb2O3-BaO-ZnO-MgO-Na2O oxide system. The separated gain and loss cores are realized with two cores with ytterbium and copper doping of the base phosphate glass. The ytterbium-doped core supports a laser (gain) activity under excitation with a pump at 1000 nm wavelength, while the CuO-doped is responsible for strong attenuation at the same wavelength. We establish conditions for an exact balance between gain and loss and investigate pulse propagation by solving a system of coupled generalized nonlinear Schrödinger equations. We predict two states of light under excitation with hyperbolic secant pulses centered at 1000 nm: 1) linear oscillation of the pulse energy between gain and loss core (P T-symmetry state), with strong power attenuation; 2) retention of the pulse in the excited gain core (broken P T-symmetry), with very modest attenuation. The optimal pulse energy levels were identified to be 100 pJ (first state) and 430 pJ (second state).