Iron-Catalyzed Electrophotochemical α-Functionalization of a Silylcyclobutanol.

Four-membered ring structure is important in organic chemistry, and selective cleavage and functionalization of these strained rings are of great interest. However, direct α-functionalization of cyclobutanols is rarely reported because of the high O-H bond dissociation energy and the occurrence of ß-scission of C-C bonds in these alcohols. Recently, transition-metal catalysis has facilitated alkoxy radical generation. Herein, we report a method for electrophotochemical α-functionalization of a silylcyclobutanol via visible-light-induced LMCT reactions of M-alkoxy complexes. Introduction of the silyl group into the cyclobutanol structure favored fast [1,2]-silyl transfer over ring opening, thus allowing the generation of α-functionalized products.

The involvement of krüppel-like transcription factor 2 in megakaryocytic differentiation induction by phorbol 12-myrestrat 13-acetate.

BACKGROUND: Megakaryocytic differentiation is a complicated process regulated by a series of transcription factors in a context- and stage-dependent manner. Recent studies have suggested that krüppel-like transcription factor 2 (KLF2) is involved in the control of embryonic erythroid precursor cell differentiation and maturation. However, the function and mechanism of KLF2 in regulating megakaryocytic differentiation remain unclear. METHODS: The expression patterns of krüppel-like transcription factors (KLFs) during megakaryocytic differentiation were identified from public databases. Phorbol 12-myristate 13-acetate (PMA) treatment of the myeloid-erythroid-leukemic cell lines K562 and HEL were used as cellular megakaryocytic differentiation models. A lentiviral transduction system was utilized to achieve the goal of amplifying or reducing KLF2. The expression of KLF2 was examined using real-time PCR and western blot. The impact of KLF2 on the megakaryocytic differentiation of K562 cells was examined by flow cytometry, Giemsa staining, Phalloidin staining and western blot. RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) technologies were used to identify the KLF2-regulated targets. RESULTS: KLF2 is increased in the maturation process of megakaryocytes. KLF2 overexpression accelerated the PMA-induced megakaryocytic differentiation, as reflected by an increased percentage of CD41/CD61 cells, an increased number of polyploid cells, and an elevated expression of P21 and P27. KLF2 knockdown exhibited the opposite results, indicating that KLF2 knockdown suppressed the megakaryocytic differentiation. Further, combination of the RNA-seq and ChIP-seq results suggested that chimerin 1 (CHN1) and potassium voltage-gated channel subfamily Q member 5 (KCNQ5) may be target genes regulated of KLF2. Both CHN1 and KCNQ5 knockdown could block the megakaryocytic differentiation to some content. CONCLUSION: This study implicated a regulatory role of KLF2 in megakaryocytic differentiation, which may suggest KLF2 as a target for illness with abnormal megakaryocytic differentiation.

[The Value of sFLC and Serum Calcium in the Diagnosis and Prognosis of Multiple Myeloma Patients].

OBJECTIVE: To investigate the value of serum free light chain (sFLC) and serum calcium ion in the diagnosis and prognosis of multiple myeloma (MM). METHODS: Forty patients with MM treated in Henan Provincial People's Hospital from January 2018 to January 2022 were selected as the observation group, and 40 healthy volunteers were selected as the control group. The differences of sFLC-κ、sFLC-λ、sFLC-κ/λ, serum calcium ions, etc between the two groups were compared. Meanwhile, the differences of sFLC-κ、sFLC-λ、sFLC-κ/λ, serum calcium ions, etc in different international staging systems (ISS), chemotherapy efficacy and prognosis patients were analyzed. RESULTS: The levels of sFLC-κï¼»(98.39±21.19) vs (12.01±4.45) mg/Lï¼½, sFLC-λï¼»(210.20±45.54) vs (14.10±5.11) mg/Lï¼½ and proportions of hypocalcemia （65% vs 0） in the observation group were significantly higher than those in the control group (P < 0.05), while sFLC-κ/ λ ratio［（0.44±0.10） vs (0.87±0.12)ï¼½ and serum calcium ions ［（1.98±0.46） vs （2.42±0.40）mmol/Lï¼½ were significantly lower than those in the control group (P < 0.05). The sFLC-κ, sFLC-λ, the proportion of hypocalcemia and the course of hypocalcemia in ISS stage III patients in the observation group were significantly higher than those in stage I and II patients (P < 0.05), while sFLC-κ/λ ratio, and serum calcium ions were significantly lower than those in stage I and II patients (P < 0.05). The levels of sFLC-κ ［（107.76±21.22） vs （94.67±20.11）mg/Lï¼½, sFLC- λ［（245.54±41.12） vs （205.54±50.22）mg/Lï¼½ of patients with hypocalcemia in the observation group was significantly higher than those without hypocalcemia (P < 0.05), while the sFLC-κ/λ ratio was significantly lower than those without hypocalcemia ［（0.42±0.04） vs （0.47±0.06）；P < 0.05ï¼½. The levels of sFLC-κ ï¼»(107.29±20.14） vs （ 91.11±18.92）mg/Lï¼½, sFLC-λ［（247.98±42.26） vs （179.29±39.32）mg/Lï¼½ in patients with ineffective chemotherapy were significantly higher than those in patients with effective chemotherapy (P < 0.05), while the sFLC-κ/λ ratio was significantly lower than those in patients with effective chemotherapy ï¼»(0.43±0.10) vs (0.50±0.09)；P < 0.05）］. The area under the ROC curve for sFLC-κ, sFLC-λ, sFLC-κ/λ predicting ineffective chemotherapy was 0.803, 0.793 and 0.699 respectively, P < 0.05. There was no significant difference in sFLC-κ, sFLC-λ, sFLC-κ/λ ratio, serum calcium ion, hypocalcemia ratio and hypocalcemia course between survival and death patients (P >0.05). CONCLUSION: sFLC and serum calcium are related to ISS stage of MM patients. sFLC level has a certain value to predict the curative effect of chemotherapy in MM patients. However, the prognostic values of sFLC and serum calcium are not yet confirmed for MM patients.

[99mTc]Tc-labeled cyc-DX600-HYNIC as a SPECT probe for ACE2-specific pancreatic cancer imaging.

As a regulator in renin-angiotensin-aldosterone system, angiotensin-converting enzyme 2 (ACE2) closely correlated with tumor progression of pancreatic cancer, meantime, was easily affected by a variety of factors. [99mTc]Tc-cyc-DX600 SPECT was established as an ACE2-specific imaging protocol to figure out the ACE2 status in pancreatic tumor. BALB/C-NU mice were used to prepare the subcutaneous cell derived xenograft (CDX) models with HEK-293T or HEK-293T/hACE2 cells to validate ACE2 specificity of [99mTc]Tc-cyc-DX600 SPECT and establish SPECT imaging protocol. On the basis of [99mTc]Tc-cyc-DX600 SPECT and [18F]F-FDG PET/CT, ACE2-dependence on tumor size and tumor metabolism were further verified on orthotopic pancreatic cancer model with KPC cells. Immunohistochemical analysis was used to demonstrate the findings on ACE2 SPECT. [99mTc]Tc-cyc-DX600 was of superior tumor uptake in HEK-293T/hACE2 CDX than wild type (6.74 ± 0.31 %ID/mL vs 1.83 ± 0.26 %ID/mL at 1.5 h post injection (p.i.); 3.14 ± 0.31 %ID/mL vs 1.16 ± 0.15 %ID/mL at 4.5 h p.i.). For the CDX models with PANC-1 cells, a significant negative correlation between the slope of tumor volume and tumor uptake was observed (r = -0.382 for the 1-4th day; r = -0.146 for the 1-5th day; r = -0.114 for the 1-6th day; r = -0.152 for the 1-7th day; but P > 0.05 for all). For orthotopic pancreatic cancer model, the linear correlation between FDG PET and ACE2 SPECT of the pancreatic lesions was negative (r = -0.878), the quantitative values of ACE2 SPCET was positively correlated with the volume of primary lesions (r = 0.752) and also positively correlated with the quantitative values of ACE2 immunohistochemical analysis (r = 0.991). Conclusively, [99mTc]Tc-cyc-DX600 SPECT is an ACE2-specific imaging protocol with clinical translational potential, adding multidimensional information on the disease progression of pancreatic cancer.

PTEN: an emerging target in rheumatoid arthritis?

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a critical tumor suppressor protein that regulates various biological processes such as cell proliferation, apoptosis, and inflammatory responses by controlling the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PI3K/AKT) signaling pathway. PTEN plays a crucial role in the pathogenesis of rheumatoid arthritis (RA). Loss of PTEN may contribute to survival, proliferation, and pro-inflammatory cytokine release of fibroblast-like synoviocytes (FLS). Also, persistent PI3K signaling increases myeloid cells' osteoclastic potential, enhancing localized bone destruction. Recent studies have shown that the expression of PTEN protein in the synovial lining of RA patients with aggressive FLS is minimal. Experimental upregulation of PTEN protein expression could reduce the damage caused by RA. Nonetheless, a complete comprehension of aberrant PTEN drives RA progression and its interactions with other crucial molecules remains elusive. This review is dedicated to promoting a thorough understanding of the signaling mechanisms of aberrant PTEN in RA and aims to furnish pertinent theoretical support for forthcoming endeavors in both basic and clinical research within this domain.

Extramedullary infiltration in pediatric acute myeloid leukemia: Results from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative.

BACKGROUND: The outcome of extramedullary infiltration (EMI) in pediatric acute myeloid leukemia (AML) is controversial, and little is known about the implications of stem cell transplantation (SCT) and gemtuzumab ozogamicin (GO) treatment on patients with EMI. METHODS: We retrieved the clinical data of 713 pediatric patients with AML from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset, and analyzed the clinical and prognostic characteristics of patients with EMI at diagnosis and relapse. RESULTS: A total of 123 patients were identified to have EMI at diagnosis and 64 presented with EMI at relapse. The presence of EMI was associated with age ≤2 years, M5 morphology, abnormal karyotype, and KMT2A rearrangements. Hyperleukocytosis and complex karyotype were more prevalent in patients with EMI at relapse. Additionally, patients with EMI at diagnosis had a reduced incidence of FLT3 ITD-/NPM1+, whereas those with EMI at relapse displayed a lower frequency of FLT3 ITD+. Patients with EMI at diagnosis exhibited a lower complete remission (CR) rate at the end of Induction Course 1 and higher relapse incidence. Importantly, EMI at diagnosis independently predicted both shorter event-free survival (EFS) and overall survival (OS). Regarding relapse patients, the occurrence of EMI at relapse showed no impact on OS. However, relapse patients with myeloid sarcoma (MS)/no central nervous system (CNS) exhibited poorer OS compared to those with CNS/no MS. Furthermore, regarding patients with EMI at diagnosis, SCT failed to improve the survival, whereas GO treatment potentially enhanced OS. CONCLUSION: EMI at diagnosis is an independent adverse prognostic risk factor for pediatric AML, and GO treatment potentially improves survival for patients with EMI at diagnosis.

NRP1 downregulation correlates with enhanced ILC2 responses during IL-33 challenge.

Group 2 innate lymphoid cells (ILC2s) play critical roles in driving the pathogenesis of allergic airway inflammation. The mechanisms underlying the regulation of ILC2s remain to be fully understood. Here, we identified neuropilin-1 (NRP1) as a surface marker of ILC2s in response to IL-33 stimulation. NRP1 was abundantly expressed in ILC2s from lung under steady state, which was significantly reduced upon IL-33 stimulation. ILC2s with high expression of NRP1 (NRP1high) displayed lower response to IL-33, as compared with NRP1low ILC2s. Transcriptional profiling and flow cytometric analysis showed that downregulation of AKT-mTOR signalling participated in the diminished functionality of NRP1high ILC2s. These observations revealed a potential role of NRP1 in ILC2s responses under allergic inflammatory condition.

A blastic plasmacytoid dendritic cell neoplasm-like immunophenotype is negatively associated with CEBPA bZIP mutation and predicts unfavorable prognosis in acute myeloid leukemia.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy which characteristically expresses an atypical phenotype including CD123+, CD56+, and CD4+. We are aimed to investigate the clinical and prognostic characteristics of AML patients exhibiting BPDCN-like immunophenotype and provide additional insights for risk stratification of AML. A total of 241 newly diagnosed AML patients were enrolled in this retrospective study and categorized into BPDCN-like positive (n = 125)/negative (n = 116) groups, determined by the present with CD123+ along with either CD56+ or CD4+, or both. Subsequently, an analysis was conducted to examine the general clinical characteristics, genetic profiles, and prognosis of the two respective groups. Patients with BPDCN-like immunophenotype manifested higher frequencies of acute myelomonocytic leukemia and acute monoblastic leukemia. Surprisingly, the presence of the BPDCN-like immunophenotype exhibited an inverse relationship with CEBPA bZIP mutation. Notably, patients with BPDCN-like phenotype had both worse OS and EFS compared to those without BPDCN-like phenotype. In the CN-AML subgroups, the BPDCN-like phenotype was associated with worse EFS. Similarly, a statistically significant disparity was observed in both OS and EFS within the favorable-risk subgroup, while only OS was significant within the adverse-risk subgrouMoreover, patients possessing favorable-risk genetics without BPDCN-like phenotype had the longest survival, whereas those who had both adverse-risk genetics and BPDCN-like phenotype exhibited the worst survival. Our study indicated that BPDCN-like phenotype negatively associated with CEBPA bZIP mutation and revealed a significantly poor prognosis in AML. Moreover, the 2022 ELN classification, in combination with the BPDCN-like phenotype, may better distinguish between different risk groups.

LeaNet: Lightweight U-shaped architecture for high-performance skin cancer image segmentation.

Skin cancer diagnosis often relies on image segmentation as a crucial aid, and a high-performance segmentation can lower misdiagnosis risks. Part of the medical devices often have limited computing power for deploying image segmentation algorithms. However, existing high-performance algorithms for image segmentation primarily rely on computationally intensive large models, making it challenging to meet the lightweight deployment requirement of medical devices. State-of-the-art lightweight models are not able to capture both local and global feature information of lesion edges due to their model structures, result in pixel loss of lesion edge. To tackle this problem, we propose LeaNet, a novel U-shaped network for high-performance yet lightweight skin cancer image segmentation. Specifically, LeaNet employs multiple attention blocks in a lightweight symmetric U-shaped design. Each blocks contains a dilated efficient channel attention (DECA) module for global and local contour information and an inverted external attention (IEA) module to improve information correlation between data samples. Additionally, LeaNet uses an attention bridge (AB) module to connect the left and right sides of the U-shaped architecture, thereby enhancing the model's multi-level feature extraction capability. We tested our model on ISIC2017 and ISIC2018 datasets. Compared with large models like ResUNet, LeaNet improved the ACC, SEN, and SPEC metrics by 1.09 %, 2.58 %, and 1.6 %, respectively, while reducing the model's parameter number and computational complexity by 570x and 1182x. Compared with lightweight models like MALUNet, LeaNet achieved improvements of 2.07 %, 4.26 %, and 3.11 % in ACC, SEN, and SPEC, respectively, reducing the parameter number and computational complexity by 1.54x and 1.04x.

Investigations of the reaction mechanism of sodium with hydrogen fluoride to form sodium fluoride and the adsorption of hydrogen fluoride on sodium fluoride monomer and tetramer.

CONTEXT: The reaction between Na and HF is a typical harpooning reaction which is of great interest due to its significance in understanding the elementary chemical reaction kinetics. This work aims to investigate the detailed reaction mechanisms of sodium with hydrogen fluoride and the adsorption of HF on the resultant NaF as well as the (NaF)4 tetramer. The results suggest that the reaction between Na and HF leads to the formation of sodium fluoride salt NaF and hydrogen gas. Na interacts with HF to form a complex HF···Na, and then the approaching of F atom of HF to Na results in a transition state H···F···Na. Accompanied by the broken of H-F bond, the bond forms between F and Na atoms as NaF, then the product NaF is yielded due to the removal of H atom. The resultant NaF can further form (NaF)4 tetramer. The interaction of NaF with HF leads to the complex NaF···HF; the form I as well as II of (NaF)4 can interact with HF to produce two complexes (i.e., (NaF)4(I-1)···HF, (NaF)4(I-2)···HF, (NaF)4(II-1)···HF and (NaF)4(II-2)···HF), but the form III of (NaF)4 can interact with HF to produce only one complex (NaF)4(III)···HF. These complexes were explored in terms of noncovalent interaction (NCI) and quantum theory of atoms in molecules (QTAIM) analyses. NCI analyses confirm the existences of attractive interactions in the complexes HF···Na, NaF···HF, (NaF)4(I-1)···HF, (NaF)4(I-2)···HF, (NaF)4(II-1)···HF and (NaF)4(II-2)···HF, and (NaF)4(III)···HF. QTAIM analyses suggest that the F···Na interaction forms in the HF···Na complex while the F···H hydrogen bonds form in NaF···HF, (NaF)4(I-1)···HF, (NaF)4(I-2)···HF, (NaF)4(II-1)···HF and (NaF)4(II-2)···HF, and (NaF)4(III)···HF complexes. Natural bond orbital (NBO) analyses were also applied to analyze the intermolecular donor-acceptor orbital interactions in these complexes. These results would provide valuable insight into the chemical reaction of Na and HF and the adsorption interaction between sodium fluoride salt and HF. METHODS: The calculations were carried out at the M06-L/6-311++G(2d,2p) level of theory which were performed using the Gaussian16 program. Intrinsic reaction coordinate (IRC) calculations were carried out at the same level of theory to confirm that the obtained transition state was true. The molecular surface electrostatic potential (MSEP) was employed to understand how the complex forms. Quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI) analysis was used to know the topology parameters at bond critical points (BCPs) and intermolecular interactions in the complex and intermediate. The topology parameters and the BCP plots were obtained by the Multiwfn software.

A sodium alginate intervention strategy to enhance therapeutic effects of bone-targeted alpha therapy via remodeling 223RaCl2 distribution.

Radium-223 dichloride is the first approved alpha particle-emitting radiopharmaceutical for patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. A large percentage of intestinal enrichment and a slow clearance rate were the main causes of gastrointestinal adverse events after 223RaCl2 administration. The molecular weight of sodium alginate in aqueous solution was determined to be 656 kDa. Sodium alginate exhibits a higher affinity for adsorbing Ra2+ compared to other metal ions belonging to the second main group. Sodium alginate as low as 0.5 g/rat reduced intestinal damage by remodeling 223RaCl2 distribution without affecting bone resorption. Intestinal villi were preserved and enterocyte activity was maintained after sodium alginate intervention. Sodium alginate reduced DNA oxidative damage and lipid peroxidation and maintained endogenous antioxidant status by increasing superoxide dismutase levels and total antioxidant capacity. Furthermore, sodium alginate treatment mitigated DNA damage and apoptosis. The administration of sodium alginate effectively maintained the integrity of the intestinal microbiota, which had undergone perturbations due to radiation exposure. This study demonstrated that sodium alginate could be applied to reduce the adverse effects caused by radiation exposure to the intestine during 223RaCl2-treated and reduced intestinal damage resulted from 223RaCl2 accumulation without affecting bone uptake.

Active metabolites and potential mechanisms of Notopterygium incisum against obstructive sleep apnea Syndrome (OSAS): network analysis and experimental assessment.

Background: Notopterygium incisum K.C. Ting ex H.T. Chang, a synonym of Hansenia weberbaueriana (Fedde ex H. Wolff) Pimenov & Kljuykov, is an anti-inflammatory medicinal plant. Although abrnotopterol has been reported to be its primary active metabolite, the other metabolites and their mechanisms of action remain unclear. This study aims to investigate the potential mechanisms by which its active metabolites treat Obstructive Sleep Apnea Syndrome (OSAS) through network analysis and experimental assessment. Methods: The metabolites and potential targets of Notopterygium incisum were extracted from public databases. We searched for OSAS-related genes in the Genecards, OMIM, PharmGkb, TTD, and DrugBank databases. Cytoscape 3.9.0 was used to construct the drug-target-disease network and screen for hub genes. Human bronchial epithelial (HBE) cells were cultivated in normoxia and chronic intermittent hypoxia (CIH) medium for 24 h. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2) were quantified using enzyme-linked immunosorbent assay (ELISA). Prostaglandin-endoperoxide synthase 2(PTGS2) mRNA was detected using RT-qPCR, while PTGS2 and nuclear factor-kappa B (NF-κB) proteins were identified using Western blot analysis. Co-Immunoprecipitation (CoIP) and Western blotting were utilized to evaluate the ubiquitination of PTGS2 in HBE cells. Results: Pterostilbene and notopterol, isolated from Notopterygium incisum, had potential therapeutic effects on OSAS. The PTGS2 and estrogen receptor alpha (ESR1) hub genes were associated with OSAS. The pathway enrichment analysis focuses on the NF-κB, apoptosis, and HIF-1A pathways. In response to CIH, pterostilbene and notopterol decreased IL-6, TNF-α, and PGE2 levels. The NF-κB pathway was activated by an increase in PTGS2 levels. Pterostilbene promoted proteasome-mediated ubiquitination of PTGS2 protein and reduced PTGS2 levels, inhibiting the NF-κB pathway. Conclusion: This study reveals the active metabolites of Notopterygium incisum and hub genes involved in treating OSAS, which provide a basis for the follow-up development and exploitation of the botanical drug.

CAP2 promotes gastric cancer metastasis by mediating the interaction between tumor cells and tumor-associated macrophages.

The metastasis of cancer cells is the main cause of death in patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of tumor-associated macrophages in promoting tumor invasion and metastasis; however, the interaction between tumor cells and macrophages in GC is largely unknown. In this study, we demonstrated that cyclase-associated protein 2 (CAP2) was upregulated in GC, especially in cases with lymph node metastasis, and was correlated with a poorer prognosis. The transcription factor JUN directly bound to the promoter region of CAP2 and activated CAP2 transcription. The N-terminal domain of CAP2 bound to the WD5 to WD7 domains of receptor for activated C kinase 1 (RACK1) and induced M2 macrophage polarization by activating the SRC/focal adhesion kinase (FAK)/ERK signaling pathway, which resulted in IL-4 and IL-10 secretion. Polarized M2 macrophages induced premetastatic niche formation and promoted GC metastasis by secreting TGFB1, which created a TGFB1/JUN/CAP2 positive-feedback loop to activate CAP2 expression continuously. Furthermore, we identified salvianolic acid B as an inhibitor of CAP2, which effectively inhibited GC cell invasion capabilities by suppressing the SRC/FAK/ERK signaling pathway. Our data suggest that CAP2, a key molecule mediating the interaction between GC cells and tumor-associated macrophages, may be a promising therapeutic target for suppressing tumor metastasis in GC.

Mesoporous polydopamine delivering 8-gingerol for the target and synergistic treatment to the spinal cord injury.

In the treatment of spinal cord injury (SCI), the complex process of secondary injury is mainly responsible for preventing SCI repair or even exacerbating the injury. In this experiment, we constructed the 8-gingerol (8G)-loaded mesoporous polydopamine (M-PDA), M@8G, as the in vivo targeting nano-delivery platform, and investigated the therapeutic effects of M@8G in secondary SCI and its related mechanisms. The results indicated that M@8G could penetrate the blood-spinal cord barrier to enrich the spinal cord injury site. Mechanism research has shown that all of the M-PDA,8G and M@8G displayed the anti-lipid peroxidation effect, and then M@8G can inhibit the secondary SCI by suppressing the ferroptosis and inflammation. In vivo assays showed that M@8G significantly diminished the local injury area, reduced axonal and myelin loss, thus improving the neurological and motor recovery in rats. Based on the analysis of cerebrospinal fluid samples from patients, ferroptosis occurred locally in SCI and continued to progress in patients during the acute phase of SCI as well as the stage after their clinical surgery. This study showcases effective treatment of SCI through the aggregation and synergistic effect of M@8G in focal areas, providing a safe and promising strategy for the clinical treatment of SCI.

Pathogenesis, clinical characteristics and personalized managements of multiple myeloma with chromosome 1 abnormalities.

Multiple myeloma (MM) is a biologically heterogeneous malignancy defined by the proliferation of monoclonal plasma cells. Despite the tremendous advancement in MM treatment over the past decades, relapse remains a major problem which is inevitable for most patients. In particular, a partial of patients with early relapse and poor outcomes are classified as a high-risk group. Apart from the clinical stage, genetic aberrations are now recognized as important prognostic factors for identifying high-risk patients. Chromosome 1 abnormalities (C1As), particularly 1q21 gain or amplification, have been identified as common genetic aberrations in patients with MM and are often considered unfavorable prognostic markers for progression-free survival and overall survival. However, more effective therapeutic approaches are still needed to overcome the negative impact of C1As. Therefore, we summarize the prevalence, pathogenesis, clinical significance and present therapeutic condition of C1As in MM, and attempt to conclude the precise and personalized management for patients with C1As.

Pterostilbene mediates glial and immune responses to alleviate chronic intermittent hypoxia-induced oxidative stress in nerve cells.

Chronic intermittent hypoxia (CIH) induces oxidative stress in the brain, causing sleep disorders. Herein, we investigated the role of pterostilbene (Pte) in CIH-mediated oxidative stress in the brain tissue. A CIH mouse model was constructed by alternately reducing and increasing oxygen concentration in a sealed box containing the mouse; brain tissue and serum were then collected after intragastric administration of Pte. Neurological function was evaluated through field experiments. The trajectory of the CIH mice to the central region initially decreased and then increased after Pte intervention. Pte increased the number of neuronal Nissl bodies in the hippocampus of CIH mice, upregulated the protein levels of Bcl-2, occludin, and ZO-1 as well as the mRNA and protein levels of cAMP-response element binding protein (CREB) and p-BDNF, and reduced the number of neuronal apoptotic cells, Bax protein levels, IBA-1, and GFAP levels. Simultaneously, Pte reversed the decreased levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and BDNF and increased levels of malondialdehyde (MDA) in the serum of CIH mice. Pte increased Th2 cells, Treg cells, IL-4, IL-10, and TGF-ß1 levels and decreased Th1 cells, Th17 cells, IFN-γ, IL-6, and IL- 17A levels in activated BV2 cells and hippocampus in CIH mice. The protein levels of p-ERK1/2, TLR4, p-p38, p-p65, and Bax, apoptosis rate, MDA concentration, Bcl-2 protein level, cell viability, and SOD and GSH-PX concentrations decreased after the activation of BV2 cells. Pte inhibited gliocytes from activating T-cell immune imbalance through p-ERK signaling to alleviate oxidative stress injury in nerve cells.

A flexible wearable device coupled with injectable Fe3O4 nanoparticles for capturing circulating tumor cells and triggering their deaths.

Elimination of circulating tumor cells (CTCs) in the blood can be an effective therapeutic approach to disrupt metastasis. Here, a strategy is proposed to implement flexible wearable electronics and injectable nanomaterials to disrupt the hematogenous transport of CTCs. A flexible device containing an origami magnetic membrane is used to attract Fe3O4@Au nanoparticles (NPs) that are surface modified with specific aptamers and intravenously injected into blood vessels, forming an invisible hand and fishing line/bait configuration to specifically capture CTCs through bonding with aptamers. Thereafter, thinned flexible AlGaAs LEDs in the device offer an average fluence of 15.75 mW mm-2 at a skin penetration depth of 1.5 mm, causing a rapid rise of temperature to 48 °C in the NPs and triggering CTC death in 10 min. The flexible device has been demonstrated for intravascular isolation and enrichment of CTCs with a capture efficiency of 72.31% after 10 cycles in a simulated blood circulation system based on a prosthetic upper limb. The fusion of nanomaterials and flexible electronics reveals an emerging field that utilizes wearable and flexible stimulators to activate biological effects offered by nanomaterials, leading to improved therapeutical effects and postoperative outcomes of diseases.

[Effect and Mechanism of Atorvastatin on Reversing Drug Resistance in Leukemia by Regulating Glycolysis through PTEN/mTOR Pathway].

OBJECTIVE: To investigate the influence and mechanism of atorvastatin on glycolysis of adriamycin resistant acute promyelocytic leukemia (APL) cell line HL-60/ADM. METHODS: HL-60/ADM cells in logarithmic growth phase were treated with different concentrations of atorvastatin, then the cell proliferation activity was measured by CCK-8 assay, the apoptosis was detected by flow cytometry, the glycolytic activity was checked by glucose consumption test, and the protein expressions of PTEN, p-mTOR, PKM2, HK2, P-gp and MRP1 were detected by Western blot. After transfection of PTEN-siRNA into HL-60/ADM cells, the effects of low expression of PTEN on atorvastatin regulating the behaviors of apoptosis and glycolytic metabolism in HL-60/ADM cells were further detected. RESULTS: CCK-8 results showed that atorvastatin could inhibit the proliferation of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.872, r=0.936), and the proliferation activity was inhibited most significantly when treated with 10 µmol/L atorvastatin for 24 h, which was decreased to (32.3±2.18)%. Flow cytometry results showed that atorvastatin induced the apoptosis of HL-60/ADM cells in a concentration-dependent manner (r=0.796), and the apoptosis was induced most notably when treated with 10 µmol/L atorvastatin for 24 h, which reached to (48.78±2.95)%. The results of glucose consumption test showed that atorvastatin significantly inhibited the glycolytic activity of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.915, r=0.748), and this inhibition was most strikingly when treated with 10 µmol/L atorvastatin for 24 h, reducing the relative glucose consumption to (46.53±1.71)%. Western blot indicated that the expressions of p-mTOR, PKM2, HK2, P-gp and MRP1 protein were decreased in a concentration-dependent manner (r=0.737, r=0.695, r=0.829, r=0.781, r=0.632), while the expression of PTEN protein was increased in a concentration-dependent manner (r=0.531), when treated with different concentrations of atorvastatin for 24 h. After PTEN-siRNA transfected into HL-60/ADM cells, it showed that low expression of PTEN had weakened the promoting effect of atorvastatin on apoptosis and inhibitory effect on glycolysis and multidrug resistance. CONCLUSION: Atorvastatin can inhibit the proliferation, glycolysis, and induce apoptosis of HL-60/ADM cells. It may be related to the mechanism of increasing the expression of PTEN, inhibiting mTOR activation, and decreasing the expressions of PKM2 and HK2, thus reverse drug resistance.

Acellular dermal matrix for one-stage treatment of lower extremity full-thickness skin defect: a case series.

BACKGROUND: Self-repair of lower limb wounds has always been one of the research hotspots. Flaps and skin graft are the preferred treatment for lower extremity wound reconstruction. However, these treatments have many disadvantages, such as secondary damage, poor healing quality. In recent years, the use of acellular dermal matrix has emerged as an alternative treatment option for extremity ulcers. METHODS: This study aimed to explore whether acellular dermal matrix can be used as a single treatment to promote wound healing. 7 patients with lower extremities cutaneous deficiency exposing bone or tendon, were covered by Pelnac, which was an acellular dermal matrix product approved by China Food and Drug Administration. All the wound was treated by Pelnac without flaps and skin graft. The external dressing was changed every 10 days. RESULTS: After a maximum of 20 weeks, all the wounds were completely healed. During the 12 months follow-up period none of the patients developed skin wear on the treatment area. All patients maintained their postoperative ambulatory ability. All patients were satisfied with the appearance and feeling after wound healing. CONCLUSION: These findings may mean acellular dermal matrix is a novel method offering opportunity for treatment of lower extremities cutaneous deficiency exposing bone or tendon. It also has the potential to close wounds of all uninfected, non-ischemic, full-thickness cutaneous deficiency.

Microneedle-mediated drug delivery for cutaneous diseases.

Microneedles have garnered significant interest as transdermal drug delivery route owing to the advantages of nonselective loading capacity, minimal invasiveness, simple operation, and good biocompatibility. A number of therapeutics can be loaded into microneedles, including hydrophilic and hydrophobic small molecular drugs, and macromolecular drugs (proteins, mRNA, peptides, vaccines) for treatment of miscellaneous diseases. Microneedles feature with special benefits for cutaneous diseases owing to the direct transdermal delivery of therapeutics to the skin. This review mainly introduces microneedles fabricated with different technologies and transdermal delivery of various therapeutics for cutaneous diseases, such as psoriasis, atopic dermatitis, skin and soft tissue infection, superficial tumors, axillary hyperhidrosis, and plantar warts.