Conformal thyroidectomy is a feasible option in papillary thyroid microcarcinoma: a retrospective cohort study with 10-year follow-up results.

BACKGROUND: In recent years, there has been an increasing prevalence of patients with papillary thyroid microcarcinoma (PTMC) without lymph node involvement in medical centers worldwide. For patients who are unable to undergo active surveillance (AS) and are afraid of postoperative complications, conformal thyroidectomy may be a suitable option to ensure both preservation of function and complete removal of the tumor. METHODS: The patients in the cohort during 2010 to 2015 were retrospectively enrolled strictly following the inclusion and exclusion criteria. The observation and control groups were defined based on the surgical approach, with patients in the observation group undergoing conformal thyroidectomy and patients in the control group undergoing lobectomy. Event-free survival (EFS), the interval from initial surgery to the detection of recurrent or metastatic disease, was defined as the primary observation endpoint. RESULTS: A total of 319 patients were included in the study, with 124 patients undergoing conformal thyroidectomy and 195 patients undergoing lobectomy. When compared to lobectomy, conformal thyroidectomy demonstrated reduced hospital stays, shorter operative times, and lower rates of vocal cord paralysis and hypoparathyroidism. Furthermore, the mean bleeding volume during the operation and the rate of permanent hypothyroidism were also lower in the conformal thyroidectomy group than in the lobectomy group. However, there was no statistically significant difference observed in the 5- and 10-year EFS between the two groups. CONCLUSIONS: Conformal thyroidectomy had advantages in perioperative management and short-term complication rates, with an EFS that was not inferior to that of lobectomy. Thus, conformal thyroidectomy is a feasible option for low-risk PTMC patients.

Pleiotropic Role of Rainbow Trout CXCRs in Response to Disease and Environment: Insights from Transcriptional Signatures and Structure Analysis.

Chemokines are cytokines with chemoattractant capacities that exert their physiological functions through the binding of chemokine receptors. Thus, chemokine and receptor complexes exert important roles in regulating development and homeostasis during routine immune surveillance and inflammation. Compared to mammals, the physiology and structure of chemokine receptors in fish have not been systematically studied. Furthermore, the salmonid-specific whole genome duplication has significantly increased the number of functional paralogs of chemokine receptors. In this context, in the current study, trout exhibited 17 cxcr genes, including 12 newly identified and 5 previously identified receptors. Interestingly, gene expression of brain cxcr1 and cxcr4, kidney cxcr3 and cxcr4, and spleen cxcr3, cxcr4, and cxcr5 subtypes were altered by bacterial infection, whereas brain cxcr1, kidney cxcr1 and cxcr7, and liver cxcr2, cxcr3, and cxcr4 subtypes were changed in response to environmental changes. Based on protein structures predicted by ColabFold, the conserved amino acids in binding pockets between trout CXCR4.1 subtypes and human CXCR4 were also analyzed. Our study is valuable from a comparative point of view, providing new insights into the identification and physiology of salmonid chemokine receptors.

WSB1/2 target chromatin-bound lysine-methylated RelA for proteasomal degradation and NF-κB termination.

Proteasome-mediated degradation of chromatin-bound NF-κB is critical in terminating the transcription of pro-inflammatory genes and can be triggered by Set9-mediated lysine methylation of the RelA subunit. However, the E3 ligase targeting methylated RelA remains unknown. Here, we find that two structurally similar substrate-recognizing components of Cullin-RING E3 ligases, WSB1 and WSB2, can recognize chromatin-bound methylated RelA for polyubiquitination and proteasomal degradation. We showed that WSB1/2 negatively regulated a subset of NF-κB target genes via associating with chromatin where they targeted methylated RelA for ubiquitination, facilitating the termination of NF-κB-dependent transcription. WSB1/2 specifically interacted with methylated lysines (K) 314 and 315 of RelA via their N-terminal WD-40 repeat (WDR) domains, thereby promoting ubiquitination of RelA. Computational modeling further revealed that a conserved aspartic acid (D) at position 158 within the WDR domain of WSB2 coordinates K314/K315 of RelA, with a higher affinity when either of the lysines is methylated. Mutation of D158 abolished WSB2's ability to bind to and promote ubiquitination of methylated RelA. Together, our study identifies a novel function and the underlying mechanism for WSB1/2 in degrading chromatin-bound methylated RelA and preventing sustained NF-κB activation, providing potential new targets for therapeutic intervention of NF-κB-mediated inflammatory diseases.

Platycodin D facilitates antiviral immunity through inhibiting cytokine storm via targeting K63-linked TRAF6 ubiquitination.

Influenza virus infection is a worldwide challenge that causes heavy burdens on public health. The mortality rate of severe influenza patients is often associated with hyperactive immunological abnormalities characterized by hypercytokinemia. Due to the continuous mutations and the occurrence of drug-resistant influenza virus strains, the development of host-directed immunoregulatory drugs is urgently required. Platycodon grandiflorum is among the top 10 herbs of traditional Chinese medicine used to treat pulmonary diseases. As one of the major terpenoid saponins extracted from Platycodon grandiflorum, Platycodin D (PD) has been reported to play several roles, including anti-inflammation, analgesia, anti-cancer, hepatoprotection, and immunoregulation. However, the therapeutic roles of PD to treat influenza virus infection remains unknown. Here, we show that PD can protect the body weight loss in severely infected influenza mice, alleviate lung damage, and thus improve the survival rate. More specifically, PD protects flu mice via decreasing the immune cell infiltration into lungs and downregulating the overactivated inflammatory response. Western blot and immunofluorescence assays exhibited that PD could inhibit the activation of TAK1/IKK/NF-κB and MAPK pathways. Besides that, CETSA, SPR and immunoprecipitation assays indicated that PD binds with TRAF6 to decrease its K63 ubiquitination after R837 stimulation. Additionally, siRNA interference experiments exhibited that PD could inhibit the secretion of IL-1ß and TNF-α in TRAF6-dependent manner. Altogether, our results suggested that PD is a promising drug candidate for treating influenza. Our study also offered a scientific explanation for the commonly used Platycodon grandiflorum in many anti-epidemic classic formulas. Due to its host-directed regulatory role, PD may serve as an adjuvant therapeutic drug in conjunction with other antiviral drugs to treat the flu.

Dynamical characteristics of honeycomb two-dimensional gyroscopic metamaterials.

Suppression of noise and vibration suppression is important in various fields, such as the living environment, industrial development, and national defense and security. The bandgap properties of phononic crystal metamaterials provide an approach for controlling and eliminating harmful vibrations in equipment and noise in the environment. In this study, we used two types of two-dimensional honeycomb gyroscopic metamaterials: free and constrained. The dynamic equations of the two systems were established using angular momentum and Lagrange theorems. The dispersion relations of the two systems were obtained based on the Bloch theorem, and the influence of the gyroscope angular momentum or gyroscope speed on the dispersion relations was analyzed. Numerical simulations were conducted to analyze the wave propagation characteristics and polarization under different excitation conditions in a limited space for both types of metamaterial structures. The constrained-type and free-type metamaterials were compared, and the regularities of the dispersion relations and wave propagation characteristics by the gyroscope effect were summarized. This study provided a comprehensive and in-depth understanding of the bandgap and wave propagation properties of gyroscopic metamaterials and provided ideas for the design of bandgap modulation in metamaterials.

Irisflorentin promotes bacterial phagocytosis and inhibits inflammatory responses in macrophages during bacterial infection.

Bacterial infection remains a big concern in the patients of ICU, which is the main cause of life-threatening organ dysfunction, or even sepsis. The poor control of bacterial infection caused by antibiotic resistance, etc. or the overwhelming immune response are the most important patho genic factors in intensive care unit (ICU) patients. As main pathogens, antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), impose serious challenges during sepsis and require alternative therapeutic options. Irisflorentin (IFL) is one of the major bioactive compounds isolated from the roots of Belamcanda chinensis (Shegan). In this study, IFL could suppress inflammatory response induced by MRSA or a synthetic mimic of bacterial lipoprotein (Pam3CSK4). IFL treatment enhanced the ability of macrophages to phagocytose bacteria likely through up-regulating the expression of phagocytic receptors SR-A1 and FcγR2a. Furthermore, IFL inhibited Pam3CSK4-induced production of pro-inflammatory cytokines, including IL-6 and TNF-α in Raw 264.7 cells, mouse primary macrophages or dendritic cells. IFL treatment also inhibited heat-killed MRSA-induced secretion of IL-6 and TNF-α in mouse bone marrow-derived macrophages. Moreover, IFL attenuated M1 polarization of macrophages as indicated by the down-regulated expression of its polarization markers CD86 and iNOS. Mechanistically, IFL markedly decreased the Pam3CSK4-induced activation of ERK, JNK or p38 MAPK pathways in macrophages. Taken together, IFL may serve as a promising compound for the therapy of bacterial infection, particularly those caused by antibiotic-resistant bacteria, such as MRSA.

A Versatile Strategy for the Generation of Air-stable Radical-functionalized Materials.

The exploration of a facile approach to create structurally versatile substances carrying air-stable radicals is highly desired, but still a huge challenge in chemistry and materials science. Herein, a non-contact method to generate air-stable radicals by exposing pyridine/imidazole ring-bearing substances to volatile cyanuric chloride vapor, harnessed as a chemical fuel is reported. This remarkable feat is accomplished through a nucleophilic substitution reaction, wherein an intrinsic electron transfer event transpires spontaneously, originating from the chloride anion (Cl- ) to the cationic nitrogen (N+ ) atom, ultimately giving rise to pyridinium/imidazolium radicals. Impressively, the generated radicals exhibit noteworthy stability in the air over one month owing to the delocalization of the unpaired electron through the extended and highly fused π-conjugated pyridinium/imidazolium-triazine unit. Such an approach is universal to diverse substances, including organic molecules, metal-organic complexes, hydrogels, polymers, and organic cage materials. Capitalizing on this versatile technique, surface radical functionalization can be readily achieved across diverse substrates. Moreover, the generated radical species showcase a myriad of high-performance applications, including mimicking natural peroxidase to accelerate oxidation reactions and achieving high-efficiency near-infrared photothermal conversion and photothermal bacterial inhibition.

A tumor-targeted and enzyme-responsive gold nanorod-based nanoplatform with facilitated endo-lysosomal escape for synergetic photothermal therapy and protein therapy.

To tackle the obstacles related to tumor targeting and overcome the limitations of single treatment models, we have developed a nanoplatform that is both tumor-targeted and enzyme-responsive. This nanoplatform integrates photothermal gold nanorods (AuNRs) and protein drugs into a single system. This nanosystem, known as AuNRs@HA-mPEG-Deta-LA, was fabricated by modifying gold nanorods (AuNRs) with a polymeric ligand called hyaluronic acid-grafted-(mPEG/diethylenetriamine-conjugated-lipoic acid). The purpose of this fabrication was to load cytochrome c (CC) and utilize it for the synergetic protein-photothermal therapy of cancer. The resulting nanoplatform exhibited a high efficiency in loading proteins and demonstrated excellent stability in different biological environments. Additionally, CC-loaded AuNRs@HA-mPEG-Deta-LA not only enabled localized hyperthermia for photothermal therapy (PTT) with laser irradiation but also facilitated the release of CC under the action of hyaluronidase, an enzyme known to be overexpressed in tumor cells. The confocal imaging results demonstrated that the presence of a specific polymeric ligand on this nanoparticle enhances the internalization of CD44-positive cancer cells, accelerates endo/lysosomal escape, and facilitates the controlled release of CC within the cells. Furthermore, the results of the MTT assay also showed that AuNRs@HA-mPEG-Deta-LA as a protein nanocarrier demonstrated excellent biocompatibility. Importantly, this synergistic therapeutic strategy effectively induced apoptosis in A549 cancer cells by increasing the intracellular concentration of CC and utilizing the photothermal conversion of AuNRs, which was observed to be more effective compared to using only protein therapy or PTT. Therefore, this study showcased a nanoplatform based on AuNRs that has great potential for tumor-targeted protein delivery in combination with PTT in cancer treatment.

Safety and effectiveness of lurasidone in the treatment of Chinese schizophrenia patients: An interim analysis of post-marketing surveillance.

BACKGROUND: Schizophrenia is a psychiatric disorder characterized by chronic or recurrent symptoms. Lurasidone was licensed in China in 2019 for the treatment of adult schizophrenia in adults with a maximum dose of 80 mg/d. However, post-market surveillance (PMS) with an adequate sample size is required for further validation of the drug's safety profile and effectiveness. AIM: To conduct PMS in real-world clinical settings and evaluate the safety and effectiveness of lurasidone in the Chinese population. METHODS: A prospective, multicenter, open-label, 12-wk surveillance was conducted in mainland China. All patients with schizophrenia from 10 sites who had begun medication with lurasidone between September 2019 and August 2022 were eligible for enrollment. Safety assessments included adverse events (AEs), adverse drug reactions (ADRs), extrapyramidal symptoms (EPS), akathisia, use of EPS drugs, weight gain, and laboratory values as metabolic parameters and the QTc interval. The effectiveness was assessed using the brief psychiatric rating scale (BPRS) from baseline to the end of treatment. RESULTS: A total of 965 patients were enrolled in the full analysis set and 894 in the safety set in this interim analysis. The average daily dose was 61.7 ± 19.08 mg (mean ± SD) during the treatment. AEs and ADRs were experienced by 101 patients (11.3%) and 78 patients (8.7%), respectively, which were mostly mild. EPS occurred in 25 individuals with a 2.8% incidence, including akathisia in 20 individuals (2.2%). Moreover, 59 patients received drugs for treating EPS during the treatment, with an incidence of 6.6% which dropped to 5.4% at the end of the treatment. The average weight change was 0.20 ± 2.36 kg (P = 0.01687) with 0.8% of patients showing a weight gain of ≥ 7% at week 12 compared with that at the baseline. The mean values of metabolic parameters and the QTc interval at baseline and week 12 were within normal ranges. The mean changes in total BPRS scores were -8.9 ± 9.76 (n = 959), -13.5 ± 12.29 (n = 959), and -16.8 ± 13.97 (n = 959) after 2/4, 6/8, and 12 wk, respectively (P < 0.001 for each visit compared with the baseline) using the last-observation-carried-forward method. CONCLUSION: The interim analysis of the PMS of adult patients with schizophrenia demonstrate the safety and effectiveness of lurasidone in the Chinese population. No new safety or efficacy concerns were identified.

Multi-message multi-receiver signcryption scheme based on blockchain.

In conventional message communication systems, the practice of multi-message multi-receiver signcryption communication encounters several challenges, including the vulnerability to Key Generation Center (KGC) attacks, privacy breaches and excessive communication data volume. The KGC necessitates a secure channel to transmit partial private keys, thereby rendering the security of these partial private keys reliant on the integrity of the interaction channel. This dependence introduces concerns regarding the confidentiality of the private keys. Our proposal advocates for the substitution of the KGC in traditional certificateless schemes with blockchain and smart contract technology. Parameters are publicly disclosed on the blockchain, leveraging its tamper-proof property to ensure security. Furthermore, this scheme introduces conventional encryption techniques to achieve user identity privacy in the absence of a secure channel, effectively resolving the issue of user identity disclosure inherent in blockchain-based schemes and enhancing communication privacy. Moreover, users utilize smart contract algorithms to generate a portion of the encrypted private key, thereby minimizing the possibility of third-party attacks. In this paper, the scheme exhibits resilience against various attacks, including KGC leakage attacks, internal privilege attacks, replay attacks, distributed denial of service attacks and Man-in-the-Middle (MITM) attacks. Additionally, it possesses desirable security attributes such as key escrow security and non-repudiation. The proposed scheme has been theoretically and experimentally analyzed under the random oracle model, based on the computational Diffie-Hellman problem and the discrete logarithm problem. It has been proven to possess confidentiality and unforgeability. Compared with similar schemes, our scheme has lower computational cost and shorter ciphertext length. It has obvious advantages in communication and time overhead.

Tuning ferroelectric photovoltaic performance in R3c-CuNbO3 through compressive strain engineering: a first-principles study.

Most ferroelectric oxides exhibit relatively wide bandgaps, which pose limitations on their suitability for photovoltaics application. CuNbO3 possesses potential ferroelectric properties with an R3c polar structure that facilitate the separation of charge carriers under illumination, promoting the generation of photovoltaic effects. The optical and ferroelectric properties of R3c-CuNbO3, as well as the effect of strain on the properties are investigated by first-principles calculation in this paper. The calculated results indicate that R3c-CuNbO3 possesses a moderate band gap to absorb visible light. The interaction of Cu-O and Nb-O bonds is considered to have a crucial role in the photovoltaic properties of CuNbO3, contributing to the efficient absorption of visible light. The bandgap of CuNbO3 becomes smaller and the density of states near the conduction and valence bands becomes relatively uniform in distribution under compressive conditions, which improves the photoelectric conversion efficiency to 29.9% under conditions of bulk absorption saturation. The ferroelectric properties of CuNbO3 are driven by the Nb-O bond interactions, which are not significantly weakened by the compressive strain. CuNbO3 is expected to be an excellent ferroelectric photovoltaic material by modulation of compressive strain due to the stronger visible light absorption and excellent ferroelectric behavior.

Leukemic transformation during anti-tuberculosis treatment in aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome: A case report and review of literature.

BACKGROUND: Accumulating evidence demonstrates that autoimmune hematopoietic failure and myeloid neoplasms have an intrinsic relationship with regard to clonal hematopoiesis and disease evolution. In approximately 10%-15% of patients with severe aplastic anemia (SAA), the disease phenotype is transformed into myeloid neoplasms following antithymocyte globulin plus cyclosporine-based immunosuppressive therapy. In some of these patients, myeloid neoplasms appear during or shortly after immunosuppressive therapy. Leukemic transformation in SAA patients during anti-tuberculosis treatment has not been reported. CASE SUMMARY: A middle-aged Chinese female had a 6-year history of non-SAA and a 2-year history of paroxysmal nocturnal hemoglobinuria (PNH). With aggravation of systemic inflammatory symptoms, severe pancytopenia developed, and her hemoglobinuria disappeared. Laboratory findings in cytological, immunological and cytogenetic analyses of bone marrow samples met the diagnostic criteria for "SAA." Definitive diagnosis of disseminated tuberculosis was made in the search for infectious niches. Remarkable improvement in hematological parameters was achieved within 1 mo of anti-tuberculosis treatment, and complete hematological remission was achieved within 4 mo of treatment. Frustratingly, the hematological response lasted for only 3 mo, and pancytopenia reemerged. At this time, cytological findings (increased bone marrow cellularity and an increased percentage of myeloblasts that accounted for 16.0% of all nucleated hematopoietic cells), immunological findings (increased percentage of cluster of differentiation 34+ cells that accounted for 12.28% of all nucleated hematopoietic cells) and molecular biological findings (identification of somatic mutations in nucleophosmin-1 and casitas B-lineage lymphoma genes) revealed that "SAA" had transformed into acute myeloid leukemia with mutated nucleophosmin-1. The transformation process suggested that the leukemic clones were preexistent but were suppressed in the PNH and SAA stages, as development of symptomatic myeloid neoplasm through acquisition and accumulation of novel oncogenic mutations is unlikely in an interval of only 7 mo. Aggravation of inflammatory stressors due to disseminated tuberculosis likely contributed to the repression of normal and leukemic hematopoiesis, and the relief of inflammatory stressors due to anti-tuberculosis treatment contributed to penetration of neoplastic hematopoiesis. The concealed leukemic clones in the SAA and PNH stages raise the possibility of an inflammatory stress-fueled antileukemic mechanism. CONCLUSION: Aggravated inflammatory stressors can repress normal and leukemic hematopoiesis, and relieved inflammatory stressors can facilitate penetration of neoplastic hematopoiesis.

Association of High Plasma Levels of Serpin E1, IGFBP2, and CCL5 With Refractory Epilepsy in Children by Cytokine Profiling.

Inflammatory cytokines participate in the pathology of epilepsy and the development of drug resistance. In this study, we combined a cytokine array and enzyme-linked immunosorbent assay to identify new cytokines in the plasma from children on early stage of the onset of epilepsy (EOE) and children with drug-resistant epilepsy (DRE). Compared with healthy controls, a broad up-regulation of cytokines was observed in patients with EOE, and many of the cytokines were not previously reported. In patients with DRE, most of these up-regulated cytokines maintained at relatively low levels close to those in controls; only a few of them, including CCL5, Serpin E1, and IGFBP2, remained at high levels. The dramatic difference in cytokine profile could be a strong clue for the incidence of DRE, and DRE-associated cytokines appeared to have the potential to be new biomarkers for epilepsy prognosis and therapeutic targets.

Blockchain-based multi-authority revocable data sharing scheme in smart grid.

In view of the problems of inefficient data encryption, non-support of malicious user revocation and data integrity checking in current smart grid data sharing schemes, this paper proposes a blockchain-based multi-authority revocable data sharing scheme in the smart grid. Using online/offline encryption technology with hybrid encryption technology enhances the encryption performance for the data owner. The use of user binary tree technology enables the traceability and revocability of malicious users. The introduction of multiple attribute authorization authorities eliminates the threat of collusive attacks that exist in traditional data-sharing schemes. In addition, the semi-honest problem of third-party servers is solved by uploading data verification credentials to the blockchain. The security analysis results show that the scheme can resist selective plaintext attacks and collusion attacks. The performance analysis results show that the proposed scheme has lower computational overhead and better functionality than similar schemes, which is suitable for secure data sharing in smart grids.

Identification, characterization, and transcription of serotonin receptors in rainbow trout (Oncorhynchus mykiss) in response to bacterial infection and salinity changes.

Serotonergic system is involved in the regulation of physiological functions and behavioral traits including cognition, memory, aggression, stress coping, appetite and immunomodulation. Serotonin exerts its functions via binding distinct serotonin receptors which are classified into 7 groups. Salmonid exhibits expanded functional gene copies due to salmonid-specific whole genome duplication. However, serotonin receptor (htr) repertoire is not fully identified in rainbow trout (Oncorhynchus mykiss). In this study, we identified 39 htr genes, including 14 htr1, 4 htr2, 4 htr2 like, 3 htr3, 4 htr4, 2 htr5, 2 htr6, and 6 htr7 subtypes. We investigated physiological functions of serotonin receptors in response to bacterial pathogens exposure and salinity changes. We showed htr1, htr2, htr4 and htr7 subtypes were associated with immunomodulation in response to Vibrio anguillarum or Aeromonas salmonicida infection. Saltwater (salinity of 15) transfer significantly altered htr1, htr2, htr4, and htr7 subtypes, suggesting trout Htr was associated with osmoregulation. We further showed residues interacted with inverse agonist (methiothepin) and serotonin analogue (5-Carboxamidotryptamine) were conserved between trout and human, suggesting exogenous ligands targeting human HTRs might have a role in aquaculture. This study showed duplicated trout Htrs might be physiologically neofunctionalized and potentially exhibit pleiotropic effects in regulating immunomodulation and osmoregulation.

Tuberculosis-induced aplastic crisis and atypical lymphocyte expansion in advanced myelodysplastic syndrome: A case report and review of literature.

BACKGROUND: Myelodysplastic syndrome (MDS) is caused by malignant proliferation and ineffective hematopoiesis. Oncogenic somatic mutations and increased apoptosis, necroptosis and pyroptosis lead to the accumulation of earlier hematopoietic progenitors and impaired productivity of mature blood cells. An increased percentage of myeloblasts and the presence of unfavorable somatic mutations are signs of leukemic hematopoiesis and indicators of entrance into an advanced stage. Bone marrow cellularity and myeloblasts usually increase with disease progression. However, aplastic crisis occasionally occurs in advanced MDS. CASE SUMMARY: A 72-year-old male patient was definitively diagnosed with MDS with excess blasts-1 (MDS-EB-1) based on an increase in the percentages of myeloblasts and cluster of differentiation (CD)34+ hematopoietic progenitors and the identification of myeloid neoplasm-associated somatic mutations in bone marrow samples. The patient was treated with hypomethylation therapy and was able to maintain a steady disease state for 2 years. In the treatment process, the advanced MDS patient experienced an episode of progressive pancytopenia and bone marrow aplasia. During the aplastic crisis, the bone marrow was infiltrated with sparsely distributed atypical lymphocytes. Surprisingly, the leukemic cells disappeared. Immunological analysis revealed that the atypical lymphocytes expressed a high frequency of CD3, CD5, CD8, CD16, CD56 and CD57, suggesting the activation of autoimmune cytotoxic T-lymphocytes and natural killer (NK)/NKT cells that suppressed both normal and leukemic hematopoiesis. Elevated serum levels of inflammatory cytokines, including interleukin (IL)-6, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), confirmed the deranged type I immune responses. This morphological and immunological signature led to the diagnosis of severe aplastic anemia secondary to large granule lymphocyte leukemia. Disseminated tuberculosis was suspected upon radiological examinations in the search for an inflammatory niche. Antituberculosis treatment led to reversion of the aplastic crisis, disappearance of the atypical lymphocytes, increased marrow cellularity and 2 mo of hematological remission, providing strong evidence that disseminated tuberculosis was responsible for the development of the aplastic crisis, the regression of leukemic cells and the activation of CD56+ atypical lymphocytes. Reinstitution of hypomethylation therapy in the following 19 mo allowed the patient to maintain a steady disease state. However, the patient transformed the disease phenotype into acute myeloid leukemia and eventually died of disease progression and an overwhelming infectious episode. CONCLUSION: Disseminated tuberculosis can induce CD56+ lymphocyte infiltration in the bone marrow and in turn suppress both normal and leukemic hematopoiesis, resulting in the development of aplastic crisis and leukemic cell regression.

Flared inflammatory episode transforms advanced myelodysplastic syndrome into aplastic pancytopenia: A case report and literature review.

BACKGROUND: Myelodysplastic syndrome (MDS) is a hematological neoplasm, and an increase in myeloblasts is representative of leukemic hematopoiesis in advanced MDS. Low-risk MDS usually exhibits deranged autoimmunity resembling that of aplastic anemia (AA), whereas advanced MDS is characterized by a phenotype of immune exhaustion. MDS can be normo/hyperplastic or hypoplastic. Generally, bone marrow cellularity and myeloblasts increase with disease progression. Transformation from advanced MDS to AA-like syndrome with leukemic cell regression has not previously been reported. CASE SUMMARY: A middle-aged Chinese woman had a 4-year history of leukocytopenia. Six months prior to admission, the patient developed gradually worsening fatigue and performance status. The leukocytopenia further progressed. She was diagnosed with MDS with excess blasts-2 based on increased bone marrow cellularity and an increased percentage of myeloblasts on marrow and blood smears, an increased percentage of cluster of differentiation (CD)34+CD33+ progenitors in immunotyping analysis, a normal karyotype in cytogenetic analysis, and the identification of somatic mutations in CBL, KMT2D and NF1 in molecular analysis. Initially, neutropenia was the predominant hematological abnormality, with mild anemia and thrombocytosis, and the degree of fatigue was far more severe than the degree of anemia. In the following months, the patient experienced several febrile episodes. Intravenous antibiotic treatments were able to control the febrile episodes, but the elevated inflammatory indices persisted. The hematological parameters dramatically fluctuated with the waxing and waning of the inflammatory episodes. With recurrent flares of the inflammatory condition, agranulocytosis and severe anemia developed, with mild thrombocytopenia. During the patient's hospitalization, computed tomography (CT) scans revealed the presence of extensive inflammatory lesions involving the lungs, mediastinum, pleura, gastrointestinal tract, peritoneum and urinary tract, with imaging features suggestive of the reactivation of disseminated tuberculosis. Reevaluation of the bone marrow smears revealed that the cellularity became hypoplastic, and the leukemic cells regressed, suggesting that both normal and leukemic hematopoiesis had been heavily suppressed. Immunological analysis of the bone marrow samples revealed a decreased percentage of CD34+ cells and an immunological signature resembling that of severe AA (SAA), confirming the regression of the leukemic cells by autoimmune-mediated attacks. The patient demonstrated resistance to multiple drugs, including antituberculotics, recombinant human granulocyte colony-stimulating factor, broad-spectrum antibiotics, voriconazole, ganciclovir, immune suppressants, eltrombopag and intravenous immunoglobulin, which further worsened the hematological injury and patient's performance status. The patient eventually died of overwhelming infection and multidrug resistance. CONCLUSION: Advanced MDS can transform to aplastic cytopenia with leukemic cell regression and an immunological signature of SAA during inflammatory flare-ups.

Drought stress-induced the formation of heteromorphic leaves of Populus euphratica Oliv: evidence from gene transcriptome.

Populus euphratica Oliv., a dominant species of arid desert community, grows heteromorphic leaves at different crown positions. Whether heteromorphic leaves are a strategy of plant adaptation to drought stress is rarely reported. This study sequenced the transcriptome of three typical heteromorphic leaves (lanceolate, ovate and broad-ovate leaves) of P. euphratica, and measured their drought stress. We wanted to reveal the molecular mechanisms underlying the formation of heteromorphic leaves. Drought stress was increased significantly from lanceolate to ovate to broad-ovate leaves. Gene ontology (GO) and KEGG enrichment analysis showed that the MADs-box gene regulated the expression of peroxidase (POD) in the phenylpropane biosynthetic pathway. The up-regulated expression of the chalcone synthase (CHS) gene in broad-ovate leaves significantly activated the flavonoid biosynthetic pathway. In the process of leaf shape change, the different expressions of homeodomain leucine zipper (HD-ZIP) among the three heteromorphic leaves had potential interactions on the AUX and ABA pathways. The expression of Sucrose phosphate synthase (SPS) and sucrose synthase (SUS) increased from lanceolate to broad-ovate leaves, resulting in a consistent change in starch and sucrose content. We concluded that these resistance-related pathways are expressed in parallel with leaf formation genes, thereby inducing the formation of heteromorphic leaves. Our work provided a new insights for desert plants to adapt to drought stress.

One stone two birds: anti-inflammatory bronchodilators as a potential pharmacological strategy for COVID-19.

The ongoing Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has imposed a huge threat to public health across the world. While vaccinations are essential for reducing virus transmission and attenuating disease severity, the nature of high mutation rate of SARS-CoV-2 renders vaccines less effective, urging quick development of effective therapies for COVID-19 disease. However, developing novel drugs remains extremely challenging due to the lengthy process and high cost. Alternatively, repurposing of existing drugs on the market represents a rapid and safe strategy for combating COVID-19 pandemic. Bronchodilators are first line drugs for inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Compared to other anti-inflammatory drugs repurposed for COVID-19, bronchodilators are unique in that they have both anti-inflammatory and bronchodilating properties. Whether the dual properties of bronchodilators empower them greater potential to be repurposed for COVID-19 is worth exploring. In fact, clinical and preclinical studies have recently emerged to investigate the benefits of bronchodilators such assalbutamol, formoterol and theophylline in treating COVID-19, and many of them have shown encouraging efficacy on attenuating disease severity of pneumonia and other associated symptoms. To comprehensively understand the latest progress on COVID-19 intervention with bronchodilators, this review will summarize recent findings in this area and highlight the promising clinical benefits and possible adverse effects of bronchodilators as therapeutic options for COVID-19 with a focus on ß2 receptor agonists, anticholinergic drugs and theophylline.

Association of elevated plasma CCL5 levels with high risk for tic disorders in children.

Abnormal levels of some peripheral cytokines have been reported in children patients with tic disorders (TDs), but none of these cytokines can be a biomarker for this disease. Our aim was to systemically profile differentially expressed cytokines (DECs) in the blood of TD patients, examine their associations with TD development, and identify from them potential biomarkers for the prediction and management of the risk for TDs. In this study, a cytokine array capable of measuring 105 cytokines was used to screen for DECs in the plasma from 53 comorbidity-free and drug-naïve TD patients and 37 age-matched healthy controls. DECs were verified by ELISA and their associations with TD development were evaluated by binary logistic regression analysis. Elevation of a set of cytokines was observed in TD patients compared with controls, including previously uncharacterized cytokines in tic disorders, CCL5, Serpin E1, Thrombospondin-1, MIF, PDGF-AA, and PDGF-AB/BB. Further analysis of DECs revealed a significant association of elevated CCL5 with TD development (p = 0.005) and a significant ROC curve for CCL5 as a risk factor [AUC, 0.801 (95% CI: 0.707-0.895), p < 0.0001]. Conclusion: This study identifies associations of a set of circulating cytokines, particularly CCL5 with TD development, and provides evidence that high blood CCL5 has potential to be a risk factor for TD development. Clinical Trial Registration: identifier ChiCTR-2000029616.