Tripartite motif 2b (trim2b) restricts spring viremia of carp virus by degrading viral proteins and negative regulators NLRP12-like receptors.

Tripartite motif (TRIM) proteins are involved in different cellular functions, including regulating virus infection. In teleosts, two orthologous genes of mammalian TRIM2 are identified. However, the functions and molecular mechanisms of piscine TRIM2 remain unclear. Here, we show that trim2b-knockout zebrafish are more susceptible to spring viremia of carp virus (SVCV) infection than wild-type zebrafish. Transcriptomic analysis demonstrates that NOD-like receptor (NLR), but not RIG-I-like receptor (RLR), signaling pathway is significantly enriched in the trim2b-knockout zebrafish. In vitro, overexpression of Trim2b fails to degrade RLRs and those key proteins involved in the RLR signaling pathway but does for negative regulators NLRP12-like proteins. Zebrafish Trim2b degrades NLRP12-like proteins through its NHL_TRIM2_like and IG_FLMN domains in a ubiquitin-proteasome degradation pathway. SVCV-N and SVCV-G proteins are also degraded by NHL_TRIM2_like domains, and the degradation pathway is an autophagy lysosomal pathway. Moreover, zebrafish Trim2b can interfere with the binding between NLRP12-like protein and SVCV viral RNA and can completely block the negative regulation of NLRP12-like protein on SVCV infection. Taken together, our data demonstrate that the mechanism of action of zebrafish trim2b against SVCV infection is through targeting the degradation of host-negative regulators NLRP12-like receptors and viral SVCV-N/SVCV-G genes.IMPORTANCESpring viremia of carp virus (SVCV) is a lethal freshwater pathogen that causes high mortality in cyprinid fish. In the present study, we identified zebrafish trim2b, NLRP12-L1, and NLRP12-L2 as potential pattern recognition receptors (PRRs) for sensing and binding viral RNA. Zebrafish trim2b functions as a positive regulator; however, NLRP12-L1 and NLRP12-L2 function as negative regulators during SVCV infection. Furthermore, we find that zebrafish trim2b decreases host lethality in two manners. First, zebrafish Trim2b promotes protein degradations of negative regulators NLRP12-L1 and NLRP12-L2 by enhancing K48-linked ubiquitination and decreasing K63-linked ubiquitination. Second, zebrafish trim2b targets viral RNAs for degradation. Therefore, this study reveals a special antiviral mechanism in lower vertebrates.

Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group.

Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, 56.7% had basophilia, and 13.3% showed eosinophilia. The median number of metaphases positive for t(9;22)(q34;q11.2) was 15, with a median of 38.5% of interphase nuclei positive for BCR::ABL1 by fluorescence in situ hybridization. The median BCR::ABL1 level was 26.14%. Remarkably, 14 (45.2%) patients were initially misdiagnosed or not diagnosed before karyotype or fluorescence in situ hybridization information for BCR::ABL1 became available. Twenty-five patients received tyrosine kinase inhibitors (TKIs). One patient developed blast crisis while on TKI treatment 8 months after initial diagnosis. With a median follow-up time of 46.1 months, 20 of 22 patients who received TKI therapy and had detailed follow-up information achieved complete cytogenetic remission or deeper, 15 achieved major molecular remission or deeper, and 10 achieved molecularly undetectable leukemia. In conclusion, given the frequent occurrence of prior or concurrent malignancies, aleukemic presentation, and low level of t(9;22)(q34;q11.2)/BCR::ABL1, misdiagnosis or delayed diagnosis is common among these patients. While these patients generally respond well to TKIs, rare patients may develop blastic transformation. It is therefore important for pathologists and hematologists to be aware of this highly unusual presentation of CML to ensure timely diagnosis and appropriate management.

A multicentre randomized double-blind placebo-controlled phase III study of the efficacy and safety of xeligekimab (GR1501) in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Xeligekimab (GR1501) is a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A and has shown potential efficacy in treating moderate-to-severe psoriasis in preliminary trials. OBJECTIVES: To evaluate the efficacy and safety of xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200 mg xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by an extension of the treatment schedule to xeligekimab every 4 weeks for a further 40 weeks. Efficacy was assessed by evaluating achievement of Physician Global Assessment (PGA) 0/1 and 75%, 90% and 100% improvement in Psoriasis Area and Severity Index (PASI 75, PASI 90 and PASI 100, respectively). The safety profile was also evaluated. RESULTS: At week 12, PASI 75, PASI 90 and PASI 100 were achieved in 90.7%, 74.4% and 30.2% of patients in the xeligekimab group vs. 8.6%, 1.4% and 0% of patients in the placebo group, respectively. PGA 0/1 was achieved in 74.4% patients in the xeligekimab group and 3.6% of patients in the placebo group. PASI 75 and PGA 0/1 were maintained until week 52. No unexpected adverse events were recorded. CONCLUSIONS: Xeligekimab showed high efficacy and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.

Psoriasis is a skin disease characterized by scaly and raised patches of skin on any part of the body. The condition can be caused by a combination of how a person's immune system works, their genes and their environment. A cytokine is a substance secreted by certain cells of the immune system that have an effect on other cells. One such cytokine, called IL-17A, has been associated with different inflammatory diseases, including psoriasis. We conducted a large trial in Chinese people with moderate-to-severe psoriasis to look at the efficacy (ability to produce the intended result) and safety of a medicine called xeligekimab (known as a 'monoclonal antibody') which works by targeting IL-17A. We randomly assigned 420 Chinese patients to receive 200 mg of xeligekimab every 2 weeks or a 'placebo' (no active medicine) for the first 12 weeks. We extended the treatment schedule of xeligekimab to every 4 weeks for a further 40 weeks. To assess how the medicine worked, we measured people's psoriasis symptoms and severity. To assess how safe the medicine was, we looked at the side-effects (or 'adverse events'). The results of this trial showed that xeligekimab improved people's psoriasis and itching starting at week 4 of receiving treatment, and more than 60% of people achieved improvement or remission by week 6, which was sustained up to week 52. The safety of xeligekimab was similar to another medicine classed as a monoclonal antibody (called secukinumab) and there were no new or unexpected adverse events reported. Overall, our findings suggest that xeligekimab is a safe and effective medicine for the treatment of psoriasis in Chinese people.

Hollow Copper Sulfide Nanocubes Loaded with Pt(IV) Complexes for Cancer Multimodal Therapy.

Chemotherapy (CT) can significantly inhibit tumor growth, metastasis, and recurrence during cancer therapy. People have widely used platinum drugs in cancer treatment. However, as most chemotherapeutic drugs, platinum drugs still have shortcomings such as poor solubility, low cell uptake, nonspecific distribution, multidrug resistance, and adverse side effects. Therefore, we synthesized hollow copper sulfide (CuS) nanocubes with photothermal and photodynamic properties as carriers for Pt(IV) drugs. Hollow CuS nanocubes have attracted considerable interest in the field of cancer photothermal therapy (PTT) using multiple biological windows. Under near-infrared (NIR) laser irradiation, Cu2+ can be reduced into Cu+ in the presence of hydrogen peroxide in the tumor microenvironment. The resulting Cu+ can be used for photodynamic therapy (PDT), which can perform a Fenton-like reaction under acidic conditions (pH 5.5-6.5) and catalyze hydrogen peroxide to produce ·OH in the tumor microenvironment. In addition, compared with Pt(II) drugs, Pt(IV) drugs not only have lower systemic toxicity but also consume glutathione (GSH), thereby increasing reactive oxygen species (ROS) levels in tumor cells and effectively promoting PDT. In this study, we oxidized ethylenediamine platinum chloride to its tetravalent state, loaded the Pt(IV) complexes using hollow CuS nanocubes, and modified the surfaces of the nanoparticles with PEG to improve the EPR effect. The Pt(IV)-loaded hollow CuS nanocubes modified with PEG (Pt(IV)-CuS@PEG) are expected to be used for tumor chemo/photothermal/photodynamic therapy.

Dual inhibition of oxidative phosphorylation and glycolysis to enhance cancer therapy.

Dual suppression of oxidative phosphorylation (OXPHOS) and glycolysis can disrupt metabolic adaption of cancer cells, inhibiting energy supply and leading to successful cancer therapy. Herein, we have developed an α-tocopheryl succinate (α-TOS)-functionalized iridium(III) complex Ir2, a highly lipophilic mitochondria targeting anticancer molecule, could inhibit both oxidative phosphorylation (OXPHOS) and glycolysis, resulting in the energy blockage and cancer growth suppression. Mechanistic studies reveal that complex Ir2 induces reactive oxygen species (ROS) elevation and mitochondrial depolarization, and triggers DNA oxidative damage. These damages could evoke the cancer cell death with the mitochondrial-relevant apoptosis and autophagy. 3D tumor spheroids experiment demonstrates that Ir2 owned superior antiproliferation performance, as the potent anticancer agent in vivo. This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.

Acidothermus cellulolyticus E1 endoglucanase expressed in planta undergoes extensive hydroxyproline-O-glycosylation and exhibits enhanced impact on biomass digestibility.

KEY MESSAGE: E1 holoenzyme was extensively Hyp-O-glycosylated at the proline rich linker region in plants, which substantially increased the molecular size and improved the enzymatic digestibility of the biomass of transgenic plants. Thermophilic E1 endo-1,4-ß-glucanase derived from Acidothermus cellulolyticus has been frequently expressed in planta to reconstruct the plant cell wall to overcome biomass recalcitrance. However, the expressed holoenzyme exhibited a larger molecular size (~ 100 kDa) than the theoretical one (57 kDa), possibly due to posttranslational modifications in the recombinant enzyme within plant cells. This study investigates the glycosylation of the E1 holoenzyme expressed in tobacco plants and determines its impact on enzyme activity and biomass digestibility. The E1 holoenzyme, E1 catalytic domain (E1cd) and E1 linker (E1Lk) were each expressed in tobacco plants and suspension cells. The accumulation of holoenzyme was 2.0- to 2.3- times higher than that of E1cd. The proline-rich E1Lk region was extensively hydroxyproline-O-glycosylated with arabinogalactan polysaccharides. Compared with E1cd, the holoenzyme displayed a broader optimal temperature range (70 to 85 ºC). When grown in greenhouse, the expression of E1 holoenzyme induced notable phenotypic changes in plants, including delayed flowering and leaf variegation post-flowering. However, the final yield of plant biomass was not significantly affected. Finally, plant biomass engineering with E1 holoenzyme showed 1.7- to 1.8-fold higher saccharification efficiency than the E1cd lines and 2.4- to 2.7-fold higher than the wild-type lines, which was ascribed to the synergetic action of the E1Lk and cellulose binding module in reducing cell wall recalcitrance.

APIP5 functions as a transcription factor and an RNA-binding protein to modulate cell death and immunity in rice.

Many transcription factors (TFs) in animals bind to both DNA and mRNA, regulating transcription and mRNA turnover. However, whether plant TFs function at both the transcriptional and post-transcriptional levels remains unknown. The rice (Oryza sativa) bZIP TF AVRPIZ-T-INTERACTING PROTEIN 5 (APIP5) negatively regulates programmed cell death and blast resistance and is targeted by the effector AvrPiz-t of the blast fungus Magnaporthe oryzae. We demonstrate that the nuclear localization signal of APIP5 is essential for APIP5-mediated suppression of cell death and blast resistance. APIP5 directly targets two genes that positively regulate blast resistance: the cell wall-associated kinase gene OsWAK5 and the cytochrome P450 gene CYP72A1. APIP5 inhibits OsWAK5 expression and thus limits lignin accumulation; moreover, APIP5 inhibits CYP72A1 expression and thus limits reactive oxygen species production and defense compounds accumulation. Remarkably, APIP5 acts as an RNA-binding protein to regulate mRNA turnover of the cell death- and defense-related genes OsLSD1 and OsRac1. Therefore, APIP5 plays dual roles, acting as TF to regulate gene expression in the nucleus and as an RNA-binding protein to regulate mRNA turnover in the cytoplasm, a previously unidentified regulatory mechanism of plant TFs at the transcriptional and post-transcriptional levels.

First Report of Collar Rot in Yellowhorn (Xanthoceras sorbifolium Bunge) Caused by Fusarium solani in Shandong Province, China.

Yellowhorn (Xanthoceras sorbifolium) is a deciduous shrub or small tree native to China. The content of oil in kernels is 52.7% to 58.0%, of which is the source of neuroic acid (3.7-4.4%). (Liang et al. 2022). In recent years, yellowhorn, as a woody oleiferous crop, has been cultivated in northern China (Xiao et al. 2023). In late June 2019, an unknown collar rot was observed on yellowhorn in Tai'an, and Weifang City, Shandong Province, China. Infected plants had dark brown to black lesions at the base of the stem, about 10 to 15 cm from the ground, bark dehiscence and rot, resulting in wilting, withering, and death of plants. The disease incidence in the field was 35-48%. Representative symptomatic samples were collected randomly from the collar of 8 plants, and 24 samples were cut from the diseased tissue into 5 mm square pieces, surface disinfected with 75% alcohol for 30s and then with 0.1% mercury bichloride for 1min, plated onto potato dextrose agar (PDA), and incubated at 28°C in the dark for 2 to 3 days. Isolation frequency of the pathogen from symptomatic collar was 83.3%. The colonies were subcultured three times on PDA to obtained the purified colonies. The colonies appeared flocculent mycelia incubated on PDA at 28°C for 7 days. The color of the surface and the reverse colony was white and cream, respectively. The chlamydosposres were smooth with thick walled, and are formed singly. Microconidia were oval or ellipsoidal, with 0-1 septum; macroconidia end cells curved to slightly, with 3- or 5-septate, and measured 17.3 to 23.1 × 4.9 to 6.5 µm (avg. 21.3 × 5.9 µm, n = 60). The morphological characteristics fit the descriptions of Fusarium spp. (Hafizi et al. 2013; Crespo et al 2019). Genomic DNA extracted from four representative isolates (XSTA4, XSTA7, XSWF6 and XSWF8), and the internal transcribed spacer region (ITS) of ribosomal DNA, translation elongation factor 1-alpha (EF1-α), RNA polymerase I beta subunit (RPB1), and RNA polymerase II beta subunit (RPB2) genes were amplified using the primer pairs ITS1/ITS4 (White et al. 1990), EF-1/EF-2, RPB-1F/1R, and RPB2-5F2/11aR (O'Donnell et al 2010), respectively. Amplicons were sequenced and compared in GenBank using a BLAST analysis. The ITS sequences (OR672118, OR669008, OR669039, and OR669279) had 100% similarity with the sequences of F. solani (MT560378, MG561938, MN989030 and OP630608, respectively). The EF1-α sequences (OR934984, OR934985, OR934986, and OR934987) matched 100% with the sequences of F. solani (OQ511088, MW332044, MW620166 and MT379886). The RPB-1 sequences (PP896852, PP896853, PP896854, and PP896855) had 100% similarity with the sequences of F. solani (OL474057, OR916019, MT305118 and MT305118, respectively). The RPB2 sequences (PP896856, PP896857, PP896858, and PP896859) matched 100% with the sequences of F. solani (OR371884, OK880266, OP784447 and OL474055, respectively). A phylogenetic analysis based on ITS, RPB2 and EF1-α sequences placed the four obtained isolates within the same clade containing the F. solani isolates A6, 91-84-1 and UCR1780. Pathogenicity tests were carried out in late-June 2020. Fifty 120-day-old healthy seedlings were wounded with 2 mm deep at stems in the collar region of plants at 5 cm above the soil for tested. The seedlings were inoculated on the wound with 3-mm mycelial discs from a 7-day-old culture of each four representative strains of 10 repeated, respectively. Ten seedlings inoculated on the wound with sterile PDA served as control. All plants were grown in an incubator with a 28°C temperature. After 20 days, the stems which were inoculated the representative strain turned brown, with 2 - 5 cm length lesion, and the plants developed typical wilting and withering symptoms which similar to those observed in the field. The control remained asymptomatic. The pathogen was reisolated from the inoculated stems and its identity confirmed with both morphology and using molecular tools. These results indicated that the pathogens of yellowhorn collar rot is F. solani. To our knowledge, this is the first report of F. solani causing collar rot of yellowhorn in China.

All-Optical Reconfigurable Excitonic Charge States in Monolayer MoS2.

Excitons are quasi-particles composed of electron-hole pairs through Coulomb interaction. Due to the atomic-thin thickness, they are tightly bound in monolayer transition metal dichalcogenides (TMDs) and dominate their optical properties. The capability to manipulate the excitonic behavior can significantly influence the photon emission or carrier transport performance of TMD-based devices. However, on-demand and region-selective manipulation of the excitonic states in a reversible manner remains challenging so far. Herein, harnessing the coordinated effect of femtosecond-laser-driven atomic defect generation, interfacial electron transfer, and surface molecular desorption/adsorption, we develop an all-optical approach to manipulate the charge states of excitons in monolayer molybdenum disulfide (MoS2). Through steering the laser beam, we demonstrate reconfigurable optical encoding of the excitonic charge states (between neutral and negative states) on a single MoS2 flake. Our technique can be extended to other TMDs materials, which will guide the design of all-optical and reconfigurable TMD-based optoelectronic and nanophotonic devices.

Quantum Emitters with Narrow Band and High Debye-Waller Factor in Aluminum Nitride Written by Femtosecond Laser.

Solid-state quantum emitters (QEs) are central components for photonic-based quantum information processing. Recently, bright QEs in III-nitride semiconductors, such as aluminum nitride (AlN), have attracted increasing interest because of the mature commercial application of the nitrides. However, the reported QEs in AlN suffer from broad phonon side bands (PSBs) and low Debye-Waller factors. Meanwhile, there is also a need for more reliable fabrication methods of AlN QEs for integrated quantum photonics. Here, we demonstrate that laser-induced QEs in AlN exhibit robust emission with a strong zero phonon line, narrow line width, and weak PSB. The creation yield of a single QE could be more than 50%. More importantly, they have a high Debye-Waller factor (>65%) at room temperature, which is the highest result among reported AlN QEs. Our results illustrate the potential of laser writing to create high-quality QEs for quantum technologies and provide further insight into laser writing defects in relevant materials.

[Retrospective cross-sectional survey of clinical characteristics and syndrome elements distribution at different stages of coronary heart disease].

The clinical data of coronary heart disease(CHD) patients treated in the First Affiliated Hospital of Guangzhou University of Chinese Medicine and Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine from January 2022 to March 2023 were retrospectively collected. This study involved the descriptive analysis of demographic characteristics, clinical symptoms, and tongue and pulse features. The χ~2 test was conducted to analyze the distribution of syndrome elements and their combinations at diffe-rent stages of CHD, so as to reveal the clinical characteristics and syndrome patterns at various pathological stages of CHD. This study extracted 28 symptom entries, 10 tongue manifestation entries, and 7 pulse manifestation entries, summarized the 5 main disease locations of the heart, lung, liver, spleen, and kidney, and the 8 main disease natures of blood stasis, phlegm turbidity, Qi stagnation, heat(fire), fluid retention, Qi deficiency, Yin deficiency, and Yang deficiency and 8 combinations of disease natures. The χ~2 test showed significant differences in the distribution of syndrome elements including the lung, liver, spleen, kidney, blood stasis, heat(fire), Qi stagnation, heat syndrome, water retention, Qi deficiency, Yin deficiency, and Yang deficiency between different disease stages. Specifically, the liver, blood stasis, heat(fire), and Qi stagnation accounted for the highest proportion during unstable stage, and the lung, spleen, kidney, water retention, Qi deficiency, Yin deficiency, and Yang deficiency accounted for the highest proportion at the end stage. The distribution of Qi deficiency varied in the different time periods after percutaneous coronary intervention(PCI). As shown by the χ~2 test of the syndrome elements combination, the distribution of single disease location, multiple disease locations, single disease nature, double disease natures, multiple natures, excess syndrome, and mixture of deficiency and excess varied significantly at different stages of CHD. Specifically, single disease location, single disease nature, and excess syndrome accounted for the highest proportion during the stable stage, and double disease natures accounted for the highest proportion during the unstable stage. Multiple disease locations, multiple disease natures, and mixture of deficiency and excess accounted for the highest proportion during the end stage. In conclusion, phlegm turbidity and blood stasis were equally serious during the stable stage, and a pathological mechanism caused by blood stasis and toxin existed during the unstable stage. The overall Qi deficiency worsened after PCI, and the end stage was accompanied by the Yin and Yang damage and the aggravation of water retention. There were significant differences in the distribution of clinical characteristics and syndrome elements at different stages of CHD. The pathological process of CHD witnessed the growth and decline of deficiency and excess and the combination of phlegm turbidity and blood stasis, which constituted the basic pathogenesis.

Conformation-Confined Organic Butterfly-Molecule with High Photoluminescence Efficiency, Deep-Blue Amplified Spontaneous Emission, and Unique Piezochromic Luminescence.

Organic fluorophores with tunable π-conjugated paths have attracted considerable attention owing to their diverse properties and promising applications. Herein, we present a tailored butterfly like molecule, 2,2'-(2,5-bis (2,2-diphenylvinyl)-1,4-phenylene)dinaphtha-lene (BDVPN), which exhibits diverse photophysical features in its two polymorphs. The BP phase crystal, with its "aligned wings" conformation, possesses emissive characteristics that are nearly identical to those in dilute solutions. In contrast, the BN phase crystal, which adopts an "orthogonal wings" conformation, exhibits an unusual hypsochromic-shifted emission compared to its dilute solution counterparts. This intriguing hypsochromic-shifted emission originates from the reduction in the effective conjugated length of the molecular skeleton. Notably, BN phase crystals also exhibit exceptional optical performance, featuring high-efficiency emission (76.6%), low-loss optical waveguides (0.571 dB mm-1), deep-blue amplified spontaneous emission (ASE) with a narrow full width at half maximum (FWHM: 6.4 nm), and a unique 200 nm bathochromic shift of piezochromic luminescence.

The Clinicopathologic Features and Molecular Signatures of Blastoid High-Grade B Cell Lymphoma, Not Otherwise Specified.

A small subset of high-grade B-cell lymphoma (HGBL) with blastoid morphology remains poorly understood. We assessed 55 cases of blastoid HGBL, not otherwise specified (NOS) and compared their clinicopathologic characteristics with those of 81 non-blastoid HGBL-NOS and 62 blastoid HGBL with MYC and BCL2, with or without BCL6 rearrangements (double/triple-hit lymphoma [D/THL]). Patients with blastoid HGBL-NOS showed similar clinicopathologic features to patients with blastoid D/THLs and non-blastoid HGBL-NOS, except more frequently with a history of low-grade B-cell lymphoma, bone marrow involvement, and BCL2 rearrangement (P < .05) compared to the latter. MYC rearrangement (MYC-R), detected in 40% of blastoid HGBL-NOS, was associated with aggressive clinicopathologic features and poorer overall survival, even worse than that of blastoid D/THL (P < .05). Transcriptome profiling revealed a distinct gene expression pattern with differentially expressed genes enriched in MYC and P53-targeted genes in MYC-R blastoid HGBL-NOS. Fifty-two percent of blastoid HGBL-NOS had a double hit-like signature, similar to non-blastoid HGBL-NOS (P = .73). The overall survival of the blastoid HGBL-NOS group was similar to that of the blastoid D/THL group but appeared poorer than that of its non-blastoid counterparts (P = .07). Taken together, blastoid HGBL-NOS is an aggressive B-cell lymphoma that shares overlapping clinicopathologic and genetic features with non-blastoid HGBL-NOS. MYC-R in patients with blastoid HGBL-NOS identifies a highly aggressive subgroup with distinct aggressive clinicopathologic features, unique molecular signatures, and a dismal clinical outcome.

Clinicopathologic Features of Therapy-Related Myeloid Neoplasms in Patients with Myeloma in the Era of Novel Therapies.

The development of therapy-related myeloid neoplasms (t-MN) is a rare complication that can occur in myeloma patients treated primarily with novel therapies. To better understand t-MNs in this context, we reviewed 66 such patients and compared them with a control group of patients who developed t-MN after cytotoxic therapies for other malignancies. The study group included 50 men and 16 women, with a median age of 68 years (range, 48-86 years). Therapies included proteasome inhibitors, immunomodulatory agents, and high-dose melphalan-based autologous stem cell transplantation (HDM-ASCT) in 64 (97%), 65 (98.5%), and 64 (97%) patients, respectively; 29 (43.9%) patients were exposed to other cytotoxic drugs besides HDM. The latency interval from therapy to t-MN was 4.9 years (range, 0.6-21.9 years). Patients who received HDM-ASCT in addition to other cytotoxic therapies had a longer latency period to t-MN compared with patients who only received HDM-ASCT (6.1 vs 4.7 years, P = .009). Notably, 11 patients developed t-MN within 2 years. Therapy-related myelodysplastic syndrome was the most common type of neoplasm (n = 60), followed by therapy-related acute myeloid leukemia (n = 4) and myelodysplastic syndrome/myeloproliferative neoplasm (n = 2). The most common cytogenetic aberrations included complex karyotypes (48.5%), del7q/-7 (43.9%), and/or del5q/-5 (40.9%). The most frequent molecular alteration was TP53 mutation, in 43 (67.2%) patients and the sole mutation in 20 patients. Other mutations included DNMT3A, 26.6%; TET2, 14.1%; RUNX1, 10.9%; ASXL1, 7.8%; and U2AF1, 7.8%. Other mutations in less than 5% of cases included SRSF2, EZH2, STAG2, NRAS, SETBP, SF3B1, SF3A1, and ASXL2. After a median follow-up of 15.3 months, 18 patients were alive and 48 died. The median overall survival after the diagnosis of t-MN in the study group was 18.4 months. Although the overall features are comparable to the control group, the short interval to t-MN (<2 years) underscores the unique vulnerable status of myeloma patients.

Kikuchi disease with an exuberant proliferation of large T-cells: a study of 25 cases that can mimic T-Cell lymphoma.

Exuberant large T-cell proliferations in Kikuchi disease can potentially be misdiagnosed as lymphoma. In this study, we explore their clinicopathological features and summarize key points that can be used to distinguish them from T-cell lymphoma. The cohort consisted of 25 cases of Kikuchi disease with an exuberant large T-cell proliferation, which, in part, mimicked lymphoma. The median age was 25 years with a female:male ratio of 4:1. By B-scan ultrasonography, patients presented with either isolated lymphadenopathy (68%) involving the cervical and axillary regions or generalized lymphadenopathy (32%). Histologically, lymph nodes showed paracortical and interfollicular expansion by sheets of large cells associated with karyorrhectic debris. Histiocytes and plasmacytoid dendritic cells were present in the background. No case showed complete effacement of lymph node architecture. The large cells were CD8-positive cytotoxic T-cells with a high proliferation rate. These T-cells showed decreased BCL-2 in 17 (68%) cases. CD5 expression was decreased in 10 (40%) cases. Histiocytes in the background were positive for myeloperoxidase. Clonal TRG and/or TRB rearrangements were detected in 2 of 10 (20%) cases. In conclusion, large T-cell proliferations in Kikuchi disease can be alarming at the morphologic and immunophenotypic levels and need to be distinguished from T-cell lymphoma. Clinical features helpful in the differential diagnosis include young patients and lymphadenopathy involving the cervical and axillary regions. Major pathologic features helpful in this differential diagnosis include partial involvement of the lymph node and the presence of karyorrhectic debris, crescent-shaped histiocytes, and/or loose aggregates of plasmacytoid dendritic cells.

DUSP22 rearrangement is associated with a distinctive immunophenotype but not outcome in patients with systemic ALK-negative anaplastic large cell lymphoma.

DUSP22 rearrangement (R) has been associated with a favorable outcome in systemic ALK-negative anaplastic large cell lymphoma (ALCL). However, a recent study found that patients with DUSP22-R ALK-negative ALCL have a poorer prognosis than was reported initially. In this study, we compared the clinicopathological features and outcomes of patients with ALKnegative ALCL with DUSP22-R (n=22) versus those without DUSP22-R (DUSP22-NR; n=59). Patients with DUSP22-R ALCL were younger than those with DUSP22-NR neoplasms (P=0.049). DUSP22-R ALK-negative ALCL cases were more often positive for CD15, CD8, and less frequently expressed pSTAT3Tyr705, PD-L1, granzyme B and EMA (all P<0.05). TP63 rearrangement (TP63-R) was detected in three of the 66 (5%) ALK-negative ALCL cases tested and none of these cases carried the DUSP22-R. Overall survival of patients with DUSP22-R ALCL was similar to that of the patients with DUSP22-NR neoplasms regardless of International Prognostic Index score, stage, age, or stem cell transplantation status (all P>0.05), but was significantly shorter than that of the patients with ALK-positive ALCL (median overall survival 53 months vs. undefined, P=0.005). Five-year overall survival rates were 40% for patients with DUSP22-R ALCL versus 82% for patients with ALK-positive ALCL. We conclude that DUSP22-R neoplasms represent a distinctive subset of ALK-negative ALCL. However, in this cohort DUSP22-R was not associated with a better clinical outcome. Therefore, we suggest that current treatment guidelines for this subset of ALK-negative ALCL patients should not be modified at present.

Reactions of Thorium Oxide Clusters with Water: The Effects of Oxygen Content.

Thorium oxide has many important applications in industry. In this article, theoretical calculations have been carried out to explore the hydrolysis reactions of the ThOn (n=1-3) clusters. The reaction mechanisms of the O-deficient ThO and the O-rich ThO3 are compared with the stoichiometric ThO2 . The theoretical results show good agreement with the prior experiments. It is shown that the hydrolysis mainly occurred on the singlet potential surface. The overall reactions consist of two hydrolysis steps which are all favourable in energy. The effects of oxygen content on the hydrolysis are elucidated. Interestingly, among them, the peroxo group O2 2- in ThO3 is converted to the HOO- ligand, behaving like the terminal O2- in the hydrolysis which is transformed into the HO- groups. In addition, natural bond orbital (NBO) analyses were employed to further understand the bonding of the pertinent species and to interpret the differences in hydrolysis.

Design and modeling for drug combination experiments with order effects.

Combinations of drugs are now ubiquitous in treating complex diseases such as cancer and HIV due to their potential for enhanced efficacy and reduced side effects. The traditional combination experiments of drugs focus primarily on the dose effects of the constituent drugs. However, with the doses of drugs remaining unchanged, different sequences of drug administration may also affect the efficacy endpoint. Such drug effects shall be called as order effects. The common order-effect linear models are usually inadequate for analyzing combination experiments due to the nonlinear relationships and complex interactions among drugs. In this article, we propose a random field model for order-effect modeling. This model is flexible, allowing nonlinearities, and interaction effects to be incorporated with a small number of model parameters. Moreover, we propose a subtle experimental design that will collect good quality data for modeling the order effects of drugs with a reasonable run size. A real-data analysis and simulation studies are given to demonstrate that the proposed design and model are effective in predicting the optimal drug sequences in administration.

Antimicrobial susceptibilities and genomic epidemiology of Neisseria gonorrhoeae in Stockholm, Sweden.

The aim of this study was to investigate the genomic epidemiology and antimicrobial susceptibilities of N. gonorrhoeae isolates in Stockholm, Sweden. In total, 6723 isolates detected in Stockholm, Sweden, from January 2016 to September 2022, were examined for antimicrobial susceptibilities by using E-test. Whole-genome sequencing (WGS) was applied to isolates in sentinel surveillance and isolates resistant to extended-spectrum cephalosporins (ESCs) or high-level azithromycin (HLAzi-R, MIC ≥ 256 mg/L). As sentinel surveillance, consecutive clinical isolates (n = 396) detected every 4th week from January 2021 to September 2022 were enrolled in the study. Of the 6723 isolates investigated, 33 isolates (< 1%) were found to be resistant to cefixime, one of which was co-resistant to ceftriaxone and ciprofloxacin and was detected in September 2022. Ten isolates presented a high level of azithromycin resistance. Resistant rates to ciprofloxacin varied from 32 in 2017 to 68-69% in 2021-2022. Elevated MIC50 and MIC90 of azithromycin were observed over the years. No resistance to spectinomycin was identified. The most frequently occurring MLST in the sentinel surveillance was ST9362 (23%), followed by ST11706 (9%), ST7359 (8%), ST10314 (7%), and ST11422 (6%). The ceftriaxone-resistant isolate belonged to ST8130 and the novel NG-STAR ST4859. Genomic resistance traits found in this strain included mutations in genes mtrR (A39T), parC (S87N), and gyrA (S91F and D95A), as well as the presence of blaTEM-135 and tetM genes. A predominance of ST9362 was observed in Stockholm. The high number of azithromycin and ciprofloxacin-resistant isolates and the emergence of a strain with a novel NG-STAR are of great concern.

A randomized, double-blind, placebo-controlled phase II study to evaluate the efficacy and safety of ivarmacitinib (SHR0302) in adult patients with moderate-to-severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is a CD8+ T cell-mediated autoimmune disease characterized by nonscarring hair loss. Ivarmacitinib, which is a selective oral Janus kinase 1 inhibitor, may interrupt certain cytokine signaling implicated in the pathogenesis of AA. OBJECTIVE: To evaluate the efficacy and safety of ivarmacitinib in adult patients with AA who have ≥25% scalp hair loss. METHODS: Eligible patients were randomized 1:1:1:1 to receive ivarmacitinib 2, 4, or 8 mg once daily or placebo for 24 weeks. The primary end point was the percentage change from baseline in the Severity of Alopecia Tool score at week 24. RESULTS: A total of 94 patients were randomized. At week 24, the least squares mean difference in the percentage change from baseline in the Severity of Alopecia Tool score for ivarmacitinib 2, 4, and 8 mg and placebo groups were -30.51% (90% CI, -45.25, -15.76), -56.11% (90% CI, -70.28, -41.95), -51.01% (90% CI, -65.20, -36.82), and -19.87% (90% CI, -33.99, -5.75), respectively. Two serious adverse events-follicular lymphoma and COVID-19 pneumonia-were reported. LIMITATIONS: A small sample size limits the generalizability of the results. CONCLUSION: Treatment with ivarmacitinib 4 and 8 mg doses in patients with moderate and severe AA for 24 weeks was efficacious and generally tolerated.