Lysyl Oxidase (LOX) Family Proteins: Key Players in Breast Cancer Occurrence and Progression.

The lysyl oxidase (LOX) family proteins are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like 1-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumours, whereby a corrupt tumour microenvironment (TME) takes shape. Additionally, dysregulation and aberrant expression of LOX family proteins have been implicated in the occurrence and progression of various types of human cancers, including lung cancer, hepatocellular carcinoma, gastric cancer, renal cell carcinoma, and colorectal cancer. Breast cancer is the most prevalent malignant tumour in women worldwide, and its incidence rate is increasing annually. In recent years, a growing body of evidence has revealed significant upregulation of LOX family proteins in breast cancer, which contributes to cancer cell proliferation, invasion, and metastasis. Furthermore, elevated expression of LOX family proteins is closely associated with poor prognosis in breast cancer patients. We herein review the structure, regulation, function, and mechanisms of LOX family proteins in the occurrence and progression of breast cancer. In addition, we highlight recent insights into their mechanisms and their potential involvement in the clinical value and novel biological roles of LOX family members in tumour progression and the TME of breast cancer. This review will provide a theoretical basis and reference for clinical diagnosis and treatment of breast cancer, as well as for the screening of effective LOX-specific inhibitors.

Upadacitinib monotherapy versus methotrexate monotherapy in patients with rheumatoid arthritis: efficacy and safety through 5 years in the SELECT-EARLY randomized controlled trial.

BACKGROUND: To evaluate the efficacy and safety of upadacitinib monotherapy versus methotrexate (MTX) monotherapy over 5 years among MTX-naïve patients with moderately to severely active rheumatoid arthritis (RA) in the long-term extension (LTE) of the phase 3 SELECT-EARLY trial. METHODS: Patients were randomized to receive upadacitinib 15 mg or 30 mg or MTX. Patients who did not achieve CDAI remission and had < 20% improvement in tender and swollen joint counts at week 26 received rescue therapy (addition of MTX in the upadacitinib group and addition of upadacitinib in the MTX group). Efficacy assessments were evaluated over 5 years and are reported as observed (AO) for patients who received continuous monotherapy with upadacitinib 15/30 mg or MTX and by randomized group applying non-responder imputation (NRI). Treatment-emergent adverse events (TEAEs) per 100 patient-years were summarized over 5 years. RESULTS: Of 945 patients randomized and treated, 775 (82%) completed week 48 and entered the LTE on study drug. Higher proportions of patients consistently achieved disease activity targets over 5 years with upadacitinib than MTX. In AO analyses, 53%/59% of patients attained CDAI remission with upadacitinib 15/30 mg versus 43% with MTX at week 260. NRI analyses showed better CDAI, DAS28(CRP), and ACR responses with upadacitinib relative to MTX at week 260 (all comparisons, nominal P < .001). Upadacitinib treatment also resulted in numerically greater inhibition of structural joint progression through week 260 compared to MTX. Most TEAEs, serious AEs, and AEs leading to discontinuation were numerically higher in patients receiving upadacitinib 30 mg. Rates of serious infections, herpes zoster, creatine phosphokinase elevation, nonmelanoma skin cancer, and neutropenia were numerically higher with upadacitinib than MTX. The observed safety profile of upadacitinib over 5 years was consistent with earlier trial results and integrated phase 3 safety analyses. CONCLUSIONS: Upadacitinib showed better clinical responses versus MTX in patients with RA throughout the 5-year trial. Higher rates of several AEs were observed with upadacitinib, especially in the 30 mg group, compared to MTX. When used as monotherapy in MTX-naïve patients, the approved upadacitinib 15 mg dose showed better long-term efficacy versus MTX and an overall favorable benefit-risk profile. TRIAL REGISTRATION: NCT02706873.

FANCI Inhibition Induces PARP1 Redistribution to Enhance the Efficacy of PARP Inhibitors in Breast Cancer.

Breast cancer is a global public health concern with high mortality rates, necessitating the development of innovative treatment strategies. PARP inhibitors have shown efficacy in certain patient populations, but their application is largely limited to cancers with homologous recombination deficiency. Here, we identified the suppression of FANCI as a therapeutic strategy to enhance the efficacy of PARP inhibitors in breast cancer. Elevated FANCI expression in breast cancer was associated with poor prognosis and increased cell proliferation and migration. FANCI interacted with PARP1, and suppressing FANCI limited the nuclear localization and functionality of PARP1. Importantly, FANCI inhibition sensitized breast cancer cells to the PARP inhibitor talazoparib in the absence of BRCA mutations. Additionally, the CDK4/6 inhibitor palbociclib enhanced the sensitivity of breast cancer cells to talazoparib through FANCI inhibition. These findings highlight the potential of targeting FANCI to enhance the efficacy of PARP inhibitors in treating breast cancer.

Roles of THEM4 in the Akt pathway: a double-edged sword. / THEM4在Akt通路中的作用：一把双刃剑.

The protein kinase B (Akt) pathway can regulate the growth, proliferation, and metabolism of tumor cells and stem cells through the activation of multiple downstream target genes, thus affecting the development and treatment of a range of diseases. Thioesterase superfamily member 4 (THEM4), a member of the thioesterase superfamily, is one of the Akt kinase-binding proteins. Some studies on the mechanism of cancers and other diseases have shown that THEM4 binds to Akt to regulate its phosphorylation. Initially, THEM4 was considered an endogenous inhibitor of Akt, which can inhibit the phosphorylation of Akt in diseases such as lung cancer, pancreatic cancer, and liver cancer, but subsequently, THEM4 was shown to promote the proliferation of tumor cells by positively regulating Akt activity in breast cancer and nasopharyngeal carcinoma, which contradicts previous findings. Considering these two distinct views, this review summarizes the important roles of THEM4 in the Akt pathway, focusing on THEM4 as an Akt-binding protein and its regulatory relationship with Akt phosphorylation in various diseases, especially cancer. This work provides a better understanding of the roles of THEM4 combined with Akt in the treatment of diseases.

Generation and Characterization of Induced Pluripotent Stem Cells Carrying An ASXL1 Mutation.

Additional sex combs-like 1 (ASXL1) is an epigenetic modulator frequently mutated in myeloid malignancies, generally associated with poor prognosis. Current models for ASXL1-mutated diseases are mainly based on the complete deletion of Asxl1 or overexpression of C-terminal truncations in mice models. However, these models cannot fully recapitulate the pathogenesis of myeloid malignancies. Patient-derived induced pluripotent stem cells (iPSCs) provide valuable disease models that allow us to understand disease-related molecular pathways and develop novel targeted therapies. Here, we generated iPSCs from a patient with myeloproliferative neoplasm carrying a heterozygous ASXL1 mutation. The iPSCs we generated exhibited the morphology of pluripotent cells, highly expressed pluripotent markers, excellent differentiation potency in vivo, and normal karyotype. Subsequently, iPSCs with or without ASXL1 mutation were induced to differentiate into hematopoietic stem/progenitor cells, and we found that ASXL1 mutation led to myeloid-biased output and impaired erythroid differentiation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that terms related to embryonic development, myeloid differentiation, and immune- and neural-related processes were most enriched in the differentially expressed genes. Western blot demonstrated that the global level of H2AK119ub was significantly decreased when mutant ASXL1 was present. Chromatin Immunoprecipitation Sequencing showed that most genes associated with stem cell maintenance were upregulated, whereas occupancies of H2AK119ub around these genes were significantly decreased. Thus, the iPSC model carrying ASXL1 mutation could serve as a potential tool to study the pathogenesis of myeloid malignancies and to screen targeted therapy for patients.

Upadacitinib in Active Non-radiographic Axial Spondyloarthritis: 1-Year Data From a Double-Blind, Randomized, Placebo-Controlled, Phase 3 Trial.

OBJECTIVE: Upadacitinib improved the signs and symptoms of non-radiographic axial spondyloarthritis (nr-axSpA) versus placebo over 14 weeks in the primary analysis of the SELECT-AXIS 2 nr-axSpA study. Here, we evaluated the efficacy and safety of upadacitinib through 1 year in patients with nr-axSpA in SELECT-AXIS 2. METHODS: Patients aged at least 18 years diagnosed with nr-axSpA who fulfilled the 2009 Assessment of SpondyloArthritis International Society (ASAS) classification criteria and were receiving stable background therapy were randomized to upadacitinib 15 mg once daily or placebo for the 52-week double-blind period. Efficacy was assessed using non-responder imputation incorporating multiple imputation (NRI-MI) and as-observed analyses for binary endpoints, and mixed-effects model repeated measures for continuous endpoints. RESULTS: Of 314 randomized patients, 259 (upadacitinib, n = 129; placebo, n = 130) completed 52 weeks of treatment. More patients receiving upadacitinib versus placebo achieved ≥40% improvement in ASAS at week 52 (63% vs 43%, NRI-MI; nominal P < 0.001). Similar treatment effects were observed for the achievement of axSpA Disease Activity Score inactive disease (33% v 11%, NRI-MI; nominal P < 0.001). Overall, patients receiving upadacitinib versus placebo showed greater improvement in disease activity, inflammation, pain, function, enthesitis, and quality of life through 52 weeks. Adverse events were generally comparable between the treatment groups. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, inflammatory bowel disease, or deaths were reported in those receiving upadacitinib. CONCLUSION: Treatment with upadacitinib showed sustained efficacy versus placebo with no new safety findings identified through 1 year. These results support the continued favorable benefit-risk profile of upadacitinib treatment for nr-axSpA.

Extraordinary linear non-enhancing brainstem leptomeningeal metastasis from lung adenocarcinoma: A case report.

In patients with lung adenocarcinoma, angiogenesis-altering drugs can alter the appearance of leptomeningeal metastasis on magnetic resonance imaging (MRI) scans. In the ventral brainstem, this can manifest as a unique, linear, non-enhancing T2-hyperintense signal.

Intact quantitation of cysteine-conjugated antibody-drug conjugates using native mass spectrometry.

RATIONALE: A common strategy for antibody-drug conjugate (ADC) quantitation from in vivo study samples involves measurement of total antibody, conjugated ADC, and free payload concentrations using multiple reaction monitoring (MRM) mass spectrometry. This not only provides a limited picture of biotransformation but can also involve lengthy method development. Quantitation of ADCs directly at the intact protein level in native conditions using high-resolution mass spectrometers presents the advantage of measuring exposure readout as well as monitoring the change in average drug-to-antibody ratio (DAR) and in vivo stability of new linker payloads with minimal method development. Furthermore, site-specific cysteine-conjugated ADCs often rely on non-covalent association to retain their quaternary structure, which highlights the unique capabilities of native mass spectrometry (nMS) for intact ADC quantitation. METHODS: We developed an intact quantitation workflow involving three stages: automated affinity purification, nMS analysis, and data processing in batch fashion. The sample preparation method was modified to include only volatile ion-pairing reagents in the buffer systems. A capillary size-exclusion chromatography (SEC) column was coupled to a quadrupole time-of-flight high-resolution mass spectrometer for high-throughput nMS analysis. Samples from two mouse pharmacokinetic (PK) studies were analyzed using both intact quantitation workflow and the conventional MRM-based approach. RESULTS: A linear dynamic range of 5-100 µg/mL was achieved using 20 µL of serum sample volume. The results of mouse in vivo PK measurement using the intact quantitation workflow and the MRM-based approach were compared, revealing excellent method agreement. CONCLUSIONS: We demonstrated the feasibility of utilizing nMS for the quantitation of ADCs at the intact protein level in preclinical PK studies. Our results indicate that this intact quantitation workflow can serve as an alternative generic method for high-throughput analysis, enabling an in-depth understanding of ADC stability and safety in vivo.

Long-term safety and efficacy of upadacitinib versus adalimumab in patients with rheumatoid arthritis: 5-year data from the phase 3, randomised SELECT-COMPARE study.

OBJECTIVES: To assess the safety and efficacy of upadacitinib versus adalimumab from SELECT-COMPARE over 5 years. METHODS: Patients with rheumatoid arthritis and inadequate response to methotrexate were randomised to receive upadacitinib 15 mg once daily, placebo or adalimumab 40 mg every other week, all with concomitant methotrexate. By week 26, patients with insufficient response to randomised treatment were rescued; patients remaining on placebo switched to upadacitinib. Patients completing the 48-week double-blind period could enter a long-term extension. Safety and efficacy were assessed through week 264, with radiographic progression analysed through week 192. Safety was assessed by treatment-emergent adverse events (TEAEs). Efficacy was analysed by randomised group (non-responder imputation (NRI)) or treatment sequence (as observed). RESULTS: Rates of TEAEs were generally similar with upadacitinib versus adalimumab, although numerically higher rates of herpes zoster, lymphopenia, creatine phosphokinase elevation, hepatic disorder and non-melanoma skin cancer were reported with upadacitinib. Numerically greater proportions of patients randomised to upadacitinib versus adalimumab achieved clinical responses (NRI); Clinical Disease Activity Index remission (≤2.8) and Disease Activity Score based on C reactive protein <2.6 were achieved by 24.6% vs 18.7% (nominal p=0.042) and 31.8% vs 23.2% (nominal p=0.006), respectively. Radiographic progression was numerically lower with continuous upadacitinib versus adalimumab at week 192. CONCLUSION: The safety profile of upadacitinib through 5 years was consistent with the known safety profile of upadacitinib, with no new safety risks. Clinical responses were numerically higher with upadacitinib versus adalimumab at 5 years. Upadacitinib demonstrates a favourable benefit-risk profile for long-term rheumatoid arthritis treatment. TRIAL REGISTRATION NUMBER: NCT02629159.

Reniformin A suppresses non-small cell lung cancer progression by inducing TLR4/NLRP3/caspase-1/GSDMD-dependent pyroptosis.

Pyroptosis is an inflammatory form of programmed cell death that plays an important role in regulating tumor progression. Reniformin A (RA) is a natural compound isolated from the medicinal herb Isodon excisoides that has been applied as folk medicine in the treatment of esophageal cancer. However, whether RA has an individual function in cancer and the molecular mechanisms remain unclear. Here, we show that in non-small-cell lung cancer (NSCLC), RA inhibits tumor growth by functioning as a pyroptosis inducer to promote TLR4/NLRP3/caspase-1/GSDMD axis. Specially, RA treatment increased Toll-like receptor 4 (TLR4) protein expression level by enhancing the TLR4 stability. Based on the molecular docking, we identified that RA directly bound to TLR4 to activate the NLRP3 inflammasome and promote pyroptosis in A549 cells. Moreover, TLR4 is essential for RA-induced pyroptosis, and loss of TLR4 abolished RA-induced pyroptosis and further reduced the inhibitory effect of RA on NSCLC. In vivo experiments confirmed that RA inhibited the growth of lung tumors in mice by affecting pyroptosis in a dose-dependent manner. Furthermore, TLR4 knockdown abolished RA-induced pyroptosis and inhibited the effect of RA chemotherapy in vivo. In conclusion, we propose that RA has a significant anticancer effect in NSCLC by inducing TLR4/NLRP3/caspase-1/GSDMD-mediated pyroptosis, which may provide a potential strategy for the treatment of NSCLC.

Real-world impact of chemotherapy on overall survival in craniomaxillofacial osteosarcoma.

OBJECTIVES: The goal of this study was to identify the survival benefit of chemotherapy in craniomaxillofacial osteosarcoma (CMFO) patients based on a US population. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to select patients with CMFO from 1988 to 2016. Age and tumor size were grouped by X-tail. Cox analysis were used to estimate hazards ratios (HR) among patients. All of patients were divided into two cohorts by using Propensity Score Matching (PSM) method to evaluate the effect of chemotherapy. All prognostic factors were included in the nomograms which predict the median survival time. RESULTS: 410 patients were included in our study. The results of survival rate, Kaplan-Meier and Cox regression were showed no significant difference between the group of chemotherapy performed and the group without chemotherapy. PSM analysis also demonstrated the limited survival advantage of chemotherapy. Moreover, all factors were further incorporated to construct the novel nomograms and its concordance indices (C-index) for internal validation of OS prediction were 0.749 (95 %CI:0.731-0.767). CONCLUSIONS: Our study did not show the advantage of chemotherapy on the overall survival outcome of CMFO. Although neoadjuvant chemotherapy was currently recommended in clinical treatment, more rigorous randomized controlled trials are still needed. Nomograms would assist clinicians in making more accurate survival evaluation and choosing the optimal medical treatment.

Aptamers combined with immune checkpoints for cancer detection and targeted therapy: A review.

In recent years, remarkable strides have been made in the field of immunotherapy, which has emerged as a standard treatment for many cancers. As a kind of immunotherapy drug, monoclonal antibodies employed in immune checkpoint therapy have proven beneficial for patients with diverse cancer types. However, owing to the extensive heterogeneity of clinical responses and the complexity and variability of the immune system and tumor microenvironment (TME), accurately predicting its efficacy remains a challenge. Recent advances in aptamers provide a promising approach for monitoring alterations within the immune system and TME, thereby facilitating targeted immunotherapy, particularly focused on immune checkpoint blockade, with enhanced antitumor efficiency. Aptamers have been widely used in tumor cell detection, biosensors, drug discovery, and biomarker screening due to their high specificity and high affinity with their targets. This review aims to comprehensively examine the research status and progress of aptamers in cancer diagnosis and immunotherapy, with a specific emphasis on those related to immune checkpoints. Additionally, we will discuss the future research directions and potential therapeutic targets for aptamer-based immune checkpoint therapy, aiming to provide a theoretical basis for targeting immunotherapy molecules and blocking tumor immune escape.

Altered Neuromagnetic Activity in the Default Mode Network in Migraine and Its Subgroups (Episodic Migraine and Chronic Migraine).

BACKGROUND: The differences in the resting state spectral power and functional connectivity of the default mode network between people with migraine without aura (MwoA) and its subgroups differentiated by frequency (episodic migraine (EM) and chronic migraine (CM)) and healthy controls (HC) were investigated using magnetoencephalography. METHODS: In the resting state, the topological spatial structure of the brain in 33 MwoA patients and 22 HC was first studied using magnetoencephalography, followed by probing the neuroelectrical activity of 17 CM and 16 EM patients, to identify damage to their default mode network (DMN). The techniques used to investigate both spectral power and functional connectivity were minimum-paradigm estimation combined with Welch's technique and corrected amplitude envelope correlation. RESULTS: The differences between MwoA and its subgroups (CM and EM) and HC based on spectral power were mainly in the delta, theta, and alpha bands, while the differences in functional connectivity were primarily in the delta, alpha, and beta bands. In the delta and theta bands, the spectral power of MwoA and its subgroups (CM and EM) was higher than in the HC group. The spectral power of MwoA and its subgroups (CM and EM) was lower in the alpha band. In terms of functional connectivity, the corrected amplitude envelope correlation of MwoA and its subgroups (CM and EM) was lower than the HC group in the bands with spectral differences. People with EM and CM differed in the spectral power in the left medial prefrontal cortex and the right lateral temporal cortex in the alpha band, where correlation analysis and logistic regression analysis showed that the intensity of the spectral power of the left medial prefrontal cortex was negatively correlated with headache frequency. CONCLUSIONS: The spectral power of the left medial prefrontal cortex in the alpha band may serve as a biomarker that is associated with the number of monthly headache attacks and may be a potential neuromodulatory target for controlling migraine chronicity.

FLOT2 promotes nasopharyngeal carcinoma progression through suppression of TGF-ß pathway via facilitating CD109 expression.

In nasopharyngeal carcinoma (NPC), the TGF-ß/Smad pathway genes are altered with inactive TGF-ß signal, but the mechanisms remain unclear. RNA-sequencing results showed that FLOT2 negatively regulated the TGF-ß signaling pathway via up-regulating CD109 expression. qRT-PCR, western blot, ChIP, and dual-luciferase assays were used to identify whether STAT3 is the activating transcription factor of CD109. Co-IP immunofluorescence staining assays were used to demonstrate the connection between FLOT2 and STAT3. In vitro and in vivo experiments were used to detect whether CD109 could rescue the functional changes of NPC cells resulting from FLOT2 alteration. IHC and Spearman correlation coefficients were used to assay the correlation between FLOT2 and CD109 expression in NPC tissues. Our results found that FLOT2 promotes the development of NPC by inhibiting TGF-ß signaling pathway via stimulating the expression of CD109 by stabilizing STAT3, which provides a potential therapeutic strategy for NPC treatment.

Bone Organoids: Recent Advances and Future Challenges.

Bone defects stemming from tumorous growths, traumatic events, and diverse conditions present a profound conundrum in clinical practice and research. While bone has the inherent ability to regenerate, substantial bone anomalies require bone regeneration techniques. Bone organoids represent a new concept in this field, involving the 3D self-assembly of bone-associated stem cells guided in vitro with or without extracellular matrix material, resulting in a tissue that mimics the structural, functional, and genetic properties of native bone tissue. Within the scientific panorama, bone organoids ascend to an esteemed status, securing significant experimental endorsement. Through a synthesis of current literature and pioneering studies, this review offers a comprehensive survey of the bone organoid paradigm, delves into the quintessential architecture and ontogeny of bone, and highlights the latest progress in bone organoid fabrication. Further, existing challenges and prospective directions for future research are identified, advocating for interdisciplinary collaboration to fully harness the potential of this burgeoning domain. Conclusively, as bone organoid technology continues to mature, its implications for both clinical and research landscapes are poised to be profound.

The effects of doxorubicin loaded aptamer S3-linked DNA tetrahedrons on nasopharyngeal carcinoma.

OBJECTIVE: Our research group in the early stage identified CD109 as the target of aptamer S3 in nasopharyngeal carcinoma (NPC). This study was to use S3 to connect DNA tetrahedron (DT) and load doxorubicin (Dox) onto DT to develop a targeted delivery system, and explore whether S3-DT-Dox can achieve targeted therapy for NPC. METHODS: Aptamer S3-conjugated DT was synthesized and loaded with Dox. The effects of S3-DT-Dox on NPC cells were investigated with laser confocal microscopy, flow cytometry, and MTS assays. A nude mouse tumor model was established from NPC 5-8F cells, and the in vivo anti-tumor activity of S3-DT-Dox was examined by using fluorescent probe labeling and hematoxylin-eosin staining. RESULTS: The synthesized S3-DT had high purity and stability. S3-DT specifically recognized 5-8F cells and NPC tissues in vitro. When the ratio of S3-DT to Dox was 1:20, S3-DT had the best Dox loading efficiency. The drug release rate reached the maximum (0.402 ± 0.029) at 48 h after S3-DT-Dox was prepared and mixed with PBS. S3-DT did not affect Dox toxicity to 5-8F cells, but reduced Dox toxicity to non-target cells. Meanwhile, S3-DT-Dox was able to specifically target the transplanted tumors and inhibit their growth in nude mice, with minor damage to normal tissues. CONCLUSION: Our study highlights the ability and safety of S3-DT-Dox to target NPC cells and inhibit the development NPC.

Efficacy and safety of upadacitinib in patients with ankylosing spondylitis refractory to biologic therapy: 1-year results from the open-label extension of a phase III study.

BACKGROUND: Upadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study. METHODS: Patients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported. RESULTS: Of 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population. CONCLUSIONS: Upadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure. TRIAL REGISTRATION: NCT02049138.

Probing the effects of silicon amendment on combined stressors on rice: Lead pollution and blast fungus (Magnaporthe oryzae) infection.

As agroecology deteriorates, agricultural production is threatened by the combined stressors of exposure to environmental pollutants and pathogenic microbes. Proper agronomic practices for crop growth management and fertilization require understanding plant tolerance strategies. Both rice blast and heavy metals substantially impair rice crops, while silicon (Si) is an effective amendment to alleviate the combined stressors. Herein, this study was conducted to investigate the rice physiology and pathology perspective on the mechanism of Si alleviation against both lead (Pb) toxicity and Magnaporthe oryzae infection, utilizing pot experiments with inoculation of the virulent Magnaporthe oryzae strain. Exogenous Si reduced the phyto-availability and plant absorption of Pb, resulting in a 73.5% reduction in exchangeable Pb concentration in soil and a 40.23% reduction in rice plants. Furthermore, Si addition boosted the plant antioxidant system by increasing the activities of related enzymes, as the activities of catalase, superoxide dismutase, and polyphenol oxidase were significantly improved while the activity of peroxidase in rice panicles decreased. As a result, an improvement in dry matter quantity by 19.19% was observed compared to treatments without Si application, and the panicle blast severity (PBS) was reduced by 0.4-37.52%. Notwithstanding the interaction between the combined stressors, this study revealed that the speciation of Pb formation in the rhizosphere was the primary contributor to the alleviation of abiotic stresses, whereas the regulation of oxidative stress by enzymatic antioxidants played a dominant role in alleviating Magnaporthe oryzae colonization and impairments. The regulation process may reveal the mechanism of siliceous fertilizer functioning in the paddy system. Thereby the role of exogenous Si in anti-fungal, heavy metal toxicology, and plant physiology needs further study to fully elucidate the role of Si amendment, which is proposed to be considered from the perspective of soil chemistry and plant physiology.

Glomus tumour: an institutional experience of 31 cases.

BACKGROUND: Glomus tumour is an uncommon soft tissue tumour which commonly occurs in the distal extremities, particularly the subungual region of the finger. Due to its rarity, there is a paucity of literature concerning glomus tumour. Therefore, this paper aims to report a case series based on our institution's experience. METHODS: A retrospective cross sectional study was performed in a single tertiary institution in Singapore. All patients diagnosed with glomus tumour confirmed on histology from January 2019 to October 2022 were included in the study. Patient demographics and clinical information (presenting signs and symptoms, tumour parameters and presence of recurrence) were retrieved from existing medical records. RESULTS: A total of 31 cases of glomus tumour were diagnosed from January 2019 to October 2022, and the relevant demographics and clinical presentation were reported. Majority of glomus tumours occurred in the finger (61.3%). Pain was present in almost all the cases (96.8%), while a lump was visible in less than half (48.4%). An average of 44.0 months elapsed before patients were properly diagnosed and treated. There were no cases of recurrence despite involved margins in three cases. CONCLUSION: Glomus tumour can be easily missed if clinicians do not have an index of suspicion for it, resulting in delayed treatment. Once diagnosed, glomus tumour can be treated with complete excision with good outcomes.