[Consistency evaluation of multidimensional quality attributes of Atractylodis Macrocephalae Rhizoma by fusion of multi-source information].

The quality control of Chinese medicinal decoction pieces is one of the key tasks in the traditional Chinese medicine industry. In this study, multi-source information fusion was employed to fuse the data from near-infrared spectroscopy, electronic tongues, and other tests and establish an overall quality consistency evaluation method for Atractylodis Macrocephalae Rhizoma, which provided methodological support for the overall quality evaluation of Atractylodis Macrocephalae Rhizoma. The near-infrared spectroscopy information was measured in both static and dynamic states for 23 batches of Atractylodis Macrocephalae Rhizoma samples from different sources, and the electronic tongue sensory information, moisture content, and leachate content were measured. The overall quality of Atractylodis Macrocephalae Rhizoma was evaluated by multi-source information fusion. The results showed that the near-infrared spectroscopy information of 16122103, 801000509, 801000352, 701003656, HX21L01, and 160956 was different from that of other batches of Atractylodis Macrocephalae Rhizoma powder in the static state, and 701003298, 16122103, 701003656, 701003107, 801000229, and 18090404 were the different batches in the dynamic state. The moisture content showed no significant difference between batches. The leachate content in the batch 801000509 was different from that in other batches. The electronic tongue sensory information of 150721004, 151237, 160703004, HX21M01, HX21K04, HX21K01, and 601003516 was different from that of other batches. Furthermore, data layer fusion was employed to analyze the overall quality of Atractylodis Macrocephalae Rhizoma. Four batches, 150721004, HX21M01, HX21K04, and HX21K01, showed the parameters exceeding the 95% control limits and differed from the other samples in terms of the overall quality. This study integrated the information of moisture, near-infrared spectroscopy, and other sources to evaluate the quality consistency among 23 batches of Atractylodis Macrocephalae Rhizoma samples, which provides a reference for the quality consistency evaluation of Chinese medicinal decoction pieces.

Inflammatory risk contributes to post-COVID endothelial dysfunction through anti-ACKR1 autoantibody.

Subclinical vascular impairment can be exacerbated in individuals who experience sustained inflammation after COVID-19 infection. Our study explores the prevalence and impact of autoantibodies on vascular dysfunction in healthy COVID-19 survivors, an area that remains inadequately investigated. Focusing on autoantibodies against the atypical chemokine receptor 1 (ACKR1), COVID-19 survivors demonstrated significantly elevated anti-ACKR1 autoantibodies, correlating with systemic cytokines, circulating damaged endothelial cells, and endothelial dysfunction. An independent cohort linked these autoantibodies to increased vascular disease outcomes during a median 6.7-yr follow-up. We analyzed a single-cell transcriptome atlas of endothelial cells from diverse mouse tissues, identifying enriched Ackr1 expressions in venous regions of the brain and soleus muscle vasculatures, which holds intriguing implications for tissue-specific venous thromboembolism manifestations reported in COVID-19. Functionally, purified immunoglobulin G (IgG) extracted from patient plasma did not trigger cell apoptosis or increase barrier permeability in human vein endothelial cells. Instead, plasma IgG enhanced antibody-dependent cellular cytotoxicity mediated by patient PBMCs, a phenomenon alleviated by blocking peptide or liposome ACKR1 recombinant protein. The blocking peptide uncovered that purified IgG from COVID-19 survivors possessed potential epitopes in the N-terminal extracellular domain of ACKR1, which effectively averted antibody-dependent cellular cytotoxicity. Our findings offer insights into therapeutic development to mitigate autoantibody reactivity in blood vessels in chronic inflammation.

Rapid expansion and international spread of M1UK in the post-pandemic UK upsurge of Streptococcus pyogenes.

The UK observed a marked increase in scarlet fever and invasive group A streptococcal infection in 2022 with severe outcomes in children and similar trends worldwide. Here we report lineage M1UK to be the dominant source of invasive infections in this upsurge. Compared with ancestral M1global strains, invasive M1UK strains exhibit reduced genomic diversity and fewer mutations in two-component regulator genes covRS. The emergence of M1UK is dated to 2008. Following a bottleneck coinciding with the COVID-19 pandemic, three emergent M1UK clades underwent rapid nationwide expansion, despite lack of detection in previous years. All M1UK isolates thus-far sequenced globally have a phylogenetic origin in the UK, with dispersal of the new clades in Europe. While waning immunity may promote streptococcal epidemics, the genetic features of M1UK point to a fitness advantage in pathogenicity, and a striking ability to persist through population bottlenecks.

Identification of genomic regions controlling spikelet degeneration under FRIZZLE PANICLE (FZP) defect genetic background in rice.

The FZP gene plays a critical role in the formation of lateral branches and spikelets in rice panicle architecture. This study investigates the qSBN7 allele, a hypomorphic variant of FZP, and its influence on panicle architectures in different genetic backgrounds. We evaluated two backcross inbred lines (BILs), BC5_TCS10sbn and BC3_TCS10sbn, each possessing the homozygous qSBN7 allele but demonstrating differing degrees of spikelet degeneration. Our analysis revealed that BC5_TCS10sbn had markedly low FZP expression, which corresponded with an increase in axillary branches and severe spikelet degeneration. Conversely, BC3_TCS10sbn exhibited significantly elevated FZP expression, leading to fewer secondary and tertiary branches, and consequently decreased spikelet degeneration. Compared to BC5_TCS10sbn, BC3_TCS10sbn carries three additional chromosomal substitution segments from its donor parent, IR65598-112-2. All three segments significantly enhance the expression of FZP and reduce the occurrence of tertiary branch and spikelet degeneration. These findings enhance our understanding of the mechanisms regulating FZP and aid rice breeding efforts.

Targeted inhibition of branched-chain amino acid metabolism drives apoptosis of glioblastoma by facilitating ubiquitin degradation of Mfn2 and oxidative stress.

Glioblastoma is one of the most challenging malignancies with high aggressiveness and invasiveness and its development and progression of glioblastoma highly depends on branched-chain amino acid (BCAA) metabolism. The study aimed to investigate effects of inhibition of BCAA metabolism with cytosolic branched-chain amino acid transaminase (BCATc) Inhibitor 2 on glioblastoma, elucidate its underlying mechanisms, and explore therapeutic potential of targeting BCAA metabolism. The expression of BCATc was upregulated in glioblastoma and BCATc Inhibitor 2 precipitated apoptosis both in vivo and in vitro with the activation of Bax/Bcl2/Caspase-3/Caspase-9 axis. In addition, BCATc Inhibitor 2 promoted K63-linkage ubiquitination of mitofusin 2 (Mfn2), which subsequently caused lysosomal degradation of Mfn2, and then oxidative stress, mitochondrial fission and loss of mitochondrial membrane potential. Furthermore, BCATc Inhibitor 2 treatment resulted in metabolic reprogramming, and significant inhibition of expression of ATP5A, UQCRC2, SDHB and COX II, indicative of suppressed oxidative phosphorylation. Moreover, Mfn2 overexpression or scavenging mitochondria-originated reactive oxygen species (ROS) with mito-TEMPO ameliorated BCATc Inhibitor 2-induced oxidative stress, mitochondrial membrane potential disruption and mitochondrial fission, and abrogated the inhibitory effect of BCATc Inhibitor 2 on glioblastoma cells through PI3K/AKT/mTOR signaling. All of these findings indicate suppression of BCAA metabolism promotes glioblastoma cell apoptosis via disruption of Mfn2-mediated mitochondrial dynamics and inhibition of PI3K/AKT/mTOR pathway, and suggest that BCAA metabolism can be targeted for developing therapeutic agents to treat glioblastoma.

Germination Increases the Glucomoringin Content in Moringa Sprouts via Transforming Tyrosine.

Moringa seeds are an excellent dietary source of phytochemicals (i.e., glucosinolates, GSLs; isothiocyanates, ITCs) with health-beneficial effects. Although numerous studies have been conducted on moringa seeds, the effect of germination on the regulation of GSLs remains scarcely explored. The present study investigated the dynamic changes of GSLs in moringa seeds during germination (at 25, 30, and 35 °C for 6 days in the dark) through an untargeted metabolomics approach and compared the antioxidant capacity of ungerminated and germinated moringa seeds. Our results showed that germination significantly increased the total GSL content from 150 (day 0) to 323 µmol/g (35 °C, day 6) on a dry weight (DW) basis, especially glucomoringin (GMG), the unique glucosinolate in moringa seeds, which was significantly upregulated from 61 (day 0) to 149 µmol/g DW (35 °C, day 4). The upregulation of GMG corresponded to the metabolism of tyrosine, which might be the initial precursor for the formation of GMG. In addition, germination enhanced the total ITC content from 85 (day 0) to 239 µmol SE/g DW (35 °C, day 6), indicating that germination may have also increased the activity of myrosinase. Furthermore, germination remarkably increased the total phenolic content (109-507 mg GAE/100 g DW) and antioxidant capacity of moringa seeds. Our findings suggest that moringa sprouts could be promoted as a novel food and/or ingredient rich in GMG.

Loss of mGlu5 receptors in somatostatin-expressing neurons alters negative emotional states.

Subtype 5 metabotropic glutamate receptors (mGlu5) are known to play an important role in regulating cognitive, social and valence systems. However, it remains largely unknown at which circuits and neuronal types mGlu5 act to influence these behavioral domains. Altered tissue- or cell-specific expression or function of mGlu5 has been proposed to contribute to the exacerbation of neuropsychiatric disorders. Here, we examined how these receptors regulate the activity of somatostatin-expressing (SST+) neurons, as well as their influence on behavior and brain rhythmic activity. Loss of mGlu5 in SST+ neurons elicited excitatory synaptic dysfunction in a region and sex-specific manner together with a range of emotional imbalances including diminished social novelty preference, reduced anxiety-like behavior and decreased freezing during retrieval of fear memories. In addition, the absence of mGlu5 in SST+ neurons during fear processing impaired theta frequency oscillatory activity in the medial prefrontal cortex and ventral hippocampus. These findings reveal a critical role of mGlu5 in controlling SST+ neurons excitability necessary for regulating negative emotional states.

Uridine diphosphate glucosyltransferase is vital for fenpropathrin resistance in Bombyx mori (Lepidoptera).

The silkworm (Bombyx mori) is an important model lepidopteran insect and can be used to identify pesticide resistance-related genes of great significance for biological control of pests. Uridine diphosphate glucosyltransferases (UGTs), found in all organisms, are the main secondary enzymes involved in the metabolism of heterologous substances. However, it remains uncertain if silkworm resistance to fenpropathrin involves UGT. This study observes significant variations in BmUGT expression among B. mori strains with variable fenpropathrin resistance post-feeding, indicating BmUGT's role in fenpropathrin detoxification. Knockdown of BmUGT with RNA interference and overexpression of BmUGT significantly decreased and increased BmN cell activity, respectively, indicating that BmUGT plays an important role in the resistance of silkworms to fenpropathrin. In addition, fenpropathrin residues were significantly reduced after incubation for 12 h with different concentrations of a recombinant BmUGT fusion protein. Finally, we verified the conservation of UGT to detoxify fenpropathrin in Spodoptera exigua: Its resistance to fenpropathrin decreased significantly after knocking down SeUGT. In a word, UGT plays an important role in silkworm resistance to fenpropathrin by directly degrading the compound, a function seen across other insects. The results of this study are of great significance for breeding silkworm varieties with high resistance and for biological control of pests.

Expression of Early Growth Response 3 in Skin Cancers.

OBJECTIVE: To assess the expression of early growth response 3 (EGR3) in normal skin and different types of skin tumors: cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), melanoma (MM), and cutaneous adnexal tumors containing sebaceous carcinoma (SC), trichoepithelioma (TE) and clear cell hidradenoma (CCH). BACKGROUND: EGR3, expressed in multiple organs, including skin, plays an important role in cell differentiation and tumor growth. Previous studies have shown that EGR3 suppresses tumor growth and is downregulated in various malignancies. However, its distribution in normal skin and its expression especially in skin tumors have not been studied. MATERIALS AND METHODS: Samples of normal cases (n = 4), cSCC (n = 12), BCC (n = 12), MM (n = 12), SC (n = 4), TE (n = 4), and CCH (n = 4) were collected from patients treated in our department between 2018 and 2023. Immunohistochemistry was used to investigate the expression of EGR3. The results were analyzed with the description of the staining pattern and the histochemical score. RESULTS: Immunohistochemical staining showed that EGR3 was uniquely expressed in normal skin in the granular layer and upper part of the stratum spinosum, as well as in sebaceous glands and hair follicles, but not in sweat glands. In skin cancers, BCC, SC, and TE showed positive EGR3 staining, whereas cSCC, MM, and CCH were negative. CONCLUSIONS: EGR3 has a specific expression pattern in normal skin and in skin tumors, which is important for the differential diagnosis of skin tumors, in particular for cSCC and sebaceous gland carcinoma.

A Robotics Experimental Design Method Based on PDCA: A Case Study of Wall-Following Robots.

There is a lack of research that proposes a complete and interoperable robotics experimental design method to improve students' learning outcomes. Therefore, this study proposes a student-oriented method based on the plan-do-check-act (PDCA) concept to design robotics experiments. The proposed method is based on our teaching experience and multiple practical experiences of allowing students to do hands-on experiments. It consists of eight steps, mainly including experimental goals, experimental activities, robot assembly, robot control, in-class evaluation criteria, and after-class report requirements. The after-class report requirements designed in the proposed method can help students improve their report-writing abilities. A wall-following robotics experiment designed using the PDCA method is proposed, and some students' learning outcomes and after-class reports in this experiment are presented to illustrate the effectiveness of the proposed method. This experiment also helps students to understand the fundamental application of multi-sensor fusion technology in designing an autonomous mobile robot. We can see that the proposed reference examples allow students to quickly assemble two-wheeled mobile robots with four different sensors and to design programs to control these assembled robots. In addition, the proposed in-class evaluation criteria stimulate students' creativity in assembling different wall-following robots or designing different programs to achieve this experiment. We present the learning outcomes of three stages of the wall-following robotics experiment. Three groups of 42, 37, and 44 students participated in the experiment in these three stages, respectively. The ratios of the time required for the robots designed by students to complete the wall-following experiment, less than that of the teaching example, are 3/42 = 7.14%, 26/37 = 70.27%, and 44/44 = 100%, respectively. From the comparison of learning outcomes in the three stages, it can be seen that the proposed PDCA-based design method can indeed improve students' learning outcomes and stimulate their active learning and creativity.

Kimura's disease treated with dupilumab: A case report and literature review.

BACKGROUND: Kimura's disease (KD) is a rare chronic inflammatory disorder characterised by painless, deep subcutaneous nodules that most commonly affect the head and neck region of Asian men. Due to high relapse rates and side effects of current therapies, the treatment of KD is challenging. OBJECTIVES: To present a case of KD that was successfully treated with dupilumab and to review the literature with a focus on the evaluation of the efficacy and safety of dupilumab in KD. METHODS: A review of the available literature on the treatment of KD with dupilumab was performed and a new case was analyzed. To gain further insight into this promising therapy, literature review of 8 articles published between January 2016 and January 2024 were included in this study using the PubMed database. RESULTS: Our patient with KD was successfully treated with dupilumab 300 mg every 2 weeks, at an initial dose of 600 mg. The treatment was well tolerated. In the past, only nine patients with KD treated with dupilumab have been reported and reviewed, half of whom had failed prior treatment. All patients achieved significant efficacy after treatment with dupilumab, with no relapses during an average follow-up of 10.4 months (ranged from 4 to 16 months). CONCLUSION: Dupilumab may be an emerging alternative treatment option for KD patients. Larger randomized controlled studies are needed to confirm these findings.

Bombyx mori voltage-dependent anion-selective channel induces programmed cell death to defend against Bombyx mori nucleopolyhedrovirus infection.

BACKGROUND: Voltage-dependent anion-selective channels (VDACs) serve as pore proteins within the mitochondrial membrane, aiding in the regulation of cell life and cell death. Although the occurrence of cell death is crucial for defense against virus infection, the function played by VDAC in Bombyx mori, in response to the influence of Bombyx mori nucleopolyhedrovirus (BmNPV), remains unclear. RESULTS: BmVDAC was found to be relatively highly expressed both during embryonic development, and in the Malpighian tubule and midgut. Additionally, the expression levels of BmVDAC were found to be different among silkworm strains with varying levels of resistance to BmNPV, strongly suggesting a connection between BmVDAC and virus infection. To gain further insight into the function of BmVDAC in BmNPV, we employed RNA interference (RNAi) to silence and overexpress it by pIZT/V5-His-mCherry. The results revealed that BmVDAC is instrumental in developing the resistance of host cells to BmNPV infection in BmN cell-line cells, which was further validated as likely to be associated with initiating programmed cell death (PCD). Furthermore, we evaluated the function of BmVDAC in another insect, Spodoptera exigua. Knockdown of the BmVDAC homolog in S. exigua, SeVDAC, made the larvae more sensitive to BmNPV. CONCLUSION: We have substantiated the pivotal role of BmVDAC in conferring resistance against BmNPV infection, primarily associated with the initiation of PCD. The findings of this study shine new light on the molecular mechanisms governing the silkworm's response to BmNPV infection, thereby supporting innovative approaches for pest biocontrol. © 2024 Society of Chemical Industry.

Breast Milk Excretion of Dinalbuphine Sebacate Injection Administered After Cesarean Section.

Ensuring the safety of analgesics during lactation is crucial for women of childbearing potential. Available data regarding the transfer of nalbuphine for postoperative acute pain via breast milk are limited to the postmarketing experience. This lactation study aimed to assess nalbuphine and dinalbuphine sebacate concentrations in breast milk from lactating women with postoperative pain treated with dinalbuphine sebacate extended-release injection (150 mg dinalbuphine sebacate/2 mL Naldebain). Breast milk was collected throughout the 5-day posthospitalization interval from 20 mothers injected with one dose of extended-release dinalbuphine sebacate intramuscularly. Maternal safety was assessed during the study period. Nalbuphine was detectable in 71% of milk samples collected from all mothers, whereas dinalbuphine sebacate was undetectable or below the quantitation limit (0.1 ng/mL). The mean nalbuphine concentration in milk was approximately 10.55 ng/mL, with the peak concentration reaching up to 12.7 ng/mL. The mean relative infant dose was 0.39% (coefficient of variation, 65%). The mean pain intensity at rest was reduced to mild pain from Day 2 morning to discharge. Overall, the maternal safety profile was tolerable. The breast milk of women who receive one dose of dinalbuphine sebacate injection postpartum contains low nalbuphine concentration. In addition, dinalbuphine sebacate injection potentially reduces maternal pain intensity during the first postpartum week and offers low toxicity risk among breastfed infants.

Self-Healing Hydrogel Containing Decellularized Liver Matrix and Endothelial Cell-Covered Hepatocyte Spheroids for Rescue of Injured Hepatocytes.

Liver fibrosis occurs in many chronic liver diseases, while severe fibrosis can lead to liver failure. A chitosan-phenol based self-healing hydrogel (CP) integrated with decellularized liver matrix (DLM) is proposed in this study as a 3D gel matrix to carry hepatocytes for possible therapy of liver fibrosis. To mimic the physiological liver microenvironment, DLM is extracted from pigs and mixed with CP hydrogel to generate DLM-CP self-healing hydrogel. Hepatocyte spheroids coated with endothelial cells (ECs) are fabricated using a customized method and embedded in the hydrogel. Hepatocytes injured by exposure to CCl4-containing medium are used as the in vitro toxin-mediated liver fibrosis model, where the EC-covered hepatocyte spheroids embedded in the hydrogel are co-cultured with the injured hepatocytes. The urea synthesis of the injured hepatocytes reaches 91% of the normal level after 7 days of co-culture, indicating that the hepatic function of injured hepatocytes is rescued by the hybrid spheroid-laden DLM-CP hydrogel. Moreover, the relative lactate dehydrogenase activity of the injured hepatocytes is decreased 49% by the hybrid spheroid-laden DLM-CP hydrogel after 7 days of co-culture, suggesting reduced damage in the injured hepatocytes. The combination of hepatocyte/EC hybrid spheroids and DLM-CP hydrogel presents a promising therapeutic strategy for hepatic fibrosis.

Studying the role of Bombyx mori molybdenum cofactor sulfurase in Bombyx mori nucleopolyhedrovirus infection.

Molybdenum cofactor sulfurase (MoCoS) is a key gene involved in the uric acid metabolic pathway that activates xanthine dehydrogenase to synthesise uric acid. Uric acid is harmful to mammals but plays crucial roles in insects, one of which is the immune responses. However, the function of Bombyx mori MoCoS in response to BmNPV remains unclear. In this study, BmMoCoS was found to be relatively highly expressed in embryonic development, gonads and the Malpighian tubules. In addition, the expression levels of BmMoCoS were significantly upregulated in three silkworm strains with different levels of resistance after virus infection, suggesting a close link between them. Furthermore, RNAi and overexpression studies showed that BmMoCoS was involved in resistance to BmNPV infection, and its antivirus effects were found to be related to the regulation of uric acid metabolism, which was uncovered by inosine- and febuxostat-coupled RNAi and overexpression. Finally, the BmMoCoS-mediated uric acid pathway was preliminarily confirmed to be a potential target to protect silkworms from BmNPV infection. Overall, this study provides new evidence for elucidating the molecular mechanism of silkworms in response to BmNPV infection and new strategies for the prevention of viral infections in sericulture.

Natural Products in Liver Fibrosis Management: A Five-year Review.

Liver fibrosis, characterized by the overproduction of extracellular matrix proteins within liver tissue, poses a rising global health concern. However, no approved antifibrotic drugs are currently available, highlighting the critical need for understanding the molecular mechanisms of liver fibrosis. This knowledge could not only aid in developing therapies but also enable early intervention, enhance disease prediction, and improve our understanding of the interaction between various underlying conditions and the liver. Notably, natural products used in traditional medicine systems worldwide and demonstrating diverse biochemical and pharmacological activities are increasingly recognized for their potential in treating liver fibrosis. This review aims to comprehensively understand liver fibrosis, emphasizing the molecular mechanisms and advancements in exploring natural products' antifibrotic potential over the past five years. It also acknowledges the challenges in their development and seeks to underscore their potency in enhancing patient prognosis and reducing the global burden of liver disease.

Atypical plaque psoriasis: a clinicopathological study of 20 cases.

BACKGROUND: Plaque psoriasis is relatively straightforward to identify. When diagnostic concerns arise in atypical cases, a biopsy is needed. It is widely accepted that the Munro microabscess and the spongiform pustule of Kogoj are diagnostic pathological features. However, the diagnostic dilemma is likely to arise in cases without these specific pathological changes and typical clinical features. This study aimed to investigate clinical and pathological clues in distinguishing atypical plaque psoriasis from its mimics. METHODS: We evaluated the clinicopathological features of 20 cases of atypical plaque psoriasis and 40 cases of psoriasis mimics as controls including pityriasis rosea (n = 10), pityriasis lichenoides chronica (n = 8), and subacute dermatitis (n = 22). RESULTS: A retrospective analysis of the clinicopathological characteristics of patients with atypical plaque psoriasis and controls was performed. Pathologically, there were significant differences between the two groups in the types of parakeratosis (P = 0.046), epidermal capture of extravasated erythrocytes (P = 0.011), focal basal liquefied degeneration (P = 0.017), types of inflammatory cells (P = 0.000), and depth of inflammation (P = 0.000). Clinically, we found the presence of scales and crusts was significantly different between the two groups. CONCLUSION: This study offers insight into the clinicopathological features of atypical plaque psoriasis. These differential diagnostic features, compared with its mimics, are proposed to assist the clinician in the diagnosis and treatment of atypical plaque psoriasis.

Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide.

BACKGROUND: Precision treatment of glioblastoma is increasingly focused on molecular subtyping, with the mesenchymal subtype particularly resistant to temozolomide. Here, we aim to develop a targeted therapy for temozolomide resensitization in the mesenchymal subtype. METHODS: We integrated kinomic profiles and kinase inhibitor screens from patient-derived proneural and mesenchymal glioma-propagating cells public clinical datasets to identify key protein kinases implicated in temozolomide resistance. RNAseq, apoptosis assays and comet assays were used to examine the role of p38MAPK signaling and adaptive chemoresistance in mesenchymal cells. The efficacy of dual p38MAPK and MEK/ERK inhibition using ralimetinib (selective orally active p38MAPK inhibitor; phase I/II for glioblastoma) and binimetinib (approved MEK1/2 inhibitor for melanoma; phase II for high-grade glioma) in primary and recurrent mesenchymal tumors was evaluated using an intracranial patient-derived tumor xenograft model, focusing on survival analysis. RESULTS: Our transcriptomic-kinomic integrative analysis revealed p38MAPK as the prime target whose gene signature enables patient stratification based on their molecular subtypes and provides prognostic value. Repurposed p38MAPK inhibitors synergize favourably with temozolomide to promote intracellular retention of temozolomide and exacerbate DNA damage. Mesenchymal cells exhibit adaptive chemoresistance to p38MAPK inhibition through a pH-/calcium-mediated MEK/ERK pathway. Dual p38MAPK and MEK inhibition effectively maintains temozolomide sensitivity in primary and recurrent intracranial mesenchymal glioblastoma xenografts. CONCLUSION: Temozolomide resistance in mesenchymal glioblastoma is associated with p38MAPK activation. Adaptive chemoresistance in p38MAPK-resistant cells is mediated by MEK/ERK signaling. Adjuvant therapy with dual p38MAPK and MEK inhibition prolongs temozolomide sensitivity, which can be developed into a precision therapy for the mesenchymal subtype.

Modified Chinese disabilities of arm, shoulder and hand tool: Validity and reliability for upper extremity injuries.

DESIGN: Clinimetric evaluation study. INTRODUCTION: The Chinese Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire has necessitated the development of a revised version to the specific needs of individuals with upper extremity injuries with the progress of times and lifestyle changes. PURPOSE OF THE STUDY: This research aimed to evaluate the reliability and validity of Modified Chinese Disability of Arm, Shoulder and Hand (MC-DASH) questionnaire in individuals with upper extremity injuries. METHODS: One hundred and one individuals with upper extremity injuries (UEI) were recruited. The function of upper extremity was measured using the electronic version of MC-DASH, and compared against the Chinese Disability of Arm, Shoulder and Hand. The MC-DASH was reassessed within three days in all individuals. We investigated the internal consistency, test-retest reliability, content validity, criterion validity, and construct validity of MC-DASH. RESULTS: The internal consistency was deemed sufficient, as indicated by a Cronbach's alpha of 0.986 and an intraclass correlation coefficient of 0.957. Moreover, the mean total scores of MC-DASH on the first-test and retest were 37.86 and 38.19, respectively (ICC: 0.957, 95 %CI: 0.937-0.971, p < 0.001). Furthermore, the MC-DASH version exhibited satisfactory content validity evidenced by its strong correlation (R= 0.903, p < 0.001) with the Chinese DASH. Three major influencing factors were identified from 37 items. The cumulative variance contribution rate of the MC-DASH questionnaire was 75.76 %, confirming its construct validity. CONCLUSION: The Modified Chinese Disability of Arm, Shoulder and Hand questionnaire has been shown to be a valid, reliable, and practical tool for use in patients with upper extremity injuries.