Clinicopathologic and prognostic significance of tumor-associated macrophages in cervical cancer: a systematic review and meta-analysis.

OBJECTIVES: The role of tumor-associated macrophages (TAMs) in cervical cancer (CC) remains controversial. Here, we report a meta-analysis of the association between TAMs infiltration and clinical outcomes. METHODS: PubMed, Embase, Web of Science, and CNKI were searched systematically from inception until December 20, 2023. Studies involving TAMs and prognosis, clinical, or pathological features were included. Quality assessments of the selected studies were assessed. The fixed-effect or random-effects model, standard mean difference (SMD), odds ratios (OR), or hazard ratios (HR) with 95% confidence intervals (CIs) were used as the effect size estimate. RESULTS: 26 eligible studies with 2,295 patients were identified. Our meta-analysis revealed that TAMs were overexpressed in CC (OR = 12.93, 95% CI = 7.73-21.61 and SMD = 1.58, 95% CI = 0.95-2.21) and that elevated TAM levels were strongly associated with lymph node metastasis (LNM) (SMD = 0.51, 95% CI = 0.90-2.01) and FIGO stages (SMD = 0.46, 95% CI = 0.08-0.85). Subgroup analysis indicated a significant positive correlation between LNM and TAMs density in tumor stroma, but not in cancer nests (SMD = 0.58, 95% CI = 0.31-0.58). Furthermore, in early stage, a stronger correlation exists between LNM and TAM density (SMD = 1.21, 95% CI = 0.75-1.66). In addition, it revealed that patients with high TAMs expression had poorer overall survival (OS) (HR = 2.55 95% CI = 1.59-4.07) and recurrence-free survival (RFS) (HR = 2.17, 95% CI = 1.40-3.35). CONCLUSIONS: Our analyses suggest that a high density of TAMs predicts adverse outcomes in CC.

DDB2 promotes melanoma cell growth by transcriptionally regulating the expression of KMT2A and predicts a poor prognosis.

Identification of potential key targets of melanoma, a fatal skin malignancy, is critical to the development of new cancer therapies. Lysine methyltransferase 2A (KMT2A) promotes melanoma growth by activating the human telomerase reverse transcriptase (hTERT) signaling pathway; however, the exact mechanism remains elusive. This study aimed to reveal new molecular targets that regulate KMT2A expression and melanoma growth. Using biotin-streptavidin-agarose pull-down and proteomics, we identified Damage-specific DNA-binding protein 2 (DDB2) as a KMT2A promoter-binding protein in melanoma cells and validated its role as a regulator of KMT2A/hTERT signaling. DDB2 knockdown inhibited the expression of KMT2A and hTERT and inhibited the growth of melanoma cells in vitro. Conversely, overexpression of DDB2 activated the expression of KMT2A and promoted the growth of melanoma cells. Additionally, we demonstrated that DDB2 expression was higher in tumor tissues of patients with melanoma than in corresponding normal tissues and was positively correlated with KMT2A expression. Kaplan-Meier analysis showed a poor prognosis in patients with high levels of DDB2 and KMT2A. Overall, our data suggest that DDB2 promotes melanoma cell growth through the transcriptional regulation of KMT2A expression and predicts poor prognosis. Therefore, targeting DDB2 may regulate the effects of KMT2A on melanoma growth and progression, providing a new potential therapeutic strategy for melanoma.

Oncological outcomes of fertility-sparing surgery versus radical surgery in stage - epithelial ovarian cancer: a systematic review and meta-analysis.

BACKGROUND: The oncological outcomes of fertility-sparing surgery (FSS) compared to radical surgery (RS) in patients with stage I epithelial ovarian cancer (EOC) remain a subject of debate. We evaluated the risk ratios (RRs) for outcomes in patients with stage I EOC who underwent FSS versus RS. METHODS: We conducted a systematic search of PubMed, Web of Science, and Embase for articles published up to November 29, 2023. Studies that did not involve surgical procedures or included pregnant patients were excluded. We calculated the RRs for disease-free survival, overall survival, and recurrence rate. The quality of the included studies was assessed using the Cochrane Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool. The meta-analysis was registered on PROSPERO (CRD42024546460). RESULTS: From the 5,529 potentially relevant articles, we identified 83 articles for initial screening and included 12 articles in the final meta-analysis, encompassing 2,906 patients with epithelial ovarian cancer. There were no significant differences between the two groups in disease-free survival (RR [95% confidence interval {CI}], 0.90 [0.51, 1.58]; P = 0.71), overall survival (RR [95% CI], 0.74 [0.53, 1.03]; P = 0.07), and recurrence rate (RR [95% CI], 1.10 [0.69, 1.76]; P = 0.68). In sensitivity analyses, the significant difference was observed only for overall survival (before exclusion: RR [95% CI], 0.74 [0.53-1.03], P = 0.07; after exclusion: RR [95% CI], 0.70 [0.50-0.99]; P = 0.04). CONCLUSIONS: This is the first and only individual patient data meta-analysis comparing disease-free survival, overall survival, and recurrence rate of patients with early-stage epithelial ovarian cancer undergoing FSS and RS. FSS was associated with similar disease-free survival and risk of recurrence as RS. We hypothesized that the decreased overall survival in the FSS group could not be attributed to distant metastases from epithelial ovarian cancer.

Synergy of lytic phage pB23 and meropenem combination against carbapenem-resistant Acinetobacter baumannii.

Phage-antibiotic combination treatment is a novel noteworthy drug delivery method in anti-infection. In the current study, we have isolated a new phage, pB23, against carbapenem-resistant Acinetobacter baumannii 2023. Synergistic antibacterial effect between phage pB23 and meropenem combination could be more stable, using moderate doses of phage (multiplicity of infection ranging from 0.1 to 1,000) based on results of in vitro antibacterial activity. Phage pB23 and meropenem combination could effectively clear mature biofilms and prevent biofilm formation of carbapenem-resistant Acinetobacter baumannii in vitro. Phage pB23 and meropenem combination also has good synergistic antibacterial effects against carbapenem-resistant Acinetobacter baumannii in different growth phases under static culture conditions. The pig skin explant model shows that phage pB23 and meropenem combination has a synergistic effect to remove bacteria from wounds ex vivo. Phage pB23 and meropenem combination also exhibited a synergistic antibacterial effect in vivo using a zebrafish infection mode. The potential promotion of phage proliferation by meropenem and the sensitivity recovery of phage-resistant bacteria to meropenem might elucidate the mechanism of the synergistic antimicrobial activity. In summary, our study illustrates that phage pB23 and meropenem combination could produce synergistic antibacterial effects against carbapenem-resistant Acinetobacter baumannii under static growth conditions. This study also demonstrates that phage-antibiotic combination will become an effective strategy to enhance antibacterial activity of individual drug and provide a new idea of the drug development for the treatment of infections due to carbapenem-resistant Acinetobacter baumannii and other multidrug-resistant bacteria.

Inhibition of endoplasmic reticulum stress attenuates morphine protracted abstinence-induced anxiety-like behaviors in the male mice.

The anxiety caused by morphine protracted abstinence is considered to be an important factor contributes to drug-seeking and relapse. Endoplasmic reticulum (ER) stress plays important roles in many kinds of mental disorders including drug addiction and anxiety, but it is unclear whether ER stress is involved in anxiety-like behaviors induced by morphine withdrawal. In this study, by using behavioral test, western blot, immunofluorescence, electron transmission microscope, we found that: (1) Inhibition of endoplasmic reticulum stress by 4-Phenylbutyric acid (4-PBA) could attenuate anxiety-like behaviors induced by morphine withdrawal. (2) The endoplasmic reticulum stress-related proteins in the lateral habenula (LHb) but not in the nucleus accumbens (NAc), ventral pallidum (VP), basolateral amygdala (BLA) and CA1 of hippocampus was upregulated by morphine withdrawal, upregulation of endoplasmic reticulum stress-related proteins in the lateral habenula induced by morphine withdrawal was inhibited by 4-PBA. (3) Endoplasmic reticulum stress-related protein CHOP and eIF2α were expressed in neurons but not in microglia in the LHb. (4) Morphine withdrawal induced neuronal morphological change in the LHb, which was attenuated by 4-PBA.

Identification of COQ2 as a regulator of proliferation and lipid peroxidation through genome-scale CRISPR-Cas9 screening in myeloma cells.

Multiple myeloma (MM) is the second most common malignant haematological disease with a poor prognosis. The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome-wide CRISPR-Cas9 loss-of-function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in vivo. Mechanistically, COQ2 promoted the activation of the MEK/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2-deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4-CBA enhanced the sensitivity to RSL3 in primary CD138+ myeloma cells and in a xenograft mouse model. Nevertheless, co-treatment of 4-CBA and RSL3 induced cell death in bortezomib-resistant MM cells. Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK/ERK/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients.

Risk factors of neuropathic pain in multiple sclerosis: a retrospective case-cohort study.

Background: Pain is a common symptom in multiple sclerosis (MS), especially neuropathic pain, which has a significant impact on patients' mental and physical health and quality of life. However, risk factors that related to neuropathic pain, still remain unclear. Objective: The study aimed to explore the risk factors of neuropathic pain among MS patients. Materials and methods: This retrospective study examined the consecutive patients diagnosed with MS in the Department of Neurology of Guangdong Provincial Hospital of Chinese Medicine between August 2011 and October 2022. Neuropathic pain was defined as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system". Demographic and clinical features were obtained from the electronic system of the hospital. Results: Our cohort revealed that the prevalence of patients with neuropathic pain in MS was 34.1%. The results indicated that the longer the spinal lesions, the greater the neuropathic pain risks (2-4: OR, 13.3(2.1-82), >5: OR, 15.2(2.7-86.8), p for tread: 0.037). Meanwhile, multivariate regression analysis showed that cervical and thoracic lesions (OR 4.276, 95% CI 1.366-13.382, P = 0.013), upper thoracic lesions (T1-T6) (OR 3.047, 95% CI 1.018-9.124, P = 0.046) were positively correlated with neuropathic pain, while basal ganglia lesions (OR 0.188, 95% CI 0.044-0.809, P = 0.025) were negatively correlated with neuropathic pain among MS patients. Conclusion: Extended spinal lesions (≥3 spinal lesions), cervical and thoracic lesions, upper thoracic lesions were independent risk factors of neuropathic pain among MS patients. Furthermore, our study found that the longer the spinal lesions, the greater the neuropathic pain risks.

Inflammatory Factor IL1α Induces Aberrant Astrocyte Proliferation in Spinal Cord Injury Through the Grin2c/Ca2+/CaMK2b Pathway.

Spinal cord injury (SCI) is one of the most devastating traumas, and the aberrant proliferation of astrocytes usually causes neurological deficits. However, the mechanism underlying astrocyte over-proliferation after SCI is unclear. Grin2c (glutamate ionotropic receptor type 2c) plays an essential role in cell proliferation. Our bioinformatic analysis indicated that Grin2c and Ca2+ transport functions were inhibited in astrocytes after SCI. Suppression of Grin2c stimulated astrocyte proliferation by inhibiting the Ca2+/calmodulin-dependent protein kinase 2b (CaMK2b) pathway in vitro. By screening different inflammatory factors, interleukin 1α (IL1α) was further found to inhibit Grin2c/Ca2+/CaMK2b and enhance astrocyte proliferation in an oxidative damage model. Blockade of IL1α using neutralizing antibody resulted in increased Grin2c expression and the inhibition of astrocyte proliferation post-SCI. Overall, this study suggests that IL1α promotes astrocyte proliferation by suppressing the Grin2c/Ca2+/CaMK2b pathway after SCI, revealing a novel pathological mechanism of astrocyte proliferation, and may provide potential targets for SCI repair.

Upregulation of FAM83F by c-Myc promotes cervical cancer growth and aerobic glycolysis via Wnt/ß-catenin signaling activation.

Cervical cancer (CC) seriously affects women's health. Therefore, elucidation of the exact mechanisms and identification of novel therapeutic targets are urgently needed. In this study, we identified FAM83F, which was highly expressed in CC cells and tissues, as a potential target. Our clinical data revealed that FAM83F protein expression was markedly elevated in CC tissues and was positively correlated with poor prognosis. Moreover, we observed that FAM83F knockdown significantly inhibited cell proliferation, induced apoptosis, and suppressed glycolysis in CC cells, while its overexpression displayed opposite effects. Mechanistically, FAM83F regulated CC cell growth and glycolysis by the modulation of Wnt/ß-catenin pathway. The enhancing effects of FAM83F overexpression on CC cell proliferation and glycolysis could be impaired by the Wnt/ß-catenin inhibitor XAV939. Moreover, we found that c-Myc bound to the FAM83F promoter and activated the transcription of FAM83F. Notably, knockdown of FAM83F impaired the enhancement of cell proliferation and glycolysis induced by ectopic c-Myc. Consistent with in vitro findings, results from a xenograft mouse model confirmed the promoting role of FAM83F. In summary, our study demonstrated that FAM83F promoted CC growth and glycolysis through regulating the Wnt/ß-catenin pathway, suggesting that FAM83F may be a potential molecular target for CC treatment. Schematic summary of c-Myc-activated FAM83F transcription to promote cervical cancer growth and glycolysis by targeting the Wnt/ß-catenin signal pathway.

Jagged1 contained in MSC-derived small extracellular vesicles promotes squamous differentiation of cervical cancer by activating NOTCH pathway.

PURPOSE: Cervical cancer is the fourth most common cancer in women and poses a major threat to women's health, urgently requiring new treatment methods. METHODS: This study first successfully extracted and identified small extracellular vesicles secreted by human umbilical cord-derived mesenchymal stem cells. We studied the effects of MSC-sEV on the squamous differentiation levels of cervical cancer CaSki cells in vitro, and explored the effects of MSC-sEV on the NOTCH pathway, the growth, proliferation, migration abilities and squamous differentiation levels of cervical cancer cells. The roles of MSC-sEV were also verified in human keratinocyte HaCaT cells. RESULTS: The results showed that Jagged1 protein on MSC-sEV can bind to NOTCH1 on cervical cancer cells, activate NOTCH signaling, and promote squamous differentiation levels in CaSki cells, thus inhibiting the growth, proliferation and migration abilities of CaSki cells. MSC-sEV can also activate the NOTCH pathway in HaCaT cells, but promote the viability of HaCaT cells. CONCLUSION: MSC-sEV can activate the NOTCH pathway to promote squamous differentiation of CaSki cells and inhibit the growth proliferation and migration abilities of CaSki cells which may be a new mechanism for cervical cancer treatment.

Relationship Between Gestational Diabetes Mellitus and Postpartum Diastasis Recti Abdominis in Women in the First Year Postdelivery.

OBJECTIVE: Postpartum diastasis recti abdominis (DRA) influences women's appearance and health. Gestational diabetes mellitus (GDM) can affect the structure of the rectus abdominis muscles. However, the relationship between GDM and postpartum DRA is unknown. The objective of this study was to investigate the relationship between GDM and postpartum DRA. METHODS: This retrospective cohort study included 241 women in the first year postdelivery. Women with GDM were matched with those without GDM using propensity score matching. They underwent an oral glucose tolerance test during pregnancy and a random blood glucose test before delivery. At follow-up, DRA was diagnosed by palpation, and interrectus distance was measured using ultrasound to evaluate the severity of DRA. The strength of the rectus abdominis was evaluated using the manual muscle testing method. RESULTS: Among the 241 participants, 174 (72.2%) had postpartum DRA, and 46 women with GDM were matched with 46 women without GDM on the basis of propensity scores. Women with GDM had higher odds of experiencing postpartum DRA (adjusted odds ratio = 4.792; 95% CI = 1.672 to 13.736) and larger interrectus distance values at the upper part of the rectus abdominis than those without GDM. There was a weak and positive correlation between the fasting oral glucose tolerance test level and the interrectus distance values (0.267 ≤ r ≤ 0.367). CONCLUSION: GDM was associated with postpartum DRA in women in the first year of delivery. Women with GDM had larger interrectus distance values at the upper part of the rectus abdominis than those without GDM. The fasting oral glucose tolerance test level showed a positive and weak correlation with the severity of postpartum DRA. IMPACT: Women with GDM have higher odds of experiencing postpartum DRA than those without GDM. The upper part of the rectus abdominis deserves increased focus during and after rehabilitation. Controlling the fasting oral glucose tolerance test level may help reduce the severity of postpartum DRA.

A case of herpes simplex virus induced peripheral neuropathy and encephalitis with positive GM3 and CASPR2 antibody.

BACKGROUND: We reported on a case involving an older patient with HSV-1 encephalitis who simultaneously experienced the onset of peripheral nerve symptoms associated with the presence of anti-GM3 immunoglobulin G (IgG). CASE PRESENTATION: A 77-year-old male was admitted to hospital with high fever, weakness of both lower limbs, and an unstable gait. A CSF test revealed a strikingly increased protein level (1,002 mg/L, normative values: 150-450 mg/L) and MRI revealed hyper-signal lesions in the right temporal lobe, right hippocampus, right insula, and right cingulate gyrus. The CSF was positive for HSV PCR (HSV-1,17870). In addition, the serum samples were positive for CASPR2 antibodies (antibody titer: 1/10) and anti-GM3 immunoglobulin G (IgG) (+). The patient was diagnosed with HSV-1-induced peripheral nerve symptoms that were associated with encephalitis and the presence of anti-GM3 IgG and anti-CASPR2 antibodies. The patient had received included intravenous immunoglobulin, intravenous acyclovir, and corticosteroids therapy. At the one-year follow-up examination, he had regained the necessary skills associated with daily life. CONCLUSIONS: Herpes simplex virus infection often induces encephalitis, and reaction to the virus may trigger an autoimmune response. Early diagnosis and treatment can avoid the progression of the disease to include autoimmune encephalitis.

Human umbilical cord mesenchymal stem cells derived extracellular vesicles alleviate salpingitis by promoting M1-to-M2 transformation.

Background: With an increasing number of patients experiencing infertility due to chronic salpingitis after Chlamydia trachomatis (CT) infection, there is an unmet need for tissue repair or regeneration therapies. Treatment with human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EV) provides an attractive cell-free therapeutic approach. Methods: In this study, we investigated the alleviating effect of hucMSC-EV on tubal inflammatory infertility caused by CT using in vivo animal experiments. Furthermore, we examined the effect of hucMSC-EV on inducing macrophage polarization to explore the molecular mechanism. Results: Our results showed that tubal inflammatory infertility caused by Chlamydia infection was significantly alleviated in the hucMSC-EV treatment group compared with the control group. Further mechanistic experiments showed that the application of hucMSC-EV induced macrophage polarization from the M1 to the M2 type via the NF-κB signaling pathway, improved the local inflammatory microenvironment of fallopian tubes and inhibited tube inflammation. Conclusion: We conclude that this approach represents a promising cell-free avenue to ameliorate infertility due to chronic salpingitis.

Sulforaphane alleviated vascular remodeling in hypoxic pulmonary hypertension via inhibiting inflammation and oxidative stress.

Hypoxic pulmonary hypertension (HPH) is a cardiopulmonary disease featured by pulmonary vascular remodeling, which is due to abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunction of endothelial cells (ECs). Sulforaphane (SFN) is a natural isothiocyanate extracted from cruciferous vegetables with promising anti-inflammatory and anti-oxidative activities. This study aimed to explore the effect and mechanism of SFN on HPH. Male mice were exposed to persistent chronic hypoxia for 4 weeks to induce HPH. The results demonstrated that SFN repressed the increased right ventricular systolic pressure (RVSP) and attenuated the right ventricular hypertrophy and pulmonary arteries remodeling in HPH mice. In particular, after SFN treatment, the CD68 positive cells in lung sections were reduced; TNF-α and IL-6 levels in lungs and serum declined; activation of NF-κB in PASMCs was inhibited in response to hypoxia. Besides, SFN enhanced the superoxide dismutase (SOD) activity in serum, SOD2 expression, total glutathione levels, and GSH/GSSG ratio in PASMCs, along with a decrease in malondialdehyde (MDA) contents in serum and ROS production in PASMCs after hypoxia exposure. Notably, SFN, as an Nrf2 activator, reversed the reduction in Nrf2 expression in hypoxic PASMCs. In vitro, SFN treatment inhibited hyperproliferation and promoted apoptosis of PASMCs under hypoxia conditions. SFN also prevented the apoptosis of pulmonary microvascular ECs caused by hypoxia. Therefore, these data suggested that SFN could significantly restrain the inflammation and oxidative stress, thereby inhibiting PASMCs proliferation, promoting PASMCs apoptosis, and reversing hypoxia injury in ECs to improve pulmonary vascular remodeling.

Cell Infiltrative Inner Connected Porous Hydrogel Improves Neural Stem Cell Migration and Differentiation for Functional Repair of Spinal Cord Injury.

The disadvantages of cell-adaptive microenvironments and cellular diffusion out of the lesion have limited hydrogel-based scaffold transplantation treatment for neural connectivity, leading to permanent neurological disability from spinal cord injury. Herein, porous GelMA scaffold was prepared, in which the inner porous structure was optimized. The average pore size was 168 ± 71 µm with a porosity of 77.1%. The modulus of porous hydrogel was 593 ± 4 Pa compared to 1535 ± 85 Pa of bulk GelMA. The inner connected porous structure provided a cell-infiltrative matrix for neural stem cell migration and differentiation in vitro and eventually enhanced neuron differentiation and hindlimb strength and movement of animals in in vivo experiments. Furthermore, inflammation response and apoptosis were also alleviated after implantation. This work demonstrated that the porous hydrogel with appropriately connected micropores exhibit favorable cellular responses compared with traditional non-porous GelMA hydrogel. Taken together, our findings suggest that porous hydrogel is a promising scaffold for future delivery of stem cells and has prospects in material design for the treatment of spinal cord injury.

Global Burden and Improvement Gap of Non-Rheumatic Calcific Aortic Valve Disease: 1990-2019 Findings from Global Burden of Disease Study 2019.

The aim of this study was to explore the most updated changing trends of non-rheumatic calcific aortic valve disease (nrCAVD) and reveal possible improvements. We analyzed the age-standardized rates (ASRs) of prevalence, incidence, disability-adjusted life-years (DALYs), and mortality trends of nrCAVD from 1990 to 2019 using data from the Global Burden of Disease (GBD) study 2019. The relations between ASRs and socio-demographic index (SDI) were analyzed with Pearson's correlation coefficients. Decomposition and frontier analysis were employed to reveal the contribution proportion of influence factors and regions where improvement can be achieved. In 2019, there were 9.40 million (95% uncertainty interval (UI): 8.07 to 10.89 million) individuals with nrCAVD globally. From 1990 to 2019, the prevalence rate of nrCAVD increased by 155.47% (95% IU: 141.66% to 171.7%), with the largest increase observed in the middle SDI region (821.11%, 95% UI: 709.87% to 944.23%). Globally, there were no significant changes in the mortality rate of nrCAVD (0.37%, 95% UI: -8.85% to 7.99%). The global DALYs decreased by 10.97% (95% UI: -17.94% to -3.46%). The population attributable fraction (PAF) of high systolic blood pressure increased in the population aged 15-49 years, while it declined slightly in population aged 50+ years. Population growth was the main contributing factor to the increased DALYs across the globe (74.73%), while aging was the driving force in the high-SDI region (80.27%). The Netherlands, Finland, Luxembourg, Germany, and Norway could reduce DALY rates of nrCAVD using their socio-demographic resources. According to these results, we revealed that the burden of nrCAVD increased markedly from 1990 to 2019 in high-SDI and high-middle-SDI regions. There was a downward trend in the mortality due to nrCAVD since 2013, which is possibly owing to profound advances in transcatheter aortic valve replacement. Some countries may reduce burdens of nrCAVD using their socio-demographic resources.

Prognostic value of JAK3 promoter methylation and mRNA expression in clear cell renal cell carcinoma.

INTRODUCTION: Janus kinase 3 (JAK3) is a well-established oncogene in clear cell renal cell carcinoma (ccRCC). The methylation status of oncogene promoters has emerged as biomarkers for cancer diagnosis and prognosis. OBJECTIVE: This study aims to investigate the biological and clinical significance of JAK3 promoter methylation in ccRCC. METHODS: We analyzed the relationship of JAK3 promoter methylation with its mRNA expression, overall survival, and immune cell infiltration in a cohort obtained from The Cancer Genome Atlas (TCGA), which was further validated by another independent cohort. We further validated correlations of JAK3 promoter methylation with JAK3 expression, overall survival, and immune cell infiltration in an independent ccRCC cohort (Sun Yat-sen University Cancer Center (SYSUCC) cohort) by methods of immunohistochemistry (IHC) and pyrosequencing. RESULTS: We found JAK3 promoter was significantly hypomethylated in tumor tissues compared to normal adjacent tissues in ccRCC, and JAK3 promoter hypomethylation was strongly correlated with high JAK3 mRNA expression in all three ccRCC cohorts we examined. JAK3 promoter hypomethylation predicted advanced clinicopathological characteristics and shorter overall survival (TCGA cohort and SYSUCC cohort). Furthermore, we found that JAK3 promoter methylation was significantly associated with immune cell infiltration and expression of immune checkpoint molecules (TCGA cohort and CPTAC cohort). Finally, our SYSUCC cohort validated that JAK3 promoter methylation was correlated with CD4+ and CD8+ T cell infiltration in ccRCC tumor tissues. CONCLUSION: Our data demonstrated that the crucial role of JAK3 promoter methylation in its expression regulation and tumor microenvironment. JAK3 promoter methylation and expression are associated with clinicopathological characteristics, overall survival, and immune cell infiltration in ccRCC. We propose a rationale for further validation of JAK3 promoter methylation as a molecular biomarker for predicting responses to immune checkpoint inhibitors in ccRCC.

The risk factors of neuropathic pain in neuromyelitis optica spectrum disorder: a retrospective case-cohort study.

BACKGROUND: Neuropathic pain is a common complication in neuromyelitis optica spectrum disorder (NMOSD), which seriously affects the quality of life of NMOSD patients, with no satisfactory treatment. And risk factors of neuropathic pain are still uncertain. OBJECTIVE: To investigate the risk factors of neuropathic pain in a NMOSD cohort. MATERIALS AND METHODS: Our study was a retrospective case-cohort study, the patients diagnosed with NMOSD in the Department of Neurology from the Second Affiliated Hospital of Guangzhou University of Chinese Medicine from January 2011 to October 2021 were screened. Inclusion criteria were: (1) patients diagnosed as NMOSD according to the International Panel for NMO Diagnosis (IPND) criteria, (2) the aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) test was performed. Patients without AQP4-IgG antibody were excluded. Clinical data, including sex, age of the first onset, symptoms of the first episode including neuropathic pain and attack types, localization of lesions of the first episode on Magnetic Resonance Imaging (MRI), Extended disability status Scale (EDSS) of the first onset, treatment of immunosuppression in the first acute phase, disease modifying therapy (DMT), treatment of neuropathic pain and APQ4-IgG status were collected from the hospital system database. Neuropathic pain was defined according to the International Association for the Study of Pain criteria and was described as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system". RESULTS: One hundred nineteen patients were screened and finally 86 patients fulfilling the inclusion and exclusion criteria were enrolled in our study. The prevalence of neuropathic pain in patients with NMOSD was 43.0%. Univariate analysis showed that the factors associated with neuropathic pain were the age at the onset, the attack type of optic neuritis, the attack type of myelitis, length of spinal cord involvement, localization of thoracic lesion, optic lesion, upper thoracic lesions, lower thoracic lesions, extended spinal cord lesions (≥ 3 spinal lesions), extended thoracic lesions (≥ 4 thoracic lesions), intravenous immunoglobulin and mycophenolate mofetil. Multivariate regression analysis showed that extended thoracic lesions (OR 20.21 [1.18-346.05], P = 0.038) and age (OR 1.35 (1-1.81) P = 0.050) were independently associated with neuropathic pain among NMOSD patients and that gender (OR 12.11 (0.97-151.64) P = 0.053) might be associated with neuropathic pain among NMOSD patients. CONCLUSION: Extended thoracic lesions (≥ 4 thoracic lesions), age and gender might be independent risk factors of neuropathic pain among patients with NMOSD. However, with a small sample size and predominantly female, caution must be applied and these results need validating in further cohorts.

Atezolizumab-associated encephalitis in metastatic breast cancer: A case report.

Immune checkpoint inhibitors have been critical in the treatment of advanced malignancies in recent years. Encephalitis caused by atezolizumab is an uncommon immune-related adverse event. The case of a 65-year-old female diagnosed with encephalitis closely associated with atezolizumab medication for metastatic advanced breast cancer is presented in the current study. Following a fourth atezolizumab dose 10 days previously, the patient fell into a deep coma. Initial brain magnetic resonance imaging revealed multiple patchy T2 hyperintensities in the bilateral cerebellar hemisphere, vermis of the cerebellum, bilateral frontal lobe, temporal lobe, parietal lobe and occipital cortex. Meanwhile, there were aberrant signs on diffusion-weighted imaging. The diagnosis of atezolizumab-induced encephalitis seemed probable after ruling out other possible causes of encephalitis. Subsequently, the condition of the patient worsened and there were indications of cardiac and respiratory arrest. Chest compressions were provided immediately, as well as a balloon mask for assisted ventilation, a medication boost, stimulated breathing and other symptomatic therapy. The patient's vital signs temporarily stabilised after this series of rescue measures. The patient refused further therapy and insisted on being discharged, and died a few days after being discharged from the hospital. In this case, the patient's encephalitis symptoms associated with atezolizumab were not as typical as previously documented. The patient's condition swiftly deteriorated to heartbeat apnea, and steroid pulse therapy was not received in a timely manner, resulting in an unfavourable outcome.