The Efficacy and Tolerability of Radiosurgery in Treating Benign Meningiomas: A Dose Comparison Study from a Single-Center Analysis.

This retrospective study aimed to evaluate the impact of radiation dose on the outcomes of stereotactic radiosurgery (SRS) for benign meningiomas and determine an optimal dosing strategy for balancing tumor control and treatment-related toxicity. Clinical data of 147 patients with 164 lesions treated between 2014 and 2022 were reviewed. Primary outcomes included progression-free survival (PFS), local control rate (LCR), and radiation-induced toxicity, with secondary outcomes focusing on LCR and radiation-induced peritumoral edema (PTE) in two dose groups (≥14 Gy and <14 Gy). The results revealed a median follow-up duration of 47 months, with 1-year, 2-year, and 5-year PFS rates of 99.3%, 96.7%, and 93.8%, respectively, and an overall LCR of 95.1%. Radiation-induced toxicity was observed in 24.5% of patients, primarily presenting mild symptoms. Notably, no significant difference in LCR was found between the two dose groups (p = 0.628), while Group 2 (<14 Gy) exhibited significantly lower PTE (p = 0.039). This study concludes that SRS with a radiation dose < 14 Gy demonstrates comparable tumor control with reduced toxicity, advocating consideration of such dosing to achieve a balance between therapeutic efficacy and safety.

Hashimoto Thyroiditis and Mortality in Patients with Differentiated Thyroid Cancer: The National Epidemiologic Survey of Thyroid Cancer in Korea and Meta-Analysis.

BACKGRUOUND: Many studies have shown that Hashimoto's thyroiditis (HT) acts as a protective factor in differentiated thyroid cancer (DTC), but little is known about its effects on mortality. Therefore, this study was performed to reveal the prognosis of HT on mortality in patients with DTC. METHODS: This study included two types of research. RESULTS: retrospective cohort study using the National Epidemiologic Survey of Thyroid cancer (NEST) in Korea and meta-analysis study with the NEST data and eight selected studies. RESULTS: Of the 4,398 patients with DTC in NEST, 341 patients (7.8%) died during the median follow-up period of 15 years (interquartile range, 12.3 to 15.6). Of these, 91 deaths (2.1%) were related to DTC. HT was associated with a smaller tumor size and less aggressive DTC. In Cox regression analysis after adjusting for age and sex, patients with HT showed a significantly lower risk of all-cause death (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52 to 0.96) and DTC-related death (HR, 0.33; 95% CI, 0.14 to 0.77). The analysis with inverse probability of treatment weight data adjusted for age, sex, and year of thyroid cancer registration showed similar association. The meta-analysis showed that patients with HT showed a lower risk of all-cause mortality (risk ratio [RR], 0.24; 95% CI, 0.13 to 0.47) and thyroid cancer-related mortality (RR, 0.23; 95% CI, 0.13 to 0.40) in comparison with patients without HT. CONCLUSION: This study showed that DTC co-presenting with HT is associated with a low risk of advanced DTC and presents a low risk for all-cause and DTC-related death.

Thrap3 promotes nonalcoholic fatty liver disease by suppressing AMPK-mediated autophagy.

Autophagy functions in cellular quality control and metabolic regulation. Dysregulation of autophagy is one of the major pathogenic factors contributing to the progression of nonalcoholic fatty liver disease (NAFLD). Autophagy is involved in the breakdown of intracellular lipids and the maintenance of healthy mitochondria in NAFLD. However, the mechanisms underlying autophagy dysregulation in NAFLD remain unclear. Here, we demonstrate that the hepatic expression level of Thrap3 was significantly increased in NAFLD conditions. Liver-specific Thrap3 knockout improved lipid accumulation and metabolic properties in a high-fat diet (HFD)-induced NAFLD model. Furthermore, Thrap3 deficiency enhanced autophagy and mitochondrial function. Interestingly, Thrap3 knockout increased the cytosolic translocation of AMPK from the nucleus and enhanced its activation through physical interaction. The translocation of AMPK was regulated by direct binding with AMPK and the C-terminal domain of Thrap3. Our results indicate a role for Thrap3 in NAFLD progression and suggest that Thrap3 is a potential target for NAFLD treatment.

Macrophage transcription factor TonEBP promotes systemic lupus erythematosus and kidney injury via damage-induced signaling pathways.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by autoreactive B cells and dysregulation of many other types of immune cells including myeloid cells. Lupus nephritis (LN) is a common target organ manifestations of SLE. Tonicity-responsive enhancer-binding protein (TonEBP, also known as nuclear factor of activated T-cells 5 (NFAT5)), was initially identified as a central regulator of cellular responses to hypertonic stress and is a pleiotropic stress protein involved in a variety of immunometabolic diseases. To explore the role of TonEBP, we examined kidney biopsy samples from patients with LN. Kidney TonEBP expression was found to be elevated in these patients compared to control patients - in both kidney cells and infiltrating immune cells. Kidney TonEBP mRNA was elevated in LN and correlated with mRNAs encoding inflammatory cytokines and the degree of proteinuria. In a pristane-induced SLE model in mice, myeloid TonEBP deficiency blocked the development of SLE and LN. In macrophages, engagement of various toll-like receptors (TLRs) that respond to damage-associated molecular patterns induced TonEBP expression via stimulation of its promoter. Intracellular signaling downstream of the TLRs was dependent on TonEBP. Therefore, TonEBP can act as a transcriptional cofactor for NF-κB, and activated mTOR-IRF3/7 via protein-protein interactions. Additionally, TonEBP-deficient macrophages displayed elevated efferocytosis and animals with myeloid deficiency of TonEBP showed reduced Th1 and Th17 differentiation, consistent with macrophages defective in TLR signaling. Thus, our data show that myeloid TonEBP may be an attractive therapeutic target for SLE and LN.

In-Memory-Computed Low-Frequency Noise Spectroscopy for Selective Gas Detection Using a Reducible Metal Oxide.

Concerns about indoor and outdoor air quality, industrial gas leaks, and medical diagnostics are driving the demand for high-performance gas sensors. Owing to their structural variety and large surface area, reducible metal oxides hold great promise for constructing a gas-sensing system. While many earlier reports have successfully obtained a sufficient response to various types of target gases, the selective detection of target gases remains challenging. In this work, a novel method, low-frequency noise (LFN) spectroscopy is presented, to achieve selective detection using a single FET-type gas sensor. The LFN of the sensor is accurately modeled by considering the charge fluctuation in both the sensing material and the FET channel. Exposure to different target gases produces distinct corner frequencies of the power spectral density that can be used to achieve selective detection. In addition, a 3D vertical-NAND flash array is used with the fast Fourier transform method via in-memory-computing, significantly improving the area and power efficiency rate. The proposed system provides a novel and efficient method capable of selectively detecting a target gas using in-memory-computed LFN spectroscopy and thus paving the way for the further development in gas sensing systems.

Lactate oxidase/catalase-displaying nanoparticles efficiently consume lactate in the tumor microenvironment to effectively suppress tumor growth.

The aggressive proliferation of tumor cells often requires increased glucose uptake and excessive anaerobic glycolysis, leading to the massive production and secretion of lactate to form a unique tumor microenvironment (TME). Therefore, regulating appropriate lactate levels in the TME would be a promising approach to control tumor cell proliferation and immune suppression. To effectively consume lactate in the TME, lactate oxidase (LOX) and catalase (CAT) were displayed onto Aquifex aeolicus lumazine synthase protein nanoparticles (AaLS) to form either AaLS/LOX or AaLS/LOX/CAT. These complexes successfully consumed lactate produced by CT26 murine colon carcinoma cells under both normoxic and hypoxic conditions. Specifically, AaLS/LOX generated a large amount of H2O2 with complete lactate consumption to induce drastic necrotic cell death regardless of culture condition. However, AaLS/LOX/CAT generated residual H2O2, leading to necrotic cell death only under hypoxic condition similar to the TME. While the local administration of AaLS/LOX to the tumor site resulted in mice death, that of AaLS/LOX/CAT significantly suppressed tumor growth without any severe side effects. AaLS/LOX/CAT effectively consumed lactate to produce adequate amounts of H2O2 which sufficiently suppress tumor growth and adequately modulate the TME, transforming environments that are favorable to tumor suppressive neutrophils but adverse to tumor-supportive tumor-associated macrophages. Collectively, these findings showed that the modular functionalization of protein nanoparticles with multiple metabolic enzymes may offer the opportunity to develop new enzyme complex-based therapeutic tools that can modulate the TME by controlling cancer metabolism.

RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts.

Monocyte/macrophage lineage cells are highly plastic and can differentiate into various cells under different environmental stimuli. Bone-resorbing osteoclasts are derived from the monocyte/macrophage lineage in response to receptor activator of NF-κB ligand (RANKL). However, the epigenetic signature contributing to the fate commitment of monocyte/macrophage lineage differentiation into human osteoclasts is largely unknown. In this study, we identified RANKL-responsive human osteoclast-specific superenhancers (SEs) and SE-associated enhancer RNAs (SE-eRNAs) by integrating data obtained from ChIP-seq, ATAC-seq, nuclear RNA-seq and PRO-seq analyses. RANKL induced the formation of 200 SEs, which are large clusters of enhancers, while suppressing 148 SEs in macrophages. RANKL-responsive SEs were strongly correlated with genes in the osteoclastogenic program and were selectively increased in human osteoclasts but marginally presented in osteoblasts, CD4+ T cells, and CD34+ cells. In addition to the major transcription factors identified in osteoclasts, we found that BATF binding motifs were highly enriched in RANKL-responsive SEs. The depletion of BATF1/3 inhibited RANKL-induced osteoclast differentiation. Furthermore, we found increased chromatin accessibility in SE regions, where RNA polymerase II was significantly recruited to induce the extragenic transcription of SE-eRNAs, in human osteoclasts. Knocking down SE-eRNAs in the vicinity of the NFATc1 gene diminished the expression of NFATc1, a major regulator of osteoclasts, and osteoclast differentiation. Inhibiting BET proteins suppressed the formation of some RANKL-responsive SEs and NFATc1-associated SEs, and the expression of SE-eRNA:NFATc1. Moreover, SE-eRNA:NFATc1 was highly expressed in the synovial macrophages of rheumatoid arthritis patients exhibiting high-osteoclastogenic potential. Our genome-wide analysis revealed RANKL-inducible SEs and SE-eRNAs as osteoclast-specific signatures, which may contribute to the development of osteoclast-specific therapeutic interventions.

Red blood cell indices as an effective marker for the existence and severity of endometriosis (STROBE).

To evaluate the association between red blood cell (RBC) indices (mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], MCH concentration [MCHC], red cell distribution width [RDW], hemoglobin [Hb], hematocrit [Hct], and neutrophil-to-lymphocyte ratio [NLR]) and the severity of endometriosis. Data were obtained from the medical records of 200 patients with endometriosis (stage I/II and stage III/IV groups), and 100 patients with benign ovarian tumors (control group), treated between September 2011 and April 2021. The mean Hb and Hct were significantly lower in the stage III/IV group compared to those in the control and stage I/II group (P = .015 and P = .004, respectively). The mean MCV, MCH, and Hb at postoperative day (POD)#1 were significantly lower in the stage III/IV group compared to those in the control and stage I/II group (P = .007, P = .032, and P < .0001, respectively). In addition, NLR at POD#1 was significantly higher in stage III/IV group compared to that in the control and stage I/II group. Multivariate analysis revealed that younger age (≤38 years old), lower preoperative MCV (≤88.5 fL), lower POD#1 Hb (<11.6g/dL), and higher POD#1 NLR (>2.5) were independent risk factors of stage III/IV endometriosis. Lower levels of RBC indices, including preoperative MCV and postoperative Hb, and higher postoperative NLR were significantly associated with the severity of endometriosis, which is potentially derived from a dysregulation in iron metabolism and inflammation.

YouTube as a source of information and education on endometriosis.

Many patients seek information online, including on social media, regarding various health topics. This study aimed to investigate whether YouTube videos on endometriosis could be a useful source for the general population, surgical trainees, and specialists. A YouTube search was conducted on December 26, 2021, using the search terms "endometriosis," "endometrioma," and "endometriotic cyst." Videos were sorted by view count, and the 100 videos with the highest view counts were chosen. After excluding 48 videos for various reasons, 52 were included in the final analysis. The number of views, duration, likes and dislikes, content type, and source of each video were recorded. We referred to a previous study to evaluate video quality. The 52 videos related to endometriosis had a total of 35,220,141 views (median 233,688, range 48,874-10,452,366). Based on authorship, the videos were categorized into videos uploaded by the medical group and the nonmedical group. The medical group mainly uploaded videos directly related to endometriosis, such as explanations or detailed surgical procedures for endometriosis (26/27, 96%), whereas the nonmedical group mainly uploaded videos about personal experiences and others (24/25, 96%; P <.001). Evaluating the score by each type of content, videos containing personal experiences (median score 6, range 3-10) scored significantly lower than videos containing other content such as explanations of the disease (median score 14, range 7-18; P < .001) and surgical procedures (median score 9, range 5-17; P < .001). Analysis according to the source, the number of views and video power index was significantly higher in the videos uploaded by the nonmedical group (P < .05). YouTube is currently not an appropriate source for patients to gain information on endometriosis. Credible videos with accurate information and clear, high-quality operative clips with proper scientific commentary should be uploaded by medical professionals and medical institutions to critically and rapidly appraise the quality of online video-disseminated information on endometriosis. In addition, advanced filtering using categories by YouTube's staff appears to be necessary.

Particulate matter 2.5 promotes inflammation and cellular dysfunction via reactive oxygen species/p38 MAPK pathway in primary rat corneal epithelial cells.

PURPOSE: Numerous studies have linked particulate matter2.5 (PM2.5) to ocular surface diseases, but few studies have been conducted on the biological effect of PM2.5 on the cornea. The objective of this study was to evaluate the harmful effect of PM2.5 on primary rat corneal epithelial cells (RCECs) in vitro and identify the toxic mechanism involved. MATERIALS AND METHODS: Primary cultured RCECs were characterized by pan-cytokeratin (CK) staining. In PM2.5-exposed RCECs, cell viability, microarray gene expression, inflammatory cytokine levels, mitochondrial damage, DNA double-strand break, and signalling pathway were investigated. RESULTS: Exposure to PM2.5 induced cytotoxicity and morphological changes in RCECs. In addition, PM2.5 markedly up-regulated pro-inflammatory mediators but down-regulated the wound healing-related transforming growth factor-ß. Furthermore, PM2.5 promoted mitochondrial reactive oxygen species (ROS) production and mediated cellular damage to mitochondria and DNA, whereas these cellular alterations induced by PM2.5 were markedly suppressed by a potential ROS scavenger. Noteworthy, removal of ROS selectively down-regulated the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and the activation of the nuclear factor-κB (NF-κB) p65 in PM2.5-stimulated cells. Additionally, SB203580, a p38 MAPK inhibitor, markedly suppressed these PM2.5-mediated cellular dysfunctions. CONCLUSIONS: Taken together, our findings show that PM2.5 can promote the ROS/p38 MAPK/NF-κB signalling pathway and lead to mitochondrial damage and DNA double-strand break, which is ultimately caused inflammation and cytotoxicity in RCECs. These findings indicate that the ROS/p38 MAPK/NF-κB signalling pathway is one mechanism involved in PM2.5-induced ocular surface disorders.

Inhibition of L-type voltage-gated calcium channel-mediated Ca2+ influx suppresses the collective migration and invasion of ameloblastoma.

OBJECTIVES: Ameloblastoma (AM) has been known as a benign but locally invasive tumour with high recurrence rates. Invasive behaviour of the AM results in destruction of the adjacent jawbone and the non-detectable remnants during surgery, interrupting the complete elimination of cancer cells. METHODS: To explore novel targets for the tumour cell invasion, a transcriptomic analysis between AM and odontogenic keratocyst were performed through next-generation sequencing in detail. RESULTS: Enrichment of CACNA1C gene (encoding Cav1.2) in AM, a subunit of the L-type voltage-gated calcium channel (VGCC) was observed for the first time. The expression and channel activity of Cav1.2 was confirmed by immunostaining and calcium imaging in the patient samples or primary cells. Verapamil, L-type VGCC blocker revealed suppression of the Ca2+ -induced cell aggregation and collective invasion of AM cells in vitro. Furthermore, the effect of verapamil in suppressing AM invasion into the adjacent bone was confirmed through orthotopic xenograft model specifically. CONCLUSION: Taken together, Cav1.2 maybe considered to be a therapeutic candidate to decrease the collective migration and invasion of AM.

The antioxidant enzyme Peroxiredoxin-1 controls stroke-associated microglia against acute ischemic stroke.

Ischemic stroke is the leading cause of immortal disability and death worldwide. For treatment in the acute phase, it is necessary to control excessive reactive oxygen species (ROS) damage during ischemia/reperfusion (I/R). Microglia are well known to be closely associated with excessive ROS response in the early stage of I/R. However, the precise roles of microglia associated with mitigating ROS damage, and molecular markers of heterogenetic microglia in the I/R damaged brain has not been clarified. Here, we identified a new type of microglia associated with stroke in the I/R injured brain. Single-cell RNA sequencing (scRNA-seq) was used to assess transcriptional changes of microglia and immune cells in the contralateral (CL) and ipsilateral (IL) hemispheres after transient middle cerebral artery occlusion (tMCAO) surgery to mimic ischemic stroke. We classified a unique type of microglia with enhanced antioxidant function and markers similar to those of disease-associated microglia (DAM), designated them as stroke-associated microglia (SAM). The representative antioxidant enzyme, Peroxiredoxin-1 (Prdx1), was predominantly expressed in SAM and mediated ROS defense genes, including Txn1, Srx1, Mt1, and Mt2. In the Prdx1-/- I/R damaged brain, we observed significantly increased infarction, as assessed by TTC staining, and FACS analysis detected severe microglial cell death. Importantly, scRNA transcriptomics data showed that the SAM population was specifically decreased in Prdx1-/- mice and that these mice exhibited decreased ROS damage resistance. Inflammatory responses which were detected by ELISA and qPCR, were also increased in Prdx1-/- IL hemispheres. Finally, Prdx1-dependent antioxidative SAM were found to be essential for increasing the transcription levels of stroke-protective molecules, such as osteopontin and ferritin. A novel microglia type (SAM) is specifically activated in response to stroke I/R injury, and that Prdx1 expression is required for the activation and enhanced antioxidant function of SAM.

Comparison of 3-month cytogenetic and molecular assays for early assessment of long-term clinical impact after BCR-ABL1 tyrosine kinase inhibitor treatment in chronic myeloid leukemia.

To compare the clinical significance of 3-month cytogenetic and molecular monitoring, we analyzed 1,410 paired cytogenetic and molecular data from 705 chronic-phase chronic myeloid leukemia patients. Based on early cytogenetic response (ECyR, Ph+≤35 %) and molecular response (EMR, BCR-ABL1IS≤10 %) at 3 months, the patients were divided into four groups (group 1: ECyR + EMR, n = 560; group 2: no ECyR + EMR, n = 27; group 3: ECyR + no EMR, n = 55; group 4: no ECyR + no EMR, n = 63). By 10 years, major molecular response (MMR), deep molecular response (MR4.5), overall survival (OS), and progression-free survival (PFS) rates were significantly high in group 1 (P < 0.001). Comparing groups 2 and 3, the MMR (P = 0.096), MR4.5 (P = 0.945), OS (P = 0.832), and PFS (P = 0.627) rates tended to be higher in group 2, although not significantly. Thus, the cytogenetic assay can not only be useful but its addition may also provide a more precise prediction of MR4.5.

Evaluation of Combined Cancer Markers With Lactate Dehydrogenase and Application of Machine Learning Algorithms for Differentiating Benign Disease From Malignant Ovarian Cancer.

BACKGROUND: The differential diagnosis of ovarian cancer is important, and there has been ongoing research to identify biomarkers with higher performance. This study aimed to evaluate the diagnostic utility of combinations of cancer markers classified by machine learning algorithms in patients with early stage ovarian cancer, which has rarely been reported. METHODS: In total, 730 serum samples were assayed for lactate dehydrogenase (LD), neutrophil-to-lymphocyte ratio (NLR), human epididymis protein 4 (HE4), cancer antigen 125 (CA125), and risk of ovarian malignancy algorithm (ROMA). Among them, 53 were diagnosed with early stage ovarian cancer, and the remaining 677 were diagnosed with benign disease. RESULTS: The areas under the receiver operating characteristic curves (ROC-AUCs) of the ROMA, HE4, CA125, LD, and NLR for discriminating ovarian cancer from non-cancerous disease were .707, .680, .643, .657, and .624, respectively. ROC-AUC of the combination of ROMA and LD (.709) was similar to that of single ROMA in the total population. In the postmenopausal group, ROC-AUCs of HE4 and CA125 combined with LD presented the highest value (.718). When machine learning algorithms were applied to ROMA combined with LD, the ROC-AUC of random forest was higher than that of other applied algorithms in the total population (.757), showing acceptable performance. CONCLUSION: Our data suggest that the combinations of ovarian cancer-specific markers with LD classified by random forest may be a useful tool for predicting ovarian cancer, particularly in clinical settings, due to easy accessibility and cost-effectiveness. Application of an optimal combination of cancer markers and algorithms would facilitate appropriate management of ovarian cancer patients.

B7-H3 regulates osteoclast differentiation via type I interferon-dependent IDO induction.

While their function, as immune checkpoint molecules, is well known, B7-family proteins also function as regulatory molecules in bone remodeling. B7-H3 is a receptor ligand of the B7 family that functions primarily as a negative immune checkpoint. While the regulatory function of B7-H3 in osteoblast differentiation has been established, its role in osteoclast differentiation remains unclear. Here we show that B7-H3 is highly expressed in mature osteoclasts and that B7-H3 deficiency leads to the inhibition of osteoclastogenesis in human osteoclast precursors (OCPs). High-throughput transcriptomic analyses reveal that B7-H3 inhibition upregulates IFN signaling as well as IFN-inducible genes, including IDO. Pharmacological inhibition of type-I IFN and IDO knockdown leads to reversal of B7-H3-deficiency-mediated osteoclastogenesis suppression. Although synovial-fluid macrophages from rheumatoid-arthritis patients express B7-H3, inhibition of B7-H3 does not affect their osteoclastogenesis. Thus, our findings highlight B7-H3 as a physiologic positive regulator of osteoclast differentiation and implicate type-I IFN-IDO signaling as its downstream mechanism.

Anti-Mullerian Hormone Changes Following Laparoscopic Ovarian Cystectomy: A Prospective Comparative Study.

PURPOSE: To investigate whether laparoscopic ovarian cystectomy (LOC) affects ovarian reserve. PATIENTS AND METHODS: In 46 premenopausal women, who underwent either LOC (study group, n=26) or laparoscopic myomectomy (LM) (control group, n=20), serum anti-Mullerian hormone (AMH) levels were measured pre-operatively (AMH0), and postoperatively at 7 days (AMH1), 2 months (AMH2), and 6 months (AMH3). Changes in AMH from baseline level (AMH0) in each group were compared. RESULTS: AMH0 did not differ between the two groups (3.5 ± 3.33 in LOC vs 2.4 ± 2.72 in LM, P=0.250). AMH1, AMH2, and AMH3 in each group were also similar. However, a significant decline of AMH (ie more than 50% decrease compared to AMH0) at postoperative 6 months occurred more frequently in the LOC group than in the LM group. In the sub-analysis of the LOC group, a significant decline of AMH at postoperative 2 months and 6 months was highly correlated with bilateral ovarian tumors (P=0.001). CONCLUSION: Compared to LM, serum AMH level showed a minimal decrease after 1 week following LOC, which did not revert to normal over 6 months of follow-up. In addition, a significant decline of ovarian reserve at postoperative 6 months was significantly more frequent in the LOC group, suggesting that LOC may have more adverse effects on ovarian reserve compared to the LM (control) group. Thus, care is required during the LOC procedure, specifically in women with bilateral tumors.

Single-cell transcriptome of bronchoalveolar lavage fluid reveals sequential change of macrophages during SARS-CoV-2 infection in ferrets.

Few studies have used a longitudinal approach to describe the immune response to SARS-CoV-2 infection. Here, we perform single-cell RNA sequencing of bronchoalveolar lavage fluid cells longitudinally obtained from SARS-CoV-2-infected ferrets. Landscape analysis of the lung immune microenvironment shows distinct changes in cell proportions and characteristics compared to uninfected control, at 2 and 5 days post-infection (dpi). Macrophages are classified into 10 distinct subpopulations with transcriptome changes among monocyte-derived infiltrating macrophages and differentiated M1/M2 macrophages, notably at 2 dpi. Moreover, trajectory analysis reveals gene expression changes from monocyte-derived infiltrating macrophages toward M1 or M2 macrophages and identifies a macrophage subpopulation that has rapidly undergone SARS-CoV-2-mediated activation of inflammatory responses. Finally, we find that M1 or M2 macrophages show distinct patterns of gene modules downregulated by immune-modulatory drugs. Overall, these results elucidate fundamental aspects of the immune response dynamics provoked by SARS-CoV-2 infection.

Re-evaluation of possible vulnerable sites in the lateral pelvic cavity to local recurrence during robot-assisted total mesorectal excision.

BACKGROUND: Despite mechanical and technical improvements in laparoscopic and robot-assisted (LAR) rectal cancer procedures, the absence of prognostic disparities among various approaches cannot improve the quality of TME. The present study re-evaluated robot-assisted total mesorectal excision (TME) procedures to determine whether these procedures may reveal technical faults that may increase the rate of local recurrence (LR). METHODS: This study enrolled 886 consecutive patients with rectal cancer, who underwent curative robot-assisted LAR at Asan Medical Center (Seoul, Korea) between July 2010 and August 2017 (the first vs second period; n = 399 vs 487). The quality of TME and lateral pelvic mesorectal excision (LPME) were analyzed, as were LR rates and survival outcomes. RESULTS: Complete TME and LPME were achieved in 89.2% and 80.1% of these patients, respectively, with ≤ 1% having incomplete TME excluding intramesorectal excision. LR rates were 13.5 and 14.5 times higher in patients with incomplete TME and LPME, respectively, than in patients with complete TME and LPME (14.8% vs 1.1% and 8.7% vs 0.6%; p < 0.001 each by univariate analyses). Multivariate analyses showed that defective LPME was independently associated with incomplete TME and vice versa (p < 0.001). Cox regression analysis showed that defective LPME was independently correlated with reduced 5-year disease-free survival rate (hazard ratio, 1.563; 95% confidence interval, 1.052-2.323; p = 0.027). CONCLUSIONS: LR in rectal cancer patients was largely due to incomplete LPME, which was significantly associated with incomplete TME. Complete LPME may enhance the likelihood of complete TME, reducing LR rates.

Anti-Inflammatory Actions of Soluble Ninjurin-1 Ameliorate Atherosclerosis.

BACKGROUND: Macrophages produce many inflammation-associated molecules, released by matrix metalloproteinases, such as adhesion molecules, and cytokines, as well, which play a crucial role in atherosclerosis. In this context, we investigated the relationship between Ninjurin-1 (Ninj1 [nerve injury-induced protein]), a novel matrix metalloproteinase 9 substrate, expression, and atherosclerosis progression. METHODS: Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from patients with coronary artery disease and healthy controls, and atheroprone apolipoprotein e-deficient (Apoe-/-) and wild-type mice, as well. Apoe-/- mice lacking systemic Ninj1 expression (Ninj1-/-Apoe-/-) were generated to assess the functional effects of Ninj1. Bone marrow transplantation was also used to generate low-density lipoprotein receptor-deficient (Ldlr-/-) mice that lack Ninj1 specifically in bone marrow-derived cells. Mice were fed a Western diet for 5 to 23 weeks, and atherosclerotic lesions were investigated. The anti-inflammatory role of Ninj1 was verified by treating macrophages and mice with the peptides Ninj11-56 (ML56) and Ninj126-37 (PN12), which mimic the soluble form of Ninj1 (sNinj1). RESULTS: Our in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1-deficient macrophages promoted proinflammatory gene expression by activating mitogen-activated protein kinase and inhibiting the phosphoinositide 3-kinase/Akt signaling pathway. Whole-body and bone marrow-specific Ninj1 deficiencies significantly increased monocyte recruitment and macrophage accumulation in atherosclerotic lesions through elevated macrophage-mediated inflammation. Macrophage Ninj1 was directly cleaved by matrix metalloproteinase 9 to generate a soluble form that exhibited antiatherosclerotic effects, as assessed in vitro and in vivo. Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages, thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of this disorder in mice, regardless of the presence of Ninj1. CONCLUSIONS: Ninj1 is a novel matrix metalloproteinase 9 substrate in macrophages, and sNinj1 is a secreted atheroprotective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis. Moreover, sNinj1-mediated anti-inflammatory effects are conserved in human macrophages and likely contribute to human atherosclerosis.

Classification of cervical neoplasms on colposcopic photography using deep learning.

Colposcopy is widely used to detect cervical cancers, but experienced physicians who are needed for an accurate diagnosis are lacking in developing countries. Artificial intelligence (AI) has been recently used in computer-aided diagnosis showing remarkable promise. In this study, we developed and validated deep learning models to automatically classify cervical neoplasms on colposcopic photographs. Pre-trained convolutional neural networks were fine-tuned for two grading systems: the cervical intraepithelial neoplasia (CIN) system and the lower anogenital squamous terminology (LAST) system. The multi-class classification accuracies of the networks for the CIN system in the test dataset were 48.6 ± 1.3% by Inception-Resnet-v2 and 51.7 ± 5.2% by Resnet-152. The accuracies for the LAST system were 71.8 ± 1.8% and 74.7 ± 1.8%, respectively. The area under the curve (AUC) for discriminating high-risk lesions from low-risk lesions by Resnet-152 was 0.781 ± 0.020 for the CIN system and 0.708 ± 0.024 for the LAST system. The lesions requiring biopsy were also detected efficiently (AUC, 0.947 ± 0.030 by Resnet-152), and presented meaningfully on attention maps. These results may indicate the potential of the application of AI for automated reading of colposcopic photographs.