BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells.

The transcription factors nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1; Fos-Jun) cooperate to promote the effector functions of T cells, but NFAT in the absence of AP-1 imposes a negative feedback program of T cell hyporesponsiveness (exhaustion). Here, we show that basic leucine zipper ATF-like transcription factor (BATF) and interferon regulatory factor 4 (IRF4) cooperate to counter T cell exhaustion in mouse tumor models. Overexpression of BATF in CD8+ T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumor-infiltrating CAR T cells, increased the production of effector cytokines, decreased the expression of inhibitory receptors and the exhaustion-associated transcription factor TOX and supported the generation of long-lived memory T cells that controlled tumor recurrence. These responses were dependent on BATF-IRF interaction, since cells expressing a BATF variant unable to interact with IRF4 did not survive in tumors and did not effectively delay tumor growth. BATF may improve the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.

Strategy to develop broadly effective multivalent COVID-19 vaccines against emerging variants based on Ad5/35 platform.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron strain has evolved into highly divergent variants with several sub-lineages. These newly emerging variants threaten the efficacy of available COVID-19 vaccines. To mitigate the occurrence of breakthrough infections and re-infections, and more importantly, to reduce the disease burden, it is essential to develop a strategy for producing updated multivalent vaccines that can provide broad neutralization against both currently circulating and emerging variants. We developed bivalent vaccine AdCLD-CoV19-1 BA.5/BA.2.75 and trivalent vaccines AdCLD-CoV19-1 XBB/BN.1/BQ.1.1 and AdCLD-CoV19-1 XBB.1.5/BN.1/BQ.1.1 using an Ad5/35 platform-based non-replicating recombinant adenoviral vector. We compared immune responses elicited by the monovalent and multivalent vaccines in mice and macaques. We found that the BA.5/BA.2.75 bivalent and the XBB/BN.1/BQ.1.1 and XBB.1.5/BN.1/BQ.1.1 trivalent vaccines exhibited improved cross-neutralization ability compared to their respective monovalent vaccines. These data suggest that the developed multivalent vaccines enhance immunity against circulating Omicron subvariants and effectively elicit neutralizing antibodies across a broad spectrum of SARS-CoV-2 variants.

NR4A transcription factors limit CAR T cell function in solid tumours.

T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies1,2. CAR T cells have been less effective against solid tumours3-5, in part because they enter a hyporesponsive ('exhausted' or 'dysfunctional') state6-9 triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19+ tumour-bearing mice. CD8+CAR+ tumour-infiltrating lymphocytes and CD8+ endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells)10-12. CD8+ T cells from humans with cancer or chronic viral infections13-15 expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A transcription factors (Nr4a triple knockout) promoted tumour regression and prolonged the survival of tumour-bearing mice. Nr4a triple knockout CAR tumour-infiltrating lymphocytes displayed phenotypes and gene expression profiles characteristic of CD8+ effector T cells, and chromatin regions uniquely accessible in Nr4a triple knockout CAR tumour-infiltrating lymphocytes compared to wild type were enriched for binding motifs for NF-κB and AP-1, transcription factors involved in activation of T cells. We identify NR4A transcription factors as having an important role in the cell-intrinsic program of T cell hyporesponsiveness and point to NR4A inhibition as a promising strategy for cancer immunotherapy.

Decoding and overcoming T cell exhaustion: Epigenetic and transcriptional dynamics in CAR-T cells against solid tumors.

T cell exhaustion, which is observed in various chronic infections and malignancies, is characterized by elevated expression of multiple inhibitory receptors, impaired effector functions, decreased proliferation, and reduced cytokine production. Notably, while adoptive T cell therapies, such as chimeric antigen receptor (CAR)-T therapy, have shown promise in treating cancer and other diseases, the efficacy of these therapies is often compromised by T cell exhaustion. It is imperative, therefore, to understand the mechanisms underlying this exhaustion to promote advances in T cell-related therapies. Here, we divided exhausted T cells into three distinct subsets according to their developmental and functional profiles: stem-like progenitor cells, intermediately exhausted cells, and terminally exhausted cells. These subsets are carefully regulated by synergistic mechanisms that involve transcriptional and epigenetic modulators. Key transcription factors, such as TCF1, BACH2, and TOX, are crucial for defining and sustaining exhaustion phenotypes. Concurrently, epigenetic regulators, such as TET2 and DNMT3A, shape the chromatin dynamics that direct T cell fate. The interplay of these molecular drivers has recently been highlighted in CAR-T research, revealing promising therapeutic directions. Thus, a profound understanding of exhausted T cell hierarchies and their molecular complexities may reveal innovative and improved tumor treatment strategies.

Paradoxical association of TET loss of function with genome-wide DNA hypomethylation.

Cancer genomes are characterized by focal increases in DNA methylation, co-occurring with widespread hypomethylation. Here, we show that TET loss of function results in a similar genomic footprint. Both 5hmC in wild-type (WT) genomes and DNA hypermethylation in TET-deficient genomes are largely confined to the active euchromatic compartment, consistent with the known functions of TET proteins in DNA demethylation and the known distribution of 5hmC at transcribed genes and active enhancers. In contrast, an unexpected DNA hypomethylation noted in multiple TET-deficient genomes is primarily observed in the heterochromatin compartment. In a mouse model of T cell lymphoma driven by TET deficiency (Tet2/3 DKO T cells), genomic analysis of malignant T cells revealed DNA hypomethylation in the heterochromatic genomic compartment, as well as reactivation of repeat elements and enrichment for single-nucleotide alterations, primarily in heterochromatic regions of the genome. Moreover, hematopoietic stem/precursor cells (HSPCs) doubly deficient for Tet2 and Dnmt3a displayed greater losses of DNA methylation than HSPCs singly deficient for Tet2 or Dnmt3a alone, potentially explaining the unexpected synergy between DNMT3A and TET2 mutations in myeloid and lymphoid malignancies. Tet1-deficient cells showed decreased localization of DNMT3A in the heterochromatin compartment compared with WT cells, pointing to a functional interaction between TET and DNMT proteins and providing a potential explanation for the hypomethylation observed in TET-deficient genomes. Our data suggest that TET loss of function may at least partially underlie the characteristic pattern of global hypomethylation coupled to regional hypermethylation observed in diverse cancer genomes, and highlight the potential contribution of heterochromatin hypomethylation to oncogenesis.

TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion.

T cells expressing chimeric antigen receptors (CAR T cells) have shown impressive therapeutic efficacy against leukemias and lymphomas. However, they have not been as effective against solid tumors because they become hyporesponsive ("exhausted" or "dysfunctional") within the tumor microenvironment, with decreased cytokine production and increased expression of several inhibitory surface receptors. Here we define a transcriptional network that mediates CD8+ T cell exhaustion. We show that the high-mobility group (HMG)-box transcription factors TOX and TOX2, as well as members of the NR4A family of nuclear receptors, are targets of the calcium/calcineurin-regulated transcription factor NFAT, even in the absence of its partner AP-1 (FOS-JUN). Using a previously established CAR T cell model, we show that TOX and TOX2 are highly induced in CD8+ CAR+ PD-1high TIM3high ("exhausted") tumor-infiltrating lymphocytes (CAR TILs), and CAR TILs deficient in both TOX and TOX2 (Tox DKO) are more effective than wild-type (WT), TOX-deficient, or TOX2-deficient CAR TILs in suppressing tumor growth and prolonging survival of tumor-bearing mice. Like NR4A-deficient CAR TILs, Tox DKO CAR TILs show increased cytokine expression, decreased expression of inhibitory receptors, and increased accessibility of regions enriched for motifs that bind activation-associated nuclear factor κB (NFκB) and basic region-leucine zipper (bZIP) transcription factors. These data indicate that Tox and Nr4a transcription factors are critical for the transcriptional program of CD8+ T cell exhaustion downstream of NFAT. We provide evidence for positive regulation of NR4A by TOX and of TOX by NR4A, and suggest that disruption of TOX and NR4A expression or activity could be promising strategies for cancer immunotherapy.

Differentiation of c-Kit+ CD24+ natural killer cells into myeloid cells in a GATA-2-dependent manner.

Myeloid progenitor cells have generally been considered the predominant source of myeloid cells under steady-state conditions. Here we show that NK cells contributed to a myeloid cell lineage pool in naïve and tumor-bearing mice. Using fate tracing of NKp46+ cells, we found that myeloid cells could be derived from NK cells. Notably, among mature CD11b+ CD27+ NK cells, c-Kit+ CD24+ NK cells were capable of differentiating into a range of myeloid lineages in vitro and produced neutrophils and monocytes in vivo. The differentiation was completely inhibited by NK-stimulating cytokines. In addition to the potential for differentiation into myeloid cells, c-Kit+ CD24+ NK cells retained NK cell phenotypes and effector functions. Mechanistically, GATA-2 was necessary for the differentiation of c-Kit+ CD24+ NK cells. Therefore, we discovered that GATA-2-dependent differentiation of c-Kit+ CD24+ NK cells contributes to myeloid cell development and identified a novel pathway for myeloid lineage commitment under physiological conditions.

Stroke Volume Variation and Stroke Volume Index Can Predict Fluid Responsiveness after Mini-Volume Challenge Test in Patients Undergoing Laparoscopic Cholecystectomy.

Background and Objectives: For using appropriate goal-directed fluid therapy during the surgical conditions of pneumoperitoneum in the reverse Trendelenburg position, we investigated the predictability of various hemodynamic parameters for fluid responsiveness by using a mini-volume challenge test. Materials and Methods: 42 adult patients scheduled for laparoscopic cholecystectomy were enrolled. After general anesthesia was induced, CO2 pneumoperitoneum was applied and the patient was placed in the reverse Trendelenburg position. The mini-volume challenge test was carried out with crystalloid 4 mL/kg over 10 min. Hemodynamic parameters, including stroke volume variation (SVV), cardiac index (CI), stroke volume index (SVI), mean arterial pressure (MAP), and heart rate (HR), were measured before and after the mini-volume challenge test. The positive fluid responsiveness was defined as an increase in stroke volume index ≥10% after the mini-volume challenge. For statistical analysis, a Shapiro-Wilk test was used to test the normality of the data. Continuous variables were compared using an unpaired t-test or the Mann-Whitney rank-sum test. Categorical data were compared using the chi-square test. A receiver operating characteristic curve analysis was used to assess the predictability of fluid responsiveness after the mini-volume challenge. Results: 31 patients were fluid responders. Compared with the MAP and HR, the SVV, CI, and SVI showed good predictability for fluid responsiveness after the mini-volume challenge test (area under the curve was 0.900, 0.833, and 0.909, respectively; all p-values were <0.0001). Conclusions: SVV and SVI effectively predicted fluid responsiveness after the mini-volume challenge test in patients placed under pneumoperitoneum and in the reverse Trendelenburg position.

Face-to-face intubation using a lightwand in a patient with severe thoracolumbar kyphosis: a case report.

BACKGROUND: Severe deformity of the thoracolumbar spine may cause difficulty in airway management during induction of anesthesia. Therefore, special attention must be devoted to patient safety. CASE PRESENTATION: A 65-year-old male with severe thoracolumbar kyphosis was scheduled to undergo posterior spinal fusion under general anesthesia. Due to his inability to lie supine, conventional tracheal intubation under direct laryngoscopy was difficult. Alternatively, face-to-face tracheal intubation using a lightwand in the semi-recumbent position was performed. Intubation was successful on the first attempt without any complications. CONCLUSIONS: The face-to-face intubation technique using a lightwand is one of several alternative techniques for tracheal intubation in patients who cannot lie supine.

Introducing EzBioCloud: a taxonomically united database of 16S rRNA gene sequences and whole-genome assemblies.

The recent advent of DNA sequencing technologies facilitates the use of genome sequencing data that provide means for more informative and precise classification and identification of members of the Bacteria and Archaea. Because the current species definition is based on the comparison of genome sequences between type and other strains in a given species, building a genome database with correct taxonomic information is of paramount need to enhance our efforts in exploring prokaryotic diversity and discovering novel species as well as for routine identifications. Here we introduce an integrated database, called EzBioCloud, that holds the taxonomic hierarchy of the Bacteria and Archaea, which is represented by quality-controlled 16S rRNA gene and genome sequences. Whole-genome assemblies in the NCBI Assembly Database were screened for low quality and subjected to a composite identification bioinformatics pipeline that employs gene-based searches followed by the calculation of average nucleotide identity. As a result, the database is made of 61 700 species/phylotypes, including 13 132 with validly published names, and 62 362 whole-genome assemblies that were identified taxonomically at the genus, species and subspecies levels. Genomic properties, such as genome size and DNA G+C content, and the occurrence in human microbiome data were calculated for each genus or higher taxa. This united database of taxonomy, 16S rRNA gene and genome sequences, with accompanying bioinformatics tools, should accelerate genome-based classification and identification of members of the Bacteria and Archaea. The database and related search tools are available at www.ezbiocloud.net/.

A Randomized Crossover Study Comparing Cervical Spine Motion During Intubation Between Two Lightwand Intubation Techniques in Patients With Simulated Cervical Immobilization: Laryngoscope-Assisted Versus Conventional Lightwand Intubation.

BACKGROUND: In patients with cervical immobilization, jaw thrust can cause cervical spine movement. Concurrent use of a laryngoscope may facilitate lightwand intubation, allowing midline placement and free movement of the lightwand in the oral cavity without jaw thrust. We compared the effects of laryngoscope-assisted lightwand intubation (LALI) versus conventional lightwand intubation (CLI) on cervical spine motion during intubation in patients with simulated cervical immobilization. METHODS: In this randomized crossover study, the cervical spine angle was measured before and during intubation at the occiput-C1, C1-C2, and C2-C5 segments in 20 patients with simulated cervical immobilization who underwent intubation using both the LALI and CLI techniques. Cervical spine motion was defined as the change from baseline in angle measured at each cervical segment during intubation. RESULTS: Cervical spine motion at the occiput-C1 segment was 5.6° (4.3) and 9.3° (4.5) when we used the LALI and CLI techniques, respectively (mean difference [98.33% CI]; -3.8° [-7.2 to -0.3]; P = .007). At other cervical segments, it was not significantly different between the 2 techniques (-0.1° [-2.6 to 2.5]; P = .911 in the C1-C2 segment and -0.2° [-2.8 to 2.5]; P = .795 in the C2-C5 segment). CONCLUSIONS: The LALI technique produces less upper cervical spine motion during intubation than the CLI technique in patients with simulated cervical immobilization.

A proposal of a simple epidural simulator for training novice anesthesiologists.

PURPOSE: Confirming the epidural space during epidural anesthesia relies mainly on feel and experience, which are difficult techniques for a trainee to learn. We designed an epidural simulator for trainees to experience loss of resistance (LOR) and various degrees of pressure resistance. METHODS: The simulator consists of a Perifix(®) LOR syringe and 1-, 5-, 10- and 50-mL syringes assembled by three-way stopcocks. A total of 89 anesthesiologists evaluated the simulator, given the choice of either the intermittent technique with air or continuous technique with saline. Sudden LOR and applicability of the simulator for training purposes were assessed using the numerical rating score (NRS). Pressure resistance at each lumbar structure was evaluated by the anesthesiologists using the intermittent technique with air. RESULTS: Seventy-four anesthesiologists used the intermittent technique with air and 15 used the continuous technique with saline. The NRSs for sudden LOR and the applicability for training purposes were 8 and 9 (median), respectively. The pressure resistance to a 50-mL syringe was regarded as the epidural space (odds ratio 602.3 for 5-mL syringe and 144.4 for 10-mL syringe) by 89 % of anesthesiologists using air for LOR. Resistance to the 10-mL syringe was most frequently considered as muscle, subcutaneous fat, or the interspinous ligament, while resistance to the 1-mL syringe was considered as the ligamentum flavum (odds ratio 2.3 for 5-mL syringe and 18.6 for 10-mL syringe). CONCLUSIONS: Our epidural simulator is a simple, low-cost device that can be easily constructed. It was shown to provide valid haptic feedback as a promising tool for training novice anesthesiologists.

Serum amyloid A3 exacerbates cancer by enhancing the suppressive capacity of myeloid-derived suppressor cells via TLR2-dependent STAT3 activation.

Myeloid-derived suppressor cells (MDSCs), which suppress diverse innate and adaptive immune responses and thereby provide an evasion mechanism for tumors, are emerging as a key population linking inflammation to cancer. Although many inflammatory factors that induce MDSCs in the tumor microenvironment are known, the crucial components and the underlying mechanisms remain elusive. In this study, we proposed a novel mechanism by which serum amyloid A3 (SAA3), a well-known inflammatory factor, connects MDSCs with cancer progression. We found that SAA3 expression in BALB/c mice increased in monocytic MDSCs (Mo MDSCs) with tumor growth. The induction of SAA3 by apo-SAA treatment in Mo MDSCs enhanced their survival and suppressive activity, while it inhibited GM-CSF-induced differentiation. Endogenous SAA3 itself contributed to the increase in the survival and suppressive activity of Mo MDSCs. We demonstrated that SAA3 induced TLR2 signaling, in turn increasing the autocrine secretion of TNF-α, that led to STAT3 activation. In addition, activated STAT3 enhanced the suppressive activity of Mo MDSCs. Furthermore, SAA3 induction in Mo MDSCs contributed to accelerating tumor progression in vivo. Collectively, these data suggest a novel mechanism by which Mo MDSCs mediate inflammation through SAA3-TLR2 signaling and thus exacerbate cancer progression by a STAT3-dependent mechanism.

Preoperative hypoalbuminemia and anemia as predictors of transfusion in radical nephrectomy for renal cell carcinoma: a retrospective study.

BACKGROUND: The only curative therapy for renal cell carcinoma is the complete removal of malignant tissue. Surgical bleeding during radical nephrectomy may require blood transfusion. Blood transfusion, however, is associated with postoperative morbidity and mortality. This study investigated predictive factors of transfusion requirement in patients undergoing radical nephrectomy, as well as the effects of transfusion on postoperative outcomes. METHODS: This study retrospectively enrolled 526 patients who underwent open radical nephrectomy for renal cell carcinoma between 2010 and 2012. Univariate and multivariate logistic regression analyses were used to determine independent predictive factors of a requirement for packed red blood cell (PRBC) transfusion. Postoperative outcomes included an admission to the intensive care unit (ICU) and lengths of ICU and hospital stay. RESULTS: Of the 526 patients, 93 (17.7 %) required PRBC transfusion, with these patients requiring a mean 5.5 units. Preoperative hypoalbuminemia (serum albumin <3.5 g/dL) was observed in 75 (14.3 %) patients, and preoperative anemia (hemoglobin <12.0 g/dL) in 121 (23.0 %). Multivariate logistic regression analysis showed that preoperative hypoalbuminemia, preoperative anemia, and a high cancer stage were independent factors significantly associated with PRBC transfusion in open radical nephrectomy. The transfused group had higher incidence of ICU admission and longer lengths of ICU and hospital stay than the non-transfused group. CONCLUSIONS: Preoperative hypoalbuminemia and anemia are important predictors of PRBC transfusion during radical nephrectomy for renal cell carcinoma. Furthermore, transfusion is associated with poor postoperative outcomes.

Sonographic optic nerve sheath diameter as a surrogate measure for intracranial pressure in anesthetized patients in the Trendelenburg position.

BACKGROUND: It remains to be elucidated whether the Trendelenburg position increases intracranial pressure (ICP). ICP can be evaluated by measuring the sonographic optic nerve sheath diameter (ONSD). We investigated the effect of the isolated Trendelenburg position on ONSD in patients undergoing robot-assisted laparoscopic radical prostatectomy. Additionally, we evaluated the effect of the Trendelenburg position combined with pneumoperitoneum on ONSD. METHODS: Twenty-one patients scheduled for robot-assisted laparoscopic radical prostatectomy were enrolled. Sonographic ONSDs and hemodynamic parameters were measured at specific time points: in the supine position after induction of anesthesia, 3 min after the steep Trendelenburg position (35° incline), 3 min after the steep Trendelenburg position combined with pneumoperitoneum, and in the supine position after desufflation of the pneumoperitoneum. RESULTS: The ONSD 3 min after the steep Trendelenburg position was significantly higher than that of the supine position after induction of anesthesia (5.1 ± 0.3 mm vs. 4.5 ± 0.4 mm). In addition, the ONSD 3 min after the steep Trendelenburg position combined with pneumoperitoneum was higher than that of the supine position after induction of anesthesia (4.9 ± 0.4 mm vs. 4.5 ± 0.4 mm). The ONSD in the supine position after desufflation of the pneumoperitoneum was similar to that in the supine position after induction of anesthesia. CONCLUSIONS: Use of the isolated steep Trendelenburg position, for even a short duration, increased the sonographic ONSD, providing a better understanding of the effect of only a transient steep Trendelenburg position on ONSD as a surrogate measure for ICP.

Effect of glycopyrrolate versus atropine coadministered with neostigmine for reversal of rocuronium on postoperative catheter-related bladder discomfort in patients undergoing transurethral resection of bladder tumor: a prospective randomized study.

BACKGROUND: Muscarinic receptors are involved in the mechanism of postoperative catheter-related bladder discomfort (CRBD). Glycopyrrolate and atropine as adjuncts to reversal of neuromuscular blockers have differential inhibitory effects on muscarinic receptors. This study was conducted to compare the effect of glycopyrrolate versus atropine on postoperative CRBD in patients undergoing transurethral resection of a bladder tumor (TURBT). METHODS: Seventy-four patients undergoing TURBT were randomly allocated to receive either glycopyrrolate 10 µg/kg (glycopyrrolate group, n = 37) or atropine 15 µg/kg (atropine group, n = 37) in combination with neostigmine 25 µg/kg at the end of surgery for reversal of neuromuscular blockade. The incidence and severity (mild/moderate/severe) of CRBD were assessed at 0, 1, 6, and 24 h postoperatively. Tramadol 50-100 mg was administered intravenously if the patients complained of moderate or severe CRBD. RESULTS: The incidence of CRBD was significantly lower in the glycopyrrolate group than in the atropine group at 0 h (65 % vs. 89 %, p = 0.025) and 1 h (54 % vs. 89 %, p = 0.002) postoperatively. The severity of postoperative CRBD was less severe in the glycopyrrolate group than in the atropine group at 0 h (p = 0.013) and 1 h (p = 0.006). Fewer patients required tramadol in the glycopyrrolate group than in the atropine group (3 % vs. 12 %, p = 0.024). CONCLUSIONS: Glycopyrrolate as an adjunct to reversal of neuromuscular blockers decreased the incidence of early postoperative CRBD and postoperative tramadol requirements in patients undergoing TURBT when compared to atropine.

Change of periodontal inflammatory indicators through a 4-week weight control intervention including caloric restriction and exercise training in young Koreans: a pilot study.

BACKGROUND: Recent cross-sectional studies indicate that obesity is a risk factor for periodontal disease. Exercise training in high fat mice or rats can inhibit gingival inflammation effectively. The objective of this human intervention study was to investigate whether short-term weight control could affect periodontal indexes and serum and gingival crevicular fluid (GCF) biomarkers in young Koreans. METHODS: Forty-one obese volunteers (body mass index (BMI) > 25.0) and 12 normal weight subjects (18.5 ≤ BMI ≤ 23.0) participated in a four-week weight control program to analyze the changes in anthropometric criteria, the concentrations of C-reactive protein (CRP), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides in serum, gingival index, bleeding on probing, periodontal biomarkers in GCF, and dental plaque index at the first and the 27th days. RESULTS: The means of obesity measures decreased significantly more in the obese group (BMI 2.53 ± 0.96, waist-to-hip ratio (WHR) 4.88 ± 1.58 %, LDL 35.85 ± 21.74 mgdL(-1)) than in the normal weight group (BMI 0.78 ± 0.72, WHR 2.00 ± 0.95 %, LDL 15.58 ± 18.07 mgdL(-1)). While the obese group showed significant decreases in the biomarkers in GCF (IL-1ß 58.38 ± 65.55 pgmL(-1), MMP-8 4.19 ± 5.61 ngmL(-1), MMP-9 3.36 ± 6.30 ngmL(-1)), the mean changes for the normal weight group (IL-1ß 10.07 ± 21.08 pgmL(-1), MMP-8 1.49 ± 4.61 ngmL(-1), MMP-9 -1.52 ± 9.71 ngmL(-1)) were not statistically significant. Anthropometric measures and the amounts of GCF biomarkers had weak positive correlations (0.242 ≤ r ≤ 0.340), and LDL in serum correlated with MMP-8 (r = 0.332) and IL-1ß (r = 0.342) in the obese group. Stepwise multiple linear regression analysis in the obese group showed that the relationship between the amount of IL-1ß in GCF and predictor variables including LDL and BMI was highly significant and accounted for 19.1 % of the variance in IL-1ß in GCF. CONCLUSIONS: In periodontally healthy subjects, weight control could reduce the amounts of MMP-8, MMP-9, and IL-1ß in GCF of the obese subjects. Further studies with periodontally unhealthy and obese people are needed to identify the mechanism of decreases in inflammation biomarkers in GCF through weight control. TRIAL REGISTRATION: ISRCTN86753073 (2015.08.14).

Effects of a Task-specific Exercise Program on Balance, Mobility, and Muscle Strength in the Elderly.

[Purpose] The aim of this study was to investigate the effects of a task-specific exercise program based on motor learning on balance ability and strength of the lower extremity in the elderly with/without falling experiences. [Subjects and Methods] Individuals who had experiences of falling over 2 times within the past 6 months were included in the falling group. The task-specific exercise program consisted of 3 stages (weeks 1-2, 3-4, and 5-6) and was conducted according to the level of difficulty in this study. [Results] The scores of the Korean version of the Activities-Specific Balance Confidence Scale and Performance-Oriented Mobility Assessment were significantly changed in both the falling group and non-falling group after the task-specific exercise program. In comparisons between the falling group and non-falling group, there were also significant differences in the Korean version of the Activities-Specific Balance Confidence Scale and muscle strength of the semitendinosus and gastrocnemius. [Conclusion] The task-specific exercise program has a positive effect on balance ability and muscle strength related to falls in the elderly.

IL-17 and IL-21: Their Immunobiology and Therapeutic Potentials.

Studies over the last 2 decades have identified IL-17 and IL-21 as key cytokines in the modulation of a wide range of immune responses. IL-17 serves as a critical defender against bacterial and fungal pathogens, while maintaining symbiotic relationships with commensal microbiota. However, alterations in its levels can lead to chronic inflammation and autoimmunity. IL-21, on the other hand, bridges the adaptive and innate immune responses, and its imbalance is implicated in autoimmune diseases and cancer, highlighting its important role in both health and disease. Delving into the intricacies of these cytokines not only opens new avenues for understanding the immune system, but also promises innovative advances in the development of therapeutic strategies for numerous diseases. In this review, we will discuss an updated view of the immunobiology and therapeutic potential of IL-17 and IL-21.

Intraoperative infusion of 0.6-0.9 µg·kg(-1)·min(-1) remifentanil induces acute tolerance in young children after laparoscopic ureteroneocystostomy.

BACKGROUND: Intraoperative infusion of opioids has been associated with increased postoperative pain and analgesic requirements, but the development of tolerance in young children is less clear. This prospective, randomized, double-blinded study was designed to test the hypothesis that the intraoperative administration of remifentanil results in postoperative opioid tolerance in a dose-related manner in young children. METHODS: We enrolled 60 children (aged 1-5 yr) who were undergoing elective laparoscopic ureteroneocystostomy. Patients were randomized and received an intraoperative infusion of 0, 0.3, 0.6, or 0.9 µg·kg·min remifentanil. Postoperative pain was managed by a parent/nurse-controlled analgesia pump using fentanyl. The primary outcome included the total fentanyl consumptions at 24 and 48 h postsurgery. Secondary outcomes were the postoperative pain scores and adverse effects. RESULTS: The children who received 0.6 and 0.9 µg·kg·min remifentanil required more postoperative fentanyl than the children who received saline or 0.3 µg·kg·min remifentanil (all P < 0.001) for 24 h after surgery. The children who received 0.3-0.9 µg·kg·min intraoperative remifentanil reported higher pain scores at 1 h after surgery than the children who received saline (P = 0.002, P = 0.023, and P = 0.006, respectively). No significant intergroup differences in recovery variables were observed, but vomiting was more frequent in the 0.9 µg·kg·min remifentanil group than in the other groups (P = 0.027). CONCLUSIONS: The intraoperative use of 0.3 µg·kg·min remifentanil for approximately 3 h (range: 140-265 min) did not induce acute tolerance, but the administration of 0.6 and 0.9 µg·kg·min remifentanil to young children resulted in acute tolerance for 24 h after surgery in an apparently dose-related manner.