Frailty and Humoral Immune Responses Following COVID-19 Vaccination among Patients Undergoing Hemodialysis.

BACKGROUND: Patients with end-stage kidney disease who are undergoing dialysis have reduced immune responses to COVID-19 vaccination. Frailty is extremely common among dialysis patients and may contribute to the impaired immunogenicity. This study aimed to determine the association between frailty and humoral immune responses following COVID-19 vaccination in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS: Adult hemodialysis patients without prior SARS-CoV-2 infection who received a priming dose of ChAdOx1 nCoV-19, an adenovirus-vectored vaccine, were assessed for eligibility. Participants were categorized as robust, pre-frail, or frail using the Fried frailty criteria. Humoral responses were assessed 28 days after vaccination by measuring titers of anti-spike IgG antibodies. The primary outcome was anti-spike antibody seroconversion, defined as antibody levels ≥50 AU/mL. Multivariable-adjusted logistic regression models were used to assess the association between frailty status and the primary outcome. RESULTS: A total of 206 participants (mean age 67 ± 13 years, 50% women) were included in the study, of whom 50 (24%) were characterized as frail, 86 (42%) were characterized as pre-frail, and 70 (34%) were characterized as robust. Anti-spike antibody levels were progressively lower with more advanced stages of frailty (P <0.001). Compared with robust patients, a significantly smaller proportion of pre-frail and frail patients developed anti-spike antibody seroconversion (87%, 66%, and 40%, respectively; P <0.001). Frailty was associated with the absence of humoral responses after adjustment for age, sex, body mass index, diabetes, coronary artery disease, serum albumin, and lymphocyte count (OR=0.25; 95% CI, 0.08-0.80). CONCLUSIONS: Frailty is independently associated with impaired humoral responses following COVID-19 vaccination among hemodialysis patients. Strategies aimed at preventing or attenuating frailty in the dialysis population are warranted.

[Tough choice of surgical treatment for duodenal gastrointestinal stromal tumor: pancreaticoduodenectomy or local resection?]

The therapeutic choice of duodenal gastrointestinal stromal tumor (GIST) has always been the focus of surgeons because of its special anatomy location. So far, surgery is the preferable treatment for primary duodenal GIST, including pancreaticoduodenectomy (PD) and local resection (LR). Researches reveal that the prognosis of duodenal GIST is determined by the pathologic factors of the tumor itself, and is not significantly associated with the surgical procedure. The intervention with targeted drugs such as imatinib has given the duodenal GIST more opportunities for LR. Meanwhile, the technique development of the laparoscopy combined with endoscopic surgery and robotic surgery ensures the steps of minimally invasive treatment for duodenal GIST into a new era.

Deficiency in VHR/DUSP3, a suppressor of focal adhesion kinase, reveals its role in regulating cell adhesion and migration.

Vaccinia H1-related phosphatase (VHR/DUSP3) is a member of the dual-specificity phosphatase family. Deregulation of VHR is observed in various malignant diseases. We identified focal adhesion kinase (FAK) as a VHR-interacting molecule. Over-expression of VHR decreased tyrosine phosphorylation of FAK and decreasing VHR promoted FAK tyrosine phosphorylation. In vitro assays proved that recombinant VHR directly dephosphorylated FAK and paxillin. VHR-knockout mice did not have obvious abnormality; however, VHR-knockout cells showed decreased expression of integrins and FAK but stronger FAK and paxillin phosphorylation upon attachment to fibronectin. Additionally, VHR-knockout fibroblast and lung epithelial cells had elevated ligand-induced epidermal growth factor receptor (EGFR) phosphorylation. Inducible expression of VHR suppressed directional cell migration, and VHR deficiency resulted in a higher cell migratory ability. VHR-knockout cells have stronger FAK phosphorylation in cell adhesions, long-lasting trailing ends and slower turnover of focal adhesions. These collective data indicate that VHR is a FAK phosphatase and participates in regulating the formation and disassembly of focal adhesions.

Clinico-biological significance of suppressor of cytokine signaling 1 expression in acute myeloid leukemia.

Suppressor of cytokine signaling 1 (SOCS1) protein, which encodes a member of signal transducers and activators of transcription-induced inhibitors, takes part in a negative regulation of cytokine signaling. The mechanism of SOCS1 in tumor carcinogenesis is complex and there have been no studies concerning the clinic-biologic implication of SOCS1 expression in acute myeloid leukemia (AML). Here, we first identified that higher bone marrow (BM) SOCS1 expression was closely associated with older age, FLT3-ITD, NPM1 and DNMT3A mutations, but negatively correlated with CEBPA mutation in patients with de novo AML. Compared to patients with lower SOCS1 expression, those with higher expression had lower complete remission rates and shorter overall survival. Further, higher expression of SOCS1 in the BM was an independent unfavorable prognostic factor irrespective of age, white blood cell, cytogenetics and gene mutations. Next, we generated zebrafish model overexpressing SOCS1 by spi1 promoter, which showed kidney marrow from adult SOCS1 zebrafish had increased myelopoiesis, myeloid progenitors and the kidney or spleen structure were effaced and distorted, mimicking leukemia phenotype. The SOCS1/FLT3-ITD double transgenic fish could further facilitate the leukemic process. The results indicate SOCS1 plays an important role in AML and its higher expression serves as a new biomarker to risk-stratify AML patients.

Micro-autologous Fat Transplantation (MAFT) for Forehead Volumizing and Contouring.

BACKGROUND: Frontal fullness in Asians is often considered to indicate one's public popularity and leadership skills. Numerous materials and techniques have been applied clinically to recontour or volumize the frontal area, with variable results. The micro-autologous fat transplantation (MAFT) technique proposed by Lin et al. (2nd academic congress of Taiwan Cosmetic Association Taipei, Taiwan) in 2007 has demonstrated its feasibility in facial rejuvenation. In the present study, we used an innovative instrument to apply the MAFT technique to frontal augmentation with fat grafting and reported the results. METHODS: MAFT was performed on 178 patients (167 female, 11 male) during a 5-year period starting in January 2010. Fat was harvested by liposuction, processed and refined by centrifugation at 1200×g for 3 min. The purified fat was micro-transplanted for frontal contouring with the assistance of an instrument, the MAFT-GUN. The patients were followed up regularly, and photographs were taken for comparison. RESULTS: On average, the MAFT procedure took 52 min to complete. The average amount of delivered fat was 10.2 mL. The follow-up period was 34 months on average. No complications, including neurovascular injury, skin necrosis, abscess, nodulation, calcification or irregularity, were noted. A patient-rated satisfaction 5-point Likert scale demonstrated that 83.1% of all patients had favorable results (48.3% were satisfied, and 34.8% were very satisfied). CONCLUSION: The concept and technique of MAFT has changed fat grafting from an operation with unpredictable clinical results to an easy, reliable and consistent procedure. Furthermore, the use of a precisely controlled instrument enabled surgeons to perform highly accurate micro-fat grafting. In comparison with other strategies for volume restoration, the MAFT procedure demonstrated high patient satisfaction with the long-term results. Therefore, the use of MAFT as an alternative approach to forehead contouring and volumizing was addressed. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Helicobacter pylori infection increases the risk of adult-onset asthma: a nationwide cohort study.

Helicobacter pylori infection (HPI) appears to reduce risk of childhood-onset asthma, but the relationship between HPI and adult-onset asthma is inconclusive. This study explored the potential association between HPI and risk of adult-onset asthma. We conducted a national insurance retrospective cohort study using the longitudinal health insurance database (LHID 2000) in Taiwan. We enrolled the HPI group consisting of 1664 patients with HPI diagnosis between 2000 and 2007, and the non-HPI group consisting of 6,656 age- and sex-matched subjects without HPI. All study participants had been followed up from index date to the diagnostic date of asthma, withdrawal from the National Health Insurance program, or the end of 2011, which came first. We analyzed risk of adult-onset asthma with respect to sex, age, and comorbidities by using Cox models. Cigarette smoking status, which could not be obtained from the program, was adjusted indirectly by considering chronic obstructive pulmonary diseases in our statistical models because the disease is related to heavy smoking. After adjustment for sex, age, and comorbidities, HPI was significantly associated with an increased 1.38-fold risk of adult-onset asthma. Moreover, among people without comorbidities, the 1.85-fold risk of adult-onset asthma remained higher for the HPI population compared with the non-HPI population. In this study, patients with HPI exhibited a significantly higher risk of adult-onset asthma than did the subjects without HPI.

Inverse Association Between Serum Osteoprotegerin and Bone Mineral Density in Renal Transplant Recipients.

BACKGROUND: Osteoprotegerin (OPG) has pleiotropic effects on bone metabolism as well as endocrine function. Our aim was to evaluate the relationship between bone mineral density (BMD) and serum OPG concentration in renal transplant recipients. METHODS: Fasting blood samples were obtained from 69 renal transplant recipients. BMD was measured in lumbar vertebrae (L2-L4) by dual-energy X-ray absorptiometry. Eight patients (11.6%) had BMD values indicative of osteoporosis, 28 patients (40.6%) had BMD values indicative of osteopenia, and 33 patients had normal BMD values. Increased serum OPG levels (P < .001), decreased body mass index (BMI) (P = .033), and decreased body weight (P = .010) were significantly correlated with low lumbar T-score cut-off points between groups (normal, osteopenia, and osteoporosis). RESULTS: Women had significantly lower lumbar BMD values than men (P = .013). Menopause (P = .005), use of tacrolimus (P = .020), and use of cyclosporine (P = .046) were associated with lower lumbar BMD in renal transplant recipients. Univariate linear regression analysis revealed that lumbar BMD was positively correlated with height (P = .016), body weight (P = .001), and BMI (P = .015) and negatively correlated with age (P = .039) and log-OPG (P = .001). Multivariate linear regression analysis revealed that log-OPG (ß: -0.275, R(2) change = 0.154, P = .014), body weight (ß: 0.334, R(2) change = 0.073, P = .004), and age (ß: -0.285, R(2) change = 0.079, P = .008) were independent predictors of lumbar BMD values in renal transplant recipients. CONCLUSIONS: Serum OPG concentration correlated negatively with lumbar BMD values in renal transplant recipients.

Candidate tumor suppressor B-cell translocation gene 3 impedes neoplastic progression by suppression of AKT.

BTG3 (B-cell translocation gene 3) is a p53 target that also binds and inhibits E2F1. Although it connects two major growth-regulatory pathways functionally and is downregulated in human cancers, whether and how BTG3 acts as a tumor suppressor remain largely uncharacterized. Here we present evidence that BTG3 binds and suppresses AKT, a kinase frequently deregulated in cancers. BTG3 ablation results in increased AKT activity that phosphorylates and inhibits glycogen synthase kinase 3ß. Consequently, we also observed elevated ß-catenin/T-cell factor activity, upregulation of mesenchymal markers, and enhanced cell migration. Consistent with these findings, BTG3 overexpression suppressed tumor growth in mouse xenografts, and was associated with diminished AKT phosphorylation and reduced ß-catenin in tissue specimens. Significantly, a short BTG3-derived peptide was identified, which recapitulates these effects in vitro and in cells. Thus, our study provides mechanistic insights into a previously unreported AKT inhibitory pathway downstream of p53. The identification of an AKT inhibitory peptide also unveils a new avenue for cancer therapeutics development.

Monocyte-derived fibrocytes induce an inflammatory phenotype in airway smooth muscle cells.

BACKGROUND: Infiltration of fibrocytes (FC) in the airway smooth muscle is a feature of asthma, but the pathological significance is unknown. OBJECTIVE: We sought to explore whether FC modulate the phenotype of airway smooth muscle cells (ASMC) in asthmatic vs. control subjects. METHODS: Fibrocytes were isolated from CD14+ monocytes from asthmatic and normal subjects. Proliferation of ASMC of asthmatic or normal subjects was analysed by (3) H-thymidine incorporation, cell number counting and Ki-67 expression after treatment of ASMC with FC-conditioned medium (FCCM) or co-culture with FC. ASMC-associated cytokines/chemokines implicated in asthma (TGF-ß1, eotaxin, IL-6 and IL-8) were measured in co-culture or transwell culture of ASMC + FC by ELISA. Immunofluorescence staining was performed to localize these cytokines in ASMC. Cytokine secretion was measured in the transwell culture of ASMC + FC, where NF-κB-p65 or ERK1/2 in ASMC was silenced by siRNA. Contractile phenotype of ASMC in transwell culture was assessed by immunoblotting of α-smooth muscle actin (α-SMA) and myosin light chain kinase (MLCK). RESULTS: Fibrocytes did not affect ASMC proliferation and expression of TGF-ß1, eotaxin, α-SMA and MLCK; however, ASMC production of IL-8 and IL-6 was increased in the co-culture and transwell culture by FC. ASMC treated with FCCM were immunopositive for IL-8/IL-6 and produced more IL-8/IL-6. Furthermore, siRNA silencing of NF-κB-p65 or ERK1/2 in transwell cultures of asthmatic ASMC with normal subject FC decreased IL-8 and IL-6 production. CONCLUSIONS AND CLINICAL RELEVANCE: Fibrocytes promoted IL-8 and IL-6 production by ASMC, demonstrating a proinflammatory role for FC and a possible mechanism of the inflammatory phenotype in asthma.

Right mini-parasternotomy may be a good minimally invasive alternative to full sternotomy for cardiac valve operations-a propensity-adjusted analysis.

AIM: Limited realworld data existed for miniparasternotomy approach with good sample size in Asian cohorts and most previous studies were eclipsed by case heterogeneity. The goal of this study was to compare safety and quality outcomes of cardiac noncoronary valve operations by miniparasternotomy and full sternotomy approaches on riskadjusted basis. METHODS: From our hospital database, we retrieved the cases of non-coronary valve operations from 1 January 2005 to 31 December 2012, including re-do, emergent, and combined procedures. Estimated EuroScore-II and propensity score for choosing mini-parasternotomy were adjusted for in the regression models on hospital mortality, complications (pneumonia, stroke, sepsis, etc.), and quality parameters (length of stay, ICU time, ventilator time, etc.). Non-complicated cases, defined as survival to discharge, ventilator use not over one week, and intensive care unit stay not over two weeks, were used for quality parameters. RESULTS: There were 283 miniparasternotomy and 177 full sternotomy cases. EuroScore-II differed significantly (medians 2.1 vs. 4.7, p<0.001). Propensity scores for choosing miniparasternotomy were higher with lower EuroScore-II (OR=0.91 per 1%, p<0.001), aortic regurgitation (OR=2.3, p=0.005), and aortic non-mitral valve disease (OR=3.9, p<0.001). Adjusted for propensity score and EuroScore-II, mini-parasternotomy group had less pneumonia (OR=0.32, p=0.043), less sepsis (OR=0.31, p=0.045), and shorter non-complicated length of stay (coefficient=7.2 (day), p<0.001) than full sternotomy group, whereas Kaplan-Meier survival, non-complicated ICU time, non-complicated ventilator time, and 30-day mortality did not differ significantly. CONCLUSION: The propensity-adjusted analysis demonstrated encouraging safety and quality outcomes for mini-parasternotomy valve operation in carefully selected patients.

Metastatic abscess formation in a preexisting chest wall tumor: a rare initial presentation of Klebsiella pneumoniae liver abscess.

The common infectious agents in the chest wall include Mycobacterium tuberculosis, Actinomyces, fungi, Nocardia, Entamoeba histolytica, and other aerobes and anaerobes. Klebsiella pneumoniae is an uncommon etiological agent. We describe a case of ankylosing spondylitis in a 45-year-old man, who had exhibited a painless lump in the left posterior chest wall for 3 months and who presented with acute-onset pain, erythematous change, and fever in the 2 weeks before admission. Cultures of the blood and chest wall abscess both showed Gram-negative bacilli, which were classified as K. pneumoniae. A contrast-enhanced computed tomography scan of the abdomen revealed a nonenhancing cystic abscess measuring 4.9 × 6.5 × 6.4 cm in segment 6 of the liver and communicating with the chest wall. Drainage of the liver abscess under ultrasound guidance and open surgical drainage of the chest wall abscess combined with adequate antibiotic treatment resolved the abscess.

Necrotizing pneumonia caused by nanC-carrying serotypes is associated with pneumococcal haemolytic uraemic syndrome in children.

Streptococcus pneumoniae infection is a leading cause of morbidity and mortality worldwide. One of the most severe complications of invasive pneumococcal disease (IPD) is haemolytic uraemic syndrome (HUS). This study was undertaken to determine the risk factors and role of pneumococcal neuraminidases in HUS in children with IPD. Eighteen cases of HUS and 54 patients with IPD without HUS were identified. The controls were patients with culture-confirmed IPD without HUS. Clinical and laboratory characteristics of the two groups of patients were compared. Bacterial isolates from both groups were serotyped, sequence typed and examined for their carriage of three neuraminidase genes. Necrotizing pneumonia and serotype 3 infection were significantly associated with HUS in children with IPD, suggesting that a severe pulmonary suppurating disease increase the risk of HUS. Serotype 14 was associated with necrotizing pneumonia but not HUS. Children with HUS were more likely to require surgery and had a longer duration of hospitalization. The study identified a significantly higher carriage of a neuraminidase gene, nanC, in the causative pneumococcal isolates from patients with HUS (89% versus 41%, p 0.001). The sensitivity and specificity of nanC to predict HUS were 89% and 59%, respectively. In conclusion, necrotizing pneumonia, serotype 3 infection and neuraminidase gene nanC were associated with HUS in children with IPD. The result suggests that NanC could provide an additive effect to NanA and NanB in the overall activity of pneumococcal neuraminidases to expose Thomsen-Friedenreich antigen on various cells in patients with HUS.

Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis.

The B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG gene family and a downstream target of p53. BTG3 also binds and inhibits E2F1. Although it connects functionally two major growth-regulatory pathways, the physiological role of BTG3 remains largely uncharacterized. Here, we present evidence that loss of BTG3 in normal cells induced cellular senescence, which was correlated with enhanced ERK-AP1 signaling and elevated expression of the histone H3K27me3 demethylase JMJD3/KDM6B, leading to acute induction of p16(INK4a). Importantly, we also found that BTG3 expression is specifically downregulated in prostate cancer, thus providing a physiological link with human cancers. Our data suggest that BTG3 may have a fail-safe role against tumorigenic progression.

PTEN, tau-AP-3, thymidylate synthase immunohistochemistry scoring expression in patients with uterine leiomyomas, uterine smooth muscle tumors of uncertain malignancy potential and uterine leiomyosarcomas.

Uterine smooth muscle tumors are frequently classified as benign and malignant. However, an assortment of mitotic counts and nuclear atypia can be indecisive between uncertain malignant potential, and malignant uterine smooth muscle tumors. We applied three immunohistochemical parameters to distinguish between cases of benign, malignant, and those with uncertain malignant histology.

Absolute lymphocyte count is a novel prognostic indicator in extranodal natural killer/T-cell lymphoma, nasal type.

BACKGROUND: extranodal natural killer (NK)/T-cell lymphoma (ENKL) is a heterogeneous entity with poor survival, requiring risk stratification in affected patients. We proposed absolute lymphocyte count (ALC) as a new prognostic factor in ENKL. PATIENTS AND METHODS: we retrospectively analyzed 128 patients newly diagnosed with ENKL. Independent prognostic factors of survival were determined by Cox regression analysis. RESULTS: patients with low ALC (<1.0 × 10(9)/l) at diagnosis tended to have more adverse clinical features. Patients with high ALC (≥1.0 × 10(9)/l) at diagnosis had better overall survival (OS; P < 0.0001) and progression-free survival (PFS; P<0.0001), and achieved higher complete remission rates (P=0.001). Multivariate analysis with known prognostic factors showed that ALC, B symptoms and advanced stage were independent predictors for OS and PFS. Using the International Prognostic Index, Prognostic Index for Peripheral T-cell lymphoma unspecified, or Korean Prognostic Index for nasal NK/T-cell lymphoma, the majority of patients were in the low-risk category (with no or one adverse factor). ALC was helpful to differentiate the low-risk patients with different survival outcomes (P < 0.0001). CONCLUSIONS: our data suggest that ALC at diagnosis is a novel, powerful predictor of prognosis in ENKL. Immune status at diagnosis might have an important influence on survival in patients with ENKL.

Comparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy.

During chemotherapy for lymphoma, the administration of cytotoxic agents and rituximab often results in hepatitis B reactivation (incidence, 14-72%). This study was designed to compare the efficacy of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients. Between January 2007 and February 2009, patients treated in four hospitals in China were screened to identify those most appropriate for analysis. These patients received either entecavir or lamivudine during chemotherapy and for 6 months after completion of chemotherapy. A total of 34 patients received entecavir and 89 patients received lamivudine. Compared with the lamivudine group, the entecavir group had significantly lower rates of hepatitis (5.9 vs 27.0%, P = 0.007), hepatitis B reactivation (0 vs 12.4%, P = 0.024) and disruption of chemotherapy (5.9 vs 20.2%, P = 0.042). All patients with hepatitis B reactivation had B-cell non-Hodgkin's lymphoma (stage III-IV). In lymphoma patients under chemotherapy treatment, entecavir is more effective than lamivudine in preventing hepatitis B reactivation. For patients with advanced stage disease, entecavir should be considered the primary preventive therapy.

p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control.

The p53 tumor suppressor protein is widely known for its role as a sequence-specific transcription factor that regulates the expression of stress response genes. Here, we report the identification of LIMK2, which encodes a kinase that regulates actin dynamics through phosphorylation of cofilin, as a p53 target upregulated by DNA damage. Interestingly, the splice variant LIMK2b, but not LIMK2a, was induced in a p53-dependent manner through an intronic consensus p53-binding site. Depletion of LIMK2b leads to early exit of G2/M arrest after DNA damage, whereas its overexpression prolongs the arrest. These responses are recapitulated by ectopic expression of the active cofilin S3A mutant and the inactive cofilin S3D mutant, respectively, suggesting that LIMK2b may modulate G2/M arrest through cofilin phosphorylation. Furthermore, in support of its potential role as a tumor suppressor, LIMK2b was downregulated in esophageal and thyroid cancers, as well as in a number of established cancer cell lines, and its expression suppresses cancer cell migration. Taken together, our results unveil a novel pathway whereby LIMK2b, acting downstream of p53, ensures proper execution of checkpoint arrest by modulating the dynamics of actin polymerization.

Verification of the accuracy of BNCT treatment planning system THORplan.

THORplan is a treatment planning system developed at Tsing Hua University, Taiwan, for boron neutron capture therapy (BNCT) purpose. It is recently developed with user-friendly interface using Interactive Data Language. In this article the accuracy of THORplan is verified by comparing results of Snyder phantom calculation with the analytical model results of MCNP. Neutron source from THOR epithermal neutron beam is used as the source for the calculation. The thermal neutron flux calculated by THORplan is very close to the reference results. SERA overestimates thermal neutron flux by 2-5%. NCTPlan underestimates thermal neutron flux by 4-9% in most locations. The total weighted dose calculated by THORplan is accurate to within 3% except at the tissue interface. SERA overestimates the total weighted dose at depth >1.5 cm by 2-5%. NCTPlan underestimates the total weighted dose by approximately 10% at depth >1cm.