A Pt(IV)-conjugated brain penetrant macrocyclic peptide shows pre-clinical efficacy in glioblastoma.

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median survival of approximately 15 months. Treatment is limited by the blood-brain barrier (BBB) which restricts the passage of most drugs to the brain. We previously reported the design and synthesis of a BBB-penetrant macrocyclic cell-penetrating peptide conjugate (M13) covalently linked at the axial position of a Pt(IV) cisplatin prodrug. Here we show the Pt(IV)-M13 conjugate releases active cisplatin upon intracellular reduction and effects potent in vitro GBM cell killing. Pt(IV)-M13 significantly increased platinum uptake in an in vitro BBB spheroid model and intravenous administration of Pt(IV)-M13 in GBM tumor-bearing mice led to higher platinum levels in brain tissue and intratumorally compared with cisplatin. Pt(IV)-M13 administration was tolerated in naïve nude mice at higher dosage regimes than cisplatin and significantly extended survival above controls in a murine GBM xenograft model (median survival 33 days for Pt(IV)-M13 vs 24 days for Pt(IV) prodrug, 22.5 days for cisplatin and 22 days for control). Increased numbers of γH2AX nuclear foci, biomarkers of DNA damage, were observed in tumors of Pt(IV)-M13-treated mice, consistent with elevated platinum levels. The present work provides the first demonstration that systemic injection of a Pt(IV) complex conjugated to a brain-penetrant macrocyclic peptide can lead to increased platinum levels in the brain and extend survival in mouse GBM models, supporting further development of this approach and the utility of brain-penetrating macrocyclic peptide conjugates for delivering non-BBB penetrant drugs to the central nervous system.

Risk assessment of malignant transformation of oral leukoplakia in patients with previous oral squamous cell carcinoma.

The aim of this study was to identify the risk factors associated with developing oral squamous cell carcinoma (OSCC) from surgically excised oral leukoplakia (OL) in patients with previous oral cavity cancer. Clinicopathological data of 84 patients who were treated for OL between July 2002 and July 2020 and who had previously received treatment for OSCC were reviewed retrospectively. The follow-up time ranged from 0.69 to 17.99 years (mean 6.78 ± 4.25 years). The overall cumulative malignant transformation rate was 25% and the annual transformation rate was 5.73%. Kaplan-Meier survival analysis and the log-rank test showed that Candida infection (P = 0.010) was a risk factor associated with malignant transformation. In the multivariate Cox regression analysis, tongue and floor of the mouth as the location of the leukoplakia (P = 0.039), multifocal lesions of OL (P = 0.047), and Candida infection (P = 0.018) were the three independent prognostic factors related to the development of OSCC from the treated OL. A cautious approach to OL of the tongue with Candida infection or multifocal disease in this group of patients would be appropriate.

A case of GNE myopathy mimicking hereditary motor neuropathy.

A 36-year-old woman who presented with upper limb distal weakness since the age of 15 years, with gradual progression to the lower limbs, is reported. Hereditary motor neuropathy was initially suspected based on distal weakness and hyporeflexia; however, whole exome sequencing accidentally revealed a compound heterozygous variant in the GNE gene, and ultrasound revealed increased homogeneous echogenicity in the involved muscles, which is characteristic of myopathic changes. Muscle magnetic resonance imaging revealed fatty infiltration in all limb muscles, sparing the triceps brachii, vastus lateralis and vastus medialis. Muscle biopsy revealed intracytoplasmic rimmed vacuole, supporting the diagnosis of GNE myopathy.

Pleural fluid lactate as a point-of-care adjunct diagnostic aid to distinguish tuberculous and complicated parapneumonic pleural effusions during initial thoracentesis: Potential use in a tuberculosis endemic setting.

BACKGROUND: Tuberculous pleural effusions (TBEs) and parapneumonic pleural effusion (PPEs) have similar clinical presentations and fluid biochemistry. A pleural biopsy is usually required to diagnose TBE but complete fluid evacuation may not be necessary, contrasting with complicated PPE (CPPE). A point-of-care test that distinguishes between TBE and CPPE enables the appropriate procedures to be performed during the initial diagnostic thoracentesis. Lactate is a metabolic product measurable by a blood-gas analyzer. This study measured pleural fluid (Pf) lactate levels in TBE and compared them with those in PPE/CPPE. We hypothesized that Pf lactate would be significantly higher in PPE because of active metabolic activities than in TBE which is driven by delayed hypersensitivity. METHODS: All patients undergoing an initial diagnostic thoracentesis over 18 months with Pf lactate measured using a calibrated point-of-care blood gas analyzer were assessed. RESULTS: The diagnoses of the enrolled patients (n = 170) included TBE (n = 49), PPE (n = 47), malignancy (n = 63), and transudate (n = 11). Pf lactate level in TBE, median 3.70 (inter-quartile range 2.65-4.90) mmol/l, was significantly lower than in PPE and CPPE. In the subgroup of TBE and CPPE patients whose initial Pf pH and glucose could suggest either condition, Pf lactate was significantly higher in those with CPPE. Pf lactate (cutoff ≥7.25 mmol/l) had a sensitivity of 79.3%, specificity 100%, positive predictive value 100%, and negative predictive value 89.1% for discriminating CPPE from TBE (area under the curve 0.947, p < 0.001, 95% confidence interval 0.89-0.99). CONCLUSIONS: Point-of-care Pf lactate measurements may have practical value in early separation of TBE or CPPE during initial thoracentesis, and warrants further investigation.

Comparison of lateral and supine positions for tracheal extubation in children : A randomized clinical trial.

BACKGROUND: The lateral position is known to be advantageous for maintaining airway patency. This study compared the lateral and supine positions for tracheal extubation in pediatric patients when performing deep extubation. OBJECTIVE: The hypothesis was that tracheal extubation in the lateral position would improve airway obstruction that often occurs immediately after extubation and can be a practical method. MATERIAL AND METHODS: This prospective randomized trial was performed in operating rooms in a tertiary care hospital and included 92 patients (3-12 years old) undergoing elective strabismus surgery. The patients were randomly divided into two groups: deep extubation in the supine position (group S) and deep extubation in the lateral position (group L). Oxygen saturation (SpO2) and the incidence of stridor, laryngospasm, and coughing after tracheal extubation were assessed. RESULTS: The mean ± standard deviation of the lowest SpO2 values within 5 min after extubation was significantly higher in group L (98.3 ± 2.1%) than in group S (96.8 ± 2.5%, mean difference 1.5, 95% confidence interval, CI 0.5-2.5, p = 0.003). The incidences of stridor and laryngospasm of group L were significantly lower than those of group S (1/45, 2% vs. 8/45, 18%, respectively; relative risk 1.9, 95% CI 1.4-2.7, p = 0.03). The incidence of desaturation and coughing were not significantly different between groups. CONCLUSION: In pediatric patients deep extubation in the lateral position improved SpO2 and reduced the incidence of stridor and laryngospasm in the early emergence period when compared to extubation in the supine position.

Normative values and factors affecting water-perfused esophageal high-resolution impedance manometry for a Chinese population.

BACKGROUND: Combined esophageal high-resolution impedance manometry (HRIM) measures multiple pressures and bolus transit simultaneously, facilitating detailed assessment of esophageal motility. Currently, normative values for water-perfused HRIM systems for Chinese populations are lacking. METHODS: Healthy volunteers were enrolled for comprehensive anthropometric measures, blood biochemistry tests, and an HRIM study using 22 water-perfused pressure sensors and 12 impedance channels. Ten 5-mL liquid swallows of saline at 30-second intervals were conducted. The following parameters were calculated: distal contractile integral (DCI), distal latency (DL), lower esophageal sphincter (LES) basal pressure, 4-second integrated relaxation pressure (IRP-4s), and complete bolus transit percentage. Normal values were established based on the 5th and 95th percentiles. KEY RESULTS: All 66 participants (34 male, 32 female, aged 21-64 years) completed the study and tolerated the HRIM procedure well. The upper normal limit (95th percentile) of IRP-4 second was 20 mmHg. The 5th-95th percentile range for DCI, DL, and complete bolus transit was 99-2186 mmHg●s●cm, 6.2-11.3 second, and 50%-100%, respectively. Age was negatively correlated with DL. Females had significantly higher upper limits for IRP-4s and median DCI than males. Multivariate analyses confirmed that IRP-4s was higher in females, and that higher body mass index and waist circumference were associated with reduced DL and better bolus transit, respectively. CONCLUSIONS AND INFERENCES: We established normative values for the water-perfused HRIM system for a Chinese population. Gender and anthropometric factors may affect various major HRIM parameters and should be taken into account when interpreting HRIM results in clinical practice.

Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties.

Growing evidence indicates that resistin-an obesity-related cytokine-is upregulated in breast cancer patients, yet its impact on breast cancer behavior remains to be ascertained. Similarly, Toll-like receptor 4 (TLR4) has been implicated in breast cancer progression, however, its clinically relevant endogenous ligand remains elusive. In this study, we observed that high serum resistin levels in breast cancer patients positively correlated with tumor stage, size and lymph node metastasis. These findings were replicated in animal models of breast cancer tumorigenesis and metastasis. Resistin was found to promote epithelial-mesenchymal transition and stemness in breast cancer cells-mechanisms critical to tumorigenesis and metastasis-through a TLR4/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and negated by TLR4-specific antibody and antagonist. These findings provide clear evidence that resistin is a clinically relevant endogenous ligand for TLR4, which promotes tumor progression via TLR4/NF-κB/STAT3 signaling, providing insights into a novel therapeutic target in breast cancer.

Integration of radiotherapy and chemotherapy for abdominal lymph node recurrence in gastric cancer

Purpose. Abdominal lymph node (ALN) recurrence in gastric cancer (GC) is rare and usually unresectable. We investigated the effects of integration of radiotherapy (RT) and chemotherapy against ALN recurrence in GC. Methods. We retrospectively categorized GC patients with ALN recurrence treated between 2005 and 2013 into two groups: those treated with integration of RT and chemotherapy (RCT) and those who received systemic chemotherapy only (CT). The median follow-up period after ALN recurrence for all patients was 20 months. Results. Of 53 patients, 31 and 22 were in the RCT and CT groups, respectively. Isolated distant failure (DF; 35.5%) without local progression (LP) was the dominant pattern of failure (POF) in the RCT group (median DF-free period, 26 months). LP followed by DF (31.8%) was the dominant POF in the CT group; LP (median LP-free period, 8 months) occurred 10 months earlier than DF (median DF-free period, 18 months). RCT patients had significantly longer median progression-free survival (PFS) compared to CT patients (25 vs. 8 months; P = 0.021). On multivariate analysis, treatment (CT vs. RCT) was an independent prognostic factor for PFS (hazard ratio 2.085; 95% confidence interval 1.073-4.050; P = 0.013). Conclusions. Integration of RT and chemotherapy achieved long-term local control and prolonged PFS in GC patients with ALN recurrence. Local RT is feasible for treating isolated ALN recurrences (AU)

No disponible

Feasibility of objectively measured physical activity and sedentary behavior in patients with malignant pleural effusion.

PURPOSE: Malignant pleural effusion (MPE) affects 1 million people worldwide annually and can significantly impair physical activity. Accelerometry is a validated method of objectively assessing physical activity. The purpose of this study was to determine the compliance in patients with MPE to accelerometry and describe their activity. METHODS: Patients with MPE wore an Actigraph GT3X accelerometer over a 7-day continuous wear protocol. Compliance was measured as the percent of patients who had ≥4 valid days (i.e., 8-h/day of waking wear-time). Eastern Cooperative Oncology Group performance status was documented the day of actigraphy initialization. RESULTS: Forty-six patients with MPE received accelerometers; 44 (95.7%) returned their device. No complications were reported on their use. Forty subjects (90.9%) had ≥4 valid days of wear-time. Patients spent most of their waking hours sedentary [mean 11.0 h (SD 1.95)], with limited participation in moderate and vigorous physical activity [mean 9.5 min (SD 14.16)]. Compared to patients with better performance status (n = 32), patients with poorer performance status (n = 11) spent significantly more hours/day sedentary [mean difference 2.1 (CI 0.86-3.32); p = 0.001], as did those who survived <3 months (n = 5) compared to >12 months (n = 27) [mean difference 2.6 (CI 0.49-4.77); p = 0.013). CONCLUSION: Accelerometry was applied successfully in patients with MPE with high compliance and no adverse events. This is the first reported objectively measured physical activity in patients with MPE and revealed high sedentary behavior and low physical activity. The data reflected patient performance status and discriminated between survival groups. Accelerometry can provide a useful measure for future interventional studies in patients with MPE.

Lower urinary cotinine level is associated with a trend toward more myopic refractive errors in Korean adolescents.

PurposeTo investigate the association between urinary cotinine levels as an objective biological marker for exposure to nicotine and refractive status.Patients and methodsThis cross-sectional study analyzed data from the Korea National Health and Nutrition Examination Survey between 2008 and 2011. A total of 1139 Korean adolescents aged 12-18 years were enrolled. Urinary cotinine concentrations and other potential risk factors for myopia were examined. Correlation analyses and multivariate regression analysis were performed to investigate the association between urinary cotinine level and refractive error.ResultsSpherical equivalent correlated significantly with urinary cotinine concentration (r=0.104, P=0.011). Lower urinary cotinine level was associated with a trend toward more myopic refractive errors (P for trend=0.003). After adjusting for age, sex, area of residence, physical activity, serum 25-hydroxyvitamin D level, parental income level, and receipt of basic livelihood security, subjects with a low urinary cotinine level had a significantly increased risk of myopia <-0.5 D (odds ratio (OR) 1.95, 95% confidence interval (CI) 1.18-3.21), <-3.0 D (OR 2.03, 95% CI 1.29-3.2), and <-6.0 D (OR 2.2, 95% CI, 1.15-4.23) when compared with subjects with a high urinary cotinine level. As urinary cotinine level decreased, the risks of myopia <-0.5 D, <-3.0 D, and <-6.0 D increased significantly (P for trend <0.05).ConclusionA trend toward less myopic refractive error was observed among Korean adolescents with higher urinary cotinine levels. This result provides the epidemiologic evidence implying nicotine as a potential modulator related with refractive development. Further studies with full consideration for myopia-associated risk factors are required to yield clear answers on the direct effect of smoking to the refractive status.

A novel DNAJB6 mutation causes dominantly inherited distal-onset myopathy and compromises DNAJB6 function.

BACKGROUND: Mutations in the DNAJB6 gene have been identified as a rare cause of dominantly inherited limb-girdle muscular dystrophy or distal-onset myopathy. MATERIALS AND METHODS: Exome sequencing was performed to investigate a Taiwanese family with a dominantly inherited distal-onset myopathy. Functional effects of the causal mutation were investigated in vitro. RESULTS: Exome sequencing of the two affected individuals in this family identified a heterozygous mutation, c.287C>T (p.Pro96Leu) in the DNAJB6 gene, which co-segregated with the myopathy within all 12 family members. Notably, this mutation is novel and localizes within the glycine and phenylalanine-rich (G/F) domain and alters an amino acid residue previously reported with a different mutation. Furthermore, immunofluorescence analyses and filter trap assay demonstrated that the c.287C>T (p.Pro96Leu) mutation possessed a dominant negative effect on the anti-aggregation function of DNAJB6 protein. CONCLUSION: This study expands the molecular spectrum of DNAJB6 mutations and also emphasizes the pathogenic role of DNAJB6 dysfunction in distal-onset myopathy.

The role of oral hygiene in head and neck cancer: results from International Head and Neck Cancer Epidemiology (INHANCE) consortium.

BACKGROUND: Poor oral hygiene has been proposed to contribute to head and neck cancer (HNC) risk, although causality and independency of some indicators are uncertain. This study investigates the relationship of five oral hygiene indicators with incident HNCs. METHODS: In a pooled analysis of 8925 HNC cases and 12 527 controls from 13 studies participating in the International Head and Neck Cancer Epidemiology Consortium, comparable data on good oral hygiene indicators were harmonized. These included: no denture wear, no gum disease (or bleeding), <5 missing teeth, tooth brushing at least daily, and visiting a dentist ≥once a year. Logistic regression was used to estimate the effects of each oral hygiene indicator and cumulative score on HNC risk, adjusting for tobacco smoking and alcohol consumption. RESULTS: Inverse associations with any HNC, in the hypothesized direction, were observed for <5 missing teeth [odds ratio (OR) = 0.78; 95% confidence interval (CI) 0.74, 0.82], annual dentist visit (OR = 0.82; 95% CI 0.78, 0.87), daily tooth brushing (OR = 0.83, 95% CI 0.79, 0.88), and no gum disease (OR = 0.94; 95% CI 0.89, 0.99), and no association was observed for wearing dentures. These associations were relatively consistent across specific cancer sites, especially for tooth brushing and dentist visits. The population attributable fraction for ≤ 2 out of 5 good oral hygiene indicators was 8.9% (95% CI 3.3%, 14%) for oral cavity cancer. CONCLUSION: Good oral hygiene, as characterized by few missing teeth, annual dentist visits, and daily tooth brushing, may modestly reduce the risk of HNC.

Combined body mass index with high-sensitivity C-reactive protein as independent predictors for chronic kidney disease in a relatively healthy population in Taiwan.

BACKGROUND/OBJECTIVES: Obesity, a chronic inflammatory state, increases risk of cardiovascular disease and insulin resistance, which are the leading cause of end-stage renal disease (ESRD). We evaluated the relationship between body mass index (BMI) and high-sensitivity C-reactive protein (hsCRP) level and impaired kidney function to determine the predictive value of both markers for estimating chronic kidney disease (CKD) risk in a healthy adult population in Taiwan. SUBJECTS/METHODS: In a retrospective cross-sectional study of 4100 subjects ⩾18 years, a multivariate logistic regression model was used to assess the relationship among BMI, high hsCRP levels and CKD. Receiver-operating characteristic curve and Youden index were developed to define the discrimination power of combining BMI with hsCRP for CKD prediction and to determine the best predictive index. RESULTS: Overweight/obese subjects with high hsCRP levels had the highest odds ratio for CKD (P=0.048). In females, combining BMI with hsCRP for CKD prediction was superior to that of males (0.890 vs 0.623, respectively; both P<0.001). For females, the Youden index was 25.65 kg/m(2) for BMI and 1.04 µg/ml for hsCRP. CONCLUSIONS: Overweight/obesity with higher hsCRP levels is associated with reduced renal function and increased risk for CKD. BMI and hsCRP levels can be used as surrogate markers for CKD risk, especially for females.

Systematic review with meta-analysis: 10- or 14-day sequential therapy vs. 14-day triple therapy in the first line treatment of Helicobacter pylori infection.

BACKGROUND: Whether 10-day or 14-day sequential therapy is superior to 14-day triple therapy in the first-line treatment of Helicobacter pylori remains controversial. AIM: To compare the efficacy of 10-day or 14-day sequential therapy vs. 14-day triple therapy. METHODS: Randomised controlled trials (RCTs) comparing 10-day or 14-day sequential therapy and 14-day triple therapy as first-line treatment in adults were searched from the PubMed and Cochrane databases from 2000 to October 2015. Abstracts from international annual conferences were also searched. The primary and secondary outcomes were the eradication rate according to the intention-to-treat analysis and adverse effects, respectively. RESULTS: Of the 109 articles identified, 13 RCTs including 2749 patients in the sequential therapy group and 2424 patients in the 14-day triple therapy group were eligible. Overall, sequential therapy for 10 or 14 days was not significantly superior to 14-day triple therapy [Risk ratio (RR) 1.04, 95% confidence interval (CI) 0.99-1.08, P = 0.145]. However, there was significant heterogeneity (I(2) = 57.6%, P = 0.005). In the subgroup analysis of four trials, we found that 14-day sequential therapy was significantly more effective than 14-day triple therapy (RR: 1.09, 95% CI: 1.04-1.16, P = 0.002), and there was no significant heterogeneity (I(2) = 0%, P = 0.624) in this comparison. Sequential therapy given for 10 days was not superior to 14-day triple therapy (RR: 1.03, 95% CI: 0.98-1.09, P = 0.207). There was no significant difference in the risk of adverse effects. CONCLUSION: Sequential therapy given for 14 days, but not 10 days, was more effective than 14-day triple therapy as first-line treatment.

Vitamin E intake from natural sources and head and neck cancer risk: a pooled analysis in the International Head and Neck Cancer Epidemiology consortium.

BACKGROUND: Evidence for the possible effect of vitamin E on head and neck cancers (HNCs) is limited. METHODS: We used individual-level pooled data from 10 case-control studies (5959 cases and 12 248 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium to assess the association between vitamin E intake from natural sources and cancer of the oral cavity/pharynx and larynx. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models applied to quintile categories of non-alcohol energy-adjusted vitamin E intake. RESULTS: Intake of vitamin E was inversely related to oral/pharyngeal cancer (OR for the fifth vs the first quintile category=0.59, 95% CI: 0.49-0.71; P for trend <0.001) and to laryngeal cancer (OR=0.67, 95% CI: 0.54-0.83, P for trend <0.001). There was, however, appreciable heterogeneity of the estimated effect across studies for oral/pharyngeal cancer. Inverse associations were generally observed for the anatomical subsites of oral and pharyngeal cancer and within covariate strata for both sites. CONCLUSION: Our findings suggest that greater vitamin E intake from foods may lower HNC risk, although we were not able to explain the heterogeneity observed across studies or rule out certain sources of bias.

Traumatic brain injury causes frontotemporal dementia and TDP-43 proteolysis.

Traumatic brain injury (TBI) is a major risk factor for dementia. Recently, TBI has also been suggested as a risk factor for frontotemporal dementia (FTD), and plasma immunoreactivity to the TAR-DNA binding protein 43 (TDP-43) has been observed in both patients with acute TBI and long-term survivors of this condition. We used a population-based study to estimate and compare the risk of FTD in individuals with and without TBI. Furthermore, we used a rat model of TBI to show that increased TDP-43 proteolysis following TBI produces FTD-like impairments, including abnormal limb-clasping, and impaired performances in the Morris water maze. We recruited 24,585 patients who received ambulatory or hospital care for TBI and 122,925 patients without TBI for this study. Each individual was investigated for 4years to evaluate FTD development, and data were analyzed by Cox proportional hazard regression. In the TBI rat model, behavior and TDP-43 inclusions were assessed following intracranial administration of a caspase-3 inhibitor or vehicle. FTD was more likely to occur in the TBI group than in the group without TBI (adjusted hazard ratio, 4.43; 95% confidence interval, 3.85-5.10; P<0.001). Rats developed behavioral impairments similar to those in patients with FTD after TBI. Further, the behavioral impairments were likely associated with TDP-43 short fragment mislocalization and accumulation. Our findings suggest that in humans, TBI is associated with a greater occurrence of FTD. Moreover, clinical FTD manifestations may be associated with TDP-43 proteolysis, since impaired behaviors in TBI rats were reminiscent of those in humans with FTD.

The INHANCE consortium: toward a better understanding of the causes and mechanisms of head and neck cancer.

The International Head and Neck Cancer Epidemiology (INHANCE) consortium is a collaboration of research groups leading large epidemiology studies to improve the understanding of the causes and mechanisms of head and neck cancer. The consortium includes investigators of 35 studies who have pooled their data on 25 500 patients with head and neck cancer (i.e., cancers of the oral cavity, oropharynx, hypopharynx, and larynx) and 37 100 controls. The INHANCE analyses have confirmed that tobacco use and alcohol intake are key risk factors of these diseases and have provided precise estimates of risk and dose response, the benefit of quitting, and the hazard of smoking even a few cigarettes per day. Other risk factors include short height, lean body mass, low education and income, and a family history of head and neck cancer. Risk factors are generally similar for oral cavity, pharynx, and larynx, although the magnitude of risk may vary. Some major strengths of pooling data across studies include more precise estimates of risk and the ability to control for potentially confounding factors and to examine factors that may interact with each other. The INHANCE consortium provides evidence of the scientific productivity and discoveries that can be obtained from data pooling projects.