Quantum spin nematic phase in a square-lattice iridate.

Spin nematic is a magnetic analogue of classical liquid crystals, a fourth state of matter exhibiting characteristics of both liquid and solid1,2. Particularly intriguing is a valence-bond spin nematic3-5, in which spins are quantum entangled to form a multipolar order without breaking time-reversal symmetry, but its unambiguous experimental realization remains elusive. Here we establish a spin nematic phase in the square-lattice iridate Sr2IrO4, which approximately realizes a pseudospin one-half Heisenberg antiferromagnet in the strong spin-orbit coupling limit6-9. Upon cooling, the transition into the spin nematic phase at TC ≈ 263 K is marked by a divergence in the static spin quadrupole susceptibility extracted from our Raman spectra and concomitant emergence of a collective mode associated with the spontaneous breaking of rotational symmetries. The quadrupolar order persists in the antiferromagnetic phase below TN ≈ 230 K and becomes directly observable through its interference with the antiferromagnetic order in resonant X-ray diffraction, which allows us to uniquely determine its spatial structure. Further, we find using resonant inelastic X-ray scattering a complete breakdown of coherent magnon excitations at short-wavelength scales, suggesting a many-body quantum entanglement in the antiferromagnetic state10,11. Taken together, our results reveal a quantum order underlying the Néel antiferromagnet that is widely believed to be intimately connected to the mechanism of high-temperature superconductivity12,13.

Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial.

BACKGROUND: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. PATIENTS AND METHODS: We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. RESULTS: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). CONCLUSIONS: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.

The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration. PATIENTS AND METHODS: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks. RESULTS: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76). CONCLUSIONS: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected.

The transport-structural correspondence across the nematic phase transition probed by elasto X-ray diffraction.

Electronic nematicity in iron pnictide materials is coupled to both the lattice and the conducting electrons, which allows both structural and transport observables to probe nematic fluctuations and the order parameter. Here we combine simultaneous transport and X-ray diffraction measurements with in-situ tunable strain (elasto X-ray diffraction) to measure the temperature dependence of the shear modulus and elastoresistivity above the nematic transition and the spontaneous orthorhombicity and resistivity anisotropy below the nematic transition, all within a single sample of Ba(Fe0.96Co0.04)2As2. The ratio of transport to structural quantities is nearly temperature independent over a 74 K range and agrees between the ordered and disordered phases. These results show that elasto X-ray diffraction is a powerful technique to probe the nemato-elastic and nemato-transport couplings, which have important implications to the nearby superconductivity. It also enables the measurement in the large strain limit, where the breakdown of the mean-field description reveals the intertwined nature of nematicity.

Polar metals by geometric design.

Gauss's law dictates that the net electric field inside a conductor in electrostatic equilibrium is zero by effective charge screening; free carriers within a metal eliminate internal dipoles that may arise owing to asymmetric charge distributions. Quantum physics supports this view, demonstrating that delocalized electrons make a static macroscopic polarization, an ill-defined quantity in metals--it is exceedingly unusual to find a polar metal that exhibits long-range ordered dipoles owing to cooperative atomic displacements aligned from dipolar interactions as in insulating phases. Here we describe the quantum mechanical design and experimental realization of room-temperature polar metals in thin-film ANiO3 perovskite nickelates using a strategy based on atomic-scale control of inversion-preserving (centric) displacements. We predict with ab initio calculations that cooperative polar A cation displacements are geometrically stabilized with a non-equilibrium amplitude and tilt pattern of the corner-connected NiO6 octahedral--the structural signatures of perovskites--owing to geometric constraints imposed by the underlying substrate. Heteroepitaxial thin-films grown on LaAlO3 (111) substrates fulfil the design principles. We achieve both a conducting polar monoclinic oxide that is inaccessible in compositionally identical films grown on (001) substrates, and observe a hidden, previously unreported, non-equilibrium structure in thin-film geometries. We expect that the geometric stabilization approach will provide novel avenues for realizing new multifunctional materials with unusual coexisting properties.

Pilot study of fractional microneedling radiofrequency for hidradenitis suppurativa assessed by clinical response and histology.

BACKGROUND: Hidradenitis suppurativa (HS) is a devastating chronic inflammatory skin disease with frequent recurrences. Various systemic treatments and procedures have been used but the efficacy of fractional microneedling radiofrequency (FMR) has not been reported. AIM: To evaluate the clinical and histological efficacy of FMR in the treatment of HS lesions. METHODS: An 8-week, prospective, split-body, unblinded study was conducted, which enrolled 10 adult patients with mild to moderate HS to receive 3 sessions of FMR treatment biweekly. HS severity was assessed using the number and type of lesions, HS Physician Global Assessment (HS-PGA) and the modified Sartorius score (mSS). Skin biopsies were performed on participants to assess change in inflammation before and after FMR. RESULTS: Severity of HS was significantly reduced on the FMR-treated side of the body, but not on the control side. Inflammatory HS lesions were significantly reduced after 4 weeks, while HS-PGA and mSS were significantly decreased after 6 weeks. Immunohistochemistry staining showed decreased expression of inflammatory markers including neutrophil elastases, interleukin (IL)-8 and IL-17, tumour necrosis factor-α, transforming growth factor-ß1 and matrix metalloproteinases. CONCLUSION: FMR may be a viable treatment option for mild to moderate HS.

Associations of marijuana with markers of chronic lung disease in people living with HIV.

OBJECTIVES: The relationship between marijuana use and markers of chronic lung disease in people living with HIV (PLWH) is poorly understood. METHODS: We performed a cross-sectional analysis of the Examinations of HIV-Associated Lung Emphysema (EXHALE) study, including 162 HIV-positive patients and 138 participants without HIV. We modelled marijuana exposure as: (i) current daily or weekly marijuana smoking vs. monthly or less often; or (ii) cumulative marijuana smoking (joint-years). Linear and logistic regression estimated associations between marijuana exposure and markers of lung disease, adjusted for tobacco smoking and other factors. RESULTS: In PLWH, current daily or weekly marijuana use was associated with a larger forced vital capacity (FVC), larger total lung capacity and increased odds of radiographic emphysema compared with marijuana non-smokers in adjusted models; these associations were not statistically significant in participants without HIV. Marijuana joint-years were associated with higher forced expiratory volume in 1 s and FVC in PLWH but not with emphysema. CONCLUSIONS: In PLWH, marijuana smoking was associated with higher lung volumes and potentially with radiographic emphysema. No consistently negative associations were observed between marijuana and measures of chronic lung health.

Population-based, three-dimensional analysis of age- and sex-related femur shaft geometry differences.

This study deals with differences of femoral geometric focus on the bowing and width. Analysis using three-dimensional skeletonization showed increase of femoral bowing and femur width over life (more in women), and widening of the medullary canal only in women after 50 years old, not in men. INTRODUCTION: The changes in femur geometry that occur with aging and lead to fragility or insufficiency fracture remain unclear. The role of the lower limb geometry, including the femur and femoral bowing, has become a point of discussion, especially in atypical femur fracture. This study aimed to analyze femur shaft geometry using three-dimensional skeletonization. METHODS: We acquired computed tomography images of both femurs obtained. A total of 1400 age- and sex-stratified participants were enrolled and were divided into subgroups according to age (by decade) and sex. The computed tomography images were used to produce 3-dimensional samplings of anatomical elements of the human femur using reconstruction and parametrization from these datasets. The process of skeletonization was conducted to obtain compact representation of the femur. With the skeletonization, we were able to compare all parameters according to age and sex. RESULTS: The femur length was 424.4 ± 28.6 mm and was longer in men (P < 0.001). The minimum diameter of the medullary canal was 8.9 ± 2.0 mm. The radius of curvature (ROC) was 906.9 ± 193.3 mm. Men had a larger femur length, femur outer diameter, and the narrowest medullary diameter (P < 0.001, respectively). Women had significantly smaller ROC (P < 0.001). ROC decreased by 19.4% in men and 23.6% in women between the ages of 20 to 89 years. Femur width increased over life by 11.4% in men and 24.5% in women. Between the ages of 50 and 89 years, the medullary canal appears to have increased by 32.7% in women. CONCLUSION: This geometry analysis demonstrated that femoral bowing and femoral width increased related to aging, and that the medullary canal widened after the age of 50 years in women. This cross-sectional study revealed important age- and sex-related differences in femur shaft geometry that occur with aging.

Effect of dipeptidyl peptidase IV inhibitors, thiazolidinedione, and sulfonylurea on osteoporosis in patients with type 2 diabetes: population-based cohort study.

The population-based cohort study used the Korean National Health Insurance claims database to evaluate the effect of anti-diabetic drugs on osteoporosis. The use of DPP-IV inhibitors does not increase the risk of osteoporosis compared with the use of sulfonylureas in patients with type 2 diabetes mellitus, while a weak association was found between thiazolidinediones and increased risk of osteoporosis. PURPOSE: The current study aimed to evaluate the effect of dipeptidyl peptidase IV inhibitors (DPP-IVi), thiazolidinedione (TZD), and sulfonylurea (SU) on osteoporosis in patients with type 2 diabetes. METHODS: A population-based cohort study was conducted in the Republic of Korea using the Korean National Health Insurance claims database. Data from 2012 to 2017 for patients of 50-99 years of age who were prescribed DPP-IVi, TZD, or SU during 2013-2015 were extracted from the database. Based on pre-defined criteria, a total of 381,404 patients were analyzed after inverse probability of treatment weighting. The association between the study drugs and osteoporosis was estimated using Cox proportional hazards models. Data of 220,166 patients who were prescribed DPP-IVi, 18,630 who were prescribed TZD, and 142,608 patients who were prescribed SU were set. RESULTS: In the multivariate-adjusted analysis, the hazard ratio (HR) of osteoporosis in the DPP-IVi group was not significantly different from that of the SU group (HR: 0.97; 95% confidence interval (CI) 0.94-1.00), whereas the HR of osteoporosis in the TZD group was higher (HR: 1.13; 95% CI 1.06-1.20). In the subgroup analysis, the HRs of osteoporosis were higher with pioglitazone (HR: 1.14; 95% CI 1.06-1.23) in the TZD group and with glibenclamides (HR: 1.39; 95% CI 1.09-1.77) in the SU group, whereas drugs with lower HR in the DPP-IVi group were saxagliptin (HR: 0.93; 95% CI 0.87-0.99) and sitagliptin (HR: 0.93; 95% CI 0.89-0.97). CONCLUSION: DPP-IV inhibitors do not increase the risk of osteoporosis compared with sulfonylureas in patients with type 2 diabetes mellitus, while a weak association was found between thiazolidinediones and increased risk of osteoporosis.

Safety and efficacy of transarterial embolisation for treatment of dorsal pancreatic artery haemorrhage.

AIM: To evaluate the safety and efficacy of transarterial embolisation (TAE) of dorsal pancreatic artery (DPA) haemorrhage. MATERIALS AND METHODS: Nineteen consecutive patients (M:F = 16:3, mean age 59.6 years) who underwent TAE of DPA in three tertiary medical centres between January 2001 to January 2020 were reviewed retrospectively. Angiographic features and the technical and clinical outcomes of TAE were analysed. RESULTS: The clinical presentations were a bloody drain from the Jackson-Pratt drainage tube (n=8), melaena (n=7), abdominal pain (n=4), and haematochezia (n=3). Angiographic findings included pseudoaneurysm (n=14), contrast media extravasation (n=4), or abrupt cut-off of the arterial branch (n=1). The NBCA (N-butyl-cyanoacrylate; n=4), microcoils (n=4), and a combination of these agents (n=7) were used as embolic agents. The most common origin of the DPA in the present study cohort was the splenic artery (n=7), followed by the coeliac trunk (n=4), common hepatic artery (n=4), and superior mesenteric artery (n=4). Technical and clinical success rates were 100% and 84.2% (16/19), respectively. Of the three clinically unsuccessful cases, two patients were revealed to have newly developed bleeding from another artery. The other patient expired 1 day after the TAE procedure due to a progression of hepatic failure. In one patient, an asymptomatic non-target embolisation occurred in the right posterior tibial artery as a procedure-related complication. No major complications were observed. CONCLUSION: TAE is safe and effective for the management of bleeding from the DPA. It is important to be aware of the DPA as a potential bleeding source, including the relevant clinical characteristics.

Investigation of photodarkening in tandem-pumped Yb-doped fibers.

Investigation of photodarkening (PD) in Yb-doped fibers tandem-pumped at 1018 nm is reported. For a homemade Yb-doped aluminosilicate double-clad fiber (YADF), the transmitted power of a 633 nm probe beam is reduced by 2.4% over 2 hours for the tandem pumping configuration at 1018 nm, which is significantly smaller than 33.3% for a laser diode (LD) pumping at 976 nm. A tandem-pumped Yb fiber amplifier also shows a much smaller decrease in the amplified output power over time than a LD-pumped Yb fiber amplifier. Based on fluorescence spectra of the YADF, we can not only associate PD of the YADF to intrinsic oxygen deficiency centers or Tm3+ impurities but also confirm the impact of the excited Yb3+ ion density on PD. The benefits of the tandem pumping in a high-power Yb fiber laser system will be discussed.

Possible Quantum Paramagnetism in Compressed Sr_{2}IrO_{4}.

The effect of compression on the magnetic ground state of Sr_{2}IrO_{4} is studied with x-ray resonant techniques in the diamond anvil cell. The weak interlayer exchange coupling between square-planar 2D IrO_{2} layers is readily modified upon compression, with a crossover between magnetic structures around 7 GPa mimicking the effect of an applied magnetic field at ambient pressure. Higher pressures drive an order-disorder magnetic phase transition with no magnetic order detected above 17-20 GPa. The persistence of strong exchange interactions between J_{eff}=1/2 magnetic moments within the insulating IrO_{2} layers up to at least 35 GPa points to a highly frustrated magnetic state in compressed Sr_{2}IrO_{4}, opening the door for realization of novel quantum paramagnetic phases driven by extended 5d orbitals with entangled spin and orbital degrees of freedom.

Acute pancreatitis after percutaneous insertion of metallic biliary stents in patients with unresectable pancreatic cancer.

AIM: To investigate the incidence and clinical characteristics of acute pancreatitis following percutaneous insertion of metallic biliary stents in patients with unresectable pancreatic cancer. The clinical efficacy of metallic stent insertion was also evaluated. MATERIALS AND METHODS: Data from 143 patients (75 men, 68 women; mean age, 65.8 years; range, 35-88 years) with unresectable pancreatic cancer who underwent percutaneous metallic biliary stent insertion between March 2007 and December 2017 were evaluated retrospectively. The incidence and clinical characteristics of acute pancreatitis were analysed. Stent patency and patient survival rates were calculated by Kaplan-Meier analysis. RESULTS: Technical success was achieved in all patients. Among 31 patients with serum amylase levels above normal values (30-110 U/l), only nine had symptoms of acute pancreatitis (incidence, 6.4%). No statistically significant risk factors were identified. Pancreatitis was successfully managed with conservative treatment at a mean of 2.9 days (range, 1-4 days). The median stent patency and patient survival times were 117 days (95% confidence interval [CI], 87-148 days) and 150 days (95% CI, 125-174.9 days), respectively. CONCLUSIONS: Acute pancreatitis was a relatively rare complication after percutaneous insertion of metallic biliary stents in patients with unresectable pancreatic cancer, and no significant risk factors were identified. Therefore, insertion of metallic biliary stents was seen to be a feasible and effective treatment approach in this patient group.

Interventional treatment of arterial injury during blind central venous catheterisation in the upper thorax: experience from two centres.

AIM: To evaluate the safety and clinical efficacy of interventional treatment for arterial injury during blind, central venous catheterisation in the upper thorax at two tertiary medical centres. MATERIALS AND METHODS: Eighteen consecutive patients (37-81 years; M:F=8:10) who underwent interventional treatment for the arterial injuries that occurred during central venous catheterisation without any imaging guidance between November 2007 and December 2018 were included. Clinical data, angiographic findings, detailed interventional procedures, and technical and clinical outcomes were analysed retrospectively. RESULTS: Arterial injury sites were the subclavian artery/branches (n=12), axillary artery/branches (n=2), and common carotid artery (n=4). The target vein was not correlated with the corresponding artery/branches in eight patients (44.4%); internal jugular vein to subclavian artery branches. Angiographic findings were pseudoaneurysm (66.7%, 12/18), contrast medium extravasation (22.2%, 4/18), or both (11.1%, n=2). A stent graft was inserted for the main trunk injuries in nine patients, with (n=2) or without (n=7) prior arterial branch embolisation to prevent potential endoleak, while embolisation for the arterial branch injuries was performed in nine patients. Direct percutaneous access with thrombin injection to the pseudoaneurysm or residual arteriovenous fistula was utilised in two. The technical and clinical success rate was 94.4% (17/18) each. There were no procedure-related complications. In one patient without immediate clinical success, there was a persistent pseudoaneurysm after stent graft placement, which was treated with in-stent balloon dilation. CONCLUSION: Interventional treatment serves as a safe and effective treatment modality for inadvertent arterial injury related to blind, central venous access catheterisation in the upper thorax.

Development of Novel Continuous and Interval Exercise Programs by Applying the FITT-VP Principle in Dogs.

Although proper exercise training induces positive physiological effects, improper exercise can lead to injury, fatigue, and poor performance. The frequency, intensity, time/duration, type, volume, and progression (FITT-VP) are the essential components of exercise training to maintain or improve physical fitness and health. The purpose of this study was to develop specific exercise programs by applying the FITT-VP principle and to examine the effects on heart rate (HR) and hematological and biochemical parameters in dogs. The healthy male Beagles (n = 4) included in this study performed continuous and interval exercises, comprising 12 protocols. The HR monitoring elicited an affirmative response to activities but varied depending on the protocols. The hematologic parameters (e.g., red blood cell count, white blood cell count, hemoglobin, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration) were within the reference ranges both before and after exercise. The creatine kinase level significantly increased, and the cholesterol level decreased after exercises. In conclusion, the continuous and interval exercise program elicits an appropriate HR reaction, has no adverse effects on the serum parameters, and provides valuable insight for healthcare in dogs.

Landscape of Elderly Suicide in South Korea: Its Trend According to Age, Gender, and Educational Attainment.

South Korea has one of the highest suicide rates in the world, and the most alarming suicide rate is among its elders. This study aims to understand the social, historical, and cultural context of the Korean older adults and examine suicide trends based on that understanding. The results show that the suicide risk increases with age, the male suicide rate outweighs that of females, and the suicide rate decreases with educational attainment. In addition, several suggestions for reducing elderly suicide rate are addressed, including differentiating the existing social services for elders by age and expanding suicide prevention programs beyond schools to communities so that all people in need can access them.

Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer.

OBJECTIVE: The AGO-OVAR16 study was designed to test the efficacy, safety, and tolerability of pazopanib maintenance after first-line chemotherapy in patients with newly diagnosed advanced ovarian cancer (AOC). METHODS: Nine hundred and forty patients with histologically confirmed AOC, International Federation of Gynecology and Obstetrics (FIGO) stage II-IV, were randomized in a 1:1 ratio to receive either 800 mg pazopanib once daily or placebo for up to 24 months, unless there was disease progression, toxicity, withdrawal of consent, or death. The primary endpoint (investigator-assessed progression-free survival [PFS]) was met and previously reported. The results of final analyses of overall survival (OS) are reported here. RESULTS: A third OS interim analysis showed futility and led to study closure and a final OS analysis after last patient last visit. At the time of the final OS analysis, 494 (89.7% of the planned 551) events had occurred. No difference was observed in OS between pazopanib and placebo. The hazard ratio (HR) was 0.960 (95% confidence interval [CI]: 0.805-1.145), and the median OS from randomization was 59.1 months in pazopanib and 64.0 months in placebo arms. For the East Asian patients, similar to the first three interim OS analyses, a numerical negative trend was observed favoring placebo (HR, 1.332; 95% CI: 0.863-2.054). Exploratory analyses showed a trend for a longer time to first subsequent anti-cancer therapy or death with pazopanib over placebo (HR, 0.829; 95% CI: 0.713-0.965), with a median estimate of 19.0 and 14.5 months, respectively. No new safety signals were observed. CONCLUSION: Although pazopanib prolonged PFS, this was not associated with improvement in median OS. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov: NCT00866697.

TLR5 activation induces expression of the pro-inflammatory mediator Urokinase Plasminogen Activator via NF-κB and MAPK signalling pathways in human dental pulp cells.

AIM: To explore the involvement of TLR5 in pulp inflammation and to examine the effects of TLR5 activation with its ligand, FlaB protein, on pro-inflammatory gene expression. METHODOLOGY: TLR5 expression in dental pulp tissues and human dental pulp cells (hDPCs) were determined by immunohistochemistry, immunocytochemistry, Western blots and RT-PCR analyses. To examine the role of TLR5, hDPCs were treated with recombinant FlaB protein (500 ng mL-1 ) to activate the receptor or with a small interfering RNA against TLR5 (si-TLR5) to downregulate the receptor. After exposure to FlaB, the expression of inflammation-related proteins was screened using a protein array kit. Western blots or qRT-PCR analyses were performed to identify changes in the expression of uPA (urokinase plasminogen activator), TIMPs (tissue inhibitor of metalloproteinases), and IL-6 and to determine their signalling pathways. Statistical analysis was performed using one-way analysis of variance (anova) with Tukey post hoc test; P < 0.05 was considered statistically significant. RESULT: TLR5 expression was identified in pulp tissues and hDPCs. In the protein array analysis, treatment with FlaB significantly increased uPA expression (P < 0.01) and significantly decreased TIMP1/4 (P < 0.05). FlaB treatment also significantly increased expression of the inflammatory marker IL-6 (P < 0.01). FlaB treatment increased phosphorylation of the NF-κB p65 subunit, JNK, p38 and ERK. Chemical inhibitors of NF-κB (Bay11-7082), p38 (SB202190) or ERK (U0126) decreased the FlaB induction of uPA expression. Downregulation of TLR5 expression by siRNA decreased the FlaB induction of uPA protein and p65 phosphorylation. CONCLUSION: TLR5 activation with FlaB treatment induced the expression of uPA via the NF-κB and MAPK signalling pathways. Flagellin-bearing oral bacteria may cause pulp inflammation through TLR5. The findings provide new clues to control pulpal diseases by targeting TLR5 signalling pathways.

Streptococcus pneumoniae PspC Subgroup Prevalence in Invasive Disease and Differences in Contribution to Complement Evasion.

The pneumococcal capsular serotype is an important determinant of complement resistance and invasive disease potential, but other virulence factors have also been found to contribute. Pneumococcal surface protein C (PspC), a highly variable virulence protein that binds complement factor H to evade C3 opsonization, is divided into two subgroups: choline-bound subgroup I and LPxTG-anchored subgroup II. The prevalence of different PspC subgroups in invasive pneumococcal disease (IPD) and functional differences in complement evasion are unknown. The prevalence of PspC subgroups in IPD isolates was determined in a collection of 349 sequenced strains of Streptococcus pneumoniae isolated from adult patients. pspC deletion mutants and isogenic pspC switch mutants were constructed to study differences in factor H binding and complement evasion in relation to capsule thickness. Subgroup I pspC was far more prevalent in IPD isolates than subgroup II pspC The presence of capsule was associated with a greater ability of bound factor H to reduce complement opsonization. Pneumococcal subgroup I PspC bound significantly more factor H and showed more effective complement evasion than subgroup II PspC in isogenic encapsulated pneumococci. We conclude that variation in the PspC subgroups, independent of capsule serotypes, affects pneumococcal factor H binding and its ability to evade complement deposition.

Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy.

Background: Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. Methods and materials: Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25. Results: Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). Conclusions: DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. ClinicalTrials.gov: NCT01839773.