Inhibiting PRMT5 induces DNA damage and increases anti-proliferative activity of Niraparib, a PARP inhibitor, in models of breast and ovarian cancer.

BACKGROUND: Inhibitors of Poly (ADP-Ribose) Polymerases (PARP) provide clinical benefit to patients with breast and ovarian cancers, by compromising the DNA repair activity of cancer cells. Although these agents extend progression-free survival in many patients, responses can be short lived with many patients ultimately progressing. Identification of combination partners that increase dependence of cancer cells to the DNA repair activity of PARPs may represent a strategy to increase the utility of PARP inhibitors. Protein arginine methyltransferase 5 (PRMT5) regulates DNA damage response pathways through splicing and protein modification, and inhibitors of PRMT5 have recently entered clinical trials. METHODS: The effect of PRMT5 inhibition on the levels of DNA damage and repair markers including γH2AX, RAD51, and 53BP1 was determined using high content immunofluorescent imaging. The anti-proliferative activity of the combination of PRMT5 and PARP inhibitors was evaluated using in vitro models of breast and ovarian cancers using both cell lines and ex vivo patient derived xenografts. Finally, the combinations of PRMT5 and PARP inhibitors were evaluated in cell line xenograft models in vivo. RESULTS: Inhibition of PRMT5 by GSK3326595 led to increased levels of markers of DNA damage. The addition of GSK3326595 to the PARP inhibitor, niraparib, resulted in increased growth inhibition of breast and ovarian cancer cell lines and patient derived spheroids. In vivo, the combination improved the partial effects on tumor growth inhibition achieved by either single agent, producing complete tumor stasis and regression. CONCLUSION: These data demonstrate that inhibition of PRMT5 induced signatures of DNA damage in models of breast and ovarian cancer. Furthermore, combination with the PARP inhibitor, Niraparib, resulted in increased anti-tumor activity in vitro and in vivo. Overall, these data suggest inhibition of PRMT5 as a mechanism to broaden and enhance the clinical application of PARP inhibitors.

Efficacy and Safety of Asenapine Versus Olanzapine in Combination With Divalproex for Acute Mania: A Randomized Controlled Trial.

BACKGROUND: Atypical antipsychotics are used for the treatment of acute mania, either as monotherapy or in combination with lithium or divalproex, which have a better tolerability profile as compared with typical antipsychotics. Asenapine, a newer atypical antipsychotic, has been found to be effective for the treatment of mania, with efficacy similar to olanzapine. The objective of the study was to compare the efficacy and safety of asenapine and olanzapine when used in combination with divalproex in patients with acute mania. METHODS: One hundred twenty patients aged 18 to 55 years, diagnosed with manic episode, were randomized to receive either flexible dose of sublingual asenapine (10-20 mg/d) or tablet olanzapine (10-20 mg/d), in combination with valproate 20 mg/kg per day for a period of 6 weeks. Efficacy was measured as change in Young Mania Rating Scale and Clinical Global Impression-Bipolar using intention-to-treat analysis with last observation carried forward, and safety was measured using Udvalg for Kliniske Undersøgelser scale and Modified Simpson-Angus Extrapyramidal Side Effects Scale. RESULTS: There was a significant reduction in Young Mania Rating Scale and Clinical Global Impression-Bipolar scores over time in both groups, with a significantly higher reduction in the olanzapine group as shown by the group × time interaction effect. Higher weight gain, increased sleep and appetite, and tremors were seen in the olanzapine-treated patients as compared with asenapine-treated patients; however, tongue hypesthesia was seen in the asenapine group only. CONCLUSIONS: This study found that asenapine was an effective and well-tolerated atypical antipsychotic alternative to olanzapine in combination with divalproex for the short-term management of acute mania.

Ligand based design and synthesis of pyrazole based derivatives as selective COX-2 inhibitors.

The design and synthesis of novel pyrazole based derivatives has been carried out using the ligand based approach like pharmacophore and QSAR modelling of reported pyrazoles from the available literature to investigate the chemical features that are essential for the design of selective and potent COX-2 inhibitors. Both pharmacophore and QSAR models with good statistical parameters were selected for the design of the lead molecule. Also by exploiting the chemical structures of selective and marketed COX-2 inhibitors, celecoxib and SC-558 were used in designing the molecules which are used in the treatment of inflammation and related disorders. The therapeutic action of the Non-Steroidal Anti-inflammatory Agents (NSAIDs) is based primarily on the COX-2 inhibition. With this background we have synthesized some azomethine derivatives of 3-methyl-1-substituted-4-phenyl-6-[{(1E)-phenylmethylene}amino]-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile 6(a-o) and were characterized by 1HNMR, 13CNMR and Mass spectral techniques. All the synthesized pyrazole derivatives were tested for in vitro membrane stability property in both COX-1 & COX-2 inhibition studies and in vivo anti-inflammatory activity by carrageenan induced rat paw edema model. Among them, compound 6k showed very good activity by in vivo anti-inflammatory activity with 0.8575 mmol/kg as ED50. Similarly compounds 6m, 6o, 6i and 6h exhibited comparable anti-inflammatory activity to standard drugs. Also the active compounds were further screened for ulcerogenic activity and were found be safer with less ulcer index compared to the marketed drugs like aspirin, ibuprofen and celecoxib.

Amisulpride Augmentation in Acute Catatonia.

Benzodiazepines are the first-line treatment of catatonia, but a substantial number of patients do not respond to them. Amisulpride is one of the atypical antipsychotic that has been effective for negative symptoms of schizophrenia. We examined the effect of augmentation of oral low doses of amisulpride with lorazepam on resolution of catatonic symptoms. Fifteen patients with catatonia were treated with a combination of oral lorazepam (2-4 mg) with amisulpride (100 mg). Catatonic symptoms were rated using the Bush Francis Catatonia Rating Scale at the baseline and daily thereafter. There was complete resolution of catatonic symptoms on the third day in all patients. There was significant reduction of the total Bush Francis Catatonia Rating Scale score over time (F = 181.38, P < 0.001) with a strong effect size (partial η = 0.96). Augmentation of lorazepam with low-dose amisulpride can be a reliable strategy for management of catatonia.

Computer Navigation Helps Reduce the Incidence of Noise After Ceramic-on-Ceramic Total Hip Arthroplasty.

BACKGROUND: Noise after ceramic-on-ceramic (CoC) total hip arthroplasty (THA) is a well-recognized problem. Computer navigation has been shown to achieve desired implant orientation. Our aim was (1) to compare the incidence of noise between navigated and conventional CoC THAs and (2) to determine the factors associated with noise. METHODS: All patients undergoing CoC THA between March 2009 and August 2012 were considered for this study. Information regarding hip noise was obtained via telephone or postal interview. A comparable cohort of patients in navigated and conventional groups was used to evaluate the incidence of noise. RESULTS: A total of 375 CoC THAs using the same implant (202 navigated and 173 conventional) were evaluated. Patients <65 years of age had significantly greater incidence of noise (22.4% vs 6.1%; P < .001). To ensure similarity, a subgroup of cohort <65 years and a 32-mm head size was used to compare the incidence of noise between the navigated (68 THAs) and conventional (118 THAs) groups. Overall incidence of noise was significantly greater in the conventional group (28%) as compared with the navigated group (10%; P = .005). The relative risk of noise for the conventional vs the navigated group was 2.7 (P = .01), and for squeaking was 1.9 (P = .2). Squeaking THAs had significantly lower cup anteversion (13.4° ± 5.2°) as compared with the silent THAs (17.6° ± 6.9°; P = .01). CONCLUSION: Navigated CoC THAs were 2.7× less likely to have noise as compared with the conventional ones. Squeaking THAs had significantly lower cup anteversion as compared with the silent ones. Patients of age <65 years had significantly greater incidence of noise after CoC THA.

Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells.

Exosomes have recently come into focus as "natural nanoparticles" for use as drug delivery vehicles. Our objective was to assess the feasibility of an exosome-based drug delivery platform for a potent chemotherapeutic agent, paclitaxel (PTX), to treat MDR cancer. Herein, we developed different methods of loading exosomes released by macrophages with PTX (exoPTX), and characterized their size, stability, drug release, and in vitro antitumor efficacy. Reformation of the exosomal membrane upon sonication resulted in high loading efficiency and sustained drug release. Importantly, incorporation of PTX into exosomes increased cytotoxicity more than 50 times in drug resistant MDCKMDR1 (Pgp+) cells. Next, our studies demonstrated a nearly complete co-localization of airway-delivered exosomes with cancer cells in a model of murine Lewis lung carcinoma pulmonary metastases, and a potent anticancer effect in this mouse model. We conclude that exoPTX holds significant potential for the delivery of various chemotherapeutics to treat drug resistant cancers. FROM THE CLINICAL EDITOR: Exosomes are membrane-derived natural vesicles of ~40 - 200 nm size. They have been under extensive research as novel drug delivery vehicles. In this article, the authors developed exosome-based system to carry formulation of PTX and showed efficacy in the treatment of multi-drug resistant cancer cells. This novel system may be further developed to carry other chemotherapeutic agents in the future.

Drug-induced diseases (DIDs): An experience of a tertiary care teaching hospital from India.

BACKGROUND & OBJECTIVES: Drug-induced diseases (DIDs) are well known but least studied. Data on DIDs from India are not available. Hence, this retrospective cross-sectional study was undertaken using suspected adverse drug reaction (ADR) data collected form Pharmacovigilance Programme of India (PvPI) to evaluate profile of DIDs over two years, in a tertiary care teaching hospital from north India. METHODS: The suspected ADRs in the form of DID were evaluated for drug and disease related variables and were classified in terms of causality. RESULTS: DID rate was 38.80 per cent. Mean duration of developing DIDs was 26.05 ± 9.6 days; 25.16 per cent had more than one co-morbid condition. Geriatric population (53.99%) accounted for maximum DIDs followed by adult (37.79%) and paediatric (8.21%). Maximum events were probable (93.98%) followed by possible (6.04%). All DIDs required intervention. Gastritis (7.43%), diarrhoea (5.92%), anaemia (4.79%), hypotension (2.77%), hepatic dysfunction (2.69%), hypertension (1.51%), myalgia (1.05%), and renal dysfunction (1.01%) were some of the DIDs. Anti tubercular treatment (ATT), anti retroviral treatment (ART), ceftriaxone injection, steroids, non-steroidal anti-inflammatory drugs, antimicrobials and anticancer drugs were found as commonly offending drugs. INTERPRETATION & CONCLUSIONS: Our findings show that DIDs are a significant health problem in our country, which need more attention.

Reproduction of Hip Offset and Leg Length in Navigated Total Hip Arthroplasty: How Accurate Are We?

This study assesses how accurately we can restore hip offset and leg length in navigated total hip arthroplasty (THA). 152 consecutive patients with navigated THA formed the study group. The contra-lateral hip formed control for measuring hip offset and leg length. All radiological measurements were made using Orthoview digital software. In the normal hip offset group, the mean is 75.73 (SD- 8.61). In the reconstructed hip offset group, the mean is 75.35 (SD - 7.48). 95.39% had hip offset within 6 mm of opposite side while 96.04% had leg length restored within 6 mm of contra-lateral side. Equivalence test revealed that the two groups of hip offsets were essentially the same. We conclude that computer navigation can successfully reproduce hip offset and leg length accurately.

Evidence for vital role of endo-ß-N-acetylglucosaminidase in the resistance of Arthrobacter protophormiae RKJ100 towards elevated concentrations of o-nitrobenzoate.

Arthrobacter protophormiae RKJ100 was previously characterized for its ability to tolerate extremely high concentrations of o-nitrobenzoate (ONB), a toxic xenobiotic environmental pollutant. The physiological responses of strain RKJ100 to ≥30 mM ONB indicated towards a resistance mechanism manifested via alteration of cell morphology and cell wall structure. In this study, we aim to characterize gene(s) involved in the resistance of strain RKJ100 towards extreme concentrations (i.e. 150 mM) of ONB. Transposon mutagenesis was carried out to generate a mutant library of strain RKJ100, which was then screened for ONB-sensitive mutants. A sensitive mutant was defined and selected as one that could not tolerate ≥30 mM ONB. Molecular and biochemical characterization of this mutant showed that the disruption of endo-ß-N-acetylglucosaminidase (ENGase) gene caused the sensitivity. ENGase is an important enzyme for oligosaccharide processing and cell wall recycling in bacteria, fungi, plants and animals. Previous reports have already indicated several possible roles of this enzyme in cellular homeostasis. Results presented here provide the first evidence for its involvement in bacterial resistance towards extreme concentrations of a toxic xenobiotic compound and also suggest that strain RKJ100 employs ENGase as an important component in osmotic shock response for resisting extreme concentrations of ONB.

Fatal adverse drug reactions: Experience of adverse drug reactions in a tertiary care teaching hospital of North India - A case series.

Medical burden of fatal adverse drug reactions (FADRs) is significant. The epidemiological data on FADR do exist from the western world, but there is scanty from India. We hereby report a case series of FADRs recorded in a 2 years period. Point prevalence of FADRs was 0.223%. Point prevalence of all cause death in the hospital was 1.20%. The drugs causing FADRs were injection bupivacaine, amphotericin B, directly observed treatment short-course Category-1, injection streptokinase, and tablet ferrous sulfate. All these FADR were labeled as possible expect one case as probable. All FADR were labeled as type A. In three out of five the central nervous system was involved, while the hepatic system and multiorgan failure accounted for one case each. Two cases each were acute and subacute, while one was latent in nature. Reporting of FADRs shall go a long way in patient safety.

Ultralow thermal conductivity of W-Janus bilayers (WXY: X, Y = S, Se, and Te) for thermoelectric devices.

Lattice thermal conductivity (κ) in tungsten dichalcogenide Janus (WXY, where X, Y = S, Se, and Te) monolayers and heterostructures (HSs) have been investigated using ab initio DFT simulations. Tungsten-based Janus monolayers show semiconducting behavior with the bandgap in the semiconducting range for WSSe (1.70 eV), WSTe (1.26 eV), and WSeTe (1.34 eV). When Janus monolayers are stacked to form HSs with weak van der Waals (vdW) interactions, the bandgap reduces to 0.19 eV, 0.40 eV, and 0.24 eV, respectively, for WSeTe/WSTe, WSSe/WSTe, and WSSe/WSeTe HSs. Thermal vibrational characteristics of Janus monolayers are modified when these are stacked in 2D HSs with the introduction of interlayer hybrid phonon modes. Large longitudinal-transverse optical (LO-TO) splitting is noticed at the Brillouin zone-center (Γ-point): 135 cm-1, 140 cm-1, and 150 cm-1 for WSeTe/WSTe, WSSe/WSeTe and WSSe/WSTe HSs, respectively. Thermal conductivity calculations show ultra-low κ values for WSeTe/WSTe (0.01 W m-1 K-1), WSSe/WSTe (0.02 W m-1 K-1) and WSSe/WSeTe HS (0.004 W m-1 K-1) at 300 K. The results can be attributed to the hybrid phonon modes with frequencies very close to acoustic modes at the gamma point, low Debye temperature (θD) and specific heat capacity. Our results highlight the possible applications of these HSs in designing thermoelectric interfaces at the nanoscale.

Correction: Specific transfection of inflamed brain by macrophages: A new therapeutic strategy for neurodegenerative diseases.

[This corrects the article DOI: 10.1371/journal.pone.0061852.].

Single- versus double-bundle ACL reconstruction: is there any difference in stability and function at 3-year followup?

BACKGROUND: Despite a number of studies comparing postoperative stability and function after anatomic double-bundle and single-bundle anterior cruciate ligament reconstruction (ACLR), it remains unclear whether double-bundle reconstruction improves stability or function. QUESTIONS/PURPOSES: We therefore asked whether patients having single- and double-bundle ACLR using semitendinosus (ST) alone differed with regard to (1) postoperative stability; (2) ROM; and (3) five functional scores. METHODS: We prospectively followed 60 patients with an isolated anterior cruciate ligament (ACL) injury. Thirty patients underwent single-bundle and 30 patients underwent double-bundle ACL reconstruction. Clinically we assessed stability and range of motion (ROM); anteroposterior stability was assessed by Rolimeter and rotational stability by a pivot shift test. Function was assessed by IKDC, Noyes, Lysholm, Marx, and Tegner activity scales. The minimum followup was 36 months (mean, 46.2 months; range, 36-60 months). RESULTS: Residual anteroposterior laxity at 3 years postoperatively was similar in both groups: 1.4 ± 0.3 mm versus 1.4 ± 0.2 mm, respectively. We observed no difference in the pivot shift test. ROM was similar in both groups, although double-bundle patients required more physical therapy sessions to gain full ROM. IKDC, Noyes, Lysholm, Marx, and Tegner scores were similar at final followup. CONCLUSION: Double-bundle reconstruction of the ACL did not improve function or stability compared with single-bundle reconstruction. LEVEL OF EVIDENCE: Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Tibial plateau fracture after primary anatomic double-bundle anterior cruciate ligament reconstruction: a case report.

Tibial plateau fracture after primary anatomic double-bundle anterior cruciate ligament (ACL) reconstruction is rare. To our knowledge, this is the first case report of a tibial plateau fracture after primary anatomic double-bundle ACL reconstruction. In our patient the tibial plateau fracture occurred after a torsional injury to the involved extremity. The fracture occurred 4.5 years after the ACL reconstruction. The fracture was intra-articular Schatzker type IV and had a significant displacement. The patient was treated operatively by open reduction-internal fixation. He recovered well.

Safe zone for the approach to the posterior sole (heel): a cadaver study.

BACKGROUND: Surgical approach to the posterior sole or heel is commonly used for various orthopedic procedures. The objective of this cadaver study was to identify the risks to local neurovascular structures using an approach to the posterior sole or heel and to define the safe zone for minimizing the risk of injury. METHODS: Eleven fresh-frozen cadaver limbs were used. A layered dissection was performed from skin to neurovascular structures. Distances of the entire foot length, the lateral plantar nerve from the heel, the calcaneocuboid joint from the heel, the nerve to abductor digiti minimi from the heel, and the lateral plantar nerve from the calcaneocuboid joint; and depth of the lateral plantar nerve from skin of sole in the midline, and angle of the lateral plantar nerve to the midline axis were measured. RESULTS: The mean entire foot length was 2,29.1 (range 215-250) mm. Location of the lateral plantar nerve from the heel in the dissecting midline axis was a mean of 93.5 (range 86-104) mm. Calcaneocuboid joint was located at a mean of 75.7 (range 70-85) mm from heel in the midline axis. The nerve to abductor digiti minimi was located at a mean of 48.1 (range 41-55) mm from the heel. Lateral plantar nerve was located at a mean of 19.4 (range 16-23) mm distal to the calcaneocuboid joint in the midline level. The angle at which the lateral plantar nerve crossed the dissecting midline incision was at a mean of 13.8° (range 9-20°). CONCLUSIONS: Based on these results, we defined the safe zone for the surgical approach to the posterior sole as anterior to the nerve to the abductor digiti minimi in the midline axis and posterior to the calcaneocuboid joint. There were no significant neurovascular structures observed in this zone.

Orientation of Transverse Acetabular Ligament With Reference to Anterior Pelvic Plane.

BACKGROUND: Transverse acetabular ligament (TAL) is a 3-dimensional structure which cannot be defined by a single plane. Therefore, we aimed at describing the orientation of different parts of TAL with respect to anterior pelvic plane (APP) and correlate it with gender, body mass index (BMI), and Lewinnek's safe zone. METHODS: A total of 109 consecutive patients undergoing imageless navigated THA were prospectively studied. Computer navigation was used as the measurement tool. APP was registered for navigation. After excision of osteophytes, a trial component matching the size of unreamed acetabular cavity was aligned with acetabular rim, outer and inner margins, and middle of TAL to record cup orientation with computer tracker. RESULTS: Ninety-nine patients (41 males and 58 females, mean BMI of 28.8kg/m2) were studied after applying exclusion criteria. Mean acetabular inclination was 55.15°, 53.00°, 47.70°, and 42.60° respectively, for acetabular rim, outer, middle, and inner margins of the TAL. Corresponding mean acetabular anteversion was 6.63°, 7.41°, 11.23° and 14.90°respectively. Overall, 17.17%, 28.28%, 47.47% and 71.71% of cup orientation corresponding to acetabular rim, outer, middle, and inner margin of TAL respectively, were within Lewinnek's safe zone. No association was established between BMI and acetabular orientation. Males had overall lesser anteversion than females. CONCLUSION: We describe orientation of outer, middle, and inner margins of TAL, as reference planes for TAL, in relation to APP. The anteversion differs significantly with gender. A knowledge about these will assist surgeon in component placement during THA, with inner margin of TAL providing the best chance of orientation out of the studied landmarks.

Leg length discrepancy in computer navigated total hip arthroplasty - how accurate are we?

INTRODUCTION: The success of total hip arthroplasty (THA) depends on the restoration of 2 important parameters - hip offset and leg length. Leg length discrepancy (LLD) after THA is associated with back pain, gait disorder, general patient dissatisfaction and aseptic loosening. Hence it is of utmost importance to minimise LLD. METHODS: This is a retrospective study where we compared the reproduction of leg lengths between navigated THA group (152 patients) and nonnavigated THA group (57 patients). The leg lengths were measured radiologically using Ranawat technique on AP pelvic radiograph. RESULTS: In the navigated group, the leg lengths of the reconstructed hips were restored to within 6 mm of the opposite leg in 146 patients (96.05%) while 6 patients (3.94%) had LLD of more than 6 mm. In the nonnavigated group, 29 patients (51%) had their leg lengths restored within 6 mm of the opposite leg while the remaining 28 patients (49%) had their LLD greater than 6 mm. Statistical analysis of the 2 pairs of LLD measurements (navigated hip and nonnavigated group) using Mann-Whitney U-test revealed significant difference between these two groups (p<0.001). CONCLUSIONS: Based on our results we conclude that computer navigation is an excellent tool to facilitate the successful reproduction of leg length in THA.

Bleomycin Containing Chemotherapeutic Regimen Induced Acquired Partial Lipodystrophy.

Bleomycin toxicity predominantly affects the skin and lungs. Cutaneous toxicity classically known to present with bleomycin are flagellate erythema and drug rash. We hereby report an isolated case of (bleomyicn)-induced acquired partial (lipodytrophy) having potential cosmetic implications in a young women prescribed postoperatively following a case of germ cell carcinoma of ovary (endodermal sinus tumor).