FORMULATION AND EVALUATION OF LEVOFLOXACIN-CHITOSAN / β- CYCLODEXTRIN NANOPARTICLES BY IONIC GELATION

Background: Levofloxacin is a broad spectrum anti-infective agent, which is rapidly and completely absorbed after oral administration. The half life of Levofloxacin is 6-8 h after conventional dosing. The objective of the present work was to develop Levofloxacin nanoparticles to retain the dosage form in the absorption site more than the half life of the drug, enhance the bioavailability of drugs, reduce dose frequency, toxicity and patient compliance. Methods: The compositions of different formulations of Levofloxacin nanoparticles by the ionic gelation method using biodegradable polymer chitosan and tripolyphosphate as cross linking agent. Result and Discussion: The particle size lies of the prepared nanoparticles between 199 and 369 nm and the drug content found between 51.13± 0.28 and 71.12 ± 0.14 %. The particle size of nanoparticles increased with increasing concentration of polymer matrix density and this may be due to the increased viscosity of the inner phase and decreased with increasing concentration of β-cyclodextrin. Scanning electron microscopy indicated that the prepared nanoparticles were discrete, uniform and spherical with a smooth surface. The in vitro release showed that the drug release from the prepared nanoparticles was characterized by an initial fast release and followed by a delayed release phase. During and at the end of the accelerated stability study, the tested formulation showed almost same drug content, in vitro drug release and no colour changes were observed from that observed at the opening of the study. Conclusion: Among all the formulations (GIA, GIB, GIC, GID, GIE and GIF), the formulations G1C, G1E and G1F followed the drug release in a controlled manner. The in vitro release profile showed that this is a potential drug delivery for Levofloxacin and has to confirm in the in vivo settings as a separate investigation in future. Key words: Controlled drug delivery, In vitro drug release, Nanoparticle, Particle size, Stability studies, Surface morpholog

Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

TDP-43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP-43 function at physiological levels both in vitro and in vivo Interestingly, we find that mutations within the C-terminal domain of TDP-43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP-43 loss- and gain-of-function effects. TDP-43 gain-of-function effects in these mice reveal a novel category of splicing events controlled by TDP-43, referred to as "skiptic" exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain-of-function mutation in endogenous Tardbp causes an adult-onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain-of-function and skiptic exons in ALS patient-derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP-43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages

Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma

Abstract The standard of care for most patients with non-muscle-invasive bladder cancer (NMIBC) is immunotherapy with intravesical Bacillus Calmette-Guérin (BCG), which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit. Urologic best-practice guidelines and consensus reports have been developed and strengthened based on data on the timing, dose, and duration of therapy from randomized clinical trials, as well as by critical evaluation of criteria for progression. However, these reports have not penetrated the community, and many patients do not receive appropriate therapy. Additionally, several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease. The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of expanded use for both advanced and, potentially, localized disease. To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer, the Society for Immunotherapy of Cancer (SITC) convened a Task Force of experts, including physicians, patient advocates, and nurses, to address issues related to patient selection, toxicity management, clinical endpoints, as well as the combination and sequencing of therapies. Following the standard approach established by the Society for other cancers, a systematic literature review and analysis of data, combined with consensus voting was used to generate guidelines. Here, we provide a consensus statement for the use of immunotherapy in patients with bladder cancer, with plans to update these recommendations as the field progresses

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Study of the B−→Λc+Λˉc−K−B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-} decay

The decay $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ is studied in proton-proton collisions at a center-of-mass energy of $\sqrt{s}=13$ TeV using data corresponding to an integrated luminosity of 5 $\mathrm{fb}^{-1}$ collected by the LHCb experiment. In the $\Lambda_{c}^+ K^{-}$ system, the $\Xi_{c}(2930)^{0}$ state observed at the BaBar and Belle experiments is resolved into two narrower states, $\Xi_{c}(2923)^{0}$ and $\Xi_{c}(2939)^{0}$, whose masses and widths are measured to be $$m(\Xi_{c}(2923)^{0}) = 2924.5 \pm 0.4 \pm 1.1 \,\mathrm{MeV}, \\ m(\Xi_{c}(2939)^{0}) = 2938.5 \pm 0.9 \pm 2.3 \,\mathrm{MeV}, \\ \Gamma(\Xi_{c}(2923)^{0}) = \phantom{000}4.8 \pm 0.9 \pm 1.5 \,\mathrm{MeV},\\ \Gamma(\Xi_{c}(2939)^{0}) = \phantom{00}11.0 \pm 1.9 \pm 7.5 \,\mathrm{MeV},$$ where the first uncertainties are statistical and the second systematic. The results are consistent with a previous LHCb measurement using a prompt $\Lambda_{c}^{+} K^{-}$ sample. Evidence of a new $\Xi_{c}(2880)^{0}$ state is found with a local significance of $3.8\,\sigma$, whose mass and width are measured to be $2881.8 \pm 3.1 \pm 8.5\,\mathrm{MeV}$ and $12.4 \pm 5.3 \pm 5.8 \,\mathrm{MeV}$, respectively. In addition, evidence of a new decay mode $\Xi_{c}(2790)^{0} \to \Lambda_{c}^{+} K^{-}$ is found with a significance of $3.7\,\sigma$. The relative branching fraction of $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ with respect to the $B^{-} \to D^{+} D^{-} K^{-}$ decay is measured to be $2.36 \pm 0.11 \pm 0.22 \pm 0.25$, where the first uncertainty is statistical, the second systematic and the third originates from the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb public pages

Measurement of the ratios of branching fractions R(D∗)\mathcal{R}(D^{*}) and R(D0)\mathcal{R}(D^{0})

The ratios of branching fractions $\mathcal{R}(D^{*})\equiv\mathcal{B}(\bar{B}\to D^{*}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(\bar{B}\to D^{*}\mu^{-}\bar{\nu}_{\mu})$ and $\mathcal{R}(D^{0})\equiv\mathcal{B}(B^{-}\to D^{0}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(B^{-}\to D^{0}\mu^{-}\bar{\nu}_{\mu})$ are measured, assuming isospin symmetry, using a sample of proton-proton collision data corresponding to 3.0 fb${ }^{-1}$ of integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The tau lepton is identified in the decay mode $\tau^{-}\to\mu^{-}\nu_{\tau}\bar{\nu}_{\mu}$. The measured values are $\mathcal{R}(D^{*})=0.281\pm0.018\pm0.024$ and $\mathcal{R}(D^{0})=0.441\pm0.060\pm0.066$, where the first uncertainty is statistical and the second is systematic. The correlation between these measurements is $\rho=-0.43$. Results are consistent with the current average of these quantities and are at a combined 1.9 standard deviations from the predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb public pages

Determination of quantum numbers for several excited charmed mesons observed in B- -> D*(+)pi(-) pi(-) decays

A four-body amplitude analysis of the B − → D * + π − π − decay is performed, where fractions and relative phases of the various resonances contributing to the decay are measured. Several quasi-model-independent analyses are performed aimed at searching for the presence of new states and establishing the quantum numbers of previously observed charmed meson resonances. In particular the resonance parameters and quantum numbers are determined for the D 1 ( 2420 ) , D 1 ( 2430 ) , D 0 ( 2550 ) , D ∗ 1 ( 2600 ) , D 2 ( 2740 ) and D ∗ 3 ( 2750 ) states. The mixing between the D 1 ( 2420 ) and D 1 ( 2430 ) resonances is studied and the mixing parameters are measured. The dataset corresponds to an integrated luminosity of 4.7     fb − 1 , collected in proton-proton collisions at center-of-mass energies of 7, 8 and 13 TeV with the LHCb detector

Updated measurement of decay-time-dependent CP asymmetries in D-0 -> K+ K- and D-0 -> pi(+)pi(-) decays

A search for decay-time-dependent charge-parity (CP) asymmetry in D0 \u2192 K+ K 12 and D0 \u2192 \u3c0+ \u3c0 12 decays is performed at the LHCb experiment using proton-proton collision data recorded at a center-of-mass energy of 13 TeV, and corresponding to an integrated luminosity of 5.4 fb^ 121. The D0 mesons are required to originate from semileptonic decays of b hadrons, such that the charge of the muon identifies the flavor of the neutral D meson at production. The asymmetries in the effective decay widths of D0 and anti-D0 mesons are determined to be A_\u393(K+ K 12) = ( 124.3 \ub1 3.6 \ub1 0.5) 7 10^ 124 and A_\u393(\u3c0+ \u3c0 12) = (2.2 \ub1 7.0 \ub1 0.8) 7 10^ 124 , where the uncertainties are statistical and systematic, respectively. The results are consistent with CP symmetry and, when combined with previous LHCb results, yield A_\u393(K+ K 12) = ( 124.4 \ub1 2.3 \ub1 0.6) 7 10^ 124 and A_\u393(\u3c0+ \u3c0 12) = (2.5 \ub1 4.3 \ub1 0.7) 7 10^ 124