Humans are fast and accurate when they recognize familiar faces. Previous neurophysiological studies have shown enhanced representations for the dichotomy of familiar vs. unfamiliar faces. As familiarity is a spectrum, however, any neural correlate should reflect graded representations for more vs. less familiar faces along the spectrum. By systematically varying familiarity across stimuli, we show a neural familiarity spectrum using electroencephalography. We then evaluated the spatiotemporal dynamics of familiar face recognition across the brain. Specifically, we developed a novel informational connectivity method to test whether peri-frontal brain areas contribute to familiar face recognition. Results showed that feed-forward flow dominates for the most familiar faces and top-down flow was only dominant when sensory evidence was insufficient to support face recognition. These results demonstrate that perceptual difficulty and the level of familiarity influence the neural representation of familiar faces and the degree to which peri-frontal neural networks contribute to familiar face recognition.

Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator’s choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC).

Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population.

A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did novement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.

Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents.

Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0.

A total of PIs and anti-HER2 therapies.We investigated the effects of mineral oil on statin pharmacokinetics and inflammatory markers in animal models. A new synthesis strategy produced regioisomers that facilitated the characterization of the main metabolite (M1) of atorvastatin, a lipophilic statin, in C57BL/6NCrl mice. The chemical structure of M1 in mice was confirmed as ortho-hydroxy β-oxidized atorvastatin. Atorvastatin and M1 pharmacokinetics and inflammatory markers were assessed in C57BL6/J mice given atorvastatin 5 mg/kg/day or 10 mg/kg/day, as a single dose or for 21 days, with or without 10 µL or 30 µL mineral oil. No consistent differences in plasma exposure of atorvastatin or M1 were observed in mice after single or repeat dosing of atorvastatin with or without mineral oil. However, mice administered atorvastatin 10 mg/kg with 30 µL mineral oil for 21 days had significantly increased plasma levels of serum amyloid A (mean 9.6 µg/mL vs 7.9 µg/mL without mineral oil; p less then 0.01) and significantly increased proportions of C62Lhigh B cells (mean 18% vs 12% without mineral oil; p = 0.04). There were no statistically significant differences for other inflammatory markers assessed. In dogs, pharmacokinetics of atorvastatin, its two hydroxy metabolites and pravastatin (a hydrophilic statin) were evaluated after single administration of atorvastatin 10 mg plus pravastatin 40 mg with or without 2 g mineral oil. Pharmacokinetics of atorvastatin, hydroxylated atorvastatin metabolites or pravastatin were not significantly different after single dosing with or without mineral oil in dogs. Collectively, the results in mice and dogs indicate that mineral oil does not affect atorvastatin or pravastatin pharmacokinetics, but could cause low-grade inflammation with chronic oral administration, which warrants further investigation.Bis-benzamidines are a diverse group of compounds with high potential in pharmacotherapy, and among them, pentamidine is a drug of great therapeutic significance in Pneumocystis jiroveci pneumonia (PJP) prophylaxis and therapy. Pharmacokinetic properties of these cationic species such as transport, acid/base equilibria, and interactions with potential target molecules are still of interest, especially for recently designed compounds. To broaden our knowledge drug-likeness, human serum albumin binding, and acidity constants (Ka) were experimentally and theoretically examined for five pentamidine analogues 1 – 5 with -NH-CO-chain-CO-NH-bridges of increasing length and O, N, and S atoms in the chain. The studied analogues display very marked activity against Pneumocystis carinii without cytotoxicity that inspired us to perform an in silico analysis of their mode of action based on the hypothesis that the small DNA groove of rich in adenine-thymine pairs is their molecular target. These studies allowed us to classify them as very promising lead molecules.In the last update of the RECIST criteria in 2009, it was proposed that the number of target lesions to be followed over time for response-to-treatment assessment be reduced from 10 to 5 lesions maximum, with up to 2 per organ. We explored the impact of reducing the number of target lesion on the assessment of drug effect in a randomised phase III clinical trial using a tumour growth inhibition (TGI) model. Tumour size measurements from 441 (out of 456) patients were used to build two datasets for which observations were the sum of longest diameters of all measurable lesions (ALL dataset) or following the RECIST 1.1 recommendations (R1.1 dataset). TGI models incorporating a categorical covariate for treatment group or a pharmacokinetic metric (i.e. dose; simulated area under the curve) were used to describe the longitudinal tumour size kinetics. Drug exposure was not superior to treatment group at describing drug effect. ALL and R1.1 individual estimates of drug effect appeared to be strongly correlated (r2=0.88). Including pharmacokinetic metrics in TGI models should be conducted carefully when no pharmacokinetic samples are available. Reducing the number of target lesion did not seem to compromise the determination of drug effect using TGI models.Estrogen receptor (ER) is a potential target receptor for ER-positive cancer therapy including breast cancers, gastric cancers, and human acute myeloblastic leukaemia. In order to reduce the side-effects of mitoxantrone (MTO), estrone-targeted liposomes for MTO delivery via ER were designed for selectively targeting cancer cells. In previous studies, MTO-loaded estrogen receptor targeted and sterically stabilized liposome (ES-SSL-MTO; ES estrone, is known to bind the ER) had been synthesized and showed a very high antiproliferative effect with IC50 value of 0.7 ng/mL. Based on these, further studies including in vivo targeting efficacy and antitumor activity, acute toxicity and pharmacokinetics of MTO liposomes were carried out. The results showed SSL (sterically stabilized liposome, PEGylated liposome, PEG Polyethylene Glycol) could reduce drug metabolism, improve the stability of liposomes, prolong in vivo circulation time of drugs, reduce the toxicity of MTO. But SSL could not be enriched in tumor tissues. However, estrone (ES)-targeted liposomes could be delivered to tumor sites. ES-SSL could effectively enter into ER-expressing tumor cellsand be accumulated, prolong the circulation time in vivo, reduce side effects of drug. ES-SSL-MTO could provide higher bioavailability than MTO, enhance the anti-tumor effect and the safety of MTO, reduce the toxicity and side effects of MTO and improve the therapeutic effect of MTO. These facts proved ES-SSL is a useful tumor-targeting drug delivery system for MTO.The treatment of posterior segment disorders of the eye requires therapeutic strategies to achieve drug effects over prolonged times. Innovative colloidal delivery systems can be designed to deliver drugs to the retina and prolong their intravitreal permanence. In order to exploit pullulan (Pull) as polymeric drug carrier for intravitreal drug delivery, derivatives of hydrophobic model molecule rhodamine B (RhB) were conjugated to the pullulan backbone through linkers with different stability, namely ether (Et), hydrazone (Hy) or ester (Es) bond to obtain Pull-Et-RhB, Pull-Hy-RhB and Pull-Es-RhB, respectively. Dynamic light scattering and transmission electron microscopy analyses showed that the polymer conjugates self-assembled into 20-25 nm particles. Pull-Et-RhB was fairly stable at all tested pH values. At the vitreal pH of 7.4, 50% of RhB was released from Pull-Hy-RhB and Pull-Es-RhB in 11 and 6 days, respectively. At endosomal pH (5.5), 50% of RhB was released from Pull-Hy-RhB and Pull-Es-RhB in 4 and 1 days, respectively. Multiple particle tracking analyses in ex vivo porcine eye model showed that the diffusivity of the bioconjugates in the vitreous was about 103 times lower than in water. Flow cytometry and confocal microscopy analyses showed that bioconjugates are remarkably taken up by the retinal RPE cells. In vivo studies showed that after intravitreal injection to mice, the bioconjugates localize in the ganglion cell layer and in the inner and outer plexiform layers. Pull-Hy-RhB particles were detected also inside the retinal blood vessels. These results demonstrate that pullulan with tailored linkers for drug conjugation is a promising vehicle for long-acting intravitreal injectables that are capable to permeate to the retina.Though polyurethane (PU) hydrogel had great potential in topical drug delivery system, drug skin delivery behavior from hydrogel and the underlying molecular mechanism were still unclear. In this study, PU and Carbomer (CP as control) hydrogels were prepared with lidocaine (LID) and ofloxacin (OFX) as model drugs. In vitro skin permeation and tissue distribution study were conducted to evaluate the drug delivery behaviors. The underlying molecular mechanisms were characterized by drug release with octanol as release medium, rheological study, ATR-FTIR, NMR, and molecular simulation. The results showed that the skin permeation amount of LID-PU (45.50 ± 7.12 μg) was lower than LID-CP (45.50 ± 7.12 μg). And the LID diffusion coefficient of PU (26.21 μg/h0.5) was also lower than CP (31.30 μg/h0.5), which attributed to H-bonding between LID (-CONH) and PU (-NHCOO). However, the OFX-PU showed a higher skin permeation amount (10.06 ± 1.29 μg) than OFX-CP (5.28 ± 1.39 μg). And the OFX-PU also showed a higher diffusion coefficient (30.