Miracle-dz/UniFAR-FTUs huggingface dataset:
Five computational developability guidelines for therapeutic antibody profiling

Significance Immunogenicity, instability, self-association, high viscosity, polyspecificity, or poor expression can all preclude an antibody from becoming a therapeutic. Early identification of these negative characteristics is essential. Akin to the Lipinski guidelines, which measure druglikeness in small molecules, our Therapeutic Antibody Profiler highlights antibodies that possess characteristics that are rare/unseen in clinical-stage mAb therapeutics. The only required input is the variable domain sequence. We show examples where our approach would have advised against manufacturing antibodies that were found to aggregate or have poor expression. Therapeutic mAbs must not only bind to their target but must also be free from “developability issues” such as poor stability or high levels of aggregation. While small-molecule drug discovery benefits from Lipinski’s rule of five to guide the selection of molecules with appropriate biophysical properties, there is currently no in silico analog for antibody design. Here, we model the variable domain structures of a large set of post-phase-I clinical-stage antibody therapeutics (CSTs) and calculate in silico metrics to estimate their typical properties. In each case, we contextualize the CST distribution against a snapshot of the human antibody gene repertoire. We describe guideline values for five metrics thought to be implicated in poor developability: the total length of the complementarity-determining regions (CDRs), the extent and magnitude of surface hydrophobicity, positive charge and negative charge in the CDRs, and asymmetry in the net heavy- and light-chain surface charges. The guideline cutoffs for each property were derived from the values seen in CSTs, and a flagging system is proposed to identify nonconforming candidates. On two mAb drug discovery sets, we were able to selectively highlight sequences with developability issues. We make available the Therapeutic Antibody Profiler (TAP), a computational tool that builds downloadable homology models of variable domain sequences, tests them against our five developability guidelines, and reports potential sequence liabilities and canonical forms. TAP is freely available at opig.stats. ox.ac. uk/webapps/sabdab-sabpred/TAP.php.
Management of vulvar lymphedema of filarial origin in a pregnant woman and its outcome: A case report

Lymphedema of filarial origin affecting the vulva is extremely rare. It is a dilemma if seen in a pregnant woman as there are no guidelines regarding excision and the mode of delivery. With the World Health Organization‐driven global program to eradicate filaria, it is unfortunate to see such cases. We report of a woman who had massive lymphedema of both the labia majora following filarial infection with a small secondary ulcer. She presented to our outpatient department in early pregnancy. After detailed counseling with the couple, a decision was taken for excision. The same was carried out. The wound healed well but the lymphedema recurred after 6 weeks. She was thereafter managed symptomatically. Pregnancy advanced without any complication. Her intrapartum management for a successful vaginal delivery is outlined in the report.
The HMG box transcription factors Sox1a and Sox1b specify a new class of glycinergic interneuron in the spinal cord of zebrafish embryos

ABSTRACT Specification of neurons in the spinal cord relies on extrinsic and intrinsic signals, which in turn are interpreted by expression of transcription factors. V2 interneurons develop from the ventral aspects of the spinal cord. We report here a novel neuronal V2 subtype, named V2s, in zebrafish embryos. Formation of these neurons depends on the transcription factors sox1a and sox1b. They develop from common gata2a- and gata3-dependent precursors co-expressing markers of V2b and V2s interneurons. Chemical blockage of Notch signalling causes a decrease in V2s and an increase in V2b cells. Our results are consistent with the existence of at least two types of precursor arranged in a hierarchical manner in the V2 domain. V2s neurons grow long ipsilateral descending axonal projections with a short branch at the ventral midline. They acquire a glycinergic neurotransmitter type during the second day of development. Unilateral ablation of V2s interneurons causes a delay in touch-provoked escape behaviour, suggesting that V2s interneurons are involved in fast motor responses. Summary: A novel spinal neuronal V2 subtype, V2s, is described in zebrafish embryos and proposed to be required for fast escape responses.
BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells

Purpose: BRAF and MEK inhibitors (BRAFi and MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAFV600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study, we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T-cell therapy (ACT) in melanoma resistant to BRAFi. Experimental Design: Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as patient-derived xenografts (PDX) derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT. Results: Herein we report that in human melanoma cell lines, senstitive and resistant to BRAFi and in PDX from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient upregulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TILs. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TILs demonstrated a significant increase of M6PR expression on tumors during vemurafenib treatment. Conclusions: BRAF-targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease. See related commentary by Goff and Rosenberg, p. 2682
Fully Printed Zinc Oxide Electrolyte-Gated Transistors on Paper

Fully printed and flexible inorganic electrolyte gated transistors (EGTs) on paper with a channel layer based on an interconnected zinc oxide (ZnO) nanoparticle matrix are reported in this work. The required rheological properties and good layer formation after printing are obtained using an eco-friendly binder such as ethyl cellulose (EC) to disperse the ZnO nanoparticles. Fully printed devices on glass substrates using a composite solid polymer electrolyte as gate dielectric exhibit saturation mobility above 5 cm2 V−1 s−1 after annealing at 350 °C. Proper optimization of the nanoparticle content in the ink allows for the formation of a ZnO channel layer at a maximum annealing temperature of 150 °C, compatible with paper substrates. These devices show low operation voltages, with a subthreshold slope of 0.21 V dec−1, a turn on voltage of 1.90 V, a saturation mobility of 0.07 cm2 V−1 s−1 and an Ion/Ioff ratio of more than three orders of magnitude.
Activity of a Long-Acting Injectable Bedaquiline Formulation in a Paucibacillary Mouse Model of Latent Tuberculosis Infection

The potent antituberculosis activity and long half-life of bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. ABSTRACT The potent antituberculosis activity and long half-life of bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: an untreated negative-control regimen; positive-control regimens of daily rifampin (10 mg/kg of body weight), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily bedaquiline at 2.67 mg/kg (B2.67), 5.33 mg/kg (B5.33), or 8 mg/kg (B8) to deliver the same total amount of bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative- and positive-control regimens performed as expected. One, two, and three doses of BLAI-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively, by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.
Ifosfamide, Carboplatin and Etoposide in Recurrent Malignant Glioma

After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse.
Social Media and Clinical Care: Ethical, Professional, and Social Implications

It is an exciting time to practice medicine during our digital “coming of age. ” Social media, the freely available Web-based platforms that facilitate information sharing of user-generated content, such as social networking sites, media-sharing sites, blogs, microblogs, and wikis, have transformed the way we communicate as a society. Through community building, message amplification, rapid dissemination, and engagement, social media has changed our interactions with others and, by direct consequence, our relationships. For health care, this represents a veritable social revolution. 1 Indeed, medicine is constantly evolving to adapt to new technologies. These advances have led to new therapies, diagnostic tools, and ways of communicating. As physicians and lifelong learners, it has been imperative to embrace the new when it has meant better and more efficient patient care while holding on to the stable tenets of medicine that root our profession: humanism, integrity, ethics, professionalism, and trust. Patients have been active on social media to find health information, find support through discussion groups and forums, and chronicle their illness journeys.2 Naturally, they are also interested in using social media to facilitate communication between themselves and their providers. In a survey of patients of an outpatient family practice clinic, 56% wanted their providers to use social media for appointment setting and reminders, diagnostic test results reporting, health information sharing, prescription notifications, and answering general questions.3 For those patients who do not use social media, many would start if they knew that they could connect with their providers there.3 Physicians are also exploring ways to use social media, both personally and professionally, although personal use is more common.4–6 Some physicians use social media professionally to find and share health information, communicate/network with colleagues and trainees, disseminate their research, market their practice, or engage in health advocacy. In …
Sclareol attenuates the development of atopic dermatitis induced by 2,4-dinitrochlorobenzene in mice

Abstract Context: Atopic dermatitis is a common chronic inflammatory skin disease affecting up to 20% of children and 1% of adults worldwide. Treatment of atopic dermatitis include corticosteroids and immunosuppressants, such as calcineurin inhibitors and methotrexate. However, these treatments often bring about adverse effects including skin atrophy, osteoporosis, skin cancer, and metabolic syndrome. Objective: In this study, we evaluated the therapeutic effects and mechanisms of sclareol, a natural diterpene, on atopic dermatitis (AD)-like skin lesions induced by 2,4-dinitrochlorobenzene (DNCB) in mice. Materials and methods: To evaluate the effect of sclareol in vivo model, BALB/c mice were repeatedly injected intraperitoneally with sclareol (50 and 100 mg/kg) in 2,4-dinitrochlorobenzene (DNCB)-induced AD-like murine model. Major assays were enzyme-linked immunosorbent assay, histological analysis, flow cytometry, western blot analysis. Results: Intraperitoneal administration of sclareol (50 and 100 mg/kg) significantly attenuated AD-like symptoms, such as serum IgE levels, epidermal/dermal hyperplasia, and the numbers of infiltrated mast cells. In addition, systemic sclareol treatments reduced local pro-inflammatory cytokine concentrations, including IL-6, IL-1b, TNF-a, IL-4, IFN-g, and IL-17A, on AD-like lesions. Furthermore, we demonstrated that sclareol also suppressed T cell activation and the capability of cytokine productions (IFN-g, IL-4 and IL-17A) in response to DNCB stimulation. By examining the skin homogenate, we found that sclareol inhibited the AD-like severity likely through suppressions of both NF-kB translocation and phosphorylation of the MAP kinase pathway. Discussion and conclusions: Cumulatively, our results indicate that sclareol induced anti-inflammatory effects against the atopic dermatitis elicited by DNCB. Thus, sclareol is worth of being further evaluated for its potential therapeutic benefits for the clinical treatment of AD.
Effect of Glucose Improvement on Spirometric Maneuvers in Patients With Type 2 Diabetes: The Sweet Breath Study

OBJECTIVE Type 2 diabetes exerts a deleterious effect on lung function. However, it is unknown whether an improvement in glycemic control ameliorates pulmonary function. RESEARCH DESIGN AND METHODS Prospective interventional study with 60 patients with type 2 diabetes and forced expiratory volume in 1 s (FEV1) ≤90% of predicted. Spirometric maneuvers were evaluated at baseline and after a 3-month period in which antidiabetic therapy was intensified. Those with an HbA1c reduction of ≥0.5% were considered to be good responders (n = 35). RESULTS Good responders exhibited a significant improvement in spirometric values between baseline and the end of the study (forced vital capacity [FVC]: 78.5 ± 12.6% vs. 83.3 ± 14.7%, P = 0.029]; FEV1: 75.6 ± 15.3% vs. 80.9 ± 15.4%, P = 0.010; and peak expiratory flow [PEF]: 80.4 ± 21.6% vs. 89.2 ± 21.0%, P = 0.007). However, no changes were observed in the group of nonresponders when the same parameters were evaluated (P = 0.586, P = 0.987, and P = 0.413, respectively). Similarly, the initial percentage of patients with a nonobstructive ventilatory defect and with an abnormal FEV1 decreased significantly only among good responders. In addition, the absolute change in HbA1c inversely correlated to increases in FEV1 (r = −0.370, P = 0.029) and PEF (r = −0.471, P = 0.004) in the responders group. Finally, stepwise multivariate regression analysis showed that the absolute change in HbA1c independently predicted increased FEV1 (R2 = 0.175) and PEF (R2 = 0.323). In contrast, the known duration of type 2 diabetes, but not the amelioration of HbA1c, was related to changes in forced expiratory flow between 25% and 75% of the FVC. CONCLUSIONS In type 2 diabetes, spirometric measurements reflecting central airway obstruction and explosive muscle strength exhibit significant amelioration after a short improvement in glycemic control.
Effects of protease and phytase supplements on small intestinal microbiota and amino acid digestibility in broiler chickens

ABSTRACT The objective of this study was to determine the effects of protease origin and dosage on the prececal (pc) amino acid (AA) digestibility and the influence on composition of the microbial community in the small intestine. In addition, the effects of phytase supplementation were investigated. A total of 8 dietary treatments were included. The basal diet contained mainly corn and soybean meal. Three protease products were added to the basal diet, each at the level recommended by the supplier and at an 8-fold level. Phytase was supplemented in another dietary treatment. Each dietary treatment was allocated to 8 replicates of 15 birds each. The experimental diets were offered from day 15 to 21 for ad libitum consumption. The effect of protease supplementation on the pc AA digestibility depended on the protease product type and the amount supplemented. The pc AA digestibility was significantly increased by 1 protease product when supplemented at high level and when phytase was supplemented. In all the other treatments, protease supplementation had no significant influence or it decreased pc AA digestibility, when compared with the treatment with no enzymes added. In general, Firmicutes was the most abundant phylum among the ileal microbiota across all the treatments. Significant effects on microbiota composition were observed at the genus level for some but not all protease treatments and phytase supplementation. The genera Streptococcus, Lactobacillus, and uncultured Clostridiaceae were responsible for these differences. Furthermore, microbial networks established for each diet showed either high or low number of intergeneric interactions, but without a consistent enzyme effect. We conclude that enzyme supplementation effects were evident in the terminal small intestine microbiota composition, and to a lesser extent, in pc AA digestibility. However, the changes in microbiota composition and pc AA digestibility could not be correlated, indicating absence of a causal relationship.
The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo

Despite recent advances in the development of novel therapies against castration-resistant prostate cancer, the advanced form of the disease remains a major treatment challenge. Aberrant sphingolipid signaling through sphingosine kinases and their product, sphingosine-1-phosphate, can promote proliferation, drug resistance, angiogenesis, and inflammation. The sphingosine kinase 2 inhibitor ABC294640 is undergoing clinical testing in cancer patients, and in this study we investigated the effects this first-in-class inhibitor in castration-resistant prostate cancer. In vitro, ABC294640 decreased prostate cancer cell viability as well as the expression of c-Myc and the androgen receptor, while lysosomal acidification increased. ABC294640 also induced a greater than 3-fold increase in dihydroceramides that inversely correlated with inhibition of dihydroceramide desaturase (DEGS) activity. Expression of sphingosine kinase 2 was dispensable for the ABC294640-mediated increase in dihydroceramides. In vivo, ABC294640 diminished the growth rate of TRAMP-C2 xenografts in syngeneic hosts and elevated dihydroceramides within tumors as visualized by MALDI imaging mass spectroscopy. The plasma of ABC294640-treated mice contained significantly higher levels of C16- and C24:1-ceramides (but not dihydro-C16-ceramide) compared with vehicle-treated mice. In summary, our results suggest that ABC294640 may reduce the proliferative capacity of castration-resistant prostate cancer cells through inhibition of both sphingosine kinase 2 and dihydroceramide desaturase, thereby providing a foundation for future exploration of this small-molecule inhibitor for the treatment of advanced disease. Mol Cancer Ther; 14(12); 2744–52. ©2015 AACR.
Temporal network alignment via GoT-WAVE

Motivation Network alignment (NA) finds conserved regions between two networks. NA methods optimize node conservation (NC) and edge conservation (EC). Dynamic graphlet degree vectors (DGDVs) are a state-of-the-art dynamic NC measure, used within the fastest and most accurante NA method for temporal networks: DynaWAVE. Here, we use graphlet-orbit transitions (GoTs), a different graphlet-based measure of temporal node similarity, as a new dynamic NC measure within DynaWAVE, resulting in GoT-WAVE. Results On synthetic networks, GoT-WAVE improves DynaWAVE's accuracy by 30% and speed by 64%. On real networks, when optimizing only dynamic NC, the methods are complementary. Furthermore, only GoT-WAVE supports directed edges. Hence, GoT-WAVE is a promising new temporal NA algorithm, which efficiently optimizes dynamic NC.We provide a user-friendly user interface and source code for GoT-WAVE. Availability and implementation http://www.dcc. fc.up. pt/got-wave/.