Systematic investigation of cytokine signaling activity at the tissue and single-cell levels.

Cytokines are critical for intercellular communication in human health and disease, but the investigation of cytokine signaling activity has remained challenging due to the short half-lives of cytokines and the complexity/redundancy of cytokine functions. To address these challenges, we developed the Cytokine Signaling Analyzer (CytoSig; https://cytosig.ccr.cancer.gov/ ), providing both a database of target genes modulated by cytokines and a predictive model of cytokine signaling cascades from transcriptomic profiles. We collected 20,591 transcriptome profiles for human cytokine, chemokine and growth factor responses. This atlas of transcriptional patterns induced by cytokines enabled the reliable prediction of signaling activities in distinct cell populations in infectious diseases, chronic inflammation and cancer using bulk and single-cell transcriptomic data. CytoSig revealed previously unidentified roles of many cytokines, such as BMP6 as an anti-inflammatory factor, and identified candidate therapeutic targets in human inflammatory diseases, such as CXCL8 for severe coronavirus disease 2019.

Usefulness of ultrasound in confirming the correct placement of Ryle's tube compared to the traditional method of auscultation in normal versus overweight and obese patients.

Background and Aims: Auscultation to verify Ryle's tube position is difficult in obese patients. We compared the usefulness of ultrasonography (USG) versus auscultation in confirming the correct Ryle's tube placement in normal versus overweight or obese patients, time taken for confirmation, and incidence of reinsertion. Material and Methods: A prospective, observational study was carried out on 80 patients. Patients with a body mass index (BMI)>25 kg/m2 formed group O and those with BMI <25 kg/m2 constituted group N. After Ryle's tube insertion correct placement was first confirmed by auscultation. The presence of a gurgling sound over the epigastrium was graded (definite/doubtful/absent). During USG evaluation, if Ryle's tube was not visualized at the subxiphoid region, 20mL of air was injected, looking for dynamic fogging in the stomach. If auscultation yielded doubtful or absent results and USG also failed to confirm, Ryle's tube was repositioned and confirmed. Results: Group O had a significantly higher BMI. Auscultation time and the time taken for USG confirmation were significantly longer in group O. The percentage of patients with definite auscultatory signs was significantly higher in group N. Significantly higher number of patients in group O had doubtful/absent auscultatory signs. Ryle's tube and fogging visualization with USG and the requirement of reinsertion were comparable in both groups. The percentage of patients with definite auscultatory confirmation and definite USG confirmation were comparable in group N. However, in group O, significantly lesser patients had definite auscultatory confirmation compared to definite USG signs. Conclusion: Confirmation of the correct placement of Ryle's tube using ultrasound is easier than auscultation in overweight and obese patients. In normal patients, both techniques are equally useful.

SymD webserver: a platform for detecting internally symmetric protein structures.

Internal symmetry of a protein structure is the pseudo-symmetry that a single protein chain sometimes exhibits. This is in contrast to the symmetry with which monomers are arranged in many multimeric protein complexes. SymD is a program that detects proteins with internal symmetry. It proved to be useful for analyzing protein structure, function and modeling. This web-based interactive tool was developed by implementing the SymD algorithm. To the best of our knowledge, SymD webserver is the first tool of its kind with which users can easily study the symmetry of the protein they are interested in by uploading the structure or retrieving it from databases. It uses the Galaxy platform to take advantage of its extensibility and displays the symmetry properties, the symmetry axis and the sequence alignment of the structures before and after the symmetry transformation via an interactive graphical visualization environment in any modern web browser. An Example Run video displays the workflow to help users navigate. SymD webserver is publicly available at http://symd.nci.nih.gov.

A T cell resilience model associated with response to immunotherapy in multiple tumor types.

Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (tumor-resilient T cell), a computational model utilizing single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as transforming growth factor-ß1, tumor necrosis factor-related apoptosis-inducing ligand and prostaglandin E2. Tres reliably predicts clinical responses to immunotherapy in melanoma, lung cancer, triple-negative breast cancer and B cell malignancies using bulk T cell transcriptomic data from pre-treatment tumors from patients who received immune-checkpoint inhibitors (n = 38), infusion products for chimeric antigen receptor T cell therapies (n = 34) and pre-manufacture samples for chimeric antigen receptor T cell or tumor-infiltrating lymphocyte therapies (n = 84). Further, Tres identified FIBP, whose functions are largely unknown, as the top negative marker of tumor-resilient T cells across many solid tumor types. FIBP knockouts in murine and human donor CD8+ T cells significantly enhanced T cell-mediated cancer killing in in vitro co-cultures. Further, Fibp knockout in murine T cells potentiated the in vivo efficacy of adoptive cell transfer in the B16 tumor model. Fibp knockout T cells exhibit reduced cholesterol metabolism, which inhibits effector T cell function. These results demonstrate the utility of Tres in identifying biomarkers of T cell effectiveness and potential therapeutic targets for immunotherapies in solid tumors.

Repair of a Perforation Defect With Calcium Silicate-Based Cement Using an Internal Matrix.

This case report describes the nonsurgical endodontic management of a distolingual floor perforation in a mandibular first molar using an internal matrix and mineral trioxide aggregate (MTA) cement. The pulp chamber was properly cleaned, and after placement of a synthetic collagen material that served as a barrier at the level of furcation, MTA was used to repair the perforation defect. Root canal treatment was completed and the tooth was restored with a composite restoration followed by a porcelain-fused-to-metal crown.

Diagnosis, Evaluation, and Endodontic Management of Rare Four-Rooted Mandibular Second Molar Using CBCT.

When endodontically diagnosing and evaluating the morphology and anatomy of roots and root canals, especially in multirooted teeth, clinicians must exercise extremely keen vision and give careful attention to minute details. Fundamental knowledge of the most common anatomic characteristics and the possible variations of these characteristics is necessary to provide successful endodontic therapy. While all mandibular molars have significant variations in roots and root canal configuration, mandibular second molars perhaps present the biggest challenge. This article highlights the endodontic management of a mandibular second molar with four roots (two mesial and two distal) with one canal in each root and the cone-beam computed tomography (CBCT) evaluation of the tooth, along with orifice location assessment using developmental root fusion lines.