p-Tolyl bis­(o-tolyl­amido)­phosphinate

In the title compound, C21H23N2O2P, the P atom has a distorted tetra­hedral configuration. The O atom of the OC6H4-4-CH3 group and the N atoms show sp 2 character. In the crystal, adjacent mol­ecules are linked by N—H⋯O hydrogen bonds into helical chains parallel to the b axis

N-(2-Fluoro­benzo­yl)-N′,N′′-bis­(4-methyl­phen­yl)phospho­ric triamide

The P atom in the title compound, C21H21FN3O2P, is in a tetra­hedral coordination environment and the environment of each N atom is essentially planar (sums of angles = 359.7, 359.9 and 358.4°). The phosphoryl and carbonyl groups adopt anti orientations with respect to each other. In the crystal, adjacent mol­ecules are linked via N—H⋯O=P and two N—H⋯O=C hydrogen bonds into an extended chain parallel to the a axis

N-(2,6-Difluoro­benzo­yl)-P,P-bis­(pyrrolidin-1-yl)phosphinic amide

The phosphoryl and carbonyl groups in the title compound, C15H20F2N3O2P, are anti with respect to each other (but the P- and C-groups are separated by another atom) and the P atom is in a tetra­hedral coordination environment. Two C atoms in one of the pyrrolidinyl fragments are disordered over two sets of sites with occupancies of 0.746 (8) and 0.254 (8). The environments of the pyrrolidinyl N atoms show a slight deviation from planarity and none of the three N atoms is involved in any hydrogen bond as an acceptor. In the crystal, pairs of inter­molecular N—H⋯O hydrogen bonds form inversion dimers

Virotheranostics, a double-barreled viral gun pointed toward cancer; Ready to shoot?

Compared with conventional cancer treatments, the main advantage of oncolytic virotherapy is its tumor-selective replication followed by the destruction of malignant cells without damaging healthy cells. Accordingly, this kind of biological therapy can potentially be used as a promising approach in the field of cancer management. Given the failure of traditional monitoring strategies (such as immunohistochemical analysis (in providing sufficient safety and efficacy necessary for virotherapy and continual pharmacologic monitoring to track pharmacokinetics in real-time, the development of alternative strategies for ongoing monitoring of oncolytic treatment in a live animal model seems inevitable. Three-dimensional molecular imaging methods have recently been considered as an attractive approach to overcome the limitations of oncolytic therapy. These noninvasive visualization systems provide real-time follow-up of viral progression within the cancer tissue by the ability of engineered oncolytic viruses (OVs) to encode reporter transgenes based on recombinant technology. Human sodium/iodide symporter (hNIS) is considered as one of the most prevalent nuclear imaging reporter transgenes that provides precise information regarding the kinetics of gene expression, viral biodistribution, toxicity, and therapeutic outcomes using the accumulation of radiotracers at the site of transgene expression. Here, we provide an overview of pre-clinical and clinical applications of hNIS-based molecular imaging to evaluate virotherapy efficacy. Moreover, we describe different types of reporter genes and their potency in the clinical trials

Correction to: Virotheranostics, a double-barreled viral gun pointed toward cancer; ready to shoot? (Cancer Cell International, (2020), 20, 1, (131), 10.1186/s12935-020-01219-6)

An amendment to this paper has been published and can be accessed via the original article. © 2020, The Author(s)

Role of γδ T cells in controlling viral infections with a focus on influenza virus: implications for designing novel therapeutic approaches

Influenza virus infection is among the most detrimental threats to the health of humans and some animals, infecting millions of people annually all around the world and in many thousands of cases giving rise to pneumonia and death. All those health crises happen despite previous and recent developments in anti-influenza vaccination, suggesting the need for employing more sophisticated methods to control this malign infection. Main body The innate immunity modules are at the forefront of combating against influenza infection in the respiratory tract, among which, innate T cells, particularly gamma-delta (γδ) T cells, play a critical role in filling the gap needed for adaptive immune cells maturation, linking the innate and adaptive immunity together. Upon infection with influenza virus, production of cytokines and chemokines including CCL3, CCL4, and CCL5 from respiratory epithelium recruits γδ T cells at the site of infection in a CCR5 receptor-dependent fashion. Next, γδ T cells become activated in response to influenza virus infection and produce large amounts of proinflammatory cytokines, especially IL-17A. Regardless of γδ T cells’ roles in triggering the adaptive arm of the immune system, they also protect the respiratory epithelium by cytolytic and non-cytolytic antiviral mechanisms, as well as by enhancing neutrophils and natural killer cells recruitment to the infection site. Conclusion: In this review, we explored varied strategies of γδ T cells in defense to influenza virus infection and how they can potentially provide balanced protective immune responses against infected cells. The results may provide a potential window for the incorporation of intact or engineered γδ T cells for developing novel antiviral approaches or for immunotherapeutic purposes

Molecular detection of TEM broad spectrum β-lactamase in clinical isolates of Escherichia coli

Resistance to β-lactam antibiotics, along with clinical isolates, frequently results to production of β- lactamase enzymes. In recent years, the production of extended spectrum β-lactamases (ESBLs) among clinical isolates, especially Escherichia coli has greatly increased. On the other hand, β lactamase genes have several subfamilies, and designing universal primers could be valuable to detect all of them. The beta lactamase enzyme producing E. coli, resistant to β-lactam antibiotics, created many problems for the patients. The TEM gene is responsible for β-lactamase resistance. The purpose of this study was to find out the percentage of E. coli strains that carry TEM in genes. In total, 500 clinical samples were collected from different Hospitals in Tehran. All the samples were isolated on EMB and MacConkey agar and incubated at 37°C for 24 h. The identification was carried out by conventional biochemical tests. Out of the 500 samples, 200 were identified as E. coli. The TEM gene was determined by PCR method on the isolates, which were already identified as Phenotypic by disk diffusion agar and combined disk. Out of the 200 isolated E. coli strains, 128 (64%) were producing ESBls. The PCR results show that 74 isolates of E. coli (57.8%) had the TEM gene. Our findings show that the majority of the ESBL positive clinical isolates of E. coli carried the TEM gene.Key words: Escherichia coli, β-lactamase enzymes, TEM-type extended spectrum beta-lactamases

A Weighted Prognostic Covariate Adjustment Method for Efficient and Powerful Treatment Effect Inferences in Randomized Controlled Trials

A crucial task for a randomized controlled trial (RCT) is to specify a statistical method that can yield an efficient estimator and powerful test for the treatment effect. A novel and effective strategy to obtain efficient and powerful treatment effect inferences is to incorporate predictions from generative artificial intelligence (AI) algorithms into covariate adjustment for the regression analysis of a RCT. Training a generative AI algorithm on historical control data enables one to construct a digital twin generator (DTG) for RCT participants, which utilizes a participant's baseline covariates to generate a probability distribution for their potential control outcome. Summaries of the probability distribution from the DTG are highly predictive of the trial outcome, and adjusting for these features via regression can thus improve the quality of treatment effect inferences, while satisfying regulatory guidelines on statistical analyses, for a RCT. However, a critical assumption in this strategy is homoskedasticity, or constant variance of the outcome conditional on the covariates. In the case of heteroskedasticity, existing covariate adjustment methods yield inefficient estimators and underpowered tests. We propose to address heteroskedasticity via a weighted prognostic covariate adjustment methodology (Weighted PROCOVA) that adjusts for both the mean and variance of the regression model using information obtained from the DTG. We prove that our method yields unbiased treatment effect estimators, and demonstrate via comprehensive simulation studies and case studies from Alzheimer's disease that it can reduce the variance of the treatment effect estimator, maintain the Type I error rate, and increase the power of the test for the treatment effect from 80% to 85%~90% when the variances from the DTG can explain 5%~10% of the variation in the RCT participants' outcomes.Comment: 49 pages, 6 figures, 12 table

Preclinical and clinical characterization of fibroblast-derived neuregulin-1 on trastuzumab and pertuzumab activity in HER2-positive breast cancer

[Purpose]: To characterize expression of neuregulin-1 (NRG1), an HER3 ligand, in HER2-positive breast cancer and its relation with the efficacy of trastuzumab with or without pertuzumab.[Experimental Design]: Characterization of NRG1 expression in tumor cell lines, in tumor specimens, and in cancer-associated fibroblasts (CAFs). Patient-derived CAFs were used to investigate NRG1 impact on the activity of trastuzumab with or without pertuzumab in HER2-positive breast cancer cells. The relationship between NRG1 expression and pathologic response to anti-HER2–based neoadjuvant therapy was assessed in a retrospective patient cohort and in the NeoSphere trial.[Results]: NRG1 was expressed in HER2-positive breast cancer–derived fibroblasts at significantly higher levels than in cancer cells. NRG1 and the conditioned media (CM) from CAFs phosphorylated HER3 and AKT in cancer cells and mediated trastuzumab resistance. Stable genetic depletion of NRG1 from CAFs overcame trastuzumab resistance. Pertuzumab effectively suppressed trastuzumab resistance mediated by either NRG1 or CAF's CM. NRG1 engaged an epithelial-to-mesenchymal transition that was prevented by trastuzumab and pertuzumab. In clinical samples, stromal and/or tumor cell expression of NRG1 determined by immunohistochemistry was uncommon (13.2%) yet significantly linked with residual disease following trastuzumab-based neoadjuvant therapy. In the NeoSphere trial, the magnitude of the difference of pathologic complete response rates favoring the pertuzumab arm was higher in the NRG1-high group.[Conclusions]: CAF-derived NRG1 mediates trastuzumab resistance through HER3/AKT, which might be reverted by pertuzumab. In patients with HER2-positive breast cancer, high expression of NRG1 was associated to poor response to trastuzumab, but not in combination with pertuzumab.This work is supported by ISCIII (CIBERONC CB16/12/00481, CB16/12/00241, PI18/00382, PI18/00006, PI18/01219 and by Generalitat de Catalunya (2017 SGR 507). S. Menendez is supported by Department de Salut, Generalitat de Catalunya (PERIS SLT006/17/00040). MARBiobanc is supported by ISCiii/FEDER (PT17/0015/0011) and by “Xarxa de Bancs de tumors” sponsored by Pla Director d’ Oncologia de Catalunya (XBTC) and Fundacion Jimenez Díaz Biobanks Platform by PT13/0010/0012 grant. Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R) and the CRIS Cancer Foundation provides support to A. Pandiella. Work carried out in our laboratories receive support from the European Community through the Regional Development Funding Program (FEDER). J.C. Montero is funded by the ISCIII through a Miguel Servet program (CPII17/00015) and receives research support from the same institution (PI18/00796). J. Albanell is supported by Breast Cancer Research Foundation (BCRF20-08), Instituto de Salud Carlos III Project Reference number AC15/00062 and the EC under the framework of the ERA-NET TRANSCAN-2 initiative co-financed by FEDER, Instituto de Salud Carlos III (CB16/12/00449 and PI19/01181), and Asociacion Espanola Contra el Cáncer (AECC)

The first inherited retinal disease registry in Iran: Research protocol and results of a pilot study

Background: To describe the protocol for developing a national inherited retinal disease (IRD) registry in Iran and present its initial report. Methods: This community-based participatory research was approved by the Ministry of Health and Medical Education of Iran in 2016. To provide the minimum data set (MDS), several focus group meetings were held. The final MDS was handed over to an engineering team to develop a web-based software. In the pilot phase, the software was set up in two referral centers in Iran. Final IRD diagnosis was made based on clinical manifestations and genetic findings. Ultimately, patient registration was done based on all clinical and non-clinical manifestations. Results: Initially, a total of 151 data elements were approved with Delphi technique. The registry software went live at www.IRDReg.org based on DHIS2 open source license agreement since February 2016. So far, a total of 1001 patients have been registered with a mean age of 32.41±15.60 years (range, 3 months to 74 years). The majority of the registered patients had retinitis pigmentosa (42, 95 CI: 38.9 to 45). Genetic testing was done for approximately 20 of the registered individuals. Conclusion: Our study shows successful web-based software design and data collection as a proof of concept for the first IRD registry in Iran. Multicenter integration of the IRD registry in medical centers throughout the country is well underway as planned. These data will assist researchers to rapidly access information about the distribution and genetic patterns of this disease. © 2020 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited