The New Method Developed for Evaluation of Anthelmintic Activity by Housefly Worms and Compared with Conventional Earthworm Method

Evaluation of anthelmintic activity of any drug when carried out in laboratory conditions by using the isolated worms from nature cannot be adaptable with artificial laboratory conditions. Therefore, the present study aims at developing a new adaptable method for evaluation of anthelmintic activity. The present anthelmintic activity study reveals a new methodology with housefly worms cultured in laboratory conditions that resemble parasitic pinworms found in human being. We studied the anthelmintic activities of various drugs on housefly worms and earthworms. The results showed that the housefly worms had taken more time for paralysis and death. Even after paralysis the time taken for death is more in housefly worms in spite of smaller size and lesser weight of the worms compared to earthworms. The study concluded that the earthworms have not adapted to the artificial laboratory conditions leading to erratic results. Therefore, culturing of housefly worms was carried out to evaluate the anthelmintic activity and found an easy, prominent, eco-friendly, and reproducible method in all aspects such as equal age, size, and weight of worms used for the experiment

Protective and susceptibility effects of hSKCa3 allelic variants on juvenile myoclonic epilepsy

This article does not have an abstract

A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer

Funding Information: D.B. has consulted for NanoString, reports honoraria from AstraZeneca and has a patent (PCT/GB2020/050221) issued on methods for cancer prognostication. J.R. and M.A.B. have consulted for Achilles Therapeutics. N.M. has stock options in and has consulted for Achilles Therapeutics. N.M. holds European patents relating to targeting neoantigens (PCT/EP2016/059401), identifying patient response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA loss of heterozygosity (PCT/GB2018/052004) and predicting survival rates of patients with cancer (PCT/GB2020/050221). A.H. attended one advisory board for Abbvie, Roche and GRAIL, and reports personal fees from Abbvie, Boehringer Ingelheim, Takeda, AstraZeneca, Daiichi Sankyo, Merck Serono, Merck/MSD, UCB and Roche for delivering general education/training in clinical trials. A.H. owned shares in Illumina and Thermo Fisher Scientific (sold in 2020) and receives fees for membership of Independent Data Monitoring Committees for Roche-sponsored clinical trials. S.A.Q. is co-founder and Chief Scientific Officer of Achilles Therapeutics. A.C.H. is a board member and equity holder in ImmunoQure, AG and Gamma Delta Therapeutics, and is an equity holder in Adaptate Biotherapeutics and chair of the scientific advisory board. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer Ingelheim, Archer Dx Inc (collaboration in minimal residual disease-sequencing technologies) and Ono Pharmaceuticals, is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial. C.S has consulted for Amgen, AstraZeneca, Bicycle Therapeutics, Bristol Myers Squibb, Celgene, Genentech, GlaxoSmithKline, GRAIL, Illumina, Medixci, Metabomed, MSD, Novartis, Pfizer, Roche-Ventana and Sarah Cannon Research Institute. C.S. has stock options in Apogen Biotechnologies, Epic Biosciences and GRAIL, and has stock options and is co-founder of Achilles Therapeutics. C.S. holds patents relating: to assay technology to detect tumor recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA loss of heterozygosity (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221); to treating cancer by targeting Insertion/deletion (indel) mutations (PCT/GB2018/051893); to identifying indel mutation targets (PCT/GB2018/051892); to methods for lung cancer detection (PCT/US2017/028013); and to identifying responders to cancer treatment (PCT/GB2018/051912). The remaining authors declare no competing interests. Funding Information: We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant no. 203141/Z/16/Z) for the generation and initial processing of the RNA-seq data from sorted TILs. We thank S. Bola for technical support and S. Vanloo for administrative support. The GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Y.W. was supported by a Wellcome Trust Clinical Research Career Development Fellowship (no. 220589/Z/20/Z), an Academy of Medical Sciences Starter Grant for Clinical Lecturers, a National Institute for Health Research (NIHR) Academic Clinical Lectureship and the NIHR University College London Hospitals Biomedical Research Centre. D.B. was supported by funding from the NIHR University College London Hospitals Biomedical Research Centre, the ideas 2 innovation translation scheme at the Francis Crick Institute, the Breast Cancer Research Foundation (BCRF) and a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award. M.J.H. is a CRUK Fellow and has received funding from CRUK, NIHR, Rosetrees Trust, UKI NETs and the NIHR University College London Hospitals Biomedical Research Centre. C.S. is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute which receives its core funding from CRUK (no. FC001169), the UK Medical Research Council (no. FC001169) and the Wellcome Trust (no. FC001169). This research was funded in whole, or in part, by the Wellcome Trust (no. FC001169). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. C.S. is funded by CRUK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), CRUK Lung Cancer Centre of Excellence (no. C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Professorship Enhancement Award (no. RP/EA/180007), the NIHR Biomedical Research Centre at University College London Hospitals, the CRUK–University College London Centre, Experimental Cancer Medicine Centre and the BCRF. This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant no. SU2C-AACR-DT23-17 to S. M. Dubinett and A. E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. receives funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (no. FP7/2007-2013) Consolidator Grant (no. FP7-THESEUS-617844), European Commission ITN (no. FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the ERC under the European Union’s Horizon 2020 research and innovation program (grant no. 835297), and Chromavision from the European Union’s Horizon 2020 research and innovation program (grant no. 665233). Publisher Copyright: © 2022, The Author(s).Peer reviewedPublisher PD

Bronchiectasis in India:results from the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) and Respiratory Research Network of India Registry

BACKGROUND: Bronchiectasis is a common but neglected chronic lung disease. Most epidemiological data are limited to cohorts from Europe and the USA, with few data from low-income and middle-income countries. We therefore aimed to describe the characteristics, severity of disease, microbiology, and treatment of patients with bronchiectasis in India. METHODS: The Indian bronchiectasis registry is a multicentre, prospective, observational cohort study. Adult patients ( 6518 years) with CT-confirmed bronchiectasis were enrolled from 31 centres across India. Patients with bronchiectasis due to cystic fibrosis or traction bronchiectasis associated with another respiratory disorder were excluded. Data were collected at baseline (recruitment) with follow-up visits taking place once per year. Comprehensive clinical data were collected through the European Multicentre Bronchiectasis Audit and Research Collaboration registry platform. Underlying aetiology of bronchiectasis, as well as treatment and risk factors for bronchiectasis were analysed in the Indian bronchiectasis registry. Comparisons of demographics were made with published European and US registries, and quality of care was benchmarked against the 2017 European Respiratory Society guidelines. FINDINGS: From June 1, 2015, to Sept 1, 2017, 2195 patients were enrolled. Marked differences were observed between India, Europe, and the USA. Patients in India were younger (median age 56 years [IQR 41-66] vs the European and US registries; p<0\ub70001]) and more likely to be men (1249 [56\ub79%] of 2195). Previous tuberculosis (780 [35\ub75%] of 2195) was the most frequent underlying cause of bronchiectasis and Pseudomonas aeruginosa was the most common organism in sputum culture (301 [13\ub77%]) in India. Risk factors for exacerbations included being of the male sex (adjusted incidence rate ratio 1\ub717, 95% CI 1\ub703-1\ub732; p=0\ub7015), P aeruginosa infection (1\ub729, 1\ub710-1\ub750; p=0\ub7001), a history of pulmonary tuberculosis (1\ub720, 1\ub707-1\ub734; p=0\ub7002), modified Medical Research Council Dyspnoea score (1\ub732, 1\ub725-1\ub739; p<0\ub70001), daily sputum production (1\ub716, 1\ub703-1\ub730; p=0\ub7013), and radiological severity of disease (1\ub703, 1\ub701-1\ub704; p<0\ub70001). Low adherence to guideline-recommended care was observed; only 388 patients were tested for allergic bronchopulmonary aspergillosis and 82 patients had been tested for immunoglobulins. INTERPRETATION: Patients with bronchiectasis in India have more severe disease and have distinct characteristics from those reported in other countries. This study provides a benchmark to improve quality of care for patients with bronchiectasis in India. FUNDING: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis Consortium, European Respiratory Society, and the British Lung Foundation

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Which method is best for the induction of labour?: A systematic review, network meta-analysis and cost-effectiveness analysis

Background: More than 150,000 pregnant women in England and Wales have their labour induced each year. Multiple pharmacological, mechanical and complementary methods are available to induce labour. Objective: To assess the relative effectiveness, safety and cost-effectiveness of labour induction methods and, data permitting, effects in different clinical subgroups. Methods: We carried out a systematic review using Cochrane methods. The Cochrane Pregnancy and Childbirth Group’s Trials Register was searched (March 2014). This contains over 22,000 reports of controlled trials (published from 1923 onwards) retrieved from weekly searches of OVID MEDLINE (1966 to current); Cochrane Central Register of Controlled Trials (The Cochrane Library); EMBASE (1982 to current); Cumulative Index to Nursing and Allied Health Literature (1984 to current); ClinicalTrials.gov; the World Health Organization International Clinical Trials Registry Portal; and hand-searching of relevant conference proceedings and journals. We included randomised controlled trials examining interventions to induce labour compared with placebo, no treatment or other interventions in women eligible for third-trimester induction. We included outcomes relating to efficacy, safety and acceptability to women. In addition, for the economic analysis we searched the Database of Abstracts of Reviews of Effects, and Economic Evaluations Databases, NHS Economic Evaluation Database and the Health Technology Assessment database. We carried out a network meta-analysis (NMA) using all of the available evidence, both direct and indirect, to produce estimates of the relative effects of each treatment compared with others in a network. We developed a de novo decision tree model to estimate the cost-effectiveness of various methods. The costs included were the intervention and other hospital costs incurred (price year 2012–13). We reviewed the literature to identify preference-based utilities for the health-related outcomes in the model. We calculated incremental cost-effectiveness ratios, expected costs, utilities and net benefit. We represent uncertainty in the optimal intervention using cost-effectiveness acceptability curves. Results: We identified 1190 studies; 611 were eligible for inclusion. The interventions most likely to achieve vaginal delivery (VD) within 24 hours were intravenous oxytocin with amniotomy [posterior rank 2; 95% credible intervals (CrIs) 1 to 9] and higher-dose (≥ 50 μg) vaginal misoprostol (rank 3; 95% CrI 1 to 6). Compared with placebo, several treatments reduced the odds of caesarean section, but we observed considerable uncertainty in treatment rankings. For uterine hyperstimulation, double-balloon catheter had the highest probability of being among the best three treatments, whereas vaginal misoprostol (≥ 50 μg) was most likely to increase the odds of excessive uterine activity. For other safety outcomes there were insufficient data or there was too much uncertainty to identify which treatments performed ‘best’. Few studies collected information on women’s views. Owing to incomplete reporting of the VD within 24 hours outcome, the cost-effectiveness analysis could compare only 20 interventions. The analysis suggested that most interventions have similar utility and differ mainly in cost. With a caveat of considerable uncertainty, titrated (low-dose) misoprostol solution and buccal/sublingual misoprostol had the highest likelihood of being cost-effective. Limitations: There was considerable uncertainty in findings and there were insufficient data for some planned subgroup analyses. Conclusions: Overall, misoprostol and oxytocin with amniotomy (for women with favourable cervix) is more successful than other agents in achieving VD within 24 hours. The ranking according to safety of different methods was less clear. The cost-effectiveness analysis suggested that titrated (low-dose) oral misoprostol solution resulted in the highest utility, whereas buccal/sublingual misoprostol had the lowest cost. There was a high degree of uncertainty as to the most cost-effective intervention

Maternal periodontal disease and preeclampsia in Jaipur population

Background: Preeclampsia is identified as an important cause for mother and newborn mortality. Inspite of extensive research, the exact etiological relations have not been established. Hence, an attempt has been made in this study to evaluate the relationship between the preeclampsia and maternal periodontal disease. Materials and Methods: The case–control study comprised of thirty pregnant women distributed equally in the case (preeclampsia) and control (healthy) group. Gingival index, plaque index, bleeding on probing, clinical probing depth, and clinical attachment level were measured in both groups. Microbiologic examination for identification of one red complex organism Porphyromonas gingivalis and one orange complex organism Fusobacterium nucleatum were done in plaque and placental blood of cases and controls. The clinical examinations and collection of placental blood were done 24 h before delivery. Results: Periodontal condition in the preeclamptic women was statistically worse compared with the normotensive women. There was no statistically significant association between microorganisms in plaque and placental blood between normotensive control and preeclamptic pregnant women. The preeclamptic women had significantly higher chances of having newborns weighing <2.5 kg than the normotensive women. Conclusion: The preeclamptic women were associated with significantly higher periodontitis and lower fetal birth weight than normotensive women