Eksperimentalna infektivna pneumokonioza

Quartz and coal-mine dusts were introduced into the lungs of rats by inhalation, in a high concentration, for four months, and then groups of these dusted animals were infected with a virulent strain of human tubercle bacillus (37 Rv). Dusting was continued for a further period of ten months in the case of coal-mine dust. No variation in lung pathology was seen in the quartz groups, although both produced classical silicotic nodules. In the coal-mine dust the infective group showed slightly more fibrosis, diffuse in nature, than either the noninfected or the tuberculous control group. These are preliminary experiments, and the results must be considered as both tentative and not very conclusive. Work is being continued.Prašina kvarca i ugljenokopna prašina bile su unesene inhalacijom u pluća štakora. Koncentracija je bila visoka, a ekspozicija je trajala 4 mjeseca Nakon toga su grupe zaprašenih životinja bile inficirane virulentnim sojom humanog tuberkuloznog bacila (H 37 Rv). Kod grupe životinja, koje su bile izvrgnute djelovanju ugljenokopne prašine, nastavljeno je zaprašivanje daljih 10 mjeseci. U kvarcnim grupama nije bilo razlike s obzirom na patologiju pluća, iako je u obje grupe došlo do stvaranja klasičnih silikotičnih čvorova. U grupi životinja, koje su bile izvrgnute ugljenokopnoj prašini, nađeno je nešto više fibroze, koja je bila difuzna, nego bilo u neinficiranoj ili tuberkuloznoj kontrolnoj grupi. Ti eksperimenti su preliminarni i ne treba ih smatrati previše konkluzivnima. Rad se nastavlja

Histone deacetylase 11 inhibition promotes breast cancer metastasis from lymph nodes

Lymph node (LN) metastases correspond with a worse prognosis in nearly all cancers, yet the occurrence of cancer spreading from LNs remains controversial. Additionally, the mechanisms explaining how cancers survive and exit LNs are largely unknown. Here, we show that breast cancer patients frequently have LN metastases that closely resemble distant metastases. In addition, using a microsurgical model, we show how LN metastasis development and dissemination is regulated by the expression of a chromatin modifier, histone deacetylase 11 (HDAC11). Genetic and pharmacologic blockade of HDAC11 decreases LN tumor growth, yet substantially increases migration and distant metastasis formation. Collectively, we reveal a mechanism explaining how HDAC11 plasticity promotes breast cancer growth as well as dissemination from LNs and suggest caution with the use of HDAC inhibitors

Pulmonary Delivery of Nanoparticle-Bound Toll-like Receptor 9 Agonist for the Treatment of Metastatic Lung Cancer

CpG oligodeoxynucleotides are potent toll-like receptor (TLR) 9 agonists and have shown promise as anticancer agents in preclinical studies and clinical trials. Binding of CpG to TLR9 initiates a cascade of innate and adaptive immune responses, beginning with activation of dendritic cells and resulting in a range of secondary effects that include the secretion of pro-inflammatory cytokines, activation of natural killer cells, and expansion of T cell populations. Recent literature suggests that local delivery of CpG in tumors results in superior antitumor effects as compared to systemic delivery. In this study, we utilized PRINT (particle replication in nonwetting templates) nanoparticles as a vehicle to deliver CpG into murine lungs through orotracheal instillations. In two murine orthotopic metastasis models of non-small-cell lung cancer-344SQ (lung adenocarcinoma) and KAL-LN2E1 (lung squamous carcinoma), local delivery of PRINT-CpG into the lungs effectively promoted substantial tumor regression and also limited systemic toxicities associated with soluble CpG. Furthermore, cured mice were completely resistant to tumor rechallenge. Additionally, nanodelivery showed extended retention of CpG within the lungs as well as prolonged elevation of antitumor cytokines in the lungs, but no elevated levels of proinflammatory cytokines in the serum. These results demonstrate that PRINT-CpG is a potent nanoplatform for local treatment of lung cancer that has collateral therapeutic effects on systemic disease and an encouraging toxicity profile and may have the potential to treat lung metastasis of other cancer types

A community jury study exploring the public acceptability of using risk stratification to determine eligibility for cancer screening

Introduction Using risk stratification to determine eligibility for cancer screening is likely to improve the efficiency of screening programmes by targeting resources towards those most likely to benefit. We aimed to explore the implications of this approach from a societal perspective by understanding public views on the most acceptable stratification strategies. Methods We conducted three online community juries with 9 or 10 participants in each. Participants were purposefully sampled by age (40–79 years), sex, ethnicity, social grade and English region. On the first day, participants were informed of the potential benefits and harms of cancer screening and the implications of different ways of introducing stratification using scenarios based on phenotypic and genetic risk scores. On the second day, participants deliberated to reach a verdict on the research question, ‘Which approach(es) to inviting people to screening are acceptable, and under what circumstances?’ Deliberations and feedback were recorded and analysed using thematic analysis. Results Across the juries, the principle of risk stratification was generally considered to be an acceptable approach for determining eligibility for screening. Disregarding increasing capacity, the participants considered it to enable efficient resource allocation to high-risk individuals and could see how it might help to save lives. However, there were concerns regarding fair implementation, particularly how the risk assessment would be performed at scale and how people at low risk would be managed. Some favoured using the most accurate risk prediction model whereas others thought that certain risk factors should be prioritized (particularly factors considered as non-modifiable and relatively stable, such as genetics and family history). Transparently justifying the programme and public education about cancer risk emerged as important contributors to acceptability. Conclusion Using risk stratification to determine eligibility for cancer screening was acceptable to informed members of the public, particularly if it included risk factors they considered fair and when communicated transparently. Patient or Public Contribution Two patient and public involvement representatives were involved throughout this study. They were not involved in synthesizing the results but contributed to producing study materials, co-facilitated the community juries and commented on the interpretation of the findings and final report

A Group-Theoretical Method for Natanzon Potentials in Position-Dependent Mass Background

A new manner for deriving the exact potentials is presented. By making use of conformal mappings, the general expression of the effective potentials deduced under su(1,1) algebra can be brought back to the general Natanzon hypergeometric potentials

Factor XIIIA-expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking

Lung cancer is the leading cause of cancer-related deaths worldwide, and lung squamous carcinomas (LUSC) represent about 30% of cases. Molecular aberrations in lung adenocarcinomas have allowed for effective targeted treatments, but corresponding therapeutic advances in LUSC have not materialized. However, immune checkpoint inhibitors in sub-populations of LUSC patients have led to exciting responses. Using computational analyses of The Cancer Genome Atlas, we identified a subset of LUSC tumors characterized by dense infiltration of inflammatory monocytes (IMs) and poor survival. With novel, immunocompetent metastasis models, we demonstrated that tumor cell derived CCL2-mediated recruitment of IMs is necessary and sufficient for LUSC metastasis. Pharmacologic inhibition of IM recruitment had substantial anti-metastatic effects. Notably, we show that IMs highly express Factor XIIIA, which promotes fibrin cross-linking to create a scaffold for LUSC cell invasion and metastases. Consistently, human LUSC samples containing extensive cross-linked fibrin in the microenvironment correlated with poor survival

A circle RNA regulatory axis promotes lung squamous metastasis via CDR1-mediated regulation of golgi trafficking

Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis. Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of circRNA is through miRNA sponging, we found that miR-671-5pmore potently silenced an axis of CDR1as and its antisense transcript, cerebellar degeneration related protein 1 (CDR1). Silencing of CDR1as or CDR1 significantly inhibited LUSC metastases and CDR1 was sufficient to promote migration and metastases. CDR1, which directly interacted with adaptor protein 1 (AP1) complex subunits and coatomer protein I (COPI) proteins, no longer promoted migration upon blockade of Golgi trafficking. Therapeutic inhibition of the CDR1as/CDR1 axis with miR-671-5p mimics reduced metastasis in vivo. This report demonstrates a novel role for CDR1 in promoting metastasis and Golgi trafficking. These findings reveal an miRNA/ circRNA axis that regulates LUSC metastases through a previously unstudied protein, CDR1. Significance: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1. Significance: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1

Association of a novel mutation in the plasmodium falciparum chloroquine resistance transporter with decreased piperaquine sensitivity

Background. Amplified copy number in the plasmepsin II/III genes within Plasmodium falciparum has been associated with decreased sensitivity to piperaquine. To examine this association and test whether additional loci might also contribute, we performed a genome-wide association study of ex vivo P. falciparum susceptibility to piperaquine. Methods. Plasmodium falciparum DNA from 183 samples collected primarily from Cambodia was genotyped at 33 716 genomewide single nucleotide polymorphisms (SNPs). Linear mixed models and random forests were used to estimate associations between parasite genotypes and piperaquine susceptibility. Candidate polymorphisms were evaluated for their association with dihydroartemisinin- piperaquine treatment outcomes in an independent dataset. Results. Single nucleotide polymorphisms on multiple chromosomes were associated with piperaquine 90% inhibitory concentrations (IC90) in a genome-wide analysis. Fine-mapping of genomic regions implicated in genome-wide analyses identified multiple SNPs in linkage disequilibrium with each other that were significantly associated with piperaquine IC90, including a novel mutation within the gene encoding the P. falciparum chloroquine resistance transporter, PfCRT. This mutation (F145I) was associated with dihydroartemisinin-piperaquine treatment failure after adjusting for the presence of amplified plasmepsin II/III, which was also associated with decreased piperaquine sensitivity. Conclusions. Our data suggest that, in addition to plasmepsin II/III copy number, other loci, including pfcrt, may also be involved in piperaquine resistance

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy

peer reviewedBackground: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. Objective: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. Methods: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non–oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. Results: For non–OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. Conclusions: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction. © 202