Infect Drug Resist. 2023 Jun 20;16:3955-3963. doi: 10.2147/IDR.S415197. eCollection 2023.

ABSTRACT

BACKGROUND: Mycobacterium abscessus (M. abscessus) is a rapidly growing bacterium (RGM) that causes refractory pulmonary and extrapulmonary infections. However, studies investigating pharyngeal and laryngeal M. abscessus infections are limited.

CASE PRESENTATION: A 41-year-old immunocompetent woman complaining of bloody sputum was referred to our hospital. Although her sputum culture tested positive for M. abscessus subsp. abscessus, radiological findings were not indicative of pulmonary infection or sinusitis. Further diagnostic workup, including laryngeal endoscopy and positron emission tomography/computed tomography (PET/CT), confirmed the presence of nasopharyngeal M. abscessus infection. The patient was initially treated with intravenous amikacin, imipenem/cilastatin, azithromycin, and clofazimine for 28 days, after which the patient was provided with amikacin, azithromycin, clofazimine, and sitafloxacin for four months. After the completion of antibiotic therapy, the patient showed negative results on sputum smear and culture and normal findings on PET/CT and laryngeal endoscopy. Whole-genome sequencing of this strain revealed that it belonged to the ABS-GL4 cluster, which has a functional erythromycin ribosomal methylase gene, although it is not a major lineage in non-cystic fibrosis (CF) patients in Japan and Taiwan and in CF patients in European countries. We conducted a literature review and identified seven patients who developed pharyngeal/laryngeal non-tuberculous mycobacterium (NTM) infection. Four of the eight patients had a history of immunosuppressant use, including steroids. Seven of the eight patients responded well to their treatment regimens.

CONCLUSION: Patients whose sputum culture tests are positive for NTM and who meet the diagnostic criteria for NTM infection but do not have intrapulmonary lesions should be evaluated for otorhinolaryngological infections. Our case series revealed that immunosuppressant use is a risk factor for pharyngeal/laryngeal NTM infection and that patients with pharyngeal/laryngeal NTM infections respond relatively well to antibiotic therapy.

PMID:37361939 | PMC:PMC10290463 | DOI:10.2147/IDR.S415197

Front Public Health. 2023 Jun 9;11:1122769. doi: 10.3389/fpubh.2023.1122769. eCollection 2023.

ABSTRACT

INTRODUCTION: Absence from school is more frequent for children with chronic health conditions (CHCs) than their peers and may be one reason why average academic attainment scores are lower among children with CHCs.

METHODS: We determined whether school absence explains the association between CHCs and academic attainment through a systematic review of systematic reviews of comparative studies involving children with or without CHCs and academic attainment. We extracted results from any studies that tested whether school absence mediated the association between CHCs and academic attainment.

RESULTS: We identified 27 systematic reviews which included 441 unique studies of 7, 549, 267 children from 47 jurisdictions. Reviews either covered CHCs generally or were condition-specific (e.g., chronic pain, depression, or asthma). Whereas reviews found an association between a range of CHCs (CHCs generally, cystic fibrosis, hemophilia A, end-stage renal disease (pre-transplant), end-stage kidney disease (pre-transplant), spina bifida, congenital heart disease, orofacial clefts, mental disorders, depression, and chronic pain) and academic attainment, and though it was widely hypothesized that absence was a mediator in these associations, only 7 of 441 studies tested this, and all findings show no evidence of absence mediation.

CONCLUSION: CHCs are associated with lower academic attainment, but we found limited evidence of whether school absence mediates this association. Policies that focus solely on reducing school absence, without adequate additional support, are unlikely to benefit children with CHCs.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=285031, identifier: CRD42021285031.

PMID:37361156 | PMC:PMC10288991 | DOI:10.3389/fpubh.2023.1122769

Microbiol Spectr. 2023 Jun 26:e0155623. doi: 10.1128/spectrum.01556-23. Online ahead of print.

ABSTRACT

Individuals with cystic fibrosis (CF) suffer from frequent and recurring microbial airway infections. The Gram-negative bacterium Pseudomonas aeruginosa is one of the most common organisms isolated from CF patient airways. P. aeruginosa establishes chronic infections that persist throughout a patient's lifetime and is a major cause of morbidity and mortality. Throughout the course of infection, P. aeruginosa must evolve and adapt from an initial state of early, transient colonization to chronic colonization of the airways. Here, we examined isolates of P. aeruginosa from children under the age of 3 years old with CF to determine genetic adaptations the bacterium undergoes during this early stage of colonization and infection. These isolates were collected when early aggressive antimicrobial therapy was not the standard of care and therefore highlight strain evolution under limited antibiotic pressure. Examination of specific phenotypic adaptations, such as lipid A palmitoylation, antibiotic resistance, and loss of quorum sensing, did not reveal a clear genetic basis for such changes. Additionally, we demonstrate that the geography of patient origin, within the United States or among other countries, does not appear to significantly influence genetic adaptation. In summary, our results support the long-standing model that patients acquire individual isolates of P. aeruginosa that subsequently become hyperadapted to the patient-specific airway environment. This study provides a multipatient genomic analysis of isolates from young CF patients in the United States and contributes data regarding early colonization and adaptation to the growing body of research about P. aeruginosa evolution in the context of CF airway disease. IMPORTANCE Chronic lung infection with Pseudomonas aeruginosa is of major concern for patients with cystic fibrosis (CF). During infection, P. aeruginosa undergoes genomic and functional adaptation to the hyperinflammatory CF airway, resulting in worsening lung function and pulmonary decline. All studies that describe these adaptations use P. aeruginosa obtained from older children or adults during late chronic lung infection; however, children with CF can be infected with P. aeruginosa as early as 3 months of age. Therefore, it is unclear when these genomic and functional adaptations occur over the course of CF lung infection, as access to P. aeruginosa isolates in children during early infection is limited. Here, we present a unique cohort of CF patients who were identified as being infected with P. aeruginosa at an early age prior to aggressive antibiotic therapy. Furthermore, we performed genomic and functional characterization of these isolates to address whether chronic CF P. aeruginosa phenotypes are present during early infection.

PMID:37358436 | DOI:10.1128/spectrum.01556-23

Int Forum Allergy Rhinol. 2023 Jun 26. doi: 10.1002/alr.23226. Online ahead of print.

NO ABSTRACT

PMID:37358402 | DOI:10.1002/alr.23226

Free Radic Biol Med. 2023 Jun 23:S0891-5849(23)00508-7. doi: 10.1016/j.freeradbiomed.2023.06.021. Online ahead of print.

ABSTRACT

Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanous acid (HOSCN), respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis (CF) and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell (AEC) exposure to its oxidants. In this study, we investigated how equal dose-rate exposures of MPO-derived oxidants differentially impact the metabolome of human AECs (BEAS-2B cells). We utilized enzymatic oxidant production with rate-limiting glucose oxidase (GOX) coupled to MPO, and chloride, bromide (Br-), or thiocyanate (SCN-) as substrates. AECs exposed to GOX/MPO/SCN- (favoring HOSCN) were viable after 24 h, while exposure to GOX/MPO (favoring HOCl) or GOX/MPO/Br- (favoring HOBr) developed cytotoxicity after 6 h. Cell glutathione and peroxiredoxin-3 oxidation were insufficient to explain these differences. However, untargeted metabolomics revealed GOX/MPO and GOX/MPO/Br- diverged significantly from GOX/MPO/SCN- for dozens of metabolites. We noted methionine sulfoxide and dehydromethionine were significantly increased in GOX/MPO- or GOX/MPO/Br--treated cells, and analyzed them as potential biomarkers of lung damage in bronchoalveolar lavage fluid from 5-year-olds with CF (n = 27). Both metabolites were associated with increasing bronchiectasis, neutrophils, and MPO activity. This suggests MPO production of HOCl and/or HOBr may contribute to inflammatory lung damage in early CF. In summary, our in vitro model enabled unbiased identification of exposure-specific metabolite products which may serve as biomarkers of lung damage in vivo. Continued research with this exposure model may yield additional oxidant-specific biomarkers and reveal explicit mechanisms of oxidant byproduct formation and cellular redox signaling.

PMID:37356776 | DOI:10.1016/j.freeradbiomed.2023.06.021

Nutrition. 2023 May 22;114:112091. doi: 10.1016/j.nut.2023.112091. Online ahead of print.

ABSTRACT

OBJECTIVE: Nutritional status and growth is well associated with disease outcomes and lung function in patients with cystic fibrosis (CF). Current dietary guidelines for the management of CF suggest a high-calorie, high-fat diet. Pancreatic insufficiency (PI) is present in most patients and contributes to malabsorption and malnutrition, but a considerable number of patients have pancreatic sufficiency (PS). The aim of this study was to compare weight status, clinical characteristics, and dietary intake of children with CF, with PS or PI.

METHODS: Patients with a diagnosis of CF (sweat test ≥60 mmol/L) and/or two known mutations for CF, ages 1 to 19 y were included in the study. Weight status, pulmonary characteristics, and blood lipid concentrations were evaluated. Dietary intake was evaluated through four 24-h recalls and energy, macronutrient intake, and intake in terms of food groups were assessed.

RESULTS: Included in the present analyses were 134 patients with CF (30 with PS and 104 with PI). The percentage of overweight/obesity (47%) was higher in children with PS than in those with PI (22%). Overall, children with PS had higher body mass index, blood lipid levels, and pulmonary function levels than those with PI (all P < 0.05). Total energy intake was lower in children with PS than in those with PI (P < 0.001), even after adjustment for age and sex (Padj < 0.001).

CONCLUSIONS: Weight status, dietary intake, pulmonary function, and lipid profile differed significantly in children with CF by pancreatic status. Nevertheless, the percentage of overweight and obesity was higher in children with PS than in those with PI. To avoid obesity, dietary recommendations for a high-calorie, high-fat diet should be reconsidered in patients with CF regarding their pancreatic status.

PMID:37356169 | DOI:10.1016/j.nut.2023.112091

J Cyst Fibros. 2023 Jun 23:S1569-1993(23)00818-4. doi: 10.1016/j.jcf.2023.06.004. Online ahead of print.

NO ABSTRACT

PMID:37357035 | DOI:10.1016/j.jcf.2023.06.004

J Cyst Fibros. 2023 Jun 23:S1569-1993(23)00180-7. doi: 10.1016/j.jcf.2023.06.002. Online ahead of print.

ABSTRACT

BACKGROUND: Life expectancy for people with CF (PwCF) continues to increase. However, a trend of overweight and obesity is emerging along with concern of developing comorbitities. Body composition (BC) is associated with several health indices. However, body mass index (BMI) does not provide information on BC.

METHODS: BMI, fat mass (FM), fat free mass (FFM), using bioelectrical impedance, lung function and sweat chloride (SwCl) were assessed in adult PwCF in routine clinic before and after commencement of the CFTR modulator Elexacaftor/Tezacaftor/Ivacaftor.

RESULTS: 109 PwCF (76 male) underwent assessments at both time points. In all PwCF a significant upward trend in BMI was observed (p < 0.001). Males significantly gained more FFM compared to females (p0.03), whilst prevalence of normal weight obesity increased primarily in females (25-38%).

CONCLUSION: Routine BC assessment identifies individuals with elevated FM or depleted FFM enabling individualised care with the focus of optimising BC.

PMID:37355345 | DOI:10.1016/j.jcf.2023.06.002

FASEB J. 2023 Jul;37(7):e23052. doi: 10.1096/fj.202300756R.

ABSTRACT

The ion channels in sperm tail play an important role in triggering key physiological reactions, e.g., progressive motility, hyperactivation, required for successful fertilization. Among them, CatSper and KSper have been shown to be important ion channels for the transport of Ca2+ and K+ . Moreover, the voltage-gated proton channel Hv1, the sperm-specific sodium-hydrogen exchanger (sNHE), the epithelial sodium channel (ENaC), members of the temperature-sensitive TRP channel family, and the cystic fibrosis transmembrane regulator (CFTR) are also found in the flagellum. This review focuses on the latest advances in ion channels located at the flagellum, describes how they affect sperm physiological function, and summarizes some primary mutual regulation mechanism between ion channels, including PH, membrane potential, and cAMP. These ion channels may be promising targets for clinical application in infertility.

PMID:37352114 | DOI:10.1096/fj.202300756R

Ann Am Thorac Soc. 2023 Jun 23. doi: 10.1513/AnnalsATS.202210-857OC. Online ahead of print.

ABSTRACT

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete.

OBJECTIVES: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population?

METHODS: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analyses and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline FEV1 and FEV1/FVC. In linear mixed effects models we investigated the associations of baseline protein levels with rate of FEV1 decline (mL/year) in 2,777 participants with up to 7 years of follow-up spirometry.

RESULTS: We identified 254 proteins associated with FEV1 in our discovery analyses with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (Discovery β=0.0561, Q=4.05×10-10, β=0.0421, Q=1.12×10-3, β=0.0358, Q=1.67×10-3, respectively). In longitudinal analyses within cohorts with follow up spirometry, we identified 15 proteins associated with FEV1 decline (Q<0.05), including elafin leukocyte elastase inhibitor and mucin-associated trefoil factor 2 (β=-4.3 mL/year, Q=0.049; β=-6.1 mL/year, Q=0.032; respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis and coagulation.

CONCLUSION: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. Additionally, we identify novel protein markers associated with FEV1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for endophenotyping and risk stratification, as well novel molecular targets for treatment of COPD.

PMID:37351609 | DOI:10.1513/AnnalsATS.202210-857OC

Biophys Rep (N Y). 2023 Apr 14;3(2):100108. doi: 10.1016/j.bpr.2023.100108. eCollection 2023 Jun 14.

ABSTRACT

In this paper we present a transistor circuit model for cystic fibrosis transmembrane conductance regulator (CFTR) that seeks to map the functional form of CFTR both in wild type and mutants. The circuit architecture is configured so that the function, and as much as possible the form, faithfully represents what is known about CFTR from cryo-electron microscopy and molecular dynamics. The model is a mixed analog-digital topology with an AND gate receiving the input from two separate ATP-nucleotide-binding domain binding events. The analog portion of the circuit takes the output from the AND gate as its input. The input to the circuit model and its noise characteristics are extracted from single-channel patch-clamp experiments. The chloride current predicted by the model is then compared with single-channel patch-clamp recordings for wild-type CFTR. We also consider the patch-clamp recordings from CFTR with a G551D point mutation, a clinically relevant mutant that is responsive to therapeutic management. Our circuit model approach enables bioengineering approaches to CFTR and allows biophysicists to use efficient circuit simulation tools to analyze its behavior.

PMID:37351179 | PMC:PMC10282560 | DOI:10.1016/j.bpr.2023.100108

Pediatr Pulmonol. 2023 Jun 23. doi: 10.1002/ppul.26533. Online ahead of print.

ABSTRACT

BACKGROUND: Hypoglycemia is common in people with cystic fibrosis (pwCF) during oral glucose tolerance tests (OGTTs) and in the free-living setting, yet its pathophysiology remains unclear.

OBJECTIVE: To evaluate hypoglycemia in children and young adults with CF by OGTT and continuous glucose monitoring (CGM).

METHODS: A 3-h OGTT was performed in children and young adults with CF and healthy controls (HC). Individuals were classified as experiencing hypoglycemia on OGTT (glucose <70 mg/dL) or not. Insulin, C-peptide, glucose, glucagon, and incretins were measured. CGM was performed for 7 days in the free-living setting. Measures of insulin sensitivity, beta cell function accounting for insulin sensitivity, and insulin clearance were calculated.

RESULTS: A total of 57 participants (40 CF and 17 HC) underwent assessment. Rates of hypoglycemia by OGTT were similar in pwCF (53%, 21/40) compared to HC (35%, 6/17), p = 0.23. PwCF compared to HC had higher A1c; on OGTT higher and later glucose peaks, later insulin peaks; and on CGM more glucose variability. CF Hypo+ versus CF Hypo- had higher lung function, higher insulin sensitivity, higher beta cell function accounting for insulin sensitivity, and decreased CGM variability. When comparing CF Hypo+ to HC Hypo+, although rates of hypoglycemia are similar, pwCF had blunted glucagon responses to hypoglycemia. OGTT hypoglycemia was not associated with CGM hypoglycemia in any group.

CONCLUSION: Youth with CF have increased insulin sensitivity and impaired glucagon response to hypoglycemia on OGTT. Hypoglycemia on OGTT did not associate with free-living hypoglycemia.

PMID:37350354 | DOI:10.1002/ppul.26533

BMC Res Notes. 2023 Jun 22;16(1):111. doi: 10.1186/s13104-023-06388-x.

ABSTRACT

OBJECTIVE: Cystic fibrosis (CF) is a genetic condition that causes abnormal mucus secretions in affected organs. MUC5AC and MUC5B are gel-forming mucins and frequent targets for investigations in CF tissues. Our objective was to qualify MUC5AC and MUC5B immunohistochemical techniques to provide a useful tool to identify, localize and interpret mucin expression in ferret tissues.

RESULTS: MUC5AC and MUC5B mucins were detected most commonly in large airways and least in small airways, consistent with reported goblet cell density in airway surface epithelia. We evaluated whether staining method affected the detection of goblet cell mucins in serial sections of bronchial surface epithelia. Significant differences between stains were not observed suggesting common co-expression MUC5AC and MUC5B proteins in goblet cells of airway surface epithelia. Gallbladder and stomach tissues are reported to have differential mucin enrichment, so we tested these tissues in wildtype ferrets. Stomach tissues were enriched in MUC5AC and gallbladder tissues enriched in MUC5B, mucin enrichment similar to human tissues. Mucin immunostaining techniques were further qualified for specificity using lung tissue from recently generated MUC5AC-/- and MUC5B-/- ferrets. Qualified techniques for MUC5AC and MUC5B immunohistochemistry will be useful tools for mucin tissue studies in CF and other ferret models.

PMID:37349833 | DOI:10.1186/s13104-023-06388-x

Sci Rep. 2023 Jun 22;13(1):10137. doi: 10.1038/s41598-023-36863-1.

ABSTRACT

The human airways are complex structures with important interactions between cells, extracellular matrix (ECM) proteins and the biomechanical microenvironment. A robust, well-differentiated in vitro culture system that accurately models these interactions would provide a useful tool for studying normal and pathological airway biology. Here, we report the development and characterization of a physiologically relevant air-liquid interface (ALI) 3D airway 'organ tissue equivalent' (OTE) model with three novel features: native pulmonary fibroblasts, solubilized lung ECM, and hydrogel substrate with tunable stiffness and porosity. We demonstrate the versatility of the OTE model by evaluating the impact of these features on human bronchial epithelial (HBE) cell phenotype. Variations of this model were analyzed during 28 days of ALI culture by evaluating epithelial confluence, trans-epithelial electrical resistance, and epithelial phenotype via multispectral immuno-histochemistry and next-generation sequencing. Cultures that included both solubilized lung ECM and native pulmonary fibroblasts within the hydrogel substrate formed well-differentiated ALI cultures that maintained a barrier function and expressed mature epithelial markers relating to goblet, club, and ciliated cells. Modulation of hydrogel stiffness did not negatively impact HBE differentiation and could be a valuable variable to alter epithelial phenotype. This study highlights the feasibility and versatility of a 3D airway OTE model to model the multiple components of the human airway 3D microenvironment.

PMID:37349353 | DOI:10.1038/s41598-023-36863-1

Expert Rev Respir Med. 2023 Jun 22. doi: 10.1080/17476348.2023.2228194. Online ahead of print.

ABSTRACT

INTRODUCTION: Gastrointestinal (GI) related symptoms, complications, and comorbidities in cystic fibrosis (CF) are common and research to reduce their burden is a priority to the CF community. To enable future research, this review aimed to summarize the range of GI symptoms, complications and comorbidities seen in CF, the underlying pathophysiology, and treatments.

AREAS COVERED: This was a rapid systematic review undertaken using the recommendations from the Cochrane Rapid Reviews Methods Group. We searched databases including PubMed, Embase, Medline and the Cochrane database and identified those studies reporting GI related symptoms, complications or comorbidities in CF or their treatment. Our searches identified 2,930 studies and a total 119 studies met our inclusion criteria. Where a prevalence could be determined, GI symptoms were reported in 33.7% of study participants. The range of symptoms reported was broad and the highest median prevalence included flatulence (43.5%), bloating and abdominal distension (36%) and fatty stool (36%). Meconium ileus was reported in 12% and distal intestinal obstruction syndrome in 8.5.

EXPERT OPINION: GI related symptoms, complications and comorbidities in CF are common. More consistent characterization and recording of these symptoms in clinical studies may help achieve the priority of reducing the burden of GI disease in CF.

PMID:37345513 | DOI:10.1080/17476348.2023.2228194

Tuberk Toraks. 2023 Jun;71(2):113-122. doi: 10.5578/tt.20239914.

ABSTRACT

INTRODUCTION: This study aimed to investigate whether inspiratory muscle strength was associated with bacterial colonization and other clinical outcomes and whether bacterial colonization was associated with clinical outcomes in patients with non-cystic fibrosis bronchiectasis (NCFB).

MATERIALS AND METHODS: Eighty-six patients were enrolled in a cross-sectional study. Patients were divided into two groups according to the presence of inspiratory muscle weakness and bacterial colonization. Parameters were compared between groups.

RESULT: Bronchiectasis etiologies were post-infectious, Kartagener's syndrome, and primary ciliary dyskinesia. The median value of MIP was -68, and MEP was 89 cm H2O in all patients. Although the ratio of bacterial colonization was similar to patients without inspiratory muscle weakness, the inspiratory muscle weakness group had a higher number of females, lower FEV1, FVC, ISWT, CRQ, higher MRC, E-FACED, SGRQ, number of hospitalization (p<0.05). When colonized and non-colonized patients were compared, MIP, and MEP were similar in spite of adjusted BMI, age, and sex. FEV1, FVC, ISWT, and ESWT were lower, and E-FACED scores (p<0.05) were higher in colonized patients.

CONCLUSIONS: Although inspiratory muscle strength was not associated with bacterial colonization in NCFB patients, it is an important factor that could be linked to disease severity, pulmonary functions, quality of life, and exercise capacity. Bacterial colonization was also associated with severe disease, deteriorated pulmonary functions, and exercise capacity.

PMID:37345393 | DOI:10.5578/tt.20239914

J Immunother Cancer. 2023 Jun;11(6):e007117. doi: 10.1136/jitc-2023-007117.

ABSTRACT

BACKGROUND: Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied mouse strain, C57BL/6, is also the only one for which multiple genetic variants are available to facilitate the exploration of the cancer-immunity dialog. Driven by the fact that no hormone receptor-positive (HR+) C57BL/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines.

METHODS: BC was induced in female C57BL/6 mice using a synthetic progesterone analog (medroxyprogesterone acetate, MPA) combined with a DNA damaging agent (7,12-dimethylbenz[a]anthracene, DMBA). Cell lines were established from these tumors and selected for dual (estrogen+progesterone) receptor positivity, as well as transplantability into C57BL/6 immunocompetent females.

RESULTS: One cell line, which we called B6BC, fulfilled these criteria and allowed for the establishment of invasive estrogen receptor-positive (ER+) tumors with features of epithelial to mesenchymal transition that were abundantly infiltrated by myeloid immune populations but scarcely by T lymphocytes, as determined by single-nucleus RNA sequencing and high-dimensional leukocyte profiling. Such tumors failed to respond to programmed cell death-1 (PD-1) blockade, but reduced their growth on treatment with ER antagonists, as well as with anthracycline-based chemotherapy, which was not influenced by T-cell depletion. Moreover, B6BC-derived tumors reduced their growth on CD11b blockade, indicating tumor sustainment by myeloid cells. The immune environment and treatment responses recapitulated by B6BC-derived tumors diverged from those of ER+ TS/A cell-derived tumors in BALB/C mice, and of ER- E0771 cell-derived and MPA/DMBA-induced tumors in C57BL/6 mice.

CONCLUSIONS: B6BC is the first transplantable HR+ BC cell line derived from C57BL/6 mice and B6BC-derived tumors recapitulate the complex tumor microenvironment of locally advanced HR+ BC naturally resistant to PD-1 immunotherapy.

PMID:37344100 | DOI:10.1136/jitc-2023-007117

Eur Respir J. 2023 Jun 21:2100960. doi: 10.1183/13993003.00960-2021. Online ahead of print.

ABSTRACT

RATIONALE: In people with cystic fibrosis (CF), regular nebulisation of 6% or 7% saline improves lung function, however these concentrations are not always tolerable. Clinically, some CF patients report using lower concentrations of saline to improve tolerability, yet the effects of lower concentrations are unknown. This study therefore aimed to evaluate the relative effectiveness and tolerability of 0.9% versus 3% versus 6% saline nebulised twice daily with an eFlow® rapid.

METHODS: Randomised, blinded, placebo-controlled, parallel-group, multi-centre study where subjects inhaled 4 mL of 0.9% or 3% or 6% saline twice daily for 16 weeks. Primary outcome was FEV1. Secondary outcomes were: FEF25-75 and FVC; quality of life; exercise capacity; acquisition or loss of bacterial organisms in expectorated sputum; tolerability of nebulised saline; pulmonary exacerbations and adverse events.

RESULTS: 140 participants were randomised to 0.9% (n=47), 3% (n=48) or 6% (n=45) saline. 134 participants (96%) contributed to the intention to treat analysis. 3% saline significantly improved lung function and increased the time to first pulmonary exacerbation compared to 0.9% saline, but did not improve quality of life. 6% saline had similar benefits to 3% saline but also significantly improved quality of life compared to 3% saline. Only 6% saline delayed the time to intravenous antibiotics for pulmonary exacerbation. Tolerability and adherence were similar.

CONCLUSION: Dilution of 6% saline to 3% maintains the benefits for lung function and exacerbation prevention however the positive impacts of 6% saline on quality of life and time to intravenous antibiotics for pulmonary exacerbations are lost.

PMID:37343977 | DOI:10.1183/13993003.00960-2021

AAPS J. 2023 Jun 21;25(4):62. doi: 10.1208/s12248-023-00828-z.

ABSTRACT

Itraconazole is a potent inhibitor of cytochrome P450 3A4 (CYP3A4), associated with numerous drug-drug interactions (DDI). PUR1900, a dry powder formulation of itraconazole for oral inhalation, results in high lung and low systemic exposure. This project used physiologically based pharmacokinetic (PBPK) modeling to assess the DDI potential of inhaled PUR1900, using midazolam as a "victim drug." The basic and mechanistic static models evaluated the DDI potential of PUR1900, assuming 5 mg of midazolam coadministration at steady-state itraconazole exposure. Subsequently, Simcyp® PBPK simulation software and pharmacokinetic data from a Phase 1 clinical trial with PUR1900 (NCT03479411) were used to optimize an existing itraconazole PBPK model. The model was applied to investigate the potential for CYP3A4 DDI when 5 mg of midazolam is co-administered with inhaled PUR1900 at a steady state in a virtual healthy population at PUR1900 doses up to 40 mg per day. The basic static and mechanistic static models suggested a strong likelihood for DDI with inhaled PUR1900. The PBPK model was consistent with PUR1900 Phase 1 trial data. The geometric mean Cmax and AUC ratios of midazolam at a maximum dose of 40 mg PUR1900 were 1.14 and 1.26, respectively, indicating a minimal likelihood of DDI with inhaled PUR1900. The low systemic exposure of itraconazole when administered as PUR1900 results in minimal to no CYP3A4 inhibition, reducing the concern of drug-drug interactions. As the risk of CYP3A4 DDI is predicted to be significantly lower when itraconazole is administered via oral inhalation as PUR1900, it is likely that PUR1900 can be safely used for the treatment of pulmonary fungal infections in patients taking pharmaceuticals currently contraindicated with oral itraconazole.

PMID:37344751 | DOI:10.1208/s12248-023-00828-z

Pediatr Infect Dis J. 2023 Jun 19. doi: 10.1097/INF.0000000000004000. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a genetic disease associated with lung disease characterized by chronic pulmonary infection, increasingly caused by multiple drug-resistant pathogens after repeated antibiotic exposure, limiting antibiotic treatment options. Bacteriophages can provide a pathogen-specific bactericidal treatment used with antibiotics to improve microbiologic and clinical outcomes in CF.

METHODS: Achromobacter species isolates from sputum of a chronically infected person with CF, were assessed for susceptibility to bacteriophages: 2 highly active, purified bacteriophages were administered intravenously every 8 hours, in conjunction with a 14-day piperacillin/tazobactam course for CF exacerbation. Sputum and blood were collected for metagenome analysis during treatment, with sputum analysis at 1-month follow-up. Assessments of clinical status, pulmonary status and laboratory evaluation for safety were conducted.

RESULTS: Bacteriophage administration was well-tolerated, with no associated clinical or laboratory adverse events. Metagenome analysis documented an 86% decrease in the relative proportion of Achromobacter DNA sequence reads in sputum and a 92% decrease in blood, compared with other bacterial DNA reads, comparing pretreatment and posttreatment samples. Bacteriophage DNA reads were detected in sputum after intravenous administration during treatment, and at 1-month follow-up. Reversal of antibiotic resistance to multiple antibiotics occurred in some isolates during treatment. Stabilization of lung function was documented at 1-month follow-up.

CONCLUSIONS: Bacteriophage/antibiotic treatment decreased the host pulmonary bacterial burden for Achromobacter assessed by metagenome analysis of sputum and blood, with ongoing bacteriophage replication documented in sputum at 1-month follow-up. Prospective controlled studies are needed to define the dose, route of administration and duration of bacteriophage therapy for both acute and chronic infection in CF.

PMID:37343220 | DOI:10.1097/INF.0000000000004000