BACKGROUND:The incidence of Mycobacterium avium complex (MAC)-pulmonary disease (PD) is increasing in South Korea, posing significant diagnostic and therapeutic challenges. Treatment guidelines recommend initiating therapy after serial computed tomography monitoring. Patients with the nodular bronchiectatic (NB) form often respond positively to drug therapy, whereas those with the fibrocavitary (FC) form frequently experience persistent disease despite treatment. Identifying phenotype-specific transcriptomic biomarkers could improve early diagnosis and inform personalized therapeutic strategies. METHODS:We utilized surgically resected lung specimens from 21 MAC-PD patients, a valuable clinical resource, as lung surgery is uncommon in MAC-PD management. Each patient provided paired samples of affected and unaffected lung tissues, enabling direct transcriptomic comparisons. Quantitative RNA sequencing was performed on samples from 11 NB and 10 FC cases. Comprehensive bioinformatics and in silico analyses, including gene ontology (GO) and protein-protein interaction (PPI) network analyses, were conducted to identify key diagnostic signatures and biological pathways. RESULTS:RNA sequencing revealed distinct and shared transcriptomic signatures correlated with radiological phenotypes. GO and PPI analyses identified significant gene clusters involved in B cell proliferation and immune regulation across both NB and FC forms. Additionally, NB-specific signatures highlighted genes predominantly regulating antimicrobial immune responses, while FC-specific signatures enriched genes related to extracellular matrix remodeling. CONCLUSIONS:This study is the first to characterize transcriptomic differences between MAC-PD phenotypes using paired lung tissue samples. Although the identified transcriptomic markers require functional validation, their strong correlation with radiologic subtypes provides preliminary evidence supporting their potential diagnostic value. These findings lay the groundwork for precision diagnostics in MAC-PD and require further validation in larger patient cohorts and through functional assays.

The serum acylcarnitine 18:2 to linoleamide ratio robustly predicts rapid progression in noncavitary MAC-PD, validated in two independent cohorts and a mouse model, offering a biologically grounded biomarker for early risk stratification https://bit.ly/3NlOi43.

BACKGROUND:Pulmonary infectious diseases caused by Mycobacterium species, including Mycobacterium tuberculosis and Mycobacterium avium complex (MAC), remain significant public health threats. However, current gold-standard diagnostics are time-consuming and have limited ability to differentiate these clinically similar presentations. This study investigated serum metabolic distinctions between tuberculosis (TB) and MAC pulmonary disease (MAC-PD) to identify biomarkers with supportive diagnostic value for differential diagnosis. METHODS:We performed LC/MS-based metabolic profiling of 181 serum samples from TB and MAC-PD patients. The study cohort was subsequently divided into a training set (TB, n = 30; MAC-PD, n = 30) and a validation set (TB, n = 51; MAC-PD, n = 70). RESULTS:Five key metabolites were identified, including four sphingoid base lipids that were decreased in TB compared with MAC-PD, and 2-hydroxyglutaric acid (2-HG), which was increased. Logistic regression using this five-metabolite panel achieved strong discriminatory performance, with an area under the curve of 0.988 (95 % CI: 0.970-1.000) in the training set and 0.997 (95 % CI: 0.991-1.000) in the validation set. Consistent performance across multiple machine learning models reinforces the stability and supportive diagnostic value of the five-metabolite panel. CONCLUSIONS:This study provides a novel approach for the differential diagnosis of two major mycobacterial pulmonary diseases. The identified metabolites, particularly alterations in sphingoid base lipids and 2-HG, demonstrated robust discriminative potential. These findings support their potential role as biomarkers in clinical practice, enabling earlier and more accurate differentiation of TB and MAC-PD.

Background: Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic respiratory infection primarily caused by Mycobacterium avium complex (MAC) and Mycobacterium abscessus. These species differ markedly in antibiotic susceptibility and treatment response, yet the contribution of the respiratory microbiome to this clinical variability remains unclear. To date, however, comparative analyses of microbiome differences between MAC-PD and M. abscessus-PD and their associations with disease severity are limited. Methods: We conducted microbiome analysis of sputum from 37 patients with NTM-PD. Patients were antibiotic-naïve and classified into MAC-PD (n = 29) and M. abscessus-PD (n = 8) groups. Disease severity was determined using radiologic extent on chest computed tomography. Bacterial communities were profiled by 16S rRNA gene sequencing, and differential taxa and predicted functional pathways were analyzed using LEfSe and KEGG orthology databases. Results: Distinct microbiome profiles were observed between MAC-PD and M. abscessus-PD. Three anaerobic species-Porphyromonas pasteri, Fusobacterium periodonticum, and Prevotella nanceiensis-were significantly enriched in M. abscessus-PD (LDA effect size > 3, p < 0.05). Functional biomarker analysis revealed significant enrichment of the cobalamin (vitamin B12) biosynthesis pathway in patients with severe disease, while the C19/C18 steroid hormone biosynthesis pathway was enriched in those with mild disease (p < 0.05). Conclusions: In conclusion, our study demonstrates distinct differences in the respiratory microbiome between MAC-PD and M. abscessus-PD and identifies specific functional pathways associated with disease severity in NTM-PD. These findings highlight the potential value of microbial metabolic signatures as biomarkers for disease assessment.

Despite guideline-based therapy, some patients with Mycobacterium avium complex pulmonary disease (MAC-PD) experience treatment failure. We analyzed the clinical courses of 271 patients with treatment-refractory MAC-PD who discontinued therapy after at least 12 months. Patients were categorized into two groups-the retreatment group, who resumed antibiotics due to clinical or radiological deterioration, and the stable group, who did not require antibiotics. Of the study patients, 138 (51%) were in the retreatment group, whereas 133 (49%) were in the stable group. In the multivariate analysis models, an elevated erythrocyte sedimentation rate (adjusted hazard ratio [aHR] =1.01), the presence of a cavity (aHR = 1.75), and the number of lobes affected by bronchiectasis (aHR = 1.21) were associated with the need for retreatment. Our data indicated that approximately 50% of the patients with refractory MAC-PD who discontinued antibiotics eventually required retreatment, which was influenced by the extent of lung destruction or inflammation. These findings can aid in determining treatment strategies for patients with refractory diseases.

Although the interest in latent growth models (LGMs) with categorical indicator variables has recently increased, there are still difficulties regarding the selection of estimation methods and the interpretation of model estimates. However, difficulties in estimating and interpreting categorical LGMs can be avoided by understanding the scaling process. Depending on which parameter constraint methods are selected at each step of the scaling process, the scale applied to the model changes, which can produce significant differences in the estimation results and interpretation. In other words, if a different method is chosen for any of the steps in the scaling process, the estimation results will not be comparable. This study organizes the scaling process and its relationship with estimation methods for categorical LGMs. Specifically, this study organizes the parameter constraint methods included in the scaling process of categorical LGMs and extensively considers the effect of parameter constraints at each step on the meaning of estimates. This study also provides evidence for the scale suitability and interpretability of model estimates through a simple illustration. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Limited data are available regarding the in vitro activity of SPR719, a derivative of benzimidazole, against diverse nontuberculous mycobacteria (NTM) species. We investigated the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of SPR719 against clinical NTM isolates, including clarithromycin- and amikacin-resistant strains. NTM isolates were obtained from patients with NTM-pulmonary disease caused by various NTM species, including Mycobacterium avium complex, M. abscessus (subspecies abscessus and massiliense), M. kansasii, and M. fortuitum. Regardless of clarithromycin or amikacin resistance, the MIC and MBC values of SPR719 were comparable among these major pathogenic NTM species. In over 70% of the isolates, the MIC values were ≤2 μg/mL with MBC values of ≤4 μg/mL. The MIC and MBC values of M. kansasii were relatively lower than those of the other species with little difference between them, demonstrating the bactericidal properties of SPR719. The in vitro activity of SPR719 against major clinical NTM species suggests that SPR719 can serve as a novel treatment option for NTM-pulmonary disease.

Mycobacterium avium complex pulmonary disease (MAC-PD) has a heterogeneous clinical course. However, immune profiles associated with MAC-PD clinical course are limited. We performed single-cell RNA sequencing of peripheral blood mononuclear cells from 21 MAC-PD patients divided into three clinical courses: group A, spontaneous culture conversion; group B, stable disease without antibiotic treatment; and group C, progressive disease with antibiotic treatment. A lower proportion of NK cells and higher proportion of monocytes were noted in group C compared to combined groups A and B. The proportion of classical monocytes was higher in group C compared to groups A and B, while the proportion of non-classical monocytes decreased. EGR1, HSPA1A, HSPA1B, and CD83 were up-regulated in spontaneous culture conversion group A compared to progressive disease group C. Up-regulation of MYOM2 and LILRA4 and down-regulation of MT-ATP8, CD83, and CCL3L1 was found in progressive disease group C. PCBP1, FOS, RGCC, S100B, G0S2, AREG, and LYN were highly expressed in favorable treatment response compared to unfavorable response. Our findings may offer a comprehensive understanding of the host immune profiles that influence a particular MAC-PD clinical course and could suggest an immunological mechanism associated with the disease progression of MAC-PD.

Abstract Study Background: Bruton tyrosine kinase (BTK) is a key signaling molecule that plays a central role in B-cell receptor transduction. The development of agents that inhibit BTK has transformed the management of patients with B-cell malignancies. However, therapy using covalent BTK inhibitors such as ibrutinib, as well as non-covalent inhibitors such as pirtobrutinib, can still result in resistance, primarily due to the development of mutations in BTK including residues C481 and L528. AC676 is designed as a chimeric degrader to target and degrade BTK using Accutar's proprietary Protein-Protein Interaction Targeting Chimeras (PPI-TAC) platform. By effectively linking a BTK ligand to the cereblon E3-ligase recruiting ligand, AC676 brings BTK in proximity to cereblon, thereby inducing subsequent ubiquitination and degradation of BTK. AC676 degrades BTK proteins irrespective of mutations; including C481, kinase dead L528 and others, and thus may be effective for the treatment of patients who have progressed on both covalent and non-covalent BTK inhibitors. Notably, it is also effective in cell lines expressing gain of function PLCG2 mutants, suggesting that it removes BTK’s scaffolding function. AC676 does not degrade cereblon neo-substrates, so neutropenia is not expected to be an on-target effect. This abstract describes an ongoing first in human Phase 1 trial of AC676. Study Description: AC676-001 is a Phase 1 dose-escalation study of AC676 administered orally once daily as monotherapy in patients with relapsed and refractory B-cell malignancies. Approximately 60 patients may be enrolled. Eligible patients must be ≥ 18 years, and have one of the following histologically confirmed relapsed or refractory disease types: chronic lymphocytic leukemia and small lymphocytic lymphoma, diffuse large B cell lymphoma – non-GCB subtype, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma including Waldenstrom macroglobulinemia. Patients must have received at least two prior systemic therapies or have no other standard of care therapies to provide significant clinical benefit. Patients must have measurable disease per disease-specific response criteria and Eastern Cooperative Oncology Group performance status ≤ 1. Dose-escalation will begin with an accelerated titration phase, followed by a standard 3+3 phase. AC676 is administered orally once daily on a 28 day per cycle schedule at doses ranging from 50mg to 600mg. The primary objective of the study is to evaluate the safety and tolerability of AC676. Secondary objectives include the evaluation of anti-tumor activity and the pharmacokinetic profile following single and multiple doses. Study enrollment began April in 2023 with five sites currently open in the United States (NCT05780034). Citation Format: Manish R Patel, Michael Tees, Farrukh T Awan, Nadia Khan, Nancy Mota, Hui Zhang, Su Young Kim, Jennifer Woyach. AC676 a BTK Chimeric Degrader: Phase 1 study in patients with B-cell Malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-009.

Abstract Background We evaluated whether the sputum bacterial microbiome differs between nontuberculous mycobacteria pulmonary disease (NTM-PD) patients with stable disease not requiring antibiotic treatment and those requiring antibiotics. Methods We collected sputum samples from 21 clinically stable NTM-PD patients (stable group) and 14 NTM-PD patients needing antibiotic treatment (treatment group). We also obtained 13 follow-up samples from the stable group. We analyzed the 48 samples using 16S rRNA gene sequencing (V3–V4 region) and compared the groups. Results In the linear discriminant analysis effect size (LEfSe) analysis, the species Porphyromonas pasteri, Haemophilus parahaemolyticus, Prevotella nanceiensis, and Gemella haemolysans were significantly more prevalent in the sputum of the stable group compared to the treatment group. No taxa showed significant differences in alpha-/beta-diversity or LEfSe between the 21 baseline and 13 follow-up sputum samples in the stable group. In the stable group, the genus Bergeyella and species Prevotella oris were less common in patients who achieved spontaneous culture conversion (n = 9) compared to those with persistent NTM positivity (n = 12) (effect size 3.04, p = 0.039 for Bergeyella; effect size 3.64, p = 0.033 for P. oris). In the treatment group, H. parainfluenzae was more common in patients with treatment success (n = 7) than in treatment-refractory patients (n = 7) (effect size 4.74, p = 0.013). Conclusions Our study identified distinct bacterial taxa in the sputum of NTM-PD patients based on disease status. These results suggest the presence of a microbial environment that helps maintain disease stability.

Supplementary Figure 1 - PDF file 1233K, Supplemental Figure 1: Representative array comparative genomic hybridization (aCGH) results of genomic copy number near-normal GIST (left column, n=5) and genomic copy number abnormal GIST (right column, n=5) (Agilent 180K catalogue assay)

Supplementary Table 2 XLSX file 490K, Illumina GoldenGate Methylation Standard Cancer Panel I Target CpG Annotations and differential methylation significance values for group comparisons listed in Table

Supplementary Table 1 XLS file 22K, Tumors and reference tissues for methylation microarray analysis

Limited data exist on longitudinal changes in the sputum bacterial microbiome during treatment in nontuberculous mycobacterial pulmonary disease (NTM-PD) patients. We prospectively collected serial sputum samples from 14 NTM-PD patients during treatment, at the start (n = 14) and at 1 (n = 10), 3 (n = 10), 6 (n = 12), and 12 (n = 7) months. The bacterial microbiome changes were analyzed using 16S rRNA sequences (V3–V4 regions). Subgroup analysis included culture conversion (n = 9) and treatment refractory (n = 5) groups. In all patients, sputum alpha-diversity (ACE, Chao1, and Jackknife) significantly decreased during antibiotic treatment at 1, 3, 6, and 12 months compared to treatment initiation levels. Within the culture conversion group, genus/species-level beta-diversity showed differences at 1, 3, 6, and 12 months compared to treatment initiation (all p < 0.05). However, in the refractory group, there were no differences in beta-diversity at the genus/species levels in the sputum at any time point. In the linear discriminant analysis (LDA) effect sizes (LEfSe) analysis, the culture conversion group exhibited decreasing taxa at various levels (phylum/genus/species), but no significant increase in taxa was observed. LEfSe analysis of the refractory patient group revealed multiple taxa decreased during treatment. However, proportions of Veillonella dispar (LDA = 4.78), Fusobacterium periodonticum (LDA = 4.35), and Pseudomonas aeruginosa (LDA = 2.92) increased as the treatment period progressed in the refractory group. Sputum microbiota diversity decreases during NTM-PD treatment. In the culture conversion group, most taxa decrease, while some increase in the refractory group. These findings suggest that a distinct respiratory microbial community may exist in refractory NTM-PD patients compared to responsive antibiotic-treated patients.

본 연구는 영유아기 자녀를 둔 맞벌이 부부의 일-가정 갈등이 우울에 영향을 미치는 과정에서 결혼 만족에 의해 조절되는 양육 스트레스의 매개효과를 살펴보고자 하였다. 2021년 1월에 막내 자녀의 나이가 만 4세 이하인 자녀를 양육하는 맞벌이 부부를 대상으로 군집표본추출방법을 사용하여 자료를 수집하였다. 이 중 성실히 응답한 393쌍의 쌍자료를 SPSS22.0과 Mplus8.3을 사용하여 조절된 매개효과 모형으로 분석하였다. 주요한 연구 결과는 다음과 같다. 첫째, 맞벌이 부부의 일-가정 갈등이 우울에 영향을 미치는 과정에서 양육 스트레스는 매개 효과를 나타냈다. 둘째, 맞벌이 부부의 양육 스트레스와 우울 사이에서 결혼 만족은 조절 효과를 나타냈다. 셋째, 맞벌이 부부의 일-가정 갈등, 양육 스트레스, 우울의 관계에서 부부의 결혼 만족, 특히 아내의 결혼 만족은 조절된 매개 효과를 나타내었다. 이러한 결과는 부부의 결혼 만족, 특히 아내의 결혼 만족이 맞벌이 부부의 일-가정 갈등으로부터 발생하는 양육 스트레스를 낮춤으로써 우울을 낮출 수 있는 보호기제로 작용함을 확인해 주는 것이다. 본 연구 결과는 일-가정 갈등을 경험하는 맞벌이 부부의 우울 수준을 낮추기 위해서는 부부의 양육 스트레스 감소 및 결혼 만족도를 증가시키는 것의 중요성을 다시 한번 확인했다.

We evaluated the in vitro activity of rifamycin derivatives, including rifampin, rifapentine, rifaximin, and rifabutin, against clinical nontuberculous mycobacteria (NTM) isolates. Of the rifamycin derivatives, rifabutin showed the lowest MICs against all NTM species, including Mycobacterium avium complex, M. abscessus, and M. kansasii Rifabutin also had effective in vitro activity against macrolide- and aminoglycoside-resistant NTM isolates. Rifabutin could be worth considering as a therapeutic option for NTM disease, particularly drug-resistant disease.

Limited data are available regarding the in vitro activity of clofazimine against nontuberculous mycobacteria (NTM) or on outcomes of clofazimine-containing regimens in NTM-pulmonary disease (PD). Therefore, we evaluated the in vitro activity of clofazimine and the clinical outcomes of clofazimine-containing regimens. We evaluated clofazimine in vitro activity for 303 NTM isolates from NTM-PD patients. Fifty-seven clarithromycin-resistant and 35 amikacin-resistant isolates were also analyzed. Culture conversion after a 12-month treatment regimen containing clofazimine was evaluated in 58 NTM-PD patients, including 20 patients with drug-resistant isolates. Most of the 303 isolates (238/303) had minimum inhibitory concentrations (MICs) ≤ 0.25 µg/mL for clofazimine (57/63 Mycobacterium avium, 53/57 M. intracellulare, 49/52 M. kansasii, 22/64 M. abscessus, and 57/67 M. massiliense). For the 57 clarithromycin-resistant and 35 amikacin-resistant isolates, most had MICs ≤ 0.25 µg/mL (47/57 and 32/35, respectively). Among the 38 NTM-PD patients without resistance to clarithromycin or amikacin, 47% achieved culture conversion (8/27 M. abscessus, 9/9 M. massiliense, 0/1 M. avium, and 1/1 M. intracellulare). The conversion rate was higher in the MIC ≤ 0.25 µg/mL group than in the MIC = 0.5 µg/mL group (13/18 vs. 5/20, p = 0.004), and an MIC ≤ 0.25 µg/mL remained a significant factor in multivariable analysis. Culture conversion was achieved in 20% of 20 patients with clarithromycin- or amikacin-resistant isolates. However, a clofazimine MIC ≤ 0.25 µg/mL was not significant for culture conversion in the 58 NTM-PD patients, regardless of the drug resistance pattern. Clofazimine was effective in vitro against NTM species. Some patients on clofazimine-containing regimens achieved culture conversion.

We evaluated the in vitro activities of oxazolidinone antibiotics, including linezolid, sutezolid, and delpazolid, against clinical nontuberculous mycobacteria (NTM) isolates. Regardless of macrolide resistance, for Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium kansasii, sutezolid showed the lowest MIC and minimal bactericidal concentration (MBC) values among oxazolidinone antibiotics. However, for Mycobacterium abscessus and Mycobacterium massiliense, the MIC and MBC for all oxazolidinone antibiotics showed similar values. Oxazolidinone antibiotics warrant further investigation as potential treatment for NTM.