PubMed

(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])

Filters applied: from 2025/2/1 - 2025/2/28

1. J Adv Res. 2025 Feb;68:341-357. doi: 10.1016/j.jare.2024.02.023. Epub 2024 Mar 2.

Baicalein induces apoptosis by inhibiting the glutamine-mTOR metabolic pathway in lung cancer.

Li J(1), Zhang D(1), Wang S(1), Yu P(1), Sun J(1), Zhang Y(1), Meng X(2), Li J(3)

INTRODUCTION: Baicalein, a bioactive component of Scutellaria baicalensis Georgi, has been shown to promote apoptosis in non-small cell lung cancer cells. However, previous studies have not determined if baicalein exerts proapoptotic effects by modulating the metabolic pathways.

OBJECTIVE: To investigate if baicalein induces apoptosis in lung cancer cells by modulating the glutamine-mTOR metabolic pathway.

METHODS: The in vivo anti-lung cancer activity of baicalein (50, 100, and 200 mg/kg) was evaluated using a xenograft model. In vitro experiments were used to assess the efficacy of baicalein (for H1299: 12.5, 25, and 50 μM; for A549: 10, 20, and 40 μM) on lung cancer cell proliferation, colony formation, and apoptosis. Metabolomics analysis was performed using liquid chromatography-mass spectrometry. The binding of baicalein to glutamine transporters and glutaminase was examined using molecular docking. The overexpression of glutamine transporters was validated using qRT-PCR and western blot analyses. The levels of ASCT2, LAT1, GLS1, p-mTOR, mTOR, and apoptosis-related proteins were evaluated using western blot analysis.

RESULTS: Baicalein inhibited lung cancer xenograft tumor growth in vivo and suppressed proliferation and promoted apoptosis in lung cancer cells in vitro. Additionally, baicalein altered amino acid metabolites, especially glutamine metabolites, in H1299 and A549 cells. Mechanistically, baicalein interacted with glutamine transporters as well as glutaminase and inhibited their activation. The expression of mTOR, an apoptosis-related protein and downstream target of glutamine metabolism, was also inhibited by baicalein treatment. Importantly, we next demonstrated the suppression of mTOR signaling and the induction of apoptosis by baicalein were achieved by regulating glutamine metabolism.

CONCLUSION: Baicalein inhibited the mTOR signaling pathway and induced apoptosis by downregulating glutamine metabolism. The potential of baicalein to induce apoptosis in lung cancer cells by selectively targeting the glutamine-mTOR pathway suggests an encouraging approach for treating lung cancer.

PMID: 38432394 [Indexed for MEDLINE]

2. Cell. 2025 Mar 6;188(5):1248-1264.e23. doi: 10.1016/j.cell.2025.01.024. Epub 2025 Feb 6.

GUK1 activation is a metabolic liability in lung cancer.

Schneider JL(1), Kurmi K(2), Dai Y(3), Dhiman I(2), Joshi S(2), Gassaway BM(2)

Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged ("ALK+") patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.

PMID: 39919745 [Indexed for MEDLINE]

3. Mol Cancer. 2025 Feb 26;24(1):57. doi: 10.1186/s12943-025-02245-6.

Traditional Chinese medicine in lung cancer treatment.

Xi Z(#)(1)(2), Dai R(#)(1)(2), Ze Y(1)(2), Jiang X(1)(2), Liu M(3)(4), Xu H(5)(6)

Lung cancer remains a major global health challenge and one of the leading causes of cancer-related deaths worldwide. Despite significant advancements in treatment, challenges such as drug resistance, side effects, metastasis and recurrence continue to impact patient outcomes and quality of life. In response, there is growing interest in complementary and integrative approaches to cancer care. Traditional Chinese medicine (TCM), with its long history, abundant clinical experience, holistic perspective and individualized approach, has garnered increasing attention for its role in lung cancer prevention and management. This review provides a comprehensive overview of the advances in TCM for lung cancer treatment, covering its theoretical foundation, treatment principles, clinical experiences and evidence supporting its efficacy. We also provide a systematic summary of the preclinical mechanisms, through which TCM impacts lung cancer, including the induction of cell death, reversal of drug resistance, inhibition of metastasis and modulation of immune responses. Additionally, future prospects for TCM in lung cancer treatment are discussed, offering insights into its expanded application and integration with modern medicine to address this challenging disease.

PMID: 40001110 [Indexed for MEDLINE]

4. Eur Respir J. 2025 Feb 27;65(2):2401484. doi: 10.1183/13993003.01484-2024. Print 2025 Feb.

Pirfenidone and risk of lung cancer development in idiopathic pulmonary fibrosis: a nationwide population-based study.

Yoon HY(1), Kim H(2), Bae Y(2), Song JW(3)

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) carries a high risk of lung cancer, but the effect of pirfenidone on lung cancer development remains uncertain. We investigated the association between pirfenidone use and lung cancer development in patients with IPF.

METHODS: We included 9938 patients with IPF from the Korean national claims database. Propensity score analysis with inverse probability of treatment weighting (IPTW) and landmark analyses were employed to evaluate lung cancer occurrence according to pirfenidone use. The association was evaluated using Cox regression models adjusted for clinical and socioeconomic variables. A single-centre IPF clinical cohort (n=941) was used for validating the findings.

RESULTS: The mean patient age was 69.4 years, 73.7% were men and 32.1% received pirfenidone. Lung cancer developed in 766 patients with IPF (7.7%; 21.9 cases per 1000 person-years) during a median follow-up of 3.0 years. After IPTW, the pirfenidone group showed lower incidence (10.4 versus 27.9 cases per 1000 person-years) than the no pirfenidone group. Landmark analysis at 6 months after IPF diagnosis also showed lower incidence of lung cancer in the pirfenidone group than in the no pirfenidone group. Pirfenidone use was independently associated with a reduced lung cancer risk (weighted adjusted hazard ratio (HR) 0.347, 95% CI 0.258-0.466). A clinical cohort showed similar association (weighted adjusted HR 0.716, 95% CI 0.517-0.991). The association persisted across subgroups defined by age or sex.

CONCLUSION: Pirfenidone use may be associated with a reduced lung cancer risk in patients with IPF.

PMID: 39510556 [Indexed for MEDLINE]

5. Nat Commun. 2025 Feb 26;16(1):1976. doi: 10.1038/s41467-025-57309-4.

Comprehensive characterization of early-onset lung cancer, in Chinese young adults.

Tian Y(#)(1), Ma R(#)(1), Zhao W(#)(2), Wang S(3), Zhou C(4), Wu W(5), Yang B(6)

Early-onset lung cancer in young adults represents a less studied clinical entity with increasing incidence which still affects a large number of cancer patients. Here we perform a comprehensive analysis of early-onset lung cancer for the clinicopathological features, genomic alterations, gene expression, and immune landscape by establishing a cohort enrolling 421 non-small cell lung cancer (NSCLC) patients from ten medical centers in China. Comparative analysis reveals a distinct genomic alteration between younger and elder patients with NSCLC, with ERBB2 mutations and ALK-rearrangement strikingly more frequent in younger group. Transcriptome profiling indicates altered cellular metabolism and immune-related genes in tumors from younger patients. Immunological analysis reveals a decreased infiltration of immune cells (notably T cells) in tumors from younger patients. Cellular and mechanistic studies show that the prevalent ERBB2 mutants in cancer from younger patients can indeed drive tumorigenesis by elevating AKT signaling. Importantly, meta-analysis of clinical trials and our clinical practice further validate the promise of HER2-targeted therapy to treat early-onset NSCLC in East Asian patients. Our comprehensive and integrative analysis not only reveal multiple unrecognized characteristics of early-onset lung cancer, but also inform actionable therapeutics to manage this type of cancer.

PMID: 40000630 [Indexed for MEDLINE]

6. Lancet Infect Dis. 2025 Feb;25(2):188-197. doi: 10.1016/S1473-3099(24)00494-8. Epub 2024 Sep 20.

Sequential and parallel testing for microbiological confirmation of tuberculosis disease in children in five low-income and middle-income countries: a secondary analysis of the RaPaed-TB study.

Olbrich L(1), Franckling-Smith Z(2), Larsson L(3), Sabi I(4), Ntinginya NE(4)

BACKGROUND: Despite causing high mortality worldwide, paediatric tuberculosis is often undiagnosed. We aimed to investigate optimal testing strategies for microbiological confirmation of tuberculosis in children younger than 15 years, including the yield in high-risk subgroups (eg, children younger than 5 years, with HIV, or with severe acute malnutrition [SAM]).

METHODS: For this secondary analysis, we used data from RaPaed-TB, a multicentre diagnostic accuracy study evaluating novel diagnostic assays and testing approaches for tuberculosis in children recruited from five health-care centres in Malawi, Mozambique, South Africa, Tanzania, and India conducted between Jan 21, 2019, and June 30, 2021. Children were included if they were younger than 15 years and had signs or symptoms of pulmonary or extrapulmonary tuberculosis; they were excluded if they weighed less than 2 kg, had received three or more doses of anti-tuberculosis medication at time of enrolment, were in a condition deemed critical by the local investigator, or if they did not have at least one valid microbiological result. We collected tuberculosis-reference specimens via spontaneous sputum, induced sputum, gastric aspirate, and nasopharyngeal aspirates. Microbiological tests were Xpert MTB/RIF Ultra (hereafter referred to as Ultra), liquid culture, and Löwenstein-Jensen solid culture, which were followed by confirmatory testing for positive cultures. The main outcome of this secondary analysis was categorising children as having confirmed tuberculosis if culture or Ultra positive on any sample, unconfirmed tuberculosis if clinically diagnosed, and unlikely tuberculosis if neither of these applied.

FINDINGS: Of 5313 children screened, 975 were enrolled, of whom 965 (99%) had at least one valid microbiological result. 444 (46%) of 965 had unlikely tuberculosis, 282 (29%) had unconfirmed tuberculosis, and 239 (25%) had confirmed tuberculosis. Median age was 5·0 years (IQR 1·8-9·0); 467 (48%) of 965 children were female and 498 (52%) were male. 155 (16%) of 965 children had HIV and 110 (11%) children had SAM. 196 (82%) of 239 children with microbiological detection tested positive on Ultra. 110 (46%) of 239 were confirmed by both Ultra and culture, 86 (36%) by Ultra alone, and 43 (18%) by culture alone. 'Trace' was the most common semiquantitative result (93 [40%] of 234). 481 (50%) of 965 children had only one specimen type collected, 99 (21%) of whom had M tuberculosis detected. 484 (50%) of 965 children had multiple specimens collected, 141 (29%) of whom were positive on at least one specimen type. Of the 102 children younger than 5 years with M tuberculosis detected, 80 (78%) tested positive on sputum. 64 (80%) of 80 children who tested positive on sputum were positive on sputum alone; 61 (95%) of 64 were positive on induced sputum, two (3%) of 64 were positive on spontaneous sputum, and one (2%) was positive on both.

INTERPRETATION: High rates of microbiological confirmation of tuberculosis in children can be achieved via parallel sampling and concurrent testing procedures. Sample types and choice of test to be used sequentially should be considered when applying to groups such as children younger than 5 years, living with HIV, or with SAM.

FUNDING: European and Developing Countries Clinical Trials Partnership programme, supported by the EU, the UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung, the German Center for Infection Research, and Beckman Coulter.

PMID: 39312914 [Indexed for MEDLINE]

7. Lancet Microbe. 2025 Feb;6(2):100961. doi: 10.1016/j.lanmic.2024.100961. Epub 2024 Dec 19.

Effectiveness of the primary Bacillus Calmette-Guérin vaccine against the risk of Mycobacterium tuberculosis infection and tuberculosis disease: a meta-analysis of individual participant data.

Pelzer PT(1), Stuck L(2), Martinez L(3), Richards AS(4), Acuña-Villaorduña C(5)

BACKGROUND: Tuberculosis vaccine trials using disease as the primary endpoint are large, time consuming, and expensive. An earlier immunological measure of the protection against disease would accelerate tuberculosis vaccine development. We aimed to assess whether the effectiveness of the Bacillus Calmette-Guérin (BCG) vaccine for prevention of Mycobacterium tuberculosis infection was consistent with that for prevention of tuberculosis disease.

METHODS: We conducted an individual participant data (IPD) meta-analysis on experimental and observational longitudinal studies before April 6, 2018, identified through systematic reviews, known to us through expert knowledge in the field, reporting on BCG vaccination status, M tuberculosis infection test (QuantiFERON IFN-γ release assay [IGRA] and tuberculin skin test [TST]), and tuberculosis incidence. Cohort studies were included only for countries with a mandatory neonatal BCG vaccination policy. Exclusion criteria were previous or current tuberculosis disease, HIV infection, tuberculosis preventive treatment usage, and for household contacts, a positive baseline IGRA or TST test and young children aged 0-2 years; for randomised controlled trials, TST results within 2 years after random assignation were excluded. We contacted the investigators of the identified studies to provide IPD. We compared the protective efficacy of the BCG vaccine against M tuberculosis infection with that against tuberculosis disease using mixed-effects, multivariable proportional hazards modelling, by study type, M tuberculosis infection test (IGRA and TST), cutoff for defining test positivity, age, sex, and latitude.

FINDINGS: We identified 79 studies eligible for full screening and of these, IPD datasets from 14 studies were included in our analysis: 11 household contact studies (29 147 participants), two adolescent cohort studies (11 368 participants), and one randomised controlled trial (2963 participants). Among 28 188 participants we found no protection by the BCG vaccine against TST conversion regardless of cutoff in any type of study. Among 1491 household contacts, but not among 5644 adolescents, the BCG vaccine protected against QuantiFERON conversion at the primary cutoff of 0·7 IU/mL or more with the adjusted hazard ratio (0·65, 95% CI 0·51-0·82) being consistent with that for protection against disease (0·68, 0·18-2·59). Protection against QuantiFERON conversion at cutoff of 0·35 IU/mL or more (0·64, 0·51-0·81) was similar.

INTERPRETATION: Protection from the BCG vaccination against M tuberculosis infection, measured as QuantiFERON conversion, is inconsistent across different groups. Among groups with recent household exposure, QuantiFERON conversion is consistent with protection against disease and could be evaluated as a proxy for disease in tuberculosis vaccine trials. We found that TST lacks value for prevention in phase 2b proof-of-concept trials.

PMID: 39709975 [Indexed for MEDLINE]

8. Lancet Public Health. 2025 Feb 25:S2468-2667(25)00014-3. doi: 10.1016/S2468-2667(25)00014-3. Online ahead of print.

Confronting the growing epidemic of silicosis and tuberculosis among small-scale miners.

Howlett P(1), Said B(2), Mwanga E(2), Mbuya A(2), Nota M(3), Kon OM(4)

An estimated 49·5 million small-scale miners worldwide are exposed to high concentrations of silica during their work. The substantial morbidity and mortality of silicosis and tuberculosis among workers exposed to such intensities have been documented. This Viewpoint raises concern at the failure to respond to a growing epidemic of lung disease (predominantly silicosis and tuberculosis) among small-scale miners. The Viewpoint is framed around four arguments: outlining the huge burden of lung disease among SSMs; critically examining these figures in the context of high silica exposures; illustrating the failure to support research; and examining historical, socioeconomic, and political factors influencing the epidemic. We then outline a strategy for response. An urgent and coordinated response is needed to address the devastating health effects of silicosis and tuberculosis in small-scale miners and their preventable workplace causes.

PMID: 40020695

9. Nat Rev Cancer. 2025 Feb 24. doi: 10.1038/s41568-025-00791-1. Online ahead of print.

Translating premalignant biology to accelerate non-small-cell lung cancer interception.

Mazzilli SA(1), Rahal Z(2), Rouhani MJ(3), Janes SM(3), Kadara H(2), Dubinett SM(4)

Over the past decade, substantial progress has been made in the development of targeted and immune-based therapies for patients with advanced non-small-cell lung cancer. To further improve outcomes for patients with lung cancer, identifying and intercepting disease at the earliest and most curable stages are crucial next steps. With the recent implementation of low-dose computed tomography scan screening in populations at high risk, there is an emerging unmet need for new diagnostic, prognostic and therapeutic tools to help treat patients suspected of harbouring premalignant lesions and minimally invasive non-small-cell lung cancer. Continued advances in the identification of the earliest drivers of lung carcinogenesis are poised to address these unmet needs. Employing multimodal approaches to chart the temporal and spatial maps of the molecular events driving lung premalignant lesion progression will refine our understanding of early carcinogenesis. Elucidating the molecular drivers of premalignancy is critical to the development of biomarkers to detect those incubating a premalignant lesion, to stratify risk for progression to invasive cancer and to identify novel therapeutic targets to intercept that process. In this Review, we summarize emerging insights into the earliest cellular and molecular events associated with lung squamous and adenocarcinoma carcinogenesis and highlight the growing opportunity for translating these insights into clinical tools for early detection and disease interception to transform the outcomes for those at risk for lung cancer.

PMID: 39994467

10. Lancet Respir Med. 2025 Feb 3:S2213-2600(24)00428-4. doi: 10.1016/S2213-2600(24)00428-4. Online ahead of print.

Estimated worldwide variation and trends in incidence of lung cancer by histological subtype in 2022 and over time: a population-based study.

Luo G(1), Zhang Y(2), Rumgay H(1), Morgan E(1), Langselius O(1), Vignat J(1)

BACKGROUND: Lung cancer is the most common cancer worldwide, yet the current epidemiological profile of lung-cancer incidence by histological subtype is only partly understood. We aimed to assess geographical variation in incidence of lung cancer by subtype worldwide in 2022, geographical variation in adenocarcinoma incidence attributable to ambient particulate matter (PM) pollution worldwide in 2022, temporal trends in lung-cancer incidence by subtype from 1988 to 2017 in 19 countries, and generational changes.

METHODS: For this population-based study, we used data from the Global Cancer Observatory (GLOBOCAN) 2022, Cancer Incidence in Five Continents Volumes VII-XII, and members of the African Cancer Registry Network. To obtain national estimates of lung cancer in 2022 for the four main histological subtypes (ie, adenocarcinoma, squamous cell carcinoma [SCC], small-cell carcinoma, and large-cell carcinoma) by year, sex, and age group, we combined national estimates with representative, subsite-specific incidence proportions of lung cancer on the basis of recorded incidence data compiled in Cancer Incidence in Five Continents Volume XII and from members of the African Cancer Registry Network. We calculated country-specific, sex-specific, and age-specific proportions of and sex-specific and age-specific incidence rates per 100 000 people for all four histological subtypes. To account for differences in age composition between populations by country, we calculated age-standardised incidence rates (ASRs) per 100 000 people for lung cancer by subtype and sex at national and regional levels. We also quantified the burden of adenocarcinoma incidence attributable to ambient PM pollution for 179 countries in 2022. We conducted joinpoint regression and age-period-cohort analysis to assess temporal trends in ASRs in 19 countries by sex.

FINDINGS: In 2022, we estimated that there were 1 572 045 new cases of lung cancer worldwide among male individuals, of which 717 211 (45·6%) were adenocarcinoma, 461 171 (29·4%) were SCC, 180 063 (11·5%) were small-cell carcinoma, and 101 861 (6·5%) were large-cell carcinoma. In 2022, we estimated that there were 908 630 new cases of lung cancer worldwide among female individuals, of which 541 971 (59·7%) were adenocarcinoma, 155 598 (17·1%) were SCC, 87 902 (9·7%) were small-cell carcinoma, and 59 271 (6·5%) were large-cell carcinoma. Among male individuals, the highest ASRs were in east Asia for adenocarcinoma (27·12 [95% CI 27·04-27·21] per 100 000 people), east Europe for SCC (21·70 [21·51-21·89] per 100 000 people) and small-cell carcinoma (9·85 [9·72-9·98] per 100 000 people), and north Africa for large-cell carcinoma (4·33 [4·20-4·45] per 100 000 people). Among female individuals, the highest ASRs were in east Asia for adenocarcinoma (19·04 [18·97-19·11] per 100 000 people), north America for SCC (5·28 [5·21-5·35] per 100 000 people) and small-cell carcinoma (4·28 [4·21-4·35] per 100 000 people), and north Europe for large-cell carcinoma (2·87 [2·78-2·96] per 100 000 people). We estimated that 114 486 adenocarcinoma cases among male individuals and 80 378 adenocarcinoma cases among female individuals were attributable to ambient PM pollution worldwide in 2022, with ASRs of 2·35 (95% CI 2·33-2·36) per 100 000 male individuals and 1·46 (1·45-1·47) per 100 000 female individuals. Temporal trends in lung-cancer incidence by subtype and sex during 1988-2017 varied considerably across the 19 countries.

INTERPRETATION: Estimated geographical and temporal distribution of lung-cancer incidence varied across the four main subtypes worldwide. Our study highlights the need for future studies that identify possible causal factors that contribute to the changing risk patterns of lung cancer.

PMID: 39914442

11. Nat Commun. 2025 Feb 24;16(1):1934. doi: 10.1038/s41467-025-56888-6.

Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosis.

Earp JC(#)(1), Garaeva AA(#)(1), Meikle V(#)(2), Niederweis M(3), Seeger MA(4)(5)

To replicate and cause disease, Mycobacterium tuberculosis secretes siderophores called mycobactins to scavenge iron from the human host. Two closely related transporters, MmpL4 and MmpL5, are required for mycobactin secretion and drug efflux. In clinical strains, overproduction of MmpL5 confers resistance towards bedaquiline and clofazimine, key drugs to combat multidrug resistant tuberculosis. Here, we present cryogenic-electron microscopy structures of MmpL4 and identify a mycobactin binding site, which is accessible from the cytosol and also required for bedaquiline efflux. An unusual coiled-coil domain predicted to extend 130 Å into the periplasm is essential for mycobactin and bedaquiline efflux by MmpL4 and MmpL5. The mycobacterial acyl carrier protein MbtL forms a complex with MmpL4, indicating that mycobactin synthesis and export are coupled. Thus, MmpL4 and MmpL5 constitute the core components of a unique multi-subunit machinery required for iron acquisition and drug efflux by M. tuberculosis.

PMID: 39994240 [Indexed for MEDLINE]

12. Lancet Infect Dis. 2025 Feb;25(2):e86-e98. doi: 10.1016/S1473-3099(24)00597-8. Epub 2024 Nov 26.

Representativeness and adverse event reporting in late-phase clinical trials for rifampin-susceptible tuberculosis: a systematic review.

Burman W(1), Luczynski P(2), Horsburgh CR(3), Phillips PPJ(4), Johnston J(5)

We did a systematic review and meta-analysis of trials of treatment for rifampicin-susceptible tuberculosis to evaluate the representativeness of participants compared with characteristics of the global population of people with tuberculosis, and the adequacy of adverse event reporting. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from Jan 1, 2000, to Dec 10, 2023, for trials that had greater than or equal to 50 participants per arm and had follow-up to at least treatment completion. Studies were excluded if they compared different formulations of standard drugs (eg, fixed-dose combination tablets); aimed to primarily enrol participants with isoniazid-resistant or rifampicin-resistant tuberculosis; evaluated treatment to prevent tuberculosis infection; tested dietary or vitamin supplementation; tested vaccines or other immune-based interventions; tested adherence support or system-related mechanisms; or enrolled participants with tuberculosis, but tuberculosis treatment itself was not randomised (ie, trials of the timing of antiretroviral therapy initiation). Trial protocols and trials not available in English were also excluded. The outcomes were inclusion and exclusion criteria, characteristics of participants, and adverse event reporting. This systematic review was prospectively registered (PROSPERO ID CRD42022373954). We identified 7328 articles, of which 40 were eligible for analysis. Demographic characteristics, including sex, were reported for 20 420 participants, of which 6663 (33%) were female and 13 757 (67%) were male. We found that people who were greatly affected by the global tuberculosis pandemic were frequently excluded from participation: of the 40 trials, 25 (62·5%) excluded people younger than 18 years, 12 (30·0%) excluded people aged 65 years or older, 34 (85·0%) excluded pregnant or lactating people, 12 (30·0%) excluded people with diabetes, and 11 (27·5%) excluded people with excessive alcohol use, drug use, or both. In the nine trials that reported enrolment of people with diabetes, the pooled proportion of participants with diabetes (9%) was lower than global estimates for the proportion of people with tuberculosis who have diabetes (16%). There were important gaps in adverse event ascertainment, analysis, and interpretation. Of the 40 trials, a minority reported measures of regimen acceptability: 14 (35·0%) reported study withdrawal, eight (20·0%) reported temporary and 16 (40·0%) reported permanent discontinuation of assigned therapy, and 11 (27·5%) reported adherence. Participants in trials were not representative of the global tuberculosis pandemic in demographic and clinical characteristics, restricting the generalisability of trial outcomes. Adverse event reporting could be improved through the use of patient-reported outcomes, standardised definitions of key outcomes, and uniform reporting of measures of regimen acceptability. There was no funding for this systematic review.

PMID: 39612926 [Indexed for MEDLINE]

13. J Thorac Oncol. 2025 Feb 13:S1556-0864(25)00072-3. doi: 10.1016/j.jtho.2025.02.013. Online ahead of print.

Overdiagnosis of Lung Cancer Due to the Introduction of Low-Dose Computed Tomography in Average-Risk Populations in the People's Republic of China.

Xie D(1), Zhang L(2), He N(1), Yang C(2), Zhang R(1), Chen H(3), Liu X(1), Suo C(1)

INTRODUCTION: Low-dose computed tomography (LDCT) has been widely used in health check-ups in China since 2011. The introduction of LDCT in average-risk populations may have led to substantial overdiagnosis of lung cancer.

METHODS: This registry-based study included 46,978 incident cases and 34,475 deaths of lung cancer derived from a population of approximately 3.21 million in the Pudong New Area of Shanghai, People's Republic of China, from 2002 to 2020. We calculated the age-standardized rates of overall, stage- and histology-specific incidence and overall mortality by sex. The numbers and proportions of cases attributable to overdiagnosis were estimated on the basis of the comparison between the shape of the age-specific curve with that before the introduction of LDCT in average-risk populations since 2011.

RESULTS: The age-standardized incidence of lung cancer increased rapidly since 2011 in both male and female individuals, whereas the age-standardized mortality declined over the period. The upward trends in incidence were mainly observed in women with early-stage cancer and lung adenocarcinoma. Overall, no significant overdiagnosis was observed in men, whereas the overdiagnosis rate grew from 22% in 2011 to 2015 to 50% in 2016 to 2020 in women. Further analysis reported elevated numbers (proportions) of lung adenocarcinoma cases attributable to overdiagnosis, which rose from 182 cases (8%) in 2011 to 2015 to 827 cases (22%) in 2016 to 2020 in men, and from 1842 cases (85%) to 4171 cases (89%) in women.

CONCLUSION: This study demonstrates considerable and increasing overdiagnosis of lung adenocarcinoma in Chinese men and women. The guideline is urgently needed to maximize the benefits of LDCT screening and reduce the potential overdiagnosis of lung cancer.

PMID: 39954810

14. Sci Transl Med. 2025 Feb 5;17(784):eadi4000. doi: 10.1126/scitranslmed.adi4000. Epub 2025 Feb 5.

Selection and prioritization of candidate combination regimens for the treatment of tuberculosis.

Strydom N(1), van Wijk RC(1), Wang Q(1), Ernest JP(1), Chaba L(1), Li Z(1)

Accelerated tuberculosis drug discovery has increased the number of plausible multidrug regimens. Testing every drug combination in vivo is impractical, and varied experimental conditions make it challenging to compare results between experiments. Using published treatment efficacy data from a mouse tuberculosis model treated with candidate combination regimens, we trained and externally validated integrative mathematical models to predict relapse in mice and to rank both previously experimentally studied and unstudied regimens by their sterilization potential. We generated 18 datasets of 18 candidate regimens (comprising 11 drugs of six classes, including fluoroquinolone, nitroimidazole, diarylquinolines, and oxazolidinones), with 2965 relapse and 1544 colony-forming unit (CFU) observations for analysis. Statistical and machine learning techniques were applied to predict the probability of relapse in mice. The locked down mathematical model had an area under the receiver operating characteristic curve (AUROC) of 0.910 and showed that bacterial kill measured by longitudinal CFU cannot account for relapse alone and that sterilization is drug dependent. The diarylquinolines had the highest predicted sterilizing activity in the mouse model, and the addition of pyrazinamide to drug regimens provided the shortest estimated tuberculosis treatment duration to cure in mice. The mathematical model predicted the effect of treatment combinations, and these predictions were validated by conducting 11 experiments on previously unstudied regimens, achieving an AUROC of 0.829. We surmise that the next generation of tuberculosis drugs are highly effective at treatment shortening and suggest that there are several promising three- and four-drug regimens that should be advanced to clinical trials.

PMID: 39908348 [Indexed for MEDLINE]

15. Lancet Infect Dis. 2025 Feb 6:S1473-3099(24)00816-8. doi: 10.1016/S1473-3099(24)00816-8. Online ahead of print.

Effects of conditional cash transfers and pre-test and post-test tuberculosis counselling on patient outcomes and loss to follow-up across the continuum of care in South Africa: a randomised controlled trial.

Ismail N(1), Moultrie H(2), Mwansa-Kambafwile J(3), Copas A(4), Izu A(5), Moyo S(6)

BACKGROUND: Economic and behavioural factors lead to poor outcomes in patients with tuberculosis. We investigated the effects of a package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers on patient outcomes in adults undergoing investigation for pulmonary tuberculosis.

METHODS: This pragmatic, open-label, individual randomised controlled trial was done in nine clinics in Johannesburg, South Africa. Participants (aged ≥18 years) undergoing investigation for tuberculosis were randomly assigned (1:1) to the intervention group or control group (standard of care) via permuted block randomisation, stratified by clinic; group assignment was concealed using opaque envelopes. The intervention group received pre-test and post-test tuberculosis counselling, and for participants diagnosed with rifampicin-susceptible tuberculosis, a digital payment (R150; approximately US$10) at treatment initiation and each monthly treatment visit. Payments were contingent on timely attendance: 14 days from initial sputum sample collection and within 7 days on either side of their scheduled monthly appointment. The primary endpoint was successful patient outcome (patients who were cured or completed treatment) or unsuccessful patient outcome (pretreatment loss-to-follow-up, on-treatment loss-to-follow-up, development of rifampicin-resistant tuberculosis while on treatment, treatment failure [ie, smear or culture positive at 5 months or later after commencing treatment], or death). The primary outcome was analysed in the modified intention-to-treat population, defined as all randomly assigned participants with rifampicin-susceptible tuberculosis confirmed before the commencement of tuberculosis treatment. Weighted outcome prevalence, relative risks (RRs), and risk differences were calculated using a multivariable Poisson model with robust standard errors. This trial is registered with the Pan African Clinical Trials Registry (PACTR202410708311054) and is completed.

FINDINGS: Between Oct 25, 2018, and Dec 9, 2019, 4110 participants were enrolled and randomly assigned, 2059 to the intervention group and 2051 to the control group. 381 (9·3%) participants had microbiologically confirmed rifampicin-susceptible pulmonary tuberculosis (195 [9·5%] of 2059 in the intervention group vs 186 [9·1%] of 2051 in the control group; median age 37 years [IQR 30 to 45], 257 [67·5%] male, 124 [32·5%] female). At study closure, primary outcome data were available for 128 (65·6%) of 195 participants in the intervention group and 139 (74·7%) of 186 participants in the control group. 105 (82·0%) of 128 participants in the intervention group and 93 (66·9%) of 139 participants in the control group had a successful patient outcome; 23 (18·0%) of 128 participants in the intervention group and 46 (33·1%) of 139 participants in the control group had an unsuccessful patient outcome. The weighted regression analysis showed a substantial reduction in the risk of unsuccessful patient outcomes in the intervention group compared with the control group (weighted prevalence 15·9% vs 28·6%; RR in weighted population 0·52, 95% CI 0·33 to 0·82; risk difference in weighted population -14·1 percentage points, 95% CI -23·3 to -4·8). Pretreatment loss to follow-up was lower in the intervention group than in the control group (unweighted population: five [3·9%] of 128 participants vs 22 [15·8%] of 139 participants; risk difference in weighted population -9·6 percentage points, 95% CI -14·9 to -4·2).

INTERPRETATION: The package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers significantly reduced the risk of unsuccessful tuberculosis patient outcomes, bringing one of the 90-90-90 targets within reach (ie, achieving 90% tuberculosis treatment success). Furthermore, reduction in pretreatment loss to follow-up is expected to reduce transmission and lower incidence of the disease over time.

FUNDING: South African Medical Research Council, UK Medical Research Council, and Newton Fund.

PMID: 39923785

16. Nat Microbiol. 2025 Feb;10(2):482-494. doi: 10.1038/s41564-024-01913-5. Epub 2025 Jan 10.

Engineered Mycobacterium tuberculosis triple-kill-switch strain provides controlled tuberculosis infection in animal models.

Wang X(#)(1), Su H(#)(2)(3), Wallach JB(#)(2), Wagner JC(#)(1), Braunecker BJ(1)

Human challenge experiments could accelerate tuberculosis vaccine development. This requires a safe Mycobacterium tuberculosis (Mtb) strain that can both replicate in the host and be reliably cleared. Here we genetically engineered Mtb strains encoding up to three kill switches: two mycobacteriophage lysin operons negatively regulated by tetracycline and a degron domain-NadE fusion, which induces ClpC1-dependent degradation of the essential enzyme NadE, negatively regulated by trimethoprim. The triple-kill-switch (TKS) strain showed similar growth kinetics and antibiotic susceptibilities to wild-type Mtb under permissive conditions but was rapidly killed in vitro without trimethoprim and doxycycline. It established infection in mice receiving antibiotics but was rapidly cleared upon cessation of treatment, and no relapse was observed in infected severe combined immunodeficiency mice or Rag-/- mice. The TKS strain had an escape mutation rate of less than 10-10 per genome per generation. These findings suggest that the TKS strain could be a safe, effective candidate for a human challenge model.

PMID: 39794471 [Indexed for MEDLINE]

17. Nat Commun. 2025 Feb 25;16(1):1957. doi: 10.1038/s41467-025-57090-4.

Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate.

Singh DK(1), Ahmed M(2), Akter S(2), Shivanna V(1), Bucşan AN(3), Mishra A(4)

The need for novel vaccination strategies to control tuberculosis (TB) is underscored by the limited and variable efficacy of the currently licensed vaccine, Bacille Calmette-Guerin (BCG). SigH is critical for Mycobacterium tuberculosis (Mtb) to mitigate oxidative stress, and in its absence Mtb is unable to scavenge host oxidative/nitrosative bursts. The MtbΔsigH (ΔsigH) isogenic mutant induces signatures of the innate immunity in macrophages and protects rhesus macaques from a lethal Mtb challenge. To understand the immune mechanisms of protection via mucosal vaccination with ΔsigH, we employed the resistant cynomolgus macaque model; and our results show that ΔsigH vaccination significantly protects against lethal Mtb challenge in this species. ΔsigH-vaccinated macaques are devoid of granulomas and instead generate inducible bronchus associated lymphoid structures, and robust antigen-specific CD4+ and CD8+ T cell responses, driven by a hyper-immune, trained immunity-like phenotype in host macrophages with enhanced antigen presentation. Correlates of protection in ΔsigH-vaccinated macaques include gene signatures of T cell activation, IFNG production, including IFN-responsive, activated T cells, concomitant with IFNG production, and suppression of IDO+ Type I IFN-responsive macrophage recruitment. Thus, ΔsigH is a promising lead candidate for further development as an antitubercular vaccine.

PMID: 40000643 [Indexed for MEDLINE]

18. J Infect. 2025 Feb;90(2):106404. doi: 10.1016/j.jinf.2024.106404. Epub 2025 Jan 2.

Blood-based diagnosis of pediatric tuberculosis: A prospective cohort study in South Africa and Dominican Republic.

Li L(1), Mao L(2), van der Zalm MM(3), Olivo J(4), Liu S(1), Vergara C(4)

OBJECTIVES: Pediatric tuberculosis (TB) diagnosis is complicated by challenges in obtaining invasive respiratory specimens that frequently contain few Mycobacterium tuberculosis (Mtb) bacilli. We report the diagnostic performance of an Mtb antigen-derived peptide (MAP-TB) assay and its ability to monitor TB treatment response.

METHODS: Study cohorts enrolled children who presented with presumptive TB at two hospitals in South Africa from 2012 to 2017 (157 children aged<13 years) and at community-based clinics in the Dominican Republic from 2019 to 2023 (101 children aged <18 years). Children were evaluated for TB at enrollment and six months post-enrollment and assigned confirmed, unconfirmed, or unlikely TB diagnoses using the 2015 NIH diagnostic criteria for pediatric TB. MAP-TB assay performance was evaluated using serum collected at baseline and at regular intervals post-enrollment following STARD guidelines.

RESULTS: MAP-TB sensitivity for confirmed and unconfirmed TB was comparable to culture and Xpert sensitivity for confirmed TB, but MAP-TB specificity revealed age-dependence, decreasing from 98·1% to 78·4%, when including children aged<1 year. MAP-TB values decreased by six months post-treatment initiation in children with symptom improvement.

CONCLUSIONS: Serum MAP-TB results can effectively diagnose pediatric TB, including unconfirmed and extrapulmonary TB missed by current methods, and correspond to effective treatment.

PMID: 39755278 [Indexed for MEDLINE]

19. J Infect. 2025 Feb;90(2):106399. doi: 10.1016/j.jinf.2024.106399. Epub 2024 Dec 27.

The molecular bacterial load assay predicts treatment responses in patients with pre-XDR/XDR-tuberculosis more accurately than GeneXpert Ultra MTB/Rif.

Neumann M(1), Reimann M(2), Chesov D(3), Popa C(4), Dragomir A(4), Popescu O(4)

OBJECTIVES: Early detection of treatment failure is essential to improve the management of drug-resistant tuberculosis (DR-TB). We evaluated the molecular bacterial load assay (MBLA) in comparison to standard diagnostic tests for monitoring therapy of patients affected by drug-resistant TB.

METHODS: The performance of MBLA in tracking treatment response in a prospective cohort of patients with pulmonary MDR/RR- and pre-XDR/XDR-TB was compared with mycobacterial culture, mycobacterial DNA detection using GeneXpert (Xpert) and microscopy detection of sputum acid-fast-bacilli.

RESULTS: Mycobacterium tuberculosis culture conversion was used as the read-out for treatment responses. The MBLA was most concordant during the early phase of treatment, detecting changes in bacterial load with similar accuracy to microscopy and outperforming Xpert. When considering all timepoints, concordance with MGIT results was 72.1% for MBLA, 57.4% for Xpert and 76.7% for microscopy. The AUC for culture conversion was higher for MBLA (0.88, CI 0.84-0.95) than for Xpert (0.78, CI 0.72-0.85) and microscopy (0.77, CI 0.71-0.83).

CONCLUSIONS: MBLA was superior in the early identification of successful culture conversion compared to microscopy and Xpert and could be a useful biomarker to evaluate novel entities in Phase IIA early-bactericidal-activity drug trials regardless of the degree of M. tuberculosis drug resistance.

PMID: 39733827 [Indexed for MEDLINE]

20. J Infect. 2025 Feb 24;90(4):106449. doi: 10.1016/j.jinf.2025.106449. Online ahead of print.

Clustering Mycobacterium tuberculosis-specific CD154(+)CD4(+) T cells for distinguishing tuberculosis disease from infection based on single-cell RNA-seq analysis.

Wang X(1), Jiang K(1), Xing W(1), Xin Q(2), Hu Q(3), Wu S(1), Sun Z(1), Hou H(4)

BACKGROUND: Distinguishing between active tuberculosis disease (TBD) and latent tuberculosis infection (TBI) is crucial for TB control but remains challenging.

METHODS: Single-cell RNA sequencing was conducted on purified Mycobacterium tuberculosis (MTB)-specific CD154+CD4+ T cells.

RESULTS: We observe a superior role of CD154 in detecting MTB infection, whereas its ability in distinguishing TBD from TBI is still limited due to patient heterogeneity. Single-cell RNA sequencing of MTB-specific CD154+CD4+ T cells identifies 10 distinct clusters, including Treg, T_act, Th1_pex, Th1_eff, Tfh, T_na, Th17_ex, Th2, NKT, and Th1_cyt. Notably, effector and apoptotic Th1 cells are predominant in CD154+CD4+ T cells of TBD. However, Tfh cells are the primary component in TBI. Most Th1_pex cells are positioned at the end of the developmental trajectory and are regulated by key genes associated with apoptosis and early exhaustion, such as GADD45B, FOS, and EZH2. Oxidative stress-induced metabolic disorder, marked by increased metabolism of nitrogen, cysteine, and glutathione, also contributes to the apoptosis of Th1_pex cells. Using seven features including NA, CM, EM, EMRA, CXCR3+ Th1, IFN-γ+ Th1, and Tfh of CD154+CD4+ T cells, both TBD and TBI can be classified into different subtypes, and a further established random forest model can accurately differentiate TBD from TBI. Additionally, the key checkpoints of exhausted MTB-specific Th1 cells are identified and blocking ADORA2A efficiently restores their function.

CONCLUSIONS: We depict the cellular compositions, transcriptional characteristics, and developmental trajectories of MTB-specific CD154+CD4+ T cells from TBI to TBD, putting forward a new direction in the diagnosis and prognosis of disease.

PMID: 40010539

21. Mol Cancer. 2025 Feb 4;24(1):43. doi: 10.1186/s12943-025-02242-9.

Multimodal lung cancer theranostics via manganese phosphate/quercetin particle.

Qiu C(#)(1)(2), Xia F(#)(2), Tu Q(#)(2)(3), Tang H(#)(2), Liu Y(2), Liu H(1)

The diagnosis and treatment of non-small cell lung cancer in clinical settings face serious challenges, particularly due to the lack of integration between the two processes, which limit real-time adjustments in treatment plans based on the patient's condition and drive-up treatment costs. Here, we present a multifunctional pH-sensitive core-shell nanoparticle containing quercetin (QCT), termed AHA@MnP/QCT NPs, designed for the simultaneous diagnosis and treatment of non-small cell lung cancer. Mechanistic studies indicated that QCT and Mn2+ exhibited excellent peroxidase-like (POD-like) activity, catalysing the conversion of endogenous hydrogen peroxide into highly toxic hydroxyl radicals through a Fenton-like reaction, depleting glutathione (GSH), promoting reactive oxygen species (ROS) generation in mitochondria and endoplasmic reticulum, and inducing ferroptosis. Additionally, Mn2+ could activate the cGAS-STING signalling pathway and promote the maturation of dendritic cells and infiltration of activated T cells, thus inducing tumor immunogenic cell death (ICD). Furthermore, it exhibited effective T2-weighted MRI enhancement for tumor imaging, making them valuable for clinical diagnosis. In vitro and in vivo experiments demonstrated that AHA@MnP/QCT NPs enabled non-invasive imaging and tumor treatment, which presented a one-stone-for-two-birds strategy for combining tumor diagnosis and treatment, with broad potential for clinical application in non-small cell lung cancer therapy.

PMID: 39905491 [Indexed for MEDLINE]

22. Nat Microbiol. 2025 Feb;10(2):468-481. doi: 10.1038/s41564-024-01895-4. Epub 2025 Jan 10.

A BCG kill switch strain protects against Mycobacterium tuberculosis in mice and non-human primates with improved safety and immunogenicity.

Smith AA(#)(1)(2), Su H(#)(3)(4), Wallach J(#)(3), Liu Y(3), Maiello P(1)(2)

Improved vaccination strategies for tuberculosis are needed. Intravenous (i.v.) delivery of live attenuated Mycobacterium bovis BCG provides protection against Mycobacterium tuberculosis (Mtb) in macaques but poses safety challenges. Here we genetically engineered two strains, BCG-TetON-DL and BCG-TetOFF-DL, to either induce or inhibit expression of two phage lysin operons, respectively, upon tetracycline exposure. We show that lysin expression kills BCG in vitro, in infected macrophages, and following infection of immunocompetent (C57BL/6) and immunocompromised (SCID) mice. Modified BCG elicited similar immune responses and provided similar protection against Mtb challenge as wild-type BCG in mice. In macaques, cessation of tetracycline treatment reduced i.v.-administered BCG-TetOFF-DL numbers. Intravenous BCG-TetOFF-DL increased pulmonary CD4 T-cell responses compared with wild-type BCG-induced responses and provided robust protection against Mtb challenge. Sterilizing immunity occurred in 6 of 8 macaques compared with 2 of 8 wild-type BCG-immunized macaques. Thus, a 'kill-switch' BCG strain provides additional safety and robust protection against Mtb infection.

PMID: 39794473 [Indexed for MEDLINE]

23. Nat Commun. 2025 Feb 4;16(1):1345. doi: 10.1038/s41467-025-56546-x.

Spatially mapping the tumour immune microenvironments of non-small cell lung cancer.

Desharnais L(#)(1)(2), Sorin M(#)(1)(2), Rezanejad M(1), Liu B(1), Karimi E(1)

Lung cancer is the leading cause of cancer-related deaths. An enhanced understanding of the immune microenvironments within these tumours may foster more precise and efficient treatment, particularly for immune-targeted therapies. The spatial architectural differences between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are relatively unexplored. Here, we applied imaging mass cytometry to a balanced cohort of LUAD and LUSC patients, matched for clinical factors such as age, sex, and smoking history, to analyze 204 histopathology images of tumours from 102 individuals with non-small cell lung cancer (NSCLC). By analyzing interactions and broader cellular networks, we interrogate the tumour microenvironment to understand how immune cells are spatially organized in clinically matched adenocarcinoma and squamous cell carcinoma subsets. This spatial analysis revealed distinct patterns of immune cell aggregation, particularly among macrophage populations, that correlated with patient prognosis differentially in adenocarcinoma and squamous cell carcinoma, suggesting potential new strategies for therapeutic intervention. Our findings underscore the importance of analyzing NSCLC histological subtypes separately when investigating the spatial immune landscape, as microenvironmental characteristics and cellular interactions differed by subtype. Recognizing these distinctions is essential for designing precision therapies tailored to each subtype's unique immune architecture, ultimately enhancing patient outcomes.

PMID: 39905080 [Indexed for MEDLINE]

24. Drug Resist Updat. 2025 May;80:101213. doi: 10.1016/j.drup.2025.101213. Epub 2025 Feb 15.

Sanfetrinem, an oral β-lactam antibiotic repurposed for the treatment of tuberculosis.

Ramón-García S(1), González Del Río R(2), Arenaz-Callao MP(3), Boshoff HI(4)

Update of

    bioRxiv. 2024 Oct 10:2024.10.10.617558. doi: 10.1101/2024.10.10.617558.

Tuberculosis (TB) is historically the world's deadliest infectious disease. New TB drugs that can avoid pre-existing resistance are desperately needed. The β-lactams are the oldest and most widely used class of antibiotics to treat bacterial infections but, for a variety of reasons, they were largely ignored until recently as a potential treatment option for TB. Recently, a growing body of evidence indicates that later-generation carbapenems in the presence of β-lactamase inhibitors could play a role in TB treatment. However, most of these drugs can only be administered intravenously in the clinic. We performed a screening of β-lactams against intracellular Mycobacterium tuberculosis (Mtb) and identified sanfetrinem cilexetil as a promising oral β-lactam candidate. Preclinical in vitro and in vivo studies demonstrated that: (i) media composition impacts the activity of sanfetrinem against Mtb, being more potent in the presence of physiologically relevant cholesterol as the only carbon source, compared to the standard broth media; (ii) sanfetrinem shows broad spectrum activity against Mtb clinical isolates, including MDR/XDR strains; (iii) sanfetrinem is rapidly bactericidal in vitro against Mtb despite being poorly stable in the assay media; (iv) there are strong in vitro synergistic interactions with amoxicillin, ethambutol, rifampicin and rifapentine and, (v) sanfetrinem cilexetil is active in an in vivo model of infection. These data, together with robust pre-clinical and clinical studies of broad-spectrum carbapenem antibiotics carried out in the 1990s by GSK, identified sanfetrinem as having potential for treating TB and catalyzed a repurposing proof-of-concept Phase 2a clinical study (NCT05388448) in South Africa.

PMID: 40020440 [Indexed for MEDLINE]

25. ACS Nano. 2025 Mar 4;19(8):8212-8226. doi: 10.1021/acsnano.4c17899. Epub 2025 Feb 23.

Tumor Microenvironment-Responsive Nano-Immunomodulators for Enhancing Chimeric Antigen Receptor-T Cell Therapy in Lung Cancer.

Chen Q(1)(2), Sun J(3), Ling S(1), Yang H(1), Li T(1), Yang X(1), Li M(1), Du M(1)

Chimeric antigen receptor (CAR)-T cells have shown unparalleled efficacy in treating hematologic cancers, but their application in solid tumor treatment remains challenging due to the immunosuppressive tumor microenvironment (TME). It is highly significant to develop safe and efficient TME regulatory strategies for the adoptive cellular immunotherapy of tumors. Herein, a TME-responsive nanoimmunomodulator (FMANAC) is designed using a multicomponent coordination self-assembly method to reconstruct the immune chemokine gradient and overcome the suppression of CAR-T cell immunoactivity, thereby improving the infiltration and killing efficiency of CAR-T cells within tumors. The acidic TME induces the disassembly of FMANAC, followed by the drug release, in which C-C chemokine ligand 5 (CCL5) improves the disrupted chemotactic gradient within tumors, increasing CAR-T cell recruitment and infiltration into deep tissue; and NLG919 reverses indoleamine 2,3-dioxygenase (IDO)-mediated immunosuppression in TME to create a favorable environment for CAR-T cells to exert their killing function. In the H460 lung cancer animal model, this nanoregulatory strategy combined with engineered CD276 CAR-T cells, guided by multiplexed near-infrared-II fluorescence imaging for programmed administration, achieved significantly enhanced tumor treatment efficacy.

PMID: 39988897 [Indexed for MEDLINE]

26. J Am Chem Soc. 2025 Feb 5;147(5):4552-4570. doi: 10.1021/jacs.4c16528. Epub 2025 Jan 2.

Image-Based Phenotypic Profiling Enables Rapid and Accurate Assessment of EGFR-Activating Mutations in Tissues from Lung Cancer Patients.

Lei Q(1)(2)(3), Zhou X(4), Li Y(1)(2)(3), Zhao S(1), Yang N(2), Xiao Z(1)(2)(3)

Determining mutations in the kinase domain of the epidermal growth factor receptor (EGFR) is critical for the effectiveness of EGFR tyrosine kinase inhibitors (TKIs) in lung cancer. Yet, DNA-based sequencing analysis of tumor samples is time-consuming and only provides gene mutation information on EGFR, making it challenging to design effective EGFR-TKI therapeutic strategies. Here, we present a new image-based method involving the rational design of a quenched probe based on EGFR-TKI to identify mutant proteins, which permits specific and "no-wash" real-time imaging of EGFR in living cells only upon covalent targeting of the EGFR kinase. We also show that the probe enables distinguishing EGFR mutant tumor-bearing mice from wild-type tumor-bearing mice via fluorescence-intensity-based imaging with high signal contrast. More interestingly, the image-based phenotypic approach can be used to predict EGFR mutations in tumors from lung cancer patients with an accuracy of 94%. Notably, when immunohistochemistry analysis is integrated, an improved accuracy of 98% is achieved. These data delineate a drug-based phenotypic imaging approach for in-biopsy visualization and define functional groups of EGFR mutants that can effectively guide EGFR-TKI therapeutic decision-making besides gene mutation analysis.

PMID: 39745025 [Indexed for MEDLINE]

27. Lancet Glob Health. 2025 Feb;13(2):e355-e363. doi: 10.1016/S2214-109X(24)00467-4.

24-week, all-oral regimens for pulmonary rifampicin-resistant tuberculosis in TB-PRACTECAL trial sites: an economic evaluation.

Sweeney S(1), Laurence YV(2), Berry C(3), Singh MP(4), Dodd M(4), Fielding K(4)

BACKGROUND: New 6-month rifampicin-resistant tuberculosis treatment regimens containing bedaquiline, pretomanid, and linezolid (BPaL) with or without moxifloxacin or clofazimine, could improve treatment efficacy, safety, and tolerability, and free up resources within the health system. Following a change to WHO rifampicin-resistant tuberculosis treatment guidelines, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines. We aimed to assess the probability of BPaL-based regimens being cost-saving using data collected in the TB-PRACTECAL trial.

METHODS: This economic evaluation using a cost-utility analysis was embedded in five TB-PRACTECAL trial sites in Belarus, Uzbekistan, and South Africa. Between Nov 19, 2020, and Sept 27, 2022, we collected detailed primary unit cost data in six hospitals and four ambulatory health facilities and collected data on patient-incurred costs from 73 trial participants. The primary efficacy endpoint of the main trial, a composite of unfavourable outcomes (death, disease recurrence, treatment failure, early discontinuation of therapy, withdrawal, or loss to follow-up) and clinically important safety outcomes by 72 weeks of follow-up were incorporated into the analysis. Societal perspective cost data and effect outcome data were input into a Markov model to estimate the cost per disability-adjusted life-year (DALY) averted by BPaL-based regimens compared with the standard of care over a 20-year time horizon. We conducted a range of univariate and probabilistic sensitivity analyses to test our findings.

FINDINGS: BPaL-based regimens averted a mean of 1·28 DALYs and saved a mean of US$14 868 (SD 291) per person from the provider perspective compared with standard-of-care regimens over 20 years. Patient-incurred costs were reduced by a mean of $172 (SD 0·84) in BPaL-based regimen groups compared with standard of care. The main cost drivers for both providers and patients were inpatient bed-days; the duration of the inpatient period varied across countries. Varying a range of model parameters affected the degree of cost savings but did not change the finding that BPaL-based regimens are cost-saving compared with standard of care.

INTERPRETATION: This trial-based evidence adds to consistent indications from modelling studies that BPaL-based regimens are cost-saving for both the patient and health system. Urgent implementation of BPaL-based regimens in countries with a high burden of tuberculosis could improve treatment of rifampicin-resistant tuberculosis, reduce pill burden, and free up desperately needed resources within the health system.

PMID: 39890235 [Indexed for MEDLINE]

28. Drug Resist Updat. 2025 Feb 25;81:101215. doi: 10.1016/j.drup.2025.101215. Online ahead of print.

Resistance to immunotherapy in non-small cell lung cancer: Unraveling causes, developing effective strategies, and exploring potential breakthroughs.

Dong S(1), Li X(1), Huang Q(1), Li Y(1), Li J(2), Zhu X(1), Xue C(1), Chen R(1)

Over the last two decades, advancements in deciphering the intricate interactions between oncology and immunity have fueled a meteoric rise in immunotherapy for non-small cell lung cancer, typified by an explosive growth of immune checkpoint inhibitors. However, resistance to immunotherapy remains inevitable. Herein we unravel the labyrinthine mechanisms of resistance to immunotherapy, characterized by their involvement of nearly all types of cells within the body, beyond the extrinsic cancer cells, and importantly, such cells are not only (inhibitory or excitatory, or both) signal recipients but also producers, acting in a context-dependent manner. At the molecular level, these mechanisms underlie genetic and epigenetic aberrations, which are regulated by or regulate various protein kinases, growth factors, and cytokines with inherently dynamic and spatially heterogeneous properties. Additionally, macroscopic factors such as nutrition, comorbidities, and the microbiome within and around organs or tumor cells are involved. Therefore, developing therapeutic strategies combined with distinct action informed by preclinical, clinical, and real-world evidence, such as radiotherapy, chemotherapy, targeted therapy, antibody-drug conjugates, oncolytic viruses, and cell-based therapies, may stand as a judicious reality, although the ideality is to overcome resistance point-by-point through a novel drug. Notably, we highlight a realignment of treatment aims, moving the primary focus from eliminating cancer cells -- such as through chemotherapy and radiotherapy -- to promoting immune modulation and underscore the value of regulating various components within the host macro- or micro-environment, as their effects, even if seemingly minimal, can cumulatively contribute to visible clinical benefit when applied in combination with ICIs. Lastly, this review also emphasizes the current hurdles scattered throughout preclinical and clinical studies, and explores evolving directions in the landscape of immunotherapy for NSCLC.

PMID: 40081220

29. J Hematol Oncol. 2025 Feb 5;18(1):14. doi: 10.1186/s13045-025-01667-5.

Transcriptional regulatory network analysis identifies GRN as a key regulator bridging chemotherapy and immunotherapy response in small cell lung cancer.

Yoo S(#)(1), Patel AS(#)(2)(3), Karam S(2)(3), Zhong Y(1), Wang L(1), Jiang F(2)(3)

Small cell lung cancer (SCLC) is an aggressive and heterogeneous subtype, representing 15% of lung cancer cases. Although SCLC initially responds to etoposide and platinum (EP) chemotherapy, nearly all patients relapse with resistant tumors. While recent advances in immunotherapy have shown promise, only 10-20% of patients benefit, and effective stratification methods are lacking. The mechanisms of resistance to both therapeutics remain obscure. In this study, we aimed to gain insights into those leveraging a recent surge in the field of SCLC genomics. We constructed a regulatory network for SCLC and identified granulin precursor (GRN) as a hub of EP response associated genes. GRN-low patients showed improved survival with chemotherapy, while GRN-high patients exhibited resistance. GRN overexpression in SCLC cells conferred resistance to EP treatment and suppressed neuroendocrine features. GRN and its associated genes were linked to cancer cell intrinsic immunogenicity, and single-cell RNA-seq data revealed that GRN expression is particularly high in subsets of tumor-associated macrophages. In concordance with these findings, GRN-low tumors showed significantly better survival with chemo-immunotherapy, while GRN-high tumors did not benefit from additional immunotherapy. GRN-high tumors, associated with non-neuroendocrine (non-NE) subtypes, had a higher level of macrophage infiltration, potentially contributing to immunotherapy resistance. These results highlight GRN as a critical regulator of chemo-resistance and a potential biomarker for immunotherapy resistance in SCLC. Targeted therapeutic strategies for GRN-low patients could improve outcomes, while new approaches are needed for GRN-high patients. Overall, our findings implicate GRN as a bridge between chemotherapy and immunotherapy resistance through GRN-mediated mechanisms.

PMID: 39910394 [Indexed for MEDLINE]

30. Cancer Cell. 2025 Mar 10;43(3):519-536.e5. doi: 10.1016/j.ccell.2025.01.012. Epub 2025 Feb 20.

Integrative spatial analysis reveals tumor heterogeneity and immune colony niche related to clinical outcomes in small cell lung cancer.

Chen H(1), Deng C(2), Gao J(3), Wang J(4), Fu F(3), Wang Y(5), Wang Q(4)

Recent advances have shed light on the molecular heterogeneity of small cell lung cancer (SCLC), yet the spatial organizations and cellular interactions in tumor immune microenvironment remain to be elucidated. Here, we employ co-detection by indexing (CODEX) and multi-omics profiling to delineate the spatial landscape for 165 SCLC patients, generating 267 high-dimensional images encompassing over 9.3 million cells. Integrating CODEX and genomic data reveals a multi-positive tumor cell neighborhood within ASCL1+ (SCLC-A) subtype, characterized by high SLFN11 expression and associated with poor prognosis. We further develop a cell colony detection algorithm (ColonyMap) and reveal a spatially assembled immune niche consisting of antitumoral macrophages, CD8+ T cells and natural killer T cells (MT2) which highly correlates with superior survival and predicts improving immunotherapy response in an independent cohort. This study serves as a valuable resource to study SCLC spatial heterogeneity and offers insights into potential patient stratification and personalized treatments.

PMID: 39983726 [Indexed for MEDLINE]

31. Cell. 2025 Feb 6;188(3):851-867.e17. doi: 10.1016/j.cell.2024.11.010. Epub 2024 Dec 18.

Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer.

Zucker M(1), Perry MA(2), Gould SI(3), Elkrief A(4), Safonov A(5)

The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.

PMID: 39701102 [Indexed for MEDLINE]

32. Lancet Child Adolesc Health. 2025 Feb;9(2):100-111. doi: 10.1016/S2352-4642(24)00330-4.

Characteristics of children and adolescents with multidrug-resistant and rifampicin-resistant tuberculosis and their association with treatment outcomes: a systematic review and individual participant data meta-analysis.

Garcia-Prats AJ(1), Garcia-Cremades M(2), Cox V(3), Kredo T(4), Dunbar R(5)

Erratum in

    Lancet Child Adolesc Health. 2025 Mar;9(3):e9. doi: 10.1016/S2352-4642(25)00038-0.

BACKGROUND: There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population.

METHODS: We conducted a systematic review and individual participant data meta-analysis. Databases were searched from Oct 1, 2014, to March 30, 2020. To be eligible, studies must have included more than five children or adolescents (0-19 years of age) treated for microbiologically confirmed or clinically diagnosed MDR or RR tuberculosis within a defined treatment cohort, and reported on regimen composition and treatment outcomes. Abstracts were screened independently by two authors to identify potentially eligible records. Full texts were reviewed by two authors independently to identify studies meeting the eligiblity criteria. For studies meeting eligiblity criteria, anonymised individual patient data was requested and individiual level data included for analysis. The main outcome assessed was treatment outcome defined as treatment success (cure or treatment completed) versus unfavourable outcome (treatment failure or death). Multivariable logistic regression models were used to identify associations between clinical and treatment factors and treatment outcomes. This study is registered with Prospero (CRD42020187230).

FINDINGS: 1417 studies were identified through database searching. After removing duplicates and screening for eligibility, the search identified 23 369 individual participants from 42 studies, mostly from India and South Africa. Overall, 16 825 (72·0%) were successfully treated (treatment completed or cured), 2848 died (12·2%), 722 (3·1%) had treatment failure, and 2974 (12·7%) were lost to follow-up. In primary analyses, the median age was 16 (IQR 13-18) years. Of the 17 764 (87·1%) participants with reported HIV status, 2448 (13·8%) were living with HIV. 17 707 (89·6%) had microbiologically confirmed tuberculosis. After adjusting for significant factors associated with treatment outcome, the use of two (adjusted odds ratio [OR] 1·41 [95% CI 1·09-1·82]; p=0·008) or three (2·12 [1·61-2·79]; p<0·0001) WHO-classified group A drugs (bedaquiline, moxifloxacin, levofloxacin, and linezolid) compared with the use of no group A drugs at all was positively associated with treatment success.

INTERPRETATION: Younger and clinically diagnosed children are underrepresented among those treated for MDR and RR tuberculosis and should be a focus for case-finding efforts. Overall treatment outcomes in our analysis were better than in adults but lower than the international targets of 90% or more individuals successfully treated. Treatment with more group A drugs was associated with better treatment outcomes in children and adolescents, highlighting the need for more rapid access to these drugs and improved regimens.

PMID: 39855750 [Indexed for MEDLINE]

33. Am J Respir Crit Care Med. 2025 Feb 7. doi: 10.1164/rccm.202408-1661OC. Online ahead of print.

Long-Term Fine Particulate Matter Exposure on Lung Cancer Incidence and Mortality in Chinese Nonsmokers.

Zhu M(1), Han Y(2), Mou Y(3), Meng X(4), Ji C(5), Zhu X(5), Yu C(2), Sun D(2)

Rationale: The association between fine particulate matter (PM2.5) and lung cancer incidence in non-smokers (LCINS) remains inconsistent. Objectives: To investigate the association between long-term PM2.5 exposure and LCINS in a Chinese population and to assess the modifying effect of genetic factors.

Methods: Time-dependent Cox proportional hazard models were employed to evaluate the hazard ratios (HR) and 95% confidence interval (CI) of PM2.5 with LCINS risk and LCINS-related mortality. The polygenic risk score (PRS) was constructed to further explore the interactions between genetic risk and PM2.5 exposure. Additionally, the population attributable fraction (PAF) of PM2.5 to lung cancer risk and mortality was calculated. Measurements and Main Results: The results demonstrated significant associations between PM2.5 exposure and LCINS incidence (HR: 1.10, 95% confidence interval [CI]: 1.04-1.17, per 10 µg/m3) and mortality (HR: 1.17, 95% CI: 1.08-1.27, per 10 µg/m3). Compared to the lowest-risk group, individuals exposed to the high PM2.5 level (≥50.9 µg/m3) and high genetic risk (top 30%) exhibited the highest LCINS incidence (HR: 2.01, 95% CI: 1.39-2.87) and mortality (HR: 2.30, 95% CI: 1.38-3.82). A significant additive interaction between PM2.5 and genetic risk on LCINS incidence was observed. Approximately 33.6% of LCINS cases and 48.5% of LCINS-related deaths in China could be prevented if PM2.5 concentrations were reduced to meet WHO guidelines.

Conclusion: Long-term exposure to outdoor PM2.5 increases LCINS risk and LCINS-related mortality, especially in populations with high genetic risk. Strengthening air pollution control measures in China has the potential to significantly reduce the burden of LCINS.

PMID: 39918842