PubMed

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

Filters applied: from 2024/9/1 - 2024/9/30

1. Trends Mol Med. 2024 Sep 3: S1471-4914(24)00218-1. doi: 10.1016/j.molmed.2024.08.004. Online ahead of print.

PMID: 39232927

Cell-free and extrachromosomal DNA profiling of small cell lung cancer.

Behrouzi R (1), Clipson A(2), Simpson KL(3), Blackhall F(4), Rothwell DG(2), Dive C(3), Mouliere F(5).

Small cell lung cancer (SCLC) is highly aggressive with poor prognosis. Despite a relative prevalence of circulating tumour DNA (ctDNA) in SCLC, liquid biopsies are not currently implemented, unlike non-SCLC where cell-free DNA (cfDNA) mutation profiling in the blood has utility for guiding targeted therapies and assessing minimal residual disease. cfDNA methylation profiling is highly sensitive for SCLC detection and holds promise for disease monitoring and molecular subtyping; cfDNA fragmentation profiling has also demonstrated clinical potential. Extrachromosomal DNA (ecDNA), that is often observed in SCLC, promotes tumour heterogeneity and chemotherapy resistance and can be detected in blood. We discuss how these cfDNA profiling modalities can be harnessed to expand the clinical applications of liquid biopsy in SCLC.

2. Nat Commun. 2024 Sep 12;15(1):7995. doi: 10.1038/s41467-024-52356-9.

PMID: 39266564 [Indexed for MEDLINE]

Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes.

Long E(#)(1)(2), Yin J(#)(1), Shin JH(#)(3), Li Y(#)(2), Li B(1), Kane A(1), Patel H(1), Sun X(2), Wang C(2), Luong T(1), Xia J(4), Han Y(5), Byun J(5), Zhang T(1), Zhao W(1), Landi MT(1), Rothman N(1), Lan Q(1), Chang YS(3), Yu F(6), Amos CI(5), Shi J(1), Lee JG(7), Kim EY(8), Choi J(9).

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Identified candidate cis-regulatory elements (cCREs) are largely cell type-specific, with 37% detected in one cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs combined with transcription factor footprinting prioritize the variants for 68% of the GWAS loci. CCV-colocalization and trait relevance score indicate that epithelial and immune cell categories, including rare cell types, contribute to lung cancer susceptibility the most. A multi-level cCRE-gene linking system identifies candidate susceptibility genes from 57% of the loci, where most loci display cell-category-specific target genes, suggesting context-specific susceptibility gene function.

3. J Infect. 2024 Sep;89(3):106231. doi: 10.1016/j.jinf.2024.106231. Epub 2024 Jul 18.

PMID: 39032519 [Indexed for MEDLINE]

Disseminated tuberculosis is associated with impaired T cell immunity mediated by non-canonical NF-κB pathway.

Jiang J (1), Cao Z (2), Li B(1), Ma X(1), Deng X(3), Yang B(2), Liu Y(2), Zhai F(2), Cheng X(4).

OBJECTIVES: The mechanism that leads to disseminated tuberculosis in HIV-negative patients is still largely unknown. T cell subsets and signaling pathways that were associated with disseminated tuberculosis were investigated.

METHODS: Single-cell profiling of whole T cells was performed to identify T cell subsets and enriched signaling pathways that were associated with disseminated tuberculosis. Flow cytometric analysis and blocking experiment were used to investigate the findings obtained by transcriptome sequencing.

RESULTS: Patients with disseminated tuberculosis had depleted Th1, Tc1 and Tc17 cell subsets, and IFNG was the most down-regulated gene in both CD4 and CD8 T cells. Gene Ontology analysis showed that non-canonical NF-κB signaling pathway, including NFKB2 and RELB genes, was significantly down-regulated and was probably associated with disseminated tuberculosis. Expression of several TNF superfamily ligands and receptors, such as LTA and TNF genes, were suppressed in patients with disseminated tuberculosis. Blocking of TNF-α and soluble LTα showed that TNF-α was involved in IFN-γ production and LTα influenced TNF-α expression in T cells.

CONCLUSIONS: Impaired T cell IFN-γ response mediated by suppression of TNF and non-canonical NF-κB signaling pathways might be responsible for disseminated tuberculosis.

4. Am J Respir Crit Care Med. 2024 Sep 1;210(5):548-571. doi: 10.1164/rccm.202406-1168ST.

PMCID: PMC11389570

Premalignant Progression in the Lung: Knowledge Gaps and Novel Opportunities for Interception of Non-Small Cell Lung Cancer. An Official American Thoracic Society Research Statement.

Moghaddam SJ, Savai R, Salehi-Rad R, Sengupta S, Kammer MN, Massion P, Beane JE, Ostrin EJ, Priolo C, Tennis MA, Stabile LP, Bauer AK, Sears CR, Szabo E, Rivera MP, Powell CA, Kadara H, Jenkins BJ, Dubinett SM, Houghton AM, Kim CF, Keith RL.

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. Results: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. Conclusions: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, together with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.

5. Bioact Mater. 2024 May 17; 39:106-134. doi: 10.1016/j.bioactmat.2024.05.013. eCollection 2024 Sep.

PMID: 38783925

Breaking barriers: The potential of nanosystems in antituberculosis therapy.

Carnero Canales CS (1), Marquez Cazorla JI(1), Marquez Cazorla RM(2), Roque-Borda CA(3), Polinário G(3), Figueroa Banda RA(2), Sábio RM(4)(5), Chorilli M(4), Santos HA(5)(6), Pavan FR(3).

Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to pose a significant threat to global health. The resilience of TB is amplified by a myriad of physical, biological, and biopharmaceutical barriers that challenge conventional therapeutic approaches. This review navigates the intricate landscape of TB treatment, from the stealth of latent infections and the strength of granuloma formations to the daunting specters of drug resistance and altered gene expression. Amidst these challenges, traditional therapies often fail, contending with inconsistent bioavailability, prolonged treatment regimens, and socioeconomic burdens. Nanoscale Drug Delivery Systems (NDDSs) emerge as a promising beacon, ready to overcome these barriers, offering better drug targeting and improved patient adherence. Through a critical approach, we evaluate a spectrum of nanosystems and their efficacy against MTB both in vitro and in vivo. This review advocates for the intensification of research in NDDSs, heralding their potential to reshape the contours of global TB treatment strategies.

6. Cancer Res. 2024 Sep 23. doi: 10.1158/0008-5472.CAN-24-0585. Online ahead of print.

PMID: 39312191

The Innate Immune System and TRAIL-BCL-XL Axis Mediate a Sex Bias in Lung Cancer and Confer a Therapeutic Vulnerability in Females.

May L(1), Hu B(2), Jerajani P(1), Jagdeesh A(1), Alhawiti O(1), Cai L(1), Semenova N(3), Guo C(4), Isbell M(5), Deng X(1), Faber A(2), Pillappa R(6), Bandyopadhyay D(5), Wang XY(2), Neuwelt A(7), Koblinski J(2), Bos PD(2), Li H(8), Martin R(1), Landry JW(1).

There is a significant sex-bias in lung cancer with males showing increased mortality compared to females. A better mechanistic understanding of these differences could help identify therapeutic targets to personalize cancer therapies to each sex. After observing a clear sex-bias in humanized mice, with male patient-derived xenograft (PDX) lung tumors being more progressive and deadlier than female PDX lung tumors, we identified mouse tumor models of lung cancer with the same sex-bias. This sex-bias was not observed in models of breast, colon, melanoma, and renal cancers. In vivo, the sex-bias in growth and lethality required intact ovaries, functional innate natural killer (NK) cells and monocytes/macrophages, and the activating receptor NKG2D. Ex vivo cell culture models were sensitized to the anti-cancer effects of NKG2D-mediated NK cell and macrophage killing through the TRAIL-BCL-XL axis when cultured with serum from female mice with intact ovaries. In both flank and orthotopic models, the BCL-XL inhibitor navitoclax (ABT-263) improved tumor growth control in female mice and required NK cells, macrophages, and the TRAIL signaling pathway. This research suggests that navitoclax and TRAIL pathway agonists could be used as a personalized therapy to improve outcomes in women with lung cancer.

7. Acta Pharm Sin B. 2024 Sep;14(9):3855-3875. doi: 10.1016/j.apsb.2024.06.010. Epub 2024 Jun 20.

PMID: 39309489

Recent advances to address challenges in extracellular vesicle-based applications for lung cancer.

Huang G(1)(2), Zheng W(2), Zhou Y(1), Wan M(3)(4), Hu T(2).

Lung cancer, highly prevalent and the leading cause of cancer-related death globally, persists as a significant challenge due to the lack of definitive tumor markers for early diagnosis and personalized therapeutic interventions. Recently, extracellular vesicles (EVs), functioning as natural carriers for intercellular communication, have received increasing attention due to their ability to traverse biological barriers and deliver diverse biological cargoes, including cytosolic proteins, cell surface proteins, microRNA, lncRNA, circRNA, DNA, and lipids. EVs are increasingly recognized as a valuable resource for non-invasive liquid biopsy, as well as drug delivery platforms, and anticancer vaccines for precision medicine in lung cancer. Herein, given the diagnostic and therapeutic potential of tumor-associated EVs for lung cancer, we discuss this topic from a translational standpoint. We delve into the specific roles that EVs play in lung cancer carcinogenesis and offer a particular perspective on how advanced engineering technologies can overcome the current challenges and expedite and/or enhance the translation of EVs from laboratory research to clinical settings.

8. Lancet Infect Dis. 2024 Sep 20: S1473-3099(24)00494-8. doi: 10.1016/S1473-3099(24)00494-8. Online ahead of print.

PMID: 39312914

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), Khosa C(5), Banze D(5), Nliwasa M(6), Corbett EL(7), Semphere R(6), Verghese VP(8)

BACKGROUND: Despite causing high mortality worldwide, paediatric tuberculosis is often undiagnosed. We aimed to investigate optimal testing strategies formicrobiological 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.

9. Angew Chem Int Ed Engl. 2024 Sep 23;63(39): e202408473. doi: 10.1002/anie.202408473. Epub 2024 Aug 21.

PMID: 38979839 [Indexed for MEDLINE]

N-Phenyl-2-Pyridone-Derived Endoperoxide Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis Progression by Three-Pronged Action.

Wang L(1), Wu H(1), Liu Z(1), Sun R(1), Li Y(1), Si Y(1), Nie Y(1), Qiao Y(1), Qian X(1), Zhang S(1), Li G(1), Sun W(1), Pan Y(1), Akkaya EU(1).

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone (P5), thus targeting multiple mechanisms for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half-life of 8.3 hours without the generation of other by-products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of hypoxia-inducible factor 1α (HIF-1α) protein, but also inhibits the transforming growth factor β1 (TGF-β1) induced fibrosis in vitro. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3-methyl-N-phenyl-2-pyridone for these two lung diseases, and triplet oxygen could downregulate HIF-1α and relieve tumor hypoxia which is a critical issue in photodynamic therapy (PDT). Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases.

10. Lancet Glob Health. 2024 Sep;12(9): e1446-e1455. doi: 10.1016/S2214-109X(24)00221-3.

PMID: 39151980 [Indexed for MEDLINE]

Cost-effectiveness and health impact of screening and treatment of Mycobacterium tuberculosis infection among formerly incarcerated individuals in Brazil: a Markov modelling study.

van Lieshout Titan A(1), Klaassen F(2), Pelissari DM(3), de Barros Silva JN Júnior(3), Alves K(3), Alves LC(4), Sanchez M(5), Bartholomay P(5), Johansen FDC(3), Croda J(6), Andrews JR(7), Castro MC(2), Cohen T(8), Vuik C(9), Menzies NA(10).

BACKGROUND: Individuals who were formerly incarcerated have high tuberculosis incidence, but are generally not considered among the risk groups eligible for tuberculosis prevention. We investigated the potential health impact and cost-effectiveness of Mycobacterium tuberculosis infection screening and tuberculosis preventive treatment (TPT) for individuals who were formerly incarcerated in Brazil.

METHODS: Using published evidence for Brazil, we constructed a Markov state transition model estimating tuberculosis-related health outcomes and costs among individuals who were formerly incarcerated, by simulating transitions between health states over time. The analysis compared tuberculosis infection screening and TPT, to no screening, considering a combination of M tuberculosis infection tests and TPT regimens. We quantified health effects as reductions in tuberculosis cases, tuberculosis deaths, and disability-adjusted life-years (DALYs). We assessed costs from a tuberculosis programme perspective. We report intervention cost-effectiveness as the incremental costs per DALY averted, and tested how results changed across subgroups of the target population.

FINDINGS: Compared with no intervention, an intervention incorporating tuberculin skin testing and treatment with 3 months of isoniazid and rifapentine would avert 31 (95% uncertainty interval 14-56) lifetime tuberculosis cases and 4·1 (1·4-5·8) lifetime tuberculosis deaths per 1000 individuals, and cost US$242 per DALY averted. All test and regimen combinations were cost-effective compared with no screening. Younger age, longer incarceration, and more recent prison release were each associated with significantly greater health benefits and more favourable cost-effectiveness ratios, although the intervention was cost-effective for all subgroups examined.

INTERPRETATION: M tuberculosis infection screening and TPT for individuals who were formerly incarcerated appears cost-effective, and would provide valuable health gains.

11. Nat Commun. 2024 Sep 1;15(1):7604. doi: 10.1038/s41467-024-52122-x.

PMID: 39217183 [Indexed for MEDLINE]

Mycobacterium tuberculosis cough aerosol culture status associates with host characteristics and inflammatory profiles.

Nduba V (1), Njagi LN(1), Murithi W(1), Mwongera Z(1), Byers J(2), Logioia G(3), Peterson G(3), Segnitz RM(3), Fennelly K(4), Hawn TR(3), Horne DJ(5)(6).

Interrupting transmission events is critical to tuberculosis control. Cough-generated aerosol cultures predict tuberculosis transmission better than microbiological or clinical markers. We hypothesize that highly infectious individuals with pulmonary tuberculosis (positive for cough aerosol cultures) have elevated inflammatory markers and unique transcriptional profiles compared to less infectious individuals. We performed a prospective, longitudinal study using cough aerosol sampling system. We enrolled 142 participants with treatment-naïve pulmonary tuberculosis in Kenya and assessed the association of clinical, microbiologic, and immunologic characteristics with Mycobacterium tuberculosis aerosolization and transmission in 129 household members. Contacts of the forty-three aerosol culture-positive participants (30%) are more likely to have a positive interferon-gamma release assay (85% vs 53%, P = 0.006) and higher median IFNγ level (P < 0.001, 4.28 IU/ml (1.77-5.91) vs. 0.71 (0.01-3.56)) compared to aerosol culture-negative individuals. We find that higher bacillary burden, younger age, larger mean upper arm circumference, and host inflammatory profiles, including elevated serum C-reactive protein and lower plasma TNF levels, associate with positive cough aerosol cultures. Notably, we find pre-treatment whole blood transcriptional profiles associate with aerosol culture status, independent of bacillary load. These findings suggest that tuberculosis infectiousness is associated with epidemiologic characteristics and inflammatory signatures and that these features may identify highly infectious persons.

12. Adv Mater. 2024 Sep;36(38): e2406143. doi: 10.1002/adma.202406143. Epub 2024 Jul 28.

PMID: 39072892 [Indexed for MEDLINE]

NIR-II AIE Luminogen-Based Erythrocyte-Like Nanoparticles with Granuloma-Targeting and Self-Oxygenation Characteristics for Combined Phototherapy of Tuberculosis.

Wang H(1)(2), Li B(3), Sun Y(4), Ma Q(1), Feng Y(5), Jia Y(3), Wang W(5), Su M(3), Liu X(3), Shu B(5), Zheng J(5), Sang S(3), Yan Y(5), Wu Y(5), Zhang Y(5), Gao Q(2), Li P(5), Wang J(5), Ma F(3), Li X(5), Yan D(4), Wang D(4), Zou X(1), Liao Y(2)(3).

Tuberculosis, a fatal infectious disease caused by Mycobacterium tuberculosis (M.tb), is difficult to treat with antibiotics due to drug resistance and short drug half-life. Phototherapy represents a promising alternative to antibiotics in combating M.tb. Exploring an intelligent material allowing effective tuberculosis treatment is definitely appealing, yet a significantly challenging task. Herein, an all-in-one biomimetic therapeutic nanoparticle featured by aggregation-induced second near-infrared emission, granuloma-targeting, and self-oxygenation is constructed, which can serve for prominent fluorescence imaging-navigated combined phototherapy toward tuberculosis. After camouflaging the biomimetic erythrocyte membrane, the nanoparticles show significantly prolonged blood circulation and increased selective accumulation in tuberculosis granuloma. Upon laser irradiation, the loading photosensitizer of aggregation-induced emission photosensitizer elevates the production of reactive oxygen species (ROS), causing M.tb damage and death. The delivery of oxygen to relieve the hypoxic granuloma microenvironment supports ROS generation during photodynamic therapy. Meanwhile, the photothermal agent, Prussian blue nanoparticles, plays the role of good photothermal killing effect on M.tb. Moreover, the growth and proliferation of granuloma and M.tb colonies are effectively inhibited in the nanoparticle-treated tuberculous granuloma model mice, suggesting the combined therapeutic effects of enhancing photodynamic therapy and photothermal therapy.

13. J Thorac Oncol. 2024 Sep;19(9):1272-1283. doi: 10.1016/j.jtho.2024.05.006. Epub 2024 May 16.

PMID: 38762120 [Indexed for MEDLINE]

A Real-World Assessment of Stage I Lung Cancer Through Electronic Nose Technology.

Rocco G(1), Pennazza G(2), Tan KS(3), Vanstraelen S(4), Santonico M(5), Corba RJ(4), Park BJ(4), Sihag S(4), Bott MJ(4), Crucitti P(6), Isbell JM(4), Ginsberg MS(7)

INTRODUCTION: Electronic nose (E-nose) technology has reported excellent sensitivity and specificity in the setting of lung cancer screening. However, the performance of E-nose specifically for early-stage tumors remains unclear. Therefore, the aim of our study was to assess the diagnostic performance of E-nose technology in clinical stage I lung cancer.

METHODS: This phase IIc trial (NCT04734145) included patients diagnosed with a single greater than or equal to 50% solid stage I nodule. Exhalates were prospectively collected from January 2020 to August 2023. Blinded bioengineers analyzed the exhalates, using E-nose technology to determine the probability of malignancy. Patients were stratified into three risk groups (low-risk, [<0.2]; moderate-risk, [≥0.2-0.7]; high-risk, [≥0.7]). The primary outcome was the diagnostic performance of E-nose versus histopathology (accuracy and F1 score). The secondary outcome was the clinical performance of the E-nose versus clinicoradiological prediction models.

RESULTS: Based on the predefined cutoff (<0.20), E-nose agreed with histopathologic results in 86% of cases, achieving an F1 score of 92.5%, based on 86 true positives, two false negatives, and 12 false positives (n = 100). E-nose would refer fewer patients with malignant nodules to observation (low-risk: 2 versus 9 and 11, respectively; p = 0.028 and p = 0.011) than would the Swensen and Brock models and more patients with malignant nodules to treatment without biopsy (high-risk: 27 versus 19 and 6, respectively; p = 0.057 and p < 0.001).

CONCLUSIONS: In the setting of clinical stage I lung cancer, E-nose agrees well with histopathology. Accordingly, E-nose technology can be used in addition to imaging or as part of a "multiomics" platform.

14. Lancet Infect Dis. 2024 Sep;24(9):e559-e575. doi: 10.1016/S1473-3099(24)00144-0. Epub 2024 Mar 22.

PMID: 38527475 [Indexed for MEDLINE]

The epidemiology, transmission, diagnosis, and management of drug-resistant tuberculosis-lessons from the South African experience.

Naidoo K(1), Perumal R(2), Cox H(3), Mathema B(4), Loveday M(5), Ismail N(6), Omar SV(7), Georghiou SB(8), Daftary A(9), O'Donnell M(10), Ndjeka N(11).

Drug-resistant tuberculosis (DR-TB) threatens to derail tuberculosis control efforts, particularly in Africa where the disease remains out of control. The dogma that DR-TB epidemics are fueled by unchecked rates of acquired resistance in inadequately treated or non-adherent individuals is no longer valid in most high DR-TB burden settings, where community transmission is now widespread. A large burden of DR-TB in Africa remains undiagnosed due to inadequate access to diagnostic tools that simultaneously detect tuberculosis and screen for resistance. Furthermore, acquisition of drug resistance to new and repurposed drugs, for which diagnostic solutions are not yet available, presents a major challenge for the implementation of novel, all-oral, shortened (6-9 months) treatment. Structural challenges including poverty, stigma, and social distress disrupt engagement in care, promote poor treatment outcomes, and reduce the quality of life for people with DR-TB. We reflect on the lessons learnt from the South African experience in implementing state-of-the-art advances in diagnostic solutions, deploying recent innovations in pharmacotherapeutic approaches for rapid cure, understanding local transmission dynamics and implementing interventions to curtail DR-TB transmission, and in mitigating the catastrophic socioeconomic costs of DR-TB. We also highlight globally relevant and locally responsive research priorities for achieving DR-TB control in South Africa.

15. Nat Commun. 2024 Sep 5;15(1):7114. doi: 10.1038/s41467-024-51266-0.

PMID: 39237504 [Indexed for MEDLINE]

Genetic diversity within diagnostic sputum samples is mirrored in the culture of Mycobacterium tuberculosis across different settings.

Mariner-Llicer C(1), Goig GA(2)(3), Torres-Puente M(1), Vashakidze S(4)(5), Villamayor LM(6), Saavedra-Cervera B(7)(8)(9), Mambuque E(8), Khurtsilava I(4), Avaliani Z(4)(10)

Culturing and genomic sequencing of Mycobacterium tuberculosis (MTB) from tuberculosis (TB) cases is the basis for many research and clinical applications. The alternative, culture-free sequencing from diagnostic samples, is promising but poses challenges to obtain and analyse the MTB genome. Paradoxically, culture is assumed to impose a diversity bottleneck, which, if true, would entail unexplored consequences. To unravel this paradox we generate high-quality genomes of sputum-culture pairs from two different settings after developing a workflow for sequencing from sputum and a tailored bioinformatics analysis. Careful downstream comparisons reveal sources of sputum-culture incongruences due to false positive/negative variation associated with factors like low input MTB DNA or variable genomic depths. After accounting for these factors, contrary to the bottleneck dogma, we identify a 97% variant agreement within sputum-culture pairs, with a high correlation also in the variants' frequency (0.98). The combined analysis from five different settings and more than 100 available samples shows that our results can be extrapolated to different TB epidemic scenarios, demonstrating that for the cases tested culture accurately mirrors clinical samples.

16. Nat Microbiol. 2024 Sep;9(9):2369-2382. doi: 10.1038/s41564-024-01777-9. Epub 2024 Aug 22.

PMID: 39174703 [Indexed for MEDLINE]

Fc-engineered antibodies promote neutrophil-dependent control of Mycobacterium tuberculosis.

Irvine EB(1)(2), Nikolov A(1)(2), Khan MZ(1), Peters JM(1)(3), Lu R(1), Sixsmith J(2), Wallace A(4), van Woudenbergh E(1), Shin S(1), Karpinski W(1), Hsiao JC(1)(3)

Mounting evidence indicates that antibodies can contribute towards control of tuberculosis (TB). However, the underlying mechanisms of humoral immune protection and whether antibodies can be exploited in therapeutic strategies to combat TB are relatively understudied. Here we engineered the receptor-binding Fc (fragment crystallizable) region of an antibody recognizing the Mycobacterium tuberculosis (Mtb) capsule, to define antibody Fc-mediated mechanism(s) of Mtb restriction. We generated 52 Fc variants that either promote or inhibit specific antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole-blood model of infection. While there is likely no singular Fc profile that universally drives control of Mtb, here we found that several Fc-engineered antibodies drove Mtb restriction in a neutrophil-dependent manner. Single-cell RNA sequencing analysis showed that a restrictive Fc-engineered antibody promoted neutrophil survival and expression of cell-intrinsic antimicrobial programs. These data show the potential of Fc-engineered antibodies as therapeutics able to harness the protective functions of neutrophils to promote control of TB.

17. Clin Microbiol Infect. 2024 Sep;30(9):1176-1182. doi: 10.1016/j.cmi.2024.06.003. Epub 2024 Jun 6.

PMID: 38851427 [Indexed for MEDLINE]

Tuberculosis infection among close contacts of patients with pulmonary tuberculosis in China: a population-based, multicentered study.

Zhang C(1), Liu Y(1), Yao Y(2), Gong D(3), Lei R(4), Xia Y(1), Xu C(1), Chen H(1), Cheng J(1), Zhang H(5).

OBJECTIVES: Limited information is currently available on the prevalence of and risk factors for tuberculosis infection (TBI) among close contacts of patients with pulmonary TB (PTB) in China. In this study, we estimated the burden of TBI among close contacts using QuantiFERON-TB Gold In-Tube assay (QFT) and identified factors associated with TB transmission among this high-risk population.

METHODS: From January 1, 2018 to August 31, 2020, we identified laboratory-confirmed patients with PTB from a population-based, multicentered, cluster-randomized control trial for tuberculosis preventive treatment. Close contacts of these patients were identified, interviewed, and tested using the QFT assay. We estimated TBI prevalence and calculated ORs and 95% CIs for TBI risk factors.

RESULTS: A total of 3138 index cases and 8117 close contacts were identified. Of these contacts, 36 had PTB (a prevalence of 443.51 cases/100 000 population). Among the remaining 7986 close contacts; 3124 (39.12%) reported a positive QFT result. QFT positivity was significantly associated with older age (adjusted OR, 1.77; [95% CI, 1.27-2.47], 2.20; [95% CI, 1.59-3.05], and 2.74; [95% CI, 1.96-3.82]) for age groups: 35-44, 45-54, and 55-64, respectively) when compared with a younger age group: 5-14; longer contact duration (adjusted OR, 1.44; 95% CI, 1.22-1.69); and sharing of a bedroom (adjusted OR, 1.39; 95% CI, 1.18-1.65).

DISCUSSION: Our findings indicate a high TBI burden among the close contacts of PTB. The results also highlighted that contact tracing and investigation for TBI are necessary and beneficial, particularly for those who are older, have had a longer contact duration, and share a bedroom.

18. Angew Chem Int Ed Engl. 2024 Sep 29:e202413127. doi: 10.1002/anie.202413127. Online ahead of print.

PMID: 39343740

Nebulized Immunotherapy of Orthotopic Lung Cancer by Mild Magnetothermal-based Innate Immunity Activations.

Chen L(1), Hu P(2), Fang W(2), Wu T(1), Shi J(3).

Advances in adaptive immunity have greatly contributed to the development of cancer immunotherapy. However, its over-low efficacy and insufficient invasion of immune cells in the tumor tissue, and safety problems caused by cytokine storm, have seriously impeded further clinical application for solid tumor immunotherapy. Notably, the immune microenvironment of the lungs is naturally enriched with alveolar macrophages (AMs). Herein, we introduce a novel nebulized magnetothermal immunotherapy strategy to treat orthotopic lung cancer by using magnetothermal nanomaterial (Zn-CoFe2O4@Zn-MnFe2O4-PEG, named ZCMP), which can release iron ions via an acid/thermal-catalytic reaction to maximize the use of lung's immune environment through the cascade activations of AMs and natural killer (NK) cells. Nebulized administration greatly enhance drug bioavailability by localized drug accumulation at the lesion site. Upon mild magnetic hyperthermia, the released iron ions catalyze endogenous H2O2 decomposition to produce reactive oxygen species (ROS), which triggers the M1 polarization of AMs, and the resultant inflammatory cytokine IFN-β, IL-1β and IL-15 releases to activate c-Jun, STAT5 and GZMB related signaling pathways, promoting NK cells proliferation and activation. This innovative strategy optimally utilizes the lung's immune environment and shows excellent immunotherapeutic outcomes against orthotopic lung cancer.

19. Nat Commun. 2024 Sep 11;15(1):7952. doi: 10.1038/s41467-024-51824-6.

PMID: 39261450 [Indexed for MEDLINE]

An observational and genetic investigation into the association between psoriasis and risk of malignancy.

Li R(#)(1), Luo W(#)(2), Chen X(2), Zeng Q(2), Yang S(2), Wang P(1), Hu J(3), Chen A(4).

The relationship between psoriasis and site-specific cancers remains unclear. Here, we aim to investigate whether psoriasis is causally associated with site-specific cancers. We use observational and genetic data from the UK Biobank, obtaining GWAS summary data, eQTL analysis data, TCGA data, and GTEx data from public datasets. We perform PheWAS, polygenic risk score analysis, and one-sample and two-sample Mendelian randomization analyses to investigate the potential causal associations between psoriasis and cancers. In the unselected PheWAS analysis, psoriasis is associated with higher risks of 16 types of cancer. Using one-sample Mendelian randomization analyses, it is found that genetically predicted psoriasis is associated with higher risks of anal canal cancer, breast cancer, follicular non-Hodgkin's lymphoma and nonmelanoma skin cancer in women; and lung cancer and kidney cancer in men. Our two-sample Mendelian randomization analysis indicates that psoriasis is causally associated with breast cancer and lung cancer. Gene annotation shows that psoriasis-related genes, such as ERAP1, are significantly different in lung and breast cancer tissues. Taken together, clinical attention to lung cancer and breast cancer may be warranted among patients with psoriasis.

20. Bioact Mater. 2024 May 17;39:59-73. doi: 10.1016/j.bioactmat.2024.05.019. eCollection 2024 Sep.

PMID: 38800720

Dynamic microphysiological system chip platform for high-throughput, customizable, and multi-dimensional drug screening.

Zhu Y(1)(2), Jiang D(1)(3), Qiu Y(1), Liu X(1), Bian Y(1), Tian S(1), Wang X(1), Hsia KJ(4), Wan H(1)(3), Zhuang L(1)(2), Wang P(1)(3)(5)(2).

Spheroids and organoids have attracted significant attention as innovative models for disease modeling and drug screening. By employing diverse types of spheroids or organoids, it is feasible to establish microphysiological systems that enhance the precision of disease modeling and offer more dependable and comprehensive drug screening. High-throughput microphysiological systems that support optional, parallel testing of multiple drugs have promising applications in personalized medical treatment and drug research. However, establishing such a system is highly challenging and requires a multidisciplinary approach. This study introduces a dynamic Microphysiological System Chip Platform (MSCP) with multiple functional microstructures that encompass the mentioned advantages. We developed a high-throughput lung cancer spheroids model and an intestine-liver-heart-lung cancer microphysiological system for conducting parallel testing on four anti-lung cancer drugs, demonstrating the feasibility of the MSCP. This microphysiological system combines microscale and macroscale biomimetics to enable a comprehensive assessment of drug efficacy and side effects. Moreover, the microphysiological system enables evaluation of the real pharmacological effect of drug molecules reaching the target lesion after absorption by normal organs through fluid-based physiological communication. The MSCP could serves as a valuable platform for microphysiological system research, making significant contributions to disease modeling, drug development, and personalized medical treatment.

21. Drug Resist Updat. 2024 Sep 28; 77:101154. doi: 10.1016/j.drup.2024.101154.

Online ahead of print.

PMID: 39366066

E3 ubiquitin ligase DTX2 fosters ferroptosis resistance via suppressing NCOA4-mediated ferritinophagy in non-small cell lung cancer.

Liu Z(1), Liu C(2), Fan C(2), Li R(2), Zhang S(2), Liu J(2), Li B(2), Zhang S(3), Guo L(4), Wang X(5), Qi Z(6), Shen Y(7).

Non-small cell lung cancer (NSCLC) remains the foremost contributor to cancer-related fatalities globally, with limited effective therapeutic modalities. Recent research has shed light on the role of ferroptosis in various types of cancers, offering a potential avenue for improving cancer therapy. Herein, we identified E3 ubiquitin ligase deltex 2 (DTX2) as a potential therapeutic target candidate implicated in promoting NSCLC cell growth by inhibiting ferroptosis. Our investigation revealed a significant upregulation of DTX2 in NSCLC cells and tissues, which was correlated with poor prognosis. Downregulation of DTX2 suppressed NSCLC cell growth both in vitro and in vivo, while its overexpression accelerated cell proliferation. Moreover, knockdown of DTX2 promoted ferroptosis in NSCLC cells, which was mitigated by DTX2 overexpression. Mechanistically, we uncovered that DTX2 binds to nuclear receptor coactivator 4 (NCOA4), facilitating its ubiquitination and degradation via the K48 chain, which subsequently dampens NCOA4-driven ferritinophagy and ferroptosis in NSCLC cells. Notably, DTX2 knockdown promotes cisplatin-induced ferroptosis and overcomes drug resistance of NSCLC cells. These findings underscore the critical role of DTX2 in regulating ferroptosis and NCOA4-mediated ferritinophagy, suggesting its potential as a novel therapeutic target for NSCLC.

22. Eur Urol. 2024 Sep 12:S0302-2838(24)02567-3. doi: 10.1016/j.eururo.2024.08.029.  Online ahead of print.

PMID: 39271419

Abdominal Noncontrast Computed Tomography Scanning to Screen for Kidney Cancer and Other Abdominal Pathology Within Community-based Computed Tomography for Lung Cancer: Results of the Yorkshire Kidney Screening Trial.

Stewart GD(1), Godoy A(2), Farquhar F(3), Kitt J(4), Cartledge J(5), Kimuli M(5), Rossi SH(4), Shinkins B(6), Burbidge S(7), Burge SW(2), Caglic I(8), Collins E(9)

BACKGROUND AND OBJECTIVE: The Yorkshire Kidney Screening Trial (YKST) assessed the feasibility of adding abdominal noncontrast computed tomography (NCCT) to lung cancer screening to screen for kidney cancer and other abdominal pathology.

METHODS: A prospective diagnostic study offered abdominal NCCT to 55-80-yr-old ever-smokers attending a UK randomised lung cancer screening trial (May 2021 to October 2022). The exclusion criteria were dementia, frailty, previous kidney/lung cancer, and computed tomography (CT) of the abdomen and thorax within previous 6 and 12 mo, respectively. Six-month follow-up was undertaken.

KEY FINDINGS AND LIMITATIONS: A total of 4438 people attended lung screening, of whom 4309 (97%) were eligible for and 4019 (93%) accepted abdominal NCCT. Only 3.9% respondents regretted participating. The additional time to conduct the YKST processes was 13.3 min. Of the participants, 2586 (64%) had a normal abdominal NCCT, whilst 787 (20%) required an abdominal NCCT imaging review but no further action and 611 (15%) required further evaluation (investigations and/or clinic). Of the participants, 211 (5.3%) had a new serious finding, including 25 (0.62%) with a renal mass/complex cyst, of whom ten (0.25%) had histologically proven kidney cancer; ten (0.25%) with other cancers; and 60 (1.5%) with abdominal aortic aneurysms (AAAs). Twenty-five (0.62%) participants

had treatment with curative intent. Of the participants, 1017 (25%) had nonserious findings, most commonly benign renal cysts (727 [18%]), whereas only 259 (6.4%) had nonserious findings requiring further tests. The number needed to screen to detect one serious abdominal finding was 18; it was 93 to detect one suspicious renal lesion and 402 to detect one histologically confirmed renal cancer. Limitations of the cohort were fixed age range and being prior lung cancer screening attendees.

CONCLUSIONS AND CLINICAL IMPLICATIONS: In this first prospective risk-stratified screening study of abdominal NCCT offered alongside CT thorax, uptake and participant satisfaction were high. The prevalence of serious findings, cancers, and AAAs, is in the range of established screening programmes such as bowel cancer. Longer-term outcomes and cost effectiveness should now be evaluated.

23. Nat Commun. 2024 Sep 4;15(1):7719. doi: 10.1038/s41467-024-51934-1.

PMID: 39231966 [Indexed for MEDLINE]

Inducible auto-phosphorylation regulates a widespread family of nucleotidyltransferase toxins.

Arrowsmith TJ(1), Xu X(2), Xu S(3), Usher B(1), Stokes P(4), Guest M(1), Bronowska AK(3), Genevaux P(5), Blower TR(6).

Nucleotidyltransferases (NTases) control diverse physiological processes, including RNA modification, DNA replication and repair, and antibiotic resistance. The Mycobacterium tuberculosis NTase toxin family, MenT, modifies tRNAs to block translation. MenT toxin activity can be stringently regulated by diverse MenA antitoxins. There has been no unifying mechanism linking antitoxicity across MenT homologues. Here we demonstrate through structural, biochemical, biophysical and computational studies that despite lacking kinase motifs, antitoxin MenA1 induces auto-phosphorylation of MenT1 by repositioning the MenT1 phosphoacceptor T39 active site residue towards bound nucleotide. Finally, we expand this predictive model to explain how unrelated antitoxin MenA3 is similarly able to induce auto-phosphorylation of cognate toxin MenT3. Our study reveals a conserved mechanism for the control of tuberculosis toxins, and demonstrates how active site auto-phosphorylation can regulate the activity of widespread NTases.

24. Cancer Cell. 2024 Sep 9;42(9):1598-1613.e4. doi: 10.1016/j.ccell.2024.08.013.

PMID: 39255777 [Indexed for MEDLINE]

Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer.

Xu J(1), Wan R(1), Cai Y(2), Cai S(2), Wu L(3), Li B(4), Duan J(1), Cheng Y(5), Li X(6), Wang X(7), Han L(8), Wu X(9), Fan Y(10), Yu Y(11), Lv D(12), Shi J(13), Huang J(14)

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

25. Mol Cancer. 2024 Sep 2;23(1):184. doi: 10.1186/s12943-024-02099-4.

PMID: 39223601 [Indexed for MEDLINE]

LAMTOR1 decreased exosomal PD-L1 to enhance immunotherapy efficacy in non-small cell lung cancer.

Wu B(1), Huang X(2), Shi X(3), Jiang M(4), Liu H(5), Zhao L(6).

Great progress has been made in utilizing immune checkpoint blockade (ICB) for the treatment of non-small-cell lung cancer (NSCLC). Therapies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, expressed on tumor cells, have demonstrated potential in improving patient survival rates. An unresolved issue involves immune suppression induced by exosomal PD-L1 within the tumor microenvironment (TME), particularly regarding CD8+ T cells. Our study unveiled the crucial involvement of LAMTOR1 in suppressing the exosomes of PD-L1 and promoting CD8+ T cell infiltration in NSCLC. Through its interaction with HRS, LAMTOR1 facilitates PD-L1 lysosomal degradation, thereby reducing exosomal PD-L1 release. Notably, the ability of LAMTOR1 to promote PD-L1 lysosomal degradation relies on a specific ubiquitination site and an HRS binding sequence. The findings suggest that employing LAMTOR1 to construct peptides could serve as a promising strategy for bolstering the efficacy of immunotherapy in NSCLC. The discovery and comprehension of how LAMTOR1 inhibits the release of exosomal PD-L1 offer insights into potential therapeutic strategies for improving immunotherapy. It is imperative to conduct further research and clinical trials to investigate the feasibility and efficacy of targeting LAMTOR1 in NSCLC treatment.

26. Mol Cancer. 2024 Sep 28;23(1):208. doi: 10.1186/s12943-024-02120-w.

PMID: 39342185 [Indexed for MEDLINE]

CircLIFRSA/miR-1305/PTEN axis attenuates malignant cellular processes in non-small cell lung cancer by regulating AKT phosphorylation.

Jiang M(1), Bai H(1), Fang S(1), Zhou C(2), Shen W(3), Gong Z(4)(5).

BACKGROUND: Non-small cell lung cancer (NSCLC) is typically diagnosed at advanced stages, which limits the effectiveness of therapeutic interventions. The present study aimed to explore the role of the newly identified circLIFRSA in the PTEN/AKT signaling pathway and its involvement in the malignant processes of NSCLC.

METHODS: CircLIFRSA expression was identified through microarray analysis, and its levels in NSCLC samples were quantified by RT-qPCR. The impact of circLIFRSA on cell growth, proliferation, apoptosis, and cell cycle were evaluated by MTT assay, colony formation assay, and flow cytometry. Additionally, Western blotting was employed to analyze the expression of PTEN and phosphorylated AKT (pAKT) in NSCLC cells.

RESULTS: The expression of circLIFRSA was found to be significantly reduced in NSCLC cells and tissues. This downregulation correlated with various clinicopathological characteristics and indicated its potential as an early diagnostic biomarker for NSCLC. Importantly, circLIFRSA was shown to inhibit cell growth and proliferation while promoting apoptosis in NSCLC cells. Mechanically, circLIFRSA was found to attenuate the malignant processes of NSCLC cells via the miR-1305/PTEN axis and the suppression of AKT phosphorylation.

CONCLUSIONS: These findings indicate that circLIFRSA/miR-1305/PTEN axis attenuates malignant processes by regulating AKT phosphorylation, and provide new insights into the potential of circLIFRSA as a biomarker for early diagnosis and as a promising therapeutic target in NSCLC.

27. Nat Rev Dis Primers. 2024 Sep 26;10(1):71. doi: 10.1038/s41572-024-00551-9.

PMID: 39327441 [Indexed for MEDLINE]

Non-small-cell lung cancer.

Hendriks LEL(#)(1), Remon J(#)(2), Faivre-Finn C(3), Garassino MC(4), Heymach JV(5), Kerr KM(6), Tan DSW(7), Veronesi G(8), Reck M(9).

Non-small-cell lung cancer (NSCLC) is one of the most frequent cancer types and is responsible for the majority of cancer-related deaths worldwide. The management of NSCLC has improved considerably, especially in the past 10 years. The systematic screening of populations at risk with low-dose CT, the implementation of novel surgical and radiotherapeutic techniques and a deeper biological understanding of NSCLC that has led to innovative systemic treatment options have improved the prognosis of patients with NSCLC. In non-metastatic NSCLC, the combination of various perioperative strategies and adjuvant immunotherapy in locally advanced disease seem to enhance cure rates. In metastatic NSCLC, the implementation of novel drugs might prolong disease control together with preserving quality of life. The further development of predictive clinical and genetic markers will be essential for the next steps in individualized treatment concepts.

28. Ann Intern Med. 2024 Sep;177(9):1222-1232. doi: 10.7326/M23-3250. Epub 2024 Aug 20.

PMID: 39159457 [Indexed for MEDLINE]

The Development and Performance of Alternative Criteria for Lung Cancer Screening.

Kearney LE(1), Belancourt P(2), Katki HA(3), Tanner NT(4), Wiener RS(5), Robbins HA(6), Landy R(3), Caverly TJ(7).

BACKGROUND: The recommendation for lung cancer screening (LCS) developed by the U.S. Preventive Services Task Force (USPSTF) may exclude some high-benefit people.

OBJECTIVE: To determine whether alternative criteria can identify these high-benefit people.

DESIGN: Model-based projections.

SETTING: United States.

PARTICIPANTS: People from the 1997-2014 National Health Interview Survey (NHIS) to develop alternative criteria using fast-and-frugal tree algorithms and from the 2014-2018 NHIS and the 2022 Behavioral Risk Factor Surveillance System for comparisons of USPSTF criteria versus alternative criteria.

MEASUREMENTS: Life-years gained from LCS were estimated using the life-years gained from screening computed tomography (LYFS-CT) model. "High-benefit" was defined as gaining an average of at least 16.2 days of life from 3 annual screenings, which reflects high lung cancer risk and substantial life gains if lung cancer is detected by screening.

RESULTS: The final alternative criteria were 1) people who smoked any amount each year for at least 40 years, or 2) people aged 60 to 80 years with at least 40 pack-years of smoking. The USPSTF and alternative criteria selected similar numbers of people for LCS. Compared with the USPSTF criteria, the alternative criteria had higher sensitivity (91% vs. 78%; P < 0.001) and specificity (86% vs. 84%; P < 0.001) for identifying high-benefit people. For racial and ethnic minorities, the alternative criteria provided greater gains in sensitivity than the USPSTF criteria (Black: 83% vs. 56% [P < 0.001]; Hispanic: 95% vs. 73% [P = 0.086]; Asian: 94% vs. 68% [P = 0.171]) at similar specificity. The alternative criteria identify high-risk, high-benefit groups excluded by the USPSTF criteria (those with a smoking duration of ≥40 years but<20 pack-years="" and="" a="" quit="" history="" of="">15 years), many of whom are members of racial and ethnic minorities.

LIMITATION: The results were based on model projections.

CONCLUSION: These results suggest that simple alternative LCS criteria can identify substantially more high-benefit people, especially in some racial and ethnic groups.

29. Bioact Mater. 2024 May 30;39:544-561. doi: 10.1016/j.bioactmat.2024.04.016.

eCollection 2024 Sep.

PMID: 38883314

Targeting nanoplatform synergistic glutathione depletion-enhanced chemodynamic, microwave dynamic, and selective-microwave thermal to treat lung cancer bone metastasis.

Shu M(1)(2)(3), Wang J(4), Xu Z(5)(3), Lu T(5)(3), He Y(5)(3), Li R(1)(3), Zhong G(5)(3), Yan Y(6), Zhang Y(5)(3), Chu X(5)(7)(3), Ke J(1)(3).

Once bone metastasis occurs in lung cancer, the efficiency of treatment can be greatly reduced. Current mainstream treatments are focused on inhibiting cancer cell growth and preventing bone destruction. Microwave ablation (MWA) has been used to treat bone tumors. However, MWA may damage the surrounding normal tissues. Therefore, it could be beneficial to develop a nanocarrier combined with microwave to treat bone metastasis. Herein, a microwave-responsive nanoplatform (MgFe2O4@ZOL) was constructed. MgFe2O4@ZOL NPs release the cargos of Fe3+, Mg2+ and zoledronic acid (ZOL) in the acidic tumor microenvironment (TME). Fe3+ can deplete intracellular glutathione (GSH) and catalyze H2O2 to generate •OH, resulting in chemodynamic therapy (CDT). In addition, the microwave can significantly enhance the production of reactive oxygen species (ROS), thereby enabling the effective implementation of microwave dynamic therapy (MDT). Moreover, Mg2+ and ZOL promote osteoblast differentiation. In addition, MgFe2O4@ZOL NPs could target and selectively heat tumor tissue and enhance the effect of microwave thermal therapy (MTT). Both in vitro and in vivo experiments revealed that synergistic targeting, GSH depletion-enhanced CDT, MDT, and selective MTT exhibited significant antitumor efficacy and bone repair. This multimodal combination therapy provides a promising strategy for the treatment of bone metastasis in lung cancer patients.

30. Nat Microbiol. 2024 Sep 6. doi: 10.1038/s41564-024-01797-5. Online ahead of print.

PMID: 39242815

Mycobacterium tuberculosis virulence lipid PDIM inhibits autophagy in mice.

Mittal E(1), Prasad GVRK(2)(3), Upadhyay S(2)(3), Sadadiwala J(2)(3), Olive AJ(4), Yang G(2)(3), Sassetti CM(4), Philips JA(5)(6).

Mycobacterium tuberculosis (Mtb) infects several lung macrophage populations, which have distinct abilities to restrict Mtb. What enables Mtb survival in certain macrophage populations is not well understood. Here we used transposon sequencing analysis of Mtb in wild-type and autophagy-deficient mouse macrophages lacking ATG5 or ATG7, and found that Mtb genes involved in phthiocerol dimycocerosate (PDIM) virulence lipid synthesis confer resistance to autophagy. Using ppsD mutant Mtb, we found that PDIM inhibits LC3-associated phagocytosis (LAP) by inhibiting phagosome recruitment of NADPH oxidase. In mice, PDIM protected Mtb from LAP and classical autophagy. During acute infection, PDIM was dispensable for Mtb survival in alveolar macrophages but required for survival in non-alveolar macrophages in an autophagy-dependent manner. During chronic infection, autophagy-deficient mice succumbed to infection with PDIM-deficient Mtb, with impairments in B-cell accumulation in lymphoid follicles. These findings demonstrate that PDIM contributes to Mtb virulence and immune evasion, revealing a contributory role for autophagy in B-cell responses.

31. Nat Commun. 2024 Sep 25;15(1):8146. doi: 10.1038/s41467-024-52324-3.

PMID: 39322643 [Indexed for MEDLINE]

Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade.

Anastasiou P(1), Moore C(1), Rana S(1), Tomaschko M(1), Pillsbury CE(1), de Castro A(1), Boumelha J(1), Mugarza E(1), de Carné Trécesson S(1), Mikolajczak A(2), Blaj C(3), Goldstone R(4), Smith JAM(3), Quintana E(3), Molina-Arcas M(5), Downward J(6).

Mutant selective drugs targeting the inactive, GDP-bound form of KRASG12C have been approved for use in lung cancer, but resistance develops rapidly. Here we use an inhibitor, (RMC-4998) that targets RASG12C in its active, GTP-bound form, to treat KRAS mutant lung cancer in various immune competent mouse models. RAS pathway reactivation after RMC-4998 treatment could be delayed using combined treatment with a SHP2 inhibitor, which not only impacts tumour cell RAS signalling but also remodels the tumour microenvironment to be less immunosuppressive. In an immune inflamed model, RAS and SHP2 inhibitors in combination drive durable responses by suppressing tumour relapse and inducing development of immune memory. In an immune excluded model, combined RAS and SHP2 inhibition sensitises tumours to immune checkpoint blockade, leading to efficient tumour immune rejection. These preclinical results demonstrate the potential of the combination of RAS(ON) G12C-selective inhibitors with SHP2 inhibitors to sensitize tumours to immune checkpoint blockade.

32. Mol Cell. 2024 Sep 14:S1097-2765(24)00731-7. doi: 10.1016/j.molcel.2024.08.035.

Online ahead of print.

PMID: 39321805

Hydrogen sulfide-mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small cell lung cancer.

Zheng H(1), Chen H(1), Cai Y(1), Shen M(1), Li X(1), Han Y(1), Deng X(1), Cao H(2), Liu J(1), Li H(1), Liu B(1), Li G(3), Wang X(1), Chen H(1), Hou J(4), Lin SH(5), Zong L(3), Zhang Y(6).

Hydrogen sulfide (H₂S), a metabolite of the transsulfuration pathway, has been implicated in ferroptosis, a unique form of cell death caused by lipid peroxidation. While the exact mechanisms controlling ferroptosis remain unclear, our study reveals that H₂S sensitizes human non-small cell lung cancer (NSCLC) cells to this process, particularly when cysteine levels are low. Combining H₂S with cystine depletion significantly enhances the effectiveness of ferroptosis-based cancer therapy. Mechanistically, H₂S persulfidates the 195th cysteine on S-adenosyl homocysteine hydrolase (SAHH), reducing its enzymatic activity. This leads to decreased homocysteine levels, subsequently lowering cysteine and glutathione concentrations under cystine depletion conditions. These changes ultimately increase the vulnerability of NSCLC cells to ferroptosis. Our findings establish H₂S as a key regulator of homocysteine metabolism and a critical factor in determining NSCLC cell susceptibility to ferroptosis. These results highlight the potential of H₂S-based therapies to improve the efficacy of ferroptosis-targeted cancer treatments for NSCLC.

33. Autophagy. 2024 Sep 11:1-17. doi: 10.1080/15548627.2024.2395134. Online ahead of print.

PMID: 39178916

USP8 promotes intracellular infection by enhancing ESCRT-mediated membrane repair, limiting xenophagy, and reducing oxidative stress.

Chandra P(1), Philips JA(1)(2).

The host ESCRT-machinery repairs damaged endolysosomal membranes. If damage persists, selective macroautophagy/autophagy clears the damaged compartment. Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that damages the phagosomal membrane and targets ESCRT-mediated repair as part of its virulence program. The E3 ubiquitin ligases PRKN and SMURF1 promote autophagic capture of damaged, Mtb-containing phagosomes. Because ubiquitination is a reversible process, we anticipated that host deubiquitinases (DUBs) would also be involved. Here, we screened all predicted mouse DUBs for their role in ubiquitin targeting and control of intracellular Mtb. We show that USP8 (ubiquitin specific peptidase 8) colocalizes with intracellular Mtb, recognizes phagosomal membrane damage, and is required for ESCRT-dependent membrane repair. Furthermore, we show that USP8 regulates the NFE2L2/NRF2-dependent antioxidant signature. Taken together, our study demonstrates a central role of USP8 in promoting Mtb intracellular growth by promoting phagosomal membrane repair, limiting ubiquitin-driven selective autophagy, and reducing oxidative stress.Abbreviation: BMDMs: bone marrow-derived macrophages; CFUs: colony-forming units; DUB: deubiquitinase; ESCRT: endosomal sorting complexes required for transport; LLOMe: L-leucyl-L-leucine methyl ester; MFI: mean fluorescence intensity; MOI: multiplicity of infection; Mtb: Mycobacterium tuberculosis; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; PMA: phorbol 12-myristate 13-acetate; ROS: reactive oxygen species; USP8: ubiquitin specific peptidase 8.

34. Bioact Mater. 2024 May 21;39:191-205. doi: 10.1016/j.bioactmat.2024.05.017. eCollection 2024 Sep.

PMID: 38808157

A DNA tetrahedron-based nanosuit for efficient delivery of amifostine and multi-organ radioprotection.

Yang Y(1)(2), Yang J(3), Zhu J(4), Chen X(1)(2), Zhou L(5), Ma W(1)(2), Lin Y(1)(2)(6).

Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages to normal cells and organs, leading to serious physiological and even life-threatening consequences. Amifostine (AMF) is a validated radioprotectant extensively applied in radiation and chemotherapy medicine, but the short half-life limits its bioavailability and clinical applications, remaining as a great challenge to be addressed. DNA-assembled nanostructures especially the tetrahedral framework nucleic acids (tFNAs) are promising nanocarriers with preeminent biosafety, low biotoxicity, and high transport efficiency. The tFNAs also have a relative long-term maintenance for structural stability and excellent endocytosis capacity. We therefore synthesized a tFNA-based delivery system of AMF for multi-organ radioprotection (tFNAs@AMF, also termed nanosuit). By establishing the mice models of accidental total body irradiation (TBI) and radiotherapy model of Lewis lung cancer, we demonstrated that the nanosuit could shield normal cells from IR-induced DNA damage by regulating the molecular biomarkers of anti-apoptosis and anti-oxidative stress. In the accidental total body irradiation (TBI) mice model, the nanosuit pretreated mice exhibited satisfactory alteration of superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents, and functional recovery of hematopoietic system, reducing IR-induced pathological damages of multi-organ and safeguarding mice from lethal radiation. More importantly, the nanosuit showed a selective radioprotection of the normal organs without interferences of tumor control in the radiotherapy model of Lewis lung cancer. Based on a conveniently available DNA tetrahedron-based nanocarrier, this work presents a high-efficiency delivery system of AMF with the prolonged half-life and enhanced radioprotection for multi-organs. Such nanosuit pioneers a promising strategy with great clinical translation potential for radioactivity protection.

35 Adv Sci (Weinh). 2024 Sep;11(35): e2310126. doi: 10.1002/advs.202310126. Epub 2024 Jul 23.

PMID: 39044361 [Indexed for MEDLINE]

Targeting Transient Receptor Potential Melastatin-2 (TRPM2) Enhances Therapeutic Efficacy of Third Generation EGFR Inhibitors against EGFR Mutant Lung Cancer.

Chen Z(1), Vallega KA(1), Boda VK(2), Quan Z(3), Wang D(1), Fan S(3), Wang Q(4), Ramalingam SS(1), Li W(2), Sun SY(1).

There is an urgent need to fully understand the biology of third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, and to develop mechanism-driven strategies to manage their acquired resistance. Transient receptor potential melastatin-2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR-TKIs and acquired resistance to EGFR-TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR-TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy-optimized TRPM2 inhibitors.

36. Mol Cancer. 2024 Sep 6;23(1):187. doi: 10.1186/s12943-024-02098-5.

PMID: 39242519 [Indexed for MEDLINE]

Acyl-coenzyme a binding protein (ACBP) - a risk factor for cancer diagnosis and an inhibitor of immunosurveillance.

Montégut L(1)(2)(3), Liu P(1)(2), Zhao L(1)(2), Pérez-Lanzón M(1)(2), Chen H(1)(2)(3), Mao M(1)(2), Zhang S(1)(2)(4), Derosa L(3)(5), Naour JL(1)(2)(3), Lambertucci F(1)(2), Mingoia S(1)(6), Nogueira-Recalde U(1)(2)(7), Mena-Osuna R(8), Herranz-Montoya I(9), Djouder N(9), Baulande S(10), Pan H(1)(2)(3)

BACKGROUND: The plasma concentrations of acyl coenzyme A binding protein (ACBP, also known as diazepam-binding inhibitor, DBI, or 'endozepine') increase with age and obesity, two parameters that are also amongst the most important risk factors for cancer.

METHODS: We measured ACBP/DBI in the plasma from cancer-free individuals, high-risk patients like the carriers of TP53 or BRCA1/2 mutations, and non-syndromic healthy subjects who later developed cancer. In mice, the neutralization of ACBP/DBI was used in models of non-small cell lung cancer (NSCLC) and breast cancer development and as a combination treatment with chemoimmunotherapy (chemotherapy + PD-1 blockade) in the context of NSCLC and sarcomas. The anticancer T cell response upon ACBP/DBI neutralization was characterized by flow cytometry and single-cell RNA sequencing.

RESULTS: Circulating levels of ACBP/DBI were higher in patients with genetic cancer predisposition (BRCA1/2 or TP53 germline mutations) than in matched controls. In non-syndromic cases, high ACBP/DBI levels were predictive of future cancer development, and especially elevated in patients who later developed lung cancer. In preclinical models, ACBP/DBI neutralization slowed down breast cancer and NSCLC development and enhanced the efficacy of chemoimmunotherapy in NSCLC and sarcoma models. When combined with chemoimmunotherapy, the neutralizing monoclonal antibody against ACBP/DBI reduced the frequency of regulatory T cells in the tumor bed, modulated the immune checkpoint profile, and increased activation markers.

CONCLUSION: These findings suggest that ACBP/DBI acts as an endogenous immune suppressor. We conclude that elevation of ACBP/DBI constitutes a risk factor for the development of cancer and that ACBP/DBI is an actionable target for improving cancer immunosurveillance.

37. Adv Sci (Weinh). 2024 Sep 5:e2309697. doi: 10.1002/advs.202309697. Online ahead of print.

PMID: 39234811

Targeting Dual Immune Checkpoints PD-L1 and HLA-G by Trispecific T Cell Engager for Treating Heterogeneous Lung Cancer.

Lin YC(1)(2), Chen MC(1), Huang SW(1)(3)(4), Chen Y(5), Ho JH(2)(6)(7)(8), Lin FY(1), Tan XT(1), Chiang HC(2)(9), Huang CC(2)(10), Tu CY(11)(12), Cho DY(1)(3)(13)(14), Chiu SC(1)(2)(3)(13).

Immunotherapy targeting immune checkpoints (ICPs), such as programmed death-ligand-1 (PD-L1), is used as a treatment option for advanced or metastatic non-small cell lung cancer (NSCLC). However, overall response rate to anti-PD-L1 treatment is limited due to antigen heterogeneity and the immune-suppressive tumor microenvironment. Human leukocyte antigen-G (HLA-G), an ICP as well as a neoexpressed tumor-associated antigen, is previously demonstrated to be a beneficial target in combination with anti-PD-L1. In this study, a nanobody-based trispecific T cell engager (Nb-TriTE) is developed, capable of simultaneously binding to T cells, macrophages, and cancer cells while redirecting T cells toward tumor cells expressing PD-L1- and/or HLA-G. Nb-TriTE shows broad spectrum anti-tumor effects in vitro by augmenting cytotoxicity mediated by human peripheral blood mononuclear cells (PBMCs). In a humanized immunodeficient murine NSCLC model, Nb-TriTE exhibits superior anti-cancer potency compared to monoclonal antibodies and bispecific T cell engagers. Nb-TriTE, at the dose with pharmacoactivity, does not induce additional enhancement of circulating cytokines secretion from PMBCs. Nb-TriTE effectively prolongs the survival of mice without obvious adverse events. In conclusion, this study introduces an innovative therapeutic approach to address the challenges of immunotherapy and the tumor microenvironment in NSCLC through utilizing the dual ICP-targeting Nb-TriTE.

38. Drug Resist Updat. 2024 Sep;76:101117. doi: 10.1016/j.drup.2024.101117. Epub 2024 Jul 2.

PMID: 38996549 [Indexed for MEDLINE]

Circulating tumor cells with increasing aneuploidy predict inferior prognosis and therapeutic resistance in small cell lung cancer.

Xie Z(1), Wang Y(1), Chen T(2), Fan W(3), Wei L(4), Liu B(5), Situ X(4), Zhan Q(4), Fu T(4), Tian T(6), Li S(7), He Q(7), Zhou J(7), Wang H(8), Du J(8), Tseng HR(9), Lei Y(10), Tang KJ(11), Ke Z(12).

AIMS: Treatment resistance commonly emerges in small cell lung cancer (SCLC), necessitating the development of novel and effective biomarkers to dynamically assess therapeutic efficacy. This study aims to evaluate the clinical utility of aneuploid circulating tumor cells (CTCs) for risk stratification and treatment response monitoring.

METHODS: A total of 126 SCLC patients (two cohorts) from two independent cancer centers were recruited as the study subjects. Blood samples were collected from these patients and aneuploid CTCs were detected. Aneuploid CTC count (ACC) and aneuploid CTC score (ACS), were used to predict progression-free survival (PFS) and overall survival (OS). The performance of the ACC and the ACS was evaluated by calculating the area under the receiver operating characteristic (ROC) curve (AUC).

RESULTS: Compared to ACC, ACS exhibited superior predictive power for PFS and OS in these 126 patients. Moreover, both univariate and multivariate analyses revealed that ACS was an independent prognostic factor. Dynamic ACS changes reflected treatment response, which is more precise than ACC changes. ACS can be used to assess chemotherapy resistance and is more sensitive than radiological examination (with a median lead time of 2.8 months; P < 0.001). When patients had high ACS levels (> 1.115) at baseline, the combination of immunotherapy and chemotherapy resulted in longer PFS (median PFS, 7.7 months; P = 0.007) and OS (median OS, 16.3 months; P = 0.033) than chemotherapy alone (median PFS, 4.9 months; median OS, 13.6 months).

CONCLUSIONS: ACS could be used as a biomarker for risk stratification, treatment response monitoring, and individualized therapeutic intervention in SCLC patients.

39. J Extracell Vesicles. 2024 Sep;13(9):e12508. doi: 10.1002/jev2.12508.

PMID: 39323378 [Indexed for MEDLINE]

Scalable production of siRNA-encapsulated extracellular vesicles for the inhibition of KRAS-mutant cancer using acoustic shock waves.

Kim HK(1), Choi Y(1), Kim KH(1), Byun Y(1), Kim TH(1), Kim JH(1), An SH(1), Bae D(1), Choi MK(1), Lee M(1), Kang G(2), Chung J(1), Kim SH(1), Kwon K(1)(3).

Extracellular vesicles (EVs) have emerged as a potential delivery vehicle for nucleic-acid-based therapeutics, but challenges related to their large-scale production and cargo-loading efficiency have limited their therapeutic potential. To address these issues, we developed a novel "shock wave extracellular vesicles engineering technology" (SWEET) as a non-genetic, scalable manufacturing strategy that uses shock waves (SWs) to encapsulate siRNAs in EVs. Here, we describe the use of the SWEET platform to load large quantities of KRASG12C-targeting siRNA into small bovine-milk-derived EVs (sBMEVs), with high efficiency. The siRNA-loaded sBMEVs effectively silenced oncogenic KRASG12C expression in cancer cells; they inhibited tumour growth when administered intravenously in a non-small cell lung cancer xenograft mouse model. Our study demonstrates the potential for the SWEET platform to serve as a novel method that allows large-scale production of cargo-loaded EVs for use in a wide range of therapeutic applications.