2023年
No.12
PubMed
(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])
Filters applied: from 2023/12/1 - 2023/12/31.
1. Cell. 2023 Dec 7;186(25):5536-5553.e22. doi: 10.1016/j.cell.2023.11.002. Epub
2023 Nov 28.
Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis.
Kotov DI(1), Lee OV(2), Fattinger SA(2), Langner CA(2), Guillen JV(2), Peters
JM(3), Moon A(4), Burd EM(4), Witt KC(2), Stetson DB(5), Jaye DL(4), Bryson
BD(3), Vance RE(6).
Author information:
(1)Division of Immunology and Molecular Medicine, University of California,
Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University
of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:
dkotov@berkeley.edu.
(2)Division of Immunology and Molecular Medicine, University of California,
Berkeley, Berkeley, CA 94720, USA.
(3)Department of Biological Engineering, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA; Ragon Institute of Mass General, MIT, and Harvard,
Cambridge, MA 02139, USA.
(4)Department of Pathology and Laboratory Medicine, Emory University, Atlanta,
GA 30322, USA.
(5)Department of Immunology, University of Washington, Seattle, WA 98195, USA.
(6)Division of Immunology and Molecular Medicine, University of California,
Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University
of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:
rvance@berkeley.edu.
Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active
tuberculosis correlates with a neutrophil-driven type I interferon (IFN)
signature, but the cellular mechanisms underlying tuberculosis pathogenesis
remain poorly understood. We found that interstitial macrophages (IMs) and
plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN during
Mtb infection in mice and non-human primates, and pDCs localize near human Mtb
granulomas. Depletion of pDCs reduces Mtb burdens, implicating pDCs in
tuberculosis pathogenesis. During IFN-driven disease, we observe abundant
DNA-containing neutrophil extracellular traps (NETs) described to activate pDCs.
Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act
on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates
that type I IFN-responsive cells are defective in their response to IFNγ, a
cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act
on IMs to permit bacterial replication, driving further neutrophil recruitment
and active tuberculosis disease.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2023.11.002
PMCID: PMC10757650
PMID: 38029747 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests R.E.V. consults for
Ventus Therapeutics, Tempest Therapeutics, and X-biotix Therapeutics.
2. J Clin Oncol. 2023 Dec 1;41(34):5274-5284. doi: 10.1200/JCO.23.01372. Epub 2023 Oct 23.
Germline EGFR Mutations and Familial Lung Cancer.
Oxnard GR(1), Chen R(1), Pharr JC(1), Koeller DR(1), Bertram AA(1), Dahlberg
SE(1), Rainville I(1), Shane-Carson K(2), Taylor KA(3), Sable-Hunt A(4), Sholl
LM(5), Teerlink CC(6), Thomas A(7), Cannon-Albright LA(6), Fay AP(8),
Ashton-Prolla P(8), Yang H(9), Salvatore MM(9), Addario BJ(4), Jänne PA(1),
Carbone DP(2), Wiesner GL(3), Garber JE(1).
Author information:
(1)Dana-Farber Cancer Institute, Boston, MA.
(2)Ohio State University Medical Center, Columbus, OH.
(3)Vanderbilt-Ingram Cancer Center, Nashville, TN.
(4)Addario Lung Cancer Medical Institute (ALCMI), San Carlos, CA.
(5)Brigham and Women's Hospital, Boston, MA.
(6)Huntsman Cancer Center, Salt Lake City, UT.
(7)Division of Epidemiology, University of Utah School of Medicine, Salt Lake
City, UT.
(8)PUCRS School of Medicine, Porto Alegre, Brazil.
(9)Columbia University Medical Center, New York, NY.
PURPOSE: The genomic underpinnings of inherited lung cancer risk are poorly
understood. This prospective study characterized the clinical phenotype of
patients and families with germline EGFR pathogenic variants (PVs).
METHODS: The Investigating Hereditary Risk from T790M study (ClinicalTrials.gov
identifier: NCT01754025) enrolled patients with lung cancer whose tumor
profiling harbored possible germline EGFR PVs and their relatives, either in
person or remotely, providing germline testing and follow-up.
RESULTS: A total of 141 participants were enrolled over a 5-year period, 100
(71%) remotely. Based upon previous genotyping, 116 participants from 59
kindreds were tested for EGFR T790M, demonstrating a pattern of Mendelian
inheritance with variable lung cancer penetrance. In confirmed or obligate
carriers of a germline EGFR PV from 39 different kindreds, 50/91 (55%) were
affected with lung cancer with 34/65 (52%) diagnosed by age 60 years. Somatic
testing of lung cancers in carriers revealed that 35 of 37 (95%) had an EGFR
driver comutation. Among 36 germline carriers without a cancer diagnosis, 15 had
computed tomography (CT) imaging and nine had lung nodules, including a
28-year-old with >10 lung nodules. Given geographic enrichment of germline EGFR
T790M in the southeast United States, genome-wide haplotyping of 46 germline
carriers was performed and identified a 4.1-Mb haplotype shared by 41 (89%),
estimated to originate 223-279 years ago.
CONCLUSION: To our knowledge, this is the first prospective description of
familial EGFR-mutant lung cancer, identifying a recent founder germline EGFR
T790M variant enriched in the Southeast United States. The high prevalence of
EGFR-driver lung adenocarcinomas and lung nodules in germline carriers supports
effort to identify affected patients and family members for investigation of
CT-based screening for these high-risk individuals.
DOI: 10.1200/JCO.23.01372
PMID: 37579253 [Indexed for MEDLINE]
3. J Thorac Oncol. 2023 Dec 7:S1556-0864(23)02411-5. doi:
10.1016/j.jtho.2023.12.006. Online ahead of print.
The International Association for the Study of Lung Cancer Lung Cancer Staging
Project: Proposals for the Revisions of the T-Descriptors in the Forthcoming
Ninth Edition of the TNM Classification for Lung Cancer.
Van Schil PE(1), Asamura H(2), Nishimura KK(3), Rami-Porta R(4), Kim YT(5),
Bertoglio P(6), Cangir AK(7), Donington J(8), Fang W(9), Giroux DJ(3), Lievens
Y(10), Liu H(11), Lyons G(12), Sakai S(13), Travis WD(14), Ugalde P(15), Jeffrey
Yang CF(16), Yotsukura M(17), Detterbeck F(18); Members of the International
Association for the Study of Lung Cancer Staging and Prognostic Factors
Committee, Advisory Boards and Participating Institutions.
Author information:
(1)Department of Thoracic and Vascular Surgery, Antwerp University Hospital and
Antwerp University, Antwerp, Belgium. Electronic address: paul.van.schil@uza.be.
(2)Division of Thoracic Surgery, Keio University School of Medicine, Tokyo,
Japan.
(3)Cancer Research And Biostatistics, Seattle, Washington.
(4)Department of Thoracic Surgery, Hospital Universitari Mútua Terrassa,
University of Barcelona; CIBERES Lung Cancer Group, Terrassa, Barcelona, Spain.
(5)Department of Thoracic and Cardiovascular Surgery, Seoul National University
Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
(6)Division of Thoracic Surgery, IRCCS Azienda Ospedaliera-Universitaria di
Bologna, Bologna, Italy.
(7)Faculty of Medicine, Ankara University, Ankara, Turkey.
(8)Department of Surgery, University of Chicago, Chicago, Illinois.
(9)Department of Thoracic Surgery, Shanghai Chest Hospital, Jiaotong University
Medical School, Shanghai, People's Republic of China.
(10)Department of Radiation Oncology, Ghent University Hospital and Ghent
University, Ghent, Belgium.
(11)Sun Yat-Sen University Cancer Center, Guangdong Sheng, People's Republic of
China.
(12)Thoracic Surgery Department, Buenos Aires British Hospital, Buenos Aires,
Argentina.
(13)Department of Diagnostic Imaging and Nuclear Medicine, Tokyo Women's Medical
University, Tokyo, Japan.
(14)Department of Pathology, Memorial Sloan Kettering Cancer Center, New York,
New York.
(15)Department of Thoracic Surgery, Brigham & Women's Hospital, Boston,
Massachusetts.
(16)Division of Thoracic Surgery, Department of Surgery, Massachusetts General
Hospital, Massachusetts.
(17)Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo,
Japan.
(18)Department of Thoracic Surgery, Yale University School of Medicine, New
Haven, Connecticut.
INTRODUCTION: An international database was created by the International
Association for the Study of Lung Cancer to inform on the ninth edition of the
TNM classification of lung cancer. The present analyses concern its T component.
METHODS: Data on 124,581 patients diagnosed with lung cancer from January 1,
2011 to December 31, 2019 were submitted to the International Association for
the Study of Lung Cancer database. Of these, 33,982 met the inclusion criteria
for the clinical T analysis, and 30,715 met the inclusion criteria for the
pathologic postsurgical analysis. Survival was measured from the date of
diagnosis or operation for clinically and pathologically staged tumors,
respectively. T descriptors were evaluated in univariate analysis and
multivariable Cox regression analysis adjusted for age, sex, pathologic type,
and geographic region.
RESULTS: Comprehensive survival analysis revealed that the existing eighth
edition T component criteria performed adequately in the ninth edition data set.
Although pathologic chest wall or parietal pleura involvement (PL 3) yielded a
worse survival compared with the other T3 descriptors, with a similar survival
as T4 tumors, this difference was not observed for clinical chest wall or PL 3
tumors. Because of these inconsistent findings, no reallocation of chest wall or
PL 3 tumors is advised.
CONCLUSIONS: The T subcommittee members proposed not to implement any changes
and keep the current eighth-edition T descriptors for the ninth edition.
Copyright © 2023 International Association for the Study of Lung Cancer.
Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jtho.2023.12.006
PMID: 38070600
4. Adv Sci (Weinh). 2023 Dec 10:e2303904. doi: 10.1002/advs.202303904. Online ahead
of print.
The Interplay Between HIF-1α and EZH2 in Lung Cancer and Dual-Targeted Drug
Therapy.
Wang J(1)(2), Yang C(1)(2), Xu H(3), Fan X(4), Jia L(1)(2), Du Y(3), Liu
S(1)(2), Wang W(1)(2), Zhang J(1)(2), Zhang Y(1)(2), Wang X(1)(2), Liu Z(5), Bao
J(6), Li S(1), Yang J(1)(2), Wu C(1)(2), Tang J(6), Chen G(3), Wang L(1)(2).
Author information:
(1)School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical
University, Shenyang, 110016, P. R. China.
(2)Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical
University, Benxi, 117004, P. R. China.
(3)Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of
Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical
University, Shenyang, 110016, P. R. China.
(4)Department of Pharmacy, Shengjing Hospital of China Medical University,
Shenyang, 110004, P. R. China.
(5)School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, P.
R. China.
(6)Research Program in Systems Oncology, Faculty of Medicine, University of
Helsinki, Helsinki, 00290, Finland.
Interactions between oncogenic proteins contribute to the phenotype and drug
resistance. Here, EZH2 (enhancer of zest homolog 2) is identified as a crucial
factor that mediates HIF-1 (hypoxia-inducible factor) inhibitor resistance.
Mechanistically, targeting HIF-1 enhanced the activity of EZH2 through
transcription activation of SUZ12 (suppressor of zest 12 protein homolog).
Conversely, inhibiting EZH2 increased HIF-1α transcription, but not the
transcription of other HIF family members. Additionally, the negative feedback
regulation between EZH2 and HIF-1α is confirmed in lung cancer patient tissues
and a database of cell lines. Moreover, molecular prediction showed that a newly
screened dual-target compound, DYB-03, forms multiple hydrogen bonds with HIF-1α
and EZH2 to effectively inhibit the activity of both targets. Subsequent studies
revealed that DYB-03 could better inhibit migration, invasion, and angiogenesis
of lung cancer cells and HUVECs in vitro and in vivo compared to single agent.
DYB-03 showed promising antitumor activity in a xenograft tumor model by
promoting apoptosis and inhibiting angiogenesis, which could be almost abolished
by the deletion of HIF-1α and EZH2. Notably, DYB-03 could reverse 2-ME2 and
GSK126-resistance in lung cancer. These findings clarified the molecular
mechanism of cross-regulation of HIF-1α and EZH2, and the potential of DYB-03
for clinical combination target therapy.
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.
DOI: 10.1002/advs.202303904
PMID: 38072662
5. EClinicalMedicine. 2023 Nov 17;66:102332. doi: 10.1016/j.eclinm.2023.102332.
eCollection 2023 Dec.
Beyond latent and active tuberculosis: a scoping review of conceptual
frameworks.
Zaidi SMA(1)(2)(3), Coussens AK(4)(5)(6), Seddon JA(7)(8), Kredo T(9), Warner
D(6)(10), Houben RMGJ(11), Esmail H(1)(2)(6).
Author information:
(1)WHO Centre for Tuberculosis Research and Innovation, Institute for Global
Health, University College London, UK.
(2)MRC Clinical Trials Unit at University College London, UK.
(3)Department of Public Health, National University of Medical Sciences,
Pakistan.
(4)Division of Infectious Diseases and Immune Defence, Walter and Eliza Hall
Institute of Medical Research, Australia.
(5)Department of Medical Biology, University of Melbourne, Australia.
(6)Centre for Infectious Diseases Research in Africa, Institute of Infectious
Disease and Molecular Medicine, University of Cape Town, South Africa.
(7)Department of Infectious Disease, Imperial College London, UK.
(8)Desmond Tutu TB Centre, Department of Paediatrics and Child Health,
Stellenbosch University, South Africa.
(9)Health Systems Research Unit, South African Medical Research Council, Cape
Town, South Africa.
(10)Molecular Mycobacteriology Research Unit and Division of Medical
Microbiology, Department of Pathology, University of Cape Town, South Africa.
(11)TB Modelling Group, TB Centre, London School of Hygiene and Tropical
Medicine, UK.
There is growing recognition that tuberculosis (TB) infection and disease exists
as a spectrum of states beyond the current binary classification of latent and
active TB. Our aim was to systematically map and synthesize published conceptual
frameworks for TB states. We searched MEDLINE, Embase and EMcare for review
articles from 1946 to September 2023. We included 40 articles that explicitly
described greater than two states for TB. We identified that terminology,
definitions and diagnostic criteria for additional TB states within these
articles were inconsistent. Eight broad conceptual themes were identified that
were used to categorize TB states: State 0: Mycobacterium tuberculosis (Mtb)
elimination with innate immune response (n = 25/40, 63%); State I: Mtb
elimination by acquired immune response (n = 31/40, 78%); State II: Mtb
infection not eliminated but controlled (n = 37/40, 93%); State III: Mtb
infection not controlled (n = 24/40, 60%); State IV: bacteriologically positive
without symptoms (n = 26/40, 65%); State V: signs or symptoms associated with TB
(n = 39/40, 98%); State VI: severe or disseminated TB disease (n = 11/40, 28%);
and State VII: previous history of TB (n = 5/40, 13%). Consensus on a non-binary
framework that includes additional TB states is required to standardize
scientific communication and to inform advancements in research, clinical and
public health practice.
© 2023 The Author(s).
DOI: 10.1016/j.eclinm.2023.102332
PMCID: PMC10772263
PMID: 38192591
Conflict of interest statement: AKC received funding from the Center for
Infectious Diseases Research in Africa (CIDRI-Africa), National Institutes of
Health and the Bill and Melinda Gates Foundation to support the 1st
International Symposium on New Concepts in Early TB. DW has received funding
from National Institutes of Health, South African Medical Research Council, Bill
& Melinda Gates Foundation and Research Council of Norway. HE is a Data Safety
Monitoring Board member for the StatinTB Trial.
6. J Am Acad Dermatol. 2023 Dec;89(6):1091-1103. doi: 10.1016/j.jaad.2021.12.063.
Epub 2022 Feb 8.
Cutaneous tuberculosis. Part I: Pathogenesis, classification, and clinical features.
Kaul S(1), Kaur I(2), Mehta S(3), Singal A(4).
Author information:
(1)Department of Internal Medicine, John H Stroger Hospital of Cook County,
Chicago, Illinois.
(2)Dermosphere Clinic, New Delhi, India.
(3)Division of Dermatology, John H Stroger Hospital of Cook County, Chicago,
Illinois. Electronic address: shilpaderm@gmail.com.
(4)Department of Dermatology, University College of Medical Sciences & GTB
Hospital, Delhi, India.
Tuberculosis is an ancient disease that continues to affect an estimated 10
million people per year and is responsible for 1.4 million deaths per year.
Additionally, the HIV epidemic and multidrug resistance present challenges to
disease control. Cutaneous tuberculosis is an uncommon, often indolent,
manifestation of mycobacterial infection that has a varied presentation. Its
diagnosis is challenging, as lesions mimic other, more common conditions and
microbiological confirmation is often not possible. Cutaneous tuberculosis can
be broadly categorized into multibacillary and paucibacillary forms.
Approximately one-third of skin tuberculosis is associated with systemic
involvement. By recognizing cutaneous tuberculosis early, dermatologists can
play an important role in disease control. The first article in this 2-part
continuing medical education series describes the latest epidemiology,
microbiology, and pathogenesis of tuberculosis. Furthermore, we review the
classification, clinical manifestations, common clinical differentials, and
systemic involvement that occur in cutaneous tuberculosis.
Published by Elsevier Inc.
DOI: 10.1016/j.jaad.2021.12.063
PMID: 35149149 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of interest None disclosed.
7. Cell Death Differ. 2023 Dec;30(12):2477-2490. doi: 10.1038/s41418-023-01234-w.
Epub 2023 Oct 30.
YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent
ferroptosis suppression in lung cancer.
Yuan S(#)(1), Xi S(#)(1), Weng H(#)(1), Guo MM(1), Zhang JH(1), Yu ZP(1), Zhang
H(2), Yu Z(3), Xing Z(2), Liu MY(1), Ming DJ(1), Sah RK(2), Zhou Y(2), Li G(4),
Zeng T(3), Hong X(2)(5), Li Y(6), Zeng XT(7), Hu H(8)(9).
Author information:
(1)Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of
Wuhan University, Wuhan, China.
(2)Department of Biochemistry, School of Medicine, Southern University of
Science and Technology, Shenzhen, China.
(3)Department of Urology, The Second Affiliated Hospital of Nanchang University,
Nanchang, China.
(4)Cancer Center, Faculty of Health Sciences, MoE Frontier Science Center for
Precision Oncology, University of Macau, Taipa, Macau, SAR, China.
(5)Key University Laboratory of Metabolism and Health of Guangdong, Southern
University of Science and Technology, Shenzhen, China.
(6)Department of Epidemiology, College of Preventive Medicine, Army Medical
University, Chongqing, China. liyafei2008@hotmail.com.
(7)Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of
Wuhan University, Wuhan, China. zengxiantao1128@whu.edu.cn.
(8)Department of Biochemistry, School of Medicine, Southern University of
Science and Technology, Shenzhen, China. huhl@sustech.edu.cn.
(9)Key University Laboratory of Metabolism and Health of Guangdong, Southern
University of Science and Technology, Shenzhen, China. huhl@sustech.edu.cn.
(#)Contributed equally
Ferroptosis is a regulated cell death process initiated by iron-dependent
phospholipid peroxidation and is mainly suppressed by GPX4-dependent and
FSP1-dependent surveillance mechanisms. However, how the ferroptosis
surveillance system is regulated during cancer development remains largely
unknown. Here, we report that the YTHDC1-mediated m6A epigenetic regulation of
FSP1 alleviates the FSP1-dependent ferroptosis suppression that partially
contributes to the tumor suppressive role of YTHDC1 in lung cancer progression.
YTHDC1 knockdown promoted the lung tumor progression and upregulated FSP1
protein level that resulted in ferroptosis resistance of lung cancer cells.
Silencing FSP1 abrogated YTHDC1 knockdown-induced proliferation increase and
ferroptosis resistance. Mechanistically, YTHDC1 binding to the m6A sites in the
FSP1 3'-UTR recruited the alternative polyadenylation regulator CSTF3 to
generate a less stable shorter 3'-UTR contained FSP1 mRNA, whereas YTHDC1
downregulation generated the longer 3'-UTR contained FSP1 mRNA that is
stabilized by RNA binding protein HuR and thus led to the enhanced FSP1 protein
level. Therefore, our findings identify YTHDC1 as a tumor progression suppressor
in lung cancer and a ferroptosis regulator through modulating the FSP1 mRNA
stability and thus suggest a ferroptosis-related therapeutic option for
YTHDC1high lung cancer.
© 2023. The Author(s), under exclusive licence to ADMC Associazione
Differenziamento e Morte Cellulare.
DOI: 10.1038/s41418-023-01234-w
PMCID: PMC10733405
PMID: 37903990 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
8. J Am Acad Dermatol. 2023 Dec;89(6):1107-1119. doi: 10.1016/j.jaad.2021.12.064.
Epub 2022 Feb 8.
Cutaneous tuberculosis. Part II: Complications, diagnostic workup,
histopathologic features, and treatment.
Kaul S(1), Jakhar D(2), Mehta S(3), Singal A(4).
Author information:
(1)Department of Internal Medicine, John H Stroger Hospital of Cook County,
Chicago, Illinois.
(2)Dermosphere Clinic, New Delhi, India.
(3)Division of Dermatology, John H Stroger Hospital of Cook County, Chicago,
Illinois. Electronic address: shilpaderm@gmail.com.
(4)Department of Dermatology, University College of Medical Sciences & GTB
Hospital, Delhi, India.
Despite the availability of effective treatment regimens for cutaneous
tuberculosis, challenges to disease control result from delayed diagnosis,
infection with multidrug-resistant mycobacterial strains, and coinfection with
HIV. Delayed diagnosis can be mitigated when dermatologists are sensitized to
the clinical signs and symptoms of infection and by the incorporation of
appropriate diagnostic tests. All cases of cutaneous tuberculosis should be
confirmed with histopathology and culture with or without molecular testing. In
each case, a thorough evaluation for systemic involvement is necessary.
Mycobacteria may not be isolated from cutaneous tuberculosis lesions and
therefore, a trial of antituberculosis treatment may be required to confirm the
diagnosis. The second article in this 2-part continuing medical education series
describes the sequelae, histopathology, and treatment of tuberculosis.
Published by Elsevier Inc.
DOI: 10.1016/j.jaad.2021.12.064
PMID: 35149148 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of interest The authors have no
conflicts of interest to disclose.
9. JAMA Netw Open. 2023 Dec 1;6(12):e2347176. doi:
10.1001/jamanetworkopen.2023.47176.
Opportunistic Screening With Low-Dose Computed Tomography and Lung Cancer
Mortality in China.
Wang L(1)(2)(3), Qi Y(4), Liu A(5), Guo X(6), Sun S(4), Zhang L(7), Ji H(8), Liu
G(9), Zhao H(4), Jiang Y(10), Li J(10), Song C(7), Yu X(4), Yang L(7), Yu J(9),
Feng H(4), Yang F(4), Xue F(1)(2)(11).
Author information:
(1)Department of Biostatistics, School of Public Health, Cheeloo College of
Medicine, Shandong University, Jinan, China.
(2)Healthcare Big Data Research Institute, School of Public Health, Cheeloo
College of Medicine, Shandong University, Jinan, China.
(3)Department of Endocrinology, Shandong Provincial Hospital Affiliated to
Shandong First Medical University, Jinan, China.
(4)Department of Oncology, Weihai Municipal Hospital, Cheeloo College of
Medicine, Shandong University, Weihai, China.
(5)Department of Pulmonary and Critical Care Medicine, Weihai Municipal
Hospital, Cheeloo College of Medicine, Shandong University, Weihai, China.
(6)Department for Chronic and Non-Communicable Disease Control and Prevention,
Shandong Center for Disease Control and Prevention, Jinan, China.
(7)Department of Chemotherapy, Weihai Municipal Hospital, Cheeloo College of
Medicine, Shandong University, Weihai, China.
(8)Department of Thoracic Surgery, Weihai Municipal Hospital, Cheeloo College of
Medicine, Shandong University, Weihai, China.
(9)Department of Radiology, Weihai Municipal Hospital, Cheeloo College of
Medicine, Shandong University, Weihai, China.
(10)Department of Radiotherapy, Weihai Municipal Hospital, Cheeloo College of
Medicine, Shandong University, Weihai, China.
(11)Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan,
China.
IMPORTANCE: Despite the recommendations of lung cancer screening guidelines and
the evidence supporting the effectiveness of population-based lung screening, a
common barrier to effective lung cancer screening is that the participation
rates of low-dose computed tomography (LDCT) screening among individuals with
the highest risk are not large. There are limited data from clinical practice
regarding whether opportunistic LDCT screening is associated with reduced
lung-cancer mortality.
OBJECTIVE: To evaluate whether opportunistic LDCT screening is associated with
improved prognosis among adults with lung cancer in mainland China.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study included patients diagnosed
with lung cancer at Weihai Municipal Hospital Healthcare Group, Weihai City,
China, from 2016 to 2021. Data were analyzed from January 2022 to February 2023.
EXPOSURES: Data collected included demographic indicators, tumor
characteristics, comorbidities, blood indexes, and treatment information.
Patients were classified into screened and nonscreened groups on the basis of
whether or not their lung cancer diagnosis occurred through opportunistic
screening.
MAIN OUTCOMES AND MEASURES: Follow-up outcome indicators included lung
cancer-specific mortality and all-cause mortality. Propensity score matching
(PSM) was adopted to account for potential imbalanced factors between groups.
The associations between LDCT screening and outcomes were analyzed using Cox
regression models based on the matched data. Propensity score regression
adjustment and inverse probability treatment weighting were used for sensitivity
analysis.
RESULTS: A total of 5234 patients (mean [SD] baseline age, 61.8 [9.8] years;
2518 [48.1%] female) with complete opportunistic screening information were
included in the analytical sample, with 2251 patients (42.91%) receiving their
lung cancer diagnosis through opportunistic screening. After 1:1 PSM, 2788
patients (1394 in each group) were finally included. The baseline
characteristics of the matched patients were balanced between groups.
Opportunistic screening with LDCT was associated with a 49% lower risk of lung
cancer death (HR, 0.51; 95% CI, 0.42-0.62) and 46% lower risk of all-cause death
(HR, 0.54; 95% CI, 0.45-0.64).
CONCLUSIONS AND RELEVANCE: In this cohort study of patients with lung cancer,
opportunistic lung cancer screening with LDCT was associated with lower lung
cancer mortality and all-cause mortality. These findings suggest that
opportunistic screening is an important supplement to population screening to
improve prognosis of adults with lung cancer.
DOI: 10.1001/jamanetworkopen.2023.47176
PMCID: PMC10716726
PMID: 38085543 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest Disclosures: None reported.
10. Emerg Microbes Infect. 2023 Dec;12(1):2178243. doi:
10.1080/22221751.2023.2178243.
Designing molecular diagnostics for current tuberculosis drug regimens.
Georghiou SB(1), de Vos M(1), Velen K(1), Miotto P(2), Colman RE(1)(3), Cirillo
DM(2), Ismail N(4), Rodwell TC(1)(3), Suresh A(1), Ruhwald M(1).
Author information:
(1)FIND, the Global Alliance for Diagnostics, Geneva, Switzerland.
(2)IRCCS San Raffaele Scientific Institute, Milan, Italy.
(3)Department of Medicine, University of California, San Diego, La Jolla, CA,
USA.
(4)World Health Organization, Geneva, Switzerland.
Diagnostic development must occur in parallel with drug development to ensure
the longevity of new treatment compounds. Despite an increasing number of novel
and repurposed anti-tuberculosis compounds and regimens, there remains a large
number of drugs for which no rapid and accurate molecular diagnostic option
exists. The lack of rapid drug susceptibility testing for linezolid,
bedaquiline, clofazimine, the nitroimidazoles (i.e pretomanid and delamanid) and
pyrazinamide at any level of the healthcare system compromises the effectiveness
of current tuberculosis and drug-resistant tuberculosis treatment regimens. In
the context of current WHO tuberculosis treatment guidelines as well as
promising new regimens, we identify the key diagnostic gaps for initial and
follow-on tests to diagnose emerging drug resistance and aid in regimen
selection. Additionally, we comment on potential gene targets for inclusion in
rapid molecular drug susceptibility assays and sequencing assays for novel and
repurposed drug compounds currently prioritized in current regimens, and
evaluate the feasibility of mutation detection given the design of existing
technologies. Based on current knowledge, we also propose design priorities for
next generation molecular assays to support triage of tuberculosis patients to
appropriate and effective treatment regimens. We encourage assay developers to
prioritize development of these key molecular assays and support the continued
evolution, uptake, and utility of sequencing to build knowledge of tuberculosis
resistance mechanisms and further inform rapid treatment decisions in order to
curb resistance to critical drugs in current regimens and achieve End TB
targets.Trial registration: ClinicalTrials.gov identifier: NCT05117788..
DOI: 10.1080/22221751.2023.2178243
PMCID: PMC9980415
PMID: 36752055 [Indexed for MEDLINE]
Conflict of interest statement: SBG, MdV, KV, REC, TCR, AS and MR are
consultants or employees of FIND, the global alliance for diagnostics, a
not-for-profit foundation that supports the evaluation of publicly prioritized
TB assays and the implementation of WHO-approved (guidance and prequalification)
assays using donor grants. FIND has product evaluation agreements with several
private sector companies that design diagnostics for TB and other diseases.
These agreements strictly define FIND’s independence and neutrality with regard
to these private sector companies. MR, PM and DMC are members of the NDWG StopTB
Partnership. TCR is a cofounder, board member, and shareholder of Verus
Diagnostics, a company that was founded with the intent of developing diagnostic
assays. Verus Diagnostics was not involved in any way with data collection,
analysis or publication of the results, and TCR has not received any financial
support from Verus Diagnostics. University of California, San Diego (UCSD)
Conflict of Interest office has reviewed and approved TCR’s role in Verus
Diagnostics. TCR is a coinventor of a provisional patent for a TB diagnostic
assay (provisional patent 63/048.989). TCR is also a coinventor on a patent
associated with the processing of TB sequencing data (European Patent
Application No. 14840432.0 & USSN 14/912,918), and has agreed to “donate all
present and future interest in and rights to royalties from this patent” to UCSD
to ensure that he does not receive any financial benefits from this patent.
11. Cancer Res. 2023 Dec 20. doi: 10.1158/0008-5472.CAN-23-0900. Online ahead of
print.
CYP2A6 activity and cigarette consumption interact in smoking-related lung
cancer susceptibility.
Du M(1), Xin J(2), Zheng R(3), Yuan Q(4), Wang Z(5), Liu H(6), Liu H(2), Cai
G(7), Albanes D(8), Lam S(9), Tardon A(10), Chen C(11), Bojesen SE(12), Landi
MT(13), Johansson M(14), Risch A(15), Bickeböller H(16), Wichmann HE(17),
Rennert G(18), Arnold S(19), Brennan P(14), Field JK(20), Shete SS(21), Le
Marchand L(22), Liu G(23), Andrew AS(24), Kiemeney LA(25), Zienolddiny S(26),
Grankvist K(27), Johansson M(27), Caporaso NE(28), Cox A(29), Hong YC(30), Yuan
JM(31), Schabath MB(32), Aldrich MC(33), Wang M(2), Shen H(34), Chen F(35),
Zhang Z(2), Hung RJ(36), Amos CI(37), Wei Q(38), Lazarus P(39), Christiani
DC(5).
Author information:
(1)Harvard University, Boston, United States.
(2)Nanjing Medical University, Nanjing, China.
(3)Nanjing Medical University, China.
(4)Harvard T.H. Chan School of Public Health, Boston, MA, United States.
(5)Harvard School of Public Health, Boston, MA, United States.
(6)Duke University School of Medicine, Durham, NC, United States.
(7)University of South Carolina, Columbia, United States.
(8)National Cancer Institute, Bethesda, MD, United States.
(9)British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
(10)Universidad de Oviedo, Public Health Department, Oviedo, Asturias, Spain.
(11)Fred Hutchinson Cancer Center, Seattle, WA, United States.
(12)Copenhagen University Hospital and University of Copenhagen, Herlev,
Denmark.
(13)National Cancer Institute, National Institutes of Health, DHHS, Bethesda,
MD, United States.
(14)International Agency For Research On Cancer, Lyon, France.
(15)University of Salzburg, Salzburg, Austria.
(16)University Medical Center, Georg-August-University Göttingen, Göttingen,
Germany.
(17)Institute of Epidemiology, Germany.
(18)Carmel Medical Center, Haifa, Israel.
(19)University of Kentucky, Lexington, KY, United States.
(20)University of Liverpool, Liverpool UK, United Kingdom.
(21)The University of Texas MD Anderson Cancer Center, Houston, TX, United
States.
(22)University of Hawaii Cancer Center, Honolulu, Hawaii, United States.
(23)Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
(24)Geisel School of Medicine at Dartmouth, Lebanon, NH, United States.
(25)Radboud University Medical Centre, Nijmegen, Netherlands.
(26)National Institute of Occupational Health, Oslo, Oslo, Norway.
(27)Umeå University, Umea, Sweden.
(28)National Cancer Institute, Rockville, MD, United States.
(29)University of Sheffield, Sheffield, United Kingdom.
(30)Seoul National University College of Medicine, Seoul, Korea (South),
Republic of.
(31)UPMC Hillman Cancer Center, Pittsburgh, PA, United States.
(32)H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
(33)Vanderbilt University Medical Center, Nashville, United States.
(34)Nanjing Medical University, Nanjing, jiangsu, China.
(35)School of Public Health (SPH), Nanjing Medical University, Nanjing, Jiangsu,
China.
(36)Sinai Health System, Toronto, Canada.
(37)Baylor College of Medicine, Houston, TX, United States.
(38)Duke University Medical Center, Durham, NC, United States.
(39)College of Pharmacy and Pharmaceutical Sciences, Washington State
University, Spokane, Washington, United States.
Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer.
However, not all smokers develop lung cancer, highlighting the importance of the
interaction between host susceptibility and environmental exposure in
tumorigenesis. Here, we aimed to delineate the interaction between metabolizing
ability of tobacco carcinogens and smoking intensity in mediating genetic
susceptibility to smoking-related lung tumorigenesis. Single-variant and
gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung
cancer were analyzed using summary statistics and individual-level genetic data,
followed by causal inference of Mendelian randomization, mediation analysis, and
structural equation modeling. Cigarette smoke-exposed cell models were used to
detect gene expression patterns in relation to specific alleles. Data from the
International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK
Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant
rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with
decreased lung cancer risk among smokers [odds ratio (OR) = 0.88, 95% confidence
interval = 0.85-0.91, P = 2.18×10-16], which might interact (Pinteraction =
0.028) with and partially be mediated (ORindirect = 0.987) by smoking status.
Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung
cancer risk but entirely mediated the genetic effect of rs56113850.
Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6
caused by cigarette smoke exposure, potentially through preferential recruitment
of transcription factor HLTF. Together, this study provides additional insights
into the interplay between host susceptibility and carcinogen exposure in
smoking-related lung tumorigenesis.
DOI: 10.1158/0008-5472.CAN-23-0900
PMID: 38117513
12. Cancer Res. 2023 Dec 21:OF1-OF2. doi: 10.1158/0008-5472.CAN-23-3929. Online
ahead of print.
Harnessing p53 to Improve Immunotherapy for Lung Cancer Treatment.
Niu X(1), Martinez L(2).
Author information:
(1)Department of Pathology, Stony Brook University, Stony Brook, New York.
(2)Stony Brook Cancer Center, Department of Pathology, Renaissance School of
Medicine, Stony Brook University, Stony Brook, New York.
Immunotherapy, especially immune checkpoint blockade (ICB), has become a
critical therapy for lung cancer treatment in recent years. Tumor mutational
burden (TMB) is one of the decisive biomarkers for predicting ICB effect.
Writing in Cancer Cell, Zhu and colleagues use autochthonous and syngeneic mouse
models to show that p53 mutation and tumor heterogeneity may be responsible for
resistance in patients with lung cancer. Pole-induced high TMB shows enhanced
immunogenicity in KrasG12D mice, however, loss of p53 in KrasG12D PoleP286/+
mice can lead to an immune suppressive profile of lung tumors, which diminishes
immune response to ICB. Moreover, high TMB causes high shared mutations, which
helps promote immune protection and immune memory. Heterogeneity can drive
immune escape to tumor cells causing resistance to ICB. Decreased cGAS/STING
signaling may explain possible resistance to ICB. On the basis of the new model
found by Zhu and colleagues for lung cancer, combined ICB with STING agonists or
p53 inducers may be new therapeutic options to improve the efficacy of ICB for
patients with lung cancer with high TMB.
©2023 American Association for Cancer Research.
DOI: 10.1158/0008-5472.CAN-23-3929
PMID: 38128037
13. Cancer Res. 2023 Dec 14. doi: 10.1158/0008-5472.CAN-23-3929. Online ahead of
print.
Harnessing p53 to improve immunotherapy for lung cancer treatment.
Niu X(1), Martinez L(2).
Author information:
(1)Stony Brook University.
(2)Stony Brook Medicine, Stony Brook, NY, United States.
Immunotherapy, especially immune checkpoint blockade (ICB), has become a
critical therapy for lung cancer treatment in recent years. Tumor mutational
burden (TMB) is one of the decisive biomarkers for predicting immune checkpoint
blockade effect. Writing in Cancer Cell, Zhu and colleagues use autochthonous
and syngeneic mouse models to show that p53 mutation and tumor heterogeneity may
be responsible for resistance in lung cancer patients. Pole-induced high-TMB
shows enhanced immunogenicity in KrasG12D mice, however, loss of p53 in KrasG12D
PoleP286/+ mice can lead to an immune suppressive profile of lung tumors which
diminishes immune response to ICB. Moreover, high TMB causes high shared
mutations which helps promote immune protection and immune memory. Heterogeneity
can drive immune escape to tumor cells causing resistance to ICB. Decreased
cGAS/STING signaling may explain possible resistance to ICB. Based on the new
model found by Zhu and colleagues for lung cancer, combined ICB with STING
agonists or p53 inducers may be new therapeutic options to improve the efficacy
of ICB for lung cancer patients with high TMB.
DOI: 10.1158/0008-5472.CAN-23-3929
PMID: 38095514
14. Lancet Infect Dis. 2023 Dec;23(12):1395-1407. doi:
10.1016/S1473-3099(23)00372-9. Epub 2023 Sep 8.
Burden of tuberculosis among vulnerable populations worldwide: an overview of
systematic reviews.
Litvinjenko S(1), Magwood O(2), Wu S(1), Wei X(3).
Author information:
(1)Dalla Lana School of Public Health, University of Toronto, Toronto, ON,
Canada.
(2)Bruyère Research Institute, Ottawa, ON, Canada; Interdisciplinary School of
Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON,
Canada.
(3)Dalla Lana School of Public Health, University of Toronto, Toronto, ON,
Canada. Electronic address: xiaolin.wei@utoronto.ca.
Erratum in
Lancet Infect Dis. 2023 Nov;23(11):e467.
BACKGROUND: Tuberculosis is a communicable disease of public health concern that
inequitably impacts the most vulnerable populations worldwide. Vulnerable
populations are those with a high risk for tuberculosis disease and whose
disadvantaged or marginalised socioeconomic position limits their access to the
health system. We conducted an overview of reviews that aimed to assess the
burden (ie, prevalence and incidence) of tuberculosis disease among 12
vulnerable populations globally.
METHODS: We did an overview of reviews using a systematic search in MEDLINE,
Embase, and the Cochrane Database for Systematic Reviews for articles published
in English, French, and Chinese, from Jan 1, 2010 to March 8, 2023. We did an
initial search on Oct 28, 2021, and updated our search on March 8, 2023. We
included systematic and scoping reviews reporting on the prevalence or incidence
of active tuberculosis among 12 vulnerable populations. Evidence gaps were
supplemented with primary or secondary database studies. Study characteristics
and outcome data related to tuberculosis burden were tabulated, including
prevalence ratios and incidence rate ratios, and evidence was synthesised
narratively. This trial is registered with PROSPERO (CRD42022324421).
FINDINGS: We screened 13 169 citations and included 44 publications (23 reviews
and 21 primary or database studies) in the final synthesis. The
comprehensiveness and methodological quality of the evidence differed across
population groups. Prevalence of more than 1000 cases per 100 000 were reported
in all vulnerable populations. On the basis of pooled estimates, prevalence
ratios were often more than 25 among people experiencing homelessness,
incarcerated populations, refugees, asylum seekers, and people living with HIV
compared with the general population. Incidence was infrequently reported, with
the best-available incidence rate ratios documented for people who were
incarcerated. There was scarce evidence specific to miners, nomadic populations,
sex workers, men who have sex with men, and transgender individuals.
INTERPRETATION: The burden of tuberculosis is substantially higher among
vulnerable populations than general populations, suggesting a need for improved
integration of these groups, including dedicated efforts for their
identification, targeted screening and prevention measures, as well as treatment
support.
FUNDING: WHO.
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All
rights reserved.
DOI: 10.1016/S1473-3099(23)00372-9
PMCID: PMC10665202
PMID: 37696278 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests We declare no competing
interests.
15. CMAJ. 2023 Dec 10;195(48):E1651-E1659. doi: 10.1503/cmaj.230228.
The prevalence of tuberculosis infection among foreign-born Canadians: a
modelling study.
Jordan AE(1), Nsengiyumva NP(1), Houben RMGJ(1), Dodd PJ(1), Dale KD(1), Trauer
JM(1), Denholm JT(1), Johnston JC(1), Khan FA(1), Campbell JR(2), Schwartzman
K(2).
Author information:
(1)Department of Epidemiology, Biostatistics, and Occupational Health (Jordan),
McGill University; McGill International Tuberculosis Centre (Jordan,
Nsengiyumva, Ahmad Khan, Campbell, Schwartzman); Respiratory Epidemiology and
Clinical Research Unit (Nsengiyumva, Ahmad Khan, Campbell, Schwartzman), Centre
for Outcomes Research & Evaluation, Research Institute of the McGill University
Health Centre, Montréal, Que.; Department of Infectious Disease Epidemiology and
Tuberculosis Centre (Houben), Tuberculosis Modelling Group, London School of
Hygiene and Tropical Medicine, London, UK; School of Health and Related Research
(Dodd), University of Sheffield, Sheffield, UK; Victorian Tuberculosis Program
(Dale, Denholm), Melbourne Health, at the Peter Doherty Institute for Infection
and Immunity; School of Public Health and Preventive Medicine (Trauer), Monash
University; Department of Infectious Diseases (Denholm), University of Melbourne
at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia;
British Columbia Centre for Disease Control (Johnston); Department of Medicine
(Johnston), University of British Columbia, Vancouver, BC; Departments of
Medicine and of Global and Public Health (Campbell), McGill University,
Montréal, Que.
(2)Department of Epidemiology, Biostatistics, and Occupational Health (Jordan),
McGill University; McGill International Tuberculosis Centre (Jordan,
Nsengiyumva, Ahmad Khan, Campbell, Schwartzman); Respiratory Epidemiology and
Clinical Research Unit (Nsengiyumva, Ahmad Khan, Campbell, Schwartzman), Centre
for Outcomes Research & Evaluation, Research Institute of the McGill University
Health Centre, Montréal, Que.; Department of Infectious Disease Epidemiology and
Tuberculosis Centre (Houben), Tuberculosis Modelling Group, London School of
Hygiene and Tropical Medicine, London, UK; School of Health and Related Research
(Dodd), University of Sheffield, Sheffield, UK; Victorian Tuberculosis Program
(Dale, Denholm), Melbourne Health, at the Peter Doherty Institute for Infection
and Immunity; School of Public Health and Preventive Medicine (Trauer), Monash
University; Department of Infectious Diseases (Denholm), University of Melbourne
at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia;
British Columbia Centre for Disease Control (Johnston); Department of Medicine
(Johnston), University of British Columbia, Vancouver, BC; Departments of
Medicine and of Global and Public Health (Campbell), McGill University,
Montréal, Que. jonathon.campbell@mcgill.ca kevin.schwartzman@mcgill.ca.
BACKGROUND: The prevalence of tuberculosis infection is critical to the design
of tuberculosis prevention strategies, yet is unknown in Canada. We estimated
the prevalence of tuberculosis infection among Canadian residents born abroad.
METHODS: We estimated the prevalence of tuberculosis infection by age and year
of migration to Canada for people from each of 168 countries by constructing
country-specific and calendar year-specific trends for annual risk of infection
using a previously developed model. We combined country-specific prevalence
estimates with Canadian Census data from 2001, 2006, 2011, 2016 and 2021 to
estimate the overall prevalence of tuberculosis infection among foreign-born
Canadian residents.
RESULTS: The estimated overall prevalence of tuberculosis infection among
foreign-born people in Canada was 25% (95% uncertainty interval [UI] 20%-35%)
for census year 2001, 24% (95% UI 20%-33%) for 2006, 23% (95% UI 19%-30%) for
2011, 22% (95% UI 19%-28%) for 2016 and 22% (95% UI 19%-27%) for 2021. The
prevalence increased with age at migration and incidence of tuberculosis in the
country of origin. In 2021, the estimated prevalence of infection among
foreign-born residents was lowest in Quebec (19%, 95% UI 16%-24%) and highest in
Alberta (24%, 95% UI 21%-28%) and British Columbia (24%, 95% UI 20%-30%). Among all foreign-born Canadian residents with tuberculosis infection in 2021, we
estimated that only 1 in 488 (95% UI 185-1039) had become infected within the 2
preceding years.
INTERPRETATION: About 1 in 4 foreign-born Canadian residents has tuberculosis
infection, but very few were infected within the 2 preceding years (the highest
risk period for progression to tuberculosis disease). These data may inform
future tuberculosis infection screening policies.
© 2023 CMA Impact Inc. or its licensors.
DOI: 10.1503/cmaj.230228
PMCID: PMC10718277
PMID: 38081633 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: James Johnston reports
support from the Michael Smith Foundation for Health Research BC. Faiz Ahmad
Khan reports support from the Canadian Institutes of Health Research, the
National Research Council of Canada, Fonds de Recherche du Québec – Santé, Fonds
de Recherche du Québec – Nature et technologies, Fonds de recherche du Québec –
Société et culture, and Institut nordique du Québec. Delft and qure.ai have
provided Faiz Ahmad Khan’s laboratory with use of their software for chest
radiography analysis at academic-use pricing. Contractual agreements are in
place to ensure the companies do not have input in any aspect of research
design, conduct or reporting. Kevin Schwartzman reports support from the Bill
and Melinda Gates Foundation and participation on a data safety monitoring board
for Laurent Pharmaceuticals. He is a volunteer board member and executive
committee member with the International Union Against Tuberculosis and Lung
Disease. No other competing interests were declared.
16. Adv Sci (Weinh). 2023 Dec;10(35):e2303975. doi: 10.1002/advs.202303975. Epub
2023 Oct 24.
A Novel Cytochrome P450 2E1 Inhibitor Q11 Is Effective on Lung Cancer via
Regulation of the Inflammatory Microenvironment.
Jia L(1), Gao F(1), Hu G(1), Fang Y(1), Tang L(1), Wen Q(1), Gao N(1), Xu H(2),
Qiao H(1).
Author information:
(1)Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan,
450001, China.
(2)School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan,
450001, China.
Lung cancer is the leading cause of death among all cancers. A persistent
chronic inflammatory microenvironment is highly correlated with lung cancer.
However, there are no anti-inflammatory agents effective against lung cancer.
Cytochrome P450 2E1 (CYP2E1) plays an important role in the inflammatory
response. Here, it is found that CYP2E1 is significantly higher in the
peritumoral tissue of non-small cell lung cancer (NSCLC) patients and lung tumor
growth is significantly impeded in Cyp2e1-/- mice. The novel CYP2E1 inhibitor
Q11, 1-(4-methyl-5-thialzolyl) ethenone, is effective in the treatment of lung
cancer in mice, which can inhibit cancer cells by changing macrophage
polarization rather than directly act on the cancer cells. It is also clarify
that the benefit of Q11 may associated with the IL-6/STAT3 and MAPK/ERK
pathways. The data demonstrate that CYP2E1 may be a novel inflammatory target
and that Q11 is effective on lung cancer by regulation of the inflammatory
microenvironment. These findings provide a molecular basis for targeting CYP2E1
and illustrate the potential druggability of the CYP2E1 inhibitor Q11.
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.
DOI: 10.1002/advs.202303975
PMCID: PMC10724398
PMID: 37875398 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
17. Lancet Glob Health. 2023 Dec;11(12):e1922-e1930. doi:
10.1016/S2214-109X(23)00451-5. Epub 2023 Oct 30.
Cost-effectiveness of community-based household tuberculosis contact management
for children in Cameroon and Uganda: a modelling analysis of a
cluster-randomised trial.
Mafirakureva N(1), Tchounga BK(2), Mukherjee S(3), Youngui BT(2), Ssekyanzi
B(4), Simo L(2), Okello RF(5), Turyahabwe S(6), Kuate Kuate A(7), Cohn J(8),
Vasiliu A(9), Casenghi M(10), Atwine D(11), Bonnet M(12), Dodd PJ(13).
Author information:
(1)Health Economics and Decision Science, University of Sheffield, Sheffield,
UK. Electronic address: n.mafirakureva@sheffield.ac.uk.
(2)Elizabeth Glaser Pediatric AIDS Foundation, Yaounde, Cameroon.
(3)Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, USA.
(4)Epicentre, Mbarara, Uganda.
(5)Elizabeth Glaser Pediatric AIDS Foundation, Mbarara, Uganda.
(6)National Tuberculosis and Leprosy Program, Ministry of Health, Kampala,
Uganda.
(7)National Tuberculosis Control Program, Ministry of Health, Yaounde, Cameroon.
(8)Perelman School of Medicine at the University of Pennsylvania, Philadelphia,
PA, USA.
(9)Baylor College of Medicine, Department of Pediatrics, Global TB Program,
Houston, TX, USA; University Montpellier, TransVIHMI, IRD, Inserm, Montpellier,
France.
(10)Elizabeth Glaser Pediatric AIDS Foundation, Geneva, Switzerland.
(11)Epicentre, Mbarara, Uganda; Mbarara University of Science and Technology,
Mbarara, Uganda.
(12)University Montpellier, TransVIHMI, IRD, Inserm, Montpellier, France.
(13)Health Economics and Decision Science, University of Sheffield, Sheffield,
UK.
Erratum in
Lancet Glob Health. 2024 Jan;12(1):e32.
BACKGROUND: WHO recommends household contact management (HCM) including contact
screening and tuberculosis-preventive treatment (TPT) for eligible children. The
CONTACT trial found increased TPT initiation and completion rates when community
health workers were used for HCM in Cameroon and Uganda.
METHODS: We did a cost-utility analysis of the CONTACT trial using a
health-system perspective to estimate the health impact, health-system costs,
and cost-effectiveness of community-based versus facility-based HCM models of
care. A decision-analytical modelling approach was used to evaluate the
cost-effectiveness of the intervention compared with the standard of care using
trial data on cascade of care, intervention effects, and resource use. Health
outcomes were based on modelled progression to tuberculosis, mortality, and
discounted disability-adjusted life-years (DALYs) averted. Health-care resource
use, outcomes, costs (2021 US$), and cost-effectiveness are presented.
FINDINGS: For every 1000 index patients diagnosed with tuberculosis, the
intervention increased the number of TPT courses by 1110 (95% uncertainty
interval 894 to 1227) in Cameroon and by 1078 (796 to 1220) in Uganda compared
with the control model. The intervention prevented 15 (-3 to 49) tuberculosis
deaths in Cameroon and 10 (-20 to 33) in Uganda. The incremental
cost-effectiveness ratio was $620 per DALY averted in Cameroon and $970 per DALY
averted in Uganda.
INTERPRETATION: Community-based HCM approaches can substantially reduce child
tuberculosis deaths and in our case would be considered cost-effective at
willingness-to-pay thresholds of $1000 per DALY averted. Their impact and
cost-effectiveness are likely to be greatest where baseline HCM coverage is
lowest.
FUNDING: Unitaid and UK Medical Research Council.
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All
rights reserved.
DOI: 10.1016/S2214-109X(23)00451-5
PMID: 37918416 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests MB has received grants
(paid to her institution) from Unitaid and Expertise France for the TB-Speed
project on childhood tuberculosis diagnosis, from ANRS for a COVID-19 prevalence
study in children with presumptive tuberculosis, and from EDCTP-2 for two
therapeutic trials for the treatment of adults with tuberculosis meningitis
(INTENSE-TBM) and adults with advanced HIV-TB co-infection (DATURA). All other
authors declare no competing interests.
18. Lancet Glob Health. 2023 Dec;11(12):e1911-e1921. doi:
10.1016/S2214-109X(23)00430-8. Epub 2023 Oct 30.
Effectiveness of a community-based approach for the investigation and management
of children with household tuberculosis contact in Cameroon and Uganda: a
cluster-randomised trial.
Bonnet M(1), Vasiliu A(2), Tchounga BK(3), Cuer B(4), Fielding K(5), Ssekyanzi
B(6), Tchakounte Youngui B(3), Cohn J(7), Dodd PJ(8), Tiendrebeogo G(9),
Tchendjou P(3), Simo L(3), Okello RF(10), Kuate Kuate A(11), Turyahabwe S(12),
Atwine D(13), Graham SM(14), Casenghi M(7); CONTACT study group.
Collaborators: Chauvet S, de Carvalho E, Ouedraogo S, Leguicher G, Tiam A,
Oziemkowska M, Atieno Ayuo E, Mafirakureva N, Berset M, Lemaire JF, Sih C, Kana
R, Youm E, Guedem Nekame JL, Manguele PW, Bindzi P, Ndongo MA, Ndjang Kombou D,
Tsigaing PN, Mbunka Awolu M, Seuleu Ndjamakou LG, Sitamze Kaptue N, Ngounou Moyo
DF, Patouokoumche Ngouh R, Kouotou Mouliom JS, Abogo Abatsong HA, Essebe Ngangue
RC, Djeumene R, Maguia Tatiane Kouam LT, Nono Djilo LF, Bakmano Raïssa MJ,
Njikeh KD, Bissek AC, Arinaitwe R, Otai D, Kamanzi H, Natukunda A, Natukunda E,
Kyarimpa R, Kyomuhendo D, Sanyu S, Ssemanya J, Nabbuto J, Lugoose S, Rachael K,
Tebylwa Beryta J, Kitakule F, Atuhaire S, Kembabazi M, Abok F, Kakinda M, Odongo
D, Ijjo H, Kyomugisha C, Aryatuhwera J, Ashaba B, Nuwamanya P, Arinaitwe M,
Natukunda P, Muhangi C, Muhumuza D, Ndyeimuka G, Bagabe J, Tiboruhanga J,
Tibaijuka F, Nahabwe M.
Author information:
(1)TransVIHMI, University Montpellier, Institut de Recherche pour le
Développement, INSERM, Montpellier, France. Electronic address:
maryline.bonnet@ird.fr.
(2)TransVIHMI, University Montpellier, Institut de Recherche pour le
Développement, INSERM, Montpellier, France; Department of Pediatrics, Baylor
College of Medicine, Houston, TX, USA.
(3)Elizabeth Glaser Pediatric AIDS Foundation, Yaoundé, Cameroon.
(4)TransVIHMI, University Montpellier, Institut de Recherche pour le
Développement, INSERM, Montpellier, France.
(5)London School of Hygiene & Tropical Medicine, London, UK.
(6)Epicentre, Mbarara, Uganda.
(7)Department of Innovation and New Technology, Elizabeth Glaser Pediatric AIDS
Foundation, Geneva, Switzerland.
(8)School of Health and Related Research, University of Sheffield, Sheffield,
UK.
(9)University Montpellier, Institut de Recherche pour le Développement, INSERM,
Montpellier, France.
(10)Elizabeth Glaser Pediatric AIDS Foundation, Mbarara, Uganda.
(11)National Tuberculosis Control Program, Yaounde, Cameroon.
(12)National Tuberculosis Control Program, Kampala, Uganda.
(13)Clinical Research Department, Epicentre Mbarara Research Centre, Mbarara,
Uganda.
(14)Royal Children's Hospital, University of Melbourne Department of Paediatrics
and Murdoch Children's Research Institute, Melbourne, Australia; International
Union Against Tuberculosis and Lung Disease, Paris, France.
BACKGROUND: Globally, the uptake of tuberculosis-preventive treatment (TPT)
among children with household tuberculosis contact remains low, partly due to
the necessity of bringing children to health facilities for investigations. This
study aimed to evaluate the effect on TPT initiation and completion of
community-based approaches to tuberculosis contact investigations in Cameroon
and Uganda.
METHODS: We did a parallel, cluster-randomised, controlled trial across 20
clusters (consisting of 25 district hospitals and primary health centres) in
Cameroon and Uganda, which were randomised (1:1) to receive a community-based
approach (intervention group) or standard-of-care facility-based approach to
contact screening and management (control group). The community-based approach
consisted of symptom-based tuberculosis screening of all household contacts by
community health workers at the household, with referral of symptomatic contacts
to local facilities for investigations. Initiation of TPT (3-month course of
rifampicin-isoniazid) was done by a nurse in the household, and home visits for
TPT follow-up were done by community health workers. Index patients were people
aged 15 years or older with bacteriologically confirmed, drug-susceptible,
pulmonary tuberculosis diagnosed less than 1 month before inclusion and who
declared at least one child or young adolescent (aged 0-14 years) household
contact. The primary endpoint was the proportion of declared child contacts in
the TPT target group (those aged<5 years irrespective of HIV status, and
children aged 5-14 years living with HIV) who commenced and completed TPT,
assessed in the modified intention-to-treat population (excluding enrolled index
patients and their contacts who did not fit the eligibility criteria).
Descriptive cascade of care assessment and generalised linear mixed modelling
were used for comparison. This study is registered with ClinicalTrials.gov
(NCT03832023).
FINDINGS: The study included nine clusters in the intervention group (after
excluding one cluster that did not enrol any index patients for >2 months) and
ten in the control group. Between Oct 14, 2019 and Jan 13, 2022, 2894 child
contacts were declared by 899 index patients with bacteriologically confirmed
tuberculosis. Among all child contacts declared, 1548 (81·9%) of 1889 in the
intervention group and 475 (47·3%) of 1005 in the control group were screened
for tuberculosis. 1400 (48·4%) child contacts were considered to be in the TPT
target group: 941 (49·8%) of 1889 in the intervention group and 459 (45·7%) of
1005 in the control group. In the TPT target group, TPT was commenced and
completed in 752 (79·9%) of 941 child contacts in the intervention group and 283
(61·7%) of 459 in the control group (odds ratio 3·06 [95% CI 1·24-7·53]).
INTERPRETATION: A community-based approach using community health workers can
significantly increase contact investigation coverage and TPT completion among
eligible child contacts in a tuberculosis-endemic setting.
FUNDING: Unitaid.
TRANSLATION: For the French translation of the abstract see Supplementary
Materials section.
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd..
All rights reserved.
DOI: 10.1016/S2214-109X(23)00430-8
PMID: 37918417 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests MB has received grants
(paid to her institution) from Unitaid and Expertise France for the TB-Speed
project on childhood tuberculosis diagnosis, from ANRS for a COVID-19 prevalence
study in children with presumptive tuberculosis, and from EDCTP-2 for two
therapeutic trials for the treatment of adults with tuberculosis meningitis
(INTENSE-TBM) and adults with advanced HIV-TB co-infection (DATURA). All other
authors declare no competing interests.
19. Clin Microbiol Infect. 2023 Dec 6:S1198-743X(23)00574-8. doi:
10.1016/j.cmi.2023.12.001. Online ahead of print.
Treatment outcomes and risk factors for an unsuccessful outcome among patients
with highly drug-resistant tuberculosis in Ukraine.
Pedersen OS(1), Butova T(2), Kapustnyk V(3), Miasoiedov V(3), Kuzhko M(4),
Hryshchuk L(5), Kornaha S(5), Borovok N(6), Raznatovska O(7), Fedorec A(8),
Bogomolov A(9), Tkhorovskiy M(9), Akymenko O(6), Klymenko I(10), Kulykova O(11),
Karpenko Z(12), Shapoval T(12), Chursina N(13), Kondratyuk N(14), Parkhomenko
O(15), Sazonenko I(16), Ostrovskyy M(17), Makoida I(17), Markovtsiy L(18), Skryp
V(18), Lubenko V(19), Hrankina N(20), Bondarenko L(21), Hlynenko V(22), Dahl
VN(23), Butov D(24).
Author information:
(1)Department of Respiratory Diseases and Allergy, Aarhus University Hospital,
Aarhus, Denmark.
(2)Outpatient Department, Merefa Central District Hospital, Merefa, Ukraine.
(3)Kharkiv National Medical University, Kharkiv, Ukraine.
(4)Department of Chemoresistant Tuberculosis, National Institute of Phthisiology
and Pulmonology named after F. G. Yanovskyi NAMS of Ukraine, Kiev, Ukraine.
(5)Department of Internal Medicine Propedeutics and Phthisiology, I.
Horbachevsky Ternopil National Medical University, Ternopil, Ukraine.
(6)Medical Department No. 3, Regional Anti-tuberculosis Dispensary No 1 in
Kharkiv, Kharkiv, Ukraine.
(7)Phthisiology and Pulmonology, Zaporizhzhia State Medical and Pharmaceutical
University, Zaporizhzhia, Ukraine.
(8)The Pulmonary Tuberculosis Department No. 2, Zaporizhzhia Regional
Phthisiology and Pulmonology Clinical Treatment and Diagnostic Center,
Zaporizhzhia, Ukraine.
(9)Phthisiology, Clinical Immunology and Allergology, National Pirogov Memorial
Medical University, Vinnytsya, Ukraine.
(10)Regional Clinical Dispensary, Kramatorsk, Ukraine.
(11)Outpatient Department, Regional Clinical Tuberculosis Dispensary,
Kramatorsk, Ukraine.
(12)Phthisiatry Center, Chernihiv Regional Hospital, Chernihiv, Ukraine.
(13)Volyn Regional Phthisiopulmonological Center, Lutsk, Ukraine.
(14)Bacteriological Laboratory, Volyn Regional Phthisiopulmonological Center,
Lutsk, Ukraine.
(15)Mykolaiv Regional Phthisio-pulmonological Medical Center, Mykolaiv, Ukraine.
(16)Phthisiology, Mykolaiv Regional Phthisiology and Pulmonology Medical Center,
Mykolaiv, Ukraine.
(17)Phthisiology and Pulmonology Rate of Occupational Diseases, Ivano-Frankivsk
National Medical University, Ivano-Frankivsk, Ukraine.
(18)Center of Pulmonary Diseases, Uzhhorod, Ukraine.
(19)Information and Analytical Department, Phthisiopulmonology Center, Kyiv,
Ukraine.
(20)Infectious Diseases and Phthisiology, Krivoy Rig Tuberculosis Dispensary,
Dnipro, Ukraine.
(21)Administration, Sumy Regional Clinical Anti-tuberculosis Dispensary, Sumy,
Ukraine.
(22)Outpatient Department, Sumy Regional Clinical Anti-tuberculosis Dispensary,
Sumy, Ukraine.
(23)Department of Infectious Diseases, Aarhus University Hospital, Aarhus,
Denmark; Center for Global Health, Aarhus University (GloHAU), Aarhus, Denmark;
International Reference Laboratory of Mycobacteriology, Statens Serum Institut,
Copenhagen, Denmark. Electronic address: victordahl@gmail.com.
(24)Infectious Diseases and Phthisiology, Kharkiv National Medical University,
Kharkiv, Ukraine.
OBJECTIVES: To describe demographics, clinical features, and treatment outcomes
of patients with highly drug-resistant tuberculosis (TB) in Ukraine, and to evaluate risk factors for an unsuccessful outcome.
METHODS: Data from patients with multi-, pre-extensively, or extensively
drug-resistant TB were collected prospectively from TB dispensaries in 15 out of
24 Ukrainian oblasts (regions) from 2020 to 2021. Treatment outcomes were
evaluated using WHO definitions. Risk factors for an unsuccessful outcome were
identified using a multivariable logistic regression model.
RESULTS: Among 1748 patients, the overall proportion of successful outcomes was
58% (95% confidence interval [95% CI] 56-60) (n = 1015/1748), ranging from 65%
(95% CI: 62-69) (n = 531/814) for multidrug-resistant TB to 54% (95% CI: 49-58)
(n = 301/563) for pre-extensively drug-resistant TB and 49% (95% CI: 44-55)
(n = 183/371) for extensively drug-resistant TB. Results were similar across
oblasts, with few exceptions. The strongest risk factors for an unsuccessful
outcome were extensively drug-resistant TB (adjusted OR [aOR] 3.23; 95% CI:
1.88-5.53), total serum protein below 62 g/L in adults and below 57 g/L for
children and adolescents (aOR 2.79; 95% CI: 1.93-4.04), psychiatric illness (aOR
2.79; 95% CI: 1.46-5.33), age at TB diagnosis >65 years (aOR 2.50; 95% CI:
1.42-4.42), and alcohol misuse (aOR 2.48; 95% CI: 1.89-3.26).
DISCUSSION: The overall proportion of successful outcomes among Ukrainians
treated for highly drug-resistant TB was 58%, notably better compared with
previous years, but still low for extensively drug-resistant TB. Risk factors
for unsuccessful outcomes highlight that addressing socioeconomic factors in TB
management is crucial. Efforts in maintaining TB dispensaries during and
following the ongoing war are highly warranted.
Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.cmi.2023.12.001
PMID: 38065363
20. Nat Microbiol. 2024 Jan;9(1):120-135. doi: 10.1038/s41564-023-01523-7. Epub 2023 Dec 8.
BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility.
Amaral EP(1), Namasivayam S(2), Queiroz ATL(3), Fukutani E(3), Hilligan KL(2),
Aberman K(2), Fisher L(2)(4), Bomfim CCB(2), Kauffman K(5), Buchanan J(5),
Santuo L(5), Gazzinelli-Guimaraes PH(6), Costa DL(2)(7)(8), Teixeira MA(9),
Barreto-Duarte B(3)(9)(10), Rocha CG(11)(12), Santana MF(13)(14)(15),
Cordeiro-Santos M(14)(15)(16), Barber DL(5), Wilkinson RJ(17)(18)(19), Kramnik
I(20), Igarashi K(21), Scriba T(22), Mayer-Barber KD(23), Andrade
BB(3)(9)(10)(11)(24)(25)(26)(27), Sher A(28).
Author information:
(1)Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH,
Bethesda, MD, USA. eduardo.amaral@nih.gov.
(2)Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH,
Bethesda, MD, USA.
(3)Laboratório de Inflamação e Biomarcadores, Instituto Gonçalo Moniz, Fundação
Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil.
(4)Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine
Graduate School of Medical Sciences, New York, NY, USA.
(5)T lymphocyte Biology Section, Laboratory of Parasitic Diseases, National
Institutes of Allergy and Infectious Disease, National Institutes of Health,
Bethesda, MD, USA.
(6)Helminth Immunology Section, Laboratory of Parasitic Diseases, National
Institutes of Allergy and Infectious Disease, National Institutes of Health,
Bethesda, MD, USA.
(7)Departmento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão
Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
(8)Programa de Pós-Graduação em Imunologia Básica e Aplicada, Faculdade de
Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
(9)Multinational Organization Network Sponsoring Translational and
Epidemiological Research (MONSTER) Initiative, Salvador, Brazil.
(10)Curso de Medicina, Universidade Salvador (UNIFACS), Laureate Universities,
Salvador, Bahia, Brazil.
(11)Department of Pathology, School of Medicine of the Federal University of
Bahia, Salvador, Bahia, Brazil.
(12)Center for Biotechnology and Cell Therapy, D'Or Institute for Research and
Education (IDOR), Sao Rafael Hospital, Salvador, Bahia, Brazil.
(13)Departmento de Ensino e Pesquisa, Fundação Centro de Controle de Oncologia
do Estado do Amazonas-FCECON, Manaus, Amazonas, Brazil.
(14)Fundação Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Amazonas,
Brazil.
(15)Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do
Amazonas, Manaus, Amazonas, Brazil.
(16)Faculdade de Medicina, Universidade Nilton Lins, Manaus, Amazonas, Brazil.
(17)Wellcome Centre for Infectious Disease Research in Africa, Institute of
Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town,
South Africa.
(18)The Francis Crick Institute, London, UK.
(19)Department of Infectious Disease, Imperial College London, London, UK.
(20)Boston University School of Medicine, Boston, MA, USA.
(21)Department of Biochemistry, Tohoku University Graduate School of Medicine,
Sendai, Japan.
(22)South African Tuberculosis Vaccine Initiative, Institute of Infectious
Disease and Molecular Medicine and Division of Immunology, Department of
Pathology, University of Cape Town, Observatory, South Africa.
(23)Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and
Microbiology, NIAID, NIH, Bethesda, MD, USA.
(24)Curso de Medicina, Escola Bahiana de Medicina e Saúde Pública, Salvador,
Bahia, Brazil.
(25)Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Bahia,
Brazil.
(26)Curso de Medicina, Universidade Faculdade de Tecnologia e Ciências (UniFTC),
Salvador, Bahia, Brazil.
(27)Division of Infectious Diseases, Department of Medicine, Vanderbilt
University School of Medicine, Nashville, TN, USA.
(28)Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH,
Bethesda, MD, USA. asher@niaid.nih.gov.
Oxidative stress triggers ferroptosis, a form of cellular necrosis characterized
by iron-dependent lipid peroxidation, and has been implicated in Mycobacterium
tuberculosis (Mtb) pathogenesis. We investigated whether Bach1, a transcription
factor that represses multiple antioxidant genes, regulates host resistance to
Mtb. We found that BACH1 expression is associated clinically with active
pulmonary tuberculosis. Bach1 deletion in Mtb-infected mice increased
glutathione levels and Gpx4 expression that inhibit lipid peroxidation. Bach1-/-
macrophages exhibited increased resistance to Mtb-induced cell death, while
Mtb-infected Bach1-deficient mice displayed reduced bacterial loads, pulmonary
necrosis and lipid peroxidation concurrent with increased survival. Single-cell
RNA-seq analysis of lungs from Mtb-infected Bach1-/- mice revealed an enrichment
of genes associated with ferroptosis suppression. Bach1 depletion in
Mtb-infected B6.Sst1S mice that display human-like necrotic lung pathology also
markedly reduced necrosis and increased host resistance. These findings identify
Bach1 as a key regulator of cellular and tissue necrosis and host resistance in
Mtb infection.
© 2023. This is a U.S. Government work and not under copyright protection in the
US; foreign copyright protection may apply.
DOI: 10.1038/s41564-023-01523-7
PMCID: PMC10769877
PMID: 38066332 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
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