2022年
No.8
PubMed Filters applied: from 2022/8/1 - 2022/8/31.
1. Nat Genet. 2022 Aug;54(8):1167-1177. doi: 10.1038/s41588-022-01115-x. Epub 2022 Aug 1.
Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls
identifies new susceptibility loci contributing to lung cancer.
Byun J(#)(1)(2), Han Y(#)(1)(2), Li Y(#)(1)(2)(3), Xia J(#)(1)(4), Long E(#)(5),
Choi J(5), Xiao X(1), Zhu M(6), Zhou W(1), Sun R(7), Bossé Y(8), Song Z(1)(4),
Schwartz A(9)(10), Lusk C(9)(10), Rafnar T(11), Stefansson K(11), Zhang T(5),
…
Author information:
(1)Institute for Clinical and Translational Research, Baylor College of
Medicine, Houston, TX, USA.
(2)Section of Epidemiology and Population Sciences, Department of Medicine,
Baylor College of Medicine, Houston, TX, USA.
(3)Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine,
Houston, TX, USA.
…
To identify new susceptibility loci to lung cancer among diverse populations, we
performed cross-ancestry genome-wide association studies in European, East Asian
and African populations and discovered five loci that have not been previously
reported. We replicated 26 signals and identified 10 new lead associations from
previously reported loci. Rare-variant associations tended to be specific to
populations, but even common-variant associations influencing smoking behavior,
such as those with CHRNA5 and CYP2A6, showed population specificity.
Fine-mapping and expression quantitative trait locus colocalization nominated
several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA
damage assays of prioritized genes in lung fibroblasts indicated that a subset
of these genes, including the pleiotropic gene IRF4, potentially exert effects
by promoting endogenous DNA damage.
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41588-022-01115-x
PMCID: PMC9373844
PMID: 35915169 [Indexed for MEDLINE]
2. Cell. 2022 Aug 18;185(17):3214-3231.e23. doi: 10.1016/j.cell.2022.06.038. Epub
2022 Jul 30.
Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated
necroptosis.
Weindel CG(1), Martinez EL(1), Zhao X(2), Mabry CJ(1), Bell SL(3), Vail KJ(4),
Coleman AK(1), VanPortfliet JJ(1), Zhao B(5), Wagner AR(1), Azam S(1), Scott
HM(1), Li P(5), West AP(1), Karpac J(2), Patrick KL(6), Watson RO(7).
Author information:
(1)Department of Microbial Pathogenesis and Immunology, Texas A&M Health,
College of Medicine, Bryan, TX 77807, USA.
(2)Department of Molecular and Cellular Medicine, Texas A&M Health, College of
Medicine, Bryan, TX 77807, USA.
(3)Department of Microbial Pathogenesis and Immunology, Texas A&M Health,
College of Medicine, Bryan, TX 77807, USA; Department of Microbiology,
Biochemistry & Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ
07103, USA.
…
Comment in
Curr Biol. 2022 Aug 22;32(16):R891-R894.
Although mutations in mitochondrial-associated genes are linked to inflammation
and susceptibility to infection, their mechanistic contributions to immune
outcomes remain ill-defined. We discovered that the disease-associated
gain-of-function allele Lrrk2G2019S (leucine-rich repeat kinase 2) perturbs
mitochondrial homeostasis and reprograms cell death pathways in macrophages.
When the inflammasome is activated in Lrrk2G2019S macrophages, elevated
mitochondrial ROS (mtROS) directs association of the pore-forming protein
gasdermin D (GSDMD) to mitochondrial membranes. Mitochondrial GSDMD pore
formation then releases mtROS, promoting a switch to RIPK1/RIPK3/MLKL-dependent
necroptosis. Consistent with enhanced necroptosis, infection of Lrrk2G2019S mice
with Mycobacterium tuberculosis elicits hyperinflammation and severe
immunopathology. Our findings suggest a pivotal role for GSDMD as an executer of
multiple cell death pathways and demonstrate that mitochondrial dysfunction can
direct immune outcomes via cell death modality switching. This work provides
insights into how LRRK2 mutations manifest or exacerbate human diseases and
identifies GSDMD-dependent necroptosis as a potential target to limit
Lrrk2G2019S-mediated immunopathology.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2022.06.038
PMCID: PMC9531054
PMID: 35907404 [Indexed for MEDLINE]
3. Cancer Cell. 2022 Aug 30:S1535-6108(22)00377-4. doi:
10.1016/j.ccell.2022.08.013. Online ahead of print.
Analyses of rare predisposing variants of lung cancer in 6,004 whole genomes in
Chinese.
Wang C(1), Dai J(2), Qin N(2), Fan J(2), Ma H(3), Chen C(2), An M(2), Zhang
J(2), Yan C(2), Gu Y(4), Xie Y(5), He Y(4), Jiang Y(6), Zhu M(2), Song C(2),
Jiang T(7), Liu J(8), Zhou J(2), Wang N(2), Hua T(2), Liang S(2), Wang L(8), Xu
J(9), Yin R(10), Chen L(9), Xu L(10), Jin G(6), Lin D(11), Hu Z(12), Shen H(13).
Author information:
(1)Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative
Innovation Center for Cancer Personalized Medicine, Nanjing Medical University,
Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine,
Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of
Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical
University, Nanjing 211166, Jiangsu, China; Department of Bioinformatics, School
of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing
211166, Jiangsu, China.
…
We present the largest whole-genome sequencing (WGS) study of non-small cell
lung cancer (NSCLC) to date among 6,004 individuals of Chinese ancestry, coupled
with 23,049 individuals genotyped by SNP array. We construct a high-quality
haplotype reference panel for imputation and identify 20 common and
low-frequency loci (minor allele frequency [MAF] ≥ 0.5%), including five loci
that have never been reported before. For rare loss-of-function (LoF) variants
(MAF < 0.5%), we identify BRCA2 and 18 other cancer predisposition genes that
affect 5.29% of individuals with NSCLC, and 98.91% (181 of 183) of LoF variants
have not been linked previously to NSCLC risk. Promoter variants of BRCA2 also
have a substantial effect on NSCLC risk, and their prevalence is comparable with
BRCA2 LoF variants. The associations are validated in an independent
case-control study including 4,410 individuals and a prospective cohort study
including 23,826 individuals. Our findings not only provide a high-quality
reference panel for future array-based association studies but depict the whole
picture of rare pathogenic variants for NSCLC.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2022.08.013
PMID: 36113475
4. Cancer Cell. 2022 Sep 12;40(9):1010-1026.e11. doi: 10.1016/j.ccell.2022.08.003.
Epub 2022 Aug 25.
Personalized neoantigen vaccine NEO-PV-01 with chemotherapy and anti-PD-1 as
first-line treatment for non-squamous non-small cell lung cancer.
Awad MM(1), Govindan R(2), Balogh KN(3), Spigel DR(4), Garon EB(5), Bushway
ME(3), Poran A(3), Sheen JH(3), Kohler V(3), Esaulova E(3), Srouji J(3), Ramesh
S(3), Vyasamneni R(3), Karki B(5), Sciuto TE(3), Sethi H(6), Dong JZ(3), Moles
MA(3), Manson K(3), Rooney MS(3), Khondker ZS(3), DeMario M(3), Gaynor RB(7),
Srinivasan L(8).
Author information:
(1)Dana Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical
School, Boston, MA, USA.
(2)Washington University School of Medicine, St. Louis, MO, USA.
(3)BioNTech US, Cambridge, MA, USA.
…
Comment in
Cancer Cell. 2022 Sep 12;40(9):903-905.
Neoantigens arising from mutations in tumor DNA provide targets for immune-based
therapy. Here, we report the clinical and immune data from a Phase Ib clinical
trial of a personalized neoantigen-vaccine NEO-PV-01 in combination with
pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced
non-squamous non-small cell lung cancer (NSCLC). This analysis of 38 patients
treated with the regimen demonstrated no treatment-related serious adverse
events. Multiple parameters including baseline tumor immune infiltration and
on-treatment circulating tumor DNA levels were highly correlated with clinical
response. De novo neoantigen-specific CD4+ and CD8+ T cell responses were
observed post-vaccination. Epitope spread to non-vaccinating neoantigens,
including responses to KRAS G12C and G12V mutations, were detected
post-vaccination. Neoantigen-specific CD4+ T cells generated post-vaccination
revealed effector and cytotoxic phenotypes with increased CD4+ T cell
infiltration in the post-vaccine tumor biopsy. Collectively, these data support
the safety and immunogenicity of this regimen in advanced non-squamous NSCLC.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2022.08.003
PMID: 36027916 [Indexed for MEDLINE]
5. Nat Med. 2022 Aug 25. doi: 10.1038/s41591-022-01977-y. Online ahead of print.
Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung
cancer: a randomized, controlled, double-blind phase 3 trial.
Gogishvili M(1), Melkadze T(2), Makharadze T(3), Giorgadze D(4), Dvorkin M(5),
Penkov K(6), Laktionov K(7), Nemsadze G(8), Nechaeva M(9), Rozhkova I(10),
Kalinka E(11), Gessner C(12)(13), Moreno-Jaime B(14), Passalacqua R(15), Li
S(16), McGuire K(16), Kaul M(16), Paccaly A(16), Quek RGW(16), Gao B(16),
Seebach F(16), Weinreich DM(16), Yancopoulos GD(16), Lowy I(16), Gullo G(16),
Rietschel P(16).
Author information:
(1)High Technology Medical Centre, University Clinic Ltd., Tbilisi, Georgia.
mirandagogishvili@yahoo.com.
(2)Acad. F. Todua Medical Center, Tbilisi, Georgia.
(3)LTD High Technology Hospital Med Center, Batumi, Georgia.
…
First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has
previously shown significant improvement in overall survival (OS) and
progression-free survival (PFS) versus chemotherapy in patients with advanced
non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%.
EMPOWER-Lung 3 ( NCT03409614 ), a double-blind, placebo-controlled, phase 3
study, examined cemiplimab plus platinum-doublet chemotherapy as first-line
treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this
study, 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic
tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg (n = 312)
or placebo (n = 154) every 3 weeks for up to 108 weeks in combination with four
cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as
indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2%
(397/466 patients) had stage IV disease. The primary endpoint was OS. The trial
was stopped early per recommendation of the independent data monitoring
committee, based on meeting preset OS efficacy criteria: median OS was
21.9 months (95% confidence interval (CI), 15.5-not evaluable) with cemiplimab
plus chemotherapy versus 13.0 months (95% CI, 11.9-16.1) with placebo plus
chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53-0.93; P = 0.014). Grade ≥3
adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312
patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is
only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both
monotherapy and in combination with chemotherapy for both squamous and
non-squamous histologies.
© 2022. The Author(s).
DOI: 10.1038/s41591-022-01977-y
PMID: 36008722
6. Lancet Oncol. 2022 Sep;23(9):1180-1188. doi: 10.1016/S1470-2045(22)00451-X. Epub 2022 Aug 11.
Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely
resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label,
randomised, phase 3 trial.
Westeel V(1), Foucher P(2), Scherpereel A(3), Domas J(4), Girard P(5), Trédaniel
J(6), Wislez M(7), Dumont P(8), Quoix E(9), Raffy O(10), Braun D(11), Derollez
M(12), Goupil F(13), Hermann J(14), Devin E(15), Barbieux H(16), Pichon E(17),
Debieuvre D(18), Ozenne G(19), Muir JF(19), Dehette S(20), Virally J(21),
Grivaux M(22), Lebargy F(23), Souquet PJ(24), Freijat FA(25), Girard N(26),
Courau E(27), Azarian R(28), Farny M(29), Duhamel JP(30), Langlais A(31), Morin
F(31), Milleron B(7), Zalcman G(32), Barlesi F(33).
Author information:
(1)Department of Pneumology, University Hospital of Besançon, INSERM UMR1098,
Université de Bourgogne-Franche-Comté, Besançon, France. Electronic address:
virginie.westeel@univ-fcomte.fr.
(2)Department of Pneumology, University Hospital Bocage, Dijon, France.
(3)University of Lille, CHU Lille, Thoracic Oncology Department, CNRS, Inserm,
Institut Pasteur de Lille, UMR9020-UMR-S 1277-Canther, Lille, France.
…
Comment in
Lancet Oncol. 2022 Sep;23(9):1115-1116.
BACKGROUND: Even after resection of early-stage non-small-cell lung cancer
(NSCLC), patients have a high risk of developing recurrence and second primary
lung cancer. We aimed to assess efficacy of a follow-up approach including
clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus
clinical visits and chest x-rays after surgery for resectable NSCLC.
METHODS: In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302),
patients aged 18 years or older and after complete resection of pathological
stage I-IIIA NSCLC according to the sixth edition of the TNM classification were
enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in
France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic
visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy
for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays)
after surgery for NSCLC, by means of a computer-generated sequence using the
minimisation method. Procedures were repeated every 6 months for the first 2
years and yearly until 5 years. The primary endpoint was overall survival
analysed in the intention-to-treat population. Secondary endpoints, also
analysed in the intention-to-treat population, included disease-free survival.
This trial is registered with ClinicalTrials.gov, NCT00198341, and is active,
but not enrolling.
FINDINGS: Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and
randomly assigned to a follow-up group (888 patients to the minimal follow-up
group; 887 patients to the CT-based follow-up group). Median overall survival
was not significantly different between follow-up groups (8·5 years [95% CI
7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events
related to the trial procedures were reported.
INTERPRETATION: The addition of thoracic CT scans during follow-up, which
included clinic visits and chest x-rays after surgery, did not result in longer
survival among patients with NSCLC. However, it did enable the detection of more
cases of early recurrence and second primary lung cancer, which are more
amenable to curative-intent treatment, supporting the use of CT-based follow-up,
especially in countries where lung cancer screening is already implemented,
alongside with other supportive measures.
FUNDING: French Health Ministry, French National Cancer Institute,
Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly
Oncology.
TRANSLATION: For the French translation of the abstract see Supplementary
Materials section.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00451-X
PMID: 35964621 [Indexed for MEDLINE]
7. Genes Dev. 2022 Aug 1;36(15-16):936-949. doi: 10.1101/gad.349659.122. Epub 2022 Sep 29.
Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation
alveolar type 2 organoid platform.
Naranjo S(#)(1)(2), Cabana CM(#)(1)(2), LaFave LM(1), Romero R(1)(2), Shanahan
SL(1)(2), Bhutkar A(1), Westcott PMK(1), Schenkel JM(1)(3)(4), Ghosh A(1), Liao
LZ(2), Del Priore I(1), Yang D(1)(5), Jacks T(1)(2).
Author information:
(1)David H. Koch Institute for Integrative Cancer Research, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02142, USA.
(2)Department of Biology, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02142, USA.
(3)Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
02115, USA.
(4)Harvard Medical School, Boston, Massachusetts 02115, USA.
(5)Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142,
USA.
(#)Contributed equally
Lung cancer is the leading cause of cancer-related death worldwide. Lung
adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of
all cases. While existing genetically engineered mouse models (GEMMs)
recapitulate the histological progression and transcriptional evolution of human
LUAD, they are time-consuming and technically demanding. In contrast, cell line
transplant models are fast and flexible, but these models fail to capture the
full spectrum of disease progression. Organoid technologies provide a means to
create next-generation cancer models that integrate the most advantageous
features of autochthonous and transplant-based systems. However, robust and
faithful LUAD organoid platforms are currently lacking. Here, we describe
optimized conditions to continuously expand murine alveolar type 2 (AT2) cells,
a prominent cell of origin for LUAD, in organoid culture. These organoids
display canonical features of AT2 cells, including marker gene expression, the
presence of lamellar bodies, and an ability to differentiate into the AT1
lineage. We used this system to develop flexible and versatile immunocompetent
organoid-based models of KRAS, BRAF, and ALK mutant LUAD. Notably,
organoid-based tumors display extensive burden and complete penetrance and are
histopathologically indistinguishable from their autochthonous counterparts.
Altogether, this organoid platform is a powerful, versatile new model system to
study LUAD.
© 2022 Naranjo et al.; Published by Cold Spring Harbor Laboratory Press.
DOI: 10.1101/gad.349659.122
PMID: 36175034 [Indexed for MEDLINE]
8. Nat Commun. 2022 Aug 30;13(1):5105. doi: 10.1038/s41467-022-32455-1.
Transcontinental spread and evolution of Mycobacterium tuberculosis W148
European/Russian clade toward extensively drug resistant tuberculosis.
Merker M(#)(1)(2)(3), Rasigade JP(#)(4)(5)(6), Barbier M(#)(4)(5), Cox H(7),
Feuerriegel S(1)(2), Kohl TA(1)(2), Shitikov E(8), Klaos K(9), Gaudin C(10),
Antoine R(11), Diel R(12)(13), Borrell S(14)(15), Gagneux S(14)(15),
Nikolayevskyy V(16), Andres S(17), Crudu V(18), Supply P(19), Niemann S(20)(21),
Wirth T(22)(23).
Author information:
(1)Molecular and Experimental Mycobacteriology, Research Center Borstel,
Borstel, Germany.
(2)German Center for Infection Research, Partner site
Hamburg-Lübeck-Borstel-Riems, Borstel, Germany.
(3)Evolution of the Resistome, Research Center Borstel, Borstel, Germany.
…
Transmission-driven multi-/extensively drug resistant (M/XDR) tuberculosis (TB)
is the largest single contributor to human mortality due to antimicrobial
resistance. A few major clades of the Mycobacterium tuberculosis complex
belonging to lineage 2, responsible for high prevalence of MDR-TB in Eurasia,
show outstanding transnational distributions. Here, we determined factors
underlying the emergence and epidemic spread of the W148 clade by genome
sequencing and Bayesian demogenetic analyses of 720 isolates from 23 countries.
We dated a common ancestor around 1963 and identified two successive epidemic
expansions in the late 1980s and late 1990s, coinciding with major
socio-economic changes in the post-Soviet Era. These population expansions
favored accumulation of resistance mutations to up to 11 anti-TB drugs, with MDR
evolving toward additional resistances to fluoroquinolones and second-line
injectable drugs within 20 years on average. Timescaled haplotypic density
analysis revealed that widespread acquisition of compensatory mutations was
associated with transmission success of XDR strains. Virtually all W148 strains
harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent
emergence of prpR mutation-mediated drug tolerance was detected. The outstanding
genetic arsenal of this geographically widespread M/XDR strain clade represents
a "perfect storm" that jeopardizes the successful introduction of new
anti-M/XDR-TB antibiotic regimens.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-32455-1
PMCID: PMC9426364
PMID: 36042200 [Indexed for MEDLINE]
9. J Clin Oncol. 2022 Aug 26:JCO2200428. doi: 10.1200/JCO.22.00428. Online ahead of print.
Updated Overall Survival and Exploratory Analysis From Randomized, Phase II EVAN
Study of Erlotinib Versus Vinorelbine Plus Cisplatin Adjuvant Therapy in Stage
IIIA Epidermal Growth Factor Receptor+ Non-Small-Cell Lung Cancer.
Yue D(1), Xu S(2), Wang Q(3), Li X(4), Shen Y(5), Zhao H(6), Chen C(7), Mao
W(8), Liu W(9), Liu J(10), Zhang L(11), Ma H(12), Li Q(13), Yang Y(14), Liu
Y(15), Chen H(16), Zhang Z(1), Zhang B(1), Wang C(1).
Author information:
(1)Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
(2)Harbin Medical University Cancer Hospital, Harbin, China.
(3)Zhongshan Hospital, Fudan University, Shanghai, China.
…
Clinical trials frequently include multiple end points that mature at different
times. The initial report, typically based on the primary end point, may be
published when key planned co-primary or secondary analyses are not yet
available. Clinical Trial Updates provide an opportunity to disseminate
additional results from studies, published in JCO or elsewhere, for which the
primary end point has already been reported.The randomized, open-label, phase II
EVAN study investigated the efficacy (disease-free survival [DFS] and 5-year
overall survival [OS]) and safety of erlotinib versus vinorelbine/cisplatin as
adjuvant chemotherapy after complete resection (R0) for stage III epidermal
growth factor receptor (EGFR) mutation+ non-small-cell lung cancer. We describe
the updated results at the 43-month follow-up. In EVAN, patients were randomly
assigned (1:1) to erlotinib (n = 51) or vinorelbine/cisplatin (n = 51). The
median follow-up was 54.8 and 63.9 months in the erlotinib and chemotherapy
arms, respectively. With erlotinib, the respective 5-year DFS by Kaplan-Meier
analysis was 48.2% (95% CI, 29.4 to 64.7) and 46.2% (95% CI, 27.6 to 62.9) in
the intention-to-treat and per-protocol populations. The median OS was 84.2
months with erlotinib versus 61.1 months with chemotherapy (hazard ratio, 0.318;
95% CI, 0.151 to 0.670). The 5-year survival rates were 84.8% and 51.1% with
erlotinib and chemotherapy, respectively. In whole-exome sequencing analysis,
frequent genes with variants co-occurring at baseline were TP53, MUC16, FAM104B,
KMT5A, and DNAH9. With erlotinib, a single-nucleotide polymorphism mutation in
UBXN11 was associated with significantly worse DFS (P = .01). To our knowledge,
this study is the first to demonstrate clinically meaningful OS improvement with
adjuvant erlotinib compared with chemotherapy in R0 stage III EGFR+
non-small-cell lung cancer.
DOI: 10.1200/JCO.22.00428
PMID: 36027483
10. J Clin Invest. 2022 Aug 25:e157917. doi: 10.1172/JCI157917. Online ahead of
print.
IL20RB mediates tumoral response to osteoclastic niches and promotes bone
metastasis of lung cancer.
He Y(1), Luo W(1), Liu Y(1), Wang Y(1), Ma C(1), Wu Q(1), Tian P(1), He D(1),
Jia Z(1), Lv X(1), Ma YS(2), Yang H(3), Xu K(3), Zhang X(1), Xiao Y(1), Zhang
P(1), Liang Y(1), Fu D(2), Yao F(3), Hu G(1).
Author information:
(1)CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute
of Nutrition and Health, Shanghai, China.
(2)Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Shanghai,
China.
(3)Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai, China.
Bone is a common site of metastasis in lung cancer but the regulatory mechanism
remains incompletely understood. Osteoclasts are known to play crucial roles in
osteolytic bone metastasis by digesting bone matrix and indirectly enhancing
tumor colonization. In this study, we found that IL20RB mediated a direct
tumoral response to osteoclasts. Tumoral expression of IL20RB was associated
with bone metastasis of lung cancer, and functionally IL20RB promoted metastatic
growth of lung cancer cells in bone. Mechanistically, tumor cells induced
osteoclasts to secrete the IL20RB ligand IL19, and IL19 stimulated
IL20RB-expressing tumor cells to activate the downstream JAK1-STAT3 signaling
and enhanced proliferation of tumor cells in bone. Importantly, blocking IL20RB
with a neutralizing antibody significantly suppressed bone metastasis of lung
cancer. Overall, our data revealed a direct pro-tumor role of osteoclastic niche
in bone metastasis and supported IL20RB-targeting approaches for metastasis
treatment.
DOI: 10.1172/JCI157917
PMID: 36006737
11. Nat Chem Biol. 2022 Aug 22. doi: 10.1038/s41589-022-01102-7. Online ahead of
print.
Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium
tuberculosis.
Imai Y(#)(1)(2), Hauk G(#)(3), Quigley J(1), Liang L(1), Son S(1), Ghiglieri
M(1), Gates MF(1), Morrissette M(1), Shahsavari N(1), Niles S(1), Baldisseri
D(4), Honrao C(5), Ma X(5), Guo JJ(5)(6), Berger JM(7), Lewis K(8).
Author information:
(1)Antimicrobial Discovery Center, Department of Biology, Northeastern
University, Boston, MA, USA.
(2)Department of Biomolecular Innovation, Institute for Biomedical Sciences,
Shinshu University, Nagano, Japan.
(3)Department of Biophysics and Biophysical Chemistry, Johns Hopkins University
School of Medicine, Baltimore, MD, USA.
…
The antimicrobial resistance crisis requires the introduction of novel
antibiotics. The use of conventional broad-spectrum compounds selects for
resistance in off-target pathogens and harms the microbiome. This is especially
true for Mycobacterium tuberculosis, where treatment requires a 6-month course
of antibiotics. Here we show that a novel antimicrobial from Photorhabdus
noenieputensis, which we named evybactin, is a potent and selective antibiotic
acting against M. tuberculosis. Evybactin targets DNA gyrase and binds to a site
overlapping with synthetic thiophene poisons. Given the conserved nature of DNA
gyrase, the observed selectivity against M. tuberculosis is puzzling. We found
that evybactin is smuggled into the cell by a promiscuous transporter of
hydrophilic compounds, BacA. Evybactin is the first, but likely not the only,
antimicrobial compound found to employ this unusual mechanism of selectivity.
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41589-022-01102-7
PMID: 35996001
12. J Natl Cancer Inst. 2022 Aug 22:djac154. doi: 10.1093/jnci/djac154. Online ahead of print.
Facilitators and Barriers to Implementation of Lung Cancer Screening: A
Framework Driven Systematic Review.
Sedani AE(1), Davis OC(2), Clifton SC(3), Campbell JE(1), Chou AF(4).
Author information:
(1)Department of Biostatistics and Epidemiology, Hudson College of Public
Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
(2)College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma
City, OK, USA.
(3)Robert M. Bird Health Sciences Library, University of Oklahoma Health
Sciences Center, Oklahoma City, OK, USA.
(4)Department of Family and Preventive Medicine, College of Medicine, University
of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
BACKGROUND: The purpose of this study is to undertake a comprehensive systematic
review to describe multi-level factors (barriers and facilitators) that may
influence the implementation of low-dose chest computed tomography (LDCT) for
lung cancer screening in the United States.
METHODS: Systematic literature searches were performed using six online
databases and citation indexes for peer-reviewed studies, for articles published
from 2013-2021. Studies were classified into three perspectives, based on the
study's unit of analysis: system, healthcare provider, and patient. Barriers and
facilitators identified for each study included in our final review were then
coded and categorized using the Consolidate Framework for Implementation
Research (CFIR) domains.
RESULTS: At the system level, the two most common constructs were external
policy and incentives, and executing the implementation process. At the provider
level, the most common constructs were evidence strength and quality of the
intervention characteristics, patient needs and resources, implementation
climate, and individual's knowledge and beliefs about the intervention. At the
patient-level, the most common constructs were patient needs and resources,
individual's knowledge and beliefs about the intervention, and engaging in the
implementation process. These constructs can act both as facilitators or
barriers to lung cancer screening implementation.
CONCLUSIONS: Applying the CFIR domains and constructs to understand and specify
factors facilitating uptake of lung cancer screening, as well as cataloguing the
lessons learned from previous efforts, help to inform the development and
implementation processes of lung cancer screening programs in the community
setting.
REGISTRATION: PROSPERO, CRD42021247677.
© The Author(s) 2022. Published by Oxford University Press.
DOI: 10.1093/jnci/djac154
PMID: 35993616
13. Lancet Infect Dis. 2022 Aug 10:S1473-3099(22)00500-X. doi:
10.1016/S1473-3099(22)00500-X. Online ahead of print.
Ending tuberculosis in a post-COVID-19 world: a person-centred, equity-oriented
approach.
Ryckman T(1), Robsky K(2), Cilloni L(3), Zawedde-Muyanja S(4), Ananthakrishnan
R(5), Kendall EA(6), Shrestha S(3), Turyahabwe S(7), Katamba A(8), Dowdy DW(9).
Author information:
(1)Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, MD, USA. Electronic address: tryckma1@jh.edu.
(2)Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, MD, USA; Uganda Tuberculosis Implementation Research Consortium,
Kampala, Uganda.
(3)Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, MD, USA.
…
The COVID-19 pandemic has disrupted systems of care for infectious
diseases-including tuberculosis-and has exposed pervasive inequities that have
long marred efforts to combat these diseases. The resulting health disparities
often intersect at the individual and community levels in ways that heighten
vulnerability to tuberculosis. Effective responses to tuberculosis (and other
infectious diseases) must respond to these realities. Unfortunately, current
tuberculosis programmes are generally not designed from the perspectives of
affected individuals and fail to address structural determinants of health
disparities. We describe a person-centred, equity-oriented response that would
identify and focus on communities affected by disparities, tailor interventions
to the mechanisms by which disparities worsen tuberculosis, and address upstream
determinants of those disparities. We detail four key elements of the approach
(data collection, programme design, implementation, and sustainability). We then
illustrate how organisations at multiple levels might partner and adapt current
practices to incorporate these elements. Such an approach could generate more
substantial, sustainable, and equitable reductions in tuberculosis burden at the
community level, highlighting the urgency of restructuring post-COVID-19 health
systems in a more person-centred, equity-oriented way.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00500-X
PMCID: PMC9365311
PMID: 35963272
14. Nat Commun. 2022 Aug 12;13(1):4731. doi: 10.1038/s41467-022-32085-7.
Mycobacterial resistance to zinc poisoning requires assembly of
P-ATPase-containing membrane metal efflux platforms.
Boudehen YM(#)(1)(2), Faucher M(#)(1), Maréchal X(3)(4), Miras R(3), Rech J(5),
Rombouts Y(1), Sénèque O(3), Wallat M(1)(6), Demange P(1), Bouet JY(5), Saurel
O(1), Catty P(3), Gutierrez C(1), Neyrolles O(7).
Author information:
(1)Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de
Toulouse, CNRS, UPS, Toulouse, France.
(2)Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche
en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier,
France.
(3)University Grenoble Alpes, CNRS, CEA, IRIG, Laboratoire de Chimie et Biologie
des Métaux, 38054, Grenoble, France.
…
The human pathogen Mycobacterium tuberculosis requires a P1B-ATPase metal
exporter, CtpC (Rv3270), for resistance to zinc poisoning. Here, we show that
zinc resistance also depends on a chaperone-like protein, PacL1 (Rv3269). PacL1
contains a transmembrane domain, a cytoplasmic region with glutamine/alanine
repeats and a C-terminal metal-binding motif (MBM). PacL1 binds Zn2+, but the
MBM is required only at high zinc concentrations. PacL1 co-localizes with CtpC
in dynamic foci in the mycobacterial plasma membrane, and the two proteins form
high molecular weight complexes. Foci formation does not require flotillin nor
the PacL1 MBM. However, deletion of the PacL1 Glu/Ala repeats leads to loss of
CtpC and sensitivity to zinc. Genes pacL1 and ctpC appear to be in the same
operon, and homologous gene pairs are found in the genomes of other bacteria.
Furthermore, PacL1 colocalizes and functions redundantly with other PacL
orthologs in M. tuberculosis. Overall, our results indicate that PacL proteins
may act as scaffolds that assemble P-ATPase-containing metal efflux platforms
mediating bacterial resistance to metal poisoning.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-32085-7
PMCID: PMC9374683
PMID: 35961955 [Indexed for MEDLINE]
15. J Clin Oncol. 2022 Aug 12:JCO2102911. doi: 10.1200/JCO.21.02911. Online ahead of print.
Updated Analysis of NEJ009: Gefitinib-Alone Versus Gefitinib Plus Chemotherapy
for Non-Small-Cell Lung Cancer With Mutated EGFR.
Miyauchi E(1), Morita S(2), Nakamura A(3), Hosomi Y(4), Watanabe K(5), Ikeda
S(6), Seike M(7), Fujita Y(8), Minato K(9), Ko R(10), Harada T(11), Hagiwara
K(12), Kobayashi K(13), Nukiwa T(14), Inoue A(15); North-East Japan Study Group.
Author information:
(1)Department of Respiratory Medicine, Tohoku University Hospital, Sendai,
Japan.
(2)Department of Biomedical Statistics and Bioinformatics, Kyoto University
Graduate School of Medicine, Kyoto, Japan.
(3)Department of Respiratory Medicine, Sendai Kosei Hospital, Sendai, Japan.
…
Clinical trials frequently include multiple end points that mature at different
times. The initial report, typically based on the primary end point, may be
published when key planned coprimary or secondary analyses are not yet
available. Clinical Trial Updates provide an opportunity to disseminate
additional results from studies, published in JCO or elsewhere, for which the
primary end point has already been reported.In a randomized, open-label, phase
III NEJ009 study, gefitinib plus chemotherapy significantly improved
progression-free survival (PFS) and overall survival (OS) compared with
gefitinib-alone in patients with untreated non-small-cell lung cancer harboring
mutations in epidermal growth factor receptor. Herein, we report the updated
survival outcome and long-term tolerability. Patients were randomly assigned to
gefitinib (gefitinib 250 mg orally, once daily) and gefitinib combined with
carboplatin plus pemetrexed (GCP in a 3-week cycle for six cycles followed by
concurrent gefitinib and pemetrexed maintenance) groups. At the data cutoff (May
22, 2020), GCP demonstrated significantly better PFS2 (hazard ratio, 0.77; 95%
CI, 0.62 to 0.97; P = .027) than gefitinib. However, the updated median OS was
38.5 months (95% CI, 31.1 to 47.1) and 49.0 months (95% CI, 41.8 to 56.7) in the
gefitinib and GCP groups, respectively (hazard ratio, 0.82; 95% CI, 0.64 to
1.06; P = .127). The OS in both groups was similar for the overall patient
population. No severe adverse events occurred since the first report. This
updated analysis revealed that the GCP regimen improved PFS and PFS2 with an
acceptable safety profile compared with gefitinib-alone. GCP is more efficient
than gefitinib monotherapy as a first-line treatment for non-small-cell lung
cancer with epidermal growth factor receptor mutations.
DOI: 10.1200/JCO.21.02911
PMID: 35960896
16. Am J Respir Crit Care Med. 2022 Aug 11. doi: 10.1164/rccm.202201-0144OC. Online ahead of print.
Forgiveness Is the Attribute of the Strong: Nonadherence and Regimen-Shortening
in Drug-Sensitive TB.
Stagg HR(1), Thompson JA(2), Lipman MC(3), Sloan DJ(4), Flook M(5), Fielding
KL(2); Critical Path to TB Drug Regimens.
Author information:
(1)University of Edinburgh, Usher Institute of Population Health Sciences and
Informatics, Edinburgh, United Kingdom of Great Britain and Northern Ireland;
helen.stagg@ed.ac.uk.
(2)London School of Hygiene and Tropical Medicine, London, United Kingdom of
Great Britain and Northern Ireland.
(3)University College London, Respiratory Medicine, London, United Kingdom of
Great Britain and Northern Ireland.
(4)University of St Andrews, Medicine, St Andrews, United Kingdom of Great
Britain and Northern Ireland.
(5)University of Edinburgh, Usher Institute of Population Health Sciences and
Informatics, Edinburgh, United Kingdom of Great Britain and Northern Ireland.
RATIONALE: 'Forgiveness' charts the ability of a drug or regimen to withstand
non-adherence without negative clinical consequences.
OBJECTIVES: We aimed to determine the influence of regimen length, regimen drugs
and dosing, and when during treatment non-adherence occurs on the forgiveness of
anti-tuberculosis regimens.
METHODS: Using data from three randomised controlled trials comparing
experimental four-month regimens for drug-sensitive tuberculosis with the
standard six-month regimen, we used generalised linear models to examine how the
risk of a negative composite outcome changed as dose-taking decreased. The
percentage of doses taken and absolute number of doses missed were calculated,
during the intensive and continuation phases of treatment, and overall. A
mediation analysis was undertaken to determine how much of the association
between intensive phase dose-taking and the negative composite outcome was
mediated through continuation phase dose-taking.
MEASUREMENTS AND MAIN RESULTS: Forgiveness of the four-month and six-month
regimens did not differ for any treatment period. Importantly, four-month
regimens were no less forgiving of small numbers of absolute missed doses than
the six-month regimen (e.g. for 3-7 missed doses versus no missed doses
(baseline), six-month regimen adjusted risk ratio 1.65 (95% confidence interval
0.80-3.41) and four-month regimens 1.80 (1.33-2.45)). No four-month regimen was
conclusively more forgiving than another. We found evidence of mediation by
continuation phase dose-taking on the intensive phase dose-taking and negative
composite outcome relationship.
CONCLUSIONS: With the current appetite for, and progress towards, shorter
drug-sensitive tuberculosis regimens worldwide, we offer reassurance that
shorter regimens are not necessarily less forgiving of non-adherence. Given the
importance of continuation phase adherence, patient support during this period
should not be neglected.
DOI: 10.1164/rccm.202201-0144OC
PMID: 35952354
17. PLoS Biol. 2022 Aug 9;20(8):e3001755. doi: 10.1371/journal.pbio.3001755.
eCollection 2022 Aug.
Genome-wide association studies of global Mycobacterium tuberculosis resistance
to 13 antimicrobials in 10,228 genomes identify new resistance mechanisms.
The CRyPTIC Consortium.
Collaborators: Earle SG, Wilson DJ, Barilar I, Battaglia S, Borroni E, Brandao
AP, Brankin A, Cabibbe AM, Carter J, Chetty D, Cirillo DM, Claxton P, Clifton
DA, …
Comment in
A data compendium associating the genomes of 12,289 Mycobacterium
tuberculosis isolates with quantitative resistance phenotypes to 13 antibiotics.
The emergence of drug-resistant tuberculosis is a major global public health
concern that threatens the ability to control the disease. Whole-genome
sequencing as a tool to rapidly diagnose resistant infections can transform
patient treatment and clinical practice. While resistance mechanisms are well
understood for some drugs, there are likely many mechanisms yet to be uncovered,
particularly for new and repurposed drugs. We sequenced 10,228 Mycobacterium
tuberculosis (MTB) isolates worldwide and determined the minimum inhibitory
concentration (MIC) on a grid of 2-fold concentration dilutions for 13
antimicrobials using quantitative microtiter plate assays. We performed
oligopeptide- and oligonucleotide-based genome-wide association studies using
linear mixed models to discover resistance-conferring mechanisms not currently
catalogued. Use of MIC over binary resistance phenotypes increased sample
heritability for the new and repurposed drugs by 26% to 37%, increasing our
ability to detect novel associations. For all drugs, we discovered uncatalogued
variants associated with MIC, including in the Rv1218c promoter binding site of
the transcriptional repressor Rv1219c (isoniazid), upstream of the vapBC20
operon that cleaves 23S rRNA (linezolid) and in the region encoding an α-helix
lining the active site of Cyp142 (clofazimine, all p < 10-7.7). We observed that
artefactual signals of cross-resistance could be unravelled based on the
relative effect size on MIC. Our study demonstrates the ability of very
large-scale studies to substantially improve our knowledge of genetic variants
associated with antimicrobial resistance in M. tuberculosis.
DOI: 10.1371/journal.pbio.3001755
PMCID: PMC9363015
PMID: 35944070 [Indexed for MEDLINE]
18. PLoS Biol. 2022 Aug 9;20(8):e3001721. doi: 10.1371/journal.pbio.3001721.
eCollection 2022 Aug.
A data compendium associating the genomes of 12,289 Mycobacterium tuberculosis
isolates with quantitative resistance phenotypes to 13 antibiotics.
The CRyPTIC Consortium.
Collaborators: Brankin A, Malone KM, Barilar I, Battaglia S, Borroni E, Brandao
AP, Cabibbe AM, Carter J, …
Comment in
Genome-wide association studies of global Mycobacterium tuberculosis
resistance to thirteen antimicrobials in 10,228 genomes identify new resistance
mechanisms.
The Comprehensive Resistance Prediction for Tuberculosis: an International
Consortium (CRyPTIC) presents here a data compendium of 12,289 Mycobacterium
tuberculosis global clinical isolates, all of which have undergone whole-genome
sequencing and have had their minimum inhibitory concentrations to 13
antitubercular drugs measured in a single assay. It is the largest matched
phenotypic and genotypic dataset for M. tuberculosis to date. Here, we provide a
summary detailing the breadth of data collected, along with a description of how
the isolates were selected, collected, and uniformly processed in CRyPTIC
partner laboratories across 23 countries. The compendium contains 6,814 isolates
resistant to at least 1 drug, including 2,129 samples that fully satisfy the
clinical definitions of rifampicin resistant (RR), multidrug resistant (MDR),
pre-extensively drug resistant (pre-XDR), or extensively drug resistant (XDR).
The data are enriched for rare resistance-associated variants, and the current
limits of genotypic prediction of resistance status (sensitive/resistant) are
presented by using a genetic mutation catalogue, along with the presence of
suspected resistance-conferring mutations for isolates resistant to the newly
introduced drugs bedaquiline, clofazimine, delamanid, and linezolid. Finally, a
case study of rifampicin monoresistance demonstrates how this compendium could
be used to advance our genetic understanding of rare resistance phenotypes. The
data compendium is fully open source and it is hoped that it will facilitate and
inspire future research for years to come.
DOI: 10.1371/journal.pbio.3001721
PMCID: PMC9363010
PMID: 35944069 [Indexed for MEDLINE]
19. Am J Respir Crit Care Med. 2022 Aug 9. doi: 10.1164/rccm.202112-2758OC. Online ahead of print.
In Utero and Childhood/Adolescence Exposure to Tobacco Smoke, Genetic Risk and
Lung Cancer Incidence and Mortality in Adulthood.
He H(1), He MM(2), Wang H(3), Qiu W(3), Liu L(4), Long L(5), Shen Q(3), Zhang
S(3), Qin S(3), Lu Z(3), Cai Y(3), Zhang M(3), Niu S(3), Li J(6), Shen N(4), Zhu
Y(7), Tian J(7), Chang J(3), Miao X(7), Zhong R(8).
Author information:
(1)Huazhong University of Science and Technology, School of Public Health,
Tongji Medical College, Wuhan, Hubei , China.
(2)Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
(3)Huazhong University of Science and Technology, Wuhan, Hubei , China.
…
RATIONALE: The individual effects of early-life tobacco smoke exposure and its
interactions with genetic factors on lung cancer in adulthood remain unclear.
OBJECTIVES: To investigate the associations between early-life tobacco exposures
as well as their interactions with polygenic risk scores (PRSs) and lung cancer
incidence and mortality.
METHODS: A total of 432,831 participants from the UK Biobank study were
included. We estimated the associations of in utero exposure to tobacco smoke,
the age of smoking initiation and their interactions with PRSs with lung cancer
incidence and mortality in adulthood using Cox proportional hazard models.
MEASUREMENTS AND MAIN RESULTS: Lung cancer incidence [hazard ratio (HR): 1.59,
95% confidence interval (CI), 1.44-1.76] increased among participants with in
utero tobacco exposure. Multivariable-adjusted HRs (with 95% CIs) of lung cancer
incidence for smoking initiation in adulthood, adolescence, and childhood (vs.
never smokers) were 6.10 (5.25-7.09), 9.56 (8.31-11.00), and 15.15 (12.90-17.79)
(Ptrend<0.001). Similar findings were observed in lung cancer mortality.
Participants with high PRSs and in utero tobacco exposure (vs. low PRSs
participants without in utero exposure) had HR of 2.35 for lung cancer incidence
(95%CI, 1.97-2.80, Pinteraction=0.089) and 2.43 for mortality (95% CI,
2.05-2.88, Pinteraction=0.032). High PRSs with smoking initiation in childhood
(vs. never smokers with low PRSs) had HR of 18.71 for incidence (95% CI,
14.21-24.63, Pinteraction=0.004) and 19.74 for mortality (95%CI, 14.98-26.01,
Pinteraction=0.033).
CONCLUSIONS: In utero and childhood/adolescence exposure to tobacco smoke and
its interaction with genetic factors may substantially increase the risks of
lung cancer incidence and mortality in adulthood.
DOI: 10.1164/rccm.202112-2758OC
PMID: 35943859
20. Nat Commun. 2022 Aug 8;13(1):4455. doi: 10.1038/s41467-022-32043-3.
A long-acting formulation of rifabutin is effective for prevention and treatment
of Mycobacterium tuberculosis.
Kim M(#)(1)(2)(3), Johnson CE(#)(1)(2)(3), Schmalstig AA(4), Annis A(4), Wessel
SE(1)(2)(3), Van Horn B(5), Schauer A(5), Exner AA(6), Stout JE(7), Wahl
A(1)(2)(3), Braunstein M(4), Victor Garcia J(8)(9)(10), Kovarova M(11)(12)(13).
Author information:
(1)International Center for the Advancement of Translational Science, University
of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
(2)Division of Infectious Diseases, Department of Medicine, University of North
Carolina at Chapel Hill, Chapel Hill, NC, USA.
(3)Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel
Hill, NC, USA.
…
Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis
(Mtb) and is a major cause of morbidity and mortality. Successful treatment
requires strict adherence to drug regimens for prolonged periods of time.
Long-acting (LA) delivery systems have the potential to improve adherence. Here,
we show the development of LA injectable drug formulations of the anti-TB drug
rifabutin made of biodegradable polymers and biocompatible solvents that
solidifies after subcutaneous injection. Addition of amphiphilic compounds
increases drug solubility, allowing to significantly increase formulation drug
load. Solidified implants have organized microstructures that change with
formulation composition. Higher drug load results in smaller pore size that
alters implant erosion and allows sustained drug release. The translational
relevance of these observations in BALB/c mice is demonstrated by (1) delivering
high plasma drug concentrations for 16 weeks, (2) preventing acquisition of Mtb
infection, and (3) clearing acute Mtb infection from the lung and other tissues.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-32043-3
PMCID: PMC9360445
PMID: 35941109 [Indexed for MEDLINE]
21. Lancet Infect Dis. 2022 Aug 4:S1473-3099(22)00425-X. doi:
10.1016/S1473-3099(22)00425-X. Online ahead of print.
Nationwide tuberculosis outbreak in the USA linked to a bone graft product: an
outbreak report.
Schwartz NG(1), Hernandez-Romieu AC(2), Annambhotla P(3), Filardo TD(4),
Althomsons SP(5), Free RJ(3), Li R(2), Wyatt Wilson W(2), Deutsch-Feldman M(4),
Drees M(6), Hanlin E(7), White K(8), Lehman KA(9), Thacker TC(9), Brubaker
SA(10), Clark B(10), Basavaraju SV(3), Benowitz I(3), Burton Glowicz J(3), Cowan
LS(5), Starks AM(5), Bamrah Morris S(5), LoBue P(5), Stewart RJ(5), Wortham
JM(5), Haddad MB(5); Bone Allograft Tuberculosis Investigators.
Author information:
(1)Division of Tuberculosis Elimination, National Center for HIV, Viral
Hepatitis, STD, and TB Prevention, US Centers for Disease Control and
Prevention, Atlanta, GA, USA; Epidemic Intelligence Service, US Centers for
Disease Control and Prevention, Atlanta, GA, USA. Electronic address:
nschwartz@cdc.gov.
(2)Epidemic Intelligence Service, US Centers for Disease Control and Prevention,
Atlanta, GA, USA; Division of Healthcare Quality Promotion, National Center for
Emerging and Zoonotic Infectious Diseases, US Centers for Disease Control and
Prevention, Atlanta, GA, USA.
(3)Division of Healthcare Quality Promotion, National Center for Emerging and
Zoonotic Infectious Diseases, US Centers for Disease Control and Prevention,
Atlanta, GA, USA.
…
BACKGROUND: Mycobacterium tuberculosis transmission through solid organ
transplantation has been well described, but transmission through transplanted
tissues is rare. We investigated a tuberculosis outbreak in the USA linked to a
bone graft product containing live cells derived from a single deceased donor.
METHODS: In this outbreak report, we describe the management and severity of the
outbreak and identify opportunities to improve tissue transplant safety in the
USA. During early June, 2021, the US Centers for Disease Control and Prevention
(CDC) worked with state and local health departments and health-care facilities
to locate and sequester unused units from the recalled lot and notify, evaluate,
and treat all identified product recipients. Investigators from CDC and the US
Food and Drug Administration (FDA) reviewed donor screening and tissue
processing. Unused product units from the recalled and other donor lots were
tested for the presence of M tuberculosis using real-time PCR (rt PCR) assays
and culture. M tuberculosis isolates from unused product and recipients were
compared using phylogenetic analysis.
FINDINGS: The tissue donor (a man aged 80 years) had unrecognised risk factors,
symptoms, and signs consistent with tuberculosis. Bone was procured from the
deceased donor and processed into 154 units of bone allograft product containing
live cells, which were distributed to 37 hospitals and ambulatory surgical
centres in 20 US states between March 1 and April 2, 2021. From March 3 to June
1, 2021, 136 (88%) units were implanted into 113 recipients aged 24-87 years in
18 states (some individuals received multiple units). The remaining 18 units
(12%) were located and sequestered. 87 (77%) of 113 identified product
recipients had microbiological or imaging evidence of tuberculosis disease.
Eight product recipients died 8-99 days after product implantation (three deaths
were attributed to tuberculosis after recognition of the outbreak). All 105
living recipients started treatment for tuberculosis disease at a median of 69
days (IQR 56-81) after product implantation. M tuberculosis was detected in all
eight sequestered unused units tested from the recalled donor lot, but not in
lots from other donors. M tuberculosis isolates from unused product and
recipients were more than 99·99% genetically identical.
INTERPRETATION: Donor-derived transmission of M tuberculosis via bone allograft
resulted in substantial morbidity and mortality. All prospective tissue and
organ donors should be routinely assessed for tuberculosis risk factors and
clinical findings. When these are present, laboratory testing for M tuberculosis
should be strongly considered.
FUNDING: None.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00425-X
PMID: 35934016
22. Immunol Rev. 2022 Aug;309(1):97-122. doi: 10.1111/imr.13116. Epub 2022 Jul 12.
Transcriptomics for child and adolescent tuberculosis.
Kaforou M(1), Broderick C(1), Vito O(1), Levin M(1), Scriba TJ(2), Seddon
JA(1)(3).
Author information:
(1)Department of Infectious Disease, Imperial College London, London, UK.
(2)South African Tuberculosis Vaccine Initiative, Institute of Infectious
Disease and Molecular Medicine and Division of Immunology, Department of
Pathology, University of Cape Town, Cape Town, South Africa.
(3)Desmond Tutu TB Centre, Department of Paediatrics and Child Health,
Stellenbosch University, Cape Town, South Africa.
Tuberculosis (TB) in humans is caused by Mycobacterium tuberculosis (Mtb). It is
estimated that 70 million children (<15 years) are currently infected with Mtb,
with 1.2 million each year progressing to disease. Of these, a quarter die. The
risk of progression from Mtb infection to disease and from disease to death is
dependent on multiple pathogen and host factors. Age is a central component in
all these transitions. The natural history of TB in children and adolescents is
different to adults, leading to unique challenges in the development of
diagnostics, therapeutics, and vaccines. The quantification of RNA
transcripts in specific cells or in the peripheral blood, using high-throughput
methods, such as microarray analysis or RNA-Sequencing, can shed light into the
host immune response to Mtb during infection and disease, as well as
understanding treatment response, disease severity, and vaccination, in a global
hypothesis-free manner. Additionally, gene expression profiling can be used for
biomarker discovery, to diagnose disease, predict future disease progression and
to monitor response to treatment. Here, we review the role of transcriptomics in
children and adolescents, focused mainly on work done in blood, to understand
disease biology, and to discriminate disease states to assist clinical
decision-making. In recent years, studies with a specific pediatric and
adolescent focus have identified blood gene expression markers with diagnostic
or prognostic potential that meet or exceed the current sensitivity and
specificity targets for diagnostic tools. Diagnostic and prognostic gene
expression signatures identified through high-throughput methods are currently
being translated into diagnostic tests.
© 2022 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.
DOI: 10.1111/imr.13116
PMID: 35818983 [Indexed for MEDLINE]
23. Lancet Infect Dis. 2022 Aug;22(8):1172-1180. doi: 10.1016/S1473-3099(22)00149-9. Epub 2022 May 17.
Prevalence of bacteriologically confirmed pulmonary tuberculosis in South
Africa, 2017-19: a multistage, cluster-based, cross-sectional survey.
Moyo S(1), Ismail F(2), Van der Walt M(3), Ismail N(4), Mkhondo N(5), Dlamini
S(6), Mthiyane T(3), Chikovore J(7), Oladimeji O(7), Mametja D(8), Maribe P(3),
Seocharan I(3), Ximiya P(6), Law I(4), Tadolini M(9), Zuma K(7), Manda S(3),
Sismanidis C(4), Pillay Y(10), Mvusi L(6).
Author information:
(1)Human Sciences Research Council, Cape Town, South Africa; School of Public
Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
Electronic address: smoyo@hsrc.ac.za.
(2)Centre for Tuberculosis, National Institute for Communicable Diseases,
Johannesburg, South Africa; Department of Medical Microbiology, University of
Pretoria, Pretoria, South Africa.
(3)South African Medical Research Council, Cape Town, South Africa.
…
Erratum in
Lancet Infect Dis. 2022 Jul;22(7):e177.
Comment in
Lancet Infect Dis. 2022 Aug;22(8):1094-1096.
Lancet Infect Dis. 2022 Sep;22(9):1273.
BACKGROUND: Tuberculosis remains an important clinical and public health issue
in South Africa, which has one of the highest tuberculosis burdens in the world.
We aimed to estimate the burden of bacteriologically confirmed pulmonary
tuberculosis among people aged 15 years or older in South Africa.
METHODS: This multistage, cluster-based, cross-sectional survey included
eligible residents (age ≥15 years, who had slept in a house for ≥10 nights in
the preceding 2 weeks) in 110 clusters nationally (cluster size of 500 people;
selected by probability proportional-to-population size sampling). Participants
completed face-to-face symptom questionnaires (for cough, weight loss, fever,
and night sweats) and manually read digital chest X-ray screening. Screening was
recorded as positive if participants had at least one symptom or an abnormal
chest X-ray suggestive of tuberculosis, or a combination thereof. Sputum samples
from participants who were screen-positive were tested by the Xpert MTB/RIF
Ultra assay (first sample) and Mycobacteria Growth Indicator Tube culture
(second sample), with optional HIV testing. Participants with a positive
Mycobacterium tuberculosis complex culture were considered positive for
bacteriologically confirmed pulmonary tuberculosis; when culture was not
positive, participants with a positive Xpert MTB/RIF Ultra result with an
abnormal chest X-ray suggestive of active tuberculosis and without current or
previous tuberculosis were considered positive for bacteriologically confirmed
pulmonary tuberculosis.
FINDINGS: Between Aug 15, 2017, and July 28, 2019, 68 771 people were enumerated
from 110 clusters, with 53 250 eligible to participate in the survey, of whom
35 191 (66·1%) participated. 9066 (25·8%) of 35 191 participants were
screen-positive and 234 (0·7%) were identified as having bacteriologically
confirmed pulmonary tuberculosis. Overall, the estimated prevalence of
bacteriologically confirmed pulmonary tuberculosis was 852 cases (95% CI
679-1026) per 100 000 population; the prevalence was highest in people aged
35-44 years (1107 cases [95% CI 703-1511] per 100 000 population) and those aged
65 years or older (1104 cases [680-1528] per 100 000 population). The estimated
prevalence was approximately 1·6 times higher in men than in women (1094 cases
[95% CI 835-1352] per 100 000 population vs 675 cases [494-855] per 100 000
population). 135 (57·7%) of 234 participants with tuberculosis screened positive
by chest X-ray only, 16 (6·8%) by symptoms only, and 82 (35·9%) by both. 55
(28·8%) of 191 participants with tuberculosis with known HIV status were
HIV-positive.
INTERPRETATION: Pulmonary tuberculosis prevalence in this survey was high,
especially in men. Despite the ongoing burden of HIV, many participants with
tuberculosis in this survey did not have HIV. As more than half of the
participants with tuberculosis had an abnormal chest X-ray without symptoms,
prioritising chest X-ray screening could substantially increase case finding.
FUNDING: Global Fund, Bill & Melinda Gates Foundation, USAID.
World Health Organization; licensee Elsevier. This is an Open Access article
published under the CC BY 3.0 IGO license which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is
properly cited. In any use of this article, there should be no suggestion that
WHO endorses any specific organisation, products or services. The use of the WHO
logo is not permitted. This notice should be preserved along with the article's
original URL.
DOI: 10.1016/S1473-3099(22)00149-9
PMCID: PMC9300471
PMID: 35594897 [Indexed for MEDLINE]
24. J Clin Oncol. 2022 Aug 1;40(22):2491-2507. doi: 10.1200/JCO.22.00687. Epub 2022 May 16.
Exercise, Diet, and Weight Management During Cancer Treatment: ASCO Guideline.
Ligibel JA(1), Bohlke K(2), May AM(3), Clinton SK(4), Demark-Wahnefried W(5),
Gilchrist SC(6), Irwin ML(7), Late M(8), Mansfield S(9), Marshall TF(10),
Meyerhardt JA(1), Thomson CA(11), Wood WA(12), Alfano CM(13).
Author information:
(1)Dana-Farber Cancer Institute, Boston, MA.
(2)American Society of Clinical Oncology, Alexandria, VA.
(3)University Medical Center Utrecht, Utrecht University, Utrecht, the
Netherlands.
…
PURPOSE: To provide guidance on exercise, diet, and weight management during
active cancer treatment in adults.
METHODS: A systematic review of the literature identified systematic reviews and
randomized controlled trials evaluating the impact of aerobic and resistance
exercise, specific diets and foods, and intentional weight loss and avoidance of
weight gain in adults during cancer treatment, on quality of life, treatment
toxicity, and cancer control. PubMed and the Cochrane Library were searched from
January 2000 to May 2021. ASCO convened an Expert Panel to review the evidence
and formulate recommendations.
RESULTS: The evidence base consisted of 52 systematic reviews (42 for exercise,
nine for diet, and one for weight management), and an additional 23 randomized
controlled trials. The most commonly studied types of cancer were breast,
prostate, lung, and colorectal. Exercise during cancer treatment led to
improvements in cardiorespiratory fitness, strength, fatigue, and other
patient-reported outcomes. Preoperative exercise in patients with lung cancer
led to a reduction in postoperative length of hospital stay and complications.
Neutropenic diets did not decrease risk of infection during cancer treatment.
RECOMMENDATIONS: Oncology providers should recommend regular aerobic and
resistance exercise during active treatment with curative intent and may
recommend preoperative exercise for patients undergoing surgery for lung cancer.
Neutropenic diets are not recommended to prevent infection in patients with
cancer during active treatment. Evidence for other dietary and weight loss
interventions during cancer treatment was very limited. The guideline discusses
special considerations, such as exercise in individuals with advanced cancer,
and highlights the critical need for more research in this area, particularly
regarding diet and weight loss interventions during cancer treatment.Additional
information is available at www.asco.org/supportive-care-guidelines.
DOI: 10.1200/JCO.22.00687
PMID: 35576506 [Indexed for MEDLINE]
25. Nat Rev Clin Oncol. 2022 Aug;19(8):499-514. doi: 10.1038/s41571-022-00639-9.
Epub 2022 May 9.
Third-generation EGFR and ALK inhibitors: mechanisms of resistance and
management.
Cooper AJ(1), Sequist LV(1), Lin JJ(2).
Author information:
(1)Department of Medicine, Massachusetts General Hospital Cancer Center, Boston,
MA, USA.
(2)Department of Medicine, Massachusetts General Hospital Cancer Center, Boston,
MA, USA. jjlin1@partners.org.
Erratum in
Nat Rev Clin Oncol. 2022 Aug 15;:
The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic
drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed
treatment paradigm for patients with advanced-stage disease. Numerous EGFR and
ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients
with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in
the availability of the highly effective third-generation TKIs osimertinib and
lorlatinib, respectively. Despite their marked efficacy, resistance to these
agents remains an unsolved fundamental challenge. Both 'on-target' mechanisms
(largely mediated by acquired resistance mutations in the kinase domains of EGFR
or ALK) and 'off-target' mechanisms of resistance (mediated by non-target kinase
alterations such as bypass signalling activation or phenotypic transformation)
have been identified in patients with disease progression on osimertinib or
lorlatinib. A growing understanding of the biology and spectrum of these
mechanisms of resistance has already begun to inform the development of more
effective therapeutic strategies. In this Review, we discuss the development of
third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance,
and approaches to tackling resistance in the clinic, ranging from novel
fourth-generation TKIs to combination regimens and other investigational
therapies.
© 2022. Springer Nature Limited.
DOI: 10.1038/s41571-022-00639-9
PMID: 35534623 [Indexed for MEDLINE]
26. J Natl Cancer Inst. 2022 Aug 8;114(8):1159-1166. doi: 10.1093/jnci/djac087.
Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation
Burden.
Gabriel AAG(1), Atkins JR(1), Penha RCC(1), Smith-Byrne K(1)(2), Gaborieau V(1),
Voegele C(1), Abedi-Ardekani B(1), Milojevic M(1), Olaso R(3), Meyer V(3),
Boland A(3), Deleuze JF(3), Zaridze D(4), Mukeriya A(4), Swiatkowska B(5),
Janout V(6), Schejbalová M(7), Mates D(8), Stojšić J(9), Ognjanovic M(10); ILCCO
consortium, Witte JS(11), Rashkin SR(11)(12), Kachuri L(11), Hung RJ(13), Kar
S(14)(15), Brennan P(1), Sertier AS(16), Ferrari A(16), Viari A(16)(17),
Johansson M(1), Amos CI(18), Foll M(1), McKay JD(1).
Author information:
(1)Genomic Epidemiology Branch, International Agency for Research on
Cancer/World Health Organization (IARC/WHO), Lyon, France.
(2)Cancer Epidemiology Unit, Nuffield Department of Population Health,
University of Oxford, Oxford, England.
(3)Université Paris-Saclay, The French Alternative Energies and Atomic Energy
Commission (CEA), Centre National de Recherche en Génomique Humaine (CNRGH),
Evry, France.
…
BACKGROUND: Germline genetic variation contributes to lung cancer (LC)
susceptibility. Previous genome-wide association studies (GWAS) have implicated
susceptibility loci involved in smoking behaviors and DNA repair genes, but
further work is required to identify susceptibility variants.
METHODS: To identify LC susceptibility loci, a family history-based genome-wide
association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387
controls) was combined with a previous LC GWAS (29 266 patients, 56 450
controls) by meta-analysis. Colocalization was used to explore candidate genes
and overlap with existing traits at discovered susceptibility loci. Polygenic
risk scores (PRS) were tested within an independent validation cohort (1 666 LC
patients vs 6 664 controls) using variants selected from the LC susceptibility
loci and a novel selection approach using published GWAS summary statistics.
Finally, the effects of the LC PRS on somatic mutational burden were explored in
patients whose tumor resections have been profiled by exome (n = 685) and genome
sequencing (n = 61). Statistical tests were 2-sided.
RESULTS: The GWAx-GWAS meta-analysis identified 8 novel LC loci. Colocalization
implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking
propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these
variants, as well as subgenome-wide significant variants related to expression
quantitative trait loci and/or smoking propensity, assisted in LC genetic risk
prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45;
P < .001). Patients with higher genetic PRS loads of smoking-related variants
tended to have higher mutation burdens in their lung tumors.
CONCLUSIONS: This study has expanded the number of LC susceptibility loci and
provided insights into the molecular mechanisms by which these susceptibility
variants contribute to LC development.
© The Author(s) 2022. Published by Oxford University Press.
DOI: 10.1093/jnci/djac087
PMCID: PMC9360465
PMID: 35511172 [Indexed for MEDLINE]
