2022年
No.12
Filters applied: from 2022/12/1 - 2022/12/25.
1. Lancet. 2022 Dec 20:S0140-6736(22)01694-4. doi: 10.1016/S0140-6736(22)01694-4. Online ahead of print.
Lung cancer screening.
Adams SJ(1), Stone E(2), Baldwin DR(3), Vliegenthart R(4), Lee P(5), Fintelmann
FJ(6).
Author information:
(1)Department of Radiology, Massachusetts General Hospital, Boston, MA, USA;
Harvard Medical School, Boston, MA, USA. Electronic address:
scott.adams@usask.ca.
(2)Faculty of Medicine, University of New South Wales and Department of Lung
Transplantation and Thoracic Medicine, St Vincent's Hospital, Sydney, NSW,
Australia.
(3)Respiratory Medicine Unit, David Evans Research Centre, Nottingham University
Hospitals NHS Trust, Nottingham, UK.
(4)Department of Radiology, University Medical Center Groningen, Groningen,
Netherlands.
(5)Division of Respiratory and Critical Care Medicine, National University
Hospital and National University of Singapore, Singapore.
(6)Department of Radiology, Massachusetts General Hospital, Boston, MA, USA;
Harvard Medical School, Boston, MA, USA.
Randomised controlled trials, including the National Lung Screening Trial (NLST)
and the NELSON trial, have shown reduced mortality with lung cancer screening
with low-dose CT compared with chest radiography or no screening. Although
research has provided clarity on key issues of lung cancer screening,
uncertainty remains about aspects that might be critical to optimise clinical
effectiveness and cost-effectiveness. This Review brings together current
evidence on lung cancer screening, including an overview of clinical trials,
considerations regarding the identification of individuals who benefit from lung
cancer screening, management of screen-detected findings, smoking cessation
interventions, cost-effectiveness, the role of artificial intelligence and
biomarkers, and current challenges, solutions, and opportunities surrounding the
implementation of lung cancer screening programmes from an international
perspective. Further research into risk models for patient selection,
personalised screening intervals, novel biomarkers, integrated cardiovascular
disease and chronic obstructive pulmonary disease assessments, smoking cessation
interventions, and artificial intelligence for lung nodule detection and risk
stratification are key opportunities to increase the efficiency of lung cancer
screening and ensure equity of access.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(22)01694-4
PMID: 36563698
2. N Engl J Med. 2022 Dec 22;387(25):2331-2343. doi: 10.1056/NEJMoa2117166.
A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.
Nyang'wa BT(1), Berry C(1), Kazounis E(1), Motta I(1), Parpieva N(1), Tigay
Z(1), Solodovnikova V(1), Liverko I(1), Moodliar R(1), Dodd M(1), Ngubane N(1),
Rassool M(1), McHugh TD(1), Spigelman M(1), Moore DAJ(1), Ritmeijer K(1), du
Cros P(1), Fielding K(1); TB-PRACTECAL Study Collaborators.
Author information:
(1)From the Public Health Department, Operational Center Amsterdam (OCA),
Médecins sans Frontières, Amsterdam (B.-T.N., K.R.); the Public Health
Department, OCA, Médecins sans Frontières (C.B., E.K., I.M.), the London School
of Hygiene and Tropical Medicine (B.-T.N., M.D., D.A.J.M., K.F.), and University
College London (T.D.M.) - all in London; the Republican Specialized Scientific
and Practical Medical Center of Phthisiology and Pulmonology, Tashkent (N.P.,
I.L.), and the Republican Phthisiological Hospital No. 2, Nukus (Z.T.) - both in
Uzbekistan; the Republican Scientific and Practical Center for Pulmonology and
Tuberculosis, Minsk, Belarus (V.S.); THINK TB and HIV Investigative Network,
Durban (R.M.), and Wits Health Consortium, Johannesburg (N.N., M.R.) - both in
South Africa; the Global Alliance for TB Drug Development, New York (M.S.); and
the Burnet Institute, Melbourne, VIC, Australia (P.C.).
BACKGROUND: In patients with rifampin-resistant tuberculosis, all-oral treatment
regimens that are more effective, shorter, and have a more acceptable
side-effect profile than current regimens are needed.
METHODS: We conducted an open-label, phase 2-3, multicenter, randomized,
controlled, noninferiority trial to evaluate the efficacy and safety of three
24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis.
Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or
older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage
2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and
moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen.
The primary outcome was an unfavorable status (a composite of death, treatment
failure, treatment discontinuation, loss to follow-up, or recurrence of
tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12
percentage points.
RESULTS: Recruitment was terminated early. Of 301 patients in stage 2 of the
trial, 145, 128, and 90 patients were evaluable in the intention-to-treat,
modified intention-to-treat, and per-protocol populations, respectively. In the
modified intention-to-treat analysis, 11% of the patients in the BPaLM group and
48% of those in the standard-care group had a primary-outcome event (risk
difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22).
In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of
those in the standard-care group had a primary-outcome event (risk difference,
-9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the
incidence of adverse events of grade 3 or higher or serious adverse events was
lower in the BPaLM group than in the standard-care group (19% vs. 59%).
CONCLUSIONS: In patients with rifampin-resistant pulmonary tuberculosis, a
24-week, all-oral regimen was noninferior to the accepted standard-care
treatment, and it had a better safety profile. (Funded by Médecins sans
Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2117166
PMID: 36546625 [Indexed for MEDLINE]
3. Cell. 2022 Dec 8;185(25):4682-4702. doi: 10.1016/j.cell.2022.10.025.
Immune cell interactions in tuberculosis.
Flynn JL(1), Chan J(2).
Author information:
(1)Department of Microbiology and Molecular Genetics and the Center for Vaccine
Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Electronic address: joanne@pitt.edu.
(2)Department of Medicine, Center for Emerging Pathogens, Public Health Research
Institute, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
Electronic address: jc2864@njms.rutgers.edu.
Despite having been identified as the organism that causes tuberculosis in 1882,
Mycobacterium tuberculosis has managed to still evade our understanding of the
protective immune response against it, defying the development of an effective
vaccine. Technology and novel experimental models have revealed much new
knowledge, particularly with respect to the heterogeneity of the bacillus and
the host response. This review focuses on certain immunological elements that
have recently yielded exciting data and highlights the importance of taking a
holistic approach to understanding the interaction of M. tuberculosis with the
many host cells that contribute to the development of protective immunity.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2022.10.025
PMID: 36493751 [Indexed for MEDLINE]
4. Science. 2022 Dec 9;378(6624):1111-1118. doi: 10.1126/science.abq2787. Epub 2022 Dec 8.
Tuberculosis treatment failure associated with evolution of antibiotic
resilience.
Liu Q(#)(1), Zhu J(#)(1), Dulberger CL(1)(2)(3), Stanley S(1), Wilson S(2),
Chung ES(4)(5), Wang X(1), Culviner P(1), Liu YJ(1), Hicks ND(1), Babunovic
GH(1), Giffen SR(1), Aldridge BB(4)(5), Garner EC(2), Rubin EJ(1), Chao MC(1),
Fortune SM(1)(6).
Author information:
(1)Department of Immunology and Infectious Diseases, Harvard T. H. Chan School
of Public Health, Boston, MA 02115, USA.
(2)Department of Molecular and Cellular Biology, Harvard University, Boston, MA,
USA.
(3)Present address: BioNTech US, Cambridge, MA, USA.
(4)Department of Molecular Biology and Microbiology, Tufts University School of
Medicine, Boston, MA 02111, USA.
(5)Department of Biomedical Engineering, Tufts University School of Engineering,
Medford, MA 02115, USA.
(6)Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
(#)Contributed equally
The widespread use of antibiotics has placed bacterial pathogens under intense
pressure to evolve new survival mechanisms. Genomic analysis of 51,229
Mycobacterium tuberculosis (Mtb)clinical isolates has identified an essential
transcriptional regulator, Rv1830, herein called resR for resilience regulator,
as a frequent target of positive (adaptive) selection. resR mutants do not show
canonical drug resistance or drug tolerance but instead shorten the
post-antibiotic effect, meaning that they enable Mtb to resume growth after drug
exposure substantially faster than wild-type strains. We refer to this phenotype
as antibiotic resilience. ResR acts in a regulatory cascade with other
transcription factors controlling cell growth and division, which are also under
positive selection in clinical isolates of Mtb. Mutations of these genes are
associated with treatment failure and the acquisition of canonical drug
resistance.
DOI: 10.1126/science.abq2787
PMID: 36480634 [Indexed for MEDLINE]
5. Cancer Cell. 2022 Dec 7:S1535-6108(22)00562-1. doi: 10.1016/j.ccell.2022.11.015. Online ahead of print.
KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to
RTK-RAS inhibition.
Pan Y(1), Han H(1), Hu H(1), Wang H(2), Song Y(3), Hao Y(4), Tong X(2), Patel
AS(1), Misirlioglu S(1), Tang S(1), Huang HY(1), Geng K(1), Chen T(1), Karatza
A(1), Sherman F(1), Labbe KE(1), Yang F(1), Chafitz A(1), Peng C(1), Guo C(2),
Moreira AL(5), Velcheti V(1), Lau SCM(1), Sui P(2), Chen H(6), Diehl JA(7),
Rustgi AK(8), Bass AJ(8), Poirier JT(1), Zhang X(3), Ji H(9), Zhang H(10), Wong
KK(11).
Author information:
(1)Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY,
USA.
(2)State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and
Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy
of Sciences, Shanghai, China.
(3)State Key Laboratory of Genetic Engineering, School of Life Sciences,
Zhongshan Hospital, Fudan University, Shanghai, China.
…
Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer
with limited treatment options. KMT2D is one of the most frequently mutated
genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown.
Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d
deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases
activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through
reprogramming the chromatin landscape to repress the expression of protein
tyrosine phosphatases. These events provoke a robust elevation in the oncogenic
RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor
afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in
patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study
identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and
suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS
inhibition.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2022.11.015
PMID: 36525973
6. Cancer Cell. 2022 Dec 12;40(12):1503-1520.e8. doi: 10.1016/j.ccell.2022.10.008.
Epub 2022 Nov 10.
High-resolution single-cell atlas reveals diversity and plasticity of
tissue-resident neutrophils in non-small cell lung cancer.
Salcher S(1), Sturm G(2), Horvath L(1), Untergasser G(1), Kuempers C(3), Fotakis
G(2), Panizzolo E(2), Martowicz A(4), Trebo M(1), Pall G(1), Gamerith G(1),
Sykora M(1), Augustin F(5), Schmitz K(6), Finotello F(7), Rieder D(2), Perner
S(8), Sopper S(1), Wolf D(1), Pircher A(9), Trajanoski Z(10).
Author information:
(1)Department of Internal Medicine V, Haematology & Oncology, Comprehensive
Cancer Center Innsbruck (CCCI) and Tyrolean Cancer Research Institute (TKFI),
Medical University of Innsbruck, Innsbruck, Austria.
(2)Biocenter, Institute of Bioinformatics, Medical University of Innsbruck,
Innsbruck, Austria.
(3)Institute of Pathology, University of Luebeck and University Hospital
Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
…
Non-small cell lung cancer (NSCLC) is characterized by molecular heterogeneity
with diverse immune cell infiltration patterns, which has been linked to therapy
sensitivity and resistance. However, full understanding of how immune cell
phenotypes vary across different patient subgroups is lacking. Here, we dissect
the NSCLC tumor microenvironment at high resolution by integrating 1,283,972
single cells from 556 samples and 318 patients across 29 datasets, including our
dataset capturing cells with low mRNA content. We stratify patients into
immune-deserted, B cell, T cell, and myeloid cell subtypes. Using bulk samples
with genomic and clinical information, we identify cellular components
associated with tumor histology and genotypes. We then focus on the analysis of
tissue-resident neutrophils (TRNs) and uncover distinct subpopulations that
acquire new functional properties in the tissue microenvironment, providing
evidence for the plasticity of TRNs. Finally, we show that a TRN-derived gene
signature is associated with anti-programmed cell death ligand 1 (PD-L1)
treatment failure.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2022.10.008
PMCID: PMC9767679
PMID: 36368318 [Indexed for MEDLINE]
7. Nat Rev Microbiol. 2022 Dec;20(12):750-766. doi: 10.1038/s41579-022-00763-4.
Epub 2022 Jul 25.
Immune evasion and provocation by Mycobacterium tuberculosis.
Chandra P(#)(1)(2), Grigsby SJ(#)(1)(2), Philips JA(3)(4).
Author information:
(1)Division of Infectious Diseases, Department of Medicine, Washington
University School of Medicine, St Louis, MO, USA.
(2)Department of Molecular Microbiology, Washington University School of
Medicine, St Louis, MO, USA.
(3)Division of Infectious Diseases, Department of Medicine, Washington
University School of Medicine, St Louis, MO, USA. philips.j.a@wustl.edu.
(4)Department of Molecular Microbiology, Washington University School of
Medicine, St Louis, MO, USA. philips.j.a@wustl.edu.
(#)Contributed equally
Mycobacterium tuberculosis, the causative agent of tuberculosis, has infected
humans for millennia. M. tuberculosis is well adapted to establish infection,
persist in the face of the host immune response and be transmitted to uninfected
individuals. Its ability to complete this infection cycle depends on it both
evading and taking advantage of host immune responses. The outcome of M.
tuberculosis infection is often a state of equilibrium characterized by
immunological control and bacterial persistence. Recent data have highlighted
the diverse cell populations that respond to M. tuberculosis infection and the
dynamic changes in the cellular and intracellular niches of M. tuberculosis
during the course of infection. M. tuberculosis possesses an arsenal of protein
and lipid effectors that influence macrophage functions and inflammatory
responses; however, our understanding of the role that specific bacterial
virulence factors play in the context of diverse cellular reservoirs and
distinct infection stages is limited. In this Review, we discuss immune evasion
and provocation by M. tuberculosis during its infection cycle and describe how a
more detailed molecular understanding is crucial to enable the development of
novel host-directed therapies, disease biomarkers and effective vaccines.
© 2022. Springer Nature Limited.
DOI: 10.1038/s41579-022-00763-4
PMCID: PMC9310001
PMID: 35879556 [Indexed for MEDLINE]
8. J Clin Invest. 2022 Dec 22:e162434. doi: 10.1172/JCI162434. Online ahead of
print.
The UBE2C/CDH1/DEPTOR axis is an oncogene-tumor suppressor cascade in lung
cancer cells.
Zhang S(1), You X(2), Zheng Y(3), Shen Y(2), Xiong X(2), Sun Y(4).
Author information:
(1)Department of Breast Surgery and Oncology, Zhejiang University School of
Medicine, Hangzhou, China.
(2)Cancer Institute, Zhejiang University School of Medicine, Hangzhou, China.
(3)Institute of Translational Medicine, Zhejiang University School of Medicine,
Hangzhou, China.
(4)Zhejiang University School of Medicine, Hangzhou, China.
Ubiquitin-conjugating enzyme E2C (UBE2C) mediates the ubiquitylation chain
formation via the K11 linkage. While previous in vitro studies showed that UBE2C
plays a growth-promoting role in cancer cell lines, the underlying mechanism
remains elusive. Still unknown is whether and how UBE2C plays a promoting role
in vivo. Here we reported that UBE2C is indeed essential for growth and survival
of lung cancer cells harboring Kras mutations, and UBE2C is required for
KrasG12D-induced lung tumorigenesis, since Ube2c deletion significantly inhibits
tumor formation and extends the life-span of mice. Mechanistically, KrasG12D
induces expression of UBE2C, which couples with APC/CCDH1 E3 ligase to promote
ubiquitylation and degradation of DEPTOR, leading to activation of the mTORC
signals. Importantly, DEPTOR levels are fluctuated during cell cycle progression
in a manner dependent of UBE2C and CDH1, indicating their physiological
connection. Finally, Deptor deletion fully rescues the tumor inhibitory effect
of Ube2c deletion in the KrasG12D lung tumor model, indicating a causal role of
Deptor. Taken together, our study shows that the UBE2C/CDH1/DEPTOR axis forms an
oncogene-tumor suppressor cascade that regulates cell cycle progression and
autophagy and validates that UBE2C is an attractive target for lung cancer
associated with Kras mutations.
DOI: 10.1172/JCI162434
PMID: 36548081
9. J Clin Oncol. 2022 Dec 19:JCO2202124. doi: 10.1200/JCO.22.02124. Online ahead of print.
Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO
Living Guideline, Version 2022.2.
Owen DH(1), Singh N(2), Ismaila N(3), Blanchard E(4), Celano P(5), Florez N(6),
Jain D(7), Leighl NB(8), Mamdani H(9), Masters G(10), Moffitt PR(11), Naidoo
J(12), Phillips T(13), Riely GJ(14), Robinson AG(15), Schenk E(16), Schneider
BJ(17), Sequist L(18), Spigel DR(19), Jaiyesimi IA(20).
Author information:
(1)Ohio State University, Columbus, OH.
(2)Postgraduate Institute of Medical Education and Research, Chandigarh, India.
(3)American Society of Clinical Oncology, Alexandria, VA.
…
Update of
J Clin Oncol. 2022 Oct 1;40(28):3310-3322.
Living guidelines are developed for selected topic areas with rapidly evolving
evidence that drives frequent change in recommended clinical practice. Living
guidelines are updated on a regular schedule by a standing expert panel that
systematically reviews the health literature on a continuous basis, as described
in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the
ASCO Conflict of Interest Policy Implementation for Clinical Practice
Guidelines. Living Guidelines and updates are not intended to substitute for
independent professional judgment of the treating provider and do not account
for individual variation among patients. See Appendix 1 (online only) for
disclaimers and other important information. Updates are published regularly and
can be found at https://ascopubs.org/nsclc-da-living-guideline.
DOI: 10.1200/JCO.22.02124
PMID: 36534938
10. J Clin Oncol. 2022 Dec 19:JCO2202121. doi: 10.1200/JCO.22.02121. Online ahead of print.
Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO
Living Guideline, Version 2022.2.
Owen DH(1), Singh N(2), Ismaila N(3), Blanchard E(4), Celano P(5), Florez N(6),
Jain D(7), Leighl NB(8), Mamdani H(9), Masters G(10), Moffitt PR(11), Naidoo
J(12), Phillips T(13), Riely GJ(14), Robinson AG(15), Schenk E(16), Schneider
BJ(17), Sequist L(18), Spigel DR(19), Jaiyesimi IA(20).
Author information:
(1)Ohio State University, Columbus, OH.
(2)Postgraduate Institute of Medical Education and Research, Chandigarh, India.
(3)American Society of Clinical Oncology, Alexandria, VA.
…
Update of
J Clin Oncol. 2022 Oct 1;40(28):3323-3343.
Living guidelines are developed for selected topic areas with rapidly evolving
evidence that drives frequent change in recommended clinical practice. Living
guidelines are updated on a regular schedule by a standing expert panel that
systematically reviews the health literature on a continuous basis, as described
in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the
ASCO Conflict of Interest Policy Implementation for Clinical Practice
Guidelines. Living Guidelines and updates are not intended to substitute for
independent professional judgment of the treating provider and do not account
for individual variation among patients. See Appendix 1 (online only) for
disclaimers and other important information. Updates are published regularly and
can be found at https://ascopubs.org/nsclc-non-da-living-guideline.
DOI: 10.1200/JCO.22.02121
PMID: 36534935
11. Nat Commun. 2022 Dec 14;13(1):7751. doi: 10.1038/s41467-022-35453-5.
A Mycobacterium tuberculosis fingerprint in human breath allows tuberculosis
detection.
Mosquera-Restrepo SF(#)(1), Zuberogoïtia S(#)(2), Gouxette L(#)(2), Layre E(2),
Gilleron M(2), Stella A(2), Rengel D(2), Burlet-Schiltz O(2), Caro AC(3), Garcia
LF(1), Segura C(4), Peláez Jaramillo CA(3), Rojas M(5)(6), Nigou J(7).
Author information:
(1)Cellular Immunology and Immunogenetics Group (GICIG), Institute of Medical
Research, Faculty of Medicine, University Research Headquarters (SIU),
University of Antioquia (UdeA), Medellin, Colombia.
(2)Institute of Pharmacology and Structural Biology (IPBS), University of
Toulouse, CNRS, University of Toulouse III-Paul Sabatier, Toulouse, France.
(3)Interdisciplinary Group for Molecular Studies (GIEM), Institute of Chemistry,
Faculty of Exact and Natural Sciences. University of Antioquia (UdeA), Medellin,
Colombia.
…
An estimated one-third of tuberculosis (TB) cases go undiagnosed or unreported.
Sputum samples, widely used for TB diagnosis, are inefficient at detecting
infection in children and paucibacillary patients. Indeed, developing
point-of-care biomarker-based diagnostics that are not sputum-based is a major
priority for the WHO. Here, in a proof-of-concept study, we tested whether
pulmonary TB can be detected by analyzing patient exhaled breath condensate
(EBC) samples. We find that the presence of Mycobacterium tuberculosis
(Mtb)-specific lipids, lipoarabinomannan lipoglycan, and proteins in EBCs can
efficiently differentiate baseline TB patients from controls. We used EBCs to
track the longitudinal effects of antibiotic treatment in pediatric TB patients.
In addition, Mtb lipoarabinomannan and lipids were structurally distinct in EBCs
compared to ex vivo cultured bacteria, revealing specific metabolic and
biochemical states of Mtb in the human lung. This provides essential information
for the rational development or improvement of diagnostic antibodies, vaccines
and therapeutic drugs. Our data collectively indicate that EBC analysis can
potentially facilitate clinical diagnosis of TB across patient populations and
monitor treatment efficacy. This affordable, rapid and non-invasive approach
seems superior to sputum assays and has the potential to be implemented at
point-of-care.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-35453-5
PMCID: PMC9751131
PMID: 36517492 [Indexed for MEDLINE]
12. Sci Transl Med. 2022 Dec 14;14(675):eabq0021. doi: 10.1126/scitranslmed.abq0021. Epub 2022 Dec 14.
Combination bezafibrate and nivolumab treatment of patients with advanced
non-small cell lung cancer.
Tanaka K(1), Chamoto K(2), Saeki S(3), Hatae R(2)(4), Ikematsu Y(5), Sakai K(6),
Ando N(1), Sonomura K(7)(8), Kojima S(9), Taketsuna M(9), Kim YH(10), Yoshida
H(10), Ozasa H(10), Sakamori Y(11), Hirano T(2), Matsuda F(7), Hirai T(10),
Nishio K(6), Sakagami T(3), Fukushima M(12), Nakanishi Y(1)(13), Honjo T(2),
Okamoto I(1).
Author information:
(1)Department of Respiratory Medicine, Graduate School of Medical Sciences,
Kyushu University, Fukuoka 812-8582, Japan.
(2)Department of Immunology and Genomic Medicine, Center for Cancer
Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University,
Kyoto 606-8501, Japan.
(3)Department of Respiratory Medicine, Kumamoto University Hospital, Kumamoto
860-8556, Japan.
…
Despite the success of cancer immunotherapies such as programmed cell death-1
(PD-1) and PD-1 ligand 1 (PD-L1) inhibitors, patients often develop resistance.
New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this
issue. Bezafibrate, a ligand of peroxisome proliferator-activated receptor-γ
coactivator 1α/peroxisome proliferator-activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by
activation of mitochondria in T cells. We have therefore now performed a phase 1
trial (UMIN000017854) of bezafibrate with nivolumab in previously treated
patients with advanced non-small cell lung cancer. The primary end point was the
percentage of patients who experience dose-limiting toxicity, and this
combination regimen was found to be well tolerated. Preplanned comprehensive
analysis of plasma metabolites and gene expression in peripheral cytotoxic T
cells indicated that bezafibrate promoted T cell function through up-regulation
of mitochondrial metabolism including fatty acid oxidation and may thereby have
prolonged the duration of response. This combination strategy targeting T cell
metabolism thus has the potential to maintain antitumor activity of immune
checkpoint inhibitors and warrants further validation.
DOI: 10.1126/scitranslmed.abq0021
PMID: 36516270 [Indexed for MEDLINE]
13. Nat Commun. 2022 Dec 12;13(1):7690. doi: 10.1038/s41467-022-34889-z.
Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in
EGFR-mutant lung cancer.
Adua SJ(1), Arnal-Estapé A(1)(2), Zhao M(1), Qi B(1), Liu ZZ(1), Kravitz C(1),
Hulme H(3), Strittmatter N(3), López-Giráldez F(4), Chande S(1), Albert AE(5),
Melnick MA(2), Hu B(1), Politi K(1)(2)(6), Chiang V(2)(7), Colclough N(8),
Goodwin RJA(3), Cross D(9), Smith P(10), Nguyen DX(11)(12)(13).
Author information:
(1)Department of Pathology, Yale University School of Medicine, New Haven, CT,
USA.
(2)Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
(3)Imaging and Data Analytics, Clinical Pharmacology and Safety Sciences,
AstraZeneca, Cambridge, UK.
…
The brain is a major sanctuary site for metastatic cancer cells that evade
systemic therapies. Through pre-clinical pharmacological, biological, and
molecular studies, we characterize the functional link between drug resistance
and central nervous system (CNS) relapse in Epidermal Growth Factor
Receptor- (EGFR-) mutant non-small cell lung cancer, which can progress in the
brain when treated with the CNS-penetrant EGFR inhibitor osimertinib. Despite
widespread osimertinib distribution in vivo, the brain microvascular tumor
microenvironment (TME) is associated with the persistence of malignant cell
sub-populations, which are poised to proliferate in the brain as
osimertinib-resistant lesions over time. Cellular and molecular features of this
poised state are regulated through a Ras homolog family member A (RhoA) and
Serum Responsive Factor (SRF) gene expression program. RhoA potentiates the
outgrowth of disseminated tumor cells on osimertinib treatment, preferentially
in response to extracellular laminin and in the brain. Thus, we identify
pre-existing and adaptive features of metastatic and drug-resistant cancer
cells, which are enhanced by RhoA/SRF signaling and the brain TME during the
evolution of osimertinib-resistant disease.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-34889-z
PMCID: PMC9744876
PMID: 36509758 [Indexed for MEDLINE]
14. Adv Drug Deliv Rev. 2022 Dec 9;192:114641. doi: 10.1016/j.addr.2022.114641.
Online ahead of print.
Imaging drug delivery to the lungs: Methods and applications in oncology.
Man F(1), Tang J(2), Swedrowska M(1), Forbes B(1), T M de Rosales R(3).
Author information:
(1)School of Cancer & Pharmaceutical Sciences, King's College London, London,
SE1 9NH, United Kingdom.
(2)School of Biomedical Engineering & Imaging Sciences, King's College London,
London SE1 7EH, United Kingdom.
(3)School of Biomedical Engineering & Imaging Sciences, King's College London,
London SE1 7EH, United Kingdom. Electronic address: rafael.torres@kcl.ac.uk.
Direct delivery to the lung via inhalation is arguably one of the most logical
approaches to treat lung cancer using drugs. However, despite significant
efforts and investment in this area, this strategy has not progressed in
clinical trials. Imaging drug delivery is a powerful tool to understand and
develop novel drug delivery strategies. In this review we focus on imaging
studies of drug delivery by the inhalation route, to provide a broad overview of
the field to date and attempt to better understand the complexities of this
route of administration and the significant barriers that it faces, as well as
its advantages. We start with a discussion of the specific challenges for drug
delivery to the lung via inhalation. We focus on the barriers that have
prevented progress of this approach in oncology, as well as the most recent
developments in this area. This is followed by a comprehensive overview of the
different imaging modalities that are relevant to lung drug delivery, including
nuclear imaging, X-ray imaging, magnetic resonance imaging, optical imaging and
mass spectrometry imaging. For each of these modalities, examples from the
literature where these techniques have been explored are provided. Finally the
different applications of these technologies in oncology are discussed, focusing
separately on small molecules and nanomedicines. We hope that this comprehensive
review will be informative to the field and will guide the future preclinical
and clinical development of this promising drug delivery strategy to maximise
its therapeutic potential.
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.addr.2022.114641
PMID: 36509173
15. J Clin Oncol. 2022 Dec 8:JCO2200857. doi: 10.1200/JCO.22.00857. Online ahead of print.
Clonal Hematopoiesis and Risk of Incident Lung Cancer.
Tian R(1)(2), Wiley B(3), Liu J(3), Zong X(1), Truong B(4)(5)(6), Zhao S(7),
Uddin MM(4)(6), Niroula A(6)(8)(9), Miller CA(3)(10), Mukherjee S(11)(12),
Heiden BT(13), Luo J(1)(10), Puri V(13), Kozower BD(13), Walter MJ(3)(10), Ding
L(3)(10)(14), Link DC(3)(10), Amos CI(15)(16)(17), Ebert BL(9)(18)(19), Govindan
R(3)(10), Natarajan P(4)(6)(20), Bolton KL(3), Cao Y(1)(10).
Author information:
(1)Division of Public Health Sciences, Department of Surgery, Washington
University School of Medicine, St Louis, MO.
(2)Brown School, Washington University in St Louis, St Louis, MO.
(3)Division of Oncology, Department of Medicine, Washington University School of
Medicine, St Louis, MO.
…
PURPOSE: To prospectively examine the association between clonal hematopoiesis
(CH) and subsequent risk of lung cancer.
METHODS: Among 200,629 UK Biobank (UKBB) participants with whole-exome
sequencing, CH was identified in a nested case-control study of 832 incident
lung cancer cases and 3,951 controls (2006-2019) matched on age and year at
blood draw, sex, race, and smoking status. A similar nested case-control study
(141 cases/652 controls) was conducted among 27,975 participants with
whole-exome sequencing in the Mass General Brigham Biobank (MGBB, 2010-2021). In
parallel, we compared CH frequency in published data from 5,003 patients with
solid tumor (2,279 lung cancer) who had pretreatment blood sequencing performed
through Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable
Cancer Targets.
RESULTS: In UKBB, the presence of CH was associated with increased risk of lung
cancer (cases: 12.5% v controls: 8.7%; multivariable-adjusted odds ratio [OR],
1.36; 95% CI, 1.06 to 1.74). The association remained robust after excluding
participants with chronic obstructive pulmonary disease. No significant
interactions with known risk factors, including polygenic risk score and
C-reactive protein, were identified. In MGBB, we observed similar enrichment of
CH in lung cancer (cases: 15.6% v controls: 12.7%). The meta-analyzed OR (95%
CI) of UKBB and MGBB was 1.35 (1.08 to 1.68) for CH overall and 1.61 (1.19 to
2.18) for variant allele frequencies ≥ 10%. In Memorial Sloan
Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, CH with a
variant allele frequency ≥ 10% was enriched in pretreatment lung cancer compared
with other tumors after adjusting for age, sex, and smoking (OR for lung v
breast cancer: 1.61; 95% CI, 1.03 to 2.53).
CONCLUSION: Independent of known risk factors, CH is associated with increased
risk of lung cancer.
DOI: 10.1200/JCO.22.00857
PMID: 36480766
16. Am J Respir Crit Care Med. 2022 Dec 1. doi: 10.1164/rccm.202208-1475OC. Online ahead of print.
Assessing Pretomanid for Tuberculosis (APT), a Randomized Phase 2 Trial of
Pretomanid-containing Regimens for Drug-sensitive TB: 12-Week Results.
Dooley KE(1), Hendricks B(2), Gupte N(3), Barnes G(4), Narunsky K(5), Whitelaw
C(2), Smit T(2), Ignatius EH(6), Friedman A(2), Dorman SE(7), Dawson R(2);
Assessing Pretomanid for Tuberculosis (APT) Study Team.
Author information:
(1)Vanderbilt University School of Medicine, 12327, Medicine, Nashville,
Tennessee, United States; kelly.e.dooley@vumc.org.
(2)University of Cape Town Lung Institute, 108145, Rondebosch, Western Cape,
South Africa.
(3)Johns Hopkins School of Medicine, Baltimore, Maryland, United States.
(4)Johns Hopkins University, Medicine, Baltimore, Maryland, United States.
(5)University of Cape Town, Department of Respiratory Medicine, Cape Town, South
Africa.
(6)Johns Hopkins University, Baltimore, Maryland, United States.
(7)Medical University of South Carolina, 2345, Charleston, South Carolina,
United States.
RATIONALE: Pretomanid is a new nitroimidazole with proven treatment-shortening
efficacy in drug-resistant tuberculosis. Pretomanid-rifamycin-pyrazinamide
combinations are potent in mice but have not been tested clinically. Rifampicin,
but not rifabutin, reduces pretomanid exposures.
OBJECTIVE: Evaluate the safety and efficacy of pretomanid-rifamycin-pyrazinamide
containing regimens among participants with drug-sensitive pulmonary
tuberculosis.
METHODS: Phase 2 twelve-week open-label randomized trial of isoniazid,
pyrazinamide, plus (a) pretomanid and rifampicin (Arm 1); (b) pretomanid and
rifabutin (Arm 2) or (c) rifampicin and ethambutol (standard of care, Arm 3).
Safety labs and sputum cultures were collected at Weeks 1, 2, 3, 4, 6, 8, 10,
12. Time to culture conversion on liquid media was the primary outcome.
RESULTS: Among 157 participants, 125 (80%) had cavitary disease. Median time to
liquid culture negativity in the modified intention to treat (mITT) population
(n=150) was 41 (Arm 1), 28 (Arm 2), and 55 (Arm 3) days (p=0.01)(adjusted hazard
ratios of 1.41 (0.93-2.12, p=0.10), Arm 1 vs. Arm 3) and 1.89 (1.24-2.87,
p=0.003, Arm 2 vs. Arm 3)). Eight-week liquid culture conversion was 79%, 89%,
and 69%, respectively. Grade >3 adverse events occurred in 3/56 (5%), 5/53 (9%),
and 2/56 (4%) of participants. Six participants were withdrawn owing to elevated
transaminases (5 in Arm 2, 1 in Arm 1).There were 3 serious adverse events (Arm
2) and no deaths.
CONCLUSIONS: Pretomanid enhanced the microbiologic activity of
rifamycin-pyrazinamide containing regimens. Efficacy and hepatic adverse events
appeared highest with the pretomanid and rifabutin-containing regimen. Whether
this is due to higher pretomanid concentrations merits exploration. Clinical
trial registration available at www.
CLINICALTRIALS: gov, ID: NCT02256696.
DOI: 10.1164/rccm.202208-1475OC
PMID: 36455068
17. J Exp Med. 2022 Dec 5;219(12):e20221449. doi: 10.1084/jem.20221449. Epub 2022
Oct 10.
Eating away T cell responses in lung cancer.
Ferrara R(1), Roz L(2).
Author information:
(1)Thoracic Oncology Unit, Department of Medical Oncology and Molecular
Immunology Unit, Department of Research; Fondazione IRCCS Istituto Nazionale dei
Tumori, Milan, Italy.
(2)Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto
Nazionale dei Tumori, Milan, Italy.
Comment on
J Exp Med. 2022 Dec 5;219(12):
Despite evidence for clinical benefit in patients suffering from lung cancer
following treatment with immune checkpoint inhibitors (ICI), it is still
uncertain how to predict which patients are likely to experience a significant
response. In their work, Valencia et al. (2022. J. Exp.
Med.https://doi.org/10.1084/jem.20220726) identify the DSTYK kinase as a cancer
cell-intrinsic modulator of response to immunotherapy. Through regulation of the
mTOR pathway and stimulation of protective autophagy, DSTYK blunts CD8+ T
cell-mediated killing of cancer cells. Accordingly, lung cancers with increased
expression of DSTYK are less responsive to ICI treatment. These observations
could be useful in the clinic towards the development of predictive biomarkers
and novel therapeutic strategies.
© 2022 Ferrara and Roz.
DOI: 10.1084/jem.20221449
PMCID: PMC9555064
PMID: 36214813 [Indexed for MEDLINE]
18. Clin Microbiol Rev. 2022 Dec 21;35(4):e0018019. doi: 10.1128/cmr.00180-19. Epub 2022 Oct 6.
The Changing Paradigm of Drug-Resistant Tuberculosis Treatment: Successes,
Pitfalls, and Future Perspectives.
Dookie N(#)(1), Ngema SL(#)(1), Perumal R(1)(2), Naicker N(1)(2), Padayatchi
N(1)(2), Naidoo K(1)(2).
Author information:
(1)Centre for the AIDS Programme of Research in South Africagrid.428428.0,
University of KwaZulu-Natal, Durban, South Africa.
(2)South African Medical Research Council-CAPRISA HIV-TB Pathogenesis and
Treatment Research Unit, Durban, South Africa.
(#)Contributed equally
Drug-resistant tuberculosis (DR-TB) remains a global crisis due to the
increasing incidence of drug-resistant forms of the disease, gaps in detection
and prevention, models of care, and limited treatment options. The DR-TB
treatment landscape has evolved over the last 10 years. Recent developments
include the remarkable activity demonstrated by the newly approved anti-TB drugs
bedaquiline and pretomanid against Mycobacterium tuberculosis. Hence, treatment
of DR-TB has drastically evolved with the introduction of the short-course
regimen for multidrug-resistant TB (MDR-TB), transitioning to injection-free
regimens and the approval of the 6-month short regimens for rifampin-resistant
TB and MDR-TB. Moreover, numerous clinical trials are under way with the aim to
reduce pill burden and shorten the DR-TB treatment duration. While there have
been apparent successes in the field, some challenges remain. These include the
ongoing inclusion of high-dose isoniazid in DR-TB regimens despite a lack of
evidence for its efficacy and the inclusion of ethambutol and pyrazinamide in
the standard short regimen despite known high levels of background resistance to
both drugs. Furthermore, antimicrobial heteroresistance, extensive cavitary
disease and intracavitary gradients, the emergence of bedaquiline resistance,
and the lack of biomarkers to monitor DR-TB treatment response remain serious
challenges to the sustained successes. In this review, we outline the impact of
the new drugs and regimens on patient treatment outcomes, explore evidence
underpinning current practices on regimen selection and duration, reflect on the
disappointments and pitfalls in the field, and highlight key areas that require
continued efforts toward improving treatment approaches and rapid biomarkers for
monitoring treatment response.
DOI: 10.1128/cmr.00180-19
PMCID: PMC9769521
PMID: 36200885 [Indexed for MEDLINE]
19. J Exp Med. 2022 Dec 5;219(12):e20220726. doi: 10.1084/jem.20220726. Epub 2022
Sep 28.
DSTYK inhibition increases the sensitivity of lung cancer cells to T
cell-mediated cytotoxicity.
Valencia K(1)(2)(3)(4), Echepare M(1)(5)(3), Teijeira Á(2)(3)(6), Pasquier
A(1)(3), Bértolo C(1), Sainz C(1)(3), Tamayo I(3)(7), Picabea B(1), Bosco G(8),
Thomas R(8)(9)(10), Agorreta J(1)(11), López-Picazo JM(12), Frigola J(13), Amat
R(13), Calvo A(1)(5)(2)(3), Felip E(13)(14), Melero I(2)(3)(12), Montuenga
LM(1)(5)(2)(3).
Author information:
(1)Program in Solid Tumors, Center for Applied Medical Research
(CIMA)-University of Navarra, Pamplona, Spain.
(2)Consorcio de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid,
Spain.
(3)Navarra Health Research Institute (IDISNA), Pamplona, Spain.
…
Comment in
J Exp Med. 2022 Dec 5;219(12):
Lung cancer remains the leading cause of cancer-related death worldwide. We
identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein
kinase, as a novel actionable target altered in non-small cell lung cancer
(NSCLC). We also show DSTYK's association with a lower overall survival (OS) and
poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation
of DSTYK in lung cancer experimental systems prevents mTOR-dependent
cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and
induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely
affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK
sensitizes lung cancer cells to TNF-α-mediated CD8+-killing and immune-resistant
lung tumors to anti-PD-1 treatment. Finally, in a series of lung cancer
patients, DSTYK copy number gain predicts lack of response to the immunotherapy.
In summary, we have uncovered DSTYK as new therapeutic target in lung cancer.
Prioritization of this novel target for drug development and clinical testing
may expand the percentage of NSCLC patients benefiting from immune-based
treatments.
© 2022 Valencia et al.
DOI: 10.1084/jem.20220726
PMCID: PMC9524203
PMID: 36169652 [Indexed for MEDLINE]
20. J Natl Cancer Inst. 2022 Dec 8;114(12):1665-1673. doi: 10.1093/jnci/djac176.
Lung Cancer Absolute Risk Models for Mortality in an Asian Population using the
China Kadoorie Biobank.
Warkentin MT(1)(2), Tammemägi MC(3), Espin-Garcia O(2)(4), Budhathoki S(1), Liu
G(2)(5), Hung RJ(1)(2).
Author information:
(1)Prosserman Center for Population Health Research, Lunenfeld-Tanenbaum
Research Institute, Sinai Health, Toronto, ON, Canada.
(2)Department of Public Health Sciences, Dalla Lana School of Public Health,
University of Toronto, Toronto, ON, Canada.
(3)Department of Health Sciences, Brock University, St. Catharines, ON, Canada.
(4)Department of Biostatistics, Princess Margaret Cancer Centre, University
Health Network, Toronto, ON, Canada.
(5)Department of Medical Oncology and Hematology, Princess Margaret Cancer
Centre, Toronto, ON, Canada.
BACKGROUND: Lung cancer is the leading cause of cancer mortality globally. Early
detection through risk-based screening can markedly improve prognosis. However,
most risk models were developed in North American cohorts of smokers, whereas
less is known about risk profiles for never-smokers, which represent a growing
proportion of lung cancers, particularly in Asian populations.
METHODS: Based on the China Kadoorie Biobank, a population-based prospective
cohort of 512 639 adults with up to 12 years of follow-up, we built Asian Lung
Cancer Absolute Risk Models (ALARM) for lung cancer mortality using flexible
parametric survival models, separately for never and ever-smokers, accounting
for competing risks of mortality. Model performance was evaluated in a 25%
hold-out test set using the time-dependent area under the curve and by comparing
model-predicted and observed risks for calibration.
RESULTS: Predictors assessed in the never-smoker lung cancer mortality model
were demographics, body mass index, lung function, history of emphysema or
bronchitis, personal or family history of cancer, passive smoking, and indoor
air pollution. The ever-smoker model additionally assessed smoking history. The
5-year areas under the curve in the test set were 0.77 (95% confidence interval
= 0.73 to 0.80) and 0.81 (95% confidence interval = 0.79 to 0.84) for
ALARM-never-smokers and ALARM-ever smokers, respectively. The maximum 5-year
risk for never and ever-smokers was 2.6% and 12.7%, respectively.
CONCLUSIONS: This study is among the first to develop risk models specifically
for Asian populations separately for never and ever-smokers. Our models
accurately identify Asians at high risk of lung cancer death and may identify
those with risks exceeding common eligibility thresholds who may benefit from
screening.
© The Author(s) 2022. Published by Oxford University Press. All rights reserved.
For permissions, please email: journals.permissions@oup.com.
DOI: 10.1093/jnci/djac176
PMID: 36083018 [Indexed for MEDLINE]
21. J Clin Oncol. 2022 Dec 1;40(34):3912-3917. doi: 10.1200/JCO.22.00428. Epub 2022 Aug 26.
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 [Indexed for MEDLINE]
22. Am J Respir Crit Care Med. 2022 Dec 15;206(12):1480-1494. doi:
10.1164/rccm.202110-2358OC.
Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage
Subtype of Small-Cell Lung Cancer.
Kong R(1)(2)(3), Patel AS(2)(3)(4), Sato T(2)(3)(5)(6), Jiang F(2)(3), Yoo
S(7)(8), Bao L(9), Sinha A(2)(3), Tian Y(2)(3), Fridrikh M(2)(3), Liu S(10),
Feng J(11), He X(12)(13), Jiang J(1), Ma Y(1), Grullon K(2)(3), Yang
D(2)(3)(14), Powell CA(2)(3), Beasley MB(15), Zhu J(3)(7)(8), Snyder
EL(16)(17)(18), Li S(1), Watanabe H(2)(3)(7).
Author information:
(1)Department of Thoracic Surgery and.
(2)Division of Pulmonary, Critical Care and Sleep Medicine.
(3)Tisch Cancer Institute.
…
Comment in
Am J Respir Crit Care Med. 2022 Dec 15;206(12):1441-1443.
Rationale: The current molecular classification of small-cell lung cancer (SCLC)
on the basis of the expression of four lineage transcription factors still
leaves its major subtype SCLC-A as a heterogeneous group, necessitating more
precise characterization of lineage subclasses. Objectives: To refine the
current SCLC classification with epigenomic profiles and to identify features of
the redefined SCLC subtypes. Methods: We performed unsupervised clustering of
epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1
(NK2 homeobox 1) was evaluated by cell growth, apoptosis, and xenograft using
clustered regularly interspaced short palindromic repeats-Cas9
(CRISPR-associated protein 9)-mediated deletion. NKX2-1-specific cistromic
profiles were determined using chromatin immunoprecipitation followed by
sequencing, and its functional transcriptional partners were determined using
coimmunoprecipitation followed by mass spectrometry. Rb1flox/flox;
Trp53flox/flox and Rb1flox/flox; Trp53flox/flox; Nkx2-1flox/flox mouse models
were engineered to explore the function of Nkx2-1 in SCLC tumorigenesis.
Epigenomic landscapes of six human SCLC specimens and 20 tumors from two mouse
models were characterized. Measurements and Main Results: We identified two
epigenomic subclusters of the major SCLC-A subtype: SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found that
NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα.
In addition, we found that maintenance of this neural identity in SCLC-Aα is
mediated by collaborative transcriptional activity with another neuronal
transcriptional factor, SOX1 (SRY-box transcription factor 1). Conclusions: We
comprehensively describe additional epigenomic heterogeneity of the major SCLC-A
subtype and define the SCLC-Aα subtype by the core regulatory circuitry of
NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain
neuronal linage state.
DOI: 10.1164/rccm.202110-2358OC
PMCID: PMC9757094
PMID: 35848993 [Indexed for MEDLINE]
23. Lancet Infect Dis. 2022 Dec;22(12):e359-e369. doi:
10.1016/S1473-3099(22)00227-4. Epub 2022 May 27.
Mycobacterial infections in adults with haematological malignancies and
haematopoietic stem cell transplants: guidelines from the 8th European
Conference on Infections in Leukaemia.
Bergeron A(1), Mikulska M(2), De Greef J(3), Bondeelle L(4), Franquet T(5),
Herrmann JL(6), Lange C(7), Spriet I(8), Akova M(9), Donnelly JP(10), Maertens
J(11), Maschmeyer G(12), Rovira M(13), Goletti D(14), de la Camara R(15);
European Conference on Infections in Leukaemia group.
Author information:
(1)Division of Pulmonology, Geneva University Hospitals, Geneva, Switzerland;
University of Paris, ECSTRRA Team, Inserm, Paris, France. Electronic address:
anne.bergeron@hcuge.ch.
(2)Division of Infectious Diseases, Department of Health Sciences, University of
Genoa, Genoa, Italy; San Martino Polyclinic Hospital, Genoa, Italy.
(3)Division of Internal Medicine and Infectious Diseases, Saint-Luc University
Clinics, Catholic University of Louvain, Brussels, Belgium.
…
Mycobacterial infections, both tuberculosis and nontuberculous, are more common
in patients with haematological malignancies and haematopoietic stem cell
transplant recipients than in the general population-although these infections
remain rare. Mycobacterial infections pose both diagnostic and therapeutic
challenges. The management of mycobacterial infections is particularly
complicated for patients in haematology because of the many drug-drug
interactions between antimycobacterial drugs and haematological and
immunosuppressive treatments. The management of mycobacterial infections must
also consider the effect of delaying haematological management. We surveyed the
management practices for latent tuberculosis infection (LTBI) in haematology
centres in Europe. We then conducted a meticulous review of the literature on
the epidemiology, diagnosis, and management of LTBI, tuberculosis, and
nontuberculous mycobacterial infections among patients in haematology, and we
formulated clinical guidelines according to standardised European Conference on
Infections in Leukaemia (ECIL) methods. In this Review, we summarise the
available literature and the recommendations of ECIL 8 for managing
mycobacterial infections in patients with haematological malignancies.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00227-4
PMID: 35636446 [Indexed for MEDLINE]
24. Autophagy. 2022 Dec;18(12):2926-2945. doi: 10.1080/15548627.2022.2054240. Epub 2022 Apr 5.
Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range
of pathogenic bacteria.
Lee YJ(1), Kim JK(2)(3)(4), Jung CH(1), Kim YJ(2)(3)(4), Jung EJ(1), Lee SH(1),
Choi HR(1), Son YS(5), Shim SM(1), Jeon SM(2)(3)(4), Choe JH(2)(3)(4), Lee
SH(6), Whang J(7), Sohn KC(3)(8), Hur GM(3)(8), Kim HT(9), Yeom J(1)(10), Jo
EK(2)(3)(4), Kwon YT(1)(9)(11)(12).
Author information:
(1)Cellular Degradation Biology Center and Department of Biomedical Sciences,
College of Medicine, Seoul National University, Seoul, Republic of Korea.
(2)Department of Microbiology, Chungnam National University School of Medicine,
Daejeon, Korea.
(3)Department of Medical Science, Chungnam National University School of
Medicine, Daejeon, Korea.
…
The N-degron pathway is a proteolytic system in which the N-terminal degrons
(N-degrons) of proteins, such as arginine (Nt-Arg), induce the degradation of
proteins and subcellular organelles via the ubiquitin-proteasome system (UPS) or
macroautophagy/autophagy-lysosome system (hereafter autophagy). Here, we
developed the chemical mimics of the N-degron Nt-Arg as a pharmaceutical means
to induce targeted degradation of intracellular bacteria via autophagy, such as
Salmonella enterica serovar Typhimurium (S. Typhimurium), Escherichia coli, and
Streptococcus pyogenes as well as Mycobacterium tuberculosis (Mtb). Upon binding
the ZZ domain of the autophagic cargo receptor SQSTM1/p62 (sequestosome 1),
these chemicals induced the biogenesis and recruitment of autophagic membranes
to intracellular bacteria via SQSTM1, leading to lysosomal degradation. The
antimicrobial efficacy was independent of rapamycin-modulated core autophagic
pathways and synergistic with the reduced production of inflammatory cytokines.
In mice, these drugs exhibited antimicrobial efficacy for S. Typhimurium,
Bacillus Calmette-Guérin (BCG), and Mtb as well as multidrug-resistant Mtb and
inhibited the production of inflammatory cytokines. This dual mode of action in
xenophagy and inflammation significantly protected mice from inflammatory
lesions in the lungs and other tissues caused by all the tested bacterial
strains. Our results suggest that the N-degron pathway provides a therapeutic
target in host-directed therapeutics for a broad range of drug-resistant
intracellular pathogens.Abbreviations: ATG: autophagy-related gene; BCG:
Bacillus Calmette-Guérin; BMDMs: bone marrow-derived macrophages;
CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CFUs: colony-forming
units; CXCL: C-X-C motif chemokine ligand; EGFP: enhanced green fluorescent
protein; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; LIR:
MAP1LC3/LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1
light chain 3; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of
rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PB1:
Phox and Bem1; SQSTM1/p62: sequestosome 1; S. Typhimurium: Salmonella enterica
serovar Typhimurium; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis
factor; UBA: ubiquitin-associated.
DOI: 10.1080/15548627.2022.2054240
PMCID: PMC9673928
PMID: 35316156 [Indexed for MEDLINE]
25. Autophagy. 2022 Dec;18(12):3033-3034. doi: 10.1080/15548627.2022.2069439. Epub 2022 May 9.
Mitophagy: a new actor in the efficacy of chemo-immunotherapy.
Limagne E(1)(2)(3)(4), Ghiringhelli F(1)(2)(3)(4)(5).
Author information:
(1)Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Equipe
Labellisée Ligue Contre le Cancer, Dijon, France.
(2)Centre de Recherche, INSERM LNC-UMR1231, Dijon, France.
(3)Cancer Biology Transfer Platform, Univ. Bourgogne Franche-Comté, Dijon,
France.
(4)Cancer Biology Transfer Platform, Genetic and Immunology Medical Institute,
Dijon, France.
(5)Department of Medical Oncology, Centre Georges-François Leclerc, Dijon,
France.
Resistance to chemo-immunotherapy is a major issue for the treatment of
non-small cell lung cancer. In a recent paper we unravel the role of MAPK in the
capacity of restraining the therapeutic efficacy of chemo-immunotherapy.
Inhibition of the MAPK pathway using a MAP2K/MEK inhibitor in combination with
chemotherapy could promote OPTN (optineurin)-dependent mitophagy of cancer
cells. Mitochondria then degrade via autophagosomes and amphisomes and release
mitochondrial DNA, which interacts with TLR9 located in these compartments. TLR9
activation promotes the production of the chemokine CXCL10 by cancer cells,
which could further improve T cell recruitment and improve the efficacy of
immunotherapy.
DOI: 10.1080/15548627.2022.2069439
PMCID: PMC9673945
PMID: 35532360 [Indexed for MEDLINE]
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