2021年
No.12
Filters applied:?from 2021/10/1 - 2021/10/31
1. Autophagy. 2021 Oct 31:1-15. doi: 10.1080/15548627.2021.1987671. Online ahead of print.
Mycobacterium bovis induces mitophagy to suppress host xenophagy for its
intracellular survival.
Song Y(1), Ge X(1), Chen Y(1), Hussain T(1)(2), Liang Z(1), Dong Y(1), Wang
Y(1), Tang C(3), Zhou X(1).
Author information:
(1)Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture,
National Animal Transmissible Spongiform Encephalopathy Laboratory, College of
Veterinary Medicine, China Agricultural University, Beijing, China.
(2)College of Veterinary Sciences, The University of Agriculture Peshawar,
Peshawar, Pakistan.
(3)Department of Nephrology, the Second Xiangya Hospital, Central South
University, Changsha, Hunan, China.
Mitophagy is a selective autophagy mechanism for eliminating damaged
mitochondria and plays a crucial role in the immune evasion of some viruses and
bacteria. Here, we report that Mycobacterium bovis (M. bovis) utilizes host
mitophagy to suppress host xenophagy to enhance its intracellular survival. M.
bovis is the causative agent of animal tuberculosis and human tuberculosis. In
the current study, we show that M. bovis induces mitophagy in macrophages, and
the induction of mitophagy is impaired by PINK1 knockdown, indicating the
PINK1-PRKN/Parkin pathway is involved in the mitophagy induced by M. bovis.
Moreover, the survival of M. bovis in macrophages and the lung bacterial burden
of mice are restricted by the inhibition of mitophagy and are enhanced by the
induction of mitophagy. Confocal microscopy analysis reveals that induction of
mitophagy suppresses host xenophagy by competitive utilization of p-TBK1.
Overall, our results suggest that induction of mitophagy enhances M. bovis
growth while inhibition of mitophagy improves growth restriction. The findings
provide a new insight for understanding the intracellular survival mechanism of
M. bovis in the host.
DOI: 10.1080/15548627.2021.1987671
PMID: 34720021
2. J Am Chem Soc. 2021 Oct 27;143(42):17666-17676. doi: 10.1021/jacs.1c07970. Epub 2021 Oct 19.
Mechanism-Based Inactivation of Mycobacterium tuberculosis Isocitrate Lyase 1 by
(2R,3S)-2-Hydroxy-3-(nitromethyl)succinic acid.
Mellott DM(1), Torres D(2), Krieger IV(1), Cameron SA(2)(3), Moghadamchargari
Z(4), Laganowsky A(4), Sacchettini JC(1)(4), Meek TD(1), Harris LD(2)(3).
Author information:
(1)Department of Biochemistry and Biophysics, Texas A&M University, College
Station, Texas 77843, United States.
(2)The Ferrier Research Institute, Victoria University of Wellington, Wellington
5046, New Zealand.
(3)The Maurice Wilkins Centre for Molecular Biodiscovery, The University of
Auckland, Auckland 1010, New Zealand.
(4)Department of Chemistry, Texas A&M University, College Station, Texas 77843,
United States.
The isocitrate lyase paralogs of Mycobacterium tuberculosis (ICL1 and 2) are
essential for mycobacterial persistence and constitute targets for the
development of antituberculosis agents. We report that
(2R,3S)-2-hydroxy-3-(nitromethyl)succinic acid (5-NIC) undergoes apparent
retro-aldol cleavage as catalyzed by ICL1 to produce glyoxylate and
3-nitropropionic acid (3-NP), the latter of which is a covalent-inactivating
agent of ICL1. Kinetic analysis of this reaction identified that 5-NIC serves as
a robust and efficient mechanism-based inactivator of ICL1 (kinact/KI = (1.3 ±
0.1) × 103 M-1 s-1) with a partition ratio<1. Using enzyme kinetics, mass
spectrometry, and X-ray crystallography, we identified that the reaction of the
5-NIC-derived 3-NP with the Cys191 thiolate of ICL1 results in formation of an
ICL1-thiohydroxamate adduct as predicted. One aspect of the design of 5-NIC was
to lower its overall charge compared to isocitrate to assist with cell
permeability. Accordingly, the absence of the third carboxylate group will
simplify the synthesis of pro-drug forms of 5-NIC for characterization in
cell-infection models of M. tuberculosis.
DOI: 10.1021/jacs.1c07970
PMID: 34664502
3. FEMS Microbiol Rev. 2021 Oct 12:fuab050. doi: 10.1093/femsre/fuab050. Online
ahead of print.
Critical discussion on drug efflux in Mycobacterium tuberculosis.
Remm S(1), Earp JC(1), Dick T(2)(3), Dartois V(2)(3), Seeger MA(1).
Author information:
(1)Institute of Medical Microbiology, University of Zürich, Switzerland.
(2)Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New
Jersey, USA.
(3)Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.
Mycobacterium tuberculosis (Mtb) can withstand months of antibiotic treatment.
An important goal of tuberculosis research is shortening the treatment to reduce
the burden on patients, increase adherence to the drug regimen and thereby slow
the spread of drug resistance. Inhibition of drug efflux pumps by small
molecules has been advocated as a promising strategy to attack persistent Mtb
and shorten therapy. Although mycobacterial drug efflux pumps have been broadly
investigated, mechanistic studies are scarce. In this critical review, we shed
light on drug efflux in its larger mechanistic context by considering the
intricate interplay between membrane transporters annotated as drug efflux
pumps, membrane energetics, efflux inhibitors and cell wall biosynthesis
processes. We conclude that a great wealth of data on mycobacterial transporters
is insufficient to distinguish by what mechanism they contribute to drug
resistance. Recent studies suggest that some drug efflux pumps transport
structural lipids of the mycobacterial cell wall and that the action of certain
drug efflux inhibitors involves dissipation of the proton-motive force, thereby
draining the energy source of all active membrane transporters. We propose
recommendations on the generation and interpretation of drug efflux data to
reduce ambiguities and promote assigning novel roles to mycobacterial membrane
transporters.
The Author(s) 2021. Published by Oxford University Press on behalf of FEMS.
DOI: 10.1093/femsre/fuab050
PMID: 34637511
4. Lancet Infect Dis. 2021 Oct 7:S1473-3099(21)00452-7. doi:
10.1016/S1473-3099(21)00452-7. Online ahead of print.
Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and
capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre
diagnostic accuracy study.
Penn-Nicholson A(1), Georghiou SB(2), Ciobanu N(3), Kazi M(4), Bhalla M(5),
David A(6), Conradie F(6), Ruhwald M(2), Crudu V(3), Rodrigues C(4), Myneedu
VP(5), Scott L(6), Denkinger CM(7), Schumacher SG(2); Xpert XDR Trial
Consortium.
Author information:
(1)FIND, Geneva, Switzerland. Electronic address:
adam.penn-nicholson@finddx.org.
(2)FIND, Geneva, Switzerland.
(3)Phthisiopneumology Institute "Chiril Draganiuc", Chi?in?u, Moldova.
…
BACKGROUND: The WHO End TB Strategy requires drug susceptibility testing and
treatment of all people with tuberculosis, but second-line diagnostic testing
with line-probe assays needs to be done in experienced laboratories with
advanced infrastructure. Fewer than half of people with drug-resistant
tuberculosis receive appropriate treatment. We assessed the diagnostic accuracy
of the rapid Xpert MTB/XDR automated molecular assay (Cepheid, Sunnyvale, CA,
USA) to overcome these limitations.
METHODS: We did a prospective study involving individuals presenting with
pulmonary tuberculosis symptoms and at least one risk factor for drug resistance
in four sites in India (New Delhi and Mumbai), Moldova, and South Africa between
July 31, 2019, and March 21, 2020. The Xpert MTB/XDR assay was used as a reflex
test to detect resistance to isoniazid, fluoroquinolones, ethionamide, amikacin,
kanamycin, and capreomycin in adults with positive results for Mycobacterium
tuberculosis complex on Xpert MTB/RIF or Ultra (Cepheid). Diagnostic performance
was assessed against a composite reference standard of phenotypic
drug-susceptibility testing and whole-genome sequencing. This study is
registered with ClinicalTrials.gov, number NCT03728725.
FINDINGS: Of 710 participants, 611 (86%) had results from both Xpert MTB/XDR and
the reference standard for any drug and were included in analysis. Sensitivity
for Xpert MTB/XDR detection of resistance was 94% (460 of 488, 95% CI 92-96) for
isoniazid, 94% (222 of 235, 90-96%) for fluoroquinolones, 54% (178 of 328,
50-61) for ethionamide, 73% (60 of 82, 62-81) for amikacin, 86% (181 of 210,
81-91) for kanamycin, and 61% (53 of 87, 49-70) for capreomycin. Specificity was
98-100% for all drugs. Performance was equivalent to that of line-probe assays.
The non-determinate rate of Xpert MTB/XDR (ie, invalid M tuberculosis complex
detection) was 2·96%.
INTERPRETATION: The Xpert MTB/XDR assay showed high diagnostic accuracy and met
WHO's minimum target product profile criteria for a next-generation drug
susceptibility test. The assay has the potential to diagnose drug-resistant
tuberculosis rapidly and accurately and enable optimum treatment.
FUNDING: German Federal Ministry of Education and Research through KfW, Dutch
Ministry of Foreign Affairs, and Australian Department of Foreign Affairs and
Trade.
Copyright ? 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(21)00452-7
PMID: 34627496
5. Lancet Infect Dis. 2021 Oct 1:S1473-3099(21)00261-9. doi:
10.1016/S1473-3099(21)00261-9. Online ahead of print.
The diagnostic performance of novel skin-based in-vivo tests for tuberculosis
infection compared with purified protein derivative tuberculin skin tests and
blood-based in vitro interferon-γ release assays: a systematic review and
meta-analysis.
Krutikov M(1), Faust L(2), Nikolayevskyy V(3), Hamada Y(1), Gupta RK(1), Cirillo
D(4), Mateelli A(5), Korobitsyn A(6), Denkinger CM(7), Rangaka MX(8).
Author information:
(1)Institute for Global Health, University College London, London, UK.
(2)McGill International Tuberculosis Centre and Department of Epidemiology,
Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada.
(3)UK National Mycobacterium Reference Service, Public Health England, London,
UK; Department of Infectious Diseases, Imperial College London, London, UK.
…
BACKGROUND: Novel skin-based tests for tuberculosis infection might present
suitable alternatives to current tests; however, diagnostic performance of new
tests compared with the purified protein derivative-tuberculin skin test (TST)
or interferon-γ release assays (IGRA) needs systematic assessment.
METHODS: In this systematic review and meta-analysis, we searched English
(Medline OVID), Chinese (Chinese Biomedical Literature Database and the China
National Knowledge Infrastructure), and Russian (e-library) databases from the
inception of each database to May 15, 2019, (with updated search of the Russian
and English databases on Oct, 20 2020) using terms "ESAT6" OR "CFP10" AND "skin
test" AND "Tuberculosis" OR "C-Tb" OR "Diaskintest". We included studies
reporting on the performance of index tests alone or compared with a comparator.
Inclusion criteria varied according to review objectives and performance
outcome, but reporting of test cut-offs for positivity applied to study
population was required from all studies. We used a hierarchy of reference
standards for tuberculosis infection consistent with the 2020 WHO framework to
evaluate diagnostic performance. Two authors independently reviewed the titles
and abstracts for English and Chinese (LF and MK) and Russian studies (MK and
VN). Study quality was assessed with QUADAS-2. Pooled random-effects estimates
are presented when appropriate for total agreement proportion, sensitivity in
microbiologically confirmed tuberculosis and specificity in cohorts with low
risk of tuberculosis infection. This study is registered with PROSPERO,
CRD42019135572.
FINDINGS: We identified 1466 original articles, of which 37 (2·5%) studies,
including 10?915 individuals (7111 Diaskintest, 2744 C-Tb, 887 EC, 173 DPPD),
were included in the qualitative analysis (29 [78%] studies of Diaskintest, five
[15%] studies of C-Tb, two [5%] studies of EC-skintest, and one [3%] study of
DPPD). 22 (1·5%) studies including 5810 individuals (3143 Diaskintest, 2129
C-Tb, 538 EC-skintest) were included in the quantitative analysis: 15 (68%) of
Diaskintest, five (23%) of C-Tb, and two (9%) of EC-skintest. Tested
sub-populations included individuals with HIV, children (0-18 years), and
individuals exposed to tuberculosis. Studies were heterogeneous with moderate to
high risk of bias. Nine head-to-head studies of index test versus TST and IGRA
permitted direct comparisons and pooling. In a mixed cohort of people with and
without tuberculosis, Diaskintest pooled agreement with IGRA was 87·16% (95% CI
79·47-92·24) and 55·45% (46·08-64·45) with TST-5 mm cut-off (TST5 mm).
Diaskintest sensitivity was 91·18% (95% CI 81·72-95·98) compared with 88·24%
(78·20-94·01) for TST5 mm, 89·66 (78·83-95·28) for IGRA QuantiFERON, and 90·91% (79·95-96·16) for TSPOT.TB. C-Tb agreement with IGRA in individuals with active tuberculosis was 79·80% (95% CI 76·10-83·07) compared with 78·92% (74·65-82·63) for TST5 mm/15 mm cut-off (TST5 mm/15 mm). TST5/15mm reflects threshold in cohorts that applied stratified cutoffs: 5 mm for HIV-infected,
immunocompromised, or BCG-naive individuals, and 15mm for BCG-vaccinated
immunocompetent individuals. C-Tb sensitivity was 74·52% (95% CI 70·39-78·25)
compared with a sensitivity of 78·18% (67·75-85·94) for TST5 mm/15 mm, and
71·67% (63·44-78·68) for IGRA. Specificity was 97·85% (95% CI 93·96-99·25) for C-Tb versus 93·31% (90·22-95·48) for TST 15 mm cut-off and 99·15% (79·66-99·97) for IGRA. EC-skintest sensitivity was 86·06% (95% CI 82·39-89·07).
INTERPRETATION: Novel skin-based tests for tuberculosis infection appear to
perform similarly to IGRA or TST; however, study quality varied. Evaluation of
test performance, patient-important outcomes, and diagnostic use in current
clinical algorithms will inform implementation in key populations.
FUNDING: StopTB (New Diagnostics Working Group) and FIND.
TRANSLATIONS: For the Chinese and Russian translations of the abstract see
Supplementary Materials section.
Copyright ? 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(21)00261-9
PMID: 34606768
6. J Exp Med. 2021 Oct 4;218(10):e20210915. doi: 10.1084/jem.20210915. Epub 2021
Sep 7.
Blood transcriptomics reveal the evolution and resolution of the immune response
in tuberculosis.
Tabone O(#)(1), Verma R(#)(2), Singhania A(1), Chakravarty P(3), Branchett
WJ(1), Graham CM(1), Lee J(2), Trang T(4), Reynier F(4), Leissner P(4), Kaiser
K(5), Rodrigue M(6), Woltmann G(2), Haldar P(#)(2), O'Garra A(#)(1)(7).
Author information:
(1)Laboratory of Immunoregulation and Infection, The Francis Crick Institute,
London, UK.
(2)Department of Respiratory Sciences, National Institute for Health Research
Respiratory Biomedical Research Centre, University of Leicester, UK.
(3)Bioinformatics Core, The Francis Crick Institute, London, UK.
…
Blood transcriptomics have revealed major characteristics of the immune response
in active TB, but the signature early after infection is unknown. In a unique
clinically and temporally well-defined cohort of household contacts of active TB
patients that progressed to TB, we define minimal changes in gene expression in
incipient TB increasing in subclinical and clinical TB. While increasing with
time, changes in gene expression were highest at 30 d before diagnosis, with
heterogeneity in the response in household TB contacts and in a published cohort
of TB progressors as they progressed to TB, at a bulk cohort level and in
individual progressors. Blood signatures from patients before and during anti-TB
treatment robustly monitored the treatment response distinguishing early and
late responders. Blood transcriptomics thus reveal the evolution and resolution
of the immune response in TB, which may help in clinical management of the
disease.
2021 Tabone et al.
DOI: 10.1084/jem.20210915
PMCID: PMC8493863
PMID: 34491266 [Indexed for MEDLINE]
7. Ann Intern Med. 2021 Oct;174(10):1367-1376. doi: 10.7326/M20-7577. Epub 2021 Aug 24.
Annual Tuberculosis Preventive Therapy for Persons With HIV Infection : A
Randomized Trial.
Churchyard G(1), Cárdenas V(2), Chihota V(3), Mngadi K(2), Sebe M(2), Brumskine
W(2), Martinson N(4), Yimer G(5), Wang SH(5), Garcia-Basteiro AL(6), Nguenha
D(6), Masilela L(2), Waggie Z(2), van den Hof S(7), Charalambous S(3), Cobelens
F(8), Chaisson RE(9), Grant AD(10), Fielding KL(11); WHIP3TB Study Team.
Author information:
(1)The Aurum Institute, Parktown, South Africa, Vanderbilt University,
Nashville, Tennessee, and University of the Witwatersrand, Johannesburg, South
Africa (G.C.).
(2)The Aurum Institute, Parktown, South Africa (V.C., K.M., M.S., W.B., L.M.,
Z.W.).
(3)The Aurum Institute, Parktown, South Africa, and University of the
Witwatersrand, Johannesburg, South Africa (V.C., S.C.).
…
Comment in
Ann Intern Med. 2021 Oct;174(10):1462-1463.
BACKGROUND: Tuberculosis preventive therapy for persons with HIV infection is
effective, but its durability is uncertain.
OBJECTIVE: To compare treatment completion rates of weekly isoniazid-rifapentine
for 3 months versus daily isoniazid for 6 months as well as the effectiveness of
the 3-month rifapentine-isoniazid regimen given annually for 2 years versus
once.
DESIGN: Randomized trial. (ClinicalTrials.gov: NCT02980016).
SETTING: South Africa, Ethiopia, and Mozambique.
PARTICIPANTS: Persons with HIV infection who were receiving antiretroviral
therapy, were aged 2 years or older, and did not have active tuberculosis.
INTERVENTION: Participants were randomly assigned to receive weekly
rifapentine-isoniazid for 3 months, given either annually for 2 years or once,
or daily isoniazid for 6 months. Participants were screened for tuberculosis
symptoms at months 0 to 3 and 12 of each study year and at months 12 and 24
using chest radiography and sputum culture.
MEASUREMENTS: Treatment completion was assessed using pill counts. Tuberculosis
incidence was measured over 24 months.
RESULTS: Between November 2016 and November 2017, 4027 participants were
enrolled; 4014 were included in the analyses (median age, 41 years; 69.5% women;
all using antiretroviral therapy). Treatment completion in the first year for
the combined rifapentine-isoniazid groups (n?= 3610) was 90.4% versus 50.5% for
the isoniazid group (n?= 404) (risk ratio, 1.78 [95% CI, 1.61 to 1.95]).
Tuberculosis incidence among participants receiving the rifapentine-isoniazid
regimen twice (n?= 1808) or once (n?= 1802) was similar (hazard ratio, 0.96 [CI,
0.61 to 1.50]).
LIMITATION: If rifapentine-isoniazid is effective in curing subclinical
tuberculosis, then the intensive tuberculosis screening at month 12 may have
reduced its effectiveness.
CONCLUSION: Treatment completion was higher with rifapentine-isoniazid for 3
months compared with isoniazid for 6 months. In settings with high tuberculosis
transmission, a second round of preventive therapy did not provide additional
benefit to persons receiving antiretroviral therapy.
PRIMARY FUNDING SOURCE: The U.S. Agency for International Development through
the CHALLENGE TB grant to the KNCV Tuberculosis Foundation.
DOI: 10.7326/M20-7577
PMID: 34424730 [Indexed for MEDLINE]
8. J Clin Oncol. 2021 Oct 1;39(28):3118-3127. doi: 10.1200/JCO.21.00639. Epub 2021 Aug 11.
Randomized Phase III Trial of Prophylactic Cranial Irradiation With or Without
Hippocampal Avoidance for Small-Cell Lung Cancer (PREMER): A GICOR-GOECP-SEOR
Study.
Rodríguez de Dios N(1)(2)(3), Cou?ago F(4), Murcia-Mejía M(5), Rico-Oses M(6),
Calvo-Crespo P(7), Samper P(8), Vallejo C(9), Luna J(10), Trueba I(11), Sotoca
A(12), Cigarral C(13), Farré N(14), Manero RM(15), Durán X(2), Gispert
JD(2)(3)(16)(17), Sánchez-Benavides G(2)(16)(18), Rognoni T(19), Torrente
M(20)(21), Capellades J(22), Jiménez M(23), Cabada T(24), Blanco M(25), Alonso
A(26), Martínez-San Millán J(27), Escribano J(28), González B(13), López-Guerra
JL(29).
Author information:
(1)Radiation Oncology, Hospital del Mar, Barcelona, Spain.
(2)IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
(3)Pompeu Fabra University, Barcelona, Spain.
…
Comment in
J Clin Oncol. 2021 Oct 1;39(28):3093-3096.
PURPOSE: Radiation dose received by the neural stem cells of the hippocampus
during whole-brain radiotherapy has been associated with neurocognitive decline.
The key concern using hippocampal avoidance-prophylactic cranial irradiation
(HA-PCI) in patients with small-cell lung cancer (SCLC) is the incidence of
brain metastasis within the hippocampal avoidance zone.
METHODS: This phase III trial enrolled 150 patients with SCLC (71.3% with
limited disease) to standard prophylactic cranial irradiation (PCI; 25 Gy in 10
fractions) or HA-PCI. The primary objective was the delayed free recall (DFR) on
the Free and Cued Selective Reminding Test (FCSRT) at 3 months; a decrease of 3
points or greater from baseline was considered a decline. Secondary end points
included other FCSRT scores, quality of life (QoL), evaluation of the incidence
and location of brain metastases, and overall survival (OS). Data were recorded
at baseline, and 3, 6, 12, and 24 months after PCI.
RESULTS: Participants' baseline characteristics were well balanced between the
two groups. The median follow-up time for living patients was 40.4 months.
Decline on DFR from baseline to 3 months was lower in the HA-PCI arm (5.8%)
compared with the PCI arm (23.5%; odds ratio, 5; 95% CI, 1.57 to 15.86; P =
.003). Analysis of all FCSRT scores showed a decline on the total recall (TR;
8.7% v 20.6%) at 3 months; DFR (11.1% v 33.3%), TR (20.3% v 38.9%), and total
free recall (14.8% v 31.5%) at 6 months, and TR (14.2% v 47.6%) at 24 months.
The incidence of brain metastases, OS, and QoL were not significantly different.
CONCLUSION: Sparing the hippocampus during PCI better preserves cognitive
function in patients with SCLC. No differences were observed with regard to
brain failure, OS, and QoL compared with standard PCI.
DOI: 10.1200/JCO.21.00639
PMID: 34379442 [Indexed for MEDLINE]
9. J Exp Med. 2021 Oct 4;218(10):e20210469. doi: 10.1084/jem.20210469. Epub 2021
Aug 4.
Eosinophils are part of the granulocyte response in tuberculosis and promote
host resistance in mice.
Bohrer AC(#)(1), Castro E(#)(1), Hu Z(#)(2)(3), Queiroz ATL(4), Tocheny CE(1),
Assmann M(1), Sakai S(5), Nelson C(5), Baker PJ(1), Ma H(2)(3), Wang L(3)(6),
Zilu W(3)(6), du Bruyn E(7), Riou C(7), Kauffman KD(5); Tuberculosis Imaging
Program, Moore IN(8), Del Nonno F(9), Petrone L(10), Goletti D(10), Martineau
AR(11), Lowe DM(11), Cronan MR(12)(13), Wilkinson RJ(7)(14)(15), Barry
CE(7)(16), Via LE(17)(16), Barber DL(5), Klion AD(18), Andrade BB(4), Song
Y(3)(6), Wong KW(2)(3), Mayer-Barber KD(1).
Author information:
(1)Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and
Microbiology, National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, MD.
(2)Department of Scientific Research, Shanghai Public Health Clinical Center,
Fudan University, Shanghai, China.
(3)Tuberculosis Center, Shanghai Emerging and Re-emerging Infectious Disease
Institute, Fudan University, Shanghai, China.
…
Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the
activities of multiple leukocyte subsets, yet the roles of the different innate
effector cells during tuberculosis are incompletely understood. Here we uncover
an unexpected association between eosinophils and Mtb infection. In humans,
eosinophils are decreased in the blood but enriched in resected human
tuberculosis lung lesions and autopsy granulomas. An influx of eosinophils is
also evident in infected zebrafish, mice, and nonhuman primate granulomas, where
they are functionally activated and degranulate. Importantly, using
complementary genetic models of eosinophil deficiency, we demonstrate that in
mice, eosinophils are required for optimal pulmonary bacterial control and host
survival after Mtb infection. Collectively, our findings uncover an unexpected
recruitment of eosinophils to the infected lung tissue and a protective role for
these cells in the control of Mtb infection in mice.
2021 Bohrer et al.
DOI: 10.1084/jem.20210469
PMCID: PMC8348215
PMID: 34347010 [Indexed for MEDLINE]
10. Mol Aspects Med. 2021 Oct;81:101002. doi: 10.1016/j.mam.2021.101002. Epub 2021 Jul 31.
Protein synthesis in Mycobacterium tuberculosis as a potential target for
therapeutic interventions.
Kumar N(1), Sharma S(1), Kaushal PS(2).
Author information:
(1)Structural Biology & Translation Regulation Laboratory, Regional Centre for
Biotechnology, NCR Biotech Science Cluster, Faridabad, 121 001, India.
(2)Structural Biology & Translation Regulation Laboratory, Regional Centre for
Biotechnology, NCR Biotech Science Cluster, Faridabad, 121 001, India.
Electronic address: prem.kaushal@rcb.res.in.
Mycobacterium tuberculosis (Mtb) causes one of humankind's deadliest diseases,
tuberculosis. Mtb protein synthesis machinery possesses several unique
species-specific features, including its ribosome that carries two mycobacterial
specific ribosomal proteins, bL37 and bS22, and ribosomal RNA segments. Since
the protein synthesis is a vital cellular process that occurs on the ribosome, a
detailed knowledge of the structure and function of mycobacterial ribosomes is
essential to understand the cell's proteome by translation regulation. Like in
many bacterial species such as Bacillus subtilis and Streptomyces coelicolor,
two distinct populations of ribosomes have been identified in Mtb. Under
low-zinc conditions, Mtb ribosomal proteins S14, S18, L28, and L33 are replaced
with their non-zinc binding paralogues. Depending upon the nature of
physiological stress, species-specific modulation of translation by stress
factors and toxins that interact with the ribosome have been reported. In
addition, about one-fourth of messenger RNAs in mycobacteria have been reported
to be leaderless, i.e., without 5' UTR regions. However, the mechanism by which
they are recruited to the Mtb ribosome is not understood. In this review, we
highlight the mycobacteria-specific features of the translation apparatus and
propose exploiting these features to improve the efficacy and specificity of
existing antibiotics used to treat tuberculosis.
Copyright ? 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.mam.2021.101002
PMID: 34344520 [Indexed for MEDLINE]
11. J Clin Oncol. 2021 Oct 20;39(30):3391-3402. doi: 10.1200/JCO.21.00662. Epub 2021 Aug 2.
Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer
Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I
Study.
Park K(1), Haura EB(2), Leighl NB(3), Mitchell P(4), Shu CA(5), Girard N(6),
Viteri S(7), Han JY(8), Kim SW(9), Lee CK(10), Sabari JK(11), Spira AI(12), Yang
TY(13), Kim DW(14), Lee KH(15), Sanborn RE(16), Trigo J(17), Goto K(18), Lee
JS(19), Yang JC(20), Govindan R(21), Bauml JM(22), Garrido P(23), Krebs MG(24),
Reckamp KL(25), Xie J(26), Curtin JC(26), Haddish-Berhane N(26), Roshak A(26),
Millington D(26), Lorenzini P(26), Thayu M(26), Knoblauch RE(26), Cho BC(27).
Author information:
(1)Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
South Korea.
(2)H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
(3)Princess Margaret Cancer Centre, Toronto, Canada.
…
Comment in
J Clin Oncol. 2021 Oct 20;39(30):3403-3406.
Nat Rev Clin Oncol. 2021 Oct;18(10):604.
PURPOSE: Non-small-cell lung cancer (NSCLC) with epidermal growth factor
receptor (EGFR) exon 20 insertion (Exon20ins) mutations exhibits inherent
resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET
bispecific antibody with immune cell-directing activity, binds to each
receptor's extracellular domain, bypassing resistance at the tyrosine kinase
inhibitor binding site.
METHODS: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion
study, which included a population with EGFR Exon20ins NSCLC. The primary end
points were dose-limiting toxicity and overall response rate. We report findings
from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended
phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for
the first 4 weeks and then once every 2 weeks starting at week 5.
RESULTS: In the efficacy population (n = 81), the median age was 62 years
(range, 42-84 years); 40 patients (49%) were Asian, and the median number of
previous lines of therapy was two (range, 1-7). The overall response rate was
40% (95% CI, 29 to 51), including three complete responses, with a median
duration of response of 11.1 months (95% CI, 6.9 to not reached). The median
progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety
population (n = 114), the most common adverse events were rash in 98 patients
(86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The
most common grade 3-4 adverse events were hypokalemia in six patients (5%) and
rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each.
Treatment-related dose reductions and discontinuations were reported in 13% and
4% of patients, respectively.
CONCLUSION: Amivantamab, via its novel mechanism of action, yielded robust and
durable responses with tolerable safety in patients with EGFR Exon20ins
mutations after progression on platinum-based chemotherapy.
DOI: 10.1200/JCO.21.00662
PMID: 34339292 [Indexed for MEDLINE]
12. Lancet Infect Dis. 2021 Oct;21(10):e303-e317. doi:
10.1016/S1473-3099(20)30728-3. Epub 2021 Apr 20.
Quantifying the rates of late reactivation tuberculosis: a systematic review.
Dale KD(1), Karmakar M(2), Snow KJ(3), Menzies D(4), Trauer JM(5), Denholm
JT(6).
Author information:
(1)Victorian Tuberculosis Program, Royal Melbourne Hospital, Peter Doherty
Institute for Infection and Immunity, The University of Melbourne, Melbourne,
VIC, Australia; Department of Microbiology and Immunology, Peter Doherty
Institute for Infection and Immunity, The University of Melbourne, Melbourne,
VIC, Australia. Electronic address: katie.dale@mh.org.au.
(2)Department of Microbiology and Immunology, Peter Doherty Institute for
Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia;
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
(3)Centre for International Child Health, Department of Paediatrics, Royal
Children's Hospital, University of Melbourne, Parkville, VIC, Australia;
Australia Department of Paediatrics, University of Melbourne, Parkville, VIC,
Australia.
…
The risk of tuberculosis is greatest soon after infection, but Mycobacterium
tuberculosis can remain in the body latently, and individuals can develop
disease in the future, sometimes years later. However, there is uncertainty
about how often reactivation of latent tuberculosis infection (LTBI) occurs. We
searched eight databases (inception to June 25, 2019) to identify studies that
quantified tuberculosis reactivation rates occurring more than 2 years after
infection (late reactivation), with a focus on identifying untreated study
cohorts with defined timing of LTBI acquisition (PROSPERO registered:
CRD42017070594). We included 110 studies, divided into four methodological
groups. Group 1 included studies that documented late reactivation rates from
conversion (n=14) and group 2 documented late reactivation rates in LTBI cohorts
from exposure (n=11). Group 3 included 86 studies in LTBI cohorts with an
unknown exposure history, and group 4 included seven ecological studies. Since
antibiotics have been used to treat tuberculosis, only 11 studies have
documented late reactivation rates in infected, untreated cohorts from either
conversion (group 1) or exposure (group 2); six of these studies lasted at least
4 years and none lasted longer than 10 years. These studies found that
tuberculosis rates declined over time, reaching approximately 200 cases per
100?000 person-years or less by the fifth year, and possibly declining further
after 5 years but interpretation was limited by decreasing or unspecified cohort
sizes. In cohorts with latent tuberculosis and an unknown exposure history
(group 3), tuberculosis rates were generally lower than those seen in groups 1
and 2, and beyond 10 years after screening, rates had declined to less than 100
per 100?000 person-years. Reinfection risks limit interpretation in all studies
and the effect of age is unclear. Late reactivation rates are commonly estimated
or modelled to prioritise tuberculosis control strategies towards tubuculosis
elimination, but significant gaps remain in our understanding that must be
acknowledged; the relative importance of late reactivation versus early
progression to the global burden of tuberculosis remains unknown.
Copyright ? 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(20)30728-3
PMID: 33891908 [Indexed for MEDLINE]
13. Nat Chem. 2021 Dec;13(12):1248-1256. doi: 10.1038/s41557-021-00804-0. Epub 2021 Oct 25.
Photoacoustic imaging of elevated glutathione in models of lung cancer for
companion diagnostic applications.
Lucero MY(1), Chan J(2).
Author information:
(1)Department of Chemistry and Beckman Institute for Advanced Science and
Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
(2)Department of Chemistry and Beckman Institute for Advanced Science and
Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
jeffchan@illinois.edu.
Companion diagnostics (CDx) are powerful tests that can provide physicians with
crucial biomarker information that can improve treatment outcomes by matching
therapies to patients. Here, we report a photoacoustic imaging-based CDx (PACDx)
for the selective detection of elevated glutathione (GSH) in a lung cancer
model. GSH is abundant in most cells, so we adopted a physical organic chemistry
approach to precisely tune the reactivity to distinguish between normal and
pathological states. To evaluate the efficacy of PACDx in vivo, we designed a
blind study where photoacoustic imaging was used to identify mice bearing lung
xenografts. We also employed PACDx in orthotopic lung cancer and liver
metastasis models to image GSH. In addition, we designed a matching prodrug,
PARx, that uses the same SNAr chemistry to release a chemotherapeutic with an
integrated PA readout. Studies demonstrate that PARx can inhibit tumour growth
without off-target toxicity in a lung cancer xenograft model.
2021. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41557-021-00804-0
PMCID: PMC8629919
PMID: 34697400 [Indexed for MEDLINE]
14. Cancer Cell. 2021 Nov 8;39(11):1479-1496.e18. doi: 10.1016/j.ccell.2021.09.008. Epub 2021 Oct 14.
Signatures of plasticity, metastasis, and immunosuppression in an atlas of human
small cell lung cancer.
Chan JM(1), Quintanal-Villalonga ?(2), Gao VR(3), Xie Y(3), Allaj V(2),
Chaudhary O(4), Masilionis I(4), Egger J(2), Chow A(2), Walle T(5), Mattar M(6),
Yarlagadda DVK(4), Wang JL(7), Uddin F(2), Offin M(2), Ciampricotti M(2), Qeriqi
B(6), Bahr A(6), de Stanchina E(8), Bhanot UK(9), Lai WV(2), Bott MJ(10), Jones
DR(10), Ruiz A(11), Baine MK(11), Li Y(11), Rekhtman N(11), Poirier JT(12), Nawy
T(4), Sen T(13), Mazutis L(14), Hollmann TJ(11), Pe'er D(15), Rudin CM(16).
Author information:
(1)Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering
Cancer Center, New York, NY 10065, USA; Program for Computational and Systems
Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New
York, NY 10016, USA.
(2)Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering
Cancer Center, New York, NY 10065, USA.
(3)Program for Computational and Systems Biology, Sloan Kettering Institute,
Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA; Weill Cornell
Medical College, New York, NY 10065, USA.
…
Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes
defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N,
and -P, respectively). To define the heterogeneity of tumors and their
associated microenvironments across subtypes, we sequenced 155,098
transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes.
We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by
canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC
phenotype with stem-like, pro-metastatic features that recurs across subtypes
and predicts worse overall survival. SCLC exhibits greater immune sequestration
and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less
immune infiltrate and greater T?cell dysfunction than SCLC-A. We identify a
profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors
that is particularly associated with the recurrent, PLCG2-high subpopulation.
Copyright ? 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2021.09.008
PMCID: PMC8628860
PMID: 34653364 [Indexed for MEDLINE]
15. Lancet Oncol. 2021 Oct;22(10):1448-1457. doi: 10.1016/S1470-2045(21)00401-0.
Epub 2021 Sep 13.
Stereotactic ablative radiotherapy for operable stage I non-small-cell lung
cancer (revised STARS): long-term results of a single-arm, prospective trial
with prespecified comparison to surgery.
Chang JY(1), Mehran RJ(2), Feng L(3), Verma V(4), Liao Z(4), Welsh JW(4), Lin
SH(4), O'Reilly MS(4), Jeter MD(4), Balter PA(5), McRae SE(6), Berry D(3),
Heymach JV(7), Roth JA(2); STARS Lung Cancer Trials Group.
Collaborators: Antonoff M, Hofstetter W, Rajaram R, Rice D, Sepesi B, Swisher S,
Vaporciyan A, Walsh G, DeGraaf C, Correa A, Chen A, Gandhi S, Komaki R, Lee P,
Nguyen QN, Ning M, Gao S, Pollard-Larkin J, Nitsch P, Sadagopan R, Wang X.
Author information:
(1)Department of Radiation Oncology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA. Electronic address: jychang@mdanderson.org.
(2)Department of Thoracic and Cardiovascular Surgery, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA.
(3)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA.
…
Comment in
Lancet Oncol. 2021 Dec;22(12):e534.
Lancet Oncol. 2021 Dec;22(12):e535.
Lancet Oncol. 2021 Dec;22(12):e536.
Lancet Oncol. 2021 Dec;22(12):e537-e538.
BACKGROUND: A previous pooled analysis of the STARS and ROSEL trials showed
higher survival after stereotactic ablative radiotherapy (SABR) than with
surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that
analysis had notable limitations. This study reports long-term results of the
revised STARS trial, in which the SABR group was re-accrued with a larger sample
size, along with a protocol-specified propensity-matched comparison with a
prospectively registered, contemporary institutional cohort of patients who
underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph
node dissection (VATS L-MLND).
METHODS: This single-arm prospective trial was done at the University of Texas
MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years
or older with a Zubrod performance status of 0-2, newly diagnosed and
histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma,
large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or
less. This trial did not include patients from the previous pooled analysis.
SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in
four fractions (for central tumours; simultaneous integrated boost to gross
tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival.
For the propensity-matching analysis, we used a surgical cohort from the MD
Anderson Department of Thoracic and Cardiovascular Surgery's prospectively
registered, institutional review board-approved database of all patients with
clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment
in this trial. Non-inferiority could be claimed if the 3-year overall survival
rate after SABR was lower than that after VATS L-MLND by 12% or less and the
upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965.
Propensity matching consisted of determining a propensity score using a
multivariable logistic regression model including several covariates (age,
tumour size, histology, performance status, and the interaction of age and sex);
based on the propensity scores, one patient in the SABR group was randomly
matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match
algorithm. This study is registered with ClinicalTrials.gov, NCT02357992.
FINDINGS: Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and
included in efficacy and safety analyses. Median follow-up time was 5·1 years
(IQR 3·9-5·8). Overall survival was 91% (95% CI 85-98) at 3 years and 87%
(79-95) at 5 years. SABR was tolerated well, with no grade 4-5 toxicity and one
(1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung
fibrosis. No serious adverse events were recorded. Overall survival in the
propensity-matched VATS L-MLND cohort was 91% (95% CI 85-98) at 3 years and 84%
(76-93) at 5 years. Non-inferiority was claimed since the 3-year overall
survival after SABR was not lower than that observed in the VATS L-MLND group.
There was no significant difference in overall survival between the two patient
cohorts (hazard ratio 0·86 [95% CI 0·45-1·65], p=0·65) from a multivariable
analysis.
INTERPRETATION: Long-term survival after SABR is non-inferior to VATS L-MLND for
operable stage IA NSCLC. SABR remains promising for such cases but
multidisciplinary management is strongly recommended.
FUNDING: Varian Medical Systems and US National Cancer Institute (National
Institutes of Health).
Copyright ? 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(21)00401-0
PMCID: PMC8521627
PMID: 34529930 [Indexed for MEDLINE]
16. Lancet. 2021 Oct 9;398(10308):1344-1357. doi: 10.1016/S0140-6736(21)02098-5.
Epub 2021 Sep 20.
Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA
non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label,
phase 3 trial.
Felip E(1), Altorki N(2), Zhou C(3), Cs?szi T(4), Vynnychenko I(5), Goloborodko
O(6), Luft A(7), Akopov A(8), Martinez-Marti A(9), Kenmotsu H(10), Chen YM(11),
Chella A(12), Sugawara S(13), Voong D(14), Wu F(15), Yi J(14), Deng Y(14),
McCleland M(14), Bennett E(14), Gitlitz B(14), Wakelee H(16); IMpower010
Investigators.
Author information:
(1)Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital,
Barcelona, Spain. Electronic address: efelip@vhio.net.
(2)Division of Thoracic Surgery, Weill Cornell Medicine, New York-Presbyterian
Hospital, New York, NY, USA.
(3)Department of Oncology, Tongji University Affiliated Shanghai Pulmonary
Hospital, Shanghai, China.
…
Erratum in
Lancet. 2021 Sep 23;:
Comment in
Lancet. 2021 Oct 9;398(10308):1281-1283.
BACKGROUND: Novel adjuvant strategies are needed to optimise outcomes after
complete surgical resection in patients with early-stage non-small-cell lung
cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best
supportive care after adjuvant platinum-based chemotherapy in these patients.
METHODS: IMpower010 was a randomised, multicentre, open-label, phase 3 study
done at 227 sites in 22 countries and regions. Eligible patients were 18 years
or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the
Union Internationale Contre le Cancer and American Joint Committee on Cancer
staging system (7th edition). Patients were randomly assigned (1:1) by a
permuted-block method (block size of four) to receive adjuvant atezolizumab
(1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care
(observation and regular scans for disease recurrence) after adjuvant
platinum-based chemotherapy (one to four cycles). The primary endpoint,
investigator-assessed disease-free survival, was tested hierarchically first in
the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or
more of tumour cells (SP263), then all patients in the stage II-IIIA population,
and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was
evaluated in all patients who were randomly assigned and received atezolizumab
or best supportive care. IMpower010 is registered with ClinicalTrials.gov,
NCT02486718 (active, not recruiting).
FINDINGS: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled
after complete resection. 1269 received adjuvant chemotherapy, of whom 1005
patients were eligible for randomisation to atezolizumab (n=507) or best
supportive care (n=498); 495 in each group received treatment. After a median
follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population,
atezolizumab treatment improved disease-free survival compared with best
supportive care in patients in the stage II-IIIA population whose tumours
expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88;
p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81
(0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%).
INTERPRETATION: IMpower010 showed a disease-free survival benefit with
atezolizumab versus best supportive care after adjuvant chemotherapy in patients
with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose
tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety
signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment
option for patients with resected early-stage NSCLC.
FUNDING: F Hoffmann-La Roche and Genentech.
Copyright ? 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(21)02098-5
PMID: 34555333 [Indexed for MEDLINE]
下一篇： No.11
