Medical Abstracts ( IF > 10)

1. Nature. 2020 Dec 9. doi: 10.1038/s41586-020-3004-3. Online ahead of print.

Structure of mycobacterial ATP synthase bound to the tuberculosis drug

bedaquiline.

Guo H(1)(2), Courbon GM(1)(2), Bueler SA(1), Mai J(3), Liu J(3), Rubinstein

JL(4)(5)(6).

Author information:

(1)Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario,

Canada.

(2)Department of Medical Biophysics, The University of Toronto, Toronto,

Ontario, Canada.

(3)Department of Molecular Genetics, The University of Toronto, Toronto,

Ontario, Canada.

...

Tuberculosis-the world's leading cause of death by infectious disease-is

increasingly resistant to current first-line antibiotics1. The bacterium

Mycobacterium tuberculosis (which causes tuberculosis) can survive low-energy

conditions, allowing infections to remain dormant and decreasing their

susceptibility to many antibiotics2. Bedaquiline was developed in 2005 from a

lead compound identified in a phenotypic screen against Mycobacterium

smegmatis3. This drug can sterilize even latent M. tuberculosis? infections4 and

has become a cornerstone of treatment for multidrug-resistant and extensively

drug-resistant tuberculosis1,5,6. Bedaquiline targets the mycobacterial ATP

synthase3, which is an essential enzyme in the obligate aerobic Mycobacterium

genus3,7, but how it binds the intact enzyme is unknown. Here we determined

cryo-electron microscopy structures of M. smegmatis ATP synthase alone and in

complex with bedaquiline. The drug-free structure suggests that hook-like

extensions from the α-subunits prevent the enzyme from running in reverse,

inhibiting ATP hydrolysis and preserving energy in hypoxic conditions.

Bedaquiline binding induces large conformational changes in the ATP synthase,

creating tight binding pockets at the interface of subunits a and c that explain

the potency of this drug as an antibiotic for tuberculosis.

DOI: 10.1038/s41586-020-3004-3

PMID: 33299175

2. Lancet Oncol. 2020 Dec;21(12):1589-1601. doi: 10.1016/S1470-2045(20)30475-7.

Epub 2020 Oct 27.

Biomarker-driven therapies for previously treated squamous non-small-cell lung

cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol.

Redman MW(1), Papadimitrakopoulou VA(2), Minichiello K(3), Hirsch FR(4), Mack

PC(4), Schwartz LH(5), Vokes E(6), Ramalingam S(7), Leighl N(8), Bradley J(9),

Miao J(3), Moon J(3), Highleyman L(10), Miwa C(11), LeBlanc ML(3), Malik S(12),

Miller VA(13), Sigal EV(14), Adam S(15), Wholley D(15), Sigman C(16), Smolich

B(16), Blanke CD(17), Kelly K(18), Gandara DR(18), Herbst RS(19).

Author information:

(1)SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research

Center, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer

Research Center, Seattle, WA, USA. Electronic address: mredman@fredhutch.org.

(2)Department of Thoracic Head and Neck Medical Oncology, Division of Cancer

Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

(3)SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research

Center, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson

Cancer Research Center, Seattle, WA, USA.

...

BACKGROUND: The Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed

biomarker-driven master protocol designed to address an unmet need for better

therapies for squamous non-small-cell lung cancer. Lung-MAP (S1400) was created

to establish an infrastructure for biomarker screening and rapid regulatory

intent evaluation of targeted therapies and was the first biomarker-driven

master protocol initiated with the US National Cancer Institute (NCI).

METHODS: Lung-MAP (S1400) was done within the National Clinical Trials Network

of the NCI using a public-private partnership. Eligible patients were aged 18

years or older, had stage IV or recurrent squamous non-small-cell lung cancer,

had previously been treated with platinum-based chemotherapy, and had an Eastern

Cooperative Oncology Group (ECOG) performance status of 0-2. The study included

a screening component using the FoundationOne assay (Foundation Medicine,

Cambridge, MA, USA) for next-generation sequencing, and a clinical trial

component with biomarker-driven substudies and non-match substudies for patients

who were ineligible for biomarker-driven substudies. Patients were pre-screened

and received their substudy assignment upon progression, or they were screened

at progression and received their substudy assignment upon completion of

testing. Patients could enrol onto additional substudies after progression on a

substudy. The study is registered with ClinicalTrials.gov, NCT02154490, and all

research related to Lung-MAP (S1400) is completed.

FINDINGS: Between June 16, 2014, and Jan 28, 2019, 1864 patients enrolled and

1841 (98·9%) submitted tissue. 1674 (90·9%) of 1841 patients had biomarker

results, and 1404 (83·9%) of 1674 patients received a substudy assignment. Of

the assigned patients, 655 (46·7%) registered to a substudy. The

biomarker-driven substudies evaluated taselisib (targeting PIK3CA alterations),

palbociclib (cell cycle gene alterations), AZD4547 (FGFR alteration),

rilotumumab plus erlotinib (MET), talazoparib (homologous recombination repair

deficiency), and telisotuzumab vedotin (MET). The non-match substudies evaluated

durvalumab, and nivolumab plus ipilimumab for anti-PD-1 or anti-PD-L1-naive

disease, and durvalumab plus tremelimumab for anti-PD-1 or anti-PD-L1 relapsed

disease. Combining data from the substudies, ten (7·0%) of 143 patients

responded to targeted therapy, 53 (16·8%) of 315 patients responded to anti-PD-1

or anti-PD-L1 therapy for immunotherapy-naive disease, and three (5·4%) of 56

responded to docetaxel in the second line of therapy. Median overall survival

was 5·9 months (95% CI 4·8-7·8) for the targeted therapy groups, 7·7 months

(6·7-9·2) for the docetaxel groups, and 10·8 months (9·4-12·3) for the anti-PD-1

or anti-PD-L1-containing groups. Median progression-free survival was 2·5 months

(95% CI 1·7-2·8) for the targeted therapy groups, 2·7 months (1·9-2·9) for the

docetaxel groups, and 3·0 months (2·7-3·9) for the anti-PD-1 or

anti-PD-L1-containing groups.

INTERPRETATION: Lung-MAP (S1400) met its goal to quickly address

biomarker-driven therapy questions in squamous non-small-cell lung cancer. In

early 2019, a new screening protocol was implemented expanding to all

histological types of non-small-cell lung cancer and to add focus on

immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed

disease. With these changes, Lung-MAP continues to meet its goal to focus on

unmet needs in the treatment of advanced lung cancers.

FUNDING: US National Institutes of Health, and AbbVie, Amgen, AstraZeneca,

Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the

National Institutes of Health.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(20)30475-7

PMID: 33125909

3. JAMA. 2020 Dec 22;324(24):2521-2535. doi: 10.1001/jama.2020.23130.

Association of First Primary Cancer With Risk of Subsequent Primary Cancer Among

Survivors of Adult-Onset Cancers in the United States.

Sung H(1), Hyun N(2), Leach CR(3), Yabroff KR(1), Jemal A(1).

Author information:

(1)Department of Data Science, American Cancer Society, Atlanta, Georgia.

(2)Institute for Health and Equity, Medical College of Wisconsin, Milwaukee.

(3)Department of Population Science, American Cancer Society, Atlanta, Georgia.

IMPORTANCE: The number of cancer survivors who develop new cancers is projected

to increase, but comprehensive data on the risk of subsequent primary cancers

(SPCs) among survivors of adult-onset cancers are limited.

OBJECTIVE: To quantify the overall and cancer type-specific risks of SPCs among

adult-onset cancer survivors by first primary cancer (FPC) types and sex.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study from 12

Surveillance, Epidemiology, and End Results registries in the United States,

that included 1?537?101 persons aged 20 to 84 years diagnosed with FPCs from

1992-2011 (followed up until December 31, 2017) and who survived at least 5

years.

EXPOSURES: First primary cancer.

MAIN OUTCOMES AND MEASURES: Incidence and mortality of SPCs per 10?000

person-years; standardized incidence ratio (SIR) and standardized mortality

ratio (SMR) compared with those expected in the general population.

RESULTS: Among 1?537?101 survivors (mean age, 60.4 years; 48.8% women), 156?442

SPC cases and 88?818 SPC deaths occurred during 11?197?890 person-years of

follow-up (mean, 7.3 years). Among men, the overall risk of developing any SPCs

was statistically significantly higher for 18 of the 30 FPC types, and risk of

dying from any SPCs was statistically significantly higher for 27 of 30 FPC

types as compared with risks in the general population. Among women, the overall

risk of developing any SPCs was statistically significantly higher for 21 of the

31 FPC types, and risk of dying from any SPCs was statistically significantly

higher for 28 of 31 FPC types as compared with risks in the general population.

The highest overall SIR and SMR were estimated among survivors of laryngeal

cancer (SIR, 1.75 [95% CI, 1.68-1.83]; incidence, 373 per 10?000 person-years)

and gallbladder cancer (SMR, 3.82 [95% CI, 3.31-4.39]; mortality, 341 per 10?000

person-years) among men, and among survivors of laryngeal cancer (SIR, 2.48 [95%

CI, 2.27-2.72]; incidence, 336 per 10?000 person-years; SMR, 4.56 [95% CI,

4.11-5.06]; mortality, 268 per 10?000 person-years) among women. Substantial

variation existed in the associations of specific types of FPCs with specific

types of SPC risk; however, only a few smoking- or obesity-associated SPCs, such

as lung, urinary bladder, oral cavity/pharynx, colorectal, pancreatic, uterine

corpus, and liver cancers constituted considerable proportions of the total

incidence and mortality, with lung cancer alone accounting for 31% to 33% of

mortality from all SPCs.

CONCLUSIONS AND RELEVANCE: Among survivors of adult-onset cancers in the United

States, several types of primary cancer were significantly associated with

greater risk of developing and dying from an SPC, compared with the general

population. Cancers associated with smoking or obesity comprised substantial

proportions of overall SPC incidence and mortality among all survivors and

highlight the importance of ongoing surveillance and efforts to prevent new

cancers among survivors.

DOI: 10.1001/jama.2020.23130

PMID: 33351041

4. Cancer Cell. 2020 Dec 1:S1535-6108(20)30597-3. doi: 10.1016/j.ccell.2020.11.005.

Online ahead of print.

Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and

Improves Antitumor Efficacy when Combined with Checkpoint Blockade.

Srivastava S(1), Furlan SN(2), Jaeger-Ruckstuhl CA(3), Sarvothama M(3), Berger

C(3), Smythe KS(3), Garrison SM(3), Specht JM(4), Lee SM(4), Amezquita RA(5),

Voillet V(5), Muhunthan V(3), Yechan-Gunja S(3), Pillai SPS(6), Rader C(7),

Houghton AM(3), Pierce RH(3), Gottardo R(5), Maloney DG(4), Riddell SR(4).

Author information:

(1)Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle,

WA, USA. Electronic address: ssrivas2@fredhutch.org.

(2)Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle,

WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.

(3)Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle,

WA, USA....

Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells)

is effective in hematologic but not epithelial malignancies, which cause the

greatest mortality. In breast and lung cancer patients, CAR-T cells targeting

the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1

(ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for

enhancing efficacy, we adapted the KrasLSL-G12D/+;p53f/f autochthonous model of

lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells

transferred after lymphodepletion with cyclophosphamide (Cy) transiently control

tumor growth but infiltrate tumors poorly and lose function, similar to what is

seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen

activates tumor macrophages to express T-cell-recruiting chemokines, resulting

in improved CAR-T cell infiltration, remodeling of the tumor microenvironment,

and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy

and anti-PD-L1 synergistically improves CAR-T cell-mediated tumor control and

survival, providing a strategy to improve CAR-T cell efficacy in the clinic.

Copyright © 2020 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2020.11.005

PMID: 33357452

5. Sci Transl Med. 2020 Nov 25;12(571):eabc6659. doi: 10.1126/scitranslmed.abc6659.

Systemic cancer therapy with engineered adenovirus that evades innate immunity.

Atasheva S(1), Emerson CC(2), Yao J(1), Young C(1), Stewart PL(3), Shayakhmetov

DM(4)(5)(6)(7).

Author information:

(1)Lowance Center for Human Immunology, Departments of Pediatrics and Medicine,

Emory University School of Medicine, Atlanta, GA 30322, USA.

(2)Department of Pharmacology and Cleveland Center for Membrane and Structural

Biology, Case Western Reserve University, Cleveland, OH 44106, USA.

(3)Department of Pharmacology and Cleveland Center for Membrane and Structural

Biology, Case Western Reserve University, Cleveland, OH 44106, USA.

pls47@case.edu dmitryshay@emory.edu.

...

Oncolytic virus therapy is a cancer treatment modality that has the potential to

improve outcomes for patients with currently incurable malignancies. Although

intravascular delivery of therapeutic viruses provides access to disseminated

tumors, this delivery route exposes the virus to opsonizing and inactivating

factors in the blood, which limit the effective therapeutic virus dose and

contribute to activation of systemic toxicities. When human species C adenovirus

HAdv-C5 is delivered intravenously, natural immunoglobulin M (IgM) antibodies

and coagulation factor X rapidly opsonize HAdv-C5, leading to virus

sequestration in tissue macrophages and promoting infection of liver cells,

triggering hepatotoxicity. Here, we showed that natural IgM antibody binds to

the hypervariable region 1 (HVR1) of the main HAdv-C5 capsid protein hexon.

Using compound targeted mutagenesis of hexon HVR1 loop and other functional

sites that mediate virus-host interactions, we engineered and obtained a

high-resolution cryo-electron microscopy structure of an adenovirus vector,

Ad5-3M, which resisted inactivation by blood factors, avoided sequestration in

liver macrophages, and failed to trigger hepatotoxicity after intravenous

delivery. Systemic delivery of Ad5-3M to mice with localized or disseminated

lung cancer led to viral replication in tumor cells, suppression of tumor

growth, and prolonged survival. Thus, compound targeted mutagenesis of

functional sites in the virus capsid represents a generalizable approach to

tailor virus interactions with the humoral and cellular arms of the immune

system, enabling generation of "designer" viruses with improved therapeutic

properties.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American

Association for the Advancement of Science. No claim to original U.S. Government

Works.

DOI: 10.1126/scitranslmed.abc6659

PMID: 33239388

6. PLoS Med. 2020 Dec 11;17(12):e1003466. doi: 10.1371/journal.pmed.1003466.

eCollection 2020 Dec.

The potential impact of urine-LAM diagnostics on tuberculosis incidence and

mortality: A modelling analysis.

Ricks S(1), Denkinger CM(2)(3), Schumacher SG(3), Hallett TB(1), Arinaminpathy

N(1).

Author information:

(1)MRC Centre for Global Infectious Disease Analysis, Imperial College London,

London, United Kingdom.

(2)Center of Infectious Disease, University of Heidelberg, Heidelberg, Germany.

(3)Foundation for Innovative New Diagnostics, Geneva, Switzerland.

BACKGROUND: Lateral flow urine lipoarabinomannan (LAM) tests could offer

important new opportunities for the early detection of tuberculosis (TB). The

currently licensed LAM test, Alere Determine TB LAM Ag ('LF-LAM'), performs best

in the sickest people living with HIV (PLHIV). However, the technology continues

to improve, with newer LAM tests, such as Fujifilm SILVAMP TB LAM

('SILVAMP-LAM') showing improved sensitivity, including amongst HIV-negative

patients. It is important to anticipate the epidemiological impact that current

and future LAM tests may have on TB incidence and mortality.

METHODS AND FINDINGS: Concentrating on South Africa, we examined the impact that

widening LAM test eligibility would have on TB incidence and mortality. We

developed a mathematical model of TB transmission to project the impact of LAM

tests, distinguishing 'current' tests (with sensitivity consistent with LF-LAM),

from hypothetical 'future' tests (having sensitivity consistent with

SILVAMP-LAM). We modelled the impact of both tests, assuming full adoption of

the 2019 WHO guidelines for the use of these tests amongst those receiving HIV

care. We also simulated the hypothetical deployment of future LAM tests for all

people presenting to care with TB symptoms, not restricted to PLHIV. Our model

projects that 2,700,000 (95% credible interval [CrI] 2,000,000-3,600,000) and

420,000 (95% CrI 350,000-520,000) cumulative TB incident cases and deaths,

respectively, would occur between 2020 and 2035 if the status quo is maintained.

Relative to this comparator, current and future LAM tests would respectively

avert 54 (95% CrI 33-86) and 90 (95% CrI 55-145) TB deaths amongst inpatients

between 2020 and 2035, i.e., reductions of 5% (95% CrI 4%-6%) and 9% (95% CrI

7%-11%) in inpatient TB mortality. This impact in absolute deaths averted

doubles if testing is expanded to include outpatients, yet remains <1% of

country-level TB deaths. Similar patterns apply to incidence results. However,

deploying a future LAM test for all people presenting to care with TB symptoms

would avert 470,000 (95% CrI 220,000-870,000) incident TB cases (18% reduction,

95% CrI 9%-29%) and 120,000 (95% CrI 69,000-210,000) deaths (30% reduction, 95%

CrI 18%-44%) between 2020 and 2035. Notably, this increase in impact arises

largely from diagnosis of TB amongst those with HIV who are not yet in HIV care,

and who would thus be ineligible for a LAM test under current guidelines.

Qualitatively similar results apply under an alternative comparator assuming

expanded use of GeneXpert MTB/RIF ('Xpert') for TB diagnosis. Sensitivity

analysis demonstrates qualitatively similar results in a setting like Kenya,

which also has a generalised HIV epidemic, but a lower burden of HIV/TB

coinfection. Amongst limitations of this analysis, we do not address the cost or

cost-effectiveness of future tests. Our model neglects drug resistance and

focuses on the country-level epidemic, thus ignoring subnational variations in

HIV and TB burden.

CONCLUSIONS: These results suggest that LAM tests could have an important effect

in averting TB deaths amongst PLHIV with advanced disease. However, achieving

population-level impact on the TB epidemic, even in high-HIV-burden settings,

will require future LAM tests to have sufficient performance to be deployed more

broadly than in HIV care.

DOI: 10.1371/journal.pmed.1003466

PMCID: PMC7732057

PMID: 33306694

7. PLoS Med. 2020 Dec 2;17(12):e1003456. doi: 10.1371/journal.pmed.1003456.

eCollection 2020 Dec.

Trade-offs between cost and accuracy in active case finding for tuberculosis: A

dynamic modelling analysis.

Cilloni L(1), Kranzer K(2)(3)(4), Stagg HR(5), Arinaminpathy N(1).

Author information:

(1)MRC Centre for Global Infectious Disease Analysis, School of Public Health,

Imperial College London, London, United Kingdom.

(2)Clinical Research Department, London School of Hygiene & Tropical Medicine,

London, United Kingdom.

(3)Biomedical Research and Training Institute, Harare, Zimbabwe.

...

BACKGROUND: Active case finding (ACF) may be valuable in tuberculosis (TB)

control, but questions remain about its optimum implementation in different

settings. For example, smear microscopy misses up to half of TB cases, yet is

cheap and detects the most infectious TB cases. What, then, is the incremental

value of using more sensitive and specific, yet more costly, tests such as Xpert

MTB/RIF in ACF in a high-burden setting?

METHODS AND FINDINGS: We constructed a dynamic transmission model of TB,

calibrated to be consistent with an urban slum population in India. We applied

this model to compare the potential cost and impact of 2 hypothetical approaches

following initial symptom screening: (i) 'moderate accuracy' testing employing a

microscopy-like test (i.e., lower cost but also lower accuracy) for

bacteriological confirmation and (ii) 'high accuracy' testing employing an

Xpert-like test (higher cost but also higher accuracy, while also detecting

rifampicin resistance). Results suggest that ACF using a moderate-accuracy test

could in fact cost more overall than using a high-accuracy test. Under an

illustrative budget of US$20 million in a slum population of 2 million,

high-accuracy testing would avert 1.14 (95% credible interval 0.75-1.99, with p

= 0.28) cases relative to each case averted by moderate-accuracy testing. Test

specificity is a key driver: High-accuracy testing would be significantly more

impactful at the 5% significance level, as long as the high-accuracy test has

specificity at least 3 percentage points greater than the moderate-accuracy

test. Additional factors promoting the impact of high-accuracy testing are that

(i) its ability to detect rifampicin resistance can lead to long-term cost

savings in second-line treatment and (ii) its higher sensitivity contributes to

the overall cases averted by ACF. Amongst the limitations of this study, our

cost model has a narrow focus on the commodity costs of testing and treatment;

our estimates should not be taken as indicative of the overall cost of ACF.

There remains uncertainty about the true specificity of tests such as smear and

Xpert-like tests in ACF, relating to the accuracy of the reference standard

under such conditions.

CONCLUSIONS: Our results suggest that cheaper diagnostics do not necessarily

translate to less costly ACF, as any savings from the test cost can be strongly

outweighed by factors including false-positive TB treatment, reduced

sensitivity, and foregone savings in second-line treatment. In resource-limited

settings, it is therefore important to take all of these factors into account

when designing cost-effective strategies for ACF.

DOI: 10.1371/journal.pmed.1003456

PMCID: PMC7710036

PMID: 33264288

Conflict of interest statement: The authors have declared that no competing

interests exist.

8. Nat Commun. 2020 Nov 30;11(1):6092. doi: 10.1038/s41467-020-19959-4.

Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in

Mycobacterium tuberculosis.

Mackenzie JS(1), Lamprecht DA(2), Asmal R(1), Adamson JH(1), Borah K(3), Beste

DJV(3), Lee BS(4), Pethe K(4)(5), Rousseau S(6), Krieger I(6), Sacchettini

JC(6), Glasgow JN(7), Steyn AJC(8)(9)(10).

Author information:

(1)Africa Health Research Institute, Durban, 4001, South Africa.

(2)Janssen Pharmaceutica, Global Public Health, Turnhoutseweg 30, 2340, Beerse,

Belgium.

(3)Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.

...

The approval of bedaquiline (BDQ) for the treatment of tuberculosis has

generated substantial interest in inhibiting energy metabolism as a therapeutic

paradigm. However, it is not known precisely how BDQ triggers cell death in

Mycobacterium tuberculosis (Mtb). Using 13C isotopomer analysis, we show that

BDQ-treated Mtb redirects central carbon metabolism to induce a metabolically

vulnerable state susceptible to genetic disruption of glycolysis and

gluconeogenesis. Metabolic flux profiles indicate that BDQ-treated Mtb is

dependent on glycolysis for ATP production, operates a bifurcated TCA cycle by

increasing flux through the glyoxylate shunt, and requires enzymes of the

anaplerotic node and methylcitrate cycle. Targeting oxidative phosphorylation

(OXPHOS) with BDQ and simultaneously inhibiting substrate level phosphorylation

via genetic disruption of glycolysis leads to rapid sterilization. Our findings

provide insight into the metabolic mechanism of BDQ-induced cell death and

establish a paradigm for the development of combination therapies that target

OXPHOS and glycolysis.

DOI: 10.1038/s41467-020-19959-4

PMCID: PMC7705017

PMID: 33257709 [Indexed for MEDLINE]

9. Nat Commun. 2020 Nov 30;11(1):6119. doi: 10.1038/s41467-020-19973-6.

CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint

immunotherapy to non-small cell lung cancer.

Zhang M(1)(2)(3), Yang W(1)(2)(3), Wang P(1)(2)(3), Deng Y(4), Dong YT(5)(6),

Liu FF(7), Huang R(8), Zhang P(7), Duan YQ(5)(6), Liu XD(8), Lin D(9), Chu

Q(10), Zhong B(11)(12)(13).

Author information:

(1)Department of Gastrointestinal Surgery, Medical Research Institute, Zhongnan

Hospital of Wuhan University, Wuhan, 430071, China.

(2)Frontier Science Center for Immunology and Metabolism, Wuhan University,

Wuhan, 430071, China.

(3)Department of Virology, College of Life Sciences, Wuhan University, Wuhan,

430072, China.

...

The efficacy of checkpoint immunotherapy to non-small cell lung cancer (NSCLC)

largely depends on the tumor microenvironment (TME). Here, we demonstrate that

CCL7 facilitates anti-PD-1 therapy for the KrasLSL-G12D/+Tp53fl/fl (KP) and the

KrasLSL-G12D/+Lkb1fl/fl (KL) NSCLC mouse models by recruiting conventional DC 1

(cDC1) into the TME to promote T cell expansion. CCL7 exhibits high expression

in NSCLC tumor tissues and is positively correlated with the infiltration of

cDC1 in the TME and the overall survival of NSCLC patients. CCL7 deficiency

impairs the infiltration of cDC1 in the TME and the subsequent expansion of CD8+

and CD4+ T cells in bronchial draining lymph nodes and TME, thereby promoting

tumor development in the KP mouse model. Administration of CCL7 into lungs alone

or in combination with anti-PD-1 significantly inhibits tumor development and

prolongs the survival of KP and KL mice. These findings suggest that CCL7

potentially serves as a biomarker and adjuvant for checkpoint immunotherapy of

NSCLC.

DOI: 10.1038/s41467-020-19973-6

PMCID: PMC7704643

PMID: 33257678 [Indexed for MEDLINE]

10. Nano Lett. 2020 Dec 9;20(12):8903-8911. doi: 10.1021/acs.nanolett.0c03982. Epub

2020 Nov 24.

Enhanced Cancer-targeted Drug Delivery Using Precoated Nanoparticles.

Yu L(1), Xu M(1), Xu W(1), Xiao W(1), Jiang XH(1), Wang L(1), Gao H(1).

Author information:

(1)Key Laboratory of Drug-Targeting and Drug Delivery System of the Education

Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan

Research Center for Drug Precision Industrial Technology, West China School of

Pharmacy, Sichuan University, Chengdu 610041, China.

While protein coronas (PCs) are an important barrier in the clinical application

of nanomedicines, the specific effects of PCs on nanoparticles (NPs) in vivo are

unclear. Herein, we demonstrated that PCs from clinical sources greatly

influenced the active targeting capacities of transferrin-modified NPs (Tf-NPs).

Compared to PCs from healthy volunteers, PCs from the plasma of patients with

nonsmall cell lung cancer (NSCLC) decreased the A549 uptake of Tf-NPs to a

greater degree. The PC proteome revealed that this difference may be mediated by

certain proteins in plasma. To attenuate the negative influence of PCs from

patients, precoating Tf-NPs with PCs derived from healthy mice significantly

enhanced active targeting capacities. Paclitaxel-loaded Tf-NPs with PCs derived

from healthy mice showed the strongest antitumor effects in mice with NSCLC.

This work illustrates the influence of PCs of ligand-modified NPs in clinical

practice and proposes the use of corona-enabled active targeting for precision

nanomedicine.

DOI: 10.1021/acs.nanolett.0c03982

PMID: 33232167

11. Microbiol Mol Biol Rev. 2020 Sep 2;84(4):e00082-19. doi: 10.1128/MMBR.00082-19.

Print 2020 Nov 18.

Modeling Tubercular ESX-1 Secretion Using Mycobacterium marinum.

Chirakos AE(1), Balaram A(2), Conrad W(3), Champion PA(4).

Author information:

(1)Department of Biological Sciences, University of Notre Dame, Notre Dame,

Indiana, USA.

(2)Department of Biology, Lake Forest College, Lake Forest, Illinois, USA.

(3)Department of Chemistry, Lake Forest College, Lake Forest, Illinois, USA

conrad@mx.lakeforest.edu pchampio@nd.edu.

...

Pathogenic mycobacteria cause chronic and acute diseases ranging from human

tuberculosis (TB) to nontubercular infections. Mycobacterium tuberculosis causes

both acute and chronic human tuberculosis. Environmentally acquired

nontubercular mycobacteria (NTM) cause chronic disease in humans and animals.

Not surprisingly, NTM and M. tuberculosis often use shared molecular mechanisms

to survive within the host. The ESX-1 system is a specialized secretion system

that is essential for virulence and is functionally conserved between M.

tuberculosis and Mycobacterium marinum M. marinum is an NTM found in both salt

water and freshwater that is often used to study mycobacterial virulence. Since

the discovery of the secretion system in 2003, the use of both M. tuberculosis

and M. marinum has defined the conserved molecular mechanisms underlying protein

secretion and the lytic and regulatory activities of the ESX-1 system. Here, we

review the trajectory of the field, including key discoveries regarding the

ESX-1 system. We highlight the contributions of M. marinum studies and the

conserved and unique aspects of the ESX-1 secretion system.

Copyright © 2020 American Society for Microbiology.

DOI: 10.1128/MMBR.00082-19

PMID: 32878966

12. Lancet Infect Dis. 2020 Dec 11:S1473-3099(20)30598-3. doi:

10.1016/S1473-3099(20)30598-3. Online ahead of print.

Comparing accuracy of lipoarabinomannan urine tests for diagnosis of pulmonary

tuberculosis in children from four African countries: a cross-sectional study.

Nkereuwem E(1), Togun T(2), Gomez MP(1), Székely R(3), Macé A(3), Jobe D(1),

Schumacher SG(3), Kampmann B(4), Denkinger CM(5); Reach4KidsAfrica (R4KA)

Consortium.

Author information:

(1)Vaccines and Immunity Theme, Medical Research Council Unit The Gambia at

London School of Hygiene & Tropical Medicine, Banjul, The Gambia.

(2)Vaccines and Immunity Theme, Medical Research Council Unit The Gambia at

London School of Hygiene & Tropical Medicine, Banjul, The Gambia; Faculty of

Infectious and Tropical Diseases, London, UK.

(3)FIND (Foundation for Innovative New Diagnostics), Geneva, Switzerland.

...

BACKGROUND: A sensitive and specific non-sputum-based test would be

groundbreaking for the diagnosis of childhood tuberculosis. We assessed side by

side the diagnostic accuracy of the urine-based lipoarabinomannan assays

Fujifilm SILVAMP TB LAM (FujiLAM) and Alere Determine TB LAM Ag (AlereLAM) for

detection of childhood tuberculosis.

METHODS: In this cross-sectional study, we tested urine samples from children

younger than 15 years with presumed pulmonary tuberculosis. Children were

consecutively recruited from four dedicated outpatient childhood tuberculosis

clinics in The Gambia, Mali, Nigeria, and Tanzania. Biobanked urine samples were

thawed and tested using FujiLAM and AlereLAM assays. We measured diagnostic

performance against a microbiological reference standard (confirmed

tuberculosis) and a composite reference standard (confirmed and unconfirmed

tuberculosis). Sensitivity and specificity were estimated with bivariate

random-effects meta-analyses.

FINDINGS: Between July 1, 2017, and Dec 1, 2018, we obtained and stored urine

samples from 415 children. 63 (15%) children had confirmed tuberculosis, 113

(27%) had unconfirmed tuberculosis, and 239 (58%) were unlikely to have

tuberculosis. 61 children were HIV-positive (prevalence 15%). Using the

microbiological reference standard, the sensitivity of FujiLAM was 64·9% (95% CI

43·7-85·2; positive in 40 of 63 confirmed samples) and the sensitivity of

AlereLAM was 30·7% (8·6-61·6; 19 of 63). The specificity of FujiLAM was 83·8%

(95% CI 76·5-89·4; negative in 297 of 352 unconfirmed and unlikely samples) and

the specificity of AlereLAM was 87·8% (79·0-93·7; 312 of 352). Against the

composite reference standard, both assays had decreased sensitivity; the

sensitivity of FujiLAM was 32·9% (95% CI 24·6-41·9; positive in 58 of 176

confirmed and unconfirmed samples) and the sensitivity of AlereLAM was 20·2%

(12·3-29·4; 36 of 176). The specificity of FujiLAM was 83·3% (95% CI 71·8-91·7;

negative in 202 of 239 unlikely samples) and the specificity of AlereLAM was

90·0% (81·6-95·6; 216 of 239).

INTERPRETATION: By comparison with AlereLAM, FujiLAM showed higher sensitivity

and similar specificity. FujiLAM could potentially add value to the rapid

diagnosis of tuberculosis in children.

FUNDING: German Federal Ministry of Education and Research, the Global Health

Innovative Technology Fund, the UK Research and Innovation Global Challenges

Research Fund, and the UK Medical Research Council.

Copyright © 2017 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(20)30598-3

PMID: 33316214

13. Lancet Infect Dis. 2020 Dec 3:S1473-3099(20)30556-9. doi:

10.1016/S1473-3099(20)30556-9. Online ahead of print.

Performance and operational feasibility of two diagnostic tests for

cryptosporidiosis in children (CRYPTO-POC): a clinical, prospective, diagnostic

accuracy study.

Johansen ØH(1), Abdissa A(2), Zangenberg M(3), Mekonnen Z(2), Eshetu B(4),

Bjørang O(5), Alemu Y(2), Sharew B(2), Langeland N(6), Robertson LJ(7), Hanevik

K(6).

Author information:

(1)Department of Clinical Science, University of Bergen, Bergen, Norway;

Department of Microbiology, Vestfold Hospital Trust, Tønsberg, Norway.

Electronic address: haarklau@gmail.com.

(2)School of Medical Laboratory Sciences, Jimma University, Jimma, Ethiopia.

(3)Department of Immunology and Microbiology, Centre for Medical Parasitology,

University of Copenhagen, Copenhagen, Denmark; Department of Clinical

Microbiology, Copenhagen University Hospital (Rigshospitalet), Copenhagen,

Denmark.

...BACKGROUND: Cryptosporidiosis is a common cause of diarrhoea in young children

(aged younger than 24 months) in low-resource settings but is currently

challenging to diagnose. Light-emitting diode fluorescence microscopy with

auramine-phenol staining (LED-AP), recommended for tuberculosis testing, can

also detect Cryptosporidium species. A lateral-flow test not requiring

refrigerator storage (by contrast with most immunochromatographic lateral-flow

assays) has also recently been developed for Cryptosporidium spp detection. We

aimed to evaluate the diagnostic accuracy and operational feasibility of LED-AP

and the lateral-flow test strip for cryptosporidiosis in children.

METHODS: We did a prospective diagnostic accuracy study in two health-care

facilities in Ethiopia, in a consecutive series of children younger than 5 years

of age with diarrhoea (three or more loose stools within the previous 24 h) or

dysentery (at least one loose stool with stains of blood within the previous 24

h). Stool samples were tested for Cryptosporidium spp by LED-AP and the

lateral-flow test strip; accuracy of each test was estimated by independent and

blind comparison with a composite reference standard comprising quantitative

immunofluorescent antibody test (qIFAT), ELISA, and quantitative PCR (qPCR).

Quantitative cutoff values for diarrhoea-associated infection were established

in an embedded case-control substudy, with cases of cryptosporidiosis coming

from the 15 districts in and around Jimma and the eight districts surrounding

Serbo, and community controls without diarrhoea in the previous 48 h recruited

by weekly frequency matching by geographical district of the household, age

group, and enrolment week.

FINDINGS: Stool samples from 912 children with diarrhoea or dysentery and 706

controls from the case-control substudy were tested between Dec 22, 2016, and

July 6, 2018. Estimated reference-standard cutoff values for cryptosporidiosis

positivity were 2·3?×?105 DNA copies per g of wet stool for qPCR, and 725

oocysts per g for qIFAT. LED-AP had a sensitivity for cryptosporidiosis of 88%

(95% CI 79-94; 66 of 75 samples) and a specificity of 99% (98-99; 717 of 726

samples); the lateral-flow test strip had a sensitivity of 89% (79-94; 63 of 71

samples) and a specificity of 99% (97-99; 626 of 635 samples).

INTERPRETATION: LED-AP has high sensitivity and specificity for

cryptosporidiosis and should be considered as a dual-use technology that can be

easily integrated with existing laboratory infrastructures in low-resource

settings. The lateral-flow test strip has similar sensitivity and specificity

and provides an alternative that does not require microscopy, although purchase

cost of the test strip is unknown as it is not yet available on the market.

FUNDING: Norwegian Research Council GLOBVAC fund, The Bill & Melinda Gates

Foundation, Norwegian Society for Medical Microbiology, University of Bergen,

and Vestfold Hospital Trust.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open

Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All

rights reserved.

DOI: 10.1016/S1473-3099(20)30556-9

PMID: 33278916

14. Lancet Infect Dis. 2020 Dec;20(12):1457-1469. doi:

10.1016/S1473-3099(20)30276-0. Epub 2020 Jul 13.

Interferon-γ release assays or tuberculin skin test for detection and management

of latent tuberculosis infection: a systematic review and meta-analysis.

Zhou G(1), Luo Q(2), Luo S(1), Teng Z(3), Ji Z(1), Yang J(1), Wang F(1), Wen

S(1), Ding Z(1), Li L(1), Chen T(1), Abi ME(1), Jian M(4), Luo L(4), Liu A(5),

Bao F(6).

Author information:

(1)Department of Microbiology and Immunology, Kunming Medical University,

Kunming, Yunnan Province, China.

(2)School of Basic Medical Sciences, Department of Medical Imaging, Affiliated

Yanan Hospital, Kunming Medical University, Kunming, Yunnan Province, China.

(3)Department of Orthopedic Surgery, The 6th Affiliated Hospital, Kunming

Medical University, Kunming, Yunnan Province, China.

...

Comment in

Lancet Infect Dis. 2020 Dec;20(12):1359-1360.

Lancet Infect Dis. 2020 Dec;20(12):1371-1372.

Lancet Infect Dis. 2020 Dec;20(12):1372-1373.

BACKGROUND: Use of an interferon-γ (IFN-γ) release assay or tuberculin skin test

for detection and management of latent tuberculosis infection is controversial.

For both types of test, we assessed their predictive value for the progression

of latent infection to active tuberculosis disease, the targeting value of

preventive treatment, and the necessity of dual testing.

METHODS: In this systematic review and meta-analysis, we searched PubMed,

Embase, Web of Science, and the Cochrane Library, with no start date or language

restrictions, on Oct 18, 2019, using the keywords ("latent tuberculosis" OR

"latent tuberculosis infection" OR "LTBI") AND ("interferon gamma release

assays" OR "Interferon-gamma Release Test" OR "IGRA" OR "QuantiFERON®-TB in

tube" OR "QFT" OR "T-SPOT.TB") AND ("tuberculin skin test" OR "tuberculin test"

OR "Mantoux test" OR "TST"). We included articles that used a cohort study

design; included information that individuals with latent tuberculosis infection

detected by IFN-γ release assay, tuberculin skin test, or both, progressed to

active tuberculosis; reported information about treatment; and were limited to

high-risk populations. We excluded studies that included patients with active or

suspected tuberculosis at baseline, evaluated a non-commercial IFN-γ release

assay, and had follow-up of less than 1 year. We extracted study details (study

design, population investigated, tests used, follow-up period) and the number of

individuals observed at baseline, who progressed to active tuberculosis, and who

were treated. We then calculated the pooled risk ratio (RR) for disease

progression, positive predictive value (PPV), and negative predictive value

(NPV) of IFN-γ release assay versus tuberculin skin test.

FINDINGS: We identified 1823 potentially eligible studies after exclusion of

duplicates, of which 256 were eligible for full-text screening. From this

screening, 40 studies (50?592 individuals in 41 cohorts) were identified as

eligible and included in our meta-analysis. Pooled RR for the rate of disease

progression in untreated individuals who were positive by IFN-γ release assay

versus those were negative was 9·35 (95% CI 6·48-13·49) compared with 4·24

(3·30-5·46) for tuberculin skin test. Pooled PPV for IFN-γ release assay was

4·5% (95% CI 3·3-5·8) compared with 2·3% (1·5-3·1) for tuberculin skin test.

Pooled NPV for IFN-γ release assay was 99·7% (99·5-99·8) compared with 99·3%

(99·0-99·5) for tuberculin skin test. Pooled RR for rates of disease progression

in individuals positive by IFN-γ release assay who were untreated versus those

who were treated was 3·09 (95% CI 2·08-4·60) compared with 1·11 (0·69-1·79) for

the same populations who were positive by tuberculin skin test. Pooled

proportion of disease progression for individuals who were positive by IFN-γ

release assay and tuberculin skin test was 6·1 (95% CI 2·3-11·5). Pooled RR for

rates of disease progression in individuals who were positive by IFN-γ release

assay and tuberculin skin test who were untreated versus those who were treated

was 7·84 (95% CI 4·44-13·83).

INTERPRETATION: IFN-γ release assays have a better predictive ability than

tuberculin skin tests. Individuals who are positive by IFN-γ release assay might

benefit from preventive treatment, but those who are positive by tuberculin skin

test probably will not. Dual testing might improve detection, but further

confirmation is needed.

FUNDING: National Natural Science Foundation of China and Natural Foundation of

Yunnan Province.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(20)30276-0

PMID: 32673595

15. J Natl Cancer Inst. 2020 Dec 14;112(12):1204-1212. doi: 10.1093/jnci/djaa034.

Ethnic Disparities in Imaging Utilization at Diagnosis of Non-Small Cell Lung

Cancer.

Morgan RL(1), Karam SD(2), Bradley CJ(3).

Author information:

(1)Department of Radiology, University of Colorado, Denver, CO 80045, USA.

(2)Department of Radiation Oncology, University of Colorado, Denver, CO 80045,

USA.

(3)Department of Health Systems, Management, and Policy, Colorado School of

Public Health, Aurora, CO 80045, USA.

Comment in

doi: 10.1093/jnci/djaa035.

BACKGROUND: Prior research demonstrated statistically significant racial

disparities related to lung cancer treatment and outcomes. We examined

differences in initial imaging and survival between blacks, Hispanics, and

non-Hispanic whites.

METHODS: The linked Surveillance, Epidemiology, and End Results-Medicare

database between 2007 and 2015 was used to compare initial imaging modality for

patients with lung cancer. Participants included 28 881 non-Hispanic whites,

3123 black, and 1907 Hispanics, patients age 66 years and older who were

enrolled in Medicare fee-for-service and diagnosed with lung cancer. The primary

outcome was comparison of positron emission tomography (PET) imaging with

computerized tomography (CT) imaging use between groups. A secondary outcome was

12-month cancer-specific survival. Information on stage, treatment, and

treatment facility was included in the analysis. Chi-square test and logistic

regression were used to evaluate factors associated with imaging use.

Kaplan-Meier method and Cox proportional hazards regression were used to

calculate adjusted hazard ratios and survival. All statistical tests were

two-sided.

RESULTS: After adjusting for demographic, community, and facility

characteristics, blacks were less likely to undergo PET or CT imaging at

diagnosis compared with non-Hispanic whites odds ratio (OR) = 0.54 (95%

confidence interval [CI] = 0.50 to 0.59; P < .001). Hispanics were also less

likely to receive PET with CT imaging (OR = 0.72, 95% CI = 0.65 to

0.81; P < .001). PET with CT was associated with improved survival (HR = 0.61,

95% CI = 0.57 to 0.65; P < .001).

CONCLUSIONS: Blacks and Hispanics are less likely to undergo

guideline-recommended PET with CT imaging at diagnosis of lung cancer, which may

partially explain differences in survival. Awareness of this issue will allow

for future interventions aimed at reducing this disparity.

© The Author(s) 2020. Published by Oxford University Press. All rights reserved.

For permissions, please email: journals.permissions@oup.com.

DOI: 10.1093/jnci/djaa034

PMCID: PMC7735772

PMID: 32134453