Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990???2013: a systematic analysis for the Global Burden of Disease Study 2013

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(17)30079-6.pdf

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

The worldwide emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis threatens to make this disease incurable. Drug resistance mechanisms are only partially understood, and whether the current understanding of the genetic basis of drug resistance in M. tuberculosis is sufficiently comprehensive remains unclear. Here we sequenced and analyzed 161 isolates with a range of drug resistance profiles, discovering 72 new genes, 28 intergenic regions (IGRs), 11 nonsynonymous SNPs and 10 IGR SNPs with strong, consistent associations with drug resistance. On the basis of our examination of the dN/dS ratios of nonsynonymous to synonymous SNPs among the isolates, we suggest that the drug resistance-associated genes identified here likely contain essentially all the nonsynonymous SNPs that have arisen as a result of drug pressure in these isolates and should thus represent a near-complete set of drug resistance-associated genes for these isolates and antibiotics. Our work indicates that the genetic basis of drug resistance is more complex than previously anticipated and provides a strong foundation for elucidating unknown drug resistance mechanisms.

Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance

A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable drugs on treatment outcome. Compared with treatment failure, relapse and death, treatment success was higher in MDR-TB patients infected with strains without additional resistance (n=4763; 64%, 95% CI 57-72%) or with resistance to second-line injectable drugs only (n=1130; 56%, 95% CI 45-66%), than in those having resistance to fluoroquinolones alone (n=426; 48%, 95% CI 36-60%) or to fluoroquinolones plus second-line injectable drugs (extensively drug resistant (XDR)-TB) (n=405; 40%, 95% CI 27-53%). In XDR-TB patients, treatment success was highest if at least six drugs were used in the intensive phase (adjusted OR 4.9, 95% CI 1.4-16.6; reference fewer than three drugs) and four in the continuation phase (OR 6.1, 95% CI 1.4-26.3). The odds of success in XDR-TB patients was maximised when the intensive phase reached 6.6-9.0 months duration and the total duration of treatment 20.1-25.0 months. In XDR-TB patients, regimens containing more drugs than those recommended in MDR-TB but given for a similar duration were associated with the highest odds of success. All data were from observational studies and methodologies varied between centres, therefore, the bias may be substantial. Better quality evidence is needed to optimise regimens.

https://erj.ersjournals.com/content/erj/42/1/156.full.pdf

Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes

Methods We estimated the proportion of tuberculosis cases in China that were resistant to drugs by means of cluster-randomized sampling of tuberculosis cases in the public health system and testing for resistance to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and streptomycin and the second-line drugs ofloxacin and kanamycin. We used the results from this survey and published estimates of the incidence of tuberculosis to estimate the incidence of drug-resistant tuberculosis. Information from patient interviews was used to identify factors linked to drug resistance. Results Among 3037 patients with new cases of tuberculosis and 892 with previously treated cases, 5.7% (95% confidence interval [CI], 4.5 to 7.0) and 25.6% (95% CI, 21.5 to 29.8), respectively, had multidrug-resistant (MDR) tuberculosis (defined as disease that was resistant to at least isoniazid and rifampin). Among all patients with tuberculosis, approximately 1 of 4 had disease that was resistant to isoniazid, rifampin, or both, and 1 of 10 had MDR tuberculosis. Approximately 8% of the patients with MDR tuberculosis had extensively drug-resistant (XDR) tuberculosis (defined as disease that was resistant to at least isoniazid, rifampin, ofloxacin, and kanamycin). In 2007, there were 110,000 incident cases (95% CI, 97,000 to 130,000) of MDR tuberculosis and 8200 incident cases (95% CI, 7200 to 9700) of XDR tuberculosis. Most cases of MDR and XDR tuberculosis resulted from primary transmission. Patients with multiple previous treatments who had received their last treatment in a tuberculosis hospital had the highest risk of MDR tuberculosis (adjusted odds ratio, 13.3; 95% CI, 3.9 to 46.0). Among 226 previously treated patients with MDR tuberculosis, 43.8% had not completed their last treatment; most had been treated in the hospital system. Among those who had completed treatment, tuberculosis developed again in most of the patients after their treatment in the public health system. Conclusions China has a serious epidemic of drug-resistant tuberculosis. MDR tuberculosis is linked to inadequate treatment in both the public health system and the hospital system, especially tuberculosis hospitals; however, primary transmission accounts for most cases. (Funded by the Chinese Ministry of Health.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1108789

National Survey of Drug-Resistant Tuberculosis in China

Purpose The function of BZRAP1-AS1 is unknown in lung cancer. We evaluated the clinicopathologic significance of BZRAP1-AS1, and its role in non-small-cell lung cancer (NSCLC) progression. Patient and methods Sixty-three NSCLC patients from Beijing Chest Hospital were included. The expression of BZRAP1-AS1 was detected by real-time quantitative polymerase chain reaction (RT-qPCR) in tumor tissues and adjacent normal tissues. Then, the clinicopathological significance and prognostic value of BZRAP1-AS1 were analyzed by using our cohort and TCGA cohort. Finally, the effect of BZRAP1-AS1 on proliferation and motility of NSCLC cell lines were evaluated by cell growth assay, colony formation assay, xenograft tumorigenesis experiment in nude mice and transwell assays respectively. Results Compared with adjacent normal tissues, BZRAP1-AS1 showed lower expression in NSCLC tumor tissues. As for the relationship between BZRAP1-AS1 and clinical characteristics, our results were consistent with those of TCGA data. BZRAP1-AS1 was lower in T1 than T2–T4 patients, N1-N3 than N0 patients. Low level BZRAP1-AS1 was related to shorter overall survival time (OS) in lung adenocarcinoma (LUAD), and poor first progression time (FP) in LUAD and lung squamous cell carcinoma (LUSC) patients. BZRAP1-AS1 was significantly associated with the prognosis of NSCLC patients. Overexpression of BZRAP1-AS1 inhibited proliferation and migration of H1299 and HCC827 cells. Conclusion BZRAP1-AS1 expression decreases in tumor tissues with the increase of malignancy grades in NSCLC. BZRAP1-AS1 plays an anticancer role by inhibiting cell proliferation, invasion, and metastasis, and has a potential prognostic value in NSCLC. BZRAP1-AS1 may serve as a diagnostic marker and therapeutic target for NSCLC.

Long non-coding RNA BZRAP1-AS1 functions in malignancy and prognosis for non-small-cell lung cancer

Although Cisplatin (DDP) is a widely used first-line chemotherapy medication, DDP resistance is one of the main causes of treatment failure in advanced lung cancer. Therefore, it is urgent to identify DDP sensitizers and investigate the underlying molecular mechanisms. Here we utilized DDP-resistant organoids established from tumor biopsies of patients with relapsed lung cancers. In this study, we identified Solamargine as a potential DDP sensitizer through screening a natural product library. Mechanically, Solamargine induced G0/G1-phase arrest and apoptosis in DDP-resistant lung cancer cell lines. Gene expression analysis and KEGG pathway analysis indicated that the hedgehog pathway was suppressed by Solamargine. Moreover, Gli responsive element (GRE) reporter gene assay and BODIPY-cyclopamine binding assay showed that Solamargine inhibited the hedgehog pathway via direct binding to SMO protein. Interestingly, Solamargine and DDP showed a synergetic effect in inhibiting DDP-resistant lung cancer cell lines. Taken together, our work herein revealed Solamargine as a hedgehog pathway inhibitor and DDP-sensitizer, which might provide a new direction for further treatment of advanced DDP-resistant lung cancer patients.

/pdf/identification-of-solamargine-as-a-cisplatin-sensitizer-mv2qs8jo.pdf

Identification of solamargine as a cisplatin sensitizer through phenotypical screening in cisplatin-resistant NSCLC organoids

The Effects of Programmed Intermittent Paravertebral Bolus Infusion on Postoperative Analgesia in Patients Undergoing Video-Assisted Thoracoscopic Surgery: A Prospective, Randomized, Controlled Study.

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) with a Ku70/Ku80 heterodimer constitutes the intact DNA-PK kinase, which is an upstream component of the DNA repair machinery that signals the DNA damage, orchestrates the DNA repair, and serves to maintain genome integrity. Beyond its role in DNA damage repair, the DNA-PK kinase is also implicated in transcriptional regulation and RNA metabolism, with an illuminated impact on tumor progression and therapeutic responses. However, the efforts to identify DNA-PK regulated transcriptomes are limited by short-read sequencing to resolve the full complexity of the transcriptome. Therefore, we leveraged the PacBio Single Molecule, Real-Time (SMRT) Sequencing platform to study the transcriptome after DNA-PK inactivation to further underscore the importance of its role in diseases. Our analysis revealed additional novel transcriptome and complex gene structures in the DNA-PK inactivated cells, identifying 8,355 high-confidence new isoforms from 3,197 annotated genes and 523 novel genes. Among them, 380 lncRNAs were identified. We validated these findings using computational approaches and confirmatory transcript quantification with short-read sequencing. Several novel isoforms representing distinct splicing events have been validated through PCR experiments. Our analyses provide novel insights into DNA-PK function in transcriptome regulation and RNA metabolism.

/pdf/long-read-sequencing-annotation-of-the-transcriptome-in-dna-3cfd18zy.pdf

Shaofa Xu

Papers

National Survey of Drug-Resistant Tuberculosis in China

Long non-coding RNA BZRAP1-AS1 functions in malignancy and prognosis for non-small-cell lung cancer

Identification of solamargine as a cisplatin sensitizer through phenotypical screening in cisplatin-resistant NSCLC organoids

The Effects of Programmed Intermittent Paravertebral Bolus Infusion on Postoperative Analgesia in Patients Undergoing Video-Assisted Thoracoscopic Surgery: A Prospective, Randomized, Controlled Study.

Long-Read Sequencing Annotation of the Transcriptome in DNA-PK Inactivated Cells