Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Cancer therapeutics: Extending a drug's reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy. The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity

Visualizing Orbital Content of Electronic Bands in Anisotropic 2D Semiconducting ReSe2

Many properties of layered materials change as they are thinned from their bulk forms down to single layers, with examples including indirect-to-direct band gap transition in 2H semiconducting transition metal dichalcogenides as well as thickness-dependent changes in the valence band structure in post-transition metal monochalcogenides and black phosphorus. Here, we use angle-resolved photoemission spectroscopy to study the electronic band structure of monolayer ReSe$_{2}$, a semiconductor with a distorted 1T structure and in-plane anisotropy. By changing the polarization of incoming photons, we demonstrate that for ReSe$_{2}$, in contrast to the 2H materials, the out-of-plane transition metal $d_{z^{2}}$ and chalcogen $p_{z}$ orbitals do not contribute significantly to the top of the valence band which explains the reported weak changes in the electronic structure of this compound as a function of layer number. We estimate a band gap of 1.7 eV in pristine ReSe$_{2}$ using scanning tunneling spectroscopy and explore the implications on the gap following surface-doping with potassium. A lower bound of 1.4 eV is estimated for the gap in the fully doped case, suggesting that doping-dependent many-body effects significantly affect the electronic properties of ReSe$_{2}$. Our results, supported by density functional theory calculations, provide insight into the mechanisms behind polarization-dependent optical properties of rhenium dichalcogenides and highlight their place amongst two-dimensional crystals.Comment: 37 pages (including Supporting Information), 7 figures in the main tex

Evaluation of the synergistic impact of needle and forceps biopsy with electromagnetic navigation bronchoscopy: the CONFIDENT-ENB trial design

Background : Electromagnetic navigation bronchoscopy (ENB) is an emerging advanced imaging-guided bronchoscopy technique for diagnosing peripheral lung lesions. However, the selection strategy for the optimal biopsy device and whether adopting a multi-tool strategy increases the diagnostic yield remains undetermined. The CONFIDENT-ENB trial (NCT05110131) is a prospective randomized study on ENB, performed in a least-invasive setting. The primary aim is to evaluate whether a combination of needle aspiration and forceps biopsy improves the diagnostic performance, and assess the comparative diagnostic value and discordance of the two devices. Methods : The trial will recruit 142 participants with lung lesions suspected of malignancy who are eligible for an elective ENB procedure under moderate sedation. Participants will undergo ENB-guided needle aspiration and forceps biopsy in a randomized order without the use of any complementary techniques. All participants will be followed up subsequently for up to 12 months to conclude the final diagnosis of the biopsied lesions. Primary outcomes include the diagnostic yield and sensitivity of each biopsy modality and the diagnostic yield of the combined modalities. Discussion : The CONFIDENT-ENB trial will prospectively evaluate the synergistic effectiveness and comparative accuracy of ENB-guided needle aspiration and forceps biopsy in a least-invasive setting. The results are expected to improve our understanding of the optimal tool-selection strategy for ENB. Trial registration: ClinicalTrials.gov (NCT05110131). Prospectively registered on 5 November 2021.This study is supported by the Seoul National University Bundang Hospital (grant number 06-2021-0454). The funder of the study has no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript

Novel method of real-time PCR-based screening for common fetal trisomies

Background The non-invasive prenatal test (NIPT) is based on next generation sequencing (NGS) and is used for screening for fetal trisomy. However, it is time-consuming and technically difficult. Recently, peptide nucleic acid (PNA) probe-based real-time polymerase chain reaction (RT-PCR) was developed. This study aimed to examine the performance of the RT-PCR-based NIPT for screening of common fetal trisomies Methods From stored maternal plasma, RT-PCR was performed using Patio™ NIPT Detection Kit. In melting curve analysis, the height of melting peaks of target chromosome and reference chromosome was calculated as a peak ratio. The adjusted peak ratio of 8 markers with correction factors in each target chromosome was summated and calculated to z-score. The cut-off value for each target chromosome was established for classification (low risk vs. high risk for trisomy) whose performance was obtained in the validation phase. Results 330 plasma samples from pregnant women with normal fetus and 22 trisomy cell-line samples were used to establish the optimal cut-off values for z-score of each target chromosome. In the validation phase, 1023 samples from pregnant women including 22 cases with fetal trisomy and 1001 cases of normal control were used. The RT-PCR-based NIPT showed 95.45% sensitivity [95% confidence interval (CI) 77.16–99.88%], 98.60% specificity (95% CI 97.66–99.23%), and 98.53% accuracy (95% CI 97.59–99.18%) for the identification of trisomy 21, 18, or 13. Of 1023 samples, fifteen cases were mismatched for classification [one case as a false negative (false negative rate: 4.5%) and 14 cases as false positives (false positive rate: 1.4%)]. Conclusion The RT-PCR-based NIPT showed high sensitivity and specificity for the detection of common fetal trisomies and it could be a feasible alternative to NGS-based NIPT.This study was supported by the Technology Innovation Program (or Industrial Strategic Technology Development Program) (N0002392) funded by the Ministry of Trade, Industry & Energy (MOTIE, Korea). And this work was funded by grants (HI16C0628) from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Treatment Response and Long Term Follow-up Results of Nonspecific Interstitial Pneumonia

The purpose of this study was to investigate the long-term clinical course of non-specific interstitial pneumonia (NSIP) and to determine which factors are associated with a response to steroid therapy and relapse. Thirty-five patients with pathologically proven NSIP were included. Clinical, radiological, and laboratory data were reviewed retrospectively. The male-to-female ratio was 7:28 (median age, 52 yr). Thirty (86%) patients responded to steroid therapy, and the median follow-up was 55.2 months (range, 15.9-102.0 months). Five patients (14%) showed sustained disease progression and three died despite treatment. In the five with sustained disease progression, NSIP was associated with various systemic conditions, and the seropositivity of fluorescent antinuclear antibody was significantly associated with a poor response to steroids (P = 0.028). The rate of relapse was 25%, but all relapsed patients improved after re-treatment. The initial dose of steroids was significantly low in the relapse group (P = 0.020). In conclusion, progression is associated with various systemic conditions in patients who show progression. A low dose of initial steroids is significantly associated with relapse

Treatment shortening of drug-sensitive pulmonary tuberculosis using high-dose rifampicin for 3 months after culture conversion (Hi-DoRi-3): a study protocol for an open-label randomized clinical trial

Background : The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted. Methods : This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited. Discussion : This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB. Trial registration : ClinicalTrials.gov NCT04485156.Registered on July 24, 2020.This work was supported by a grant from the Korea National Institute of Health (2020-ER5201-01), Republic of Korea. High-dose rifampicin tablets and capsules were donated from Yuhan (Seoul, Republic of Korea) for this study. The funder and donor had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Discovery of a Novel hsp65 Genotype within Mycobacterium massiliense Associated with the Rough Colony Morphology

So far, genetic diversity among strains within Mycobacterium massiliense has rarely been studied. To investigate the genetic diversity among M. massiliense, we conducted phylogenetic analysis based on hsp65 (603-bp) and rpoB (711-bp) sequences from 65 M. massiliense Korean isolates. We found that hsp65 sequence analysis could clearly differentiate them into two distinct genotypes, Type I and Type II, which were isolated from 35 (53.8%) and 30 patients (46.2%), respectively. The rpoB sequence analysis revealed a total of four genotypes (R-I to R-IV) within M. massiliense strains, three of which (R-I, R-II and R-III) correlated with hsp65 Type I, and other (R-IV), which correlated with Type II. Interestingly, genotyping by the hsp65 method agreed well with colony morphology. Despite some exceptions, Type I and II correlated with smooth and rough colonies, respectively. Also, both types were completely different from one another in terms of MALDI-TOF mass spectrometry profiles of whole lipid. In addition, we developed PCR-restriction analysis (PRA) based on the Hinf I digestion of 644-bp hsp65 PCR amplicons, which enables the two genotypes within M. massiliense to be easily and reliably separated. In conclusion, two distinct hsp65 genotypes exist within M. massiliense strains, which differ from one another in terms of both morphology and lipid profile. Furthermore, our data indicates that Type II is a novel M. massiliense genotype being herein presented for the first time. The disparity in clinical traits between these two hsp65 genotypes needs to be exploited in the future study

Clinical features and outcomes of gastric variceal bleeding: retrospective Korean multicenter data

Background/AimsWhile gastric variceal bleeding (GVB) is not as prevalent as esophageal variceal bleeding, it is reportedly more serious, with high failure rates of the initial hemostasis (>30%), and has a worse prognosis than esophageal variceal bleeding. However, there is limited information regarding hemostasis and the prognosis for GVB. The aim of this study was to determine retrospectively the clinical outcomes of GVB in a multicenter study in Korea.MethodsThe data of 1,308 episodes of GVB (males:females=1062:246, age=55.0±11.0 years, mean±SD) were collected from 24 referral hospital centers in South Korea between March 2003 and December 2008. The rates of initial hemostasis failure, rebleeding, and mortality within 5 days and 6 weeks of the index bleed were evaluated.ResultsThe initial hemostasis failed in 6.1% of the patients, and this was associated with the Child-Pugh score [odds ratio (OR)=1.619; P<0.001] and the treatment modality: endoscopic variceal ligation, endoscopic variceal obturation, and balloon-occluded retrograde transvenous obliteration vs. endoscopic sclerotherapy, transjugular intrahepatic portosystemic shunt, and balloon tamponade (OR=0.221, P<0.001). Rebleeding developed in 11.5% of the patients, and was significantly associated with Child-Pugh score (OR=1.159, P<0.001) and treatment modality (OR=0.619, P=0.026). The GVB-associated mortality was 10.3%; mortality in these cases was associated with Child-Pugh score (OR=1.795, P<0.001) and the treatment modality for the initial hemostasis (OR=0.467, P=0.001).ConclusionsThe clinical outcome for GVB was better for the present cohort than in previous reports. Initial hemostasis failure, rebleeding, and mortality due to GVB were universally associated with the severity of liver cirrhosis