Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy

The biodistribution and safety of adenoviral vectors encoding the human REIC/Dkk-3 tumor suppressor gene (Ad-REIC) were examined in this preclinical study for in?situ prostate cancer gene therapy. First, the in vitro apoptotic effects of Ad-REIC in normal and cancer cells derived from the prostate and liver were examined. Significant apoptotic effects were observed at 100 MOI (multiplicity of infection) in prostate cancer cells (LNCaP, PC3) and hepatoma cells (HEP3B and HEPG2); however, no effects were seen in normal cells. To analyze the safety of intraprostatic Ad-REIC administration, the biodistribution and histology after Ad-REIC injection were evaluated in various organs of normal male C57BL6 mice. In a supporting study, vector dissemination following intravenous injection of Ad-REIC into tail veins was determined. To evaluate whether Ad-REIC was present in the collected tissue specimens, human REIC gene detection was performed using DNA-PCR. Intraprostatic treatment administered at lower doses showed vector biodistribution into the colon, urinary bladder and prostate. At higher doses, vector dissemination was observed in tissues more distant from the prostate, including the lung, thymus, heart, liver and adrenal gland. After intravenous injection of Ad-REIC, dissemination was observed in the liver and spleen. These results indicate that the biodistribution of Ad-REIC is determined by the dose and route of administration. Although acute inflammatory effects were observed in the prostate after intraprostatic administration at higher doses, no abnormal histological findings were noted in the other tissues, including those of intravenously treated mice. Regarding the safety of Ad-REIC administration, no deaths and no signs of toxicity or unusual behavior were observed in the mice in any treatment group. Based on these preclinical experiments, adenovirus-mediated in situ REIC/Dkk-3 gene therapy is considered to be safe for use as a treatment for human prostate cancer.     

Association between BRCA Mutation Status,Pathological Findings,and Magnetic Resonance Imaging Features in Patients with Breast Cancer at Risk for the Mutation

Purpose

We investigated the relationship between BRCA mutations, pathological findings, and magnetic resonance imaging (MRI) features in patients with breast cancer at risk for the mutation.

Methods

Genetic testing for BRCA mutations was performed in 275 breast cancer patients with at least one risk factor for the mutation. Using the breast imaging reporting and data system MR lexicon, morphological and kinetic features were reviewed on MRI scans of 230 tumors in 209 patients. The relationship between BRCA mutations, pathologic findings, and MRI data was examined, and disease recurrence was estimated.

Results

BRCA mutations were detected in 48 patients (23.0%), of which 21 (10.0%) were in BRCA1, and 25 (12.0%) in BRCA2. Additionally, two patients (1.0%) had mutations in both genes. Cancers in patients with BRCA1 mutations more frequently showed a higher nuclear grade (p=0.0041), and triple-negative (TN) phenotype (p<0.0001). On MRI scans, the cancers were seen as mass-type in 182 out of 230 lesions (79.1%), and nonmass type in 48 cases (20.9%). Among the features indentified by MRI, rim enhancement was significantly associated with molecular subtypes based on immunohistochemistry (p<0.0001), and nuclear grade (p=0.0387) in multiple logistic regression analysis. Rim enhancement on MRI, along with advanced pathologic N stage, was associated with increased disease recurrence (p=0.0023) based on multivariate analysis. However, the proportion of mass and nonmass tumors, and the distribution of morphological shape, margin, internal enhancement, and kinetic features assessed by MRI were not different according to BRCA mutation status.

Conclusion

BRCA1 mutations were associated with aggressive pathological characteristics, and the TN phenotype. Rim enhancement was frequently seen on MRI scans of high-grade cancers and in the TN phenotype. And it was a significant predictor of disease recurrence. However, a direct association with BRCA mutations was not observed.     

Protons offer reduced bone marrow,small bowel,and urinary bladder exposure for patients receiving neoadjuvant radiotherapy for resectable rectal cancer

Background

To assess the potential benefit of proton therapy (PT) over photon therapy, we compared 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and PT plans in patients undergoing neoadjuvant chemoradiation for resectable rectal cancer at our institution.

Methods

Eight consecutive patients with resectable (T2-T3) rectal cancers underwent 3DCRT, IMRT, and 3-dimensional conformal PT treatment planning. Initial target volumes (PTV1) were contoured using the Radiation Therapy Oncology Group anorectal atlas guidelines. Boost target volumes (PTV2) consisted of the gross rectal tumor plus a uniform 2-cm expansion. Plans delivered 45 Gray (Gy) or Cobalt Gray Equivalent (CGE) to the PTV1 and a 5.4-Gy (CGE) boost to the PTV2. Ninety-five percent of the PTVs received 100% of the target dose and 100% of the PTVs received 95% of the target dose. Standard normal-tissue constraints were utilized. Wilcoxon paired t-tests were performed to compare various dosimetric points between the 3 plans for each patient.

Results

All plans met all normal-tissue constraints and were isoeffective in terms of PTV coverage. The proton plans offered significantly reduced median normal-tissue exposure over the 3DCRT and IMRT plans with respect to pelvic bone marrow at the V5Gy, V10Gy, V15Gy, and V20Gy levels and the small bowel space at the V10Gy and V20Gy levels. The proton plans also offered significantly reduced median normal-tissue exposure over the 3DCRT plans with respect to the small bowel at the V30Gy and V40Gy levels and the urinary bladder at the V40Gy level.

Conclusions

By reducing bone marrow exposure, PT may reduce the acute hematologic toxicity of neoadjuvant chemoradiation and increase the likelihood of uninterrupted chemotherapy delivery. Bone marrow sparing may also facilitate the delivery of salvage chemotherapy for patients who subsequently develop hematogenous metastasis. Reduced small bowel exposure using PT may also reduce toxicity and possibly facilitate the use of more-aggressive chemotherapy with radiotherapy.     

Severe Pneumonia Caused by Corynebacterium striatum in Adults,Seoul, South Korea, 2014–2019

We investigated the proportion and characteristics of severe Corynebacterium striatum pneumonia in South Korea during 2014–2019. As part of an ongoing observational study of severe pneumonia among adult patients, we identified 27 severe C. striatum pneumonia cases. Most (70.4%) cases were hospital-acquired, and 51.9% of patients were immunocompromised. C. striatum cases among patients with severe hospital-acquired pneumonia (HAP) increased from 1.0% (2/200) during 2014–2015 to 5.4% (10/185) during 2018–2019, but methicillin-resistant Staphylococcus aureus (MRSA) infections among severe HAP cases decreased from 12.0% to 2.7% during the same timeframe. During 2018–2019, C. striatum was responsible for 13.3% of severe HAP cases from which bacterial pathogens were identified. The 90-day mortality rates were similarly high in the C. striatum and MRSA groups. C. striatum was a major cause of severe HAP and had high mortality rates. This pathogen is emerging as a possible cause for severe pneumonia, especially among immunocompromised patients.     

Surgical treatment of giant cavernous hemangiomas of the liver--analysis of 7 patients.

Seven patients with giant cavernous hemangioma of the liver were treated surgically with success at Pusan Gospel Hospital, Kosin Medical College, Pusan, from 1980 through 1989. They were 3 males and 4 females, and their ages ranged from 6 to 59 years. The tumors were located on the right lobe of the liver in 5 patients and on the left lobe in 2. The lesions were solitary in all patients, and their sizes varied from 4cm to 15cm in diameter. All patients underwent hepatic resection: 1 right hepatic lobectomy and 4 partial resections for tumors on the right lobe, and 1 left lobectomy and 1 left lateral segmentectomy for tumors on the left lobe. There was no surgical death, but 1 patient had a postoperative complication: multiple stress ulcers on the stomach and ileum. The pathologic diagnosis was cavernous hemangioma in all cases. In the long-term follow-up, there was no recurrence of preoperative symptoms in any patient.     

Identification and In Vivo Functional Characterization of Novel Compound Heterozygous BMP1 Variants in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal‐dominant inheritance, but many autosomal‐recessive genes have been reported. We applied whole‐exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypofunctional nature of the two variants was demonstrated in a zebrafish assay.     

Insulin‐like growth factor‐1 receptor is associated with better prognosis in classical Hodgkin's lymphoma: Correlation with MET expression

The purpose of this study was to examine the prognostic significance of insulin‐like growth factor‐1 receptor (IGF‐1R) expression alone and in relation to the expression of the MET‐ receptor and the MET‐homologous receptor RON, in classical Hodgkin's lymphoma (cHL). Tumour samples from patients with cHL (n = 202; median age 37.5 years) were analysed retrospectively for IGF‐R1, MET or RON expression by immunohistochemistry using tissue microarrays. The median follow‐up time was 3.7 years (range, 0.1–20 years). Twenty‐nine patients (14.3%) expressed IGF‐1R protein in Hodgkin/Reed–Sternberg (HRS) cells, which was associated with a better overall survival (OS) (P = 0.036). IGF‐1R expression was closely associated with MET receptor expression and low level of lactate dehydrogenase. In patients with cHL receiving doxorubicin, bleomycin, vinblastine and dacarbazine, those expressing IGF‐1R showed a trend towards better OS and event‐free survival than IGF‐1R‐negative patients (P = 0.129 and P = 0.115 respectively), but statistical significance was not reached. This study suggests that IGF‐1R expression could be associated with better clinical outcome in cHL but is significantly associated with the expression of MET receptor.     

Automatically Detecting Failures in Natural Language Processing Tools for Online Community Text

Background

The prevalence and value of patient-generated health text are increasing, but processing such text remains problematic. Although existing biomedical natural language processing (NLP) tools are appealing, most were developed to process clinician- or researcher-generated text, such as clinical notes or journal articles. In addition to being constructed for different types of text, other challenges of using existing NLP include constantly changing technologies, source vocabularies, and characteristics of text. These continuously evolving challenges warrant the need for applying low-cost systematic assessment. However, the primarily accepted evaluation method in NLP, manual annotation, requires tremendous effort and time.

Objective

The primary objective of this study is to explore an alternative approach—using low-cost, automated methods to detect failures (eg, incorrect boundaries, missed terms, mismapped concepts) when processing patient-generated text with existing biomedical NLP tools. We first characterize common failures that NLP tools can make in processing online community text. We then demonstrate the feasibility of our automated approach in detecting these common failures using one of the most popular biomedical NLP tools, MetaMap.

Methods

Using 9657 posts from an online cancer community, we explored our automated failure detection approach in two steps: (1) to characterize the failure types, we first manually reviewed MetaMap’s commonly occurring failures, grouped the inaccurate mappings into failure types, and then identified causes of the failures through iterative rounds of manual review using open coding, and (2) to automatically detect these failure types, we then explored combinations of existing NLP techniques and dictionary-based matching for each failure cause. Finally, we manually evaluated the automatically detected failures.

Results

From our manual review, we characterized three types of failure: (1) boundary failures, (2) missed term failures, and (3) word ambiguity failures. Within these three failure types, we discovered 12 causes of inaccurate mappings of concepts. We used automated methods to detect almost half of 383,572 MetaMap’s mappings as problematic. Word sense ambiguity failure was the most widely occurring, comprising 82.22% of failures. Boundary failure was the second most frequent, amounting to 15.90% of failures, while missed term failures were the least common, making up 1.88% of failures. The automated failure detection achieved precision, recall, accuracy, and F1 score of 83.00%, 92.57%, 88.17%, and 87.52%, respectively.

Conclusions

We illustrate the challenges of processing patient-generated online health community text and characterize failures of NLP tools on this patient-generated health text, demonstrating the feasibility of our low-cost approach to automatically detect those failures. Our approach shows the potential for scalable and effective solutions to automatically assess the constantly evolving NLP tools and source vocabularies to process patient-generated text.     

Solvent-induced ion selective transport properties of a crosslinked poly(L-glutamic acid) membrane

Ion-selective transport of alkali metal chlorides (LiCl, NaCl, KCl and CsCl) is reported for a crosslinked poly(L -glutamic acid) membrane immersed in aqueous alcohols CH₃OH, C₂H₅OH and 2-propanol ((CH₃)₂CHOH). In aqueous CH₃OH and C₂H₅OH, an appreciable ionselectivity was observed for the permeability coefficient, i.e., Li⁺ < Na⁺ < Cs⁺ ≤ K⁺, in a higher alcohol composition region. This counterion sequence results from a significant increase in the salt solubility coefficient of KCl and CsCl and a substantial decrease in the diffusion coefficient of LiCl and NaCl in the relevant alcohol composition region. Membrane conductivity measurements, which were performed concomitantly for the aq. C₂H₅OH system, suggest the same ion specificity for the counterion mobility as for permeability. It has been suggested that the specific counterion binding to polymer charges is an essential factor for ion specificity.