Effects of ribonucleotides on cis-diamminedichloroplatinum(II) (cisplatin)-mediated DNA damage were studied by incubating pUC18 DNA with cisplatin in the presence of nucleotide, and by monitoring conformational change and sensitivity change to restriction enzyme HpaII of the DNA due to the platinum-DNA adduct formation. The cisplatin-mediated DNA damage was inhibited in a dose-dependent fashion by ATP or GTP, substantially at their physiological intracellular concentrations, and almost completely by 5 mM ATP or 2 mM GTP. The inhibitory effect of nucleotide on the platination of DNA was in the order of GTP > ATP >> CTP > UTP, and of nucleoside triphosphate > nucleoside diphosphate > nucleoside monophosphate. Nucleoside did not show any significant effect on platination of DNA. To elucidate the mechanism of the nucleotide effects on platination of DNA, interaction between ATP or GTP and cisplatin was analyzed by high-performance liquid chromatography. The results suggested that ATP inhibits cisplatin-mediated DNA damage both by forming a platinum-ATP adduct and by non-covalent ionic interaction with cisplatin, while GTP acts largely by forming platinum-GTP adducts.

BACKGROUND: Positive-margin resection of external auditory canal squamous cell carcinoma (EAC-SCC) is still a major cause of recurrence. The aim of this study is to examine the clinical impact of positive-margin resection of EAC-SCCs. METHODS: We retrospectively reviewed 40 surgical cases with en bloc temporal bone resection of EAC-SCC at a tertiary referral center from October 2016 to March 2022. RESULTS: Two-year disease-specific, overall, and disease-free survival rates for all 40 cases reviewed were 85.2%, 88.85%, and 76.96%, respectively. En bloc resection with a negative margin significantly improved patient prognosis (p < 0.001). Positive-margin resection was observed in 9/40 cases (22.5%). Insufficient assessment of preoperative images was the cause in two of these cases. Postoperative lymph node metastasis and distant metastasis were observed in cases in which vascular, lymphatic duct or perineural invasion was found on postoperative pathological examination. In addition, three cases in which no vascular, lymphatic duct, or perineural invasion was found exhibited local recurrence during the follow-up period. Of the nine positive-margin resection cases, only two showed no postoperative recurrence. CONCLUSIONS: Once positive-margin resections are confirmed, cases might have a high risk of tumor recurrence, even with the addition of postoperative adjuvant chemoradiotherapy.

Infants diagnosed with acute myeloid leukemia (AML) frequently harbor cytogenetically cryptic fusions involving KMT2A, NUP98 or GLIS2. Those with AML driven specifically by CBFA2T3::GLIS2 fusions have a dismal prognosis and are currently risk-stratified to receive hematopoietic stem cell transplantation (HSCT) in first remission. Here we report an infant with AML who was refractory to multiple lines of chemotherapy but lacked an identifiable fusion despite cytogenetic, fluorescence in situ hybridization (FISH) and targeted next generation sequencing (NGS) testing. Research-grade RNASeq from a relapse sample revealed in-frame CBFA2T3::GLIS3 and GLIS3::CBFA2T3 fusions. A patient-derived xenograft (PDX) generated from this patient has a short latency period and represents a strategy to test novel agents that may be effective in this aggressive subtype of AML. This report describes the first case of AML with a CBFA2T3::GLIS3 fusion and highlights the need for unbiased NGS testing including RNASeq at diagnosis, as patients with CBFA2T3::GLIS3 fusions should be considered for HSCT in first remission.

Background

Remote wireless follow-up of implanted pacemakers (PM) has become an attractive method of follow-up. Although wireless PM follow-up has several advantages compared with transtelephonic and office-based follow-up, its utility depends on successful transmission.

Hypothesis

Initial in-office setup of wireless PM will improve transmission rate as compared with home setup.

Methods

A total of 202 consecutive patients from 2 medical centers were included in this retrospective study. Patients in the home setup group (N = 101) had traditional home setup of wireless PM, whereas patients in the in-office group (N = 101) had setup of PMs by allied health professionals during the postoperative office visit. Successful transmission was defined as successful initial wireless transmission of PM data by 2 months postimplant.

Results

Of the 101 patients in the home setup group, 22 (22%) patients had successful transmission. Of the 101 patients in the in-office group, 92 (91%) patients had successful transmission (P < 0.0001). Logistic regression analysis showed that that the in-office group was independently associated with successful transmission (odds ratio: 114.5; 95% confidence interval: 32.1-408.4; P < 0.0001).

Conclusions

In patients implanted with PM capable of remote wireless data transmission, initial home setup of the wireless monitoring device was frequently unsuccessful. In-office PM setup was associated with a significantly higher rate of successful transmission.

Squamous cell carcinoma of the external auditory canal (EACSCC) is an extraordinarily rare and aggressive malignant disease. Establishment of EACSCC cell line with robust molecular characteristics is essential for the basic and translational research of EACSCC. Here, we show the newly established EACSCC cell line SCEACono2, derived from a patient with well-to-moderately differentiated EACSCC. We analyzed histologic and genetic features of SCEACono2 hiring multiple experiments, including next-generation sequencing (NGS). Immunocytochemical staining of SCEACono2 showed positivity of p53 and SCC1/2. Furthermore, SCEACono2 exhibited a unique characteristic that cytokeratin, vimentin as well as cancer stem cell markers (CD44, CD133, ALP and Oct3/4) were positive. SCEACono2 had an ability to form tumors at the temporal lesion xenograft nude mice model. NGS revealed that SCEACono2 harbored the somatic mutations of TP53 (p.G245S) and NOTCH1 (p.A465T). RNA-seq and downstream bioinformatics analysis revealed significant enrichment of genes involved in inflammation and cell adhesion in SCEACono2 compared to SCC-9 and HSC-4. STR profiling indicated no evidence of cross-contamination. In conclusion, SCEACono2 could serves as a promising and robust research resource of EACSCC in vitro and in vivo.

In this clinical validation study, we developed and validated a urinary Q-Score generated from the quantitative test QSant, formerly known as QiSant, for the detection of biopsy-confirmed acute rejection in kidney transplants. Using a cohort of 223 distinct urine samples collected from three independent sites and from both adult and pediatric renal transplant patients, we examined the diagnostic utility of the urinary Q-Score for detection of acute rejection in renal allografts. Statistical models based upon the measurements of the six QSant biomarkers (cell-free DNA, methylated-cell-free DNA, clusterin, CXCL10, creatinine, and total protein) generated a renal transplant Q-Score that reliably differentiated stable allografts from acute rejections in both adult and pediatric renal transplant patients. The composite Q-Score was able to detect both T cell-mediated rejection and antibody-mediated rejection patients and differentiate them from stable non-rejecting patients with a receiver-operator characteristic curve area under the curve of 99.8% and an accuracy of 98.2%. Q-Scores < 32 indicated the absence of active rejection and Q-Scores ≥ 32 indicated an increased risk of active rejection. At the Q-Score cutoff of 32, the overall sensitivity was 95.8% and specificity was 99.3%. At a prevalence of 25%, positive and negative predictive values for active rejection were 98.0% and 98.6%, respectively. The Q-Score also detected subclinical rejection in patients without an elevated serum creatinine level but identified by a protocol biopsy. This study confirms that QSant is an accurate and quantitative measurement suitable for routine monitoring of renal allograft status.

Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report the pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that pharmacologic SHP2 inhibition unveils an Achilles' heel of RTK-driven AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

Desmoplasia describes the deposition of extensive extracellular matrix and defines primary pancreatic ductal adenocarcinoma (PDA). The acellular component of this stroma has been implicated in PDA pathogenesis and is being targeted therapeutically in clinical trials. By analyzing the stromal content of PDA samples from numerous annotated PDA data sets and correlating stromal content with both anatomic site and clinical outcome, we found PDA metastases in the liver, the primary cause of mortality to have less stroma, have higher tumor cellularity than primary tumors. Experimentally manipulating stromal matrix with an anti-lysyl oxidase like-2 (anti-LOXL2) antibody in syngeneic orthotopic PDA mouse models significantly decreased matrix content, led to lower tissue stiffness, lower contrast retention on computed tomography, and accelerated tumor growth, resulting in diminished overall survival. These studies suggest an important protective role of stroma in PDA and urge caution in clinically deploying stromal depletion strategies.

In April 2023, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by one new family, 14 new genera, and 140 new species. Two genera and 538 species were renamed. One species was moved, and four were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.

In March 2022, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by two new families (bunyaviral Discoviridae and Tulasviridae), 41 new genera, and 98 new species. Three hundred forty-nine species were renamed and/or moved. The accidentally misspelled names of seven species were corrected. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.