Hvidhanson4663

These results allow us to define distinct protonation and activation steps in pH-stimulated conformational cycling in GLIC, including interfacial rearrangements largely conserved in the pentameric channel family.

Almost all cervical cancers (CC) are caused by human papillomavirus (HPV) and patients with advanced stage are at high risk for relapse. Circulating HPV DNA (HPV ctDNA) may serve as a residual tumor marker at the end of chemo-radiation or to predict relapse during the follow-up period.

We analyzed serum samples from 94 HPV16- or HPV18-related CCs from the BioRAIDs prospective cohort. Samples were collected before and after treatment and during an 18-month follow-up period. Using digital droplet PCR (ddPCR), we assessed the relevance of circulating HPV

gene as a marker for residual disease compared to HPV integration site and

mutations. Finally, the prognostic impact of circulating HPV

gene was assessed with its prediction value of relapse.

HPV

gene was the most sensitive tumor marker, superior to both HPV integration sites and

mutations in serum. Circulating HPV DNA (HPV ctDNA) was detected in 63% (59/94) of patients, before treatment. HPV ctDNA detection in serum sample was associated with high FIGO stage (p=0.02) and para-aortic lymph node involvement (p=0.01). The level of HPV ctDNA was positively correlated with HPV copy number in the tumor (R=0.39, p<0.001). Complete clearance of HPV ctDNA by the end of treatment was significantly associated with a longer PFS (p<0.0001). Patients with persistent HPV ctDNA in serum relapsed with a median time of 10 months (range, 2-15) from HPV ctDNA detection.

HPV ctDNA detection is a useful marker to predict relapse in CC.

HPV ctDNA detection is a useful marker to predict relapse in CC.

Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell carcinoma (ccRCC) and is a confounding factor for therapy selection. Most approaches to evaluate ITH are limited by two-dimensional

tissue analyses. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can noninvasively assess the spatial landscape of entire tumors in their natural milieu. To assess the potential of DCE-MRI, we developed a vertically integrated radiogenomics colocalization approach for multi-region tissue acquisition and analyses. We investigated the potential of spatial imaging features to predict molecular subtypes using histopathologic and transcriptome correlatives.

We report the results of a prospective study of 49 patients with ccRCC who underwent DCE-MRI prior to nephrectomy. Surgical specimens were sectioned to match the MRI acquisition plane. RNA sequencing data from multi-region tumor sampling (80 samples) were correlated with percent enhancement on DCE-MRI in spatialing-based approaches.

Immunotherapy efficacy data on appendiceal cancer from clinical trials does not exist, due to appendiceal cancer incidence of 0.97 per 100,000. The goal of this study was to preclinically explore the application of immunotherapy in treating appendiceal cancer in a personalized organoid model.

Patient tumor organoids (PTO) were fabricated using unsorted tumor cells with and without enrichment with patient-matched immune components derived from peripheral blood leukocytes, spleen, or lymph nodes [immune-enhanced PTOs (iPTO)]. Organoids were cultured for 7 days, followed by treatment with immunotherapy (pembrolizumab, ipilimumab, nivolumab), and assessed for treatment efficacy.

Between September 2019 and May 2021, 26 patients were enrolled in the study. Successful testing was conducted in 19 of 26 (73.1%) patients, with 13 of 19 (68.4%) and 6 of 19 (31.6%) patients having low-grade appendiceal (LGA) and high-grade appendiceal (HGA) primaries, respectively. Immunotherapy response, with increased expression .

M-protein is a well-established biomarker used for multiple myeloma (MM) monitoring. Current improvements in MM treatment created the need to monitor minimal residual disease (MRD) with high sensitivity. Measuring residual levels of M-protein in serum by mass spectrometry (MS) was established as a sensitive assay for disease monitoring. In this study we evaluated the performance of EasyM - a non-invasive, sensitive, MS-based assay for M-protein monitoring.

Twenty-six patients enrolled in MCRN-001 clinical trial of 2 high dose alkylating agents as conditioning followed by lenalidomide maintenance were selected for the study. All selected patients achieved CR during treatment, while 5 experienced progressive disease on study. The M-protein of each patient was first sequenced from the diagnostic serum using our

protein sequencing platform. The patient-specific M-protein peptides were then measured by targeted MS assay to monitor the response to treatment.

The M-protein doubling over 6 months measured by EasyM could predict the relapse in four out of five relapsed patients 2-11 months earlier than conventional testing. In 21 disease-free patients, the M-protein was still detectable by EasyM despite normal FLC and MRD negativity. Importantly, out of 72 MRD negative samples with CR status, 62 were positive by EasyM. Curcumin analog C1 The best sensitivity achieved by EasyM, detecting 0.58 mg/L of M-protein, was 1000- and 200-fold higher compared to SPEP and IFE, respectively.

EasyM was demonstrated to be a non-invasive, sensitive assay with superior performance compared to other assays, making it ideal for MM monitoring and relapse prediction.

EasyM was demonstrated to be a non-invasive, sensitive assay with superior performance compared to other assays, making it ideal for MM monitoring and relapse prediction.

Systems biology approaches can identify critical targets in complex cancer signaling networks to inform new therapy combinations that may overcome conventional treatment resistance.

We performed integrated analysis of 1,046 childhood B-ALL cases and developed a data-driven network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a common high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance.

We identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Genetic cotargeting of the synergistic key regulator pair

and

associated athanogene 1 (

) significantly reduced leukemia cell viability

. Pharmacologic inhibition with dual small molecule inhibitor therapy targeting this pair of key nodes further demonstrated enhanced antileukemia efficacy of combining the BCL-2 inhibitor venetoclax with the tyrosine kinase inhibitors ruxolitinib or dasatinib

in human Ph-like ALL cell lines and

in multiple childhood Ph-like ALL patient-derived xenograft models.