Selection of a Fluorinated Aptamer Targeting the Viral RNA Frameshift Element with Different Chiralities.

The development of RNA aptamers with high specificity and affinity for target molecules is a critical advancement in the field of therapeutic and diagnostic applications. This study presents the selection of a 2'-fluoro-modified mirror-image RNA aptamer through the in vitro SELEX process. Using a random RNA library, we performed iterative rounds of selection and amplification to enrich aptamers that bind specifically to the viral attenuator hairpin RNA containing the opposite chirality, which is an important part of the frameshift element.

Accurate in silico predictions of modified RNA interactions to a prototypical RNA-binding protein with λ-dynamics.

RNA-binding proteins shape biology through their widespread functions in RNA biochemistry. Their function requires the recognition of specific RNA motifs for targeted binding. These RNA binding elements can be composed of both unmodified and chemically modified RNAs, of which over 170 chemical modifications have been identified in biology.

A phase II study evaluating safety and efficacy of niraparib in patients with previously treated homologous recombination defective metastatic esophageal/gastroesophageal junction/proximal gastric adenocarcinoma.

Introduction: Esophageal adenocarcinoma (EAC) remains a devastating disease and second line treatment options in the metastatic space are limited. Homologous recombination (HR) defects have been described in EAC in up to 40% of patients. Poly (ADP-ribose) polymerase (PARP)1 and PARP2 inhibitors have shown efficacy in HR defective prostate and ovarian cancers.

Survey of Changes in Absolute Lymphocyte Counts and Peripheral Immune Repertoire Diversity after External Beam Radiotherapy.

Radiation-induced lymphopenia (RIL) is associated with worse outcomes in patients with multiple solid tumors. Hypofractionated radiation therapy (HFRT) reduces RIL compared with conventionally fractionated radiation therapy (CFRT). However, fractionation effects on immune repertoire (IR) diversity are unknown.

Renal L-2-hydroxyglutarate dehydrogenase activity promotes hypoxia tolerance and mitochondrial metabolism in Drosophila melanogaster.

Objectives: The mitochondrial enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH) regulates the abundance of L-2-hydroxyglutarate (L-2HG), a potent signaling metabolite capable of influencing chromatin architecture, mitochondrial metabolism, and cell fate decisions. Loss of L2hgdh activity in humans induces ectopic L-2HG accumulation, resulting in neurodevelopmental defects, altered immune cell function, and enhanced growth of clear cell renal cell carcinomas. To better understand the molecular mechanisms that underlie these disease pathologies, we used the fruit fly Drosophila melanogaster to investigate the endogenous functions of L2hgdh.

Frameless Stereotactic Biopsy of Brainstem Tumors Using the Stealth Autoguide: A Technical Note.

Background And Objectives: In the molecular era of neuro-oncology, it is increasingly necessary to obtain tissue for next-generation sequencing and methylome profile for prognosis and targeted oncological management. Brainstem tumors can be technically challenging to biopsy in the pediatric population. Frame-based and frameless techniques have previously been described and proven to be safe and efficacious in children.

Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice.

Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress-responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eIF2α. In T1D, maladaptive unfolded protein response (UPR) in insulin-producing β cells renders these cells susceptible to autoimmunity.

Inhibition of the eukaryotic initiation factor-2α kinase PERK decreases risk of autoimmune diabetes in mice.

Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress-responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eukaryotic translation initiation factor-2α (eIF2α). In T1D, maladaptive unfolded protein response (UPR) in insulin-producing β cells renders these cells susceptible to autoimmunity.

Common variation in a long non-coding RNA gene modulates variation of circulating TGF-β2 levels in metastatic colorectal cancer patients (Alliance).

Background: Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC). The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms.

In silico λ-dynamics predicts protein binding specificities to modified RNAs.

RNA modifications shape gene expression through a smorgasbord of chemical changes to canonical RNA bases. Although numbering in the hundreds, only a few RNA modifications are well characterized, in part due to the absence of methods to identify modification sites. Antibodies remain a common tool to identify modified RNA and infer modification sites through straightforward applications.

Machine Learning Predicts Oxaliplatin Benefit in Early Colon Cancer.

Purpose: A combination of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is the standard for adjuvant therapy of resected early-stage colon cancer (CC). Oxaliplatin leads to lasting and disabling neurotoxicity. Reserving the regimen for patients who benefit from oxaliplatin would maximize efficacy and minimize unnecessary adverse side effects.

Premature endocycling of Drosophila follicle cells causes pleiotropic defects in oogenesis.

Endocycling cells grow and repeatedly duplicate their genome without dividing. Cells switch from mitotic cycles to endocycles in response to developmental signals during the growth of specific tissues in a wide range of organisms. The purpose of switching to endocycles, however, remains unclear in many tissues.

Association of sun-seeking behaviors with indoor tanning behavior in US white females during high school/college in Nurses' Health Study II.

Background: Frequent exposure to ultraviolet light has more detrimental and longer-term effects on the skin in early life than in adulthood. Teenagers with strong sun-seeking behaviors may be more likely to use an indoor tanning bed than those who seek less sun. We aimed to examine associations between sun-seeking behaviors and indoor tanning behavior during high school/college in US females.

A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma.

Background And Objective: Checkpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC.

Premature endocycling of follicle cells causes pleiotropic defects in oogenesis.

Endocycling cells grow and repeatedly duplicate their genome without dividing. Cells switch from mitotic cycles to endocycles in response to developmental signals during the growth of specific tissues in a wide range of organisms. The purpose of switching to endocycles, however, remains unclear in many tissues.

Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non-Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175.

Background: Combination chemotherapy and immunotherapy regimens have significantly improved survival for patients with previously untreated advanced non-small cell lung cancer (NSCLC). Improvements in overall survival (OS) in two separate pembrolizumab trials have demonstrated survival improvements over chemotherapy alone, regardless of PD-L1 status. The optimal chemotherapy backbone for combination with immunotherapy is unknown.

Utility of Urine Cultures During Febrile Neutropenia Workup in Hematopoietic Stem Cell Transplantation Recipients Without Urinary Symptoms.

The utility of obtaining screening urine cultures for febrile neutropenia (FN) during hematopoietic stem cell transplant (HCT) is unknown. In 667 adult HCT patients with FN, only 40 (6%) were found with bacteriuria. Antibiotics were modified in 3 patients (0.

Epigenetic aging in older breast cancer survivors and noncancer controls: preliminary findings from the Thinking and Living with Cancer Study.

Background: Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes.

Methods: Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency-matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy-Cognitive Function) and physical (Medical Outcomes Study Short Form-12) function assessments at approximately 24 to 36 and 60 months after enrollment.

Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules.

Chemically modified antisense oligonucleotides (ASO) currently in pre-clinical and clinical experiments mainly focus on the 2'-position derivatizations to enhance stability and targeting affinity. Considering the possible incompatibility of 2'-modifications with RNase H stimulation and activity, we have hypothesized that the atom specific modifications on nucleobases can retain the complex structure and RNase H activity, while enhancing ASO's binding affinity, specificity, and stability against nucleases. Herein we report a novel strategy to explore our hypothesis by synthesizing the deoxynucleoside phosphoramidite building block with the seleno-modification at 5-position of thymidine, as well as its Se-oligonucleotides.