Oncologic Outcomes of Sequential Intravesical Gemcitabine and Docetaxel Compared with Bacillus Calmette-Guérin in Patients with Bacillus Calmette-Guérin-Unresponsive Non-Muscle Invasive Bladder Cancer.

Background And Objective: Non-muscle-invasive bladder cancer (NMIBC) patients treated with additional bacillus Calmette-Guérin (BCG) may become unresponsive to BCG. Recently, sequential intravesical gemcitabine and docetaxel (gem/doce) are being used for NMIBC. This study aims to compare oncologic outcomes between sequential intravesical gem/doce versus additional BCG in patients with BCG-unresponsive NMIBC.

The efficacy of sequential intravesical gemcitabine and docetaxel versus BCG for the treatment of European association of urology very-high risk non-muscle invasive bladder cancer.

Background: The European Association of Urology (EAU) recommends early radical cystectomy (RC) for very-high-risk (VHR) nonmuscle invasive bladder cancer (NMIBC), in part due to suboptimal efficacy from BCG in this setting. Effective bladder-sparing alternatives are needed. We compared the oncological outcomes of Gemcitabine/Docetaxel (Gem/Doce) to BCG therapy in patients with VHR NMIBC.

Cilia structure and intraflagellar transport differentially regulate sensory response dynamics within and between C. elegans chemosensory neurons.

Sensory neurons contain morphologically diverse primary cilia that are built by intraflagellar transport (IFT) and house sensory signaling molecules. Since both ciliary structural and signaling proteins are trafficked via IFT, it has been challenging to decouple the contributions of IFT and cilia structure to neuronal responses. By acutely inhibiting IFT without altering cilia structure and vice versa, here we describe the differential roles of ciliary trafficking and sensory ending morphology in shaping chemosensory responses in Caenorhabditis elegans.

DNA polymerase ζ has robust reverse transcriptase activity relative to other cellular DNA polymerases.

Cell biology and genetic studies have demonstrated that DNA double-strand break (DSB) repair can be performed using an RNA transcript that spans the site of the DNA break as a template for repair. This type of DSB repair requires a reverse transcriptase to convert an RNA sequence into DNA to facilitate repair of the break, rather than copying from a DNA template as in canonical DSB repair. Translesion synthesis (TLS) DNA polymerases (Pol) are often more promiscuous than DNA Pols, raising the notion that reverse transcription could be performed by a TLS Pol.

DNA polymerase ζ is a robust reverse transcriptase.

Cell biology and genetic studies have demonstrated that DNA double strand break (DSB) repair can be performed using an RNA transcript that spans the site of the DNA break as a template for repair. This type of DSB repair requires a reverse transcriptase to convert an RNA sequence into DNA to facilitate repair of the break, rather than copying from a DNA template as in canonical DSB repair. Translesion synthesis (TLS) DNA polymerases (Pol) are often more promiscuous than DNA Pols, raising the notion that reverse transcription could be performed by a TLS Pol.

Structures of the human leading strand Polε-PCNA holoenzyme.

In eukaryotes, the leading strand DNA is synthesized by Polε and the lagging strand by Polδ. These replicative polymerases have higher processivity when paired with the DNA clamp PCNA. While the structure of the yeast Polε catalytic domain has been determined, how Polε interacts with PCNA is unknown in any eukaryote, human or yeast.

Deintensification of Treatment for Low-grade Bladder Tumors: A Collaborative Review by the International Bladder Cancer Group (IBCG).

Background And Objective: Management of low-grade (LG) urothelium-confined (Ta stage) non-muscle-invasive bladder cancer (NMIBC) poses a distinct therapeutic challenge. Transurethral resection of bladder tumor (TURBT), the standard treatment, frequently has to be repeated because of high tumor recurrence rates. This places a considerable strain on both patients and health care infrastructure, underscoring the need for alternative management approaches.

Direct dorsal root ganglia (DRG) injection in mice for analysis of adeno-associated viral (AAV) gene transfer to peripheral somatosensory neurons.

Background: Delivering optogenetic genes to the peripheral sensory nervous system provides an efficient approach to study and treat neurological disorders and offers the potential to reintroduce sensory feedback to prostheses users and those who have incurred other neuropathies. Adeno-associated viral (AAV) vectors are a common method of gene delivery due to efficiency of gene transfer and minimal toxicity. AAVs are capable of being designed to target specific tissues, with transduction efficacy determined through the combination of serotype and genetic promoter selection, as well as location of vector administration.

Mechanism of PCNA loading by Ctf18-RFC for leading-strand DNA synthesis.

The proliferating cell nuclear antigen (PCNA) clamp encircles DNA to hold DNA polymerases (Pols) to DNA for processivity. The Ctf18-RFC PCNA loader, a replication factor C (RFC) variant, is specific to the leading-strand Pol (Polε). We reveal here the underlying mechanism of Ctf18-RFC specificity to Polε using cryo-electron microscopy and biochemical studies.

Prognostic role of the neutrophil/lymphocyte ratio in high-risk BCG-naïve non-muscle-invasive bladder cancer treated with intravesical gemcitabine/docetaxel.

Objectives: To investigate the role of pretreatment neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in the prediction of response to sequential intravesical therapy, gemcitabine and docetaxel (Gem/Doce), given to patients with bacille Calmette-Guérin (BCG)- naïve high-risk non-muscle-invasive bladder cancer (NMIBC).

Patients And Methods: A retrospective analysis was conducted on 115 patients who received intravesical Gem/Doce for high-risk NMIBC between January 2011 and December 2021. Data were computed as the median (interquartile range [IQR]) or mean (standard deviation [sd]).

Sequential Endoluminal Gemcitabine and Cabazitaxel with Intravenous Pembrolizumab as a Bladder-Preserving Strategy for Docetaxel-Unresponsive Non-Muscle Invasive Urothelial Carcinoma Following Transurethral Resection of Bladder Tumor.

Growing evidence suggests that many patients with high-risk non-muscle invasive urothelial carcinoma (NMIUC) can undergo bladder-sparing management with salvage intravesical therapies. However, inherent or developed disease resistance, particularly after multiple lines of prior salvage therapy, implores the continued pursuit of new treatment combinations. Herein, we describe the outcomes of 26 patients (31 treated units; 24 lower tract, 7 upper tract) with high-risk NMIUC treated with sequential intravesical gemcitabine and cabazitaxel with concomitant intravenous pembrolizumab (GCP) at the University of Iowa from August 2020 to February 2023.

Advancing Clinical Trial Design for Non-Muscle Invasive Bladder Cancer.

Background: Despite recent drug development for non-muscle invasive bladder cancer (NMIBC), few therapies have been approved by the US Food and Drug Administration (FDA), and there remains an unmet clinical need. Bacillus Calmette-Guerin (BCG) supply issues underscore the importance of developing safe and effective drugs for NMIBC.

Objective: On November 18-19, 2021, the FDA held a public virtual workshop to discuss NMIBC research needs and potential trial designs for future development of effective therapies.

Hemospray® (hemostatic powder TC-325) as monotherapy for acute gastrointestinal bleeding: a multicenter prospective study.

Background: Hemostatic powders are used as second-line treatment in acute gastrointestinal (GI) bleeding (AGIB). Increasing evidence supports the use of TC-325 as monotherapy in specific scenarios. This prospective, multicenter study evaluated the performance of TC-325 as monotherapy for AGIB.

A Multinational, Multi-Institutional Study Assessing the Impact of Diabetes Mellitus on the Prognosis of Patients with Non-Muscle Invasive Bladder Cancer Treated with Bacillus Calmette-Guérin.

The study aimed to examine the impact of diabetes mellitus type 2 (DMII) on the oncological outcomes of non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) using comprehensive real-world data. We performed an analysis of data on NMIBC patients treated with BCG from the United States (US) National Phase II BCG/Interferon (IFN) trial database (125 centers) and pooled databases from three tertiary care institutions: France (FR), Lebanon (LB) (2000-2021), and the US (University of Iowa) (2011-2021). There were 867 patients from the Phase II trial, 1232 from the FR/LB cohort, and 233 from the US (Iowa) cohort ( = 2332).

Establishing an Intravesical Doublet Chemotherapy Clinic for Nonmuscle-Invasive Bladder Cancer Patients.

Introduction: Intravesical sequential doublet chemotherapy (SDC) is being used increasingly as a rescue treatment for nonmuscle-invasive bladder cancer failing bacillus Calmette-Guérin (BCG), as single-agent chemotherapies are less effective, especially for carcinoma in situ. Considering the current BCG shortage, intravesical SDC also provides an efficacious alternative to BCG. Our aim is to detail the implementation to assist with establishing an efficient and practical intravesical SDC clinic for urologic practice.

Proton-driven sodium secretion in a saline water animal.

Aquatic animals residing in saline habitats either allow extracellular sodium concentration to conform to environmental values or regulate sodium to lower levels. The latter strategy requires an energy-driven process to move sodium against a large concentration gradient to eliminate excess sodium that diffuses into the animal. Previous studies of invertebrate and vertebrate species indicate a sodium pump, Na/K ATPase, powers sodium secretion.