Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity.

The Discovery of a Novel Antimetastatic Bcl3 Inhibitor.

The development of antimetastatic drugs is an urgent healthcare priority for patients with cancer, because metastasis is thought to account for around 90% of cancer deaths. Current antimetastatic treatment options are limited and often associated with poor long-term survival and systemic toxicities. Bcl3, a facilitator protein of the NF-κB family, is associated with poor prognosis in a range of tumor types.

Does Femoral Component Cementation Affect Costs or Clinical Outcomes After Hip Arthroplasty in Medicare Patients?

Background: Bundled payment initiatives were introduced to reduce costs and improve quality of care. Cemented vs cementless femoral fixation is a modifiable variable that may influence the cost and quality of care. New bundled payment data from the Centers for Medicare and Medicaid Services allowed us to study the influence of femoral fixation strategy on (1) 90-day costs; (2) readmission rates; (3) reoperation rates; (4) length of stay (LOS); and (5) discharge disposition for Medicare patients undergoing total hip arthroplasty.

Bcl-3 promotes multi-modal tumour cell migration via NF-κB1 mediated regulation of Cdc42.

A key challenge in the implementation of anti-metastatics as cancer therapies is the multi-modal nature of cell migration, which allows tumour cells to evade the targeted inhibition of specific cell motility pathways. The nuclear factor-kappaB (NF-κB) co-factor B-cell lymphoma 3 (Bcl-3) has been implicated in breast cancer cell migration and metastasis, yet it remains to be determined exactly which cell motility pathways are controlled by Bcl-3 and whether migrating tumour cells are able to evade Bcl-3 intervention. Addressing these questions and the mechanism underpinning Bcl-3's role in this process would help determine its potential as a therapeutic target.

Patient Blood Management Program Improves Blood Use and Clinical Outcomes in Orthopedic Surgery.

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Although randomized trials show that patients do well when given less blood, there remains a persistent impression that orthopedic surgery patients require a higher hemoglobin transfusion threshold than other patient populations (8 g/dl vs. 7 g/dl). The authors tested the hypothesis in orthopedic patients that implementation of a patient blood management program encouraging a hemoglobin threshold less than 7 g/dl results in decreased blood use with no change in clinical outcomes.

Hospital Charges and Length of Stay Following Radical Cystectomy in the Enhanced Recovery After Surgery Era.

Objective: To report our center's experience with enhanced recovery after surgery (ERAS) pathway for radical cystectomy (RC), specifically evaluating complications, LOS, 30- and 90-day readmissions, and hospital charges. Pathways of this type have been shown to decrease the length of stay (LOS) and postoperative ileus. However, concerns persist that ERAS is costly and increases readmissions.

Blood utilization in revision versus first-time cardiac surgery: an update in the era of patient blood management.

Background: Relative to first-time (primary) cardiac surgery, revision cardiac surgery is associated with increased transfusion requirements, but studies comparing these cohorts were performed before patient blood management (PBM) and blood conservation measures were commonplace. The current study was performed as an update to determine if this finding is still evident in the PBM era.

Study Design And Methods: Primary and revision cardiac surgery cases were compared in a retrospective database analysis at a single tertiary care referral center.

A comprehensive Choosing Wisely quality improvement initiative reduces unnecessary transfusions in an Academic Department of Surgery.

Background: We implemented a comprehensive Choosing Wisely initiative to reduce unnecessary transfusions in an Academic Department of Surgery.

Methods: We conducted a survey- and lecture-based educational intervention to increase awareness about published transfusion guidelines. Monthly transfusion reports were subsequently distributed to all faculty, fellows, residents, and mid-level practitioners.

Physiologic correlates of intraoperative blood transfusion among patients undergoing major gastrointestinal operations.

Background: Guidelines for transfusion focus on nadir levels of hemoglobin. Hemoglobin triggers may not be helpful, however, in defining appropriate intraoperative use of packed red blood cells. We sought to define the use of intraoperative packed red blood cells relative to quantitative physiologic factors at the time of operation.

Single-unit transfusions and hemoglobin trigger: relative impact on red cell utilization.

Background: Patient blood management (PBM) programs can reduce unnecessary transfusions, but the optimal methods used to achieve this effect are unclear. We tested the hypothesis that encouraging single-unit red blood cell (RBC) transfusions in stable patients would have a greater impact on blood use than compliance with a specific hemoglobin (Hb) transfusion trigger alone.

Study Design And Methods: We analyzed blood utilization data at three community hospitals without previous PBM efforts before and after implementing a PBM program.

DNA polymerase ζ generates tandem mutations in immunoglobulin variable regions.

Low-fidelity DNA polymerases introduce nucleotide substitutions in immunoglobulin variable regions during somatic hypermutation. Although DNA polymerase (pol) η is the major low-fidelity polymerase, other DNA polymerases may also contribute. Existing data are contradictory as to whether pol ζ is involved.

Development of a novel pulsatile bioreactor for tissue culture.

The construction of tissue-engineered parts such as heart valves and arteries requires more than just the seeding of cells onto a biocompatible/biodegradable polymeric scaffold. It is essential that the functionality and mechanical integrity of the cell-seeded scaffold be investigated in vitro prior to in vivo implantation. The correct hemodynamic conditioning would lead to the development of tissues with enhanced mechanical strength and cell viability.

Transient fluid-structure coupling for simulation of a trileaflet heart valve using weak coupling.

In this article, a three-dimensional transient numerical approach coupled with fluid-structure interaction for the modeling of an aortic trileaflet heart valve at the initial opening stage is presented. An arbitrary Lagrangian-Eulerian kinematical description together with an appropriate fluid grid was used for the coupling strategy with the structural domain. The fluid dynamics and the structure aspects of the problem were analyzed for various Reynolds numbers and times.

Normal hypermutation in antibody genes from congenic mice defective for DNA polymerase iota.

Several low fidelity DNA polymerases participate in generating mutations in immunoglobulin genes. Polymerase eta is clearly involved in the process by causing substitutions of A:T base pairs, whereas polymerase iota has a controversial role. Although the frequency of mutations was decreased in the BL2 cell line deficient for polymerase iota, hypermutation was normal in the 129 strain of mice, which has a natural nonsense mutation in the Poli gene.

Deoxyuridine is generated preferentially in the nontranscribed strand of DNA from cells expressing activation-induced cytidine deaminase.

Activation-induced cytidine deaminase (AID) is required for somatic hypermutation and class switch recombination of Ig genes in B cells. Although AID has been shown to deaminate deoxycytidine to deoxyuridine in DNA in vitro, there is no physical evidence for increased uracils in DNA from cells expressing AID in vivo. We used several techniques to detect uracil bases in a gene that was actively transcribed in Escherichia coli cells expressing AID.

Different mutation signatures in DNA polymerase eta- and MSH6-deficient mice suggest separate roles in antibody diversification.

Hypermutation in immunoglobulin genes produces a high frequency of substitutions of all four bases, which are likely generated by low-fidelity DNA polymerases. Indeed, humans deficient for DNA polymerase (pol) eta have decreased substitutions of A.T base pairs in variable and switch regions.

A role for Msh6 but not Msh3 in somatic hypermutation and class switch recombination.

Somatic hypermutation is initiated by activation-induced cytidine deaminase (AID), and occurs in several kilobases of DNA around rearranged immunoglobulin variable (V) genes and switch (S) sites before constant genes. AID deaminates cytosine to uracil, which can produce mutations of C:G nucleotide pairs, and the mismatch repair protein Msh2 participates in generating substitutions of downstream A:T pairs. Msh2 is always found as a heterodimer with either Msh3 or Msh6, so it is important to know which one is involved.

Absence of DNA polymerase eta reveals targeting of C mutations on the nontranscribed strand in immunoglobulin switch regions.

Activation-induced cytosine deaminase preferentially deaminates C in DNA on the nontranscribed strand in vitro, which theoretically should produce a large increase in mutations of C during hypermutation of immunoglobulin genes. However, a bias for C mutations has not been observed among the mutations in variable genes. Therefore, we examined mutations in the mu and gamma switch regions, which can form stable secondary structures, to look for C mutations.