Preoperative Short-Course Radiotherapy and Surgery versus Surgery Alone for Patients with Rectal Cancer: A Propensity Score-Matched Analysis at 18-Year Follow-Up.

A significant problem for long-term rectal cancer survivors may be the late toxicity of radiotherapy. It creates the possible risk of developing second primary malignancy and a theoretical decrease in overall survival. This study aimed to assess the influence of short-course preoperative radiotherapy in patients with locally advanced rectal cancer on overall survival, local recurrence rate, and second malignancy at 18-year follow-up. The rectal cancer trial was conducted in a single tertiary center between February 1992 and June 2006. A total of 389 patients with locally advanced rectal cancer (cT2-cT4, cN0/+, cM0) were included in the study. Preoperative radiotherapy was conducted in 148 patients and 241 patients underwent surgery alone. The propensity-matched group consisted of 105 patients operated on after radiotherapy and 105 controls. The number of local recurrences was 7 (6.7%) in the preoperative radiotherapy group and 22 (21%) in the surgery alone group (p = 0.016). The 18-year survival analysis showed no survival benefit in the preoperative radiotherapy group (38% versus 48%, p = 0.107) but improved recurrence-free survival (81% versus 58%, p = 0.001). The preoperative short-course radiotherapy significantly decreases the risk of local recurrence in locally advanced rectal cancer and may improve recurrence-free survival without an increased risk of second primary malignancy.

SARS-CoV-2: Pathogenesis, and Advancements in Diagnostics and Treatment.

The emergence and rapid spread of SARS-CoV-2 in December 2019 has brought the world to a standstill. While less pathogenic than the 2002-2003 SARS-CoV, this novel betacoronavirus presents a global threat due to its high transmission rate, ability to invade multiple tissues, and ability to trigger immunological hyperactivation. The identification of the animal reservoir and intermediate host were important steps toward slowing the spread of disease, and its genetic similarity to SARS-CoV has helped to determine pathogenesis and direct treatment strategies. The exponential increase in cases has necessitated fast and reliable testing procedures. Although RT-PCR remains the gold standard, it is a time-consuming procedure, paving the way for newer techniques such as serologic tests and enzyme immunoassays. Various clinical trials using broad antiviral agents in addition to novel medications have produced controversial results; however, the advancement of immunotherapy, particularly monoclonal antibodies and immune modulators is showing great promise in clinical trials. Non-orthodox medications such as anti-malarials have been tested in multiple institutions but definitive conclusions are yet to be made. Adjuvant therapies have also proven to be effective in decreasing mortality in the disease course. While no formal guidelines have been established, the multitude of ongoing clinical trials as a result of unprecedented access to research data brings us closer to halting the SARS-CoV-2 pandemic.

Phosphorylation Alters the Residual Structure and Interactions of the Regulatory L1 Linker Connecting NBD1 to the Membrane-Bound Domain in SUR2B.

ATP-sensitive potassium (KATP) channels in vascular smooth muscle are comprised of four pore-forming Kir6.1 subunits and four copies of the sulfonylurea receptor 2B (SUR2B), which acts as a regulator of channel gating. Recent electron cryo-microscopy (cryo-EM) structures of the pancreatic KATP channel show a central Kir6.2 pore that is surrounded by the SUR1 subunits. Mutations in the L1 linker connecting the first membrane-spanning domain and the first nucleotide binding domain (NBD1) in SUR2B cause cardiac disease; however, this part of the protein is not resolved in the cryo-EM structures. Phosphorylation of the L1 linker, by protein kinase A, disrupts its interactions with NBD1, which increases the MgATP affinity of NBD1 and KATP channel gating. To elucidate the mode by which the L1 linker regulates KATP channels, we have probed the effects of phosphorylation on its structure and interactions using nuclear magnetic resonance (NMR) spectroscopy and other techniques. We demonstrate that the L1 linker is an intrinsically disordered region of SUR2B but possesses residual secondary and compact structure, both of which are disrupted with phosphorylation. NMR binding studies demonstrate that phosphorylation alters the mode by which the L1 linker interacts with NBD1. The data show that L1 linker residues with the greatest α-helical propensity also form the most stable interaction with NBD1, highlighting a hot spot within the L1 linker. This hot spot is the site of disease-causing mutations and is associated with other processes that regulate KATP channel gating. These data provide insights into the mode by which the phospho-regulatory L1 linker regulates KATP channels.