Harnessing the Intrinsic Photochemistry of Isoxazoles for the Development of Chemoproteomic Crosslinking Methods

Photo-crosslinking is a powerful technique for identifying both coarse- and fine-grained information on protein binding by small molecules. However, the scope of useful functional groups remains limited, with most studies focusing on diazirine, aryl azide, or benzophenone-containing molecules. Here, we report a unique method for photo-crosslinking, employing the intrinsic photochemistry of the isoxazole, a common heterocycle in medicinal chemistry, to offer an alternative to existing strategies using more perturbing, extrinsic crosslinkers. In this initial report, this technique is applied both in vitro and ex vivo, used in a variety of common chemoproteomic workflows, and validated across multiple proteins, demonstrating the utility of isoxazole photo-crosslinking in a wide range of biologically relevant experiments.

Monocyte-to-Lymphocyte Ratio as a Predictor of Worse Long-Term Survival after Off-Pump Surgical Revascularization-Initial Report

Background and objective: Coronary artery disease is one of the leading causes of deaths nowadays and the trends in diagnosis and revascularization are still in plateau despite well-known factors. Simple whole blood count parameters may be used to measure inflammatory reactions that are involved in processes of atherosclerosis progression. The aim of our study was to analyse the association between simply available hematologic indices and long-term mortality following off-pump coronary artery bypass grafting (OPCAB). Material and Methods: The study group comprised 129 consecutive patients (16 females and 113 males, mean age 66 ± 6 years) who underwent surgical revascularization with off-pump technique between January 2014 and September 2019. The mean follow-up was 4.7 +/−1.9 years. A receiver operating characteristics curve was applied to estimate demographical and perioperative parameters including MLR for mortality. Results: Cox regression analysis revealed chronic pulmonary obstructive disease (HR = 2.86, 95%CI 1.05–7.78), MLR (HR = 3.81, 95%CI 1.45–10.06) and right coronary artery blood flow (HR = 1.06, 95%CI 1.00–1.10) as significant factors predicting increased mortality risk. In the presented model, the MLR > 1.44 on 1st postoperative day was a significant predictor of late mortality after the OPCAB procedure (HR = 3.82, 95%CI 1.45–10.06). Conclusions: Pronounced inflammatory reaction after off-pump surgery measured by MLR > 1.44 can be regarded as a worse long-term prognostic factor.

Recurrent de novo pathogenic variant of WASF1 in a Japanese patient with neurodevelopmental disorder with absent language and variable seizures

A recurrent de novo pathogenic variant of WASF1, NM_003931:c.1516C>T [p.Arg506*], was identified in a 6-year-old female Japanese patient with severe developmental delay, hypotonia, hyperkinetic behavior, and distinctive facial features. The initial report of five adult patients with WASF1 variants was the only previous report regarding variants of this gene; this is the second such report, reaffirming that rare but recurrent truncating variants of WASF1 are associated with severe neurodevelopmental disorders.

Deep Learning Plus Three-Dimensional Printing in the Management of Giant (>15 cm) Sporadic Renal Angiomyolipoma: An Initial Report

ObjectiveTo evaluate the feasibility and effectivity of deep learning (DL) plus three-dimensional (3D) printing in the management of giant sporadic renal angiomyolipoma (RAML).MethodsThe medical records of patients with giant (>15 cm) RAML were retrospectively reviewed from January 2011 to December 2020. 3D visualized and printed kidney models were performed by DL algorithms and 3D printing technology, respectively. Patient demographics and intra- and postoperative outcomes were compared between those with 3D-assisted surgery (3D group) or routine ones (control group).ResultsAmong 372 sporadic RAML patients, 31 with giant ones were eligible for analysis. The median age was 40.6 (18–70) years old, and the median tumor size was 18.2 (15–28) cm. Seventeen of 31 (54.8%) had a surgical kidney removal. Overall, 11 underwent 3D-assisted surgeries and 20 underwent routine ones. A significant higher success rate of partial nephrectomy (PN) was noted in the 3D group (72.7% vs. 30.0%). Patients in the 3D group presented a lower reduction in renal function but experienced a longer operation time, a greater estimated blood loss, and a higher postoperative morbidity. Subgroup analysis was conducted between patients undergoing PN with or without 3D assistance. Despite no significant difference, patients with 3D-assisted PN had a slightly larger tumor size and higher nephrectomy score, possibly contributing to a relatively higher rate of complications. However, 3D-assisted PN lead to a shorter warm ischemia time and a lower renal function loss without significant difference. Another subgroup analysis between patients under 3D-assisted PN or 3D-assisted RN showed no statistically significant difference. However, the nearness of tumor to the second branch of renal artery was relatively shorter in 3D-assisted PN subgroup than that in 3D-assisted RN subgroup, and the difference between them was close to significant.Conclusions3D visualized and printed kidney models appear to be additional tools to assist operational management and avoid a high rate of kidney removal for giant sporadic RAMLs.

Frequency and Survival of T-Cell Lymphomas in Peru: Initial Report of a Peruvian Registry Experience

Introduction: T-cell lymphomas are a relatively rare and heterogeneous group of lymphoid neoplasms. Its incidence relies on viral infections incidence as Human T-cell lymphotropic virus type I-II (HTLV-I/II) and Ebstein Bar virus (EBV). Specifically, these viruses have a significantly higher incidence in Latin-American populations. Our objective was to calculate the incidence and survival of T-cell lymphomas in the largest Peruvian population based on a national registry. Methods: We conducted a multicenter, retrospective registry study of non-Hodgkin T cell lymphoma. The data was extracted from Instituto Nacional de Enfermedades Neoplasicas and Oncosalud-AUNA, Lima-Peru, from January 2010 to December 2019, a total of 948 patients who were diagnosed as mature T cell non-Hodgkin lymphoma based on the World Health Organization Classification 2008 were enrolled. T-lymphoblastic lymphoma/leukemia was excluded. Overall survival was calculated based on death dates from the Peruvian national identification registry (RENIEC). Results: The median age was 51 years (range, 1-94), and male and female patients were 512 (54%) and 436 (46%). Among the 948 patients enrolled, Peripheral T-cell lymphoma was the common neoplasm accounting for 23% (n=221), and Extra-Nodal NK T-lymphoma (22%, n=213), Adult T-cell lymphoma (22%, n=205), Anaplasic Large cell lymphoma (14%, n=131), Cutaneous T-cell lymphoma (14%, n=129) (Figure 1a). At the time of diagnosis, extranodal disease was found in 68.6% (650) of patients. By July 2021, only 15.3% of cases were in remission and 37% (350) were alive. Median global overall survival of T-cell lymphomas was 1 year (0.8-1.1), Cutaneous T-cell lymphoma had the highest survival and Adult T-cell lymphoma had the lowest survival (Table 1 and Figure 1b). Conclusion: This initial report shows a relatively high frequency of mature T-cell lymphomas in Latin-America real-world setting, and confirms that T-cell lymphomas patients had a dismal outcome. The clinical outcome for patients with T-cell lymphomas subtypes is poor with standard therapies, and novel agents and new modalities are needed to improve survival. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Population Based Mean Vitamin-D Levels In 19 European Countries & COVID-19 Mortality

Background: Reports early in the epidemic linking low mean national Vitamin D level with increased COVID-19 death, and until recently little research on the impact of Vitamin-D deficiency on severity of COVID-19, led to this update of the initial report studying mortality up to the end of January 2021. Methods: Coronavirus pandemic data for 19 European countries were downloaded from Our World in Data, which was last updated on January 24, 2021. Data from March 21, 2020 to January 22, 2021 were included in the statistical analysis. Vitamin-D (25)-HD mean data were collected by literature review. Poisson mixed-effect model was used to model the data. Results: European countries with Vitamin-D (25)-HD mean less than or equal to 50 have higher COVID-19 death rates as compared with European countries with Vitamin-D (25)-HD mean greater than 50, relative risk of 2.155 (95% CI: 1.068 - 4.347, p-value = 0.032). A statistically significant negative moderate Spearman rank correlation was observed between Vitamin-D (25)-HD mean and the number of COVID-19 deaths for each 14-day period during the COVID-19 pandemic time period. Conclusions: The observation of the significantly lower COVID-19 mortality rates in countries with lowest annual sun exposure but highest mean Vitamin-D (25)-HD levels provides support for the use of food fortification. The need to consider re-configuring vaccine strategy due to emergence of large number of COVID-19 variants provides an opportunity to undertake such therapeutic randomized control trials.

Biophysical characterisation of SMALPs

Membrane proteins such as receptors, ion channels and transport proteins are important drug targets. The structure-based study of membrane proteins is challenging, especially when the target protein contains both soluble and insoluble domains. Most membrane proteins are insoluble in aqueous solvent and embedded in the plasma membrane lipid bilayer, which significantly complicates biophysical studies. Poly(styrene-co-maleic acid) (SMA) and other polymer derivatives are increasingly common solubilisation agents, used to isolate membrane proteins stabilised in their native lipid environment in the total absence of detergent. Since the initial report of SMA-mediated solubilisation, and the formation of SMA lipid particles (SMALPs), this technique can directly isolate therapeutic targets from biological membranes, including G-protein coupled receptors (GPCRs). SMA now allows biophysical and structural analyses of membrane proteins in solution that was not previously possible. Here, we critically review several existing biophysical techniques compatible with SMALPs, with a focus on hydrodynamic analysis, microcalorimetric analysis and optical spectroscopic techniques.