Design,Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists

The PD-1/PD-L1 axis has proven to be a highly efficacious target for cancer immune checkpoint therapy with several approved antibodies. Also, small molecules based on a biphenyl core can antagonize PD-1/PD-L1, leading to the in vitro formation of PD-L1 dimers. However, their development remains challenging, as we do not yet fully understand their mode of action. In this work, we designed a new scaffold based on our previously solved high-resolution structures of low-molecular-weight inhibitors bound to PD-L1. A small compound library was synthesized using the Groebke–Blackburn–Bienaymé multicomponent reaction (GBB-3CR), resulting in the structure–activity relationship of imidazo[1,2-a]pyridine-based inhibitors. These inhibitors were tested for their biological activity using various biophysical assays giving potent candidates with low-micromolar PD-L1 affinities. An obtained PD-L1 cocrystal structure reveals the binding to PD-L1. Our results open the door to an interesting bioactive scaffold that could lead to a new class of PD-L1 antagonists.     

Przeszczepianie płuc u chorych na mukowiscydozę

Lung transplantation is widely recognized as the only effective treatment for patients with end-stage chronic lung disease (e.g. cystic fibrosis, interstitial lung disease, pulmonary hypertension, COPD). It gives the opportunity to extend the life of patients and to improve its quality.     

When Information CAN SAVE LIVES

In certain cases of sudden death, forensic experts may discover during an investigation or autopsy that family members of the deceased are also at risk of harm—from genetic disease, for instance. But do they have a duty to warn them? Looking at similar duties of physicians and researchers to warn third parties of risk suggests they do.     

Takotsubo Cardiomyopathy During Anti-HER2 Therapy for Metastatic Breast Cancer

Human epidermal growth factor receptor 2 (HER2)-targeted antibodies, including pertuzumab and trastuzumab, improve overall survival and progression-free survival among women with HER2-positive metastatic breast cancer, but grade ≥3 cardiotoxicity occurs in approximately 8% of cases. Here we report a case of Takotsubo cardiomyopathy associated with the use of dual anti-HER2 therapy in a 63-year-old woman who presented to the emergency department with an 8- to 10-hour history of progressive dyspnea after completing her third cycle of pertuzumab plus trastuzumab in addition to nab-paclitaxel chemotherapy. To our knowledge, this patient represents the first reported case of Takotsubo cardiomyopathy associated with pertuzumab plus trastuzumab combination therapy in the literature.     

99mTc-EDDA/HYNIC-TOC scintigraphy in the differential diagnosis of solitary pulmonary nodules

Forty-three consecutive patients with solitary pulmonary nodules (SPNs) on chest radiographs were studied scintigraphically after administration of the somatostatin analogue ^99mTc-EDDA/HYNIC-TOC. The objective of the study was to assess the usefulness of the procedure for differentiation of SPNs as malignant or benign. The administered activity was 740–925 MBq, and a single-photon emission computed tomography imaging technique was employed. Verification of the nodule aetiology was based on histology or cytology and bacteriology. A stable tumour size on chest radiography for at least 3 years was accepted as an additional criterion of benignity. In 29 patients, nodules were found to be malignant. The diagnoses included ten adenocarcinomas, five squamous cell carcinomas, two large cell carcinomas, six non-small cell lung cancers without specification of the more detailed morphology, two small cell lung cancers, two typical carcinoids and two metastatic tumours (leiomyosarcoma and malignant melanoma). In 14 patients the following benign tumours were diagnosed: four tuberculomas, one other granuloma, three hamartomas, one non-specific inflammatory infiltrate, one abscess, one peripheral carcinoid with the morphological characteristics of a benign tumour, one ectopic lesion of thyroid tissue and two benign tumours of unspecified aetiology with a stable size over 3 and 5 years respectively. Positive scintigraphic results were obtained in 26 of the 29 patients (90%) with malignant SPNs; among these, 24 of the 25 (96%) cases of primary pulmonary carcinoma yielded positive results. The remaining two false negative cases were the metastatic tumours, liposarcoma and melanoma. Of the 14 benign lesions, ten (71%) did not accumulate the radiopharmaceutical. The remaining four benign tumours that were visible on scintigrams comprised one tuberculoma, one hamartoma, one abscess and one case in which the diagnosis could not be established (the tumour had a stable size over 3 years). In conclusion, scintigraphy with ^99mTc-EDDA/HYNIC-TOC appears to be an effective procedure for differentiation between malignant and benign SPNs. A fully credible assessment of the clinical efficacy of this procedure requires further study in a larger number of patients.     

Patterns of dyslipidemia in young patients with seronegative spondyloarthropathies without cardiovascular diseases

ObjectivesPatients with seronegative spondyloarthritis (SpA) – psoriatic arthritis (PsA) and ankylosing spondylitis (AS) – have a higher risk of cardiovascular morbidity and mortality. The aim of the present study was to evaluate the incidence and type of dyslipidemia, a potent atherosclerosis risk factor, in SpA patients.Material and methodsIt was a two-center, case-control study. Patients diagnosed with PsA and AS aged 23–60 years, with disease duration < 10 years, were enrolled. The inflammatory activity, serum levels of C-reactive protein (CRP) and lipid profile were evaluated in each patient. In patients > 40 years old, the 10-year risk of fatal cardiovascular disease (CVD), using Systematic Coronary Risk Evaluation (SCORE), was estimated.ResultsIn total 79 patients with SpA were included in the study, with PsA diagnosed, n = 39 (mean age 45.1 ±9.6 years; 21, 53.9%, women), and with AS diagnosed, n = 40 (age 40.3 ±9.5; 12.3%, women), control group (CG): n = 88 (age 42.3 ±8.1; 42, 47.7% women). Based on the interview and laboratory tests, dyslipidemia was diagnosed in 19 (47.5%) patients with AS and in 28 (71.8%) patients with PsA. Most patients had hypercholesterolemia or mixed hyperlipidemia. Types of dyslipidemia were similar. In SpA patients (PsA and AS), the level of triglycerides (TG) and atherogenic index (AI) were significantly higher than in the CG, respectively TG in SpA: 116 (83–156) and in the CG: 91.2 (72.6–134.6) mg/dl, p = 0.0182; AI in SpA: 3.77 ±1.26 and in the CG: 2.58 ±1.27, p < 0.0001.The low-density cholesterol (LDL) level was significantly lower in SpA patients than in the CG, SpA: 109.1 ±29.4 vs. CG: 125.2 ±35.9 mg/dl, p = 0.0023. There was a strong negative correlation between CRP levels and HDL cholesterol levels in patients with PsA, rho = 0.42, p = 0.0132. Mean SCORE values were 2.33% in PsA patients and 2.38% in AS patients, which results in moderate 10-year risk of death from CVD.ConclusionsIn young patients with spondyloarthropathies, inflammatory factors significantly influence dyslipidemia patterns, which result in higher TG and lower LDL cholesterol levels. In patients with PsA, dyslipidemia was diagnosed more often than in patients with AS.     

Kikuchi–Fujimoto and Kimura diseases: the selected, rare causes of neck lymphadenopathy

Kikuchi–Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a benign and self-limiting disease typically characterized by the enlargement of regional lymph nodes and accompanied by fever. KFD affects predominantly young adult females of Asian origin and is rarely seen in European countries, where it may cause diagnostic difficulties. Kimura disease is a rare and benign chronic inflammatory soft tissue disorder of unknown origin, characterized by a triad of painless subcutaneous masses in the head or neck region accompanied by regional lymphadenopathy, blood and tissue eosinophilia, and markedly elevated serum immunoglobulin E levels. Although most cases of Kimura disease have originated in China, Japan or Southeast Asia, there have been sporadic case reports from Europe and America. Herein, we review in detail the clinical presentations, complications and current concepts in the pathogenesis, diagnosis and treatment of these diseases.