No abstract

Background: The role of the standard bronchoscope as a method of diagnosis of peripheral lung lesions is limited. Objectives: To evaluate the role of the ultrathin bronchoscope as an adjunct to standard bronchoscopy in the diagnosis of peripheral lung lesions. Methods: Seventeen consecutive patients with a peripheral lung lesion on chest radiography or chest CT. All patients underwent a bronchoscopic examination with a standard size bronchoscope, and if there was no evidence of endobronchial lesion, these patients were subsequently examined with an Olympus 3C40 ultrathin bronchoscope (external diameter of 3.6 mm). Under fluoroscopic guidance, cytological brushing samples were taken with the ultrathin bronchoscope followed by a reexamination with the standard bronchoscope which followed the same ‘pathway’ to the lesion established by the 3C40 ultrathin bronchoscope. Transbronchial biopsies (TBB) and cytological samples were taken with the standard bronchoscope. Results: The size of the lesions ranged from 1.5 to 7.0 cm. A positive bronchoscopic diagnosis by TBB was obtained in 11 out of 17 patients (64.7%) and a diagnosis of atypical cells suspicious for malignancy noted in a further 3 patients. For lesions less than 3 cm in size, a positive diagnosis by TBB was achieved in 7 out of 10 of these cases. The lesion was directly visualized with the ultrathin bronchoscope in 4 cases. Conclusions: Ultrathin bronchoscopy appears to be a useful adjunct to standard bronchoscopy by providing an accurate pathway to the lesion in question. However, further studies with larger patient groups are warranted.

Natural bisindole alkaloids such as Hyrtinadine A and Alocasin A, which are known to exhibit diverse bioactivities, provide promising chemical scaffolds for drug development. By optimizing the Masuda borylation–Suzuki coupling sequence, a library of various natural product-derived and non-natural (di)­azine-bridged bisindoles was created. While unsubstituted bisindoles were devoid of antibacterial activity, 5,5′-chloro derivatives were highly active against methicillin-resistant Staphylococcus aureus (MRSA) and further Gram-positive pathogens at minimal inhibitory concentrations ranging from 0.20 to 0.78 μM. These compounds showed strong bactericidal killing effects but only moderate cytotoxicity against human cell lines. Furthermore, the two front-runner compounds 4j and 4n exhibited potent in vivo efficacy against MRSA in a mouse wound infection model. Although structurally related bisindoles were reported to specifically target pyruvate kinase in MRSA, antibacterial activity of 4j and 4n is independent of pyruvate kinase. Rather, these compounds lead to bacterial membrane permeabilization and cellular efflux of low-molecular-weight molecules.

Due to an error in the preparation of Table 2, the figures in part B) and part C) are not in the right position. The corrected Table 2 now reads as follows:

DNA mismatch repair (MMR) is essential for correction of DNA replication errors. Germline mutations of the human MMR gene MLH1 are the major cause of Lynch syndrome, a heritable cancer predisposition. In the MLH1 protein, a non-conserved, intrinsically disordered region connects two conserved, catalytically active structured domains of MLH1. This region has as yet been regarded as a flexible spacer, and missense alterations in this region have been considered non-pathogenic. However, we have identified and investigated a small motif (ConMot) in this linker which is conserved in eukaryotes. Deletion of the ConMot or scrambling of the motif abolished mismatch repair activity. A mutation from a cancer family within the motif (p.Arg385Pro) also inactivated MMR, suggesting that ConMot alterations can be causative for Lynch syndrome. Intriguingly, the mismatch repair defect of the ConMot variants could be restored by addition of a ConMot peptide containing the deleted sequence. This is the first instance of a DNA mismatch repair defect conferred by a mutation that can be overcome by addition of a small molecule. Based on the experimental data and AlphaFold2 predictions, we suggest that the ConMot may bind close to the C-terminal MLH1-PMS2 endonuclease and modulate its activation during the MMR process.