Gastrointestinal tract metastasis of lung cancer: The PD-L1 expression and correlated clinicopathological variables

The gastrointestinal tract is a rare site for metastatic lung cancer. Programmed cell death-ligand 1 (PD-L1) expression in lung cancer is a biomarker for the response to anti-PD-1/PD-L1 therapy. We investigated clinicopathological features and PD-L1 expression in 25 gastrointestinal metastatic tumors from the lung and primary adenocarcinoma of the small bowel. The small bowel was the most common site (16/25; 64%) of gastrointestinal tract lung cancer metastasis. A total of 19 (76%) of the gastrointestinal metastasis showed PD-L1 expression in ≥5% of tumor cells, with 14 (56%) showing high expression levels (≥50%). In contrast, 21 (84%) expressed PD-L1 in ≥5% immune cells, including 4 (16%) showing a high expression levels (≥50%). The PD-L1 expression on tumor cells and immune cells in primary lung cancer and corresponding gastrointestinal metastasis was concordant in 13 (68%) and 11 (58%) of the 19 paired cases, respectively. Small-bowel metastasis of lung cancer was characterized by a higher incidence of perforation (31% vs. 0%), ulcerated mass (83% vs. 60%), and neoplastic PD-L1 expression (75% vs. 0%) compared to primary small-bowel adenocarcinoma. Gastrointestinal metastasis from lung cancer might be a potential target for immune checkpoint inhibitor therapy, given its high expression of PD-L1.     

Streamlined human antibody generation and optimization by exploiting designed immunoglobulin loci in a B cell line

Monoclonal antibodies (mAbs) are widely utilized as therapeutic drugs for various diseases, such as cancer, autoimmune diseases, and infectious diseases. Using the avian-derived B cell line DT40, we previously developed an antibody display technology, namely, the ADLib system, which rapidly generates antigen-specific mAbs. Here, we report the development of a human version of the ADLib system and showcase the streamlined generation and optimization of functional human mAbs. Tailored libraries were first constructed by replacing endogenous immunoglobulin genes with designed human counterparts. From these libraries, clones producing full-length human IgGs against distinct antigens can be isolated, as exemplified by the selection of antagonistic mAbs. Taking advantage of avian biology, effective affinity maturation was achieved in a straightforward manner by seamless diversification of the parental clones into secondary libraries followed by single-cell sorting, quickly affording mAbs with improved affinities and functionalities. Collectively, we demonstrate that the human ADLib system could serve as an integrative platform with unique diversity for rapid de novo generation and optimization of therapeutic or diagnostic antibody leads. Furthermore, our results suggest that libraries can be constructed by introducing exogenous genes into DT40 cells, indicating that the ADLib system has the potential to be applied for the rapid and effective directed evolution and optimization of proteins in various fields beyond biomedicine.     

Bone mineral density evaluation of patients with type 2 diabetes mellitus

[Purpose] Diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion, insulin action, or both. A consequence of this is chronic hyperglycemia with disturbances in carbohydrate, fat and protein metabolism. We investigated whether there is any difference among DM patients and a control group in terms of lumbar and femur BMD (bone mineral density), and standard deviation scores (Z score and T score). [Subjects and Methods] This randomized, prospective, controlled, single-blind study was conducted in the Physical Medicine and Rehabilitation Department Faculty of Medicine, Bezm-i Alem Vakıf University. Patients with type 2 diabetes mellitus were included in the patient groups. Healthy individuals were included in the control group. [Results] A total of 126 patients completed the study (63 in the study group, 63 in the control group). There was no significant difference in the results of the laboratory examinations of the cases. The bone mineral densities of the cases were found to be significantly low in terms of the lumbar (L1–4) T scores in the type 2 diabetes group. [Conclusion] Although osteoporosis is one of the potential complications of type 1 diabetes, its effect on bone mineral density in type 2 DM is controversial. In different studies, the bone mineral density values have increased, decreased or remained normal. With the exception of the lumbar (L1–4) T score, similar results were obtained in this study.Key words: Type 2 diabetes mellitus, Osteoporosis, Bone mineral density     

Susceptibility of muridae cell lines to ecotropic murine leukemia virus and the cationic amino acid transporter 1 viral receptor sequences: implications for evolution of the viral receptor

Ecotropic murine leukemia viruses (Eco-MLVs) infect mouse and rat, but not other mammalian cells, and gain access for infection through binding the cationic amino acid transporter 1 (CAT1). Glycosylation of the rat and hamster CAT1s inhibits Eco-MLV infection, and treatment of rat and hamster cells with a glycosylation inhibitor, tunicamycin, enhances Eco-MLV infection. Although the mouse CAT1 is also glycosylated, it does not inhibit Eco-MLV infection. Comparison of amino acid sequences between the rat and mouse CAT1s shows amino acid insertions in the rat protein near the Eco-MLV-binding motif. In addition to the insertion present in the rat CAT1, the hamster CAT1 has additional amino acid insertions. In contrast, tunicamycin treatment of mink and human cells does not elevate the infection, because their CAT1s do not have the Eco-MLV-binding motif. To define the evolutionary pathway of the Eco-MLV receptor, we analyzed CAT1 sequences and susceptibility to Eco-MLV infection of other several murinae animals, including the southern vole (Microtus rossiaemeridionalis), large Japanese field mouse (Apodemus speciosus), and Eurasian harvest mouse (Micromys minutus). Eco-MLV infection was enhanced by tunicamycin in these cells, and their CAT1 sequences have the insertions like the hamster CAT1. Phylogenetic analysis of mammalian CAT1s suggested that the ancestral CAT1 does not have the Eco-MLV-binding motif, like the human CAT1, and the mouse CAT1 is thought to be generated by the amino acid deletions in the third extracellular loop of CAT1.     

The fifth neurohypophysial hormone receptor is structurally related to the V2-type receptor but functionally similar to V1-type receptors

The neurohypophysial peptides of the vasopressin (VP) and oxytocin (OT) families regulate salt and water homeostasis and reproduction through distinct G protein-coupled receptors. The current thinking is that there are four neurohypophysial hormone receptors (V1aR, V1bR, V2R, and OTR) in vertebrates, and their evolutionary history is still debated. We report the identification of a fifth neurohypophysial hormone receptor (V2bR) from the holocephalan elephant fish. This receptor is similar to conventional V2R (V2aR) in sequence, but induced Ca(2+) signaling in response to vasotocin (VT), the non-mammalian VP ortholog; such signaling is typical of V1-type receptors. In addition, V1aR, V1bR and OTR were also isolated from the elephant fish. Further screening revealed that orthologous V2bRs are widely distributed throughout the jawed vertebrates, and that the V2bR family is subdivided into two subfamilies: the fish specific type-1, and a type-2 that is characteristically found in tetrapods. Analysis suggested that the mammalian V2bR may have lost its function. Based on molecular phylogenetic, synteny and functional analyses, we propose a new evolutionary history for the neurohypophysial hormone receptors in vertebrates as follows: the first duplication generated V1aR/V1bR/OTR and V2aR/V2bR lineages; after divergence from the V2bR lineage, the V2aRs evolved to use cAMP as a second messenger, while the V2bRs retained the original Ca(2+) signaling system. Future studies on the role of V2bR in the brain, heart, kidney and reproductive organs, in which it is highly expressed, will open a new research field in VP/VT physiology and evolution.