IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis.

Rationale: Nab-paclitaxel (Abx) is widely employed in malignant tumor therapy. In tumor cells and pro-tumoral M2-type macrophages, the IL4 receptor (IL4R) is upregulated. This study aimed to elucidate the selective delivery of Abx to M2-type macrophages by targeting IL4R and reprogramming them into an anti-tumoral M1-type. Methods: Abx was conjugated with the IL4R-binding IL4RPep-1 peptide using click chemistry (IL4R-Abx). Cellular internalization, macrophage reprogramming and signal pathways, and tumor growth and metastasis by IL4R-Abx were examined. Results: IL4R-Abx was internalized into M2 macrophages more efficiently compared to the unmodified Abx and control peptide-conjugated Abx (Ctrl-Abx), which was primarily inhibited using an anti-IL4R antibody and a receptor-mediated endocytosis inhibitor compared with a macropinocytosis inhibitor. IL4R-Abx reprogrammed the M2-type macrophages into M1-like phenotype and increased reactive oxygen species (ROS) levels and extracellular release of high mobility group box 1 (HMGB1) in M2 macrophages at higher levels than Abx and Ctrl-Abx. The conditioned medium of IL4R-Abx-treated M2 macrophages skewed M2 macrophages into the M1-like phenotype, in which an anti-HMGB1 antibody and a toll-like receptor 4 (TLR4) inhibitor induced a blockade. IL4R-Abx accumulated at tumors, heightened immune-stimulatory cells while reducing immune-suppressing cells, and hampered tumor growth and metastasis in mice more efficiently than Abx and Ctrl-Abx. Conclusions: These results indicate that IL4R-targeting allows enhancement of M2-macrophage shaping into M1-like phenotype by Abx through the ROS-HMGB1-TLR4 axis, improvement of antitumor immunity, and thereby inhibition of tumor growth and metastasis, presenting a new approach to cancer immunotherapy.

Partial Venous Inflow Occlusion under Mild Hypothermia for Membranectomy in a Dog with Cor Triatriatum Dexter.

Cor triatriatum dexter (CTD) is an uncommon congenital cardiac anomaly in dogs. This case report describes successful membranectomy for CTD via partial venous inflow occlusion under mild hypothermia in a dog. A 7-month-old intact male mixed-breed dog weighing 20.5 kg presented with a history of abdominal distention, lethargy, and anorexia. Clinical examination, radiography, echocardiography, microbubble testing, and computed tomography revealed a remnant right atrium membrane obscuring the venous blood inflow from the vena cava. Considering the potential risk of re-stenosis following interventional treatment, curative resection involving surgical membranectomy via venous inflow occlusion was performed. By performing partial venous inflow occlusion under mild hypothermia (34.5 °C), sufficient time was obtained to explore the defect and resect the remnant membrane. The dog recovered without any complications, and the clinical signs were relieved. This case illustrates that partial venous inflow occlusion under mild hypothermia is feasible for achieving curative resection of cor triatriatum dexter in dogs.

GaN-Based 4-MHz Full-Bridge Electrosurgical Generator Using Zero-Voltage Switching Over Wide Load Impedance Range.

In this article, a 4-MHz full-bridge inverter system for an electrosurgical generator (ESG) is presented with zero-voltage switching (ZVS) turn-on over a wide load impedance range based on wideband gap material gallium nitride (GaN) technology. The proposed resonant circuit is used for impedance matching and limits the current when the load is short state while performing ZVS over a wide load impedance range. It also ensures high power performance at high frequencies for electric surgery. The implementation methods of the GaN switch at 4 MHz with high output performance are guided by the low inductance from the gate-driver output to the switch gate node and the effective heating management structure of the GaN-based inverter. The proposed generator achieved a maximum output power of 99 W to the load and a maximum overall efficiency of 89% with overcurrent of <3 A at short state of the load. The ESG can generate constant output power of 20, 50, 70 W through mode control of 2, 5, and 7 s. The overcurrent Moreover, the proposed generator is tested on porcine tissue samples to verify its effectiveness as an ESG.

Peptides as multifunctional players in cancer therapy.

Peptides exhibit lower affinity and a shorter half-life in the body than antibodies. Conversely, peptides demonstrate higher efficiency in tissue penetration and cell internalization than antibodies. Regardless of the pros and cons of peptides, they have been used as tumor-homing ligands for delivering carriers (such as nanoparticles, extracellular vesicles, and cells) and cargoes (such as cytotoxic peptides and radioisotopes) to tumors. Additionally, tumor-homing peptides have been conjugated with cargoes such as small-molecule or chemotherapeutic drugs via linkers to synthesize peptide-drug conjugates. In addition, peptides selectively bind to cell surface receptors and proteins, such as immune checkpoints, receptor kinases, and hormone receptors, subsequently blocking their biological activity or serving as hormone analogs. Furthermore, peptides internalized into cells bind to intracellular proteins and interfere with protein-protein interactions. Thus, peptides demonstrate great application potential as multifunctional players in cancer therapy.

Causes of death among cancer patients in the era of cancer survivorship in Korea: Attention to the suicide and cardiovascular mortality.

BACKGROUND: Improved cancer survival is expected to increase noncancer deaths; however, detailed causes of death have rarely been discussed. Changing landscapes in mortality patterns and noncancer mortality risks in patients with cancer require evaluation. METHODS: We identified cancer and noncancer-related causes of death using data from the 2000-2016 national cancer registry in Korea (n = 2 707 520), and we characterized the leading causes of death and proportionate mortalities over time. Risks of noncancer deaths relative to the general population were estimated using standardized mortality ratios (SMRs). RESULTS: Of 1 105 607 identified deaths, 87% were due to the primary cancer. Proportionate mortalities of primary cancer among overall deaths remained high in patients with liver (86%) and lung (70%) cancers and in female patients with breast cancer (77%), even 5 to 10 years following diagnosis, whereas proportionate mortalities reduced to ≤50% in patients with stomach (men, 39%; women, 48%), prostate (47%), and female thyroid (27%) cancers. Despite the predominance of index cancer deaths, the proportion of noncancer deaths among all deaths increased over time. There was a 20-fold increase in cardiovascular disease deaths among patients with cancer from 2000 to 2016, and the risk of suicide among patients with cancer was higher than that among the general population (SMR: 1.68 [95% confidence interval (CI): 1.63-1.74] in men, SMR: 1.42 [95% CI: 1.33-1.55] in women). CONCLUSIONS: Deaths from primary cancer remain a major concern; however, follow-up is required for both cancer and noncancer-related health issues in cancer survivors, especially concerning suicide and cardiovascular deaths.

Complete Chloroplast Genome of Nicotiana otophora and its Comparison with Related Species.

Nicotiana otophora is a wild parental species of Nicotiana tabacum, an interspecific hybrid of Nicotiana tomentosiformis and Nicotiana sylvestris. However, N. otophora is least understood as an alternative paternal donor. Here, we compared the fully assembled chloroplast (cp) genome of N. otophora and with those of closely related species. The analysis showed a cp genome size of 156,073 bp and exhibited a typical quadripartite structure, which contains a pair of inverted repeats separated by small and large single copies, containing 163 representative genes, with 165 microsatellites distributed unevenly throughout the genome. Comparative analysis of a gene with known function across Nicotiana species revealed 76 protein-coding sequences, 20 tRNA sequences, and 3 rRNA sequence shared between the cp genomes. The analysis revealed that N. otophora is a sister species to N. tomentosiformis within the Nicotiana genus, and Atropha belladonna and Datura stramonium are their closest relatives. These findings provide a valuable analysis of the complete N. otophora cp genome, which can identify species, elucidate taxonomy, and reconstruct the phylogeny of genus Nicotiana.

Optimal intervention strategy for prevention tuberculosis using a smoking-tuberculosis model.

In this paper, we developed a dynamic model of smoking-tuberculosis (TB) transmission in South Korea, and investigated the effects of control strategies on the number of incidence of TB using optimal control theory. Model parameters regarding TB and smoking are estimated through least-squares fitting to real data. We considered three TB controls (distancing, case-finding, and case-holding) and two smoking controls (distancing and quitting), in order to minimize the number of exposed and infectious individuals and the cost of control. Numerical simulations for the various control strategies highlight that implementing the smoking controls, not with TB controls, can effectively reduce the incidence of TB transmission.