Delivery of small interfering ribonucleic acid using lipid nanoparticles prepared with pH-responsive dipeptide-conjugated lipids.

The development of lipid nanoparticles (LNPs) has enabled the clinical application of small interfering ribonucleic acid (siRNA)-based therapies. Accordingly, various unique ionizable lipids have been explored for efficient siRNA delivery. However, safety concerns related to the structure of ionizable lipids have been raised. Here, we developed a pH-responsive dipeptide-conjugated lipid (DPL) for efficient, high safety siRNA delivery. We synthesized a DPL library by varying the dipeptide sequence and established a strong correlation between the knockdown efficiency of the DPL-based LNPs and the dipeptide sequence. The LNPs prepared with a DPL containing arginine (R) and glutamic acid (E) (DPL-ER) exhibited the highest knockdown efficiency. In addition, the DPL-ER-based LNPs with relatively long lipid tails (DPL-ER-C22:C22) exhibited a higher knockdown efficiency than those with short ones (DPL-ER-18:C18). The zeta potential of the DPL-ER-C22:C22-based LNPs increased as the pH decreased from 7.4 (physiological condition) to 5.5 (endosomal condition). Importantly, the DPL-ER-C22:C22-based LNPs exhibited a higher knockdown efficiency than the LNPs prepared using commercially available ionizable lipids. These results suggest that the DPL-based LNPs are safe and efficient siRNA delivery carriers.

Sensitivity of endoscopic ultrasound-guided fine-needle aspiration cytology and biopsy for a diagnosis of pancreatic ductal adenocarcinoma: A comparative analysis.

The utility of endoscopic ultrasound fine-needle aspiration cytology (EUS-FNAC) or endoscopic ultrasound fine-needle aspiration biopsy (EUS-FNAB) for diagnosis of small and large pancreatic ductal adenocarcinomas (PDACs) remains in question. We addressed this by analyzing 97 definitively diagnosed cases of PDAC, for which both EUS-FNAC and EUS-FNAB had been performed. We subclassified the 97 solid masses into small (n = 35) or large (n = 62) according to the maximum tumor diameter (<24 mm or ≥24 mm) and compared the diagnostic sensitivity (truly positive rate) of EUS-FNAC and of EUS-FNAB for small and large masses. Diagnostic sensitivity of EUS-FNAC did not differ between large and small masses (79.0% vs. 60.0%; p = 0.0763). However, the diagnostic sensitivity of EUS-FNAB was significantly higher for large masses (85.5% vs. 62.9%; p = 0.0213). Accurate EUS-FNAC-based diagnosis appeared to depend on the degree of cytological atypia of cancer cells, which was not associated with quantity of cancer cells. The accuracy of EUS-FNAB-based diagnosis appeared to depend on cancer cell viability in large masses and cancer volume in small masses. Based on the advantages or disadvantages in each modality, both modalities play an important role in the qualitative diagnosis of PDAC as a complementary procedure.

Subserosal Layer and/or Pancreatic Invasion Based on Anatomical Features as a Novel Prognostic Indicator in Patients with Distal Cholangiocarcinoma.

The American Joint Committee on Cancer (AJCC) 8th edition T-staging system for distal cholangiocarcinoma (DCC) proposes classification according to the depth of invasion (DOI); nevertheless, DOI measurement is complex and irreproducible. This study focused on the fibromuscular layer and evaluated whether the presence or absence of penetrating fibromuscular invasion of DCC contributes to recurrence and prognosis. In total, 55 patients pathologically diagnosed with DCC who underwent surgical resection from 2002 to 2022 were clinicopathologically examined. Subserosal layer and/or pancreatic (SS/Panc) invasion, defined as penetration of the fibromuscular layer and invasion of the subserosal layer or pancreas by the cancer, was assessed with other clinicopathological prognostic factors to investigate recurrence and prognostic factors. According to the AJCC 8th edition, there were 11 T1, 28 T2, and 16 T3 cases, with 44 (80%) cases of SS/Panc invasion. The DOI was not significantly different for both recurrence and prognostic factors. In the multivariate analysis, only SS/Panc was identified as an independent factor for prognosis (hazard ratio: 16.1; 95% confidence interval: 2.1-118.8, p = 0.006). In conclusion, while the determination of DOI in DCC does not accurately reflect recurrence and prognosis, the presence of SS/Panc invasion may contribute to the T-staging system.

Alteration of a motor learning rule under mirror-reversal transformation does not depend on the amplitude of visual error.

Human's sophisticated motor learning system paradoxically interferes with motor performance when visual information is mirror-reversed (MR), because normal movement error correction further aggravates the error. This error-increasing mechanism makes performing even a simple reaching task difficult, but is overcome by alterations in the error correction rule during the trials. To isolate factors that trigger learners to change the error correction rule, we manipulated the gain of visual angular errors when participants made arm-reaching movements with mirror-reversed visual feedback, and compared the rule alteration timing between groups with normal or reduced gain. Trial-by-trial changes in the visual angular error was tracked to explain the timing of the change in the error correction rule. Under both gain conditions, visual angular errors increased under the MR transformation, and suddenly decreased after 3-5 trials with increase. The increase became degressive at different amplitude between the two groups, nearly proportional to the visual gain. The findings suggest that the alteration of the error-correction rule is not dependent on the amplitude of visual angular errors, and possibly determined by the number of trials over which the errors increased or statistical property of the environment. The current results encourage future intensive studies focusing on the exact rule-change mechanism.