Effect of molecular structure on membrane diffusion: Triphenylmethanes across Escherichia coli studied by second harmonic light scattering.

Understanding how the structure of molecules affects their permeability across cell membranes is crucial for many topics in biomedical research, including the development of drugs. In this work, we examine the transport rates of structurally similar triphenylmethane dyes, malachite green (MG) and brilliant green (BG), across the membranes of living Escherichia coli (E. coli) cells and biomimetic liposomes. Using the time-resolved second harmonic light scattering technique, we found that BG passively diffuses across the E. coli cytoplasmic membrane (CM) 3.8 times faster than MG. In addition, BG exhibits a diffusion rate 3.1 times higher than MG across the membranes of liposomes made from E. coli polar lipid extracts. Measurements on these two molecules, alongside previously studied crystal violet (CV), another triphenylmethane molecule, are compared against the set of propensity rules developed by Lipinski and co-workers for assessing the permeability of hydrophobic ion-like drug molecules through biomembranes. It indicates that BG's increased diffusion rate is due to its higher lipophilicity, with a distribution coefficient 25 times greater than MG. In contrast, CV, despite having similar lipophilicity to MG, shows negligible permeation through the E. coli CM on the observation scale, attributed to its more hydrogen bonding sites and larger polar surface area. Importantly, cell viability tests revealed that BG's antimicrobial efficacy is ∼2.4 times greater than that of MG, which aligns well with its enhanced diffusion into the E. coli cytosol. These findings offer valuable insights for drug design and development, especially for improving the permeability of poorly permeable drug molecules.

Paclitaxel liposome for injection (Lipusu) plus cisplatin versus gemcitabine plus cisplatin in the first-line treatment of locally advanced or metastatic lung squamous cell carcinoma: A multicenter, randomized, open-label, parallel controlled clinical study.

BACKGROUND: Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small-scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first-line treatment in locally advanced or metastatic LSCC. METHODS: Patients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45-Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses. RESULTS: The median duration of follow-up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF-α, IFN-γ, IL-6, and IL-8, demonstrating an overlapping trend. CONCLUSION: The LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.

The Initiation of Swallowing Can Indicate the Prognosis of Disorders of Consciousness: A Self-Controlled Study.

Objective: To detect the initiation of swallowing in patients with disorders of consciousness (DOC) as well as the relationship between the initiation of swallowing and the prognosis of DOC patients. Methods: Nineteen DOC patients were included in this study, and a self-controlled trial compared five different stimuli. The five different stimuli were as follows: (1) one command, as recommended by the Coma Recovery Scale-Revised (CRS-R), which was "open your mouth"; (2) placing a spoon in front of the patient's mouth without a command; (3) placing a spoon filled with water in front of the patient's mouth without a command; (4) one command-"there is a spoon; open your mouth"-with a spoon in front of the patient's mouth; (5) one command, "there is a spoon with water; open your mouth," with a spoon filled with water in front of the patient's mouth. All 19 patients were given these five stimuli randomly, and any one of the commands was presented four times to a patient, one at a time, at 15-s intervals. The sensitivity and specificity of the initiation of swallowing in detecting conscious awareness were determined. Results: None of the patients responded to the first four stimuli. However, six patients showed initiated swallowing toward the fifth stimulus. Among those six, five patients showed improvement in their consciousness state 6 months later. The sensitivity and specificity of the initiation of swallowing for DOC patients was 83.33% [95% CIs (36%, 100%)] and 92.31% [95% CIs (64%, 100%)], respectively. Conclusions: The initiation of swallowing can be an early indication of conscious behavior and can likely provide evidence of conscious awareness. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03508336; Date of registration: 2018/4/16.

Long-acting and broad-spectrum antimicrobial electrospun poly (ε-caprolactone)/gelatin micro/nanofibers for wound dressing.

Trimethoxysilylpropyl octadecyldimethyl ammonium chloride (QAS), which forms facile bonds with hydroxyl groups, acts asa cationic antibacterial agent. In this work, QAS was introduced into a polycaprolactone (PCL)/gelatin hybrid in increasing concentrations to fabricate a long-acting and broad-spectrum antimicrobial micro/nanofiber membrane as a novel wound dressing. The physical interactions and chemical bonding between QAS/PCL and QAS/gelatin were demonstrated by infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS. Measured water contact angle between the PCL-gelatin/QAS (PG-Q) nanofiber membranes suggested a hydrophobic surface, which has been shown to aid in removal of wound dressings. The mechanical strength of the membranes was sufficient to meet the clinical requirements. Furthermore, the 15% QAS (PG-Q15) and 20% QAS (PG-Q20) formulated nanofiber membranes showed a considerable increase in their bacteriostatic activity towards Staphylococcus aureus (gram-positive) and Pseudomonas aeruginosa (gram-negative) bacteria, suggesting a broad-spectrum bactericidal effect by the PG-Q membranes. The PG-Q membranes with various QAS formulations demonstrated little cytotoxicity. Therefore, the long-acting and broad-spectrum antimicrobial electrospun PG-Q micro/nanofibers membrane demonstrate potential efficacy asan antibacterial wound dressing.

[CLINICAL APPLICATION OF NASOLABIAL ISLAND PEDICLED FLAP FOR REPAIRING MOUTH FLOOR DEFECTS].

OBJECTIVE: To investigate the effectiveness of nasolabial island pedicled flap in repairing mouth floor defects. METHODS: Between July 2010 and July 2013, 13 cases of mouth floor defects were repaired with nasolabial island pedicled flap. There were 7 males and 6 females, aged 36-73 years (mean, 58 years). Defects were caused by lesion resection, including 4 cases of leukoplakias, 2 cases of erythema, 1 case of mucoepidermoid carcinoma, 2 cases of the month floor cancer, and 4 cases of tongue cancer. The locations of defects were the mouth floor in 5 cases, the mouth floor and tongue body in 6 cases, and the mouth floor and gingival in 2 cases; the mucosa and submucosa were involved in 6 cases, and the sublingual gland, tongue muscle or alveolar process in 7 cases. The size of defect was 1-4 cm. The size of the flaps ranged from 4.5 cm x 2.0 cm to 6.5 cm x 3.5 cm. RESULTS: The operation was successfully performed in all patients; the flaps survived; and the primary healing of incisions at donor site and recipient site were obtained. Thirteen patients were followed up 5-24 months (mean, 11 months). No tumor recurrence was observed; the patients had normal functions of eating, swallowing, and speech. The facial appearance was satisfactory. No obvious deformity was observed at donor sites. CONCLUSION: The nasolabial island pedicled flap is fit for repairing small or middle sized defects of the mouth floor, and it has the advantages of flexible flap transplantation, less injury at donor site, easy operation, and high flap survival rate.

[Submandibular sialoadenectomy by a modified retroauricular approach].

OBJECTIVE: To evaluate the efficacy and the surgical procedures of submandibular sialoadenectomy by a modified retroauricular approach. METHODS: Between October 2008 and April 2009, 8 patients with benign submandibular gland disorders underwent removal of benign submandibular gland lesions using a retroauricular approach. There were 4 males and 4 females with an average age of 38.5 years (range, 32-54 years), including 3 pleomorphic adenoma and 5 chronic sialadenitis with sialolithiasis. The disease duration was from 2 months to 5 years. The anterior facial vein and the facial artery were reserved only by the ligation of branching vessels in the submandibular gland. RESULTS: Submandibular sialoadenectomy were successfully performed in 8 cases. The operative time was 45-75 minutes (mean, 60 minutes). All incisions obtained healing by first intention. No nerve paralysis occurred, including marginal mandibular branch of the facial nerve, the lingual nerve, and hypoglossal nerve. One patient had poor blood circulation of flap due to excessive traction during operation, but it returned normal after 24 hours without special treatment. Other flaps had good blood circulation. All patients were followed up 1-6 months (mean, 3 months). The incision scars were hidden with satisfactory appearance. CONCLUSION: The modified retroauricular approach has some advantages such as simple operation, better cosmetic outcome, and no complication.