Minimizing higher-order aggregation maximizes iron mobilization by small molecules.

The natural product hinokitiol mobilizes iron across lipid bilayers at low concentrations and restores hemoglobinization in iron transporter protein-deficient systems. But hinokitiol fails to similarly mobilize iron at higher concentrations, limiting its uses in chemical biology and medicine. Here we show that at higher concentrations, hinokitiol3:Fe(III) complexes form large, higher-order aggregates, leading to loss of transmembrane iron mobilization. Guided by this understanding and systematic structure-function studies enabled by modular synthesis, we identified FeM-1269, which minimally aggregates and dose-dependently mobilizes iron across lipid bilayers even at very high concentrations. In contrast to hinokitiol, FeM-1269 is also well-tolerated in animals at high doses for extended periods of time. In a mouse model of anemia of inflammation, FeM-1269 increases serum iron, transferrin saturation, hemoglobin and hematocrit. This rationally developed iron-mobilizing small molecule has enhanced potential as a molecular prosthetic for understanding and potentially treating iron transporter deficiencies.

Evaluation of the anti-cancer efficacy of lipid nanoparticles containing siRNA against HPV16 E6/E7 combined with cisplatin in a xenograft model of cervical cancer.

OBJECTIVE: To investigate the anti-cancer efficacy of ENB101-LNP, an ionizable lipid nanoparticles (LNPs) encapsulating siRNA against E6/E7 of HPV 16, in combination therapy with cisplatin in cervical cancer in vitro and in vivo. METHODS: CaSki cells were treated with ENB101-LNP, cisplatin, or combination. Cell viability assessed the cytotoxicity of the treatment. HPV16 E6/E7 gene knockdown was verified with RT-PCR both in vitro and in vivo. HLA class I and PD-L1 were checked by flow cytometry. A xenograft model was made using CaSki cells in BALB/c nude mice. To evaluate anticancer efficacy, mice were grouped. ENB101-LNP was given three times weekly for 3 weeks intravenously, and cisplatin was given once weekly intraperitoneally. Tumor growth was monitored. On day 25, mice were euthanized; tumors were collected, weighed, and imaged. Tumor samples were analyzed through histopathology, immunostaining, and western blot. RESULTS: ENB101-LNP and cisplatin synergistically inhibit CaSki cell growth. The combination reduces HPV 16 E6/E7 mRNA and boosts p21 mRNA, p53, p21, and HLA class I proteins. In mice, the treatment significantly blocked tumor growth and promoted apoptosis. Tumor inhibition rates were 29.7% (1 mpk ENB101-LNP), 29.6% (3 mpk), 34.0% (cisplatin), 47.0% (1 mpk ENB101-LNP-cisplatin), and 68.8% (3 mpk ENB101-LNP-cisplatin). RT-PCR confirmed up to 80% knockdown of HPV16 E6/E7 in the ENB101-LNP groups. Immunohistochemistry revealed increased p53, p21, and HLA-A expression with ENB101-LNP treatments, alone or combined. CONCLUSION: The combination of ENB101-LNP, which inhibits E6/E7 of HPV 16, with cisplatin, demonstrated significant anticancer activity in the xenograft mouse model of cervical cancer.

Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis.

Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The susceptibility of cancer cells to VCP inhibition is attributed to the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to translational rebound and amplification of proteotoxic stress. Furthermore, the ATF4/DDIT4 axis augments VCP inhibition-mediated paraptosis by activating Akt. Given that hyperactive Akt counteracts chemotherapeutic-induced apoptosis, VCP inhibition presents a promising therapeutic avenue to exploit Akt-associated vulnerabilities in cancer cells by triggering paraptosis while safeguarding normal cells.

Contribution of Enhanced Locoregional Control to Improved Overall Survival with Consolidative Durvalumab After Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: Insights from Real-World Data.

Purpose: This study aimed to assess the real-world clinical outcomes of consolidative durvalumab in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) and to explore the role of radiotherapy in the era of immunotherapy. Materials and Methods: This retrospective study assessed 171 patients with unresectable LA-NSCLC who underwent concurrent chemoradiotherapy (CCRT) with or without consolidative durvalumab at Asan Medical Center between May 2018 and May 2021. Primary outcomes included freedom from locoregional failure (FFLRF), distant metastasis free survival (DMFS), progression free survival (PFS), and overall survival (OS). Results: Durvalumab following CCRT demonstrated a prolonged median PFS of 20.9 months (p=0.048) and a 3-year FFLRF rate of 57.3% (p=0.008), compared to 13.7 months and 38.8%, respectively, with CCRT alone. Furthermore, the incidence of in-field recurrence was significantly greater in the CCRT alone group compared to the durvalumab group (26.8% vs. 12.4%, p=0.027). While median OS was not reached with durvalumab, it was 35.4 months in patients receiving CCRT alone (p=0.010). Patients positive for programmed cell death ligand 1 (PD-L1) expression showed notably better outcomes, including FFLRF, DMFS, PFS, and OS. Adherence to PACIFIC trial eligibility criteria identified 100 patients (58.5%) as ineligible. The use of durvalumab demonstrated better survival regardless of eligibility criteria. Conclusion: The use of durvalumab consolidation following CCRT significantly enhanced locoregional control and OS in patients with unresectable LA-NSCLC, especially in those with PD-L1-positive tumors, thereby validating the role of durvalumab in standard care.

Chromosome-level genome assembly and annotation of the Antarctica whitefin plunderfish Pogonophryne albipinna.

The Antarctic whitefin plunderfish Pogonophryne albipinna belongs to the family Artedidraconidae, a key component of Antarctic benthic ecosystems within the order Perciformes and the suborder Notothenioidei. While genome research on P. albipinna using short-read sequencing is available, high-quality genome assembly and annotation employing long-read sequencing have yet to be performed. This study presents a chromosome-scale genome assembly and annotation for P. albipinna, utilizing a combination of Illumina short-read, PacBio long-read, and Hi-C sequencing technologies. The resulting genome assembly spans approximately 1.07 Gb, with a longest scaffold measuring 59.39 Mb and an N50 length of 41.76 Mb. Of the 1,111 Hi-C scaffolds, 23 exceeded 10 Mb and were thus classified as chromosome-level. BUSCO completeness was assessed at 95.6%. The assembled genome comprises 50.68% repeat sequences, and a total of 31,128 protein-coding genes were predicted. This study will enhance our understanding of the genomic characteristics of cryonotothenioids and facilitate comparative analyses of their adaptation and evolution in extreme environments.

Identifying facilitators of and barriers to the adoption of dynamic consent in digital health ecosystems: a scoping review.

BACKGROUND: Conventional consent practices face ethical challenges in continuously evolving digital health environments due to their static, one-time nature. Dynamic consent offers a promising solution, providing adaptability and flexibility to address these ethical concerns. However, due to the immaturity of the concept and accompanying technology, dynamic consent has not yet been widely used in practice. This study aims to identify the facilitators of and barriers to adopting dynamic consent in real-world scenarios. METHODS: This scoping review, conducted in December 2022, adhered to the PRISMA Extension for Scoping Reviews guidelines, focusing on dynamic consent within the health domain. A comprehensive search across Web of Science, PubMed, and Scopus yielded 22 selected articles based on predefined inclusion and exclusion criteria. RESULTS: The facilitators for the adoption of dynamic consent in digital health ecosystems were the provision of multiple consent modalities, personalized alternatives, continuous communication, and the dissemination of up-to-date information. Nevertheless, several barriers, such as consent fatigue, the digital divide, complexities in system implementation, and privacy and security concerns, needed to be addressed. This study also investigated current technological advancements and suggested considerations for further research aimed at resolving the remaining challenges surrounding dynamic consent. CONCLUSIONS: Dynamic consent emerges as an ethically advantageous method for digital health ecosystems, driven by its adaptability and support for continuous, two-way communication between data subjects and consumers. Ethical implementation in real-world settings requires the development of a robust technical framework capable of accommodating the diverse needs of stakeholders, thereby ensuring ethical integrity and data privacy in the evolving digital health landscape.

Outcome of dose-escalated intensity-modulated radiotherapy for limited disease small cell lung cancer.

PURPOSE: An optimal once-daily radiotherapy (RT) regimen is under investigation for definitive concurrent chemoradiotherapy (CCRT) in limited disease small cell lung cancer (LD-SCLC). We compared the efficacy and safety of dose escalation with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Between January 2016 and March 2021, patients treated with definitive CCRT for LD-SCLC with IMRT were retrospectively reviewed. Patients who received a total dose <50 Gy or those with a history of thoracic RT or surgery were excluded. The patients were divided into two groups (standard and dose-escalated) based on the total biologically effective dose (BED, α/ß = 10) of 70 Gy. The chemotherapeutic regimen comprised four cycles of etoposide and cisplatin. RESULTS: One hundred and twenty-two patients were analyzed and the median follow-up was 27.8 months (range, 4.4 to 76.9 months). The median age of the patients was 63 years (range, 35 to 78 years) and the majority had a history of smoking (86.0%). The 1- and 3-year overall survival rates of the escalated dose group were significantly higher than those of the standard group (93.5% and 50.5% vs. 76.7% and 33.3%, respectively; p = 0.008), as were the 1- and 3-year freedom from in-field failure rates (91.4% and 66.5% vs. 73.8% and 46.9%, respectively; p = 0.018). The incidence of grade 2 or higher acute and late pneumonitis was not significantly different between the two groups (p = 0.062, 0.185). CONCLUSION: Dose-escalated once-daily CCRT with IMRT led to improved locoregional control and survival, with no increase in toxicity.

A chromosome-level reference genome of the Antarctic blackfin icefish Chaenocephalus aceratus.

The blackfin Icefish (Chaenocephalus aceratus) belongs to the family Channichthyidae and the suborder Notothenioidei which lives in the Antarctic. We corrected the mis-scaffolds in the previous linkage map results by Hi-C analysis to obtain improved results for chromosome-level genome assembly. The final assembly analysis resulted in a total of 3,135 scaffolds, a genome size of 1,065.72 Mb, and an N50 of 33.46 Mb. 820.24 Mb, representing 88.88% of the total genome, is anchored to 24 chromosomes. The final gene set of 38,024 genes, including AFGPs, was annotated using RNA evidence, proteins, and ab-initio predictions. The complete percentage of BUSCO analysis is 92.7%. In this study, we aim to contribute to the study of polar fishes by improving the genome sequences of the blackfin icefish with the AFGP genes belonging to the Notothenoidei.

ITC-6102RO, a novel B7-H3 antibody-drug conjugate, exhibits potent therapeutic effects against B7-H3 expressing solid tumors.

BACKGROUND: The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS: In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS: ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS: Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

Targeting phosphomevalonate kinase enhances radiosensitivity via ubiquitination of the replication protein A1 in lung cancer cells.

Radiotherapy (RT) plays an important role in localized lung cancer treatments. Although RT locally targets and controls malignant lesions, RT resistance prevents RT from being an effective treatment for lung cancer. In this study, we identified phosphomevalonate kinase (PMVK) as a novel radiosensitizing target and explored its underlying mechanism. We found that cell viability and survival fraction after RT were significantly decreased by PMVK knockdown in lung cancer cell lines. RT increased apoptosis, DNA damage, and G2/M phase arrest after PMVK knockdown. Also, after PMVK knockdown, radiosensitivity was increased by inhibiting the DNA repair pathway, homologous recombination, via downregulation of replication protein A1 (RPA1). RPA1 downregulation was induced through the ubiquitin-proteasome system. Moreover, a stable shRNA PMVK mouse xenograft model verified the radiosensitizing effects of PMVK in vivo. Furthermore, PMVK expression was increased in lung cancer tissues and significantly correlated with patient survival and recurrence. Our results demonstrate that PMVK knockdown enhances radiosensitivity through an impaired HR repair pathway by RPA1 ubiquitination in lung cancer, suggesting that PMVK knockdown may offer an effective therapeutic strategy to improve the therapeutic efficacy of RT.

Comparison of remimazolam and propofol induction on hemodynamic response in hypertensive patients.

BACKGROUND: Hemodynamic variations during the induction of general anesthesia are more profound in hypertensive patients, and the risk of hypoperfusion-induced organ damage followed by hypotensive episodes is higher in hypertensive patients than in normotensive patients. Thus, we compared the effects of remimazolam and propofol on hemodynamics during general anesthesia induction in hypertensive patients. METHODS: Patients were randomly divided into the remimazolam (Group R, n = 48) and propofol (Group P, n = 48) groups: remimazolam was continued at 6 mg/kg/hour until the patient lost consciousness, followed by 1 mg/kg/hour until 5 minutes after tracheal intubation. Propofol was administered as a slow bolus of 1.5 to 2 mg/kg, followed by 3 to 6 mg/kg/hour 5 minutes after tracheal intubation. Hemodynamic parameters including mean blood pressure (MBP), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and incidence of hypotension were analyzed during the induction period, pre-induction (T1), immediately after loss of consciousness (T2), at 1 and 3 minutes after neuromuscular blockade (T3, T4), immediately after tracheal intubation (T5), and at 1, 3, and 5 minutes after tracheal intubation (T6, T7, T8). RESULTS: The MBP, SBP, and DBP were significantly lower in the propofol group than in the remimazolam group (MBP: at T2, T3, T4, and T5; SBP: at T2, T3, and T4; DBP: at T5). HR was significantly lower in the propofol group at T3, T4, and T8. The incidence of hypotension was significantly higher in the propofol group than that in the remimazolam group. The incidence of bradycardia was comparable between the groups. CONCLUSIONS: Remimazolam induction was more stable than propofol induction in preserving normal hemodynamics and was associated with a relatively lower incidence of hypotension. Remimazolam may be preferable to propofol for induction of anesthesia in patients with hypertension.

Moral Distress Regarding End-of-Life Care Among Healthcare Personnel in Korean University Hospitals: Features and Differences Between Physicians and Nurses.

BACKGROUND: Healthcare professionals often experience moral distress while providing end-of-life care. This study explored how physicians and nurses experienced moral distress when they cared for critically and terminally ill patients in tertiary hospitals in South Korea. METHODS: This study used semi-structured in-depth interviews. A total of 22 people in two tertiary hospitals were interviewed, nine (40.9%) of which were physicians and 13 (59.1%) were nurses. The recorded interview files and memos were analyzed using grounded theory. RESULTS: Most physicians and nurses encountered similar feelings of anger, helplessness, and burden owing to a lack of appropriate resources for end-of-life care. However, the factors and contexts of their moral distress differed. Nurses mainly addressed poorly organized end-of-life care, intensive labor conditions without support for nurses, and providing care without participation in decision-making. Meanwhile, physicians addressed the prevailing misperceptions on end-of-life care, communication failure between physicians owing to hierarchy and fragmented disciplines, the burden of responsibility in making difficult decisions, and the burden of resource allocation. CONCLUSION: Differences in moral distress between physicians and nurses leave them isolated and can affect communication regarding healthcare. Mutual understanding between job disciplines will enhance their communication and help resolve conflicts in end-of-life care.

Anesthetic Management and Bispectral Index in a Child with Miller-Dieker Syndrome: A Case Report.

Miller-Dieker syndrome (MDS) is a genetic disorder characterized by classic lissencephaly, distinctive facial features, intellectual disability, seizures, and early death. The anesthetic management of patients with MDS should focus on airway manipulation with the risk of potentially difficult intubation, seizure control due to lissencephaly, and any other clinical complications. Herein, we report a case of anesthetic management in a child with MDS and describe relevant clinical features in a perioperative anesthetic setting. This case highlights the importance of difficult airway manipulation using a videolaryngoscope, seizure management with regard to anesthetics use, and the low validity of BIS monitoring in patients with MDS.

Paradoxical vocal fold motion masquerading as post-anesthetic respiratory distress: A case report.

BACKGROUND: Functional vocal cord disorders can be a differential diagnosis for postoperative upper airway obstruction requiring urgent intervention. However, this may be unfamiliar to anesthesiologists who would favor inappropriate airway intervention and increased morbidity. CASE SUMMARY: A 61-year-old woman underwent cervical laminectomy, followed by laparoscopic cholecystectomy 10 mo later. Despite adequate reversal of neuromuscular blockade, the patient experienced repetitive respiratory difficulty with inspiratory stridor after extubation. After the second operation, the patient was diagnosed with paradoxical vocal fold motion (PVFM) by an otolaryngologist based on the clinical features and fiberoptic bronchoscopy results, and the patient was successfully treated. CONCLUSION: PVFM should be considered a differential diagnosis if a patient presents with stridor after general anesthesia.

Effect of dexmedetomidine and remifentanil infusion on postoperative sore throat after lumbar spine surgery in the prone position.

BACKGROUND: A sore throat is an adverse postoperative consequence of tracheal intubation under general anesthesia. Recently, dexmedetomidine, an anesthetic adjuvant, has shown beneficial effects in postoperative sore throat (POST). Herein, we compared the effects of dexmedetomidine and remifentanil on POST after spinal surgery in the prone position, which is a risk factor for developing POST. METHODS: Ninety-eight patients were enrolled in the dexmedetomidine and remifentanil groups. Each drug was continuously infused using the following protocol: 1 µg/kg over 10 minutes followed by 0.2 to 0.8 µg/kg/h of dexmedetomidine, 3 to 4 ng/mL during induction followed by 1 to 3 ng/mL of remifentanil intraoperatively. The incidence and severity of POST were assessed serially at 24 hours postoperatively. Postoperative hoarseness, nausea, and pain scores were measured. RESULTS: The incidence and severity of POST were significantly lower in the dexmedetomidine group than that in the remifentanil group. However, the incidence of hoarseness was comparable between the 2 groups. Postoperative nausea was lower in the dexmedetomidine group at 1 hour postoperatively; however, the postoperative pain score and analgesic requirements did not differ significantly. CONCLUSIONS: Dexmedetomidine infusion as an adjuvant during sevoflurane anesthesia significantly reduced the incidence and severity of POST in patients who underwent lumbar surgery 24 hours postoperatively.

Peripheral nerve block with ropivacaine in Brugada syndrome patient: Anesthetic consideration.

Brugada syndrome has a lethal arrhythmogenic risk during surgery or anesthesia. Perioperative drugs, electrolytic disturbances, and autonomic imbalance can trigger cardiac rhythm disturbances and even sudden cardiac death. Patients with this syndrome are at high risk during the perioperative period. However, the safest anesthetic management is still unknown. We report successful anesthetic management with peripheral nerve block (five points) using ropivacaine for lower-limb surgery in a patient with Brugada syndrome.

Effects of remote ischemic postconditioning on hepatic injury in lipopolysaccharide-induced endotoxemic rats.

BACKGROUND: Remote ischemic postconditioning (RIPoC) is induced by several cycles of brief, reversible, mechanical blood flow occlusion, and reperfusion of the distal organs thereby protecting target organs. We investigated if RIPoC ameliorated liver injury in a lipopolysaccharide (LPS)-induced endotoxemic rats. METHODS: Protocol 1) Rats were administered LPS and samples collected at 0, 2, 6, 12, and 18 h. 2) After RIPoC at 2, 6, and 12 h (L+2R+18H, L+6R+18H, and L+12R+18H), samples were analyzed at 18 h. 3) RIPoC was performed at 2 h, analysis samples at 6, 12, 18 h (L+2R+6H, L+2R+12H, L+2R+18H), and RIPoC at 6 h, analysis at 12 h (L+6R+12H). 4) Rats were assigned to a control group while in the RIPoC group, RIPoC was performed at 2, 6, 10, and 14 h, with samples analyzed at 18 h. RESULTS: Protocol 1) Liver enzyme, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB) levels increased while superoxide dismutase (SOD) levels decreased over time. 2) Liver enzyme and MDA levels were lower while SOD levels were higher in L+12R+18H and L+6R+18H groups when compared with L+2R+18H group. 3) Liver enzyme and MDA levels were lower while SOD levels were higher in L+2R+6H and L+6R+12H groups when compared with L+2R+12H and L+2R+18H groups. 4) Liver enzyme, MDA, TNF-α, and NF-κB levels were lower while SOD levels were higher in RIPoC group when compared with control group. CONCLUSIONS: RIPoC attenuated liver injury in the LPS-induced sepsis model by modifying inflammatory and oxidative stress response for a limited period.

Effect on music therapy on quality of recovery and postoperative pain after gynecological laparoscopy.

BACKGROUND: Music therapy is safe, inexpensive, simple, and has relaxing properties for mental and physical capacities, as well as few side effects. Moreover, it improves patient satisfaction and reduces postoperative pain. Thus, we intended to evaluate the effect of music intervention on the quality of comprehensive recovery using quality of recovery 40 (QoR-40) survey in patients undergoing gynecological laparoscopic surgery. METHODS: Patients were randomly assigned to music intervention group or control group: 41 patients each. After anesthetic induction, headphones were placed on the patients, and then classical music selected by an investigator was started in the music group with individual comfortable volume during surgery, while the player was not started in the control group. On postoperatively 1 day, the QoR-40 (5 categories: emotions, pain, physical comfort, support, and independence) survey was evaluated, while postoperative pain, nausea, and vomiting were assessed at 30 minutes and 3, 24, and 36 hours postoperatively. RESULTS: Total QoR-40 score was statistically better in the music group, and among the 5 categories, the music group had a higher pain category score than the control group. The postoperative pain score was significantly lower in the music group at 36 hours postoperatively, although the requirement for rescue analgesics was similar in both groups. The incidence of postoperative nausea did not differ at any time point. CONCLUSION: Intraoperative music intervention enhanced postoperative functional recovery and reduced postoperative pain in patients who underwent laparoscopic gynecological surgery.