A novel surgical approach using the "lateral corridor" for minimally invasive oblique lumbar interbody fusion at L5-S1: a clinical series and technical note.

PURPOSE: The minimally invasive oblique lumbar interbody fusion (MI-OLIF) L5-S1 was introduced to overcome the limitations of conventional fusion techniques, however, MI-OLIF is not possible using the standard method due to vascular structures in some cases. We aimed to introduce the "lateral corridor" and report the details of the surgical technique with a clinical case series. METHODS: We utilized the lateral access route of the left common iliac vein and named it the "lateral corridor", to distinguish the technique from the standard technique (central corridor). The type and frequency of branch vessels that required additional manipulations were reviewed, and the frequency of intraoperative vascular injury was investigated. RESULTS: Among the 107 patients who underwent MI-OLIF L5-S1, 26 patients (24.3%) who received the "lateral corridor" technique were included. Branch vessel ligation was required in 42.3% of the patients. The types of branch vessels that required ligation were seven cases (26.9%) of the iliolumbar vein (ILV) and six cases (23.1%) of ascending lumbar vein (ALV). The ILV and ALV were ligated in two cases. None of the patients developed intraoperative vascular injuries. CONCLUSION: We introduced the "lateral corridor" as an alternative approach for MI-OLIF L5-S1, implemented it in 24.3% of the patient cohort, and reported favorable outcomes devoid of vascular complications. The "lateral corridor" necessitated ligation of the ILV or ALV in 42.3% of cases. The "lateral corridor" approach appears to be a promising surgical technique, offering feasibility even in instances where the vascular anatomy precludes the employment of the conventional approach.

Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

Orthopedic postoperative infection profile and antibiotic sensitivity of 2038 patients across 24 countries - Call for region and institution specific surgical antimicrobial prophylaxis.

Purpose: Improper utilization of surgical antimicrobial prophylaxis frequently leads to increased risks of morbidity and mortality.This study aims to understand the common causative organism of postoperative orthopedic infection and document the surgical antimicrobial prophylaxis protocol across various institutions in to order to strengthen surgical antimicrobial prophylaxis practice and provide higher-quality surgical care. Methods: This multicentric multinational retrospective study, includes 24 countries from five different regions (Asia Pacific, South Eastern Africa, Western Africa, Latin America, and Middle East). Patients who developed orthopedic surgical site infection between January 2021 and December 2022 were included. Demographic details, bacterial profile of surgical site infection, and antibiotic sensitivity pattern were documented. Results: 2038 patients from 24 countries were included. Among them 69.7 % were male patients and 64.1 % were between 20 and 60 years. 70.3 % patients underwent trauma surgery and instrumentation was used in 93.5 %. Ceftriaxone was the most common preferred in 53.4 %. Early SSI was seen in 55.2 % and deep SSI in 59.7 %. Western Africa (76 %) and Asia-Pacific (52.8 %) reported a higher number of gram-negative infections whereas gram-positive organisms were predominant in other regions. Most common gram positive organism was Staphylococcus aureus (35 %) and gram-negative was Klebsiella (17.2 %). Majority of the organisms showed variable sensitivity to broad-spectrum antibiotics. Conclusion: Our study strongly proves that every institution has to analyse their surgical site infection microbiological profile and antibiotic sensitivity of the organisms and plan their surgical antimicrobial prophylaxis accordingly. This will help to decrease the rate of surgical site infection, prevent the emergence of multidrug resistance and reduce the economic burden of treatment.

Effectiveness of vancomycin powder for preventing postoperative spinal infection.

OBJECTIVE: This study aimed to assess the effectiveness of Vancomycin Power (VP) and the occurrence of resistant organisms after four-year of routine VP use. METHODS: The study included 1063 patients who underwent posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) between January 2010 and February 2020. Intrawound VP was applied to all instrumented fusions starting in January 2016. The patients were divided into two groups: those who did not apply VP (non-VP) (n = 605) between 2010 and 2015, and those who did apply VP (VP) (n = 458) between 2016 and 2020. The baseline characteristics, clinical symptoms, infection rate, and causative organisms were compared between the two groups. RESULTS: The rate of PSI was not significantly different between the non-VP group (1.32 %, n = 8) and the VP group (1.09 %, n = 5). Although adjusted by diabetes mellitus, VP still did not show statistical significance (OR = 0.757 (0.245-2.345), p = 0.630). There were no critical complications that were supposed to relation with vancomycin powder. In the 13 cases of PSI, seven pathogens were isolated, with a gram-negative organism identified in the non-VP group. However, the type of organism was not significantly different between the two groups. CONCLUSIONS: The use of intrawound VP may not affect the PSI and occurrence of resistant organism and may not cause critical complications. Therefore, clinicians may decide whether to use VP for preventing PSI not worrying about its safety.

PRMT1 promotes pancreatic cancer development and resistance to chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of and potential as a therapeutic target for PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy.

Unstable Vancouver B1 periprosthetic femoral fracture fixation: A biomechanical comparison between a novel C-shaped memory alloy implant and cerclage wiring.

BACKGROUND: To compare the biomechanical stability of a novel, C-shaped nickel-titanium shape memory alloy (SMA) implant (C-clip) with traditional cerclage wiring in the fixation of a Vancouver B1 (VB1) periprosthetic femoral fracture (PFF). METHODS: In total, 18 synthetic femoral fracture models were constructed to obtain unstable VB1 fracture with an oblique fracture line 8 cm below the lesser trochanter. For each model, the distal portion was repaired using a 10-hole locking plate and four distal bi-cortical screws. The proximal portion was repaired using either three, threaded cerclage wirings or three, novel C-shaped implants. Specimens underwent biomechanical testing using axial compression, torsional and four-point bending tests. Each test was performed on three specimens. RESULTS: The C-clip was statistically significantly stronger (i.e., stiffer) than cerclage wiring in the three biomechanical tests. For axial compression, medians (ranges) were 39 (39-41) and 35 (35-35) N/mm, for the C-clip and cerclage wiring, respectively. For torsion, medians (ranges) were, 0.44 (0.44-0.45) and 0.30 (0.30-0.33) N/mm for the C-clip and cerclage wiring, respectively. For the four-point bending test, medians (ranges) were 39 (39-41) and 28 (28-31) N/mm; for the C-clip and cerclage wiring, respectively. CONCLUSION: Results from this small study show that the novel, C-shaped SMA appears to be biomechanically superior to traditional cerclage wiring in terms of stiffness, axial compression, torsion and four-point bending, and may be a valuable alternative in the repair of VB1 PFF. Further research is necessary to support these results.

Correlation between Time to Hyperbaric Oxygen Therapy and Delayed Neurological Sequelae in Acute Carbon Monoxide Poisoning Patients.

Carbon monoxide (CO) is one of the most common causes of intoxication. Delayed neurologic sequelae (DNS) have a major impact on prognosis of CO poisoning patients. Hyperbaric oxygen therapy (HBOT) is widely used to treat DNS. However, there is no consensus regarding the optimal timing of HBOT. This prospective study enrolled patients who visited the hospital from November 2019 to October 2022. The cutoff value for the latency to HBOT after CO exposure was determined, and the area under the receiver operating characteristic curve (AUC) was estimated. In total, 167 patients were divided into non-DNS and DNS groups. The initial Glasgow Coma Scale (GCS) score, CO exposure time, latency to HBOT after CO exposure, median length of hospital stay (p < 0.001) and creatine kinase (p = 0.016) showed significant differences. A GCS score ≤ 9 had an odds ratio (OR) of 5.059 (95% confidence interval [CI]: 1.602-15.976, p = 0.006), and latency to HBOT after CO exposure ≥ 200 min had an OR of 18.971 (95% CI: 4.310-83.508, p < 0.001). The AUC was 0.8235 (95% CI: 0.7504-0.8966). A GCS score ≤ 9 and latency to HBOT ≥ 200 min may be significant risk factors for DNS.

Accuracy of visual estimation of ejection fraction in patients with heart failure using augmented reality glasses.

OBJECTIVE: Left ventricular ejection fraction (LVEF) is measured to assess haemodynamic status and cardiac function. It may be difficult to accurately measure in patients with heart failure (HF) as they are often poorly echogenic. The augmented reality (AR) technology is expected to provide real-time guidance that will enable more accurate measurements. METHODS: A prospective, randomised, case-crossover simulation study was conducted to confirm the effect of AR glasses on echocardiographic interpretation in patients with HF. 22 emergency physicians participated. The participants were randomly assigned to two groups. Group A estimated the visual ejection fraction of echocardiographic video clips without the AR glasses, while group B estimated them with glasses. After a washout period, the two groups crossed over. The estimates were then compared with the ejection fraction measurements obtained by echocardiologists; intraclass correlation coefficient (ICC) was calculated. RESULTS: The ICC with glasses (0.969, 95% CI 0.966 to 0.971) was higher than without glasses (0.705, 95% CI 0.681 to 0.727) among all participants. In the subgroup analysis, the first-year and second-year residents showed the most significant difference, with an ICC of 0.568 (95% CI 0.508 to 0.621) without glasses compared with 0.963 (95% CI 0.958 to 0.968) with glasses. For the third-year and fourth-year residents group, the ICC was 0.754 (95% CI 0.720 to 0.784) without glasses and 0.972 (95% CI 0.958 to 0.968) with glasses. Among the group of attending physicians, the ICC was 0.807 (95% CI 0.775 to 0.834) without glasses and 0.973 (95% CI 0.969 to 0.977) with glasses. CONCLUSIONS: AR glasses could be helpful in measuring LVEF and could be more helpful to those with little visual estimation experience.

Development and Verification of a 480 nm Blue Light Enhanced/Reduced Human-Centric LED for Light-Induced Melatonin Concentration Control.

With the inherent sleep and wake cycle regulated by natural sunlight, the human body has evolved over millennia to be active during the day and to rest at night. However, maintaining an optimal 24 h cycle has become increasingly problematic in modern society as more people spend the majority of the day indoors. Many research groups have reported that inadequate artificial lighting interferes with melatonin production and disrupts the circadian rhythm. This study considered biological functions for light-emitting diodes (LEDs) of next-generation illumination, and LED packages and spectra suitable for both daytime and nighttime applications were designed. The prepared daytime human-centric (HC)-LEDs had a melanopic/photopic (M/P) ratio that was up to 26% higher than that of conventional (c)-LEDs, whereas the nighttime HC-LEDs exhibited up to a 26% lower M/P ratio compared to the c-LEDs. Nevertheless, because the HC-LED is designed to have almost the same color coordinates as the c-LED having the same correlated-color temperature (CCT), there is no change in the perceived color. To substantiate the biological effect, melatonin level data were obtained from 22 voluntary participants in c- and HC-LED lighting environments. In the HC-LED lighting environment, melatonin was suppressed by 21.9% after waking, and nocturnal melatonin secretion was increased by up to 12.2%. As human-centric lighting, our HC-LEDs are expected to become an essential element for modern life, where people spend most of their time indoors.

A Cell-Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer-Specific Synthetic Lethality.

Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof-of-principle evidence is presented that a cell-penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene-addicted cancer cells through transcription activity-independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2-p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome-wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C-resistant cancers. This study enhances the understanding of ACP52C-induced cancer-specific apoptosis induction and supports the use of ACP52C in anticancer drug development.

Improved prediction of protein-protein interactions by a modified strategy using three conventional docking software in combination.

Proteins play a crucial role in many biological processes, where their interaction with other proteins are integral. Abnormal protein-protein interactions (PPIs) have been linked to various diseases including cancer, and thus targeting PPIs holds promise for drug development. However, experimental confirmation of the peculiarities of PPIs is challenging due to their dynamic and transient nature. As a complement to experimental technologies, multiple computational molecular docking (MD) methods have been developed to predict the structures of protein-protein complexes and their dynamics, still requiring further improvements in several issues. Here, we report an improved MD method, namely three-software docking (3SD), by employing three popular protein-peptide docking software (CABS-dock, HPEPDOCK, and HADDOCK) in combination to ensure constant quality for most targets. We validated our 3SD performance in known protein-peptide interactions (PpIs). We also enhanced MD performance in proteins having intrinsically disordered regions (IDRs) by applying the modified 3SD strategy, the three-software docking after removing random coiled IDR (3SD-RR), to the comparable crystal PpI structures. At the end, we applied 3SD-RR to the AlphaFold2-predicted receptors, yielding an efficient prediction of PpI pose with high relevance to the experimental data regardless of the presence of IDRs or the availability of receptor structures. Our study provides an improved solution to the challenges in studying PPIs through computational docking and has the potential to contribute to PPIs-targeted drug discovery. SIGNIFICANCE STATEMENT: Protein-protein interactions (PPIs) are integral to life, and abnormal PPIs are associated with diseases such as cancer. Studying protein-peptide interactions (PpIs) is challenging due to their dynamic and transient nature. Here we developed improved docking methods (3SD and 3SD-RR) to predict the PpI poses, ensuring constant quality in most targets and also addressing issues like intrinsically disordered regions (IDRs) and artificial intelligence-predicted structures. Our study provides an improved solution to the challenges in studying PpIs through computational docking and has the potential to contribute to PPIs-targeted drug discovery.

Adaptive designs for IVPT data with mixed scaled average bioequivalence.

In vitro permeation tests (IVPT) offer accurate and cost-effective development pathways for locally acting drugs, such as topical dermatological products. For assessment of bioequivalence, the FDA draft guidance on generic acyclovir 5% cream introduces a new experimental design, namely the single-dose, multiple-replicate per treatment group design, as IVPT pivotal study design. We examine the statistical properties of its hypothesis testing method-namely the mixed scaled average bioequivalence (MSABE). Meanwhile, some adaptive design features in clinical trials can help researchers make a decision earlier with fewer subjects or boost power, saving resources, while controlling the impact on family-wise error rate. Therefore, we incorporate MSABE in an adaptive design combining the group sequential design and sample size re-estimation. Simulation studies are conducted to study the passing rates of the proposed methods-both within and outside the average bioequivalence limits. We further consider modifications to the adaptive designs applied for IVPT BE trials, such as Bonferroni's adjustment and conditional power function. Finally, a case study with real data demonstrates the advantages of such adaptive methods.

SYMPATHETIC NERVE ENTRAPMENT POINT INJECTION AS AN ADJUVANT TREATMENT FOR INTRACTABLE CLUSTER HEADACHE: A CASE REPORT.

BACKGROUND: Cluster headache (CH) is characterized by severe unilateral pain ranging from the orbital to the temporal regions with ipsilateral autonomic manifestations. Although most patients respond to drugs or oxygen inhalation, some do not. In this case report, we introduce sympathetic nerve entrapment point injection (SNEPI), a new adjuvant treatment for CH. CASE REPORT: We introduce two CH patients who did not respond well to pharmacological treatment or 100% oxygen inhalation, but who improved after SNEPI. Patient 1, a 42-year-old man, visited the Emergency Department (ED) with severe periorbital right frontal headache accompanied by ipsilateral rhinorrhea, conjunctival injection, and eyelid edema. The symptoms did not fully respond to drugs or oxygen inhalation, but improved after SNEPI into the tender point of the splenius capitis (SC) muscle; there was no further pain for 1 month thereafter. Patient 2, a 26-year-old woman, presented to the ED complaining of severe headache in the right supraorbital-temporal-occipital region with ipsilateral lacrimation and conjunctival congestion. The patient was taking various drugs for CH, but there was no improvement; the symptoms improved dramatically after SNEPI into the tender points of the SC and paraspinal deep muscles (levels T1-2), and the pain was well managed with reduced drug doses for 3 months. Why Should an Emergency Physician Be Aware of This? CH can cause severe acute pain, and sometimes pharmacological treatment or oxygen inhalation is not effective. SNEPI, which is inexpensive and can be easily performed, may be considered as an adjuvant treatment for intractable CH in the ED.

Multiple Cerebral Infarctions and Rhabdomyolysis After Sildenafil Citrate (Viagra®) Intoxication: A Case Report.

BACKGROUND: Sildenafil citrate (Viagra®) is used to treat male erectile dysfunction; however, little is known about the effects of sildenafil overdose and intoxication. We report a patient who presented with cerebral infarction and rhabdomyolysis after intentional sildenafil intoxication. CASE REPORT: A 61-year-old man visited the Emergency Department complaining of dysarthria about 1 h after taking more than 30 sildenafil tablets with the intention to commit suicide. Dysarthria and dizziness were observed, but there were no other neurological symptoms. The creatine kinase level was elevated to 3118 U/L, and the patient was diagnosed with rhabdomyolysis. Brain magnetic resonance imaging revealed multiple scattered acute cerebral infarctions in both midbrain artery branches. At 4 h post-intoxication, the dysarthria had improved and we initiated dual antiplatelet therapy for cerebral infarction. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be able to anticipate and treat complications like cerebral infarction and rhabdomyolysis after sildenafil intoxication.

Dexamethasone therapy prevents delayed neuropsychiatric sequelae after carbon monoxide poisoning: a prospective registry-based study.

BACKGROUND: Delayed neuropsychiatric sequelae are major complications of carbon monoxide poisoning; carbon monoxide triggers brain oxidation and inflammation. Corticosteroids such as dexamethasone modulate neurological damage after carbon monoxide poisoning through anti-inflammatory actions and immune response inhibition. However, it is not known whether corticosteroids prevent delayed neuropsychiatric sequelae. We thus studied whether dexamethasone reduced the incidence of delayed neuropsychiatric sequelae. METHODS: This registry-based study enrolled patients with carbon monoxide poisoning treated in a Korean tertiary care hospital from March 1st, 2020 to November 30th, 2021. Data of patients were prospectively collected during the study period, and retrospectively analyzed. One group received intravenous dexamethasone. We performed multivariable logistic regression analysis to identify factors associated with delayed neuropsychiatric sequelae. RESULTS: A total of 128 patients were enrolled, of which 99 patients received dexamethasone therapy and 29 patients did not. The incidences of delayed neuropsychiatric sequelae in the dexamethasone and non-dexamethasone groups were 16.2% and 37.9%, respectively. Multivariable logistic regression analysis revealed that dexamethasone use (odds ratio = 0.122, 95% confidence interval 0.031-0.489) and a higher Glasgow Coma Scale (odds ratio = 0.818, 95% confidence interval 0.682-0.981) was associated with a lower incidence of delayed neuropsychiatric sequelae. CONCLUSION: Early dexamethasone treatment was significantly associated with a decreased incidence of delayed neuropsychiatric sequelae. A higher Glasgow Coma Scale at presentation also was associated with a lower incidence of delayed neuropsychiatric sequelae.

Computed Tomography Evaluation of Percutaneous Pedicle Screws Inserted during Minimally Invasive Transforaminal Lumbar Interbody Fusion: Long-term Follow-up Results of Screw Violation.

Background: To evaluate the accuracy of percutaneous pedicle screw (PPS) insertion in degenerative lumbar disease treated with minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) and to analyze risk factors and long-term clinical outcomes of screw violation. Methods: Sixty-two consecutive patients (262 screws) were included. Based on postoperative computed tomography (CT) axial images, a PPS that perforated out of the pedicle was classified into a violation group, while screws surrounded by pedicular cortical bone were classified into a correct group. A logistic regression model was used for risk factor analysis of violation. We also observed the long-term clinical outcomes using the Oswestry disability index and visual analog scale. Results: Of the 262 screws, 14 (5.3%) were considered to be violated (10 medial violations and 4 lateral violations). All violations of S1 and L5 were in the medial direction. In contrast, entire violations of L4 were always lateral and of the 2 violations of L3, one was lateral and the other was medial. There were no cases of superior or inferior violation. The mean pedicle convergence angle (CA) was significantly higher in the violation group (mean ± standard deviation, 27.0° ± 6.2°) than in the correct group (21.7° ± 5.4°). There were no significant differences according to vertebral rotational angle, body mass index, bone mineral density, and surgical timing (learning curve) between the two groups. Logistic regression analyses demonstrated that a high CA was a significant risk factor for pedicle wall violation (p = 0.002). There were no significant differences in clinical or radiographic results between the two groups in 60 patients who were followed up for more than 1 year and in 40 patients who were followed up for more than 5 years. There were 2 patients who required reoperation to replace a screw due to leg pain. Conclusions: With PPS insertion during MI-TLIF, the rate of pedicle violation was 5.3% (14/262). An understanding of the anatomical characteristics of each vertebra and the unique structures of the patient is essential to prevent pedicle violations. Even in the violation group, PPS fixation was found to be a safe and useful procedure with successful long-term radiographic and clinical outcomes.

3D human induced pluripotent stem cell-derived bioengineered skeletal muscles for tissue, disease and therapy modeling.

Skeletal muscle is a complex tissue composed of multinucleated myofibers responsible for force generation that are supported by multiple cell types. Many severe and lethal disorders affect skeletal muscle; therefore, engineering models to reproduce such cellular complexity and function are instrumental for investigating muscle pathophysiology and developing therapies. Here, we detail the modular 3D bioengineering of multilineage skeletal muscles from human induced pluripotent stem cells, which are first differentiated into myogenic, neural and vascular progenitor cells and then combined within 3D hydrogels under tension to generate an aligned myofiber scaffold containing vascular networks and motor neurons. 3D bioengineered muscles recapitulate morphological and functional features of human skeletal muscle, including establishment of a pool of cells expressing muscle stem cell markers. Importantly, bioengineered muscles provide a high-fidelity platform to study muscle pathology, such as emergence of dysmorphic nuclei in muscular dystrophies caused by mutant lamins. The protocol is easy to follow for operators with cell culture experience and takes between 9 and 30 d, depending on the number of cell lineages in the construct. We also provide examples of applications of this advanced platform for testing gene and cell therapies in vitro, as well as for in vivo studies, providing proof of principle of its potential as a tool to develop next-generation neuromuscular or musculoskeletal therapies.

SUMOylation-mediated PSME3-20S proteasomal degradation of transcription factor CP2c is crucial for cell cycle progression.

Transcription factor CP2c (also known as TFCP2, α-CP2, LSF, and LBP-1c) is involved in diverse ubiquitous and tissue/stage-specific cellular processes and in human malignancies such as cancer. Despite its importance, many fundamental regulatory mechanisms of CP2c are still unclear. Here, we uncover an unprecedented mechanism of CP2c degradation via a previously unidentified SUMO1/PSME3/20S proteasome pathway and its biological meaning. CP2c is SUMOylated in a SUMO1-dependent way, and SUMOylated CP2c is degraded through the ubiquitin-independent PSME3 (also known as REGγ or PA28)/20S proteasome system. SUMOylated PSME3 could also interact with CP2c to degrade CP2c via the 20S proteasomal pathway. Moreover, precisely timed degradation of CP2c via the SUMO1/PSME3/20S proteasome axis is required for accurate progression of the cell cycle. Therefore, we reveal a unique SUMO1-mediated uncanonical 20S proteasome degradation mechanism via the SUMO1/PSME3 axis involving mutual SUMO-SIM interaction of CP2c and PSME3, providing previously unidentified mechanistic insights into the roles of dynamic degradation of CP2c in cell cycle progression.

Analysis of Factors Contributing to the Occurrence of Systemic Toxicity in Patients with Hydrofluoric Acid Skin Exposure Injury: An Individual Participant Data Meta-Analysis of 125 Clinical Cases from 1979 to 2020.

The purpose of this study is to analyze the factors contributing to the occurrence of systemic toxicity in patients injured after skin exposure to hydrofluoric acid (HFA) and to present guidelines for active treatment intervention based on this analysis. Data were acquired from EMBASE, PubMed, and Cochrane library for individual participant data (IPD) meta-analysis. Key searching terms included calcium gluconate (CAG), hydrofluoric acid, and case. This research consisted of case studies published between 1979 and 2020. Systemic toxicity was set as the main outcome. Data sets from 50 case studies (N = 125 participants) were analyzed. Multivariate binary logistic regression analyses of IPD found significant association effect of the total body surface area (TBSA) burned, indicating systemic toxicity [Regression coefficient estimate, 0.82; SE, 0.41; Odds ratio, 2.28; [95% confidence interval, 1.03-5.06], and p = 0.0424]. The optimal cutoff point (sensitivity; specificity) of the receiver operating characteristic curve of the total body surface area (TBSA) burned for contributing occurrence of systemic toxicity was 2.38(0.875; 0.959). IPD meta-analysis indicates that existing evidence supports the positive proportional association of the TBSA burned for systemic toxicity. If the TBSA burned (%) in patients exposed to hydrofluoric acid is greater than 2.38, early aggressive treatment intervention, including decontamination and various CAG application, should be recommended as the guideline.