The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism.

Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

Clinical Practice Guideline for Stroke Rehabilitation in Korea-Part 1: Rehabilitation for Motor Function (2022).

This clinical practice guideline (CPG) is the fourth edition of the Korean guideline for stroke rehabilitation, which was last updated in 2016. The development approach has been changed from a consensus-based approach to an evidence-based approach using the Grading of Recommendations Assessment Development and Evaluation (GRADE) method. This change ensures that the guidelines are based on the latest and strongest evidence available. The aim is to provide the most accurate and effective guidance to stroke rehabilitation teams, and to improve the outcomes for stroke patients in Korea. Fifty-five specialists in stroke rehabilitation and one CPG development methodology expert participated in this development. The scope of the previous clinical guidelines was very extensive, making it difficult to revise at once. Therefore, it was decided that the scope of this revised CPG would be limited to Part 1: Rehabilitation for Motor Function. The key questions were selected by considering the preferences of the target population and referring to foreign guidelines for stroke rehabilitation, and the recommendations were completed through systematic literature review and the GRADE method. The draft recommendations, which were agreed upon through an official consensus process, were refined after evaluation by a public hearing and external expert evaluation.

Clinical Practice Guidelines for Oropharyngeal Dysphagia.

OBJECTIVE: Dysphagia is a common clinical condition characterized by difficulty in swallowing. It is sub-classified into oropharyngeal dysphagia, which refers to problems in the mouth and pharynx, and esophageal dysphagia, which refers to problems in the esophageal body and esophagogastric junction. Dysphagia can have a significant negative impact one's physical health and quality of life as its severity increases. Therefore, proper assessment and management of dysphagia are critical for improving swallowing function and preventing complications. Thus a guideline was developed to provide evidence-based recommendations for assessment and management in patients with dysphagia. METHODS: Nineteen key questions on dysphagia were developed. These questions dealt with various aspects of problems related to dysphagia, including assessment, management, and complications. A literature search for relevant articles was conducted using Pubmed, Embase, the Cochrane Library, and one domestic database of KoreaMed, until April 2021. The level of evidence and recommendation grade were established according to the Grading of Recommendation Assessment, Development and Evaluation methodology. RESULTS: Early screening and assessment of videofluoroscopic swallowing were recommended for assessing the presence of dysphagia. Therapeutic methods, such as tongue and pharyngeal muscle strengthening exercises and neuromuscular electrical stimulation with swallowing therapy, were effective in improving swallowing function and quality of life in patients with dysphagia. Nutritional intervention and an oral care program were also recommended. CONCLUSION: This guideline presents recommendations for the assessment and management of patients with oropharyngeal dysphagia, including rehabilitative strategies.

Correction: Aggregation or phase separation can be induced in highly charged proteins by small charged biomolecules.

Correction for 'Aggregation or phase separation can be induced in highly charged proteins by small charged biomolecules' by Minchae Kang et al., Soft Matter, 2022, 18, 3313-3317, https://doi.org/10.1039/D2SM00384H.

Phosphorylation of OTUB1 at Tyr 26 stabilizes the mTORC1 component, Raptor.

Raptor plays a critical role in mTORC1 signaling. High expression of Raptor is associated with resistance of cancer cells to PI3K/mTOR inhibitors. Here, we found that OTUB1-stabilized Raptor in a non-canonical manner. Using biochemical assays, we found that the tyrosine 26 residue (Y26) of OTUB1 played a critical role in the interaction between OTUB1 and Raptor. Furthermore, non-receptor tyrosine kinases (Src and SRMS kinases) induced phosphorylation of OTUB1 at Y26, which stabilized Raptor. Interestingly, phosphorylation of OTUB1 at Y26 did not affect the stability of other OTUB1-targeted substrates. However, dephosphorylation of OTUB1 destabilized Raptor and sensitized cancer cells to anti-cancer drugs via mitochondrial reactive oxygen species-mediated mitochondrial dysfunction. Furthermore, we detected high levels of phospho-OTUB1 and Raptor in samples of patients with renal clear carcinoma. Our results suggested that regulation of OTUB1 phosphorylation may be an effective and selective therapeutic target for treating cancers via down-regulation of Raptor.

Aggregation or phase separation can be induced in highly charged proteins by small charged biomolecules.

Protein phase separation in biological systems has captured the attention of scientists in the last decade; however, the main mechanism underlying protein phase separation in cells remains unclear. Biologists, physicists, and chemists have all tried to understand this important biological phenomenon, each using their own unique techniques and language. Each subject has its advantages in explaining protein phase separation; however, in this study, we find that the chemical language of molecular structure is the key to explaining the mechanism underlying protein phase separation. Using fluroescence microscopy and molecular dynamics, this study identifies small multivalently charged biomolecules, such as nucleoside triphosphate (negatively charged) and polyamine (positively charged), as important drivers of phase separation of highly charged proteins in cells.

Reconstruction of temporal hollowing deformities using silicone implants made using a toy-clay model: a report of three cases.

Severe temporal hollowing deformities can occur in patients who undergo craniectomy after intracranial hemorrhage. Reconstruction surgery for cosmetic purposes using silicone implants in patients with temporal hollowing deformities after craniectomy is advantageous because the procedure is simple and rapid, with a short recovery time, resulting in lower overall treatment costs. Of paramount importance, this option yields highly satisfactory results for patients. The authors present three cases of simple and fast surgery using silicone implants where highly satisfactory outcomes were obtained.

Analysis and Guidelines for Revisional Malarplasty; Most Common Facial Skeletal Contouring Surgery.

BACKGROUND: Revisional malarplasty is the most frequently performed and difficult to perform revision surgery among facial contouring surgeries. The incidence of postoperative complications and need for revision surgery is increasing because of indiscriminate malar reduction through a narrow surgical space. The authors analyzed cases of revisional malarplasty secondary to complications. METHODS: The authors analyzed the time required and technique used in 172 patients who underwent revisional malarplasty in the past 3 years. The incision made for the approach and the graft material used for reconstruction were also investigated. RESULTS: Of 172 patients, 35 (20.3%) underwent emergency revision. Furthermore, 71 (41.2%) required an intraoral incision, and 101 (58.8%) required a coronal incision. A total of 81(47.1%) patients required artificial or autogenous bone grafts. CONCLUSIONS: Patients with failed malarplasty should receive immediate intervention to prevent functional and cosmetic problems. When bone resorption occurs due to unfavorable union or nonunion, reconstruction using appropriate autologous tissue can prevent functional impairment and long-term cosmetic problems.

Correlation of Body Composition via Bioelectrical Impedance Analysis and Motor Function and Recovery of Upper Extremity in Patients Undergoing Stroke Rehabilitation.

Bioelectrical impedance analysis (BIA) has been used to investigate the body compositions and predict functional outcomes in patients with stroke, while the role of BIA to predict motor function or recovery in stroke has not been clarified. This study aimed to investigate relationship between body composition measured by BIA and upper limb motor function and recovery. Body compositions (soft tissue lean mass, phase angle, body fat mass and body water) of fifty patients who are admitted to the stroke rehabilitation unit were segmentally analyzed via BIA. The motor recovery of upper extremity (UE) was evaluated via Fugl-Meyer Assessment (UE-FMA) at the time of transfer and discharge. Correlations between body composition and UE-FMA at discharge were analyzed using Spearman correlation coefficient. Multiple regression analysis was used to determine the regression between body composition and motor function and recovery. The Δ Phase angle, the difference of both sides was significantly linearly inversely correlated with UE-FMA at discharge. However, in multiple regression analysis, body compositions including phase angle did not significantly predict motor function at discharge or motor recovery. The Δ Phase angle is related to the severity of upper limb motor function at discharge in subacute stroke patients, and further studies are needed to determine its value as a predictor for motor recovery.

Concurrence of Congenital Muscular Torticollis and Congenital Torticollis Due to Other Anomalies: Two Case Reports.

Introduction: Congenital muscular torticollis (CMT) is the most common cause of torticollis in infants; other causes, including osseous, ocular, and central nervous system torticollis can easily be overlooked. We report two rare cases of CMT with concurrent osseous or ocular torticollis. Case 1: A 1-month-old female infant with a right neck mass and right-tilting head posture was referred. Neck ultrasonography showed diffuse hypertrophy and hyperechoic findings on the right sternocleidomastoid (SCM) muscle, which was consistent with right CMT. A clavicle X-ray imaging was conducted to identify an associated fracture due to birth trauma on the same day and a suspected congenital vertebral anomaly was coincidentally found. Subsequent three-dimensional computed tomography of the cervical spine showed a T1 hemivertebra causing the right-tilting head. The patient was diagnosed with the concurrent manifestation of CMT and congenital osseous torticollis. Case 2: A 3-month-old male infant with a 20° head tilt to the right with a limited cervical range of motion was referred. Neck ultrasonography showed a fibromatosis colli in the right SCM, suggesting CMT. He proceeded to physical therapy for seven months; however, there was little clinical improvement in his head and neck posture. The patient underwent an additional ophthalmologic examination and orbital magnetic resonance imaging (MRI) at 10 months of age. The result showed congenital agenesis of the left fourth cranial nerve with hypoplasia of the superior oblique muscle causing the right-tilting of the head. Ultimately, the boy was diagnosed with a concurrent manifestation of CMT and congenital ocular torticollis. Conclusion: Unless careful examinations are conducted, congenital vertebral anomalies and congenital agenesis of the fourth cranial nerve can go unnoticed in the present two cases. If a patient with CMT displays unusual features or does not respond to physical therapy, clinicians should consider not only a differential diagnosis but also concurrence with other causes of congenital torticollis.

Volumetric change of the latissimus dorsi muscle after postoperative chemotherapy and radiotherapy in immediate breast reconstruction with an extended latissimus dorsi musculocutaneous flap: final results from serial studies.

BACKGROUND: Breast reconstruction using an extended latissimus dorsi (eLD) flap can supplement more volume than reconstruction using various local flaps after partial mastectomy, and it is a valuable surgical method since the reconstruction area is not limited. However, when performing reconstruction, the surgeon should consider latissimus dorsi (LD) volume reduction due to postoperative chemotherapy (POCTx) and postoperative radiotherapy (PORTx). To evaluate the effect of POCTx and PORTx on LD volume reduction, the effects of each therapy-both separately and jointly-need to be demonstrated. The present study quantified LD volume reduction in patients who underwent POCTx and PORTx after receiving breast-conserving surgery (BCS) with an eLD flap. METHODS: This study included 48 patients who received immediate breast reconstruction using an eLD flap from January 2013 to March 2017, had chest computed tomography (CT) 7-10 days after surgery and 10-14 months after radiotherapy completion, and were observed for more than 3 years postoperatively. One surgeon performed the breast reconstruction procedures, and measurements of breast volume were obtained from axial CT views, using a picture archiving and communication system. A P-value <0.05 was the threshold for statistical significance. RESULTS: The average volume reduction of LD at 10-14 months after completing POCTx and PORTx was 64.5% (range, 42.8%-81.4%) in comparison to the volume measured 7-10 days after surgery. This change was statistically significant (P<0.05). CONCLUSIONS: Based on the findings of this study, when harvesting an eLD flap, surgeons should anticipate an average LD volume reduction of 64.5% if chemotherapy and radiotherapy are scheduled after BCS with an eLD flap.

The effects of additional electrical stimulation combined with repetitive transcranial magnetic stimulation and motor imagery on upper extremity motor recovery in the subacute period after stroke: A preliminary study.

BACKGROUND: To evaluate the therapeutic effects of additional electrical stimulation (ES) combined with low frequency (LF)-repetitive transcranial magnetic stimulation (rTMS) and motor imagery (MI) training on upper extremity (UE) motor function following stroke. METHODS: The participants with subacute stroke in the experimental group (n = 8) received LF rTMS + MI + active ES interventions, and those in control group (n = 9) received LF rTMS + MI + sham ES interventions. Interventions were performed 5 days a week for 2 weeks, for a total of 10 sessions. All participants were given the same dosage of conventional rehabilitation during the study period. The primary outcome measure was the UE Fugl-Meyer Assessment (FMA). The secondary outcome measures were the shoulder abduction and finger extension scores, modified Barthel Index, Purdue Pegboard Test, and finger tapping test. All scores were measured before and just after the intervention. RESULTS: After the 2-week intervention period, the FMA and modified Barthel Index scores were improved in both groups compared to baseline assessment (P < .001 in the experimental group and P = .008 in the control group). Of note, the change in FMA scores was significantly higher in the experimental group compared with that of the control group (P = .04). CONCLUSION: These results suggest that the use of LF rTMS + MI combined with additional ES lead to greater improvement of UE motor function after stroke. As such, this intervention may be a promising adjuvant therapy in UE motor training.

Molecular Analysis of the Interaction between Human PTPN21 and the Oncoprotein E7 from Human Papillomavirus Genotype 18.

Human papillomaviruses (HPVs) cause cellular hyperproliferation-associated abnormalities including cervical cancer. The HPV genome encodes two major viral oncoproteins, E6 and E7, which recruit various host proteins by direct interaction for proteasomal degradation. Recently, we reported the structure of HPV18 E7 conserved region 3 (CR3) bound to the protein tyrosine phosphatase (PTP) domain of PTPN14, a well-defined tumor suppressor, and found that this intermolecular interaction plays a key role in E7-driven transformation and tumorigenesis. In this study, we carried out a molecular analysis of the interaction between CR3 of HPV18 E7 and the PTP domain of PTPN21, a PTP protein that shares high sequence homology with PTPN14 but is putatively oncogenic rather than tumor-suppressive. Through the combined use of biochemical tools, we verified that HPV18 E7 and PTPN21 form a 2:2 complex, with a dissociation constant of 5 nM and a nearly identical binding manner with the HPV18 E7 and PTPN14 complex. Nevertheless, despite the structural similarities, the biological consequences of the E7 interaction were found to differ between the two PTP proteins. Unlike PTPN14, PTPN21 did not appear to be subjected to proteasomal degradation in HPV18-positive HeLa cervical cancer cells. Moreover, knockdown of PTPN21 led to retardation of the migration/invasion of HeLa cells and HPV18 E7-expressing HaCaT keratinocytes, which reflects its protumor activity. In conclusion, the associations of the viral oncoprotein E7 with PTPN14 and PTPN21 are similar at the molecular level but play different physiological roles.

Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer.

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

Comparison of breast volume change between oncoplastic breast-conserving surgery with radiation therapy and a simultaneous contralateral balancing procedure through the inverted-T scar technique.

BACKGROUND: Reduction mammoplasty or mastopexy is performed as an additional balancing procedure in patients with large or ptotic breasts who undergo breast-conserving surgery (BCS). Radiation therapy on breasts that have undergone surgery may result in changes in the volume. This study presents a comparative analysis of patients who received post-BCS balancing procedures to determine whether volume changes were larger in breasts that received radiation therapy than on the contralateral side. METHODS: Thirty-six participants were selected among patients who received BCS using the inverted-T scar technique between September 2012 and July 2017, were followed up for 2 or more years, and had pre-radiation therapy computed tomography images and post-radiation therapy images taken between 12 and 18 months after completion. The average age of the participants was 53.5 years, their average body mass index was 26.62 kg/m2. RESULTS: The pre- and post-radiation therapy volumes of the breasts receiving BCS were 666.08±147.48 mL and 649.33±130.35 mL, respectively. In the contralateral breasts, the volume before radiation therapy was 637.69±145.72 mL, which decreased to 628.14±166.41 mL after therapy. The volume ratio of the affected to the contralateral breasts was 1.05±0.10 before radiation therapy and 1.06±0.12 after radiation therapy. CONCLUSIONS: The ratio of the volume between the two breasts immediately after surgery and at roughly 18 months postoperatively was not significantly different (P=0.98). For these reasons, we recommend a simultaneous single-stage balancing procedure as a reasonable option for patients who require radiation therapy after BCS without concerns regarding volume change.

Value of the Frontal Assessment Battery Tool for Assessing the Frontal Lobe Function in Stroke Patients.

OBJECTIVE: To examine the correlation between the Frontal Assessment Battery (FAB) test, which is used to assess the frontal lobe function, and anatomical lesions as well as the ability of the test to detect frontal lobe dysfunction. METHODS: Records of stroke patients undergoing a FAB test and Mini-Mental State Examination (MMSE) were retrospectively reviewed. The patients were divided into three groups according to the lesions determined by an imaging study: frontal lobe cortex lesions, frontal subcortical circuit lesions, and other lesions. The FAB scores of the three groups were compared using the Kruskal-Wallis test. The validity of the FAB test to detect frontal lobe dysfunction was assessed by a comparison with the Computerized Neuropsychological Function Test (CNT) using the Spearman correlation coefficient. The correlation coefficients between the FAB test and MMSE were analyzed further based on the MMSE cutoff score. RESULTS: Patients with frontal cortex lesions had significantly lower total and subtest scores according to the FAB test than the other patients. The FAB test correlated better with the CNT than the MMSE, particularly in the executive function and memory domains. A high MMSE score (r=0.435) indicated a lower correlation with the FAB test score than a low MMSE score (r=0.714). CONCLUSION: The FAB test could differentiate frontal lobe lesions from others in stroke patients and showed a good correlation with the CNT. Moreover, the FAB test can be used in patients with high MMSE scores to detect frontal lobe dysfunction and determine the treatment strategies for stroke patients.

Volumetric change of the latissimus dorsi muscle after postoperative radiotherapy in immediate breast reconstruction with an extended latissimus dorsi musculocutaneous flap.

BACKGROUND: This study aimed to determine the magnitude of volume reduction of the latissimus dorsi (LD) muscle after treatment using only postoperative radiotherapy (PORTx) in patients who underwent immediate breast reconstruction using an extended LD musculocutaneous (eLDMC) flap after partial mastectomy. METHODS: We retrospectively reviewed 28 patients who underwent partial mastectomy and an eLDMC flap, received only PORTx, and underwent chest computed tomography (CT) 7 to 10 days after surgery and 18±4 months after the end of radiotherapy, from March 2011 to June 2016. The motor nerve to the LD was resected in all patients. One plastic surgeon performed the procedures, and the follow-up period was at least 36 months (mean, 46.6 months). The author obtained LD measurements from axial CT views, and the measurements were verified by an experienced radiologist. The threshold for statistical significance was set at P<0.05. RESULTS: A statistically significant decrease in the LD volume was found after the end of PORTx (range, 61.19%-80.82%; mean, 69.04%) in comparison to the measurements obtained 7 to 10 days postoperatively (P<0.05). All cases were observed clinically for over 3 years. CONCLUSIONS: The size of an eLDMC flap should be determined considering an average LD reduction of 69% after PORTx. Particular care should be taken in determining the size of an eLDMC flap if the LD is thick or if it occupies a large portion of the flap.

Attachment distribution of pectoral muscle origins identified in dual-plane breast implant insertion.

BACKGROUND: Implant-based dual-plane augmentation mammoplasty requires accurate separation of the pectoralis major muscle (PMM) at its origins. The authors identified the PMM origins during breast reconstruction surgery with the goal of providing additional information on subpectoral implant insertion for reconstructive or aesthetic purposes. METHODS: This study was conducted on 67 patients who underwent breast reconstruction surgery at the breast center of our hospital between November 2016 and June 2018. In total, 34 left and 39 right hemithoraces were examined. The left and right hemithoraces were each divided into 15 zones to determine the percentage of PMM attachments in each zone. The distribution of PMM origins in each zone was examined to identify any statistically significant differences. RESULTS: There were no statistically significant differences in the origins of the PMM between the right and left hemithoraces. The percentage of attachments increased moving from the fourth to the sixth rib and from the lateral to the medial aspect. CONCLUSIONS: The anatomical findings of this study could be used as a reference for accurate dissection of the origins of the PMM for the preparation of the subpectoral pocket for subpectoral implant placement.

Effect of lidocaine on pain caused by nasal pack removal after closed reduction of nasal bone fractures.

BACKGROUND: Pain caused by nasal pack removal after closed reduction of nasal bone fractures is a common problem. This study investigated the effect of infiltrating lidocaine into nasal packs on the pain caused by pack removal after closed reduction of nasal bone fractures. METHODS: Seventy-five patients who underwent closed reduction of nasal bone fractures between March 2016 and March 2018 were enrolled in this prospective, randomized, single-blind study. Merocel (hydroxylated polyvinyl acetate) packs were applied bilaterally and retained for 5 days. Twenty minutes before removal, both packs were rehydrated with 6 mL of 2% lidocaine in 26 patients and with 6 mL of saline in 24 patients; the packs were not rehydrated in 25 patients. Visual analog scale (VAS) scores for pain on removal were recorded. RESULTS: The mean VAS score was 5.3±2.0 in all patients, 3.8±1.5 in the lidocaine group, 5.8±1.4 in the saline group, and 6.3±2.1 in the non-rehydrated group. There was a significant difference in the pain score between the lidocaine and saline groups (P<0.001) but not between the saline and non-rehydrated groups (P=0.186). CONCLUSIONS: Infiltration of lidocaine into Merocel packs reduced the pain caused by pack removal after closed reduction of nasal bone fractures.

Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization.

Cathepsin K (Cat K) is expressed in cancer cells, but the effect of Cat K on apoptosis is still elusive. Here, we showed that inhibition of Cat K sensitized the human carcinoma cells to anti-cancer drug through up-regulation of Bim. Inhibition of Cat K increased USP27x expression, and knock down of USP27x markedly blocked Cat K-induced up-regulation of Bim expression. Furthermore, inhibition of Cat K induced proteasome-dependent degradation of regulatory associated protein of mammalian target of rapamycin (Raptor). Down-regulation of Raptor expression increased mitochondrial ROS production, and mitochondria specific superoxide scavengers prevented USP27x-mediated stabilization of Bim by inhibition of Cat K. Moreover, combined treatment with Cat K inhibitor (odanacatib) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reduced tumor growth and induced cell death in a xenograft model. Our results demonstrate that Cat K inhibition enhances anti-cancer drug sensitivity through USP27x-mediated the up-regulation of Bim via the down-regulation of Raptor.