The Expression and Amplification of HER2 Has a Significant Impact on the Prognosis of Endometrial Carcinoma in Korean Patients.

Objective: The purpose of this study was to analyze the protein overexpression and gene amplification of HER2 in endometrial carcinoma (EC) and to evaluate its role as a prognostic factor in Korean women. Methods: A tissue microarray (TMA) was constructed from samples from 191 patients with diverse histologic types of EC. HER2 protein expression and gene amplification status were analyzed using immunohistochemistry (IHC) and silver in situ hybridization (SISH), respectively. All patients were treated and followed up at a single tertiary medical center in Seoul, Korea, between July 2009 and October 2020. Results: In terms of histological type, among the 191 EC patients, 157 had endometrioid carcinoma, nine had uterine serous papillary carcinoma (USPC), one had clear cell carcinoma, one had squamous cell carcinoma, eight had mixed carcinoma, and 15 had uterine carcinosarcoma (UC). HER2 protein overexpression was observed in eight of the 191 (4.2%) EC patients; of these patients, five had IHC scores of 2+, and three had IHC scores of 3+. The HER2 overexpression rates of USPC, UC, and endometrioid carcinomas were 33.3%, 26.6%, and 0.6%, respectively. HER2 protein overexpression was significant in USPC and UC tissues (p < 0.000) and was associated with poor overall survival (OS) (p < 0.001). HER2 gene amplification was confirmed in seven of 184 patients (3.8%), including three patients with USPC and four patients with UC. OS was significantly shorter in patients who had HER2 amplification (p < 0.001). On multivariate analysis, HER2 expression and HER2 amplification were statistically significantly associated with worse OS (p = 0.006). However, HER2 expression without amplification was not statistically associated with OS (p = 0.993). Conclusions: HER2 protein overexpression and gene amplification are significantly correlated with shorter OS in Korean women. HER2 can be considered an important predictor of survival outcomes in EC patients.

Therapeutic Singing and Semi-Occluded Vocal Tract Exercises for Individuals with Parkinson's Disease: A Randomized Controlled Trial of a Single Session Intervention.

Individuals with Parkinson's disease (PD) experience speech and voice-related symptoms that diminish communication and quality of life. Semi-occluded vocal tract (SOVT) exercises are targeted interventions that, when combined with the positive psychosocial benefits of therapeutic group singing (TGS), may affect outcomes. The purpose of this study was to explore the effectiveness of SOVT exercises, specifically straw phonation combined with TGS, to improve voice quality and mood for individuals with PD. We used a true experimental pretest-posttest between-subjects design (i.e., randomized controlled trial) facilitated by a board-certified music therapist. All participants (N = 27) were randomly assigned to one of three groups (a) straw phonation combined with TGS (SP + TGS, n = 10), (b) TGS (n = 10), and (c) speaking-only control group (n = 7). Participants completed voice recordings for acoustic measures and the Visual Analogue Mood Scale for mood analysis before and after a 30-min intervention. The results demonstrated significant improvement in voice quality evidenced by decreasing Acoustic Voice Quality Index scores following a single session for both SP + TGS and TGS intervention groups when compared to the control. Happiness scores improved in the experimental groups when compared to control. Although not statistically significant, participants in the experimental groups (SP + TGS, TGS) demonstrated better mean mood scores on happiness, anxiety, and angry when compared to control, indicating a positive psychological response to the singing interventions. Overall, this study indicated the effectiveness of SP + TGS and TGS as promising therapeutic interventions for voice quality and mood in individuals with PD.

[Imaging of Sequestered Lumbar Discs]. / 요추 분리추간판의 영상 소견.

Intervertebral disc herniation is frequently encountered in radiological practice. Sequestered disc herniation occurs when the disc material undergoes degeneration and completely loses continuity with the parent nucleus pulposus. Sequestered discs can reside within and outside the spinal canal, exerting a mass effect on adjacent structures, compressing nerve pathways, and eliciting a range of clinical symptoms. In particular, sequestered discs within the dura cannot be identified without durotomy. Therefore, precise preoperative localization is crucial for surgical planning. On MRI, the signal intensity of the sequestered disc may vary due to independent degeneration processes. Additionally, most sequestered disc fragments show varying degrees of peripheral enhancement depending on the degree of angiogenesis and granulation around the isolated tissue. In this article, we review various imaging findings and the location of the sequestered disc to provide patients with an accurate diagnosis and appropriate treatment direction.

Photocatalytic intermolecular bromonitroalkylation of styrenes: synthesis of cyclopropylamine derivatives and their evaluation as LSD1 inhibitors.

A mild and efficient method for photoredox-catalyzed bromonitroalkylation of alkenes is described herein. In this reaction, bromonitromethane serves as a source of both nitroalkyl and bromine for direct and regioselective formation of C-Br and C-C bonds from alkenes, and additional cyclization provides C-C bonds to the cyclopropylamine core as an LSD1 inhibitor.

Impact of resident participation on surgical outcomes in laparoscopically assisted vaginal hysterectomy.

OBJECTIVE: To compare surgical outcomes in patients with benign diseases who underwent laparoscopically assisted vaginal hysterectomy (LAVH) to determine the association between surgical outcomes and resident participation in the gynecologic field. METHODS: A single-center retrospective study was conducted of patients diagnosed with benign gynecologic diseases who underwent LAVH between January 2010 and December 2015. Clinicopathologic characteristics and surgical outcomes were compared between the resident involvement and non-involvement groups. The primary endpoint was the 30-day postoperative morbidity. Observers were propensity matched for 17 covariates for resident involvement or non-involvement. RESULTS: Of the 683 patients involved in the study, 165 underwent LAVH with resident involvement and 518 underwent surgery without resident involvement. After propensity score matching (157 observations), 30-day postoperative morbidity occurred in 6 (3.8%) and 4 (2.5%) patients in the resident involvement and non-involvement groups, respectively (P = 0.501). The length of hospital stay differed significantly between the two groups: 5 days in the resident involvement group and 4 days in the non-involvement group (P < 0.001). On multivariate analysis, Charlson Comorbidity Index >2 (odds ratio [OR] 8.01, 95% confidence interval [CI] 2.68-23.96; P < 0.001), operative time (OR 1.02, 95% CI 1.01-1.03; P < 0.001), and estimated blood loss (OR 1.00, 95% CI 1.00-1.00; P < 0.001) were significantly associated with 30-day morbidity, but resident involvement was not statistically significant. CONCLUSION: There was no significant difference in the 30-day morbidity rate when residents participated in LAVH. These findings suggest that resident participation in LAVH may be a viable approach to ensure both residency education and patient safety.

Intradural Extramedullary Ependymoma with Hemorrhage: A Case Report.

In adults, spinal ependymomas are usually found in intramedullary locations. However, intradural extramedullary spinal ependymomas are rare. Additionally, spinal ependymomas usually show iso to hypointensity on T1-weighted images without hemorrhage. Herein, we present a rare case of a 43-year-old female with a pathologically confirmed intradural extramedullary ependymoma that showed hyperintensity on T1-weighted imaging accompanied by hemorrhage.

Identification and Biological Evaluation of a Potent and Selective JAK1 Inhibitor for the Treatment of Pulmonary Fibrosis.

Janus kinase 1 (JAK1) plays a pivotal role in regulating inflammation and fibrosis via the JAK/STAT signaling pathway, making it a promising target for associated diseases. In this study, we explored the modification of an N-methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate core, leading to the identification of 4-(((2S,4S)-1-(4-trifluoromethyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (36b) as a highly potent and selective JAK1 inhibitor. Compound 36b exhibited an impressive IC50 value of 0.044 nM for JAK1 and demonstrated remarkable selectivity of 382-fold, 210-fold, and 1325-fold specificity over JAK2, JAK3, and TYK2, respectively. The kinase panel assays further confirmed its specificity, and cell-based experiments established its efficacy in inhibiting JAK1-STAT phosphorylation in human L-132 or SK-MES-1 cells. Pharmacokinetic studies revealed that compound 36b boasts an oral bioavailability exceeding 36%. In a bleomycin-induced fibrosis mouse model, compound 36b significantly reduced STAT3 phosphorylation, resulting in improvement in body weight and reduced collagen deposition, all achieved without significant side effects.

Subunit gating resulting from individual protonation events in Kir2 channels.

Inwardly rectifying potassium (Kir) channels open at the 'helix bundle crossing' (HBC), formed by the M2 helices at the cytoplasmic end of the transmembrane pore. Introduced negative charges at the HBC (G178D) in Kir2.2 channels forces opening, allowing pore wetting and free movement of permeant ions between the cytoplasm and the inner cavity. Single-channel recordings reveal striking, pH-dependent, subconductance behaviors in G178D (or G178E and equivalent Kir2.1[G177E]) mutant channels, with well-resolved non-cooperative subconductance levels. Decreasing cytoplasmic pH shifts the probability towards lower conductance levels. Molecular dynamics simulations show how protonation of Kir2.2[G178D], or the D173 pore-lining residues, changes solvation, K+ ion occupancy, and K+ conductance. Ion channel gating and conductance are classically understood as separate processes. The present data reveal how individual protonation events change the electrostatic microenvironment of the pore, resulting in step-wise alterations of ion pooling, and hence conductance, that appear as 'gated' substates.

Unusual Manifestation of Immunoglobulin G4-Related Disease Involving the Upper Arm: A Case Report.

Immunoglobulin G4 (IgG4)-related disease is a rare systemic fibroinflammatory condition characterized by organomegaly or tumefactive lesions associated with lymphoplasmacytic infiltration rich in IgG4 plasma cells. We report a case of IgG4-related disease involving the subcutaneous layer of the left upper arm in a 48-year-old female presenting with an unusual soft tissue mass. US and MRI showed an irregular infiltrative soft tissue mass, indicating possible malignancy or inflammation. We discuss the diagnostic criteria, histopathologic features, radiological features, and treatment of IgG4-related disease.

Image quality and lesion detectability of deep learning-accelerated T2-weighted Dixon imaging of the cervical spine.

OBJECTIVES: To validate the subjective image quality and lesion detectability of deep learning-accelerated Dixon (DL-Dixon) imaging of the cervical spine compared with routine Dixon imaging. MATERIALS AND METHODS: A total of 50 patients underwent sagittal routine Dixon and DL-Dixon imaging of the cervical spine. Acquisition parameters were compared and non-uniformity (NU) values were calculated. Two radiologists independently assessed the two imaging methods for subjective image quality and lesion detectability. Interreader and intermethod agreements were estimated with weighted kappa values. RESULTS: Compared with the routine Dixon imaging, the DL-Dixon imaging reduced the acquisition time by 23.76%. The NU value is slightly higher in DL-Dixon imaging (p value: 0.015). DL-Dixon imaging showed superior visibility of all four anatomical structures (spinal cord, disc margin, dorsal root ganglion, and facet joint) for both readers (p value: < 0.001 ~ 0.002). The motion artifact scores were slightly higher in the DL-Dixon images than in routine Dixon images (p value = 0.785). Intermethod agreements were almost perfect for disc herniation, facet osteoarthritis, uncovertebral arthritis, central canal stenosis (κ range: 0.830 ~ 0.980, all p values < 0.001) and substantial to almost perfect for foraminal stenosis (κ = 0.955, 0.705 for each reader). There was an improvement in the interreader agreement of foraminal stenosis by DL-Dixon images, from moderate to substantial agreement. CONCLUSION: The DLR sequence can substantially decrease the acquisition time of the Dixon sequence with subjective image quality at least as good as the conventional sequence. And no significant differences in lesion detectability were observed between the two sequence types.

Oxidation Driven Reversal of PIP2-dependent Gating in GIRK2 Channels.

Physiological activity of G protein gated inward rectifier K+ (GIRK, Kir3) channel, dynamically regulated by three key ligands, phosphoinositol-4,5-bisphosphate (PIP2), Gßγ, and Na+, underlies cellular electrical response to multiple hormones and neurotransmitters in myocytes and neurons. In a reducing environment, matching that inside cells, purified GIRK2 (Kir3.2) channels demonstrate low basal activity, and expected sensitivity to the above ligands. However, under oxidizing conditions, anomalous behavior emerges, including rapid loss of PIP2 and Na+-dependent activation and a high basal activity in the absence of any agonists, that is now paradoxically inhibited by PIP2. Mutagenesis identifies two cysteine residues (C65 and C190) as being responsible for the loss of PIP2 and Na+-dependent activity and the elevated basal activity, respectively. The results explain anomalous findings from earlier studies and illustrate the potential pathophysiologic consequences of oxidation on GIRK channel function, as well as providing insight to reversed ligand-dependence of Kir and KirBac channels.

Laparoscopic radical hysterectomy without uterine manipulator or vaginal tube use.

In the Laparoscopic Approach to Cervical Cancer trial, minimally invasive surgery (MIS) has been associated with significantly lower disease-free survival and overall survival rates. The proposed reasons for the increased recurrence and mortality associated with MIS are uterine manipulation, the effect of insufflation gas (CO2), and intracorporeal colpotomy. We applied 2 techniques during surgery to reduce tumor spillage in laparoscopic radical hysterectomy (LRH), which included avoiding using a uterine manipulator and containing the colpotomy using an endoscopic stapler. We aimed to introduce an easy and comfortable traction method with tagged uterine sutures instead of a manipulator or vaginal tube for minimally invasive radical hysterectomy (RH). The patient underwent LRH. After entering the peritoneal cavity, tubal ligation was performed with an endoscopic clip to prevent tumor spillage via the fallopian tubes. Then, the uterine fundus was tied with needle-straightened multifilament Vicryl 2-0, and the tagged uterus was manipulated. Thereafter, pelvic lymphadenectomy was performed before RH. Thereafter, we performed intracorporeal colpotomy by resecting the vagina twice using an endoscopic stapler. Finally, the stapled vaginal stump was resected to retrieve the specimen via the vaginal opening using monopolar scissors after the vagina was washed several times with sterile water. After removing the specimen, the vaginal stump was endoscopically closed with a barbed suture. LRH can be feasibly performed in patients with uterine cervical neoplasm by retracting tagged uterine sutures without the use of a uterine manipulator.

Surgical Treatment Outcomes of Gynecologic Cancer in Older Patients: A Retrospective Study.

This study aimed to evaluate oncologic characteristics and surgical outcomes in older patients with gynecologic cancers. This retrospective study included patients aged ≥65 years who were diagnosed with gynecologic cancers and underwent surgical treatment between 2005 and 2020. We reviewed the medical records for age at diagnosis, body mass index, American Society of Anesthesiologists score, comorbidities, postoperative complications, cancer stage, histologic type, surgical treatment, postoperative outcome, and survival rate. Data were compared between groups according to the age at the time of diagnosis: <75 years (young-old) and ≥75 years (old-old). In total, 131 patients were identified: 53 (40.5%) with ovarian or primary peritoneal cancer (OC), 44 (33.6%) with endometrial cancer (EC), 30 (22.9%) with cervical cancer, and 4 (3.1%) with leiomyosarcoma. The patients' mean age was 70 (range, 65-83) years; 106 (80.9%) were young-old and 25 (19.1%) were old-old. Postoperative complications occurred in 19 (14.5%) patients. Four patients died within six months after surgery, and three died because of disease progression. There was no difference in the survival rates between the two groups among those with OC and EC. Older patients with gynecologic cancers showed good surgical outcomes and tolerable postoperative complications. Therefore, we can safely offer surgical treatment to older patients.

Subunit gating resulting from individual protonation events in Kir2 channels.

Inwardly rectifying potassium (Kir) channels play a critical role in stabilizing the membrane potential, thus controlling numerous physiological phenomena in multiple tissues. Channel conductance is activated by cytoplasmic modulators that open the channel at the 'helix bundle crossing' (HBC), formed by the coming together of the M2 helices from each of the four subunits, at the cytoplasmic end of the transmembrane pore. We introduced a negative charge at the bundle crossing region (G178D) in classical inward rectifier Kir2.2 channel subunits that forces channel opening, allowing pore wetting and free movement of permeant ions between the cytoplasm and the inner cavity. Single-channel recordings reveal a striking pH-dependent subconductance behavior in G178D (or G178E and equivalent Kir2.1[G177E]) mutant channels that reflects individual subunit events. These subconductance levels are well resolved temporally and occur independently, with no evidence of cooperativity. Decreasing cytoplasmic pH shifts the probability towards lower conductance levels, and molecular dynamics simulations show how protonation of Kir2.2[G178D] and, additionally, the rectification controller (D173) pore-lining residues leads to changes in pore solvation, K+ ion occupancy, and ultimately K+ conductance. While subconductance gating has long been discussed, resolution and explanation have been lacking. The present data reveals how individual protonation events change the electrostatic microenvironment of the pore, resulting in distinct, uncoordinated, and relatively long-lasting conductance states, which depend on levels of ion pooling in the pore and the maintenance of pore wetting. Gating and conductance are classically understood as separate processes in ion channels. The remarkable sub-state gating behavior of these channels reveals how intimately connected 'gating' and 'conductance' are in reality.

ABCA1-Mediated EMT Promotes Papillary Thyroid Cancer Malignancy through the ERK/Fra-1/ZEB1 Pathway.

Papillary thyroid cancer (PTC) is the most prevalent histological type of thyroid cancer (TC) worldwide. Although tumor metastasis occurs in regional lymph nodes, distant metastasis (DM) may also occur. Radioactive iodine (RAI) therapy is an effective treatment for TC; however, resistance to RAI occurs in patients with DM. Therefore, in this study, we investigated the efficacy of DM-related biomarkers as therapeutic targets for PTC therapy. ABCA1 expression was higher in aggressive BCPAP cells than in other PTC cells in terms of migration and invasion capacity. The knockdown of ABCA1 substantially decreased the expression of the epithelial-mesenchymal transition (EMT) marker, N-cadherin, and EMT regulator (ZEB1), resulting in suppressed migration and invasion of BCPAP cells. ABCA1 knockdown also reduced ERK activity and Fra-1 expression, which correlated with the effects of an ERK inhibitor or siRNA-mediated inhibition of ERK or Fra-1 expression. Furthermore, ABCA1-knocked-down BCPAP cells suppressed cell migration and invasion by reducing Fra-1 recruitment to Zeb1 promoter; lung metastasis was not observed in mice injected with ABCA1-knocked-down cells. Overall, our findings suggest that ABCA1 regulates lung metastasis in TC cells.

Seeing spermine blocking of K+ ion movement through inward rectifier Kir2.2 channels.

Inwardly rectifier potassium (Kir) channels are a major potassium channel sub-class whose function is regulated by ligand-dependent gating and highly voltage-dependent block by polyamines. With molecular dynamics simulations over previously unattainable timescales, Jogini et al. (J. Gen. Physiol. https://doi.org/10.1085/jgp.202213085) provide unprecedented visualization of K+ conduction through open Kir2.2 channels and of the molecular details of channel block by spermine.

Diffuse Large B-Cell Lymphoma Associated with a Chronic Inflammatory Condition Induced by Metallic Implants: A Case Report.

Chronic inflammatory condition associated with metallic implant insertion is a risk factor for diffuse large B-cell lymphoma (DLBCL). Metal ions play a role in the pathogenesis of lymphoma. We report a rare case of DLBCL in a patient who had a metallic implant in the proximal tibia for 15 months. Radiologic studies, including US and MRI, showed disproportionately large extraosseous soft-tissue mass and bone marrow involvement without prominent bone destruction. Multiple complications are associated with metallic implants, and misdiagnosis may lead to inappropriate treatment. Therefore, distinguishing lymphomas caused by a metallic implant-induced chronic inflammatory condition from other periprosthetic benign lesions and malignant soft tissue masses is challenging, but it is critical.

Comparison of MR Findings between Patients with Septic Arthritis and Acute Gouty Arthritis of the Knee.

Purpose: To compare the MR findings of septic and acute gouty arthritis of the knee joint. Materials and Methods: This retrospective study included patients who underwent knee MRI for septic or gouty arthritis at our hospital between October 2012 and October 2018. The MR findings were analyzed for the presence of bone marrow edema, soft tissue edema, abscess, pattern of synovial thickening (frondlike, lamellated, diffuse linear), maximum thickness of the synovium, and joint effusion volume. The gouty (n = 5) and septic arthritis (n = 10) groups were compared using the Wilcoxon rank-sum test and Fisher's exact test. Results: No statistically significant differences were observed for each item. One patient in the gouty arthritis group and seven in the septic arthritis group had bone marrow edema. Soft tissue abscess formation was only observed in the septic group. The incidence of each synovial thickening pattern was as follows: 100% (diffuse linear) in the gouty arthritis group and 20% (frondlike), 50% (lamellated), and 30% (diffuse linear) in the septic arthritis group. Conclusion: Differentiation of gouty arthritis and septic arthritis based on imaging findings is difficult. However, lamellated synovial thickening patterns, bone marrow edema, and soft tissue abscess formation are more commonly observed in patients with septic arthritis than in those with gouty arthritis.

Centella asiatica-Derived Endothelial Paracrine Restores Epithelial Barrier Dysfunction in Radiation-Induced Enteritis.

Radiation-induced enteritis is frequently observed following radiotherapy for cancer or occurs due to radiation exposure in a nuclear accident. The loss of the epithelial integrity leads to 'leaky gut', so recovery of damaged epithelium is an important strategy in therapeutic trials. Centella asiatica (CA), a traditional herbal medicine, is widely used for wound healing by protecting against endothelial damage. In this study, we investigated the radio-mitigating effect of CA, focusing on the crosstalk between endothelial and epithelial cells. CA treatment relieved radiation-induced endothelial dysfunction and mitigated radiation-induced enteritis. In particular, treatment of the conditioned media from CA-treated irradiated endothelial cells recovered radiation-induced epithelial barrier damage. We also determined that epidermal growth factor (EGF) is a critical factor secreted by CA-treated irradiated endothelial cells. Treatment with EGF effectively improved the radiation-induced epithelial barrier dysfunction. We also identified the therapeutic effects of CA-induced endothelial paracrine in a radiation-induced enteritis mouse model with epithelial barrier restoration. Otherwise, CA treatment did not show radioprotective effects on colorectal tumors in vivo. We showed therapeutic effects of CA on radiation-induced enteritis, with the recovery of endothelial and epithelial dysfunction. Thus, our findings suggest that CA is an effective radio-mitigator against radiation-induced enteritis.

Zileuton Alleviates Radiation-Induced Cutaneous Ulcers via Inhibition of Senescence-Associated Secretory Phenotype in Rodents.

Radiation-induced cutaneous ulcers are a challenging medical problem for patients receiving radiation therapy. The inhibition of cell senescence has been suggested as a prospective strategy to prevent radiation ulcers. However, there is no effective treatment for senescent cells in radiation ulcers. In this study, we investigated whether zileuton alleviated radiation-induced cutaneous ulcer by focusing on cell senescence. We demonstrate increased cell senescence and senescence-associated secretory phenotype (SASP) in irradiated dermal fibroblasts and skin tissue. The SASP secreted from senescent cells induces senescence in adjacent cells. In addition, 5-lipoxygenase (5-LO) expression increased in irradiated dermal fibroblasts and skin tissue, and SASP and cell senescence were regulated by 5-LO through p38 phosphorylation. Finally, the inhibition of 5-LO following treatment with zileuton inhibited SASP and mitigated radiation ulcers in animal models. Our results demonstrate that inhibition of SASP from senescent cells by zileuton can effectively mitigate radiation-induced cutaneous ulcers, indicating that inhibition of 5-LO might be a viable strategy for patients with this condition.