Multiple machine learning methods aided virtual screening of NaV 1.5 inhibitors.

Nav 1.5 sodium channels contribute to the generation of the rapid upstroke of the myocardial action potential and thereby play a central role in the excitability of myocardial cells. At present, the patch clamp method is the gold standard for ion channel inhibitor screening. However, this method has disadvantages such as high technical difficulty, high cost and low speed. In this study, novel machine learning models to screen chemical blockers were developed to overcome the above shortage. The data from the ChEMBL Database were employed to establish the machine learning models. Firstly, six molecular fingerprints together with five machine learning algorithms were used to develop 30 classification models to predict effective inhibitors. A validation and a test set were used to evaluate the performance of the models. Subsequently, the privileged substructures tightly associated with the inhibition of the Nav 1.5 ion channel were extracted using the bioalerts Python package. In the validation set, the RF-Graph model performed best. Similarly, RF-Graph produced the best result in the test set in which the Prediction Accuracy (Q) was 0.9309 and Matthew's correlation coefficient was 0.8627, further indicating the model had high classification ability. The results of the privileged substructures indicated Sulfa structures and fragments with large Steric hindrance tend to block Nav 1.5. In the unsupervised learning task of identifying sulfa drugs, MACCS and Graph fingerprints had good results. In summary, effective machine learning models have been constructed which help to screen potential inhibitors of the Nav 1.5 ion channel and key privileged substructures with high affinity were also extracted.

HER2 Genetic Intratumor Heterogeneity Is Associated With Resistance to Trastuzumab and Trastuzumab Emtansine Therapy in Recurrent High-Grade Endometrial Cancer.

Anti-HER2 targeted therapies have recently demonstrated clinical activity in the treatment of high-grade endometrial carcinomas (ECs), particularly serous carcinomas with HER2 amplification and/or overexpression. Intratumor heterogeneity of HER2 amplification or HER2 genetic intratumor heterogeneity (G-ITH) has been associated with resistance to anti-HER2 therapies in breast and gastroesophageal cancers; however, its clinical relevance in EC is unknown. To characterize HER2 G-ITH in EC, archival specimens from a clinically annotated cohort of 57 ECs treated with trastuzumab or trasutuzmab emtansine in the recurrent (n = 38) or adjuvant (n = 19) setting were subjected to central pathology review, HER2 assessment by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and next-generation sequencing. HER2 G-ITH, defined as HER2 amplification in 5% to 50% of tumor cells examined by FISH, was identified in 36% (19/53) of ECs and was associated with lower HER2 copy number and levels of protein expression. HER2 IHC revealed spatially distinct areas of strong expression juxtaposed with areas of low/absent expression in tumors with the "cluster" pattern of G-ITH, whereas the "mosaic" pattern was typically associated with a diffuse admixture of cells with variable levels of HER2 expression. HER2 G-ITH was frequently observed in cases with IHC/FISH or FISH/next-generation sequencing discrepancies and/or with an equivocal/negative FISH result (9/13, 69%). Although the objective response rate to anti-HER2 therapy in recurrent ECs was 52% (13/25) for tumors lacking HER2 G-ITH, none (0%, 0/10) of the patients with HER2 G-ITH achieved a complete or partial response (P = .005). HER2 G-ITH was significantly associated with worse progression-free survival (hazard ratio, 2.88; 95% CI, 1.33-6.27; P = .005) but not overall survival. HER2 IHC score, HER2/CEP17 ratio, HER2 copy number, histologic subtype, and other genetic alterations, including PIK3CA hotspot mutations, were not significantly associated with therapeutic response or survival outcomes. Treatment responses were not restricted to serous carcinomas, supporting consideration of anti-HER2 therapy in patients with HER2-positive high-grade ECs of non-serous histology. Our results demonstrate that HER2 G-ITH is an important determinant of response to trastuzumab and trastuzumab emtansine in EC, providing a rationale for the development of novel therapeutic strategies to target HER2-nonamplified resistant tumor subpopulations, such as HER2 antibody-drug conjugates with bystander effects.

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer.

OBJECTIVE: To evaluate adverse events (AEs) of combination lenvatinib plus pembrolizumab for the treatment of recurrent endometrial cancer (EC) and to assess outcomes by lenvatinib starting dose. METHODS: We retrospectively reviewed patients with recurrent EC treated with lenvatinib plus pembrolizumab at our institution between 10/1/2019-11/30/2021. Starting dose of lenvatinib was defined as standard (20 mg) or reduced (10 mg/14 mg). AEs were manually extracted through chart review and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. PFS, overall survival (OS), and duration of response (DOR) were analyzed. RESULTS: Forty-three patients were identified; median age was 67 years (range, 54-85). The most common histologies were serous (35%), endometrioid (23%), and carcinosarcoma (21%). Starting lenvatinib doses were 10 mg (n = 10), 14 mg (n = 10), and 20 mg (n = 23). Median number of cycles received was 8 (range, 1-42). Twenty-four patients (56%) required ≥1 lenvatinib dose reduction; 3 (7%) discontinued lenvatinib, and 1 (2%) discontinued pembrolizumab for intolerance or AE. Thirty-six patients (84%) experienced grade ≥ 3 AEs; hypertension, weight loss, anemia, fatigue, and thrombocytopenia were most common. The standard dose group experienced significantly shorter observed PFS vs the reduced dose group (P = .02). There was no difference in DOR (P = .09) or OS (P = .27) between the groups. CONCLUSION: In clinical practice, AEs associated with combination lenvatinib plus pembrolizumab were common and comparable to Study 309/KEYNOTE-775 findings. AEs were similar regardless of starting lenvatinib dose. Further dose optimization studies of lenvatinib plus pembrolizumab may be indicated in recurrent EC. Clinical trial data remain the gold standard to guide starting lenvatinib dosing.

Synoptic Reporting for Pretreatment CT Examination in Patients With Advanced Ovarian Cancer: Impact on Documentation of Disease Sites and Physician Satisfaction.

BACKGROUND. Imaging reports that consistently document all disease sites with a potential to increase surgical complexity or morbidity can facilitate ovarian cancer treatment planning. OBJECTIVE. The aims of this study were to compare simple structured reports and synoptic reports from pretreatment CT examinations in patients with advanced ovarian cancer in terms of completeness of documenting involvement of clinically relevant anatomic sites as well as to evaluate physician satisfaction with synoptic reports. METHODS. This retrospective study included 205 patients (median age, 65 years) who underwent contrast-enhanced abdominopelvic CT before primary treatment of advanced ovarian cancer from June 1, 2018, to January 31, 2022. A total of 128 reports generated on or before March 31, 2020, used a simple structured report (free text organized into sections); 77 reports generated on or after April 1, 2020, used a synoptic report (a list of 45 anatomic sites relevant to ovarian cancer management, each of which was classified in terms of disease absence versus presence). Reports were reviewed for completeness of documentation of involvement of the 45 sites. For patients who underwent neoadjuvant chemotherapy based on diagnostic laparoscopy findings or underwent primary debulking surgery with suboptimal resection, the EMR was reviewed to identify surgically established sites of disease that were unresectable or challenging to resect. Gynecologic oncology surgeons were electronically surveyed. RESULTS. The mean report turnaround time was 29.8 minutes for simple structured reports versus 54.5 minutes for synoptic reports (p < .001). A mean of 17.6 of 45 sites (range, four to 43 sites) were mentioned by simple structured reports versus 44.5 of 45 sites (range, 39-45) for synoptic reports (p < .001). Forty-three patients had surgically established unresectable or challenging-to-resect disease; involvement of anatomic site(s) with such disease was mentioned in 37% (11/30) of simple structured reports versus 100% (13/13) of synoptic reports (p < .001). All eight surveyed gynecologic oncology surgeons completed the survey. CONCLUSION. A synoptic report improved completeness of pretreatment CT reports in patients with advanced ovarian cancer, including for established sites of unresectable or challenging-to-resect disease. CLINICAL IMPACT. The findings indicate the role of disease-specific synoptic reports in facilitating referrer communication and potentially guiding clinical decision-making.

Factors affecting interictal unilateral and bilateral discharges and ictal diffusion patterns of scalp electroencephalogram in temporal lobe epilepsy.

BACKGROUND: The interictal discharges of temporal lobe epilepsy (TLE) can be unilateral or bilateral. In addition, the ictal electroencephalogram (EEG) showed the discharges also tend to spread to the contralateral brain in TLE. OBJECTIVE: The factors influencing unilateral and bilateral interictal discharges in TLE as well as ictal diffusion patterns in scalp EEG during onset of seizure were evaluated in the present study. MATERIALS AND METHODS: This was a retrospective analysis of 129 patients with TLE. Cases were classified into unilateral and bilateral discharge groups based on interictal discharge patterns in the EEG. Differences between the two groups in age, gender, disease duration, seizure frequency, magnetic resonance imaging (MRI) findings, origin of TLE, antiepileptic drug (AED) administration, and ictal diffusion patterns during seizures were statistically analyzed. In addition, the differences in ictal diffusion patterns between left and right TLE were statistically analyzed. RESULTS: Statistically significant differences were not observed in gender, disease duration, seizure frequency, MRI findings, administration of AEDs, and ictal diffusion patterns between interictal unilateral and bilateral discharge groups but with statistically significant differences in age and side of origin of the TLE. In addition, whether the EEG-recorded diffusion pattern was confined to the same hemisphere or spread to both hemispheres was investigated and shown statistically significant differences between the left and right temporal lobes. CONCLUSIONS: Age and side of origin of TLE affects the TLE interictal discharge patterns. Older patients are more prone to bilateral discharges. Bilateral discharges are more common in right TLE, and the onset of EEG more likely to bilateral diffusion in right TLE.

Bevacizumab in advanced endometrial cancer.

OBJECTIVE: Prospective data have demonstrated the efficacy of bevacizumab monotherapy in the treatment of advanced endometrial cancer. Bevacizumab is used off-label, and real-world data regarding the role of bevacizumab in endometrial cancer treatment are scant. In this largest single-institution retrospective study of its kind, we report our experience with bevacizumab monotherapy in the treatment of advanced/recurrent endometrial cancer. METHODS: All eligible patients (n = 101) had histologically confirmed endometrial cancer and were treated with bevacizumab at our institution from 2004 to 2017. Demographic data and tumor characteristics were obtained through chart review. Primary objective was response to therapy determined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1). RESULTS: Analysis included 13 grade 1/2 endometrioid, 15 grade 3 endometrioid, 44 serous, 8 carcinosarcoma, and 21 other/mixed histologies. No patients achieved complete (CR) or partial (PR) responses; 19 achieved stable disease (SD). The clinical benefit rate (CBR; CR + PR + SD) was 19% (95% CI: 12-28%). The CBRs were 7%, 17%, 21%, and 23% for patients with 1, 2, 3, and ≥ 4 prior treatment lines. Median PFS ranged from 2.6 months (2 lines) to 4.9 months (≥4 lines). The 3-year OS rate was 58% (95% CI: 47-67%). The median OS was 3.4 years (95% CI: 2.9-4.2), ranging from 2.5 years (2 lines) to 4.5 years (≥4 lines). The most common treatment-related adverse event was hypertension; 35 (78%) of 45 were grade 1 or 2. CONCLUSIONS: In heavily pretreated advanced endometrial cancer, bevacizumab was associated with modest clinical efficacy and remains a viable palliative option in this setting.

A multimodality triage algorithm to improve cytoreductive outcomes in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center team ovary initiative.

OBJECTIVE: To describe outcomes using a multimodal algorithm to triage patients with advanced epithelial ovarian cancer (EOC) to primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT). METHODS: All patients with EOC treated at our institution from 04/2015-08/2018 were identified. We included patients without contraindication to PDS who underwent prospective calculation of a Resectability (R)-score. A low risk score for suboptimal cytoreduction was defined as ≤6, and a high risk score ≥7. Patients were triaged to laparotomy/PDS, laparoscopic evaluation of resectability (LSC), or NACT depending on R-score. RESULTS: Among 299 participants, 226 (76%) had a low risk score and 73 (24%) a high risk score. For patients with a low risk score, management included laparotomy/PDS, 181 (80%); LSC, 43 (19%) (with subsequent triage: PDS, 31; NACT, 12); and NACT, 2 (1%). For patients with a high risk score, management included laparotomy/PDS, 9 (12%); LSC, 51 (70%) (with subsequent triage: PDS, 28; NACT, 23); and NACT, 13 (18%). Overall, 83% underwent PDS, with a 75% CGR rate and 94% optimal cytoreduction rate. Use of the algorithm resulted in a 31% LSC rate and a 6% rate of suboptimal PDS. CONCLUSIONS: The multimodal algorithm led to excellent surgical results; 94% of patients achieved an optimal resection, with a very low rate of suboptimal cytoreduction.

Pre-Operative Interictal Discharge Patterns and Magnetic Resonance Imaging Findings Affect Prognosis of Temporal Lobe Epilepsy Surgery.

OBJECTIVE: This study investigated whether pre-operative interictal discharge patterns detected by electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings affect the surgical prognosis in temporal lobe epilepsy (TLE) patients. METHODS: A retrospective analysis of 115 cases of patients with refractory TLE was carried out from October 2010 to 2014 based on the classification of pre-operative interictal discharge patterns in EEG and MRI findings. The patients were followed up for 4 years after surgery. The ILAE method was used to assess differences in seizure-free rate among different types of interictal discharge pattern as well as in MRI findings. RESULTS: A total of 115 cases were classified according to interictal discharge patterns in EEG, including normal cases, unilateral anterior discharge, unilateral multi-region discharge, and bilateral discharge. MRI findings were classified into negative results and positive results. Unilateral anterior and bilateral discharges showed statistically significant differences in post-operative seizure-free rates (p< 0.001). MRI-positive cases showed good overall post-operative outcome, irrespective of interictal discharge pattern in the EEG, whereas MRI-negative cases showed good overall prognosis if the interictal discharge pattern in EEG occurred in the unilateral anterior region. CONCLUSION: If the pre-operative interictal discharge pattern in EEG is confined to the unilateral anterior region, prognosis is good. If there are abnormalities in MRI findings, post-operative prognosis is good, regardless of pre-operative interictal discharge patterns in EEG. Surgical intervention is highly recommended for TLE patients with normal MRI findings and interictal discharge confined to the unilateral anterior region.

ERG3 potassium channel-mediated suppression of neuronal intrinsic excitability and prevention of seizure generation in mice.

KEY POINTS: ERG3 channels have a high expression level in the central nervous system. Knockdown of ERG3 channels enhances neuronal intrinsic excitability (caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials) in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. The expression of ERG3 protein is reduced in human and mouse hippocampal epileptogenic foci. Knockdown of ERG3 channels in hippocampus enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. The results provide strong evidence that ERG3 channels have a crucial role in the regulation of neuronal intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells and are critically involved in the onset and development of epilepsy. ABSTRACT: The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements. Profound changes in intrinsic properties have been observed in various physiological and pathological processes, such as learning, memory and epilepsy. However, the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood. Here, we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability, which is mainly caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials. Interestingly, the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy. Moreover, ERG3 channel knockdown in hippocampus significantly enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. Taken together, our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy. ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.

Causes of Avascular Hypoechoic Testicular Lesions Detected at Scrotal Ultrasound: Can They Be Considered Benign?

OBJECTIVE: The purposes of this study were to determine the cause of avascular hypoechoic lesions detected at scrotal ultrasound and to assess usefulness of sonographic and clinical features in differentiating benign from malignant etiologic factors. MATERIALS AND METHODS: This retrospective study included 58 patients with avascular hypoechoic lesions detected at testicular ultrasound. The sonographic features recorded were lesion size and margins and presence of peripheral vascularity and focal calcifications. Also recorded were patient age, symptoms, risk factors, lesion palpability, and levels of serum tumor markers. The reference standard was pathologic results or at least 2-year stability documented with serial follow-up ultrasound studies. Features associated with malignant, including burnt-out, lesions and benign lesions were examined by Fisher exact test, Wilcox-on rank sum test, and the generalized estimating equations method for multivariable models. RESULTS: Sixty-three lesions were identified in 58 patients; 40 of the 63 (63.5%) were benign. Patients with malignant lesions had elevated serum tumor marker levels more often than patients who had benign lesions (26.1% versus 5.7%, p = 0.043). The clinical palpability of lesions and history of testicular cancer were not statistically significantly different between patients with malignant and those with benign lesions. Poorly defined margins of a lesion and focal calcification within the lesion were more often found in malignant lesions. Maximal size of a lesion and peripheral vascularity were not associated with either the benign or the malignant nature of a lesion. CONCLUSION: Although most avascular hypoechoic testicular lesions are benign, a substantial proportion are malignant. The ultrasound characteristics of a lesion, the patient's clinical presentation, and serum tumor marker status may be useful in differentiating malignant from benign lesions.

Ginsenoside Rh2 inhibits invasiveness of glioblastoma through modulation of VEGF-A.

The malignancy of glioblastoma multiforme (GBM) is largely due to its local invasion and the presence of the tumor in the relatively restrained region in the brain. Hence, effective prevention of the cancer cell invasion is substantially critical for controlling the growth and deterioration of GBM. We have recently reported the role of ginsenoside Rh2 (GRh2) in suppressing the growth of GBM through EGFR/PI3k/Akt/mTor signaling pathways. Here, we further showed that GRh2 efficiently inhibited the cancer vascularization in vivo. In vitro, GRh2 dose-dependently inhibited the protein, but not messenger RNA (mRNA) of vascular endothelial growth factor A (VEGF-A) in GBM cells. We then examined the underlying mechanisms and found that GRh2 increased the levels of miR-497, which bound to 3'UTR of VEGF-A mRNA to inhibit its translation. Together, our data demonstrate a previously unappreciated role for GRh2 in inhibition of GBM-associated cancer vascularization, which may contribute to the effects of GRh2 on suppression of GBM cancer growth and invasion.

Ovarian vein thrombosis after debulking surgery for ovarian cancer: epidemiology and clinical significance.

OBJECTIVE: Ovarian vein thrombosis is associated with pregnancy and pelvic surgery. Postpartum ovarian vein thrombosis is associated with infection and a high morbidity rate and is treated with anticoagulant and intravenous antibiotic therapy. The natural history of such thrombotic events after debulking surgery for ovarian cancer has not been well described. Our objective was to characterize the presentation and outcomes for patients with this condition at our institution. STUDY DESIGN: We conducted a retrospective study of patients who underwent surgical debulking for ovarian cancer at Memorial Sloan Kettering Cancer Center between the years 2001 and 2010. Patients were included if contrast computed tomography scans of both the abdomen and pelvis were performed within 12 weeks before and 12 weeks after the surgery. The images were reviewed to assess for the presence and extent of a new postoperative ovarian vein thrombosis. When available, subsequent studies were assessed for thrombus progression. Medical records were reviewed to determine whether anticoagulation was used for treatment of the thrombotic episode and to record the occurrence of any new significant venous thromboembolic event in the next year. RESULTS: One hundred fifty-nine patients had satisfactory imaging. New ovarian vein thrombosis was a common complication of debulking surgery, as found in 41 of patients (25.8%). Only 5 women with ovarian vein thrombosis were started on anticoagulation, of which 2 individuals had an independent venous thromboembolic event as indication for treatment. Only 2 of the ovarian vein thromboses (4.9%) progressed to the inferior vena cava or left renal vein on subsequent scan. The estimated cumulative incidence of venous thromboembolism 1 year after the first postoperative scan was 17.1% for patients in the new ovarian vein thrombosis group vs 15.3% of individuals for the group without a postoperative ovarian vein thrombosis (P = .78). CONCLUSION: Ovarian vein thrombosis is commonly encountered after debulking surgery for ovarian cancer. Anticoagulation is usually not indicated, and clinically meaningful thrombus progression rarely occurs.

EGFR signaling-dependent inhibition of glioblastoma growth by ginsenoside Rh2.

Glioblastoma is the most common and most aggressive malignant primary brain tumor in humans, accounting for 52 % of all functional tissue brain tumor cases and 20 % of all intracranial tumors. The typical treatment involves a combination of chemotherapy, radiation, and surgery, whereas it still achieves fairly poor patient survival. Ginsenoside Rh2 has been reported to have a therapeutic effect on some tumors, but its effect on glioblastoma has not been extensively evaluated. Here, we show that ginsenoside Rh2 can substantially inhibit the growth of glioblastoma in vitro and in vivo in a mouse model. Moreover, the inhibition of the tumor growth appears to result from combined effects on decreased tumor cell proliferation and increased tumor cell apoptosis. Further analyses suggest that ginsenoside Rh2 may have its antiglioblastoma effect through inhibition of the epidermal growth factor receptor (EGFR) signaling pathway in tumor cells. In a lose-of-function experiment, recombinant EGFR was given together with ginsenoside Rh2 to the tumor cells in vitro and in vivo, which completely blocked the antitumor effects of ginsenoside Rh2. Thus, our data not only reveal an anti-glioblastoma effect of ginsenoside Rh2 but also demonstrate that this effect may function via inhibition of EGFR signaling in glioblastoma cells.

Termination of convulsion seizures by destabilizing and perturbing seizure memory engrams.

Epileptogenesis, arising from alterations in synaptic strength, shares mechanistic and phenotypic parallels with memory formation. However, direct evidence supporting the existence of seizure memory remains scarce. Leveraging a conditioned seizure memory (CSM) paradigm, we found that CSM enabled the environmental cue to trigger seizure repetitively, and activating cue-responding engram cells could generate CSM artificially. Moreover, cue exposure initiated an analogous process of memory reconsolidation driven by mammalian target of rapamycin-brain-derived neurotrophic factor signaling. Pharmacological targeting of the mammalian target of rapamycin pathway within a limited time window reduced seizures in animals and interictal epileptiform discharges in patients with refractory seizures. Our findings reveal a causal link between seizure memory engrams and seizures, which leads us to a deeper understanding of epileptogenesis and points to a promising direction for epilepsy treatment.

ERBB2 mutations define a subgroup of endometrial carcinomas associated with high tumor mutational burden and the microsatellite instability-high (MSI-H) molecular subtype.

Anti-HER2 therapy is indicated for erb-b2 receptor tyrosine kinase 2 (ERBB2)-amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2-mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2-mutated EC. From an institutional cohort of 2638 ECs subjected to clinical tumor-normal panel sequencing, 69 (2.6%) with pathogenic ERBB2 mutation(s) were identified, of which 11 were also ERBB2-amplified. The most frequent ERBB2 hotspot mutations were V842I (38%) and R678Q (25%). ERBB2 mutations were clonal in 87% of evaluable cases. Immunohistochemistry revealed low HER2 protein expression in most ERBB2-mutated ECs (0/1+ in 66%, 2+ in 27%); all 3+ tumors (7.3%) were also ERBB2-amplified. Compared to ERBB2-wildtype ECs (with or without ERBB2 amplification), ERBB2-mutated/non-amplified ECs were enriched for the microsatellite instability-high (MSI-H) and, to a lesser extent, DNA polymerase epsilon, catalytic subunit (POLE) molecular subtypes, and associated with high tumor mutational burden and low chromosomal instability. Survival outcomes were similar between patients with ERBB2-mutated/non-amplified versus wildtype EC, whereas ERBB2 amplification was associated with worse prognosis on univariate, but not multivariate, analyses. In conclusion, ERBB2 mutation defines a rare subgroup of ECs that is pathogenically distinct from ERBB2-wildtype and ERBB2-amplified ECs.

A Novel Ubiquitin Ligase Adaptor PTPRN Suppresses Seizure Susceptibility through Endocytosis of NaV1.2 Sodium Channels.

Intrinsic plasticity, a fundamental process enabling neurons to modify their intrinsic properties, plays a crucial role in shaping neuronal input-output function and is implicated in various neurological and psychiatric disorders. Despite its importance, the underlying molecular mechanisms of intrinsic plasticity remain poorly understood. In this study, a new ubiquitin ligase adaptor, protein tyrosine phosphatase receptor type N (PTPRN), is identified as a regulator of intrinsic neuronal excitability in the context of temporal lobe epilepsy. PTPRN recruits the NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L) to NaV1.2 sodium channels, facilitating NEDD4L-mediated ubiquitination, and endocytosis of NaV1.2. Knockout of PTPRN in hippocampal granule cells leads to augmented NaV1.2-mediated sodium currents and higher intrinsic excitability, resulting in increased seizure susceptibility in transgenic mice. Conversely, adeno-associated virus-mediated delivery of PTPRN in the dentate gyrus region decreases intrinsic excitability and reduces seizure susceptibility. Moreover, the present findings indicate that PTPRN exerts a selective modulation effect on voltage-gated sodium channels. Collectively, PTPRN plays a significant role in regulating intrinsic excitability and seizure susceptibility, suggesting a potential strategy for precise modulation of NaV1.2 channels' function.

Integrative pan-cancer analysis of cuproplasia-associated genes for the genomic and clinical characterization of 33 tumors.

BACKGROUND: The molecular mechanisms driving tumorigenesis have continually been the focus of researchers. Cuproplasia is defined as copper-dependent cell growth and proliferation, including its primary and secondary roles in tumor formation and proliferation through signaling pathways. In this study, we analyzed the differences in the expression of cuproplasia-associated genes (CAGs) in pan-cancerous tissues and investigated their role in immune-regulation and tumor prognostication. METHODS: Raw data from 11,057 cancer samples were acquired from multiple databases. Pan-cancer analysis was conducted to analyze the CAG expression, single-nucleotide variants, copy number variants, methylation signatures, and genomic signatures of micro RNA (miRNA)-messenger RNA (mRNA) interactions. The Genomics of Drug Sensitivity in Cancer and the Cancer Therapeutics Response Portal databases were used to evaluate drug sensitivity and resistance against CAGs. Using single-sample Gene Set Enrichment Analysis (ssGSEA) and Immune Cell Abundance Identifier database, immune cell infiltration was analyzed with the ssGSEA score as the standard. RESULTS: Aberrantly expressed CAGs were found in multiple cancers. The frequency of single-nucleotide variations in CAGs ranged from 1% to 54% among different cancers. Furthermore, the correlation between CAG expression in the tumor microenvironment and immune cell infiltration varied among different cancers. ATP7A and ATP7B were negatively correlated with macrophages in 16 tumors including breast invasive carcinoma and esophageal carcinoma, while the converse was true for MT1A and MT2A . In addition, we established cuproplasia scores and demonstrated their strong correlation with patient prognosis, immunotherapy responsiveness, and disease progression ( P  <0.05). Finally, we identified potential candidate drugs by matching gene targets with existing drugs. CONCLUSIONS: This study reports the genomic characterization and clinical features of CAGs in pan-cancers. It helps clarify the relationship between CAGs and tumorigenesis, and may be helpful in the development of biomarkers and new therapeutic agents.

A controlled lumbar puncture procedure improves the safety of lumbar puncture.

Background: In order to improve the safety of lumbar puncture (LP), we designed a new type of LP needle, that is, an integrated and controlled LP needle, which can actively and accurately control the flow rate and retention of cerebrospinal fluid (CSF) during puncture, so as to achieve a controlled LP procedure. Objective: To evaluate whether a controlled LP procedure can improve the comfort of LP and reduce the risk of complications associated with LP. Methods: Patients requiring LP (n = 63) were pierced with an integrated and controlled LP needle or a conventional LP needle. The differences in vital signs, symptom score, comfort, operation time, CSF loss, CSF pressure fluctuation and back pain before and after puncture were analyzed. Results: An integrated and controlled LP needle (n = 35) significantly improved patients' headache symptoms before and after puncture. In addition, a controlled LP procedure significantly reduced the amount of unnecessary CSF loss (p < 0.001), shortened the time of puncture (p < 0.001), improved patient comfort (p = 0.001) and reduced the incidence of back pain (p < 0.001). For patients with high intracranial pressure (HICP), the fluctuations in pressure of the CSF were also reduced while obtaining similar amounts of CSF (p = 0.009). Conclusion: A controlled LP procedure avoids unnecessary CSF loss, prevents rapid fluctuations in CSF pressure in patients with HICP, and reduces the risks associated with LP.

Internal carotid artery stenosis: hemodynamics in the ipsilateral ACA affects CT angiography manifestations.

Objective: This study aimed to evaluate whether CT angiography (CTA) manifestations in anterior cerebral artery a1 segment (A1) were related to the hemodynamics in patients with internal carotid artery stenosis (ICAS). Methods: A total of 97 cases were selected. The degree of ICAS and symmetry of A1 were evaluated by CTA examination. Hemodynamic indexes were detected by transcranial Doppler (TCD). The differences in CTA presentations of A1 and hemodynamics between the vessels on the stenotic and contralateral sides were analyzed according to the different degrees of stenosis. The degree of ICAS according to the different manifestations of A1 and the hemodynamics of A1's adjacent vessels were also analyzed. Results: In the case of unilateral ICAS, the difference in Vm of A1 between the stenotic and the contralateral side was the most significant relative to the stenosis degree. When unilateral ICAS was ≥70%, the presentation of A1 on the stenotic side was more slender or non-visualized compared to that on the contralateral side, while in cases with unilateral stenosis <70% or bilateral stenosis with a similar degree of stenosis, A1 were mainly symmetrical. When A1 on the side of ICAS was slender or non-visualized, the Vm of A1 was significantly slower than that on the contralateral side (P < 0.001). Conclusion: The CTA manifestations of A1 on the side of ICAS embodied the overall changes of the intracranial hemodynamics after ICAS. A combination of TCD and CTA examination of A1 can assist in judging the location and degree of ICAS.

Gemcitabine for advanced endometrial cancer: a retrospective study of the Memorial sloan-Kettering Cancer Center experience.

BACKGROUND: Gemcitabine is active in several gynecologic malignancies including ovarian cancer, cervical cancer, and uterine leiomyosarcoma. It has been used in an off-label setting for the treatment of advanced endometrial cancer, despite lack of published data showing efficacy. We performed a retrospective study to determine the progression-free survival and response rate of endometrial cancer patients treated with gemcitabine at Memorial Sloan-Kettering Cancer Center. METHODS: Eligible patients had histologically confirmed advanced (stage IV or recurrent) endometrial cancer that was treated with single-agent gemcitabine at Memorial Sloan-Kettering Cancer Center between 1999 and 2009. Response to therapy was determined by review of computed tomography imaging by Response Evaluation Criteria in Solid Tumors 1.1 criteria. RESULTS: Forty-six patients were included in the analysis. Median age was 66 years (range, 52-87 years). All patients were previously treated with chemotherapy. The median number of prior lines of chemotherapy was 2 (range, 1-8). Median dose of gemcitabine administered was 800 mg/m infused on days 1 and 8 of a 21-day cycle. Predominant histology was endometrioid (48%, n = 22) followed by serous (35%, n = 16), clear cell (15%, n = 7), and undifferentiated (2%, n = 1). Overall response rate was 10.9% (95% confidence interval, 1.9%-19.9%); 5 patients (11%) achieved a partial response. Thirteen patients (28%) displayed stable disease lasting at least 3 months. Of note, 5 (71%) of the 7 patients with clear cell histology displayed stable disease or partial response (n = 5). The median progression-free survival was 3.0 months (95% confidence interval, 2.1-3.3 months). Nonhematologic grades 3 and 4 toxicities were rare. Ten patients (22%) were treated with granulocyte colony-stimulating factor during treatment. Grade 3 thrombocytopenia was seen in 4 patients (9%). There were no cases of grade 4 thrombocytopenia. CONCLUSIONS: In a mixed population of patients with previously treated advanced endometrial cancer, gemcitabine was well tolerated and showed modest activity. Patients with clear cell histology appeared to have greater likelihood of benefit.