Mechanism of polyubiquitination by human anaphase-promoting complex: RING repurposing for ubiquitin chain assembly.

Polyubiquitination by E2 and E3 enzymes is a predominant mechanism regulating protein function. Some RING E3s, including anaphase-promoting complex/cyclosome (APC), catalyze polyubiquitination by sequential reactions with two different E2s. An initiating E2 ligates ubiquitin to an E3-bound substrate. Another E2 grows a polyubiquitin chain on the ubiquitin-primed substrate through poorly defined mechanisms. Here we show that human APC's RING domain is repurposed for dual functions in polyubiquitination. The canonical RING surface activates an initiating E2-ubiquitin intermediate for substrate modification. However, APC engages and activates its specialized ubiquitin chain-elongating E2 UBE2S in ways that differ from current paradigms. During chain assembly, a distinct APC11 RING surface helps deliver a substrate-linked ubiquitin to accept another ubiquitin from UBE2S. Our data define mechanisms of APC/UBE2S-mediated polyubiquitination, reveal diverse functions of RING E3s and E2s, and provide a framework for understanding distinctive RING E3 features specifying ubiquitin chain elongation.

Old Is (Not) Gold: Midazolam Monotherapy versus Midazolam Plus Fentanyl for Sedation during Cardiac Catheterization.

OBJECTIVE: We aimed to study the differences in perception of pain during cardiac catheterization with midazolam monotherapy compared to the current standard of midazolam plus fentanyl. BACKGROUND: Procedural sedation is important to ensure comfort and safety in patients undergoing left heart catheterization. Despite the widespread use of midazolam and fentanyl for procedural sedation, the effectiveness of this dual agent approach to sedation has never been studied in comparison to midazolam monotherapy. METHODS: A total of 129 patients undergoing sedation for outpatient elective cardiac catheterization were randomly assigned to either midazolam monotherapy (n = 69) or combination of midazolam and fentanyl (n = 60). The primary outcome was assessment of pain perception prior to discharge by patient completion of a pain questionnaire. Participants were asked if they experienced any pain during their procedure (yes/no) and, if yes, asked to rate their overall pain level using a 10-point Likert scale that ranged from 1 (minimal pain) to 10 (worst pain imaginable). RESULTS: Most patients (n = 94, 73%) reported no pain during their procedure. Patients sedated with midazolam monotherapy reported similar average pain scores compared to patients sedated with the combination of midazolam and fentanyl (1.1 vs. 1.1, p=0.95). CONCLUSIONS: Among patients undergoing elective cardiac catheterization, no significant differences in pain scores were noted between sedation with midazolam alone compared to midazolam and fentanyl. Due to fentanyl's unfavorable interaction with P2Y12 agents, increased costs, and addiction potential, it is imperative that cardiologists revisit the role of effective procedural sedation with a single agent and avoid the use of fentanyl.

Endoscopic versus microscopic approach for surgical treatment of acromegaly.

Transsphenoidal surgery in the setting of acromegaly is quite challenging due to increased soft tissue mass, bony overgrowth, and bleeding. There is a debate on the endoscopic versus microscopic approach for these patients. The purpose of our study is to compare the outcomes for acromegaly after transsphenoidal surgery using both techniques. Retrospective review of 65 acromegalic patients who underwent transsphenoidal surgery in our department. Clinical remission was defined as resolution of typical acromegalic symptoms. Radiological resection was defined by volumetric criteria, and biochemical remission was defined as by the 2010 consensus on the criteria for remission of acromegaly. There was no significant difference in age, preoperative endocrine status, percent of macro adenomas, suprasellar, or infrasellar extension between both groups. Patients were assigned to both groups based on our existing referral pattern. Endoscopic approach was performed in 42 patients, while the microscopic approach was performed in 23 patients. No significant difference in remission rates was found between both groups (45.2 vs. 34.7 %, p = 0.40). The endoscopic group, however, had a significantly higher rate of gross total resections (61 vs. 42 %, p = 0.05). There was also a trend towards higher rates of gross total resections when cavernous sinus was present (48 vs. 14.2 %, p = 0.09). Postoperative diabetes insipidus occurred more in microscopic patients (34.7 vs. 17 %, p = 0.05), otherwise there was no significant difference in rates of complications. The median follow-up period was 56.6 months (range 6-156, mean 66.1). There is no significant difference in the rates of biochemical remission between the endoscopic and microscopic techniques. The endoscope technique, however, seems to be superior in achieving gross total resection especially with tumors invading the cavernous sinus.

Endoscopic transphenoidal surgery for acromegaly improves quality of life.

BACKGROUND: Acromegaly has important effects on quality of life (QOL). This is the first study to measure QOL in acromegalic patients after endoscopic transsphenoidal surgery (ETSS). METHODS: We prospectively collected the RAND-36, Center for Epidemiologic Studies Depression (CES-D), and Pituitary QOL validated questionnaires and patients' demographics, clinical presentation, endocrine laboratory results, radiological studies, development of complications and remission rates from 20 consecutive acromegalic patients who had undergone endoscopic transphenoidal surgery. RESULTS: The eleven females and nine males had an average age of 42 years; 90 percent had macroadenomas and 70% had cavernous sinus invasion on their preoperative imaging. Ninety percent had improved symptoms post-operatively and 80% stated that treatment improved their QOL. Biochemically, 35% were cured, 35% had discordant results and 30% were not cured, while pan-hypopituitarism occurred in 4 patients. Physical health subscales and pituitary-related symptoms were similar to norms. "Social," "emotional health," and "energy levels" were significantly lower than norms. Seventy percent stated that their relationship with their physician "very much so" affected their quality of life. Pan hypopituitarism and adjuvant therapy were the most significant predictors of lower QOL subscale scores. CONCLUSION: Transsphenoidal surgery improves QOL in acromegaly. Attempts to achieve a cure, avoidance of surgically induced pan-hypotpituitarism and adjuvant therapy, will improve quality of life. Our study demonstrates the important role of the patient-physician relationship to QOL and the need to measure QOL in addition to the traditional measures of outcome.

Rare tumors in pediatric age group: Single center experience from Saudi Arabia.

Rare pediatric tumors are heterogeneous group containing a variety of histopathological diseases, they represent approximately 10% of all childhood cancers. These rare tumors had a diversity of histology and clinical behaviors that pose different challenges to the investigators. Exploring different pediatric rare tumors. The data were reviewed, retrospectively, through the medical records of seven rare pediatric diseases between 2012 and 2019. Giant cell fibroblastoma (GCF) presented as painless swelling in the trunk, positive for CD34 with PTEN gene mutation. Neuroglial heterotopic tissue presented in 7 days old girl with facial asymmetry and bulging in the oral cavity, maximal de-bulking was done, histopathology was positive for GFAP and S100p. Left side neck mass, surgically excised revealed non-metastatic salivary grand mucoepidermoid carcinoma. Follow up without any chemotherapy or radiotherapy for 5 years with complete remission. Mesenchymal chondrosarcoma (MCS) presented in maxillofacial bones by persistent nasal bleeding, HEY1-NCOA2 fusion gene confirmed the diagnosis. Extra-osseous Ewing sarcoma (EES) presented as rubbery painless swelling in the scalp with fusion transcript involving EWSR1-FL11. Juvenile xanthogranuloma (JXG) presented by butter fly like skin patch in the face with foamy histiocytes in upper dermis with few Touton giant cells, extensive systemic involvement of lung and bone marrow. Metastatic ovarian choriocarcinoma with choriocarcinoma syndrome received induction two different lines of chemotherapy and consolidated with autologous stem cell transplant. Seven pediatric rare tumors, with different aspects of challenges in diagnosis and management, despite the absence of formal protocols and rarity of other center experiences.

Assessment of Health-related Quality of Life in Saudi Children with Cancer.

Advances in pediatric cancer treatment and dramatic improvement in long-term survival have made health-related quality of life (HRQOL) a priority. This study describes the HRQOL of Saudi children on cancer treatment, given the paucity of data on the subject. Parents of children undergoing cancer treatment between the ages of 2 and 12 years enrolled to answer the Arabic version of the parent proxy report PedsQL™ 3.0 cancer module. The module items were reverse-scored to a linear scale from 0 to 100, in which higher scores indicated a better HRQOL. Of the 95 study participants, 61 (64.2%) were hematological malignancies and 34 (35.8%) solid malignancies. The mean score of our sample's total HRQOL was 72.3, which is in line with the results of similar studies worldwide. The lowest scores were observed for procedural anxiety (60.14), perceived physical appearance (67.37), and treatment anxiety (67.58), while the highest were for communication (80.21), nausea (78.32), and cognitive problems (78.32). Significant associations were reported between the patients aged younger than 5 years and procedural anxiety, those aged 5 years or older and perceived physical appearance, and frequent hospital visits and worry. Healthcare professionals should consider the poor HRQOL sub-scales and their associated risks to improve treatment outcomes.

Clinicopathologic features and therapy outcome in childhood Hodgkin's lymphoma: a report from tertiary care center in Saudi Arabia.

BACKGROUND: Hodgkin lymphoma (HL) is lymphoid neoplasm usually affecting lymphatic system; it accounts 3.6% of cancers in Saudi Arabia. Modern treatment protocols had shown particular success rates in overall-survival (OS) and event-free-survival (EFS). In our study, we reviewed the medical records of 80 pediatric and young adolescent patients diagnosed HL from January 2006 to July 2020, treated at tertiary care hospital in Riyadh, Saudi Arabia. Demographic, clinical, and pathological data were explored. First line therapy was ABVD, COG, COPP, R-CHOP, or radiotherapy alone in 53/80 (66.4%), 24/80 (30%), 1/80 (1.2%), 1/80 (1.2%), or 1/80 (1.2%) patients; respectively. Response assessment was done by CT + / - PET scan after first 2 cycles then every 2 cycle and end of therapy. Another assessment was done if any clinical suspicion of recurrence. RESULTS: Median age 11 (range 3-16) years. Males to females 1.3:1. Seventy-two out of eighty (90%) patients showed first complete remission (CR1) and maintained remission for median 40 (range 7-136) months. Eight out of eighty (10%) patients showed refractory disease. Nineteen patients received salvage therapy (ICE or ESHAP/brentuximab vedotin or gemcitabine/brentuximab vedotin), 14/19 (73.7%) had 2nd complete remission (CR2) for median time 24 (ranged 9-78) months, while 5/19 (26.3%) did not show any response. Five-year OS and EFS were 95% and 75%. Two patients had 2ry malignant neoplasms, one had AML and died, the other had malignant fibrous histocytoma and still alive. None of our patients had fertility problem. Also, they did not experience chronic pulmonary or cardiotoxicity. Classic Hodgkin's lymphoma: nodular sclerosis subtype was more prominent (55%) than mixed cellularity subtype (22.5%), which is similar to several European and US studies, lymphocyte rich (11.25%) and lymphocyte depleted (0%), while nodular lymphocyte predominant Hodgkin's lymphoma (11.25%). CONCLUSIONS: Our study provided unique descriptive study of childhood HL, in Saudi Arabia, with valuable insight into the long-term outcome and late toxicity. Our results are comparable to other studies in the Middle East and European countries.