2-Methoxyestradiol ameliorates doxorubicin-induced cardiotoxicity by regulating the expression of GLUT4 and CPT-1B in female rats.

The clinical usage of doxorubicin (DOX) is hampered due to cardiomyopathy. Studies reveal that estrogen (E2) modulates DOX-induced cardiotoxicity. Yet, the exact mechanism is unclear. The objective of the current study is to evaluate the influence of E2 and more specifically its metabolite 2-methoxyestradiol (2ME) on cardiac remodeling and the reprogramming of cardiac metabolism in rats subjected to DOX cardiotoxicity. Seventy-two female rats were divided into groups. Cardiotoxicity was induced by administering DOX (2.5 mg/kg three times weekly for 2 weeks). In some groups, the effect of endogenous E2 was abolished by ovariectomy (OVX) or by using the estrogen receptor (ER) blocker Fulvestrant (FULV). The effect of administering exogenous E2 or 2ME in the OVX group was studied. Furthermore, the influence of entacapone (COMT inhibitor) on induced cardiotoxicity was investigated. The evaluated cardiac parameters included ECG, histopathology, cardiac-related enzymes (creatine kinase isoenzyme-MB (CK-MB) and lactate dehydrogenase (LDH)), and lipid profile markers (total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL)). The expression levels of key metabolic enzymes (glucose transporter-4 (GLUT4) and carnitine palmitoyltransferase-1B (CPT-1B)) were assessed. Our results displayed that co-treatment of E2 and/or 2ME with DOX significantly reduced DOX-induced cardiomyopathy and enhanced the metabolism of the heart through the maintenance of GLUT4 and CPT-1B enzymes. On the other hand, co-treatment of DOX with OVX, entacapone, or FULV increased the toxic effect of DOX by further reducing these important metabolic enzymes. E2 and 2ME abrogate DOX-induced cardiomyopathy partly through modulation of GLUT 4 and CPT-1B enzymes.

Quinazolines and thiazolidine-2,4-dions as SARS-CoV-2 inhibitors: repurposing, in silico molecular docking and dynamics simulation.

This paper presents an extensive analysis of COVID-19 with a specific focus on VEGFR-2 inhibitors as potential treatments. The investigation includes an overview of computational methodologies employed in drug repurposing and highlights in silico research aimed at developing treatments for SARS-CoV-2. The study explores the possible effects of twenty-eight established VEGFR-2 inhibitors, which include amide and urea linkers, against SARS-CoV-2. Among these, nine inhibitors exhibit highly promising in silico outcomes (designated as 3-6, 11, 24, 26, 27, and sorafenib) and are subjected to extensive molecular dynamics (MD) simulations to evaluate the binding modes and affinities of these inhibitors to the SARS-CoV-2 Mpro across a 100 ns timeframe. Additionally, MD simulations are conducted to ascertain the binding free energy of the most compelling ligand-pocket complexes identified through docking studies. The findings provide valuable understanding regarding the dynamic and thermodynamic properties of the interactions between ligands and pockets, reinforcing the outcomes of the docking studies and presenting promising prospects for the creation of therapeutic treatments targeting COVID-19.

miRNAs orchestration of gallbladder cancer - Particular emphasis on diagnosis, progression and drug resistance.

Gallbladder cancer (GBC) is characterized by a highly invasive nature and a poor prognosis, with adenocarcinoma being the main histological subtype. According to statistical data, patients diagnosed with advanced GBC have a survival rate of less than 5% for 5 years. Despite the novel therapeutic techniques, the unsatisfactory results could be related to the underlying biology of tumor cells and resistance to chemotherapy. Early diagnosis is more important than clinical therapy as it assists in determining the pathological stage of cancer and facilitates the selection of appropriate medication. Hence, it is very important to understand the precise pathogenesis of GBC and to discover potential novel biomarkers for early diagnosis of GBC. Non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, have been found to influence the transcriptional regulation of target genes associated with cancer, either directly or indirectly. microRNAs are a group of small, non-coding, single-stranded RNAs that are expressed endogenously. miRNAs play significant roles in various fundamental cellular processes. Therefore, miRNAs have the potential to serve as valuable biomarkers and therapeutic targets for GBC.

Hydroxycitric acid reverses tamoxifen resistance through inhibition of ATP citrate lyase.

Lipid metabolic reprogramming is involved in mediating tamoxifen (TAM) response in breast cancer cells. Published microarray data indicated that ATP citrate lyase (ACLY) is overexpressed in TAM-resistant BC cells. Hydroxycitric acid (HCA) is a powerful competitive inhibitor of the enzyme ACLY, which links carbohydrates and lipids metabolism. However, whether inhibition of ACLY could modulate TAM response in TAM-resistant BC cells remained unexplored. Thus the current study aimed to explore the effect of ACLY inhibition on TAM-resistant BC cells. The cytotoxicity of TAM and/or HCA on LCC2 and its TAM-sensitive counterpart MCF7 cells was evaluated. Also, the effect of TAM and/or HCA treatments on ACLY protein levels were investigated by western blotting. In addition, the effects of TAM and/or HCA on caspase-3, Bax, and Bcl2 levels were evaluated by ELISA.; besides, and flow cytometric analysis was performed for the detection of apoptosis. Moreover, cholesterol and triglyceride contents of LCC2 and MCF7 were quantified colorimetrically. Our results demonstrated that TAM/HCA co-treatment synergistically diminished LCC2 and MCF7 cell viability, with the effect being more significant on LCC2. Mechanistically, TAM/HCA co-treatment decreases the expression level of ACLY in LCC2 by 74 %, while in MCF7 by only 59 %. Moreover, apoptosis marker caspase-3 and Bax were increased, while the anti-apoptotic Bcl2 was decreased. Furthermore, the cholesterol and TG contents were increased in LCC2 than in MCF7. Our data revealed that ACLY plays a key role in TAM resistance and ACLY inhibition by HCA-mediated sensitization of BC-resistant cells to TAM.

Arthroscopic Bankart repair with remplissage versus Latarjet procedure for management of engaging Hill-Sachs lesions with subcritical glenoid bone loss in traumatic anterior shoulder instability: a systematic review and meta-analysis.

BACKGROUND: A large engaging Hill-Sachs lesion (HSL) with subcritical glenoid bone loss (GBL) is approached through either increasing the glenoid arc by the Latarjet procedure or converting the HSL to an extra-articular defect by arthroscopic Bankart repair with remplissage (BRR). Until now, there has been no evidence-based consensus about which of these 2 most appropriate procedures is the better surgical choice. The purpose of this study was to analyze the current literature comparing results of BRR vs. the Latarjet procedure in the treatment of engaging HSLs with subcritical GBL. METHODS: A comprehensive review of the PubMed and Cochrane databases was completed for studies that compared the clinical outcomes and complications of BRR vs. the Latarjet procedure with minimum follow-up of 2 years. The outcome measures analyzed included postoperative Rowe score, visual analog scale pain score, postoperative range of motion (ROM), and rates of recurrent instability and other complications. RESULTS: Overall, 4 articles (level III evidence in 3 and level II in 1) were included from an initial 804 abstracts. The study population consisted of a total of 379 patients, of whom 194 underwent BRR and 185 underwent the Latarjet procedure. There were no unacceptable differences in baseline characteristics between the 2 groups. For the rate of recurrent instability, both groups had comparable risk ratios (RRs) (N = 379; RR, 0.72; 95% confidence interval [CI], 0.37-1.41). The risk of other complications was significantly increased with the Latarjet procedure (by about 7 times) relative to the the BRR procedure (N = 379; RR, 7.37; 95% CI, 2-27). Both groups had comparable postoperative Rowe scores (n = 190; mean difference [MD], -0.9; 95% CI, -3.45 to 1.7) and visual analog scale pain scores (n = 347; MD, -0.2; 95% CI, -0.6 to 0.2). Moreover, both groups had comparable postoperative external rotation ROM (MD, -1.7°; 95% CI, -9.4° to 6°) and internal rotation ROM (MD, 1.95°; 95% CI, -5.35° to 9.25°). There was substantial heterogeneity in the effect of both procedures on postoperative pain and ROM (external rotation and internal rotation). CONCLUSION: Both the BRR and Latarjet procedures are effective for the management of engaging HSLs with subcritical GBL and give comparable clinical outcomes. However, given the fewer overall postoperative complications, remplissage may be safer. The results of the included studies were adequately consistent for most analyzed outcomes. However, for the intervention effect on postoperative pain and ROM, there was a small body of evidence, limiting the strength of the reported conclusions.

Editorial Commentary: Medial Patellofemoral Complex: Driving a Better Understanding of Medial Knee Anatomy.

Although its importance as the prime restraint to lateral patellar instability is undoubted, the anatomy of the medial patellofemoral ligament has never been agreed on. Since it was first described by Warren and Marshall in 1979, most of the anatomic studies confirmed its presence in 90% of the cases, but they usually provide inconsistent descriptions of its femoral and patellar attachments. It is proven that length changes in the reconstructed medial patellofemoral ligament depend principally on the femoral attachment site. Moreover, the femoral attachment site affects the patellar tilt, translation, and joint reaction force. Because of the early inconsistent descriptions of the medial patellofemoral ligament attachment sites, some authors have suggested that its anatomy is not fixed or may be patient specific.

Scarf versus long chevron osteotomies for the treatment of hallux valgus: A prospective randomized controlled study.

BACKGROUND: The aim of this study is to compare scarf osteotomy and long chevron osteotomy in treatment of hallux valgus deformity regarding operative time, power of correction and complications. DESIGN: A prospective randomized controlled comparative trial. METHODS: 48 cases with hallux valgus were divided randomly in 2 groups (21 treated by scarf and 22 treated by long chevron osteotomy and 5 were missed during follow up), average age 36 years, follow up time was average of 25.9 months. Patients were assessed clinically, radiologically, and functional scoring system of American College of Foot and ankle Surgeons (ACFAS)was used both pre and postoperatively. RESULTS: Operative time was 69min in scarf group compared to 63min to long chevron group, radiological correction showed no statistically significant difference between both groups while functional improvement in ACFAS score was in favour of long chevron group 69.1% compared to scarf group 57.5% CONCLUSIONS: Both osteotomies possess almost identical corrective power of the IMA (intermetatarsal angle) and similar clinical outcomes with slightly shorter operative time and subjective technical simplicity for the long chevron osteotomy.

Do functional outcomes and cuff integrity correlate after single- versus double-row rotator cuff repair? A systematic review and meta-analysis study.

PURPOSE: The purpose of this study is to perform a systematic review and meta-analysis of all available level I prospective randomized controlled trials comparing arthroscopic single-row (SR) with double-row (DR) rotator cuff repairs by both clinical outcomes and radiological re-tear rates. METHODS: PubMed, EMBASE, Google Scholar, and Cochrane databases search was done for level I RCTs comparing clinical and radiological outcomes after SR versus DR rotator cuff repair. Clinical outcomes included UCLA, ASES, Constant, WORC, and SANE scores; structural outcomes included MRI, MRA, or US. RESULTS: Seven level I studies were included (5 mid-term and 2 short-term). Postoperative ASES, Constant, WORC, and SANE scores showed nonsignificant slightly better function of DR groups. Only, UCLA score showed significantly better scores with DR repair (p = 0.007). Full-thickness re-tear incidence was reported in 15/174 (8.6%) in DR group and 20/175 (11.4%) in SR group (p = 0.44). Partial-thickness re-tear rate was reported in 18/174 patients (10.3%) in DR group and 41/175 patients (23.4%) in SR group (p = 0.009). CONCLUSION: Within the domain of level I mid-term and short-term studies, DR repair showed significant better UCLA score only. (ASES, Constant, WORC, and SANE scores showed no significance.) This may correlate weakly with the significant lower partial-thickness re-tear rates of DR repairs. In contrary, long-term level III studies showed a direct correlation of both functional outcomes and cuff structural integrity, with significant superiority of DR over SR repair techniques. LEVEL OF EVIDENCE: Level 1, systematic review and meta-analysis.

Latarjet Procedure for Anterior Shoulder Instability Due to Tramadol-Induced Seizures: A Multicenter Study.

BACKGROUND: Seizures, commonly due to epilepsy, are known to cause shoulder instability. Tramadol addiction has recently been found to induce seizures in patients who exceed the recommended dose. Because of the easy accessibility and low cost of tramadol, an increasingly alarming phenomenon of tramadol abuse has been demonstrated in recent years. PURPOSE/HYPOTHESIS: The purpose of this multicenter study was to investigate shoulder instability resulting from tramadol-induced seizure (TIS) as well as to recommended management for such shoulder instability. The hypothesis was that TIS leads to anterior shoulder dislocations with major bony defects, which favors bony reconstructive procedures as a suitable method of treatment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This prospective case series study was conducted on 73 patients (78 shoulders) who presented with anterior shoulder dislocations and a clear history of tramadol abuse. The mean age of the patients was 26.8 years, and the mean number of dislocations was 14. The mean duration of addiction was 17 months, with a mean dose of 752 mg of tramadol hydrochloride per day. Glenoid and humeral bone loss ranged from 15% to 35% and from 15% to 40%, respectively. The mean follow-up period was 28 months. All patients underwent an open Latarjet procedure. RESULTS: Postoperative mean Rowe score and American Shoulder and Elbow Surgeons score at final follow-up (24 months) improved significantly from 20 to 84 and from 44 to 91, respectively (P < .05). The patient satisfaction rate reached 95%, and the mean period of return to work was 12.8 weeks. Five patients (9%) had postoperative seizures due to relapse of the tramadol abuse, but only 3 patients (5%) had redislocations with nonunion or breakage of the graft or hardware. CONCLUSION: Tramadol addiction has evolved as an important cause of seizures that can result in shoulder dislocation. Anterior shoulder instability with TIS occurs mainly with higher levels of addiction and results in significant humeral and/or glenoid bone defects. The Latarjet procedure is recommended for these patients, after control of addiction, and provides 95% satisfaction at midterm follow-up.

Modified subpectoral biceps tenodesis.

PURPOSE: The proximal part of the long head of the biceps muscle has become a recognized cause of significant shoulder pain. Tenodesis of the long head of the biceps has been advocated as a treatment for pain resulting from biceps tendonopathy, biceps instability, and biceps tendon tears. All of these pathologies may be encountered during rotator cuff, SLAP or Bankart surgery, or in isolation. Several techniques have been described for this tenodesis, including various arthroscopic and subpectoral methods. METHODS: We present a modified bone bridge technique of Mazzocca et al., for subpectoral biceps tenodesis. In this technique we tenodese the tendon through two bone tunnels back over the muscle itself without implants. RESULTS: Application of this technique on 30 patients (ages 25-48 years) with short-term follow-up of 12-18 months showed statistically significant improvement (P value < 0.05) of the mean Constant and Oxford shoulder scores (pre-operative mean scores were 39.03 and 21.3, respectively, while postoperative mean scores were 76.43 and 44.8, respectively). CONCLUSION: This technique has potential advantages as it allows the possibility of adjusting the tension of the biceps tendon before final suturing, in addition to quicker soft tissue healing.

Midterm results of combined acromioclavicular and coracoclavicular reconstruction using nylon tape.

PURPOSE: The purpose of this study was to evaluate the radiologic and functional outcomes of an anatomic reconstruction of both acromioclavicular (AC) and coracoclavicular (CC) ligaments in types III to V AC injuries using nylon tape and no metal hardware. METHODS: A prospective case-series study was performed on 17 cases with types III to V AC injuries treated by anatomic reconstruction of the AC ligaments (anterior and superior) and CC ligaments (conoid and trapezoid) using nylon tape and no metal hardware. Clinical assessments, radiologic findings, and visual analog scale, American Shoulder and Elbow Surgeons, and Constant scores were recorded for all patients. After a minimum postoperative period of 2 years, all cases were re-evaluated and rescored. RESULTS: The case-series study comprised 17 cases with types III to V AC injuries. After a mean follow-up period of 28 months (minimum, 24 months), the patients had a significantly improved mean visual analog scale score (from 6.4 to 2.4 points), American Shoulder and Elbow Surgeons score (from 25 to 81.7 points), and Constant score (from 21 to 85 points), with overall 88.2% satisfaction. Radiographic superior displacement showed reduction from 13 to 2 mm whereas posterior displacement showed reduction from 5 to 2 mm, and both were statistically significant (P < .05). The rate of return to the patients' preinjury jobs was 82.4%, and there was 1 case of recurrent subluxation. CONCLUSIONS: Combined anatomic reconstruction of both AC and CC ligaments using nylon tape by the described technique provides overall 88.2% satisfaction, 94% radiologic reduction, and a low complication rate. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Prospective evaluation of prolonged fresh osteochondral allograft transplantation of the femoral condyle: minimum 2-year follow-up.

BACKGROUND: Focal articular cartilage lesions of the knee in young patients present a therapeutic challenge. Little information is available pertaining to the results after implantation of prolonged fresh grafts. HYPOTHESIS: Prolonged fresh osteochondral allografts present a viable option for treating large full-thickness articular cartilage lesions. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This study presents the results of 25 consecutive patients who underwent prolonged fresh osteochondral allograft transplantation for defects in the femoral condyle. The average patient age was 35 years (range, 17-49 years). The average length of follow-up was 35 months (range, 24-67 months). Prospective data were collected using several subjective scoring systems, as well as objective and radiographic assessments. RESULTS: Statistically significant improvements (P < .05) were seen for the Lysholm (39 to 67), International Knee Documentation Committee scores (29 to 58), all 5 components of the Knee injury and Osteoarthritis Outcome Score (Pain, 43 to 73; Other Disease-Specific Symptoms, 46 to 64; Activities of Daily Living Function, 56 to 83; Sport and Recreation Function, 18 to 46; Knee-Related Quality of Life, 22 to 50), and the Short Form-12 physical component score (36 to 40). Overall, patients reported 84% (range, 25% to 100%) satisfaction with their results and believed that the knee functioned at 79% (range, 35% to 100%) of their unaffected knee. Radiographically, 22 of the grafts (88%) were incorporated into host bone. CONCLUSION: Fresh osteochondral allograft transplantation is an acceptable intermediate procedure for treatment of localized osteochondral defects of the femur. At 2-year follow-up, it is well incorporated and offered consistent improvements in pain and function. CLINICAL RELEVANCE: Prolonged fresh allograft transplantation is a safe and effective technique for addressing symptomatic osteoarticular lesions in the knees of young patients.