Exploring Anticancer Properties of Medicinal Plants against Breast Cancer by Downregulating Human Epidermal Growth Factor Receptor 2.

Plants have a history of being employed in managing breast cancer. However, no scientific evidence supports the idea that these plants can effectively reduce the level of HER2 expression. In this study, extracts from 10 medicinal plants were evaluated for their anticancer properties against HER2-positive breast cancer cells through various methods, including the SRB assay, comet assay, annexin V-FITC dual staining, and immunoblotting. All extracts exerted antiproliferative activity against HER2-positive breast cancer cells. Furthermore, Terminalia chebula (T. chebula), Berberis aristata (B. aristata), and Mucuna pruriens (M. pruriens) reduced HER2 expression in tested cell lines. In addition, an increased Bax/Bcl-2 ratio was observed after the treatment. A comparative proteomics study showed modulation in the proteome profile of breast cancer cells after treatment with T. chebula, B. aristata, Punica granatum, M. pruriens, and Acorus calamus. Metabolic profiling of lead plants revealed the existence of multiple anticancer compounds. Our study demonstrates the considerable potential of the mentioned plants as innovative therapies for HER2-positive breast cancer.

Evaluation of the Outcome of Osteoarthritis among Patients Undergoing Total Knee Replacement.

Background: To assess the outcome of osteoarthritis among patients undergoing total knee replacement (TKR). Materials and Methods: One hundred and four subjects with one hundred and fifty-two cemented total knee arthroplasties have been analyzed in the current research. Functional assessment was carried out using the preoperative and postoperative Knee Injury and Osteoarthritis Outcome Score (KOOS) score and its five subscales: pain, other symptoms, function in activity of daily living (ADL), function in sport and recreation (Sport/Rec), and knee-related quality of life (QOL). Results: A significant improvement in the KOOS symptom score was seen with score grade changing to excellent from poor. The average postoperative KOOS symptom score occurred to be 89.9198, whereas the mean preoperative KOOS score was 30.7960 with a mean difference of 59.02385. The mean postoperative KOOS pain score was 94.6304 and the mean preoperative KOOS score was 18.4831 with a mean difference of 76.14731. A significant improvement in the KOOS pain score was seen with score grade changing to excellent from poor. Sixty patients of 104 (57.7%) had an excellent satisfaction level with a postoperative range of motion, twenty-eight patients (26.9%) had a good, eleven patients (10.6%) had a fair, and five patients (4.8%) had a poor satisfaction level with a postoperative range of motion. Conclusion: Surgery for a TKR is successful in reducing individuals' pain and restoring their functional ability. Preoperative expectations and KOOS subscale scores are factors in patients' satisfaction, which is determined a year following surgery.

Dengue virus induced autophagy is mediated by HMGB1 and promotes viral propagation.

Dengue virus (DENV) exploits various cellular pathways including autophagy to assure enhanced virus propagation. The mechanisms of DENV mediated control of autophagy pathway are largely unknown. Our investigations have revealed a novel role for high-mobility group box1 protein (HMGB1) in regulation of cellular autophagy process in DENV-2 infected A549 cell line. While induction of autophagy by rapamycin treatment resulted in enhanced DENV-2 propagation, the blockade of autophagy flux with bafilomycin A1 suppressed viral replication. Furthermore, siRNA-mediated silencing of HMGB1 significantly abrogated dengue induced autophagy, while LPS induced HMGB1 expression counteracted these effects. Interestingly, silencing of HMGB1 showed reduction of BECN1 and stabilization of BCL-2 protein. On the contrary, LPS induction of HMGB1 resulted in enhanced BECN1 and reduction in BCL-2 levels. This study shows that the modulation of autophagy by DENV-2 is HMGB1/BECN1 dependent. In addition, glycyrrhizic acid (GA), a potent HMGB1 inhibitor suppressed autophagy as well as DENV-2 replication. Altogether, our data suggests that HMGB1 induces BECN1 dependent autophagy to promote DENV-2 replication.

Bicompartmental Bucket Handle Meniscal Tear with Chronic ACL Deficiency Causing a Rare Triple PCL and Triple Cruciate Sign: A Case Report.

CASE: A 16-year-old football player presented with chronic ACL deficiency along with bicompartmental bucket handle meniscal tears. CONCLUSION: We present a "triple cruciate" sign in addition to the triple posterior cruciate ligament (PCL) sign seen on Magnetic Resonance Imaging (MRI) to aid in diagnosing this injury.

Surgical Outcomes After Single-Level Endoscopic Transforaminal Lumbar Interbody Fusion: A Systematic Review and Meta-Analysis.

Background and objective Novel surgical advancements have introduced endoscopic operative techniques for low back surgery, including transforaminal lumbar interbody fusion (TLIF), which theoretically allows for improved decompression with minimal invasiveness. In addition, endoscopically performed TLIF has allowed for the use of local anesthesia as an alternative method to general anesthesia for patients. We aimed to evaluate the clinical outcomes in patients undergoing endoscopic TLIF and also compare the outcomes in patients undergoing general versus local anesthesia. Methods The databases of PubMed, Medline, Embase, and the Cochrane Library were queried for all studies involving patients undergoing endoscopic TLIF. After the extraction of the data and assessment of study quality via the Newcastle-Ottawa Scale, statistical analysis was performed with the R software (The R Foundation, Vienna, Austria) metafor package. The random-effects model was used as the data was largely heterogeneous (I2 >50%). Results In total, 15 studies involving a total of 441 patients were selected for the final quantitative meta-analysis. The overall mean difference between the postoperative visual analog scale (VAS) leg scores and preoperative VAS scores was 3.45 (95% CI: 4.93-1.97, p: <0.01). Postoperative VAS low back scores revealed a mean difference of 3.36 (95% CI: 5.09-1.63, p: <0.01). The overall mean difference of ODI scores was 4.58 (95% CI: 6.76-2.40, p: <0.01). Mean blood loss was 136.32 mL and the mean operative time was 149.15 minutes. The mean length of stay postoperatively was lower in the local anesthesia group compared to the general anesthesia group (1.40 vs 5.99 days respectively). There were no outcome variables of patients undergoing general anesthesia versus local anesthesia that showed statistically significant differences in this analysis due to the small amount of data published on patients undergoing endoscopic TLIF with local anesthesia. In addition, the failure of studies in reporting standard deviations as data parameters further limited the quantitative analysis. Conclusion Endoscopic TLIF appears to be a viable option for patients undergoing lumbar interbody fusion. Initial data reveal that endoscopic TLIF with local anesthesia may offer patients outcomes similar to those in patients undergoing endoscopic TLIF with general anesthesia, with lower operative times and length of stay.

Medically Necessary Orthopaedic Surgery During the COVID-19 Pandemic: Safe Surgical Practices and a Classification to Guide Treatment.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly evolved as a viral pandemic. Countries worldwide have been affected by the recent outbreak caused by the SARS (severe acute respiratory syndrome)-CoV-2 virus. As with prior viral pandemics, health-care workers are at increased risk. Orthopaedic surgical procedures are common in health-care systems, ranging from emergency to elective procedures. Many orthopaedic surgical procedures are life or limb-saving and cannot be postponed during the COVID-19 pandemic because of potential patient harm. Our goal is to analyze how orthopaedic surgeons can perform medically necessary procedures during the pandemic and to help guide decision-making perioperatively. METHODS: We performed a review of the existing literature regarding COVID-19 and prior viral outbreaks to help guide clinical practice in terms of how to safely perform medically necessary orthopaedic procedures during the pandemic for both asymptomatic patients and high-risk (e.g., COVID-19-positive) patients. We created a classification system based on COVID-19 positivity, patient health status, and COVID-19 prevalence to help guide perioperative decision-making. RESULTS: We advocate that only urgent and emergency surgical procedures be performed. By following recommendations from the American College of Surgeons, the Centers for Disease Control and Prevention, and the recent literature, safe orthopaedic surgery and perioperative care can be performed. Screening measures are needed for patients and perioperative teams. Surgeons and perioperative teams at risk for contracting COVID-19 should use appropriate personal protective equipment (PPE), including N95 respirators or powered air-purifying respirators (PAPRs), when risk of viral spread is high. When preparing for medically necessary orthopaedic procedures during the pandemic, our classification system will help to guide decision-making. A multidisciplinary care plan is needed to ensure patient safety with medically necessary orthopaedic procedures during the COVID-19 pandemic. CONCLUSIONS: Orthopaedic surgery during the COVID-19 pandemic can be performed safely when medically necessary but should be rare for COVID-19-positive or high-risk patients. Appropriate screening, PPE use, and multidisciplinary care will allow for safe medically necessary orthopaedic surgery to continue during the COVID-19 pandemic. LEVEL OF EVIDENCE: Prognostic Level V. See Instructions for Authors for a complete description of levels of evidence.

Preoperative Estimated Width of the Patellar Tendon for Anterior Cruciate Ligament Reconstruction.

This study aims to compare the actual patellar tendon width with the skin and magnetic resonance imaging (MRI) measurements and to describe a more accurate method to predict the actual patellar tendon width before anterior cruciate ligament reconstruction (ACLR).Thirty-nine patients undergoing primary ACLR were identified. Patients with patellar tendon width of less than 30 mm by skin or MRI measurements were excluded from the study. The actual patellar tendon width was measured as an intraoperative reading taken after surgical exposure. Mean difference between the skin and actual measurement and mean difference between the MRI and actual measurement was calculated. Paired t-test was run to determine any significant differences. A difference was also calculated between the actual measurement and the average sum of skin and MRI measurements for each patient. Skin thickness was compared to Δ (Δ = preincision skin measurement of patellar tendon width minus postincision actual measurement) by Spearman's correlation test. Mean difference between skin and actual measurements was 2.5 mm, with p = 0.001. Mean difference between MRI and actual measurement was -2.7 mm with p = 0.001. However, the mean difference between the actual and the average sum of skin and MRI measurements was 0.13 mm with p = 0.76. The Pearson's correlation coefficient, r s, between average sum of skin and MRI measurements and the actual measurement was 0.6 with p = 0.001. There was no correlation found between the skin thickness and Δ∙. This study indicates that there is a significant difference between the actual patellar tendon width and the measurement of the tendon taken using a ruler on the skin or using MRI image software. However, the average sum of skin and MRI measurements, which is not significantly different from the actual width, can accurately predict the actual patellar tendon width before ACLR. The study reflects level IV evidence.

The Role of Bone Marrow Aspirate Concentrate for the Treatment of Focal Chondral Lesions of the Knee: A Systematic Review and Critical Analysis of Animal and Clinical Studies.

PURPOSE: To summarize currently available data regarding the use of bone marrow aspirate concentrate (BMAC) for the treatment of focal chondral lesions of the knee in experimental animal models and human clinical studies. METHODS: A systematic review searching for the terms "(bone marrow)" AND "(aspirate OR concentrate)" AND "(cartilage OR chondral OR osteochondral)" was performed in the databases PubMed, Cochrane Central Register of Controlled Trials, and Google Scholar regarding the use of BMAC for the treatment of focal chondral lesions of the knee. The inclusion criteria were animal and clinical studies published in English that used autologous BMAC to treat focal chondral defects of the knee. We excluded studies that evaluated nonconcentrated preparations of bone marrow aspirate or preparations that were culture expanded. RESULTS: A total of 23 studies were included: 10 studies performed in animal models and 13 human clinical studies. Animal studies showed inconsistent outcomes regarding the efficacy of BMAC for the treatment of chondral or osteochondral lesions, assessed by gross morphology, second-look arthroscopy, magnetic resonance imaging, histology, immunohistochemistry, mechanical testing, and micro-tomography. Chondral defect filling was achieved with fibrocartilage or "hyaline-like" cartilage. Cells present in BMAC did not meet the criteria to be characterized as mesenchymal stem cells according to the International Society for Cell Therapy because freshly isolated cells failed to show tri-lineage differentiation. Overall, all clinical studies, independent of the study group or level of evidence, reported improved clinical outcomes and higher macroscopic, magnetic resonance imaging, and histology scores. Comparative trials favored BMAC over microfracture and reported equivalent outcomes between BMAC and matrix-induced autologous chondrocyte implantation. However, clinical studies were scant and showed low scientific rigor, poor methodologic quality, and low levels of evidence on average. CONCLUSIONS: Although clinical success in short-term and midterm applications has been suggested for the application of BMAC for the restoration of cartilage defects in lesions of the knee, current study designs are generally of low scientific rigor. In addition, clinical applications of this technology in animal model investigations have shown inconsistent outcomes. Thus, clinicians should apply this technology cautiously. LEVEL OF EVIDENCE: Level IV, systematic review of Level II, III, and IV evidence studies.

Value of Preoperative MRI and Examination under Anesthesia for Differentiating Complete from Partial Anterior Cruciate Ligament Tears.

Partial tears of the anterior cruciate ligament (ACL) recently regained attention due to a better understanding of the two distinct bundles of the ligament and the possibility of single-bundle reconstruction procedures. An accurate diagnosis is important as it influences treatment options and patient prognosis. The aim of this study was to evaluate the value of examination under anesthesia (EUA) and magnetic resonance imaging (MRI) for differentiating partial from complete ACL tears. For this purpose, this prospective case series included 95 consecutive patients undergoing primary ACL reconstruction surgeries. MRI, EUA, and MRI combined with EUA were performed preoperatively, and results were compared with arthroscopy. Our data showed that ACL lesions were diagnosed as partial tears in 42.1% (n = 40) of EUA, 23.2% (n = 22) of MRI, and 11.6% (n = 11) of arthroscopies. EUA and MRI demonstrated sensitivity of 100 and 90.1%, and specificity of 65.5 and 85.6%, respectively. Combined EUA and MRI demonstrated sensitivity of 100% and specificity of 83.1%. Our study revealed that preoperatively MRI and EUA may help surgeons early identify partial ACL tears and influence treatment decisions.

Angiomodulin is a specific marker of vasculature and regulates vascular endothelial growth factor-A-dependent neoangiogenesis.

Blood vessel formation is controlled by the balance between pro- and antiangiogenic pathways. Although much is known about the factors that drive sprouting of neovessels, the factors that stabilize and pattern neovessels are undefined. The expression of angiomodulin (AGM), a vascular endothelial growth factor (VEGF)-A binding protein, was increased in the vasculature of several human tumors as compared to normal tissue, raising the hypothesis that AGM may modulate VEGF-A-dependent vascular patterning. To elucidate the expression pattern of AGM, we developed an AGM knockin reporter mouse (AGM(lacZ/+)), with which we demonstrate that AGM is predominantly expressed in the vasculature of developing embryos and adult organs. During physiological and pathological angiogenesis, AGM is upregulated in the angiogenic vasculature. Using the zebrafish model, we found that AGM is restricted to developing vasculature by 17 to 22 hours postfertilization. Blockade of AGM activity with morpholino oligomers results in prominent angiogenesis defects in vascular sprouting and remodeling. Concurrent knockdown of both AGM and VEGF-A results in synergistic angiogenesis defects. When VEGF-A is overexpressed, the compensatory induction of the VEGF-A receptor, VEGFR2/flk-1, is blocked by the simultaneous injection of AGM morpholino oligomers. These results demonstrate that the vascular-specific marker AGM modulates vascular remodeling in part by temporizing the proangiogenic effects of VEGF-A.

Smad1 and Smad5 differentially regulate embryonic hematopoiesis.

The bone morphogenetic protein (BMP) signaling pathway regulates multiple steps of hematopoiesis, mediated through receptor-regulated Smads, including Smad1 and Smad5. Here, we use loss-of-function approaches in zebrafish to compare the roles of Smad1 and Smad5 during embryonic hematopoiesis. We show that knockdown of Smad1 or Smad5 generates distinct and even opposite hematopoietic phenotypes. Embryos depleted for Smad1 have an increased number of primitive erythrocytes, but fail to produce mature embryonic macrophages. In contrast, Smad5-depleted embryos are defective in primitive erythropoiesis, yet have normal numbers of macrophages. Loss of either Smad1 or Smad5 causes a failure in the generation of definitive hematopoietic progenitors. To investigate the mechanism behind these phenotypes, we used rescue experiments and found that Smad5 is unable to rescue the Smad1 loss-of-function phenotype, indicating that the 2 highly related proteins have inherently distinct activities. Microarray experiments revealed that the 2 proteins redundantly regulate the key initiators of the hemato-vascular program, including scl, lmo2, and gfi1. However, each also regulates a remarkably distinct genetic program, with Smad5 uniquely regulating the BMP signaling pathway itself. Our results suggest that specificity of BMP signaling output, with respect to hematopoiesis, can be explained by differential functions of Smad1 and Smad5.

BMP signaling restricts hemato-vascular development from lateral mesoderm during somitogenesis.

The bone morphogenetic protein (BMP) signaling pathway is essential during gastrulation for the generation of ventral mesoderm, which makes it a challenge to define functions for this pathway at later stages of development. We have established an approach to disrupt BMP signaling specifically in lateral mesoderm during somitogenesis, by targeting a dominant-negative BMP receptor to Lmo2+ cells in developing zebrafish embryos. This results in expansion of hematopoietic and endothelial cells, while restricting the expression domain of the pronephric marker pax2.1. Expression of a constitutively active receptor and transplantation experiments were used to confirm that BMP signaling in lateral mesoderm restricts subsequent hemato-vascular development. The results show that the BMP signaling pathway continues to function after cells are committed to a lateral mesoderm fate, and influences subsequent lineage decisions by restricting hemato-vascular fate in favor of pronephric development.