Robotic Arm-assisted Total Hip Arthroplasty Reduces Postoperative Trochanteric Bursitis and Changes in Hip Offset.

We investigated the effect of robotic assistance in a postoperative change in hip offset and the incidence of trochanteric bursitis among total hip arthroplasty (THA) patients. As part of a retrospective study of a consecutive series of patients over a 3-year period, 211 patients (102 traditional; 109 robotic) between 2013 and 2016 who underwent posterior-lateral THA were reviewed. Hip offset was measured on preoperative and postoperative anterior-posterior (AP) pelvis radiographs. The absolute change in total hip offset was higher in patients undergoing non-robotic THA than in patients undergoing robotic THA (5.98 ± 4.47 mm vs 4.33 ± 3.98 mm; p = 0.008). The rate of symptomatic trochanteric bursitis (p = 0.02) and cortisone injection was higher in non-robotic THA patients than in robotic THA patients (p = 0.002). Robotic arm-assisted THA is associated with a decreased postoperative change in hip offset, incidence of symptomatic trochanteric bursitis, and bursal steroid injections. (Journal of Surgical Orthopaedic Advances 32(4):112-116, 2023).

Robotic-assisted Total Hip Arthroplasty and Spinopelvic Parameters: A Review.

Total hip arthroplasty (THA) is an effective treatment for osteoarthritis, and the popularity of the direct anterior approach has increased due to more rapid recovery and increased stability. Instability, commonly caused by component malposition, remains a significant concern. The dynamic relationship between the pelvis and lumbar spine, deemed spinopelvic motion, is considered an important factor in stability. Various parameters are used in evaluating spinopelvic motion. Understanding spinopelvic motion is critical, and executing a precise plan for positioning the implant can be difficult with manual instrumentation. Robotic and/or navigation systems have been developed in the effort to enhance THA outcomes and for implementing spinopelvic parameters. These systems can be classified into three categories: X-ray/fluoroscopy-based, imageless, and computed tomography (CT)-based. Each system has advantages and limitations. When using CT-based systems, preoperative CT scans are used to assist with preoperative planning and intraoperative execution, providing feedback on implant position and restoration of hip biomechanics within a functional safe zone developed according to each patient's specific spinopelvic parameters. Several studies have demonstrated the accuracy and reproducibility of robotic systems with regard to implant positioning and leg length discrepancy. Some studies have reported better radiographic and clinical outcomes with use of robotic-assisted THA. However, clinical outcomes comparable to those for manual THA have also been reported. Robotic systems offer advantages in terms of accuracy, precision, and potentially reduced rates of dislocation. Additional research, including conduct of randomized controlled trials, will be required in order to evaluate the long-term outcomes and cost-effectiveness of robotic-assisted THA.

The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities.

The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (ß-catenin dependent) and non-canonical (ß-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

Adipose-derived mesenchymal stem cells (MSCs) are a superior cell source for bone tissue engineering.

Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors, osteoinductive biofactors and biocompatible scaffold materials. Mesenchymal stem cells (MSCs) represent the most promising seed cells for bone tissue engineering. As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat, MSCs can be isolated from numerous tissues and exhibit varied differentiation potential. To identify an optimal progenitor cell source for bone tissue engineering, we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources, including immortalized mouse embryonic fibroblasts (iMEF), immortalized mouse bone marrow stromal stem cells (imBMSC), immortalized mouse calvarial mesenchymal progenitors (iCAL), and immortalized mouse adipose-derived mesenchymal stem cells (iMAD). We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation in vitro, whereas iMAD and iCAL exhibited highest osteogenic capability in BMP9-induced ectopic osteogenesis and critical-sized calvarial defect repair. Transcriptomic analysis revealed that, while each MSC line regulated a distinct set of target genes upon BMP9 stimulation, all MSC lines underwent osteogenic differentiation by regulating osteogenesis-related signaling including Wnt, TGF-ß, PI3K/AKT, MAPK, Hippo and JAK-STAT pathways. Collectively, our results demonstrate that adipose-derived MSCs represent optimal progenitor sources for cell-based bone tissue engineering.

Niclosamide (NA) overcomes cisplatin resistance in human ovarian cancer.

Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system. OC patients are usually diagnosed at advanced stages due to the lack of early diagnosis. The standard treatment for OC includes a combination of debulking surgery and platinum-taxane chemotherapy, while several targeted therapies have recently been approved for maintenance treatment. The vast majority of OC patients relapse with chemoresistant tumors after an initial response. Thus, there is an unmet clinical need to develop new therapeutic agents to overcome the chemoresistance of OC. The anti-parasite agent niclosamide (NA) has been repurposed as an anti-cancer agent and exerts potent anti-cancer activities in human cancers including OC. Here, we investigated whether NA could be repurposed as a therapeutic agent to overcome cisplatin-resistant (CR) in human OC cells. To this end, we first established two CR lines SKOV3CR and OVCAR8CR that exhibit the essential biological characteristics of cisplatin resistance in human cancer. We showed that NA inhibited cell proliferation, suppressed cell migration, and induced cell apoptosis in both CR lines at a low micromole range. Mechanistically, NA inhibited multiple cancer-related pathways including AP1, ELK/SRF, HIF1, and TCF/LEF, in SKOV3CR and OVCAR8CR cells. NA was further shown to effectively inhibit xenograft tumor growth of SKOV3CR cells. Collectively, our findings strongly suggest that NA may be repurposed as an efficacious agent to combat cisplatin resistance in chemoresistant human OC, and further clinical trials are highly warranted.

Long noncoding RNA (lncRNA) H19: An essential developmental regulator with expanding roles in cancer, stem cell differentiation, and metabolic diseases.

Recent advances in deep sequencing technologies have revealed that, while less than 2% of the human genome is transcribed into mRNA for protein synthesis, over 80% of the genome is transcribed, leading to the production of large amounts of noncoding RNAs (ncRNAs). It has been shown that ncRNAs, especially long non-coding RNAs (lncRNAs), may play crucial regulatory roles in gene expression. As one of the first isolated and reported lncRNAs, H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis, development, tumorigenesis, osteogenesis, and metabolism. Mechanistically, H19 mediates diverse regulatory functions by serving as competing endogenous RNAs (CeRNAs), Igf2/H19 imprinted tandem gene, modular scaffold, cooperating with H19 antisense, and acting directly with other mRNAs or lncRNAs. Here, we summarized the current understanding of H19 in embryogenesis and development, cancer development and progression, mesenchymal stem cell lineage-specific differentiation, and metabolic diseases. We discussed the potential regulatory mechanisms underlying H19's functions in those processes although more in-depth studies are warranted to delineate the exact molecular, cellular, epigenetic, and genomic regulatory mechanisms underlying the physiological and pathological roles of H19. Ultimately, these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.

Corrigendum to "Establishment and functional characterization of the reversibly immortalized mouse glomerular podocytes (imPODs)" [Genes & Diseases 5 (2018) 137-149].

[This corrects the article DOI: 10.1016/j.gendis.2018.04.003.].

Corrigendum to 'Modeling colorectal tumorigenesis using the organoids derived from conditionally immortalized mouse intestinal crypt cells (ciMICs)' [Genes Dis 8 (2021) 814-826].

[This corrects the article DOI: 10.1016/j.gendis.2021.01.004.].

Corrigendum to "The development of a sensitive fluorescent protein-based transcript reporter for high throughput screening of negative modulators of lncRNAs" [Genes & Diseases 5 (2018) 62-74].

[This corrects the article DOI: 10.1016/j.gendis.2018.02.001.].

Corrigendum to "Characterization of the essential role of bone morphogenetic protein 9 (BMP9) in osteogenic differentiation of mesenchymal stem cells (MSCs) through RNA interference" [Genes & Diseases 5(2018):172-184].

[This corrects the article DOI: 10.1016/j.gendis.2018.04.006.].

Paired bone marrow and peripheral blood samples demonstrate lack of widespread dissemination of some CH clones.

Clonal hematopoiesis (CH) represents clonal expansion of mutated hematopoietic stem cells detectable in the peripheral blood or bone marrow through next generation sequencing. The current prevailing model posits that CH mutations detected in the peripheral blood mirror bone marrow mutations with clones widely disseminated across hematopoietic compartments. We sought to test the hypothesis that all clones are disseminated throughout hematopoietic tissues by comparing CH in hip vs peripheral blood specimens collected at the time of hip replacement surgery. Here, we show that patients with osteoarthritis have a high prevalence of CH, which involve genes encoding epigenetic modifiers and DNA damage repair pathway proteins. Importantly, we illustrate that CH, including clones with variant allele frequencies >10%, can be confined to specific bone marrow spaces and may be eliminated through surgical excision. Future work will define whether clones with somatic mutations in particular genes or clonal fractions of certain sizes are either more likely to be localized or are slower to disseminate into the peripheral blood and other bony sites.

Threshold level of Peptest in diagnosing gastroesophageal reflux disease with extraesophageal symptoms: Evidence from Vietnam.

Background and Aim: We aimed to evaluate the application of Peptest, a novel technique to detect pepsin in the saliva, and identify its threshold level for the diagnosis of gastroesophageal reflux disease (GERD) with extraesophageal symptoms. Methods: A cross-sectional study was conducted in two groups: patients with extraesophageal GERD symptoms (symptomatic group divided into GERD and non-GERD groups according to 24-h esophageal pH-impedance monitoring [pH-I] results) and healthy controls. For the symptomatic group, endoscopy, pH 24 h, high-resolution manometry (HRM), and salivary Peptest were performed. For the healthy control group, only Peptest was done. The accuracy of Peptest was compared with that of pH-I by the Lyon consensus criteria. Results: Chronic laryngitis was the most frequent extraesophageal symptom. On saliva testing, the GERD group had a higher prevalence of positive samples and pepsin concentration than the control group. Between GERD and non-GERD groups, the optimal threshold level was 31.2 ng/mL, with a sensitivity of 86.7% and specificity of 27.5%. The optimal threshold level was 31.4 ng/mL to differentiate GERD from healthy controls, with a sensitivity of 86.7% and specificity of 66.0%. Age, number of total refluxes, DeMeester score, post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedence (MNBI) were associated with pepsin concentration. Regarding HRM metrics, there was no significant difference of pepsin concentration between low/normal upper esophageal sphincter (UES) resting pressure, low/normal lower esophageal sphincter (LES) resting pressure, low/normal 4-s integrated relaxation pressure (IRP4s), and hypomotility/normal motility. Conclusion: Patients with extraesophageal symptoms had a higher prevalence of positive Peptest. The optimum threshold level of 31.4 ng/mL had high sensitivity and moderate specificity to differentiate between patients with GERD and healthy controls.

Glycogen storage disease type I: Genetic etiology, clinical manifestations, and conventional and gene therapies.

Glycogen storage disease type I (GSDI) is an inherited metabolic disorder characterized by a deficiency of enzymes or proteins involved in glycogenolysis and gluconeogenesis, resulting in excessive intracellular glycogen accumulation. While GSDI is classified into four different subtypes based on molecular genetic variants, GSDIa accounts for approximately 80%. GSDIa and GSDIb are autosomal recessive disorders caused by deficiencies in glucose-6-phosphatase (G6Pase-α) and glucose-6-phosphate-transporter (G6PT), respectively. For the past 50 years, the care of patients with GSDI has been improved following elaborate dietary managements. GSDI patients currently receive dietary therapies that enable patients to improve hypoglycemia and alleviate early symptomatic signs of the disease. However, dietary therapies have many limitations with a risk of calcium, vitamin D, and iron deficiency and cannot prevent long-term complications, such as progressive liver and renal failure. With the deepening understanding of the pathogenesis of GSDI and the development of gene therapy technology, there is great progress in the treatment of GSDI. Here, we review the underlying molecular genetics and the current clinical management strategies of GSDI patients with an emphasis on promising experimental gene therapies.

Clinical symptoms, endoscopic findings, and lower esophageal sphincter characteristics in patients with absent contractility.

Absent contractility is a rare esophageal motility disorder defined by high-resolution manometry which remains poorly understood in pathogenesis and management. We investigated the clinical symptoms, upper gastrointestinal endoscopy findings, and lower esophageal sphincter (LES) characteristics in adult patients diagnosed with absent contractility on high resolution manometry and factors associated with erosive esophagitis that were found on endoscopy in these patients. A cross-sectional study was conducted in patients with absent contractility who were examined at the Institute of Gastroenterology and Hepatology, Vietnam between March 2018 and December 2020. Clinical symptoms, endoscopic findings, and LES metrics were collected and compared between individuals with and without erosive esophagitis. Logistic regression analysis was used to examine a variety of factors associated with erosive esophagitis. Among 7519 patients who underwent high resolution manometry, 204 (2.7%) were diagnosed with absent contractility. The mean age of the study sample was 45.9 years, 65.7% were women, and none had systemic sclerosis. The most common symptoms were regurgitation, belching, epigastric pain, and bloating. On endoscopy, 50% had erosive esophagitis, mostly Los Angeles grade A (42.9%). On manometry, 44.6% of the patients had LES hypotension and 68.1% had low integrated relaxation pressure in 4 seconds (IRP4s). Male sex (adjusted odds ratio = 2.01, 95% confidence interval: 1.04-3.89) and an IRP4s < 5 mm Hg (adjusted odds ratio = 2.21, 95% confidence interval: 1.12-4.37) were significantly associated with erosive esophagitis. Absent contractility was present in many patients without known systemic diseases. Erosive esophagitis was common and associated with male sex and low IRP4s.

Carboxymethyl chitosan prolongs adenovirus-mediated expression of IL-10 and ameliorates hepatic fibrosis in a mouse model.

Effective and safe liver-directed gene therapy has great promise in treating a broad range of liver diseases. While adenoviral (Ad) vectors have been widely used for efficacious in vivo gene delivery, their translational utilities are severely limited due to the short duration of transgene expression and solicitation of host immune response. Used as a promising polymeric vehicle for drug release and nucleic acid delivery, carboxymethyl chitosan (CMC) is biocompatible, biodegradable, anti-microbial, inexpensive, and easy accessible. Here, by exploiting its biocompatibility, controlled release capability and anti-inflammatory activity, we investigated whether CMC can overcome the shortcomings of Ad-mediated gene delivery, hence improving the prospect of Ad applications in gene therapy. We demonstrated that in the presence of optimal concentrations of CMC, Ad-mediated transgene expression lasted up to 50 days after subcutaneous injection, and at least 7 days after intrahepatic injection. Histologic evaluation and immunohistochemical analysis revealed that CMC effectively alleviated Ad-induced host immune response. In our proof-of-principle experiment using the CCl4-induced experimental mouse model of chronic liver damage, we demonstrated that repeated intrahepatic administrations of Ad-IL10 mixed with CMC effectively mitigated the development of hepatic fibrosis. Collectively, these results indicate that CMC can improve the prospect of Ad-mediated gene therapy by diminishing the host immune response while allowing readministration and sustained transgene expression.