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Background National guidelines, including the National Accreditation Program for Rectal Cancer, recommend initiation of rectal cancer treatment within 60 days of diagnosis; however, the effect of timely treatment initiation on oncologic outcomes is unclear. The purpose of this study was to evaluate the impact on oncologic outcomes of initiation of rectal cancer treatment within 60 days of diagnosis. Methods This was a retrospective review of stage II/III rectal cancer patients performed using the United States Rectal Cancer Consortium, a collaboration of 6 academic medical centers. Patients with clinical stage II/III rectal cancer who underwent radical resection between January 1, 2010 and December 31, 2018 were included. The primary exposure was treatment initiation, defined as either resection or initiation of chemotherapy or chemoradiotherapy, within 60 days of diagnosis. The primary outcome was disease recurrence, and the secondary outcome was all-cause mortality. Results A total of 1,031 patients meeting inclusion criteria were included in the analysis. Treatment was initiated within 60 days of diagnosis in 830 patients (80.5%) and after 60 days in 201 patients (20.3%). In multivariable logistic regression, older age, non-White race, and residence greater than 100 miles from the treatment center were significantly associated with delay in treatment beyond 60 days. In survival analysis, 167 patients (16.2%) experienced recurrent disease, and 127 patients (12.3%) died of any cause. In an adjusted model accounting for pathologic staging, treatment sequence, distance to care, age, comorbidities, treatment center, and receipt of adjuvant chemotherapy, neither progression-free survival nor all-cause mortality was significantly associated with timely initiation of therapy with hazard ratios of 1.09 (0.70, 1.69) and 1.03 (0.63, 1.66), respectively. Conclusion This study found no difference in oncologic outcomes with initiation of treatment beyond 60 days.

DNA amplification is known to be the most expensive step during forensic DNA analysis. This study evaluated the half-reaction amplification protocol (12.5 µL PCR product) using DNA amplification kits from Promega PowerPlex® (PowerPlex® 18D System, PowerPlex ®21System, PowerPlex® Fusion System and PowerPlex® Y23 System), which might aid in reducing sample analysis cost by half and allow the analysis of more samples. A sensitivity study (15 samples) along with testing of various blood stain samples (n=100) that were submitted to the Medico-Legal Directorate laboratory for DNA testing was accomplished to compare the DNA profiles resulting from half-reaction volume procedure to those with full-reaction volume procedure, using three differed methods along with standard protocol to evaluate the effect of half reaction volume with some variables. Results demonstrated the use of half-reaction amplification protocol preceded by washing step for all aforementioned DNA amplification kits gave a robust and reliable amplification result that aid to increase the number of samples analyzed and decreased the test cost for each kit without compromising the quality of 3DNA profiles obtained.

BACKGROUND: Current guidelines favor transabdominal radical resection (RR) over transanal local excision (TAX) followed by adjuvant therapy (TAXa) for pT1N0 rectal tumors with high-risk features. Comparison of oncologic outcomes between these approaches is limited, although the former is associated with increased postoperative morbidity. We hypothesize that such treatment strategies result in equivalent long-term survival. METHODS: A retrospective cohort study was conducted using the National Cancer Database (2010–2016) to identify patients with pT1N0 rectal adenocarcinoma with high-risk features who underwent TAX or RR for curative intent. The primary outcome was 5-year overall survival (OS), evaluated with log-rank and Cox-proportional hazards testing. RESULTS: A total of 1159 patients (age 67.4 ± 12.9 years; 56.6% male; 83.3% White) met study criteria, of which 1009 (87.1%) underwent RR and 150 (12.9%) underwent TAXa. Patients undergoing TAXa had shorter lengths of stay (RR = 6.5 days, TAXa = 2.7 days, p < 0.001). The 5-year OS was equivalent between groups. TAX without adjuvant therapy was associated with an increased risk of mortality (hazard ratio 1.81, 95% confidence interval 1.17–2.78, p = 0.01). CONCLUSIONS: This is the largest study to demonstrate equivalent 5-year OS between TAXa and RR for T1N0 rectal cancer with high-risk features. These findings may guide the development of prospective, randomized trials and influence changes in practice recommendations for early-stage rectal cancer.

BACKGROUND: Intraoperative pelvic drains are often placed during low anterior resection (LAR) to evacuate postoperative fluid collections and identify/control potential anastomotic leaks. Our aim was to assess the validity of this practice. METHODS: Patients from the US Rectal Cancer Consortium (2007–2017) who underwent curative-intent LAR for a primary rectal cancer were included. Patients were categorized as receiving a closed suction drain intraoperatively or not. Primary outcomes were superficial surgical site infection (SSI), deep SSI, intraabdominal abscess, anastomotic leak, and need for secondary drain placement. Three subgroup analyses were conducted in patients who received neoadjuvant chemoradiation, had a diverting loop ileostomy (DLI), and had low anastomoses < 6 cm from the anal verge. RESULTS: Of 996 patients 67% (n = 551) received a drain. Drain patients were more likely to be male (64 vs 54%), have a smoking history (25 vs 19%), have received neoadjuvant chemoradiation (73 vs 61%), have low tumors (56 vs 36%), and have received a DLI (80 vs 71%) (all p < 0.05). Drains were associated with an increased anastomotic leak rate (14 vs 8%, p = 0.041), although there was no difference in the need for a secondary drainage procedure to control the leak (82 vs 88%, p = 0.924). These findings persisted in all subset analyses. Drains were not associated with increased superficial SSI, deep SSI, or intraabdominal abscess in the entire cohort or each subset analysis. Reoperation (12 vs 10%, p = 0.478) and readmission rates (28 vs 31%, p = 0.511) were similar. CONCLUSIONS: Although not associated with increased infectious complications, intraoperatively placed pelvic drains after low anterior resection for rectal cancer are associated with an increase in anastomotic leak rate and no reduction in the need for secondary drain placement or reoperation. Routine drainage appears to be unnecessary.

Study objective Investigate the use of a postoperative continuous adductor canal block (cACB) after epidural analgesia to decreases opioid consumption and improve visual analog scale (VAS) scores compared to a sham catheter. Design Double-blinded randomized placebo-controlled trial. Setting Inpatient setting in tertiary care teaching hospital with outpatient follow-up. Patients One-hundred and sixty-five subjects (cACB n = 82 and sham catheter n = 83) with end-stage degenerative joint disease undergoing elective unilateral total knee arthroplasty. Interventions Patients were block randomized to receive a cACB or sham catheter. An epidural catheter was placed preoperatively and discontinued on postoperative day 1. Patients then received a cACB with bupivacaine or sham catheter which remained for the duration of the hospitalization. Measurements Primary outcome was total opioid consumption. Secondary outcomes included VAS scores, knee range of motion (ROM), ambulation distance, and WOMAC scores. Main results Seventy patients completed the study (cACB n = 38 and sham catheter n = 32). Compared to sham catheter, in the first 20 h after placement of a cACB, patients used 22.5 mg less opioid (95% CI: −43.1 to −1.94 mg, P = 0.03). VAS score area under the curve decreased 7.8 mm (95% CI: −15.5 – −0.058 mm, P = 0.04) with a cACB. At 3-week follow-up, WOMAC scores were significantly improved with the cACB with a mean difference of 8.72 (95% CI: −17.3 to −0.11, P = 0.04). There were no statistically significant differences in secondary outcomes on postoperative day 2. Paired outcomes at 6 weeks compared to baseline ROM, showed significant improvement in knee ROM with a cACB (mean difference 11.77°, 95% CI: 3.1–20.5°, P = 0.01). Conclusion A postoperative cACB after total knee arthroplasty significantly reduces total opioid consumption and pain scores compared to sham catheter. Ambulatory ability was not affected and patients recovered function earlier. ClinicalTrials.gov NCT02121392 .

This cross-sectional study compares adverse outcomes and health care use associated with primary anastomosis with proximal diversion vs Hartmann procedure for patients with acute diverticulitis., Key Points Question Among patients with acute diverticulitis treated with an urgent surgical procedure (ie, Hartmann procedure [HP] or primary anastomosis with proximal diversion [PAPD]), is the procedure used associated with index readmission outcomes and resource use? Findings In this cross-sectional study of an estimated 1 072 395 hospitalized patients with acute diverticulitis, 34 126 patients required diversion within 48 hours of admission, and PAPD was associated with comparable index outcomes vs HP but an increased rate of readmission and risk of ostomy reversal. Total index and readmission hospitalization costs were similar between procedures. Meaning These findings suggest that PAPD is associated with increased risk of ostomy reversal compared with HP and that patient characteristics that bias operative strategy selection are the primary factors associated with index patient outcomes., Importance Diverticulitis of the colon is an increasingly prevalent disease with significant implications for patient quality of life and health system resource expenditure. Although several randomized clinical trials and meta-analyses of Hartman procedure (HP) and primary anastomosis and proximal diversion (PAPD) have found surgical equipoise, questions regarding the relative performance of these treatments when applied broadly remain. Objective To examine use of and outcomes after urgent sigmoid colectomy with end colostomy (ie, HP) vs PAPD in management of complicated diverticulitis. Design, Setting, and Participants This retrospective cross-sectional study was a multicenter, population-based examination of inpatient hospitalizations, not including long-term rehabilitation facilities, using data from the 2014 to 2017 Nationwide Readmissions Database. It was performed from November 2020 to January 2021. Included patients were adults admitted with acute diverticulitis requiring HP or PAPD within 48 hours of admission. Exposures Undergoing HP vs PAPD. Main Outcomes and Measures Inverse probability treatment analysis was used to compare outcomes, including index mortality, composite complications (ie, neurologic, infectious, and cardiovascular complications), length of stay, and readmissions within 90 days. Results During the study period, an estimated 1 072 395 adults (615 954 [57.4%] women; median [IQR] age, 64 [52-76] years) required nonelective hospitalization for acute colonic diverticulutus. A total of 34 126 patients required diversion, with 32 326 patients (94.7%) undergoing HP and 1800 patients (5.3%) undergoing PAPD within 48 hours of admission. Patients undergoing PAPD had a decreased median (IQR) age (60 [51-70] years vs 65 [54-74] years; P

Osteosarcoma is the most common primary malignancy of bone in children and young adults. This tumor has a very heterogeneous genetic profile and lacks any consistent unifying event that leads to the pathogenesis of osteosarcoma. In this review, some of the important genetic events involved in osteosarcoma will be highlighted. Additionally, the clinical diagnosis of osteosarcoma will be discussed, as well as contemporary chemotherapeutic and surgical management of this tumor. Finally, the review will discuss some of the novel approaches to treating this disease.

Two recent studies provide intriguing evidence that challenges the role of the epithelial–mesenchymal transition (EMT) as a critical mediator of cancer metastasis, while revealing an unexpected role in cancer drug resistance.1,2 While these findings may not settle the EMT's role in metastasis, these studies suggest that targeting the EMT may inhibit both cancer metastasis and chemoresistance.

Current reconstructive approaches to large craniofacial skeletal defects are often complicated and challenging. Critical-sized defects are unable to heal via natural regenerative processes and require surgical intervention, traditionally involving autologous bone (mainly in the form of nonvascularized grafts) or alloplasts. Autologous bone grafts remain the gold standard of care in spite of the associated risk of donor site morbidity. Tissue engineering approaches represent a promising alternative that would serve to facilitate bone regeneration even in large craniofacial skeletal defects. This strategy has been tested in a myriad of iterations by utilizing a variety of osteoconductive scaffold materials, osteoblastic stem cells, as well as osteoinductive growth factors and small molecules. One of the major challenges facing tissue engineers is creating a scaffold fulfilling the properties necessary for controlled bone regeneration. These properties include osteoconduction, osteoinduction, biocompatibility, biodegradability, vascularization, and progenitor cell retention. This review will provide an overview of how optimization of the aforementioned scaffold parameters facilitates bone regenerative capabilities as well as a discussion of common osteoconductive scaffold materials.

Osteosarcoma (OS) is a devastating illness with rapid rates of dissemination and a poor overall prognosis, despite aggressive standard-of-care surgical techniques and combination chemotherapy regimens. Identifying the molecular mechanisms involved in disease pathogenesis and progression may offer insight into new therapeutic targets. Defects in mesenchymal stem cell differentiation, abnormal expression of oncogenes and tumor suppressors, and dysregulation within various important signaling pathways have all been implicated in development of various disease phenotypes. As such, a variety of basic science and translational studies have shown promise in identifying novel markers and modulators of these disease-specific aberrancies. Born out of these and similar investigations, a variety of emerging therapies are now undergoing various phases of OS clinical testing. They broadly include angiogenesis inhibitors, drugs that act on the bone microenvironment, receptor tyrosine kinase inhibitors, immune system modulators, and other radio- or chemo-sensitizing agents. As new forms of drug delivery are being developed simultaneously, the possibility of targeting tumors locallywhile minimizing systemic toxicityis is seemingly more achievable now than ever. In this review, we not only summarize our current understanding of OS disease processes, but also shed light on the multitude of potential therapeutic strategies the scientific community can use to make long-term improvements in patient prognosis.

Defects of articular cartilage present a unique clinical challenge due to its poor self-healing capacity and avascular nature. Current surgical treatment options do not ensure consistent regeneration of hyaline cartilage in favor of fibrous tissue. Here, we review the current understanding of the most important biological regulators of chondrogenesis and their interactions, to provide insight into potential applications for cartilage tissue engineering. These include various signaling pathways, including fibroblast growth factors (FGFs), transforming growth factor β (TGF-β)/bone morphogenic proteins (BMPs), Wnt/β-catenin, Hedgehog, Notch, hypoxia, and angiogenic signaling pathways. Transcriptional and epigenetic regulation of chondrogenesis will also be discussed. Advances in our understanding of these signaling pathways have led to promising advances in cartilage regeneration and tissue engineering.

One of the greatest obstacles to current cancer treatment efforts is the development of drug resistance by tumors. Despite recent advances in diagnostic practices and surgical interventions, many neoplasms demonstrate poor response to adjuvant or neoadjuvant radiation and chemotherapy. As a result, the prognosis for many patients afflicted with these aggressive cancers remains bleak. The insulin-like growth factor (IGF) signaling axis has been shown to play critical role in the development and progression of various tumors. Many basic science and translational studies have shown that IGF pathway modulators can have promising effects when used to treat various malignancies. There also exists a substantial body of recent evidence implicating IGF signaling dysregulation in the dwindling response of tumors to current standard-of-care therapy. By better understanding both the IGF-dependent and -independent mechanisms by which pathway members can influence drug sensitivity, we can eventually aim to use modulators of IGF signaling to augment the effects of current therapy. This review summarizes and synthesizes numerous recent investigations looking at the role of the IGF pathway in drug resistance. We offer a brief overview of IGF signaling and its general role in neoplasia, and then delve into detail about the many types of human cancer that have been shown to have IGF pathway involvement in resistance and/or sensitization to therapy. Ultimately, our hope is that such a compilation of evidence will compel investigators to carry out much needed studies looking at combination treatment with IGF signaling modulators to overcome current therapy resistance.

47 Background: The optimal level of pedicle ligation during proctectomy for rectal cancer, either at the origin of the inferior mesenteric artery (IMA) or the superior rectal artery (SRA), is still debated. Reasons for IMA ligation include facilitating a tension-free anastomosis and improved clearance of regional lymph nodes. Our aim was to determine if SRA ligation portends inferior outcomes. Methods: The US Rectal Cancer Consortium database (2007-2017) was reviewed for pts with primary, non-metastatic rectal adenocarcinoma who underwent treatment with low anterior resection or abdominoperineal resection. Primary outcomes were anastomotic leak rate and lymph node (LN) harvest. Secondary outcomes were locoregional recurrence-free survival (LRFS), recurrence-free survival (RFS), and overall survival (OS). Results: Of 877 pts, median age was 59 years (IQR52-67) and 62% were male (n = 541). 86% received an IMA ligation (n = 755) while 14% SRA (n = 122). 12% were pathologic stage 0 (n = 101), 33% stage I (n = 281), 24% stage II (n = 206), and 31% stage III (n = 269). Median follow-up was 34 mos. SRA ligation was more common in stage III disease (43vs30%, p = 0.005) while IMA ligation was more often performed with a minimally invasive approach (70vs42%, p < 0.001). SRA ligation was associated with a nearly identical anastomotic leak rate compared to IMA (9vs8%, p = 1.0). Similarly, the median number of LNs removed was the same between both ligation groups (15vs15, p = 0.38). On multivariable analysis accounting for an open approach, advanced pathologic stage, and positive resection margin status, SRA ligation was not associated with increased anastomotic leak rate or reduced LRFS, RFS, or OS (all p > 0.1). Conclusions: If a tension-free anastomosis is feasible, SRA ligation is not associated with either a worse technical outcome or inferior lymph node harvest. Furthermore, all cancer survival metrics are similar between SRA and IMA ligation. Given that either approach is safe and feasible from both a technical and oncologic standpoint, this study questions the routine practice of IMA ligation.

Breast cancer is the second-most prevalent cancer in the United States, with 234,190 new cases projected to be diagnosed in 2015. The initial diagnosis is commonly made early in its disease course due to the use of routine screening mammography. 1 Combined with advances in adjuvant chemotherapy, this has led to promising overall outcomes, including a 5-year survival rate of 89.4% and a 10%–12% rate of locoregional recurrence at 20 years for stage I/II disease. 1–3 By comparison, prognosis remains poor for patients with metastatic disease at diagnosis or for those who present after initial cure of disease with distant recurrence. 4 Among cases of distant recurrence, skeletal recurrence occurs frequently and can be accompanied by hypercalcemia, pain, and functional compromise often requiring a protracted course of palliative therapy. 5–7 The mechanisms underlying the predilection for skeletal metastases seen with breast cancer have heretofore been poorly understood. Hypotheses include expression of osteolysis-stimulating factors such as parathyroid hormone-related protein (PTHrP), interleukin-11 (IL-11), macrophage colony stimulating factor (M-CSF), and vascular endothelial growth factor (VEGF) by cancer cells. 8 Expression of these factors leads to osteoclast-mediated bone resorption and chemotaxis of tumor cells to the osteolytic lesion upon release of growth factors stored within the bone microenvironment, creating a self-perpetuating cycle. 8 In June 2015, Cox et al published their work establishing a link between expression of a copper-dependent amine oxidase, lysyl oxidase (LOX), and induction of pre-metastatic osteolytic lesions in patients with estrogen receptor-negative (ER-negative) breast cancer. It has previously been established that hypoxia in a primary breast adenocarcinoma is associated with an increased risk for metastasis secondary to expression of hypoxia-inducible factors (HIFs). 9 In the study by Cox et al, expression of a previously-established primary hypoxic tumor signature was found to be correlated to metastasis in samples from a cohort of lymph-node negative breast cancer patients who did not receive adjuvant therapy. However, the relationship held true only with samples from ER-negative breast cancers. The authors investigated this correlation further by performing mass-spectrometry-based analysis of the hypoxic secretome of the ER-negative MDA-MB-231 breast cancer parent cell line and an osteotropic clone line (MDA-BT). Compared to expression in the parental MDA-MB-231 line, expression of LOX was upregulated more than 1.5-fold in MDA-BT cells. Expression of LOX, known to be mediated by HIF-1α, appeared to be induced by hypoxia more than other osteotropic genes in the hypoxic secretome. 10 Retrospective analysis of LOX expression in both the authors’ patient cohort and a supporting patient cohort showed it to be correlated with frequency of metastasis in ER-negative breast cancers. In vivo studies were performed using 4T1-BALB/c mice, a syngeneic model of spontaneously-metastasizing ER-negative breast cancer with high levels of LOX expression. Mice were injected with 4T1Luc (control), 4T1shLOX cells which have low LOX expression compared to controls, or 4T1 scrambled control (4T1scr). Relative to the control, 4T1scr tumors were associated with increased osteolytic lesions with time while 4T1shLOX tumors led to comparatively fewer lesions. The role of tumor-secreted, hypoxia-induced factors in the development of osteolytic lesions is supported by the fact that the authors obtained similar results upon injecting tumor-free mice with tumor-conditioned media (CM) from 4T1shLOX or 4T1scr cell lines. The role of LOX in the induction of pre-metastatic osteolytic lesions has been explored across multiple cancer types and appears to be independent of tumor presence. This was demonstrated by increased frequency and size of osteolytic lesions in non-tumor-bearing mice injected with CM from originally LOX-deficient SW480 colorectal cancer cells transformed to overexpress LOX. By comparison, CM from SW480 cells overexpressing a catalytically-inactive mutant did not have a similar effect. The formation of pre-metastatic osteolytic lesion and subsequent skeletal metastases is due to disruption of bone homestasis, which normally consists of a balance between osteoid deposition and resorption (Fig. 1A). 8 The mechanism by which LOX causes or perpetuates this imbalance was studied further. When added to pre-osteoclast cultures, recombinant LOX (rLOX) stimulated osteoclastogenesis more potently than receptor activator of nuclear factor kappa-B ligand (RANKL). Absence of autocrine production of RANKL was confirmed by ELISA, allowing the effect to be attributed wholly to LOX. Greater nuclear localization of nuclear factor of activated T-cells 1 (NFATc1), a regulator of osteoclastogenesis, was demonstrated with rLOX treatment compared to treatment with RANKL. This localization was disrupted in a dose-dependent manner when osteoclast cultures were treated with anti-LOX antibody. LOX was additionally shown to increase terminal differentiation and decrease proliferation of calvarial mouse osteoblasts. This effect was also reversed by treatment with anti-LOX antibodies. Similar induction of differentiation was observed when human osteoblasts of the SaOS-2 cell line were treated with 4T1scr CM and when osteoblast and osteoclast numbers were quantified on tibial endosteal surfaces from tumor-bearing mice. In a final set of experiments, the authors established the pre-metastatic nature of osteolytic lesions induced by LOX. Mice pre-conditioned with 4T1scr CM and LOX antibody developed a reduced tumor burden than their counterparts conditioned with 4T1scr CM without the LOX antibody. Addition of bisphosphonate therapy to CM pre-conditioning reduced the number of bony metastases at 5 weeks after injection with tumor cells. Although the priming of sites before establishment of metastases has been demonstrated across multiple cancer types, this study is the first to characterize the molecular mediators of osteolytic lesion formation in ER-negative breast cancer. LOX and other proteins of the lysyl oxidase family, which primarily function to covalently cross-link collagen and/or elastin in the extracellular matrix (ECM), have previously been shown to play a role in initiation and progression of multiple tumor types. Notably, increased expression in both primary tumor cells and surrounding stroma has been linked to metastasis of several cancers, including breast cancer. 11 However, this is the first study to establish the specific mechanisms underlying this association with ER-negative breast cancer. It is also the first to characterize a RANKL-independent mechanism for osteoclastogenesis by LOX during the development of skeletal metastases (Fig. 1B). These findings suggest a role for development of novel, LOX-specific inhibitors for prophylaxis against skeletal recurrence of ER-negative breast cancers. Finally, further work is needed to resolve why the correlation between LOX expression and skeletal metastasis of breast cancer is limited to the ER-negative subtype.

Cancer death is usually caused by incurable drug-resistant and metastatic cancers. Although tremendous progress has been made in anticancer drug development during the past two decades, cancer medicine still faces unprecedented challenges associated with choosing effective treatments for individual patients. Three recent reports have offered encouraging approaches towards potentially personalized cancer drug selection.

Investigating the cellular processes underlying tendon healing can allow researchers to improve long-term outcomes after injury. However, conducting meaningful studies to uncover the injury healing mechanism at cellular and molecular levels remains challenging. This is due to the inherent difficulty in isolating, culturing, and expanding sufficient primary tenocytes, due to their limited proliferative capacity and short lifespan. In this study, we sought to establish a novel line of immortalized mouse Achilles tenocytes (iMATs) with primary tenocyte properties, but increased proliferative capacity suitable for extensive in vitro experimentation. We show that isolated primary mouse Achilles tenocytes (pMATs) can be effectively immortalized using a piggyBac transposon expressing SV40 large T antigen flanked by FLP recombination target site (FRT). The resulting iMATs exhibit markedly greater proliferation and survival, which can be reversed with FLP recombinase. Furthermore, iMATs express the same set of tendon-specific markers as that of primary cells, although in lower levels, and respond similarly to exogenous stimulation with bone morphogenetic protein 13 (BMP13) as has been previously reported with pMATs. Taken together, our results suggest that iMATs acquire long-term proliferative capacity while maintaining tenogenic properties. We believe that iMATs are a suitable model for studying not only the native cellular processes involved in injury and healing, but also potential therapeutic agents that may augment the stability of tendon repair.

Normohormonal primary hyperparathyroidism presents diagnostic and intraoperative challenges, and current literature is conflicting about management. We aim to better define normohormonal primary hyperparathyroidism in order to improve the care for these patients.In the study, 516 consecutive patients undergoing parathyroidectomy for primary hyperparathyroidism were divided into 2 groups: classic primary hyperparathyroidism (classic primary hyperparathyroidism, increased serum levels of calcium, and parathyroid hormone) and normohormonal primary hyperparathyroidism (hypercalcemia, normal serum levels of parathyroid hormone). We evaluated inter-group differences in presentation, gland weight, pathology, and complications.The normohormonal primary hyperparathyroidism group was comprised of 116 (22.5%) patients. Mean serum levels of parathyroid hormone and calcium were 62.1 pg/mL ± 10.1 and 10.6 mg/dL ± 0.63 in normohormonal primary hyperparathyroidism, and 142 ± 89.0pg/mL and 11.0 ± 0.88 (both P .01) for classic primary hyperparathyroidism. Nephrolithiasis was more common in normohormonal primary hyperparathyroidism. Multigland hyperplasia was more common in normohormonal primary hyperparathyroidism 23 (19.8%) vs 44 (11%; P = .04). Concordant imaging studies were less likely in normohormonal primary hyperparathyroidism (82 [73.2%] vs 337 [87.1%; P .01]), had a lesser total gland weight (531.8 mg ± 680.0 vs 1,039.6 mg ± 1,237.3; P .01), and lesser 2-week parathyroid hormone (32.5 pg/mL ± 18.95 vs 41.0 pg/mL ± 27.8; P = .01). There was no difference in hypoparathyroidism (parathyroid hormone15 pg/mL; P = .93) at 2 weeks postoperatively.Normohormonal primary hyperparathyroidism represents 22.5% of our primary hyperparathyroidism population, which is greater than reported previously. It is a distinct disease process from classic primary hyperparathyroidism in presentation, imaging, and operative findings. More hyperplasia and a lesser gland weight make it challenging to resect the ideal amount of tissue. Studies with long-term follow-up are needed to determine optimal operative management.

Ovarian cancer is the most lethal gynecologic malignancy with an overall cure rate of merely 30%. Most patients experience recurrence within 12–24 months of cure and die of progressively chemotherapy-resistant disease. Thus, more effective anti-ovarian cancer therapies are needed. Here, we investigate the possibility of repurposing antibiotic monensin as an anti-ovarian cancer agent. We demonstrate that monensin effectively inhibits cell proliferation, migration and cell cycle progression and induces apoptosis of human ovarian cancer cells. Monensin suppresses multiple cancer-related pathways including Elk1/SRF, AP1, NFκB and STAT and reduces EGFR expression in ovarian cancer cells. Monensin acts synergistically with EGFR inhibitors and oxaliplatin to inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Xenograft studies confirm that monensin effectively inhibits tumor growth by suppressing cell proliferation through targeting EGFR signaling. Our results suggest monensin may be repurposed as an anti-ovarian cancer agent although further preclinical and clinical studies are needed.

The canonical WNT/β-catenin signaling pathway governs a myriad of biological processes underlying the development and maintenance of adult tissue homeostasis, including regulation of stem cell self-renewal, cell proliferation, differentiation, and apoptosis. WNTs are secreted lipid-modified glycoproteins that act as short-range ligands to activate receptor-mediated signaling pathways. The hallmark of the canonical pathway is the activation of β-catenin-mediated transcriptional activity. Canonical WNTs control the β-catenin dynamics as the cytoplasmic level of β-catenin is tightly regulated via phosphorylation by the 'destruction complex', consisting of glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), the scaffold protein AXIN, and the tumor suppressor adenomatous polyposis coli (APC). Aberrant regulation of this signaling cascade is associated with varieties of human diseases, especially cancers. Over the past decade, significant progress has been made in understanding the mechanisms of canonical WNT signaling. In this review, we focus on the current understanding of WNT signaling at the extracellular, cytoplasmic membrane, and intracellular/nuclear levels, including the emerging knowledge of cross-talk with other pathways. Recent progresses in developing novel WNT pathway-targeted therapies will also be reviewed. Thus, this review is intended to serve as a refresher of the current understanding about the physiologic and pathogenic roles of WNT/β-catenin signaling pathway, and to outline potential therapeutic opportunities by targeting the canonical WNT pathway.

Successful bone tissue engineering requires at the minimum sufficient osteoblast progenitors, efficient osteoinductive factors, and biocompatible scaffolding materials. We previously demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent factors in inducing osteogenic differentiation of mesenchymal stem cells (MSCs). Here, we investigated the potential use of a biodegradable citrate-based thermosensitive macromolecule, poly(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) mixed with gelatin (PPCNG) as a scaffold for the delivery of BMP9-stimulated MSCs to promote localized bone formation. The addition of gelatin to PPCN effectively enhanced the cell adhesion and survival properties of MSCs entrapped within the gel in 3D culture. Using the BMP9-transduced MSC line immortalized mouse embryonic fibroblasts (iMEFs), we found that PPCNG facilitated BMP9-induced osteogenic differentiation of iMEFs in vivo and promoted the formation of well-ossified and vascularized trabecular bone-like structures in a mouse model of ectopic bone formation. Histologic evaluation revealed that vascularization of the bony masses retrieved from the iMEFs + PPCNG group was significantly more pronounced than that of the direct cell injection group. Accordingly, vascular endothelial growth factor (VEGF) expression was shown to be significantly higher in the bony masses recovered from the iMEFs + PPCNG group. Taken together, our results suggest that PPCNG may serve as a novel biodegradable and injectable scaffold and carrier for gene and cell-based bone tissue engineering.

Wnt signaling transduces evolutionarily conserved pathways which play important roles in initiating and regulating a diverse range of cellular activities, including cell proliferation, calcium homeostasis, and cell polarity. The role of Wnt signaling in control of cell proliferation and stem cell self-renewal is primarily carried out through the canonical pathway, which is the best characterized among the multiple Wnt signaling branches. The past 10 years has seen a rapid expansion in our understanding of the complexity of this pathway, as many new components of Wnt signaling have been identified and linked to signaling regulation, stem cell functions, and adult tissue homeostasis. Additionally, a substantial body of evidence links Wnt signaling to tumorigenesis of many cancer types and implicates it in the development of cancer drug resistance. Thus, a better understanding of the mechanisms by which dysregulation of Wnt signaling precedes the development and progression of human cancer may hasten the development of pathway inhibitors to augment current therapy. This review summarizes and synthesizes our current knowledge of the canonical Wnt pathway in development and disease. We begin with an overview of the components of the canonical Wnt signaling pathway and delve into the role this pathway has been shown to play in stemness, tumorigenesis, and cancer drug resistance. Ultimately, we hope to present an organized collection of evidence implicating Wnt signaling in tumorigenesis and chemoresistance to facilitate the pursuit of Wnt pathway modulators that may improve outcomes of cancers in which Wnt signaling contributes to aggressive disease and/or treatment resistance.