Short-course radiation with consolidation chemotherapy does not increase operative morbidity compared to long-course chemoradiation: A retrospective study of the US rectal cancer consortium.

BACKGROUND AND OBJECTIVES: Neoadjuvant short-course radiation and consolidation chemotherapy (SC TNT) remains less widely used for rectal cancer in the United States than long-course chemoradiation (LCRT). SC TNT may improve compliance and downstaging; however, a longer radiation-to-surgery interval may worsen pelvic fibrosis and morbidity with total mesorectal excision (TME). A single, US-center retrospective analysis has shown comparable risk of morbidity after neoadjuvant short-course radiation with consolidation chemotherapy (SC TNT) and long-course chemoradiation (LCRT). Validation by a multi-institutional study is needed. METHODS: The US Rectal Cancer Consortium database (2010-2018) was retrospectively reviewed for patients with nonmetastatic, rectal adenocarcinoma treated with neoadjuvant LCRT or SC TNT before TME. The primary endpoint was severe postoperative morbidity. Cohorts were compared by univariate analysis. Multivariable logistic regression modeled the odds of severe complication. RESULTS: Of 788 included patients, 151 (19%) received SC TNT and 637 (81%) LCRT. The SC TNT group had fewer distal tumors (33.8% vs. 50.2%, p < 0.0001) and more clinical node-positive disease (74.2% vs. 47.6%, p < 0.0001). The intraoperative complication rate was similar (SC TNT 5.3% vs. 4.4%, p = 0.65). There was no difference in overall postoperative morbidity (38.4% vs. 46.3%, p = 0.08). Severe morbidity was similar with low anterior resection (9.1% vs. 15.3%, p = 0.10) and abdominoperineal resection (24.4% vs. 29.7%, p = 0.49). SC TNT did not increase the odds of severe morbidity relative to LCRT on multivariable analysis (OR 0.64, 95% CI 0.37-1.10). CONCLUSIONS: SC TNT does not increase morbidity after TME for rectal cancer relative to LCRT. Concern for surgical complications should not discourage the use of SC TNT when aiming to increase the likelihood of complete clinical response.

Incidence and Outcomes of Visceral Ischemia in Acute Aortic Occlusion.

BACKGROUND: Acute aortic occlusion (AAO) is a morbid diagnosis in which mortality correlates with severity of ischemia on presentation. Visceral ischemia (VI) is challenging to diagnose and its presentation as a consequence of AAO is not well-studied. We aim to identify characteristics associated with VI in AAO to facilitate diagnosis. METHODS: Patients diagnosed with AAO who underwent revascularization were identified retrospectively from institutional records (2006-2020). The primary outcome was the development of VI (intra-abdominal ischemia). Univariate analysis was used to compare demographic, exam, imaging, and intraoperative variables between patients with and without VI in the setting of AAO. RESULTS: Ninety-one patients were included. The prevalence of VI was 20.9%. Preoperative comorbidities, time to revascularization, and operative approach did not differ between patients with and without VI. Patients with VI more frequently were transferred from outside institutions (100% vs. 53%, P = 0.02), presented with advanced acute limb ischemia (Rutherford III 36.9% vs. 7.5%, P < 0.01), and had elevated preoperative serum lactate (4.31 vs. 2.41 mmol/L, P < 0.01). VI patients had an increased occurrence of bilateral internal iliac artery (IIA) occlusion (47.4% vs. 18.1%, P = 0.01). Unilateral IIA occlusion, level of aortic occlusion, and patency of inferior mesenteric arteries were not associated with VI. Patients with VI had worse postoperative outcomes. In particular, VI conferred significant risk of mortality (odds ratio 5.45, P < 0.01). CONCLUSIONS: Visceral ischemia is a common consequence of AAO. Elevated lactate, bilateral IIA occlusion, and advanced acute limb ischemia (ALI) should increase clinical suspicion for concomitant VI with AAO and may facilitate earlier diagnosis to improve outcomes.

Vitamin D receptor gene polymorphism and serum vitamin D level as risk factors for acquiring Type II diabetes mellitus.

The studies on the relationship between type 2 diabetes mellitus (T2DM) risk and vitamin D receptor (VDR) gene polymorphisms are still inconclusive. Therefore, the objective of the study was to assess possible risks of acquiring T2DM due to polymorphisms in the VDR gene or abnormal serum levels of VD. 362 participants (181 T2DM patients and 181 healthy controls) from the Diabetic Center, Sulaimaniyah/Iraq, from December 2020 to May 2021 were volumtarily enrolled in the study. For each participant, HbA1c, fasting blood sugar (FBS), serum cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), markers of calcium homeostasis, alkaline phosphatase (ALP), phosphorus, VD and insulin were measured. In addition, FokI, TaqI, ApaI, and BsmI genotypes were also performed using Polymerase Chain Reaction (PCR). The results showed that VD level was significantly lower in T2DM compared to the control group. While, HbA1c was significantly higher in T2DM than in the control group. In contrast to  AA (P=0.034) and CC (P=0.011) genotype of ApaI (rs7975232) gene polymorphism, which were dominant among the control group, AC-genotype was significantly (P=0.0001) dominat among T2DM group. Meanwhile, TT-genotype of TaqI (rs731236) was  significantly (P=0.05) dominant among control group. While there were not any significant differences between other genotypes among T2DM and control groups. In conclusion, low VD-level is a possible risk factor for developing T2DM, and an association was found, especially between ApaI genotypes and T2DM.

Clues to Bradycardia in a Psychiatric Patient can be Revealed by Good History-Taking: A Case Report and Literature Review.

Lithium is a medication commonly used as a mood stabilizer and can have numerous long-lasting side effects. In this case report, we aim to remind clinicians of such consequences. A 68-year-old woman with a psychiatric history presented for mild COVID-19 and developed sinus bradycardia. A permanent pacemaker was planned for her but was cancelled following good history-taking which revealed prior lithium use. The patient was found to have hyperparathyroidism and hypothyroidism, treatment of which resolved the bradycardia. This case serves to remind clinicians that history-taking remains of paramount importance as in this scenario of bradycardia in a psychiatric patient. An invasive therapeutic measure was precluded by good history-taking. There are several mechanisms by which hypothyroidism and hyperparathyroidism can induce bradycardia. COVID-19 infection can also induce bradycardia. LEARNING POINTS: Clinicians should suspect lithium as a cause in any psychiatric patient with new-onset bradycardia.Lithium can induce bradycardia either directly or even after discontinuation indirectly through hypothyroidism and/or hyperparathyroidism.Invasive measures can be avoided with adequate management of these endocrine issues.

Correlation of SARS-CoV-2 infection severity with ABO blood groups and RhD antigen: a case-control study.

OBJECTIVE: The role of ABO types and RhD antigen in coronavirus disease 2019 (COVID-19) severity has been investigated in several recent studies. Thus, the objective of this study was to identify the relationship of ABO and RhD types with symptomatic COVID-19 disease and determine the groups associated with an increased risk of hospitalization. METHODS: This observational case-control study was performed in 530 Iraqi-Kurdish patients with COVID-19. Among them, 184 were severe cases that required hospitalization, while 346 were mild to moderate cases that were treated at home. ABO and RhD antigen groups were compared between cases and 1698 control records from 1 year before the pandemic. The diagnosis of COVID-19 was based on real-time polymerase chain reaction tests and high-resolution chest computed tomography scans with the typical clinical presentation. RESULTS: There were no significant differences in ABO and RhD antigen distributions between the COVID-19 cases and non-COVID controls. No ABO group was associated with the risk of hospitalization as a marker of the severity of infection. CONCLUSIONS: There was no significant association between symptomatic COVID-19 disease and any ABO group or RhD antigen type. No impact of ABO groups on hospitalization was documented.

Transanal excision with adjuvant therapy for pT1N0 rectal tumors with high-risk features offers equivalent survival to radical resection: A National Cancer Database analysis.

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.

What's the magic number? Impact of time to initiation of treatment for rectal cancer.

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.

Revisiting the Value of Drains After Low Anterior Resection for Rectal Cancer: a Multi-institutional Analysis of 996 Patients.

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.

Postoperative continuous adductor canal block for total knee arthroplasty improves pain and functional recovery: A randomized controlled clinical trial.

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.govNCT02121392.

Normohormonal primary hyperparathyroidism is a distinct form of primary hyperparathyroidism.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 hormone <15 pg/mL; P = .93) at 2 weeks postoperatively. CONCLUSION: 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.

Bone morphogenetic protein 9 (BMP9) induces effective bone formation from reversibly immortalized multipotent adipose-derived (iMAD) mesenchymal stem cells.

Regenerative medicine and bone tissue engineering using mesenchymal stem cells (MSCs) hold great promise as an effective approach to bone and skeletal reconstruction. While adipose tissue harbors MSC-like progenitors, or multipotent adipose-derived cells (MADs), it is important to identify and characterize potential biological factors that can effectively induce osteogenic differentiation of MADs. To overcome the time-consuming and technically challenging process of isolating and culturing primary MADs, here we establish and characterize the reversibly immortalized mouse multipotent adipose-derived cells (iMADs). The isolated mouse primary inguinal MAD cells are reversibly immortalized via the retrovirus-mediated expression of SV40 T antigen flanked with FRT sites. The iMADs are shown to express most common MSC markers. FLP-mediated removal of SV40 T antigen effectively reduces the proliferative activity and cell survival of iMADs, indicating the immortalization is reversible. Using the highly osteogenic BMP9, we find that the iMADs are highly responsive to BMP9 stimulation, express multiple lineage regulators, and undergo osteogenic differentiation in vitro upon BMP9 stimulation. Furthermore, we demonstrate that BMP9-stimulated iMADs form robust ectopic bone with a thermoresponsive biodegradable scaffold material. Collectively, our results demonstrate that the reversibly immortalized iMADs exhibit the characteristics of multipotent MSCs and are highly responsive to BMP9-induced osteogenic differentiation. Thus, the iMADs should provide a valuable resource for the study of MAD biology, which would ultimately enable us to develop novel and efficacious strategies for MAD-based bone tissue engineering.

Review of Osteosarcoma and Current Management.

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.

Stem cells, growth factors and scaffolds in craniofacial regenerative medicine.

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, osetoinduction, 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.

Wnt/ß-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance.

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.

A thermoresponsive polydiolcitrate-gelatin scaffold and delivery system mediates effective bone formation from BMP9-transduced mesenchymal stem cells.

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.

Immortalized Mouse Achilles Tenocytes Demonstrate Long-Term Proliferative Capacity While Retaining Tenogenic Properties.

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.

The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: implications in targeted cancer therapies.

The canonical WNT/ß-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 ß-catenin-mediated transcriptional activity. Canonical WNTs control the ß-catenin dynamics as the cytoplasmic level of ß-catenin is tightly regulated via phosphorylation by the 'destruction complex', consisting of glycogen synthase kinase 3ß (GSK3ß), 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/ß-catenin signaling pathway, and to outline potential therapeutic opportunities by targeting the canonical WNT pathway.

Transition to resistance: An unexpected role of the EMT in cancer chemoresistance.

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.