A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance.

Androgen deprivation therapy is the most effective treatment for advanced prostate cancer, but almost all cancer eventually becomes castration resistant, and the underlying mechanisms are largely unknown. Here, we show that an intrinsic constitutively activated feedforward signaling circuit composed of IκBα/NF-κB(p65), miR-196b-3p, Meis2, and PPP3CC is formed during the emergence of castration-resistant prostate cancer (CRPC). This circuit controls the expression of stem cell transcription factors that drives the high tumorigenicity of CRPC cells. Interrupting the circuit by targeting its individual components significantly impairs the tumorigenicity and CRPC development. Notably, constitutive activation of IκBα/NF-κB(p65) in this circuit is not dependent on the activation of traditional IKKß/NF-κB pathways that are important in normal immune responses. Therefore, our studies present deep insight into the bona fide mechanisms underlying castration resistance and provide the foundation for the development of CRPC therapeutic strategies that would be highly efficient while avoiding indiscriminate IKK/NF-κB inhibition in normal cells.

MRI Assessment of Extramural Venous Invasion Before and After Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer and Its Association with Disease-Free and Overall Survival.

BACKGROUND: Extramural venous invasion (EMVI) on baseline MRI is associated with poor prognosis in patients with locally advanced rectal cancer. This study investigated the association of persistent EMVI after total neoadjuvant therapy (TNT) (chemoradiotherapy and systemic chemotherapy) with survival. METHODS: Baseline MRI, post-TNT MRI, and surgical pathology data from 175 patients with locally advanced rectal cancer who underwent TNT and total mesorectal excision between 2010 and 2017 were retrospectively analyzed for evidence of EMVI. Two radiologists assessed EMVI status with disagreement adjudicated by a third. Pathologic EMVI status was assessed per departmental standards. Cox regression models evaluated the associations between EMVI and disease-free and overall survival. RESULTS: EMVI regression on both post-TNT MRI and surgical pathology was associated with disease-free survival (hazard ratio, 0.17; 95% confidence interval (CI), 0.04-0.64) and overall survival (hazard ratio, 0.11; 95% CI, 0.02-0.68). In an exploratory analysis of 35 patients with EMVI on baseline MRI, only six had EMVI on pathology compared with 18 on post-TNT MRI; these findings were not associated (p = 0.2). Longer disease-free survival was seen with regression on both modalities compared with remaining positive. Regression on pathology alone, independent of MRI EMVI status, was associated with similar improvements in survival. CONCLUSIONS: Baseline EMVI is associated with poor prognosis even after TNT. EMVI regression on surgical pathology is common even with persistent EMVI on post-TNT MRI. EMVI regression on surgical pathology is associated with improved DFS, while the utility of post-TNT MRI EMVI persistence for decision-making and prognosis remains unclear.

Early Bone Healing on Hydroxyapatite-Coated and Chemically-Modified Hydrophilic Implant Surfaces in an Ovine Model.

Implant topography affects early peri-implant bone healing by changing the osteoconduction rate in the surrounding biological environment. Implant surfaces have been designed to promote faster and stronger bone formation for rapid and stable prosthesis loading. Early peri-implant bone healing has been observed with a sandblasted, acid-etched implant that was chemically modified to be hydrophilic (cmSLA). The present study investigates whether early peri-implant bone healing extends to a rough surface implant with a high crystalline hydroxyapatite surface (TSV MP-1 HA). Three implants were randomly placed in porous trabecular bone within both medial femoral condyles of 10 sheep. Early peri-implant bone stability was measured at 3- and 6-weeks healing time following implant insertion. Results indicated a similar implant stability quotient between the implants at insertion and over time. The significant increase over time of reverse torque values with respect to insertion torque (p < 0.001) did not differ between the implants. However, the bone-to-implant contact of TSV MP-1 HA was significantly higher than that of cmSLA implants at 6 weeks (p < 0.01). These data validate previous findings of a hydrophilic implant surface and extend the observation of early osseointegration to a rough surface implant in porous trabecular bone.

Korean Society of Coloproctology (KSCP) trial of cONsolidation Chemotherapy for Locally advanced mid or low rectal cancer after neoadjUvant concurrent chemoraDiothErapy: a multicenter, randomized controlled trial (KONCLUDE).

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has been a standard treatment option for locally advanced rectal cancer with improved local control. However, systemic recurrence despite neoadjuvant CRT remained unchanged. The only significant prognostic factor proven to be important was pathologic complete response (pCR) after neoadjuvant CRT. Several efforts have been tried to improve survival of patients who treated with neoadjuvant CRT and to achieve more pCR including adding cytotoxic chemotherapeutic agents, chronologic modification of chemotherapy schedule or adding chemotherapy during the perioperative period. Consolidation chemotherapy is adding several cycles of chemotherapy between neoadjuvant CRT and TME. It could increase pCR rate, subsequently could show better oncologic outcomes. METHODS: Patients with advanced mid or low rectal cancer who received neoadjuvant CRT will be included after screening. They will be randomized and assigned to undergo TME followed by 8 cycles of adjuvant chemotherapy (control arm) or receive 3 cycles of consolidation chemotherapy before TME, and receive 5 cycles of adjuvant chemotherapy (experimental arm). The primary endpoints are pCR and 3-year disease-free survival (DFS), and the secondary endpoints are radiotherapy-related complications, R0 resection rate, tumor response rate, surgery-related morbidity, and peripheral neuropathy at 3 year after the surgery. The authors hypothesize that the experimental arm would show a 15% improvement in pCR (15 to 30%) and in 3-year DFS (65 to 80%), compared with the control arm. The accrual period is 2 years and the follow-up period is 3 years. Based on the superiority design, one-sided log-rank test with α-error of 0.025 and a power of 80% was conducted. Allowing for a drop-out rate of 10%, 358 patients (179 per arm) will need to be recruited. Patients will be followed up at every 3 months for 2 years and then every 6 months for 3 years after the last patient has been randomized. DISCUSSION: KONCLUDE trial aims to investigate whether consolidation chemotherapy shows better pCR and 3-year DFS than adjuvant chemotherapy alone for the patients who received neoadjuvant CRT for locally advanced rectal cancer. This trial is expected to provide evidence to support clear treatment guidelines for patients with locally advanced rectal cancer. TRIAL REGISTRATION: Clinicaltrials.gov NCT02843191 (First posted on July 25, 2016).

Multicenter, randomized single-port versus multiport laparoscopic surgery (SIMPLE) trial in colon cancer: an interim analysis.

BACKGROUND: Single-port laparoscopic surgery (SPLS) was recently introduced as an innovative minimally invasive surgery method. Retrospective studies have revealed the safety and feasibility of SPLS for colon cancer treatment. However, no prospective randomized trials have been performed. The multicenter, randomized SIMPLE (single-port versus multiport laparoscopic surgery) trial aimed to investigate short-term perioperative outcomes of SPLS for colon cancer treatment, compared with multiport laparoscopic surgery (MPLS). METHODS: Between August 2011 and April 2014, a total of 194 patients with colon cancer were recruited from seven hospitals in Korea. Patients were randomly allocated into the SPLS group (n = 99) or MPLS group (n = 95). The primary endpoint was postoperative complications. Operative, postoperative, and pathologic outcomes were analyzed after 50% of the patient study population had been recruited. RESULTS: The patients' demographic characteristics, operative times, estimated blood volume losses, numbers of harvested lymph nodes, and lengths of both resection margins were not significantly different between groups. In the SPLS group, the rates of conversion to MPLS and open surgery were 12.9 and 2.2%, respectively. Postoperative complications occurred in 10.8% of the SPLS, and 12.5% of the MPLS patients (p = 0.714). Times to functional recovery, pain scores, and amounts of analgesia were similar between groups. CONCLUSION: The results of this interim analysis suggested that SPLS is technically safe and appropriate when used for radical resection of colon cancer. (ClinicalTrials.gov Identifier: NCT01480128).

Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses.

Phosphatidylserine (PS) receptors contribute to two crucial biological processes: apoptotic clearance and entry of many enveloped viruses. In both cases, they recognize PS exposed on the plasma membrane. Here we demonstrate that phosphatidylethanolamine (PE) is also a ligand for PS receptors and that this phospholipid mediates phagocytosis and viral entry. We show that a subset of PS receptors, including T-cell immunoglobulin (Ig) mucin domain protein 1 (TIM1), efficiently bind PE. We further show that PE is present in the virions of flaviviruses and filoviruses, and that the PE-specific cyclic peptide lantibiotic agent Duramycin efficiently inhibits the entry of West Nile, dengue, and Ebola viruses. The inhibitory effect of Duramycin is specific: it inhibits TIM1-mediated, but not L-SIGN-mediated, virus infection, and it does so by blocking virus attachment to TIM1. We further demonstrate that PE is exposed on the surface of apoptotic cells, and promotes their phagocytic uptake by TIM1-expressing cells. Together, our data show that PE plays a key role in TIM1-mediated virus entry, suggest that disrupting PE association with PS receptors is a promising broad-spectrum antiviral strategy, and deepen our understanding of the process by which apoptotic cells are cleared.

Stenting as a Bridge to Surgery for Obstructive Colon Cancer: Does It Have Surgical Merit or Oncologic Demerit?

PURPOSE: To evaluate the surgical and oncologic outcomes of patients undergoing self-expandable metallic stent (SEMS) placement with elective curative surgery. METHODS: Data from patients admitted with obstructing colon cancer between 2000 and 2012 were analyzed retrospectively. Patients underwent either SEMS placement as a bridge to surgery (stent group, n = 67) or emergency surgery (surgery group, n = 35). Surgical and oncologic outcomes of the groups were compared. RESULTS: Placement of SEMS was technically successful in 98.5% and clinically successful in 89.6% of cases. There were eight (11.9%) stent-related complications, including three migrations (4.5%), four occlusions (6.0%), and one perforation (1.5%). The stent group had a higher laparoscopic resection rate (67.2 vs. 31.4%, p = 0.001) with a lower conversion rate (4.3 vs. 35.3%, p = 0.003). The wound infection rate was significantly higher in the surgery group (37.1 vs. 11.9%, p = 0.003) with no differences in the rate of other complications. The rates of local recurrence and distant metastasis, recurrence-free, and overall survival were not significantly different between the two groups. CONCLUSIONS: Stenting and elective surgery was associated with a higher laparoscopy rate, a lower conversion rate, and a lower wound infection rate compared to emergency surgery but did not affect recurrence or survival.

Cystic adventitial disease of the common femoral artery at a previous surgical dissection site.

Cystic adventitial disease (CAD) is a rare vascular disorder associated with nonatherosclerotic peripheral vessel disease and occurs when mucoid cysts in the adventitia compress the blood vessel. The underlying etiology and pathogenesis of CAD remain debatable as various theories have been suggested. This case is interesting because the cyst developed from the previous common femoral artery (CFA) dissection site. To our knowledge, this is the first report of CAD developed at a previous operation site. Thus, we report herein a case of CAD arising from a previous embolectomy dissection site in the CFA that was successfully treated with surgery.

Transcriptome analysis of methyl jasmonate-elicited Panax ginseng adventitious roots to discover putative ginsenoside biosynthesis and transport genes.

The Panax ginseng C.A. Meyer belonging to the Araliaceae has long been used as an herbal medicine. Although public databases are presently available for this family, no methyl jasmonate (MeJA) elicited transcriptomic information was previously reported on this species, with the exception of a few expressed sequence tags (ESTs) using the traditional Sanger method. Here, approximately 53 million clean reads of adventitious root transcriptome were separately filtered via Illumina HiSeq™2000 from two samples treated with MeJA (Pg-MeJA) and equal volumes of solvent, ethanol (Pg-Con). Jointly, a total of 71,095 all-unigenes from both samples were assembled and annotated, and based on sequence similarity search with known proteins, a total of 56,668 unigenes was obtained. Out of these annotated unigenes, 54,920 were assigned to the NCBI non-redundant protein (Nr) database, 35,448 to the Swiss-prot database, 43,051 to gene ontology (GO), and 19,986 to clusters of orthologous groups (COG). Searching in the Kyoto encyclopedia of genes and genomes (KEGG) pathway database indicated that 32,200 unigenes were mapped to 128 KEGG pathways. Moreover, we obtained several genes showing a wide range of expression levels. We also identified a total of 749 ginsenoside biosynthetic enzyme genes and 12 promising pleiotropic drug resistance (PDR) genes related to ginsenoside transport.

Selective TBK1/IKKi dual inhibitors with anticancer potency.

Increasing evidence suggests that the noncanonical IKKs play critical roles in tumor genesis and development, leading to the notion that noncanonical IKKs may be good targets for cancer therapy. Here, we demonstrate that although TBK1 is not overexpressed or constitutively activated in some tumor cells, targeting IKKi induces the activation of TBK1. Therefore, simultaneously targeting both kinases is necessary to efficiently suppress tumor cell proliferation. We show that three TBK1/IKKi dual inhibitors, which are based on a structurally rigid 2-amino-4-(3'-cyano-4'-pyrrolidine)phenyl-pyrimidine scaffold, potently inhibit cell viability in human breast, prostate and oral cancer cell lines. Treatment with these TBK1/IKKi dual inhibitors significantly impairs tumor development in xenograft and allograft mouse models. The anticancer function of these inhibitors may be partially due to their suppression of TBK1/IKKi-mediated AKT phosphorylation and VEGF expression. Most importantly, these TBK1/IKKi dual inhibitors have drug-like properties including low molecular weight, low cytochrome P450 inhibition and high metabolic stability. Therefore, our studies provide proof of concept for further drug discovery efforts that may lead to novel strategies and new therapeutics for the treatment of human cancer.

Clinical outcomes of reintroducing oxaliplatin to patients with colorectal cancer after mild hypersensitivity reactions.

OBJECTIVE: We aimed to evaluate the clinical outcomes of reintroducing oxaliplatin to patients with colorectal cancer who developed mild hypersensitivity reactions (HSRs). METHODS: A retrospective review was performed of 204 patients who received oxaliplatin-based chemotherapies between January 2003 and August 2009. Desensitization was not used. RESULTS: A total of 44 patients (21.6%) were found to have developed HSRs to oxaliplatin. After the occurrence of an HSR, a mean of three courses of oxaliplatin (range 1-8) were introduced. Following the initial episode, oxaliplatin was reintroduced to 39 patients, resulting in HSR relapse in 89.7% of the patients, including 4 patients (10.3%) with grade 3 reactions. After the second re-exposure of oxaliplatin to 22 patients, HSRs were exhibited in 81.8%, including 2 patients (9.1%) who developed grade 3 reactions. After the third and subsequent re-exposures in 12 patients, all except 1 of the patients developed mild reactions. A total of 7 patients (17.9%) exhibited severe reactions along with the progress of re-exposure. CONCLUSION: We observed that the majority of patients who experienced mild HSRs to oxaliplatin developed mild reactions on multiple re-exposures, suggesting that it may be feasible to continue oxaliplatin without using desensitization when tolerable after mild reactions.

Initial experience of single-port laparoscopic surgery for sigmoid colon cancer.

BACKGROUND: Single-port laparoscopic surgery has attracted attention in the field of minimally invasive colorectal surgery. We hypothesized that an experienced laparoscopic surgeon could perform single-port surgery for colon cancer eligible for conventional laparoscopic anterior resection. Our aim was to analyze our initial experience and immediate surgical outcomes of single-port anterior resection. METHODS: A total of 37 consecutive patients with presumed sigmoid colonic cancer underwent single-port anterior resection with standard laparoscopic instruments between May 2009 and June 2010. Each operation was performed by one of two experienced colorectal surgeons. A cohort of patients who had undergone conventional laparoscopic surgery (CLS) for the same duration a year earlier (August 2007 to September 2008) was used as a historical control. Patient demographics and perioperative outcomes were analyzed and compared with those of CLS. RESULTS: There were no significant differences in mean estimated blood loss, mean length of the resection margin, or morbidity between the two groups, but operative time for the single-port group was significantly shorter (118 ± 41 vs. 140 ± 42 min; p = 0.017). Single-port laparoscopic surgery was successfully performed in 78.4% (29/37) of the patients treated in 2010, and CLS was successfully completed in all of the patients treated the previous year (p = 0.000). The main causes of single-port surgery failure were adhesion and tumor location. CONCLUSIONS: Single-port anterior resection is a feasible and safe procedure with immediate outcomes comparable to those of conventional laparoscopy. Further studies are required to determine the feasibility of single-port surgery for colonic tumors outside the sigmoid colon and the long-term outcome.

Comparison of the Effects of Tissue Processing on the Physicochemical Properties of Bone Allografts.

Purpose: To address the hypothesis that the tissue processing methods of solvent dehydration and freeze-drying would differentially affect the physicochemical characteristics of four commercially available bone allografts and the adhesion and differentiation of human bone marrow-derived mesenchymal stromal cells (hBMSCs) on such substrates in vitro. Materials and Methods: The surface morphology, surface area, and elemental composition of four commercially available cancellous bone allografts were examined using SEM, Brunauer-Emmett-Teller (BET) gas adsorption, and inductively coupled plasma (ICP) analyses. SEM was also employed to compare the allograft surfaces to that of human bone exposed by in vitro osteoclastic resorption. The allografts were seeded with hBMSCs, and the number of adhered cells was assessed at 3 and 7 days. Alkaline phosphatase (ALP) activity was quantified as a measure of osteogenic differentiation after 21 days. Results: Marked differences were seen between the physicochemical characteristics of the solvent-dehydrated and freeze-dried allografts, as well as between their resulting bone microarchitectures and that of osteoclast-resorbed human bone. Increased hBMSC adhesion and differentiation were observed on the solvent-dehydrated allografts compared to freeze-dried allografts, which suggests a higher putative osteogenic potential. The latter was attributed to better preservation of the bone collagen microarchitecture integrity, which may provide not only a more complex substrate architecture, but also a more favorable microenvironment to allow nutrients and oxygen to flow to the adhered cells. Conclusion: Commercially available cancellous bone allografts significantly differ in their physicochemical characteristics, stemming from differences in tissue processing and sterilization methods undertaken by tissue banks. These differences impact the response of MSCs in vitro and may alter the biologic performance of the grafts in vivo. Therefore, it is important to consider these characteristics when choosing a bone substitute for clinical application, as the physicochemical properties of the grafts play a crucial role in their interactions with the biologic environment and subsequent incorporation into the native bone.

The G82S polymorphism promotes glycosylation of the receptor for advanced glycation end products (RAGE) at asparagine 81: comparison of wild-type rage with the G82S polymorphic variant.

Interaction between the receptor for advanced glycation end products (RAGE) and its ligands amplifies the proinflammatory response. N-Linked glycosylation of RAGE plays an important role in the regulation of ligand binding. Two potential sites for N-linked glycosylation, at Asn(25) and Asn(81), are implicated, one of which is potentially influenced by a naturally occurring polymorphism that substitutes Gly(82) with Ser. This G82S polymorphic RAGE variant displays increased ligand binding and downstream signaling. We hypothesized that the G82S polymorphism affects RAGE glycosylation and thereby affects ligand binding. WT or various mutant forms of RAGE protein, including N25Q, N81Q, N25Q/G82S, and N25Q/N81Q, were produced by transfecting HEK293 cells. The glycosylation patterns of expressed proteins were compared. Enzymatic deglycosylation showed that WT RAGE and the G82S polymorphic variant are glycosylated to the same extent. Our data also revealed N-linked glycosylation of N25Q and N81Q mutants, suggesting that both Asn(25) and Asn(81) can be utilized for N-linked glycosylation. Using mass spectrometry analysis, we found that Asn(81) may or may not be glycosylated in WT RAGE, whereas in G82S RAGE, Asn(81) is always glycosylated. Furthermore, RAGE binding to S100B ligand is affected by Asn(81) glycosylation, with consequences for NF-κB activation. Therefore, the G82S polymorphism promotes N-linked glycosylation of Asn(81), which has implications for the structure of the ligand binding region of RAGE and might explain the enhanced function associated with the G82S polymorphic RAGE variant.

The Journal of Minimally Invasive Surgery is indexed by PubMed Central in 2022.

The Journal of Minimally Invasive Surgery (JMIS) is the official journal of the Korean Society of Endo-Laparoscopic & Robotic Surgery (formerly the Korean Society of Endoscopic and Laparoscopic Surgeons). The editorial board of JMIS has been trying steadily for several years to be indexed by the international literature databases. As a first step, JMIS has been deposited into PubMed Central in 2022. Here I would like to show you the path that JMIS has been following over the years.

Dome-type carcinoma of the rectum mimicking a submucosal tumor: a case report and literature review.

Dome-type carcinoma (DC) has been recognized as a rare variant of adenocarcinoma, which arises in gut-associated lymphoid tissue. It has a specific morphologic feature of a dome-like protrusion associated with lymphoid tissue. We report a case of a DC of the rectum in an asymptomatic 58-year-old male. A 2-cm sized, well-demarcated, round mass masquerading as a submucosal tumor (SMT) was identified in the rectum and was resected by endoscopic submucosal dissection. The tumor was revealed as an adenocarcinoma with submucosal invasion of 3,700 µm, which consisted of dilated cystic glands and the lymphoid stroma with reactive germinal centers. On immunohistochemistry, the tumor cells revealed retained expression for mismatch repair proteins. Laparoscopic surgical resection was subsequently performed. DC is considered a distinctive subtype of colorectal adenocarcinoma with characteristic morphology and low-grade malignant potential. Careful detection of the overlying mucosal lesion is crucial to differentially diagnose DC from SMT.

Two new species of the genus Rhyacophila Pictet (Trichoptera, Rhyacophilidae) from Korea and Japan.

Two new species of the genus Rhyacophila Pictet, R. kangae Park Nozaki sp. nov. and R. yamamotoi Nozaki sp. nov., are described from Korea and Japan, respectively. Both species belong to the Rhyacophila nigrocephala Species Group, and their genitalic morphology is very similar to those of R. confissa Botosaneanu 1970 and R. vicina Botosaneanu 1970 described from the Korean Peninsula. These four species can be distinguished from each other by the shape of the complex of preanal appendages and apicodorsal lobe of segment IX in males, and by the shape of the vaginal apparatus in females. Males of the two new species bear larger compound eyes in proportion to the head widths than those of R. confissa and R. vicina.

Endo-satinsky clamp for rectal transection during laparoscopic total mesorectal excision.

BACKGROUND: We describe a technique of intracorporeal rectal transection using an endo-Satinsky clamp during laparoscopic total mesorectal excision. METHODS: We use an abdominal approach through 5 trocars. The rectum and mesorectum are mobilized completely. A flexible trocar is placed at the site of a 12-mm right lower abdominal port after the trocar originally placed there is pulled out. The 12-mm trocar originally placed in the right lower abdomen is moved to the suprapubic site, in which a Pfannenstiel incision is anticipated. The endo-Satinsky clamp is inserted through the flexible trocar, and the rectum is grasped with the endo-Satinsky clamp just above the anticipated point of transection. The endostapler is introduced through the 12-mm suprapubic port and is positioned just distal to the clamp. The rectum is then transected. The transected bowel is resected extracorporeally. Anastomosis is completed intracorporeally by use of a double-stapling technique. RESULTS: From February 2007 to March 2009, we performed low anterior resection with use of the endo-Satinsky clamp for 11 patients with rectal cancer (laparoscopic, 10 patients; robot-assisted, 1 patient). There were no operative complications or deaths. Mean operation time was 179.5 minutes (range, 120-265 min). The average number of cartridges used for rectal transection was 1.6 per patient. CONCLUSION: The endo-Satinsky clamp is a useful device for rectal transection and irrigation. The use of this device makes it easier to place an endostapler just distal to the clamp and to transect the rectum in a more appropriate position.

Postoperative Shoulder Pain after Laparoscopic Surgery.

We often encounter patients complaining of shoulder pain after laparoscopic surgery. The pain mechanism is believed to be due to the diaphragmatic overstretching under pressure in a pneumoperitoneum, which causes referred pain to the shoulder, but the exact mechanism has not been clarified.