Acid sphingomyelinase as a pathological and therapeutic target in neurological disorders: focus on Alzheimer's disease.

Over the past decade, numerous studies have highlighted the importance of acid sphingomyelinase (ASM) in disease treatment in humans. This enzyme functions primarily to generate ceramide, maintain the cellular membrane, and regulate cellular function. However, in the blood and brain of patients with neurological disorders, including major depression, ischemic stroke, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease (AD), elevated ASM levels significantly suggest disease onset or progression. In these diseases, increased ASM is profoundly involved in neuronal death, abnormal autophagy, neuroinflammation, blood-brain barrier disruption, hippocampal neurogenesis loss, and immune cell dysfunction. Moreover, genetic and pharmacological inhibition of ASM can prevent or ameliorate various diseases. The therapeutic effects of ASM inhibition have prompted the urgent need to develop ASM inhibitors, and several ASM inhibitors have been identified. In this review, we summarize the current knowledge on the critical roles and mechanisms of ASM in brain cells and blood that are associated with different neuropathological features, especially those observed in AD. Furthermore, we elucidate the potential possibility and limitations of existing ASM-targeting drugs according to experimental studies in neurological disorder mouse models.

Postoperative effects of laparoscopic Hartmann reversal: A multicenter propensity score matched study.

BACKGROUND: Although the advantages of laparoscopic Hartmann reversal (LHR) compared to open Hartmann reversal (OHR) have been reported in the literature, the number of multicenter studies with good matching investigating this topic is rare. In the present study, we aimed to confirm the advantages of LHR in terms of short-term outcomes through propensity score matching of LHR and OHR groups, using data collected from multiple institutions. METHODS: Patients who underwent Hartmann reversal at six institutions under the Catholic Medical Center of the Catholic University of Korea between January 1, 2005, and December 31, 2021, were included. The patients were divided into the LHR and OHR groups based on the technique used. The two groups were matched using propensity score matching (1:1 ratio, logistic regression with the nearest-neighbor method). The primary outcome was postoperative ileus (POI) frequency, and secondary outcomes were time to solid diet (days) and length of stay (days). RESULTS: Among 337 patients, propensity score matching was performed on 322, after excluding 15 who had undergone open conversion. Of these, 63 patients were assigned to each group through propensity score matching. There was no difference in the frequency of adhesiolysis (77.8% vs. 82.5%, p = 0.503) or the operation time. (210 (IQR 159-290) vs. 233 (IQR 160-280), p = 0.718) between the two groups. As the primary outcome, the LHR group showed significantly lower POI frequency than the OHR group. (4.8% vs. 22.2%, p = 0.0041) Regarding the secondary outcomes, the LHR group showed a shorter period to solid diet than the OHR group. The length of hospital stay was also significantly shorter in the LHR group (4 vs. 6, p < 0.0001; 9 vs. 12, p<0.0001). CONCLUSION: LHR is an effective method to ensure faster recovery of patients after surgery compared to OHR.

Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer's disease.

Acid sphingomyelinase (ASM) has been implicated in neurodegenerative disease pathology, including Alzheimer's disease (AD). However, the specific role of plasma ASM in promoting these pathologies is poorly understood. Herein, we explore plasma ASM as a circulating factor that accelerates neuropathological features in AD by exposing young APP/PS1 mice to the blood of mice overexpressing ASM, through parabiotic surgery. Elevated plasma ASM was found to enhance several neuropathological features in the young APP/PS1 mice by mediating the differentiation of blood-derived, pathogenic Th17 cells. Antibody-based immunotherapy targeting plasma ASM showed efficient inhibition of ASM activity in the blood of APP/PS1 mice and, interestingly, led to prophylactic effects on neuropathological features by suppressing pathogenic Th17 cells. Our data reveals insights into the potential pathogenic mechanisms underlying AD and highlights ASM-targeting immunotherapy as a potential strategy for further investigation.

Acid sphingomyelinase inhibition improves motor behavioral deficits and neuronal loss in an amyotrophic lateral sclerosis mouse model.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of motor neurons in the spinal cord. Main symptoms are manifested as weakness, muscle loss, and muscle atrophy. Some studies have reported that alterations in sphingolipid metabolism may be intimately related to neurodegenerative diseases, including ALS. Acid sphingomyelinase (ASM), a sphingolipid-metabolizing enzyme, is considered an important mediator of neurodegenerative diseases. Herein, we show that ASM activity increases in samples from patients with ALS and in a mouse model. Moreover, genetic inhibition of ASM improves motor function impairment and spinal neuronal loss in an ALS mouse model. Therefore, these results suggest the role of ASM as a potentially effective target and ASM inhibition may be a possible therapeutic approach for ALS. [BMB Reports 2022; 55(12): 621-626].

A study of the analgesic efficacy of rectus sheath block in single-port total laparoscopic hysterectomy: a randomized controlled study.

OBJECTIVE: To investigate the postoperative analgesic effects of rectus sheath block (RSB) in combination with patient-controlled analgesia (PCA) compared with PCA alone after single-port total laparoscopic hysterectomy (TLH). METHODS: This randomized, single-blind study enrolled female patients that underwent single-port TLH. The patients were randomized to receive either fentanyl PCA (PCA group) or RSB with the same PCA. The primary outcomes were fentanyl consumption at 8 h postoperatively and visual analogue scale (VAS) pain scores, which represented the severity of postoperative pain. RESULTS: A total of 36 patients were enrolled in the study: 18 in the PCA group and 18 in the RSB group (two patients were excluded). The primary outcome of fentanyl consumption was significantly lower at 8 h postoperatively in the RSB group than in the PCA group (148 ± 61 µg versus 222 ± 107 µg, respectively). VAS scores were significantly lower at arrival in the post-anaesthesia care unit and at 30 min after arrival in the RSB group compared with the PCA group. There were no significant differences in the nausea/vomiting score and in additional analgesic consumption between the two groups. CONCLUSIONS: RSB can be used as a multimodal approach for pain control in single-port TLH procedures.Clinical Research Information Service (no. KCT0001461).

Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

Anastomotic leakage and chronic presacral sinus after transanal total mesorectal excision (taTME) for rectal cancer: A comparative study to laparoscopic TME.

BACKGROUND: Several studies have shown that there are no significant differences in anastomotic leakage associated with Transanal total mesorectal excision (taTME) versus laparoscopic TME (lapTME) for rectal cancer; however, little is known about late anastomotic leakage, such as that primarily found in the chronic presacral sinus. We aimed to compare the occurrence of anastomotic leakage and chronic presacral sinus in rectal cancer for taTME and lapTME. METHODS: In this retrospective cohort study, data were collected for patients with rectal cancer who underwent surgery between January 2009 and September 2019. Of the 220 patients included in this study, 182 were in the lapTME group and 38 in the taTME group. We compared factors associated with anastomotic leakage and chronic presacral sinus formation between the two groups. A binary-logistic model was used to determine the risk factors for chronic presacral sinus. RESULTS: Anastomotic leakage occurred in six patients (15.8%) in the taTME group and 36 patients (19.7%) in the lapTME group. Chronic presacral sinus occurred in three patients (7.9%) in the taTME group and 15 patients (8.2%) in the lapTME group. There was no significant difference in anastomotic leakage or chronic presacral sinus between groups (P = 0.569 and P = 1.000, respectively). Pathologic stage III or higher was significantly associated with chronic presacral sinus formation (P = 0.006). CONCLUSION: There were no significant differences between taTME and lapTME regarding the incidence of anastomotic leakage or chronic presacral sinus. Almost one-third of anastomotic leakages developed into chronic presacral sinus.

Single-port laparoscopic Deloyers procedure for tension-free anastomosis after extended left colectomy or subtotal colectomy: A 6-patient case series.

Right colon-to-rectal anastomosis is performed in relatively rare conditions, including after subtotal colectomy or extended left hemicolectomy. One technique of tension-free anastomosis is the Deloyers procedure that includes cranio-caudal rotation of the right colon. As with other colon surgeries, the laparoscopic approach has been adapted for the Deloyers procedure. Nevertheless, due to its rare indications and technical specificity, only a small case series have been reported. Here, we report our experience with single-port laparoscopic (SPL) Deloyers procedures.Between June 2013 and March 2018, 6 patients underwent SPL Deloyers procedures. Three patients underwent SPL subtotal colectomy with ascending colon-to-rectal anastomosis for sigmoid colon cancer with chronic ischemic colitis, sigmoid colon cancer with left colon ischemia, and synchronous transverse and sigmoid colon cancer, respectively. The other 3 patients underwent SPL Hartmann reversal using the Deloyers procedure technique for 2 transverse colon end colostomies and 1 ascending colon end colostomy state, which were the result of a previous extended left hemicolectomy and subtotal colectomy, respectively. A commercially available single port was used with conventional straight and rigid laparoscopic instruments. The surgical procedures were similar to those performed during conventional laparoscopic surgery. For the anastomosis, the mobilized remaining ascending colon was rotated 180° counter-clockwise around the axis of the ileocolic pedicle. Tension-free colorectal anastomosis was then performed between the well-vascularized ascending colon and the rectal stump.The SPL Deloyers procedure was successful in all patients. No additional incisions for trocars or conversions to open surgery were necessary. The operative time and postoperative length of stay were 210 to 470 min and 8 to 21 days, respectively. No intraoperative complications were noted. There were 3 minor postoperative complications without anastomotic leakage. All patients had 2 to 3 bowel movements per day, and 1 patient regularly took loperamide at 6 months after surgery.The SPL Deloyers procedure was feasible and allowed patients to achieve good bowel movements. This operation may be considered an additional surgical option for experienced SPL surgeons in selected patients.

Retrospective study on prevalence of recurrent inguinal hernia: a large-scale multi-institutional study.

PURPOSE: We conducted a multi-institutional analysis to establish the epidemiological characteristics of recurrent inguinal hernia following hernia repair in patients across 4 institutions in Korea. METHODS: The retrospectively reviewed data included patient characteristics, hernia location, year of primary operation, type of hernia, timing of recurrence, primary operation type, and whether a mesh was used. RESULTS: Among 4,604 patients who underwent hernia repair surgery, 255 patients (5.5%; 13 females and 242 males; mean age, 63 years) were found to have recurrent hernia from January 2010 to April 2017. Recurrent indirect inguinal and direct hernias were observed in 47.1% and 49.4% of the patients, respectively. The recurrence of hernias within 1 year of surgery was the highest at 17.25%. Early and late recurrences was observed in 23.5% and 66.5% of the patients, respectively. Among the patients, 81.6% underwent open hernia repair at the time of initial surgery. CONCLUSION: Recurrence of hernia is most common in the first year after the initial surgery, and 23.5% of recurrent inguinal hernia was developed within 2 years. Patients underwent surgery after an average of 116 months (median value, 64 months) following the first operation. In patients with recurrent hernia, direct hernia was seen more frequent than indirect hernia whereas indirect hernia occurred more in patients with primary hernia.

N,N'-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer's disease transgenic mice.

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N'-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-ß (Aß) species and significantly improving cognitive function in the brains of 2 types of Alzheimer's disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aß clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

Characterization of the Subventricular-Thalamo-Cortical Circuit in the NP-C Mouse Brain, and New Insights Regarding Treatment.

Gliosis in Niemann-Pick type C (NP-C) disease is characterized by marked changes in microglia and astrocytes. However, the gliosis onset and progression in NP-C has not been systematically studied, nor has the mechanism underlying this finding. Here, we found early gliosis in the subventricular zone (SVZ) of NP-C mice. Neural progenitor damage by Npc1 mutation suppressed vascular endothelial growth factor (VEGF) expression and further induced microglia activation followed by astrogliosis. Interestingly, excessive astrogliosis in the SVZ induced neural progenitor retention and/or migration into thalamus via astrocyte-derived VEGF, resulting in acceleration of thalamic and cortical gliosis through thalamo-cortical pathways. Transplantation of VEGF-overexpressing neural stem cells into the SVZ improved whole-brain pathology of NP-C mice. Overall, our data provide a new pathological perspective on NP-C neural pathology, revealing abnormalities in the subventricular-thalamo-cortical circuit of NP-C mouse brain and highlighting the importance of the SVZ microenvironment as a therapeutic target for NP-C disease.

Transanal Total Proctocolectomy with Ileal Pouch-Anal Anastomosis for Synchronous Triple Colorectal Cancer.

Introduction: Transanal total mesorectal excision (TME) has been utilized as a minimally invasive surgery for colorectal cancer.1 Sylla et al. first reported the use of transanal TME and since then, various platforms have been applied for this procedure.2 The most widely used procedure is laparoscope-assisted transanal TME using a hybrid technique. de Lacy et al. introduced the Cecil procedure, which utilizes two teams (transabdominal and transanal).3 With regard to rectal cancer, a small group of authors attempted pure natural orifice transluminal endoscopic surgery (NOTES) transanal TME.4,5 The aim of this case report is to show that a transanal laparoscopic technique can be utilized for total colectomy. Except for rectal cancer, there are few reports regarding colon resection using NOTES. In this video, we perform a transanal total proctocolectomy with ileal pouch-anal anastomosis in a patient with synchronous triple colorectal cancer (ascending colon, rectosigmoid colon, and rectum). Methods: We performed transanal total proctocolectomy with ileal pouch-anal anastomosis in a patient with synchronous triple colorectal cancer (ascending colon, rectosigmoid colon, and rectum). On preoperative MRI, there was no pelvic lateral lymph node, so we did not need to perform chemoradiation therapy. After transanal dissection of the mesorectum, rectum was flipped into the intraperitoneal space for further dissection. In our setting, we used conventional laparoscopic instruments for most procedures and long-shafted instruments helped during mobilization of the splenic and hepatic flexures. The entire specimen was extracted transanally. The ileal pouch was constructed intracorporeally and ileal pouch-anal anastomosis was performed using a circular stapler. We did not create a defunctioning stoma. Results: The operating time was 328 minutes and blood loss was <50 mL. We harvested 61 lymph nodes, and 1 regional lymph node metastasis was found. The patient experienced temporary paralytic ileus and was discharged on postoperative day 10 and had no major complications. The patient had medications for loose stool but had no incontinence. The patient refused adjuvant chemotherapy. During the 24 months follow-up period, there were no recurrences or metastases in three colonoscopies and three CT scans. This operation was performed in February 2017 and transanal total colectomy has not been reported so far. Conclusion: This transanal laparoscopic technique is feasible for total colectomy and may be adapted to achieve colonic resection through a natural orifice in the future. No competing financial interests exist. Runtime of video: 9 mins 55 secs This subject was previously presented at the International Society of University Colon and Rectal Surgeons (ISUCRS), August 29-September 1, 2018, in London, United Kingdom.

Pure natural orifice transluminal endoscopic surgery for rectal cancer: Ta-TME and CME without abdominal assistance.

AIM: To report our institution's experiences with pure transanal total mesorectal excision (TME) of rectal cancer using single-port equipment and to discuss the feasibility and safety of the technique. METHODS: Between February and December 2017, 12 patients who were selected underwent NOTES TME in our institution. The preoperative assessment included blood analyses with carcinoembryonic antigen serum concentration, full colonoscopy, pelvic magnetic resonance imaging (MRI), and computed tomography (CT) of the abdomen and chest. RESULTS: Ten patients (male:female, 6:4) treated with transanal TME with colorectal anastomosis in our institution were reviewed. Pure TME was performed without laparoscopic assistance in 6 of 10 patients. The mean operative time was 303.5 min. The median distal margin was 2.1 (0.2-4.2) cm. The median number of harvested lymph nodes is 17.5. Except one patient with anastomotic leak, most patients started dietary intake on postoperative day (POD) 3 and were discharged on POD 7. Anastomotic leak was the only postoperative complication. CONCLUSION: This study showed that pure natural orifice transluminal endoscopic surgery (NOTES) TME with coloanal anastomosis for rectal cancer is safe and feasible in selected cases.

Abdominal peripheral nerve block as the only anesthetic technique for totally extraperitoneal endoscopic inguinal hernia repair: Two case reports.

RATIONALE: Laparoscopic totally extraperitoneal (TEP) inguinal hernia repair is a rapidly evolving, minimally invasive treatment modality for inguinal hernia. Compared with open hernia repair, this method requires a smaller incision, has cosmetic advantages, and facilitates rapid recovery and early return to daily activities because of less postoperative pain. Because general anesthesia is essential for TEP hernia repair, it cannot be performed on patients who have an increased risk of developing complications when placed under general anesthesia. PATIENT CONCERNS: We report 2 cases of single-port laparoscopic TEP (SP TEP) that were performed using only an abdominal peripheral nerve block (PNB) at our institute. General anesthesia and neuraxial block were dangerous for both patients owing to severe heart failure and severe chronic obstructive pulmonary disease (COPD). DIAGNOSES: They were diagnosed with an inguinal hernia requiring surgery. INTERVENTIONS: Hence, the anesthesiologist and surgeon decided to attempt a PNB to avoid complications from general anesthesia and allow faster recovery. An ipsilateral transversus abdominis plane block as well as a rectus sheath block and inguinal canal block were administered via ultrasound guidance. OUTCOMES: The patients did not report any pain, and no rescue drug was administrated. The operation times were 65 and 62minutes in patients 1 and 2, respectively. No intraoperative complications were noted. Patient 1 was discharged the day after the surgery, whereas patient 2 was discharged on the same day as the surgery. LESSONS: TEP hernia repair using abdominal PNB anesthesia seemed to be a safe and feasible technique without causing any additional complications. However, the use of abdominal PNB anesthesia alone for TEP hernia repair as an alternative to general anesthesia requires further investigation using a larger cohort.

Fibrin glue versus staple mesh fixation in single-port laparoscopic totally extraperitoneal inguinal hernia repair: A propensity score-matched analysis.

BACKGROUND: Mesh fixation minimizes the risk of recurrence following laparoscopic inguinal hernia repair. Mesh fixation using staples has been implicated as a cause of chronic inguinal pain. We investigated whether fibrin glue mesh fixation reduces acute or chronic postoperative pain in patients undergoing single-port laparoscopic totally extraperitoneal inguinal hernia repair (SP TEP). METHODS: Inguinal hernia patients undergoing SP TEP between October 2013 and September 2016 were evaluated. Propensity score matching was performed to compare short-term and chronic pain in patients undergoing mesh fixation involving either staples or fibrin glue. RESULTS: Stapling was performed in 82 patients and 78 underwent fibrin glue mesh fixation; these individuals were balanced into 50 pairs. Immediately after surgery, the fibrin glue group required significantly less analgesia than did the staple group (p = 0.023). Otherwise, no significant between-group differences in postoperative pain scores or analgesia requirements were noted during the initial 7 postoperative days. Activities of daily living (ADLs) resumed earlier in patients undergoing fibrin glue mesh fixation, compared with staples (p = 0.016). At 6 months, no significant differences in the incidence of chronic pain were observed. CONCLUSIONS: The short-term outcomes of SP TEP were comparable regardless of the mesh fixation method, but the immediate postoperative analgesia requirement was significantly less for those in the fibrin glue group. The time to resume ADLs was shorter for the fibrin glue group. Fibrin glue for mesh fixation during SP TEP may be an efficacious alternative to stapling during minimally invasive inguinal hernia repair.

Solo-Surgeon Single-Port Laparoscopic Anterior Resection for Sigmoid Colon Cancer: Comparative Study.

BACKGROUND: To report our experience with solo-surgeon, single-port laparoscopic anterior resection (solo SPAR) for sigmoid colon cancer. MATERIALS AND METHODS: Data from sigmoid colon cancer patients who underwent anterior resections (ARs) using the single-port, solo surgery technique (n = 31) or the conventional single-port laparoscopic technique (n = 45), between January 2011 and July 2016, were retrospectively analyzed. In the solo surgeries, making the transumbilical incision into the peritoneal cavity was facilitated through the use of a self-retaining retractor system. After establishing a single port through the umbilicus, an adjustable mechanical camera holder replaced the human scope assistant. Patient and tumor characteristics and operative, pathologic, and postoperative outcomes were compared. RESULTS: The operative times and estimated blood losses were similar for the patients in both treatment groups. In addition, most of the postoperative variables were comparable between the two groups, including postoperative complications and hospital stays. In the solo SPAR group, comparable lymph nodes were attained, and sufficient proximal and distal cut margins were obtained. The difference in the proximal cut margin significantly favored the solo SPAR, compared with the conventional AR group (P = .000). CONCLUSION: This study shows that solo SPAR, using a passive camera system, is safe and feasible for use in sigmoid colon cancer surgery, if performed by an experienced laparoscopic surgeon. In addition to reducing the need for a surgical assistant, the oncologic requirements, including adequate margins and sufficient lymph node harvesting, could be fulfilled. Further evaluations, including prospective randomized studies, are warranted.

Everolimus Plus Ku0063794 Regimen Promotes Anticancer Effects against Hepatocellular Carcinoma Cells through the Paradoxical Inhibition of Autophagy.

PURPOSE: Everolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells. MATERIALS AND METHODS: We compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivo models of HCCs. RESULTS: HepG2 cells treated with both agents had significantly lower rates of cell proliferation and higher apoptosis than the individual monotherapies (p < 0.05). Autophagic studies consistently indicated that, unlike the monotherapies, the combination therapy significantly reduced autophagy (p < 0.05). Autophagic blockage directly promoted the pro-apoptotic effects of combination therapy, suggesting autophagy as the survival mechanism of HCC cells. Unlike the monotherapies, combination therapy showed the potential to inhibit sirtuin 1 (SIRT1), the positive regulator of autophagy. SIRT1 overexpression abrogated the autophagy-inhibiting and pro-apoptotic effects of combination therapy. In a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with combination therapy than in mice treated with the respective monotherapies (p < 0.05). The immunohistochemical and immunofluorescence stains of the tumor obtained from the xenograft model showed that combination therapy had the potential of reducing autophagy and promoting apoptosis. CONCLUSION: The combination of everolimus and Ku0063794 potentiates anticancer effects on HCCs through a decrease in autophagy, which is prompted by SIRT1 downregulation.

Comparative analysis of outcomes after multiport and single-port laparoscopic colectomy in emergency situations: Is single-port laparoscopic colectomy safe and feasible?

BACKGROUND/OBJECTIVE: Although consensus has been reached on the superiority of laparoscopy for a majority of conditions underlying acute abdominal pain, the safety and feasibility of single-port laparoscopic colectomy (SPLC) in emergency situations have not been determined. METHODS: A prospective electronic database of all emergency patients who underwent either multiport laparoscopic colectomy (MPLC) or SPLC between April 2006 and December 2014 was used to compare the surgical outcomes of these operative methods. RESULTS: During the study period, 31 MPLCs and 76 SPLCs were performed. These two operative methods resulted in similar operating times, transfusion amounts, lengths of stay, postoperative complications, attainment of lymph nodes, and proximal and distal cut margins. However, the SPLC group had a shorter time to first flatus (2.8±1.9 days vs. 3.8±1.5 days, p=0.005), earlier reinitiation of free oral fluids (3.2±2.1 days vs. 4.4±1.8 days, p=0.002), and lesser requirement of narcotic analgesics (2.5±3.9 times vs. 4.7±4.8 times, p=0.017). CONCLUSION: SPLC could be a safe and effective alternative to MPLC, even in emergency situations when performed by surgeons who have overcome the learning curve associated with single-port laparoscopic techniques. The tendency toward earlier returns to bowel function and decreased incidence of postoperative analgesic use would be potential benefits of SPLC in emergency situations.

HSP90 inhibitor 17-DMAG exerts anticancer effects against gastric cancer cells principally by altering oxidant-antioxidant balance.

Heat shock protein 90 (HSP90) stabilizes numerous oncoproteins and, therefore, its inhibition has emerged as a promising antineoplastic strategy for diverse malignancies. In this study, we determined the therapeutic effects and mechanisms of action of a specific HSP90 inhibitor, 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), in gastric cancer cell lines (AGS, SNU-1, and KATO-III), patient-derived tissues, and a mouse xenograft model. 17-DMAG exerted anticancer effects against gastric cancer cells, manifested by significantly decreased proliferation rates (P < 0.05) and increased expression of apoptotic markers. Flow cytometry using dichlorofluorescein (DCF) diacetate revealed that 17-DMAG dose-dependently increases reactive oxygen species (ROS) levels in gastric cancer cells. Inhibition of ROS by N-acetyl-L-cysteine (NAC) abrogated the proapoptotic effects of 17-DMAG, as demonstrated by the decreased expression of proapoptotic proteins. In addition, 17-DMAG dose- and time-dependently reduced the expression of antioxidants such as catalase and glutathione peroxidase (GPx). Moreover, 17-DMAG reduced the expression of nuclear respiratory factor (NRF)-1 and NRF-2, and prevented them from migrating from the cytoplasm to the nucleus dose-dependently. Finally, in a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with 17-DMAG than in control mice (P < 0.05). Taken altogether, our results suggest that 17-DMAG exerts potent antineoplastic activity against gastric cancer cells primarily by promoting ROS generation and suppressing antioxidant enzyme activities.

Determination of optimized oxygen partial pressure to maximize the liver regenerative potential of the secretome obtained from adipose-derived stem cells.

BACKGROUND: A hypoxic-preconditioned secretome from stem cells reportedly promotes the functional and regenerative capacity of the liver more effectively than a control secretome. However, the optimum oxygen partial pressure (pO2) in the cell culture system that maximizes the therapeutic potential of the secretome has not yet been determined. METHODS: We first determined the cellular alterations in adipose tissue-derived stem cells (ASCs) cultured under different pO2 (21%, 10%, 5%, and 1%). Subsequently, partially hepatectomized mice were injected with the secretome of ASCs cultured under different pO2, and then sera and liver specimens were obtained for analyses. RESULTS: Of all AML12 cells cultured under different pO2, the AML12 cells cultured under 1% pO2 showed the highest mRNA expression of proliferation-associated markers (IL-6, HGF, and VEGF). In the cell proliferation assay, the AML12 cells cultured with the secretome of 1% pO2 showed the highest cell proliferation, followed by the cells cultured with the secretome of 21%, 10%, and 5% pO2, in that order. When injected into the partially hepatectomized mice, the 1% pO2 secretome most significantly increased the number of Ki67-positive cells, reduced serum levels of proinflammatory mediators (IL-6 and TNF-α), and reduced serum levels of liver transaminases. In addition, analysis of the liver specimens indicated that injection with the 1% pO2 secretome maximized the expression of the intermediate molecules of the PIP3/Akt and IL-6/STAT3 signaling pathways, all of which are known to promote liver regeneration. CONCLUSIONS: The data of this study suggest that the secretome of ASCs cultured under 1% pO2 has the highest liver reparative and regenerative potential of all the secretomes tested here.