PDCD4 interacting with PIK3CB and CTSZ promotes the apoptosis of multiple myeloma cells.

The role of programmed cell death 4 (PDCD4) in multiple myeloma (MM) development remains unknown. Here, we investigated its role and action mechanism in MM. Bioinformatic analysis indicated that patients with MM and high PDCD4 expression had higher overall survival than those with low PDCD4 expression. PDCD4 expression promoted MM cell apoptosis and inhibited their viability in vitro and tumor growth in vivo. RNA-binding protein immunoprecipitation sequencing analysis showed that PDCD4 is bound to the 5' UTR of the apoptosis-related genes PIK3CB, Cathepsin Z (CTSZ), and X-chromosome-linked apoptosis inhibitor (XIAP). PDCD4 knockdown reduced the cell apoptosis rate, which was rescued by adding PIK3CB, CTSZ, or XIAP inhibitors. Dual luciferase reporter assays confirmed the internal ribosome entry site (IRES) activity of the 5' UTRs of PIK3CB and CTSZ. An RNA pull-down assay confirmed binding of the 5' UTR of PIK3CB and CTSZ to PDCD4, identifying the specific binding fragments. PDCD4 is expected to promote MM cell apoptosis by binding to the IRES domain in the 5' UTR of PIK3CB and CTSZ and inhibiting their translation. Our findings suggest that PDCD4 plays an important role in MM development by regulating the expression of PIK3CB, CTSZ, and XIAP, and highlight new potential molecular targets for MM treatment.

Subxiphoid top-down endoscopic totally preperitoneal approach (eTPA) for midline ventral hernia repair.

PURPOSE: Midline abdominal wall hernia repair is among the most common surgical interventions performed worldwide. However, the optimal surgical technique remains controversial. To overcome the disadvantages of both open and transabdominal procedures, we developed a totally endoscopic preperitoneal approach (eTPA) with placement of a large mesh. METHODS: From December 2019 to October 2020, 20 consecutive patients with small to medium-sized midline ventral hernias underwent repair using a completely preperitoneal subxiphoid top-down approach. The preperitoneal space was entered directly below the xiphoid, and careful endoscopic development of the plane between the peritoneum and posterior sheath of the rectus fascia was then performed behind the linea alba. The hernia sac and its contents were identified and reduced. The hernia defect was closed with sutures, and a mesh with an adequate high defect: mesh ratio was placed in the newly created preperitoneal space. RESULTS: Twenty patients were enrolled in this study, including 14 with primary umbilical hernias, 4 with primary epigastric hernias, and 2 with recurrent umbilical hernias. 15 patients suffered from a mild concomitant diastasis recti. All operations were successfully completed without conversion to open repair. The mean operative time was 105.3 min (range, 60-220 min). Postoperative pain was mild, and the mean visual analog scale score for pain was 1.8 on the first postoperative day. The average postoperative hospital stay was 1.8 days (range, 1-4 days). One patient developed a minor postoperative seroma, but it had no adverse impact on the final outcome. No patients developed recurrence during the 3- to 10-month follow-up period. CONCLUSIONS: The subxiphoid top-down totally endoscopic preperitoneal approach (eTPA) technique is feasible and effective. It may become a valuable alternative for the treatment of primary small- (defect size < 2 cm) and medium-sized (2-4 cm) midline ventral hernias, particularly in presence of a concomitant diastasis recti.

Totally endoscopic sublay (TES) repair for midline ventral hernia: surgical technique and preliminary results.

BACKGROUND: The Rives-Stoppa procedure is used for ventral hernia repair but requires a large midline incision. This report describes a new, totally endoscopic approach to the retromuscular plane, corresponding to a reversed totally extraperitoneal procedure, to perform sublay repair of primary and secondary ventral hernias. This totally endoscopic sublay (TES) repair is described in detail, and its safety and efficacy were evaluated. METHODS: In this prospective study, we assessed 26 consecutive primary and secondary epigastric midline ventral hernias that were repaired between July 2017 and July 2018 using the TES procedure. A large mesh was placed in the retrorectus position using this minimally invasive approach. Indications for this procedure include umbilical, epigastric, incisional hernias, and rectus diastasis. RESULTS: All TES procedures were successfully performed without conversion to an open operation. The mean operative time was 106.6 ± 29.1 min (range 75-205), with average mesh area of 318.8 cm2 for an average defect area of 26.5 cm2. Postoperative pain was mild, and the mean visual analog scale (VAS) under physical stress (e.g., climbing stairs) was 2.4 at the third postoperative day. The average postoperative hospital stay was 2.8 ± 0.8 days (range 2-5). Two patients developed postoperative seroma, with no final adverse effect. No recurrence nor readmissions within 30 days was observed during a mean follow-up of 9.2 ± 4.4 months. CONCLUSIONS: Initial experiences with this technique show that the TES procedure is safe and reliable, requires no specific instruments, and is highly reproducible. There is no need for an expensive anti-adhesion mesh or fixation device, making it cost-effective.

Endoscopic totally extraperitoneal approach (TEA) technique for primary ventral hernia repair.

BACKGROUND: Up to now the totally extraperitoneal (TEP) technique is limited to the treatment of inguinal hernias. Applying this anatomical repair concept to the treatment of other abdominal wall hernias, we developed an endoscopic totally extraperitoneal approach (TEA) to treat primary midline ventral hernias, including umbilical and epigastric hernias, in which for mesh placement, an anatomical space is developed between the peritoneum and the posterior rectus sheath in the ventral part of the abdominal wall (preperitoneal space). METHODS: Between September 2017 and December 2019 according to the selection criterions, 28 consecutive primary midline ventral hernias were repaired using TEA. After extensive endoscopic development of the midline extraperitoneal plane, which was started in the suprasymphysic area, and reduction of the hernia sac, the hernia defect was closed and a large mesh was placed in the preperitoneal position to enforce the anterior abdominal wall. RESULTS: All operations were successfully performed without conversion to open surgery. The mean operation time was 103.3 min (range 85-145 min). Patient-reported postoperative pain was qualitatively mild with a mean pain visual analogue scale score of 1.9 on postoperative day 1. The average hospital stay was 1.9 days (range 1-3 days). Three patients developed minor complications and were treated with no long-term adverse effects. Readmissions within 30 days or hernia recurrences were not observed with a mean follow-up period of 18 months (range 10-27 months). CONCLUSION: In selected cases, TEA is a safe and feasible minimally invasive alternative in treating primary ventral hernias. This technique preserves the anatomical and physiological structure of the abdominal wall and may significantly reduce trauma and postoperative complications. Additionally, anti-adhesion-coated meshes and fixation tackers are not required, thus being cost-effective. Further studies are necessary to proof the true clinical efficacy in comparison to well-known alternative techniques.

Physical activity enhances the effect of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACM1 axis.

Immune checkpoint blockade therapy has demonstrated significant therapeutic effects in certain types of cancers. However, there is limited reporting on the influence of physical activity on its efficacy. This study aimed to investigate the impact of physical activity on anti-PDL-1-mediated immune checkpoint therapy and the interplay of immune cells therein. HePa1-6 tumor-bearing mice were treated with anti-PDL-1 in conjunction with physical activity to assess tumor progression. Flow cytometry was utilized to analyze immune cell infiltration and differentiation levels within the tumor. The expression of HIF-a/CEACAM1 within the tumor due to physical activity was evaluated. HePa1-6 cells with high CEACAM1 expression were validated in mice to determine their inhibitory effects on immune cell proliferation and differentiation. A CD3/CEACAM1 chimeric antibody was developed for treating CEACAM1-overexpressing tumors, and flow cytometry was employed to assess T-cell response. Physical activity enhanced the efficacy of anti-PDL1 by suppressing the HIF-a/CEACAM1 axis within the tumor. In vivo experiments revealed that tumors with high CEACAM1 expression decreased infiltration and activation of CD8 + T cells within the tumor, suppressing T cell cytotoxicity without affecting Treg infiltration. In vitro, high CEACAM1 expression impacted the proliferation and activation of CD8 + T cells in a co-culture system. The constructed CD3/CEACAM1 chimeric antibody significantly activated the TCR within CEACAM1-overexpressing tumors and inhibited tumor progression. The findings suggest that physical activity augments the effectiveness of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACM1 axis.

Totally endoscopic sublay/extraperitoneal (TES)-Sugarbaker repair for type IV parastomal hernia.

TECCHNIQUE: The totally endoscopic sublay/extraperitoneal (TES) technique has become a substantial supplement for the treatment of ventral hernias. The fundamental principle of this technique is to break down the boundaries and connect the spaces, then create a sufficient sublay/extraperitoneal space for hernia repair and mesh placement. This video demonstrates the surgical details of the TES operation for an EHS type IV parastomal hernia. The main steps include retromuscular/extraperitoneal space dissection in the lower abdomen, circumferential incision of the hernia sac, stomal bowel mobilization and lateralization, closure of each hernia defect, and final mesh reinforcement. RESULTS: The operative time was 240 min, and no blood loss occurred. No significant complications were noted during the perioperative period. Postoperative pain was mild, and the patient was discharged on postoperative day 5. During the half-year follow-up, no recurrence or chronic pain was detected. CONCLUSIONS: The TES technique is feasible for carefully selected difficult parastomal hernias. To our knowledge, this is the first reported case of endoscopic retromuscular/extraperitoneal mesh repair of a challenging EHS type IV parastomal hernia.

Modified single-port laparoscopic herniorrhaphy for pediatric inguinal hernias: based on 1,107 cases in China.

BACKGROUND: Laparoscopic surgery is an alternative procedure for pediatric inguinal hernia (PIH), with a major trend toward increasing use of extracorporeal knotting and decreasing use of working ports. We report our experience with the modified single-port laparoscopic herniorrhaphy for repair of PIH and retrospectively evaluate a consecutive series of 1,107 cases in our institution. METHODS: Between February 2006 and July 2011, 1,107 children with indirect inguinal hernia were treated by laparoscopic surgery. All patients underwent high ligation surgery with a modified single-port laparoscopic technique, mainly performed by extracorporeal suturing with an ordinary taper needle (1/2 Arc 11 × 34). The clinical data were retrospectively analyzed. RESULTS: All surgery was successful without any serious complications. During the operations, contralateral patent processus vaginalis was found and subsequently repaired in 221 cases (20.0%). The mean operative time was 11 (range 5-14) min in 815 cases of unilateral repair and 20 (range 14-27) min in 292 cases of bilateral repair. The mean of postoperative hospital stay was 48 (range 26-52) h. Complications occurred in seven cases (0.63%) and were properly managed, with no major impact on outcome of the operations. There were six recurrent cases (0.54%) in the patients who had been followed-up for 9-74 months. There was no obvious scaring visible in any patients after treatment. CONCLUSIONS: The modified single-port laparoscopic technique for the repair of PIH is a safe and reliable procedure with minimal invasion and satisfactory outcome. It is easy to perfect and to perform and therefore is a worthy choice for PIH.

[The standardized practice of laparoscopic-assisted radical right hemicolectomy in order to achieve complete mesocolic excision].

OBJECTIVE: To explore the feasibility of laparoscopic-assisted radical right hemicolectomy with the outcome being a complete mesocolic excision (CME). METHODS: Between February 2010 and June 2011, we performed the standardized surgery of laparoscopic-assisted radical right hemicolectomy with an aim of CME on 14 patients. There were 10 males and 4 females, with an average age of 57 years (range 36 to 74 years). All the pathologic results in 14 cases were primary colonic adenocarcinoma. The TNM stages were distributed as follows: 2 in II A, 3 in II B, 3 in III A, 5 in III B and 1 in III C. RESULTS: Surgery was successfully performed for all patients without open conversion. The average operation time was (178 ± 37) minutes (range 127 to 221 minutes), average intraoperative blood loss was (67 ± 23) ml (range 30 to 110 ml), while the average number of lymph node harvest was 21 ± 7 (range 14 to 31), and the postoperative hospital stay was (10.0 ± 2.2) days (range 7 to 15 days). Minor complications occured in 2 patients. Major complications and post-operative mortality were not observed. All the patients were followed up for 3 to 19 months, no tumor recurrence or metastasis was identified. CONCLUSION: The standardized surgery of laparoscopic-assisted radical right hemicolectomy with the final outcome of CME is safe and feasible.

Totally endoscopic sublay/extraperitoneal Sugarbaker mesh repair for parastomal hernia.

INTRODUCTION: Shared consensus is that a nonslit-mesh-based laparoscopic repair technique is the optimal treatment principle for parastomal hernia (PSH). MATERIALS AND SURGICAL TECHNIQUE: An 81-year-old female parastomal hernia patient who had a previous history of laparoscopic abdominoperineal resection presented for surgical treatment. We performed a novel totally endoscopic sublay/extraperitoneal Sugarbaker mesh repair (TES-Sugarbaker) for this disease. The mesh was deployed in the sublay/extraperitoneal plane in a Sugarbaker configuration. DISCUSSION: TES-Sugarbaker repair for parastomal hernia is technically feasible, it requires no anti-adhesive coated mesh and less traumatic fixation, then reduces the mesh-related complication and postoperative pain, making it more cost effective. The present described case represents an early attempt to perform endoscopic sublay/extraperitoneal mesh repair for PSH.

Internal Ring Defect Closure Technique in Laparoscopic Mesh Hernioplasty for Indirect Inguinal Hernia.

PURPOSE: The best way to reduce seroma formation after laparoscopic indirect hernia repair is debated. We noticed that internal ring defect closure in laparoscopic mesh hernioplasty could provide promising outcomes with an effect on diminishing seroma formation. We introduce our closure technique and report our experience. METHODS: This prospective study was conducted from May 2019 to May 2021. Patients with European Hernia Society classification L3 indirect or scrotal hernia were recruited and underwent laparoscopic transabdominal patch plasty (TAPP). Hernia defect closure was performed before mesh deployment. The primary outcomes were seroma formation, postoperative pain, and hernia recurrence. Perioperative data and postoperative complications were also recorded. RESULTS: Consecutive 77 patients with 89 indirect hernias (including 51 scrotal hernias) were recruited in two regional tertiary hospitals. All operations were successful without open conversion. The mean size of the hernia defect was 3.7 ± 0.5 cm (range, 2.5-5.0 cm). The mean operative time for each hernia repair (peritoneum to peritoneum) was 48.3 ± 10.8 min (range, 33-72 min), and the mean time required for internal ring closure was 6.7 ± 2.2 min (range, 4-10 min). Intraoperative bleeding was minimal. The mean visual analog scale pain score at rest on the first postoperative day was 2.2 (range, 1-4). The average postoperative length of hospital stay was 18 h (range, 14-46 h). During a mean follow-up period of 9.4 months (range, 3-23 months), no hernia recurrence or chronic pain were noted. Seroma formation was detected on six sides of unilateral hernias (6.7%) on postoperative day 7, with a mean volume of 45.8 ml (range, 24-80 ml). All seromas were mild and resolved spontaneously within 3 months, with no need for evacuation or other treatment and without major impact on the final outcome. CONCLUSIONS: Defect closure in laparoscopic mesh hernioplasty for large indirect hernias is safe and feasible and can significantly reduce postoperative seroma formation and relative complications. This approach is recommended in large indirect or scrotal hernia repair.

Tim-3 Blockade Elicits Potent Anti-Multiple Myeloma Immunity of Natural Killer Cells.

Multiple myeloma (MM) is still an incurable plasma cell tumor. Natural killer (NK) cells are characterized by efficient anti-tumor activity, and their activity is one basis of cancer immunotherapeutic strategies. Tim-3, one of the immune checkpoint molecules, negatively regulates NK cell activity. To evaluate roles of the Tim-3 pathway blocking in the regulation of NK cell mediated- anti-MM activity in vitro and in vivo, anti-Tim-3 and/or anti-its ligand (HMGB1, CEACAM1 or Galetin-9) antibodies were applied respectively to block the Tim-3 pathway in the present study. Our results showed that Tim-3 was highly expressed on NK cells, in particular on in vitro expanded NK (exNK) cells. NK cells with Tim-3 blockade displayed a significantly higher degranulation and cytolytic activity against both human MM cell lines and primary MM cells, compared to the isotype control antibody-treated NK cells. The increased NK cell cytolytic activity by Tim-3 blocking was associated with up-regulation of cytotoxicity-related molecules, including perforin, granzyme B, TNF-α and IFN-γ. Ligand (HMGB1, CEACAM1 or Galetin-9) expression on MM cells was at different levels, and accordingly, the improvement in NK cell-mediated killing activity by different ligand blocking were also varying. Tim-3 blocking showed much more efficient enhancement of NK cell cytolytic activity than its ligand blockings. More importantly, exNK cells with Tim-3 blockade significantly inhibited MM tumor growth and prolonged the survival of MM-bearing NOD/SCID mice. Our results also showed that NK cells from peripheral blood and bone marrow of MM patients expressed much higher levels of Tim-3 than their counterparts from controls. Taken together, Tim-3 may be an important target molecule used for developing an antibody and/or NK cell based immunotherapeutic strategies for MM.