Chemoimmunotherapy by combining oxaliplatin with immune checkpoint blockades reduced tumor burden in colorectal cancer animal model.

BACKGROUND: Colorectal cancer (CRC) is among one of the top common cancers worldwide. Developing novel comprehensive treatment strategies is critical for improving survival of late stage CRC patients. Recent advances in immune checkpoint blockades provided a novel strategy for treating cancers via stimulating the antitumor immune response. However, the effects of immune checkpoint blockades were limited in CRC due to intrinsic resistance. Oxaliplatin (OXA) based chemotherapy was the foundation of CRC adjuvant chemotherapy. Here, we investigated the potential roles of OXA in inducing immunogenicity and synergizing with immune checkpoints in CRC. METHOD: Immunogenicity of OXA was tested in CRC cell lines. Immune checkpoint blockades sensitive and resistant CRC models were used to study the potential synergistic roles of OXA with immune checkpoint blockades. RESULTS: We found CT26 mouse model was sensitive to immune checkpoint blockades, while MC38 mouse model was resistant. OXA could induce immunogenic cell death in several human and mouse CRC cell lines. Short term OXA treatment increased immune cell infiltration in MC38 mouse model and therefore enhanced the efficacy of immune checkpoint in MC38 mouse model. As a response to the OXA and immune checkpoint blockades combination, inhibitory immune checkpoints were down-regulated in MC38 tumors, while immune enhancing cytokines were up-regulated. Short term OXA treatment induced antitumor immune response in an immune checkpoint blockades resistant mouse model, therefore synergized with immune checkpoint blockades.

DNA-PKcs interference sensitizes colorectal cancer cells to a mTOR kinase inhibitor WAY-600.

Colorectal cancer (CRC) is one leading contributor of cancer-related mortalities. Mammalian target of rapamycin (mTOR), existing in two complexes (mTORC1/2), is a valuable target for possible CRC interference. In the current study, we showed that WAY-600, a potent mTOR inhibitor, only exerted moderate activity against primary and HT-29 CRC cells. We proposed that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) could be the major resistance factor of WAY-600 in CRC cells. DNA-PKcs inhibitors, including NU7026 and NU7441, dramatically enhanced WAY-600-induced cytotoxic and pro-apoptotic effect against the CRC cells. Further, WAY-600-exerted cytotoxicity was significantly increased in DNA-PKcs-silenced (by targeted siRNA/shRNA) CRC cells, but was attenuated with DNA-PKcs overexpression. Our evidence suggested that DNA-PKcs Thr-2609 phosphorylation might be critical for WAY-600's resistance. Mutation of this site through introducing a dominant negative DNA-PKcs (T2609A) dramatically potentiated WAY-600's sensitivity in HT-29 cells. Meanwhile, overexpression of protein phosphatase 5 (PP5) dephosphorylated DNA-PKcs at Thr-2609, and significantly increased WAY-600's sensitivity in HT-29 cells. In vivo, WAY-600-induced anti-HT-29 xenograft growth activity was significantly potentiated with NU7026 co-administration. These results suggest that DNA-PKcs could be the major resistance factor of WAY-600 in CRC cells.

Hsa_circ_0038646 promotes cell proliferation and migration in colorectal cancer via miR-331-3p/GRIK3.

Increasing evidence supports the essential roles of circular RNAs (circRNAs) and microRNAs (miRNAs/miRs) in different types of human cancer. For example, hsa_circ_0137008 functions as a sponge for mi-338-5p and inhibits the malignant phenotype in colorectal cancer. Furthermore, hsa_circ_RNA_0011780 downregulates FBXW7 by targeting miR-554a and suppressing the progression of non-small cell lung cancer. Thus far, only a single report has identified that the miRNA miR-331-3p exerts a pivotal effect on human colorectal cancer (CRC) evolution. However, both the up- and downstream regulatory mechanisms of miR-331-3p are unclear. In the present study, it was predicted via bioinformatics analysis that the circRNA, hsa_circ_0038646, and the glutamate receptor ionotropic kainate 3 (GRIK3) gene contain binding sites that can interact with miR-331-3p. Thus, hsa_circ_0038646/miR-331-3p/GRIK3 may be a novel therapeutic pathway for CRC. Reverse transcription-quantitative PCR and western blotting analyses were performed, as well as cell proliferation, luciferase reporter and Transwell migration assays. Hsa_circ_0038646 was overexpressed in both CRC cells and tissues, and this aberrant expression was positively related with increasing tumor grade. Knockdown of hsa_circ_0038646 significantly weakened human CRC cell proliferation and migration. It was shown that hsa_circ_0038646 can sponge miR-331-3p to suppress its expression, and that suppression of miR-331-3p can reverse the effects of hsa_circ_0038646 inhibition in CRC cells. It was determined that GRIK3 is a downstream target of miR-331-3p, and that hsa_circ_0038646 could increase the levels of GRIK3 by suppressing miR-331-3p in CRC cells. Restoring GRIK3 expression rescued the weakened CRC cell proliferation and migration following hsa_circ_0038646 knockdown. The present study indicated that hsa_circ_0038646 functions as a tumor promoter in CRC by increasing GRIK3 expression via sponging of miR-331-3p. The hsa_circ_0038646/miR-331-3p/GRIK3 axis may be a novel therapeutic and diagnostic target of CRC.

Reconstruction of degloved thumb with prefabricated flap.

The wrap around the toe flap from the great toe is considered to be a good reconstructive proce-dure for degloved injuries of the thumb. In this study, we used prefabricated flaps of the medial plantar skin to cover a degloved injury of the thumb of a patient unsuitable for application of this method and obtained satisfactory clinical results.

[Ilizarov technique combined with flap instant expansion technique for the treatment of the tibia deformity with skin contracture at one stage].

OBJECTIVE: To discusses the necessity and methods of replantation for complete amputation of finger composite lateral tissue. METHODS: From March 2012 to April 2015, 62 cases of complete amputated finger lateral tissue for various causes were retrospectively analyzed, including 34 males and 28 females with an average age of 29.1 years old ranging from 17 to 52 years old, involved 27 cases of thumb, index finger in 15 cases, 13 cases of middle finger, ring finger in 8 cases, 2 cases of the little finger, 2 fingers were injured in 3 cases, 14 cases involving the distal interphalangeal joint. The time from injury to treatment was 30 min to 2 hour with an average of 1 hour. The appearance of the fingers, finger tip sensation and the recovery of the functional of the patients were followed up and observed. RESULTS: Of 62 cases, 58 cases survived, the survival time was 3 to 15 months with an average of 6.5 months. According to the Chinese medical association upper part of replantation function evaluation standard to assess efficacy trial, 52 cases were excellent, 3 cases were good, 3 cases were good, the excellent and good rate was 94.8%. CONCLUSIONS: The appearance and function is good after block from the broken replantation finger lateral organizations survive, as long as the patient general condition allows, away from the broken body is complete, there are available for blood vessels and nerves anastomosis, it should strive to reattach it.

[Clinical application of vasularisied anterolateral thigh fascial flap].

OBJECTIVE: To evaluate a modified anterolateral thigh fascial flap designed for the treatment of the soft tissue defects in the forearms and hands. METHODS: From September 2000 to December 2003, a modified anterolateral thigh fascial flap combined with the intermediate split thickness skin graft was applied to the treatment of 13 patients with the soft tissue defects in the forearms or the hands. There were 8 males and 5 females, aged 19-43 years (average, 27. 6 years). Three patients had a mangled injury, 4 had a belt injury, and 6 had a crush injury; 6 patients had their tissue defects on the palm side of the forearm, 6 had their tissue defects on the dorsal side of the hand, and 1 had the defect in the index finger (dorsal side of the hand). The tissue defects ranged in size from 17. 5 cm x 7. 7 cm to 4. 6 cm x 3. 4 cm. In addition, 4 of the patients had an accompanying fracture in the forearm or the hand, and the remaining 9 had an extenor tendon injury. All the patients underwent emergency debridement and reposition with an internal fixation for the fracture; 3-5 days after the repair of the injured nerves, muscle tendons and blood vessels, the tissue defects were repaired with the anterolateral thigh fascial flap combined with the intermediate split thickness skin graft. RESULTS: No vascular crisis developed after operation. All the flaps survived except one flap that developed a parial skin necrosis (2.0 cm x 1.0 cm) in the hand, but the skin survived after another skingrafting. The follow-up for 3-12 months revealed that all the flaps and skin grafts had a good appearance with no contracture of the skin. According to the evaluation criteria for the upper limbs recommended by the Hand Society of Chinese Medical Association, 9 patients had an excellent result, 2 had a good result, I had a fair result, and 1 had a poor result, with a good/excellence rate of 85%. CONCLUSION: The modified anterolateral thigh fascial flap combined with the skin graft is one of the best methods for the treatment of the soft tissue defects in the forearms and the hands. This method has advantages of no requirement for a further flap reconstruction, no skin scar or contracture in the future, easy management for the donor site, and less wound formation.