Pancreatic stellate cells (PSC), which are implicated in desmoplasia in pancreatic cancer, enhance the malignancy of cancer cells and confer resistance to established treatments. We investigated ...whether the antifibrotic agent pirfenidone can suppress desmoplasia and exert antitumor effects against pancreatic cancer. Primary PSCs were established from pancreatic cancer tissue obtained during surgery. In vitro, pirfenidone inhibited the proliferation, invasiveness, and migration of PSCs in a dose-dependent manner. Although supernatants of untreated PSCs increased the proliferation, invasiveness, and migration of pancreatic cancer cells (PCC), supernatants of pirfenidone-treated PSCs decreased these effects. Exposure to PCC supernatant increased the production of platelet-derived growth factor-A, hepatic growth factor, collagen type I, fibronectin, and periostin in PSCs, which was significantly reduced by pirfenidone. Mice were subcutaneously implanted with PCCs (SUIT-2 cells) and PSCs into the right flank and PCCs alone into the left flank. Oral administration of pirfenidone to these mice significantly reduced tumor growth of co-implanted PCCs and PSCs, but not of PCCs alone. Pirfenidone also decreased the proliferation of PSCs and the deposition of collagen type I and periostin in tumors. In mice with orthotopic tumors consisting of PCCs co-implanted with PSCs, pirfenidone suppressed tumor growth, reduced the number of peritoneal disseminated nodules, and reduced the incidence of liver metastasis. Pirfenidone in combination with gemcitabine more effectively suppressed orthotopic tumor growth compared with pirfenidone or gemcitabine alone. In conclusion, our findings indicate that pirfenidone is a promising antitumor agent for pancreatic cancer, owing to its suppression of desmoplasia through regulating PSCs.
Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but their mechanisms of action and efficacy are not fully understood. ATRA ...inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1's active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, like Pin1 knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic targeting of Pin1 by ATO and ATRA offers an attractive approach to combating breast and other cancers.
A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for ...inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.
Minimally invasive pancreaticoduodenectomy (MIPD) has recently been safely performed by experts, and various methods for resection have been reported. This review summarizes the literature describing ...surgical approaches for MIPD.
A systematic literature search of PubMed (MEDLINE) was conducted for studies reporting robotic and laparoscopic pancreaticoduodenectomy; the reference lists of review articles were searched. Of 444 articles yielded, 23 manuscripts describing the surgical approach to dissect around the superior mesenteric artery (SMA), including hand-searched articles, were assessed.
Various approaches to dissect around the SMA have been reported. These approaches were categorized according to the direction toward the SMA when initiating dissection around the SMA: anterior approach (two articles), posterior approach (four articles), right approach (16 articles), and left approach (three articles). Thus, many reports used the right approach. Most articles provided a technical description. Some articles showed the advantage of their method in a comparison study. However, these were single-center retrospective studies with a small sample size.
Various approaches for MIPD have been reported; however, few authors have reported the advantage of their methods compared to other methods. Further discussion is needed to clarify the appropriate surgical approach to the SMA during MIPD.
Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is commonly overexpressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). While Pin1 is dispensable for viability in ...mice, it is required for activated Ras to induce tumorigenesis, suggesting a role for Pin1 inhibitors in Ras-driven tumors, such as PDAC. We report the development of rationally designed peptide inhibitors that covalently target Cys113, a highly conserved cysteine located in the Pin1 active site. The inhibitors were iteratively optimized for potency, selectivity and cell permeability to give BJP-06-005-3, a versatile tool compound with which to probe Pin1 biology and interrogate its role in cancer. In parallel to inhibitor development, we employed genetic and chemical-genetic strategies to assess the consequences of Pin1 loss in human PDAC cell lines. We demonstrate that Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and that Pin1 inhibition impairs cell viability over time in PDAC cell lines.
Drug-based strategies to overcome tumour resistance to radiotherapy (R-RT) remain limited by the single-agent toxicity of traditional radiosensitizers (for example, platinums) and a lack of targeted ...alternatives. In a screen for compounds that restore radiosensitivity in p53 mutant zebrafish while tolerated in non-irradiated wild-type animals, we identified the benzimidazole anthelmintic oxfendazole. Surprisingly, oxfendazole acts via the inhibition of IRAK1, a kinase thus far implicated in interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) immune responses. IRAK1 drives R-RT in a pathway involving IRAK4 and TRAF6 but not the IL-1R/TLR-IRAK adaptor MyD88. Rather than stimulating nuclear factor-κB, radiation-activated IRAK1 prevented apoptosis mediated by the PIDDosome complex (comprising PIDD, RAIDD and caspase-2). Countering this pathway with IRAK1 inhibitors suppressed R-RT in tumour models derived from cancers in which TP53 mutations predict R-RT. Moreover, IRAK1 inhibitors synergized with inhibitors of PIN1, a prolyl isomerase essential for IRAK1 activation in response to pathogens and, as shown here, in response to ionizing radiation. These data identify an IRAK1 radiation-response pathway as a rational chemoradiation therapy target.
Purpose
The left renal vein is technically difficult to expose during laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma despite being an important landmark for posterior ...dissection. We hereby propose a novel technique to safely expose the left renal vein while avoiding the associated anatomical pitfalls.
Methods
The anatomy of the left renal artery and vein was analyzed using multidetector computed tomography. We initially exposed the left renal vein on the left posterior side of the superior mesenteric artery followed by exposure toward the left kidney. We retrospectively examined the perioperative results of this technique in 33 patients who underwent laparoscopic distal pancreatectomy.
Results
15.7% of the patients had an accessory left renal artery coursing cranial to the vein. In 43.1%, the left renal arterial branch ventrally traversed the vein at the renal hilum, thereby posing a risk for arterial injury. The location of the left renal vein varies cranial (17.6%) or caudal (82.4%) to the pancreas. The left renal vein was exposed without any vascular injury using this technique. The median operative time was 259 min, blood loss was 18 mL, and R0 resection rate was 97.0%.
Conclusions
The initial exposure of the left renal vein should, therefore, be on the left posterior side of the superior mesenteric artery.
Objective
Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease affecting multiple organs in the body, but therapeutic options are still very limited and often come with adverse ...effects. Increasing evidence has underlined an important role of the Toll‐like receptor 7 (TLR‐7)/TLR‐9/interleukin‐1 receptor–associated kinase 1 (IRAK‐1)/interferon regulatory factor 7 (IRF‐7) pathway in the development and progression of SLE. Notably, the prolyl isomerase Pin1 is an essential regulator of IRAK‐1 in TLR‐7/TLR‐9 signaling, but its role in SLE is unknown. We undertook this study to determine whether Pin1 is activated and plays any role in the development and treatment of SLE.
Methods
Activation of Pin1 and TLR‐7/TLR‐9/IRAK‐1/IRF‐7 signaling was determined in various cell types among peripheral blood mononuclear cells from healthy controls and SLE patients. The effects of Pin1 and TLR signaling on SLE development were determined using validated Pin1 short hairpin RNA (shRNA), Pin1 genetic knockout, and the small‐molecule Pin1 inhibitor all‐trans‐retinoic acid (ATRA) in immune cells and in several strains of lupus‐prone mice.
Results
We found abnormal activation of Pin1 and its downstream targets IRAK‐1 and IRF‐7 in SLE patients. Furthermore, inhibition of Pin1 using either validated Pin1 shRNA or ATRA blocked TLR‐7–induced activation of IRAK‐1 and IRF‐7 in SLE patient–derived immune cells. Moreover, in multiple lupus‐prone animals, both Pin1 knockout and ATRA strikingly attenuated the expression of autoimmunity, including skin lesions, lymphadenopathy, splenomegaly, glomerulonephritis, proteinuria, and production of anti–double‐stranded DNA antibodies and CD4−CD8− T cells, and also prolonged overall survival in MRL/lpr and B6.lpr mice.
Conclusion
Pin1 plays a critical role in the development of SLE, and Pin1‐targeted therapy offers a promising new strategy for treating SLE.
The anatomical structure around the pancreatic head is very complex and it is important to understand its precise anatomy and corresponding anatomical approach to safely perform minimally invasive ...pancreatoduodenectomy (MIPD). This consensus statement aimed to develop recommendations for elucidating the anatomy and surgical approaches to MIPD.
Studies identified via a comprehensive literature search were classified using the Scottish Intercollegiate Guidelines Network method. Delphi voting was conducted after experts had drafted recommendations, with a goal of obtaining >75% consensus. Experts discussed the revised recommendations with the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting.
Three clinical questions were addressed, providing six recommendations. All recommendations reached at least a consensus of 75%. Preoperatively evaluating the presence of anatomical variations and superior mesenteric artery (SMA) and superior mesenteric vein (SMV) branching patterns was recommended. Moreover, it was recommended to fully understand the anatomical approach to SMA and intraoperatively confirm the SMA course based on each anatomical landmark before initiating dissection.
MIPD experts suggest that surgical trainees perform resection based on precise anatomical landmarks for safe and reliable MIPD.
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