Aptamers: an emerging navigation tool of therapeutic agents for targeted cancer therapy.

Chemotherapeutic agents have been used for the treatment of numerous cancers, but due to poor selectivity and severe systemic side effects, their clinical application is limited. Single-stranded DNA (ssDNA) or RNA aptamers could conjugate with highly toxic chemotherapy drugs, toxins, therapeutic RNAs or other molecules as novel aptamer-drug conjugates (ApDCs), which are capable of significantly improving the therapeutic efficacy and reducing the systemic toxicity of drugs and have great potential in clinics for targeted cancer therapy. In this review, we have comprehensively discussed and summarized the current advances in the screening approaches of aptamers for specific cancer biomarker targeting and development of the aptamer-drug conjugate strategy for targeted drug delivery. Moreover, considering the huge progress in artificial intelligence (AI) for protein and RNA structure predictions, automatic design of aptamers using deep/machine learning techniques could be a powerful approach for rapid and precise construction of biopharmaceutics (i.e., ApDCs) for application in cancer targeted therapy.

WITHDRAWN: Individualized and pancreatic duct diameter-based strategy for pancreaticoenteric anastomosis during pancreaticoduodenectomy.

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Novel insights into the role of aptamers in the fight against cancer.

PURPOSE: Aptamers are a class of single-stranded nucleic acid (DNA or RNA) oligonucleotides that are screened in vitro by a technique called systematic evolution of ligands by exponential enrichment (SELEX). They have stable three-dimensional structures that can bind to various targets with high affinity and specificity. Due to distinct properties such as easy synthesis, high stability, small size, low toxicity and immunogenicity, they have been largely studied as anticancer agents/tools. Consequently, aptamers are starting to play important roles in disease prevention, diagnosis and therapy. This review focuses on studies that evaluated the effect of aptamers on various aspects of cancer therapy. It also provides novel and unique insights into the role of aptamers on the fight against cancer. METHODS: We reviewed literatures about the role of aptamers against cancer from PUBMED databases in this article. RESULTS: Here, we summarized the role of aptamers on the fight against cancer in a unique point of view. Meanwhile, we presented novel ideas such as aptamer-pool-drug conjugates for the treatment of refractory cancers. CONCLUSIONS: Aptamers and antibodies should form a "coalition" against cancers to maximize their advantages and minimize disadvantages.

Rapid identification of specific DNA aptamers precisely targeting CD33 positive leukemia cells through a paired cell-based approach.

Aptamers are short single-stranded DNA or RNA molecules, which have recently been developed for potential broad applications such as clinical therapeutics, diagnosis and tumor-targeted drug delivery. However, the selection of specific aptamers is often unsatisfactory using the classical protein or cell-based SELEX. Herein, we modified the paired cell line approach to identify aptamers targeting leukemia cells expressing the CD33 antigen. Our strategy artfully used the same cells for negative (HEK293T cells) and positive (CD33 transfected-HEK293T cells) aptamer selections, and the negative selections were performed adequately before the positive selection to remove unspecific sequences. The advantages of this strategy are that it is fast and accurate, where only a few rounds of selection together with PCR amplifications are sufficient to obtain high binding affinity antigen-targeted aptamers. By using our modified approach, we successfully obtained the CD33-targeting aptamer S30, which could highly recognize the C2 domain of the CD33 antigen in vitro and in vivo. Moreover, the optimized aptamer S30-T1 (i.e., core region of S30) was conjugated with doxorubicin (Dox) to synthesize S30-T1-Dox conjugates, which could specifically inhibit CD33 positive acute myeloid leukemia HL-60 cell proliferation by arresting the cell cycle at the G2 phase. Thus, our modified approach can rapidly screen reliable, stable and high binding affinity aptamers for precise cancer treatment.

Better surgical treatment method for hepatocellular carcinoma with portal vein tumor thrombus.

Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) is a disease that is not uncommon, but the treatments vary drastically between Eastern and Western countries. In Europe and America, the first line of treatment is systemic therapy such as sorafenib and the surgical treatment is not a recommend option. While an increasing number of studies from China and Japan have suggested that surgical treatment results in better outcomes when compared to transcatheter arterial chemoembolization (TACE), sorafenib, or other nonsurgical treatments, and two classification systems, Japanese Vp classification and Chinese Cheng's classification, were very useful to guide the surgical treatment. We have also found that surgical treatment may be more effective, as we have performed surgical treatment for HCC-PVTT patients over a period of approximately 15 years and achieved good results with the longest surviving time being 13 years and onward. In this study, we review the efficacy and principles of current surgical treatments and introduce our new, more effective surgical technique named "thrombectomy first", which means the tumor thrombus in the main portal vein, the bifurcation or the contralateral portal vein should be removed prior to liver resection. Thus, compression and crushing of PVTT during the operation could be avoided and new intrahepatic metastases caused by tumor thrombus to the remnant liver minimized. The new technique is even beneficial to the prognosis of Cheng's classification Types III and IV PVTT. The vital tips and tricks for the surgical approach are described.

Pure laparoscopic radical resection for type IIIa hilar cholangiocarcinoma.

BACKGROUND: Pure laparoscopic radical resection of hilar cholangiocarcinoma is still a challenging procedure, in which laparoscopic lymphadenectomy, hemihepatectomy with caudate lobectomy, and hepaticojejunostomy were included [1-4]. Relative report is rare in the world up to now. Hilar cholangiocarcinoma has a poor prognosis, especially when it occurs with lymph node metastasis or vessel invasion [5, 6]. We recently had a patient who underwent a pure laparoscopic extended right hepatectomy and lymph node dissection and hepaticojejunostomy for a type IIIa hilar cholangiocarcinoma. METHODS: The tumor was 20 × 15 × 12 mm in diameter and located in the right bile duct and common hepatic duct. Radiological examination showed that hepatic artery and portal vein was not invaded. After the division and mutilation of the right hepatic artery and the right portal vein, short hepatic veins were divided and cut off with clip and ultrasound knife from the anterior face of the vena cava. Mobilization was performed after the devascularization of the right liver, followed by the transection of liver parenchymal with CUSA and ultrasound knife. Finally, left hepatic bile duct jejunum Roux-en-Y reconstruction was performed. RESULTS: This patient underwent successfully with a totally laparoscopic procedure. An extended right hepatectomy (right hemihepatectomy combined with caudate lobectomy) and complete lymph node dissection and hepaticojejunostomy were performed in this operation. The operation time was nearly 590 min, and the intraoperative blood loss was about 300 ml. No obvious complication was observed and the postoperative hospital stay was 11 days. The final diagnosis of the hilar cholangiocarcinoma with no lymph node metastasis was pT2bN0M0 stage II (American Joint Committee on Cancer, AJCC). CONCLUSIONS: Pure laparoscopic resection for hilar cholangiocarcinoma was proved safe and feasible, which enabled the patient to recover early and have an opportunity to receive chemotherapy as soon as possible. We present a video of the described procedure.

Evolution of associating liver partition and portal vein ligation for staged hepatectomy: Simpler, safer and equally effective methods.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been recently demonstrated as a method to induce rapid and extensive hypertrophy within a short time and has been employed for a variety of primary and metastatic liver tumors. However, controversies remain due to its high morbidity and mortality. To enable safer surgery, liver surgeons have searched for better technical modifications, such as partial ALPPS, mini-ALPPS, minimally invasive ALPPS, and Terminal branches portal vein Embolization Liver Partition for Planned hepatectomy (TELPP). It seems that TELPP is very promising, because it has the main advantage of ALPPS - the rapid increase of future liver remnant volume, but the morbidity and mortality are much lower because only one surgical operation is required.

Corrigendum: MiR-148b suppresses cell proliferation and invasion in hepatocellular carcinoma by targeting WNT1/ß-catenin pathway.

[This corrects the article DOI: 10.1038/srep08087.].

Pancreatic cancer: Open or minimally invasive surgery?

Pancreatic duct adenocarcinoma is one of the most fatal malignancies, with R0 resection remaining the most important part of treatment of this malignancy. However, pancreatectomy is believed to be one of the most challenging procedures and R0 resection remains the only chance for patients with pancreatic cancer to have a good prognosis. Some surgeons have tried minimally invasive pancreatic surgery, but the short- and long-term outcomes of pancreatic malignancy remain controversial between open and minimally invasive procedures. We collected comparative data about minimally invasive and open pancreatic surgery. The available evidence suggests that minimally invasive pancreaticoduodenectomy (MIPD) is as safe and feasible as open PD (OPD), and shows some benefit, such as less intraoperative blood loss and shorter postoperative hospital stay. Despite the limited evidence for MIPD in pancreatic cancer, most of the available data show that the short-term oncological adequacy is similar between MIPD and OPD. Some surgical techniques, including superior mesenteric artery-first approach and laparoscopic pancreatoduodenectomy with major vein resection, are believed to improve the rate of R0 resection. Laparoscopic distal pancreatectomy is less technically demanding and is accepted in more pancreatic centers. It is technically safe and feasible and has similar short-term oncological prognosis compared with open distal pancreatectomy.

Indocyanine green retention is a potential prognostic indicator after splenectomy and pericardial devascularization for cirrhotic patients.

BACKGROUND: Splenectomy and pericardial devascularization (SPD) is an effective treatment of upper gastrointestinal bleeding and hypersplenism in cirrhotic patients with portal hypertension. Indocyanine green retention at 15 minutes (ICGR15) was reported to offer better sensitivity and specificity than the Child-Pugh classification in hepatectomy, but few reports describe ICGR15 in SPD. The present study was to evaluate the prognostic value of ICGR15 for cirrhotic patients with portal hypertension who underwent SPD. METHODS: From January 2012 to January 2015, 43 patients with portal hypertension and hypersplenism caused by liver cirrhosis were admitted in our center and received SPD. The ICGR15, Child-Pugh classification, model for end-stage liver disease (MELD) score, and perioperative characteristics were analyzed retrospectively. RESULTS: Preoperative liver function assessment revealed that 34 patients were Child-Pugh class A with ICGR15 of 13.6%-43.0% and MELD score of 7-20; 8 patients were class B with ICGR15 of 22.8%-40.7% and MELD score of 7-17; 1 patient was class C with ICGR15 of 39.7% and MELD score of 22. The optimal ICGR15 threshold for liver function compensation was 31.2%, which offered a sensitivity of 68.4% and a specificity of 70.8%. Univariate analysis showed preoperative ICGR15, MELD score, surgical procedure, intraoperative blood loss, and autologous blood transfusion were significantly different between postoperative liver function compensated and decompensated groups. Multivariate regression analysis revealed that ICGR15 was an independent risk factor of postoperative liver function recovery (P=0.020). CONCLUSIONS: ICGR15 has outperformed the Child-Pugh classification for assessing liver function in cirrhotic patients with portal hypertension. ICGR15 may be a suitable prognostic indicator for cirrhotic patients after SPD.

Primary hepatic epithelioid angiomyolipoma: A malignant potential tumor which should be recognized.

AIM: To improve the clinical diagnosis and recognition of hepatic epithelioid angiomyolipoma (HEAML). METHODS: Four cases of primary HEAML were confirmed based on the pathology archive system in our hospital from January 2009 to November 2015. The general state, clinical symptoms, imaging manifestations, histological results and immunohistochemistry of these patients were retrospectively reviewed and analyzed. Studies of HEAML published in the last 15 years were collected from PubMed and MEDLINE to summarize the clinical symptoms, imaging characteristics, pathological features and management of HEAML. RESULTS: Four cases of primary HEAML were retrieved from our archives. These included three female patients and one male patient, with a mean age of 41.8 ± 11.5 years (ranging from 31 to 56 years). The mean tumor size was 7.3 ± 5.5 cm (ranging from 3.0 to 15 cm). In the contrast-enhanced imaging, the tumor was obviously enhanced in the arterial phase, but enhanced continuously or exhibited a slow-density masse during the venous and delayed phases. Histologically, the tumors mainly consisted of epithelioid cells that comprised approximately 95% of the total neoplastic mass. Although no metastases occurred in our patients, pathological studies revealed necrosis, mitotic figures and liver invasion in two patients, which indicates aggressive behavior. Immunohistochemical staining revealed that human melanoma black 45 (HMB-45) and Melan-A were positive in 4 cases. We only identified 81 cases with primary HEAML, including our present patients, from 26 articles available from PubMed and MEDLINE. The majority of the papers were published as case reports. Only 5 (5/75, 6%) cases were associated with tuberous sclerosis complex (TSC). More than half (35/66) were discovered incidentally upon physical examination. Approximately 65% (22/34) of the patients were misdiagnosed with HCC or other tumors before surgery. Approximately 10% (8/81) of the patients with HEAML had recurrence or metastasis after surgery, which was a very high and alarming rate. CONCLUSION: HEAML is a very rare primary hepatic tumor that is often misdiagnosed before surgery. Patients should be followed closely after surgery because of its malignant potential.

Successful laparoscopic common bile duct exploration in a patient with factor V deficiency, a case report and review of literature.

Factor V deficiency is a rare bleeding disorder. Fresh frozen plasma (FFP) is the only source of factor V because factor V concentrates is not available now. We present here a patient had concomitant gallbladder and common bile (CBD) stones with factor V deficiency. The patient is successfully treated by laparoscopic CBD exploration and cholecystectomy with perioperative fresh frozen plasma transfusion. To best of our knowledge, this is the first report of laparoscopic surgery successfully performed in a factor V deficiency patient. Our result suggest that laparoscopic surgery in a factor V deficient patient can be performed safely if normal coagulation profile is achieved after injection of FFP. Our experience in this case also indicate that the incidence of delayed bleeding after surgery is low once hemostasis is successfully obtained during operation and there is no need to continue FFP infusion beyond day 2 postoperative.

Management of hepatocellular carcinoma rupture in the caudate lobe.

AIM: To demonstrate that caudate lobectomy is a valid treatment in cases of hepatocellular carcinoma (HCC) rupture in the caudate lobe based on our experience with the largest case series reported to date. METHODS: A retrospective study of eight patients presenting with spontaneous rupture and hemorrhage of HCC in the caudate lobe was conducted. Two patients underwent ineffective transarterial embolization preoperatively. Caudate lobectomy was performed in all eight patients. Bilateral approach was taken in seven cases for isolated complete caudate lobectomy. Left-sided approach was employed in one case for isolated partial caudate lobectomy. Transarterial chemoembolization was performed postoperatively in all patients. RESULTS: Caudate lobectomy was successfully completed in all eight cases. The median time delay from the diagnosis to operation was 5 d (range: 0.25-9). Median operating time was 200 min (range: 120-310) with a median blood loss of 900 mL (range: 300-1500). Five patient remained in long-term follow-up, with one patient becoming lost to follow-up at 3 years and two patients currently alive at 7 and 19 mo. One patient required reoperation due to recurrence. Gamma knife intervention was performed for brain metastasis in another case. Two patients survived for 10 and 84 mo postoperatively, ultimately succumbing to multiple organ metastases. CONCLUSION: Caudate lobectomy is the salvage choice for HCC rupture in the caudate lobe. Local anatomy and physiologic features of the disease render caudate lobectomy a technically difficult operation. Postponement of surgical intervention is thus recommended while the rupture remains hemodynamically stable until an experienced surgeon becomes available. Prognosis is confounded by numerous factors, but long-term survival can be expected in the majority of cases.

Laparoscope resection of retroperitoneal ectopic insulinoma: a rare case.

Ectopic insulinoma is a very rare and dormant tumor. Here we report the case of a 79-year-old female who presented with repeated episodes of hypoglycemia and was diagnosed with insulinoma based on laboratory and imaging examinations. Computed tomography and positron emission tomography revealed a tumor in the retroperitoneum under and left of the hepatoduodenal ligament, which was resected successfully using a laparoscopic approach. Pathologic results revealed an ectopic insulinoma, which was confirmed immunohistochemically. Ectopic insulinomas are accompanied by hypoglycemia that can be misdiagnosed as drug- or disease-induced. These tumors are difficult to diagnose and locate, particularly in atypical cases or for very small tumors. Synthetic or targeted examinations, including low blood glucose, elevated insulin, proinsulin, and C-peptide levels, 48-h fasting tests, and relevant imaging methods should be considered for suspected cases of insulinoma. Surgery is the treatment of choice for patients with insulinoma, and laparoscopic resection is a feasible and effective method for select ectopic insulinoma cases.

MiR-148b suppresses cell proliferation and invasion in hepatocellular carcinoma by targeting WNT1/ß-catenin pathway.

Accumulating evidences indicate that microRNAs play a vital role in regulating tumor progression. However, the roles of miR-148b in hepatocellular carcinoma (HCC) are still largely unknown. In this study, our data showed that miR-148b was significantly downregulated in 40 pairs of human HCC tissues. Further, the deregulated miR-148b was significantly correlated with larger tumor size, more tumor number, metastasis and worse prognosis in HCC. Overexpression of miR-148b inhibited HCC HepG2 cells proliferation and tumorigenicity. Further, miR-148b induced cells apoptosis by activating caspase- 3 and caspase-9, and induced S phase arrest by regulating cyclinD1 and p21, and also inhibited cell invasion. Data from the dual-luciferase reporter gene assay showed that WNT1 was a direct target of miR-148b, and overexpressed WNT1 inversely correlated with miR-148b levels in HCC tissues. Silencing of WNT1 inhibited the growth of HCC cells, and also induced cells apoptosis and inhibited invasion, which is consistent with the effects of miR-148b overexpression. MiR-148b downregulated expression of WNT1, ß-catenin and C-myc, while upregulated E-cadherin expression. We conclude that the frequently downregulated miR-148b can regulate WNT1/ß-catenin signalling pathway and function as a tumor suppressor in HCC. These findings suggest that miR-148b may serve as a novel therapeutic target for HCC.

Cordycepin down-regulates multiple drug resistant (MDR)/HIF-1α through regulating AMPK/mTORC1 signaling in GBC-SD gallbladder cancer cells.

Gallbladder cancer is the most common malignancy of the bile duct, with low 5-year survival rate and poor prognosis. Novel effective treatments are urgently needed for the therapy of this disease. Here, we showed that cordycepin, the bioactive compound in genus Cordyceps, induced growth inhibition and apoptosis in cultured gallbladder cancer cells (Mz-ChA-1, QBC939 and GBC-SD lines). We found that cordycepin inhibited mTOR complex 1 (mTORC1) activation and down-regulated multiple drug resistant (MDR)/hypoxia-inducible factor 1α (HIF-1α) expression through activating of AMP-activated protein kinase (AMPK) signaling in gallbladder cancer GBC-SD cells. Contrarily, AMPKα1-shRNA depletion dramatically inhibited cordycepin-induced molecular changes as well as GBC-SD cell apoptosis. Further, our results showed that co-treatment with a low concentration cordycepin could remarkably enhance the chemosensitivity of GBC-SD cells to gemcitabine and 5-fluorouracil (5-FU), and the mechanism may be attributed to AMPK activation and MDR degradation. In summary, cordycepin induces growth inhibition and apoptosis in gallbladder cancer cells via activating AMPK signaling. Cordycepin could be a promising new drug or chemo-adjuvant for gallbladder cancer.

Perifosine inhibits S6K1-Gli1 signaling and enhances gemcitabine-induced anti-pancreatic cancer efficiency.

PURPOSE: The pancreatic cancer has extremely low overall 5-year survival, and gemcitabine is the only approved single agent for pancreatic cancer treatment. METHODS: In the present study, we investigated the potential effect of perifosine, a novel Akt inhibitor on gemcitabine-induced anti-pancreatic cancer effect both in vivo and in vitro. RESULTS: We showed that sub-cytotoxic low concentration of perifosine dramatically enhanced gemcitabine-induced cytotoxicity in cultured pancreatic cancer cells. Perifosine inhibited Akt-mammalian target of rapamycin and Erk-mitogen-activated protein kinase activation in pancreatic cancer cells. Meanwhile, perifosine suppressed the hedgehog signaling, as it inhibited glioma-associated oncogenes (Gli) 1 activation and decreased its target protein patched 1 (PTCH1) expression. Our data demonstrated that perifosine blocked p70S6K1 (S6K1) activation, thus disrupting S6K1-Gli1 association and subsequent Gli1 activation. The reduction of S6K1 or Gli1 expression by target siRNAs inhibited PTCH1 expression and enhanced gemcitabine-induced cytotoxicity in pancreatic cancer cells. Significantly, perifosine dramatically enhanced gemcitabine-mediated antitumor effect in a PANC-1 xenograft severe combined immunodeficiency mice model. CONCLUSIONS: In summary, we conclude that perifosine sensitizes gemcitabine-mediated anti-pancreatic cancer efficiency through regulating multiple signaling pathways.

Sirtuin 1 facilitates chemoresistance of pancreatic cancer cells by regulating adaptive response to chemotherapy-induced stress.

Chemotherapy drugs themselves may act as stressors to induce adaptive responses to promote the chemoresistance of cancer cells. Our previous research showed that sirtuin 1 (SIRT1) was overexpressed in pancreatic cancer patients and deregulation of SIRT1 with RNAi could enhance chemosensitivity. Thus, we hypothesized that SIRT1 might facilitate chemoresistance in pancreatic cancer cells through regulating the adaptive response to chemotherapy-induced stress. In the present study, SIRT1 in PANC-1, BXPC-3, and ASPC-1 cells was upregulated after treatment with gemcitabine. Moreover, the decrease in SIRT1 activity with special inhibitor EX527 had a synergic effect on chemotherapy with gemcitabine in PANC-1 and ASPC-1 cell lines, which significantly promoted apoptosis, senescence, and G0 /G1 cycle arrest. Western blot results also showed that SIRT1, acetylated-p53, FOXO3a, and p21 were upregulated after combined treatment, whereas no obvious change was evident in total p53 protein. To further confirm the role of SIRT1 in clinical chemotherapy, SIRT1 was detected in eight pancreatic cancer tissues acquired by endoscopy ultrasonography guided fine needle aspiration biopsy before and after chemotherapy. Compared to before chemotherapy, SIRT1 was significantly increased after treatment with gemcitabine in six cases. Thus, our results indicated a special role for SIRT1 in the regulation of adaptive response to chemotherapy-induced stress, which is involved in chemoresistance. Moreover, it indicates that blocking SIRT1 activity with targeting drugs might be a novel strategy to reverse the chemoresistance of pancreatic cancer.