Vimentin Is a Novel Anti-Cancer Therapeutic Target; Insights from In Vitro and In Vivo Mice Xenograft Studies

BACKGROUND:Vimentin is a ubiquitous mesenchymal intermediate filament supporting mechano-structural integrity of quiescent cells while participating in adhesion, migration, survival, and cell signaling processes via dynamic assembly/disassembly in activated cells. Soft tissue sarcomas and some epithelial cancers exhibiting "epithelial to mesenchymal transition" phenotypes express vimentin. Withaferin-A, a naturally derived bioactive compound, may molecularly target vimentin, so we sought to evaluate its effects on tumor growth in vitro and in vivo thereby elucidating the role of vimentin in drug-induced responses. METHODS AND FINDINGS:Withaferin-A elicited marked apoptosis and vimentin cleavage in vimentin-expressing tumor cells but significantly less in normal mesenchymal cells. This proapoptotic response was abrogated after vimentin knockdown or by blockade of caspase-induced vimentin degradation via caspase inhibitors or overexpression of mutated caspase-resistant vimentin. Pronounced anti-angiogenic effects of Withaferin-A were demonstrated, with only minimal effects seen in non-proliferating endothelial cells. Moreover, Withaferin-A significantly blocked soft tissue sarcoma growth, local recurrence, and metastasis in a panel of soft tissue sarcoma xenograft experiments. Apoptosis, decreased angiogenesis, and vimentin degradation were all seen in Withaferin-A treated specimens. CONCLUSIONS:In light of these findings, evaluation of Withaferin-A, its analogs, or other anti-vimentin therapeutic approaches in soft tissue sarcoma and "epithelial to mesenchymal transition" clinical contexts is warranted

Modulation of cardiac Ca2+ channels in Xenopus oocytes by protein kinase C

L-Type calcium channel was expressed in Xenopus laevis oocytes injected with RNAs coding for different cardiac Cu2+ channel subunits, or with total heart RNA. The effects of activation of protein kinase C (PKC) by the phorbol ester PMA (4β-phorbol 12-myristate 13-acetate) were studied. Currents through channels composed of the main (1) subunit alone were initially increased and then decreased by PMA. A similar biphasic modulation was observed when the 1 subunit was expressed in combination with 2/δ, β and/or γ subunits, and when the channels were expressed following injection of total rat heart RNA. No effects on the voltage dependence of activation were observed. The effects of PMA were blocked by staurosporine, a protein kinase inhibitor. β subunit moderated the enhancement caused by PMA. We conclude that both enhancement and inhibition of cardiac L-type Ca2+ currents by PKC are mediated via an effect on the 1 subunit, while the β subunit may play a mild modulatory role

Pancreatic cancer: Surgery is a feasible therapeutic option for elderly patients

<p>Abstract</p> <p>Background</p> <p>Compromised physiological reserve, comorbidities, and the natural history of pancreatic cancer may deny pancreatic resection from elderly patients. We evaluated outcomes of elderly patients amenable to pancreatic surgery.</p> <p>Methods</p> <p>The medical records of all patients who underwent pancreatic resection at our institution (1995-2007) were retrospectively reviewed. Patient, tumor, and outcomes characteristics in elderly patients aged ≥ 70 years were compared to a younger cohort (<70y).</p> <p>Results</p> <p>Of 460 patients who had surgery for pancreatic neoplasm, 166 (36%) aged ≥ 70y. Compared to patients < 70y (n = 294), elderly patients had more associated comorbidities; 72% vs. 43% (p = 0.01) and a higher rate of malignant pathologies; 73% vs. 59% (p = 0.002). Operative time and blood products consumption were comparable; however, elderly patients had more post-operative complications (41% vs. 29%; p = 0.01), longer hospital stay (26.2 vs. 19.7 days; p < 0.0001), and a higher incidence of peri-operative mortality (5.4% vs. 1.4%; p = 0.01). Multivariable analysis identified age ≥ 70y as an independent predictor of shorter disease-specific survival (DSS) among patients who had surgery for pancreatic adenocarcinoma (n = 224). Median DSS for patients aged ≥ 70y vs. < 70y were 15 months (SE: 1.6) vs. 20 months (SE: 3.4), respectively (p = 0.05). One, two, and 5-Y DSS rates for the cohort of elderly patients were 58%, 36% and 23%, respectively.</p> <p>Conclusions</p> <p>Properly selected elderly patients can undergo pancreatic resection with acceptable post-operative morbidity and mortality rates. Long term survival is achievable even in the presence of adenocarcinoma and therefore surgery should be seriously considered in these patients.</p

Primary versus Revisional One Anastomosis Gastric Bypass - Outcomes of patients with at least eight-year follow-up

Background: One anastomosis gastric bypass (OAGB) prevalence is increasing worldwide and shows good mid- to long-term results. Data on long-term outcomes of revisional OAGB (rOAGB) is limited. This study objective is to evaluate the long-term outcomes of patients undergoing primary OAGB (pOAGB) and rOAGB. Methods: A retrospective analysis of a prospectively maintained patient registry at a single-tertiary center. Patients undergoing OAGB from January 2015 to May 2016 were included and grouped to pOAGB and rOAGB. Results: There were 424 patients, of which 363 underwent pOAGB, and 61 underwent rOAGB. Baseline characteristics were insignificantly different between groups except for type 2 diabetes (T2D) rate which was higher in pOAGB (26% vs. 11.5%, p=0.01). The mean follow-up time was 98.5±3.9 months and long-term follow up data was available for 52.5% of patients. The mean total weight loss (TWL) was higher in the pOAGB group (31.3±14 vs. 24.1±17.6, p=0.006), however TWL was comparable when relating to the weight at primary surgery for rOAGB. The rate of T2D and hypertension resolution was 79% and 72.7% with no difference between groups. 13 patients (5.9%) underwent OAGB revision during follow-up, with no difference between groups. Two deaths occurred during follow-up, both non-related to OAGB. Conclusion: OAGB is effective as a primary and as a revisional procedure for severe obesity with good long-term results in terms of weight loss and resolution of associated diseases. In addition, the revisional surgery rates and chronic complications are acceptable. Further large prospective studies are required to clarify this data

Unique cellular interactions between pancreatic cancer cells and the omentum.

Pancreatic cancer is a common cause of cancer-related mortality. Omental spread is frequent and usually represents an ominous event, leading to patient death. Omental metastasis has been studied in ovarian cancer, but data on its role in pancreatic cancer are relatively scarce and the molecular biology of this process has yet to be explored. We prepared tissue explants from human omental fat, and used conditioned medium from the explants for various in vitro and in vivo experiments designed to evaluate pancreatic cancer development, growth, and survival. Mass spectrometry identified the fat secretome, and mRNA array identified specific fat-induced molecular alternations in tumor cells. Omental fat increased pancreatic cancer cellular growth, migration, invasion, and chemoresistance. We identified diverse potential molecules secreted by the omentum, which are associated with various pro-tumorigenic biological processes. Our mRNA array identified specific omental-induced molecular alternations that are associated with cancer progression and metastasis. Omental fat increased the expression of transcription factors, mRNA of extracellular matrix proteins, and adhesion molecules. In support with our in vitro data, in vivo experiments demonstrated an increased pancreatic cancer tumor growth rate of PANC-1 cells co-cultured for 24 hours with human omental fat conditioned medium. Our results provide novel data on the role of omental tissue in omental metastases of pancreatic cancer. They imply that omental fat secreted factors induce cellular reprogramming of pancreatic cancer cells, resulting in increased tumor aggressiveness. Understanding the mechanisms of omental metastases may enable us to discover new potential targets for therapy

Revisional Surgery of One Anastomosis Gastric Bypass for Severe Protein&ndash;Energy Malnutrition

Background: One anastomosis gastric bypass (OAGB) is safe and effective. Its strong malabsorptive component might cause severe protein&ndash;energy malnutrition (PEM), necessitating revisional surgery. We aimed to evaluate the safety and outcomes of OAGB revision for severe PEM. Methods: This was a single-center retrospective analysis of OAGB patients undergoing revision for severe PEM (2015&ndash;2021). Perioperative data and outcomes were retrieved. Results: Ten patients underwent revision for severe PEM. Our center&rsquo;s incidence is 0.63% (9/1425 OAGB). All patients were symptomatic. Median (interquartile range) EWL and lowest albumin were 103.7% (range 57.6, 114) and 24 g/dL (range 19, 27), respectively, and 8/10 patients had significant micronutrient deficiencies. Before revision, nutritional optimization was undertaken. Median OAGB to revision interval was 18.4 months (range 15.7, 27.8). Median BPL length was 200 cm (range 177, 227). Reversal (n = 5), BPL shortening (n = 3), and conversion to Roux-en-Y gastric bypass (RYGB) (n = 2) were performed. One patient had anastomotic leak after BPL shortening. No death occurred. Median BMI and albumin increased from 22.4 kg/m2 (range 20.6, 30.3) and 35.5 g/dL (range 29.2, 41), respectively, at revision to 27.5 (range 22.2, 32.4) kg/m2 and 39.5 g/dL (range 37.2, 41.7), respectively, at follow-up (median 25.4 months, range 3.1, 45). Complete resolution occurs after conversion to RYGB or reversal to normal anatomy, but not after BPL shortening. Conclusions: Revisional surgery of OAGB for severe PEM is feasible and safe after nutritional optimization. Our results suggest that the type of revision may be an important factor for PEM resolution. Comparative studies are needed to define the role of each revisional option

Gastric Cancer-Derived Extracellular Vesicles (EVs) Promote Angiogenesis via Angiopoietin-2

Angiogenesis is an important control point of gastric cancer (GC) progression and metastasis. Angiopoietin-2 (ANG2) is a key driver of tumor angiogenesis and metastasis, and it has been identified in primary GC tissues. Extracellular vesicles (EVs) play an important role in mediating intercellular communication through the transfer of proteins between cells. However, the expression of ANG2 in GC-EVs has never been reported. Here, we characterized the EV-mediated crosstalk between GC and endothelial cells (ECs), with particular focus on the role of ANG2. We first demonstrate that ANG2 is expressed in GC primary and metastatic tissues. We then isolated EVs from two different GC cell lines and showed that these EVs enhance EC proliferation, migration, invasion, and tube formation in vitro and in vivo. Using an angiogenesis protein array, we showed that GC-EVs contain high levels of proangiogenic proteins, including ANG2. Lastly, using Lenti viral ANG2-shRNA, we demonstrated that the proangiogenic effects of the GC-EVs were mediated by ANG2 through the activation of the PI3K/Akt signal transduction pathway. Our data suggest a new mechanism via which GC cells induce angiogenesis. This knowledge may be utilized to develop new therapies in gastric cancer

Early reoperation following pancreaticoduodenectomy: impact on morbidity, mortality, and long-term survival

Abstract Background Reoperation following PD is a surrogate marker for a complex post-operative course and may lead to devastating consequences. We evaluate the indications for early reoperation following PD and analyze its effect on short- and long-term outcome. Methods Four hundred and thirty-three patients that underwent PD between August 2006 and June 2016 were retrospectively analyzed. Results Forty-eight patients (11%; ROp group) underwent 60 reoperations within 60 days from PD. Forty-two patients underwent 1 reoperation, and 6 had up to 6 reoperations. The average time to first reoperation was 10.1 ± 13.4 days. The most common indications were anastomotic leaks (22 operations in 18 patients; 37.5% of ROp), followed by post-pancreatectomy hemorrhage (PPH) (14 reoperations in 12 patients; 25%), and wound complications in 10 (20.8%). Patients with cholangiocarcinoma had the highest reoperation rate (25%) followed by ductal adenocarcinoma (12.3%). Reoperation was associated with increased length of hospital stay and a high post-operative mortality of 18.7%, compared to 2.6% for the non-reoperated group. For those who survived the post-operative period, the overall and disease-free survival were not affected by reoperation. Conclusions Early reoperations following PD carries a dramatically increased mortality rate, but has no impact on long-term survival