1Most tumours exhibit significant heterogeneity and are best described as communities of cellular populations competing for resources. Growing experimental evidence also suggests, however, that ...cooperation between cancer clones is important as well for the maintenance of tumour heterogeneity and tumour progression. However, a role for cell communication during the earliest steps in oncogenesis is not well characterised despite its vital importance in normal tissue and clinically manifest tumours. Here, we present a simple analytical model and stochastic lattice-based simulations to study how the interaction between the mutational process and cell-to-cell communication in three-dimensional tissue architecture might contribute to shape early oncogenesis. We show that non-cell-autonomous mechanisms of carcinogenesis could support and accelerate pre-cancerous clonal expansion through the cooperation of different, non- or partially- transformed mutants. We predict the existence of a 'cell-autonomous time-horizon', a time before which cooperation between cell-to-cell communication and DNA mutations might be one of the most fundamental forces shaping the early stages of oncogenesis. The understanding of this process could shed new light on the mechanisms leading to clinically manifest cancers.
OBJECTIVE:The aim of the present study was to evaluate the clinical implications of the 2016 International Study Group for Pancreatic Surgery (ISGPS) definition and classification of postoperative ...pancreatic fistula (POPF) using a single high-volume institutional cohort of patients undergone pancreatic surgery.
BACKGROUND:The ISGPS definition and grading system of POPF has been recently updated. Although the rationale for the changes was supported by previous studies, the effect of the new definition and classification scheme on surgical series has not been established.
METHODS:A total of 775 patients undergone pancreatic surgery in our institute from 2013 to 2015 were reviewed. The parameters modified in the ISGPS classification were analyzed according to postoperative outcomes. Finally the classification was validated by external clinical and economical outcomes.
RESULTS:Applying the 2016 scheme, 17.5% of patients changed classification group compared to the 2015 system. Grade B increased from 11.5% to 22.1%, whereas grade C decreased from 15.2% to 4.6%. Biochemical leak occurred in 7% of patients, and it did not differ from the non-POPF condition in terms of surgical outcomes. Non-POPF group, grades B and C POPF differed significantly in terms of intensive care unit staying (P < 0.001), length of stay (P < 0.001), readmission rate (P < 0.001), and hospital costs (P < 0.001).
CONCLUSIONS:The present study has confirmed the pertinence of the changes introduced in the 2016 ISGPS POPF definition and grading. This updated classification is effective in identifying three conditions that differ in terms of clinical and economic outcomes. These results suggested the reliability of the new definition and scheme in classifying POPF-related outcomes.
OBJECTIVE:This multicenter study sought to prospectively evaluate a drain management protocol for pancreatoduodenectomy (PD).
BACKGROUND:Recent evidence suggests value for both selective drain ...placement and early drain removal for PD. Both strategies have been associated with reduced rates of clinically relevant pancreatic fistula (CR-POPF)—the most common and morbid complication after PD.
METHODS:The protocol was applied to 260 consecutive PDs performed at two institutions over 17 months. Risk for ISGPF CR-POPF was determined intraoperatively using the Fistula Risk Score (FRS); drains were omitted in negligible/low risk patients and drain fluid amylase (DFA) was measured on postoperative day 1 (POD 1) for moderate/high risk patients. Drains were removed early (POD 3) in patients with POD 1 DFA ≤5,000 U/L, whereas patients with POD 1 DFA >5,000 U/L were managed by clinical discretion. Outcomes were compared with a historical cohort (N = 557; 2011–2014).
RESULTS:Fistula risk did not differ between cohorts (median FRS4 vs 4; P = 0.933). No CR-POPFs developed in the 70 (26.9%) negligible/low risk patients. Overall CR-POPF rates were significantly lower after protocol implementation (11.2 vs 20.6%, P = 0.001). The protocol cohort also demonstrated lower rates of severe complication, any complication, reoperation, and percutaneous drainage (all P < 0.05). These patients also experienced reduced hospital stay (median8 days vs 9 days, P = 0.001). There were no differences between cohorts in the frequency of bile or chyle leaks.
CONCLUSIONS:Drains can be safely omitted for one-quarter of PDs. Drain amylase analysis identifies which moderate/high risk patients benefit from early drain removal. This data-driven, risk-stratified approach significantly decreases the occurrence of clinically relevant pancreatic fistula.
Cell-autonomous changes in p53 expression govern the duration and outcome of cell-cycle arrest at the G2 checkpoint for DNA damage. Here, we report that mitogen-activated protein kinase (MAPK) ...signaling integrates extracellular cues with p53 dynamics to determine cell fate at the G2 checkpoint. Optogenetic tools and quantitative cell biochemistry reveal transient oscillations in MAPK activity dependent on ataxia-telangiectasia-mutated kinase after DNA damage. MAPK inhibition alters p53 dynamics and p53-dependent gene expression after checkpoint enforcement, prolonging G2 arrest. In contrast, sustained MAPK signaling induces the phosphorylation of CDC25C, and consequently, the accumulation of pro-mitotic kinases, thereby relaxing checkpoint stringency and permitting cells to evade prolonged G2 arrest and senescence induction. We propose a model in which this MAPK-mediated mechanism integrates extracellular cues with cell-autonomous p53-mediated signals, to safeguard genomic integrity during tissue proliferation. Early steps in oncogene-driven carcinogenesis may imbalance this tumor-suppressive mechanism to trigger genome instability.
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•DNA damage elicits opposing pro-survival and pro-arrest responses via MAPK and p53•MAPK pulsations modulate p53-dependent transcription to determine cell fate•MAPK/p53 signal dynamics control the stringency of the G2 DNA damage checkpoint•MAPK/p53 integrate extracellular and intracellular cues to protect genome integrity
Cells coordinate repair and cell-cycle machinery in response to DNA damage to safeguard genomic integrity and tissue homeostasis. De et al. find that two opposing and pulsatile signals of pro-survival and pro-arrest networks permit cells to set a balance between distinct cell fates.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dopamine (DA) controls many vital physiological functions and is critically involved in several neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. The ...major function of the plasma membrane dopamine transporter (DAT) is the rapid uptake of released DA into presynaptic nerve terminals leading to control of both the extracellular levels of DA and the intracellular stores of DA. Here, we present a newly developed strain of rats in which the gene encoding DAT knockout Rats (DAT-KO) has been disrupted by using zinc finger nuclease technology. Male and female DAT-KO rats develop normally but weigh less than heterozygote and wild-type rats and demonstrate pronounced spontaneous locomotor hyperactivity. While striatal extracellular DA lifetime and concentrations are significantly increased, the total tissue content of DA is markedly decreased demonstrating the key role of DAT in the control of DA neurotransmission. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, the partial Trace Amine-Associated Receptor 1 (TAAR1) agonist RO5203648 ((S)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine) and haloperidol. DAT-KO rats also demonstrate a deficit in working memory and sensorimotor gating tests, less propensity to develop obsessive behaviors and show strong dysregulation in frontostriatal BDNF function. DAT-KO rats could provide a novel translational model for human diseases involving aberrant DA function and/or mutations affecting DAT or related regulatory mechanisms.
Here, we present a newly developed strain of rats in which the gene encoding the dopamine transporter (DAT) has been disrupted (Dopamine Transporter Knockout rats DAT-KO rats). DAT-KO rats display functional hyperdopaminergia accompanied by pronounced spontaneous locomotor hyperactivity. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, and a few other compounds exerting inhibitory action on dopamine-dependent hyperactivity. DAT-KO rats also demonstrate cognitive deficits in working memory and sensorimotor gating tests, less propensity to develop compulsive behaviors, and strong dysregulation in frontostriatal BDNF function. These observations highlight the key role of DAT in the control of brain dopaminergic transmission. DAT-KO rats could provide a novel translational model for human diseases involving aberrant dopamine functions.
IMPORTANCE: Chemotherapy is the recommended induction strategy in borderline resectable and locally advanced pancreatic ductal adenocarcinoma. However, the associated results on an intention-to-treat ...basis are poorly understood. OBJECTIVE: To investigate pragmatically the treatment compliance, conversion to surgery, and survival outcomes of patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma undergoing primary chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: This prospective study took place in a national referral center for pancreatic diseases in Italy. Consecutive patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma were enrolled at the time of diagnosis (January 2013 through December 2015) and followed up to June 2018. EXPOSURES: The chemotherapy regimen, assigned based on multidisciplinary evaluation, was delivered either at a hub center or at spoke centers. By convention, primary chemotherapy was considered completed after 6 months. After restaging, surgical candidates were selected based on radiologic and biochemical response. All surgeries were carried out at the hub center. MAIN OUTCOMES AND MEASURES: Rates of receipt and completion of chemotherapy, rates of conversion to surgery, and disease-specific survival. RESULTS: Of 680 patients, 267 (39.3%) had borderline resectable and 413 (60.7%) had locally advanced pancreatic ductal adenocarcinoma. Overall, 66 patients (9.7%) were lost to follow-up. The rate of chemotherapy receipt was 92.9% (n = 570). The chemotherapeutic regimens most commonly used included FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) (260 45.6%) and gemcitabine plus nanoparticle albumin-bound–paclitaxel (123 21.6%). Nineteen patients (3.3%) receiving chemotherapy died within 6 months, mainly for disease progression. The treatment completion rate was 71.6% (408 of 570). The overall rate of resection was 15.1% (93 of 614) (borderline resectable, 60 of 249 24.1%; locally advanced, 33 of 365 9%; resection:exploration ratio, 63.3%). Independent predictors of resection were age, borderline resectable disease, chemotherapy completion, radiologic response, and biochemical response. The median survival for the whole cohort was 12.8 (95% CI, 11.7-13.9) months. Factors independently associated with survival were completion of chemotherapy, receipt of complementary radiation therapy, and resection. In patients who underwent resection, the median survival was 35.4 (95% CI, 27.0-43.7) months for initially borderline resectable and 41.8 (95% CI, 27.5-56.1) months for initially locally advanced disease. No pretreatment and posttreatment factors were associated with survival after pancreatectomy. CONCLUSIONS AND RELEVANCE: This pragmatic observational cohort study with an intention-to-treat design provides real-world evidence of outcomes associated with the most current primary chemotherapy regimens used for borderline resectable and locally advanced pancreatic ductal adenocarcinoma.
Time-of-Flight (ToF) technologies are developed mainly for range estimations in industrial applications or consumer products. Recently, it was realized that ToF sensors could also be used for the ...detection of fluorescence and of the minute changes in the nanosecond-lived electronic states of fluorescent molecules. This capability can be exploited to report on the biochemical processes occurring within living organisms. ToF technologies, therefore, provide new opportunities in molecular and cell biology, diagnostics, and drug discovery. In this short communication, the convergence of the engineering and biomedical communities onto ToF technologies and its potential impact on basic, applied and translational sciences are discussed.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Resection of initially oligometastatic pancreatic ductal adenocarcinoma (PDAC) following response to first-line chemotherapy is controversial. We herein updated a previous case series to ...investigate the oncologic outcomes and preoperative factors that could drive the decision-making process.
Methods
This retrospective analysis was limited to patients with liver-only synchronous metastases who experienced complete regression of the metastatic component and underwent pancreatectomy between October 2008 and July 2020 at two high-volume institutions. Clinical-pathologic variables were captured, and inflammation-based prognostic scores were calculated. Recurrence and survival analyses were performed using standard statistical methods.
Results
Overall, 52 patients were included. FOLFIRINOX was the most employed chemotherapy regimen (63.5%). Post-treatment tumor size, serum carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) were significantly decreased relative to baseline evaluation. The median time from diagnosis to pancreatectomy was 10.2 months, while the median time from chemotherapy completion to pancreatectomy was 2 months. Major postoperative complications occurred in 26.9% of patients, while postoperative mortality was nil. The median disease-free survival (DFS) and overall survival (OS) from pancreatectomy were 16.5 and 23.0 months, respectively, and the median OS from diagnosis was 37.2 months. At multivariable analysis, vascular resection, operative time, prognostic nutrition index (PNI) and neutrophil-to-lymphocyte ratio (NLR) were associated with OS. Operative time, platelet × neutrophil/lymphocyte count (SII), and PNI were associated with DFS.
Conclusions
We confirm promising outcomes of selected patients who underwent pancreatectomy following downstaging of liver metastases. The absence of vascular involvement of the primary tumor, good nutritional status, and low inflammatory index scores could be useful to select candidates for resection.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A correct cultivation technique supported by scientific evidence that leads to high-quality standards can promote sustainable floriculture. It is urgent to find alternative solutions to the widely ...used chemical fertilizers and evaluate the effectiveness of other fertilizers. The liquid organic ones, already in use in organic vegetable farming, could be a good substitute if supplied together with growth-promoting products such as microbial biostimulants. In the hope of replacing the traditional chemicals with a more sustainable organic-based fertilization, the present investigation aimed to evaluate the effects of a microbial biostimulant and various combinations of organic and mineral fertilization on morphological characteristics and physiological parameters of Tagetes patula L. and Ageratum houstonianum Mill. The plants were grown in pots with a substrate inoculated or not with the microbial biostimulant and were fertigated with nutrient solutions at different concentrations of elements from mineral and/or organic sources. Six fertilization formulas were adopted: control (only water without fertilizer), 100% mineral fertilization, 50% mineral fertilization, 100% organic fertilization, 50% organic fertilization, and 50% mineral + 50% organic fertilization. For the organic fertilization, a commercial liquid fertilizer admitted in organic farming with 3-2-5.5 NPK with 3% organic nitrogen was used. Mineral fertilization was formulated to match the organic solution as closely as possible. We observed an improvement in ornamental value (stem diameter and shoot number) with the biostimulant inoculum. Generally, the 50% mineral and 50% organic fertilization did not negatively influence the morphological characteristics. The reduction by 50% in the mineral nutrients and the integration of this reduction with an organic fertilizer was feasible to produce potted plants of these species during spring in the Mediterranean area.
Plant biostimulants are of interest as they can stimulate plant growth and increase resource utilization. There is still no information on the use of plant growth-promoters under variable nutritional ...conditions in the nursery and the effects on tomato seedling growth and plant performance after transplant. This study aimed to evaluate the suitability of gibberellic acid (GA3) or bacterial biostimulant treatments to enhance the growth and quality of greenhouse-grown tomato (Solanum lycopersicum ‘Marmande’) seedlings, fertigated with increasing nutrient rates and to assess the efficacy of these treatments on the early growth of tomato plants. During autumn 2019, tomato seedlings were inoculated with 1.5 g L−1 of TNC BactorrS13 (a commercial biostimulant containing 1.3 × 108 CFU g−1 of Bacillus spp.) or sprayed with 10−5 M GA3 and fertigated with a nutrient solution containing 0, 1, 2 and 4 g L−1 of NPK fertilizer (20-20-20) when they reached the 11th BBCH growth stage for tomato. Subsequently, the seedlings were evaluated in greenhouse cultivation for 60 days until at least the 61st BBCH growth stage (January 2020). The growth of the tomato seedlings increased curvilinearly in relation to the fertigation rates. The GA3-treated seedlings showed similar or even higher growth parameters than the control seedlings fed with 4 g L−1 of fertilizer but with half of the nutrients. The inoculation of the substrate with Bacillus spp. had negative effects in the absence of fertigation but determined a greater growth at the highest fertigation rate. The bacterial inoculum of seedlings had longer-term effects than the GA3 treatment during the plant growth, but these effects were noticeable mainly when the bacterial biostimulant was associated with the highest fertigation rate.
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