Nuno Figueiredo

Anthracyclines induce DNA damage response-mediated protection against severe sepsis.

Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fanconi Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.

Effective treatment of rat adjuvant-induced arthritis by celastrol

We have previously reported an increase in interleukin (IL)-1β and IL-17 levels, and a continuous activation of caspase-1 in early rheumatoid arthritis (RA) patients. These results suggest that drugs targeting IL-1β regulatory pathways, in addition to tumor necrosis factor (TNF), may constitute promising therapeutic agents in early RA. We have recently used a THP-1 macrophage-like cell line to screen 2320 compounds for those that down-regulate both IL-1β and TNF secretion. Celastrol was one of the most promising therapeutic candidates identified in that study. Our main goal in the present work was to investigate whether administration of celastrol is able to attenuate inflammation in a rat model of adjuvant-induced arthritis (AIA). Moreover, since IL-1β is known to play a role in the polarization of Th17 cells, we also investigate whether administration of digoxin, a specific inhibitor of Th17 cells polarization, is able to attenuate inflammation in the same rat model. We found that celastrol administration significantly suppressed joint inflammation. The histological and immunohistochemical evaluation revealed that celastrol-treated rats had a normal joint structure with complete abrogation of the inflammatory infiltrate and cellular proliferation. In contrast, we observed that digoxin administration significantly ameliorated inflammation but only if administrated in the early phase of disease course (after 4days of disease induction), and it was not efficient at inhibiting the infiltration of immune cells within the joint and in preventing damage. Thus, our results suggest that celastrol has significant anti-inflammatory and anti-proliferative properties and can constitute a potential anti-inflammatory drug with therapeutic efficacy in the treatment of immune-mediated inflammatory diseases such as RA. Furthermore, we find that early inhibition of Th17 cells polarization ameliorates arthritis but it is not as effective as celastrol.

A new paradigm for rectal cancer: Organ preservation: Introducing the International Watch & Wait Database (IWWD)

Rectal cancer treatment has witnessed several changes in the past decades resulting into improved outcomes. Preoperative radiotherapy is much better tolerated than postoperative radiotherapy, and the combination with chemotherapy has proven to be very effective in downstaging rectal cancer. Implementation of standard baseline MRI staging has enabled a better selection of high risk patients who will benefit from neoadjuvant (chemo) radiation (ChRT). The recognition that histological features of the resection specimen are powerful prognostic tools helped to optimize the surgical technique into the current standard of Total Mesorectal Excision (TME). Additionally, auditing and feeding back the performance has improved surgical quality and decreased the local relapse rate. With all these changes, local control is no longer the Achilles heel in rectal cancer treatment. It is now time to shift our focus from improving oncological endpoints to reducing long-term morbidity and to improving functional outcomes. Especially for the elderly and for those with several comorbidities, rectal resections are major procedures with substantial morbidity and mortality. More than half of patients undergoing TME surgery and neoadjuvant therapies will have long-term anorectal and urogenital dysfunction. Although very low anastomoses can avoid a permanent stoma for distal tumours, there is difficult trade-off between a good-functioning stoma with a life-changing body image and the risk of a poorfunctioning intra-anal anastomosis. Surgeons have tried to minimize surgical trauma in several ways. Transanal local excision can work well for cT1 lesions with favourable features resulting in good functional recovery. Larger tumours and those with unfavourable features show higher failure rates because of residual cancer cells within the bowel wall and lymph nodes.

Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts

Significance Despite advances in targeted cancer treatments, we still lack methods to predict how a specific cancer will respond to a given therapy. As a consequence, patients go through rounds of trial-and-error approaches based on guidelines to find the best treatment, often subjected to unnecessary toxicity. Using cell lines, we used zebrafish larvae xenografts as sensors for cancer behavior and therapy guideline screening. Our data show not only sufficient resolution to distinguish functional tumor behaviors in just 4 days but also differential sensitivity to colorectal cancer therapy. As proof-of-principle, we provide evidence for similar behavior response to therapies in patients as in zebrafish patient-derived xenografts. Altogether, our results suggest zebrafish larvae xenografts as a promising in vivo screening platform for precision medicine. Cancer is as unique as the person fighting it. With the exception of a few biomarker-driven therapies, patients go through rounds of trial-and-error approaches to find the best treatment. Using patient-derived cell lines, we show that zebrafish larvae xenotransplants constitute a fast and highly sensitive in vivo model for differential therapy response, with resolution to reveal intratumor functional cancer heterogeneity. We screened international colorectal cancer therapeutic guidelines and determined distinct functional tumor behaviors (proliferation, metastasis, and angiogenesis) and differential sensitivities to standard therapy. We observed a general higher sensitivity to FOLFIRI [5-fluorouracil(FU)+irinotecan+folinic acid] than to FOLFOX (5-FU+oxaliplatin+folinic acid), not only between isogenic tumors but also within the same tumor. We directly compared zebrafish xenografts with mouse xenografts and show that relative sensitivities obtained in zebrafish are maintained in the rodent model. Our data also illustrate how KRAS mutations can provide proliferation advantages in relation to KRASWT and how chemotherapy can unbalance this advantage, selecting for a minor clone resistant to chemotherapy. Zebrafish xenografts provide remarkable resolution to measure Cetuximab sensitivity. Finally, we demonstrate the feasibility of using primary patient samples to generate zebrafish patient-derived xenografts (zPDX) and provide proof-of-concept experiments that compare response to chemotherapy and biological therapies between patients and zPDX. Altogether, our results suggest that zebrafish larvae xenografts constitute a promising fast assay for precision medicine, bridging the gap between genotype and phenotype in an in vivo setting.

Three-step standardized approach for complete mobilization of the splenic flexure during robotic rectal cancer surgery

The aim of this technical note is to describe a three‐step technique for expeditious and complete mobilization of the splenic flexure (CMSF) during single docking totally robotic rectal cancer surgery.

Potent Anti-Inflammatory and Antiproliferative Effects of Gambogic Acid in a Rat Model of Antigen-Induced Arthritis

Background. We have previously reported a continuous activation of caspase-1 and increased interleukin (IL)-1β levels in early rheumatoid arthritis (RA). These observations raised the hypothesis that drugs targeting the IL-1β pathway, in addition to tumour necrosis factor (TNF), may be particularly effective for early RA treatment. We have recently identified gambogic acid as a promising therapeutic candidate to simultaneously block IL-1β and TNF secretion. Our main goal here was to investigate whether gambogic acid administration was able to attenuate inflammation in antigen-induced arthritis (AIA) rats. Methods. Gambogic acid was administered to AIA rats in the early and late phases of arthritis. The inflammatory score, ankle perimeter, and body weight were evaluated during the period of treatment. Rats were sacrificed after 19 days of disease progression and paw samples were collected for histological and immunohistochemical evaluation. Results. We found that inflammation in joints was significantly suppressed following gambogic acid administration. Histological and immunohistochemical evaluation of treated rats revealed normal joint structures with complete abrogation of the inflammatory infiltrate and cellular proliferation. Conclusions. Our results suggest that gambogic acid has significant anti-inflammatory properties and can possibly constitute a prototype anti-inflammatory drug with therapeutic efficacy in the treatment of inflammatory diseases such as RA.

Tailored robotic abdominoperineal resection with the da Vinci Xi for a re-growth of rectal tumour after complete clinical response - a video vignette.

Controversy persists as to the optimal surgical technique for abdominoperineal excision of the rectum (APER).(1–3). Extra-levator dissection has been advocated by certain groups who claim to have better R0 resection rates and a reduced incidence of perforation (4–6). However, such a radical approach may result in poorer wound healing, prolonged hospital stay and increased wound morbidity (7). In this operative video we present an abdominoperineal resection using the da Vinci Xi on a 34-year-old lady who had a low rectal adenocarcinoma. This article is protected by copyright. All rights reserved.

The Perfect Total Mesorectal Excision Obviates the Need for Anything Else in the Management of Most Rectal Cancers

This article discusses the local control of primary rectal cancer and its locoregional spread in the light of modern advances. In recent years, the use of neoadjuvant chemoradiation has spread widely. However, its true benefit is not always balanced with its morbidities. Often total mesorectal excision (TME) is the best option. We will discuss the indications for immediate surgery for chemoradiation in advance and the importance of a delay in the management plan. To understand this selection, it is mandatory to know the true extent of tissue at risk for tumor dissemination and spread. Considering that TME may be enough for many patients and that most local recurrences are failures of surgical technique we introduce a new concept of total mesorectal irradiation. This exploits the new reality that precise, focused neoadjuvant therapy can offer a better response with fewer complications. Together these important changes in cancer board (multidisciplinary team) planning can also offer selected patients complete control of their cancer with no need for surgery.

Robotic vascular ligation, medial to lateral dissection and splenic flexure mobilization for rectal cancer - a video vignette

a pursestring suture and replaced in the abdomen. A stapled coloanal anastomosis was achieved with a CDH 29 circular stapler. A covering ileostomy was made. The robotic console time was 120 min with an estimated blood loss of 50 ml. The patient was discharged on postoperative day 5 without any significant morbidity. Sphincter-saving procedures for low rectal cancers, although technically challenging, are possible with the advanced robotic systems. The da Vinci Xi system makes multiquadrant surgery possible in the same docking position, which facilitates complete splenic flexure mobilization for better colonic length, necessary for a tension-free anastomosis. Further, well-designed trials need to be conducted to evaluate the long-term functional and oncological outcomes of Robotic ISR.

Standardized approach to robotic right colectomy - a video vignette

Robotic approach to colonic surgery is one of the latest minimal invasive techniques evolving over the last few years. Robotic platform offers the advantage of stable immersive 3D high-definition vision, fully wristed instruments leading to added precision for surgeons [1]⁠. Oncological safety of robotic colonic surgery is comparable with laparoscopic approach and this has already been established. This article is protected by copyright. All rights reserved.