SEOM clinical guideline for the management of cutaneous melanoma (2020).

Melanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I-III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immunotherapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available.

Cancer immunotherapy of patients with HIV infection.

Cancer immunotherapy with antibodies against immune checkpoints has made impressive advances in the last several years. The most relevant drugs target programmed cell death 1 (PD-1) expressed on T cells or its ligand, the programmed cell death ligand 1 (PD-L1), expressed on cancer cells, and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Unfortunately, cancer patients with HIV infection are usually excluded from cancer clinical trials, because there are concerns about the safety and the anti-tumoral activity of these novel therapies in patients with HIV infection. Several retrospective studies and some case reports now support the notion that antibodies against immune checkpoints are safe and active in cancer patients with HIV infection, but prospective data in these patients are lacking. In addition, signs of antiviral activity with increase in CD4 T cell counts, plasma viremia reduction or decrease in the viral reservoir have been reported in some of the patients treated, although no patient achieved a complete clearance of the viral reservoir. Here we briefly summarize all clinical cases reported in the literature, as well as ongoing clinical trials testing novel immunotherapy drugs in cancer patients with HIV infection.

Long-term changes on estuarine ciliates linked with modifications on wind patterns and water turbidity.

Planktonic ciliates constitute a fundamental component among microzooplankton and play a prominent role in carbon transport at the base of marine food webs. How these organisms respond to shifting environmental regimes is unclear and constitutes a current challenge under global ocean changes. Here we examine a multiannual field survey covering 25 years in the Bahía Blanca Estuary (Argentina), a shallow, flood-plain system dominated by wind and tidal energy. We found that the estuary experienced marked changes in wind dominant regimes and an increase in water turbidity driven from the joint effect of persistent long-fetch winds and the indirect effect of the Southern Annular Mode. Along with these changes, we found that zooplankton components, i.e. ciliates and the dominant estuarine copepod Acartia tonsa, showed a negative trend during the period 1986-2011. We showed that the combined effects of wind and turbidity with other environmental variables (chlorophyll, salinity and nutrients) consistently explained the variability of observed shifts. Tintinnids were more vulnerable to wind patterns and turbidity while showed a loss of synchrony with primary productivity. Water turbidity produced a dome-like pattern on tintinnids, oligotrichs and A. tonsa, implying that the highest abundance of organisms occurred under moderate values (∼50 NTU) of turbidity. In contrast, the response to wind patterns was not generalizable probably owing to species-specific traits. Observed trends denote that wind-induced processes in shallow ecosystems with internal sources of suspended sediments, are essential on ciliate dynamics and that such effects can propagate trough the interannual variability of copepods.

SEOM clinical guideline for the management of malignant melanoma (2017).

All melanoma suspected patients must be confirmed histologically and resected. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon could be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 containing therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 containing therapy. Up to 10 years follow up is reasonable for melanoma patients with dermatologic examinations and physical exams.

MRI-guided radiotherapy for head and neck cancer: initial clinical experience.

PURPOSE: To report a single-institutional experience with the use of magnetic resonance imaging (MRI)-guided radiotherapy for cancers of the head and neck. MATERIALS AND METHODS: Between October 2014 and October 2016, 18 patients with newly diagnosed cancers of the head and neck were prospectively enrolled on an institutional registry trial investigating the feasibility and efficacy of external-beam radiotherapy delivered using on-board MRI. All patients had biopsy-proven evidence of malignancy, measurable disease, and the ability to provide consent. None had previously received any treatment. Median dose was 70 Gy (range 54-70 Gy). MRI scans were obtained as part of an image-guided registration protocol for alignment prior to and during each treatment. Concurrent chemotherapy was administered to 14 patients (78%). Patient-reported outcomes were assessed using the University of Washington quality of life instrument. RESULTS: Seventeen of 18 patients completed the planned intensity-modulated radiotherapy (IMRT) treatment of which 15 (83%) had a complete response and 2 (11%) had a partial response based on initial post-therapy positron emission tomography (PET) at 3 months. The 1-year estimates of progression-free survival, overall survival, and local-regional control were 95, 96, and 95%, respectively. There were no treatment-related fatalities. The incidence of grade 3+ acute toxicity was 44%. The proportion of patients rating their health-related quality of life as "very good" or "outstanding" at 6 months and 1 year after completion of radiation therapy was 60 and 70%, respectively. CONCLUSIONS: MRI-guided radiotherapy achieves clinical outcomes comparable to contemporary series reporting on IMRT for head and neck cancer.

Salinomycin enhances doxorubicin sensitivity through reversing the epithelial-mesenchymal transition of cholangiocarcinoma cells by regulating ARK5.

Chemotherapy response rates in patients with cholangiocarcinoma remain low, primarily due to the development of drug resistance. Epithelial-mesenchymal transition (EMT) of cancer cells is widely accepted to be important for metastasis and progression, but it has also been linked to the development of chemoresistance. Salinomycin (an antibiotic) has shown some potential as a chemotherapeutic agent as it selectively kills cancer stem cells, and has been hypothesized to block the EMT process. In this study, we investigated whether salinomycin could reverse the chemoresistance of cholangiocarcinoma cells to the chemotherapy drug doxorubicin. We found that combined salinomycin with doxorubicin treatment resulted in a significant decrease in cell viability compared with doxorubicin or salinomycin treatment alone in two cholangiocarcinoma cell lines (RBE and Huh-28). The dosages of both drugs that were required to produce a cytotoxic effect decreased, indicating that these two drugs have a synergistic effect. In terms of mechanism, salinomycin reversed doxorubicin-induced EMT of cholangiocarcinoma cells, as shown morphologically and through the detection of EMT markers. Moreover, we showed that salinomycin treatment downregulated the AMP-activated protein kinase family member 5 (ARK5) expression, which regulates the EMT process of cholangiocarcinoma. Our results indicated that salinomycin reversed the EMT process in cholangiocarcinoma cells by inhibiting ARK5 expression and enhanced the chemosensitivity of cholangiocarcinoma cells to doxorubicin. Therefore, a combined treatment of salinomycin with doxorubicin could be used to enhance doxorubicin sensitivity in patients with cholangiocarcinoma.

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program.

BACKGROUND: The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS: Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS: Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION: Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.

Salinomycin enhances doxorubicin sensitivity through reversing the epithelial-mesenchymal transition of cholangiocarcinoma cells by regulating ARK5

Chemotherapy response rates in patients with cholangiocarcinoma remain low, primarily due to the development of drug resistance. Epithelial-mesenchymal transition (EMT) of cancer cells is widely accepted to be important for metastasis and progression, but it has also been linked to the development of chemoresistance. Salinomycin (an antibiotic) has shown some potential as a chemotherapeutic agent as it selectively kills cancer stem cells, and has been hypothesized to block the EMT process. In this study, we investigated whether salinomycin could reverse the chemoresistance of cholangiocarcinoma cells to the chemotherapy drug doxorubicin. We found that combined salinomycin with doxorubicin treatment resulted in a significant decrease in cell viability compared with doxorubicin or salinomycin treatment alone in two cholangiocarcinoma cell lines (RBE and Huh-28). The dosages of both drugs that were required to produce a cytotoxic effect decreased, indicating that these two drugs have a synergistic effect. In terms of mechanism, salinomycin reversed doxorubicin-induced EMT of cholangiocarcinoma cells, as shown morphologically and through the detection of EMT markers. Moreover, we showed that salinomycin treatment downregulated the AMP-activated protein kinase family member 5 (ARK5) expression, which regulates the EMT process of cholangiocarcinoma. Our results indicated that salinomycin reversed the EMT process in cholangiocarcinoma cells by inhibiting ARK5 expression and enhanced the chemosensitivity of cholangiocarcinoma cells to doxorubicin. Therefore, a combined treatment of salinomycin with doxorubicin could be used to enhance doxorubicin sensitivity in patients with cholangiocarcinoma.

Two-step identification of taro (Colocasia esculenta cv. Xinmaoyu) using specific psbE-petL and simple sequence repeat-sequence characterized amplified regions (SSR-SCAR) markers.

Colocasia esculenta cv. Xinmaoyu is an eddoe-type taro cultivar local to Taicang, Jiangsu Province, China; it is characterized by its pure flavor, glutinous texture, and high nutritional value. Due to its excellent qualities, the Trademark Office of the State Administration for Industry and Commerce of the People's Republic of China awarded Xinmaoyu, a geographical indication certification in 2014. Therefore, there is an urgent need to develop an efficient molecular marker for the specific identification of this cultivar, which would greatly facilitate the conservation and utilization of this unique germplasm resource. In the present study, amplifying the psbE-petL fragment from two dasheen-type and seven eddoe-type taro cultivars revealed three conserved insertions/deletions among sequences from the two taro types. Based on these sequence differences, a pair of site-specific primers was designed targeting the psbE-petL sequence from the dasheen-type taro, which specifically amplified a DNA band in all individuals from cultivars of this type, but not in those from the seven eddoe-type cultivars. To discriminate Xinmaoyu from the other eddoe-type taro cultivars, a pair of simple sequence repeat-sequence characterized amplified region (SSR-SCAR) primers was further developed to specifically amplify a DNA band from all Xinmaoyu individuals, but not from individuals of other eddoe-type taro cultivars. In conclusion, through a two-step-screening procedure using psbE-petL and SSR-SCAR markers, we developed a pair of primers that could specifically discriminate Xinmaoyu from nine taro cultivars commonly cultivated in Jiangsu Province and Fujian Province.

SEOM guidelines for the management of Malignant Melanoma 2015.

All melanoma patients must be confirmed histologically and resected according to Breslow. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon must be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 therapy. Up to 10 years follow up is recommended for melanoma patients with dermatologic examinations and physical exams.

Alleviation of streptozotocin-induced diabetes in nude mice by stem cells derived from human first trimester umbilical cord.

Cells isolated from human first trimester umbilical cord perivascular layer (hFTM-PV) tissues display the pluripotent characteristics of stem cells. In this study, we examined whether hFTM-PV cells can differentiate into islet-like clusters (ILCs) in vitro, and whether transplantation of the hFTM-PV cells with and without differentiation in vitro can alleviate diabetes in nude mice. The hFTM-PV cells were differentiated into ILCs in vitro through a simple stepwise culture protocol. To examine the in vivo effects of the cells, the hFTM-PV cells with and without differentiation in vitro were transplanted into the abdominal cavity of nude mice with streptozotocin (STZ)-induced diabetes. Blood glucose levels, body weight, and the survival probability of the diabetic nude mice were then statistically analyzed. The hFTM-PV cells were successfully induced into ILCs that could release insulin in response to elevated concentrations of glucose in vitro. In transplantation experiments, we observed that mice transplanted with the undifferentiated hFTM-PV cells, embryonic body-like cell aggregations, or ILCs all demonstrated normalized hyperglycemia and showed improved survival rate compared with those without cell transplantation. The hFTM-PV cells have the ability to differentiate into ILCs in vitro and transplantations of undifferentiated and differentiated cells can alleviate STZ-induced diabetes in nude mice. This may offer a potential cell source for stem cell-based therapy for treating diabetes in the future.

Expression and antibody generation of the cancer-testis antigen, BIOT2-S.

Biot2-S is a mouse cancer-testis antigen gene that was identified using the cross-reactive serological analysis of recombinant cDNA expression libraries (SEREX) technique in the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University. To express BIOT2-S and generate its antibody for further investigation, the Biot2-S prokaryotic recombinant expression vector Biot2-S/pGEX6P-1 was constructed with Escherichia coli DH5α as a cloning vector, and BIOT2-S was expressed in E. coli Rosetta (DE3). The recombinant BIOT2-S was expressed in the form of an inclusion body and the targeted recombinant BIOT2-S was produced at the level of approximately 25% total bacterial proteins after being induced with optimum conditions (0.2 mM isopropyl-ß-D-thiogalactopyranoside for 6 h at 37°C). The target protein was purified by glutathione S-transferase (GST)-trap FF affinity chromatography and detected by western blot. The purified recombinant protein was further confirmed by electrospray ionization quadrupole time-of-flight mass spectrometry after removal of the GST-tags. Then the purified BIOT2-S was used to immunize adult rabbits to generate its antibody. The antibody was purified and its specificity determined. The titer of the antibody was shown to reach 10(4) and the antibody was demonstrated to be able recognize the corresponding protein in the testes of mouse and chicken; the tumor cell lines CT-26 and S180 also reacted with the antibody. This study provides a valuable foundation for further research on the cancer-testis antigen BIOT2-S.

Microplankton dynamics under heavy anthropogenic pressure. The case of the Bahía Blanca Estuary, southwestern Atlantic Ocean.

Quantifying biotic feedbacks in response to environmental signals is fundamental to assess ecosystem perturbation. We analyzed the joint effects of eutrophication, derived from sewage pollution, and climate at the base of the pelagic food web in the Bahía Blanca Estuary (SW Atlantic Ocean). A two-year survey of environmental conditions and microplankton communities was conducted in two sites affected by contrasting anthropogenic eutrophication conditions. Under severe eutrophication, we found higher phytoplankton abundance consistently dominated by smaller sized, non siliceous species, while microzooplankton abundance remained lower and nutrient stoichiometry showed conspicuous deviations from the Redfield ratio. Phytoplankton growth in such conditions appeared controlled by phosphorous. In turn, microplankton biomass and phytoplankton size ratio (<20µm:>20µm) displayed a saturation relationship with nutrients in the highly eutrophic area, although mean phytoplankton growth was similar in both eutrophic systems. The strength of links within the estuarine network, quantified through path analysis, showed enhanced relationships under larger anthropogenic eutrophication, which fostered the climate influence on microplankton communities. Our results show conspicuous effects of severe sewage pollution on the ecological stoichiometry, i.e., N and P excess with respect to Si, altering nutrient ratios for microplankton communities. This warns on wide consequences on food web dynamics and ultimately in ecosystem assets of coastal pelagic environments.

Response of resistant melanoma to a combination of weekly paclitaxel and bevacizumab.

We report here a taxol-bevacizumab-responsive metastatic melanoma case. Although the patient had been heavily pretreated for two years, she did not show any stabilisation or objective response of her disease. After treatment with taxol and bevacizumab combination an impressive response was obtained.

Ileal carcinoid tumor with liver metastases and cardiac involvement treated with intraarterial liposomal doxorubicin and valve replacement.

Unless carcinoid are in general slow-growing tumors, some cases could be frankly malignant. The commonest cause of death in patients suffering a carcinoid tumor is liver failure due to tumor progression. When tumors have a fast evolution a multidisciplinary approach must be perform. This case report is an example of this specific situation.

Expression of fibroblast growth factor-8 and regulation of cognate receptors, fibroblast growth factor receptor-3c and -4, in bovine antral follicles.

Paracrine cell signaling is believed to be important for ovarian follicle development, and a role for some members of the fibroblast growth factor (FGF) family has been suggested. In the present study, we tested the hypothesis that FGF-8 and its cognate receptors (FGFR3c and FGFR4) are expressed in bovine antral follicles. RT-PCR was used to analyze bovine Fgf8, Fgfr3c and Fgfr4 mRNA levels in oocytes, and granulosa and theca cells. Fgf8 expression was detected in oocytes and in granulosa and theca cells; this expression pattern differs from that reported in rodents. Granulosa and theca cells, but not oocytes, expressed Fgfr3c, and expression in granulosa cells increased significantly with follicle estradiol content, a major indicator of follicle health. Fgfr4 expression was restricted to theca cells in the follicle, and decreased significantly with increasing follicle size. To investigate the potential regulation of Fgfr3c expression in the bovine granulosa, cells were cultured in serum-free medium with FSH or IGF-I; gene expression was upregulated by FSH but not by IGF-I. The FSH-responsive and developmentally regulated patterns of Fgfr3c mRNA expression suggest that this receptor is a potential mediator of paracrine signaling to granulosa cells during antral follicle growth in cattle.