Phytochemical Composition of Lichen Parmotrema hypoleucinum (J. Steiner) Hale from Algeria.

In this work, we carried out studies of the chemical composition of hexane, chloroform and ethanol extracts from two samples of the lichen Parmotrema hypoleucinum collected in Algeria. Each sample of the lichen P. hypoleucinum was collected on two different supports: Olea europaea and Quercus coccifera. Hexane extracts were prepared, in Soxhlet; each hexane extract was fractionated by its solubility in methanol; the products soluble in methanol were separated (cold): 1-Hexane, 2-Hexane; and the products insoluble in methanol (cold): 1-Cires, 2-Cires. A diazomethane esterified sample of 1-Hexane, 2-Hexane, 1-Cires and 2-Cires was analyzed by GC-MS, and the components were identified as methyl esters. In the 1-Hexane and 2-Hexane fractions, the methyl esters of the predominant fatty acids in the lichen were identified: palmitic acid, linoleic acid, oleic acid and stearic acid; a hydrocarbon was also identified: 13-methyl-17-norkaur-15-ene and several derivatives of orsellinic acid. In the 1-Cires and 2-Cires fractions, the previous fatty acids were no longer observed, and only the derivatives of orsellinic acid were found. The analysis of the 1-Hexane, 2-Hexane fractions by HPLC-MS/MS allows us to identify different chemical components, and the most characteristic products of the lichen were identified, such as Atranol, Chloroatranol, Atranorin and Chloroatranorin. In the fractions of 1-Cires and 2-Cires, the HPLC-MS/MS analysis reveals that they are very similar in their chemical components; the characteristic products of this lichen in this fraction are Atranorin and Chloroatranorin. In the extracts of chloroform, 1-Chloroform and 2-Chloroform, the analysis carried out by HPLC-MS/MS shows small differences in their chemical composition at the level of secondary products; among the products to be highlighted for this work, we have chloroatranorin, the stictic acid, norstictic acid and other derivatives. In the analysis of the most polar extracts carried out in ethanol: 1-Ethanol and 2-Ethanol, HPLC-MS/MS analysis shows very similar chemical compositions in these two extracts with small differences. In these extracts, the following acids were identified as characteristic compounds of this lichen: constictic acid, stictic acid, substictic acid and methylstictic acid. In the HPLC-MS/MS analysis of all these extracts, alectoronic acid was not found.

Prospective Real-World Gynaecological Cancer Clinical Registry with Associated Biospecimens: A Collaborative Model to Promote Translational Research between GEICO and the Spanish Biobank Network.

Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer.

RAS Mutational Status in Advanced Colorectal Adenocarcinoma Treated With Anti-angiogenics: Preliminary Experience With Liquid Biopsy.

AIM: To determinate molecular changes in the downstream epidermal growth factor receptor signaling pathway using serial liquid biopsies in patients with metastatic colorectal tumors (mCRC) under anti-angiogenic treatment. PATIENTS AND METHODS: Determination of RAS mutation in primary tissue samples from colorectal tumors was performed in the 23 patients included in the study at diagnosis using quantitative-polymerase chain reaction. Sequential mutations were studied in circulating tumor (ct) DNA obtained from plasma samples. RESULTS: Twenty-three patients with RAS-mutated primary tumors were included. In the first ctDNA determination, 17 of these patients were found to have wild-type RAS status. Remarkably, three out of these 17 wild-type cases changed to RAS-mutated in subsequent ctDNA assays. CONCLUSION: Serial liquid biopsies in patients with mCRC might be a useful tool for identifying changes in the RAS mutation status in patients who had undergone previous anti-angiogenic therapy. The understanding of these changes might help to better define the landscape of mCRC and be the path to future randomized studies.

Phytochemical Investigation of New Algerian Lichen Species: Physcia Mediterranea Nimis.

The present study provides new data concerning the chemical characterisation of Physcia mediterranea Nimis, a rare Mediterranean species belonging to the family Physciaceae. The phytochemical screening was carried out using GC-MS, HPLC-ESI-MS-MS, and NMR techniques. Hot extraction of n-hexane was carried out, followed by separation of the part insoluble in methanol: wax (WA-hex), from the part soluble in methanol (ME-hex). GC-MS analysis of the ME-hex part revealed the presence of methylbenzoic acids such as sparassol and atraric acid and a diterpene with a kaurene skeleton which has never been detected before in lichen species. Out of all the compounds identified by HPLC-ESI-MS-MS, sixteen compounds are common between WA-hex and ME-hex. Most are aliphatic fatty acids, phenolic compounds and depsides. The wax part is characterised by the presence of atranorin, a depside of high biological value. Proton 1H and carbon 13C NMR have confirmed its identification. Atranol, chloroatranol (depsides compound), Ffukinanolide (sesquiterpene lactones), leprolomin (diphenyl ether), muronic acid (triterpenes), and ursolic acid (triterpenes) have also been identified in ME-hex. The results suggested that Physcia mediterranea Nimis is a valuable source of bioactive compounds that could be useful for several applications as functional foods, cosmetics, and pharmaceuticals.

Adjuvant chemotherapy in endometrial cancer.

The role of adjuvant chemotherapy (CT) is controversial in endometrial carcinoma (EC). Surgery alone is usually curative for women who are at a low risk of disease recurrence. The treatment of EC following surgical staging is based on the risk of relapse, which is defined by the cancer stage at diagnosis, histology of the tumor and other prognostic factors such as grade differentiation, the presence of substantial lymphovascular invasion (LVSI), or depth of myometrial invasion (MI). External beam radiotherapy (EBRT) and/or vaginal brachytherapy (VBT) improved local control and are used as adjuvant treatment for early-stage disease. The role of adjuvant CT is controversial in early-stage EC, and there is no uniform approach to the treatment of women with stage III EC or early-staged non-endometrioid EC. Available evidence did not support the indication of adjuvant CT in stage I-II endometroid EC. In those cases at higher risk of relapse, defined as grade 3 tumors with substantial (no focal) LVSI, specifically with deep MI or cervical involvement, could be considered. Adjuvant CT should be administered to stage III EC patients. When RT is indicated (extensive lymph node involvement or deep MI), sequential treatment with RT or "sandwich" regimen may be considered rather than concurrent CRT. The patients with stage IA MI or IB USC may be offered adjuvant CT alone or in combination with VBT, whereas in stage II uterine serous carcinoma patients adding EBRT may be reasonable. Management approach for patients with stage IA without MI USC who underwent a comprehensive surgery remains controversial, and surveillance alone or CT plus VBT is an appropriate option. Early-stage clear-cell carcinoma patients might not benefit for adjuvant CT, but stage III patients might benefit from the combination of CT and EBRT. Stage I-III uterine carcinosarcoma patients might be offered adjuvant CT followed by RT or as a "sandwich" régimen.

Genetic polymorphisms of SCN9A are associated with oxaliplatin-induced neuropathy.

BACKGROUND: Oxaliplatin is a chemotherapy agent active against digestive tumors. Peripheral neuropathy is one of the most important dose-limiting toxicity of this drug. It occurs in around 60-80% of the patients, and 15% of them develop severe neuropathy. The pathophysiology of oxaliplatin neurotoxicity remains unclear. SCN9A is a gene codifying for a subtype sodium channel (type IX, subunit α) and mutations in this gene are involved in neuropathic perception. In this study we investigated whether SCN9A genetic variants were associated with risk of neurotoxicity in patients diagnosed of cancer on treatment with oxaliplatin. METHODS: Blood samples from 94 patients diagnosed of digestive cancer that had received oxaliplatin in adjuvant or metastatic setting were obtained from three hospitals in Madrid. These patients were classified into two groups: "cases" developed oxaliplatin-induced grade 3-4 neuropathy (n = 48), and "controls" (n = 46) had no neuropathy or grade 1. The neuropathy was evaluated by an expert neurologist and included a clinical examination and classification according to validated neurological scales: National Cancer Institute Common Toxicity Criteria (NCI-CTC), Oxaliplatin-Specific Neurotoxicity Scale (OSNS) and Total Neuropathy score (TNS). Genotyping was performed for 3 SCN9A missense polymorphisms: rs6746030 (R1150W), rs74401238 (R1110Q) and rs41268673 (P610T), and associations between genotypes and neuropathy were evaluated. RESULTS: We found that SCN9A rs6746030 was associated with protection for severe neuropathy (OR = 0.39, 95% CI = 0.16-0.96; p = 0.041). Multivariate analysis adjusting for diabetes provided similar results (p = 0.036). No significant differences in neuropathy risk were detected for rs74401238 and rs41268673. CONCLUSION: SCN9A rs6746030 was associated with protection for severe oxaliplatin-induced peripheral neuropathy. The validation of this exploratory study is ongoing in an independent series.

A bio-inspired enantioselective small-molecule artificial receptor for ß adrenergic agonists and antagonists and its application for enantioselective extraction.

Administration of enantiomerically pure ß-adrenergic agonists and antagonists increases their activity and reduces side effects. We report here a small-molecule artificial receptor (SMAR) that, by mimicking the ß-adrenergic receptor, is able to enantioselectively extract commercial ß-adrenergic interacting drugs. The selectivity is justified according to DFT calculations and X-ray diffraction experiments.

A significant response to sorafenib in a woman with advanced lung adenocarcinoma and a BRAF non-V600 mutation.

Lung adenocarcinoma includes recurrent activating oncogenic mutations (EGFR, EML4-ALK, ROS1) that have been associated with response to EGFR and ALK inhibitors. Platinum-based chemotherapy is the standard therapy for non-oncodrivers population. Sorafenib is a small molecule that blocks the activation of C-RAF, B-RAF, c-KIT, FLT-3, RET, VEGFR-2, VEGFR-3 and PDGFR approved for advanced renal cell and hepatocellular carcinoma (b, c). Many studies have evaluated sorafenib in advanced non-small-cell lung cancer (NSCLC), with different results. We present a case report of a patient with NSCLC and the BRAF G469R mutation who showed a dramatic response to sorafenib.

Oxaliplatin induced-neuropathy in digestive tumors.

Oxaliplatin is one of the main drugs used in digestive tumors treatment. Peripheral neuropathy is a well-recognized dose-limiting toxicity of OXL. Two types of neuropathy have been described with this agent: acute or transient and chronic or persistent, with different etiology, clinical manifestations and prognosis. This paper is an exhaustive review about the main aspects of oxaliplatin induced peripheral neuropathy, focus in clinical features, treatment, prevention strategies and future approach.

Lung cancer and peritoneal carcinomatosis.

Lung cancer is currently one of the most common malignancies in the world and peritoneal involvement is rare in these types of tumors. Clinical manifestations of these metastases are also uncommon and include intestinal perforation and obstruction. The present study reviewed certain aspects of the complication of peritoneal involvement and illustrated it with four cases of patients that were diagnosed with primary lung carcinoma and secondary peritoneal carcinomatosis (PC). The outcome of these patients is poor and they rarely respond to chemotherapy. Surgery is successful in the majority of cases.

Unveiling the rat urinary proteome with three complementary proteomics approaches.

Urine is a suitable biological fluid to look for markers of physiological and pathological processes, including renal and nonrenal diseases. In addition, it is an optimal body sample for diagnosis, because it is easily obtained without invasive procedures and can be sampled in large quantities at almost any time. Rats are frequently used as a model to study human diseases, and rat urine has been analyzed to search for disease biomarkers. The normal human urinary proteome has been studied extensively, but the normal rat urinary proteome has not been studied in such depth. In light of this, we were prompted to analyze the normal rat urinary proteome using three complementary proteomics platforms: SDS-PAGE separation, followed by LC-ESI-MS/MS; 2DE, followed by MALDI-TOF-TOF and 2D-liquid chromatography-chromatofocusing, followed by LC-ESI-Q-TOF. A total of 366 unique proteins were identified, of which only 5.2% of unique proteins were identified jointly by the three proteomics platforms used. This suggests that simultaneous proteomics techniques provide complementary and nonredundant information. Our analysis affords the most extensive rat urinary protein database currently available and this may be useful in the study of renal physiology and in the search for biomarkers related to renal and nonrenal diseases.

A major response to trabectedin in metastatic malignant fibrous histiocytoma of the vertebra: a case report and review of the literature.

Malignant fibrous histiocytoma is an aggressive tumor, the most common soft-tissue sarcoma of adult age. It is usually located in the extremities and retroperitoneum, and very rarely there is skeletal involvement. Surgery is the preferred treatment in early disease; in advanced disease, chemotherapy is the main therapeutic strategy. We present a 25-year-old female patient diagnosed with a vertebral mass in T5 with a severely compromised spinal cord. She underwent surgical decompression and the pathological findings were consistent with malignant fibrous histiocytoma. After several surgical treatments she had pulmonary progression and was therefore started on chemotherapy. She had a very poor response to most of the administered regimens until she initiated trabectedin 1 mg/m 2 every three weeks. She showed a significant improvement with a major response of the lung metastases. This report indicates that trabectedin is an active drug in advanced, previously treated metastatic malignant fibrous histiocytoma.

Squamous-cell carcinoma of the lungs: is it really so different?

BACKGROUND: Squamous cell carcinoma (SCC) is the predominant histological type in men, and adenocarcinoma is the most common subtype in women in the world. The incidence of SCC is decreasing in men, while the incidence of adenocarcinoma (AC) is stable or slightly increasing in western countries. There is active research on the AC subtype but SCC remains poorly studied. CONCLUSIONS: In this review, we have studied different aspects of the SCC subtype, including epidemiology, clinical features, pathology, molecular biology markers, and new therapeutic targets, treatments and prognosis implications.

Functional specific roles of H-ras and N-ras. A proteomic approach using knockout cell lines.

Ras small GTPases function as transducers of extracellular signals regulating cell survival, growth and differentiation. There are three major ras isoforms: H-, N- and K-Ras. To improve the understanding of H- and N-Ras protein signalling networks, we compared total proteome changes in mouse embryonic fibroblasts knock out for H-ras and/or N-ras, using proteomics tools combining 2DE, semi-quantitative image analysis, in-gel trypsin digestion and mass spectrometry. There are four up-regulated proteins due to the loss of expression of H-Ras (including cyclin-dependent kinase inhibitor 2A) and eight down-regulated (including stress-70 protein, dihydropyrimidinase-related-protein 3, heat shock cognate 71 kDa protein, tropomyosin beta chain, Rho GDP-dissociation inhibitor 1) and six up-regulated proteins (e.g. leukocyte elastase inhibitor A, L-lactate dehydrogenase B chain, c-Myc-responsive protein Rcl, interleukin-1 receptor antagonist protein) due to the loss of expression of both N- and H-Ras. Most of these proteins are related to Ras signalling in one way or another. Changes in expression of some of these proteins were further confirmed by Western blot. This proteomic comparative analysis from loss of function of H- and N-Ras knockout fibroblasts yields interpretable data to elucidate the differential protein expression, and contributes to evaluate the possibilities for physiological and therapeutic targets.

Relevance of breast cancer subtypes for magnetic resonance imaging response monitoring during neoadjuvant chemotherapy.

Changes in magnetic resonance imaging (MRI) during neoadjuvant chemotherapy (NAC) have been reported as predictive of pathology outcome in triple-negative and HER2-positive breast cancer. The purpose of our study was to evaluate the relevance of breast cancer subtype for MRI response in 24 women before and during NAC in our centre. Our results show that a reduction greater than 23% is associated with a pathological complete response (pCR) in Her-2-positive and ER-negative/Her2-negative breast cancer, and suggest a trend correlation between higher ADC values and pCR in these subtypes in comparison with ER-positive/Her2-negative breast cancers. Higher proliferating tumours respond better to chemotherapy and our study suggests that changes in MRI during NAC are predictive of pCR in these breast cancer subtypes.

Upregulation of trefoil factor 3 (TFF3) after rectal cancer chemoradiotherapy is an adverse prognostic factor and a potential therapeutic target.

PURPOSE: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance. METHODS: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival. RESULTS: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis. CONCLUSION: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target.

Gastric tumours in hereditary cancer syndromes: clinical features, molecular biology and strategies for prevention.

Gastric cancer is the major cause of cancer-related deaths worldwide. The majority of them are classified as sporadic, whereas the remaining 10% exhibit familial clustering. Hereditary diffuse gastric cancer (HDGC) syndrome is the most important condition that leads to hereditary gastric cancer. However, other hereditary cancer syndromes, such as hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, Peutz-Jeghers syndrome, Li-Fraumeni syndrome and hereditary breast and ovarian cancer, entail a higher risk compared to the general population for developing this kind of neoplasia. In this review, we describe briefly the most important aspects related to clinical features, molecular biology and strategies for prevention in hereditary gastric associated to different cancer syndromes.

From targeted therapy in ovarian cancer to personalizing therapy for ovarian cancer.

Epithelial ovarian carcinoma (EOC) is the most important cause of gynecological cancer-related mortality in Western societies. The majority of patients with ovarian cancer present with advanced disease, and in this group of patients, the median survival time is only 3 years. New treatment approaches are, therefore, required to improve outcome in this disease. Two strategies have emerged with promising results: poly ADP-ribose polymerase enzyme (PARP) inhibitors and targeting angiogenesis. The challenge remains to develop a convenient and accurate method to identify patients likely to benefit from targeted therapy.

Urinary levels of regenerating islet-derived protein III ß and gelsolin differentiate gentamicin from cisplatin-induced acute kidney injury in rats.

A key aspect for the clinical handling of acute kidney injury is an early diagnosis, for which a new generation of urine biomarkers is currently under development including kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin. A further diagnostic refinement is needed where one specific cause among several potentially nephrotoxic insults can be identified during the administration of multidrug therapies. In this study we identified increases in regenerating islet-derived protein III beta (reg IIIb) and gelsolin as potential differential urinary markers of gentamicin's nephrotoxicity. Indeed, urinary levels of both reg IIIb and gelsolin distinguish between the nephrotoxicity caused by gentamicin from that caused by cisplatin where these markers were not increased by the latter. Reg IIIb was found to be overexpressed in the kidneys of gentamicin-treated rats and excreted into the urine, whereas urinary gelsolin originated from the blood by glomerular filtration. Our results illustrate an etiological diagnosis of acute kidney injury through analysis of urine. Thus, our results raise the possibility of identifying the actual nephrotoxin in critically ill patients who are often treated with several nephrotoxic agents at the same time, thereby providing the potential for tailoring therapy to an individual patient, which is the aim of personalized medicine.

Paraneoplastic encephalomyelitis: Is it an oropharyngeal or a lung cancer complication?

This case report describes a patient with a locally advanced oropharyngeal cancer with a simultaneous paraneoplastic encephalomyelitis. To the best of our knowledge, a paraneoplastic neurological syndrome is a rare complication in head and neck cancer, and has previously not been reported in the literature. One year later, following initial treatment, a small cell lung cancer developed, a tumor frequently associated with this type of paraneoplastic syndrome. The dilemma, therefore, is whether this paraneoplastic symdrome was a secondary complication of the tonsilar concurrent cancer or a metachronous paraneoplastic syndrome prior to small cell lung cancer.