Therapeutic advances of targeting receptor tyrosine kinases in cancer.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

Cellular Responses Induced by NCT-503 Treatment on Triple-Negative Breast Cancer Cell Lines: A Proteomics Approach.

Breast cancer (BC) remains one of the leading causes of mortality among women, with triple-negative breast cancer (TNBC) standing out for its aggressive nature and limited treatment options. Metabolic reprogramming, one of cancer's hallmarks, underscores the importance of targeting metabolic vulnerabilities for therapeutic intervention. This study aimed to investigate the impact of de novo serine biosynthetic pathway (SSP) inhibition, specifically targeting phosphoglycerate dehydrogenase (PHGDH) with NCT-503, on three TNBC cell lines: MDA-MB-231, MDA-MB-468 and Hs 578T. First, MS-based proteomics was used to confirm the distinct expression of PHGDH and other SSP enzymes using the intracellular proteome profiles of untreated cells. Furthermore, to characterize the response of the TNBC cell lines to the inhibitor, both in vitro assays and label-free, bottom-up proteomics were employed. NCT-503 exhibited significant cytotoxic effects on all three cell lines, with MDA-MB-468 being the most susceptible (IC50 20.2 ± 2.8 µM), while MDA-MB-231 and Hs 578T showed higher, comparable IC50s. Notably, differentially expressed proteins (DEPs) induced by NCT-503 treatment were mostly cell line-specific, both in terms of the intracellular and secreted proteins. Through overrepresentation and Reactome GSEA analysis, modifications of the intracellular proteins associated with cell cycle pathways were observed in the MDA-MBs following treatment. Distinctive dysregulation of signaling pathways were seen in all TNBC cell lines, while modifications of proteins associated with the extracellular matrix organization characterizing both MDA-MB-231 and Hs 578T cell lines were highlighted through the treatment-induced modifications of the secreted proteins. Lastly, an analysis was conducted on the DEPs that exhibited greater abundance in the NCT-503 treatment groups to evaluate the potential chemo-sensitizing properties of NCT-503 and the druggability of these promising targets.

Developing New Diagnostic Tools Based on SERS Analysis of Filtered Salivary Samples for Oral Cancer Detection.

Cancer still represents one of the biggest challenges in current medical practice. Among different types of cancer, oral cancer has a huge impact on patients due to its great visibility, which is more likely to create social stigma and increased anxiety. New early diagnose methods are still needed to improve treatment efficiency and patients' life quality. Raman/SERS (Surface Enhanced Raman Spectroscopy) spectroscopy has a unique and powerful potential for detecting specific molecules that can become priceless biomarkers in different pathologies, such as oral cancer. In this study, a batch of saliva samples obtained from a group of 17 patients with oro-maxillofacial pathologies compared with saliva samples from 18 healthy donors using the aforementioned methods were evaluated. At the same time, opiorphin, potassium thiocyanate and uric acid were evaluated as potential specific biomarkers for oro-maxillofacial pathologies using multivariate analysis. A careful examination of SERS spectra collected on saliva samples showed that the spectra are dominated by the vibrational bands of opiorphin, potassium thiocyanate and uric acid. Given the fact that all these small molecules are found in very small amounts, we filtrated all the samples to get rid of large molecules and to improve our analysis. By using solid plasmonic substrates, we were able to gain information about molecular concentration and geometry of interaction. On the other hand, the multivariate analysis of the salivary spectra contributed to developing a new detection method for oral cancer.

New inequalities for p(n) and logp(n).

Let p(n) denote the number of partitions of n. A new infinite family of inequalities for p(n) is presented. This generalizes a result by William Chen et al. From this infinite family, another infinite family of inequalities for logp(n) is derived. As an application of the latter family one, for instance obtains that for n≥120, p(n)2>(1+π24n3/2-1n2)p(n-1)p(n+1).

Securing wider EU commitment to the elimination of hepatitis C virus.

In 2016, the Hepatitis B and C Public Policy Association (HepBCPPA), gathered all the main stakeholders in the field of hepatitis C virus (HCV) to launch the now landmark HCV Elimination Manifesto, calling for the elimination of HCV in the EU by 2030. Since then, many European countries have made progress towards HCV elimination. Multiple programmes-from the municipality level to the EU level-were launched, resulting in an overall decrease in viremic HCV infections and liver-related mortality. However, as of 2021, most countries are not on track to reach the 2030 HCV elimination targets set by the WHO. Moreover, the COVID-19 pandemic has resulted in a decrease in HCV diagnoses and fewer direct-acting antiviral treatment initiations in 2020. Diagnostic and therapeutic tools to easily diagnose and treat chronic HCV infection are now well established. Treating all patients with chronic HCV infection is more cost-saving than treating and caring for patients with liver-related complications, decompensated cirrhosis or hepatocellular carcinoma. It is more important than ever to reinforce and scale-up action towards HCV elimination. Yet, efforts urgently need the dedicated commitment of policymakers at all governmental and policy levels. Therefore, the third EU Policy Summit, held in March 2021, featured EU parliamentarians and other key decision makers to promote dialogue and take strides towards securing wider EU commitment to advance and achieve HCV elimination by 2030. We have summarized the key action points and reported the 'Call-to-Action' statement supported by all the major relevant European associations in the field.

Proliferating Lymphatic Endothelial Cells as a Prognostic Marker in Head and Neck Squamous Cell Carcinoma.

Podoplanin and Ki-67 are two important markers of cancer progression. The aim of this study is to evaluate double immunostaining for Ki-67 and podoplanin in head and neck squamous cell carcinoma (HNSCC), and to observe the involvement of lymphagiogenesis in tumoral and peritumoral areas, as well as the density of tumor proliferation correlated with histopathological grading. A total of 50 patients with HNSCC were included in this study. We carried out a morphological evaluation of tissue samples, after that, cases were selected for double Ki-67 and podoplanin immunostaining. Podoplanin expression was significantly correlated with histopathological grade (p < 0.05; p = 0.037) and expression of Ki-67 (p < 0.05; p = 0.050). A high expression of podoplanin, as well as of the proliferation factor Ki-67, was observed in histopathological grade G3 and the correlation between these (p < 0.05; p = 0.028), and implication of LMVD and LVI was not significant (LMVD p = 0.577; LVI p = 0.976). This study demonstrated the importance of double immunolabeling in assessing lymphagiogenesis and tumor proliferation in correlation with histopathological grades in HNSCC.

Quantifying Cytosolic Cytochrome c Concentration Using Carbon Quantum Dots as a Powerful Method for Apoptosis Detection.

BACKGROUND: Cytochrome c (Cyt c) is a key biomarker for early apoptosis, and many methods were designed to detect its release from mitochondria. For a proper evaluation of these programed cell death mechanisms, fluorescent nanoparticles are excellent candidates due to their valuable optical properties. Among all classes of nanoparticles developed thus far, carbon-based quantum dots bring qualitative and efficient imaging strategies for biomedical applications as a consequence of their biocompatibility and low cytotoxicity. METHODS: In this study, we synthesized carbon quantum dots smaller than 5 nm from sodium citrate and polyethylene imine. These nanoparticles were rigorously characterized, and their quenching capacity in apoptotic events was assessed in A549 cells treated with staurosporine and etoposide. For the evaluation of Cyt c release, a phenomenon directly correlated with apoptotic events, we ran a semiquantitative analysis using confocal laser scanning microscopy. RESULTS: Carbon quantum dots were synthesized and were successfully employed for Cyt c detection by means of fluorescence microscopy. Significant drops in fluorescence intensity were observed in the case of cells treated with apoptosis-inducing therapeutic compounds compared to untreated cells, confirming Cyt c release from mitochondria to cytosol. CONCLUSION: Considering these results, we strongly believe this method can contribute to an indirect in vitro evaluation of apoptosis.

Carcinomatous-like mastitis due to axillary lymphadenopathy in a case of nasopharyngeal carcinoma: A case report.

Nasopharyngeal carcinoma (NPC) is a rare form of malignancy, accounting for 2% of all cancers of the head and neck in Europe. Axillary lymph node metastases are very rare in these cases. This is a case report of a 40-year-old premenopausal woman diagnosed in May 2015 with T1N2M0 stage III NPC, treated with induction chemotherapy, followed by chemo-radiotherapy. Post-therapeutic computed tomography (CT) scan showed partial response (PR) on the primary tumor and complete response (CR) on the latero-cervical lymph nodes. In 2017, our patient developed left carcinomatous-like mastitis with axillary lymphadenopathy. This raised suspicions of a carcinomatous mastitis. The pathology report with immunohistochemistry (IHC) of the third biopsy highlighted axillary metastasis of a non-keratinizing squamous cell carcinoma (NSCC). There are very few references in the literature regarding axillary metastases from squamous cell carcinoma of the head and neck (HNSCC). As far as we know, this is the first case report of mastitis due to NPC. To conclude, treatment consisted of two surgical excisions of axillary lymphadenopathy associated with local radiotherapy and chemotherapy (neo-adjuvant, adjuvant). The second surgery, performed after radiotherapy, required plastic surgery. A psychiatric evaluation was necessary, revealing a reactive anxiety disorder. This case required multidisciplinary management, where oncology, plastic surgery, pathology and psychiatric specialists collaborated in deciding the therapeutic approach.

Hsa-miR-125b Therapeutic Role in Colon Cancer Is Dependent on the Mutation Status of the TP53 Gene.

Colon cancer is the third most common cancer type worldwide and is highly dependent on DNA mutations that progressively appear and accumulate in the normal colon epithelium. Mutations in the TP53 gene appear in approximately half of these patients and have significant implications in disease progression and response to therapy. miR-125b-5p is a controversial microRNA with a dual role in cancer that has been reported to target specifically TP53 in colon adenocarcinomas. Our study investigated the differential therapeutic effect of miR-125b-5p replacement in colon cancer based on the TP53 mutation status of colon cancer cell lines. In TP53 mutated models, miR-125b-5p overexpression slows cancer cells' malignant behavior by inhibiting the invasion/migration and colony formation capacity via direct downregulation of mutated TP53. In TP53 wild type cells, the exogenous modulation of miR-125b-5p did not significantly affect the molecular and phenotypic profile. In conclusion, our data show that miR-125b-5p has an anti-cancer effect only in TP53 mutated colon cancer cells, explaining partially the dual behavior of this microRNA in malignant pathologies.

Phytochemical Analysis and In Vitro Effects of Allium fistulosum L. and Allium sativum L. Extracts on Human Normal and Tumor Cell Lines: A Comparative Study.

Allium sativum L. (garlic bulbs) and Allium fistulosum L. (Welsh onion leaves) showed quantitative differences of identified compounds: allicin and alliin (380 µg/mL and 1410 µg/mL in garlic; 20 µg/mL and 145 µg/mL in Welsh onion), and the phenolic compounds (chlorogenic acid, p-coumaric acid, ferulic acid, gentisic acid, 4-hydroxybenzoic acid, kaempferol, isoquercitrin, quercitrin, quercetin, and rutin). The chemical composition determined the inhibitory activity of Allium extracts in a dose-dependent manner, on human normal cells (BJ-IC50 0.8841% garlic/0.2433% Welsh onion and HaCaT-IC50 1.086% garlic/0.6197% Welsh onion) and tumor cells (DLD-1-IC50 5.482%/2.124%; MDA-MB-231-IC50 6.375%/2.464%; MCF-7-IC50 6.131%/3.353%; and SK-MES-1-IC50 4.651%/5.819%). At high concentrations, the cytotoxic activity of each extract, on normal cells, was confirmed by: the 50% of the growth inhibition concentration (IC50) value, the cell death induced by necrosis, and biochemical determination of LDH, catalase, and Caspase-3. The four tumor cell lines treated with high concentrations (10%, 5%, 2.5%, and 1.25%) of garlic extract showed different sensibility, appreciated on the base of IC50 value for the most sensitive cell line (SK-MES-1), and the less sensitive (MDA-MB-231) cell line. The high concentrations of Welsh onion extract (5%, 2.5%, and 1.25%) induced pH changes in the culture medium and SK-MES-1 being the less sensitive cell line.

The Synergistic Antitumor Effect of 5-Fluorouracil Combined with Allicin against Lung and Colorectal Carcinoma Cells.

5-fluorouracil (5-FU) is an anticancer drug used to inhibit the proliferation of many different tumor cells. Since severe events are associated with this compound, its combination with different anticancer drugs or adjuvants would allow the use of a significantly lower dose of 5-FU. In this study, we highlighted that the combination of allicin with 5-FU inhibited the cell migration and proliferation of colorectal and lung cancer cells. 5-FU inhibited cell growth with a similar inhibitory concentration for both normal and tumor cells (~200µM), while allicin showed different inhibitory concentrations. With an IC50 of 8.625 µM, lung cancer cells were the most sensitive to allicin. Compared to 5-FU and allicin single-agent treatments, the co-treatment showed a reduced viability rate, with p < 0.05. The morphological changes were visible on all three cell lines, indicating that the treatment inhibited the proliferation of both normal and tumor cells. We highlighted different cell death mechanisms-apoptosis for lung cancer and a non-apoptotic cell death for colorectal cancer. The synergistic antitumor effect of 5-FU combined with allicin was visible against lung and colorectal carcinoma cells. Better results were obtained when a lower concentration of 5-FU was combined with allicin than the single-agent treatment at IC50.

Securing sustainable funding for viral hepatitis elimination plans.

The majority of people infected with chronic hepatitis C virus (HCV) in the European Union (EU) remain undiagnosed and untreated. During recent years, immigration to EU has further increased HCV prevalence. It has been estimated that, out of the 4.2 million adults affected by HCV infection in the 31 EU/ European Economic Area (EEA) countries, as many as 580 000 are migrants. Additionally, HCV is highly prevalent and under addressed in Eastern Europe. In 2013, the introduction of highly effective treatments for HCV with direct-acting antivirals created an unprecedented opportunity to cure almost all patients, reduce HCV transmission and eliminate the disease. However, in many settings, HCV elimination poses a serious challenge for countries' health spending. On 6 June 2018, the Hepatitis B and C Public Policy Association held the 2nd EU HCV Policy summit. It was emphasized that key stakeholders should work collaboratively since only a few countries in the EU are on track to achieve HCV elimination by 2030. In particular, more effort is needed for universal screening. The micro-elimination approach in specific populations is less complex and less costly than country-wide elimination programmes and is an important first step in many settings. Preliminary data suggest that implementation of the World Health Organization (WHO) Global Health Sector Strategy on Viral Hepatitis can be cost saving. However, innovative financing mechanisms are needed to raise funds upfront for scaling up screening, treatment and harm reduction interventions that can lead to HCV elimination by 2030, the stated goal of the WHO.

Transforming Breast Cancer Together: European elections manifesto 2019 seizing the opportunities for breast cancer patients.

With the European Parliament elections having taken place in May 2019 and a new European Commission (EC) taking office in November 2019, this year is critical for European policymakers, as goals and priorities of the European Union (EU) for the next five years will be discussed and agreed upon. This Manifesto issued by the Transforming Breast Cancer Together initiative calls upon policymakers to improve services for patients in an area still of high unmet need and reduce the societal impact of breast cancer by elevating it as a health policy priority to improve breast cancer prevention, diagnosis and care across Europe.

Hydrogels Based Drug Delivery Synthesis, Characterization and Administration.

Hydrogels represent 3D polymeric networks specially designed for various medical applications. Due to their porous structure, they are able to swollen and to entrap large amounts of therapeutic agents and other molecules. In addition, their biocompatibility and biodegradability properties, together with a controlled release profile, make hydrogels a potential drug delivery system. In vivo studies have demonstrated their effectiveness as curing platforms for various diseases and affections. In addition, the results of the clinical trials are very encouraging and promising for the use of hydrogels as future target therapy strategies.

Obtaining adequate surgical margin status in breast-conservation therapy: intraoperative ultrasound-guided resection versus specimen mammography.

BACKGROUND AND AIM: The purpose of breast-conserving surgery (BCS) for women with cancer is to perform an oncological radical procedure with disease-free margins at the final histological assessment and with the best aesthetic result possible. Intraoperative resected specimen ultrasound and intraoperative resected specimen mammography may reduce the rates of positive margins and reexcision among patients undergoing conserving therapy. Our objective is to compare the two methods with the histopathological results for a preset cut off and asses which parameters can influence the positive margin status. METHOD: A prospective study was performed on 83 patients who underwent breast conservation surgery for early breast cancer (pT1-3a pN0-1 M0) between 2014 and 2016. After excision the specimen was oriented in the operating room by the surgeon. Metallic clips and threads were placed on margins: one clip and the long thread at 12 o'clock, two clips and the short threads at 9 o'clock. The next step was intraoperative ultrasound assessment of the specimen. For the margins under 2 mm we performed selective margin shaving, followed by mammography to identify and document the lesion and finally histopathological examination of the specimen with reporting the gross and microscopic margins. The positive margins required re-excision or boost of radiation at the posterior or anterior margins, depending on the case. RESULTS: We set a cut-off at 2 mm. The sensitivity and specificity of the intraoperative margin assessment via the ultrasound method were 90.91% (95% CI 70.84-98.88%) and 67.21% (95% CI 54-78.69%) respectively. The sensitivity and specificity of the intraoperative margin assessment via the mammographic procedure were 45.45% (95% CI 24.39-67.79%) and 85.25% (95% CI 73.83-93.02%) respectively. There was positive correlation between the histopathological and intraoperative ultrasound exam (p=0.018) and negative correlation between the histopathological exam and the post-operative mammographic exam (p=0.68). We found a positive correlation between the positive margin status and age (<40), preoperative chemotherapy, intraductal carcinoma, inflammatory process around the tumor, and the immunohistochemical triple negative profile. CONCLUSIONS: According to our results, the intraoperative ultrasound of the breast specimen for a cutt-off at 2 mm can decrease the rates of margin positivity compared to the mammographic procedure and has the potential to diminish the number of subsequent undesired re-excisions.

The Andrews-Sellers family of partition congruences.

In 1994, James Sellers conjectured an infinite family of Ramanujan type congruences for 2-colored Frobenius partitions introduced by George E. Andrews. These congruences arise modulo powers of 5. In 2002 Dennis Eichhorn and Sellers were able to settle the conjecture for powers up to 4. In this article, we prove Sellers' conjecture for all powers of 5. In addition, we discuss why the Andrews-Sellers family is significantly different from classical congruences modulo powers of primes.