Deciphering the Molecular Mechanisms behind Drug Resistance in Ovarian Cancer to Unlock Efficient Treatment Options.

Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets.

MISP Is Overexpressed in Intestinal Metaplasia and Gastric Cancer.

Gastric cancer is the fifth most common cancer and the fourth cause of global cancer mortality. The identification of new biomarkers and drug targets is crucial to allow the better prognosis and treatment of patients. The mitotic spindle positioning (MISP) protein has the function of correcting mitotic spindle positioning and centrosome clustering and has been implicated in the cytokinesis and migration of cancer cells. The goal of this work was to evaluate the expression and clinical relevance of MISP in gastric cancer. MISP expression was evaluated by immunohistochemistry in a single hospital series (n = 286) of gastric adenocarcinomas and compared with normal gastric mucosa and intestinal metaplasia, a preneoplastic lesion. MISP was detected on the membrane in 83% of the cases, being overexpressed in gastric cancer compared to normal gastric mucosa (n = 10). Its expression was negatively associated with diffuse and poorly cohesive types. On the other hand, it was strongly expressed in intestinal metaplasia where it was associated with MUC2 and CDX2 expression. Furthermore, when we silenced MISP in vitro, a significant decrease in the viability of gastric carcinoma cells was observed. In conclusion, MISP is overexpressed in gastric cancer, being associated with an intestinal phenotype in gastric carcinogenesis and having a role in cellular proliferation.

Association of pulmonary black carbon accumulation with cardiac fibrosis in residents of Sao Paulo, Brazil.

Evidence suggests that myocardial interstitial fibrosis, resulting from cardiac remodeling, may possibly be influenced by mechanisms activated through the inhalation of airborne pollutants. However, limited studies have explored the relationship between lifetime exposure to carbon-based particles and cardiac fibrosis, specially using post-mortem samples. This study examined whether long-term exposure to air pollution (estimated by black carbon accumulated in the lungs) is associated with myocardial fibrosis in urban dwellers of megacity of Sao Paulo. Data collection included epidemiological and autopsy-based approaches. Information was obtained by interviewing the next of kin and through the pathologist's report. The individual index of exposure to carbon-based particles, which we designed as the fraction of black carbon (FBC), was estimated through quantification of particles on the macroscopic lung surface. Myocardium samples were collected for histopathological analysis to evaluate the fraction of cardiac fibrosis. The association between cardiac fibrosis and FBC, age, sex, smoking status and hypertension was assessed by means of multiple linear regression models. Our study demonstrated that the association of FBC with cardiac fibrosis is influenced by smoking status and hypertension. Among hypertensive individuals, the cardiac fibrosis fraction tended to increase with the increase of the FBC in both groups of smokers and non-smokers. In non-hypertensive individuals, the association between cardiac fibrosis fraction and FBC was observed primarily in smokers. Long-term exposure to tobacco smoke and environmental particles may contribute to the cardiac remodeling response in individuals with pre-existing hypertension. This highlights the importance of considering hypertension as an additional risk factor for the health effects of air pollution on the cardiovascular system. Moreover, the study endorses the role of autopsy to investigate the effects of urban environment and personal habits in determining human disease.

Pharmaceutical Formulations Containing Graphene and 5-Fluorouracil for Light-Emitting Diode-Based Photochemotherapy of Skin Cancer.

Nonmelanoma skin cancer (NMSC) is the most common cancer worldwide, among which 80% is basal cell carcinoma (BCC). Current therapies' low efficacy, side effects, and high recurrence highlight the need for alternative treatments. In this work, a partially reduced nanographene oxide (p-rGOn) developed in our laboratory was used. It has been achieved through a controlled reduction of nanographene oxide via UV-C irradiation that yields small nanometric particles (below 200 nm) that preserve the original water stability while acquiring high light-to-heat conversion efficiency. The latter is explained by a loss of carbon-oxygen single bonds (C-O) and the re-establishment of sp2 carbon bonds. p-rGOn was incorporated into a Carbopol hydrogel together with the anticancer drug 5-fluorouracil (5-FU) to evaluate a possible combined PTT and chemotherapeutic effect. Carbopol/p-rGOn/5-FU hydrogels were considered noncytotoxic toward normal skin cells (HFF-1). However, when A-431 skin cancer cells were exposed to NIR irradiation for 30 min in the presence of Carbopol/p-rGOn/5-FU hydrogels, almost complete eradication was achieved after 72 h, with a 90% reduction in cell number and 80% cell death of the remaining cells after a single treatment. NIR irradiation was performed with a light-emitting diode (LED) system, developed in our laboratory, which allows adjustment of applied light doses to achieve a safe and selective treatment, instead of the standard laser systems that are associated with damages in the healthy tissues in the tumor surroundings. Those are the first graphene-based materials containing pharmaceutical formulations developed for BCC phototherapy.

High-Throughput Drug Screening Revealed That Ciclopirox Olamine Can Engender Gastric Cancer Stem-like Cells.

Cancer stem cells (CSCs) are relevant therapeutic targets for cancer treatment. Still, the molecular circuits behind CSC characteristics are not fully understood. The low number of CSCs can sometimes be an obstacle to carrying out assays that explore their properties. Thus, increasing CSC numbers via small molecule-mediated cellular reprogramming appears to be a valid alternative tool. Using the SORE6-GFP reporter system embedded in gastric non-CSCs (SORE6-), we performed a high-throughput image-based drug screen with 1200 small molecules to identify compounds capable of converting SORE6- to SORE6+ (CSCs). Here, we report that the antifungal agent ciclopirox olamine (CPX), a potential candidate for drug repurposing in cancer treatment, is able to reprogram gastric non-CSCs into cancer stem-like cells via activation of SOX2 expression and increased expression of C-MYC, HIF-1α, KLF4, and HMGA1. This reprogramming depends on the CPX concentration and treatment duration. CPX can also induce cellular senescence and the metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis. We also disclose that the mechanism underlying the cellular reprogramming is similar to that of cobalt chloride (CoCl2), a hypoxia-mimetic agent.

O que dizem os usuário(a)s do Núcleo Ampliado de Saúde da Família sobre sua atuação clínica, pedagógica e sanitária: uma revisão integrativa

Este estudo sistematizou artigos que descreveram a perspectiva de usuário(a)s do Sistema Único de Saúde sobre o trabalho clínico, pedagógico e sanitário desenvolvido pelo Núcleo Ampliado de Saúde da Família e Atenção Básica (NASF-AB). Foi realizada uma revisão integrativa de artigos científicos com recorte temporal de 2009 a 2021. Buscas ocorreram nas bases de dados CAPES, BVS e SciELO. Após aplicação de critérios de inclusão e exclusão, nove artigos foram identificados para a análise temática que resultou em cinco núcleos de sentido: identificação da política do NASF; acesso e ampliação da assistência em saúde; autonomia e qualidade de vida; desafios para a integralidade da atenção; e fragilidades na implementação do Núcleo Ampliado de Saúde da Família. Os estudos recuperados sinalizaram que, apesar de usuário(a)s não reconhecerem nominalmente o Núcleo Ampliado de Saúde da Família, existe ciência das categorias profissionais atuantes neste dispositivo. Há relatos de alcance das mais variadas atividades multiprofissionais, além da identificação do aumento da autonomia e qualidade de vida, e, ainda, o reconhecimento de algumas nuances que são impeditivas para a implementação plena da política e as fragilidades que se interpõem. Dessa forma, o(a)s usuário(a)s percebem os benefícios e os desafios dessa atuação no território onde vivem, devendo ser implicados no processo de fortalecimento e garantia de continuidade da política, principalmente num cenário de desfinanciamento deste dispositivo.

Development of chimeric protein as a multivalent vaccine for human Kinetoplastid infections: Chagas disease and leishmaniasis.

Leishmania spp. and Trypanosoma cruzi are parasitic kinetoplastids of great medical and epidemiological importance since they are responsible for thousands of deaths and disability-adjusted life-years annually, especially in low- and middle-income countries. Despite efforts to minimize their impact, current prevention measures have failed to fully control their spread. There are still no vaccines available. Taking into account the genetic similarity within the Class Kinetoplastida, we selected CD8+ T cell epitopes preserved among Leishmania spp. and T. cruzi to construct a multivalent and broad-spectrum chimeric polyprotein vaccine. In addition to inducing specific IgG production, immunization with the vaccine was able to significantly reduce parasite burden in the colon, liver and skin lesions from T. cruzi, L. infantum and L. mexicana challenged mice, respectively. These findings were supported by histopathological analysis, which revealed decreased inflammation in the colon, a reduced number of degenerated hepatocytes and an increased proliferation of connective tissue in the skin lesions of the corresponding T. cruzi, L. infantum and L. mexicana vaccinated and challenged mice. Collectively, our results support the protective effect of a polyprotein vaccine approach and further studies will elucidate the immune profile associated with this protection. Noteworthy, our results act as conceptual proof that a single multi-kinetoplastida vaccine can be used effectively to control different infectious etiologies, which in turn can have a profound impact on the development of a new generation of vaccines.

Breast Tuberculosis: A Case Report.

Breast tuberculosis (BTB) is a rare manifestation of tuberculosis (TB), and it is more common in countries with a high incidence of TB. We describe a case of a 36-year-old Angolan woman, who had a history of breast reduction surgery, presenting with right breast enlargement, pain, purulent discharge through multiple skin openings, fever, and abdominal pain, progressively worsening in the past year. She had already undergone several surgical drainages and six months of treatment with ciprofloxacin, with no improvement. Breast ultrasound and MRI were performed, which revealed a large fluid collection, with several small abscesses and surrounding adenopathies, complicated by multiple fistulae. The fluid was drained through needle aspiration, which was found to be sterile for bacteria, mycobacteria, and fungi. A lymph node biopsy showed necrosis without granulomas, and the biopsy culture was positive for Mycobacterium tuberculosis (Mt). This case shows how a rare manifestation can simulate bacterial breast abscesses or cancer, and hence a high index of suspicion is necessary to reach the correct diagnosis and ensure appropriate treatment delivery in these patients.

Oleothorax: A Historic Chest Radiograph Finding.

Even though tuberculosis (TB) is an extremely old disease, proper effective treatment for the condition became available only around 1944, with the discovery of streptomycin's effect on Mycobacterium tuberculosis. Until then, surgical approaches had been among some of the treatments employed, which were dropped with the progressive development of antimycobacterial agents. We present a case of an 83-year-old woman, with a history of pulmonary tuberculosis (PT) at the age of 15 years, presenting with a seven-day history of cough, dark sputum, dyspnea, and pleuritic chest pain. She was submitted to a chest radiograph. The exam revealed a large oval calcified mass on the left apex, compatible with oleothorax. Oleothorax should be included in the differential diagnosis of large calcified thoracic masses in older patients.

Development of New Natural Lipid-Based Nanoparticles Loaded with Aluminum-Phthalocyanine for Photodynamic Therapy against Melanoma.

Photodynamic therapy (PDT) mediated by photosensitizers loaded in nanostructures as solid lipid nanoparticles has been pinpointed as an effective and safe treatment against different skin cancers. Amazon butters have an interesting lipid composition when it comes to forming solid lipid nanoparticles (SLN). In the present report, a new third-generation photosensitizing system consisting of aluminum-phthalocyanine associated with Amazon butter-based solid lipid nanoparticles (SLN-AlPc) is described. The SLN was developed using murumuru butter, and a monodisperse population of nanodroplets with a hydrodynamic diameter of approximately 40 nm was obtained. The study of the permeation of these AlPc did not permeate the analyzed skin, but when incorporated into the system, SLN-AlPc allowed permeation of almost 100% with 8 h of contact. It must be emphasized that SLN-AlPc was efficient for carrying aluminum-phthalocyanine photosensitizers and exhibited no toxicity in the dark. Photoactivated SLN-AlPc exhibited a 50% cytotoxicity concentration (IC50) of 19.62 nM when applied to B16-F10 monolayers, and the type of death caused by the treatment was apoptosis. The exposed phospholipid phosphatidylserine was identified, and the treatment triggered a high expression of Caspase 3. A stable Amazon butter-based SLN-AlPc formulation was developed, which exhibits strong in vitro photodynamic activity on melanoma cells.

Comparison of East-Asia and West-Europe cohorts explains disparities in survival outcomes and highlights predictive biomarkers of early gastric cancer aggressiveness.

Surgical resection with lymphadenectomy and perioperative chemotherapy is the universal mainstay for curative treatment of gastric cancer (GC) patients with locoregional disease. However, GC survival remains asymmetric in West- and East-world regions. We hypothesize that this asymmetry derives from differential clinical management. Therefore, we collected chemo-naïve GC patients from Portugal and South Korea to explore specific immunophenotypic profiles related to disease aggressiveness and clinicopathological factors potentially explaining associated overall survival (OS) differences. Clinicopathological and survival data were collected from chemo-naïve surgical cohorts from Portugal (West-Europe cohort [WE-C]; n = 170) and South Korea (East-Asia cohort [EA-C]; n = 367) and correlated with immunohistochemical expression profiles of E-cadherin and CD44v6 obtained from consecutive tissue microarrays sections. Survival analysis revealed a subset of 12.4% of WE-C patients, whose tumors concomitantly express E-cadherin_abnormal and CD44v6_very high, displaying extremely poor OS, even at TNM stages I and II. These WE-C stage-I and -II patients tumors were particularly aggressive compared to all others, invading deeper into the gastric wall (P = .032) and more often permeating the vasculature (P = .018) and nerves (P = .009). A similar immunophenotypic profile was found in 11.9% of EA-C patients, but unrelated to survival. Tumours, from stage-I and -II EA-C patients, that display both biomarkers, also permeated more lymphatic vessels (P = .003), promoting lymph node (LN) metastasis (P = .019), being diagnosed on average 8 years earlier and submitted to more extensive LN dissection than WE-C. Concomitant E-cadherin_abnormal/CD44v6_very-high expression predicts aggressiveness and poor survival of stage-I and -II GC submitted to conservative lymphadenectomy.

Gloeothece sp.-Exploiting a New Source of Antioxidant, Anti-Inflammatory, and Antitumor Agents.

Bioactive lipidic compounds of microalgae, such as polyunsaturated fatty acids (PUFA) and carotenoids, can avoid or treat oxidation-associated conditions and diseases like inflammation or cancer. This study aimed to assess the bioactive potential of lipidic extracts obtained from Gloeothece sp.-using Generally Recognized as Safe (GRAS) solvents like ethanol, acetone, hexane:isopropanol (3:2) (HI) and ethyl lactate. The bioactive potential of extracts was assessed in terms of antioxidant (ABTS•+, DPPH•, •NO and O2•assays), anti-inflammatory (HRBC membrane stabilization and Cox-2 screening assay), and antitumor capacity (death by TUNEL, and anti-proliferative by BrdU incorporation assay in AGS cancer cells); while its composition was characterized in terms of carotenoids and fatty acids, by HPLC-DAD and GC-FID methods, respectively. Results revealed a chemopreventive potential of the HI extract owing to its ability to: (I) scavenge -NO• radical (IC50, 1258 ± 0.353 µg·mL-1); (II) inhibit 50% of COX-2 expression at 130.2 ± 7.4 µg·mL-1; (III) protect 61.6 ± 9.2% of lysosomes from heat damage, and (IV) induce AGS cell death by 4.2-fold and avoid its proliferation up to 40% in a concentration of 23.2 ± 1.9 µg·mL-1. Hence, Gloeothece sp. extracts, namely HI, were revealed to have the potential to be used for nutraceutical purposes.

CD44v6 High Membranous Expression Is a Predictive Marker of Therapy Response in Gastric Cancer Patients.

In gastric cancer (GC), biomarkers that define prognosis and predict treatment response remain scarce. We hypothesized that the extent of CD44v6 membranous tumor expression could predict prognosis and therapy response in GC patients. Two GC surgical cohorts, from Portugal and South Korea (n = 964), were characterized for the extension of CD44v6 membranous immuno-expression, clinicopathological features, patient survival, and therapy response. The value of CD44v6 expression in predicting response to treatment and its impact on prognosis was determined. High CD44v6 expression was associated with invasive features (perineural invasion and depth of invasion) in both cohorts and with worse survival in the Portuguese GC cohort (HR 1.461; 95% confidence interval 1.002-2.131). Patients with high CD44v6 tumor expression benefited from conventional chemotherapy in addition to surgery (p < 0.05), particularly those with heterogeneous CD44v6-positive and -negative populations (CD44v6_3+) (p < 0.007 and p < 0.009). Our study is the first to identify CD44v6 high membranous expression as a potential predictive marker of response to conventional treatment, but it does not clarify CD44v6 prognostic value in GC. Importantly, our data support selection of GC patients with high CD44v6-expressing tumors for conventional chemotherapy in addition to surgery. These findings will allow better stratification of GC patients for treatment, potentially improving their overall survival.

Graphene Oxide Topical Administration: Skin Permeability Studies.

Nanostructured carriers have been widely used in pharmaceutical formulations for dermatological treatment. They offer targeted drug delivery, sustained release, improved biostability, and low toxicity, usually presenting advantages over conventional formulations. Due to its large surface area, small size and photothermal properties, graphene oxide (GO) has the potential to be used for such applications. Nanographene oxide (GOn) presented average sizes of 197.6 ± 11.8 nm, and a surface charge of -39.4 ± 1.8 mV, being stable in water for over 6 months. 55.5% of the mass of GOn dispersion (at a concentration of 1000 µg mL-1) permeated the skin after 6 h of exposure. GOn dispersions have been shown to absorb near-infrared radiation, reaching temperatures up to 45.7 °C, within mild the photothermal therapy temperature range. Furthermore, GOn in amounts superior to those which could permeate the skin were shown not to affect human skin fibroblasts (HFF-1) morphology or viability, after 24 h of incubation. Due to its large size, no skin permeation was observed for graphite particles in aqueous dispersions stabilized with Pluronic P-123 (Gt-P-123). Altogether, for the first time, Gon's potential as a topic administration agent and for delivery of photothermal therapy has been demonstrated.

Methylmalonic Acid Compromises Respiration and Reduces the Expression of Differentiation Markers of SH-SY5Y Human Neuroblastoma Cells.

Methylmalonic acidemia is a rare metabolic disorder caused by the deficient activity of l-methylmalonyl-CoA mutase or its cofactor 5-deoxyadenosylcobalamin and is characterized by accumulation of methylmalonic acid (MMA) and alternative metabolites. The brain is one of the most affected tissues and neurologic symptoms, characterized by seizures, mental retardation, psychomotor abnormalities, and coma, commonly appear in newborns. The molecular mechanisms of neuropathogenesis in methylmalonic acidemia are still poorly understood, specifically regarding the impairments in neuronal development, maturation, and differentiation. In this study, we investigated the effects of MMA in both undifferentiated and differentiated phenotypes of SH-SY5Y human neuroblastoma cells. We observed an increase in glucose consumption and reduction in respiratory parameters of both undifferentiated and differentiated cells after exposition to MMA, suggesting that differentiated cells are slightly more prone to perturbations in respiratory parameters by MMA than undifferentiated cells. Next, we performed qPCR of mature neuronal-specific gene markers and measured mitochondrial functioning to evaluate the role of MMA during differentiation. Our results showed that MMA impairs the respiratory parameters only at the late stage of differentiation and downregulates the transcriptional gene profile of mature neuronal markers neuron-specific enolase (ENO2) and synaptophysin (SYP). Altogether, our findings point out important changes observed during neuronal maturation and energetic stress vulnerability that can play a role in the neurological clinical symptoms at the newborn period and reveal important molecular mechanisms that could help the screening of targets to new approaches in the therapies of this disease.

Inhibition of CXCR2 plays a pivotal role in re-sensitizing ovarian cancer to cisplatin treatment.

cDNA microarray data conducted by our group revealed overexpression of CXCL2 and CXCL8 in ovarian cancer (OC) microenvironment. Herein, we have proven that the chemokine receptor, CXCR2, is a pivotal molecule in re-sensitizing OC to cisplatin, and its inhibition decreases cell proliferation, viability, tumor size in cisplatin-resistant cells, as well as reversed the overexpression of mesenchymal epithelium transition markers. Altogether, our study indicates a central effect of CXCR2 in preventing tumor progression, due to acquisition of cisplatin chemoresistant phenotype by tumor cells, and patients' high lethality rate. We found that the overexpression of CXCR2 by OC cells is persistent and anomalously confined to the cellular nuclei, thus pointing to an urge in developing highly lipophilic molecules that promptly permeate cells, bind to and inhibit nuclear CXCR2 to fight OC, instead of relying on the high-cost genetic engineered cells.

Vasculitis and Breast Cancer: Mind the Hint.

Diffuse alveolar haemorrhage related to an anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis is an extremely rare form of presentation of breast cancer. Here we report the case of a 77-year-old woman with a histological diagnosis of a papillary ductal carcinoma of the breast presenting with a diffuse alveolar haemorrhage secondary to a perinuclear ANCA-associated vasculitis. To our knowledge, this is the first case ever reported of a diffuse alveolar haemorrhage related to an ANCA-associated small vessel vasculitis as a form of presentation of breast cancer. The therapeutic approach of this paraneoplastic vasculitis included the use of corticosteroids and plasmapheresis, a very useful technique to remove endothelial aggressors (circulating antibodies) as a strategy to earn time for a proper therapeutic decision specifically directed for disease modification, but that can also be associated with several severe adverse effects, which are illustrated in our case.

Prognostic significance of MUC2, CDX2 and SOX2 in stage II colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) remains a serious health concern worldwide. Despite advances in diagnosis and treatment, about 15 to 30% of stage II CRC patients subjected to tumor resection with curative intent, develop disease relapse. Moreover, the therapeutic strategy adopted after surgery is not consensual for these patients. This supports the imperative need to find new prognostic and predictive biomarkers for stage II CRC. METHODS: For this purpose, we used a one-hospital series of 227 stage II CRC patient samples to assess the biomarker potential of the immunohistochemical expression of MUC2 mucin and CDX2 and SOX2 transcription factors. The Kaplan-Meier method was used to generate disease-free survival curves that were compared using the log-rank test, in order to determine prognosis of cases with different expression of these proteins, different mismatch repair (MMR) status and administration or not of adjuvant chemotherapy. RESULTS: In this stage II CRC series, none of the studied biomarkers showed prognostic value for patient outcome. However low expression of MUC2, in cases with high expression of CDX2, absence of SOX2 or MMR-proficiency, conferred a significantly worst prognosis. Moreover, cases with low expression of MUC2 showed a significantly clear benefit from treatment with adjuvant chemotherapy. CONCLUSION: In conclusion, we observe that patients with stage II CRC with low expression of MUC2 in the tumor respond better when treated with adjuvant chemotherapy. This observation supports that MUC2 is involved in resistance to fluorouracil-based adjuvant chemotherapy and might be a promising future predictive biomarker in stage II CRC patients.

AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo.

Axonal damage is an early step in traumatic and neurodegenerative disorders of the central nervous system (CNS). Damaged axons are not able to regenerate sufficiently in the adult mammalian CNS, leading to permanent neurological deficits. Recently, we showed that inhibition of the autophagic protein ULK1 promotes neuroprotection in different models of neurodegeneration. Moreover, we demonstrated previously that axonal protection improves regeneration of lesioned axons. However, whether axonal protection mediated by ULK1 inhibition could also improve axonal regeneration is unknown. Here, we used an adeno-associated viral (AAV) vector to express a dominant-negative form of ULK1 (AAV.ULK1.DN) and investigated its effects on axonal regeneration in the CNS. We show that AAV.ULK1.DN fosters axonal regeneration and enhances neurite outgrowth in vitro. In addition, AAV.ULK1.DN increases neuronal survival and enhances axonal regeneration after optic nerve lesion, and promotes long-term axonal protection after spinal cord injury (SCI) in vivo. Interestingly, AAV.ULK1.DN also increases serotonergic and dopaminergic axon sprouting after SCI. Mechanistically, AAV.ULK1.DN leads to increased ERK1 activation and reduced expression of RhoA and ROCK2. Our findings outline ULK1 as a key regulator of axonal degeneration and regeneration, and define ULK1 as a promising target to promote neuroprotection and regeneration in the CNS.

HMGA1 Has Predictive Value in Response to Chemotherapy in Gastric Cancer.

Gastric cancer is a serious health problem worldwide. Although its incidence is decreasing, the five-year survival rate remains low. Thus, it is essential to identify new biomarkers that could promote better diagnosis and treatment of patients with gastric cancer. High-mobility group AT-hook 1 (HMGA1) is a non-histone, chromatin-binding protein that has been found overexpressed in several tumor types. It has been correlated with invasion, metastasis, and drug resistance, leading to worse patient survival. The aim of this work was to evaluate the clinical value of HMGA1 in gastric cancer. HMGA1 expression was analyzed by immunohistochemistry in a single hospital series (n = 323) of gastric adenocarcinoma cases (stages I to IV) with clinicopathological and treatment data. In this series, HMGA1 expression showed no significant relevance as a prognostic biomarker. Nevertheless, a significantly better overall survival was observed in cases with high levels of HMGA1 when they were treated with chemotherapy, compared to the nontreated ones, implying that they can benefit more from treatment than patients with low expression of HMGA1. We thereby show for the first time that HMGA1 expression has a substantial value as a biomarker of response to chemotherapy in gastric cancer.