A novel proneural function of Asense is integrated with the sequential actions of Delta-Notch, L'sc and Su(H) to promote the neuroepithelial to neuroblast transition.

In order for neural progenitors (NPs) to generate distinct populations of neurons at the right time and place during CNS development, they must switch from undergoing purely proliferative, self-renewing divisions to neurogenic, asymmetric divisions in a tightly regulated manner. In the developing Drosophila optic lobe, neuroepithelial (NE) cells of the outer proliferation center (OPC) are progressively transformed into neurogenic NPs called neuroblasts (NBs) in a medial to lateral proneural wave. The cells undergoing this transition express Lethal of Scute (L'sc), a proneural transcription factor (TF) of the Acheate Scute Complex (AS-C). Here we show that there is also a peak of expression of Asense (Ase), another AS-C TF, in the cells neighboring those with transient L'sc expression. These peak of Ase cells help to identify a new transitional stage as they have lost NE markers and L'sc, they receive a strong Notch signal and barely exhibit NB markers. This expression of Ase is necessary and sufficient to promote the NE to NB transition in a more robust and rapid manner than that of l'sc gain of function or Notch loss of function. Thus, to our knowledge, these data provide the first direct evidence of a proneural role for Ase in CNS neurogenesis. Strikingly, we found that strong Delta-Notch signaling at the lateral border of the NE triggers l'sc expression, which in turn induces ase expression in the adjacent cells through the activation of Delta-Notch signaling. These results reveal two novel non-conventional actions of Notch signaling in driving the expression of proneural factors, in contrast to the repression that Notch signaling exerts on them during classical lateral inhibition. Finally, Suppressor of Hairless (Su(H)), which seems to be upregulated late in the transitioning cells and in NBs, represses l'sc and ase, ensuring their expression is transient. Thus, our data identify a key proneural role of Ase that is integrated with the sequential activities of Delta-Notch signaling, L'sc, and Su(H), driving the progressive transformation of NE cells into NBs.

A function of spalt major as a sequence-specific DNA binding transcription factor mediates repression of knirps in the Drosophila wing imaginal disc.

The Spalt transcriptional regulators participate in a variety of cell fate decisions during multicellular development. Vertebrate Spalt proteins have been mostly associated to the organization of heterochromatic regions, but they also contribute regulatory functions through binding to A/T rich motives present in their target genes. The developmental processes in which the Drosophila spalt genes participate are well known through genetic analysis, but the mechanism by which the Spalt proteins regulate transcription are still unknown. Furthermore, despite the prominent changes in gene expression associated to mutations in the spalt genes, the specific DNA sequences they bind are unknow. Here, we analyze a DNA fragment present in the regulatory region of the knirps gene. Spalt proteins are candidate repressors of knirps expression during the formation of the venation pattern in the wing disc, and we identified a minimal conserved 30bp sequence that binds to Spalt major both in vivo and in vitro. This sequence mediates transcriptional repression in the central region of the wing blade, constituting the first confirmed case of a direct regulatory interaction between Spalt major and its target DNA in Drosophila. Interestingly, we also find similar sequences in a set of eight novel candidate Spalt target genes, pointing to a common mechanism of transcriptional repression mediated by Spalt proteins.

Assessing mucosal recovery in celiac disease - Time to diagnosis and histological severity as determining factors.

BACKGROUND AND OBJECTIVES: there is a huge disparity in mucosal recovery among celiac patients on a gluten-free diet. We report a study to identify associated factors. METHODS: celiac cases were collected that had positive celiac serology and villous atrophy at diagnosis, and had undergone a control biopsy after at least 12 months of follow-up. RESULTS: seventy celiac patients were included and had experienced symptoms for 9.05 ± 9.48 years before being diagnosed. After follow-up for 2.93 ± 1.94 years, 34.3 % had complete mucosal recovery and 57.1 % had partial mucosal recovery. In the comparative analysis, there was no relationship between mucosal recovery and sex, age, clinical manifestations or follow-up time from diagnosis to the second biopsy. Time with clinical manifestations before diagnosis was associated with a worse outcome: 2.64 years in patients with full recovery, 4.61 years in patients with partial recovery, and 14.26 years in patients with persistent villous atrophy. Higher transglutaminase antibody titers both at diagnosis and during follow-up were associated with poorer histologic outcomes. We observed higher mucosal recovery rates in patients with mild atrophy versus severe atrophy at diagnosis. CONCLUSIONS: in spite of a gluten-free diet, a significant proportion of patients have persistent histologic changes. Time with clinical manifestations before diagnosis is key for histological severity and recovery.

SARS-CoV-2 Virus in Cancer Patients: A New Unknown in an Unsolved Equation.

INTRODUCTION: Cancer patients are more susceptible to infections, and infection can be more severe than in patients without cancer diagnosis. We conducted this retrospective study in patients admitted for SARS-CoV-2 infection in order to find differences in inflammatory markers and mortality in cancer patients compared to others. METHODS: We reviewed the electronic records of patients admitted for SARS-CoV-2 infection confirmed by PCR from March to September 2020. Data on socio-demographics, comorbidities, inflammatory makers, and cancer-related features were analyzed. RESULTS: 2,772 patients were admitted for SARS-CoV-2, to the Hospital Universitario Ramón y Cajal in Madrid during this period. Of these, 2,527 (91%) had no history of neoplastic disease, 164 (5.9%) patients had a prior history of cancer but were not undergoing oncological treatment at the time of infection, and 81 (2.9%) were in active treatment. Mortality in patients without a history of cancer was 19.5%, 28.6% for patients with a prior history of cancer, and 34% in patients with active cancer treatment. Patients in active oncology treatment with the highest mortality rate were those diagnosed with lung cancer (OR 5.6 95% CI: 2.2-14.1). In the multivariate study, active oncological treatment (OR 2.259 95% CI: 1.35-3.77) and chemotherapy treatment (OR 3.624 95% CI: 1.17-11.17), were statistically significant factors for the risk of death for the whole group and for the group with active oncological treatment, respectively. CONCLUSION: Cancer patients on active systemic treatment have an increased risk of mortality after SARS-CoV-2 infection, especially with lung cancer or chemotherapy treatment.

Quantitative collagen analysis using second harmonic generation images for the detection of basal cell carcinoma with ex vivo multiphoton microscopy.

Basal cell carcinoma (BCC) is the most common skin cancer, and its incidence is rising. Millions of benign biopsies are performed annually for BCC diagnosis, increasing morbidity, and healthcare costs. Non-invasive in vivo technologies such as multiphoton microscopy (MPM) can aid in diagnosing BCC, reducing the need for biopsies. Furthermore, the second harmonic generation (SHG) signal generated from MPM can classify and prognosticate cancers based on extracellular matrix changes, especially collagen type I. We explored the potential of MPM to differentiate collagen changes associated with different BCC subtypes compared to normal skin structures and benign lesions. Quantitative analysis such as frequency band energy analysis in Fourier domain, CurveAlign and CT-FIRE fibre analysis was performed on SHG images from 52 BCC and 12 benign lesions samples. Our results showed that collagen distribution is more aligned surrounding BCCs nests compared to the skin's normal structures (p < 0.001) and benign lesions (p < 0.001). Also, collagen was orientated more parallelly surrounding indolent BCC subtypes (superficial and nodular) versus those with more aggressive behaviour (infiltrative BCC) (p = 0.021). In conclusion, SHG signal from type I collagen can aid not only in the diagnosis of BCC but could be useful for prognosticating these tumors. Our initial results are limited to a small number of samples, requiring large-scale studies to validate them. These findings represent the groundwork for future in vivo MPM for diagnosis and prognosis of BCC.

Systemic sclerosis mortality trends in Spain from 1980 to 2019: age-period-cohort and joinpoint analysis.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune chronic rheumatic disease with a high mortality rate, which continues to be a challenge for clinicians today. AIM: To assess changes in mortality trends in the Spanish SSc population between 1980 and 2019, taking into account the independent effects of sex, age, time period and birth cohort. METHODS: SSc death records and mid-year population data were collected from the National Statistics Institute. Age-standardized mortality rates were calculated for the overall population and for each sex (male, female) and age group (5-year groups). Significant changes in mortality trends were identified by joinpoint regressions. An age-period-cohort (APC) analysis and potential years of life lost (PYLL) analysis were performed to identify the burden of SSc. RESULTS: Age-standardized mortality rates due to SSc increased from 1.87 (95% CI 1.00-3.02) per 1 000 000 inhabitants between 1980 and 1984, to 2.47 (95% CI 1.74-3.02) per 1 000 000 inhabitants between 2015 and 2019. The relative risk of mortality fell in all groups in cohorts born after 1990. The PYLL rates showed a gradual rise for both sexes. CONCLUSION: There was an increase in overall SSc mortality in Spain during the 39 years evaluated, although there was a progressive drop for men.

Cutaneous malignant melanoma mortality in Andalusia from 1979 to 2018. Toward new perspectives?

Malignant melanoma accounts for 80% of deaths due to skin cancer. Its incidence is globally increasing. However, melanoma mortality seems to be decreasing. The aim of this study was to analyze mortality rates due to melanoma in Andalusia between 1979 and 2018. Deaths due to melanoma and mid-year population in Andalusia were collected from the National Institute of Statistics. Age-adjusted mortality rates were calculated for overall population and for each sex and age group. Regression models were used to calculate significant points of change. Sex ratio and the independent effects of age, period, and cohort were also analyzed. Age-adjusted mortality due to melanoma rose from 0.61 to 1.94 deaths per 100.000 from 1979 to 2018 for the overall population. A significant change of trends was detected around 1994 when, after a steady rise from 1979, mortality rates stabilized up to the end of the period studied. The cited increase was more pronounced in >64 year males. From the end of the 2000s, there was a decrease in mortality rates to date in all population groups, producing a period effect. A stabilization in melanoma mortality rates was observed in Andalusia from 1994 with a decrease in some groups at the beginning of the 21st century. Trends observed in Andalusia do not differ substantially from those in Spain. The development of new therapies and an earlier diagnosis may have an influence in those changes. Studies that compare differences between Spanish regions are needed to define better prevention strategies.

Quantum JIDOKA. Integration of Quantum Simulation on a CNC Machine for In-Process Control Visualization.

With the advent of the Industry 4.0 paradigm, the possibilities of controlling manufacturing processes through the information provided by a network of sensors connected to work centers have expanded. Real-time monitoring of each parameter makes it possible to determine whether the values yielded by the corresponding sensor are in their normal operating range. In the interplay of the multitude of parameters, deterministic analysis quickly becomes intractable and one enters the realm of "uncertain knowledge". Bayesian decision networks are a recognized tool to control the effects of conditional probabilities in such systems. However, determining whether a manufacturing process is out of range requires significant computation time for a decision network, thus delaying the triggering of a malfunction alarm. From its origins, JIDOKA was conceived as a means to provide mechanisms to facilitate real-time identification of malfunctions in any step of the process, so that the production line could be stopped, the cause of the disruption identified for resolution, and ultimately the number of defective parts minimized. Our hypothesis is that we can model the internal sensor network of a computer numerical control (CNC) machine with quantum simulations that show better performance than classical models based on decision networks. We show a successful test of our hypothesis by implementing a quantum digital twin that allows for the integration of quantum computing and Industry 4.0. This quantum digital twin simulates the intricate sensor network within a machine and permits, due to its high computational performance, to apply JIDOKA in real time within manufacturing processes.

Patterning of the Drosophila L2 vein is driven by regulatory interactions between region-specific transcription factors expressed in response to Dpp signalling.

Pattern formation relies on the generation of transcriptional landscapes regulated by signalling pathways. A paradigm of epithelial patterning is the distribution of vein territories in the Drosophila wing disc. In this tissue, Decapentaplegic signalling regulates its target genes at different distances from the source of the ligand. The transformation of signalling into coherent territories of gene expression requires regulatory cross-interactions between these target genes. Here, we analyse the mechanisms generating the domain of knirps expression in the presumptive L2 vein of the wing imaginal disc. We find that knirps is regulated by four Decapentaplegic target genes encoding the transcription factors aristaless, spalt major, spalt-related and optix The expression of optix is activated by Dpp and repressed by the Spalt proteins, becoming restricted to the most anterior region of the wing blade. In turn, the expression of knirps is activated by Aristaless and repressed by Optix and the Spalt proteins. In this manner, the expression of knirps becomes restricted to those cells where Spalt levels are sufficient to repress optix, but not sufficient to repress knirps.

An atypical bronchogenic cyst with yeast over-infection.

Bronchogenic cysts (BC) are rare congenital anomalies that result from abnormal budding of the tracheobronchial tree during fetal development. BC are usually located in the lung and the mediastinum, an abdominal location is unusual.

Signet ring cell carcinoma in a juvenile polyp.

Juvenile polyps are hamartomatous lesions, usually unique, which appear at an early age. They are usually located in the rectosigmoid junction and are not thought to imply a higher risk of colorectal cancer. Here we report a case of signet ring cell (SRC) carcinoma in this type of lesion.

The Spalt Transcription Factors Generate the Transcriptional Landscape of the Drosophila melanogaster Wing Pouch Central Region.

The Drosophila genes spalt major (salm) and spalt-related (salr) encode Zn-finger transcription factors regulated by the Decapentaplegic (Dpp) signalling pathway in the wing imaginal disc. The function of these genes is required for cell survival and proliferation in the central region of the wing disc, and also for vein patterning in the lateral regions. The identification of direct Salm and Salr target genes, and the analysis of their functions, are critical steps towards understanding the genetic control of growth and patterning of the Drosophila wing imaginal disc by the Dpp pathway. To identify candidate Salm/Salr target genes, we have compared the expression profile of salm/salr knockdown wing discs with control discs in microarray experiments. We studied by in situ hybridization the expression pattern of the genes whose mRNA levels varied significantly, and uncovered a complex transcription landscape regulated by the Spalt proteins in the wing disc. Interestingly, candidate Salm/Salr targets include genes which expression is turned off and genes which expression is positively regulated by Salm/Salr. Furthermore, loss-of-function phenotypic analysis of these genes indicates, for a fraction of them, a requirement for wing growth and patterning. The identification and analysis of candidate Salm/Salr target genes opens a new avenue to reconstruct the genetic structure of the wing, linking the activity of the Dpp pathway to the development of this epithelial tissue.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) in Mallorca: a comparison between late- and early-onset disease.

The age of onset (AO) of hereditary ATTR amyloidosis (hATTR) is known to vary between populations, with differing characteristics reported according to AO in endemic/non-endemic foci. This was a retrospective study of patients with early AO (<50 years) and late AO (≥50 years) hATTR at our center in Mallorca. Data were collected on patient demographics, clinical disease manifestation, and physical symptoms. A total of 95 patients were analyzed, with mean follow-up of 9 years from diagnosis. The early AO group included 53 patients (33 male) and the late AO group included 42 patients (21 male). Neurologic involvement was the most common initial symptom, although it was significantly more frequent in the late AO vs. early AO group (p = 0.015). Autonomic involvement was observed in 26% of patients in the early AO group, but was rarely observed in the late AO group (5%). During follow up, cardiologic symptoms, renal involvement, and ophthalmologic symptoms were significantly more common in the late AO group (p < 0.05). This retrospective study demonstrates the variation in disease presentation and progression according to AO of hATTR at our Mallorcan center.

Role of the Drosophila non-visual ß-arrestin kurtz in hedgehog signalling.

The non-visual ß-arrestins are cytosolic proteins highly conserved across species that participate in a variety of signalling events, including plasma membrane receptor degradation, recycling, and signalling, and that can also act as scaffolding for kinases such as MAPK and Akt/PI3K. In Drosophila melanogaster, there is only a single non-visual ß-arrestin, encoded by kurtz, whose function is essential for neuronal activity. We have addressed the participation of Kurtz in signalling during the development of the imaginal discs, epithelial tissues requiring the activity of the Hedgehog, Wingless, EGFR, Notch, Insulin, and TGFß pathways. Surprisingly, we found that the complete elimination of kurtz by genetic techniques has no major consequences in imaginal cells. In contrast, the over-expression of Kurtz in the wing disc causes a phenotype identical to the loss of Hedgehog signalling and prevents the expression of Hedgehog targets in the corresponding wing discs. The mechanism by which Kurtz antagonises Hedgehog signalling is to promote Smoothened internalization and degradation in a clathrin- and proteosomal-dependent manner. Intriguingly, the effects of Kurtz on Smoothened are independent of Gprk2 activity and of the activation state of the receptor. Our results suggest fundamental differences in the molecular mechanisms regulating receptor turnover and signalling in vertebrates and invertebrates, and they could provide important insights into divergent evolution of Hedgehog signalling in these organisms.

Multi-vendor robustness analysis of a commercial artificial intelligence system for breast cancer detection.

Purpose: Population-based screening programs for the early detection of breast cancer have significantly reduced mortality in women, but they are resource intensive in terms of time, cost, and workload and still have limitations mainly due to the use of 2D imaging techniques, which may cause overlapping of tissues, and interobserver variability. Artificial intelligence (AI) systems may be a valuable tool to assist radiologist when reading and classifying mammograms based on the malignancy of the detected lesions. However, there are several factors that can influence the outcome of a mammogram and thus also the detection capability of an AI system. The aim of our work is to analyze the robustness of the diagnostic ability of an AI system designed for breast cancer detection. Approach: Mammograms from a population-based screening program were scored with the AI system. The sensitivity and specificity by means of the area under the receiver operating characteristic (ROC) curve were obtained as a function of the mammography unit manufacturer, demographic characteristics, and several factors that may affect the image quality (age, breast thickness and density, compression applied, beam quality, and delivered dose). Results: The area under the curve (AUC) from the scoring ROC curve was 0.92 (95% confidence interval = 0.89 - 0.95). It showed no dependence with any of the parameters considered, as the differences in the AUC for different interval values were not statistically significant. Conclusion: The results suggest that the AI system analyzed in our work has a robust diagnostic capability, and that its accuracy is independent of the studied parameters.

Recurrent Glioblastoma: A Review of the Treatment Options.

Glioblastoma is a disease with a poor prognosis. Multiple efforts have been made to improve the long-term outcome, but the 5-year survival rate is still 5-10%. Recurrence of the disease is the usual way of progression. In this situation, there is no standard treatment. Different treatment options can be considered. Among them would be reoperation or reirradiation. There are different studies that have assessed the impact on survival and the selection of patients who may benefit most from these strategies. Chemotherapy treatments have also been considered in several studies, mainly with alkylating agents, with data mostly from phase II studies. On the other hand, multiple studies have been carried out with target-directed treatments. Bevacizumab, a monoclonal antibody with anti-angiogenic activity, has demonstrated activity in several studies, and the FDA has approved it for this indication. Several other TKI drugs have been evaluated in this setting, but no clear benefit has been demonstrated. Immunotherapy treatments have been shown to be effective in other types of tumors, and several studies have evaluated their efficacy in this disease, both immune checkpoint inhibitors, oncolytic viruses, and vaccines. This paper reviews data from different studies that have evaluated the efficacy of different forms of relapsed glioblastoma.

Skin cancer mortality in Spain: adjusted mortality rates by province and related risk factors.

BACKGROUND: Ultraviolet radiation is the main environmental risk factor responsible for the development of skin cancer. Other occupational, socioeconomic, and environmental factors appear to be related to the risk of skin cancer. Furthermore, the factors appear to differ for melanoma and non-melanoma skin cancer (NMSC). The purpose of this study is to analyze mortality rates of skin cancer in the different provinces of Spain and to determine the influence of socioeconomic conditions and other environmental and demographic factors in rates. METHODS: Deaths from melanoma and NMSC in the period 2000-2019 were obtained as well as socioeconomic and environmental variables. Annual standardized mortality rates (SMR) were calculated for all Spanish provinces. The Pearson correlation coefficient was calculated. RESULTS: The SMR of melanoma was 2.10/100,000 inhabitants, while that of NMSC was 1.28/100,000. At the provincial level, a great variability is confirmed. Gross domestic product showed a positive correlation with melanoma mortality but a negative correlation with NMSC. Other environmental and socioeconomic variables also showed correlation, as a positive correlation between tobacco sales and melanoma and between agricultural development and the NMSC. CONCLUSIONS: There are still important differences between each province that must be taken into account when planning health care and resource distribution. This ecological and province-wise study helps to elucidate the relationship between social and ambient exposure determinants and skin cancer mortality in Spain.

Predictive value of 99mTc-MAA-based dosimetry in personalized 90Y-SIRT planning for liver malignancies.

BACKGROUND: Selective internal radiation therapy with 90Y radioembolization aims to selectively irradiate liver tumours by administering radioactive microspheres under the theragnostic assumption that the pre-therapy injection of 99mTc labelled macroaggregated albumin (99mTc-MAA) provides an estimation of the 90Y microspheres biodistribution, which is not always the case. Due to the growing interest in theragnostic dosimetry for personalized radionuclide therapy, a robust relationship between the delivered and pre-treatment radiation absorbed doses is required. In this work, we aim to investigate the predictive value of absorbed dose metrics calculated from 99mTc-MAA (simulation) compared to those obtained from 90Y post-therapy SPECT/CT. RESULTS: A total of 79 patients were analysed. Pre- and post-therapy 3D-voxel dosimetry was calculated on 99mTc-MAA and 90Y SPECT/CT, respectively, based on Local Deposition Method. Mean absorbed dose, tumour-to-normal ratio, and absorbed dose distribution in terms of dose-volume histogram (DVH) metrics were obtained and compared for each volume of interest (VOI). Mann-Whitney U-test and Pearson's correlation coefficient were used to assess the correlation between both methods. The effect of the tumoral liver volume on the absorbed dose metrics was also investigated. Strong correlation was found between simulation and therapy mean absorbed doses for all VOIs, although simulation tended to overestimate tumour absorbed doses by 26%. DVH metrics showed good correlation too, but significant differences were found for several metrics, mostly on non-tumoral liver. It was observed that the tumoral liver volume does not significantly affect the differences between simulation and therapy absorbed dose metrics. CONCLUSION: This study supports the strong correlation between absorbed dose metrics from simulation and therapy dosimetry based on 90Y SPECT/CT, highlighting the predictive ability of 99mTc-MAA, not only in terms of mean absorbed dose but also of the dose distribution.