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Summary: Pancreatic ductal adenocarcinoma (PDAC) shows limited response to chemotherapy, partly due to the absence of effective biomarkers for personalized treatment. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in 90% of PDAC cases, and tumors dependent on KRAS (dKRAS) can be identified using gene expression signature scores. Previous research indicates that dKRAS-PDAC cells are sensitive to decitabine (DEC), an FDA-approved drug for hematological cancers, though its use in solid tumors is limited by side effects. We discovered that low-dose DEC combined with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (OLA) enhances antitumor activity in dKRAS-PDAC. DEC induces DNA damage and activates the ataxia telangiectasia (ATR)/ataxia telangiectasia mutated (ATM)-mediated DNA damage response (DDR), with PARP1-mediated repair playing a key role. Inhibiting PARP with OLA further improves efficacy, even in BRCA1/2-wild-type and homologous recombination (HR)-proficient tumors but not in KRAS-independent tumors. The combination was especially effective in dKRAS-PDAC with a BRCA2 mutation, preventing metastasis growth. Our results support the clinical evaluation of DEC+OLA in PDAC.

This work presents the results of a geomatic survey conducted on the Anatomical Machines within the Sansevero Chapel in Naples, Italy. These anatomical artifacts have the unique characteristics of being upright standing skeletons with nearly intact circulatory systems. Previous research revealed that the intricate vascular systems, once believed to be natural, are instead elaborate reconstructions made using materials such as beeswax and dyes.In response to the lack of metric data of these models, a series of geomatic surveys has been conducted to create the Machines’ 3D models. This study discusses the theoretical and practical challenges associated with surveying these complex and fragile artifacts, emphasising the need for accurate extraction techniques to overcome the limitations imposed by the wooden cases in which they are encased. Two distinct approaches were used: a photogrammetric reconstruction and a laser scanning survey to overcome some logistical difficulties encountered. Despite the challenges, the 3D models' analysis gave satisfactory results.This work addresses the palaeopathological and anatomical questions related to the Anatomical Machines by leveraging non-invasive geomatic methodologies, shedding light on the complexities of surveying historically significant artifacts and aiming at further establishing a valuable foundation for improving these modelling techniques.

Abstract HER-3 (also known as ErbB-3) is a human epidermal growth factor receptor tyrosine kinases family member, and its expression in CRC (colorectal cancer) tissues was previously associated with poor prognosis. In this study, HER-3 expression was analyzed by immunohistochemistry in two cohorts of early and advanced metastatic CRC patients. The first cohort included 180 patients diagnosed with CRC in absence of lymph nodes or distant metastases (Stage I and Stage II), while the second was obtained from 53 advanced metastatic CRC patients who developed synchronous (SM) and metachronous (MM) liver metastases. In the first early-stage CRC cohort, 86 out of 180 (47.8%) tumors showed membranous expression of HER-3, with a mean percentage of positive tumor cells of 25.7%; conversely, in advanced metastatic CRC primary tumors, HER-3 was detected in all specimens, with a mean percentage of positive tumor cells of 76.1%. Kaplan–Meier curves showed that in the advanced metastatic CRC group, patients with HER-3high tumors had a significantly lower Cancer-Specific Survival (CSS) rate compared to patients with HER-3low tumors (p = 0.021). Importantly, this worse CSS rate was observed only in the MM subgroup of patients with HER-3high tumors (p = 0.002). Multivariate analysis confirmed that high HER-3 expression represents a significant and strong risk factor for death in patients developing MM liver metastases (Hazard Ratio = 64.9; 95% Confidence Interval, 4.7–886.6; p = 0.002). In addition, using a specific anti-HER-3 antibody-drug conjugate, named EV20/MMAF, we showed that HER-3 + CRC cells can be efficiently targeted in vitro and in vivo. Overall, this study confirms that surface HER-3 is highly expressed in CRC and reveals that HER-3 expression increases in metastatic CRC patients compared to early stage. Importantly, the results suggest that HER-3 has a prognostic and therapeutic value in patients developing MM liver metastases.

A care challenge that clinicians and other healthcare professionals face very frequently is the complications of bedridden syndrome. Respiratory involvement readily occurs in these patients for whom medical therapy alone is not sufficient. In this clinical case, the authors describe the results of chest physiotherapy in an elderly patient who had developed complete atelectasis of the left lung, attributable to two mechanisms: obstructive, due to mucus plugging, and compressive, due to pleural effusion. The patient was accessed in the authors’ Respiratory Rehabilitation Department, San Raffaele Pisana Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Rome, Italy, with dyspnoea at rest and high O2 requirement (venturi mask fraction of inspired O2: 40%), demonstrated by severe respiratory failure on blood gas analysis (partial pressure of O2/fraction of inspired O2: 155). Physical examination revealed marked reduction of lung sounds, especially on the left side, with diffuse rhonchi. A chest CT scan was performed to demonstrate complete left lung collapse that would have required invasive therapeutic procedures, such as bronchoscopy. However, given the high risk of periprocedural complications and the patient’s refusal, a chest physiotherapy programme was started. The lung was able to re-expand 7 days later, as evidenced by X-ray and improved gas exchange. The manuscript describes the physiotherapeutic techniques used and collects the main scientific evidence on them. The main purpose is to highlight the role of respiratory physiotherapy as an effective, safe, co-adjuvant treatment, and sometimes alternative to invasive manoeuvres in the treatment of frail patients.

In the tumor microenvironment (TME), ROS production affects survival, progression, and therapy resistance in colorectal cancer (CRC). H2O2-mediated oxidative stress can modulate Wnt/β-catenin signaling and metabolic reprogramming of the TME. Currently, it is unclear how mild/moderate oxidative stress (eustress) modulates Wnt/β-catenin/APC and JNK signaling relationships in primary and metastatic CRC cells. In this study, we determined the effects of the H2O2 concentration inducing eustress on isogenic SW480 and SW620 cells, also in combination with JNK inhibition. We assessed cell viability, mitochondrial respiration, glycolysis, and Wnt/β-catenin/APC/JNK gene and protein expression. Primary CRC cells were more sensitive to H2O2 eustress combined with JNK inhibition, showing a reduction in viability compared to metastatic cells. JNK inhibition under eustress reduced both glycolytic and respiratory capacity in SW620 cells, indicating a greater capacity to adapt to TME. In primary CRC cells, H2O2 alone significantly increased APC, LEF1, LRP6, cMYC and IL8 gene expression, whereas in metastatic CRC cells, this effect occurred after JNK inhibition. In metastatic but not in primary tumor cells, eustress and inhibition of JNK reduced APC, β-catenin, and pJNK protein. The results showed differential cross-regulation of Wnt/JNK in primary and metastatic tumor cells under environmental eustress conditions. Further studies would be useful to validate these findings and explore their therapeutic potential.

Acute testicular pain with no arterial flow on Doppler ultrasonography is highly consistent with testicular torsion. In adults, there are rare etiologies of testicular infarction other than torsion, including infection, vasculitis, and trauma. We describe a 41-year-old man with type 2 diabetes complicated by severe vasculopathy and positive SARS-CoV-2 status presenting with acute right testicular pain. Surgical exploration and pathology were concerning for arteriosclerosis and vasculitis. These observations suggest that medically complex patients presenting with acute testicular pain in the setting of COVID-19 infection could be at risk for ischemia; causes of testicular pain beyond torsion should be considered.

Abstract Despite low energy and fuel consumption levels in the rail sector, further improvements are being pursued by manufacturers and operators. Their primary efforts aim to reduce traction energy demand, replace diesel, and limit the impact of electrified overhead infrastructures. From a system‐level perspective, the integration of alternative energy sources on board rail vehicles has become a popular solution among rolling stock manufacturers. Surveys are made of many recent realizations of multimodal rail vehicles with onboard electrochemical batteries, supercapacitors, and hydrogen fuel cell systems. The ratings, technical features, and operating data of onboard sources are gathered for each application, and a comparison among different technologies is presented. Traction system architectures and energy‐control strategies of actual multimodal units are explored and compared with literature research. Moreover, the maturity and potential of recent technologies and alternative topologies of power converters for multimodal traction systems are discussed. Ultimately, onboard storage systems are compared with other solutions for energy‐saving and catenary‐free operation, with particular focus on their current techno‐economic attractiveness as an alternative to diesel propulsion.

Since 2016, it has been possible to record and collect GNSS (Global Navigation Satellite System) raw data on Android devices. This has been a game changer in low-cost device applications. Researchers in the GNSS field have tried to answer new questions regarding Android device positioning performance, the quality of their measurements, positioning techniques that could be applied, and methods to increase the accuracy and the reliability of the PNT (Position Navigation Timing) solution. Several research groups have demonstrated accurate positioning using smartphones while also showing the potential limitations of such devices. In particular, problems related to the GNSS antenna performance have been reported; indeed, in urban scenarios, where users typically operate, the presence of multiple outliers could make the navigation solution inaccurate, if not unfeasible. Hence, techniques useful for verifying the reliability of the navigation solutions have become fundamental. The reliability of the PNT solution provided by smartphones is an open research question. In this study, traditional RAIM (Receiver Autonomous Integrity Monitoring) algorithms were adapted to the case of smartphones. Navigation solution algorithms, including FDE (Fault Detection and Exclusion), were tested using a long data collection made by a smartphone located in a harsh environment in static mode. The performance of the proposed approaches was assessed in terms of horizontal and vertical errors, solution reliability, and residual distribution.

BackgroundThe waiting list for kidney transplantation is long. The creation of "vouchers" for future kidney transplants enables living donation to occur when optimal for the donor and transplantation to occur later, when and if needed by the recipient.MethodsThe donation of a kidney at a time that is optimal for the donor generates a "voucher" that only a specified recipient may redeem later when needed. The voucher provides the recipient with priority in being matched with a living donor from the end of a future transplantation chain. Besides its use in persons of advancing age with a limited window for donation, vouchers remove a disincentive to kidney donation, namely, a reluctance to donate now lest one's family member should need a transplant in the future.ResultsWe describe the first three voucher cases, in which advancing age might otherwise have deprived the donors the opportunity to provide a kidney to a family member. These 3 voucher donations functioned in a nondirected fashion and triggered 25 transplants through kidney paired donation across the United States.ConclusionsThe provision of a voucher to potential recipients whose need for a transplant makes them "chronologically incompatible" with their donors may increase the number of living donor transplants.

The paper deals with a grid-connected single-phase battery charger integrated with photovoltaic generators (PVGs). The circuit topology consists of a multilevel architecture based on a Cascaded H-Bridge (CHB) rectifier. Its main task is to charge the batteries, primarily from the PVGs, by also assuring to keep their state-of-charge (SOC) balanced. Nevertheless, when the battery SOC overcomes a predefined upper limit, beyond which the charging process could be interrupted, the available PV power can no longer be transferred to the batteries. Therefore, to avoid an undesired curtailment of PV power production, this latter can be supplied to the grid by inverting the system operation. The paper shows how to achieve this result by implementing a dedicated control action based on a multi-step procedure. Numerical investigations are carried out on a 19-level CHB converter implemented in the PLECS environment to validate the feasibility and effectiveness of the proposed control technique.

Caves have been used by humans and animals for several thousand years until present but, at these time scales, their structures can rapidly change due to erosion and concretion processes. For this reason, the availability of precise 3D models improves the data quality and quantity allowing the reconstruction of their ancient appearance, structure and origin. However, caves are usually characterised by lack of light, high percentage of relative humidity, narrow spaces and complex morphology. Thus, quite often the traditional topographic instruments cannot be employed. In the La Sassa cave (Sonnino, Italy) a huge deposit ranging from Pleistocene to the Second World War has been found and stratigraphic evidence suggested that the shape of the cave and its entrance might have been different. In this paper, the fusion of the internal and external 3D photogrammetric models of the La Sassa, made to support the archaeological excavations, is presented, A Nikon camera with a fisheye lens and a smartphone camera have been used to survey the internal part of the cave, while an aerial drone has been employed for the external area. The two models have been georeferenced and scaled using GCPs acquired by a double frequency GNSS (GPS and GLONASS) receiver. A low-resolution DTM derived from a previous aerial laser scanning survey and the 3D models have been elaborated in CloudCompare environment to highlight the complete morphology of the cave and its surroundings.

The Posidonia oceanica meadows represent a fundamental biological indicator for the assessment of the marine ecosystem’s state of health. They also play an essential role in the conservation of coastal morphology. The composition, extent, and structure of the meadows are conditioned by the biological characteristics of the plant itself and by the environmental setting, considering the type and nature of the substrate, the geomorphology of the seabed, the hydrodynamics, the depth, the light availability, the sedimentation speed, etc. In this work, we present a methodology for the effective monitoring and mapping of the Posidonia oceanica meadows by means of underwater photogrammetry. To reduce the effect of environmental factors on the underwater images (e.g., the bluish or greenish effects), the workflow is enhanced through the application of two different algorithms. The 3D point cloud obtained using the restored images allowed for a better categorization of a wider area than the one made using the original image elaboration. Therefore, this work aims at presenting a photogrammetric approach for the rapid and reliable characterization of the seabed, with particular reference to the Posidonia coverage.

Punta Licosa promontory is located in the northern part of the Cilento coast, in the southern Tyrrhenian basin. This promontory is bordered by sea cliffs connected to a wide shore platform sloping slightly towards the sea. This area has been considered stable at least since Late Pleistocene, as testified by a series of evidence well known in the literature. The aim of this research is to reconstruct the main coastal changes that have occurred in this area since the middle Holocene by means of the literature data, aerial photo interpretation, satellite images, GPS measurements, direct underwater surveys, GIS elaborations of high-resolution DTMs, bathymetric data and high-resolution orthophotos taken by UAV. Particular attention was paid to the wide platform positioned between −7.2 ± 1.2 m MSL and the present MSL, this being the coastal landform interpreted as the main consequence of sea cliff retreat. The elevation of this landform was compared with the GIA models calculated for the southern Tyrrhenian area, allowing establishing that it was shaped during the last 7.6 ± 1.1 ky BP. Moreover, the interpretation of archaeological and geomorphological markers led to the reconstruction of the shoreline evolution of this coastal sector since 7.6 ky BP. This research evaluates the cliff retreat under the effect of Holocene RSL variation on Cilento promontories, located in the western Mediterranean and characterised by the presence of monophasic platforms, and the applied method can be considered more effective and less complex and expensive if compared to other effective approaches such as those based on the usage of cosmogenic nuclides.

In the tumor microenvironment (TME), ROS production affects survival, progression, and therapy resistance in colorectal cancer (CRC). H2O2-mediated oxidative stress can modulate Wnt/β-catenin signaling and metabolic reprogramming of the TME. Currently, it is unclear how mild/moderate oxidative stress (eustress) modulates Wnt/β-catenin/APC and JNK signaling relationships in primary and metastatic CRC cells. In this study, we determined the effects of the H2O2 concentration inducing eustress on isogenic SW480 and SW620 cells, also in combination with JNK inhibition. We assessed cell viability, mitochondrial respiration, glycolysis, and Wnt/β-catenin/APC/JNK gene and protein expression. Primary CRC cells were more sensitive to H2O2 eustress combined with JNK inhibition, showing a reduction in viability compared to metastatic cells. JNK inhibition under eustress reduced both glycolytic and respiratory capacity in SW620 cells, indicating a greater capacity to adapt to TME. In primary CRC cells, H2O2 alone significantly increased APC, LEF1, LRP6, cMYC and IL8 gene expression, whereas in metastatic CRC cells, this effect occurred after JNK inhibition. In metastatic but not in primary tumor cells, eustress and inhibition of JNK reduced APC, β-catenin, and pJNK protein. The results showed differential cross-regulation of Wnt/JNK in primary and metastatic tumor cells under environmental eustress conditions. Further studies would be useful to validate these findings and explore their therapeutic potential. [ABSTRACT FROM AUTHOR]

Sometimes, the georeferencing of a cave in the global reference system can be challenging. Some difficulties may arise when narrow passages do not allow the use of classical topographic equipment or a terrestrial laser scanner. In these specific cases, the surveyor can employ a visual-based approach to produce both the followed path and the 3D model of the hypogeum. The report we are presenting is the result of a survey in the Guattari cave carried out using images taken by a Huawei P9 mobile phone and a Nikon D800E camera with a 16 mm fisheye lens. Several targets were measured in order to contain the deformation of the models. Three GCPs located just outside the cave have been used to georeference the models. The data have been acquired by a double frequency GNSS receiver in static session mode. The comparison between the two models shows a substantial concordance only in the area outside the cave where the GCPs were measured. In the innermost areas, the two models differ by as much as two meters.

GNSS (Global Navigation Satellite System) receivers are not only able to accurately determine position, but also velocity, knowledge of which could be important in several applications. The most adopted technique for velocity estimation exploits the Doppler shift due to the relative motion between the signal source and the receiver. Alternatively, the TDCP (Time-Differenced Carrier Phase) technique, based on the differences between consecutive carrier-phase measurements, can be used. TDCP is theoretically able to achieve better performance compared with the Doppler-based approach, exploiting the high precision of a carrier-phase observable, and without suffering the ambiguity issue. The main objective of this study is to analyze TDCP performance on a smartphone GNSS chip. Smartphones GNSS receivers are usually characterized by noisy observables owing to the low quality of the antenna used; it is, therefore, interesting to compare the smartphone TDCP performance with that of the Doppler-based technique. To evaluate the benefits that TDCP can provide, especially in terms of the smartphone chip, these two approaches to velocity determination are compared using three different devices: a Novatel geodetic receiver, a u-blox multi-frequency receiver, and a Xiaomi Mi8 smartphone. The results demonstrate a performance degradation in the smartphone GNSS chip when TDCP is used, compared with the performance of higher-grade receivers. In fact, the Xiaomi Mi8 maximum errors are greater than those of the Novatel geodetic receiver, but they are still acceptable as they do not exceed 6 cm/s, making the TDCP technique a valid approach for advanced algorithms; indeed, TDCP velocity demonstrates a few mm/s accuracy with a smartphone. The application of a RAIM algorithm enables error reduction and the achievement of reliable information; the obtained solution reliability is about 89%.

The survey of ancient cave can generally be performed by traditional topographic methods that allow also its georeferencing in a global reference frame; some difficulties may arise when there are narrow tunnels that do not consent the use of a total station or a terrestrial laser scanner. In such cases a visual-based approach can be used to produce, both the followed path and the 3D model of the hypogeal environment. A prompt photogrammetric survey has been used to reconstruct the morphology of the La Sassa Cave, situated in the municipality of Sonnino (Latina), in the lower Lazio region. In this cave, a very large quantity of Pleistocene animal bones was found, together with several fragments of Copper Age human bones and Bronze Age impasto potsherds. The survey was carried out using a DSLR full frame camera Nikon D800E with a Nikkor 16 mm fisheye lens pre-calibrated. During the acquisition, several targets were measured in order to contain the deformations model. The photogrammetric model has been georeferenced using 3 GCPs positioned outside the cave entrance where a double frequency GNSS receiver has acquired data in static session mode.