Human coronaviruses activate and hijack the host transcription factor HSF1 to enhance viral replication.

Organisms respond to proteotoxic-stress by activating the heat-shock response, a cellular defense mechanism regulated by a family of heat-shock factors (HSFs); among six human HSFs, HSF1 acts as a proteostasis guardian regulating severe stress-driven transcriptional responses. Herein we show that human coronaviruses (HCoV), both low-pathogenic seasonal-HCoVs and highly-pathogenic SARS-CoV-2 variants, are potent inducers of HSF1, promoting HSF1 serine-326 phosphorylation and triggering a powerful and distinct HSF1-driven transcriptional-translational response in infected cells. Despite the coronavirus-mediated shut-down of the host translational machinery, selected HSF1-target gene products, including HSP70, HSPA6 and AIRAP, are highly expressed in HCoV-infected cells. Using silencing experiments and a direct HSF1 small-molecule inhibitor we show that, intriguingly, HCoV-mediated activation of the HSF1-pathway, rather than representing a host defense response to infection, is hijacked by the pathogen and is essential for efficient progeny particles production. The results open new scenarios for the search of innovative antiviral strategies against coronavirus infections.

Decoupled High-Mobility Graphene on Cu(111)/Sapphire via Chemical Vapor Deposition.

The growth of high-quality graphene on flat and rigid templates, such as metal thin films on insulating wafers, is regarded as a key enabler for technologies based on 2D materials. In this work, the growth of decoupled graphene is introduced via non-reducing low-pressure chemical vapor deposition (LPCVD) on crystalline Cu(111) films deposited on sapphire. The resulting film is atomically flat, with no detectable cracks or ripples, and lies atop of a thin Cu2O layer, as confirmed by microscopy, diffraction, and spectroscopy analyses. Post-growth treatment of the partially decoupled graphene enables full and uniform oxidation of the interface, greatly simplifying subsequent transfer processes, particularly dry-pick up - a task that proves challenging when dealing with graphene directly synthesized on metallic Cu(111). Electrical transport measurements reveal high carrier mobility at room temperature, exceeding 104 cm2 V-1 s-1 on SiO2/Si and 105 cm2 V-1 s-1 upon encapsulation in hexagonal boron nitride (hBN). The demonstrated growth approach yields exceptional material quality, in line with micro-mechanically exfoliated graphene flakes, and thus paves the way toward large-scale production of pristine graphene suitable for high-performance next-generation applications.

Prognostic value of baseline clinicopathological characteristics in first-line chemotherapy ± immunotherapy for extensive-stage small cell lung cancer: a retrospective cohort study.

Background: The integration of chemotherapy and immunotherapy as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) has been adopted in clinical practice, yet the response to immune checkpoint inhibitors (ICIs) is variable, benefiting only a fraction of patients. The current absence of reliable biomarkers for predicting treatment response and prognosis represents a significant gap in knowledge, hindering the optimization of patient stratification and treatment planning. This retrospective cohort study aims to assess the potential predictive and prognostic significance of clinicopathological baseline features in ES-SCLC patients. Methods: Our study retrospectively analyzed the data of consecutive patients with ES-SCLC treated with first-line etoposide plus platinum chemotherapy ± immunotherapy at The Affiliated Lihuili Hospital of Ningbo University from April 2017 to April 2023. Data on clinical information, serum laboratory indicators, pathological immunohistochemical markers, and progression-free survival (PFS) times were collected. Univariate and multivariate Cox regression analyses were employed to determine whether these indicators could serve as independent prognostic factors for PFS. Further, potential predictive markers for treatment efficacy were identified using a Cox regression model that incorporated an interaction term between treatment modality and the indicator. Results: A total of 121 patients with ES-SCLC were enrolled in the study, of whom 62 received chemotherapy alone, and 59 received chemotherapy in combination with immunotherapy. Compared to chemotherapy alone, the addition of immunotherapy to first-line chemotherapy significantly extended the PFS time [P<0.001; hazard ratio (HR) =0.42; 95% confidence interval (CI): 0.28, 0.64] of the ES-SCLC patients. The multivariate analysis revealed that an immunochemotherapy regimen (P<0.001, HR =0.40; 95% CI: 0.24, 0.68), a low-density lipoprotein (LDL) level of >1.8 mmol/L (P=0.02; HR =0.41; 95% CI: 0.20, 0.85) were independent prognostic factors of favorable PFS in the first-line treatment of all ES-SCLC, while a lactate dehydrogenase (LDH) level of >273 U/L (P=0.04; HR =1.78; 95% CI: 1.03, 3.07), a neuron-specific enolase (NSE) concentration of >102.6 ng/mL (P=0.009; HR =6.49; 95% CI: 1.60, 26.32), an apolipoprotein A1 (ApoA1) concentration of >0.9 g/L (P<0.001; HR =4.15; 95% CI: 1.98, 8.71), and an apolipoprotein B (ApoB) concentration of >0.8 g/L (P=0.002; HR =2.24; 95% CI: 1.34, 3.75) were independent prognostic factors of poorer PFS. Further, the interaction effect analysis demonstrated that an LDL level of >1.8 mmol/L and the absence of bone metastasis were potential predictors of an improved response to ICI therapy compared to chemotherapy alone. Conclusions: This study showed the survival benefit of receiving a chemoimmunotherapy regimen as the first-line treatment in a real-world scenario. It also suggests the prognostic significance of pre-treatment LDL, LDH, NSE, ApoA1, and ApoB with optimal cut-off values in the first-line treatment of all ES-SCLC, and the potential utility of baseline LDL level or the presence of bone metastasis in guiding first-line treatment strategies.

Biliary atresia in a 3-month-old infant (case report).

Biliary atresia (BA) is a congenital disease that occurs when extrahepatic bile ducts are either absent or deficient, resulting in liver fibrosis, portal hypertension, and eventually cirrhosis. It is the most common cause of persistent obstructive jaundice in newborns lasting more than two weeks is this condition. Abdominal ultrasound (US) is the primary imaging technique used to diagnose BA, while computed tomography (CT) is reserved for more complex cases. The gold standard for diagnosing BA is still intraoperative cholangiogram with liver biopsy. Treatment for BA usually involves Kasai hepatoportoenterostomy, but some patients still require liver transplantation due to diagnostic delays and advanced disease. In this study, the authors present the case of a 3-month-old infant with biliary atresia and its ultrasound characteristics, who underwent liver transplantation due to advanced disease. The primary objective of imaging is to provide a prompt diagnosis, given the crucial significance of timely surgical intervention.

The prognostic role of albumin levels in lung cancer patients receiving third-line or advanced immunotherapy: a retrospective study.

Background: Immunotherapy functions by leveraging immunoregulation drugs to bolster the immune system's capacity to identify and eliminate cancerous cells. In contrast to radiotherapy and chemotherapy, immunotherapy exhibits diminished side effects, heightened efficacy, and prolonged survival rates. Nevertheless, meticulous exploration into the determinants governing the advantageous effects of immunotherapy among patients who have previously undergone multiple prior therapies has yet to be conducted. Albumin (ALB) as a nutritional indicator has not been thoroughly studied for its prognostic effect on efficacy or survival. This study aims to identify factors that influence treatment outcomes among patients undergoing third-line or later immunological therapies. Methods: A cohort of 250 lung cancer patients undergoing toripalimab or tislelizumab immunotherapy was the focal point of data collection. The determination of the median value facilitated the establishment of a cut-off point, enabling the categorization of continuous variables. After data collection, a series of statistical analyses of various clinical factors at baseline were performed, including nonparametric tests, logistic regression, and Cox proportional risk modeling. The last follow-up was in May 2022. The primary study endpoint was overall survival (OS). Results: A total of 250 patients were enrolled in the study, of which 129 patients received first- or second-line immunotherapy and 121 patients received third-line or subsequent immunotherapy. According to Cox multifactor regression analysis, in patients receiving either first- or second-line therapy, the ALB level exhibited negligible prognostic relevance (P>0.05). However, in patients subjected to immunotherapy beyond the second line, the ALB level manifested significant prognostic importance (P=0.039). Notably, patients demonstrating elevated ALB levels achieved a higher disease control rate (DCR) (70.0% vs. 52.5%, P=0.05) and displayed a tendency towards a heightened objective response rate (ORR) (20.0% vs. 16.4%, P=0.61) in comparison to those with lower ALB levels. Conclusions: Among patients undergoing immunotherapy in the third line or subsequent treatment phases, elevated ALB levels in baseline correlated with DCR and OS. Thus, the pre-immunotherapy ALB level emerges as an autonomous predictor of OS in patients subjected to third- or later line immunotherapy interventions.

A transparent machine learning algorithm uncovers HbA1c patterns associated with therapeutic inertia in patients with type 2 diabetes and failure of metformin monotherapy.

AIMS: This study aimed to identify and categorize the determinants influencing the intensification of therapy in Type 2 Diabetes (T2D) patients with suboptimal blood glucose control despite metformin monotherapy. METHODS: Employing the Logic Learning Machine (LLM), an advanced artificial intelligence system, we scrutinized electronic health records of 1.5 million patients treated in 271 diabetes clinics affiliated with the Italian Association of Medical Diabetologists from 2005 to 2019. Inclusion criteria comprised patients on metformin monotherapy with two consecutive mean HbA1c levels exceeding 7.0%. The cohort was divided into "inertia-NO" (20,067 patients with prompt intensification) and "inertia-YES" (13,029 patients without timely intensification). RESULTS: The LLM model demonstrated robust discriminatory ability among the two groups (ROC-AUC = 0.81, accuracy = 0.71, precision = 0.80, recall = 0.71, F1 score = 0.75). The main novelty of our results is indeed the identification of two main distinct subtypes of therapeutic inertia. The first exhibited a gradual but steady HbA1c increase, while the second featured a moderate, non-uniform rise with substantial fluctuations. CONCLUSIONS: Our analysis sheds light on the significant impact of HbA1c levels over time on therapeutic inertia in patients with T2D, emphasizing the importance of early intervention in the presence of specific HbA1c patterns.

Anomalous Interlayer Exciton Diffusion in WS2/WSe2 Moiré Heterostructure.

Stacking van der Waals crystals allows for the on-demand creation of a periodic potential landscape to tailor the transport of quasiparticle excitations. We investigate the diffusion of photoexcited electron-hole pairs, or excitons, at the interface of WS2/WSe2 van der Waals heterostructure over a wide range of temperatures. We observe the appearance of distinct interlayer excitons for parallel and antiparallel stacking and track their diffusion through spatially and temporally resolved photoluminescence spectroscopy from 30 to 250 K. While the measured exciton diffusivity decreases with temperature, it surprisingly plateaus below 90 K. Our observations cannot be explained by classical models like hopping in the moiré potential. A combination of ab initio theory and molecular dynamics simulations suggests that low-energy phonons arising from the mismatched lattices of moiré heterostructures, also known as phasons, play a key role in describing and understanding this anomalous behavior of exciton diffusion. Our observations indicate that the moiré potential landscape is dynamic down to very low temperatures and that the phason modes can enable efficient transport of energy in the form of excitons.

Ultrasound features of cutaneous myiasis: a rare case in a child.

Cutaneous myiasis is an infestation of the skin with larvae of some dipteran species. Among humans, Dermatobia hominis is the most frequently encountered dipteran responsible for cutaneous myiasis. This insect is endemic to tropical and subtropical regions, consequently, individuals travelling from non-endemic areas are most susceptible to infection due to a lack of prior exposure. Three clinical variants of myiasis are distinguished: furuncular, migratory, and wound myiasis. Furuncular myiasis represents the most common form among travelers, yet it is a rare cause of pediatric skin manifestations in developed countries. Limited awareness of this condition in non-endemic regions contributes to diagnostic challenges. In this scenario, ultrasound is useful in the diagnostic workup, enabling the identification of the viable larva.

Vaccinome landscape in nearly 620,000 patients with diabetes.

INTRODUCTION: Type 1 (T1D) and type 2 diabetes (T2D) are associated with an elevated incidence of infectious diseases and a higher risk of infections-related hospitalization and death. In this study, we delineated the "vaccinome" landscape obtained with a large immunization schedule offered by the Regional Government of Lombardy in a cohort of 618,396 patients with diabetes (T1D and T2D). METHODS: Between September 2021 and September 2022, immunization coverage for influenza, meningococcus, pneumococcus, and herpes zoster was obtained from the public computerized registry of the healthcare system of Lombardy Region (Italy) in 618,396 patients with diabetes and in 9,534,087 subjects without diabetes. Type of diabetes, age, mortality, and hospitalizations were retrospectively analyzed in vaccinated and unvaccinated patients. RESULTS: Among patients with diabetes (T1D and T2D), 44.6% received the influenza vaccine, 10.9% the pneumococcal vaccine, 2.5% the anti-meningococcus vaccine and 0.7% the anti-zoster vaccine. Patients with diabetes immunized for influenza, zoster and meningococcus showed a 2-fold overall reduction in mortality risk and a decrease in hospitalizations. A 3-fold lower risk of mortality and a decrease in hospitalizations for both cardiac and pulmonary causes were also observed after influenza, zoster, and meningococcus immunization in older patients with diabetes. CONCLUSIONS: Immunization coverage is still far from the recommended targets in patients with diabetes. Despite this, influenza vaccination protected nearly 3,800 per 100,000 patients with diabetes from risk of death. The overall impressive decrease in mortality and hospitalizations observed in vaccinated patients strengthens the need for scaling up the "vaccinome" landscape in patients with diabetes.

Synthesis and Polymorph Manipulation of FeSe2 Monolayers.

Polymorph engineering involves the manipulation of material properties through controlled structural modification and is a candidate technique for creating unique two-dimensional transition metal dichalcogenide (TMDC) nanodevices. Despite its promise, polymorph engineering of magnetic TMDC monolayers has not yet been demonstrated. Here we grow FeSe2 monolayers via molecular beam epitaxy and find that they have great promise for magnetic polymorph engineering. Using scanning tunneling microscopy (STM) and spectroscopy (STS), we find that FeSe2 monolayers predominantly display a 1T' structural polymorph at 5 K. Application of voltage pulses from an STM tip causes a local, reversible transition from the 1T' phase to the 1T phase. Density functional theory calculations suggest that this single-layer structural phase transition is accompanied by a magnetic transition from an antiferromagnetic to a ferromagnetic configuration. These results open new possibilities for creating functional magnetic devices with TMDC monolayers via polymorph engineering.

Effects of KEAP1 Silencing on NRF2 and NOTCH Pathways in SCLC Cell Lines.

The KEAP1/NRF2 pathway is a master regulator of several redox-sensitive genes implicated in the resistance of tumor cells against therapeutic drugs. The dysfunction of the KEAP1/NRF2 system has been correlated with neoplastic patients' outcomes and responses to conventional therapies. In lung tumors, the growth and the progression of cancer cells may also involve the intersection between the molecular NRF2/KEAP1 axis and other pathways, including NOTCH, with implications for antioxidant protection, survival of cancer cells, and drug resistance to therapies. At present, the data concerning the mechanism of aberrant NRF2/NOTCH crosstalk as well as its genetic and epigenetic basis in SCLC are incomplete. To better clarify this point and elucidate the contribution of NRF2/NOTCH crosstalk deregulation in tumorigenesis of SCLC, we investigated genetic and epigenetic dysfunctions of the KEAP1 gene in a subset of SCLC cell lines. Moreover, we assessed its impact on SCLC cells' response to conventional chemotherapies (etoposide, cisplatin, and their combination) and NOTCH inhibitor treatments using DAPT, a γ-secretase inhibitor (GSI). We demonstrated that the KEAP1/NRF2 axis is epigenetically controlled in SCLC cell lines and that silencing of KEAP1 by siRNA induced the upregulation of NRF2 with a consequent increase in SCLC cells' chemoresistance under cisplatin and etoposide treatment. Moreover, KEAP1 modulation also interfered with NOTCH1, HES1, and DLL3 transcription. Our preliminary data provide new insights about the downstream effects of KEAP1 dysfunction on NRF2 and NOTCH deregulation in this type of tumor and corroborate the hypothesis of a cooperation of these two pathways in the tumorigenesis of SCLC.

The StuA Transcription Factor and Alternative Splicing Mechanisms Drive the Levels of MAPK Hog1 Transcripts in the Dermatophyte Trichophyton rubrum.

Trichophyton rubrum is a human fungal pathogen that causes dermatophytosis, an infection that affects keratinized tissues. Integrated molecular signals coordinate mechanisms that control pathogenicity. Transcriptional regulation is a core regulation of relevant fungal processes. Previous RNA sequencing data revealed that the absence of the transcription factor StuA resulted in the differential expression of the MAPK-related high glycerol osmolarity gene (hog1) in T. rubrum. Here we validated the role of StuA in regulating the transcript levels of hog1. We showed through RT-qPCR that transcriptional regulation controls hog1 levels in response to glucose, keratin, and co-culture with human keratinocytes. In addition, we also detected hog1 pre-mRNA transcripts that underwent alternative splicing, presenting intron retention in a StuA-dependent mechanism. Our findings suggest that StuA and alternative splicing simultaneously, but not dependently, coordinate hog1 transcript levels in T. rubrum. As a means of preventing and treating dermatophytosis, our results contribute to the search for new potential drug therapies based on the molecular aspects of signaling pathways in T. rubrum.

Congenital tibial pseudarthrosis: A challenge in pediatric radiology.

Congenital pseudarthrosis of the tibia (CPT) is a rare disorder affecting the skeletal system in pediatric population with an estimated incidence of 1:140,000 to 1:250,000 newborns. It is characterized by deformity of the tibia, including anterolateral bowing of the bone diaphysis and/or narrowing of the medullary canal, leading to instability or fracture. CPT can be either idiopathic or associated with underlying conditions such as type 1 neurofibromatosis (NF1), fibrous dysplasia, or Campanacci's osteofibrous dysplasia. Diagnosis is based on clinical and imaging findings, using conventional radiography and magnetic resonance imaging (MRI). The disorder is characterized by recurrent pathological fractures of the tibia or fibula during childhood, often beginning by the age of 2 years. Treatment options include surgical and nonsurgical management.

A substitutional quantum defect in WS2 discovered by high-throughput computational screening and fabricated by site-selective STM manipulation.

Point defects in two-dimensional materials are of key interest for quantum information science. However, the parameter space of possible defects is immense, making the identification of high-performance quantum defects very challenging. Here, we perform high-throughput (HT) first-principles computational screening to search for promising quantum defects within WS2, which present localized levels in the band gap that can lead to bright optical transitions in the visible or telecom regime. Our computed database spans more than 700 charged defects formed through substitution on the tungsten or sulfur site. We found that sulfur substitutions enable the most promising quantum defects. We computationally identify the neutral cobalt substitution to sulfur (Co S 0 ) and fabricate it with scanning tunneling microscopy (STM). The Co S 0 electronic structure measured by STM agrees with first principles and showcases an attractive quantum defect. Our work shows how HT computational screening and nanoscale synthesis routes can be combined to design promising quantum defects.

Single-port video-assisted thoracoscopic sleeve lobectomy after neoadjuvant immunochemotherapy: a case report.

Background: The morbidity and mortality of lung cancer have always ranked first among malignant tumors (MTs). Previous studies have shown that neoadjuvant chemotherapy can improve the 5-year survival rate of patients with non-small cell lung cancer (NSCLC), but the benefit is limited. Studies have proven that neoadjuvant immunotherapy combined with chemotherapy has unique advantages in prolonging patient survival, reducing distant recurrence, and inducing antitumor immunity. However, its impact remains to be more comprehensively investigated. Case Description: A 59-year-old male who was admitted to the hospital with a primary complaint of repeated cough and expectoration for 6 months. Preoperative assessment showed right upper lung squamous cell carcinoma with multiple hilar and mediastinal lymph node metastasis, and the clinical stage was cT2aN2M0 stage (IIIA). After three cycles of pembrolizumab + carboplatin + paclitaxel therapy were administered, the reexamination of the tumor was evaluated as partial response (PR), and a sleeve lobectomy of the right upper lung was performed under single-port thoracoscopic surgery. The operation proceeded smoothly without conversion to thoracotomy, and R0 resection was successfully achieved. Postoperative pathological stage was ypT1bN0M0 stage IA, and postoperative pathological remission was evaluated as major pathological response (MPR). After the operation, three cycles of immunotherapy combined with chemotherapy were completed, which was followed by maintenance therapy with pembrolizumab monotherapy for 1 year, and no signs of tumor recurrence and metastasis have been found in follow-up thus far. Conclusions: Through this case, we believe that for locally advanced NSCLC sleeve lobectomy after neoadjuvant therapy may be a safe and feasible treatment option, can avoid pneumonectomy, protect the lung function of patients, and still ensure the R0 resection rate. Moreover, it may does not significantly increase the difficulty of surgical operation or reduce safety. However, further research is needed to confirm our conclusion. And then, neoadjuvant therapy in the perioperative period may induce a series of side effects or adverse reactions, and thus greater attention should be paid to its timely management.

PD-1-induced encephalopathy: a report of 2 cases on neurological toxicities with immune checkpoint inhibitors.

Background: Immune-related adverse effects (irAEs) often occur during immune checkpoint inhibitor (ICI) therapy. In the nervous system, the incidence of irAEs ranges from 0.1-12%, with 80% occurring within the first 4 months of ICI application. For complications of the nervous system, adequate diagnosis is made by signs, symptoms, imaging and cerebrospinal fluid. If severe irAEs occur, ICIs should be discontinued and patients should be treated with high-dose glucocorticoids, immunoglobulins, or immunosorbent therapy with systemic support. Patients who develop severe neurologic irAEs have a poorer prognosis. Case Description: In this article, we report 2 cases of encephalopathy induced by anti-programmed cell death protein 1 (PD-1) monoclonal antibodies at the initial diagnoses. Our findings may help clinicians to differentiate between encephalopathy caused by immunotherapy and other neurological disorders. Case 1 was a 24-year-old male patient who had undergone PD-1 immunotherapy to treat olfactory neuroblastoma. After the 6th course of therapy, he began to develop persistent epilepsy, which decreased significantly after high doses of glucocorticoid and immunosorbent therapy were administered. Based on his medical history and laboratory examination results, PD-1-induced encephalopathy was the most likely diagnosis. Case 2 was a 67-year-old female patient who had been treated with PD-1/programmed death ligand-1 therapy for lung adenocarcinoma. She began to have headaches after 1 cycle of treatment, and her cognitive function gradually decreased with the continuation of immunotherapy. Conclusions: These case reports show the difficulty in distinguishing PD-1-induced encephalopathy from other neurological disorders, especially paraneoplastic neurological syndromes. If not treated properly, patients' lives may be endangered. Thus, early identification and early treatment are very important.

An evaluation of root resorption associated with the use of photobiomodulation during orthodontic treatment with clear aligners: a retrospective cohort pilot study.

OBJECTIVES: To evaluate the change in tooth root volume using cone-beam computed tomography (CBCT) in a group of patients treated concurrently with clear aligners and an adjunctive photobiomodulation (PBM) device. MATERIALS AND METHODS: This retrospective cohort pilot study included the records of 32 consecutively treated clear aligner patients (23 female, 9 male) from the private practice of one orthodontist. The PBM group (n = 16) used the device once per day for 5 minutes per arch and was compared with a matched control group (n = 16). A semiautomated segmentation technique was used to obtain tooth volume of anterior teeth from CBCT imaging prior to (T0) and during or immediately following (T1) orthodontic treatment with clear aligners. The change in root volume between time points was assessed. RESULTS: There was no statistically significant difference between the pre- and posttreatment root volumes of maxillary and mandibular anterior teeth, regardless of which intervention group the patient belonged to (P > .05). There was also no difference in the mean percentage change in root volume between clear aligner patients in this study who were treated with the PBM device compared with a matched control group (P > .05). CONCLUSIONS: Clear aligner patients in this study who changed their aligners every 3 to 5 days and used adjunctive photobiomodulation therapy did not experience clinically relevant orthodontically induced external root resorption. Due to the small sample size and measurement error in the root segmentation process, the results should be interpreted with caution.

Molecular Signaling and Metabolic Responses during the Interaction between Human Keratinocytes (HaCaT) and the Dermatophyte Trichophyton rubrum.

Trichophyton rubrum is the leading causative agent of dermatophytosis worldwide. Keratinocytes are the first line of defense that drives an immune response against fungal invasion. Host-specific pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) to trigger immunological pathways. Fungal cell wall components are the primary sources of fungal PAMPs, and some pathogens increase cell wall rearrangement to evade the immune system. Glycolysis and enhanced lactate levels are critical for improving host immune responses to fungal infections. Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), we evaluated the transcriptional responses of human genes involved in fungal recognition and glycolytic metabolism and fungal cell-wall-related genes in a co-culture model of human keratinocytes with T. rubrum. We observed the upregulation of several Toll-like receptors (TLRs), NOD-like receptors (NLRs), and glycolytic genes. Complementarily, we measured intra- and extracellular glucose levels and the increase in lactate production in the co-culture supernatant. We noted a distinct transcriptional regulation pattern of fungal cell-wall-related genes from fungal growth on keratin as the primary carbon source compared to co-culture with human keratinocytes. Our results showed new insights into the transcriptional adaptation of keratinocytes, particularly in regulating genes involved in sensing and metabolic processes, during the interaction with T. rubrum.

Clinical impact of mixed pulmonary carcinoma and carcinoid: the driver from their mono-clonal origin.

The combination of neuroendocrine/non neuroendocrine lung tumors (CNNELT) mentioned in the last edition of the World Health Organization (WHO) of Thoracic Tumors refers to small cell carcinoma (SCLC) or large cell neuroendocrine carcinoma (LCNEC) mixed with any other non-small cell lung carcinoma (NSCLC). Typical Carcinoid (TC)/Atypical Carcinoid (AC) combined with NSCLC is not included among this category. However, case reports of TC/AC combined with NSCLC have been described. We previously reported 2 cases of lung adenocarcinoma (LUA) mixed with carcinoid sharing mutations in both components supporting the hypothesis of a clonal origin. We extended our analysis to other four cases of mixed NSCLC-carcinoid by performing targeted-DNA and RNA-based NGS analysis in both primary and their paired lymph nodes metastasis. In all cases, LUA and AC components shared at least 1 common mutation (KRAS driver mutation p.Gly12Val in cases 1 and 3, AKAP13-RET fusion in case 2, and missense KRAS driver mutation p.Gly12Ala in case 4, reinforcing the hypothesis of a clonal origin. Moreover, the same mutation was detected in the metastasis constituted only by AC (cases 2 and 4). Although it is a rare malignancy in the lung, mixed LUA and TC/AC could be included among the histotypes for which a deep molecular characterization of both components is needed to identify the presence of potential druggable genetic alterations.

Type 2 diabetes mellitus pharmacological remission with dapagliflozin plus oral semaglutide.

Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor and semaglutide, a glucagon-like peptide 1 receptor agonist, have both demonstrated efficacy in glycemic control, reducing blood pressure, body weight, risk of renal and heart failure in type 2 diabetes mellitus. In this observational, real-world, study we aimed to investigate the efficacy of the combination therapy with those two agents over glycemic control. We thus obtained the data of 1335 patients with type 2 diabetes followed by 11 Diabetes centers in Lombardia, Italy. A group of 443 patients was treated with dapagliflozin alone, the other group of 892 patients was treated with the combination therapy of dapagliflozin plus oral semaglutide. We analyzed changes in glycated hemoglobin from baseline to 6 months of follow-up, as well as changes in fasting glycemia, body weight, body mass index, systolic and diastolic pressure, heart rate, creatinine, estimated glomerular filtration rate and albuminuria. Both groups of patients showed an improvement of glycometabolic control after 6 months of treatment; indeed, the treatment with dapagliflozin plus oral semaglutide showed a reduction of glycated hemoglobin of 1.2% as compared to the 0.5% reduction observed in the dapagliflozin alone group. Significant changes were observed in body mass index, fasting plasmatic glucose, blood pressure, total cholesterol, LDL and albumin to creatinine ratio, with a high rate (55%) of near-normalization of glycated hemoglobin. Our real world data confirmed the potential of the oral combination therapy dapagliflozin with semaglutide in inducing pharmacological remission of type 2 diabetes mellitus.