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Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide and glycan motif and achieve cell-type selectivity via antigen-driven cell-surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in mouse models of breast cancer progression. This work establishes a blueprint for the development of biologics that degrade specific protein glycoforms on target cells.

PURPOSE: Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL. PATIENTS AND METHODS: Final results of the phase I study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion [Days 1, 3, 5 (Cycle 1); weekly infusions starting Day 8, Cycle 1] was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. RESULTS: Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in 1 patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n = 17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders. CONCLUSIONS: Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.

Summary: Background: The advent of disease-modifying treatments (DMT) has changed natural history in 5q Spinal muscular atrophy (SMA). The aim of this study was to report survival and functional aspects in all the Italian type I children born since 2016. Methods: The study included all symptomatic children with type I SMA born since January 1st, 2016, when DMTs became available in Italy. All the Italian SMA referral centers provided data on survival and motor, respiratory, and nutritional status. To compare survival rate pre and post DMTs approval, we also included similar data from SMA I patients born between January 1st, 2010, and December 31st, 2015. A two-proportion z-test was conducted to compare the two cohorts. The significance level was set at p 16 h/day ventilation or tracheostomy with continuous invasive ventilation. 130 of the 199 survivors (65%) achieved independent sitting, and 175 (87.9%) did not require tube feeding. Interpretation: Our study provides a picture of the ‘new natural history’ of type I SMA, confirming the impact of the new therapies on the progression of type I with longer survival r and has better motor, respiratory and nutritional. Funding: This research was partially funded by grants from the Italian Ministry of Health.

Integration of advanced digital technologies along with ensuring environmental sustainability in the logistics sector is becoming the need of the hour novel multimodal transportation concept. The rapid technological development in the era of industry 4.0 can not only create new opportunities in achieving highly efficient, intelligent, and smart logistics systems but also enable new business models for value addition, additionally, this novel system will also avoid environmental degradation and use of scarce natural resources that contribute to climate change. This paper summarizes the research trends of these technologies in multimodal logistics systems since 2005 through a systematic literature review. The results revealed a mixed picture of the situation, starting from emerging technologies like artificial intelligence, machine learning, and blockchain becoming key technological concepts for multimodal logistics systems to government policy hurdles and lack of impact breakthroughs in the industry. However, the results show that adaptation to these technologies improves the overall environmental, economic, and social sustainability of the system.

Background Survival rates for breast cancer are increasing, but many clinical needs in a larger and larger population of survivors are not properly met. During and beyond cancer treatments, patients tend to reduce their physical activity levels, gain weight and may complain about chronic pain, lymphedema, fatigue, cognitive problems, depression and anxiety, reduced social contacts and difficulties in resuming daily activities. In addition, younger women must also face fertility issues and early menopause, higher levels of distress regarding body image, sexual health, childcare and career management. Beside this, all the survivors may feel a fear for disease recurrence and many of them are not educated to identify and express their needs. Materials and Methods Tailored supportive strategies, including physical and psychological interventions, should be offered since the time of diagnosis and along the entire cancer journey and the follow up period. They should be aimed not only to the prevention and control of psychological and physical impairments (such as anxiety, stress, depression, lymphedema, genitourinary symptoms and sexual dysfunctions), but also to encourage remodulation of personal lifestyles for tertiary prevention and nurture patient’s resources that can promote a personal growth after the traumatic experience of cancer. Conclusions Toward this goal, many cancer centres worldwide including ours offer dedicated programs of psycho-oncological support, nutritional and physical activity counselling and evidence based complementary treatments (such as acupuncture, mindfulness, meditation, reflexology, herbal medicine, music therapy and more).

Abstract Background Causes and mechanisms underlying cancer cachexia are not fully understood, and currently, no therapeutic approaches are available to completely reverse the cachectic phenotype. Interleukin‐6 (IL‐6) has been extensively described as a key factor in skeletal muscle physiopathology, exerting opposite roles through different signalling pathways. Methods We employed a three‐dimensional ex vivo muscle engineered tissue (X‐MET) to model cancer‐associated cachexia and to study the effectiveness of selective inhibition of IL‐6 transignalling in counteracting the cachectic phenotype. Conditioned medium (CM) derived from C26 adenocarcinoma cells was used as a source of soluble factors contributing to the establishment of cancer cachexia in the X‐MET model. A dose of 1.2 ng/mL of glycoprotein‐130 fused chimaera (gp130Fc) was added to cachectic culture medium to neutralize IL‐6 transignalling. Results C26‐conditioned medium induced a cachectic‐like phenotype in the X‐MET, leading to a decline of muscle mass (−60%; P

This study evaluates the long-term outcomes of minimally invasive mitral valve repair (MIMVR) in patients with degenerative mitral regurgitation, focusing on survival, mitral valve repair failure, and re-operation rates. A cohort of patients undergoing three primary repair techniques—quadrangular resection, edge-to-edge repair, and artificial chordae implantation—was analyzed using time-to-event methods. The overall survival rates at 1, 10, and 20 years were high and comparable among the techniques, indicating effective long-term benefits of MIMVR. However, freedom from recurrence of moderate mitral regurgitation (MR) ≥ 2 was significantly higher in the quadrangular resection and edge-to-edge groups compared to the artificial chordae group. No significant differences were observed for recurrent MR ≥ 3. Re-operation rates were low and similar across all techniques, underscoring the durability of MIMVR. Pre-discharge residual MR ≥ 2 was identified as a strong predictor of long-term repair failure. These findings confirm the effectiveness of MIMVR, with all techniques demonstrating excellent long-term survival and durability.

Located at the crossroads of two continents and at the southeastern edge of the Mediterranean Basin, Anatolia was one of the most important Pleistocene glacial refugia in the Western Palaearctic. As part of the Irano-Anatolian, Caucasus and Mediterranean Basin biodiversity hotspots, this region is also home to a rich avian community including nearly 400 breeding species. Nevertheless, research addressing the genetic structure and diversity of local bird populations is limited, and information on glacial refugia in this region is still scant, especially when compared to other large Mediterranean peninsulas, namely the Balkan, Italian and Iberian ones. In this study, we contribute to filling this gap by addressing the biogeographic pattern of four common resident songbirds—the Eurasian blue tit (Cyanistes caeruleus), the great tit (Parus major), the Eurasian chaffinch (Fringilla coelebs) and the Eurasian blackbird (Turdus merula)—and one endemic species—the Krüper’s nuthatch (Sitta krueperi)—by amplifying two mitochondrial DNA genes in individuals from Anatolia (n = 329) and comparing their sequences to those of conspecifics from the rest of their distribution range across the western Palaearctic (n = 357) deposited in public databases. The overall genetic structure of these species is consistent with a scenario of isolation for multiple populations in different refugia across Anatolia and subsequent secondary contact in the wake of ice retreat, which makes this region a hotspot of genetic diversity for both widespread and endemic avian species.

Battery energy storage systems (BESSs) can overwhelm some of the environmental challenges of a low-carbon power sector through self-consumption with standalone photovoltaic (PV) systems. This solution can be adapted for different applications such as residential, commercial, and industrial uses. Furthermore, the option to employ second-life batteries derived from electric vehicles represents a promising opportunity for preserving the environment and improving the circular economy (CE) development. Nowadays, the industrial sector is progressively applying CE principles in their business strategies, and focusing on the potential positive consequences of CE eco-innovations on climate change mitigation. With the aim to promote the transition to an open-loop circular economy for automotive batteries, this study assesses and quantifies the potential environmental benefits resulting from the integration of a second-life battery-based BESS (SL-BESS) connected to an industrial machine. For this purpose, various scenarios involving the use of BESS, SL-BESS, and a standalone PV system are compared with a base case, where the machine is entirely powered by electricity from the grid. The examination of life cycle stages follows the life cycle assessment (LCA) cradle-to-grave methodology as outlined in ISO 14040:2006 and ISO 14044:2006/Amd 1:2017. Simapro® 9 is utilized as the software platform. Results demonstrate that the combination of the SL-BESS with a standalone photovoltaic (PV) system represents the optimal solution in terms of global warming potential (GWP) reduction, with a saving of up to −74.8%. However, manufacturing and end-of-life stages of PV and batteries contribute to abiotic depletion and human toxicity, resulting from the use of chemicals and the extraction of resources essential for their manufacture. Indeed, when BESS is made of new batteries, it demonstrates the most significant impacts in terms of AD at 1.22 × 10−1 kg Sb eq and human toxicity (HT) at 3.87 × 103 kg 1,4-DB eq, primarily attributable to the manufacturing stages of both BESS and PV systems. The findings represent a significant breakthrough, highlighting the substantial capacity of incorporating SL-BESS alongside renewable energy sources to mitigate GWP resulting from industrial applications, and the criticality of repurposing decommissioned batteries from the automotive industry for secondary use.

The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state.

Abstract Background Research on the influence of neurocognitive factors on suicide risk, regardless of the diagnosis, is inconsistent. Recently, suicide risk studies propose applying a trans-diagnostic framework in line with the launch of the Research Domain Criteria Cognitive Systems model. In the present study, we highlight the extent of cognitive impairment using a standardized battery in a psychiatric sample stratified for different degrees of suicidal risk. We also differentiate in our sample various neurocognitive profiles associated with different levels of risk. Materials and methods We divided a sample of 106 subjects into three groups stratified by suicide risk level: Suicide Attempt (SA), Suicidal Ideation (SI), Patient Controls (PC) and Healthy Controls (HC). We conducted a multivariate Analysis of Variance (MANOVA) for each cognitive domain measured through the standardized battery MATRICS Consensus Cognitive Battery (MCCB). Results We found that the group of patients performed worse than the group of healthy controls on most domains; social cognition was impaired in the suicide risk groups compared both to HC and PC. Patients in the SA group performed worse than those in the SI group. Conclusion Social cognition impairment may play a crucial role in suicidality among individuals diagnosed with serious mental illness as it is involved in both SI and SA; noteworthy, it is more compromised in the SA group fitting as a marker of risk severity.

To describe the technique of bone augmentation using Cortoss cement, in patients with osteoporosis and spondylolisthesis, eligible to posterior stabilization with rods and screws.In this technical note it is described the treatment of spondylolisthesis, up to grade 2, with associated foraminal stenosis or central stenosis, resistant to medical therapy and physiotherapy, in patients with osteopenic/osteoporotic who needs.Pre-operative MOC-DEXA, X-rays, and MRI have to be performed in order to plan.Post-operative imaging was performed with CT ad X-rays.The outcome was assessed using the VAS score, the Oswestry Disability Index and Neuropatic Pain in 4 Questions (NPSI) at a 1,6 and 12 months follow-up and also included x-rays and CT-scan with volume rendering reconstruction to evaluate the correct bone fusion and the absence of complications.Operation time was 142 min and mean postoperative time until hospital discharge was 2 days. Postoperative values for VAS scores, ODI and NPSI improved significantly compared to pre-operative data. No postprocedural sequelae were observed.This report shows a feasible and safe full percutaneous alternative procedure and represents a minimally invasive management of spondylolisthesis, up to grade 2, with stenosis of vertebral canal and low back pain resistant to medical therapy, even in patients with osteopenia/osteoporosis.

Summary: Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and

Abstract Background Histone deacetylase 4 (HDAC4) is a stress‐responsive factor that mediates multiple cellular responses. As a member of class IIa HDACs, HDAC4 shuttles between the nucleus and the cytoplasm; however, HDAC4 cytoplasmic functions have never been fully investigated. Duchenne muscular dystrophy (DMD) is a genetic, progressive, incurable disorder, characterized by muscle wasting, which can be treated with the unspecific inhibition of HDACs, despite this approach being only partially effective. More efficient strategies may be proposed for DMD only after the different HDAC members will be characterized. Methods To fully understand HDAC4 functions, we generated dystrophic mice carrying a skeletal muscle‐specific deletion of HDAC4 (mdx;KO mice). The progression of muscular dystrophy was characterized in mdx and age‐matched mdx;KO mice by means of histological, molecular, and functional analyses. Satellite cells (SCs) from these mice were differentiated in vitro, to identify HDAC4 intrinsic functions influencing the myogenic potential of dystrophic SCs. Gain‐of‐function experiments revealed the cytoplasmic functions of HDAC4 in mdx;KO muscles. Results Histone deacetylase 4 increased in the skeletal muscles of mdx mice (~3‐fold; P