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Understanding the human brain’s perception of different thermal sensations has sparked the interest of many neuroscientists. The identification of distinct brain patterns when processing thermal stimuli has several clinical applications, such as phantom-limb pain prediction, as well as increasing the sense of embodiment when interacting with neurorehabilitation devices. Notwithstanding the remarkable number of studies that have touched upon this research topic, understanding how the human brain processes different thermal stimuli has remained elusive. More importantly, very intense thermal stimuli perception dynamics, their related cortical activations, as well as their decoding using effective features are still not fully understood. In this study, using electroencephalography (EEG) recorded from three healthy human subjects, we identified spatial, temporal, and spectral patterns of brain responses to different thermal stimulations ranging from extremely cold and hot stimuli (very intense), moderately cold and hot stimuli (intense), to a warm stimulus (innocuous). Our results show that very intense thermal stimuli elicit a decrease in alpha power compared to intense and innocuous stimulations. Spatio-temporal analysis reveals that in the first 400 ms post-stimulus, brain activity increases in the prefrontal and central brain areas for very intense stimulations, whereas for intense stimulation, high activity of the parietal area was observed post-500 ms. Based on these identified EEG patterns, we successfully classified the different thermal stimulations with an average test accuracy of 84% across all subjects. En route to understanding the underlying cortical activity, we source localized the EEG signal for each of the five thermal stimuli conditions. Our findings reveal that very intense stimuli were anticipated and induced early activation (before 400 ms) of the anterior cingulate cortex (ACC). Moreover, activation of the pre-frontal cortex, somatosensory, central, and parietal areas, was observed in the first 400 ms post-stimulation for very intense conditions and starting 500 ms post-stimuli for intense conditions. Overall, despite the small sample size, this work presents novel findings and a first comprehensive approach to explore, analyze, and classify EEG-brain activity changes evoked by five different thermal stimuli, which could lead to a better understanding of thermal stimuli processing in the brain and could, therefore, pave the way for developing a real-time withdrawal reaction system when interacting with prosthetic limbs. We underpin this last point by benchmarking our EEG results with a demonstration of a real-time withdrawal reaction of a robotic prosthesis using a human-like artificial skin.

Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown 1 – 9 . Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression. Mutations in the transcription factor FOXA1 that are common in prostate cancer result in gain-of-function effects that promote changes in the differentiation of tumour cells.

In recent times, we have witnessed a push towards restoring sensory perception to upper-limb amputees, which includes the whole spectrum from gentle touch to noxious stimuli. These are essential components for body protection as well as for restoring the sense of embodiment. Notwithstanding the considerable advances that have been made in designing suitable sensors and restoring tactile perceptions, pain perception dynamics and its decoding using effective bio-markers, are still not fully understood. Here, using electroencephalography (EEG) recordings, we identified and validated a spatio-temporal signature of brain activity during innocuous, moderately more intense, and noxious stimulation of an amputee’s phantom limb using transcutaneous nerve stimulation (TENS). Based on the spatio-temporal EEG features, we developed a system for detecting pain perception and reaction in the brain, which successfully classified three different stimulation conditions with a test accuracy of 94.66%, and we investigated the cortical activity in response to sensory stimuli in these conditions. Our findings suggest that the noxious stimulation activates the pre-motor cortex with the highest activation shown in the central cortex (Cz electrode) between 450 ms and 750 ms post-stimulation, whereas the highest activation for the moderately intense stimulation was found in the parietal lobe (P2, P4, and P6 electrodes). Further, we localized the cortical sources and observed early strong activation of the anterior cingulate cortex (ACC) corresponding to the noxious stimulus condition. Moreover, activation of the posterior cingulate cortex (PCC) was observed during the noxious sensation. Overall, although this is a single case study, this work presents a novel approach and a first attempt to analyze and classify neural activity when restoring sensory perception to amputees, which could chart a route ahead for designing a real-time pain reaction system in upper-limb prostheses.

Touch-like phantom limb sensations can be elicited through targeted transcutaneous electrical nerve stimulation (tTENS) in individuals with upper limb amputation. The corresponding impact of sensory stimulation on cortical activity remains an open question. Brain network research shows that sensorimotor cortical activity is supported by dynamic changes in functional connections between relevant brain regions. These groups of interconnected regions are functional modules whose architecture enables specialized function and related neural processing supporting individual task needs. Using electroencephalographic (EEG) signals to analyze modular functional connectivity, we investigated changes in the modular architecture of cortical large-scale systems when participants with upper limb amputations performed phantom hand movements before, during, and after they received tTENS. We discovered that tTENS substantially decreased the flexibility of the default mode network (DMN). Furthermore, we found increased interconnectivity (measured by a graph theoretic integration metric) between the DMN, the somatomotor network (SMN) and the visual network (VN) in the individual with extensive tTENS experience. While for individuals with less tTENS experience, we found increased integration between DMN and the attention network. Our results provide insights into how sensory stimulation promotes cortical processing of combined somatosensory and visual inputs and help develop future tools to evaluate sensory combination for individuals with amputations.

Background People with lower-limb amputation lack sensory inputs from their missing limb, which increases their risk of falling. We recently demonstrated that spinal cord stimulation (SCS) can restore sensation in the missing lower limb. Previous studies have shown that SCS can affect motor control by exciting spinal reflex pathways after stroke or spinal cord injury. The effects of SCS on spinal reflex activation have not been studied in people with lower-limb amputation. Furthermore, it is unknown if SCS-evoked spinal reflex activation would perturb walking. Therefore, the goal of this study was to characterize SCS-evoked spinal reflexes in people with lower-limb amputation and quantify effects on gait parameters, including step cycle duration and limb alternation symmetry. Methods We implanted percutaneous SCS electrodes over the lumbosacral enlargement in 3 people with transtibial amputation (2 diabetic neuropathy; 1 traumatic) for 28 or 84 days. SCS was delivered to restore sensation in the missing limb during walking based on signals from a pressure-sensing insole in the shoe under the prosthesis. We used electromyography (EMG) to record posterior root-muscle (PRM) reflexes in the residual limb while participants were seated, standing, or walking. We characterized rate-dependent depression and recruitment properties of the PRM reflexes. We used pressure data from instrumented insoles to measure the step cycle duration and limb alternation symmetry with and without SCS. Results SCS evoked PRM reflexes in the residual limb muscles in all participants, which was confirmed by the presence of rate-dependent depression at stimulation frequencies ≥ 2 Hz. Overall, there was broad activation of residual limb muscles with SCS that varied with the position of the stimulating electrode relative to the lumbar spinal cord. PRM reflexes were also activated during walking, as confirmed by the presence of rate-dependent depression. However, SCS-evoked PRM reflexes did not disrupt gait, with similar step cycle duration or limb alternation symmetry with and without SCS. Conclusions Restoring sensation in the missing limb using SCS excites spinal reflexes according to the expected rostral-caudal myotomes but does not disrupt the step cycle duration or limb alternation symmetry in people with transtibial amputation. Therefore, SCS can restore sensory feedback in the missing limb without disrupting the existing motor activation of the residual limb muscles.

Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2–21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35–76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

Signaling pathways transmit information through protein interaction networks that are dynamically regulated by complex extracellular cues. We developed LUMIER (for luminescence-based mammalian interactome mapping), an automated high-throughput technology, to map protein-protein interaction networks systematically in mammalian cells and applied it to the transforming growth factor-{szligbeta} (TGF{szligbeta}) pathway. Analysis using self-organizing maps and k-means clustering identified links of the TGF{szligbeta} pathway to the p21-activated kinase (PAK) network, to the polarity complex, and to Occludin, a structural component of tight junctions. We show that Occludin regulates TGF{szligbeta} type I receptor localization for efficient TGF{szligbeta}-dependent dissolution of tight junctions during epithelial-to-mesenchymal transitions.

Limb difference affects millions worldwide, with prevalence expected to rise due to increasing rates of diabetes and vascular disease. Despite the need for high-quality, functional prostheses, many individuals, particularly in low- and middle-income countries, lack access to affordable, customized prostheses. 3D printing offers a promising approach to address these gaps by enabling lower-cost, highly personalized prosthetic fabrication. This narrative review examines the current state of 3D printing in prosthetics, with a focus on upper limb prostheses, socket design, and terminal attachments. Although 3D printing has been used to produce functional prostheses, particularly in non-regulated settings, clinical adoption remains limited due to concerns regarding safety, durability, and a lack of high-quality evidence. This review highlights the advantages of 3D printing, including cost-effectiveness, customization, and accessibility, while also addressing key limitations such as material performance, regulatory challenges, and insufficient clinical validation. Future research priorities include rigorous clinical trials and performance testing to establish non-inferiority compared with conventional prostheses and to support broader clinical integration.

Introduction Consultation audio recordings improve patient decision‐making but are underutilized. Patient‐administered recording apps on mobile devices may increase access, but implementation has not been evaluated. Methods We conducted a single‐arm study delivering education, coaching, and reminders for patients to record their appointment using a mobile recording app. Patients had progressive, advanced prostate cancer and an upcoming appointment where the option of docetaxel would be discussed. We used the RE‐AIM framework for evaluation. Reach was the proportion of patients who participated. Effectiveness was change in informed decision‐making pre‐ vs. post‐appointment. We used a questionnaire evaluating patient knowledge about docetaxel (0%–100% correct) and the decisional conflict scale‐informed subscale (0 = feels extremely uninformed to 100 = extremely informed) to compare means using the paired t‐test. Adoption was the proportion of providers agreeing to be recorded. Implementation was coordinator adherence to intervention delivery. We conducted semistructured interviews with patients, caregivers, and providers to assess barriers, facilitators, and suggestions for recording implementation. Results Of 102 patients approached, 50 (49%) patients participated. Mean age was 75 years, 38 (76%) were Non‐Hispanic White, and 43 (86%) had telehealth appointments. Knowledge increased from 44.7% to 49.5% (p = 0.019), particularly about palliative care (42% answering correctly to 60%, p = 0.035). Decisional conflict‐informed subscale increased from 48.9 to 70.9 (p < 0.001). Forty‐three patients (85%) made a recording, of whom 33 (77%) reported the recording helped treatment decision‐making. All 17 providers agreed to be recorded. Coordinator adherence was high. Multi‐level barriers, suggestions, and facilitators mostly related to intervention complexity and stakeholder compatibility. Conclusion Patient‐administered audio recordings had a positive effect on decision‐making, particularly for palliative care awareness. For broader implementation, efforts should focus on revising institutional policies; teaching patients or caregivers to use existing recording functions on their devices; leveraging artificial intelligence for transcription and summarization; and integrating recording into telehealth technology and electronic patient portals. Trial Registration: https://clinicaltrials.gov/study/NCT05127850

The role of polarity signaling in cancer metastasis is ill defined. Using two three-dimensional culture models of mammary epithelial cells and an orthotopic mouse model of breast cancer, we reveal that Par6 signaling, which is regulated directly by TGFβ, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGFβ-dependent loss of polarity in acini-like structures formed by non-transformed mammary cells grown in three-dimensional structures and suppressed the protrusive morphology of mesenchymal-like invasive mammary tumor cells without rescuing E-cadherin expression. Moreover, blockade of Par6 signaling in an in vivo orthotopic model of metastatic breast cancer induced the formation of ZO-1-positive epithelium-like structures in the primary tumor and suppressed metastasis to the lungs. Analysis of the pathway in tissue microarrays of human breast tumors further revealed that Par6 activation correlated with markers of the basal carcinoma subtype in BRCA1-associated tumors. These studies thus reveal a key role for polarity signaling and the control of morphologic transformation in breast cancer metastasis.