Humans-in-the-building: active thermal comfort control and validation via digital twin

openEnsuring thermal comfort in indoor environments while optimizing energy efficiency remains a significant challenge in building management. This thesis explores different control strategies for thermal regulation, integrating both conventional and innovative techniques. In particular, a novel control approach, Feedback Thermal Control, is introduced, leveraging Human-in-the-Loop (HITL) principles to dynamically adjust airflow based not only on room temperature but also on individual users' thermal preferences. This method enables a more personalized and adaptive climate control strategy, improving occupant satisfaction while maintaining energy efficiency. To evaluate its effectiveness, the study first examines traditional control methodologies, such as PID, and ON-OFF controllers, before introducing Feedback Thermal Control as an alternative approach. The performance of these control strategies is analyzed and compared through simulations in Matlab/Simulink and IDA ICE, a state-of-the-art building performance simulation tool.Ensuring thermal comfort in indoor environments while optimizing energy efficiency remains a significant challenge in building management. This thesis explores different control strategies for thermal regulation, integrating both conventional and innovative techniques. In particular, a novel control approach, Feedback Thermal Control, is introduced, leveraging Human-in-the-Loop (HITL) principles to dynamically adjust airflow based not only on room temperature but also on individual users' thermal preferences. This method enables a more personalized and adaptive climate control strategy, improving occupant satisfaction while maintaining energy efficiency. To evaluate its effectiveness, the study first examines traditional control methodologies, such as PID, and ON-OFF controllers, before introducing Feedback Thermal Control as an alternative approach. The performance of these control strategies is analyzed and compared through simulations in Matlab/Simulink and IDA ICE, a state-of-the-art building performance simulation tool

ROS-mediated EB1 phosphorylation through Akt/GSK3β pathway: implication in cancer cell response to microtubule-targeting agents

International audienceMicrotubule-targeting agents (MTAs) are largely administered in adults and children cancers. Better deciphering their mechanism of action is of prime importance to develop more convenient therapy strategies. Here, we addressed the question of how reactive oxygen species (ROS) generation by mitochondria can be necessary for MTA efficacy. We showed for the first time that EB1 associates with microtubules in a phosphorylation-dependent manner, under control of ROS. By using phospho-defective mutants, we further characterized the Serine 155 residue as critical for EB1 accumulation at microtubule plus-ends, and both cancer cell migration and proliferation. Phosphorylation of EB1 on the Threonine 166 residue triggered opposite effects, and was identified as a requisite molecular switch in MTA activities. We then showed that GSK3β activation was responsible for MTA-triggered EB1 phosphorylation, resulting from ROS-mediated inhibition of upstream Akt. We thus disclosed here a novel pathway by which generation of mitochondrial ROS modulates microtubule dynamics through phosphorylation of EB1, improving our fundamental knowledge about this oncogenic protein, and pointing out the need to reexamine the current dogma of microtubule targeting by MTAs. The present work also provides a strong mechanistic rational to the promising therapeutic strategies that currently combine MTAs with anti-Akt targeted therapies

Cyst Fluid Carcinoembryonic Antigen Level Is not Predictive of Invasive Cancer in Patients with Intraductal Papillary Mucinous Neoplasm of the Pancreas

Context Cyst fluid CEA concentration >192ng/mL has proven accurate to differentiate mucinous from non-mucinous pancreatic cystic neoplasms. It is unclear whether the degree of cyst fluid CEA elevation is predictive of malignant behavior in IPMNs. Objectives To determine whether elevated cyst fluid CEA concentrations were predictive of invasive cancer. Design Cross sectional study. Setting Single National Cancer Institute comprehensive cancer care center experience. Patients Forty-seven patients underwent preoperative EUS-FNA with cyst fluid analysis and surgical resection of an IPMN over a 9 year period. Main outcome measurements Cyst fluid CEA concentrations among the four grades associated with IPMN (low grade dysplasia, moderate dysplasia, high grade dysplasia, and invasive cancer). Results The mean±standard deviation cyst fluid CEA concentration increased as the pathology progressed from low grade dysplasia (1,261±1,679 ng/mL) to moderate dysplasia (7,171±22,210 ng/mL) to high grade dysplasia (10,807±36,203 ng/mL). However, the mean CEA level decreased (462±631 ng/mL) once invasive cancer developed (P=0.869). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of a cyst fluid CEA concentration greater than 200 ng/mL for the diagnosis of malignant IPMN (cases of high grade dysplasia and invasive IPMN) was 52.4%, 42.3%, 42.3%, 52.4% and 46.8%, respectively. Limitations Single center experience, small patient numbers, retrospective data collection. Conclusion The degree of cyst fluid CEA elevation is a poor predictor of malignant degeneration within IPMNs. Clinical management decisions regarding surgical resection should not be based upon degree of cyst fluid CEA elevation.Image: Box-plot comparing pre-operative CEA levels with surgical pathology

Vitamin E δ-tocotrienol Sensitizes Human Pancreatic Cancer Cells to TRAIL-induced Apoptosis Through Proteasome-Mediated Down-Regulation of c-FLIP

Background: Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects. Methods: We report a novel function of VEDT in augmenting tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in pancreatic cancer cells. The effects of VEDT were shown by its ability to trigger caspase-8-dependent apoptosis in pancreatic cancer cells. Results: When combined with TRAIL, VEDT significantly augmented TRAIL-induced apoptosis of pancreatic cancer cells. VEDT decreased cellular FLICE inhibitory protein (c-FLIP) levels without consistently modulating the expression of decoy death receptors 1, 2, 3 or death receptors 4 and 5. Enforced expression of c-FLIP substantially attenuated VEDT/TRAIL-induced apoptosis. Thus, c-FLIP reduction plays an important part in mediating VEDT/TRAIL-induced apoptosis. Moreover, VEDT increased c-FLIP ubiquitination and degradation but did not affect its transcription, suggesting that VEDT decreases c-FLIP levels through promoting its degradation. Of note, degradation of c-FLIP and enhanced TRAIL-induced apoptosis in pancreatic cancer cells were observed only with the anticancer bioactive vitamin E compounds δ-, γ-, and β-tocotrienol but not with the anticancer inactive vitamin E compounds α-tocotrienol and α-, β-, γ-, and δ-tocopherol. Conclusions: c-FLIP degradation is a key event for death receptor-induced apoptosis by anticancer bioactive vitamin E compounds in pancreatic cancer cells. Moreover, VEDT augmented TRAIL inhibition of pancreatic tumor growth and induction of apoptosis in vivo. Combination therapy with TRAIL agonists and bioactive vitamin E compounds may offer a novel strategy for pancreatic cancer intervention

Artificial Intelligence in Healthcare: Medical Students' Perspectives on Balancing Innovation, Ethics, and Patient-Centered Care

Artificial intelligence (AI) is transforming healthcare delivery, offering unprecedented opportunities for enhanced diagnostics, efficiency, and patient care. However, this transformation also introduces pressing ethical challenges, particularly concerning autonomy, algorithmic bias, and data privacy. In this editorial, we explore these issues through the lens of medical students and future physicians, emphasizing the need for ethical vigilance and proactive governance in the deployment of AI technologies in clinical settings. We argue that while AI can support autonomy by providing personalized insights, opaque “black box” models and lack of informed consent can undermine shared decision-making and trust. Algorithmic bias further threatens equity in care, as many AI systems are trained on unrepresentative datasets, leading to disparities in diagnosis and treatment. Additionally, concerns about data ownership, consent, and commercial use of patient information demand renewed attention to privacy and transparency. Medical education must evolve to prepare future clinicians to engage with AI critically and ethically. This includes training in bias recognition, responsible use, patient-centered communication, and contextual awareness. The integration of AI into curricula should go beyond technical literacy, fostering a deep understanding of its limitations and social implications. Finally, robust governance and regulatory oversight are essential. Institutions, policymakers, and international organizations must ensure that AI systems in healthcare align with principles of justice, beneficence, and respect for persons. AI must enhance, not replace, human judgment, and its adoption must be guided by continuous ethical reflection and patient-centered values. By embracing transparency, equity, and collaboration, AI can be a powerful tool that strengthens the foundations of ethical medical practice

Vitamin E analogues as inducers of apoptosis: structure–function relation

Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of alpha-TOS with lower number of methyl substitutions on the aromatic ring were less active than alpha-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on alpha-TOS and delta-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while italic gamma-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of italic gamma-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.Full Tex

Effect of previous heterologous flavivirus vaccinations on human antibody responses in tick-borne encephalitis and dengue virus infections

Arthropod-borne flaviviruses include a number of medically relevant human pathogens such as the mosquito-borne dengue (DEN), Zika, and yellow fever (YF) viruses as well as tick-borne encephalitis virus (TBEV). All flaviviruses are antigenically related and anamnestic responses due to prior immunity can modulate antibody specificities in subsequent infections or vaccinations. In our study, we analyzed the induction of broadly flavivirus cross-reactive antibodies in tick-borne encephalitis (TBE) and DEN patients without or with prior flavivirus exposure through TBE and/or YF vaccination, and determined the contribution of these antibodies to TBE and dengue virus (DENV) neutralization. In addition, we investigated the formation of cross-reactive antibodies in TBE-vaccination breakthroughs (VBTs). A TBEV infection without prior YF or TBE vaccination induced predominantly type-specific antibodies. In contrast, high levels of broadly cross-reactive antibodies were found in samples from TBE patients prevaccinated against YF as well as in DEN patients prevaccinated against TBE and/or YF. While these cross-reactive antibodies did not neutralize TBEV, they were effective in neutralizing DENV. This discrepancy points to structural differences between the two viruses and indicates that broadly cross-reactive epitopes are less accessible in TBEV than in DENV. In TBE VBT infections, type-specific antibodies dominated the antibody response, thus revealing no difference from that of unvaccinated TBE patients. Our results emphasize significant differences in the structural properties of different flaviviruses that have an impact on the induction of broadly cross-reactive antibodies and their functional activities in virus neutralization.Molecular basis of virus replication, viral pathogenesis and antiviral strategie

Greco-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer

Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks. Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide. Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety. In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization