Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade.

CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.

Uncovering global-scale risks from commercial chemicals in air.

Commercial chemicals are used extensively across urban centres worldwide1, posing a potential exposure risk to 4.2 billion people2. Harmful chemicals are often assessed on the basis of their environmental persistence, accumulation in biological organisms and toxic properties, under international and national initiatives such as the Stockholm Convention3. However, existing regulatory frameworks rely largely upon knowledge of the properties of the parent chemicals, with minimal consideration given to the products of their transformation in the atmosphere. This is mainly due to a dearth of experimental data, as identifying transformation products in complex mixtures of airborne chemicals is an immense analytical challenge4. Here we develop a new framework-combining laboratory and field experiments, advanced techniques for screening suspect chemicals, and in silico modelling-to assess the risks of airborne chemicals, while accounting for atmospheric chemical reactions. By applying this framework to organophosphate flame retardants, as representative chemicals of emerging concern5, we find that their transformation products are globally distributed across 18 megacities, representing a previously unrecognized exposure risk for the world's urban populations. More importantly, individual transformation products can be more toxic and up to an order-of-magnitude more persistent than the parent chemicals, such that the overall risks associated with the mixture of transformation products are also higher than those of the parent flame retardants. Together our results highlight the need to consider atmospheric transformations when assessing the risks of commercial chemicals.

Signatures of Cooper pair dynamics and quantum-critical superconductivity in tunable carrier bands.

Different superconducting pairing mechanisms are markedly distinct in the underlying Cooper pair kinematics. Quantum-critical soft modes drive pairing interactions in which the pair scattering processes are highly collinear and can be classified into two categories: forward scattering and backscattering. Conversely, in conventional phonon mechanisms, Cooper pair scattering is of a generic noncollinear character. In this study, we present a method to discern the kinematic type by observing the evolution of superconductivity while adjusting the Fermi surface geometry. To demonstrate our approach, we utilize the recently reported phase diagrams of untwisted graphene multilayers. Our analysis connects the emergence of superconductivity at "ghost crossings" of Fermi surfaces in distinct valleys to the pair kinematics of a backscattering type. Together with the observed nonmonotonic behavior of superconductivity near its onset (sharp rise followed by a drop), it lends strong support to a particular quantum-critical superconductivity scenario in which pairing is driven by intervalley coherence fluctuations. These findings offer direct insights into the genesis of pairing in these systems, providing compelling evidence for the electron-electron interactions driving superconductivity. More broadly, our work highlights the potential of tuning bands via ghost crossings as a promising means of boosting superconductivity.

Three-dimensional quantum Hall effect and metal-insulator transition in ZrTe5.

The discovery of the quantum Hall effect (QHE)1,2 in two-dimensional electronic systems has given topology a central role in condensed matter physics. Although the possibility of generalizing the QHE to three-dimensional (3D) electronic systems3,4 was proposed decades ago, it has not been demonstrated experimentally. Here we report the experimental realization of the 3D QHE in bulk zirconium pentatelluride (ZrTe5) crystals. We perform low-temperature electric-transport measurements on bulk ZrTe5 crystals under a magnetic field and achieve the extreme quantum limit, where only the lowest Landau level is occupied, at relatively low magnetic fields. In this regime, we observe a dissipationless longitudinal resistivity close to zero, accompanied by a well-developed Hall resistivity plateau proportional to half of the Fermi wavelength along the field direction. This response is the signature of the 3D QHE and strongly suggests a Fermi surface instability driven by enhanced interaction effects in the extreme quantum limit. By further increasing the magnetic field, both the longitudinal and Hall resistivity increase considerably and display a metal-insulator transition, which represents another magnetic-field-driven quantum phase transition. Our findings provide experimental evidence of the 3D QHE and a promising platform for further exploration of exotic quantum phases and transitions in 3D systems.

Safety of the JAK and TNF inhibitors in rheumatoid arthritis: real world data from the Hong Kong Biologics Registry.

OBJECTIVES: To compare the incidence of major adverse cardiovascular events (MACEs), cancer and infective complications in RA patients using Janus kinase (JAKis) and TNF (TNFis) inhibitors. METHOD: A retrospective analysis of data from the Hong Kong Biologics Registry 2008-2021 was performed. RA patients who had ever used JAKis or TNFis were included. The incidence of MACEs, cancer and infections were compared between the two groups, with adjustment for confounding factors. RESULTS: A total of 2471 courses of JAKis (n = 551) and TNFis (n = 1920) were used in 1732 RA patients (83.7% women, age 53.8 [12.5] years; follow-up 6431 patient-years). JAKi users had significantly older age, more atherosclerotic risk factors and higher frequency of past malignancies. A total of 15 and 40 MACEs developed in the JAKi and TNFi users, respectively (incidence 1.34 vs 0.75 per 100 patient-years; P = 0.22). There was no significant difference in the incidence of cancers between the two groups (0.81 [JAKi] vs 0.85 [TNFi] per 100 patient-years; P = 0.25). The adjusted hazard ratios of MACE and cancer in the JAKi users were 1.36 (95% CI: 0.62, 2.96) (P = 0.44) and 0.87 (95% CI: 0.39, 1.95) (P = 0.74), respectively. Rates of infections were significantly higher in the JAKi than TNFi users (16.3 vs 9.9 per 100 patient-years; P = 0.02), particularly herpes zoster (3.49 vs 0.94 per 100 patient-years; P < 0.001). CONCLUSIONS: In a real-life setting, there is no increase in MACEs or cancers in users of JAKis compared with TNFis. However, the incidence of non-serious infections, including herpes zoster, was increased in users of JAKis.

Metagenomics-Based Microbial Ecological Community Threshold and Indicators of Anthropogenic Disturbances in Estuarine Sediments.

Assessing the impacts of cumulative anthropogenic disturbances on estuarine ecosystem health is challenging. Using spatially distributed sediments from the Pearl River Estuary (PRE) in southern China, which are significantly influenced by anthropogenic activities, we demonstrated that metagenomics-based surveillance of benthic microbial communities is a robust approach to assess anthropogenic impacts on estuarine benthic ecosystems. Correlational and threshold analyses between microbial compositions and environmental conditions indicated that anthropogenic disturbances in the PRE sediments drove the taxonomic and functional variations in the benthic microbial communities. An ecological community threshold of anthropogenic disturbances was identified, which delineated the PRE sediments into two groups (H and L) with distinct taxa and functional traits. Group H, located nearshore and subjected to a higher level of anthropogenic disturbances, was enriched with pollutant degraders, putative human pathogens, fecal pollution indicators, and functional traits related to stress tolerance. In contrast, Group L, located offshore and subjected to a lower level of anthropogenic disturbances, was enriched with halotolerant and oligotrophic taxa and functional traits related to growth and resource acquisition. The machine learning random forest model identified a number of taxonomic and functional indicators that could differentiate PRE sediments between Groups H and L. The identified ecological community threshold and microbial indicators highlight the utility of metagenomics-based microbial surveillance in assessing the adverse impacts of anthropogenic disturbances in estuarine sediments, which can assist environmental management to better protect ecosystem health.

The Association of Metabolic Risk Factors with Advanced Adenomas in Hispanic Patients.

BACKGROUND: Obesity and metabolic syndrome (MetS) have been implicated as rising risk factors for the development of colorectal cancers. A rapid increase in the prevalence of obesity and severe obesity among Hispanic patients in the United States may present substantially increased risk for advanced colorectal neoplasia in this population. Currently, there is very little research in this area. AIMS: We sought to identify metabolic risk factors for advanced adenomas (AA) in Hispanic Americans. METHODS: We retrospectively reviewed data from the Los Angeles General (LAG) Medical Center of asymptomatic Hispanic patients above 45 years of age who underwent their first colonoscopies following a positive screening FBT. Patient demographics, metabolic characteristics, as well as colon polyp size and histology were recorded. Polyps were classified as adenomas or AA (including both high-risk adenomas and high-risk serrated polyps). Relative risk for AA was assessed by multivariate logistical regression analyses. RESULTS: Of the 672 patients in our study, 41.4% were male, 67% had adenomas, and 16% had AA. The mean BMI was 31.2 kg/m2. The mean HDL-C was 49.5 mg/dL (1.28 mmol/L) and the mean triglyceride level was 151 mg/dL. 44.6% had diabetes and 64.1% had hypertension. When comparing patients with AA to patients with no adenoma, male sex, BMI > 34.9 kg/m2, and elevated fasting triglyceride levels were associated with an increased risk of AA. FIB-4 ≥1.45 was also associated with an increased risk of AA in males. There was no significant difference in the risk of AA with diabetes, hypertension, FIB-4 score, LDL-C level, and HDL-C level. CONCLUSIONS: Hispanic patients with a positive FBT were observed to have a high incidence of AA. Class II obesity (BMI ≥ 35 kg/m2), elevated triglyceride levels were identified as risk factors among males in our study. Early interventions to address these modifiable risk factors in at-risk populations, such as multi-disciplinary weight management programs for the treatment of obesity and related co-morbidities, could potentially lead to risk reduction and CRC prevention.

Clinical heterogeneity and prognostic factors of anti-synthetase syndrome: a multi-centered retrospective cohort study.

OBJECTIVE: Anti-synthetase syndrome (ASyS) patients have heterogeneous clinical manifestations with different initial presentations, complications, and outcomes. This study aimed to assess the clinical characteristics and complications in patients with ASyS, and to identify factors that were associated with the survival of ASyS patients. METHODS: This was a retrospective multicentre longitudinal study. Patients fulfilling either the Connor's criteria or Solomon's criteria for ASyS were recruited. Electronic health records were reviewed until October 2022. Multivariate Cox-regression analysis was used to determine the independent prognostic factors. Auto-antibodies were checked by commercial immunoassays. RESULTS: A total of 205 patients (anti-Jo-1 49.3%, anti-PL-7 19.0%, anti-EJ 11.2%, anti-PL-12 10.2% and anti-OJ 3.4%) were included. The median follow-up time was 4 years. The time from symptoms onset to diagnosis was significantly longer for non-anti-Jo1 patients (median 5 vs 3 months). Common initial presentations included myositis (56.1%), arthritis (54.6%), and interstitial lung disease (ILD) (54.1%). Patients with anti-Jo-1 had significantly higher muscle enzyme levels and more arthritis. All patients with anti-EJ would develop ILD on follow-up and malignancy was noted in 28.6% of the anti-OJ positive patients. 15.6% of the patients died and pulmonary diseases (ILD or pneumonia) were the major causes. Age at diagnosis, malignancy and rapidly progressive-ILD were independently associated with mortality, while joint manifestation was a protective factor. CONCLUSION: In view of the heterogeneity of clinical presentation of ASyS, high index of suspicion and early checking of specific autoantibodies might help prompt diagnosis of ASyS and detection of related complications.

Ubiquitous Superconducting Diode Effect in Superconductor Thin Films.

The macroscopic coherence in superconductors supports dissipationless supercurrents that could play a central role in emerging quantum technologies. Accomplishing unequal supercurrents in the forward and backward directions would enable unprecedented functionalities. This nonreciprocity of critical supercurrents is called the superconducting (SC) diode effect. We demonstrate the strong SC diode effect in conventional SC thin films, such as niobium and vanadium, employing external magnetic fields as small as 1 Oe. Interfacing the SC layer with a ferromagnetic semiconductor EuS, we further accomplish the nonvolatile SC diode effect reaching a giant efficiency of 65%. By careful control experiments and theoretical modeling, we demonstrate that the critical supercurrent nonreciprocity in SC thin films could be easily accomplished with asymmetrical vortex edge and surface barriers and the universal Meissner screening current governing the critical currents. Our engineering of the SC diode effect in simple systems opens the door for novel technologies while revealing the ubiquity of the Meissner screening effect induced SC diode effect in superconducting films, and it should be eliminated with great care in the search for exotic superconducting states harboring finite-momentum Cooper pairing.

Universal Dynamics of Microbial Communities in Full-Scale Textile Wastewater Treatment Plants and System Prediction by Machine Learning.

The performance of full-scale biological wastewater treatment plants (WWTPs) depends on the operational and environmental conditions of treatment systems. However, we do not know how much these conditions affect microbial community structures and dynamics across systems over time and predictability of the treatment performance. For over a year, the microbial communities of four full-scale WWTPs processing textile wastewater were monitored. During temporal succession, the environmental conditions and system treatment performance were the main drivers, which explained up to 51% of community variations within and between all plants based on the multiple regression models. We identified the universality of community dynamics in all systems using the dissimilarity-overlap curve method, with the significant negative slopes suggesting that the communities containing the same taxa from different plants over time exhibited a similar composition dynamic. The Hubbell neutral theory and the covariance neutrality test indicated that all systems had a dominant niche-based assembly mechanism, supporting that the communities had a similar composition dynamic. Phylogenetically diverse biomarkers for the system conditions and treatment performance were identified by machine learning. Most of the biomarkers (83%) were classified as generalist taxa, and the phylogenetically related biomarkers responded similarly to the system conditions. Many biomarkers for treatment performance perform functions that are crucial for wastewater treatment processes (e.g., carbon and nutrient removal). This study clarifies the relationships between community composition and environmental conditions in full-scale WWTPs over time.